key: cord- -kt ip authors: ponce-gallegos, marco antonio; ramírez-venegas, alejandra; falfán-valencia, ramcés title: th profile in copd exacerbations date: - - journal: int j chron obstruct pulmon dis doi: . /copd.s sha: doc_id: cord_uid: kt ip copd is characterized by an ongoing inflammatory process of the airways that leads to obstruction or limitation of airflow. it is mainly associated with exposure to cigarette smoke. in addition, it is considered, at present, a serious public health problem, ranking fourth in mortality worldwide. many cells participate in the pathophysiology of copd, the most important are neutrophils, macrophages and cd + and cd + t cells. neutrophil migration to the inflammation area could be mediated largely by cytokines related to cd + th lymphocytes, because it has been shown that il- a, il- f and il- act as inducers for cxcl , cxcl , cxcl , g-csf, and gm-csf secretion by epithelial cells of the airways. the aims of these molecules are differentiation, proliferation and recruitment of neutrophils. furthermore, it is believed that cd + lymphocytes th may be involved in protection against pathogens for which th and th are not prepared to fight. in copd exacerbations, there is an increased cellularity in the lung region and respiratory tract. therefore, the increase in the number of neutrophils and macrophages in the airways and the increase in proinflammatory cytokines are directly related to the severity of exacerbations and that is the importance of the functions of th profile in this entity. copd is characterized by a continuous inflammatory process of the airways, leading to obstruction or limitation of airflow, which is mainly associated with exposure to cigarette smoke. , however, only %- % of smokers will develop the disease at some day in their life. these data lead to the belief that this disease is due to multiple factors that interact with each other. among the most prominent are genetic factors that can condition patients to have a certain susceptibility to copd. for example, deficiency of alpha -antitrypsin (aat) (responsible for inhibiting proteases, whose function is to deplete the extracellular matrix) is present in at least % of the carriers of the disease in europe and the united states and other regions around the world such as africa and australia. many cells participate in the pathophysiology of copd, the most important are neutrophils, macrophages, cd + and cd + t lymphocytes and the chemical mediators they produce (cytokines, chemokines, enzymes, growth factors, etc.). for example, neutrophil elastase (ne) is an enzyme that degrades the extracellular matrix to facilitate the migration of the neutrophil through the lung parenchyma to the inflammation area. people harboring aat deficiency alleles have a greater susceptibility to presenting the disease or presenting it at an earlier age. , on the other hand, cytokines such as tnf-α, il- β, il- , cxcl (also called il- ), il- , il- , il- a, il- f and tgf-β among others are increased in samples from patients with copd, suggesting an important role in its pathophysiology and in the exacerbations that may occur due epidemiology copd is now considered a serious public health problem, reaching the fourth place in mortality worldwide and in mexico as well. , globally, this disease is present in ~ million of people, especially in low-and middle-income countries. it is estimated that in , it will rank among the first three causes of death worldwide. copd and asthma are the airway obstructive pathologies more prevalent. the global initiative for chronic obstructive lung disease (gold) defines copd as a common and treatable disease characterized by the persistent limitation of airflow, which is usually progressive and associated with an increase in the inflammatory response in the airways and in the lungs by harmful particles and gases. also, this guide defines exacerbations as an acute event characterized by worsening of patient's respiratory symptoms that go beyond daily variations and leads to a change in medication. , , in addition, the guide also points out that a patient with frequent exacerbating copd will be considered when he has two or more exacerbations per year, where the best predictor will be the history of previous treatments for exacerbations. indeed, about half of copd patients die after years of their first episode of exacerbation. the symptomatology of copd is diverse, depending on the phenotype (emphysema and chronic bronchitis, the most common). however, there is a range of signs and symptoms that occur more frequently, such as dyspnea of small efforts, chronic cough and increased sputum production. in addition, other clinical data that may appear are hypoxemia, hypercapnia, the so-called "chest in barrel" (which appears due to lack of elasticity in the lungs and does not retract properly), weight loss, etc. , , molecular mechanisms in copd innate immunity copd is characterized by a chronic inflammatory process caused by tobacco smoke, harmful particles or gases that are capable of activating the cascade of inflammatory reactions that cause tissue destruction in the airways. pathological changes that are induced as a consequence of chronic exposure to cigarette smoke are observed more early in airway epithelium, which acts as a barrier that protects the lungs from environmental factors and also from . , toxic compounds present in tobacco smoke. toxic particles contained in the cigarette smoke generate tissue remodeling ( figure ) as a consequence of the damage they cause to airway epithelium. the most pronounced changes are shortening of the cilia (resulting in less mobility figure when airway epithelium is exposed to harmful substances, such as those contained in cigarette smoke, it changes its structure. note: these changes include the loss of close junctions between ciliated epithelial cells, shortening of cilia, hyperplasia of goblet-producing goblet cells and basal cells, in addition to squamous epithelial cell metaplasia. abbreviation: damps, damage-associated molecular patterns. international journal of copd : submit your manuscript | www.dovepress.com th profile in copd exacerbations of the mucus produced by goblet cells and less elimination of pathogens), metaplasia (change from one cell type to another, which in normal situations would not be present in a specific tissue) of squamous epithelial cells, hyperplasia of goblet-producing goblet cells and basal cells (a type of cells capable of differentiating into ciliated epithelial cells and goblet cells, caused by the action of growth factors such as the epidermal growth factor [egf]), in addition to the loss of tight junctions that, under normal conditions, work as an impermeable barrier and protect the respiratory tract from pathogens, xenobiotics and other harmful particles. , once the damage is generated in airway epithelial cells, they secrete chemical mediators (chemokines, cytokines, etc.) in order to generate and maintain an inflammatory response against foreign agents. cell death produced releases damage-associated molecular patterns (damps) such as heat shock proteins, s protein and high mobility group box (hmgb ), which are recognized by extracellular receptors present in neutrophils, macrophages and dendritic cells (dcs; such as toll-like receptors [tlrs], for example) [ ] [ ] [ ] and trigger an intracellular signaling cascade led by the transcription factors myd and nf-κb that culminate in the release of proinflammatory cytokines, such as il- β and il- (a multiprotein complex responsible for activating caspase and releasing mature forms of various cytokines), which, together with other cytokines (tnf-α, cxcl , il- , among others), are responsible for the recruitment of leukocytes to the inflammation zone. once in the area to which they were recruited, leukocytes (mainly neutrophils and macrophages) release products stored in their granules, such as enzymes responsible for destroying the extracellular matrix (mmp- , mmp- , ne), which help their migration through the lung parenchyma but, in turn, generate damage in the lung, thus promoting the progressive reduction of its functionality. mostly, adaptive immunity appears due to the action of dcs that, in the first instance, pick up the signals of damage of diverse cell types or the antigens that it recognizes as strangers and takes them to the lymph nodes and it is there where it happens the antigen presentation by major histocompatibility complex (mhc) molecules either class i or class ii, which results in the differentiation and polarization of t lymphocytes, which recognize the antigen presented by mediated t lymphocyte receptor (t cell receptor [tcr]) ( figure ). , in addition, the production of proinflammatory cytokines is required for this polarization to occur. for example, a microenvironment rich in il- will lead to the activation and differentiation of natural killer (nk) lymphocytes. it has recently been proposed that copd may be an entity of autoimmune etiology, because autoantibodies have been found against peptides present in the extracellular matrix of lung tissue. among them, the most important is elastin (anti-elastin antibodies are then formed). these autoantigens would be responsible, in large part, for mediating and perpetuating the inflammatory response present in the disease. in this context, b lymphocytes present in the peribronchial lymph nodes will be of special importance. once sensitized by cd + t lymphocytes, they will be able to synthesize and secrete antibodies (which may be directed against host peptides). migration of neutrophils to the inflammation region may be mediated largely by cytokines related to cd + th lymphocytes ( figure ), since it has been shown that il- a, il- f and il- serve as inducers for the secretion of cxcl , cxcl , g-csf, and gm-csf by airway epithelial cells, which have as their mission the differentiation, proliferation and recruitment of these cells. th cd + lymphocytes are characterized by the production of il- and are believed to be involved in protection against microorganisms for which th and th are not prepared to fight, such as certain extracellular bacteria and fungi. its differentiation from naive t lymphocytes occurs from three signals: first, the binding of the tcr to the antigen; second, the action of costimulators (for example, b binding to cd present on the lymphocyte membrane); third, the environment of cytokines that exist in the medium, for example, il- β, il- , il- , il- and tgf-β. in this way, naive t lymphocyte is polarized to th lymphocyte from transcription factors characteristic of that cell line, such as rorγt, stat- and stat- . , once polarization of the naive t lymphocyte occurs in th lymphocyte, it synthesizes il- to generate an autocrine stimulation and, thus, to activate the transcription factor rorγt for the synthesis of new cytokines, especially of the il- family. in addition, il- in combination with tgf-β also induces the activation of rorγt and subsequent expression of il- a. however, they can only do so after il- or il- has facilitated the expression of their receptors. , it has also been proposed that, in addition to participating in the recruitment of leukocytes (mainly neutrophils), il- a influences most cells in the lung parenchyma, such as macrophages and dcs, which express receptors for th profile in copd exacerbations il- a and synthesize proinflammatory cytokines such as il- and tnf-α. on the other hand, il- has been linked to multiple pathologies of an inflammatory nature, for example, psoriasis and rheumatoid arthritis, in addition to having an important role in the defense of the lungs against pathogens, especially extracellular bacteria, assisting production and release, for example, of defensins in the mucosa of the airways, in addition to maintaining the integrity of the epithelium. a study by pichavant et al showed that, during streptococcus pneumoniae infections in mice exposed to cigar smoke, cytokine levels related to th lymphocytes are decreased, leading to exacerbations. in addition, il- is associated with maintenance of the response generated by this group of cooperating t lymphocytes. table shows some of the main functions and characteristics of cytokines related to the th profile. generally, genes have characteristics common to each other but differ from one another at different levels, ranging from the locus, number of introns and exons, number of base pairs and the position in which they are within the genome (forward/reverse strand). in this case, the genes related to the th profile have similar characteristics, such as being on the same chromosome and similar size in terms of base pairs. table shows the main characteristics of these genes. in general, copd patients tend to experience frequent exacerbations. of these, the most frequent are those of infectious origin, with bacteria and viruses being the most prevalent etiological agents, with %- % and %, respectively. the clinical manifestations present during exacerbations are a consequence of the action of the virus/bacteria and of the immune response against the pathogen that assembles the host. bacteria previously, the lungs were believed to be a sterile area, free of microorganisms. however, recent studies have shown that this is not entirely true and that the lungs contain, depending on the disease or stage in which they are found, a variable content of microbiomas. in the upper airways, there are also colonizing microorganisms; nose, for example, is colonized by bacteria such as staphylococcus aureus, s. epidermidis and corynebacteria. the nasopharynx is colonized under normal conditions by non-hemolytic, α-hemolytic streptococcus and some neisseria species, in addition to s. pneumoniae and haemophilus influenzae. the presence of bacteria in patients who have had an exacerbation does not prove that these alone are sufficient to trigger the exacerbation of the symptomatology of patients with copd, because they can also be isolated in individuals who do not have this pathology. in healthy individuals, different species of bacteria are constantly inhaled. however, due of the responsiveness of their immune system that is not compromised, they are not capable of infecting the host. this response is generated mainly by the presence of antimicrobial molecules present in the respiratory mucosa such as defensins, pentraxin- , lactoferrin, lysozyme and cathelicidin, as well as immunoglobulin a (iga) and tissue resident cells. an important factor associated with the predisposition of copd patients to present exacerbations is the metaplasia of squamous epithelial cells that appears as a consequence of the damage generated to the airway epithelium by the chemical compounds of the cigarette. this event, together with the loss of ciliated epithelial cells, promotes the accumulation of induces expression of g-csf; it maintains the integrity of the epithelium by limiting cellular apoptosis and favoring regeneration processes. th cd + lymphocytes, dcs , induces the differentiation of virgin t lymphocytes in th cd +; expands and maintains the th cd + lymphocyte response. abbreviations: il, interleukin; tnf, tumor necrosis factor; nk, natural killer; dcs, dendritic cells. ponce-gallegos et al infectious agents, generating an imbalance in the pulmonary microbioma and, therefore, a greater probability of producing an infection triggering exacerbations. in addition, the loss of the tight junctions between epithelial cells acting as an impermeable barrier is a factor that helps colonization by potentially pathogenic bacteria. it has also been shown that patients with copd who are vaccinated against some pneumococcal strains are less prone to exacerbations due to this infectious agent. table shows the main bacteria causing exacerbations in patients with copd. in the past, it was believed that only bacteria were capable of generating exacerbations in patients with copd. , however, the occurrence of these in the winter and symptoms similar to cold led to the belief that viruses were also associated with the complications of this obstructive pathology of the airways. on the other hand, viral infections of the respiratory tract have been shown to influence the lung microbiome in patients with copd, which indicates that both microorganisms can coexist and predispose to exacerbations. the most prevalent viruses during acute exacerbations of copd are rhinovirus, coronavirus, influenza, respiratory syncytial virus and parainfluenza, among others. , there are many factors that influence virus infection in patients with copd. among them, icam- overexpression stands out, where, for example, rhinoviruses are anchored and more easily enter epithelial cells, favoring infection. it has been described in several studies that the functionality of nk lymphocytes in patients with copd is severely diminished, which leads to a greater propensity for virus infections (rhinovirus, respiratory syncytial virus, influenza, etc.), causal agents of a high percentage of exacerbations in this type of patients. the low antiviral activity is due, in large part, to the inhibition of the secretion of cytokines such as tnf-α, ifn-γ and il- , in addition to the low production of enzymes such as perforins, so they cannot eliminate the cells already infected by virus, so that the infection continues its course without having a response that attenuates it. it has been proposed that vitamin d ( , -dihydroxyvitamin d [ , d] ) plays a key role on lung immunity. during a viral infection, vitamin d induces iκbα (a potent inhibitor of nf-κb) expression in airway epithelial cells, favoring a reduction of proinflammatory cytokines and no change in viral clearance. this increase of , d in airways will contribute to control tissue damage, while maintaining viral clearance. in copd, vitamin d deficiency is highly prevalent and correlates with severity of copd. an important mechanism through which , d can predispose to present an exacerbation is by suppressing th (il- , ifn-γ, tnf-α) and th (il- a, il- f) cytokines and promoting regulatory t lymphocytes (treg) (il- , tgf-β) function. lower levels of , d in copd may be explained by different mechanisms, for example, the reduction of cutaneous vitamin d production caused by smoking and limited sunlight exposure. other mechanisms of vitamin d deficiency could be reduced vitamin d activation in liver and kidneys, increased vitamin d sequestration in adipose tissue and decreased intestinal absorption. as with pneumococcus, it is recommended that copd patients be immunized annually with the influenza vaccine, since it is also one of the main etiological agents of exacerbations. in addition, several studies suggest that epidemiologically speaking, influenza vaccine is more effective than pneumococcus. in copd exacerbations, there is an increase in the lungs and respiratory tracts cellularity. therefore, an increase in the number of leukocytes, such as neutrophils and macrophages th profile in copd exacerbations in the airway, and the increase in proinflammatory cytokines are directly related to the severity of the exacerbations. th cd + lymphocytes synthesize il- a that promotes the activation of bronchial fibroblasts, epithelial cells and smooth muscle cells, inducing them to produce proinflammatory cytokines responsible for the recruitment of neutrophils and their local infiltration, thus aggravating the copd symptomatology. il- a promotes inflammation by coordinating granulopoiesis and neutrophil mobilization. this cytokine is particularly central to lung immunity because it has been demonstrated that innate host defenses to respiratory pathogens are compromised in mice lacking this proinflammatory cytokine or its receptor (il- ra), leading to reduced neutrophil activation, differentiation and recruitment and increased bacterial proliferation. le rouzic et al in their study showed that chronic exposure to cigarette smoke extract (cse) inhibits s. pneumoniaeinduced monocyte-derived dendritic cells (mddc) maturation and secretion of cytokines involved in th and th t cell differentiation, among which are il- β, il- , il- and il- (which is necessary to th polarization). these events can contribute to colonization of pathogens capable of generating exacerbations. qiu et al found that il- significantly augmented t-bet expression by naive cd + t cells in th conditions. in contrast, the expression of ror-γt was dramatically suppressed by the addition of il- . both in copd patients and in mice, cigarette smoke exposure induced the upregulation of il- r (wsx- ) by naive cd + t cells. il- promotes the expression of th cells but inhibits the expression of th cells in vitro. also, il- r expression is increased during bacterial and parasitic infections, bringing on an exacerbation. receptors on the cell membrane of antigen-presenting phagocytes (apcs) such as tlrs recognize the presence of lipopolysaccharide in the membrane of bacteria such as h. influenzae and m. catharralis that colonize in a large part of the respiratory tract under normal conditions and that imbalance in the pulmonary microbiome exerts a stimulus that allows phagocytes to synthesize and release proinflammatory cytokines, in addition to phagocytosing the pathogen to subsequently present the antigen to t lymphocytes naive and allow their polarization together with the cytokine microenvironment present at that time. these data suggest that cd + th lymphocytes play an important role in the immune response to bacteria such as s. pneumoniae, s. aureus and m. catharralis. dcs are professional apcs whose principal function is linking the innate and adaptive immune responses, a central mechanism in copd. a chronic exposure to cse has been related to a deficiency in the phagolysosome trafficking in dc, secondary to low expression of maturation markers such as cd , which leads to a deficient antigenic presentation and, consequently, an inadequate response against bacteria such as s. pneumoniae. van der sluijs et al reported in their study that inhibiting the production of il- (inhibitory cytokine) by tregs decreases the likelihood of secondary s. pneumoniae infection. in the case of viruses, pathogen-associated molecular patterns are recognized by tlrs present in endolysosomes or by rig receptors (rlrs) in the cytoplasm. when this happens, the signaling pathway led by nf-κb and irf culminates in the synthesis and release of proinflammatory cytokines, in addition to type i ifns, such as ifn-α and ifn-β, creating an antiviral state that rests the infection. with the production of these ifns, inhibition of the response of this strain of cooperating t lymphocytes, such as th cd +, is generated, causing greater susceptibility to secondary bacterial infections, thus aggravating the health status of patients with copd susceptible to this type of infections. since cytokines such as il- a and il- f do not exist in the airway microenvironment, the production of neutrophil chemoattractants by airway epithelial cells such as cxcl and cxcl cannot be induced and the action required attracting neutrophils, and therefore, there is not adequate containment of extracellular bacteria. another way that has been recently described as an important mediator of th cd + inducers is a serum amyloid a (saa), which promotes expression of inflammatory mediators and neutrophil chemotaxis and survival by the alx-fpr receptor. saa is also a potent endogenous ligand that stimulates expression of th polarizing mediators and influences in vitro th differentiation of cd + t cells. mechanisms involved in infectious copd exacerbations are not entirely clear. various cellular types and molecules are involved in its pathogenesis. importantly, the th profile has been linked as one of the main participants, which involves a complex system of proinflammatory cells and molecules. for these reasons, it is essential to conduct clinical and basic studies to have a broader perspective of the molecular and cellular mechanisms that take place during copd exacerbations, which can compromise the life of patients. the initial marco antonio ponce-gallegos research for this article in the hla laboratory. the authors report no conflicts of interest in this work. concentration of ccl , cxcl and tnf-alpha in sputum and plasma of patients undergoing asthma or chronic obstructive pulmonary disease exacerbation role of th cell and autoimmunity in chronic obstructive pulmonary disease the circulating proteinase inhibitor α- antitrypsin regulates neutrophil degranulation and autoimmunity increased risk of exacerbation and hospitalization in subjects with an overlap phenotype: copd-asthma inflammation and immune response in copd: where do we stand? global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease gold executive summary chronic obstructive pulmonary disease (copd) molecular mechanisms in chronic obstructive pulmonary disease global initiative for chronic obstructive lung disease. global strategy for the diagnosis, management and prevention of copd - long-term natural history of chronic obstructive pulmonary disease: severe exacerbations and mortality effects of cigarette smoke on epithelial cells of the respiratory tract early events in the pathogenesis of chronic obstructive pulmonary disease: smoking-induced reprogramming of airway epithelial basal progenitor cells damps activating innate and adaptive immune responses in copd murine tlr is implicated in cigarette smoke-induced pulmonary inflammation cigarette smoke-induced pulmonary inflammation is tlr /myd and il- r /myd signaling dependent lung cd + t cells in copd have increased expression of bacterial tlrs the role of the nlrp inflammasome in the pathogenesis of airway disease the neutrophil in copd: too little too late, or too much too soon? human dendritic cell deficiency: the missing id? defining dendritic cells by conditional and constitutive cell ablation dendritic cells in lung immunopathology interleukin- in pulmonary host defense th cells in human disease il- s produced by th cells and drives il- production in a stat -dependent manner il- regulates experimental colitis by modulating the balance between th and th cells il- programs th- cell differentiation by promoting sequential engagement of the il- and il- pathways il- initiates an alternative pathway to induce proinflammatory th cells il- mediates mucosal host defense against gram-negative bacterial pneumonia expression of the t helper -associated cytokines il- a and il- f in asthma and copd il- defect during streptococcus pneumoniae infection triggers exacerbation of chronic obstructive pulmonary disease pathological versus protective functions of il- in airway inflammation are regulated by il- a cutting edge: crucial role 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chronic obstructive pulmonary disease relationship between bacterial flora in sputum and functional impairment in patients with acute exacerbations of copd infection as a comorbidity of copd consenso mexicano de epoc: manejo de un paciente con epoc inestable. exacerbación leve, moderada y grave [mexican consensus of copd: management of a patient with unstable copd. mild, moderate and severe exacerbation seasonality and determinants of moderate and severe copd exacerbations in the torch study outgrowth of the bacterial airway microbiome after rhinovirus exacerbation of chronic obstructive pulmonary disease rhinovirus infection induces degradation of antimicrobial peptides and secondary bacterial infection in chronic obstructive pulmonary disease respiratory viral infections in adults with and without chronic obstructive pulmonary disease impairment of human nk cell cytotoxic activity and cytokine release by cigarette smoke relation of sputum inflammatory markers to symptoms and lung function changes in copd exacerbations bacterialviral load and the immune response in stable and exacerbated copd: significance and therapeutic prospects toll-like receptors in antiviral innate immunity vitamin d decreases respiratory syncytial virus induction of nfkappab-linked chemokines and cytokines in airway epithelium while maintaining the antiviral state vitamin d deficiency is highly prevalent in copd and correlates with variants in the vitamin d-binding gene immune modulatory treatment of trinitrobenzene sulfonic acid colitis with calcitriol is associated with a change of a t helper (th) /th to a th and regulatory t cell profile chronic obstructive pulmonary disease is associated with low levels of vitamin d serum amyloid a promotes lung neutrophilia by increasing il- a levels in the mucosa and γδ t cells cigarette smoke alters the ability of human dendritic cells to promote anti-streptococcus pneumoniae th response cigarette smoke induction of interleukin- /wsx- regulates the differentiation of th and th cells in a smoking mouse model of emphysema il- is an important mediator of the enhanced susceptibility to pneumococcal pneumonia after influenza infection the authors wish to thank the programa interinstitucional para el fortalecimiento de la investigación y el posgrado del pacífico (delfin) for the scholarship obtained to carry out the international journal of copd is an international, peer-reviewed journal of therapeutics and pharmacology focusing on concise rapid reporting of clinical studies and reviews in copd. special focus is given to the pathophysiological processes underlying the disease, intervention programs, patient focused education, and self management protocols.this journal is indexed on pubmed central, medline and cas. the manuscript management system is completely online and includes a very quick and fair peer-review system, which is all easy to use. visit http://www.dovepress.com/testimonials.php to read real quotes from published authors. key: cord- -fsbemdry authors: chang, chih-hao; tsao, kuo-chien; hu, han-chung; huang, chung-chi; kao, kuo-chin; chen, ning-hung; yang, cheng-ta; tsai, ying-huang; hsieh, meng-jer title: procalcitonin and c-reactive protein cannot differentiate bacterial or viral infection in copd exacerbation requiring emergency department visits date: - - journal: int j chron obstruct pulmon dis doi: . /copd.s sha: doc_id: cord_uid: fsbemdry background: viral and bacterial infections are the most common causes of chronic obstructive pulmonary disease (copd) exacerbations. whether serum inflammatory markers can differentiate bacterial from virus infection in patients with copd exacerbation requiring emergency department (ed) visits remains controversial. methods: viral culture and polymerase chain reaction (pcr) were used to identify the viruses in the oropharynx of patients with copd exacerbations. the bacteria were identified by the semiquantitative culture of the expectorated sputum. the peripheral blood white blood cell (wbc) counts, serum c-reactive protein (crp), procalcitonin (pct), and clinical symptoms were compared among patients with different types of infections. results: viruses were isolated from ( . %) of the patients enrolled. the most commonly identified viruses were parainfluenza type , influenza a, and rhinovirus. a total of ( . %) patients had positive bacterial cultures, with the most commonly found bacteria being haemophilus influenzae and haemophilus parainfluenzae. five patients ( . %) had both positive sputum cultures and virus identification. the wbc, crp, and pct levels of the bacteria-positive and bacteria-negative groups were not statistically different. multivariate analysis showed that patients with increased sputum volumes during the copd exacerbations had higher risks of recurrent exacerbations in the -year period following the first exacerbation. conclusion: wbc, crp, or pct could not differentiate between bacterial and viral infections in patients with copd exacerbation requiring ed visits. those with increased sputum during a copd exacerbation had higher risks for recurrent exacerbations. bacterial colonization and viral respiratory pathogens play important roles in exacerbations of chronic obstructive pulmonary disease (copd), , especially in patients requiring hospitalization. viral and/or bacterial infections have been detected in up to % of patients with copd exacerbations. although bacteria are considered the major cause of copd exacerbations and antibiotics commonly used to treat exacerbations, the importance of viral infections in copd exacerbations was mentioned after the introduction and wide use of viral culture and real-time polymerase chain reaction (pcr). , the link of viral infections to copd has been emphasized in recent studies. copd patients had more airway inflammation after virus-associated exacerbations. , seemungal et al found that viral infections caused frequent copd exacerbations with prolonged symptoms. after viral infections, secondary bacterial infections were frequently detected in copd patients. biomarkers are commonly used to differentiate infective or noninfective causes of copd exacerbations. a previous study suggested that patients treated with antibiotics according to procalcitonin (pct) levels for exacerbations of copd, reduced antibiotics use. however, pct does not differentiate bacterial from viral causes of copd exacerbations requiring admission to intensive care unit or ward. , whether serum inflammatory markers, such as c-reactive protein (crp) or pct, can distinguish bacterial from viral infection or not in patients with copd exacerbations requiring emergency department (ed) visits remains controversial. this study was conducted to clarify peripheral blood white blood cell (wbc) counts, pct, and crp levels, and their relationships with viral or bacterial pathogens, in copd patients requiring ed visits for exacerbations. copd patients aged greater than years old who visited the ed of the linkou chang-gung memorial hospital due to copd exacerbations between april and august were prospectively enrolled for this study. copd was diagnosed based on the global initiatives for chronic obstructive lung disease (gold) guidelines, and an exacerbation was defined as "a worsening of the patient's respiratory symptoms that is beyond normal day-to-day variation". all the patients were current smokers or ex-smokers with a smoking history of greater than pack-years. postbronchodilator spirometry prior to the ed visit that demonstrated a ratio of forced expiratory volume in the first second (fev ) to forced vital capacity (fvc) of , % was documented. patients with a history of bronchial asthma or with abnormal chest radiographs indicating other respiratory diseases were excluded. patients who were hospitalized for cardiovascular disease, acute pulmonary edema, acute pulmonary embolism, pneumothorax, or active pneumonia were also excluded. active pneumonia was diagnosed by chest radiograph obtained in ed. medical records were reviewed and analyzed for the following data: age, sex, body mass index (bmi), medications used prior to the ed admission, clinical symptoms (worsened dyspnea, increased sputum volume and purulence, fever, cough, sore throat, and wheeze), family cluster of common cold symptoms, peripheral blood wbc count, serum crp and pct levels, spirometry, and hospital days of the current exacerbation. prior corticosteroid use was defined as having had a corticosteroid prescribed at mg or more of prednisolone per day for more than days within year before the ed visit. the anthonisen criteria were defined as the presence of one of three symptoms, including increased dyspnea, increased sputum volume, and increased sputum purulence. number of exacerbations in the following years was retrospectively collected. sputum was obtained by spontaneous production, and the specimen was sent to the central laboratory of linkou chang-gung memorial hospital for bacterial culture. a positive bacterial culture was defined as moderate to heavy growth of bacteria in the semiquantitative culture. oropharyngeal swab specimens were collected from these patients for virus identification using both virus isolation and multiplex rt-pcr (mrt-pcr) assays. oropharyngeal swab specimens were inoculated onto mk , mrc- , and mdck cells to isolate the viruses. the cell cultures were incubated at °c for weeks. the final identification of the viruses was performed using an immunofluorescence assay (ifa) screening kit (chemicon inc., temecula, ca, usa) for respiratory viruses. the mrt-pcr assay was designed to amplify the conserved regions of viral targets. the mrt-pcr was performed using . ml thin-walled pcr tubes in a bio-rad icycler or abi . the rt-pcr mixture used in the assay was the superscript ® iii one-step rt-pcr kit (invitrogen; life technologies corp, carlsbad, ca, usa). each reaction contained the following kit reagents: . pct and crp in copd exacerbation statistical analysis all statistical analyses were performed using the spss (spss for windows, spss inc., chicago, il, usa) statistical package and prism (graphpad software, inc., la jolla, ca, usa). all values are reported as means ± standard deviation (sd). differences among subgroups were compared by using the χ test or fisher's exact test when the expected number of events was less than . the significance level (α) for all statistical tests was set at . , and p, . was considered statistically significant. this study was conducted in accordance with the amended declaration of helsinki. the study was approved by the institutional review board of chang gung memorial hospital, and written informed consent was obtained from all patients. in all, copd patients with exacerbations that required ed visits were included in the study period. none of the patients were included twice. no patients received long-term oxygen therapy in this study. the mean fev was . ± . l ( . %± . % of predicted value). the baseline characteristics of the copd patients, including age, sex, bmi, fev % predicted, fvc% predicted, gold stage, pack-years of tobacco use, previous inhaled or oral medications, peripheral blood wbc counts, and serum crp and pct levels are shown in table . a total of patients ( . %) presented with two or more of the anthonisen criteria, and patients ( . %) had recurrent exacerbations that required ed visits in the subsequent -year period. a total of patients ( . %) were admitted to ward and patients discharged from the ed. four hospitalized patients were admitted to the intensive care unit for acute respiratory failure, three of whom needed mechanical ventilator support, while the last received noninvasive ventilation support. none of the patients died. viruses were detected in the oropharynx of ( . %) of the patients (table ) . parainfluenza virus type (piv ) was the most commonly detected virus ( . %), followed by influenza a (inf a) and human rhinovirus. both adenovirus and piv were identified in one patient. no influenza b or respiratory syncytial virus (rsv) was found. one patient had simultaneous detection of piv and adenovirus. patients with or without the confirmed presence of viruses were divided into two groups: patients were virus-positive and patients were virus-negative. there were no significant between-group differences in age, bmi, fev , fvc, length of hospital days, or number of exacerbation in the subsequent year. figure shows the laboratory data at the time of ed admission of the copd exacerbation patients. wbc counts, crp, and pct levels were not significantly different between the virus-positive and virus-negative group. a larger proportion of the virus-positive patients had been previously treated with oral corticosteroids than had the virus-negative patients ( . % versus . %) (p= . ). the viral-positive groups presented with more sore throat symptoms than did the viral-negative groups ( . % versus . %) (p= . ). the family cluster of common cold symptoms was significantly higher for viral-positive groups than viral-negative groups ( % versus . %) (p= . ). in all, patients ( . %) with copd exacerbations had positive sputum bacterial cultures (table ) . haemophilus influenzae was the most commonly identified bacterial strain ( %), followed by haemophilus parainfluenzae. the sputum chang et al bacterial culture of one patient grew staphylococcus aureus and acinetobacter baumannii. chlamydia species were found by mrt-pcr in two cases, but no patients were positive for mycoplasma by pcr. there were no statistically significant differences between the bacteria-positive and bacteria-negative patients in age, bmi, fev , fvc, clinical symptoms, medications used prior to ed admission, length of hospital days, or recurrent exacerbations in the subsequent year. wbc, crp, and pct levels were not significantly different between the bacteria-positive and bacteria-negative groups (figure ) . among the seven patients with pct . . ng/ml, three ( . %) had sputum that was positive for bacteria growth, but none of these subjects were positive for viruses. the only significant difference was that the bacteria-positive group had a lower fev /fvc ratio than did the bacteria-negative group ( . % versus . %) (p= . ). both virus and bacteria were identified in five patients ( . %). one had inf a and streptococcus pneumoniae, another had adenovirus and h. influenzae, the third had piv , adenovirus, and h. influenzae, the fourth had piv and h. parainfluenzae, and the last had escherichia coli and human metapneumovirus. table shows the results of univariate and multivariate analysis of variables associated with recurrent exacerbations in the subsequent -year period. the results indicated that an increased sputum volume during the copd exacerbation that required the ed visit was independently associated with a higher risk of a recurrent exacerbation during the subsequent year. the percentage of patients free from readmission to the eds in year, analyzed by kaplan-meier curves and evaluated with the log-rank test, was not significantly different between the bacteria-positive and bacteria-negative groups. the curves for patients who were virus-positive and virus-negative also did not differ significantly (figure ). when the outcomes were analyzed specifically by pct and crp levels, the percentage of patients free from readmission to the eds also showed no statistically significant differences (figure ). our study demonstrated that viruses were identified in the oropharynx of . % and bacterial infections were confirmed in . % of the patients with copd exacerbations requiring ed visits. the most commonly identified virus was piv , and the most commonly found bacterium was h. influenzae. higher percentages of the virus-positive patients presented with sore throat and with the family cluster of common cold symptoms. the analysis of maintenance medications prescribed before the ed visits showed that the percentage of patients who had oral corticosteroid treatment prior to multivariate analysis for evaluation of the risk factors for recurrent exacerbations showed a higher rate of recurrent copd exacerbation in the -year period after the original ed visit in those with an increased sputum volume during the first copd exacerbation. however, the commonly used biomarkers for infection, such as serum crp or pct levels, did not aid in differentiating between bacterial or viral infections in patients with copd exacerbations. a more rapid decline of lung function is observed in copd patients with exacerbations. the patients with exacerbations also had higher mortality rates and more frequent exacerbations requiring hospital admissions. papi et al found that infective exacerbations were detected in % of patients, with bacteria identified in . % and viruses in . %. copd exacerbations in which pathogens were identified were associated with longer hospitalization stays than noninfective exacerbations. however, the positive rates of viral identification in patients with copd exacerbations requiring hospitalization varied in different publications. in the study by kherad et al in which the samples for virus identification were obtained via nasopharyngeal swabs and the identification was performed using qualitative rt-pcr assays, the overall virus-positive rate was %. mcmanus et al showed that . % of patients hospitalized for copd exacerbations had sputum samples that were positive for viruses. in a study of patients with copd exacerbations requiring mechanical ventilation, viruses were identified in % of nasopharyngeal aspirates and posterior pharyngeal swabs. in our study, viral pathogens were detected in the oropharyngeal swabs of patients ( . %). the viruspositive rate of the oropharyngeal swabs was thus lower than in the previous studies. the possible causes of the variation may include seasonal and geographic differences in the etiology of virus-associated copd exacerbations. in a recent systematic review, the rates of detection of viruses associated with copd exacerbations were highest in europe. another possible cause of the differences in the results is the site of the sample collections. in our study, we collected oropharyngeal swabs but not nasopharyngeal swabs or sputum samples, which might result in different rates of viral detection. in this study, the commonly identified viruses in patients with copd exacerbations requiring ed visits were piv , inf a virus, and human rhinovirus. this result was similar to the finding of cameron et al from a study in australia in which the most frequently detected viral etiologies were inf a, piv , and rhinovirus. in a recent review of eight studies, picornavirus was the most common virus in western countries and influenza virus was most common in asia. h. influenzae was the most common bacterial pathogen in copd exacerbations in a previous study. pseudomonas aeruginosa and klebsiella pneumoniae were also emphasized in recent studies. , in our study, h. influenzae, h. parainfluenzae, and k. pneumoniae were the most commonly identified bacteria. our data provided worthwhile epidemiologic results of viral and bacterial etiologies of copd exacerbation, and this may have important implications for appropriate empirical selection of antibiotics and proper management of copd exacerbations. biomarkers are commonly used to differentiate infective or noninfective causes of copd exacerbations. we compared wbc, crp, and pct levels between the bacteria-positive and bacteria-negative patients, and these biomarkers did not show statistically significant between-group differences in our study. similarly, for the wbc, crp, and pct levels, the differences between the virus-positive and virus-negative patients were not statistically significant. pct is a biomarker that is more specific for bacterial infection and might be useful as a guide for decisions regarding antibiotic treatment. however, it could not distinguish bacterial from viral and noninfectious causes of copd exacerbations. daniels et al compared crp and pct as markers of clinical outcome in copd exacerbations and found that pct was not a good biomarker in copd exacerbations because patients with low pct values did benefit from antibiotics. the severity of the bacterial infections of the airways in some patients with copd exacerbations is probably insufficient to induce a significant pct production. sputum purulence has been suggested to be useful in determining the initiation of antibiotic treatment in hospitalized patients with copd exacerbations. however, there was no difference in sputum purulence between the bacteria-positive and bacteria-negative groups in our study. in a retrospective cohort study, up to % of patients hospitalized for copd exacerbations were treated with antibiotics. although the gold guidelines suggest "the use of antibiotics in exacerbations remains controversial" and "consider antibiotic when signs of bacterial infection", the study by rothberg et al supported antibiotic administration as improving the outcomes among patients hospitalized for copd exacerbations. copd exacerbation patients in whom oropharyngeal viruses were identified were more likely to have had previous corticosteroid treatment, a sore throat, and a family cluster of common cold symptoms. clinicians should consider virusinduced copd exacerbations if the patients present with a sore throat or a family cluster of common cold symptoms. international journal of copd : submit your manuscript | www.dovepress.com pct and crp in copd exacerbation a total of % of our patients had recurrent exacerbations during the subsequent -year period after the exacerbation. hurst et al reported on a cohort of patients with copd and showed that % of patients with stage , % with stage , and % with stage copd had exacerbations during the preceding year. bafadhel et al divided copd exacerbations to four distinct clusters, including bacterial, viral, eosinophilic predominant, and pauci-inflammatory, by biomarkers such as sputum il- β or serum cxcl . we analyzed the clinical variables associated with the -year recurrent exacerbation rate, and increased sputum volume during the initial copd exacerbation was the only independent risk factor for recurrent exacerbations in the subsequent -year period. our study provides additional information for further investigation about copd phenotypes of recurrent exacerbations. there are some limitations in this study, which should be mentioned. first, the techniques used in this study cannot distinguish acute infection from colonization. therefore, we selected patients requiring ed visits rather than only symptom-based exacerbations. second, although this study was conducted in a , -bed tertiary teaching hospital, it was still a single-center, not a multicenter, study, and our results were obtained for a very low number of patients. third, whether these patients had prior influenza or pneumococcal vaccinations had not been recorded. we could not clarify the influence of vaccinations in copd exacerbations from this study. further, virus was assessed both by cultures and by pcr, but bacteria were identified only by culture. finally, our virus identification was obtained from oropharyngeal swab specimens. we did not obtain specimens from nasopharyngeal swabs or the lower respiratory tract for virus identification. the actual rates of virus identification in different sampling sites were unknown. in conclusion, viruses and bacteria both play important roles in copd exacerbations. wbc, pct, and crp levels are not good indicators for bacterial infections in copd exacerbations. those with increased sputum volume in copd exacerbation had a higher rate of recurrent exacerbations in the subsequent -year period. understanding the etiologies of bacteria and viruses in copd exacerbations might aid in the appropriate management of copd exacerbations. infection in the pathogenesis and course of chronic obstructive pulmonary disease respiratory viruses in exacerbations of chronic obstructive pulmonary disease requiring hospitalisation: a case-control study prognosis of copd patients requiring frequent hospitalization: role of airway infection infections and airway inflammation in chronic obstructive pulmonary disease severe exacerbations copd clinical research network. azithromycin for prevention of exacerbations of copd viral infections in patients with chronic obstructive pulmonary disease prevalence of viral infection detected by pcr and rt-pcr in patients with acute exacerbation of copd: a systematic review relation of sputum inflammatory markers to symptoms and lung function changes in copd exacerbations inflammatory response in acute viral exacerbations of copd respiratory viruses, symptoms, and inflammatory markers in acute exacerbations and stable chronic obstructive pulmonary disease rhinovirus infection induces degradation of antimicrobial peptides and secondary bacterial infection in chronic obstructive pulmonary disease antibiotic treatment of exacerbations of copd: a randomized, controlled trial comparing procalcitonin-guidance with standard therapy utility of serum procalcitonin values in patients with acute exacerbations of chronic obstructive pulmonary disease: a cautionary note procalcitonin levels in acute exacerbation of copd admitted in icu: a prospective cohort study global initiative for chronic obstructive lung disease. global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: gold executive summary antibiotic therapy in exacerbations of chronic obstructive pulmonary disease relationship between exacerbation frequency and lung function decline in chronic obstructive pulmonary disease severe acute exacerbations and mortality in patients with chronic obstructive pulmonary disease upper-respiratory viral infection, biomarkers, and copd exacerbations respiratory viral infection in exacerbations of copd virus infection in exacerbations of chronic obstructive pulmonary disease requiring ventilation sputum bacteriology in hospitalized patients with acute exacerbation of chronic obstructive pulmonary disease in taiwan with an emphasis on klebsiella pneumoniae and pseudomonas aeruginosa pseudomonas aeruginosa in patients hospitalised for copd exacerbation: a prospective study procalcitonin vs c-reactive protein as predictive markers of response to antibiotic therapy in acute exacerbations of copd sputum purulence-guided antibiotic use in hospitalised patients with exacerbations of copd quality of care for patients hospitalized for acute exacerbations of chronic obstructive pulmonary disease antibiotic therapy and treatment failure in patients hospitalized for acute exacerbations of chronic obstructive pulmonary disease evaluation of copd longitudinally to identify predictive surrogate endpoints (eclipse) investigators. susceptibility to exacerbation in chronic obstructive pulmonary disease acute exacerbations of chronic obstructive pulmonary disease: identification of biologic clusters and their biomarkers this study was sponsored by the chang-gung research program, grant number cmrpg . the authors report no conflicts of interest in this work. submit your manuscript here: http://www.dovepress.com/international-journal-of-chronic-obstructive-pulmonary-disease-journalthe international journal of copd is an international, peer-reviewed journal of therapeutics and pharmacology focusing on concise rapid reporting of clinical studies and reviews in copd. special focus is given to the pathophysiological processes underlying the disease, intervention programs, patient focused education, and self management protocols.this journal is indexed on pubmed central, medline and cas. the manuscript management system is completely online and includes a very quick and fair peer-review system, which is all easy to use. visit http://www.dovepress.com/testimonials.php to read real quotes from published authors. key: cord- -gtwtakpr authors: holmen, heidi; larsen, marie hamilton; sallinen, merja helena; thoresen, lisbeth; ahlsen, birgitte; andersen, marit helen; borge, christine råheim; eik, hedda; wahl, astrid klopstad; mengshoel, anne marit title: working with patients suffering from chronic diseases can be a balancing act for health care professionals - a meta-synthesis of qualitative studies date: - - journal: bmc health serv res doi: . /s - - - sha: doc_id: cord_uid: gtwtakpr background: the number of patients with long-term chronic diseases is increasing. these patients place a strain on health care systems and health care professionals (hcps). presently, we aimed to systematically review the literature on hcps’ experiences working with patients with long-term chronic diseases such as type diabetes, chronic obstructive pulmonary disease (copd), and chronic kidney disease (ckd). method: a systematic search of papers published between and july was conducted in the embase, amed, psycinfo, medline, cinahl, and cochrane databases to identify studies reporting qualitative interviews addressing hcps’ experiences working with adults with copd, ckd or type diabetes. an interdisciplinary research group were involved in all phases of the study. with the help of nvivo, extracts of each paper were coded, and codes were compared across papers and refined using translational analysis. further codes were clustered in categories that in turn formed overarching themes. results: our comprehensive search identified citations. of these, papers met our inclusion criteria. regarding hcps’ experiences working with patients with copd, ckd, or type diabetes, we developed sub-categories that formed three overarching main themes of work experiences: ) individualizing one’s professional approach within the clinical encounter; ) managing one’s emotions over time; ) working to maintain professionalism. overall these three themes suggest that hcps’ work is a complex balancing act depending on the interaction between patient and professional, reality and professional ideals, and contextual support and managing one’s own emotions. conclusion: few qualitative studies highlighted hcps’ general working experiences, as they mainly focused on the patients’ experiences or hcps’ experiences of using particular clinical procedures. this study brings new insights about the complexity embedded in hcps’ work in terms of weighing different, often contrasting aspects, in order to deliver appropriate practice. acknowledging, discussing and supporting this complexity can empower hcps to avoid burning out. leaders, health organizations, and educational institutions have a particular responsibility to provide hcps with thorough professional knowledge and systematic support. trial registration: prospero number: crd . keywords: health personnel, work experiences, noncommunicable disease (ncd), clinical encounters, diabetes mellitus, type , pulmonary disease, chronic obstructive (copd), chronic kidney disease (ckd), patient-centered care, occupational burden with an increasing number of patients with chronic conditions worldwide, a growing number of health care professionals (hcps) will encounter these patients daily. as patients live longer with chronic diseases, the relationship between hcps and patients may last for years. in order to provide the best treatment for the growing number of patients with chronic conditions, we need to increase our understanding of how to keep hcps motivated in their work [ ] . this is particularly important today, as burn-out among hcps is a growing problem [ ] . the global increase of chronic diseases, often framed as non-communicable diseases (ncds), has resulted in global strategies within the world health organization (who) and the united nations to prevent or delay onset and reduce premature mortality [ ] . lifestyle choices and unhealthy lifestyle habits, such as physical inactivity, an unhealthy diet, and smoking, are commonly linked to ncds. if these chronic conditions are diagnosed at an early stage and adequate self-management strategies are applied, the prognosis can be good. self-management of chronic disease entails an active role for patients, who must make day-to-day decisions to manage symptoms, treatment, physical and psychosocial consequences of the disease, and lifestyle changes [ ] . thus, selfmanagement within long-lasting care is often individualized, goal-oriented, and facilitated in collaboration with hcps [ ] . nevertheless, these patients will often depend on support from the health care system for the rest of their lives, and the likelihood that these patients will leave the health care service once they have entered is low. patients that need long-term support thus represent a significant and growing strain on the system and on the involved hcps. for the past few decades, patients have been encouraged to take responsibility for their health to a greater degree [ ] . this is certainly the case for those living with chronic diseases, as patients are now expected to take an active role in their disease management: e.g. to follow medical regimes and comply with recommendations concerning lifestyle changes and adjustments in their daily lives. this requires that patients have easy access to information that is relevant to their specific situation. however, it may also challenge the hcp's role, as it represents a shift from a paternalistic approach, in which the hcp is the expert, to an approach in which the patient is acknowledged as an expert on his/her own life, with the right to make informed decisions regarding his/ her self-management [ ] . here, providing the tailored information and support for each individual patient at the right time, as well as involving and engaging the patients in their care, is important. the patient's expertise is highly emphasized in patient-centred care, which is defined as care "that is respectful of and responsive to individual patient preferences, needs, and values" and that ensures "that patient values guide all clinical decisions" [ ] . this definition of patient-centred care highlights the importance of clinicians and patients working together to produce the best possible outcomes. several researchers are proponents of this concept; however, the question has also been raised how hcps best should handle situations where a patient makes decisions that worsen disease outcomes [ , ] . repeated clinical encounters in which expectations regarding the patient role as expert are not met can contribute to this conflict, and possibly increase the already high strain and expectations placed on hcps. furthermore, the new hcp and patient roles are not necessarily thoroughly addressed during professional training. thus, presumably hcps must continuously balance their professional expertise with regards to responsibility and decision-making: taking responsibility and making decisions for the patient, or letting the responsibility lie with the patient, who may make decisions that include unhealthy behaviors. political statements recommend patient-centered care to a growing population of patients, many with ncds [ , ] . at the same time, health care are governed by ideals of public management requesting time-limited and effective care. however, the delivery of patientcentered care may take time and as outlined aboveeven not be effective in improving a patient's health outcomes. hence, dilemmas and challenges may arise for the hcps that cannot be easily solved in clinical practice [ ] . indeed, in studies of nurses and physicians, burnout and job dissatisfaction is associated with plans to leave their jobs [ ] . previous research on hcps' experiences of long-term patient-provider relationships is scarce, and often related to professional practice procedures rather than to the hcps' individual working experiences in general. how to understand the patient's experiences is widely researched, but how the hcps experience the patientprovider relationship, particularly when patients have a chronic disease, appears not to have generated equal interest among scientists. one qualitative study aiming to elicit providers' perspectives on caring for patients with chronic pain found that hcps internalized feelings of failure, guilt and discontent. this study highlighted the need for physicians to care not just for their patients but also to adopt self-care strategies to reduce "compassion fatigue" when caring for challenging patients [ ] . the present systematic review of qualitative empirical studies aims to provide an in-depth insight regarding how hcps experience working with patients with chronic diseases. we decided to focus on chronic obstructive pulmonary disease (copd), chronic kidney disease (ckd), and type diabetes, as these share commonality regarding the continuity of hcp-patient interactions over time and the great impact of lifestyle and self-management on prognosis. however, the three diseases also have clear differences in their treatment, their need for hcp follow up and prognosis over time, making them suitable to contrast the hcp experience. thereby, we sought new insights that could aid hcps, policymakers, and educational institutions in reducing the strain on hcps and preventing burn-out among hcps. thus, our aim was to systematically review the literature on hcps' experiences working with patients with long-term chronic diseases such as type diabetes, copd, and ckd. this systematic review was conducted between october and june . a research group comprising senior researchers (the authors), with a professional background in either nursing or physiotherapy and qualified in realist and interpretive qualitative research methods, conducted a systematic literature review of qualitative papers concerning hcps' experiences working with patients with type diabetes, ckd, and copd. the members of the research group had all worked in clinical and research settings with patients with a range of chronic diseases. whereas most of the nurses had insider knowledge from their clinical work and research on diabetes, copd, or ckd, the physiotherapists had an outsider perspective, as their experiences related mainly to chronic musculoskeletal disorders. these differences nurtured our discussions during the whole process. in order to enhance the researcher's reflexivity, shifting pairs of researchers worked together in all phases of the review process of inclusion/exclusion, appraising the methodological quality, extracting the data for further analysis, and analyzing the data. in the initial phase of the systematic review, a protocol was published in prospero. the review protocol may be accessed via prospero under the registration code crd . at beforehand, we decided to include only empirical qualitative studies published in scientific journals, and grey literature, conference proceedings, master and phd thesis were excluded as they often lack peer reviews. a systematic search strategy was developed and revised in close collaboration among the researchers and with assistance from an experienced research librarian before the final search was conducted. this comprehensive strategy aimed to ensure that relevant peer-reviewed empirical studies were identified in the search. the searches were conducted in six databases: embase, amed, psycinfo, medline, cinahl, and cochrane. the medline's medical subject headings (mesh) terms and additional keywords were used to identify relevant search terms, and the librarian added a study-specific "qualitative filter" to further tailor the search strategy. the search strategy was then adjusted to each other databases. while publication language was not limited, publication dates were limited to between and . the original search was completed by the th of november and was updated in june by the same librarian. an example of the search strategy can be found in the additional file . we based our search strategy on the "spider" framework-an acronym for sample, phenomenon of interest, design, evaluation, and research type [ ] -to identify the eligibility criteria, as shown in table . the spider framework was chosen based on its applicability for qualitative research. the final search strategy identified titles and abstracts. in the screening process, all authors participated in pairs, and the papers were independently screened by title and abstract for eligibility by the two reviewers in each pair, before the pairs met and discussed. each file represented one diagnosis; one pair sorted through the files for copd, one pair sorted through chronic kidney disease, and three pairs sorted through the files for diabetes. the inclusion and exclusion criteria were developed a priori but refined to become more precise during the inclusion process. the authors discussed each reference for which initial agreement was not reached, before a final set of references were retrieved and reviewed in full-text to assess whether they met the inclusion criteria. the included papers were then read by new pairs within the group to consolidate the agreement across the reviewers. the included papers were presented in a table drafted by the research group. this table included study specifications (author, country, and year of publication), number and gender of participants, characteristics, research purpose, stated theoretical or philosophical perspective, recruitment source, data collection, data analysis, main findings related to our research purpose, and whether the study fulfilled the methodological appraisal. to assess the methodological quality of the studies, the critical appraisal skills programme checklist (casp) for qualitative research was chosen as it is not nested to a particular epistemological perspective [ ] . in addition, one domain from the consolidated criteria for reporting qualitative research (coreq) was applied to capture methodological orientation and theory [ ] . working in pairs, the papers were first independently appraised by two researchers, before each pair met and discussed their appraisal, and the results were discussed by the group until consensus was reached about how we interpreted the items and came to a conclusion. papers of poor quality was not excluded, as papers with poor conceptual development are considered to contribute less to the results [ , ] . we argue that a methodological appraisal of the included papers is most valuable for describing the methodological quality to inform methodological discussions for future studies. after the inclusion/exclusion process, the authors read all the included papers in full text in order to identify the data at hand. our general impression from this reading was that hcps, in general, were satisfied with their work, but the general outline of several challenges could also be seen. these were discussed by the group. this overall impression guided our further (detailed) analysis of each paper, but it also enabled us to critically appraise whether our initial impression was supported by the data. the detailed, in-depth analysis was performed by groups of two or three members who each independently determined what was relevant in the primary studies' result section to inform our research question and subsequently to be extracted for further analysis. the extracts were discussed by the pairs until consensus was reached, and thereafter coded manually by the pairs. metaphors and concepts within the text were identified and used as codes whenever appropriate. we began with papers that we found presenting a richness of information and concepts in accord with what britten and pope [ ] call conceptual richness which characterize the best papers. the extracts of the next papers were then examined to see whether they could be translated into the codes we used for the previous paper; if not, new codes were developed. this approach was inspired by translational analysis, and thus involved an analytical transfer of concepts and insights between studies [ , ] . through this extensive process, recurrent or shared concepts-and points of similarity (reciprocal translation) and difference (refutational translation) within these concepts-were identified across studies and explicated iteratively. the small groups then presented their decisions for the whole group. as everyone had read all of the papers, the extracts were re-discussed until consensus was reached. the extracts and codes were transferred into the nvivo software program. here, too, all extracts and codes were read and discussed by the group and table the spider framework we included studies addressing the experience of hcps working with adults with chronic conditions, in which the relationship between the patient and hcp is assumed to be long-term. in this review, we focused on diabetes, copd, and ckd. if a study included a subset of eligible participants (e.g. a mixed population, including participants with other health conditions), we only included it if we could analyze the disaggregated data for the eligible participants separately. we excluded studies exploring any pre-existing phases of the three selected diseases, e.g. pre-diabetes, and those studies that included children aged and younger. we included any empirical, qualitative studies exploring the experiences of the relationship between hcp and patients with the selected chronic conditions reported from the hcps perspective. we also included studies addressing the hcps' feelings, attitudes, and perceptions, work satisfaction, or emotional burden regarding their relationship with these patients over time. we excluded studies addressing other phenomena, such as experiences with patients' use of specific treatments or interventions and those focusing on palliation. we included studies utilizing empirical qualitative research, including either individual or focus group interviews inspired by ethnography, narrative methods, phenomenology, grounded theory, observations, or qualitative interviews with no specific theoretical statements. we excluded: quantitative designs, mixed methods studies, studies reporting results from both patients and hcps, studies that did not address hcps' experiences working with patients with diabetes, copd, or ckd, studies exploring the experiences of surgeons, pharmacists, or students (who were assumed to not have a long-term relationship with their patients), and studies that addressed hcps experiences with specific interventions or treatments. in all the qualitative studies, quotes from interviews of the hcps had to be reported and analyzed qualitatively in the article for it to be included in the review. we included all published qualitative research, with no language restrictions. grey literature, such as conference proceedings and non-peer reviewed articles, were excluded, as they lack quality, detail, and peer review. we also excluded systematic reviews and meta-syntheses, as well as masters and phd theses. modified by looking across all the coded papers. this process generated codes ("nodes" in nvivo), which were written on post-it notes and attached to a whiteboard. the group then shared, reviewed, and discussed the codes, and finally clustered them into categories. through discussions and critical appraisals based on the group's mutual knowledge of the data material but various theoretical perspectives, we gradually developed three main overarching themes. the electronic search produced n = references ( fig. ). following the abstract review, n = publications were selected for full-text review. in total, n = publications were excluded during this screening process. the final full-text review produced papers for further analysis. the included papers concern hcps' experiences providing care to patients with ckd ( papers), copd ( papers), or type diabetes ( papers) (tables and ) . a total of hcps participated in the studies; the majority were physicians (n = ) and nurses (n = ). only two studies included physiotherapists [ , ] , one included a podiatrist [ ] , and four included dieticians in addition to nurses and physicians [ , , , ] . all eligible studies were reported in english, but there was general geographical variation among the studies: were conducted in europe, were from north america, from asia, study was from australia, and study took place in countries in europe and asia. as such, the studies cover the experiences of hcps working in a range of health care systems and cultures. overall, the to explore the reasoning of gps and respiratory physicians when managing patients with copd exacerbations in clinical encounters grounded theory ( ) stuij ( ), the netherlands [ ] to gain in-depth insight into experiences of health care professionals regarding the delivery of physical activity counseling to patients with type diabetes not stated ( ) svenningsson, hallberg and gedda ( ), sweden [ ] to generate a theory grounded in empirical data derived from a deeper understanding of health care professionals' main concerns when they consult with individuals with both diabetes and obesity and how they handle these concerns ( ); to discover escape mechanisms in case of frustration not stated ( ) methodological quality of the included papers was considered to be high ( table and in detail in additional file ). all papers had a clear statement of their research aims and were found to have appropriately applied a qualitative methodology. further, all papers clearly stated their findings. however, there was a trend across the papers that the researcher's own role in and impact on the interviews and the analysis was not discussed. likewise, the studies' methodological orientation and theoretical framework were rarely described. no studies were excluded from further analysis based on their methodological appraisal. based on our analysis of the results chapters of the included studies, three main themes were identified and developed, each addressing our overall aim to describe hcps' experiences working with patients with long-term chronic diseases: individualizing the professional approach within the clinical encounter; managing one's emotions over time; and working to maintain professionalism (table ). below, these themes are presented in detail. this theme comprises three categories illuminating the clinical encounter between the hcp and the patient: "engaging with the patient as a person," "encountering the chronic condition," and "facilitating a shared understanding of the chronic condition." the first category, "engaging with the patient as a person," describes how many hcps sought to provide individualized care and find ways to approach each patient's specific needs [ , ] . as pooley et al. [ ] stated, for hcps, this entailed getting to know the patient as a person. it was not necessarily easy for hcps to provide individualized care and recognize the person behind the diagnosis. hcps tolerated being given inaccurate information from their patients, in order to establish and maintain contact and build positive relationships with them [ , ] . other hcps, in contrast, rarely asked for personal details from their patients, as they did not see the need to do so [ , ] . in this way, they rejected the idea of tailoring their care based on information provided by their patients. the second category refers to that, although the hcps emphasized the importance of seeing and engaging in "the person behind the diagnosis," they were also obligated to "encounter the chronic condition." as such, they had to weigh the personal aspects against their professional responsibility and expertise concerning the disease. one challenge for the hcps, as shown in tonkin-crine et al. [ ] , was the discrepancy between the patient's subjective experiences on the one hand and clinical measures of the disease on the other. for example, it was a challenge to advocate diet adjustments to patients with kidney failure who had not yet experienced symptoms [ ] . it was also challenging for hcps when patients resisted modifying their lifestyle to optimize the treatment effects [ , ] , for example making decisions that might worsen symptoms and speed its progression. further, the hcps described feeling responsible for ensuring and strengthening patients' understanding of their disease in order to motivate them to make the recommended lifestyle changes [ ] . despite such efforts, the hcps felt that some patients showed a lack of interest in self-management, and they considered these patients to be passive and dependent on their hcp. doctors were especially frustrated with patients who demonstrated low adherence to prescribed treatments [ ] , and they felt that recommendations were more likely to be poorly followed by the elderly and less-educated [ ] . overall, success was perceived as challenging to predict, if it was even possible to predict [ ] . further, boström et al. pointed out that efforts to motivate patients to selfmanage their condition were perceived as timeconsuming for the staff and therefore not always prioritized [ ] . the third category, "facilitating a shared understanding of the chronic condition" among hcps and patients, " reflects that long-term chronic diseases lack curative treatment, and much depends on self-management efforts of patients. a lack of understanding among family members may negatively influence the patient's perceptions of diabetes specialist nurses' regarding their professional role are presented in five themes: "striving to be an expert," "striving to be a fosterer," "striving to be a leader," "striving to be an executive," and "striving to be a role model." diabetic nursing is a multifaceted profession with roles that cannot be easily combined. anxiety and emotional cost emerged in the face of uncertainty of prognosis and its effects on interactions with patients. the uncertain trajectory increased anxieties for health professionals in initiating discussion. there was a tendency to soften the impact of information given to the copd patients about death, and hcps felt unprepared and described anxiety and discomfort. crowshoe et al. [ ] in-depth semi-structured telephone grounded theory, using nvivo the management of acute copd exacerbations was handled within a range of concerns, from "dealing with comorbidity" through "having difficult patients" to "confronting a hopeless disease." difficulty balancing an approach to a disease that confronts the gp with his professional limits (i.e. concerning curing and saving lives), and with the patient's existential deterioration at all stages. acceptance of a disease and its severity [ ] . repeated encounters with patients and next of kin who were unwilling or unable to recognize the severity of the disease prognosis seemed to cause hopelessness among hcps [ ] . the hcps requested educational tools to assist them in facilitating patients' and family members' understanding and acceptance [ , ] . some of the hcps recommended that any change in behavior or life style, however small, to be acknowledged by hcps to keep their patients motivated [ ] . patients' specific cultural contexts could also impact their understanding of the chronic disease, which hcps had to take into account in clinical encounters. this was especially clear in the papers addressing hcps' experiences working with ethnic minority groups and indigenous patients [ , ] . ethnic minorities were perceived by hcps as more difficult to reach and cooperate with than most other patients. here, hcps also expressed challenges related to their own and colleagues' lack of knowledge and cultural competence [ ] . in particular, conducting consultations in which the hcp was dependent upon a translator complicated the patient-provider relationship [ ] . thus, reaching a mutual understanding of the disease was often a demanding process, because patients often trusted their cultural traditions more than the hcps' explanations. here, lifestyle changes related to decreasing or omitting the consumption of traditional foods was especially difficult [ ] . the theme "managing one's emotions over time" encompasses the following three categories: "the challenges connected to a long-term relationship"; "maintaining professional sympathy," and "burden of responsibility." the category "the challenges connected to a long-term relationship" includes both the challenges and the rewards associated with long-term patient-provider relationships. with respect to chronic diseases, hcps often follow the same patients over a long period of time, often spanning years. pooley et al. [ ] argued that doctors must be prepared to become responsible for managing the care of some patients for the rest of their careers. personal relationships with patients were often developed and appreciated-as shown for example in a asthma/copd nurses' experience of patient education fluctuated between insecurity and security. nurses need the support of colleagues and management and more knowledge on patient education methods to be secure. the feeling of being important to the patient is important. gp general practitioner, ckd chronic kidney disease, hcp health care professionals, nvivo software for organizing categorize and classify data from qualitative and mixed-methods data adjusting to health organizational structures study on renal nurses-and these relationships often felt similar to those hcps had with their friends and family [ ] . the hcps felt that they had to engage emotionally with their patients, and they largely regarded this as positive. however, a long-term patient-provider relationship could also lead to negative personal relationships with patients [ ] . if the relationship was poor, it could become challenging for hcps to provide individualized care. nurses working with hemodialysis handled this by maintaining a professional and emotional distance from their patients, for example, by simply accepting the patients' demands; others felt pride when they successfully managed the more difficult relationships [ ] . in some cases, hcps decided to transfer the responsibility for the treatment of a patient to a colleague [ ] . in others, hcps stayed in the struggle, and ultimately developed a better understanding of why the patients appeared to be so difficult [ ] . accordingly, clinical encounters could cause stress, frustration, and tension among the hcps. however, there were also positive aspects of having personal relationships with patients. one example from a renal ward highlights how doctors valued their long-term, friendly relationships with patients throughout the process of renal failure and dialysis, in which they could share their patients' joy when conditions improved: for example, when a kidney transplantation was successful [ ] . however, patients could also die, and if the hcps had established a positive relationship with their patients, they mourned their loss. this was made more challenging by the fact that their professional role dictated that they push their feelings aside, to better support the families and other patients who had been close to the deceased [ ] . the category "maintaining professional sympathy" centers around how hcps deemed emotional engagement, in the forms of professional sympathy and compassion, as necessary for continuing in their work [ ] . nevertheless, there was also a risk that this compassion would be diminished. over time, hcps could become desensitized to others, and dehumanization could begin as early as, for example, medical school [ ] . there was also a risk that providing patient care based on routine would be prioritized over providing individualized care. despite routine and dehumanized care, when patients were unstable or did not follow advice, hcps expressed a variety of emotions, including sadness, powerlessness, aggression, sympathy, frustration, and irritation. even the most experienced hcps reported feelings of guilt when they were unable to make patients follow their therapeutic recommendations [ ] . when the emotional engagement with their patients became overwhelming, it was a challenge for hcps to keep their frustrations from spilling over into their relationships with their patients-this was especially true when hcps were faced with patients with limited coping abilities or those who complained over minor issues [ ] . under the category "burden of responsibility" the hcps felt highly responsible for their patients' wellbeing, which they sometimes also experienced as a burden [ ] . this was especially true when patients did not follow the treatment recommendations provided by the hcp and their disease worsened. boström et al. [ ] found, for example, that while nurses valued even the smallest behavioral changes accomplished by their patients, they had to accept that, in some cases, it was likely that change would never occur. further, the nurses described the challenge of balancing their desire to help their patients while also acknowledging that the patients had to help themselves [ ] . the hcps felt highly responsible for their patients, and this frequently resulted in feelings of guilt and shame, even for the most experienced hcps [ ] . while the papers addressed the experiences of hcps from a range of cultural contexts, working with three different chronic diseases, the hcps shared the opinion that maintaining professionalism was important. the work maintaining professionals contains the following four categories: "striving to achieve the best for the patient," "collaborating with other professionals," "keeping up professional self-esteem," and "adjusting to health organizational structures." the category "striving to achieve the best for the patient" includes hcps' experiences working to meet ideals embedded in their professional role and practice context [ , ] . one goal was to establish positive relationships with the patients, gaining the patients' trust while also being decisive, flexible, capable, and qualified in their work. even experienced nurses expressed a fear of being rejected by their patients [ ] . renal nurses were uncomfortable being closely observed by other patients in the dialysis wards where nurses' professional activities with one patient could be easily observed by other patients [ ] . having a positive relationship with patients was seen as especially important when doctors had to break the news to them about a worsening of their condition [ ] . positive relationships with their patients also involved the patients' gratitude when their treatments were successful, which generated strong feelings of professional pride and personal satisfaction for the hcps. in particular, achieving success in acute situations enabled doctors to maintain a positive attitude towards patients requiring long-term chronic care [ ] . walker et al. [ ] reported that dialysis nurses found it important to have professional autonomy, as it helped them better manage patients and tailor their care. a lack of professional autonomy, in turn, made providing care more difficult and less effective; however, the nurses felt that the hierarchical system in which they worked constrained their professional autonomy, making them feel they occupied a subordinate position within the hospital hierarchy. some nurses were afraid to express their opinions and bring up critical issues related to their work [ ] . abdulhadi [ ] remarked that a heavy workload, lack of teamwork, and lack of support from superiors in a hierarchical health care system decreased hcps' trust in the system: doctors, in particular, reported feeling a lack of trust in their co-workers' competence. boström et al. [ ] showed how diabetes specialist nurses found their autonomy and self-determination hampered by being frequently told to assist others in their work. the category we labelled "collaborating with other professionals" encompasses multidisciplinary support and cooperation with colleagues, as well as the professional loneliness that arises from a lack of cooperation and support. on the one hand, colleagues were described as the most prominent source of support, mainly because they knew the context of care and were easily available for consultation [ ] . this support could take different forms, through professional discussions in multidisciplinary teams or on a one-to-one basis, and was, if successful, based on a mutual respect for one another and a shared understanding of the challenges to be solved. receiving support from colleagues was described as stimulating [ ] , enabling hcps to take on more responsibilities [ ] . supportive colleagues also contributed positively to the hcps' workflow because they provided a space for hcps to vent or seek advice after a difficult consultation [ ] . furthermore, several studies [ , , ] highlighted the value of receiving acknowledgement and support from superiors. nurses described needing support and acknowledgement from the physicians, and to some extent from the physiotherapists, while physicians described needing support from medical specialists or leaders within the health context. on the other hand, the absence of support was also highlighted in the included articles, and could result in feelings of professional loneliness. nurses, in particular, described feeling left alone with extensive responsibility [ ] . also, general practitioners felt they lacked the confidence to approach their more complex patients without the support of a medical specialist [ ] . professional collaboration was also dependent on the clinical context and the behaviors of the hcps' colleagues. for example, in cases where physicians did not treat their patients properly, this had a negative impact on the nurses' own work [ , ] . the third category represents "keeping up professional self-esteem." positive feedback from others strengthened the hcps' self-esteem, and being liked, respected, and valued by colleagues and those in charge in the ward were highlighted as important [ ] . positive patient outcomes also increased positive feelings. for nurses, this signified that their efforts in caring for their patients had an impact [ ] . feeling liked by one's patients also contributed to enhanced professional self-esteem. in one study, nurses reported that when they spent more time with patients than physicians, they had higher chances of being liked by their patients [ ] . in another, asthma and copd nurses described how acting autonomously enabled them to reach their full potential [ ] . however, the nurses also felt that their professional self-esteem decreased when they experienced professionally loneliness, subordination, and a lack of appreciation from their colleagues [ ] . the fourth category was "adjusting to health organizational structures," and this was connected to nurses' professional development and career possibilities. although specialized nursing skills were emphasized within a health organization, it was not always considered essential to support the nurses' goals of learning and mastering these skills [ ] . further, time-the lack of time, in particular-was a structural factor in the health system mentioned by hcps in several studies [ , , ] . recognizing the whole person and delivering individualized care was perceived as a time-consuming task [ ] ; the lack of time was thus seen by hcps as a threat to the quality of patient care. according to tierney [ ] , however, the hcps' compassion for their patients was not affected by time-limited encounters. the hcps' experiences working with patients with type diabetes, ckd, or copd presented in the papers included in our systematic literature review are captured by three themes: "individualizing the professional approach within the clinical encounter," "managing one's emotions over time," and "working to maintain professionalism." together, these themes describe how clinical encounters with patients depend, to a large degree, on the personal interaction between patient and professional, real clinical practice situations and professional ideals, and contextual support and managing one's own emotions. in more general terms, this means that clinical working experiences are constituted by the interactions between persons, contexts, organizational structures, and health policy claims. despite the diversity in the efficiency of interventions, treatment options, and longterm prognosis of type diabetes, copd, and ckd, in general the hcps' working experiences seem to be rather shared. today, health authorities are governed by ideals such as the patients' right to receive the best evidenced-based care and the efficiency and cost-effectiveness of the service delivery [ ] . at the same time, the democratization of health care services has led to increasing user and patient involvement in all stages of illness, including when the patient is diagnosed with a chronic disease [ , ] . the patient-centered model of care is part of the user involvement movement and has gained attraction in western societies. this is meant to counteract the paternalism embedded in the clinicians' traditional role as sole expert, and to support patients in being active agents regarding the health issues that concern their own lives [ ] . however, how patient-centered care should be practiced within the context of the public management and evidence-based practice ideals is rarely, if ever, addressed by research. our analysis suggests that this balancing act can be complex for hcps and can create several challenges. this is in line with holen and kamp [ ] , who discuss how user involvement has transformed the relationship between patients and hcps, and how hcps today face new dilemmas and challenges. of particular interest, and in keeping with findings from our study, the authors describe how in long-term patient-provider relationships-e.g. between copd patients and nurses-"new" professionalism contains relational, emotional and pedagogical aspects to motivate and coach patients. the main aim of this "new" approach is to support the patient in taking responsibility for and self-managing his/her health in a time-efficient way. however, dilemma raises if for example patients need time to understand what a disease implies for their way of living. as the present findings highlight, on the one hand, the patients' wishes and autonomy must be respected, as they should be considered experts on their own lives, but on the other, patients do not always understand the severity of their disease-related risks, nor do they necessarily make rational decisions. hcps feel they lack the tools or ability to help patients and family members understand the risks of not following the prescribed treatment plan. in this way, hcps feel they are to blame by not fulfilling their professional responsibility. this can be particularly challenging when a patient presents a desire for treatment that differs from evidence-based recommendations for best practice. in such cases, hcps must balance their acting according to patient-centered care and evidenced-based practice models. "giving up" one's professional expertise and instead taking on the role of "partner, colleague or co-worker" may be a solution, as described by alm andersen [ ] . how precisely to balance such incompatible roles needs broad debate in our society. we argue that this is too heavy burden to be placed on and solved by individual hcps. for hcps, a long-term patient-provider relationship can be both a rewarding and disheartening experience. they may establish a kind of friendship with their patients, and hold significance in their patients' lives as the one person who shares and can make sense of patients' disease experiences. as our analysis indicates, this can also be a balancing act, as hcps know that just as the progression of a disease is uncertain, so is the outcome. hcps must therefore find the balance between personal closeness to and professional distance from patients, to protect their own emotional vulnerability and maintain a supportive professional role for the patients and their families when patients' conditions deteriorate, or life ends. there is no formula for how to perform this balancing act in practice, as it is usually individually and situationally determined. in discussing burn-out among hcps, dyrbye et al. [ ] point to emotional exhaustion and frequent depersonalization as aspects of burn-out. we found traces of these aspects in our study and agree with the authors that more research to understand and improve the work lives and wellbeing of hcps is needed. our findings do indicate, however, that supportive colleagues and leaders, as well as acknowledgement and support from leaders within the health organization, can be helpful. this approach can help meet hcps' support needs, and empower them-in various ways and at different levels-to remain in highly complex work situations. we also argue that educational institutions have the responsibility to prepare future hcps to meet this complexity of clinical practice. as far as we know, this issue is largely absent in today's curricula. the contribution and trustworthiness of our metasynthesis depends on the quality of the original publications on the one hand, and on the rigor of our own methodological process on the other. one strength of this meta-synthesis is that we conducted comprehensive searches of six databases, and thereby generated a variety of data to be analyzed. by choosing three different chronic diseases on which to focus, we succeeded to find richness and variability in hcps' detailed working experiences. furthermore, the inclusion and exclusion criteria and search terms were decided in advance of the literature search, and the searches were conducted by an experienced librarian. another strength of our metasynthesis is that the study selection, study appraisals, extractions of data in primary studies to be analyzed and coding were performed independently by pairs of researchers, and the use of nvivo further ensured a rigorous and systematic process. in this part of the process, we followed procedures to ensure reliability in line with a realist perspective [ ] . in the analysis, however, we followed an interpretive approach inspired by metaethnography and a constructivist stance [ ] . this enabled us to take advantage of the various theoretical competencies in the research group. the credibility of the analysis depends on how transparent we present our analysis. we have attempted to describe our data material in the result section as close as possible and with reference to the original papers (second order data). our overall interpretation of the data (third order level) is presented in the discussion in order to make the correspondence between the descriptions in our result section and our further interpretations transparent. we argue that our shifts between rigorous methodological approach and reflexivity based on our various perspectives and understandings during the whole process have strengthened the trustworthiness of this study. therefore, it is likely that it is a balancing act to work with diabetes- , copm and ckd. furthermore, we think the complexity and dilemmas raised in these studies are likely to be transferable to the work with other chronic diseases as well. the present study has some limitations that must be noted. firstly, according to the quality appraisal, as assessed by the casp and coreq, the quality of the original articles can be considered high. however, wider methodological orientations or broader philosophical backgrounds were rarely presented or discussed in the included papers. it is also possible that the assumptions made by the authors of the original studies were continued in the meta-synthesis. secondly, it is noteworthy that although we welcomed both interview studies and observational studies in the meta-synthesis, no observational studies met our inclusion criteria. this implies a knowledge gap, as the hcp-patient relationship and their interactions require research from different vantage points. thus, further research to examine how clinical practice is performed and contextualized is needed. it is clear from this systematic literature review that hcps' experience profound stress in their work with patients with copd, ckd, or type diabetes. on the other hand, they also experience the creation and maintenance of long-term relationships with patients with chronic conditions as personally and professionally rewarding. as such, hcps must find the balance between personal closeness to and professional distance from patients. they must also balance providing patientcentered care whilst simultaneously developing and strengthening their professional expertise. this underscores the importance, for hcps, of having systematic support from colleagues, leaders, educational institutions, and health organizations. the world health report -working together for health burnout among health care professionals. a call to explore and adress this underrecognized threat to safe, high-quality care. natl acad med perspect expert voices health health care global action plan for the prevention and control of noncommunicable diseases - . geneva: world health organization improving primary care for patients with chronic illness chronic 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skills programme consolidated criteria for reporting qualitative research (coreq): a -item checklist for interviews and focus groups evaluating meta-ethnography: systematic analysis and synthesis of qualitative research meta-ethnography: synthesizing qualitative studies medicine taking for asthma: a worked example of metaethnography qualitative research on health communication: what can it contribute? pat educ couns doctors' and nurses' views on patient care for type diabetes: an interview study in primary health care in oman. prim health care res develop diabetes specialist nurses' perceptions of their multifaceted role emotional effort and perceived support in renal nursing: a comparative interview study diabetes distress among healthcare providers: a qualitative study respiratory practitioners' experience of end-of-life discussions in copd exploring canadian physicians' experiences with type diabetes care for adult indigenous patients diabetes care of dependent older adults: an exploratory study of nurses' perspectives lived experience of korean nurses caring for patients on maintenance haemodialysis nurses' perceptions of self-management in renal care the experience of the long-term doctorpatient relationship in consultant nephrologists the complexity of managing copd exacerbations: a grounded theory study of european general practice experiences of health care professionals with physical activity in type diabetes care health care professionals meeting with individuals with type diabetes and obesity: balancing coaching and caution primary care physicians' perceived barriers, facilitators and strategies to enhance conservative care for older adults with chronic kidney disease: a qualitative descriptive study enabling the flow of compassionate care: a grounded theory study gps' views on managing advanced chronic kidney disease in primary care: a qualitative study perceptions of key influences on effective predialysis nursing care gps' perspectives of type diabetes patients' adherence to treatment: a qualitative analysis of barriers and solutions general practitioners' attitudes towards patients with poorly controlled type diabetes: a qualitative study the asthma/copd nurses' experience of educating patients with chronic obstructive pulmonary disease in primary health care brugerinddragelse -ny professionalisme og nye omsorgsrum? enhancing transparency in reporting the synthesis of qualitative research: entreq springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations the authors would like to thank senior librarian kari l. mariussen at lovisenberg diaconal university college for her expertise and valuable assistance during both the initial and the final systematic literature searches, and professor kari n. solbraekke, the head of the department of interdisciplinary health sciences for her support.authors' contributions amm initiated the study and has the overall responsibility for the work. hh, mhl, mhs, lt, ba, mha, crb, he, aw, and amm contributed in planning the study, selecting papers, and the process of analyzing and developing a full manuscript. mhl and cb performed the literature search in cooperation with the librarian. hh, mhl, mhs and lt led the process of writing up the paper. no authors have been removed or added during the process. all authors read and approved the final manuscript for submission and the order of the author list. the process of designing the study, data collection, analysis, interpretation of data and writing the manuscript was not funded, but performed as a collaborative work by the members of the self-management research group at the university of oslo, norway. please contact mhl.ethics approval and consent to participate not applicable. not applicable. the authors declare that they have no competing interests. key: cord- -p s uqz authors: luyt, charles-edouard title: virus diseases in icu patients: a long time underestimated; but be aware of overestimation date: - - journal: intensive care med doi: . /s - - - sha: doc_id: cord_uid: p s uqz nan chronic obstructive pulmonary disease (copd) is the second most prevalent chronic respiratory disease. although cigarette smoking is declining as a major risk factor, its prevalence is increasing and it is predicted to become the third leading cause of death worldwide by [ ] . exacerbations are common in the natural history of copd and frequently thought to be due to viral, bacterial, or combined viral-bacterial infections of the respiratory tract. bacterial infection was recognized a long time ago as a trigger of copd exacerbations in patients requiring [ ] or not requiring mechanical ventilation [ ] . the incidence of viral infection has long been underestimated because of the scarcity of diagnostic tests. modern diagnosis methods, such as polymerase chain reaction (pcr), that can detect small amounts of viral nucleic acid, has markedly improved the identification of viral infections. in a recent prospective study, seemungal et al. showed that viruses could trigger % of copd exacerbations, rhinovirus being the main virus recovered from the upper respiratory tract [ ] . in the same study, the authors showed that respiratory viruses (except respiratory syncytial virus (rsv)) were detected in the upper respiratory tract of % of patients with stable copd, and rsv in . % [ ] . in the present issue of intensive care medicine, cameron et al. [ ] report their experience in patients with acute exacerbation of copd requiring mechanical ventilation. they used conventional pcr, real-time pcr and viral cultures in nasal and pharyngeal specimens to detect common respiratory viruses. they found that among ( %) episodes of exacerbation due to probable infection, respiratory viruses were identified in the upper respiratory tract in ( %) cases, alone in ( %) cases, and in association with another microorganism in ten ( %) cases. this study confirms that many exacerbations of copd could be triggered by upper-respiratory tract viral infections [ ] . beyond its scientific interest, i.e., the understanding of physiopathology, this paper is important, because having a better knowledge of the pattern of disease may more efficiently target potential treatments [ ] . other strengths of this paper are the broad range of viruses sought and the use of real-time pcr, which is probably the most effective technique to date for the diagnosis of viral infection. diagnoses of viral infections in the icu are in fashion [ , ] , probably partly because of the availability, feasibility and easiness of modern diagnostic tests. this deserves some comments. first, the impact of the diagnosis of viral diseases on patient outcome remains questionable. in most cases, diagnosing viral infection has no therapeutic impact, either because we lack specific treatment, except for herpes viruses and influenza, or because most patients have recovered when diagnosis is made. diagnosing viral infections has, therefore, only academic and/or epidemiologic interest. the main action could be prevention by vaccination of specific high-risk populations, such as copd patients, but the impact of such a strategy requires further investigation [ , ] . another way could be systematic antiviral treatment in copd patients with acute exacerbation and withdrawal, if the diagnosis is unlikely or ruled out. once again, this strategy has not been investigated yet and requires further investigation. second, the reliability of pcr-positive samples could be doubtful. like other diagnostic tests, there are falsepositive results, caused by contamination of pcr reactions with amplification products from previous tests or by carryover of homologous genomic dna. alternatively, false-positive results may arise from nonspecific binding of primers to irrelevant sequences [ ] . one way to minimize this bias could be the use of real-time pcr, which provides sensitivity and specificity equivalent to that of conventional pcr combined with southern blot analysis and greatly reduces the risk of contamination [ ] . in the study by cameron, the authors used real-time pcr to detect enterovirus, human metapneumovirus, rhinovirus and non-sars coronavirus [ ] . however, it is important to bear in mind that false-positive samples are not entirely eliminated with this technique. the third comment concerns the relevance of viral detection in diagnostic samples. viral excretion does not mean viral infection. for example, in mechanically ventilated patients, herpes simplex virus (hsv) detection in the lower respiratory tract does not necessarily mean hsv bronchitis or broncho-pneumonitis: it might be a local virus excretion or a contamination from mouth and/or throat [ ] . similarly, for viruses of the upper respiratory tract, viral detection does not mean infection. in the study by seemungal, respiratory viruses were detected in the upper-respiratory tract of several patients with stable copd [ ] . these data are in favor of asymptomatic carriage of respiratory viruses in the upper respiratory tract, at least in some cases. then, can we improve diagnostic procedures? for hsv or cytomegalovirus (cmv), cytology can help the clinician. these viruses cause specific cytopathic effect on infected cells, specifically nuclear inclusions for hsv and cytoplasmic inclusions for cmv. unfortunately, this concerns only very few viruses and cannot be used for viruses of the upper respiratory tract. finally, quantifying viral load might be another way to improve the diagnostic accuracy. indeed, pcr might be just too sensitive. it can detect small amounts of residual viral nucleic acid. is it relevant to detect or copies of virus in the upper-respiratory tract? probably not. therefore, quantifying the viral load might be more clinically relevant than detecting viral genome by pcr. viral load cutoff values for infectivity in copd exacerbations have not been studied, but some preliminary data showed the feasibility of the technique [ ] . real-time pcr allows viral load quantification and should become the gold standard for diagnosing viral infections [ ] . however, variations in viral load could occur because of variability in sample recovery, in bronchoalveolar lavage (bal) or nasopharyngeal aspirate for example. normalization of viral load, reported as the number of virus copies per cells recovered [ ] , might be the best way to adjust for such a variability. in conclusion, many episodes of copd exacerbations are undoubtedly triggered by viral infection of the upperrespiratory tract. but like tracheal aspirate and bacterial detection for the diagnosis of ventilator-associated pneumonia, viral genome detection in the respiratory tract has to be interpreted cautiously. viral detection does not automatically mean viral infection. viral load and normalized viral load should be evaluated to increase the operating characteristics of diagnostic tests. alternative projections of mortality and disability by cause - : global burden of disease study characterization of distal bronchial microflora during acute exacerbation of chronic bronchitis. use of the protected specimen brush technique in mechanically ventilated patients management of acute exacerbations of copd: a summary and appraisal of published evidence respiratory viruses, symptoms, and inflammatory markers in acute exacerbations and stable chronic obstructive pulmonary disease virus infection in exacerbations of chronic obstructive pulmonary disease requiring ventilation chronic obstructive pulmonary disease nosocomial viral ventilator-associated pneumonia in the intensive care unit: a prospective cohort study herpes simplex virus in the respiratory tract of critical care patients: a prospective study respiratory syncytial virus infection in elderly and high-risk adults management of chronic obstructive pulmonary disease detection and monitoring of virus infections by real-time pcr cockerill fr rd, smith tf ( ) real-time pcr in clinical microbiology: applications for routine laboratory testing relevance of human metapneumovirus in exacerbations of copd evaluation of a quantitative real-time pcr for the detection of respiratory syncytial virus in pulmonary diseases reproducibility of hpv and hpv viral load quantitation using taqman real-time pcr assays key: cord- -q wsiimn authors: rohmann, kristina; tschernig, thomas; pabst, reinhard; goldmann, thorsten; drömann, daniel title: innate immunity in the human lung: pathogen recognition and lung disease date: - - journal: cell tissue res doi: . /s - - - sha: doc_id: cord_uid: q wsiimn as the human lung is exposed to a variety of microbial pathogens in the environment, a first line of defense is built up by pulmonary cells like bronchial/alveolar epithelial cells and alveolar macrophages. these cells express several pattern recognition receptors (prrs) recognizing highly conserved microbial motifs and initiating the production of chemokines and pro- and anti-inflammatory cytokines acting as transmembrane or intracellular receptors. this might not only lead to acute but also to chronic inflammation which is discussed as an underlying mechanism in the pathogenesis of different lung diseases. the human lung is continously exposed to airborne pathogens including bacteria, viruses and fungi. to protect the organ from infectious diseases, several lines of defense have been developed belonging to the immune system. concerning the different mechanisms of the immune response, the immune system is divided into the major branches innate and acquired immunity. regarding the respiratory compartment, the innate immune system consists of the epithelial barrier, the tracheobronchial mucociliary system and constitutively expressed antimicrobial peptides, lysozyme and surfactant proteins. cells of the innate immune system include phagocytes (neutrophils, monocytes, macrophages), dendritic cells, epithelial cells, basophils, mast cells, eosinophils and natural killer cells. these cells can be found with a preferential distribution in distinct lung compartments (pabst and tschernig ) . in children, organized bronchus-associated lymphoid tissue (balt) can be found in a certain percentage. it is very likely that there are m cells in the epithelium covering (balt) which are able to take up particular antigens as demonstrated for balt in animals (tschernig et al. ). we proposed the concept that in a two-step system balt might be induced in adult man and used as an entry side for vaccination by aerosols as the second step (pabst and tschernig ) . in the conducting airways, the type and composition of epithelial cells are changing from the trachea to the terminal bronchioles, and variable numbers of subsets of dendritic cells can be found (tschernig et al. ; randall ) . the molecular components of innate responses include complement, acute-phase proteins, and cyto-and chemokines. the innate immune system also specifically eliminates bacteria after recognizing several conserved microbial motifs, the so-called pathogen-associated molecular patterns (pamps), by pattern recognition receptors (prrs). pamps are highly conserved structures present in large groups of microorganisma, for instance, bacterial lipopolysaccharide (lps), peptidoglycan (pgn) or lipoteichoic acid (lta) . prrs are present in soluble forms like mannanbinding lectin (mbl) and in form of transmembraneous or intracellular molecules that directly mediate cellular immune responses. these cell-bound receptors include toll-like receptors (tlrs), nod-like receptors (nlrs), rig-i-like receptors (rlrs) and cytosolic dna receptors. prrs are expressed by alveolar macrophages, lung epithelial cells and dendritic cells responsible for the first reactions to invading pathogens (bals and hiemstra ; opitz et al. ). relevant respiratory pathogens causing different types of pneumonia or exacerbations of asthma and copd are listed in table . tlrs are one important group of prrs consisting of members of the human tlr family. the cytoplasmic toll/ il- receptor homology (tir) domain is responsible for downstream signaling via tir adaptor molecules whereas the extracellular leucinerich repeat (lrr) domain most likely mediates ligand binding. tlrs are located either at the cell surface (tlr , , - , ) or in intracellular lysosomal/endosomal membranes (tlr , - ). in the lung, several host cells including macrophages, dendritic cells (dcs), lung epithelial and endothelial cells express tlrs. different combinations of tlrs can be found on different respiratory cells (see also table ) and the simultaneous activation of several tlrs might lead to a more pathogenspecific immune response (bals and hiemstra ; krishnan et al. ; knuefermann et al. ) . tlr activation by microbial pathogens can also lead to increased tlr expression on the surface of the stimulated cell such as h. influenzae upregulates tlr -expression on bronchial and alveolar epithelial cells (fig. a, b) . this is important to know since unstimulated epithelial cells show a weak expression of tlr (imasato et al. ) . tlr and tlr are most widely studied and are considered the major transmembrane tlrs. tlr recognizes lipoproteins and lipoteichoic acid (lta) from a variety of gram-positive and some gram-negative bacteria as well as from mycobacteria and fungi. after activation, tlr forms a heterodimer with tlr or tlr to recognize (responding to a different panel of lipoproteins) diacyl and triacyl lipopeptides. tlr binds to zymosan, a particle of yeast cell wall components, peptidoglycan, a component of the gram-positive bacteria cell wall, and pam cys-ser-(lys) hydrochloride (pam cys), a lipohexapeptide analog of the immunologically active n-terminal portion of bacterial lipoprotein (chaudhuri et al. ; henning et al. ) . the enhanced expression of tlr at the protein level and the increased expression of tlr on the cell surface leads to remarkable induction of mrna expression for il- and cxcl- and after stimulation with pgn. these gene products and others are known to be important for innate immune responses and host defense reactions, upregulated tlr in respiratory epithelial cells may consequently enhance the antimicrobial responses of the host (homma et al. ; reppe et al. ). tlr plays a central role in the response of cells to lps, a major component of the gram-negative cell wall. lps is bound by lps-binding protein (lbp), an acute phase protein produced by liver cells and epithelial cells in the lung. lbp transfers lps to cd , to constitute the tlr complex together with the extracellular protein md- . activation of the tlr receptor complex by the recognition of lps is followed by intracellular signal transduction including the adaptor molecule myd and leading to the production and secretion of proinflammatory cytokines (wieland et al. ; janardhan et al. ) . the regulation of tlr expression on the cell surface of bronchial epithelium and alveolar macrophages is discussed controversially (saito et al. ) . in addition to lps, tlr also recognizes pneumolysin (pln), an intracellular toxin found as an important virulence factor in s. pneumoniae. interaction of tlr and pln leads to enhanced cytokine production and thus to the elimination of the pathogen from the respiratory tract (dessing et al. ). tlr , tlr / and tlr act as intracellular prrs as they are located in the endosome. tlr detects doublestranded (ds)rna which is an intermediate in viral replication, as well as possibly endogenous mrna released from necrotic cells, and tlr / respond to viral singlestranded (ss)rna. tlr recognizes extracellular bacterial flagellin. tlr responds to microbial dna by recognizing cytosine-guanine pairs in the dna, the so-called cpg-dna (opitz et al. ; chaudhuri et al. ) . analogous to tlr expression of tlr is increased by bacterial pathogens (fig. c -e). the ligand for tlr has not yet been identified (bals and hiemstra ; hippenstiel et al. ). a further group of prrs is the family of cytosolic nacht-lrr receptors (nlr) with a central nucleotide-binding domain present in naip (neuronal apoptosis inhibitor protein), ciita (class ii transactivator), het-e and tp- , and extracellular leucin-rich repeats (lrr) mediating ligand binding . proteins of the nacht family appear to function independently of the tlrs and were demonstrated in macrophages and epithelial cells. nacht proteins lack a tir domain, but in contrast to tlrs include an n-terminal caspase-associated recruitment domain (card) or a pyrin domain that links bacterial pattern recognition to other effector proteins, such as procaspase- and the iκ-kinase-binding protein rip /cardiak. caspase- and rip /cardiak are necessary for the activation of proinflammatory cytokines such as pro-il- β and for the induction of nf-κb. the activation of nacht family proteins is thought to involve oligomerization via their corresponding nacht domains, triggered by binding of specific pathogen-derived molecules to the lrrs (damiano et al. ). the nlr family consists of members in humans most of which are located in the cytosol. the best studied nlrs are the card-containing molecules nod and nod that both act as cytosolic prrs. whereas nod is expressed in airway epithelial cells, endothelial cells, alveolar epithelial type ii cells and alveolar macrophages and contains one card domain, nod is mainly expressed in antigen-presenting cells like leukocytes and also in lung epithelial cells and contains two card domains to facilitate protein-protein interaction after receptor activation. nod recognizes peptidoglycanrelated molecules containing meso-diaminopimelic acid found in all gram-negative and also in some grampositive bacteria. nod recognizes the muramyldipeptide (mdp) murnac-l-ala-d-iso-gln which is conserved in peptidoglycans of all bacteria . as described by netea et al. ( ) , nod synergizes with tlr for the induction of imuune response. it was shown that both nod and tlr are required for the production of cytokines by pgn indicating an interaction between these two pathways. accordingly, the specific nod ligand mdp was found to have a synergistic effect on the induction of tnf-α, il- β, and il- upon costimulation with the specific tlr agonists pam cys (netea et al. ) . studies in mice showed that tlr and myd are essential for the host defense against h. influenzae and clearance of this pathogen from the lung (wieland et al. ; wang et al. ) , but zola et al. also indicated that nasopharyngeal clearance of encapsulated h. influenzae required nod signaling in addition to tlr and tlr , whereas individual deficiencies in each of these signaling cascades did not affect clearance of nonencapsulated strains (zola et al. ) . of the identified nlr family members, five are characterized by a card-domain (nlrc - ), whereas other members of the nlrp (nlr family, pyrin domain containing) subgroup of nlrs are characterized by a pyd domain. at least nlrp - form macromolecular protein complexes called "inflammasome". inflammasomes consist ofoneortwonlrs,inmostcasesof the adapter molecule asc (apoptosis-associated speck-like protein containing a card), and of the cysteine protease "caspase- ". inflammasomes respond to various pathogens and inhaledparticlesandfinallyleadtosecretionofil- βandil- . the nlrp (nalp ) inflammasome (also known as nalp , cryopyrin, pypaf , cias , and clr . ) mediates a caspase- -dependent processing of proil- β as well as proil- into their mature forms and regulates a caspase- -dependent cell death in certain situations. the nlrp inflammasome responds to infections with viruses such as influenza virus, bacteria including s. aureus, and fungi like candida albicans. inflammasome activation requires two signals. first of all pamp, e.g., lps or mdp, activating receptors on the cell surface or in the intracellular compartment leading to nf-κb-dependent transcription of immature cytokines (e.g., proil- β) which become processed and secreted after a second activating signal. this is mostly mediated by damage-associated molecular patterns (damps) that might be released after tissue damage from necrotic cells, like atp, hyaluronan or uric acid crystals, leading to caspase- dependent cleavage of proil- β into mature il- β. initially, stimulation with any of these second signals leads to the formation of a large complex containing nlrp , caspase- , and the adaptor protein, asc. studies in genetargeted mice suggest that the inflammatory response to these damps is crucial for the pathogenesis of, e.g., acute lung injury and perhaps other lung diseases (opitz et al. ; abdul-sater et al. ). rig-i-deficiency leads to decreased ifnα/β responses to, e.g., influenza a virus and respiratory syncytial virus, whereas mda deficiency led to decreased cytokine production induced after infection with picornaviruses. it is hypothesized that rig-i and mda mediate virus recognition in most cell types including macrophages, conventional dcs and pulmonary epithelial cells, whereas tlrs are essential for antiviral responses by plasmacytoid dcs (opitz et al. ; kato et al. ) . the intracellular portion of each known tlr contains a toll-il- -receptor domain (tir). as the tir-domain is also present in myeloid differentiation factor (myd ), tlrs and il- -receptor induce myd and four other cytoplasmic adaptor proteins containing a tir domain to initiate intracellular signaling. these additional adaptor proteins include myd adaptor-like protein (mal) also known as tir domain containing adaptor protein (tirap), toll receptor-associated activator of interferon (trif) also known as tir domain containing adaptor molecule- (ticam- ), trif related adaptor molecule (tram), also known as ticam- , and myd - the so-called αand heat-armadillo motifs. activation of different adaptor molecules results in different ways of down-stream signaling thus mediating different cellular responses. the signaling pathway involves recruitment and activation of il- -receptor associated kinase (irak)- , which phosphorylates irak- and irak- . phosphorylation and activation of tnf receptor-associated factor (traf)- and tgf-β-activated kinase (tak)- leads to phosphorylation of i-kappa kinase (ikk) and the phosphorylation and degradation of iκb, resulting in translocation of nf-κb to the nucleus and the transcription of a large number of pro-inflammatory and anti-inflammatory gene products. irak- and tak- also activate p mitogenactivated protein (map) kinase and c-jun n-terminal kinase (jnk), leading to broad intracellular kinase activation (martin and frevert ) (fig. ) . all tlrs except tlr are able to initiate a myd dependent signaling pathway leading to nf-κbdependent expression of, e.g., antimicrobial peptides and pro-inflammatory mediators such as tnfα, il- and proil- β. whereas tnfα, il- and other cytokines subsequently regulate the inflammatory response and contribute to leukocyte recruitment, proil- β needs first to be processed in a caspase- -dependent second regulatory step. in addition to stimulation of nf-κb-dependent gene expression, tlr , - , - , - , and - are capable of activating irf (ifn regulatory factor) transcription factors and mediating type i ifn responses which are essential for the antiviral defense akira and takeda ) . in general, both nod and nod activate downstream signaling through interaction with the rip-like interacting clarp kinase (rick) via a caspase recruitment domain (card)-interaction. this activates the jun n terminal kinase (jnk), p and extracellular signal-regulated kinase (erk) pathways leading to a nf-κb-dependent expression of pro-inflammatory mediators as well as to ros production (barton et al. ). opitz et al. and other groups demonstrated that even the activation of nod and nod leads to nf-κb activation by recruiting the adaptor molecules rick/ rip mediated by card-card interaction. especially after infection with s. pneumoniae, epithelial cells reveal nod -mediated nf-κb activation via the downstream molecules irak , irak and traf , similar to the tlr pathway described above (opitz et al. ; kobayashi et al. ) . beyond the pattern recognition receptors described above, there are additional systems of innate immunity for pathogen recognition in the human lung. these include the mannose receptor, dectin- and surfactant proteins a and d (kerrigan and brown ). the mannose receptor, a type-i-transmembrane protein that is characterized as a c-type lectin consisting of an extracellular region and a cytoplasmatic tail. it binds to a variety of microorganisms including candida, p. jiroveci, k. pneumoniae and s. pneumonia by recognizing mannose, fucose or n-acetylglucosamine sugar residues on the pathogens' surface and together with other binding receptors leads to cytoskeleton rearrangements and thus to phagocytosis of the pathogen (le et al. ) . another item of pathogen recognition is the type-iitransmembrane protein dectin- , a receptor for β-glucans mainly found in the cell walls of fungal species like candida spp., aspergillus spp. and p. jiroveci (brown et al. ; taylor et al. ). binding of dectin- to a pathogen or other opsonised particles enables phagocytosis as well. furthermore, surfactant proteins a and d (sp-a, sp-d) are c-type-lectins. they are mainly synthesized in the human lung in type ii alveolar epithelial cells and clara cells and are secreted into the alveolar space as the main constituent of the pulmonary surfactant. they interact with a variety of carbohydrates and glycolipids and are also able to recognize a wide range of respiratory pathogens like p. aeruginosa, s. pneumoniae, k. pneumoniae, a. fumigatus, and p. jiroveci (pastva et al. ). the surfactant proteins either function as opsonins linking pathogens to receptors on phagocytic cells or cause aggregation of pathogens. sp-a, for example, can also increase the expression of scavenger receptor a (sr-a). sr-a recognizes conserved bacterial structures like modified lipoproteins, lta or lps, and is thus a binding receptor for gram-positive and gram-negative bacteria (amiel et al. ; platt and gordon ) leading to an enhanced bacterial uptake by the phagocytic cell (kuronuma et al. ) . defective mechanisms of the innate immune system play an important role in numerous repiratory diseases. asthma and copd are mainly characterized by secretion of proinflammatory cytokines and other mediators from the airway epithelium. via differential activation of multiple prrs in lung tissue cigarette smoke and pamp´s trigger inflammatory reactions. most of the copd patients show respiratory tract colonization with respiratory pathogens like h. influenza, s. pneumoniae, p. aeruginosa and m. cartarrhalis, which contributes to chronic inflammation and airway dysfunction. change from colonization to infection is able to cause acute exacerbations of copd. increased susceptibility of copd patients to infectious complications might be related to impaired function of innate immunity mechanisms. according to this hypothesis, we demonstrated an altered phenotype of alveolar macrophages from smokers and copd patients with decreased expression of tlr (droemann et al. ). in addition, colonizing microbes might also have adapted mechanisms to lower prrmediated innate immune responses in order to evade clearance. martí-lliteras et al. demonstrated that macrophages treated with extracts of cigarette smoke showed markedly diminished ability to engulf nthi in order to eliminate the pathogen, whereas expression of proinflammatory cytokines by murine macrophages was not significantly decreased by cigarette smoke exposure (marti-lliteras et al. ). regarding nod-receptors and their role in copd, barton et al. ( ) characterized nod -expression in airway epithelial cells and in some alveolar epithelial type ii cells as well as in alveolar macrophages and endothelial cells. they also demonstrated decreased nod -expression in lung tissue of a patient with chronic bronchitis (barton et al. ). in addition, activation of the inflammasome by damps might be another mechanism contributing to the pathogenesis of copd. inhaled toxic agents, oxidative stress, infections, necrotic cell death, as well as hypoxia, hypercapnia, focal hypoperfusion and tissue acidification might lead to release of damps (e.g., uric acid, atp) by damaged lung tissue which activates the nlrp inflammasome. uric acid concentrations were increased in broncho-alveolar fluids of copd patients and smokers. furthermore, copd patients showed significantly reduced concentrations of il- β antagonists compared with controls (opitz et al. ) . thus, cigarette smoke appears to affect immune reactions in different ways, according to the pathogen and the recognition molecules as well as other factors. aberrant and chronic activation of the pulmonary innate immune system might contribute to lung remodeling, development of copd and emphysema (hansel and barnes ). domagala-kulawik et al. observed that chronic exposure to cigarette smoke causes increased production of metalloproteinases (mmp) by macrophages and proteolitic enzymes by neutrophils contributing to development of emphysema (domagala-kulawik ) . of note, we currently described the expression of the tgf-β- fig. in situ hybridization targeting s. pneumoniae dna after in vitro infection in human lung tissue (a, am; b, aec type ii. expression of pp in human lung tissue after in vitro infection (c) (scale bar μm) pseudoreceptor bmp and activin membrane-bound inhibitor (bambi) in copd lung tissue and upregulation by nthi revealing a decreased expression of tgf-β in combination with a strong proinflammatory response. this also may influence inflammation induced tissue remodelling (droemann et al. ) . regarding the different role of cell populations (i.e. alveolar macrophages and alveolar epithelial cells), epithelial cells are less responsive to microorganisms and their products like lps or lta compared to mononuclear phagocytes (bals and hiemstra ) . infection with s. pneumoniae was studied recently in in vitro experiments with human lung tissue. pneumococcal dna was found in - % of the am and only - % of aec, whereas bronchial epithelial cells (becs) were only sporadically infected. inactivated macrophages using clodronat/liposomes led to an extensive reduction of proinflammatory cytokine release from lung tissue, indicating that in this setting macrophages are the main source of proinflammatory cytokines after pneumococcal infection. respiratory infections frequently become evident as coinfection of different bacterial strains or viral-bacterial coinfections. as shown for the coinfection of pulmonary epithelial cells with s. pneumoniae and h. influenzae, the synergistic inflammatory response resulted in a stronger activation of nf-κb and synergistically increased cxc- expression (ratner et al. ) . as described by didierlaurent et al. impaired immune responses to bacterial infections, including desensitization to tlr signals, can be observed after infections with influenza virus or respiratory syncytial virus. although such desensitization may be beneficial for prevention of overwhelming immune responses, the reduced neutrophil recruitment might contribute to severe secondary bacterial pneumonia. the influence of prrs on epithelial cells and immune cells is also very important in allergic lung diseases which has recently been summarized (lloyd and murdoch ) . innate immunity in the lung is the important first line defense against respiratory pathogens. recognition of invading pathogens and cell injury-associated endogenous molecules by pattern recognition receptors expressed on phagocytes and epithelial cells lead to a differentiated immune reaction. acute inflammatory reactions are supposed to eliminate the pathogen, but also implicate tissue destruction. therefore, prrmediated signaling pathways are critical for the balance between host protection and tissue homeostasis. considering this key role in infectious and non-infectious lung diseases therapeutic approaches, targeting this system should be strengthened. many details have been characterized recently on the innate immune system. however, severaldetails are so far only known for experimental animals (mostly mice) and have to be studied in the human lung in future. inflammasomes bridge signaling between pathogen identification and the immune response toll-like receptor signalling pivotal advance: toll-like receptor regulation of scavenger receptor-a-mediated phagocytosis innate immunity in the lung: how epithelial cells fight against respiratory pathogens the pattern recognition receptor nod activates ccaat/enhancer binding protein beta signalling in lung epithelial cells dectin- mediates the biological effects of beta-glucans toll-like receptors and chronic lung disease multiple roles of clan (caspase-associated recruitment domain, leucine-rich repeat, and naip ciia het-e, and tp -containing protein) in the mammalian innate immune response toll-like receptor contributes to antibacterial defence against pneumolysin-deficient pneumococci effects of cigarette smoke on the lung and systemic immunity toll-like receptor expression is decreased on alveolar macrophages in cigarette smokers and copd patients the tgf-beta-pseudoreceptor bambi is strongly expressed in copd lungs and regulated by nontypeable haemophilus influenzae new drugs for exacerbations of chronic obstructive pulmonary disease pulmonary surfactant protein a regulates tlr expression and activity in human macrophages lung epithelium as a sentinel and effector system in pneumoniamolecular mechanisms of pathogen recognition and signal transduction corticosteroid and cytokines synergistically enhance toll-like receptor expression in respiratory epithelial cells inhibition of p mapk by glucocorticoids via induction of mapk phosphatase- enhances nontypeable haemophilus influenzae-induced expression of toll-like receptor nod-lrr proteins: role in host-microbial interactions and inflammatory disease toll like receptor- expression in lipopolysaccharide induced lung inflammation cell type specific involvement of rig-i in antiviral responses c-type lectins and phagocytosis cpg oligonucleotide activates toll-like receptor and causes lung inflammation in vivo rick/rip /cardiak mediates signalling for receptors of the innate and adaptive immune systems toll-like receptor signal transduction pulmonary surfactant protein a augments the phagocytosis of streptococcus pneumoniae by alveolar macrophages through a casein kinase -dependent increase of cell surface localization of scavenger receptor a the human macrophage mannose receptor is not a professional phagocytic receptor tolerizing allergic responses in the lung nontypeable haemophilus influenzae clearance by alveolar macrophages is impaired by exposure to cigarette smoke innate immunity in the lungs peptidoglycan signaling in innate immunity and inflammatory disease nod mediates anti-inflammatory signals induced by tlr ligands: implications for crohn's disease nucleotide-binding oligomerization domain proteins are innate immune receptors for internalized streptococcus pneumoniae innate immune recognition in infectious and noninfectious diseases of the lung bronchus-associated lymphoid tissue (balt): an entry site for antigens for successful mucosal vaccinations? immunomodulatory roles of surfactant proteins a and d: implications in lung disease is the class a macrophage scavenger receptor (sr-a) multifunctional? -the mouse's tale pulmonary dendritic cells: thinking globally, acting locally synergistic proinflammatory responses induced by polymicrobial colonization of epithelial surfaces immunostimulation with macrophage-activating lipopeptide- increased survival in murine pneumonia expression of toll-like receptor and in lipopolysaccharideinduced lung injury in mouse dectin- is required for beta-glucan recognition and control of fungal infection density of dendritic cells in the human tracheal mucosa is age dependent and site specific adaptive immune system in the developing lung-bronchi associated lymphoid tissue and dendritic cells in humans and in rat models toll-like receptor mediates innate immune responses to haemophilus influenzae infection in mouse lung the myd -dependent, but not the myd -independent, pathway of tlr signaling is important in clearing nontypeable haemophilus influenzae from the mouse lung recognition of viruses by cytoplasmic sensors mucosal clearance of capsule-expressing bacteria requires both tlr and nucleotidebinding oligomerization domain signaling key: cord- -mmdk xom authors: chen, jing; tang, yue; liu, yun; dou, yushun title: nucleic acid-based therapeutics for pulmonary diseases date: - - journal: aaps pharmscitech doi: . /s - - - sha: doc_id: cord_uid: mmdk xom nucleic acid-based therapeutics present huge potential in the treatment of pulmonary diseases ranging from lung cancer to asthma and chronic pulmonary diseases, which are often fatal and widely prevalent. the susceptibility of nucleic acids to degradation and the complex structure of lungs retard the effective pulmonary delivery of nucleic acid drug. to overcome these barriers, different strategies have been exploited to increase the delivery efficiency using chemically synthesized nucleic acids, vector encapsulation, proper formulation, and administration route. however, several limitations regarding off-target effects and immune stimulation of nucleic acid drugs hamper their translation into the clinical practice. therefore, their successful clinical application will ultimately rely on well-developed carriers and methods to ensure safety and efficacy. in this review, we provide a comprehensive overview of the nucleic acid application for pulmonary diseases, covering action mechanism of the nucleic acid drugs, the novel delivery systems, and the current formulation for the administration to lungs. the latest advances of nucleic acid drugs under clinical evaluation to treat pulmonary disorders will also be detailed. due to their location and physiological function, the lungs are directly accessible to pollutants and viruses from the outside, rendering them susceptible to diseases ranging from lung cancer to chronic pulmonary diseases. among these pulmonary diseases, chronic obstructive pulmonary disease claimed . million lives in , while lung cancer caused . million deaths ( ) . since current treatments of these diseases have limited efficacy, many studies are being conducted to find novel effective treatments. though most lung diseases are considered to be the product of a variety of endogenous and exogenous influences, and less obviously are associated with gene replacement therapy. abnormal conditions are likely to arise from an imbalance between destructive and protective mechanisms. nucleic acids can be a new class of therapeutics to reconstitute a homeostatic balance by overexpression of protective genes or the suppression of damaging genes, which offers new strategies for the treatment of respiratory diseases ( ) . the mesh-like network of blood vessels in the lungs, coupled with easy access through the pulmonary airways, enables the lungs to be targeted by both intravenous and topical routes. the latter fact makes the lung unique compared with other organs, allowing specific lung sites such as alveolar cells and bronchial epithelium to be exclusively targeted for different therapeutic applications ( ) . in this review, we focus on nucleic acid-based therapies for pulmonary diseases. we discuss the hurdles nucleic acids face for translation into clinics and recent progress in the product into clinical trials. antisense oligonucleotides (asos) are single-strand dnas or rnas that selectively bind to complementary mrnas to modulate their functions. their hybridization could result in downregulation or upregulation of gene expression by diverse mechanisms. rnase h -dependent asos could bind to target rna to form hybrid through watson-crick base pairing and downregulate translation through rnase h-induced degradation of the mrna. splice switching oligonucleotides could control the way exons skipping, modulate pre-mrna splicing, and generate novel proteins. asos can also interfere with other aspects of rna functions, such as blocking association of specific transcription factors with mrna, antagonizing microrna activities, and inhibiting rna-mediated telomerase activity ( ) ( ) ( ) . antisense oligonucleotides are the first kind of nucleic acid drugs widely used in clinical trials. among the fdaapproved nucleic acids, aso-based drugs account for the majority as for now ( table i) . as of august , only one aptamer drug and sirna drug have been approved by the fda. the first clinically approved nucleic acid drug was aso drug, vitravene (fomivirsen), indicated for cytomegalovirus retinitis in . followed by kynamro (mipomersen) targeting mrna encoding apolipoprotein b for the treatment of familial hypercholesterolemia, exondys (eteplirsen) designed to skip exon of the dystrophin protein for the treatment of duchenne muscular dystrophy, spinraza (nusinersen) inducing the inclusion of exon in the smn and smn mrna to treat spinal muscular atrophy and recently luxturna (voretigeneneparvovec-rzyl) for biallelic rpe mutation-associated retinal dystrophy ( , ) . small interference rnas(sirnas) are double-strand rna molecules of to base pairs in length designed to silence target genes in a sequence-specific manner. after introduction into the cytoplasm, sirnas interact with multifunctional protein argonaute- and form the rna-induced silencing complex (risc), where one of the strands is degraded and the other strand (mostly antisense) is left as a guide to recognizing target mrna sequences. subsequently, mrnas which are perfect or nearly perfectly complementary to the sirna antisense strand are cleaved by the activated riscs ( ) . the specific gene silencing effect of sirnas makes them indispensable tools for target identification and validation in drug discovery and development ( ) . in , onpattro (patisiran) infusion became the first fda-approved sirna drug. it is for the treatment of peripheral nerve disease caused by hereditary transthyretinmediated amyloidosis in adult patients. onpattro is designed to interfere with rna production of an abnormal form of the protein transthyretin. by preventing the production of transthyretin, the drug can help reduce the accumulation of amyloid deposits in peripheral nerves, improving symptoms, and helping patients better manage the condition. micro rnas(mirnas) are - nucleotides long, singlestranded, endogenous noncoding rna molecules that act as key regulators for a variety of cellular pathways. they can regulate gene expression by complementary binding to the core sequence in the ′-untranslated region( ′-utr) of target mrnas ( ) . either sirna or mirna could associate into the risc. unlike sirna, mirna can recognize mrna with partially complementary sequences, which means one mirna may have multiple different mrna targets ( ) . hence, delivery of exogenous micrornas or microrna mimics could be particularly useful in diseases having multiple diseaserelevant targets ( ) . mirnas mediate multiple biological processes, and alterations in mirna function have been associated with different diseases like cancer, metabolic disorders, and viral pathogenesis ( ) . mirnas related to cancer are generally classified as tumor suppressor mirnas or tumorpromoting mirnas. tumor suppressor mirnas (e.g., let- , mir- families, and mir- / ) are responsible for suppressing oncogenes and are mostly downregulated in cancer. restoration of their normal function can be achieved by mirna replacement via administration of synthetic mirna mimics functioning similarly to the endogenous counterparts. tumor-promoting mirnas (e.g., mir- , mir- - cluster, and mir- ) are known to downregulate tumor suppressor genes and have been reported to be overexpressed in cancer ( ) . asos and mirna sponges targeting tumor-promoting mirnas can be used to block aberrantly overexpressed mirnas ( ) . aptamers are short oligonucleotides with unique threedimension structures that enable them to specifically recognize and bind to targeted proteins. aptamers of interest could be selected from a pool of randomized molecules by methods known as systematic evolution of ligands through exponential enrichment. therapeutic aptamers could act as inhibitors of protein function, or as targeting moieties for drug delivery ( , ) . the use of rna-aptamers conjugates for targeted delivery of oligonucleotide molecules has been widely explored and well reviewed elsewhere ( , ) . pegaptanib, the only aptamer that has been approved by the fda, is acting through the former way. vascular endothelial growth factor (vegf) induces angiogenesis, and increases vascular permeability and inflammation, playing a central role in the progression of age-related macular degeneration. pegaptanib could selectively bind to vegf isoform, vegf , thereby preventing vegf from activating its receptors and suppressing pathological neovascularization ( ) . the therapeutic and targeting properties of aptamers could be combined to construct multifunctional molecules. using an aptamer that binds to and antagonizes the receptor tyrosine kinase axl, an aptamer-mirna conjugates was developed with synergistic therapeutic effects, owing to oncosuppressive effects of the mirna and inhibitory function of the aptamer ( , ) . barriers to nucleic acid-based therapies for pulmonary diseases the treatments for pulmonary diseases are mainly by parenteral injection and pulmonary administration through intranasal instillation, aerosol, or inhalation. hence, the first barriers that nucleic acid drugs via these two routes encounter are blood and respiratory tract (fig. ). parenteral administration of unmodified nucleic acids has been set back by their very short half-life in the bloodstream, serum nuclease degradation, quick renal clearance, and poor biodistribution. the parenteral route also exposes the whole human body to nucleic acids, which may hamper the delivery efficiency to target tissues or organs ( ) . to avoid enzymatic degradation and renal clearance, local drug administration routes have been proposed to directly deliver the drugs to the site of interest. pulmonary administration reveals a strong potentiality as it could transport therapeutic agents to diseased lung tissue in a non-invasive manner. while the degradation by nucleases is negligible comparing to systemic administration, delivery through the airway could be hampered by physiological barriers. the mucociliary clearance action, the surface liquid that covers the airway and macrophages along different parts of the airways, limits the transport of nucleic acids to the site of action ( ) . the highly viscous mucus layer in the airways traps and prevents nucleic acids reaching the underlying epithelium and propelled them out with the impact of cillated cells ( ) . thus, the development of particles that could efficiently penetrate the mucus barrier, without compromising its protective properties, is a clear challenge for improving pulmonary drug delivery ( ) . even if the nucleic acids successfully penetrate through and escape from all the extracellular barriers mentioned previously, they still face the challenge to cross the cell membrane and reach the site of action in the cytoplasm or nucleus. negative charge and large molecular weight make it hard for naked nucleic acids to enter the cell. the endocytosis of nucleic acids could be improved with the help of cationic biomaterials or targeting moieties which interact with the negative proteins or receptors on the cellular surface ( ) . one of the most challenging intracellular barriers for nucleic acids delivery is their tendency to remain entrapped in endosomes. intracellular nucleic acids are transported in early endosome vesicles where various nucleases exist and the ph further reduce to . in the process to late endosomes and lysosomes, and most nucleic acids degraded in the endosome before reaching the site of action ( ) . the classic approach has been to use small-molecule endosomolytic agents like chloroquine to disrupt endosomes and release entrapped oligonucleotides from endosomes. two similar types of small molecules have been reported recently with these molecules substantially enhanced the pharmacological activities of oligonucleotides both in cell culture and murine model ( , ) . although these endosomolytic agents significantly enhanced the delivery efficiency, they currently display a narrow therapeutic window for clinical use. to overcome these biological barriers, strategies like chemical modification, conjugation, vector encapsulation, and selection of administration route have been utilized to improve the delivery of nucleic acids to lungs. since naked nucleic acid is prone to degradation in the biological fluid, chemical modifications at the sugar, backbone, or the individual bases have been introduced to improve its stability and efficacy in biological systems. phosphorothioate(ps)-modified backbone is the most widely used chemistry modification to increase the nuclease resistance. based on ps backbones, nucleic acids designed with additional ′-sugar modifications such as ′-o-methyl ( ′-ome) or ′-o-methoxyethyl ( ′-moe) can not only further enhance stability and target affinity, but also largely block the activation of toll-like receptors and reduce immune responses ( ) . besides ps modification, peptide nucleic acids and phosphoramide morpholino oligomers are nucleotide analogs with strong nuclease resistance as the phosphodiester linkage is completely substituted by a polyamide backbone or a phosphorodiamidate group ( ) . however, ′-sugar modifications of asos might block the recruitment of rnaseh. therefore, bgapmers^was developed, that is asos containing a sequence of ps-modified backbone residues(bgap^) to facilitate rnase h activity and sugar-modified residues(bflanks^) on either side of the gap to increase resistance to degradation and enhance binding to target mrna ( ) . beside chemical modification, conjugation strategies are often exploited to enhanced stability and delivery efficiency. representative biomolecules conjugated to nucleic acids conclude targeting ligands and membrane-active molecules, such as lipids, aptamers, peptides, carbohydrates, and polymers ( ) . cholesterol attachment to nucleic acids facilitates cellular import and improves intracellular uptake via lipoproteins-mediated pathways ( ) . intravenous and intraperitoneal injection of anti-mdr cholesterol-sirna conjugate in healthy and tumor-bearing severe combined immune deficiency mice demonstrated efficient accumulation deep in the tissue and the cytoplasm of almost all the liver and tumor cells ( ) . sirnas conjugated to n-acetylgalactosamine molecule, a high-affinity ligand for the hepatocyte-specific asialoglycoprotein, are undergoing clinical trials and provided promising results ( ) . antibodies or aptamers could be conjugated directly to nucleic acids to realize targeted delivery to specific tissues or cell types. because of the advantages like good reproducibility and low system toxicity, chemical modification and conjugation of nucleic acids have been paid great attention and all the four fda-approved asos are chemically modified and used without a delivery vehicle. while compared to vectorbased systems, poor delivery efficiency and limited orientation are still great concerns of nucleic acid-conjugates for their clinical translation. besides chemical modification, vectors offer important opportunities for nucleic acids to overcome delivery challenges. ideal nucleic acid delivery vectors are expected to condense and protect nucleic acids, facilitate their transport to target cells, and subcellular compartments. viruses, as naturally evolved transfection agents, could enter the cells via endocytosis and release viral genome that could replicate and transcribe into proteins for producing multiple copies. due to their higher transfection efficiency, three major classes of viral vectors, namely, adenovirus ( ) , adeno-associated virus ( ) , and lentivirus ( ) have been extensively used in nucleic acid therapy. however, the limitation of payload, inherent immunogenicity, and the difficulty of large-scale production limited their clinical application. the advantage of non-viral vectors lies in low immunogenicity and toxicity, ease of production, and the large payload over their viral counterparts. widely investigated non-viral delivery vectors include polymers, lipids, polypeptides, and inorganic nanomaterials (such as calcium phosphate and quantum dots). most of the vectors for nucleic acids possess cationic charges that assist in loading nucleic acids through charge interactions. common non-viral delivery systems used in pulmonary diseases are listed in table ii . based on various non-viral vectors, hybrid systems made up by condensed nucleic acid/polycation complexes as the core and lipid bilayer membrane as the shell have been developed. th e use of en dogenou s pho sp holipids, su ch as dipalmitoylphosphatidylcholine, can be considered a valid approach to increase the compatibility of nanoparticles with the lung environment ( ) . researchers combined a naturalderived pulmonary surfactant shell with a sirna-loaded dextran nanogel to achieve effective sirna delivery to murine alveolar macrophages, which are difficult to transfect, resulting in a substantial gene knockdown with a relatively low dose ( ) ( ) ( ) . diverse surface modifications and conjugation of targeting agents attached to the vectors could render them desirable properties and enhance the therapeutic efficiency of nucleic acid therapy. surface modification with high molecular weight hyaluronic acid which can mediate active cd targeting in tumors and increase circulation time of cationic sirna lipoplexes improved the delivery efficiency and achieved supported reduction of the expression of luciferase mrna in tumor due to the sirna inhibition ( ) . systemic administration of nucleic acids faces serious challenges, including rapid excretion, low bioavailability, and systemic toxicity. while local administration allows lower delivery doses and reduced side effects, making it an attractive route ( ) . most of the fda-approved nucleic acid-based drugs are locally delivered: fomivirsen is delivered to the eyes by intraocular injection, spinrazais by intrathecal injection, and luxturnais by subretinal injection ( , ) . for pulmonary disease, the target organ could be reached through systemic administration or pulmonary administration. the latter route could potentially enhance retention time of nucleic acids in the desired site of action, reduce systemic toxic effects, and provide a therapeutic solution to a range of pulmonary disorders ( ) . inhalation and intranasal route represent the most common way to deliver nucleic acid into the airways due to the ease of administration and non-invasive characteristic, and are the main administration routes in clinical trials. biodistribution studies of aerosol inhalation of polyester-sirna nanoparticles to mice bearing orthotopic lung tumors showed specific accumulation in the lungs ( ) . nucleic acids can be formulated into liquid aerosol generated by an inhaler or nebulizer, or dry powder aerosol for pulmonary delivery. liquid aerosol formulations were almost exclusively adopted in clinical trials involving pulmonary delivery of nucleic acids. among the three major types of inhalation devices consisting of pressurized metered dose inhalers (pmdis), nebulizers, and dry powder inhalers (dpis), pmdis and dpis are the most portable and commonly-used devices ( ) . pmdis, in which the therapeutic agents are suspended in the hydrofluoroalkane (hfa) propellant, have been regarded as golden standard delivery system for asthma and chronic obstructive pulmonary disease therapies ( ) . a pmdi formulation containing mannitol microparticles which encapsulated sirna polyplex nanoparticles showed good aerodynamic properties for deep lung deposition and significant gene knockdown efficiency in lung a cells ( ) . dpis are usually thought as a better option to deliver therapeutic nucleic acids than pmdis because their dry particle form enhances the stability of nucleic acids and decreases the risk of microbial contamination ( ). chow et al. first formulated naked sirna into inhalable dry powders (at % w/w) using spray drying technology with the incorporation of mannitol and l-leucine; the latter acted as powder dispersibility enhancer, and the integrity of sirna was well retained ( ) . although systemic administration does not provide the aforementioned advantages of local delivery, for some indications like lung metastasis and pulmonary hypertension, the desired target sites might locate on the interstitium and lung alveolar and endothelial cells rather than the airway epithelium. lung metastases are expected to have an endothelial origin and therefore may be better accessible through blood vessel than through airways ( ) . although intravenous injection is not direct delivery to the lung, this route is still able to achieve high levels of transgene expression in the lungs. a multifunctional lipid envelopetype nanodevice developed to target the lung endothelium was found to accumulate in the lung within min after injection. this carrier did not quickly remove to other organs and remain in lungs for h. based on this carrier, systemic administration of anti-cd sirna successfully suppressed the metastatic progression ( ) . therefore, the administration route should be carefully chosen according to the therapeutic application. since the discovery of nucleic acids, their association with multiple diseases and hence the therapeutic potential have been extensively demonstrated. in the last decades, many investigations have been successfully proved the therapeutic efficiency of nucleic acids on various lung diseases ranging from cancer to pulmonary inflammatory diseases. some of the nucleic acid products have entered the clinical stage; recent clinical trials involving nucleic acid drugs for pulmonary diseases are summarized in table iii . lung cancer is the leading cause of cancer-related deaths in the usa and worldwide ( ) . according to the difference in histology, % cases of lung cancer are classified as nonsmall cell lung cancer (nsclc) and % cases are small cell lung cancer (sclc). in addition to sclc and nsclc, malignant pleural mesothelioma is a rare form of lethal cancer developing in the tissue lining of the lungs ( ). current treatments for lung cancers include surgical resection, chemotherapy, radiation therapy, and targeted drug therapy, but these existing therapeutics have limited efficacy, and survival rate of nsclc patients has remained low ( ) . therefore, studies on target treatment of lung cancers with selective nucleic acid against oncogenic pathways have drawn intensive interest and some of them have entered clinical practice. custirsen (ogx- ) is a ps-aso inhibitor of clusterin, an anti-apoptotic chaperone protein upregulated in cancer cells in response to chemotherapy and might mediate resistance ( ) . preclinical data showed that custirsen significantly decreases clusterin production, increases the sensitivity of lung cancer cells to chemotherapies, and inhibits tumor growth in lung cancer models. in the phase trial of custirsen in patients who were treated with a combination of a gemcitabine/platinum doublet, serum clusterin levels were notably reduced. a larger randomized phase study is needed to demonstrate the potential survival benefit of custirsen in patients with nsclc ( ) . imetelstat (grn l) is a base phosphoramidate oligonucleotide conjugated to a -palmitoyl lipid group against the rna component of telomerase, an enzyme responsible for maintaining telomere length and crucial for the indefinite growth of tumor cells. blocking telomerase with imetelstat leads to antineoplastic effects. in a phase study, imetelstat failed to improve progress-free survival rates in advanced nsclc patients with diverse telomere. but there was a trend toward survival improvement for patients with shorter telomeres. further investigations on short telomeres as predictive biomarkers are warranted for clinical development of imetelstat ( ) . a lot of sirna-based therapeutics are being assessed in preclinical and clinical trials of pulmonary diseases. aln-rsv , a sirna therapeutic directing against the mrna encoding the n protein of the respiratory syncytial virus, has completed phase ii clinical trials ( ) . sirnas also hold great promise as therapeutic agents for cancer through rnai silencing oncogene expression. sirna for cancer therapies are beginning to be tested in human clinical trials, such as aln-vsp(alnylam pharmaceuticals) for the treatment of liver cancer and calaa- (calando pharmaceuticals) as tumor inhibitor ( ), and they have shown promising pharmacodynamics and tolerability. however, to extend small rna therapy to other major cancer types, including lung cancer, delivery vehicles that target nonliver tissues and specific delivery route are needed. lung cancer is an attractive cancer type for local or systemic small rna delivery treatment. various therapeutic target genes (e.g., survivin, bcl , hdm ) for lung cancer therapy have already been identified and become targets of sirna therapy ( ) . mirnas play a central and complex role in cancer development and are generally classified as tumor suppressor mirnas or tumor-promoting mirnas (oncomirnas). tumor suppressor mirnas in lung cancer include let- family, mir- / family, mir- / , mir- family, and mir- ; oncomirnas in lung cancers include mir- ~ cluster, mir- , and mir- / ( ) . there are two approaches for mirna modulators to act as cancer therapies: exploiting antisense-based inhibitors of oncogenic mirnas or replacing downregulated tumor suppressor mirnas with synthetic mirna mimics ( ) . to date, there are two tumor suppressive mirna mimics of mirna- (mrx ; mirna therapeutics inc.) and mirna- (targomirs; engeneic ltd.) that have entered clinical trials. mrx is a synthetic version of mir- a encapsulated in liposomes. mir- a is a tumor suppressor often expressed at reduced levels in a broad range of cancer types, which functions to downregulate the expression of more than different oncogenes across multiple oncogenic pathways ( ) . but immune-related serious side effects caused termination of the trial of mrx . targomirs are double-strand synthetic mir- -based microrna mimics delivered by engeneic dream vectors which are deprived from nonliving bacterial minicells with a targeting moiety ( , ) . the mir- family has been implicated as tumor suppressor in a range of cancer types, and their primary targets are genes (e.g., bcl , cdk , and jun) involved in cancer progression. in vitro and in vivo studies showed that the restoration of expression of mir in malignant pleural mesothelioma induced the apoptosis of tumor cells and inhibited tumor growth. long-term survival after a short treatment period was observed in the phase study. however, the safety issue and early signs of activity of targomirs still warrant further clinical trials ( ) . asthma is a kind of chronic inflammatory airway disease with high prevalence, which could induce airway hyperresponsiveness, infiltration of inflammatory cells, and airway remodeling. it has been estimated that about million people suffer from this disease on a global scale ( ) . the current therapeutics for asthma (including inhaled β -adrenergic receptor agonists, inhaled corticosteroids, and monoclonal antibody against ige) could effectively control the disease for most patients while there are still about % of the patients still out of control under the current treatments. ( ) . besides, the current drugs fail to stop or reverse the airway remodeling and some of the drugs followed with concerns of long-term adverse effects, which means there are unmet needs for better drugs ( , ) . choi et al. developed a novel therapy combining traditional drugs with novel therapeutics. in the regimen, dexamethasone (dexa) was attached to peis to act as a controller ingredient to control the airway inflammation. while sirna against vitamin d binding protein, which is a responsible molecule of allergic asthma, was delivered by dexa-pei at the same time ( ) . this multi-target treatment effectively reduced the airway inflammation and secretion of inflammatory factors. asthma is a complex disease associated with the interaction between genetic, epigenetic, and environmental parameters, involved with a plethora of cells and cellular factors ( ) . one direction for developing new drugs to treat asthma is to target central pathways to the pathogenesis of the disease, and nucleic acid-mediated therapies silencing the specific effector or the upstream regulator can be a potential approach. ribosomal protein s (rps ) was found to bind to the subunit of nf-κb complex and enhance the downstream inflammatory effect. intratracheal delivery of rps silencing sirna effectively alleviate airway hyperresponsiveness (ahr) and immune cell infiltration, and decreased serum total ige levels were also observed ( ) . sb , a new class of aso therapeutic sequence-specific targeting and cleaving gata mrna, has entered into phase a clinical trials. the overexpression of gata was found in cells involved in allergic inflammation. the results of the trial showed that inhaled sb significantly attenuate both the early-phase and late-phase allergen-induced asthmatic responses ( ) . another aso drug tpi-asm , developed by pharmaxis, contains two types of asos targeting the βc subunit of the il- , il- , gm-csf receptors (top ), and human ccr (top ) respectively. tpi-asm showed the protective effect against ige-mediated early asthmatic response and reduced eosinophilic airway inflammation ( ) . chronic obstructive pulmonary disease (copd) is one of the most common chronic respiratory diseases of the airways with an increasing morbidity and mortality; it has been forecasted that copd will be ranked the fourth burden of disease worldwide by year ( , ) . copd is characterized by progressive airflow obstruction and airway inflammatory response. current therapeutic strategies are through inhaled long-acting β -agonists, long-acting muscarinic antagonists, and corticosteroids to dilate bronchus and suppress inflammatory, which is similar to the treatment of asthmas ( , ) . emerging drugs in copd focus on the cellular and molecular components regulating airway inflammations ( ) . phosphodiesterases (pdes) are a group of different isoenzymes (pde - ) hydrolyzing camp, increased levels of which promote airway smooth muscle relaxation and bronchodilation with anti-inflammatory responses. among the big pde family, pde is present in many types of cells relating to copd and thought to be a promising therapeutic target. tpi , a dual pde inhibitor comprising two modified asos directing against pde b/ d and a, was designed to reduce the recruitment and activation of inflammatory cells in copd and shown to reduce the neutrophil influx in bronchoalveolar lavage (bal) and inflammation of smoke-exposure or lps-challenge murine models ( ) . the phase i clinical trial of tpi was initiated in but was withdrawn due to drug development suspension. the lungs of copd patients show that the reduction of alveolar elastic fibers and self-healing ability is impaired due to chondroitin sulfate proteoglycan versican inhibiting tropoelastin assembling into fibers. wu et al. employed a small interfering rna (sirna) against versicanin primary pulmonary fibroblasts from copd patients and enhanced the deposition of tropoelastin, which offers a new direction to lung repairment in copd therapy ( ) . mirna expression has been proposed as an accessible biomarker of copd disease ( ) . multiple mirnas were found altered in copd patients and murine models and could serve as potential biomarkers for the copd detection and prognosis. for example, downregulation of mir- a, - p, c- p, , and upregulation of mir- and have intimate association with copd development ( ) . micrornas were also found to play an important role in copd muscle dysfunction and mass loss ( ) . elevated mir- - p expression in patients with muscle wasting might contribute to the inhibition of protein synthesis and loss of muscle mass ( ) . it was demonstrated that mir- a, as a suppressor of tgf-β signaling by reducing the expression of smad protein, might attribute to the maintenance of muscle mass ( ) . cystic fibrosis (cf) is a genetic disorder giving rise to the functional failure of the cystic fibrosis transmembrane conductance regulator (cftr) protein, which acts as an epithelial chloride channel. the interaction of cftr and epithelial sodium channel (enac) is responsible for the homeostasis of the airways epithelial surface. the deficiency or flaw of cftr leads to hyperactivity of epithelial sodium channel. reduced chloride secretion and increased sodium absorption subsequently result in mucus dehydration, chronic infection, and airway inflammation ( , ) . using antisense oligonucleotides that correct the basic defect at the mrna level could restore the crucial balance between enac and cftr. a recent study exploited aerosol delivery of asos in cf-like mouse models to inhibit enac activity by triggering rnase h -dependent degradation of scnn a mrna, which encodes the enac ɑ subunit. this strategy effectively reduced goblet cell hyperplasia and reversed cf-like symptoms, demonstrating that an enac antisense therapy may provide a potential therapy for cf ( ) . the drug qr- is a single-stranded antisense rna-based oligonucleotide sequence designed to hybridize the sequences adjacent to the deleted f region in the cftr mrna to restore the full function of cftr protein in patients with the f del mutation. preliminary studies in cell culture and mouse f del model showed improved chloride efflux after qr- treatment ( ) . data showed that topical administration of qr- to the nasal epithelium improved cftr function by measuring the nasal potential difference of f del cf subjects ( ) . a phase b study to evaluate the safety, tolerability, and pharmacokinetics of qr- is ongoing in cf patients with homozygous f del cystic fibrosis. acute respiratory distress syndrome (ards) is a type of acute diffuse lung injury with a high mortality rate, which is clinically characterized by pulmonary infiltrates, hypoxemic respiratory failure, and edema, ( ) . the mild form of ards is termed as acute lung injury (ali). it is suggested that approximately ~ cases of ards per , population per year. ali is more common, with rates up to per , per year reported ( ) . the common risk factors conclude sepsis, trauma, pneumonia, and toxic inhalation ( ) . current ards therapy is to improve impaired gas exchange and lung mechanics by anti-inflammatory drugs, bronchodilators, and mechanical ventilation, which show limitation in controlling the disease progression. as researchers digging into the mechanisms of ards, crucial regulatory agents participating in the initiation and progression of ards, like mirnas and cytokines, have become appealing therapeutic targets. it was found that murine ali models treated with asos against mir- gained the enhanced recovery of ali as evidenced by the reduction of bal protein and pro-inflammatory cytokines, and the number of bal cells ( ) . nf-κb is a family of dna binding proteins involved in the expression of pro-inflammatory factors and thus the development of ards. depletion of nf-κb by specific sirna targeted nf-κb p in lipopolysaccharide (lps)-induced ali rat models effectively reduced levels of the pro-inflammatory cytokines and ameliorated symptoms induced by lps ( ) . in vivo administration of the sis plyase/hmgb a/r v complex reduced the s plyase level and weakened the inflammatory response and apoptosis in an lps-induced ali model, indicating that sis plyase and hmgb a have a synergistic therapeutic effect for ali ( ) . nucleic acid drugs hold great promises as new classes of therapeutic agents for pulmonary diseases, and some candidates have entered into clinical trials (table iii) . the unique structures of lungs enable the delivery of nucleic acid to be implemented by intravenous and pulmonary routes. inhalation and intranasal routes have been found to be ideal for effective delivery. for proper therapeutic use, researchers have modified the chemical structure of nucleic acids to increase their ability against nuclease degradation and reduce immune responses. the transition from bench to bedside of nucleic acid-based therapy also depends heavily on the availability of a safe delivery system that can facilitate trafficking into site of action. the safety issue, especially the immunogenicity of nucleic acids and their vectors, is the biggest stumbling block before nucleic acid drugs for lung diseases become available in the clinic, and further work in this area need to be thoroughly investigated. it is still necessary to identify suitable carriers with the ability to successfully reach the action site in the lung and protect the activity of nucleic acids during the delivery. with the advances and ongoing clinical trials, the future of nucleic acid drugs for pulmonary diseases remains very promising. world health organization. the top causes of death gene therapy for pulmonary diseases targeted delivery of sirna to activated t cells via transferrinpolyethylenimine (tf-pei) as a potential therapy of asthma pharmacology of antisense drugs nucleic acid therapies for cystic fibrosis. nucleic acid ther [internet] rna therapeutics: beyond rna interference and antisense oligonucleotides advances in the delivery of rna therapeutics: from concept to clinical reality fda-approved oligonucleotide therapies in preclinical and clinical development of sirna-based therapeutics sirna versus mirna as therapeutics for gene silencing development of novel therapeutic agents by inhibition of oncogenic micrornas an overview of micrornas delivering the promise of mirna cancer therapeutics micrornas as cancer therapeutics: a step closer to clinical application therapeutic rna aptamers in clinical trials aptamers: molecules of great potential current progress on aptamertargeted oligonucleotide therapeutics aptamers as targeted therapeutics: current potential and challenges food and drug association on / / for macugen®, nda selective delivery of therapeutic single strand antimirs by aptamer-based conjugates multifunctional aptamer-mirna conjugates for targeted cancer therapy pulmonary administration of small interfering rna: the route to go? sirnabased therapies for pulmonary diseases carrier interactions with the biological barriers of the lung: advanced in vitro models and challenges for pulmonary drug delivery mucus-penetrating nanoparticles for drug and gene delivery to mucosal tissues overcoming cellular barriers for rna therapeutics breaking down the barriers: sirna delivery and endosome escape a novel family of small molecules that enhance the intracellular delivery and pharmacological effectiveness of antisense and splice switching oligonucleotides high-throughput screening identifies small molecules that enhance the pharmacological effects of oligonucleotides oligonucleotide therapy for obstructive and restrictive respiratory diseases nucleic-acid therapeutics: basic principles and recent applications adv drug deliv rev delivery strategies and potential targets for sirna in major cancer types. adv drug deliv rev cholesterol-containing nuclease-resistant sirna accumulates in tumors in a carrierfree mode and silences mdr gene a myeloid cell-binding adenovirus efficiently targets gene transfer to the lung and escapes liver tropism overcoming the cystic fibrosis sputum barrier to leading adeno-associated virus gene therapy vectors impact of trem- gene silencing on inflammatory response of endotoxininduced acute lung injury in mice lipid nanoparticle delivery of a microrna- inhibitor improves experimental pulmonary hypertension delivery of therapeutic sirna to the lung endothelium via novel lipoplex formulation dacc development of spray-freeze-dried sirna/pei powder for inhalation with high aerosol performance and strong pulmonary gene silencing activity tpp-dendrimer nanocarriers for sirna delivery to the pulmonary epithelium and their dry powder and metered-dose inhaler formulations anti-inflammatory effect of anti-tnf-α sirna cationic phosphorus dendrimer nanocomplexes administered intranasally in a murine acute lung injury model dendrimer-inspired nanomaterials for the in vivo delivery of sirna to lung vasculature an inhalable β -adrenoceptor ligand-directed guanidinylated chitosan carrier for targeted delivery of sirna to lung recent advances in chitosan-based nanoparticulate pulmonary drug delivery hybrid lipid/polymer nanoparticles for pulmonary delivery of sirna: development and fate upon in vitro deposition on the human epithelial airway barrier hybrid pulmonary surfactant-coated nanogels mediate efficient in vivo delivery of sirna to murine alveolar macrophages bio-inspired pulmonary surfactantmodified nanogels: a promising sirna delivery system surfactant protein b (sp-b) enhances the cellular sirna delivery of proteolipid coated nanogels for inhalation therapy efficient in vitro and in vivo pulmonary delivery of nucleic acid by carbon dot-based nanocarriers local delivery of sirna-loaded calcium phosphate nanoparticles abates pulmonary inflammation aerosol delivery of stabilized polyester-sirna nanoparticles to silence gene expression in orthotopic lung tumors inhaled gene delivery: a formulation and delivery approach gababreceptor ligand-directed trimethyl chitosan/tripolyphosphate nanoparticles and their pmdi formulation for survivin sirna pulmonary delivery dry powder formulation of plasmid dna and sirna for inhalation inhaled powder formulation of naked sirna using spray drying technology with l-leucine as dispersion enhancer delivery systems for pulmonary gene therapy t=js&page=reference&d=emed &news=-n&an= ovidweb.cgi?t=js&page=reference&d=-emed &news=n&an= lipid envelope-type nanoparticle incorporating a multifunctional peptide for systemic sirna delivery to the pulmonary endothelium micrornas and lung cancers: from pathogenesis to clinical implications nanoparticle-based targeted gene therapy for lung cancer ogx- ): a second-generation antisense inhibitor of clusterin in development for the treatment of prostate cancer phase i/ii trial of custirsen (ogx- ), an inhibitor of clusterin, in combination with a gemcitabine and platinum regimen in patients with previously untreated advanced nonsmall cell lung cancer a randomized phase ii study of the telomerase inhibitor imetelstat as maintenance therapy for advanced nonsmall-cell lung cancer a randomized, double-blind, placebocontrolled study of an rnai-based therapy directed against respiratory syncytial virus therapeutic mirna and sirna: moving from bench to clinic as hyaluronic acid-conjugated lipoplexes for targeted delivery of sirna in a murine metastatic lung cancer model delivery systems and local administration routes for therapeutic sirna pulmonary delivery of therapeutic sirna micrornas in non-small cell lung cancer: current status and future therapeutic promises phase i study of mrx , a liposomal mir- a mimic, administered twice weekly in patients with advanced solid tumors safety and activity of microrna-loaded minicells in patients with recurrent malignant pleural mesothelioma: a first-in-man, phase , open-label, dose-escalation study versatile vectors for targeted drug or si/shrna cancer therapy epidemiology and economic burden of asthma new targets for drug development in asthma new therapies for asthma: is there any progress? asthma: pathogenesis and novel drugs for treatment a new combination therapy for asthma using dual-function dexamethasone-conjugated polyethylenimine and vitamin d binding protein sirna ribosomal protein s gene silencing protects against experimental allergic asthma allergen-induced asthmatic responses modified by a gata -specific dnazyme antisense therapy against ccr and the common beta chain attenuates allergen-induced eosinophilic responses chronic obstructive pulmonary disease emerging drugs for chronic obstructive pulmonary disease emerging therapeutic strategies in copd a multi-targeted antisense oligonucleotide-based therapy directed at phosphodiesterases and for copd deposition of insoluble elastin by pulmonary fibroblasts from patients with copd is increased by treatment with versican sirna targeting microrna function in respiratory diseases: mini-review the role of micrornas in copd muscle dysfunction and mass loss: implications on the clinic mir- - p reduces ribosomal rna and protein synthesis in muscle wasting mir- a suppresses smad protein expression and promotes resistance to muscle loss cystic fibrosis inhaled enac antisense oligonucleotide ameliorates cystic fibrosis-like lung disease in mice strategies in early clinical development for the treatment of basic defects of cystic fibrosis qr- , an investigational rna therapeutic, improves cftr activity in cystic fibrosis subjects homozygous for the f del mutation mechanisms and clinical consequences of acute lung injury acute lung injury antisense oligonucleotide treatment enhances the recovery of acute lung injury through il- -secreting m -like macrophage-induced expansion of cd + regulatory t cells small interfering rna targeting nf-κb attenuates lipopolysaccharideinduced acute lung injury in rats combined delivery of hmgb- box a peptide and s plyase sirna in animal models of acute lung injury key: cord- -c vu ako authors: sherk, peter a.; grossman, ronald f. title: the chronic obstructive pulmonary disease exacerbation date: - - journal: clin chest med doi: . /s - ( ) - sha: doc_id: cord_uid: c vu ako nan peter a. sherk, md, and ronald f. grossman, md, frcpc chronic obstructive pulmonary disease (copd) is characterized by the presence of airflow obstruction caused by chronic bronchitis or emphysema. this airflow obstruction is generally progressive, may be accompanied by airway hyperreactivity, and often is partially re~ersible.~ declining lung function is almost universally caused by decades of tobacco smoke exposure and develops insidiously so that patients often do not complain of exertional dyspnea until their -second forced expiratory volume (fev,) is between % and % of its predicted value. when the fev, falls below l, patients are disabled in the activities of daily living and have a -year survival of approximately ?! . forced expiratory volume in second declines by about ml/year in healthy nonsmokers, whereas the average decline is approximately ml/year in smokers. approximately % of smokers are susceptible to the airway effects of smoking and will develop copd. these patients show accelerated rates of decline in fev, of between and m l /~e a r .~~ in , approximately million americans suffered from copd, an estimated increase of % since .'j it ranks fourth among leading causes of death in north america and is the only leading cause of death that is rising in prevalence.'j, according to estimates made by the national heart lung and blood institute, the annual total cost arising from copd was nearly $ billion dollars. this amount includes almost $ billion in direct health care expenditures, nearly $ billion in indirect morbidity costs, and $ . billion in indirect mortality costs. periods of relative clinical stability during the course of copd are interrupted by recurrent exacerbations. the definition of an acute exacerbation of copd (aecopd) is imprecise but is generally considered clinically as an episode of increased dyspnea, sputum production, and sputum purulence in a patient with copd." when these symptoms are severe and accompanied by significant hypoxemia or hypercapnia, patients may require hospitalization. this article focuses primarily on the management of hospitalized patients with ae-copd outside of the intensive care unit and reviews the evidence supporting the available therapies for copd exacerbations. cigarette smoking is the most important cause of copd.lo smoking compromises local airway defense mechanisms by damaging ciliated airway epithelium, increasing mucus viscosity, and slowing mucociliary clearance. these conditions promote bacterial colonization of the lower respiratory tract. the three major bacterial pathogens isolated from patients with copd during periods of both clinical stability and exacerbation are nontypeable haemophilus influenzae, streptococcus pneumoniae, and moraxella cafar~halis.~~ when fev, is severely reduced, enterobacteriaceae and pseudomonas aeruginosa are also commonly detected. these organisms possess a wide array of virulence factors that allow them to evade clearance from the lower airways. although a detailed discussion of the bacterial mechanisms of colonization and infection is beyond the scope of this article, several concepts are noteworthy. smokers prone to acute episodes of bronchitis have a greater degree of bacterial adherence to oropharyngeal airway epithelial cells compared with nonsmokers.'o , iz after adhering to mucus or epithelial cells, pathogenic bacteria elaborate exoproducts that stimulate excess mucous production,' disorganize and slow ciliary beatingy damage epithelial and impair immune effectorcell function.= furthermore, bacterial proteases destroy local immunoglobulin^.^^ when these bacteria loiter in the airways, a host inflammatory response is stimulated. with the movement of large numbers of neutrophils and their subsequent release of proteases and toxic oxygen radicals, epithelial surface damage may be enhanced. after the inciting impact of smoking, bacterial colonization therefore begets airway damage which, in turn, begets further inflammation and bacterial colonization. this event is the vicious circle hypothesis that has been proposed to explain how the bacteria-host interaction establishes the insidious loss of lung function. , disordered pulmonary gas exchange is characteristic of acute exacerbations of copd. patients typically are found to have severe hypoxemia with or without hypercarbia. a variety of infectious and noninfectious insults result in inflammation, bronchospasm, and mucous hypersecretion. these lead to acute airway narrowing that aggravates ventilation-perfusion (v q) mismatching and, can worsen existing hyperinflation. although v q inequality is the most important determinant of hypoxemia, low mixed venous oxygen tension (pvo ) is ' a contributing factor.i during exacerbations, the work of breathing increases to overcome increased airway resistance and dynamic hyperinflation. oxygen utilization by the respiratory muscles therefore is markedly increased, resulting in lower pvo . fortunately, among patients with adequate cardiac reserve, increases in cardiac output partly compensate for diminished pvoz to defend arterial oxygenation. among the mechanisms leading to hypercarbia, v / q mismatch is probably more important than hypoventilation, at least among patients who recover from their exacerbations without needing mechanical ventilation. this concept is supported by the observation that, during exacerbations, patients are often hypercarbic despite increased minute ventilation.' , ' hypoventilation may be an additional mechanism of hypercarbia if respiratory muscle fatigue and acute respiratory failure ensue. the relationshp between bacterial infection and copd exacerbations is not precisely understood. several lines of evidence, however, have established an important role for bacterial infection in many exacerbations. high titers of antibody against nontypeable h. influenzaes , , and m . ~a t a r r h a l i s~~ are found following aecopd. although bacterial colonization of the distal airways is common in stable copd, patients with exacerbations often have higher numbers of organisms.", table summarizes studies using protected specimen brushes to define the microflora of the distal airways in copd exacerbations. mons et a found positive bacterial cultures in % of outpatients with aecopd. compared with stable patients, exacerbated patients were twice as likely to have positive cultures (i.e., cfu/ml) and five times as likely to have bacterial counts greater than , cfu/ml. likewise, s. pneumoniae is more likely to be found in sputum during exacerbations than remission. fagon+' et a found evidence of bacterial infection in % of patients who required mechanical ventilation. streptococcus pneumoniae, h. influenzae, m . cafarrhalis, and enteric gram-negative organisms collectively accounted for % of the isolates. the investigators did not attempt to identify m . pneumoniae, c. pneumoniae, or respiratory viruses. interestingly, gram-negative bacteria accounted for % of isolates, and nearly half of these were h. parainfluenzae. yet, similar studies employing protected brush specimens have not detected h. parainfluenzae among patients with copd exacerbations. * moreover, smith et a p were unable to demonstrate rises in antibody against h. parainfluenzae following copd-related acute respiratory illnesses. it seems justified therefore to consider h. parainfluenzae as generally nonpathogenic. in contrast to the findings of fagon et al,'i a more comprehensive microbiologic survey of patients with severe exacerbations found a higher incidence of potential pathogens. overall, % of patients had at least one positive bacterial culture or positive serology for c. pneumoniae or respiratory viruses. all cultures were obtained within hours of admission, thereby reducing the likelihood of nosocomial infection. streptococcus pneumoniae, h. influenzae, and m . cafarrhalis accounted for % of potential pathogens. strikingly, gramnegative enteric bacteria and pseudomonas or stenotrophomonas represented % of potential this study suggests that a broader profile of potential pathogens may be present among patients with copd with severe exacerbations. although these findings should be confirmed in a larger study, the choice of empiric antibiotics for patients with aecopd should be based in part on the degree of exacerbation severity, and broaderspectrum initial coverage may be warranted for patients with aecopd who present with respiratory failure and require mechanical ventilation. the source of bacterial infection during a copd exacerbation may be endogenous or exogenous. in a small group of patients followed for years, exacerbations coincided with reinfection by strains of h. influenzae having either the same (i.e., endogenous) or different (i.e., exogenous) dna fingerprint. strains of h. influenzae were shown to persist for several months and antibiotic treatment was not effective in eradicating the ba~teria. ~ estimates of the proportion of copd exacerbations associated with viral infection range from % to %. this large discrepancy is because of significant differences in study design. several studies lacked adequate control by failing to record the frequency of viral infection during exacerbation-free periods.@, others, such as those by sommerville and stenhouse,l , attempted to detect only selected pathogens. variability in the definition of an exacerbation is another factor that may affect the percentage of exacerbations caused by viral illness. finally, different serologic and isolation techniques account for some of the variety in study re~ults. ~ the three most rigorous studies are summarized in table . * * the proportion of exacerbations attributed to viral (or mycoplasma) illness ranges from % to %. influenza, parainfluenza, and coronavirus were the most frequent pathogens to be significantly associated with exacerbations. more recently, goh et a p performed a prospective etiologic study of inpatients with aecopd. they collected paired sera for influenza a, b, and parainfluenza viruses as well as legionella, mycoplasma, and chlamydia. positive serology was found in patients ( %), of whom patients ( %) had viral infections. the most common organism was influenza a, with patients demonstrating positive serology ( %). five patients had positive serology for legionella, whereas no evidence was found for infections caused by mycoplasma or chlamydia. gump et a observed patients every weeks for years and documented exacerbations. they derived a striking correlation of infection with exacerbations by interpreting their data in a time-weighted analysis. they found that the incidence of infection was l"/o per patient week of exacerbation but only . % ver patient week in remission. in their -year aniiysis, buscho et alz found that % of exacerbations were associated with viral infection. this rate was twice that of viral infections during remission detected as an asymptomatic fourfold rise in antiviral antibody titers. in the largest study, smith et ap followed patients over years and analyzed more than acute respiratory illnesses. they associated nonbacterial infections with approximately % of acute respiratory illnesses but only % of illnessfree periods. in contrast with the work by buscho and gump, smith et noted a high rate of rhinoviral infection. uncontrolled studies by mcnamara and eadie ,, also reported rhinoviral infections to be associated with copd exacerbations in % and % of cases, respectively. common colds may have a deleterious effect upon lung functionz and patients with copd are more likely to develop increased cough and lower respiratory tract symptoms during rhinoviral infections than healthy smith et apz performed a -year observational study of patients to assess potential interactions between viral, mycoplasmal, and bacterial infections in patients with copd. they calculated the ratio of number of observed exacerbations to number of expected viral or bacterial associations. haemophilus influenzae and s. pneumoniae were isolated more than twice as often as expected following influenza virus infection. marked rises in titers of antibodies against h. influenzae were associated with preceding viral or mycoplasma infections, suggesting that viral infection promotes increased invasiveness of h. influenzae and subsequent infection. there are no other rigorously performed clinical studies of the interaction between viral and bacterial infections in aecopd. although the concept that viruses promote secondary bacterial infection seems biologically plausible and is supported by animal research, it remains unknown how often bacterial infection in aecopd follows an inciting viral infection. suspended particulate matter less than pm in diameter @'mi ") is produced by vehicle exhaust and many industrial processes. several epidemiologic studies*, have associated elevated pm,, levels with a wide range of respiratory outcomes, including reduced pulmonary function and increased chronic respiratory symptoms, rates of hospitalization, and mortality. similar associations exist for other pollutants, notably sulfur dioxide (so,) and nitrogen dioxide. a -year study in bar-celona reported that small increases of so, and airborne particles produced adjusted increases of % in emergency room admissions for copd in winter and % in summer. similar rates of excess hospitalizations for copd have been reported from sydney, australia ( %); detroit, michigan ( %); and birmingham, alabama ( %).*', ' although small, these effects represent a significant public health concern, particularly because they are demonstrable at pollution levels below current air-quality standards. in summary, the foregoing studies imply that bacterial pathogens can be identified in approximately half of copd exacerbations. viral pathogens are identifiable in about % of such episodes. poor air quality may account for slightly more than % of episodes of aecopd. in many copd exacerbations, no obvious pathogen or precipitating cause is found. it is not known how frequently other potential factors, such as medication noncompliance or coincidental events such as pulmonary embolism and myocardial infarction, play an inciting role in aecopd. indeed, it is often difficult to distinguish clinically between exacerbations with and without an infectious cause. this distinction is discussed subsequently in the section on antibiotic therapy. smoking cessation is the most important intervention in the management of patients with copd. the landmark lung health study confirmed that smoking cessation greatly reduces the rate of fevl decline.'" the benefit of smoking cessation is seen even in patients over the age of years. chronic sputum production often clears within weeks of stopping although nicotine replacement therapy is an effective approach to smoking cessation, counseling by a physician has been shown to be the most potent inter-ver~tion.'~~ each year, influenza and its complications are responsible for hundreds of thousands of excess hospitalizations, tens of thousands of excess deaths, and billions of dollars in health care c o s~s .~~,~~ those with chronic lung disease are at especially high risk for the consequences of influenza. despite recommendations for annual influenza vaccination, recent studies have documented inadequate vaccination rates in this risk group. , among elderly persons, including those with chronic lung disease, nichol et alb overwhelmingly demonstrated the efficacy and cost effectiveness of influenza vaccination. in a serial cohort study of more than , patients,* vaccination was associated with a % to % reduction in the rate of hospitalization for all acute and chronic respiratory conditions. another study by the same authorsa found that influenza vaccination was associated with a % reduction in the risk for death from any cause (odds ratio [or] = . ; % confidence interval [ci] = . - . ). a recent metaanalysis of cohort studies concluded that the estimates of vaccine efficacy for preventing respiratory illness, hospitalization, and death were %, % and %, respe~tively.'~~ these data clearly affirm that influenza vaccination is an indispensable part of the care of all elderly persons, especially those with copd. the value of pneumococcal vaccination for elderly patients with copd has been controversial. two randomized controlled trials evaluating the vaccine's efficacy among patients with copd were unable to show statistically significant protective benefit. , a recent meta-analysis concluded that the vaccine provides partial protection against bacteremic pneumococcal pneumonia but not against other important outcomes, including bronchitis or mortality caused by pneumococcal infection. this protective benefit was seen only in low-risk groups and not among those with copd or other highrisk patients. nevertheless, pneumococcal vaccination continues to be strongly recommended for patients with copd because it is safe and has been found to provide significant benefit for patients in case-control and indirect cohort studiesz , , ln as well as in a more recent randomized populationbased several additional novel strategies for reducing acute exacerbations of copd are under investigation. for example, om- bv is an oral immunostimulating agent containing lyophylized fractions of the eight most common respiratory pathogens. its use was associated with a % reduction in the incidence of acute exacerbations of chronic bronchitis and a % decrease in antibiotic use among elderly institutionalized patients in one trial, and the same frequency of exacerbations but less than half as many days in hospital as those given placebo in another?,, n there was a trend toward fewer hospitalizations for respiratory reasons among those receiving the immunostimulating drug. although not available in north america, om- bv has been used for many years in europe. further trials are required to properly define its role. another approach has been the subcutaneous administration of hyaluronic acid (ha), a glycosaminoglycan with neutrophil-regulating functions, to patients with chronic bronchitis. fewer acute exacerbations of bronchtis and reduced antibiotic use were noted among ha-treated patients in a placebo-controlled crossover study. other investigators found that continous administration of carbocysteine lysine salt monohydrate during winter months was effective in preventing ae-copd and reducing antibiotic consumption in patients with chronic b r~n c h t i s .~ despite these recent intriguing data suggesting that immunomodulatory agents may attenuate the development of aecopd, randomized, controlled trials are needed to clarify their potential roles in the routine management of patients with copd. the following sections provide an overview of the merits (or lack thereof) of common therapeutic interventions for aecopd. controlled oxygen (o,), bronchodilators, antibiotics, corticosteroids, noninvasive ventilation, nutritional support, and chest physiotherapy are discussed. when available, evidence from randomized controlled trials is presented. hypoxemia is the most immediate threat to life for patients with aecopd. hypercapnia is a wellrecognized consequence of , therapy. in the past, the risk of hypoventilation or even apnea resulting from , administration has been vastly overestimated, and the notion that , commonly induces clinically important hypercarbia and acidosis has been discredited.'" , , lo the traditional concept is that correction of hypoxemia with supplemental oz removes the hypoxic drive to breathe and leads to a fall in minute ventilation and subsequent carbon dioxide (co,) retention. aubier et all found that although administration of supplemental oz does reduce minute ventilation and increase arterial partial pressure of carbon dioxide (paco,), mouth occlusion pressure (an indicator of central respiratory drive) was significantly higher during acute exacerbations than during stable conditions. the drive to breathe therefore remained very high in spite of oxygen treatment. in a later study by the same authors,i patients with copd and acute respiratory failure received % , for minutes to abolish hypoxic drive. minute ventilation fell by only % and could not account for the entire increase in paco,. the authors concluded that the rise in c was caused by increased vd/vt) (i.e., increased deadspace ventilation) and that the primary mechanism of oz-induced hypercarbia is v / q mismatching, perhaps through the loss of hypoxic vasoconstriction. more recent work by dunn et a and stradling has challenged aubier's conclusions and defended the traditional concept that hypoventilation, rather than v / q mismatching, is to blame for ,-induced hypercarbia. one further mechanism that appears to contribute, albeit to a minor extent, is the haldane effect, whereby co, is displaced from hemoglobin by , causing a rise in p~c o , .~~~ nevertheless, the risks for acute hypoxemia far outweigh the risks for severe hypercarbia. as such, supplemental , administration is recommended for hypoxemic patients with aecopd. oxygen initially should be given to any hypoxemic patient with aecopd by nasal cannulae or venturi mask. if nasal cannulae are used, flow rates of to l/minute generally suffice. the inspired concentration of oxygen (fio,) usually increases by % to % for each increase of l / minute in flow but varies according to the patient's own inspiratory flow rate. venturi masks are more precise and should initially be set to deliver a fio, of % to %. on average, the pao, increases by mm hg when the fio, is increased from room air to %, and by mm hg when the fio, is increased to %. the target pao, is between and mm hg, corresponding to the pao, at which there is near-complete saturation of hemoglobin with ,. rarely, overzealous , administration produces progressive hypercapnia and respiratory acidosis. o, , for this reason, response to , must be assessed according to arterial blood gas and ph measurements. these should be obtained at baseline and within minutes of starting or changing the , concentration. if pao, remains intractably low or the ph drops as a result of increasing paco, alternate strategies to improve hypoxemia and respiratory acidosis must be devised. these include maximizing bronchodilation and the use of assisted ventilation. the role of bronchodilators in the management of stable copd is discussed in the article by ferguson on pharmacologic therapy for copd. bronchodilator agents, specifically p,-agonists and ipratropium bromide (ib), also play a central role in the management of patients with aecopd, with and without respiratory failure. these agents are generally given by inhalation to reduce side-effects and, in the acute setting, nebulizers have been traditionally preferred over metered-dose inhalers (mdis) for ease of drug administration. , * although there are few data to support the choice of either p,-agonists or ib as first-line therapy for acute exacerbations, p,-agonists are usually given as the first step, perhaps because of the longer time to peak effect for ib. , when given in recommended doses (two puffs), ib generally produces greater bronchodilation than p,-agoni~ts.~~, ipratropium bromide and p,-agonists are often used together in the acute setting, despite a lack of evidence from randomized-controlled trials that they are more efficacious in tandem than either agent alone in that ~e t t i n g .~~,~~,~~ in a doubleblind, randomized study involving patients with aecopd, the effects of . mg of ib, . mg of fenoterol, or a combination of the two agents were compared. all three regimens resulted in improved spirometric function at and minutes post-treatment, but combination therapy was no better than either agent alone. similarly, odriscoll et alas compared nebulized salbutamol ( mg) with and without ib ( . mg) in patients with aecopd. one hour following treatment, peak expiratory flow rates were not significantly different between regimens. others have examined clinical, rather than spirometric, outcomes following combined therapy in aecopd. , patients randomly assigned to a combination of isoetharine and ib were discharged from the emergency department an average of minutes sooner than those who received only isoetharine. the authors attributed this time saving to approximately five puffs of ib. interestingly, mean discharge fev, was not different between the two groups. o because these studies followed patients for only to minutes, moayyedi et a recently attempted to capture longer-term benefits of combination therapy. comparing nebulized treatments of salbutamol with and without ib among inpatients with aecopd, they found no difference in duration of stay, subjective breathlessness, or spirometric values over a -day assessment period. considerable effort has been made to establish the most effective method for delivering bronchodilator drugs to patients with acute airflow obstruction. delivery methods include mdis with or without a spacer device, nebulizers (hand-held or attached to a face mask), and dry powder inhalers. a recent systematic review of randomized studies comparing mdis and nebulizers for administration of p,-agonists in acute exacerbations of asthma and copd found the two methods to be equivalent. a reasonable approach advocated by several workers is to begin with nebulized treatments among patients who are too dyspneic to use an mdi and spacer device ~o r r e c t l y .~~,~~~ as early as is feasible patients can then be switched to mdis, which can result in considerable cost savings.m, lzo theophylline theophylline has been used for decades to ameliorate symptoms in patients with airflow obstruction.lz the use of theophylline in the management of stable copd is discussed in the article by ferguson in this issue. theophylline has now been relegated to having a minor role in the acute setting because of the development of safer and more potent bronchodilators?l, the lack of convincing, well-designed trials showing its efficacy has further contributed to the decline in its use. o, , there are only two published studies that relate specifically to the role of theophylline in the treatment of copd exacerbations. the first, by rice et al, was a small, yet rigorously controlled trial in which patients were randomized to aminophylline infusion or placebo during hospitalization for ae-copd. the drug conferred no incremental benefit over standard care in either subjective (dyspnea scores) or objective (spirometry) outcome measures. gastrointestinal side effects were more common in the aminophylline group. an emergency department-based study randomized patients with acute bronchospasm to receive either aminophylline or p a~ebo.l~~ the trial included patients with asthma and copd but failed to report the number of each. unexpectedly, there was a threefold decrease in the hospital admission rate for patients treated with aminophylline ( p = . ). the authors argued that aminophylline should be considered in selected patients with acute exacerbations of copd and asthma because reduced hospitalizations would decrease costs. although their study illustrates a potentially important clinical benefit of theophylline, a cautious approach is necessary. the effect of theophylline on admission rates was not the primary outcome variable and the reduction in admission rates did not quite reach statistical significance after adjusting for multiple comparisons. even though the magnitude of the clinical benefit was large, theophylline produced no objective improvement in pulmonary function as measured by spirometry. despite these reservations, similar reports of clinical benefit in the absence of statistically significant spirometric improvement have been found in studies of corticosteroids in acute asthma and bronchodilator therapy in acute copd.ll bacterial infections' contribution to exacerbations of copd has been inferred from studies demonstrating clinical benefit as a result of antibiotic therapy. antibiotics have been employed for prophylaxis and acute treatment of aecopd. in the s and s, attention was given to preventing exacerbations with antibiotics. murphy and sethim reviewed nine prospective, placebocontrolled trials of antibiotic prophylaxis. of these, five failed to show any reduction in the frequency of exacerbations, although two demonstrated significantly less time lost from work among patients receiving antibiotics. in contrast, compared with placebo, antibiotic prophylaxis significantly reduced the frequency of exacerbations in four studies. in these investigations, prophylaxis seemed to benefit patients suffering the largest annual number of exacerbations. some authorities therefore have recently suggested that antibiotic prophylaxis may be appropriate for individuals prone to frequent exacerbation^,'^ although this practice is not recommended as part of the regular care of all patients with copd. the prescription of antibiotics to facilitate early recovery in aecopd has become routine despite unresolved questions about their true benefit.'" , , nicotra et ap randomized inpatients with aecopd to either tetracycline or placebo for week. at days, there was no difference between groups in terms of oxygenation or lung function. in a similar, but larger, study of outpatients with uncomplicated aecopd, jorgensedl also could not demonstrate a clinically important advantage of amoxicillin over placebo. these null trials notwithstanding, the highestquality clinical study to date, by anthonisen et al," concluded that antibiotics improved outcomes. they randomized outpatients to receive either placebo or broad-spectrum antibiotic (amoxicillin, trimethoprim-sulfamethoxazole, or doxycycline) during copd exacerbations. exacerbations were classified according to severity. type (the most severe) was defined as an increase in dyspnea, sputum volume, and sputum purulence. type involved the presence of only two of the three symptoms, and type was defined as the presence of one of the three symptoms in addition to one other finding (sore throat, rhinorrhea, fever, increased wheeze, or increased cough). compared with placebo, antibiotics shortened the duration of exacerbations by about days and accelerated recovery of peak expiratory flow rate ( p < . for both). treatment success, defined as resolution of symptoms within days, occurred in % of the placebo group and . % of patients receiving active treatment (p < . ). significantly, among patients presenting with type l exacerbations, clinical deterioration was more than twice as common with placebo as with antibiotic. a clinician therefore would need to treat roughly eight exacerbations with antibiotics to achieve one treatment success beyond chance, or two in order to avoid a single deterioration. the authors concluded that avoidance of deleterious outcomes is the strongest reason to offer antibiotics to patients with ae-copd. furthermore, they stated that antibiotics are clearly indicated in type exacerbations, of no benefit in type exacerbations, and probably justifiable for patients with type presentations." similar findings were reported in another largescale, randomized trial comparing amoxicillin / clavulanate to placebo? , saint and associate^'^^ systematically reviewed the clinical efficacy of antibiotics for aecopd. they identified nine randomized, placebo-controlled trials of antibiotics in copd exacerbations in which the patients were followed for at least days. because no outcome measure was common to all nine studies, the authors derived an overall effect size to quantify the efficacy of antibiotics and concluded that a small but statistically significant improvement could be expected among patients receiving antibiotics. from the six trials that reported peak expiratory flow rates, an overall improvement of . liters per minute favoring the antibiotic group was noted. although small, such an effect may be clinically important for patients with severely compromised baseline lung function by preventing respiratory failure and hospital or intensive care unit (icu) admission. l to reduce the risk for treatment failure, antibiotics should be selected according to pertinent clinical data and the potential for antimicrobial resistance. several schemes have been proposed to stratify the patient's risk and select the most appropriate therapy.'" , , the simplest, and most recent, classification system is presented in table . g r o s~m a n~~ has classified acute exacerbations into four groups. group patients have acute simple bronclutis, likely of viral origin, for which anti- antibiotic therapy is directed at l ? aeruginosa and other commonly drug-resistant gram-negative bacteria (see table ). as noted, approaches to antibiotic therapy based upon a rational appraisal of patient risk factors and likely pathogens reduce the risk for treatment failure and avoid unnecessary medical and economic expense. there are outcome data to suggest this approach leads to improved clinical outcomes, with reduced overall a retrospective study by destache and colleagues demonstrated that, compared with the usual first-line antibiotics in the treatment of acute exacerbations of chronic bronchitis, the use of newer antibiotics reduced both the hospitalization rate and failure rate. although the acquisition cost of newer antibiotics (cephalosporins, macrolides and fluoroquinolones) was higher, the overall costs of the treated patients given these drugs were lower. in particular, the group receiving amoxicillin/ clavulanate, azithromycin, or ciprofloxacin had the lowest hospitalization rate, clinical failure rate, and costs compared with cephalosporins or first-line therapy. the hypothesis that aggressive antibiotic therapy should be offered to high-risk patients was tested in a recent, prospective, health economic study.= patients with at least three treated exacerbations of chronic bronchitis in the past year were randomized to receive either ciprofloxacin or any nonquinolone-based therapy for their next acute exacerbation. clinical endpoints (days of illness, hospitalizations, time to next exacerbation) were blended with quality-of-life measurements (nottingham health profile, st. george's hospital respiratory questionnaire, health utility index), and total respiratory costs from a societal perspective. although the overall results indicated no advantage for either treatment arm, in patients with risk factors (severe underlying lung disease, more than four exacerbations per year, duration of bronchitis greater than years, elderly, significant comorbid illness) the use of ciprofloxacin led to improved clinical outcome, higher quality of life, and fewer costs. the results of this study would suggest that aggressive antimicrobial therapy directed especially toward resistant organisms in high-risk patients is a more effective strategy than no therapy or therapy with older antimicrobials that would not be effective against the usual target organisms, particularly p-lactamase-producing h. influenzae. further studies are needed to clarify the optimal antibiotic treatment regimens for subgroups of patients with aecopd. randomized, controlled trials of the efficacy of corticosteroids for acute exacerbations of copd are summarized in table . their role in outpatient exacerbations has been evaluated in only one small study.lz compared with placebo, oral prednisone ( mg tapered to mg over days) significantly improved airflow and oxygenation and resulted in fewer treatment failures. fev, improved on average by only ml per day among patients receiving prednis ne. ~ these findings support earlier retrospective data that suggest that, among patients with aecopd presenting to an emergency department (ed), the incidence of revisit to the ed within hours is significantly reduced if corticosteroids are prescribed. corticosteroids are often given initially by ed physicians and several trials have examined this practice. z, emerman et a studied the effect of a single dose of methylprednisolone ( mg intravenously [iv]) upon pulmonary function and hospitalization rates for patients in the ed with copd exacerbations. they failed to show any improvement in spirometry or decrease in the rate of hospitalization. patients were treated for approximately . hours and the single steroid dose and short period of observation, however, have been postulated to account for the apparent lack of effi-cacy of steroids in this study. more recently, bullard et al" demonstrated a beneficial effect of steroids upon flow rates as early as hours after initiation of treatment. in , alberp provided the initial justification for the routine use of systemic steroids in the care of hospitalized patients with copd exacerbations. forty-four patients with copd and acute respiratory insufficiency were randomized to placebo or methylprednisolone . mg / kg intravenously every hours for days. those treated with steroids were significantly more likely to achieve a % or greater increase in fev, over their baseline. this effect was observed by hours following the start of treatment and persisted for hours. corticosteroids improved postbronchodilator lung function more than placebo but had minimal effect upon total symptoms in another small trial in which hospitalized patients were randomized to receive placebo or mg of oral prednisolone for days.% although the studies described have established that corticosteroids significantly increase fev, over the short term, no study was explicitly designed to capture longer-term endpoints or the adverse consequences associated with steroid therapy!" lo rostomlo studied hospitalized patients with ae-copd given placebo or methylprednisolone ( mg tapered to mg over month) and followed for month after discharge. mean fev, and fvc values were no different between the treatment groups at the end of the study. more recently, niewoehner et alas published the important systemic corticosteroids in chronic obstructive pulmonary disease exacerbations trial. they performed a three-way randomization whereby patients received an -week course of glucocorticoids, received a -week course, and re- ceived placebo. steroids resulted in faster recovery of fev, and shortened hospital stay by day (p < . ). at both and days, steroid therapy reduced treatment failures (defined as death from any cause, need for intubation, readmission, or intensification of drug therapy) by approximately %. there was no difference between and weeks of treatment with respect to spirometry or treatment failure rates, however. the dose of methylprednisolone was high ( mg every hours for days) and resulted in significantly more hyperglycemia and, possibly, increased secondary infection rates.' in summary, the evidence from randomized, controlled trials supports the conclusion that among patients with acute exacerbations, oral or intravenous corticosteroids significantly increase the fev, for up to hours and likely reduce the risk for treatment failure. there is no proved benefit for treatment longer than weeks. hyperglycemia is the most common short-term complication of steroid treatment. as further studies become available, it will be possible to better understand the risk-benefit ratio for corticosteroids and, through meta-analysis, to better define the optimum dose and duration of therapy. it is also important to investigate the long-term risk for adverse effects of intermittent corticosteroids in patients who require them for recurrent exacerbations over many years time. noninvasive positive-pressure ventilation (nppv) is arguably the most significant recent advance in the care of patients with copd with acute respiratory failure. it avoids the complications of endotracheal intubation and preserves airway defense mechanisms while allowing patients to eat, speak, and expectorate secretions. acute respira-tory failure in copd is often characterized by a vicious circle wherein the respiratory muscles must meet ever-increasing ventilatory demands under conditions of worsening hypoxemia, hypercapnia, and acidosis. when the increased metabolic requirements of the respiratory muscles cannot be matched by a commensurate rise in the cardiac output, further acidosis and muscle fatigue ensue. by allowing the muscles to rest, nppv interrupts this process, thereby preventing respiratory arrest and death.n table summarizes the randomized, controlled trials of nppv in aecopd. bott et all randomized patients with copd and hypoxemic-hypercarbic respiratory failure to either conventional treatment or volume-cycled nasal nppv. patients in both groups had similar pretreatment blood gas and spirometric abnormalities. at hour, there was a significant rise in ph and drop in paco in the nppv group compared with conventional treatment. nppv also resulted in significantly less breathlessness by day . most importantly, however, intention-to-treat analysis revealed a trend toward lower -day mortality in the nppv group ( / versus / , relative risk = . , % ci . - . , p = ns). this effect became significant after excluding the four patients randomized to nppv who did not receive it (two were confused, one was unable to breathe through his nose, one had all active treatment withdrawn). none of the patients randomized to nppv required intubation and no serious complications of nppv were reported. the study has been criticized for the lack of standardized treatment in both groups and for the unusually high mortality in the control group. kramer et af investigated the impact of nppv on need for intubation among patients with severe hypercarbic respiratory failure, most with copd exacerbations. sixteen patients ( with copd) were randomized to pressure-limited nasal nppv in addition to standard care and patients ( with copd) received standard care alone. clear a priori indications for intubation were given. significantly, only five patients ( %) in the nppv group required intubation, compared with ( %) in the standard therapy arm. furthermore, maximal inspiratory pressures increased significantly in the nppv arm over hours, indicating a rapid reversal of diaphragmatic fatigue. in contrast to work by bott,is however, there were no significant differences in pam between the treatment groups at any time over the first hours. the study was underpowered to detect differences in mortality. a more recent european multicenter trialz randomized patients to standard therapy or pressure-limited nppv by face mask. all patients required admission to an intensive care unit and were followed until death or hospital discharge. noninvasive ventilation markedly reduced the need for intubation (controls % versus nppv %). compared with standard care, nppv also significantly reduced mortality ( % versus %), complication rates ( % versus %), and mean duration of hospital stay ( days versus days) (all p < . ). more recently, celikel et a compared pressurelimited nppv by face mask with usual care among patients with moderately severe hypercarbic acute respiratory failure and copd. noninvasive positive-pressure ventilation resulted in significantly fewer treatment failures, defined as need for intubation in the nppv group and need for nppv or intubation in the control group. hospital stays were significantly shorter in the nppv group. in contrast, barb et al,i however, were unable to demonstrate any statistically significant benefit of nasal nppv over conventional treatment in terms of duration of hospitalization, dyspnea scores, arterial blood gas measurements, or maximal inspiratory pressures. patients in this trial, however, were clearly not as ill as those in other studies. indeed, no patient in either group required intubation. randomized, controlled trials of nppv for the treatment of aecopd with hypercarbic respiratory failure recently were reviewed systematially.^^ the pooled odds ratio for intubation following nppv is . ( % ci, . - . ). more importantly, however, the trials that included mortality as an outcome collectively demonstrate a strong survival benefit for nppv. * , the pooled odds ratio for death is . ( % ci, . - . ). therefore, at worst, nppv increases the patient's chance of surviving by nearly %; at best, the chance of survival is % better than that of a similar patient not receiving nppv. improvements in ph and pacoz within hour of initiating nppv and good level of consciousness at the beginning of nppv are associated with successful responses to nppv in patients with aecopd and respiratory acido~is.~ malnutrition is common among patients with copd and increases the morbidity and mortality associated with the disease. the veterans administration cooperative study of pulmonary function showed that patients with fevl less than or equal to . l weighed less than % of their ideal body weight (ibw), compared with near normal body weight in less severely impaired patients. in another study, % of patients with emphysema were found to weigh less than % of their ibw. furthermore, reported that more than % of hospitalized patients with copd had evidence of weight loss. pingletongl found that, among ventilated patients, mortality was significantly higher in those who were poorly nourished than in those with better nutritional status. poorly nourished patients also had a significantly higher frequency of hypercapnia. the principal effects of malnutrition upon the respiratory system are thought to be worsened respiratory muscle function, impairment of ventilatory drive, and immune dysfunction. malnutrition impairs muscle function by reducing the availability of energy substrates such as glycogen and phosphate and by altering the structure of muscle fibers. when combined with intercurrent airway infection and the mechanical disadvantage of the diaphragm in copd, malnutrition may have a profound effect on respiratory muscle mechanics. experimental evidence for blunted hypoxic drive in response to semistarvation suggests another mechanism by which patients with copd may be predisposed to respiratory failure. , no randomized, controlled trial has demonstrated reduced morbidity and mortality as a result of nutritional support during acute respiratory failure. nevertheless, clinicians should be able to identify malnourished patients and understand the goals of nutritional therapy. particular attention should be paid to patients with hypercatabolic states that increase the risk for protein-calorie malnutrition. the subjective global assessment and the harris-benedict equation are two valid clinical instruments for assessing malnutrition and planning nutritional therapy. they are reviewed elsewhere?" in general, the goals of nutritional supplementation among patients with acute respiratory failure consist of maintaining body weight and preventing protein breakdown. the effects of malnutrition and nutritional supplementation in patients with copd are discussed in more detail in the article by schols and wouters in this issue. the value of chest physiotherapy (postural drainage with or without chest percussion) in aecopd has not been demonstrated. studies of patients with aecopd have failed to demonstrate a beneficial effect of chest physiotherapy upon sputum volume, gas exchange, or spirometry. one trialz documented a transient but significant decrease in fev, as a result of bronchoconstriction following chest percussion and vibration. some evidence suggests that patients with larger volumes of airway secretions (> ml/d), particularly those with bronchiectasis, may benefit. in some guidelines, therefore, chest physiotherapy has been advocated in this ~ituation.~ in general, however, it is not recommended in the routine management of aecopd. ° although outcome data are important, caution is required in their interpretation. because data are generated by observing large numbers of patients, typically in tertiary referral centers, the pertinence of these data to individual patients may be limited, especially outside of major centers where most copd exacerbations are studies of prognosis in patients with copd and acute respiratory failure performed during previous decades are less relevant by today's standards. current outcomes appear to be better than those of the past, in part because of the widespread use of controlled oz therapy, corticosteroids and ib, availability of better p,-agonists, reduced use of methylxanthines, and increased use of noninvasive ventilatory support.j indeed, there is evidence to support a trend toward improved survival for hypercapnic respiratory failure over the past years. the mortality rates in studies of survival of acute respiratory failure in copd conducted from to ranged from % to %, with an overall mortality of %. for similar studies between and , the range is % to %, with an overall mortality the most recent and comprehensive evaluation of outcomes following aecopd was published by connors et a as a component of the landmark study to understand prognoses for outcomes and risks of treatment (support) they prospectively studied more than patients admitted to five us tertiary care hospitals with severe hypercarbic copd exacerbations (initial paco,~ mm hg). baseline fev, was not available for most patients. half the patients required intensive care unit admission and % required mechanical ventilation. hospital mortality was %. more striking, however, was the finding that following discharge, one third of the patients died in within months and one half within years. not surprisingly, patients who survived hospitalization had a substantial risk of discharge to a facility other than their home ( %) and of readmission to acute care over the ensuing months ( %). higher acute physiology score (acute physiology and chronic health evaluation; apache ), older age, and poor functional status prior to admission independently increased risk of death. improved survival was of %. predicted by greater bmi and albumin level, higher paoz / fio, and, surprisingly, the presence of cor pulmonale and congestive heart failure as the cause of the exacerbation. the latter findings may be explained by the good response of these two disorders to acute therapy. also supports the finding that host factors are principal determinants of outcomes of aecopd. in their retrospective analysis of exacerbations in patients with copd, severity of airflow obstruction, use of home , frequency of exacerbation, history of previous pneumonia or sinusitis, and use of maintenance corticosteroids each were independently associated with treatment failure. surprisingly, age, choice of antibiotics, and presence of comorbid conditions did not affect the treatment outcome in that study. several investigators z , l oo, iw have evaluated the prognosis of patients with copd who require icu admission for acute exacerbations. the results have been somewhat contradictory. kaelin et a , z for example, using several easily obtainable indices, were unable to discriminate between patients surviving more or less than months following intubation. in their analysis of consecutive acute copd exacerbations, neither age nor spirometric, blood gas, or nutritional indices predicted survival. in contrast, menzies et a * reported that, among their patients, higher baseline fev, and serum albumin were significantly associated with improved -year survival following mechanical ventilation. these contradictory findings are especially curious given that both studies had similar inclusion and exclusion criteria and periods of observation. moreover, their populations both had a mean percent-predicted fev, of % and nearly identical baseline values for serum albumin. more recently, rieves et alloo tried to identify clinically useful variables that predict successful weaning from mechanical ventilation and shortterm survival in patients with copd with acute respiratory failure. they observed episodes of acute respiratory failure in and patients with baseline fev, of greater and less than l respectively. only % of the cohort with severe copd survived weaning and spontaneous breathing for hours. furthermore, in the same group, -year survival was only %. absence of infiltrates on chest radiograph was the most influential predictor of survival in patients with severe copd. pneumonia accounted for most of the infiltrates that were seen in this group. baseline fev, obtained during a period of clinical stability prior to the episode of acute respiratory failure was available for all patients. the extent of baseline obstruction alone was not statistically correlated with short-term survival in either group, but the combination of severe baseline obstruction and pulmonary infiltrates markedly increased the risk for death. outcomes following aecopd associated with icu admission and respiratory failure are a study by dewan and discussed further in the article by sethi and siege in this issue. seneff et allo recently refined the discussion over the relative prognostic value of different clinical variables following copd exacerbation. they analyzed admissions for acute copd exacerbation from the apache i database. hospital mortality was %. for patients aged and older, hospital and -year mortality rates were % and % respectively. their report emphasizes that individual clinical variables have different value for predicting short-and long-term survival. patient age, for example, was a statistically significant determinant of -month survival but not influential for hospital mortality after accounting for nonrespiratory organ dysfunction. similarly, the presence of hypercarbia was of no value in predicting hospital mortality but became important over the long term; -year mortality rates for patients with admission paco of less than mm hg versus greater than mm hg were % and % respectively. the most significant predictors of short and long-term mortality are development and severity of multiple organ dysfunction syndrome. respiratory dysfunction is more important over the longer term. as the authors state: "in most cases, the acute, life-threatening components of the exacerbations can be reversed and short-term death avoided by mechanical ventilation and other appropriate treatments. however, because abnormalities in respiratory physiology reflect underlying severity of lung disease, patients with greater abnormality who survive hospitalization are at greater risk of subsequent death."io chronic obstructive pulmonary disease is the only leading cause of death with a rising prevalence. the medical and economic costs arising from acute exacerbations of copd are therefore expected to increase over the coming years. although exacerbations may be initiated by multiple factors, the most common identifiable associations are with bacterial and viral infections. these are associated with approximately % to % and % to % of copd exacerbations, respectively. in addition to smoking cessation, annual influenza vaccination is the most important method for preventing exacerbations. controlled o is the most important intervention for patients with acute hypoxic respiratory failue. evidence from randomized, controlled trials justifies the use of corticosteroids, bronchodilators (but not theophylline), noninvasive positive-pressure ventilation (in selected patients), and antibiotics, particularly for severe exacerbations. antibiotics should be chosen according to the patient's risk for treatment failure and the potential for antibiotic resistance. in the acute setting, combined treatment with p-agonist and anticholinergic bronchodilators is reasonable but not supported by randomized controlled studies. physicians should identify and, when possible, correct malnutrition. chest physiotherapy has no proven role in the management of acute exacerbations. effect of non-invasive positive pressure ventilation on mortality in patients admitted with acute respiratory failure: a meta-analysis clinical efficacy of pneumococcal vaccine in the elderly: a randomized, single-blind population-based trial randomized, prospective trial of noninvasive positive-pressure ventilation in acute respiratory failure does chest physical therapy work? respiratory viral infections in hospital patients with chronic bronchitis bronchodilating effect and side effects of p adrenoreceptor stimulants by different modes of administration efficacy of pneumococcal vaccine in severe chronic obstructive pulmonary disease aminophylline treatment in severe acute asthma. a meta-analysis a controlled trial of methylprednisolone in the emergency treatment of acute asthma lode h respiratory tract infections: when is antibiotic therapy indicated? chronic obstructive pulmonary disease acute respiratory failure viral and mycoplasma pneumoniae infections in exacerbations of chronic lung disease noninvasive positive pressure ventilation in acute respiratory failure respir care clin north am . prevention and control of pneumoccocal disease: recommendations of the advisory committee on immunization practices (acip) the interaction of pneumolysin sufficient and deficient isogenic variants of streptococcus pneumoniae with human respiratory mucosa effect of pseudomonas aeruginosa rhamnolipids on mucociliary transport and ciliary beating nebulized anticholinergic and sympathomimetic treatment of asthma and chronic obstructive airways disease in the emergency room antibody responses to bacterial antigens during exacerbations of chronic bronchitis the veterans administration cooperative study of pulmonary function-mortality in relation to respiratory function in chronic obstructive pulmonary disease aminophylline for acute exacerbations of chronic obstructive pulmonary disease severe copd and acute respiratory failure. correlates for survival at the time of tracheal intubation bacterial adhesion to oropharyngeal and chronchial epithelial cells in smokers with chronic bronchitis and in healthy nonsmokers the long-term efficacy of methylprednisolone in the treatment of acute exacerbation of copd antibiotics in chronic obstructive pulmonary disease exacerbations. a meta-analysis acute on chronic respiratory failure-assessment and management of patients with copd in the emergent setting air pollution and hospital admissions for the elderly in detroit, michigan hospital and -year survival of patients admitted to intensive care units with acute exacerbation of chronic obstructive pulmonary disease austrian r the protective efficacy of polyvalent pneumoccocal polysaccharide vaccine epidemiology of chronic obstructive pulmonary disease decreased duration of emergency department treatment of chronic obstructive pulmonary disease exacerba tions with the addition of ipratropium bromide to p-agonist therapy optimal pharmacologic treatment of the critically ill patient with obstructive airways disease interactions between viruses and bacteria in patients with chronic bronchitis association of viral and mycoplusma pneumoniae infections with acute respiratory illness in patients with chronic obstructive pulmonary disease haemophilus influenzae and haemophilus parainfluenzae in chronic obstructive pulmonary disease bronchial microbial patterns in severe exacerbations of chronic obstructive pulmonary disease (copd) requiring mechanical ventilation stark je, heath re, curwen mp: infection with influenza and parainfluenza viruses in chronic bronchitis rhinovirus infection in acute exacerbations of chronic bronchitis: a controlled prospective study hypercapnia during oxygen therapy in airways obstruction: a reappraisal aerosol bronchodilator delivery methods: relative impact on pulmonary function and cost of respiratory care air pollution and emergency room admissions for chronic obstructive pulmonary disease: a -year study comparison of anticholinergic bronchodilator ipratropium bromide with metaproterenol in chronic obstructive pulmonary disease: a -day multicentre study an alteration in the host-parasite relationship in subjects with chronic bronchitis prone to recurrent episodes of acute bronchitis the smoking cessation clinical practice guideline panel and staff: the agency for health care policy and research smoking cessation clinical practice guideline controlled trial of oral prednisone in outpatients with acute copd exacerbation predictors of mortality in chronic obstructive pulmonary disease: a -year follow-up study a review and economic evaluation of bronchodilator delivery methods in hospitalized patients tor delivery in acute airflow obstruction-a metaanalysis theophylline: recent advances in the understanding of its mode of action and uses in clinical practice subcutaneous administration of hyaluronan reduces the number of infectious exacerbations in patients with chronic bronchitis hypercapnia outcome from respiratory failure nutritional aspects of chronic obstructive pulmonary disease the biology of bacterial colonization and invasion of the respiratory mucosa the role of corticosteroids in acute exacerbations of chronic obstructive pulmonary disease (cochrane review). the cochrane library aminophylline therapy for acute bronchospastic disease in the emergency room a short-term follow-up study on ex-cigarette smokers: with special emphasis on persistent cough and weight gain key: cord- - lkkez n authors: nan title: invited speakers date: - - journal: respirology doi: . /j. - . . .x sha: doc_id: cord_uid: lkkez n nan the physiology of respiration reaches its extreme limits when man is exposed to the effects of high altitude, which is basically a decrease in ambient pressure and temperature. the process of acclimatization of humans to high altitude occurs within minutes of ascent, starting with increases in cardiac output, and ventilation. these result in acute changes in pao and paco . slower changes of acclimatization include increase in hemoglobin concentration (polycythemia), and muscle capillarity, but decrease in mitochondrial volume density and cellular aerobic capacity. through acclimatization, animals and human inhabitants of high altitude areas have developed adaptations that allow them to function as near normal as those living at sea level. humans who undergo acute ascent to high altitude could acclimatize, but some fail to do so. if there is failure to acclimatize, oxygen diffusion impairment results, due to decreased partial pressure, and lower affi nity of hb for oxygen. in addition, there is signifi cant increase in ventilation/perfusion heterogeneity. the resulting hypoxia leads to hypoxic pulmonary vasoconstiction (hpv) which results from multiple components: changes in epithelial cell wall that lead to intracellular calcium increase and/or calcium sensitization. subsequently, pulmonary hypertension develops, with actual breaks in the capillary endothelium leading to an infl ammatory process (seen more during exercise), and decrease in alveolar fl uid clearance. these mechanisms contribute to the development of alveolar edema, high altitude pulnary edema (hape), which is one of the two major diseases due to acute mountain sickness (ams). both hape and the other ams, high altitude cerebral edema (hace) could be potentially fatal, and must be recognized and treated early. knowledge of the pathophysiology of the ams would allow more rational approaches to their prevention and treatment. high altitude illnesses can develop among healthy individuals who sojourn for recreation and work: cerebral form called acute mountain sickness (ams) and potentially fatal pulmonary form called high altitude pulmonary edema (hape). ams is generally self-limited. high-altitude cerebral edema (hace) is likely a continuum of ams and the end-stage of ams. ams is not a precondition for the development of hape. hape develops in non-acclimatized mountaineers after rapid ascent to altitudes above m. hape may develop even in the absence of ams. severe ams may be a risk factor for hape. the altitude, the rate of ascent to new altitude, (> m/day to an altitude above m), and individual susceptibility are major determinants of ams and hape. on ascent to high altitudes all people have swelling of the brain. patient with ams often experience "hangover headache." other symptoms occur within the fi rst to h. these include malaise, anorexia, nausea and vomiting, and insomnia. ams patient must be evaluated for signs of global encephalopathy rather than focal fi ndings, although retinal hemorrhage is commonly seen. when these are present, the subject has hace until proven otherwise. patient may die if not treated promptly. brain herniation is the usual cause of death. the hallmark of hape is an excessively elevated pap which precedes the development of pulmonary edema. symptoms are incapacitating fatigue, chest tightness, dyspnea with effort, orthopnea, cough, and pink frothy sputum in advanced stage of disease. prevention of all altitude complications requires ascending at an increment rate to allow acclimatization. at > m, one should not spend subsequent nights m higher than the previous night. trekker must take a rest day every to days. anyone with ams should not ascend until symptoms are resolved. acetazolamide and dexamethazone are effective in prevention and treatment of ams from proceeding to hape or hace. at the fi rst sign of hace, patients should descend to a lower altitude while supplementary oxygen is given. increasing oxygenation is the highest priority in the treatment of and prevention of hape. if supplemental oxygen is unavailable, then descent, use portable hyperbaric chamber, or both become lifesaving. nifedipine is necessary only when supplemental oxygen is unavailable or descent is impossible. because of its pulmonary vasodilatory effects, phosphodiesterase inhibitors can be used for prevention and treatment of hape. rudolf virchow in described that the determinant risk factors for venous blood clot formation are stasis, endothelial injury and hypercoagulable state. dr simpson et al , a british surgeon observed that during the london blitz, the world war ii, britons who were forced to remain on sitting in cramped position and deck chairs for hours during the air raids developed fatal pulmonary embolism. it was suggested in by homans that "prolonged dependency stasis" or immobilization is one factor that predisposes patients to develop thrombosis in the deep veins of the legs. several risk factors have been identifi ed for developing venous thromboembolism (vte). travel is one of the transient risk factors. it is not confi ned to one mode of travel such as air travel. it is also incriminated to other modes of land travel such as car, bus and train. the term "economy class syndrome" was proposed by symington and stock ( ) and by the group of cruickshank ( ) for venous thromboembolism occurring in patients during air fl ight travel. it is usually seen in patients sitting in limited or cramped circumstances in the economy coach or tourist class seats, however it is also found out that patients who were also seated in the business class also develop this syndrome. factors implicated were the long duration of travel, immobilization or inactivity in sitting position, and the low cabin pressure, low humidity and dehydration during air fl ights. in several studies performed on large airports in europe, the presence of genetic factors such as factor v leiden and environmental factors such as the use of oral contraceptives predispose patients several fold to develop venous thromboembolism. signs and symptoms pertaining to vte develop not only during and after the fl ight but also several weeks after the travel. nowadays, airlines as well as bus companies have advisories and measures impose to prevent development of vte and deaths due to vte during the travel period. with the steadily increasing use of air travel, more and more patients with pulmonary disease are fl ying long distances, at high altitude in partially pressurised aircraft. this is associated with long periods of reduced mobility and exposure to reduced inspired pressures of oxygen and reduced barometric pressure. some individuals therefore may be at risk of barotrauma, hypoxia or venous thrombo-embolism (vte). therefore it is important to identify these individuals and adequately assess the real risk entailed by fl ying. the effect of reduced atmospheric pressure is a potential risk for patients with recent or pre-existing pneumothorax but otherwise is unlikely to be associated with risk other than that due to the associated reduced inspired oxygen fraction (fio ), typically . ( %) in a commercial aircraft at cruising altitude. the reduced (fio ) may be problematic for patients with hypoxic lung disease or in patients with other co-morbidities that may exacerbated by hypoxia. medical history, lung function and resting oxygen saturation will help identify patients at risk although it is diffi cult to predict the clinical effects of altitude from tests (even hypoxic challenge tests) conducted at sea level. there is currently a lack of good data defi ning the clinical outcomes due to hypoxia during fl ight in patients with lung or other diseases. the risk of vte increases with duration of fl ight above four hours, presumably related to the duration of immobility, although the role of prolonged hypoxia remains to be determined. preventive measures are now currently invoked on most airlines and guidelines for the use of antithrombotic agents are available, stratifi ed by risk. it is anticipated that guidelines will continue to be updated as new data are made available. cardio-pulmonary exercise testing is now well accepted as an appropriate test for the investigation of shortness of breath on exertion. in addition the test has been found to be useful for the assessment of pulmonary vascular dysfunction and the assessment of fi tness for major thoracic surgery. even though there are well described and internationally accepted protocols to perform the test, the interpretation of a cardio-pulmonary exercise test often leaves the interpreting physician confused. importantly with the multiple facets of the test (respiratory, cardiac, peripheral vascular) that need to be interpreted it is easy for the interpreting physician to look at a certain aspect of the test relating to their specialty and to give the other facets relatively little attention. in this presentation we review the process of interpreting cardio-pulmonary exercise tests. in addition we will interpret a number of tests based on our previous discussion on how to interpret these tests. finally we will review the literature regarding new interpretive strategies for exercise induced pulmonary vascular disease. bronchoscopy as an image-guided intervention has benefi tted from advances in optical and non-optical imaging technologies. some current bronchoscopy advances incorporate higher resolution ccd (charged-couple device) digital-"chip" technology and magnifi cation lenses to enhance the image resolution. the hope is that improved visualization combined with analysis of concomitant tissue biopsies may realize so-called "in-vivo endoscopic diagnosis" without the need for tissue biopsies, however studies of highmagnifi cation endo-cytoscopy, co-focal micro-endoscopy and optical coherence tomography (oct) remain investigational. further limiting these near-histologic resolution imaging modalities is the need for an initial screening of "highly suspicious" mucosa to focus attention upon. to facilitate identifi cation of abnormal airway mucosa, there are advances in the bronchoscopic detection of dysplastic and malignant mucosa. newer generations of autofl uorescent (af) bronchoscopes combine video ccd technology with af signaling to enhance the visual resolution of the images. non-af technologies being evaluated for the same purpose include fi ltered-light narrow band imaging (nbi) and post image-capture processing by a number of other spectral estimation technologies (set). bronchoscopic image guided interventions (bigi) also benefi tted from advances in non-traditional bronchoscopy technologies. foremost has been endobronchial ultrasound (ebus), initially designed as radial probes modeled after intravascular us and modifi ed for the airways. while useful in advancing our understanding of endobronchial mucosal structure, predicting tumor invasion depth and responsiveness to endobronchial interventions, radial ebus did not permit real-time guidance. dedicated linear-array ebus bronchoscope has changed this dramatically as the . mhz needle-puncture ebus bronchoscope has increased diagnostic accuracy of peri-bronchial lymph nodes/masses from a previous average of < % to > % for even small targets (< cm) in experienced hands. simultaneously miniaturization of radial ebus probes (thin . mm) and incorporation of guide-sheaths have increased the utility of ebus in evaluating parenchymal lung pathology. concomitant work in image processing of radiology imaging data (dicom data of chest ct images) has made available a number of "virtual bronchoscopic navigation" programs to assist the bronchoscopists in navigating towards smaller peripheral focal targets, and to improve the historic diagnostic yield of smaller (< cm) peripheral nodules from - % up to - %. these systems include passive endobronchial "road-maps" view (similar to "mapquest"/"google earth") and more technology enhanced electromagnetic navigation bronchoscopy (enb) (similar to gps guidance). all these ancillary technologies have spurred improvements in the basic bronchoscope, as thinner bronchoscopes capable of reaching peripheral segments ( . mm and . mm with . mm working channel; . mm with . mm working channel) are coupled with new biopsy instruments. the eventual development of steerable single fi ber scanning endoscopes with multi-wavelength imaging may change our current concepts of the bronchoscopes and how we can use them. journal compilation © asian pacifi c society of respirology pg - diagnostic tests pleural effusions are common and often present diagnostic challenges. the new british thoracic society guidelines on investigation of pleural effusions detailed some of the new approaches to undiagnosed pleural effusions. traditional teaching recommends measurement of blood and pleural fl uid protein and ldh levels as the fi rst step of investigation to categorize the effusion into a 'transudate' and 'exudate' using light's criteria. the need to apply this to all effusions is questionable in . current efforts focus on the development of disease-specifi c diagnostic tools incorporating clinical, radiologic and biochemical parameters. • elevated ntpro-bnp levels in pleural fl uids are useful in confi rming cardiac failure as the etiology of a pleural effusion, especially in patients whose fl uid may be falsely elevated into the 'exudative' range by concurrent diuretic therapy. • pleural ntpro-bnp levels are elevated in cardiac failure effusions, but not in other transudative effusions (eg hepatic hydrothorax). • pleural fl uid ntpro-bnp appears a better marker than pleural fl uid bnp. variations in accuracy may also in part depend on the commercial kits used. adenosine deaminase: • ada measurements in pleural fl uids are useful in the diagnosis of tb pleural effusions with a sensitivity and specifi city of and % respectively. limiting the test to lymphocytic pleural effusions will further improve the diagnostic accuracy. • ada is cheap and fast to perform and is now widely used in endemic countries. false positives can occur with bacterial infections, rheumatologic effusions, and occasionally malignant effusions. false negatives are uncommon, and therefore present a valuable 'rule-out' test in regions of low tb rates. • ada is at least as diagnostically useful as pleural fl uid total interferon-gamma levels. • igras have been tested in pleural fl uid and blood of patients with tb pleural effusions in several studies. the diagnostic sensitivity and specifi city are poor and igras are not recommended for the investigation of tb pleuritis. • serum mesothelin is a fda-approved test for the diagnosis and monitoring of mesothelioma. • pleural fl uid mesothelin adds information to pleural fl uid cytology in the diagnosis of mesothelioma, providing a diagnostic sensitivity of % (specifi city %). elevated pleural fl uid mesothelin levels suggest epithelioid or biphasic mesothelioma or occasionally metastatic carcinomas. procalcitonin: • early evidence suggest that serum level of procalcitonin may aid differentiation of pleural infection from pleural effusions of non-infective etiologies. the value of pleural fl uid procalcitonin level is limited. management strategies imaging guidance for pleural procedures: • pleural procedural complications are often under-estimated and underreported. studies have now shown that mandatory imaging guidance (especially bedside pleural ultrasound), and restricting procedural privilege to certifi ed trained clinicians can signifi cantly reduce complication rates from pleural procedures. this practice is now incorporated into many national and professional society guidelines. intrapleural therapy for pleural infection/empyema: • recent clinical trials on intrapleural delivery of fi brinolytics alone have failed to improve important clinical outcomes of pleural infection. however, the combination of tissue plasminogen activator and dnase has shown promising results. • recent studies have revealed increasing concerns of complications of talc pleurodesis, and randomized studies have shown a much lower success rate than previous non-randomized literature, even in selected patients. the concept of drainage without needing to create pleurodesis has growing appeal and the use of indwelling pleural catheters is now regarded as fi rst-line therapy in increasing number of centers. chronic respiratory disease (crd) is non-communicable respiratory disease including asthma, chronic obstructive pulmonary disease (copd), allergic rhinitis, idiopathic pulmonary hypertension, hypersensitivity pneumonitis, occupational respiratory disease. among these crd asthma and copd are important for regional health. facts of asthma million people suffer from asthma. , people died of asthma in . prevalence of asthma has increased or is increasing. asthma is the most common disease among children over % of asthma death occurs in low and lower-middle income countries. asthma is underdiagnosed and under-treated (who, ). facts of copd copd is a life-threatening lung disease that interferes with normal breathing. it is more than a "smoker's cough". an estimated million people have copd worldwide. more than million people died of copd in , which is equal to % of all deaths globally that year. almost % of copd deaths occur in low-and middle-income countries. the primary cause of copd is tobacco smoke (through tobacco use or second-hand smoke). the disease now affects men and women almost equally, due in part to increased tobacco use among women in high-income countries. copd is not curable, but treatment can slow the progress of the disease. total deaths from copd are projected to increase by more than % in the next years without interventions to cut risks, particularly tobacco smoking (who, ). prevention and control of crd in asia pacifi c were held by dokkyo medical university group, later designated as who collaborating centre for prevention and control of crd (du-wcc). seven countries and a district in asia pacifi c joined the meeting. prevalence of asthma in adults was reported from . to . % with a median of . % based on reports. prevalence of childhood asthma ( - y/o) was from . to . % with median of . % based on reports. prevalence of copd was . to . % with a median of . % based on nation-wide surveys. in spirometry-based survey reported, prevalence of copd was . % in adults years and over in japan, % in adults years and over, and . % in adults years and over in china. management in most of the countries gina and gold were adopted for their national guidelines. major risk factors for crd, especially for copd were smoking and indoor air pollution for cooking/heating. pharmacological early interventions have been reported to improve the prognosis of asthma and copd. occupational respiratory diseases are disorders which are induced by occupational and industrial conditions. providing information of the risks of industrial activities would reduce this disorder. strategic direction for the prevention and control of crd most of crd are treatable and at least partially preventable. development of user-friendly guides for prevention and control of crd for offi cials in health care, fi rst-line health-care givers and patients and their family and its implementation would decrease the burden of these crd. the scientifi c foundation of asthma diagnosis and management has grown in leaps and bounds. evidence-based strategies to control asthma and treat its exacerbation are published yearly in the gina guidelines. the -year finland study showed that these strategies work. while cases treated did increase (through better detection), the hospital days and cost per case markedly decreased. the study also showed that widespread adaption and effective implementation of these strategies is best done through a national program. cmes for medical practitioners are important but are of limited reach. all stakeholders must be enlisted to buy-in. for asthma, the target stakeholders are the health care personnel, nurses and village health volunteers included; the patients and their families; the government and its public health offi cials; the asthma advocacy groups; the community-at-large; and the pharmaceutical industry. the idea is to present the problem to them, include their inputs in the formulation of the plan, collegially decide on target indicators of success and engage them to work for the implementation of the program in the context of what each one can do best. duplicating the finnish experience is a big challenge in the asia pacifi c region. while most countries have their own adaptation of the gina guidelines, few have working national asthma programs. in developing economies, the health infrastructure is not that well developed yet to absorb all guideline recommendations. spirometry may not be widely available nor affordable. government spending for health is commonly below the % of gdp level that who recommends. in the philippines, signifi cant out-of-pocket health expense is borne by the patient. furthermore, programs like tb control, dengue treatment and malaria eradication, which are no longer concerns in developed countries, compete for the meager public health funds. for low income countries, the international recommendations may have to be rewritten to emphasize on simple algorithm for separating non-infectious from infectious respiratory illnesses; practical objective measurements for diagnosis and management such as peak fl ow; available, affordable, and low-risk medications recommended for asthma control; and a simple regimen for recognizing severe asthma (gina). to be viable, the national asthma program will have to piggy back to the existing national health delivery infrastructure which must ensure, among others, access to free or cheap medication. lung cancer and copd commonly coexist in smokers, and the presence of copd increases the risk of developing lung cancer. in addition to smoking cessation and preventing smoking initiation, understanding shared mechanisms in these smoking-related lung diseases is critical, to develop new methods of prevention, diagnosis and treatment of lung cancer and copd. common mechanisms may involve infl ammation, abnormal repair, oxidative stress, epithelial-mesenchymal transition, altered nicotine receptor biology and epigenetic alterations. strategies to study genomics and epigenomics, in addition to gene-environment interaction, will yield greater insight into the shared pathogenesis of lung cancer and copd. copd clinical guidelines are important to guide diagnosis and management of people with copd. the australian 'copdx' guidelines are evidence-based guidelines that are prepared by the australian lung foundation and thoracic society of australia and new zealand. relevant literature is searched regularly and evaluated by a clinical committee. updates are then produced regularly during the year. challenges regarding critical appraisal, resources and dissemination to clinicians will be discussed. national copd guidelines in this region are different from country to country, but basically are adapted from gold. copd prevalence in asia pacifi c countries and region estimated by regional copd working group was . %. vietnam has the highest prevalence: . %. the copd management and guideline implementation problems in the asia pacifi c region are: smoking, biomass using are common; continuous medical education (cme) for health workers are not compulsory; lack of device and personnel for performing proper spirometric tests; over burden for health workers; low access to medical care and low affordability for copd medications. all of these problems result in that copd diagnosis are mostly in late stage, high rate of emergency room visit, icu admission and hospitalization. the consensus is expected to cover following resolutions: reducing the smoking and biomass smoke exposure, screening for copd in large scale using questionnaires and confi rming by spirometry, advocacy for compulsory cme on copd, establishing asthma and copd outpatient care unit (acocu) in different levels of health care settles and introducing copd medications into insurance medication list. infections caused by environmental mycobacteria are more common than tuberculosis in many parts of the world. the more than species of mycobacteria have similarities, but generally the diseases and hosts fi t in specifi c patterns. disease due to environmental mycobacteria can be diffi cult to diagnose and treat and can confuse workup for tuberculosis. mycobacteria have low virulence and even lower invasiveness. they form biofi lms that protect them and allow long term persistence. the treatment is often frustrating for the patients and physicians. learning their metabolic mechanisms and attacking them should be the strategy for combating the disease caused by these organisms. lung cancer and copd commonly coexist in smokers, and the presence of copd increases the risk of developing lung cancer. in addition to smoking cessation and preventing smoking initiation, understanding shared mechanisms in these smoking-related lung diseases is critical, to develop new methods of prevention, diagnosis and treatment of lung cancer and copd. common mechanisms may involve infl ammation, abnormal repair, oxidative stress, epithelial-mesenchymal transition, altered nicotine receptor biology and epigenetic alterations. strategies to study genomics and epigenomics, in addition to gene-environment interaction, will yield greater insight into the shared pathogenesis of lung cancer and copd. airway epithelial cells, which are the fi rst line of cells to contact with inhaled substances such as microorganisms, play an important role in the host defense by two major mechanisms. first, they actively contribute to the innate immune system by recognition of the pathogen and production of antimicrobial substances and cytokines. second, they provide a passive barrier function that prevents invading microorganisms, air pollutants and airborne allergens into the internal milieu. on the other hands, airway epithelial cells are involved in the production of airway infl ammation in asthma and copd by excessively and un-regulatory expressing pro-infl ammatory and pro-allergic cytokines, executing apoptosis and losing barrier function. there is very close relationship between epithelial barrier function and innate immune response of epithelial cells. for instance, losing barrier function results in not only allowing foreign substance and pathogens to invade into the internal milieu but also enhancing innate immune responses. asthma and copd are different diseases, but they may have the same mechanism in the pathogenesis of exacerbation of these diseases in term of losing epithelial barrier functions. in this symposium, we will present the latest information on and the regulatory mechanism of airway barrier function and discuss in the context with asthma and copd pathogenesis and exacerbations. key words; airway epithelial cells, barrier function, asthma, copd patients with severe and diffi cult-to-treat asthma ("refractory asthma", approximately % of total asthma) have impaired health status refl ected by persistent symptoms, severe airfl ow limitation and frequent asthma exacerbations despite taking maximally recommended doses of inhaled corticosteroids and long-acting β -agonists. a better understanding is thus needed regarding factors associated with such troublesome condition and, in our cross-sectional observational study, clinical and demographic characteristics of patients fulfi lling the american thoracic society workshop criteria for refractory asthma (ajrccm, , group a) were compared with those of patients with severe persistent asthma defi ned on the basis of the gina guideline (group b). there were no signifi cant differences between the two groups with respect to age, gender, smoking status, disease duration, pulmonary function (fev , pef, dlco), or markers of airway infl ammation in the induced sputum (eosinophils, neutrophils, ecp, tryptase). however, in contrast to group b, all patients in group a were adult-onset, and % of the patients already had severe symptoms at the time of disease onset. prevalence of atopy, postbronchodilator fev /fvc ratio and fev reversibility were signifi cantly less in group a than in group b. patients in group a complained of copious amounts of phlegm associated with chronic sinusitis and/or chronic bronchitis, and showed high concentrations of mucin (muc ac + muc b) in the sputum. in addition, nasal clearance time assessed by saccharine test was signifi cantly longer in the group a than in the group b patients, indicating impairment of airway mucociliary clearance. these fi ndings and other pathophysiological and clinical data suggest that "refractory asthma" may be a different form of asthma (phenotype) rather than a progression of asthma severity during follow-up of natural history of the disease. furthermore, it is likely that irreversible airway narrowing possibly due to airway remodeling and airway mucus hypersecretion are important factors contributing to the pathogenesis of severe and diffi cult-to-treat (refractory) asthma. the results prompt for further longitudinal studies and interventions to defi ne the mechanisms of this unique phenotype of asthma. journal compilation © asian pacifi c society of respirology drug development is a long and expensive process. on average it takes at least years and more than a billion dollars to develop a compound from basic science discovery through clinical trials and fi nal approval by regulatory authorities of a new therapeutic. one of the main obstacles to development of new compounds is the diffi culty in obtaining good pre-clinical proof of effi cacy for a new drug. most of this is currently obtained from experiments using animal models of disease or cell lines, neither of which refl ect well human disease nor predict whether responsiveness in these models predicts responsiveness in human disease. recent studies have focused on developing methods that employ human cells or tissues taken from the relevant organ and from relevant patient populations. of these models, the explant model, which uses whole tissue samples, is the closest to the in vivo situation because it maintains the complex cell-to-cell interactions. in asthma, studies have shown that this model can sometime be even better than in vivo study. thus, for example, the explant model vivo offers several advantages over in vivo allergen challenge of asthmatic volunteers. first, repeat bronchoscopy to sample the airways after initial allergen challenge is not required. second, tissue responses of more severe asthmatics, who for safety reasons cannot be challenged with allergen in vivo, can be studied. third, problems of dilution of secreted mediators during bal are avoided and released mediators are not consumed by in-coming infl ammatory cells, thus increasing the sensitivity of the model. finally, and most importantly when seeking pre-clinical proof of concept of drug effi cacy, the model allows testing of novel compounds at an early stage before its full safety profi le is established, a process that is both expensive and time-consuming. we have previously shown that the asthmatic airways generate increased t cell chemotactic activity compared to healthy controls. using a highly selective ccr antagonist we have recently shown that the ccr -chemokine axis plays a key role at least in the traffi cking of t cells into the asthmatic airways. having established this, we then showed that predominantly the ccr + t cells are recruited in response to allergen stimulation. we have further shown that the selective removal of these ccr + t cell from blood signifi cantly reduced allergic infl ammation as shown by a marked reduction in the production of the th cytokines il- , il- and il- but with no consequences for th responses. taken together, our studies have strongly suggested that inhibiting the migration of t cell to the asthmatic airway by targeting ccr is likely to abrogate the allergic infl ammation in the airways without affecting immune responses that serve to protect against infection. these studies have also shown the value of using such ex vivo models of asthma to provide proof of concept for new drugs, giving the pharmaceutical industry the necessary pre-clinical proof to proceed with confi dence into further clinical development. sleep-disordered breathing (sdb) or obstructive sleep apnea (osa) is a prevalent but largely undiagnosed sleep disorder. apnea-hypopnea index (ahi: the number of apneas and hypopneas per hour of sleep) is used to classify sdb severity. in icsd- (international classifi cation of sleep disorders ver. ), "osa syndrome" was defi ned as ahi ≥ with hypersomnolence/ daytime symptoms or as ahi ≥ regardless of the symptoms. epidemiological studies clarifi ed that sdb is associated with increased likelihood of hypertension, cardiovascular disease, stroke, motor vehicle accidents, depression, diminished quality of life, and even mortality. clinical guidelines for hypertension put weights on sdb as a cause of hypertension. international diabetes federation (idf) made a consensus statement on sleep apnea and type diabetes. "overlap syndrome" (coexist of copd and sdb) was reported to have much higher mortality than sdb alone. sleepiness was thought to be a major symptom for osa syndrome. it is true that there is a signifi cant trend that the severe the sdb is the more the subjects had sleepiness. however, the majority of sdb subjects (even the majority of subjects with ahi ≥ ) do not have sleepiness (ess: epworth sleepiness scale > ). the berlin sleep questionnaire was used to screen high or low risk subjects for sdb. four-item screening tool was also developed (gender, bmi, blood pressure, snoring frequency). these tools may be useful, when certifi ed with sleep monitoring in each population. prevalence of ahi ≥ , estimated from two-stage sampling, was - % in male and - % in female. two-stage sampling is oversampling the subjects with sleepiness or snoring to perform sleep monitoring, and weighting of results to the survey sample. when all the participants underwent sleep monitoring, the prevalence of ahi ≥ was - % in male and - % in female. there is a strong need for better recognition, screening and treatment of sdb. more studies are needed, especially for long-term outcomes of asymptomatic sdb. genome-wide association studies may be useful to elucidate causes or underlying mechanisms of sdb. continuous positive airway pressure (cpap) is a standard treatment for patients with obstructive sleep apnea (osa), especially for moderate to severe osa. the mechanism of action is to provide a pneumatic splint to preserve upper airway. the pressure level required to maintain airway patency is determined by manual pressure titration by a sleep technologist during attended laboratory polysomnography (psg) to eliminate obstructive respiratory-related events (e.g., apneas, hypopneas, respiratory effort-related arousals [rera], and snoring). despite wide acceptance as a standard therapy for treatment of osa patients, very few pap titration protocols have been published so far, and there are inconsistency and variations in cpap titration protocol among clinical sleep laboratories. for this reason, the pap titration task force developed evidence-and consensus-based standardized pap titration protocol and published its guideline entitled "clinical guidelines for the manual titration of positive airway pressure in patients with obstructive sleep apnea" in journal of clinical sleep medicine . in this lecture, i will explain about manual cpap titration guidelines as below based on publications which are recommended by positive airway pressure titration task force of the american academy of sleep medicine (aasm): ( ) important considerations prior to cpap titrations. ( ) criteria for cpap pressure to be increased. ( ) minimum and maximum starting cpap pressure. ( ) an interval and minimum pressure to eliminate obstructive respiratory events. ( ) different algorithms for cpap pressure to be increased to eliminate obstructive respiratory events observed for patients ≥ years and < years. interventional bronchoscopy has typically been associated with obstructive tumor removal to regain central airways patency; such interventions, whether with rigid or fl exible instruments were also limited to the navigable fourth or fi fth generation airways. tissue destructive techniques included ablative heat techniques (laser, electrocautery and argon plasma coagulation), cold techniques (cryotherapy) and mechanical coring with the rigid bronchoscope. a current new crop of tissue debridement devices include modifi cations of established technologies: fl exible co laser fi ber usable beyond the trachea, cryotherapy using non-contact surface cryospray, rotational microdebrider devices adopted from otolaryngology, pulsating balloon resectors. the latter three devices do not involve heat that may cause post-treatment infl ammation and cartilage destruction and subsequent airway fi brosis or malacia. previous direct intra-lesional injection, with mitomycin or steroid was directed towards non-malignant fi brotic lesions, conversely on-going studies with cytotoxic agents ( fu) and compounds thought to have immune adjuvant effects (pts) are demonstrating potential utility in endobronchial tumors. photo-dynamic therapy (pdt) compounds with shorter half-lives require fewer bronchoscopies and have shortened photo-toxicity side effects. therapeutic bronchoscopic image guided interventions (bigi) have benefi tted from advances in "virtual bronchoscopic navigation" software available to improve reaching small peripheral lesions. for radiation therapy for focal lung lesions not resectable because of patient co-morbidities or preference, the accurate placement of fi ducial markers (gold) are used to direct high-dose rate external-beam intentiy modulated radiation therapy (imrt) including cyberknife machine. trials also demonstrate feasibility and effi cacy of treating peripheral lesions by high-dose rate (hdr) brachytherapy through catheters placed with image guidance. one area of new focus is bronchoscopy in the management of chronic obstructive lung diseases (old) including emphysema and severe asthma. based on lung volume reduction surgery for severe emphysema with heterogeneous distribution and air-trapping, non-surgical bronchoscopic lung volume reduction (blvr) has taken on a number of innovative approaches including exclusion by spigots (watanabe), valves (emphysys, spiration), metallic coil retraction (pneumrx), airway bypass to relieve trapped gas (broncus), atelectasis by bio-glue (aeris) or by heat steaming (uptake). although none of the clinical devices in trials have shown unqualifi ed success, some devices are now being marketed (europe), or are available on a compassionate basis for management of broncho-pleural fistulas (bpf). airway radio-frequency ablation (rfa) of airway smooth muscle is usa-fda approved for management of severe asthma. future innovations in interventional bronchoscopy will likely incorporate advances in diagnostic bronchoscopy such as video-autofl uorescence and "in-vivo biopsy" techniques to guide local endobronchial therapies for in-situ cancers; image processing software to design custom stents for compromised airways; and drug-eluting stents to maintain airway integrity in a variety of malignant and benign airway diseases. pleuroscopy describes a minimally invasive procedure that provides the physician a window into the pleural space. it refers to a procedure that is performed in an endoscopy suite or operating room with the patient under conscious sedation and local anesthesia. increasingly these procedures are being performed by nonsurgeon pulmonologists to diagnose pleural pathology such as pleural effusions or pleural carcinomatosis; talc pleurodesis and chest tube placement under direct visual guidance. pleuroscopy was fi rst conceived in a report dated , which documented the fi rst endoscopic examination of the pleural space by richard cruise in a year old girl with empyema. it did not gain widespread application until when hans christian jacobaeus published his technique also known as the jacobaeus operation. in this procedure he created a pneumothorax by severing adhesions using galvanocautery that collapsed the underlying lung, and allowed safe entry as well as unobstructed examination of the pleural space. since then, pleuroscopy has been applied both as a diagnostic and therapeutic tool. for a hundred years, rigid endoscopic instruments such as stainless steel trocars and telescopes have been pivotal in the technique. smaller telescopes and instruments have been applied with excellent views of the pleural space and comparable diagnostic yield. a signifi cant advance is the creation of fl exrigid pleuroscope that is fashioned like the fl exible bronchoscope. the fl ex-rigid pleuroscope consists of a handle, and a shaft that measures mm in outer diameter, -cm proximal rigid portion and -cm fl exible distal end. the fl exible tip is movable by a lever on the handle, which allows -way angulation degrees up and degrees down. it has a . mm-working channel that accommodates biopsy forceps, needles and other accessories, and is compatible with various electrosurgical and laser procedures. the fl ex-rigid pleuroscope allows autoclaving. a notable advantage is its easy interface with existing processors and light sources made by the manufacturer for fl exible bronchoscopy or gi endoscopy at no additional costs. although certain endoscopic characteristics such as nodules, polypoid masses and "candle wax drops" are suggestive of malignancy, early stage mesothelioma can resemble pleural infl ammation. autofl uorescence and narrow band imaging have been incorporated to white light pleuroscopy to enhance diagnostic accuracy. both modes of imaging discriminate early malignant lesions from non-specifi c infl ammation, aid in selecting appropriate sites for biopsy and better delineate tumor margins for more precise staging, but are of little value at present in clinical practice since most patients with malignant pleural effusions have extensive pleural involvement that is easy to diagnose with white light pleuroscopy for pleuroscopic guided pleural biopsies, specimens obtained with the rigid forceps are larger than those with the fl ex-rigid pleuroscope since they are limited by size of the fl exible forceps, which in turn depends on the diameter of the working channel. the fl exible forceps also lacks mechanical strength in obtaining pleural specimens of suffi cient depth, which can be overcome by the use of insulated tip (it) diathermic knife. full thickness parietal pleural biopsies are obtained with it knife, and the electrocautery knife is particularly useful when smooth thickened lesions are encountered, of which nearly half are due to mesothelioma. to improve analgesia before talc poudrage, lidocaine can be administered to the parietal pleura via spray catheter inserted through the working channel of the pleuroscope. similarly talc poudrage can be administered under visualization using the spray catheter. with the introduction of the fl ex-rigid pleuroscope, similar in design and handling to the fl exible bronchoscope, and compatible with standard light source and video processor available in most bronchoscopy suites, pleuroscopy will enjoy an expanded interest as more practitioners acquire the skill. the fl exrigid pleuroscope is a signifi cant invention in the history of minimally invasive pleural procedures and will revolutionize the practice of pulmonary medicine by replacing conventional biopsy methods in future. the common known causes of interstitial lung disease (ild) are drug toxicities, environmental exposures and collagen vascular disease (cvd). among these causes, drug or environmental exposures can be excluded by medical history. however, cvd-related ild may often be confused with idiopathic interstitial pneumonia (iip) because the radiological and histological characteristics of cvd-related ild are often indistinguishable from those of their idiopathic counterparts and occasionally, systemic manifestations of the underlying cvd develop several months or years after the diagnosis of ild. early diagnosis of occult cvd is very important in patients presenting with ild, because there are signifi cant differences in prognosis between the iip and cvd-ild groups. patients with cvd-ild survive longer than those with iip. additionally, different treatment regimens and evaluation for additional systemic involvement or malignancy may be needed in patients with cvd-ild. although, cvd-ild and iip is often considered indistinguishable, there are some clues that can help clinicians detect occult cvd in patients presenting with ild. first, a thorough medical history and physical examination can detect occult cvd. its importance cannot be overemphasized. the cvds frequently associated with ild are scleroderma, rheumatoid arthritis (ra), polymyositis/dermatomyositis (pm/dm), sjögren's syndrome, mixed connective tissue disease (mctd), undifferentiated connective tissue disease (uctd) and systemic lupus erythematosus (sle). therefore, symptoms and signs that occur frequently in these cvds should be searched for. these symptoms and signs include raynaud's phenomenon, gastro-esophageal refl ux disease, telangiectasis, dry eyes, dry mouth, arthritis, the characteristic skin lesions of dm (heliotrope rash, gottron's papule, mechanic's hand) and various serositis etc. second, certain fi ndings on hrct can help in the diagnosis of cvd. although the parenchymal abnormalities are similar to their idiopathic counterparts, the presence of airway-related abnormalities -mosaic attenuation, bronchial wall thickening, and nodules -are more common in cvd-ild. the presence of extrapulmonary abnormalities may also provide important clues to the underlying diagnosis. patients with cvd more frequently have pleural and pericardial effusions, pericardial thickening, enlarged pulmonary artery and esophageal dilatation. hrct can also show joint abnormalities or soft tissue calcifi cations. third, there are some serologic tests that can help in the diagnosis of cvd even in patients with obscure symptoms. high titers of antinuclear antibody and rheumatoid factor are often found in patients with cvd. other more disease specifi c tests currently available are anti-ssa/ssb antibody for primary sjögren's syndrome, anti-scl- antibody for systemic sclerosis, anti-jo- antibody for pm/dm, anti-u ribonucleoprotein (rnp) antibody for mctd, antibody to cyclic citrullinated peptides (ccp) for rheumatoid arthritis and so on. fourth, the frequent pathologic patterns of ild associated with cvd are nsip, uip, op, lip and dad. among them, nsip is the most frequent pathologic pattern in cvd-ild. therefore, pathologic pattern consistent with nsip should raise suspicions about the possibility of cvd. other pathologic fi ndings that may be suggestive of an underlying cvd include follicular bronchiolitis and lymphoid follicles. however, it is still impossible to diagnosis all occult cvds at the outset of ild because the initial clinical presentations can be essentially indistinguishable from those of iip. therefore, close follow up for a developing cvd is very important especially in patients with nsip. the role of pathological diagnosis for non-neoplastic lung disease is important and critical. however, agreement of pathological diagnosis in iips may not be that high. despite the expectations after publication of ats/ers classifi cation of idiopathic interstitial pneumonias (iips), interobserver variability in the pathological diagnosis of iips is still problematic. there are several major reasons for the poor agreement in pathological diagnosis of iips in which the biggest reason is a lack of specifi c and diagnostic fi nding to any type of iips. in the session, i would fi rst share the virtual steps of making diagnosis on surgical lung biopsy with audience, indicate recent data of inter-observer agreement in iips cases, and then, introduce factors behind the poor agreements followed by several possible solutions to this important issue. children's interstitial lung disease (child) differs from adult interstitial lung disease in that certain classic idiopathic pneumonias described in adults are not seen in children and unique forms of interstitial lung disease are found in infants and young children but not in adults. the most common form of idiopathic interstitial pneumonia in adults is idiopathic pulmonary fi brosis (ipf), also known as cryptogenic fi brosing alveolitis (cfa), a progressive and fatal disorder, defi ned pathologically as usual interstitial pneumonia (uip). uip is characterized by a heterogeneous mixture of normal lung, mild infl ammation, and fi brosis and the presence of fi broblastic foci, felt to be the leading edge of fi brosis. previously, although many infants and children were given the diagnosis of ipf, cfa, or uip, they did not have the characteristic fi broblastic foci. thus although the uip pattern is occasionally seen in the context of another primary disorder, such as abca mutations, true ipf/uip does not exist in children. the tendency to use the term ipf in children merely serves to obscure the real diagnosis and creates anxiety in families whose affected children may not actually have a fatal disorder. unique conditions have been described mainly in infants and young children that do not occur in adults. these include growth abnormalities, inborn errors of surfactant metabolism, neuroendocrine cell hyperplasia of infancy (nehi), and pulmonary interstitial glycogenosis (pig). growth abnormalities occur as a consequence of an early insult to the lung that results in retarded or arrested lung development and alveolar simplifi cation. risk factors associated with growth abnormalities include prematurity, congenital heart disease, and chromosomal defects, most commonly down syndrome. the major advance in child has been the discovery of genetic mutations that lead to surfactant dysfunction. these include mutations in the sp-b, sp-c, abca , ttf- , and gm-csfra genes. clinical presentation can vary from severe respiratory failure at birth leading to death (sp-b, abca mutations) to more insidious onset with chronic lung disease (sp-c, abca , ttf- , gm-csfra mutations). nehi is a chronic benign form of child presenting in the fi rst year of life with tachypnea, crackles, hypoxemia, characteristic features of symmetric ground glass densities in the right middle lobe and lingula and central lung regions on hrct, and a mixed restrictive/obstructive pattern on infant lung function testing. lung biopsy shows increased numbers of neuroendocrine cells and neuroepithelial bodies in the distal airways with otherwise normal lung architecture. pig is another benign form of child seen in infants and characterized by interstitial widening with glycogen-rich interstitial cells. pig is seen as a primary disorder ("pure" pig) and as a patchy disorder seen in the background of some other primary disorder, such as a growth abnormality ("patchy" pig). in conclusion, it is important to recognize the differences between pediatric and adult interstitial lung disease so that the proper diagnosis and prognosis can be given and the appropriate treatment applied. journal compilation © asian pacifi c society of respirology not to treat acute bronchitis with initial antibiotics, with the following exceptions. those at high risk of serious complications because of preexisting co-morbidity, patients over years of age with acute cough and two or more of the following, or patients over years of age with one or more of the following; ( ) admission to hospital in the previous year ( ) type or type diabetes ( ) history of congestive heart failure ( ) current use of oral glucocorticoids. clinicians need to address patients' concerns, perspectives, and expectations about the treatment and explain to patients that antibiotics are not necessary for a self-limiting respiratory tract infection. physicians should tell patients that antibiotic use increases the risk of an antibiotic resistant infection. and physicians also need to spend time answering questions and offer a contingency plan if symptoms worsen, and advise patients to return for a consultation if symptoms are not starting to settle in accordance with the expected course of the illness or if symptoms worsen signifi cantly. some physicians are certain that patients will benefi t from antibiotics and prescribe for expectation of fast relief. they are mostly comfortable with their prescribing decisions by their clinical experiences. taiwan's study demonstrates substantial variations among physician groups in the practice of prescribing antibiotics for viral respiratory infections. older physicians and those practicing in clinics rather than medical centers were signifi cantly more likely to prescribe antibiotics, and dispensing doctors in contrast to those without dispensing privileges or on-site pharmacists were signifi cantly highly prescribing antibiotics. statistical data from nhic in korea showed that general physicians in clinics prescribe antibiotics in % of acute bronchitis patients, while doctors at tertiary hospitals showed less but still fairly high rate of %. efforts and interventions to reduce the potentially inappropriate prescription of antibiotics should target modifi able factors. quality improvement (qi) strategies like using active clinician education, delayed prescriptions and targeting management, may yield reductions in antibiotic use. anti-tussives are occasionally useful and can be offered for short-term symptomatic relief of coughing. a meta-analysis and systematic review found that beta- -agonists were not effective for the treatment of acute bronchitis or cough of < weeks duration in children or in adults unless airfl ow obstruction was present. summary acute bronchitis is one of most commonly diagnosed and treated diseases in daily clinical practice. however, since it is mostly a self limiting disease, the standardization of diagnosis and treatment has long been neglected leaving various controversies in the management, particularly the use of antibiotics. the inappropriate prescription of antibiotics for acute bronchitis will surely lead to the emergence of resistant organisms in the community let alone the increase of socio-economic burden. further attention and research is needed for the reasonable approach to the treatment of acute bronchitis in order to prevent overuse of antibiotics and improve health-economy. prevalence acute bronchitis is one of the most common conditions encountered in clinical practice, accounted for approximately million visits to korean physicians in , and consistently ranks among the top reasons for ambulatory visits in the united states. defi nition acute bronchitis refers to a clinical syndrome distinguished by a relatively brief, self-limited infl ammatory process of large and midsized airways that is manifested predominantly by cough with or without phlegm production which lasts for up to weeks and absence of fi ndings suggestive of pneumonia. acute bronchitis should be distinguished from acute exacerbations of chronic bronchitis and acute infl ammation of the small airways -asthma or bronchiolitis. those with underlying lung disease, congestive heart failure, or a compromised immune system are considered to be at high risk for complications of acute bronchitis. etiology acute bronchitis is one of the most common causes of antibiotic abuse. in healthy communities, there is little evidence of bacterial infection in people with bronchitis, but there are few practical studies to distinguish between bacterial and viral bronchitis. within this context, the use of antibiotics to treat acute bronchitis is controversial but common in real practice. viruses are usually considered the most common cause of acute bronchitis but have been isolated in a minority of patients. those isolated in acute bronchitis include, in order of frequency of occurrence, are infl uenza, parainfl uenza, respiratory syncitial virus (rsv), coronavirus, adenovirus, and rhinovirus. the yield of specifi c pathogens varies according to several factors, including the presence or absence of an epidemic, the season of the year, and the infl uenza vaccination status of the population. bacterial pathogens are thought to play a very minimal role in acute bronchitis. the bacteria that have been causally linked to acute bronchitis in otherwise healthy individuals include only mycoplasma pneumoniae, chlamydophila pneumoniae and bordetella pertussis. antibiotic treatment of patients with pertussis is indicated to limit transmission, but there are no compelling data to support the prospect that cough will be less severe or less prolonged with antibiotic therapy. clinical manifestations acute bronchitis cannot be distinguished from upper respiratory infections in the fi rst few days. acute bronchitis is suggested by the persistence of cough for more than fi ve days, and most often lasts from to days. approximately % of patients with acute bronchitis report the production of purulent sputum. it usually represents sloughing of cells from the tracheobronchial epithelium, along with infl ammatory cells, and does not signify bacterial infection. pulmonary function test fi ndings consistent with bronchial hyperresponsiveness are common. fev less than % at the initial visit was present in % of adults from the mid western united states with no history of underlying lung disease. pft abnormalities are usually transient, typically resolving after to weeks, although they may last as long as months. fever is a relatively unusual sign in acute bronchitis and, when accompanying cough, suggests either infl uenza or pneumonia. diagnosis acute bronchitis is established in a patient who has the sudden onset of cough, with or without sputum expectoration, and without evidence of pneumonia, the common cold, acute asthma, or an acute exacerbation of chronic bronchitis. the absence of the following fi ndings reduces the likelihood of pneumonia suffi ciently to eliminate the need for a chest radiograph: ( ) heart rate > beats/min; ( ) respiratory rate > breaths/min; ( ) oral body temperature of > °c; and ( ) chest examination fi ndings of focal consolidation, egophony, or fremitus. chest radiography should be reserved for use in patients with any of these fi ndings or cough lasting > weeks. an exception, however, is a cough in elderly patients; pneumonia in elderly patients is often characterized by an absence of distinctive signs and symptoms. rapid diagnostic tests exist for several pathogens currently linked to acute bronchitis. patients with severe paroxysmal cough, with or without post-tussive vomiting should be evaluated for pertussis regardless of the immunization history. rapid tests should be used primarily when the suspected organism is treatable, the infection is known to be circulating in the community, and the patient has suggestive symptoms or signs. treatment statistical data from korea national health insurance corporation (nhic) shows that approximately - % of patients with acute bronchitis receive antibiotics despite the evidence that, with few exceptions, they are ineffective. meta-analyses of randomized, controlled trials all concluded that routine antibiotic treatment is not justifi ed. the decision not to use an antibiotic should be addressed individually and explanations should be offered because many patients expect to receive an antibiotic based on previous experiences and public expectations. main challenges for appropriate antibiotic use in acute bronchitis are the diagnosis is based on clinical fi ndings, without standardized diagnostic methods and sensitive or specifi c confi rmatory laboratory tests. how to identify accurately the few patients who are seriously ill or whose symptoms could be meaningfully ameliorated by prompt antibiotic treatment is not standardized. recent studies have suggested that the annual decline in fev is greater in gold stage ii than in later stages of the disease. ( ) if the decline in pulmonary function predominantly occurs early in the course of the disease, then it is logical that diagnosis and intervention aimed at reducing the progression of the disease should mainly occur in the early stages of the disease. severity of copd at diagnosis differs enormously on where it is done: population based studies, screening or hospital patients. epidemiologic studies: prevalence, underdiagnosis and severity there are increasingly more data on the prevalence and distribution of copd from around the world. the prevalence of chronic obstructive pulmonary disease (copd) varies from country to country, mainly due to the effects of cumulative exposure to smoking and the increased life span of the population. ( ) ( ) ( ) ( ) systematic review of epidemiological studies concluded that the prevalence of copd, in adults aged years and more, worldwide ranges around - %. ( ) these differences may be related, at least in part, to differences in genetic background, smoking habits and exposure to other environmental risk factors, and are accompanied by differences in diagnostic rates and in management of the disease around the world. there is a large underdiagnosis of copd with about only one out of three or four of all subjects fulfi lling diagnostic criteria of copd identifi ed by the health care system. ( ) ( ) ( ) copd in general population is diagnosed at earlier stages. data from latinamerica (platino), similar from those from spain, showed severity was distributed as follows: stage i, % and stage ii, . %. screening for copd screening, combined with smoking cessation advice, help motivated smokers to attempt quitting smoking. ( ) in general practice, when individuals were preselected on the basis of smoking age and respiratory symptoms chronic cough was a better predictor of airfl ow obstruction than other symptoms, such as wheeze and dyspnoea. age was also a good predictor of obstruction; smokers over with cough had a % chance of having an obstruction. ( ) diagnosis at the hospital the decrease in lung function is gradual. the disease is usually diagnosed late because patients may adapt to the condition or doctors may not notice the symptoms. by then, the patient is diagnosed at the hospital, when lung function is often poor, sometimes less than % of normal. the relationship between lung disease and increased body weight can take two forms: the effects of increased body weight on the normal respiratory system and the association of increased body weight with diseases of the respiratory system. obesity (body mass index, bmi, greater than kg/m ) can reduce normal static lung volumes (principally functional residual capacity, but also total lung capacity and residual volume at very high bmi), ventilation (particularly during sleep and exercise) and gas exchange (increased gas transfer). the epidemic of overweight and obesity has been associated with the increased prevalence of asthma through proposed mechanisms such as dietary effects, reduced lung volumes and lung recoil affecting airway responses to breathing, a general infl ammatory effect and through associated sedentary lifestyle. however more recent epidemiological data suggests the association between asthma and obesity is not as close as once thought. overweight and obesity clearly are associated with the high prevalence of obstructive sleep apnoea with increased body weight increasing the likelihood of upper airway collapse on a background of reduced upper airway dimensions and snoring and reducing minute ventilation in patients with obstructive sleep apnoea, predisposing to hypoventilation and chronic hypercapnoeic respiratory failure. the increased load to breathing also affects breathing, especially during sleep, in patients with respiratory muscle weakness or abnormal chest wall mechanics due to kyphoscoliosis or previous chest wall surgery such as thoracoplasty. increased body weight will also exacerbate the effects on symptoms of existing chronic respiratory diseases including asthma, chronic obstructive pulmonary disease and interstitial lung diseases. avoidance of weight gain and continued efforts at weight loss remain an important goal in patients with respiratory disease. this presentation will be a review of recent fi ndings and implications from imaging studies in asthma. the use of -dimensional imaging in asthma has provided useful insights into the understanding of pathophysiology of disease, which may have implications on how asthma is treated. small airways disease plays a major role in asthma and has traditionally been diffi cult to probe. however, the combined use of new imaging methods combined with complex lung function has provided useful insights into pathophysiology. findings and implications from hrct, pet, spect and mri will be discussed. the assessment of pulmonary function has changed very little over the past to years. all techniques performed in the laboratory still view the lung as a very simple single compartment unit. measures of volume and fl ow only assess disease in the medium to large airways whilst the small airways receive relatively little attention. however there are a number of emerging techniques on the horizon that have the potential to give great insight in to the periphery of the lung where most respiratory disease emanates. the measurement of mechanics using the forced oscillation technique and gas mixing using the multiple breath nitrogen washout test are now emerging as very powerful tools for assessment of peripheral lung function. in this presentation we will be discussing the state of the art in terms of assessing pulmonary function and what may we expect to see in the future. copd is a major public health problem in asia. copd prevalence was . % ( . % in males and . % in females) in china (> yrs), . % in japan (> yrs). in most of the developing countries in asia, copd is always underdiagnosed by physicians owning to lack of routine spirometry test and only based on symptomatic diagnosis. smoking is the most important risk factor contributing to development of copd. however, copd prevalence was . % in chinese non-smokers (> yrs) and . % in korea (> yrs), similar to those in mexico city ( . %) and caracas ( . %). in china, non-smokers accounted for . % of copd patients compared with . % in usa and . % in the uk. exposure to environmental tobacco smoke (passive smoking) and indoor air pollution (particularly the coal and biomass combination) may contribute to the higher prevalence of copd in developing countries. to reduce the risk factors (smoking, coal or biomass fuel for cooking, indoor and outdoor air pollution) are the priority for reducing the prevalence in the asian developing countries. government in some countries had made some effect in tobacco control and reducing air pollution. unlike hypertension or diabetes, the management of copd is only based on symptomatic treatment, owing to lack of specifi c biomarkers. annual lung function test with spirometer is the only parameter in detecting early stage of copd. data showed that more reversibility of fev was demonstrated in stages i-ii copd patients with ics/laba or tiotropine administration, as compared with those in stages iii-iv. an intervention study at the community level has shown that early intervention (improvement of indoor ventilation, bronchodilators) was able to reverse rapid annual fev, decline in copd patients. more affordable medication should be developed in the low income countries. data showed that oral administration of carbocysteine (thio compounds) reduced exacerbation rate by . %, which was consistent with inhaled administration of fluticasone/formoterol (seretide) or tiotropine. in addition, orally administered low dose teophylline ( mg, bid) improved pre-bronchodilator fev, and reduced exacerbation rate. there was a synergistic effi cacy in fev , with the combination of teophylline and inhaled corticosteroids. chronic obstructive pulmonary disease (copd) is characterized by the presence of airfl ow limitation due to loss of lung elasticity and/or airway narrowing. the pathological hallmark of loss of lung elasticity is emphysema and airway wall remodeling contributes to the airway narrowing. using computed tomography (ct) these lesions can be assessed by measuring low attenuation areas (laa) and airway wall thickness/luminal area, respectively. recently, copd has been widely recognized as a systemic infl ammatory disease, and body weight loss is one of its clinical features. traditionally, the patients who had copd with predominant emphysema and a low body mass index (bmi) were called "pink-puffers". however, the relationship between body weight loss and emphysema had not been assessed. based on these back ground, we have evaluated the body composition, emphysema and airway dimensions in copd patients using ct images. bmi was signifi cantly lower in the emphysema dominant phenotype compared to the airway dominant phenotype. furthermore, bmi correlated with laa% (ρ = − . , p < . ) but not with wa%. chest subcutaneous fat mass was also correlated with laa% (ρ = − . , p < . ). these data indicated that the "pink-puffer hypothesis" is correct in some aspects. next, we postulated that reduced leptin and leptin receptor signaling could contribute the development of emphysema. serum leptin was correlated with bmi which was correlated with dl co /v a . the expression of leptin and leptin receptor was evaluated pcr in human lung tissues. both genes were detected in the lung tissues, but the expression of leptin gene was low. the leptin receptor gene expression was signifi cantly lower in copd patients and it was signifi cantly correlated with dl co /v a . the leptin receptor gene expression in the lung did not correlated with body weight. these data suggested that the patients' physique can be associated with the relative contribution of emphysematous lesions in copd and leptin and leptin receptor system might affect the mechanism of developing emphysema. nutritional support has been one of possible clinical approaches as a copd therapy these days. however, its effect is still controversial. to clarify the relationship between low bmi and emphysema and to classify the phenotypes of copd based on the patients' physique may help to fi ne the defi nite targets for nutritional support even in the early stage of copd. journal compilation © asian pacifi c society of respirology sy - at present copd is often only treated in gold stage iii or iv . it is without question possible to diagnose copd earlier. if spirometry would be more readily performed in general practice, copd could be diagnosed in gold stage i and ii, as is evident from the practice of "spirometry days" organized by the belgian thoracic society in which the majority of the patients were diagnosed in gold stage ii . whether gold stage i and ii truly represent the "early" stages of the disease may be debated , but this defi nition of early copd could certainly be used as an operational defi nition. it is clear now that spirometry is required for early diagnosis of copd . although at present there is no irrefutable evidence that early treatment of copd is warranted, there is accumulating suggestive evidence that early treatment of copd may result in better outcomes. this evidence is primarily related to secondary analyses of the torch and uplift , studies. first, it was demonstrated in a secondary analysis of the torch study, that inhaled corticosteroids, long-acting betaagonists and their fi xed combination reduced the rate of decline of fev by , and ml, respectively . if treatment indeed reduces the progression of the disease, then an easy case for early treatment is made. in addition, a subgroup analysis demonstrated that except for the effect on the sgrq (st. george's respiratory questionnaire) all other treatment effects were numerically larger in gold stage ii than in gold stage iii and iv . a subgroup analysis of the uplift study demonstrated numerically greater treatment effects in gold stage ii as well. in addition, tiotropium reduced the rate of decline of fev in these patients (albeit only by ml/year), which was not the case in the later gold stages . finally, in patients not taking any medication at the onset of the study (maintenance naïve patients) tiotropium substantially reduced the rate of decline of fev and the rate of deterioration of the sgrqscore . taken together these data demonstrated that: ) large treatment effects were obtained in early disease; ) indications of disease modifi cation were present in early disease. hence, they support early treatment of copd. pulmonary rehabilitation is now the standard of care for patients with chronic obstructive pulmonary disease (copd) who remain symptomatic despite bronchodilator therapies. combining the best of interprofessional, personalized and evidence-informed care, pulmonary rehabilitation allows clinicians and their patients to realize signifi cant benefi ts in a variety of important patientcentered copd outcomes. the fundamental elements required for an effective pulmonary rehabilitation program will be discussed, and the scientifi c evidence supporting their effectiveness will be summarized. issues relating to optimal site of delivery, components of effective rehabilitation programming, duration of rehabilitation, timing of rehabilitation and target populations will be reviewed. recent developments in this rapidly expanding area will also be highlighted. lastly, methods to establish or enhance an existing pulmonary rehabilitation program will be discussed, with the goal of fully realizing the many substantive benefi ts of pulmonary rehabilitation in copd. however, only very low gene transfer seen after a second dose with either day and day spacing. we attribute this to rapid upregulation of neutralizing antibodies against adenovirus. anti-tumor humoral immune responses were seen almost all patients with reactions seen against known meso tumor antigens (sv large t antigen and mesothelin) and against unknown proteins in cell lysates. given the caveats of phase trials (small numbers, different doses, heavily pretreated patients), we still saw clinical responses (defi ned as prolonged stable disease, prolonged survival, partial or complete responses by modifi ed resist criteria, decreased metabolic tumor activity by pet scanning, or "mixed" responses) in about / of the patients. we are currently administering two doses spaced only three days apart. this appears to be well tolerated. based on strong preclinical data supporting the combination of gene therapy and chemotherapy, we have started a trial using ad.inf instillation into the fi rst treatment cycle of fi rst line (cisplatin/pemetrexed) or second line chemotherapy (gemcitabine). our groups is also generating "designer chimeric t cells" in which a single chain antibody fragment is linked to the transmembrane and cytoplasmic regions of the t-cell receptor. this artifi cial t-cell receptor is then transduced into t-cells that are then reinfused. the t-cells are then activated by cells expressing mesothelin. preclinical data show striking activity against mesothelin-expressing tumors in mice. mesotheliomas make large amounts of the immunoinhibitory cytokine, transforming growth factor-beta (tgf-β). preclinical studies using tgf-β blockers have shown activity in mouse models of mesothelioma and a clinical trial using an anti-tgf-β antibody is now underway at the university of pennsylvania. in summary, gene-based and immunotherapies are being actively studied in mesothelioma and have shown some promising results. future trials are focusing on combining these approaches with chemotherapy and surgery. given the relatively mild and non-overlapping toxicities, we believe these, or other gene therapy and/or immunologic approaches will soon become part of the standard therapeutic armamentarium. the burden of asbestos-related diseases (ards), in particular mesothelioma, has been shouldered mostly by the developed countries of the west. this is a consequence of the heavy dependence on asbestos use up to around the s by those countries. in contrast, the majority of asian countries started to depend on asbestos since then and has not yet reached the suffi cient latency time for the related diseases to manifest. japan is an exception, because it heavily used asbestos during the period to catch-up with the west. japan has now become one of the global epicenters of ards. it is a tragic consequence of experiencing the burden of ards that many developed countries decided to move towards banning asbestos or a de facto non-dependence. in the asia-pacifi c, this group comprises australia, new zealand, japan, korea and singapore (the "forerunner" group in terms of ards). in contrast, the many other countries in asia still use asbestos at substantial levels, turning asia into the world's center of asbestos consumption today. however, as these countries start to use up the latency time, and manage to improve medical recognition, reporting and recording, ards will soon emerge as a major public health issue in the region. early indications of this forecast do exist. not only should lessons be learnt from the experiences incurred by the "forerunner" group of countries, but more importantly, they should crystallize in international collaboration involving national administrators, academia, ngos and international organizations, for the effective recognition and countermeasures of ards. i will also refer to the progress made and hurdles encountered by the asian asbestos initiative and the who global plan of action on the elimination of asbestos-related diseases. at the international level, ards present a domino-effect that needs to be coped with. sy - interstitial pneumonia (ip) can be classifi ed into two groups in terms of known causes. pneumoconiosis, drug-induced pneumonitis, radiation-induced pneumonitis, and hypersensitivity pneunonitis (hp) are categorized as ip with known causes. on the other hand, idiopathic interstitial pneumonias (iips), which include idiopathic pulmonary fi brosis (ipf), nonspecifi c interstitial pneumonia (nsip), cryptogenic organizing pneumonia (cop), and desquamative interstitial pneumonia (dip), have no known causes. most physicians tend to diagnose of ip patients as iips without intensive examinations. however, some environmental and occupational lung diseases, especially asbestosis and chronic hp, should carefully be differentiated from iips. asbestosis is one type of pneumoconiosis, which is induced by asbestos exposure with a latent period of usually more than years. bilateral fi ne crackles can be frequently auscultated and pulmonary function test shows restrictive and diffusing impairments. chest hrct shows subpleural dot, subpleural curvilinear shadow, ground glass opacity, interlobular septal thickening, traction bronchiectasis, and honeycombing. in our case series of asbestosis (n = ) in yokosuka, a town of shipyard for more than years, honeycombing was seen in cases ( %). chronic hp is an allergic disease induced by long-term exposure to antigens. major causative antigens are avian dropping and feather, mold, and bacteria. chest hrct tends to show traction bronchiectasis and honeycombing in advanced stages, which are similar to ipf. in surgical lung biopsy, most cases are classifi ed as nsip-like and uip-like patterns. to clarify the importance of unrecognized exposure to avian antigen, we precisely reviewed patients with bird-related chronic hp. in the patients, patients were bird-breeders with direct exposure to avian antigen by contacting their own birds, whereas patients seemed to be exposed to wild birds, neighbor's birds, feather duvets, stuffed bird, and fertilizer with chicken droppings without recognition of avian contact. number of patients is very limited both in asbestosis and chronic hp, which suggests that there is a small group of subjects who are susceptible to develop pulmonary fi brosis after exposure to asbestos or antigens. however, genetic background of susceptibility to pulmonary fi brosis has not elucidated. in our case series of chronic hp (n = ), cases ( %) had the fi rst-degree family members with ip, who might have common environmental and/or genetic factors. further studies are needed to determine host susceptibility to pulmonary fi brosis, which might contribute to clarify the pathogenesis of ip. long acting beta- agonists has been in the doctors' armory of asthma medications for about years (available in in uk and in usa). there is little doubt that laba when combined with inhaled corticosteroids can improve asthma symptoms for a subsection of people with asthma, and is generally superior to add-on leukotriene receptor antagonist. indeed addition of laba to inhaled corticosteroids is in all major asthma guidelines as a step-up therapy. however, after the salmeterol multicentre asthma research trial was prematurely halted, a focus on effi cacy and safety of the wide use of laba severe pulmonary arterial hypertension (pah) is a fatal condition associated with complex pathobiology. vasoconstriction, thrombosis, and remodeling of the pulmonary vessel wall contribute to increased pulmonary vascular resistance in pah. the pathology of pulmonary hypertension can be classifi ed into endothelial, smooth muscle, and/or adventitial lesions, although not all compartments of the pulmonary artery wall are involved in each case of severe pah. the classic lesion of severe pah is the plexiform lesion, an abnormal proliferation of predominantly endothelial cells. smooth muscle thickening can be seen in all forms of the disease but is not a constant feature in the idiopathic pulmonary arterial hypertension. the adventitia is often markedly remodeled in patients with certain forms of collagen vascular diseases associated with severe pah, most notably scleroderma. the obligatory lining of pulmonary arteries with a monolayer of endothelial cells is disrupted in severe pah. the three-dimensional vascular pattern is rather suggestive of an intravascular tumor-like proliferation (tumorlet), instead of a retracted scar if this lesion would represent an abnormal healing to an injury to the vascular wall. the evidence of a tumorlike endothelial cell proliferation was provided by the demonstration that plexiform lesions in patients with idiopathic pah were preferentially monoclonal, whereas similar lesions in lung of patients with secondary pah due to congenital heart malformations were polyclonal. monoclonality was also observed in plexiform lesions of patients from anorexigen-induded pah. vasoconstriction has been related to abnormal potassium channels and to endothelial dysfunction. endothelial dysfunction leads to impaired production of vasodilators such as nitric oxide and prostacyclin along with overexpression of vasoconstrictors such as endothelin (et)- . many of these abnormalities not only elevate vascular tone and promote vascular remodeling but also represent logical pharmacological targets. recent genetic and pathophysiologic studies have emphasized the relevance of several mediators in this condition, including nitric oxide, prostacyclin, et- , serotonin, angiopoietin- , and members of the transforming-growth-factor-beta superfamily. disordered proteolysis of the extracellular matrix is also evident in pah. the unraveling of the pathobiology of severe pah may lead us to novel therapies and approaches to better treat the disease. unfractionated heparin (ufh) and low-molecular-weight-heparin (lmwh), acted by enhancing the ability of antithrombin (at) to inhibit coagulation proteases, have been used as initial anticoagulant therapy for vte. they are delivered intravenously or by subcutaneous injection. subcutaneous fondaparinux, a synthetic pentasaccharide with specifi c anti-factor xa activity, is also recommended as the initial treatment for vte according to recent guideline. oral vitamin k antagonists, acting by reducing the activity of several coagulation proteases, are used for long-term anticoagulation. the major disadvantage of vitamin k antagonists is the need for frequent coagulation monitoring to maintain a therapeutic level. new anticoagulants, including oral direct thrombin inhibitors, such as dabigatran, and oral anti-factor xa inhibitors, such as rivaroxaban and apixaban, are emerging in recent clinical trials. these new drugs may replace heparins and vitamin k antagonists, which are expected to have a huge impact on the treatment of vte in the near future. thrombolytic therapy should immediately be used in patients with massive (high risk) pte. the effect of thrombolysis in patients with submissive (intermediate risk) pte remains controversial. further stratifi cation of these patients is necessary. patients with multiple poor prognostic indicators such as right heart dysfunction, thrombolytic therapy should be considered. several countries have started to support activities raising public awareness of vte, with the goal to decrease mortality and morbidity. in us, national institutes of health (nih) and centres for disease control (cdc) have fostered thrombosis activities to improve the prevention of vte and its long-term complications. in the united kingdom, a thrombosis group has been formed to promote awareness among parliamentarians about the risk and management of vte; to increase knowledge of its causes, effects, and treatments; and to monitor the implementation of government initiatives and other researches being and this program has corrected the wrong perception that pte is a rare disease in china pulmonary hypertension (ph) is a common complication of chronic respiratory diseases, such as chronic obstructive pulmonary disease (copd) or interstitial lung diseases (ild). ph associated with respiratory diseases is classifi ed as diagnostic group iii according to the current clinical classifi cation of dana point . it is suggested that the pulmonary vascular abnormalities originate at an early stage of the diseases. the functional (hypoxic vasoconstriction) and morphological factors (vascular remodeling, destruction of the pulmonary parenchyma) explain the elevation of pulmonary vascular resistance that leads to ph. the ph is mild to moderate in copd with mean pulmonary artery pressure (mpap) usually ranging between and mmhg, however, worsening during exercise and exacerbations. a small proportion of copd patients may exhibit severe ph defi ned by a resting mpap > to mmhg, whose prognosis is particularly poor. ph is relatively frequent in advanced ild, particularly in idiopathic pulmonary fi brosis, which predicts a poor prognosis. the diagnosis of ph is suggested by doppler echocardiography, but the confi rmation still requires right heart catheterization. the potential treatments of ph associated with respiratory diseases are as follows: ) treat underlying lung disease; ) provide supplemental oxygen therapy when appropriate; ) rehabilitation; ) treat right heart failure; ) consider vasomodulator therapy; and ) consider lung transplantation when indicated. journal compilation © asian pacifi c society of respirology sy - tobacco use is the most common preventable cause of death. about half of the people who don't quit smoking will die of smoking-related problems. the epidemic varies among countries and is increasingly affecting developing countries, where most of the world's smokers ( %) live. close to half of all men in low income countries smoke daily and this has been increasing. legislation the framework convention on tobacco control (fctc) was adopted by who member countries in may to commit all countries to protect nonsmokers from tobacco smoke in public places, to eliminate all tobacco advertising, promotion and sponsorship, to require warning labels of cigarette packs and to prohibit misleading tobacco product descriptors such as "light" and "mild". even though many countries have passed legislation mandating smoke-free environments and the total global population covered by comprehensive smoke-free laws increased from . % to . % in one year, the overwhelming majority of countries still have no smoke-free laws, very limited laws, or ineffective enforcement. compliance with smoke-free laws is low. treatment to aid smoking cessation support for smoking cessation or "treatment of tobacco dependence" refers to a range of techniques including motivation, advice and guidance, counselling and appropriate pharmaceutical aids, all of which aim to encourage and help tobacco users to stop using tobacco and to avoid subsequent relapse. the success of these interventions depends on their synergistic use in the context of a comprehensive country tobacco-control strategy. in many countries, provision for treatment, training of health-care providers, education and information on the wide use of cessation is scarce. therapies, as well as fi nancial resources are limited and rarely incorporated into standard health care. also, smoking cessation is not seen as a public health priority and is not necessarily approached as a key tobacco-control strategy. smoking cessation services are most effective when they are part of a coordinated tobacco control programme. brief cessation counselling is relatively inexpensive when integrated into existing primary health-care services, is usually well received by patients, and is most effective when it includes clear, strong and personalized advice to quit. communication technologies -such as telephone quitlines, text messaging, interactive telephony, and online counselling -as well as psychological and behavioural modifi cation therapies, offer important support. cessation prescription medicines, available in many countries like nicotine replacement therapies, bupropion and varenicline can double the likelihood that someone will successfully quit. bronchiectasis is an old disease that we all treat, but surprisingly little about this disease has been well studied. the defi nition, diagnosis, natural history, pathogenesis and treatment are all uncertain. this talk examines these points in the light of new information about biofi lms and "normal" bacteria. it asks more questions than it answers, but the questions raise thoughts on whether our usual approaches are the best. the mediastinum is generally split into three compartments strictly for the purpose of classifi cation of the most likely abnormality in the individual compartment. there are no anatomical boundaries or fascial planes that divide one compartment from the other. classically, the compartments have been classifi ed as anterior, middle, and posterior. a recent change in classifi cation has used the categories of anterior, middle-posterior, and paravertebral compartments. approximately % of mediastinal tumors are located in the anterior compartment, % in the middle compartment, and % in the posterior compartment. asymptomatic masses are more likely to be benign than malignant, and symptomatic masses are more likely to be malignant than benign; however, there is a large variation the most common tumors in the anterior mediastinum consist of thymoma, lymphoma, germ cell tumors, and thyroid tumors. thymoma is by far the most common anterior mediastinal tumor and approximately / are encapsulated and non-invasive while / are invasive. the most common paraneoplastic syndromes associated with thymoma include myasthenia gravis, hypogammaglobulinemia, and pure red blood cell aplasia. benign teratomas occur in both male and females, while malignant germ cell tumors of the mediastinum are almost exclusively in males. lymphoma can occur most commonly in the anterior or middle mediastinum and may be associated with systemic symptoms and occasionally superior vena cava syndrome. the most common abnormalities in the middle mediastinum include lymphoma, granulomatous disease, and developmental cysts. bronchogenic cysts are almost always benign, although they can cause symptoms such as obstructive pneumonia and are generally treated with surgical resection. recent mediastinal compartment classifi cation has switched from posterior mediastinum to naming this the paravertebral compartment. it is located posterior to an imaginary line drawn to connect the anterior aspects of the vertebral bodies on the lateral chest radiograph. the most common tumors in this location are neurogenic tumors, meningoceles, or thoracic spine lesions. the most common neurogenic tumors in adults are neurilemomas, and they are almost always benign. neurofi bromas also occur in this compartment. they are frequently benign, but may be malignant, especially in patients with neurofi bromatosis. in these individuals, malignant tumors of the nerve sheath origin are more common. ganglioneuroma, ganglioneuroblastoma, and neuroblastoma are more common neurogenic tumors in children or adolescents.. cough is an important lung defense. in a refl ex manner, noxious agents are expelled from the airways as these are sensed by the receptors in the airway epithelium. in addition to appreciating its cleansing function, understanding cough refl ex is important in the diagnosis and treatment of common clinical conditions. most diseases associated with cough are transient. a problem arises when cough persists and becomes chronic. an in-depth search for the underlying pathology is warranted since treatment directed to the cause of the cough is curative in over % of cases. an anatomic-diagnostic protocol ensures a systematic search for cough etiology but unfortunately, this approach can be lengthy and in many settings, impractical. thus an empiric syndromic approach is now recommended. this paradigm shift is borne by the following premises: ( ) the current awareness of the relative frequency of the disorders (alone or in combination) that can cause cough; ( ) the sensitivity and specifi city of many (but not all) diagnostic tests in predicting the cause of cough has been established; ( ) a sequential evaluation and treatment for the common causes of cough using a combination of selected diagnostic tests and empiric therapy has been proven effective; and ( ) a sequential and additive therapy is often crucial because more than one cause of cough is frequently present. a recent study by dr. aileen wang on "the management of chronic cough in a tertiary center: an asian perspective" showed that even in a filipino immunocompetent population, the most common causes of chronic cough is asthma, post-nasal drip syndrome (pnds) and gastroesophageal refl ux disease (gerd). the study concluded that: ( ) the accp recommendations are generally applicable to an asian setting. research of viruses, their structure, pathogenicity and host-interactions has burgeoned. we now understand how viruses infect cells, how they replicate, how they interfere with host defences and how they interact with other tissue events and pathologies. rhinovirus infection causing the common cold is the most frequent and 'common' infection in humans. it is also implicated in most exacerbations of asthma and copd. the patho-biology of rhinovirus will be used to illustrate virus pathogenicity, virus-host-interactions and to highlight potential future therapeutic options. sy - much hope has been placed in the discovery of biomarkers to help understand the mechanisms of diseases such as copd, help stratify the disease better and guide treatment. it is also hoped that some of these could speed up drug discovery by serving as surrogate markers that respond to novel drugs within a shorter timescale than is the case with current drug trials in which the main outcome is the spirometric measurement of forced expiratory volume in one second (fev ). although studies in patients with copd have identifi ed several biomarkers, most of these need to be validated and their prognostic value is unclear. many of the markers have been identifi ed in blood and although it is recognised that there are non-pulmonary consequences of copd, some of which can be viewed as systemic biomarkers measured and/or generated in the lungs are likely to be most informative. there are several methods to identify and quantify biomarkers of copd and different biological samples (blood, bal, sputum and lung tissue) can be used to provide material for such analyses. whilst most studies to date used commercial immunoassays (elisa), there has been a keen interest in applying unbiased approaches such as proteomics. we have recently completed a large programme of work which applied -dimenshional electrophoresis and mass spectrometric analysis to identify biomarkers of copd. induced sputum was obtained from copd patients with a spectrum of disease severity and control subjects. two-dimensional gel electrophoresis and mass spectrometric identifi cation of differentially expressed proteins was fi rst applied to induced sputum from gold stage copd patients and healthy smoker control subjects. initial results thus obtained were validated by a combination of immunoassays (western blotting and elisa) applied to a large subject cohort. the biomarkers were localised to bronchial mucosa by immunohistochemistry. of individual protein spots identifi ed, were quantitatively and qualitatively different between the two groups. protein spots were subjected to tandem mass spectrometry, which identifi ed separate protein species. seven of these were further quantifi ed in induced sputum from individuals. using this sequential approach, two of these potential biomarkers (apolipoprotein a and lipocalin- ) were found to be signifi cantly reduced in copd patients when compared to healthy smokers. their levels correlated with fev /fvc, indicating their relationship to disease severity. in summary, a potential role for apolipoprotein a and lipocalin- in innate defence has been postulated previously; our discovery of their reduction in copd indicates a defi cient innate defence system in airways disease that could explain increased susceptibility to infectious exacerbations. persistent chronic infl ammation, repetitive tissue injury, and dysregulated epithelial repair leading to tissue remodeling and fi brosis are the hallmarks of chronic lung diseases, such as chronic obstructive pulmonary disease (copd), chronic asthma, pneumoconiosis, pulmonary fi brosis and sarcoidosis. the innate immunity system with its pattern recognition receptors are recently identifi ed to involve in the pathogenesis of these chronic lung diseases. the neutrophilic infi ltration of the airway mediated through t h and il- family may play an important role in steroid-resistant asthma and status asthmaticus. in addition, the epigenetic modifi cation of gene expressions and cellular senescence may modulate the progression of chronic asthma and copd. histone deacetylase (hdac ), which can be inactivated by oxidative stress or pi k-akt pathway, may regulate corticosteroid-related anti-infl ammatory response. manipulation of hdac activity is a new treatment direction in steroid-resistant asthma and copd. sirt , a nad + -dependent deacetylase, is an important signaling pathway related to cell survival, dna repair, and apoptosis. the sirt is decreased in alveolar macrophages of smokers and copd patients, and associated with pro-infl ammatory response through the activation of nf-κb. understanding the complexity of infl ammatory and epigenetic regulations in chronic lung diseases may potentiate the development of novel therapies. fibrosis is a common fi nding in chronic lung diseases, with tgf-β-related pathways play important roles. myofi broblasts are the principal effective cells in the fi brogenic process. they can be evolved from the activation of resident pulmonary fi broblasts, marrow-derived fi brocytes, or the trans-differentiation of pulmonary epithelial cells through epithelial mesenchymal transition (emt). further understandings on the emt process in lung tissue repair may help to elucidate the mechanism of lung remodeling and fi brosis. in addition, lung stem/progenitor cell study appears to be a new and potential fi eld in lung injury and repair. it is anticipated that more clear mechanisms behind lung remodeling and fi brosis can be identifi ed and new treatment modalities be developed accordingly. sy - cancers are genetic diseases with constitutional genomic variations that are present in normal cells contributing to an individual's risk of developing cancer such as lung cancer. furthermore, cancer cells acquire genetic mutations and genome wide changes in their dna as well as their epigenome compared to their normal cellular counterparts. some of these mutations have turned out to be important driver mutations and are associated with exquisite sensitivity to targetted cancer therapies. some of these genetic changes include egfr and eml -alk fusion gene mutations. epigenetic changes include methylation abnormalities as well as histone modifi cations, and possess the characteristic of potential reversibility which is attractive for the development of new therapies. the human genome project and rapid technological advances including deep dna sequencing have contributed signifi cantly to the ability to detect cancer specifi c genetic, genomic and epigenomic aberrations. these genetic and genomic abnormalities have promise across the translational spectrum from identifying individual susceptibility to cancers, early diagnosis markers, molecular pathology and tailoring of treatment (predictive biomarkers) as well as informing on outcome (prognostic biomarkers). much work remains to be done to validate clinical utility and translate these potential useful biomarkers into useful clinical tools. this session will review some of the developments in the genomics and epigenomics of lung cancer and mesothelioma. asthma is a disease that is diagnosed largely on a history of variable symptoms and the demonstration of variable airway narrowing. it is associated with airway infl ammation (cd t-lymphocytes, b-cell lymphoid aggregates, macrophages, eosinophils and, in adults, neutrophils) and airway wall remodelling (airway wall thickening, principally increased airway smooth muscle and deposition of collagen below the basement membrane, with minor encroachment on the airway lumen). it is not associated with a prominent effect on the lung parenchyma. the cause(s) of asthma remains unknown and the severity of disease remains largely constant. copd is diagnosed with a spirometer and is defi ned as a fi xed reduction in fev , relative to fvc. when caused by cigarette smoke it is associated with airway infl ammation (cd t-lymphocytes, b-cell lymphoid aggregates, macrophages and neutrophils) and airway remodelling (mild increase in airway wall thickness including airway smooth muscle with encroachment on the airway lumen) and tissue destruction (emphysema and loss of small conducting airways). the severity of copd increases with age and continued exposure to irritants. copd has many causes including smoking cigarettes, burning of biomass fuels, asthma and early life respiratory illness and exposures (viral infections, bronchopulmonary dysplasia). as a group, patients with asthma have reduced lung function, in relation to disease severity, and may have a slightly increased rate of decline in lung function. patients with asthma who smoke have reduced lung function and an accelerated decline in lung function. apart from stopping smoking there is no current treatment that can improve the rate of decline in lung function in patients with asthma or copd. therefore prevention, early intervention and uncovering the unknown environmental and genetic contributions to airway diseases remain critical. sy - situation the isaac and ariap studies have showed the different prevalence but heavy burden caused by asthma in asia pacifi c countries is common. goals with inhaled corticosteroids and other medications, the goals in managing asthma in developing countries should attain those stated in gina: control of symptoms, maintaining normal activity levels, normal pulmonary functions, preventing asthma exacerbations, avoiding adverse affects and preventing asthma mortality. in developing countries, avoiding the abuse of short-acting beta agonists, systemic corticosteroids and antibiotics is also a major problem. accessing medical care and medications is crucial. steps a core group, preferably at an university medical center, is the basic step. the asthma and copd outpatient care unit (acocu) run by this core group will help in getting experience and capacity building. the following steps are gina dissemination and implementation, patient club formation, increasing awareness, training doctors and nurses, advocacy, researches, efforts for the availability of affordable asthma drugs, and multiplying acocu in the whole country. the sustainability of acocu is assured by successful implementation of gina. a network of acocu will encourage and improve the activities of acocus. successful provincial acocu will encourage the building of district and even commune acocus. diffi culties the continuous medical education for all doctors on gina, the medication affordability, spirometers and mechanism to maintain an acocu. despite the advances in asthma diagnosis and treatment, slta cases continue to present in the er, sometimes leading to unnecessary mortalities. these are highly preventable situations with inhaled steroid based chronic therapy. with expert care, most patients get through er/icu urgent phase with good outcomes. these strategies are published and updated regularly in the international asthma guidelines. the finnish experience confi rms that a national program that pushes for implementation of guideline recommendations is able to reduce asthma hospitalizations and cost of care. not all countries have such a program but in most developed economies, the cost of asthma care including medications is covered provided the guidelines are followed. unfortunately, even in these affl uent countries, a subset on patients still lands in the er with sltas. while there may have been a failure of health care delivery, the cross-country existence of this problem raises the prospect that some patients are prone to life-threatening exacerbation. sltas may have its own specifi c risk factors that are distinct from the risk factors for simple hospital admission for acute severe asthma. by defi ning risk factors for slta within the population of those admitted to hospital with acute asthma, we may be able to develop specifi c interventional strategies to reduce its occurrence. reported slta risk factors include advancing age, chronic severe asthma, increased infl ammation markers, asthma exacerbated by pneumonia and low nutritional status. other risk factors include recent hospital admission, prior intubation, steroid dependence, non-adherence to inhaled corticosteroids, psychological or psychosocial problems, lack of access to medical care, lower fev , and current cigarette-smoking. a specifi c phenotype of severe brittle asthma has been reported. the backbone of er management for slta includes quick assessment of severity, oxygen therapy, early use of systemic steroids and repetitive saba bronchodilator administrations. enhancements include the use of saba with high intrinsic effi cacy, the addition of ipratropium in refractory cases and the concurrent administration of inhaled corticosteroid for its non-genomic, airway edema-reducing effect. mgso can also be considered for refractory cases. when ventilator support is needed, niv may be attempted in some patient. for intubated cases, the ventilatory strategy includes low tv and rr, high i : e ratio, and monitoring for the development of dynamic hyperinfl ation. the burden of the slta problem can be mitigated by identifying its phenotype a priori, providing preventive therapy before actual exacerbation occurs and putting in the er/icu the appropriate treatment protocols. journal compilation © asian pacifi c society of respirology available treatment of asthma using inhaled corticosteroids and long-acting inhaled β -agonists (labas) is highly effective and safe. importantly, it is also relatively inexpensive. however, many patients remain poorly controlled despite the use of optimal treatment. most advances in asthma therapy have been achieved by improving these drugs and more recently several promising once-a-day labas have been developed. new corticosteroids are also being developed with differential effect on trans-activation and trans-repression of pro-infl ammatory transcription factors, thus giving them a better therapeutic index. the big challenge in asthma is posed by corticosteroid unresponsiveness which is relative and therefore requires high doses to achieve symptom control which inevitably leads to side-effects. one option being pursued is to develop activators of the nuclear enzyme histone-deactylase (hdac) which is recruited to the gene initiation site of pro-infl ammatory mediators. there is an increasing appreciation that asthma is not a single disease and is increasingly seen as a syndrome consisting of several phenotypes. so far, two relatively clear subsets have been identifi ed: eosinophilic and neutrophilic forms of asthma. with this notion in mind, attempts are being made to develop more-specifi c inhibitors for a range of mediators with the hope that sub-phenotypes of asthma will be identifi ed that respond well to either single mediator inhibitors or a combination of these. a number of cytokine modulators have been tested in clinical trials, the most notable example being anti-tnf inhibitors which is felt to be more relevant to neutrophilic asthma. unfortunately, large clinical trials with tnf inhibitors have not found them to be very effective. treatment with blocking antibody for the eosinophils growth factor, il- , has been slightly more effective, with early clinical trials showing that the treatment reduces the frequency of exacerbations in patients who have eosinophilia. whilst the exact mechanisms leading to the development of these two subphenotypes is not fully understood, it is thought that eosinophilia represents a risk factor for exacerbations which has led to eosinophils counts in sputum being used as a guide to treatment; this has been benefi cial in reducing exacerbations. neutrophilic forms of asthma represent a special challenge because patients with neutrophilia tend not to respond well to corticosteroids, making them reliant on bronchodilators. such patients' asthma may be driven by mechanisms that involve il- which induces the production of neutrophil chemoattractants by the epithelium, which makes il- and its chemo-attractant axis a target for novel therapies. the major unmet need in asthma is the treatment of infections. there are early indicators of antibiotic treatment (macrolides) being effective in the treatment of severe asthma. but the real hope comes from novel strategies aimed at the effects of viruses which are the cause of most acute exacerbations, both in milder and more severe forms of disease. recent studies have identifi ed a defi ciency in type i interferons (ifn), the production of which by the bronchial epithelium -the prime target of virus infection -has been shown to be reduced when epithelial cells from asthmatic are grown in culture and infected ex vivo. in the acute care setting, niv must usually start without delay to avoid further deterioration and an increased likelihood of failure. thus, the decision to start must be made quickly based on a bedside assessment. i recommend a simple two step process, the fi rst of which is to assess the patient's need for ventilatory assistance. if the patient has increased dyspnea (moderate to severe) and evidence of increased work of breathing including tachypnea (> /min in obstructive diseases and > /min in hypoxemic respiratory failure), increased accessory muscle use or abdominal paradox, the patient needs ventilatory assistance. arterial blood gases are helpful in making this assessment, but i discourage awaiting blood gas results before starting if the need is obvious, because the window of opportunity may close if initiation is too delayed. i do recommend obtaining baseline blood gases, however, and using them for comparison with later measurements to make certain that the patient is responding. the second simple step is to make sure patients have no contraindications to niv. these include patients with a need for immediate intubation by virtue of a respiratory arrest, hypotensive shock, or uncontrolled arrhythmias or upper gastrointestinal bleeding. the inability to fi t a mask because of a facial deformity, recent facial surgery or burns is also a contraindication. relative contraindications include agitation that prevents the patient from tolerating the mask, increased secretions or diminished ability to protect the airway. patients with these contraindications are at increased risk of failure if placed on niv and should be promptly intubated. patients with multiple risk factors for niv failure should be started only by experienced personnel under very close monitoring. in patients with hypercapneic respiratory failure, these include higher acute physiology scores, marked tachypnea, greater acidemia at baseline and a worse neurological score. in hypoxemic respiratory failure, risk factors for niv failure include the diagnosis of ards or pneumonia, greater age, hypotension and the failure to improve oxygenation substantially within the fi rst hour. although patients at high risk of niv failure can still be given a trial if the clinicians judge it to be indicated, but they must be watched very closely in an icu, with plans to intubate if there is no improvement within the fi rst hour or two. just as the decision to endotracheally intubate a patient in respiratory failure is a clinical judgment that requires the consideration of multiple factors, so is the decision to implement noninvasive ventilation. in the largest rct to date, cpap and nppv performed similarly, both improving dyspnea scores and ph more rapidly than with oxygen alone, but neither lowered intubation nor mortality rate (the major outcome variable) compared to oxygen-treated controls. however, this study enrolled patients whose intubation rate was slightly below % in all of groups, including controls, suggesting that they were too mildly ill to manifest a signifi cant mortality benefi t. meta-analyses of the rcts on cpap or nppv compared with o therapy alone have confi rmed the benefi ts described above, even showing a signifi cant mortality benefi t with cpap. meta-analyses comparing the modalities show equivalency of nppv and cpap with regard to reduction of intubation, lengths of stay and mortality, and with similar myocardial infarction rates. therefore, by virtue of its greater simplicity and potentially lower cost, cpap alone is generally regarded as the initial noninvasive modality of choice for cardiogenic edema patients. but because some studies have found that nppv reduces dyspnea and improves gas exchange more rapidly than cpap alone, nppv is preferred by some initially and can be substituted for cpap if patients treated initially with cpap remain dyspneic or hypercapnic. the success of noninvasive positive pressure to treat cardiogenic pulmonary edema has encouraged its extension into the pre-hospital setting. an emerging trend is to provide cpap devices on ambulances for initial therapy of cardiogenic pulmonary edema, a practice that has been associated with decreased need for intubations in the fi eld. patients with advanced chronic obstructive pulmonary disease (copd) experience poor quality of life and very high levels of symptom burden, including intractable shortness of breath, activity limitation, fatigue, social isolation, anxiety and depression. many of the these burdens are shared with caregivers, and resources in the community to support individuals and their families with chronic illness in the community are often lacking. with the recognition that patients with advanced copd and their caregivers have so many unmet needs, there is a growing acceptance for the need to improve the care and quality of life for patients with advanced copd. while signifi cant gaps in our knowledge and understanding of this area remain, factors contributing to these adverse experiences will be discussed. the importance of prevention, relief, reduction, and soothing of symptoms, without affecting a cure, will be emphasized as an integral component of the care provided for these patients. techniques and tools to optimize the care of patients with advanced copd, including optimizing pharmacologic therapies, inter-professional team care, anticipating and appropriately initiating end-of-life planning, patient and caregiver advocacy, as well as timely and effective communication will be reviewed. withdrawal or withholding life support in medically futile cases has been recognized as an ethical and a legal procedure. it is based on the inherent right of a person to autonomy in making health care decisions. the western model however may not apply to the asian setting being widely varied in terms of cultures, religions and economic progress. more than an individual decision, it may actually be a communal decision with a heavy reliance on input of relations, especially the elders. life support withdrawal often entails complete discontinuation of all measures. efforts to avoid feelings of guilt or abandonment may make families opt for partial withdrawals even when they are not shown to be any more benefi cial. studies have shown that distrust with the medical system does play a major role. active discussions may be diffi cult with reticent cultures or when there are gender differences between patients or their families and the physicians. in this era of globalization and migrations, an understanding of these differences may minimize potential confl icts that arise out of these discussions. awareness that the western approach may not fi t the asian medical model allows the health care providers to be sensitive to the needs and wants of their patients and their families. it is hoped that the data reviewed spurs the development of asia pacifi c guidelines that try to fi nd some uniformity in the diversity of the region. screening for lung cancer is not currently recommended by any major medical organization. multiple phase ii non-randomized trials of computed tomography (ct) screening have yielded enticing results. they have demonstrated that ct screening detects smaller size lung cancer of - mm in diameter. it has been documented that the chest radiographs miss - % of the cancers detected by screening ct. in prevalence studies, - % of detected cancers are stage i. when ct screening results were compared to a validated control group, ct has been shown to detect times more lung cancer than would be expected and results in ten times more thoracic operation than would be expected. additionally, no decrease in advanced stage cancers or decrease in lung cancer deaths were observed. to date, multiple small randomized controlled screening trials (rct) have been reported, but they have been too small to assess if ct screening reduces mortality. a meta-analysis of baseline fi ndings from six small randomized controlled trials observed more stage i and more total lung cancers in the ct screened group. for every individuals screened with low dose ct, stage i nsclc and false positive nodules were detected and thoracic operations were performed for benign nodules. the two large rct of ct screening that may defi natively answer the question of ct screening and its ability to decrease lung cancer mortality are the national cancer screening trial (nlst) and the nederlands-leuvens longkanker screenings onderzoek (nelson) trial. mortality results from those two trials are anticipated in and respectively. a recent report from the nelson trial validated the use of ct volumetric assessment of nodules to assess malignancy and determine which nodules should be treated surgically. currently, there is considerable effort to identify susceptibility genes for lung cancer with particular interest in q - which is strongly associated. this region contains several genes of interest, including three genes that encode nicotinic acetylcholine receptor subunits. however, these genes may just be associated with nicotine dependence. a recent report utilizing gwas (genome wide association scan) methodology identifi ed snps at q . associated with lung cancer susceptibility in never smokers. an enormous research effort is underway related to biomarkers in airway epithelial cells, blood, sputum, breath, and urine for early diagnosis or prediction of high risk. intense efforts are devoted to develop models of risk for determining which individuals should be offered screening. journal compilation © asian pacifi c society of respirology sy - lung cancer is the leading death-related cancer worldwide. molecular targeted therapy appears to be an alternative approach for patients with non-small cell lung cancer (nsclc). the epidermal growth factor receptor (egfr) is one of these targets, responsible for the cell growth, proliferation, apoptosis and metastasis of the tumors. egfr-tyrocine kinase inhibitor (tki) has been applied to target egfr and suppress the development of tumors. some egfr-tkis, including gefi tinib and erlotinib, have been approved, while the others are still under development or in clinical trials. several studies demonstrated that egfr somatic mutations might predict the high response rate and greater survival benefi t of egfr-tki. in addition, egfr amplication, k-ras mutation, met amplication or the egfr t m mutation might predict the clinical effect of these drugs. both erlotinib and gefi tinib have been undergoing several clinical trials for nsclc treatment as a single drug or in combination with chemotherapy. br. trial showed that erlotinib improved survival with previously treated nsclc patients in a randomized multicenter during phase iii study. thus, erlotinib was approved to be the second or third-line treatment of advanced nsclc patients. however, isel failed to demonstrate a statistically important benefi t of gefi tinib in overall survival as compared with placebo. different study population, dosing and drugs of br. and isel might explain the different results. in ipass trial, clinical selected nsclc patients with asian origin and characterised by adenocarcinoma histotype were treated with gefi tinib or paclitaxel/carboplatin doublets as the fi rst line therapy. the results showed that gefi tinib had the superiority in terms of progression free survival (pfs) in patients with egfr mutation. in eortc and perol trials, gefi tinib and erlotinib maintenance therapy showed the trend of improved pfs, but not overall survival in advanced nsclc patients. the toxicity of gefi tinib and erlotinib includes diarrhea, rash, etc., which can be well-tolerated. novel egfr-tkis include vandetanib, sorafenib, sunitinib, and cediranib, of which some are under evaluation in phase iii trials as monotherapy or in combination with standard chemotherapy. vandetanib targets both egfr and vegfr and was tested in the second phase trial, suggesting the addition of vandetanib to the single chemotherapy might improve response rates and survival. sorafenib has been applied to different carcinoma histology and in combination with different chemotherapy. when combined with paclitaxel and carboplatin to treat patients with squamous cell cancer, no survival benefi t was seen. however, another clinical trial was launched to investigate the effect of sorafenib, in which squamous cell cancer were not eligible. novel egfr-tkis are under development with hope of overcoming resistance to egfr-tki gefi tinib and erlotinib. there is a great need of further clinical trials. egfr-tki is one of the important alternatives in treatment of nsclc and has shown promising potential in the future. more promising results may come out if the combination and sequence of egfr-tki with traditional therapies, like chemotherapy, radiotherapy and surgery, can be optimized. there is also a need of disease-specifi c biomarkers to predict the effect of the drugs and identify the patients most likely to benefi t from the drugs. lung cancer is the number one cause of cancer death. most cases are found after distant metastasis, and outcome of drug therapy for these patients used to be disappointing. however, we have faced a new paradigm shift, i.e., the molecular targeted therapy and the individualized therapy. many promising data has reported from not only western countries but also asian countries such as the effi cacy of egfr tki to tumors with mutated egfr, that of alk inhibitor to tumor with eml -alk fusion protein, and that of pemetrexed to non-small non-squamous cell lung cancers. new questions have emerged from these new evidences derived from some important clinical trials. among them, questions regarding with ethnic difference would be one of the most important issues. is survival data same between asian and caucasian? (data from japan lung cancer registry study as well as some global trials have shown survival of asian patients with lung cancer appears to be obviously better than that of caucasian.) why egfr mutation is frequent in asian patients? is only egfr gene status related with prognosis of lung cancer? what would be the cause of alk abnormality? is the criteria of pathological diagnosis for lung cancer same between asian countries and western countries? here, newest evidences for treatment of lung cancer will be presented, and importance of ethnic difference and asian trials will be discussed. the burden of chronic obstructive pulmonary disease (copd) is growing. despite these growing numbers, many patients with patients with copd remain undiagnosed, the greatest number being those with milder disease. delays in the diagnosis of copd are common. evidence suggests that patients with mild copd experience increased symptoms, reduced activity levels and exercise capacity, and impaired health-related quality of life. this growing body of evidence has made it clear that mild copd is not 'normal'. with recognition of this reality and efforts to appropriately recognize copd at an earlier stage, clinicians must be aware of the various therapeutic options for their patients. the defi nition of mild copd will be discussed, as well as effective strategies for the targeted early diagnosis of copd. the numerous and varied disease manifestations and consequences for patients with milder copd will be reviewed. in addition, practical and effective management options available to clinicians caring for patients with mild copd will also be examined. clinicians have been long aware that neither the traditional distinctions of "emphysema" versus "chronic bronchitis" nor the traditional clinical phenotypes of "blue bloater" and "pink puffer" are suffi cient to categorize patents that suffer from chronic obstructive pulmonary disease (copd). recently, the global initiative for chronic obstructive lung disease (gold) workshop has used quantitative measures (fev and fev /fvc ratio) to defi ne copd, but this defi nition fails to take into account the full heterogeneity of copd. with an increased understanding of pathophysiologic variation, copd now clearly represents a spectrum of overlapping diseases with important extrapulmonary consequences. a "phenotype" describes the outward physical manifestations of a particular disease, and comprises anything that is part of the observable structure, function or behavior of an individual. such phenotypic distinctions in copd include: frequent exacerbator, pulmonary cachectic, rapid decliner, airways hyperresponsiveness, impaired exercise tolerance, and emphysema versus airways disease. these variable manifestations, each with unique prognostic, clinical and physiologic implications, represent distinct phenotypes within copd. while all of these phenotypes have smoking as a common risk factor, the other risk factors that determine these phenotypes remain poorly understood. an individual smoker has variable expression of each phenotype and there is mounting evidence that copd phenotypes have different clinical outcomes. these phenotypes can be broadly classifi ed into one of three groups: clinical, physiologic and radiographic. thus, the paradigm that copd is one disease may be incorrect, and suggests that copd should be considered as a spectrum of smoking-related diseases. failure to consider copd phenotypes is likely to limit the power of therapeutic trials since not all copd patients are likely to benefi t from each therapy. the challenge to future copd researchers is to better characterize these phenotypes and identify their risk factors. measurement of fractional exhaled nitric oxide (feno) is an attractive biomarker of diseases where airway eosinophilia dominates. indeed even before any randomized controlled trials were published some were advocating treatment tailored in accordance to feno data. commercially available bench-top and portable feno analyzers are now readily available and in some countries, feno measurements attract a payment. however, despite the ease of measuring feno, it has its drawbacks in biological and measurement issues. biologically feno is signifi cantly infl uenced by atopy, intake of caffeine, exercise, ethnicity, etc on the measurement front, variabilites include: feno measured by different analyzers may provide different values and on-line vs off-line measurements. the cut-off for determining 'abnormally high results' is yet unknown. not surprisingly, there is discordance on the effi cacy of tailoring asthma medications in accordance to sputum eosinophils [ ] and feno [ ] in people with asthma, although both are eosinophilia infl ammatory markers. tailoring of medications in accordance to sputum eosinophilia (compared to standard practice) significantly reduced exacerbations in adults with asthma (odds ratio . , %ci . , . ). in contrast, the benefi t of tailoring of medications in accordance to feno was, at best, modest. the utility and limitations of using feno levels in the clinical setting will be discussed in this talk. shortness of breath and activity limitation are cardinal symptoms experienced by patients suffering from respiratory illness or disease. cardiopulmonary exercise testing (cpet) allows for the objective evaluation of these symptoms, recognizing that exercise involves the effective integration of respiratory, cardiovascular, neuromuscular and metabolic functions. the organs involved in these varied and important roles have a sizeable reserve, with the consequence that clinical manifestations of a disease state or abnormality may not become readily apparent until the functional capacity of the organ(s) is markedly impaired. objective assessment of various parameters during exercise, which places an increased physiologic demand on the functional reserve capacity of these organs, can provide a sensitive method for the early detection of abnormal function and responses(s). the results from exercise testing also parallel functional capacity and quality of life more closely than measurements obtained only at rest, and have been shown to accurately predict important outcomes, such as mortality, in a variety of patients and clinical circumstances. a brief overview of normal exercise physiology and characteristic responses demonstrated by patients with various disorders frequently assessed by the pulmonologist will be offered. in addition, a summary of the indications, conduct, and practical interpretation of cpet will be presented in this session. effect of tiotropium on outcomes in patients with moderate chronic obstructive pulmonary disease (uplift): a prespecifi ed subgroup analysis of a randomised controlled trial obstructive lung disease and low lung function in adults in the united states: data from the national health and nutrition examination survey international variation in the prevalence of copd (the bold study): a population-based prevalence study chronic obstructive pulmonary disease in fi ve latin american cities (the platino study): a prevalence study prevalence of copd in spain: impact of undiagnosed copd on quality of life and daily life activities global burden of copd: systematic review and metaanalysis prevalence of chronic obstructive pulmonary disease in china. a large, population-based survey diagnostic labeling of chronic obstructive pulmonary disease in fi ve latin american cities copd prevalence in a random population survey: a matter of defi nition treatment of copd: the sooner the better clinical copd phenotypes: a novel approach using principal component and cluster analyses offi ce spirometry signifi cantly improves early detection of copd in general practice: the didasco study salmeterol and fl uticasone propionate and survival in chronic obstructive pulmonary disease clinical trial design considerations in assessing long-term functional impacts of tiotropium in copd: the uplift trial a -year trial of tiotropium in chronic obstructive pulmonary disease mortality in the -year trial of tiotropium (uplift) in patients with chronic obstructive pulmonary disease effi cacy of salmeterol/fl uticasone propionate by gold stage of chronic obstructive pulmonary disease: analysis from the randomised, placebo-controlled torch study effects of tiotropium on outcomes in patients with moderate chronic obstructive pulmonary disease (uplift): a prespecifi ed subgroup analysis of a randomised controlled trial tiotropium as a first maintenance drug in copd: secondary analysis of the uplift trial treating tobacco use and dependence: update. clinical practice guideline tobacco atlas the mpower package. geneva, world health organization implementing smoke-free environments. geneva, world health organization curbing the epidemic: governments and the economics of tobacco control clinical and public health signifi cance of treatments to aid smoking cessation we report that pulmonary emphysematous lesions appear to be a dynamic phenomenon that involves not only the gradual loss of alveolar structure, but apoptosis, cellular proliferation, and cellular senescence as well. cellular proliferation compensates for increased alveolar cell apoptosis in chronic obstructive pulmonary disease (copd) patients. however, smoking, age, and the increased cell cycle turnover that compensates for apoptosis accelerate alveolar cell senescence, thereby halting cellular proliferation and tipping the balance toward apoptosis, which, in turn, promotes the formation of emphysematous lesions. as a result, alveolar cells disappear and the emphysematous lesions progress. at the same time, cellular senescence is thought to induce infl ammation. more specifi cally, senescent alveolar cells induce infl ammation by producing various infl ammatory cytokines in tissue. lymphocytes and clara cells may also age more rapidly in the lungs of copd patients. lymphocyte senescence may induce an autoimmune reaction and increase susceptibility to infection, and clara cell senescence may impair airway regeneration as well as sustain airway infl ammation. thus, cellular senescence may be involved in arrested tissue repair, chronic infl ammation, and increased susceptibility to infection, which are the typical features of copd. there is increasing recognition that copd is an increasing global burden. new drug treatments continue to emerge suggesting that copd is more responsive to treatments than previously thought. however, there is still much that is unknown about copd that will contribute to further advances in treatment and management. pulmonary imaging can contribute by providing information on how structure and function relate to relevant clinical parameters, such as disease progression, treatment responses and exacerbations. in other words, imaging can help characterise copd in terms of clinical outcomes or phenotypes. there have been many advances in imaging methodology, including ct, mri, spect and pet. recent fi ndings from research studies using innovative methods of studying structure and particularly function, in copd will be reviewed. their clinical implications will be discussed. the spectrum of children's interstitial lung disease (child) encompasses a large, heterogeneous group of pediatric diffuse lung disorders that are diffi cult to diagnose and treat. as the differential diagnosis is large, a systematic approach is needed for accurate diagnosis. the classic fi rst step of obtaining a detailed history and performing a careful physical examination remains essential for providing diagnostic clues as well as assessing severity of illness. as examples, a history of hemoptysis and fatigue would suggest an alveolar hemorrhage syndrome; exposure to avian antigens, hypersensitivity pneumonitis; and a history of adenovirus pneumonia, bronchiolitis obliterans. the presence of growth failure, crackles, loud p , and clubbing on physical examination would point to a severe and progressive lung process with cor pulmonale. recent advances in diagnostic modalities have greatly improved the ability of clinicians to identify these disorders. in infants and children with diffuse lung disease, genetic testing can be diagnostic for surfactant dysfunction mutations (sp-b, sp-c, abca , ttf- , gm-csfra receptor). infant lung function testing has proven useful for assisting in the diagnosis of certain disorders, such as neuroendocrine cell hyperplasia of infancy (nehi) and distinguishing nehi from surfactant mutations. hrct may detect extent and severity of disease, but can also be useful in diagnosing specifi c disorders, such as nehi (symmetric ground glass densities in the right middle lobe and lingula and the central lung regions), bronchiolitis obliterans (mosaic perfusion, vascular attenuation, and central bronchiectasis), hypersensitivity pneumonitis (ill-defi ned centrolobular micronodules), and pulmonary alveolar proteinosis (crazy-paving). bronchoalveolar lavage can aid in the diagnosis of specifi c conditions, such as alveolar hemorrhage syndromes (hemosiderin-laden macrophages), aspiration (lipid-laden macrophages), hypersensitivity pneumonitis and sarcoidosis (lymphocytosis), eosinophilic pneumonias (eosinophilia), and histiocytosis (cd a + cells). lung biopsy performed by video-assisted thoracoscopic surgery (vats) has largely supplanted conventional open lung biopsy as the procedure of choice as it is equally accurate, but associated with less morbidity. although lung biopsy remains the gold standard for diagnosis of child, it must be interpreted in the context of the clinical and radiologic fi ndings. it should be emphasized that although lung biopsy can be diagnostic in some disorders, such as bronchiolitis obliterans, it may not be necessary because less invasive studies such as hrct may be suffi cient for diagnosis. finally, some pulmonary vascular disorders, such as pulmonary vein stenosis or atresia, may mimic child. for these disorders, echocardiography, mra, or cardiac catheterization may be required for diagnosis. with a systematic approach and improved diagnostic capabilities, it is reasonable to expect that a specifi c diagnosis can now be made in the vast majority of child cases. key: cord- -j rogzm authors: stefan, mihaela s.; pekow, penelope s.; shea, christopher m.; hughes, ashley m.; hill, nicholas s.; steingrub, jay s.; lindenauer, peter k. title: protocol for two-arm pragmatic cluster randomized hybrid implementation-effectiveness trial comparing two education strategies for improving the uptake of noninvasive ventilation in patients with severe copd exacerbation date: - - journal: implement sci commun doi: . /s - - - sha: doc_id: cord_uid: j rogzm background: copd is the fourth leading cause of death in the us, and copd exacerbations result in approximately , hospitalizations annually. patients with acute respiratory failure due to severe copd exacerbation are treated with invasive (imv) or noninvasive mechanical ventilation (niv). although imv reverses hypercapnia/hypoxia, it causes significant morbidity and mortality. there is strong evidence that patients treated with niv have better outcomes, and niv is recommended as first line therapy in these patients. yet, several studies have demonstrated substantial variation in the use of niv across hospitals, leading to preventable morbidity and mortality. through a series of mixed-methods studies, we have found that successful implementation of niv requires physicians, respiratory therapists (rts), and nurses to communicate and collaborate effectively, suggesting that efforts to increase the use of niv in copd need to account for the complex and interdisciplinary nature of niv delivery and the need for team coordination. therefore, we propose to compare two educational strategies: online education (ole) and interprofessional education (ipe) which targets complex team-based care in niv delivery. methods and design: twenty hospitals with low baseline rates of niv use will be randomized to either the ole or ipe study arm. the primary outcome of the trial is change in the hospital rate of niv use among patients with copd requiring ventilatory support. in aim , we will compare the uptake change over time of niv use among patients with copd in hospitals enrolled in the two arms. in aim , we will explore mediators’ role (respiratory therapist autonomy and team functionality) on the relationship between the implementation strategies and implementation effectiveness. finally, in aim , through interviews with providers, we will assess acceptability and feasibility of the educational training. discussions: this study will be among the first to carefully test the impact of ipe in the inpatient setting. this work promises to change practice by offering approaches to facilitate greater uptake of niv and may generalize to other interventions directed to seriously-ill patients. trial registration: name of registry: clinicaltrials.gov trial registration number: nct date of registration: december , chronic obstructive pulmonary disease (copd) is the fourth leading cause of death in the us, and copd exacerbations result in approximately , hospitalizations annually [ , ] . patients who do not respond to pharmacotherapy are placed on invasive (imv) or noninvasive mechanical ventilation (niv). while invasive mechanical ventilation (imv) administered through an endotracheal tube is an effective method of treating acute respiratory, it requires treatment in an intensive care unit, and places patients at risk for a wide range of complications, including ventilator-associated pneumonia. niv (continuous positive airway pressure, cpap or bilevel positive airway pressure, bipap) provides positive pressure ventilation via a face mask without the need for intubation. multiple randomized controlled trials [ , ] , meta-analysis [ , ] , and analyses of real-world data [ , ] have demonstrated that treatment with niv, when added to usual care, reduces the risk of intubation, lowers the incidence of ventilator associated complications, and results in better short-term survival. based on this evidence, niv receives a grade a recommendation in current global initiative for chronic obstructive lung disease (gold) guidelines [ ] . furthermore, the european respiratory society and american thoracic society joint guidelines [ ] as well as british thoracic society guidelines [ ] make a strong recommendation for the use of niv as a first-line treatment for patients with copd exacerbation and acute respiratory failure. although the evidence supporting the use of niv is compelling, prior research has demonstrated substantial variation in the use of niv in routine clinical settings, highlighting a persistent gap in niv adoption. in a recent study of more than , patients with copd cared for at us hospitals, median hospital percentage of niv use among ventilated patients was . % (range . - . %) and the bottom % of hospitals offered a trial of niv to less than half of ventilated patients [ ] . more importantly, institutions with higher rates of niv had lower imv use and better clinical outcomes. thus, low hospital rates of niv in patients admitted for severe copd represents an evidence practice gap and a missed opportunity to improve the outcomes among this vulnerable population. appropriate delivery of niv is a complex, multicomponent intervention that requires timely recognition, and effective communication, and coordination across multiple disciplines. figure depicts the flow for a patient who comes to the emergency department with severe copd exacerbation and each clinician's responsibilities in the process of niv initiation and monitoring. only few studies have tested strategies for supporting niv implementation. a single site, before-after study from canada found that multidisciplinary guidelines for the use of niv in patients with stefan acute respiratory failure (arf) were associated with greater niv utilization but included only patients in the intensive care unit [ ] . for this study, we used the intervention mapping process model to develop and select implementation strategies to increase the uptake of niv [ ] . figure summarizes the steps in the development of our implementation strategy to increase the use of niv in severe copd exacerbation. in step (formative evaluation), we conducted semistructured interviews with key informants in a sample of hospitals with high rates of niv and good copd outcomes (low mortality and niv failure rates). the analysis of the interviews revealed different professional identities and roles in niv delivery: physicians, respiratory therapists (rts), and nurses. although several clinicians' tasks are distinct, fig. shows the connections between physicians, nurses, and rts indicating the need for coordination to ensure optimal patient outcomes. the three groups encounter significant professional boundary issues with regards to their work responsibilities and priorities. for example, nurses were concerned about patient's inability to eat or take medications while on niv. rts considered that nurses do not have a good understanding of the vital role of niv. however, the two professions agreed that when there was a shared understanding of the treatment plan and when the concerns from both sides were openly addressed, the collaboration was considerably improved. rts perceived themselves as experts in initiating and managing niv; in some institutions, there was a strained relation between the rts and physicians, with rts complaining about a lack of autonomy and the need to wait for physicians when niv was immediately indicated. we identified the following contextual factors and strategies associated with successful niv implementation: provider buy-in, respiratory therapists (rt) autonomy to deliver niv independently, interdisciplinary teamwork, collegial, trusting relationships between rts, physicians, and nurses, and ongoing staff education [ ] . in step , we organized the specific types of determinants that influence niv delivery using the theoretical domain framework (tdf) [ ] . the tdf was used as a guiding theory for this project because the desired behavior change is primarily at the individual level, e.g., convincing providers to consider niv in any patient with severe copd exacerbation. we summarized the barriers in the tdf domains with an eye toward choosing an implementation strategy which could overcome several of the identified barriers. eight of the domains (knowledge, skills, professional roles and identity, beliefs about capabilities, beliefs about consequences, environmental context and resources, social influences, and emotion) were present in the existing literature and our research. interdisciplinary teamwork, on-going education, providers buy-in, and rts autonomy were found as the top four determinants for successful niv delivery in copd exacerbations. these findings suggest that to succeed, implementation strategies need to account for the complex and interdisciplinary nature of niv therapy and the need for team coordination. step : to guide the selection of implementation strategies, we used the expert recommendations for implementing change (eric) [ ] . the main themes that emerged from the qualitative analysis and literature review mapped to the tdf domains and the implementation strategies most likely to address those barriers are shown in table . systematic analysis of the barriers suggested that to succeed, implementation strategies for knowledge transfer need to account for the complex and interdisciplinary nature of the niv therapy and the need for team coordination; however, these hypotheses need to be carefully tested. interprofessional, dynamic team training for physicians, rts, and nurses was the implementation strategy selected as targeting several key determinants [ , , ] . niv is delivered in high acuity environments by teams in which membership is dynamic, decisions must be made quickly, and members are not always face-to-face (asynchronously taking care of patients). this creates a critical need for effective communication, conflict management, and shared mental model [ ] skills that are well suited to ipe approaches [ ] [ ] [ ] . by contrast, conventional education regarding niv is administered to individual clinicians or groups of clinicians of the same discipline via lectures or online modules. educating individual care providers in silos does not address the interprofessional collaboration inherent to niv delivery. on the other hand, ipe competencies emphasize the importance of establishing awareness and knowledge regarding interprofessional team roles. in this way, leveraging an ipe platform enables learning via interaction between two or more professions who learn from, with, and about each other's roles and responsibilities (in this case, in regards to niv) [ , ] . the overall objective of this study is to conduct a pragmatic, parallel, -arm randomized cluster trial to compare the effectiveness of two implementation strategies: on-line education (ole) and interprofessional education (ipe) on the uptake of niv. the central hypothesis is that ipe will outperform conventional education, and that rt autonomy and/or team functionality will act as mediators. we will accomplish this goal by completing three specific aims. aim : to compare the effectiveness of ole and ipe for increasing the delivery of niv in appropriate patients hospitalized with copd exacerbation. aim : to examine the effect of ole and ipe on rt autonomy and team functionality as potential mediators of niv uptake. aim : to evaluate the acceptability and feasibility of the ole and ipe strategies to inform further refinement of the strategies. in this cluster randomized controlled -arm parallel trial, hospitals will be randomized to ope or to ipe. patients and clinicians are clustered within the hospitals because the ipe encourage facility-level change in clinicians' communication and care coordination. the study will be conducted in hospitals with riskadjusted niv proportion below median that have at least eligible copd admissions in an -month period. potential eligible hospitals are those participating with data in premier database, a voluntary, fee-supported database containing highly detailed hospital billing data pooled from more than geographically and structurally diverse hospitals whose makeup closely resembles that of us hospitals. hospitals that demonstrate interest in participating in the study will be asked to commit to form a copd-niv team composed of one physician, one rt, and one nurse that will be in close contact with the investigators and are responsible for delivering the educational intervention in their institution. eligible hospitals will be contacted in a random order until the sample of hospitals is achieved. to assess for potential participation bias, we will compare participating and refusing hospitals using available data such as size, ownership, teaching status, and location. the overall study design is shown in fig. . the explanatory continuum indicator summary (pre-cis) framework was used to assess the pragmatism of the trial (fig. ) . we will randomly allocate hospitals to one of the study arms, stratified by the baseline niv proportion and hospital bed size. a researcher not involved in the study and blinded to the identity of the hospitals will use a computer-generated randomization scheme. the randomization scheme will be concealed to the investigators. due to the character of the intervention, it will not be possible to blind participants or investigators providing the educational program; however, the investigators will not be aware of the results of the study by intervention arm until the analysis is finalized. the trial will compare two implementation strategies: one active control consisting of traditional, online education (ole) learning and a strategy of in-person interactive inter-professional education (ipe). consent for participation in the educational strategies will be sought as a waiver of consent via an email sent to all potential participants after the randomization period and prior to the implementation at each site. participants in the copd-niv teams and the training will be physicians, rts, and nurses who are involved in treating patients with severe copd exacerbation. the following domains will be targeted in the educational training interventions: the hospital-based copd-niv teams will be responsible throughout the trial period for encouraging clinicians from each specialty to complete the courses. the investigators will have a conference call with the copd- niv team after the institutions have been randomized to discuss recruitment and surveys' delivery. (e.g., rt autonomy, team functionality, and organizational readiness for implementing change). conference calls between the investigators and the individual copd-niv team will continue every quarter for the duration of the months of active implementation period with a follow-up call at the end of the study. active control group: online education (ole) sites will be given access to free continuing education modules customized for each discipline; rt and nurse online education training will be approximately min long, and physician's online education training will be about h. the modules will be delivered online through a secure website that will allow us to count the number of providers completing the course. we will use traditional powerpoint presentations with embedded whiteboard animation videos. we selected an active control instead of usual care, because it will allow stronger inferences about the benefits of ipe when compared to more traditional learning approaches. the online modules will be offered for the entire period of the study for all the new staff. it will consist of a -minute in-person interprofessional educational workshop. training of the facilitators we will organized a one day in-person training for all the niv-copd teams. the training will consist of modules: ( ) niv knowledge and skills: delivered by niv experts and ( ) ipe: delivered by an expert in ipe and team training. the didactic training regarding niv use in copd will include a review of the evidence supporting the benefits of niv, advantages of niv as compared to invasive mechanical ventilation (imv), selection of patients, contraindications to niv, and management of patients while on niv including monitoring, ventilator settings, attention to patient comfort, weaning from niv, and decision about niv failure and need for intubation. the didactic module will emphasize the importance of early initiation of niv in patients with severe copd. the second half of the training will concentrate on teaching interprofessional collaboration. specifically, the interprofessional education collaborative (ipec) recommends four key competencies in successful ipe, which include roles and responsibilities, teams and teamwork, values and ethics, and interprofessional communication [ ] . we selected the following core competencies for our interactive ipe. professional roles and identity: each team member learns about abilities, tasks, duties, responsibilities, and concerns of their fellows' team members; values/ethics: work with individuals of other professions to maintain a climate of mutual respect and shared values; teams/teamwork: apply relationship-building values and the principles of team dynamics to perform effectively in different team roles to deliver patient-center care that is safe, timely, effective, and efficient [ ] . given the demands for team coordination in niv delivery and findings in our qualitative work, we anticipate that ipe will contribute to greater rt, physician, and nurse understanding of each other's roles, increase team communication and functionality, and stimulate the development of shared mental models which facilitate coordination for niv. we will use positional clarification which involves verbally presenting team members with information about their teammates' jobs through discussion [ ] . psychological safety and speaking up will be encouraged and facilitated. for example, an rt may assume that physicians have more knowledge about niv delivery for a particular patient than they do (because physicians are generally more knowledgeable about treatments) and remain quiet; when in fact, the rt has important information about how the patient may respond (cognitive bias) [ ] . the sessions will be recorded, so that participants will have ongoing access to the content. we anticipate that the members of the copd-niv team who will become the training facilitators at their hospital will not be subject matter experts in the training context, especially the ipe. therefore, a special instructor script will be written and will be paired with the presentation. delivery of the ipe sessions at institutions randomized to ipe training sessions for clinicians at ipe sites will be led by the copd-niv teams and will include information (e.g., -min lecture), demonstration (providers will be provided with contextualized examples), and practice ( min, action-based approach with guided practice). it will contain a scenario of a patient with severe copd coming to the emergency room with shortness of breath. they will review the guidelines for patient selection and monitoring and niv settings and management. each participant will be able to try the niv mask and understand the importance of appropriate settings and attending to patient comfort. the three core competencies for interprofessional collaboration and how they apply to the niv delivery will be explained. the ipe sessions will be offered up to twice a month for months-the number will vary by institution depending on the number of providers that need to be trained. for the entire period of the study, we will continue to have every other monthly breakfast/lunch meetings where cases of patients with copd in need of niv will be presented with emphasis on interprofessional work structure, rt autonomy, and team functionality. full ipe sessions will be offered once a month every months for the new staff, as part of on-boarding. table outlines the implementation and effectiveness outcomes at the cluster (hospital) level, their implementation timing, how they will be measured, and the source of data collection. to compare the effectiveness of ole and ipe for increasing the delivery of niv in appropriate patients hospitalized with copd exacerbation. primary outcome hospital-level risk-standardized (rs) initial niv proportion among patients hospitalized with a copd exacerbation that were ventilated with niv or imv is assessed via administrative records of patients discharged from participating premier hospital who were years or older and received a principal diagnosis of copd, or a principal diagnosis of acute respiratory failure paired with a secondary diagnosis of copd. we will use a previously validated set of icd- -cm codes that achieve a reasonable balance of sensitivity and specificity while minimizing potential biases [ ] . secondary outcomes rs hospital rates of niv failure (imv after a trial of niv), mortality, length of stay, and -day readmission among all patients with copd. all outcomes will be measured at the hospital level: ( ) at baseline using prior months of data, ( ) at months post-implementation to assess immediate/short term impact, and the following months to assess sustainability. the -month assessment period is necessary to have adequate numbers of eligible copd admissions for assessing hospital rates of niv utilization. the time from randomization to the completion of the educational sessions with an expected duration of months will not be included in the calculation of rs-niv post-intervention. to examine penetration, we will measure providers' exposure to educational training using participation logs. patient and hospital information demographics, comorbidities, prior year number of admissions for copd, prior year use of niv or imv, and outcomes will be identified from icd- procedure codes and billing codes. for each participating hospital, we will record the number of beds, the annual number of admissions for copd, teaching status, geographic region, and whether it serves an urban or rural population. we will also collect information about staffing: number of rts, hospitalists, emergency room physicians, and nurses. we will record if hospitals use protocols for niv initiation and management, and if niv can be delivered on the regular medical floor or only in an intensive care unit. these factors will be used to describe participant hospitals and evaluated as potential confounders or effect modifiers. noninvasive and invasive ventilation for each patient, we will examine standardized charge codes generated daily by respiratory therapists as well as dated icd- procedure codes to determine whether or not they were treated with assisted ventilation, and, if so, whether ventilation was niv or imv. we define the primary method of ventilation as the first method by date and distinguish between patients treated with niv as an initial strategy from those in whom niv use follow exposure to invasive mechanical ventilation (imv). we have previously validated the niv icd procedure codes and respiratory therapy charge codes by retrospective medical chart review. using icd- -cm codes alone yielded a sensitivity of % ( % ci, - %) and specificity of % ( % ci, - %). the approach of using icd- -cm procedure codes and/or respiratory therapist charges increased sensitivity to % ( % ci, - %) without reducing specificity ( %, % ci, - %) [ ] . statistical analysis of aim we will generate descriptive statistics overall, by hospital and educational strategy, including counts and percentages for categorical data, means, standard deviations, and percentile distributions for continuous data. we will compare characteristics of hospitals, including staffing characteristics, in the two study arms via chi-square tests and t tests or wilcoxon tests. characteristics of patients in the enrolled hospitals in the two arms will be compared via gee models accounting for clustering by hospital. we will calculate the percentage of patients treated according to each of the primary ventilatory strategies: no assisted ventilation, niv, and imv. we will then calculate the proportion of patients initially treated with niv among those who received assisted ventilation. we will estimate a risk-standardized proportion of ventilated patients initially treated with niv (rs-niv) for each hospital and for each data collection period (baseline period, months post-intervention, and between to months post-intervention). we will use hierarchical logistic regression with a random hospital effect to model initial use of niv among patients started on ventilation, adjusting for demographics, and comorbidities. from the model, a predicted niv percentage for each hospital will be computed as the niv percentage that would be anticipated at a particular hospital by using its hospital random effect, given the patient case mix. the expected niv percentage will be computed as the rate that would be expected if the same patient mix were treated at an "average" hospital, using the average hospital effect. the rs-niv percentage is then computed as the ratio of predicted to expected niv percentage standardized by the overall unadjusted mean niv percentage for all admissions in our model. risk standardization has key advantages: it adjusts for differences in patient mix, which may impact the suitability of niv; it also provides more stabilized estimates based upon bayesian shrinkage towards the overall mean among hospitals with small numbers of ventilated patients [ , ] . the mean and median rs-niv rates of the two arms will be computed for each study period. the primary analysis will use an analysis of variance model to compare ipe to ole on change in rs-niv rates from baseline to months post-intervention. additional analyses will adjust for hospital characteristics that are unbalanced between the study arms. a secondary analysis will compare the post-intervention levels, adjusting for baseline rs-niv. to assess sustainability, similar models will be used to compare level of rs-niv after an additional months have passed. for the secondary outcomes, our analysis will calculate hospital rs-rates of niv failure, mortality, -day readmission, and length of stay among ventilated patients, as well as all copd admissions for each study period. we will compare outcomes of ole and ipe hospitals using models described above. although we assume that the patients treated in ipe hospitals will have better clinical outcomes, we do not expect it to be able to detect an effect of these strategies on secondary outcomes due to overall low outcome rate, the small projected change, and relatively small number of clusters. organizational readiness the implementation of the educational strategies to increase the use of niv in copd exacerbations will require the coordinated action of many organizational members (e.g., physicians, rts, and nurses). the organizational readiness for implementing change (oric) survey can assess this construct at the supra-individual level (team, department, or organization) [ ] . when organizational readiness is low, clinicians at these hospitals are likely to see the implementation (educational strategies) for the intervention (niv use in copd exacerbations) as undesirable and potentially avoid or resist planning for the implementation or participating in the implementation [ , ] . the oric will allow us to identify the difference between organizations resisting the change (increasing niv utilization) and sites that are unable to implement the educational strategies due to difficulties inherent in organizing and conducting the educational strategies at their hospital. to assess the readiness of the organization to implement the change, we will use a item survey adapted from the original -item organizational readiness for implementing change (oric) [ ] . this survey will measure change commitment and change efficacy of the organization towards increasing the rate of niv use for copd exacerbations. power and sample size for aim the minimal number of hospitals participating in the trial was based on the analysis of premier - data. hospital rs-niv proportions were calculated for the hospitals with at least eligible copd admissions. the median rs-niv rate among this group of hospitals was % (iqr - %). we then selected the hospitals with rs-niv proportion less than %, based on the clinical impression that these hospitals would have sufficient room for improvement, as potentially eligible sites. among these hospitals, the median number of eligible copd patients was over a -month period, ranging from to patients. the number of ventilated patients per hospital ranged from to , with a median of . to achieve stability in estimation of hospital level rs-niv, we will assess our primary endpoint at months post-intervention expecting a minimum of ventilated patients per hospital in which to assess niv rates. power analysis was conducted to determine the number of hospitals needed to assess the primary outcome of difference between the study arms in change in the hospital level risk-standardized proportion of ventilator starts that are niv (rs-niv). using a type i error rate of . , and standard deviation of change in rates over time derived from our prior work with the premier data base, a total sample of hospitals, in each arm will give % power to detect difference of % in change (e.g., % increase among ole hospitals, vs. % increase among ipe hospitals). power is > % to detect a % difference in change between the intervention groups. to examine the effect of ole and ipe on rt autonomy and team functionality as potential mediators of niv uptake. study design to complete this aim, we will survey clinicians at baseline, year, and end of the study period. participants and settings we will select a random sample of rts for the rt survey and providers ( from each discipline) for team functionality and organizational readiness for change surveys. a waiver of consent will be sent to all potential participants via email, the survey link will be included at the end of the email. to maximize participation, we will provide $ incentives to participants. rt autonomy job autonomy is defined as the degree of perceived control that an employee has over how they perform tasks and the degree to which they operate independently. prior studies showed that it mediates the relationship between employment status, work attitude, and performance [ , ] . in our previous study, indepth interviews with key stakeholders from a sample of hospitals with high use of niv suggested that rt autonomy is critical to achieving timely initiation of niv, often facilitated by the use of protocols [ ] . these results are in line with prior literature [ ] that supports the benefits of autonomous rt practice for weaning from imv [ , ] . factors identified by the interviewees to contribute to rt autonomy were rt-driven protocols, rt expertise, and collegial relationship between rt and physicians. we assume that ipe will increase the physicians trust in rts by allowing them to learn about their abilities and duties and concerns, and that ipe will facilitate team member recognition of their own knowledge with rts being more likely to "speak up" (e.g., to suggest niv use instead of intubation). to assess rt autonomy, we adapted a survey from the -item job autonomy measure from aarons et al [ ] . team functionality the iom and quality chasm reports brought widespread attention to clinical teamwork as a means of improving safety and quality in healthcare [ ] . engagement in training-related activities designed to disseminate knowledge, skills, and attitudes for teamwork (such as ipe) is one way to acquire attitudes and behaviors consistent with teamwork and improve downstream impact on care quality and safety for patients [ ] [ ] [ ] . get all clinicians (physicians, rts, and nurses) involved in the delivery of niv with the goal of promoting mutual trust and effective communication which will improve team functionality and hopefully promote niv use. to assess team functionality, we adapted questions from the -point likert scale assessment of collaborative environment survey (ace- ), a -item questionnaire which measures the perception of interprofessional "teamness" [ ] . we created an -item questionnaire that has been divided into two parts: the first is the -item measure team functionality in managing patients with copd exacerbation and the second is the -item measure team functionality in initiating niv. statistical analysis we will develop a series of models evaluating associations among the intervention, mediators, and outcome, including a structural equation model (sem) to estimate the role of mediators as well as the direct effect of intervention on the outcome [ ] [ ] [ ] [ ] . first, to evaluate the impact of educational intervention on the mediators rt autonomy and team functionality to implement change, multi-level models will be fit, clustering on hospital. additional models will adjust for hospital and practitioner characteristics. next, models for the primary rs-niv outcome will be fit, with these potential mediators as the primary predictors. main effects and interaction models will be evaluated. then, the mediators will also be included as covariates in multi-level models including intervention, to evaluate whether rt autonomy and team functionality have effects on outcome, and after controlling for intervention. finally, multi-level structural equation modeling will then be employed to estimate the indirect effect of the educational intervention on rs-niv in the presence of mediators. analysis will be performed using stata's gsem. this model will allow estimation of the direct effect of ipe intervention relative to ole, in addition to the impact through the mediators (fig. ). power and sample size for aim for aim analyses, power was assessed for educational mode impact on job autonomy for respiratory rt measured by aaron's job autonomy survey (ajas), and team functionality measured by the ace- tool. estimating sample size to achieve % power, using a type i error rate of . , a sample of rt's per hospital, will allow us to detect a moderate (cohen's d = . ) difference in ajas at a -year post-intervention. this is accounting for clustering on hospital with intraclass correlation (icc) in the range of . -. . based upon data from local area hospitals, we estimate staffing of - rts per beds. for a few smaller hospitals, we will hope to include all rts and may fall short of . similarly, for the ace- , a sample size of clinicians ( each of rts, rns, and mds) will achieve % power to detect a moderate effect size difference, accounting for clustering within hospitals, with icc in the range of . -. [ ] . to evaluate the acceptability and feasibility of the ipe and ole strategies and to inform further refinement of the strategies. study design to achieve this aim, we will perform a qualitative study using semi-structured interviews with providers to assess relative importance of various barriers and determinants on the implementation of the two strategies. participants and settings we will recruit a random sample of nurses, physicians, and rts. as it is typical in qualitative research, the total sample is not fixed; depending of the size of the program, we will select - individuals from each profession in each hospital and expect to enroll approximately - providers enabling us to reach thematic saturation. potential participants will be contacted via email by the study research assistant and invited to conduct an interview. a waiver of consent will be included in the body of the email prior to the contact information for the interview. those who are interested in participating will be contacted by telephone to arrange an interview time over the telephone. to maximize participation, we will provide $ incentives and schedule sessions at a time convenient to the participants. data collection we anticipate that interviews will last approximately min. all interviews will be audio recorded and transcribed verbatim. the interview team will consist of one research associate who will be trained by the investigator. the focus of the interviews will be to explore the implementation process-the acceptability and feasibility of the educational training strategies, participation in the training sessions, barriers to participation, adaptation made to the training sessions, and how the niv protocol was incorporated into the clinical workflow. expected outcomes this qualitative analysis will allow us to gain a broader perspective on the process of implementation from the perspective of the participants. we expect to understand and identify barriers and facilitators and their relative importance for this implementation strategy to be the most successful. the knowledge gained from this aim will be important for further application and refinement of ipe for other therapies/interventions directed to the critically ill patients. data analysis transcripts will be reviewed by the interviewer for accuracy. qualitative data management and analysis software (nvivo) will be used to organize and code the data [ ] . the nature of the interviewee role and the setting in which they work will be summarized and reported by location. we will use directed qualitative content methods to analyze interview content, beginning with a coding framework based on our prior work [ , ] . coding will occur concurrently with the interviews to ensure that the interview guide is eliciting data related to the domains of interest. two team members will be primarily responsible for coding and will be supervised by one co-investigator proficient in qualitative analysis. the first interviews will be read by each researcher with the goal of agreeing on the use of the domains and or constructs. this codebook will be used for all interviews going forward, with the team meeting periodically to discuss the emergence of any new codes or to clarify the relevance of domains and constructs to the text. each transcript will be coded twice, once by each researcher. discrepancies will be discussed until consensus is reached. through regular investigators meetings, we will generate overarching themes. the investigation will collect the following information to calculate the costs to initiate the intervention: ( ) cost of the training of the copd-niv team in the ipe arm of the study and inclusive of salary/fringe costs of the implementation specialists travel to the one day training session, ( ) cost of webinars inclusive of speaker costs and video recording costs, and ( ) cost of the continuing educational credits provided to the clinicians attending the ipe sessions at their hospitals and to the copd-niv team for their attendance of the -day session and for teaching the copd-niv-ipe course at their hospital. we propose the following strategies for dissemination: ( ) after study completion, we will host webinars to share the results with the participant hospitals; ( ) we will develop a one-page information sheet with the results and conclusion of the study and distribute it on the premier inc. website; ( ) we will develop a toolkit and implementation manual with step-by-step guidance to help other institutions implement the ipe strategy; ( ) publications and presentations at national and international respiratory and d&i conferences; and ( ) we will work with society of hospital medicine and copd foundation to share the finding of the study to their members. table present the proposed timeline for the study. potential limitation and rational for key decisions why study only education? we have carefully considered other implementation strategies such as audit and feedback, which is an electronic medical records decision support tool and academic detailing. when mapping the barriers within eric compilation of implementation strategies, we found that ipe covered several of identified barriers. additionally, we were concern that using multiple strategies would complicate our attempt to understand the educational intervention impact. interprofessional care is essential to the management of seriously ill patients and in the absence of robust studies to determine if ipe indeed impact patient outcomes, it is critical to be able to assess it in randomized controlled trial. for this pragmatic clinical trial, we need to be able to calculate hospitals' niv rates and identify low performing hospitals to be able to invite them to participate in the trial and determine the rates after the implementation period. our intention was to have these rates calculated directly from the administrative or electronic data without a need for data collection. we did not come across any other database which provides the needs for this trial. still, if the trial shows that ipe is effective in improving the niv rates, individual hospitals will be able to calculate their own rates and decide if they want to implement the ipe strategy. this study will be among the first to carefully test the impact of ipe in the inpatient setting. over the last years, there have been increasing interest in linking ipe with interprofessional collaboration and team-based care [ , ] ; however, only recently have researchers begun to look beyond the classroom and beyond learning outcomes on such issues as patient safety, patient and provider satisfaction or quality, and cost of care. consequently, the institute of medicine report "measuring the impact of interprofessional education on collaborative practice and patient outcomes" questions calls for purposeful, well-designed, robust studies to understand the link between ipe and patient and health systems outcomes [ ] . therefore, our study will add to the evidence by comparing an ipe strategy specifically designed to improve team functionality for niv delivery in a pragmatic randomized controlled trial against an active, realistic control. centers for disease control and prevention. faststats -chronic lower respiratory disease copd exacerbation frequency and its association with health care resource utilization and costs noninvasive ventilation for acute exacerbations of chronic obstructive pulmonary disease randomized, prospective trial of noninvasive positive pressure ventilation in acute respiratory failure non-invasive positive pressure ventilation to treat respiratory failure resulting from exacerbations of chronic obstructive pulmonary disease: cochrane systematic review and meta-analysis contemporary management of acute exacerbations of copd: a systematic review and metaanalysis comparative effectiveness of noninvasive ventilation vs invasive mechanical ventilation in chronic obstructive pulmonary disease patients with acute respiratory failure outcomes associated with invasive and noninvasive ventilation among patients hospitalized with exacerbations of chronic obstructive pulmonary disease nhlbi/whi global strategy for the diagnosis, management and prevention of copd bts/ics guidelines for the ventilatory management of acute hypercapnic respiratory failure in adults. british thoracic society hospital patterns of mechanical ventilation for patients with exacerbations of copd evaluation of a practice guideline for noninvasive positive-pressure ventilation for acute respiratory failure intervention mapping: theory-and evidence-based health promotion program planning: perspective and examples. front public health successful use of noninvasive ventilation in chronic obstructive pulmonary disease. how do high-performing hospitals do it? validation of the theoretical domains framework for use in behaviour change and implementation research a refined compilation of implementation strategies: results from the expert recommendations for implementing change (eric) project making psychological theory useful for implementing evidence based practice: a consensus approach. qual saf health care the behaviour change wheel: a new method for characterising and designing behaviour change interventions the influence of shared mental models on team process and performance knowledge translation interventions for critically ill patients: a systematic review* facilitators of an interprofessional approach to care in medical and mixed medical/surgical icus: a multicenter qualitative study organizational learning: creating, retaining and transferring knowledge new approaches to interprofessional education and collaborative practice: lessons from the organizational change literature a best evidence systematic review of interprofessional education: beme guide no core competencies for interprofessional collaborative practice team effectiveness - : a review of recent advancements and a glimpse into the future cross-understanding: implications for group cognition and performance psychological safety and learning behavior in work teams the validity of international classification of diseases, ninth revision clinical modification diagnosis codes for identifying patients hospitalized for copd exacerbations a s: validity of noninvasive and invasive ventilation billing and procedure codes in patients with acute respiratory failure comparison of hospital risk-standardized mortality rates calculated by using in-hospital and -day models: an observational study with implications for hospital profiling organizational readiness for implementing change: a psychometric assessment of a new measure using organization theory to understand the determinants of effective implementation of worksite health promotion programs national employment systems and job autonomy: why job autonomy is high in the nordic countries and low in the united states, canada, and australia the impact of evidence-based practice implementation and fidelity monitoring on staff turnover: evidence for a protective effect effectiveness and safety of a protocolized mechanical ventilation and weaning strategy of copd patients by respiratory therapists a randomized, controlled trial of protocol-directed versus physician-directed weaning from mechanical ventilation large scale implementation of a respiratory therapist-driven protocol for ventilator weaning crossing the quality chasm: a new health system for the st century does team training improve team performance? a meta-analysis saving lives: a meta-analysis of team training in healthcare teamwork in health care: maximizing collective intelligence via inclusive collaboration and open communication development of the assessment for collaborative environments (ace- ): a tool to measure perceptions of interprofessional "teamness practical issues in structural modeling structural equations with latent variables improper solutions, and starting values in lisrel maximum likelihood estimation the robustness of lisrel modeling revisited sample size requirements for structural equation models: an evaluation of power, bias, and solution propriety three approaches to qualitative content analysis basics of qualitative research: techniques and procedures for developing grounded theory core competencies for interprofessional collaborative practice board on global health, institute of medicine. measuring the impact of interprofessional education on collaborative practice and patient outcomes springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations karen riska acted as a research coordinator and participated in manuscript revisions. taylar clark acted as a research assistant and completed literature review activities and provided editorial feedback on manuscript drafts. authors' contributions ms designed the protocol, wrote the first draft of the manuscript, and provided senior-level conceptual feedback on manuscript revisions. pkl, psp, jss, amh, and cms acted as co-i during the implementation, participated in the design of the protocol, and provided senior-level editorial feedback on manuscript preparations. all authors read and approved the final manuscript. sources of funding: this study protocol has been approved and funded by the nhlbi (nih), r hl .availability of data and materials not applicable for this section ethics approval and consent to participate baystate irb has approved this study and deemed it ethical. baystate irb has also declared that this study is minimal risk, and therefore approved our waiver of consent for the participants of this study. key: cord- - va yyit authors: nan title: its asm date: - - journal: ir j med sci doi: . /s - - -z sha: doc_id: cord_uid: va yyit nan it is my great pleasure to welcome you to limerick, host city to the irish thoracic society annual scientific meeting. we look forward to a very exciting program, offering the best of original research and state of the art guest lectures against the backdrop of warmth and conviviality for which the meeting is known. thank you to all those who submitted abstracts and case studies this year-we received over for presentation, reflecting the high quality and innovative work taking place in research centres throughout the island and further afield. i would also like to thank the abstract review committee and judges for their time and expertise in what is never an easy task due to the increasingly high standard of submissions received. special features of the meeting include guest lectures on 'asthma genomics and the respiratory biome', 'use of niv in acute respiratory failure' and 'the role of nasal electrophysiology in the difficult cf diagnosis' as well as a symposium on 'chronic respiratory failure'. i am delighted to welcome distinguished guest speakers from the uk and usa who will share their expertise on these topics. welcome also to the patient and professional organisations represented. networking and sharing information on the wealth of activities taking place across the respiratory healthcare community has become an integral part of the meeting. i would like to extend a particular welcome to the exhibitors and sponsors of this year's meeting. we are very grateful for their continued support, without which the meeting would not be possible. we present the case of an -year-old gentleman who had an inflammatory neuropathy secondary to a thymoma. he underwent a vats thymectomy, the first case in ireland. the surgery involved a cm transverse incision above the supra-sternal notch, partial mobilization of the thymus, and -port placement with full thymic mobilization and excision. the advantages of a vats approach include lower blood loss ( vs. mls), lower post-operative ventilation rates ( . vs. . %), shorter lengths of hospitalisation ( . vs. . days), and improved cosmesis. the patient made an excellent recovery, discharged to home on post-operative day . we report a case of pleural giant b cell lymphoma in a year old man induced by immunosuppressive therapy for rheumatoid arthritis (ra). despite adequate control of his ra with anti-tnf treatment, this was substituted with leflunomide and prednisolone after a myocardial infarction. he subsequently developed recurrent bloody exudative pleural effusions containing a lymphomatous cell population. prolonged remission was obtained with the anti cd antibody therapy, rituximab. although the attribution of lymphoma with anti-tnf therapy and immunosuppressive treatment remains controversial [ ] [ ] , the association is more than spurious [ ] . despite a low risk of lymphoma from biological therapies, continued vigilance is warranted. pericardial atresia is a rare cardiothoracic malformation. it is mostly diagnosed incidentally, on surgery, or autopsy. it usually has benign symptoms, but herniation of the heart through a partial defect can be fatal. we describe an unusual case of years old zimbabwean lady who presented with severe headache, syncope, bradycardia and orthostatic hypotension. she was also noted to have elevated d-dimers and was hypoxic on room air. a chest x-ray reported cardiomegaly. a ct pulmonary angiogram demonstrated no embolism, but did show features consistent with absence of the pericardium. further cardiac mri confirmed this finding in addition to left ward rotation of heart into left thoracic cavity and four chamber dilatation. a review of the available literature on clinical presentation, diagnostic assessment and therapeutic options is presented. and soft tissue, including primitive neuroectodermal tumors (pnets). it responds relatively well to a combination of surgical resection, chemotherapy and radiation therapy. we describe a years old polish girl who presented with year history of right scapular, paraspinal and anterior chest wall pain. imaging confirmed . . cm mixed solid and cystic mass in right lung apex invading into supraclavicular muscles and neural foramen. the biopsy and immunotyping revealed small round ''blue cells'' soft tissue tumour equivalent of ees/pnet. she had neoadjuvant chemotherapy followed by surgical resection of the tumour with a good result and further planned to continue chemotherapy and evaluate treatment response. a year old man with known kartagener's associated bronchiectasis presented with increased cough and sputum production associated with pyrexia. radiologically, he had a right lower lobe infiltrate but sputum culture and urinary legionella antigen were negative. however, he failed to improve on a penicillin. bronchoscopy was performed and lavage specimens grew legionella pneumophila serogroup . he recovered following treatment with levofloxacin. there was no history of foreign travel but he did sleep in a camper van. there are known subgroups of legionella pneumophila and only serogroup is detected by urinary antigen. culture remains the gold standard. a year old lady was referred to the haematology service with a relapse of follicular lymphoma grade a. following salvage chemotherapy and pre transplant conditioning with alemtuzumab, she had a non myeloablative allogenic stem cell transplant. as part of the investigation for recurrent lower respiratory tract infections a bronchoscopy revealed a large exophytic tumour occluding the anterior orifice of the left upper lobe. biopsy and culture confirmed mycobacterium kansasii. the patient had an excellent clinical, microbiological and radiological response to treatment with resolution of the tumour at bronchoscopy. our case demonstrates an unusual presentation of mycobacterium kansasii. atypical mycobacterial infections although rare must be considered in this patient group. a -year-old woman presented in symptomatic hypercapnic respiratory failure. proximal muscle and neck flexor weakness was noted on examination. pulmonary function testing revealed restrictive physiology. creatinine kinase and serological testing were normal and acid-maltase deficiency was excluded. deltoid muscle biopsy was consistent with myofibrillar myopathy. myofibrillar myopathies are rare, encompassing a heterogenous group of sporadic and familial neuromuscular disorders characterised by slowly progressive muscular weakness. cardiac and respiratory muscles are involved in only a small subset of people. our patient has improved with non-invasive ventilation. further molecular genetic analysis is pending. a -year-old lady presented with dysphagia. she had a right lower lobe pneumonectomy for a t nomo non-small cell bronchial carcinoma years previously. a computed tomography scan of the thorax showed oesophageal dilatation, accounting for the presenting complaint, and an incidental thrombus in the pulmonary artery stump (pas). the formation of a pas thrombus is a common radiological finding following pneumonectomy [ ] . there is no strong evidence to suggest anticoagulation is beneficial in this group of patients. as no respiratory symptoms were present, anticoagulation could not be justified. a -month interval scan showed no thrombus propagation and the patient remained asymptomatic. department of respiratory medicine, beaumont hospital, dublin , ireland a year old gentleman presented to the respiratory clinic with a / history of progressive dyspnoea on exertion associated with cough. he reported longstanding lower limb weakness, progressing to involve his upper limbs. arterial blood gas demonstrated partially compensated hypercapnoeic respiratory failure whilst pfts showed a classic restrictive pattern. electromyography was abnormal and a muscle biopsy confirmed a diagnosis of nemaline myopathy. he was commenced on nocturnal non-invasive ventilation and his respiratory function improved significantly. nemaline rod myopathy is a rare congenital myopathy that typically presents in childhood. presentation in adulthood with respiratory difficulties is highly unusual. jo- positive polymyositis is an inflammatory myopathy and commonly presents with progressive muscle weakness and basal predominant interstitial lung disease. this is a case report of two women with different clinical presentations of jo- positive polymyositis who had bibasal interstitial lung disease on high resolution ct thorax. they both had worsening pulmonary function studies and one of them required icu admission and intubation for management of severe respiratory distress. they both responded to different regimens of iv cyclophosphamide and long term oral immunosuppressants. these cases illustrate the respiratory manifestations of jo- positive polymyositis and its treatment. year old male with a recent history of travelling abroad presented with week history of dry cough and day history of progressive sob on exertion and one episode of haemoptysis. cxr showed rul consolidation and rll effusion, ctpa was negative for pe. subsequently he developed recurrent spikes of temperature and septic screen was negative. he had three different antibiotics regime with no improvement. thereafter multiple blood cultures, vasculitic, typical and atypical microorganism, hiv, tb screen and bronchial washings came back as negative. repeat ctpa and serial cxr confirmed persistent bilateral consolidation. on day of admission he developed new systolic murmur, a-fib and type respiratory failure. tte and subsequent toe confirmed severe mr with mitral valve vegetation and prolapse treated with mitral valve replacement. dublin , ireland years old male admitted year ago with mesenteric ischaemia diagnosed& nstemi, had emergency small bowel resection with right hemicolectomy. admission has been complicated over year by wound infection, multiple pneumonias, multiple line infections, multiple admissions to itu, later diagnosed with short bowel syndrome, and c difficile colitis; and thrombosis of superficial venous system. due to difficult iv access and low albumin. recently admitted to itu deteriorated due to acute electrolyte disturbance. had transhepatic line (tipss) inserted by ir due to difficult iv access and low albumin. day became acutely sob, cxr complete opacification of right lung. chest drain inserted had drained litres of milky fluid, tubogram confirmed leak through diaphragm into pleura. a. mohamed, r. smyth, j.j. gilmartin university college hospital galway, co galway, ireland a year old man presented with a year history of progressive dyspnea. physical examination revealed a right pleural effusion. a chest radiograph and ct scan confirmed the presence of an effusion with thoracic lymphadenopathy and large mesenteric and para-aortic masses. a pleural aspiration was performed and litre of milky white fluid was removed. pleural fluid analysis noted a protein concentration of g/l and a triglyceride level of mg/dl. cytology revealed a wbc count of /ml with % of these being mononuclear. subsequent lymph node and bone marrow biopsy confirmed the diagnosis of chylothorax with small lymphocytic lymphoma. a -year-old gentleman presented with sub-acute onset of dyspnea associated with diffuse bilateral infiltrates on chest radiograph. his respiratory failure worsened despite broad spectrum antibiotics and he required intubation. he had recent type diabetes mellitus that was well controlled on oral hypoglycaemics. bronchial washings were positive for pcp on silver stain. despite extensive testing a cause for immunological deficiency could not be identified. he developed ards related fibrosis and died. pcp is the most common opportunistic infection in aids patients [ ] , it has been rarely reported in previously well, immunocompetent patients. an year old non-smoking female presented to the er with a week history of progressive dyspnoea and cough. the patient also recounted difficulty reclining at night to the point where she slept in a sitting position. examination revealed mild expiratory wheeze and hypoxemia on room air. initial clinical impression was of an infective exacerbation of late onset asthmatic bronchitis. cxr demonstrated a large hiatus hernia. pulmonary function studies showed a mixed obstructive and restrictive pattern. ct thorax revealed large diaphragmatic hernia with evidence of compression of the main bronchi. bronchoscopy showed dynamic airway collapse with complete obstruction of the left and right main stem bronchi and distal trachea on coughing. this represents an unusual cause of dynamic airway collapse and the imaging and literature are reviewed. a year old lifelong non-smoker with asthma presented to er with a days history of worsening breathlessness. on examination he was unable to complete sentences and reduced air entry through out chest.cxr showed right middle lobe consolidation. he had been treated as infective exacerbation of asthma. but unfortunately he deteriorated later on that day progressing to respiratory and circulatory failure and subsequently to disseminated intravascular coagulation. although having best of icu care he passed away the following day. all of his investigations including blood culture, atypical pneumonia screen, h n serology were came back negative. his post mortem examination hasn't revealed any cause other than right sided pneumonia contributing to his death. this represents a shocking but mysterious case of pneumonia as the cause of death. a year old gentleman was referred to the rapid access lung cancer service with a week history of progressive sob and new pleural effusion. of note, he had recently presented to his general practitioner with two soft tissue lesions on the right flank. on examination, axillary lymphadenopathy was palpable with a noted interval increase in the size of the cutaneous lesions. trucut biopsy of the skin lesion and pleural aspiration revealed a histological diagnosis of mantle cell lymphoma. subsequent radiology showed extensive systemic disease and chemotherapy was offered. our case illustrates the extranodal involvement that can occur in mantle cell lymphoma, however, patients rarely present with initial cutaneous involvement as in our case. a year old gentleman was referred to our lung cancer clinic with abnormal chest x-ray and palpable supraclavicular node. a staging ct thorax suggested lung primary with mediastinal and supraclavicular nodes. a biopsy of the palpable node showed hodgkin's disease (hd). a ct-guided biopsy of the lung lesion favoured lung primary and mediastinal nodal sampling revealed hd. he proceeded to lobectomy for excision of the primary lung lesion and the pathology returned a non hodgkins lymphoma. this case illustrates a presentation of dual pathologies: both hodgkins and non hodgkins lymphoma in the same patient mimicking locally advanced lung cancer. a -year-old man presented with a -month history of back pain and cough. he had a normal chest radiograph and was reassured. subsequent haemoptysis in this patient prompted ct imaging which showed a large left lower lobe mass that was concealed by the cardiac shadow. further mri imaging revealed extensive spinal metastases and thus stage iv disease. we wish to present a case series of five patients with benignappearing single plane chest radiography. further imaging revealed advanced stage lung cancer in these patients. these cases illustrate limitations of single plane radiography and identify anatomical areas where tumours may be missed such as behind the heart. they emphasise the importance of obtaining lateral films and ct imaging in patients with a reassuring single plane chest radiograph where clinical suspicion persists. a year old latvian security guard with a background of relapsing polychondritis and recurrent escherichia coli lrti's, represented to hospital with recurrent haemoptysis and pyrexia of unknown origin. hrct thorax revealed innumerable randomly distributed pulmonary micronodularity. bronchoscopy and bal were unremarkable. fresh sputum cytology confirmed the diagnosis of pulmonary nematodes consistent with strongyloides stercoralis. the patient was treated with high dose ivermectin, resulting in complete resolution of the pulmonary micronodularity. this case report discusses the diagnostic criteria for relapsing polychondritis, the international issues of pulmonary nematodes and the importance of understanding the three radiological subtypes of pulmonary micronodularity (random, centrilobular and peri-lymphatic). a year old gentleman with severe autism spectrum disorder (asd) presented acutely to the emergency department with behavioural disturbance. his prior history was notable for a right lower lobe infiltrate on chest radiography identified year prior to admission. his behavioural disturbance manifested by self harm, and had previously precluded in-hospital investigation. ct thorax confirmed right lower lobe consolidation and flexible bronchoscopy identified a . cm tree branch within a segmental bronchus of the right lower lobe. this case highlights the importance of flexible bronchoscopy and the difficulties of access to appropriate care for those patients with asd. a year old male was admitted with pleuritic chest pain after knee replacement. routine bloods, including liver function tests were normal. a chest radiograph showed right upper quadrant calcification. ct pulmonary angiography was normal but a ct abdomen showed an area of calcification in segment of the liver with low attenuation centrally consistent with a hydatid cyst. hydatid disease is caused by ingestion of the dog tapeworm echinococcus granulosus. it is uncommon within ireland. treatment includes monitoring of chronic cysts, medical therapy with antibiotics in combination with either surgery of percutaneous drainage. a year old female smoker was admitted with right sided pleuritic chest pain. ct thorax showed extensive right lung consolidation and bronchiectasis. bronchoscopy showed unexpected thickening and nodularity of the upper trachea. biopsies confirmed tracheal amyloidosis and immunohistochemical staining of the deposits was negative for serum amyloid a protein, transthyretin, and kappa and lambda immunoglobulin light chains, indicating amyloid of non-aa type. there was no evidence of amyloid at any other location. patients with tracheobronchial amyloidosis may be asymptomatic or present with dyspnoea, cough, haemoptysis or recurrent pneumonia. department of respiratory medicine, beaumont hospital, dublin , ireland a -year old male presented to beaumont hospital with dyspnoea, cough and haemoptysis due to alveolar haemorrhage, requiring icu admission for high frequency oscillatory ventilation and iv cyclophosphamide. originally diagnosed with a pauci-immune vasculitis, a lung biopsy confirmed a diagnosis of pulmonary capillaritis requiring escalating treatment with pulsed iv steroids and immunosuppression. while initially clinically stable, he has had multiple icu admissions, and during an exacerbation presents with symptoms of dyspnoea, a dropping haemoglobin and bilateral infiltrates on chest radiograph. he is now managed by an adult respiratory service with specialist advice, with iv steroids, iv ig and rituximab. we discuss a minimally invasive approach with video assisted thoracoscopic surgery (vats) in performing thymectomy procedures for cases of myasthenia gravis. a year old female was referred with a background history of myasthenia gravis. despite optimal medical therapy m.n. still experiences persistent symptoms and occasional hospitilization for iv immunoglobulins. a ct thorax showed an enlarged thymus. using a three port vats technique the thymectomy was completed and she was discharged days post operation. this case illustrates the possible benefits of minimally invasive approach to thymectomy and avoidance of sternotomy for cases of myasthenia gravis. we report the case of a y.o man who presented with classical pancoast syndrome symptoms caused by a large apical ewing's sarcoma of the chest wall. neoadjuvant chemotherapy localized the tumour to the first rib. complete enbloc surgical resection of the mm residual mass (entire first rib, partial second rib and sublobar lung) was accomplished by a combined anterior hemiclamshell and posterior approach. ypt . the c nerve root was spared and this led to a complete resolution of symptoms. we report the case of an y.o. who underwent curative resection by right sided lobectomy for a pt an adenocarcinoma. she developed this uncommon syndrome of intracardiac shunting of blood immediately post extubation. this syndrome causes profound dyspnoea as a result of arterial hypoxia which is accentuated by the upright position and relieved by recumbency. echocardiography based on clinical suspicion was diagnostic. this was successfully treated by the placement of an occluder device the patent foramen ovale. the case of a year old male smoker with a week history of haemoptysis, night sweats and dyspnoea on exertion is presented. chest radiography confirmed a right upper lobe thick-walled cavity with adjacent nodularity. both transbronchial and percutaneous biopsy sampling was non-diagnostic and microbiological testing was negative. following an episode of large volume haemoptysis he underwent emergency lobectomy. final histopathologic examination confirmed an anaplastic lymphoma kinase (alk)-negative pulmonary anaplastic lymphoma, an extremely rare cause of pulmonary cavitation. we report a g d homozygote: fev % predicted, oxygendependent with recurrent exacerbations ( in months) awaiting transplant assessment, started on ivacaftor through a named patient program. within weeks transplant assessment was deferred, fev had increased to % predicted, continuous oxygen was discontinued, sweat chloride had fallen from to mmol/l and exacerbation rate decreased to in months prospectively. a year old lady presented with headache and cough. neuroimaging raised the possibilitiy of cns mycobacterial infection. pansensitive mycobacterium tuberculosis was cultured from bronchoalveolar lavage. the patient experienced a type hypersensitivity reaction following the first dose of intravenous rifampicin. the patient was commenced therefore on iv amikacin, oral moxifloxacin and ethambutol. intravenous desensitisation to rifampicin was carried out using a day protocol. this was successful allowing the patient to return to oral therapy for the duration of her treatment. ipf and panca-positivity predating vasculitis is known but not widely appreciated. we describe two cases of ipf, initially anca-negative who became anca-positive with associated vasculitis. a -year-old, house-wife diagnosed with ipf in was anca-negative. in she was more breathless with borderlinepositive panca (repeat negative). in , she developed acute mononeuritis multiplex, with a highly positive panca, responsive to immunosuppression. ipf remained stable throughout. a -year-old male, with established ipf (anca-negative), presented acutely with alveolar haemorrhage, renal failure and now panca-positive, responsive to plasma exchange, haemodialysis and immunosuppression. these cases support the rationale for serial anca measurements in ipf. bronchoscopy in a year old female months after radical chemoradiotherapy and oesophageal stent insertion demonstrated stent erosion into the proximal trachea with recurrent oesophageal scc obstructing the carina. a mm covered ultraflex tracheal stent was deployed, with an oesophageal stent telescoped proximally into the displaced oesophageal stent. imaging out ruled a leak facilitating oral intake. six weeks later, staged cryotherapy and stenting of the carinal obstruction was successfully performed. cork university hospital, wilton, cork, ireland, mercy university hospital, cork a -year-old male was reviewed with increasing shortness of breath, hoarseness and stridor. his past medical history was remarkable for supraglottic amyloidosis. these lesions were thermally ablated in . he was followed up routinely. a ct thorax and subsequent bronchoscopy and biopsy was undertaken. at bronchoscopy he was found to have two large nodular protrusions that were biopsied. pulmonary amyloidosis is rare and manifestations include tracheobronchial infiltration, parenchymal infiltration (amyloidomas) persistent pleural effusions and pulmonary hypertension. symptoms of tracheobronchial amyloidosis can include hoarseness, stridor, dyspnoea and overt airway obstruction [ ] . treatment involves invasive bronchoscopic therapies such argon photocoagulation (apc) and occasionally surgery [ ] . we present two mushroom workers with bird fancier's lung. workers presented with progressive dyspnoea, cough and sweats, with features of hypersensitivity pneumonitis on hrct, pfts and bal/tbbx. serological studies to aspergillus fumigatus, saccharopolyspora rectivirgula, thermophilic actinomyces were negative but positive for avian proteins. workplace process analysis revealed chicken litter as fundamental in mushroom compost production. both workers received corticosteroids with symptomatic and radiological improvement. workplace relocation resulted in complete resolution of symptoms in one worker. the second worker remains exposed, wearing appropriate ppe with ongoing medical surveillance. detailed workplace analysis may be required in proper diagnosis of work-related respiratory diseases. wheeze is a continuous musical sound that lasts longer than ms [ ] . upper airway obstruction is commonly misdiagnosed as asthma. we describe four cases presenting with upper airway obstruction of different aetiologies. a -year-old female was referred with 'poorly controlled asthma'. inspiratory stridor was noted on physical exam and spirometric flow volume loops showed variable extrathoracic airway obstruction. laryngobronchoscopy confirmed paradoxical vocal cord movement. ir j med sci ( ) (suppl ):s -s a -year-old female was referred with 'poorly controlled asthma'. physical exam revealed inspiratory stridor and spirometric flow volume loops showed fixed upper airway obstruction. larynogbronchoscopy revealed subglottic stenosis. a -year-old male with a -pack-year history of smoking was referred with worsening wheeze. physical exam and investigations revealed subtotal tracheal compression secondary to a retrosternal goitre which was successfully resected with resolution of symptoms. a -year-old male was referred with wheeze, fatigue and intermittent apnoea while sleeping on his left side. physical exam revealed inspiratory stridor and spirometric flow volume loops showed fixed upper airway obstruction. ct thorax and bronchoscopy revealed a congenital double aortic arch, splitting to come around the trachea (see fig. ) causing tracheal compression. the four cases show the importance of considering misdiagnosed upper airway obstruction in the assessment of wheeze. a year male smoker with gastro oesophageal adenocarcinoma developed dyspnoea on treatment with epirubicin, oxaliplatin, and capecitabine, raynaud's phenomenon was noted and hrct showed bilateral interstitial infiltrates. scl antibodies were positive and thoracoscopic lung biopsy confirmed scleroderma-associated interstitial lung disease. patients receiving pneumotoxic agents should be assessed thoroughly for other causes before a diagnosis of drug-induced interstitial lung disease is considered. mid-western regional hospital limerick, limerick, ireland a year old woman presented with recurrent lower respiratory tract infections and weight loss of over a stone over the last months. she was a smoker of pack year. ct showed diffusely abnormalities in both lungs. there was ill-defined pulmonary nodules with small cavitating lung lesions. specimens taken from vats showed numerous airway-centred and airway-destructive nodules composed of eosinophils and large histiocytes with vesicular chromatin that are cd a positive. this is consistent with langerhans cell histiocytosis. she was advised on smoking cessation which she adhered to. follow-up cxr showed complete resolution of the multi-focal interstitial infiltrates several studies reported relationship between anca-associated vasculitides and malignancies (pre-existing or developed during patients follow up), bringing to discussion the putative role of tumor antigen in driving the auto-immune response. we describe the case of years old male with e-cadherin genetic mutation, mandibular cementoma, horse shoe kidney, alopecia and nails dystrophy who presented with haemoptysis and bilateral pulmonary infiltrates years after his first asthma diagnosis. bronchial washings demonstrated pigment laden cells consistent with alveolar haemorrhages. serological tests showed positive c-anca. there was no renal involvement. he was successfully treated with high dose of corticosteroids. we present an interesting case of endobronchial tb in patient who lacked normal host immunity. a gentleman ( years) presented with haemoptysis on a background of ulcerative colitis managed with mesalanine and azathioprine. bronchoscopy demonstrated a mass partially occluding the left main bronchus. pan-sensitive mtb was isolated and he was treated for months. four months following presentation an endobronchial resection was performed. however, repeat bronchoscopy following nine months of treatment demonstrated a persistent lesion in the left main bronchus and a new lesion in the trachea. the recurring lesion was characterised by the persistent afb, that were stainable, but did not grow. conclusion: the immune derangement, characteristic of inflammatory bowel disease patients, contributed to his aberrant persisting host response to dead organism. [ ] . in these two cases dipnech was diagnosed along side carcinoid tumour via lobectomy and mediastinal lymph node sampling. one patient was symptomatic for at least months prior to diagnosis complaining of episodic wheeze, flushing and diarrhoea. this patient was treated with a somatostatin analogue post operatively. dipnech has rarely been described and its prognosis and management have varied from several different case reports [ ] . these two cases highlight, that although a rare entity, it needs to be considered in cases of symptomatic cough and wheeze with radiological findings suggestive of discrete pulmonary nodules. in march , the first case of a subsequent outbreak of pansensitive mycobacterium tuberculosis, beijing strain, was diagnosed in a man from an irish prison. last year, the first patients in this sequence were presented. herein we discuss eight further cases connected to this outbreak. all cases, but one, are males of european origin aged between and years. clinical presentations ranged from classical symptoms of night sweats and weight loss to acute abdomen. four of the pulmonary tb cases had, on initial presentation, acid fast bacilli positive sputum on microscopy and culture. the radiological disease was primarily consolidation or cavitating lesion in the upper to mid zones. more than a year later, this case series continues to highlight the ongoing and mounting difficulties of managing this irish prison outbreak. a year-old irish male presented with a month history of dyspnoea, unsteady gait, numbness over both flanks and weight loss. he attended months earlier at another centre with swollen painful right testes. cxr demonstrated bilateral hilar lymphadenopathy, and rightsided pleural effusion. ct tap revealed marked mediastinal lymphadenopathy with right sided pleural effusion, mild splenomegaly, ill-defined right testes, and bilateral inguinal lymphadenopathy. serum ldh and ace were elevated. thoracentesis revealed serosanguinous exudative fluid. transbronchial and inguinal lymph node biopsy revealed evidence of non-caseating granulomas. mri spine revealed abnormal cystic areas throughout thoracic and lumbar spine. a diagnosis of sarcoidosis with multisystem involvement was made and high dose steroids were commenced with good clinical response. pleural and spinal cord sarcoidosis is a rare and interesting presentation. histology showed chronic inflammatory change and ulceration of the bronchi with no evidence of vasculitis or granuloma. no malignancy was evident. pulmonary changes similar to this have been described in patients with uc. alpha- antitrypsin deficiency (aatd) is an autosomal co-dominant genetic disorder associated with a substantially increased risk for the development of chronic obstructive pulmonary disease (copd) and liver disease. ats/ers guidelines recommend testing of all individuals with copd and poorly controlled asthma. the objective of the study was to investigate the diagnostic experiences of zz aatd individuals in ireland. a total of zz aatd individuals completed a questionnaire at an alpha- clinic in relation to their diagnostic experiences and clinical presentation. the mean age of symptom onset was . ± . years (range . - ); mean age of diagnosis was . ± . years (range . - ). the interval between onset of symptoms and aatd diagnosis was years. the smoking history analysis revealed % were past smokers, % never smokers and % were currently smoking. for the past smokers cohort % stopped smoking within the first months of a diagnosis of aatd; % stopped smoking after the first months of a diagnosis of aatd and % had stopped smoking prior to a diagnosis of aatd. our results further underline the need for increased awareness and early detection of symptomatic aatd individuals in the irish population, especially among the copd population. aat deficiency (aatd) results from mutations in the serpina gene, classically presenting with early-onset emphysema and/or liver disease. the most common mutation causing aatd is the z mutation, with the s mutation weakly associated with lung disease. aat deficiency is under-diagnosed and prolonged delays in diagnosis are common. ats/ers guidelines advocate screening all copd, poorlycontrolled asthma, and cryptogenic liver disease patients, as well as first degree relatives of known aatd patients. over , individuals have been screened to date following ats/ ers guidelines in the national targeted detection programme. sequencing of the serpina gene was performed to identify rare mutations. we have identified zz, sz, ss, mz, ms, and over individuals with clinically significant rare phenotypes (e.g. iz, fz, is, null, mmalton). this yields gene frequencies of . and . for s and z, respectively, in this targeted population. a number of rare and novel serpina mutations have also been identified. our results underline the need for increased awareness and early detection of aatd. all copd patients should be tested for aatd as per ats/ers guidelines. our data demonstrates that aatd in ireland is not a rare disease but a disease that is rarely diagnosed. rationale: alpha- antitrypsin (aat) deficiency (aatd) is genetic disease that results in low levels of aat and predisposes individuals to developing chronic obstructive pulmonary disease (copd). the z-allele is responsible for [ % cases of aatd. key studies have demonstrated that excessive infiltration of neutrophils into the lung and neutrophil derived proteins play a pathological role in aatd lung disease. in particular a key cytokine associated with copd disease progression is tnf-alpha which is also the cause of many problems associated with autoimmune diseases. the aim of this study was to determine if there is a novel autoimmune element driving inflammation in aatd and examine aat impact on this. methods: plasma and neutrophils were isolated from mm controls, asymptomatic zz aatd and aatd patients receiving augmentation therapy. tnf-alpha was quantified by a sandwich elisa. evaluation of neutrophil degranulation was carried out by western blot analysis of neutrophil supernatants for markers of tertiary (mmp- ) and secondary granules (lactoferrin) and via flow cytometry. autoantibodies against neutrophil granule proteins were quantified in plasma by elisa. results: our results demonstrate that there are high levels of tnfalpha in aatd plasma compared to controls (p = . ). in vitro, tnf-alpha caused an increase in the rate of degranulation of tertiary and secondary granules from zz aatd neutrophils compared to mm cells (p \ . ). analysis of autoantibodies against major neutrophil granule proteins revealed a high titer of anti-lactoferrin igg autoantibodies present in patients with zz aatd. treatment of aatd patients with aat augmentation therapy resulted in a decrease in the plasma levels of neutrophil granule proteins while also reducing the titer of anti-lactoferrin igg autoantibodies (p \ . ). conclusion: this study has uncovered that tnf-alpha inflammatory signaling pathway can result in the development of an autoimmune element in aatd. furthermore it highlights aat therapy can impact on neutrophil degranulation and thereby reduce development of novel anti-lactoferrin autoantibodies. chronic hypoxia (ch) exposure induces diaphragmatic remodelling similar to chronic obstructive pulmonary disease (copd). elucidating the underlying mechanisms may inform therapeutic strategies to combat muscle dysfunction in copd. this study investigates the effects of ch on redox homeostasis in mouse diaphragm muscle. c bl j mice were exposed to one and weeks of ch ( % f i o ) or normoxia. following treatment, excised muscles were homogenised and incubated with carbonyl-or thiol-reactive fluorophores before gel electrophoresis and fluorescence scanning. optical density (od) of fluorescence was normalised to total protein, determined by colloidal coomassie staining. a nine-fold increase in free thiol groups was observed after week of ch ( . ± . vs. . ± . ; mean od ± sem, ch v normoxia, n = per group; p = . , student's unpaired t test), while there was a significant decrease after weeks. a significant increase in carbonylation was observed after weeks of ch ( . ± . vs. . ± . ; mean od ± sem, ch vs. normoxia, n = per group; p \ . ). we have demonstrated that despite a reduction in oxygen tension and a large, initial increase in free thiol groups, weeks of ch significantly increases oxidative stress in mouse diaphragm muscle. changes in redox homeostasis are likely to affect redox-malleable proteins that are central to muscle performance. a- antitrypsin (aat) is a -kda glycosylated-protein synthesised in the liver which functions as a serine protease inhibitor. the pizz variant is associated with early onset emphysema. we hypothesize that a difference in the number of isoforms and the n-glycosylation pattern of pimm and pizz aat protein exists. the aim of this study was to compare the isoform composition of aat from pimm controls with that of pizz individuals. aat from pimm and pizz individuals was extracted and purified from plasma using alpha- -antitrypsin select-affinity chromatography medium. isoelectric-focussing of purified aat was performed followed by d-page. gels were stained with coomassie brilliant blue and were immuno-blotted for aat. eight and six isoforms of pimm and pizz-aat were identified by d-page, respectively. densitometric analysis demonstrated higher protein expression of pimm-aat compared to pizz-aat. the pi range of pimm-aat was . - . and the range for pizz-aat was . - . . the pizz-aat demonstrated a . - . pi cathodal shift of all bands, supporting the hypothesis that the pizz-aat protein is differentially n-glycosylated. this study confirms the presence of multiple isoforms of pimm-aat and demonstrates at least different isoforms of pizz-aat. this requires further investigation to establish differences in n-glycan groups and possible functional consequences. understand the therapeutic potential of alpha- antitrypsin alpha- antitrypsin (aat) is a glycosylated protease inhibitor found in human plasma. aat deficiency predisposes individuals to early onset emphysema and treatment currently consists of weekly intravenous infusions of purified plasma aat. although aat has previously been shown to exert anti-inflammatory properties by binding interleukin- and apolipoprotein b- , the latter being implicating in atherogenesis, hypothesized that aat may have multiple binding partners and that these complexes are involved in additional regulatory and anti-inflammatory pathways. the aim of this study is to identify all proteins that interact with aat as it circulates throughout the body in order to fully understand its therapeutic potential. to examine aat's interaction with potential linker proteins, permeation chromatography of plasma through su-perose / gl was performed. protein profiles were visualized by coommassie blue staining of sds-page gels and western blotting. immuno-bands were quantified by densitometry. aat eluted with molecular masses of approximately and kda indicating multiple binding partners, with the remainder eluting at the predicted molecular mass of kda. protein identification by mass spectrometry (lc ms/ms) is required to identity novel binding partners. identification of all proteins that bind to aat will progress our understanding of the molecular mechanisms by which aat regulates inflammation. ultimately identification of new functions of aat may be utilised to develop novel treatment options for chronic inflammatory diseases including cystic fibrosis, copd and severe asthma. no potential conflict of interest is reported. transthoracic echocardiography, neurocognitive/psychological assessments were also performed. on follow-up, all patients had normal renal function. two of seven had reduced respiratory and cardiac functions. had slightly reduced neurocognitive functions and had decreased feeling of well-being, and from depression. in this small follow up study of a cohort of severe h n patients, there was good recovery. given the initial severity of their respiratory decline i.e., requiring ventilation, this group did not seem to suffer severe chronic respiratory functional limitation. cryptogenic organising pneumonina (cop) is a disease of unknown cause, which can occur in the context of connective tissue disease. a more aggressive variant termed rapidly-progressive cop follows a fulminant course, leading to respiratory failure, and has high mortality [ ] . a -year-old gentleman with a history of dermatomyositis presented with dry cough and dyspnoea on exertion of -months duration. computed tomography (ct) of the chest revealed subpleural patchy ground glass opacities involving both lungs. bronchoalveolar lavage (bal) showed benign bronchial epithelial cells with % macrophages, % neutrophils, % lymphocytes and % eosinophils. staphylococcus and hemophilus were isolated on culture. broad-spectrum antibiotics and steroids were commenced. there was evident improvement clinically, and on pulmonary function tests, however, no significant change on ct chest neccesitated vats biopsy.histopathologic findings were consistent with cop. h after vats biopsy patient developed acute onset dyspnoea with respiratory failure requiring mechanical ventilation and intensivecare-unit admission. ct chest (see fig. ) showed diffuse worsening of ground glass appearance and left lung consolidation. despite best efforts to rescuscitate the patient he passed away h later. this represent a fatal case of rapidly progressive cop resistant to steroids. rapid deterioration resulted in poor prognosis with no lea way of trial of immunosupressive therapy. over a week period thirty seven patients were admitted by nchds to cork university hospital with clinical diagnosis of community acquired pneumonia. an audit was performed on the choice of antibiotic by nchd in comparison to the local antimicrobial guidelines based on a patients curb- score. this audit also compared the admitting nchd's interpretation of a chest x-ray and this was compared to the formal report given by the radiology department. the audit highlighted that antimicrobial prescribing in adherence with local guidelines weakened with an increasing curb- score. in total . % of patients were prescribed antibiotics according to the local guidelines. this fell to . % for a curb- score of / . approximately % of nchds incorrectly diagnosed an infiltrate on chest x-ray which was later refuted by the formal radiology report. antibiotic resistance is a growing global concern and adherence to selected local and regional guidelines for prescription of antibiotics is paramount in reducing the spread of resistance pathogenic bacteria [ ] . reference: rapid administration of guidelines-compliant empiric antibiotic therapy in emergency department (ed) can reduce mortality in patients admitted with community-acquired pneumonia (cap) [ ] . a -week prospective audit was conducted in january to assess adherence to local guidelines and use of curb- score in treatment of such patients. all patients admitted via ed during acute medical take with symptoms and signs of chest infection and new localising radiological shadowing were included. there were relevant admissions ( males, age - years, mean . ). curb- was calculated in ( . %) patients. seven patients ( . %) received antibiotics according to guidelines. in patients without curb- estimation adherence to guidelines was . % vs . % in those with curb- . the results of the audit were presented at hospital grand rounds and new copies of guidelines were circulated to each ward and ed. a laminated copy was placed in a prominent position in ed. a week prospective re-audit was conducted in april ( admissions, males, age - , mean . years) and demonstrated an increase in appropriate antimicrobial prescribing to . % vs . % in the original audit. appropriate antibiotics prescribing was again higher when curb- was calculated. medicine is an evolving field with increased pressure to produce an optimally functioning health care system within budget constraints. there is a current vogue of specialisation, with medical practitioners moving further from general medicine, to condition specific delivery of services. our key concern was whether the case mix breakdown warranted further stratification of the general respiratory outpatient clinic based on conditions. data of patients attending a respiratory clinic was collected for year. the primary diagnosis was coded using international classification of diseases ( th revision) coding scheme and analysed using a statistical analysis package (spss). asthma (n = , . %), copd (n = , . %) and sarcoidosis (n = , . %) accounted for . % of patients and the remainder of the top fifteen conditions were all respiratory in nature. . % (n = ) of attendances were for non-respiratory diseases as the clinic also provides follow-up for general medical patients post hospital admission. the gender mix was male (n = ) . %; female (n = ) . %. the mean age was . years (sd = . ). the difference in mean age for asthma ( . sd . ) and copd ( . sd . ) was significant at . (p = . ). the above analysis reveals a strong case for the creation of three specialist outpatient clinics, for asthma, copd and sarcoidosis. the single breath method to measure diffusion capacity requires a subject to inspire a gas mixture followed by a s (s) breath hold. we sought to determine if breath hold time reduction had a significant effect on measured lung diffusion for carbon monoxide (dlco) values. forced spirometry and co diffusion by the single breath method (dlcosb) were performed in duplicate with breath hold for s, s and s in controls (fev ± . % predicted), severe copd patients (fev . ± . % predicted), and patients with interstitial lung disease (ild) (fev . ± . % predicted). there was no significant difference between dlcosb and dlco(va) measured at , and s in the control (p = . ) and interstitial lung disease (ild) groups (p = . ). however, there was a significant difference between dlcosb (p = . ) and dlco(va) (p = . ) measured at , and s in the chronic obstructive pulmonary disease (copd) group. in the presence of severe airway obstruction the dlco decreases with breath hold time reduction. however, in healthy controls and patients with ild, there was no significant change in the dlco when breath hold time is reduced from to s. this could allow for a reduction in breath hold time when measuring the dlco in patients with advanced ild who are unable to breath hold for s. current guidelines recommend mechanical insufflation-exsufflation (mi-e) for airway clearance [ ] . the aim of this study was to determine the current use of mi-e in neurological conditions by physiotherapists in the uk. a questionnaire was sent to relevant members of the exercise has been shown to improve quality of life in respiratory patients. through exercise, pulmonary rehabilitation operated on the concept of encouraging people with chronic obstructive pulmonary disease (copd) to improve their exercise capacity and subsequently reducing the incidence of copd exacerbation and admissions to hospital. methods: this cross sectional study was conducted between january and february at the mid-western regional hospital, limerick, ireland. all patients attending our respiratory clinic over a period of weeks were invited to complete a questionnaire on arrival at the clinic. findings: the total number of participants was seventy-eight. asthma was the most frequently listed respiratory illness (n = ).fifty-two patients said they exercised ( . % of the study population). higher levels of exercise participation were seen in the younger age groups (p = . introduction: respiratory diseases, largely represented by copd, are the third most common cause of acute hospital admission.our aim was to audit the prescribing habits of inhaled, nebulised medication and oxygen by doctors in a general hospital. methods: all adult patients admitted medically with chronic respiratory diseases that were on inhaled or nebulised medication were included prospectively (jan to june ) in this study. a proforma was used to collect data from the patients. results: there were patients ( % male). the mean age was . patients ( %) had a diagnosis of copd and the others had asthma and pulmonary fibrosis. seven patients ( %) were currently smoking. four patients ( %) were on long term oxygen treatment. in only % of patients the correct dose of inhaler was prescribed. patients ( %) had the correct inhaler device charted. none of the patients had their inhaler technique checked on admission. in only % the dose of nebulised medication was charted. patients were given oxygen of which only was prescribed ( %). conclusion: this audit proves that our prescribing habits of inhaled, nebulised drugs and oxygen are not good. we intend to present this data to our colleagues and reaudit again. adherence to inhaled medications is difficult to assess. a prospective, observational study on patient inhaler usage while in hospital was carried out. the hypothesis was as inhalers are left at the bedside and not administered directly, doses are being missed. a device was designed that makes an acoustic record each time an inhaler was used. the drug prescription sheets on medical wards were screened to identify patients who were prescribed fluticasone/salmeterol via diskus. patients were then approached and asked to participate. the devices were analysed by two independent investigators. doses were classified as early if \ h and late if [ h were between doses. errors were classified as not priming the device correctly, blowing into the device, insufficient inhalation, inadequate breath hold. among patients, taking doses, ( %) doses were taken too early, while separately ( %) doses were missed. in addition, patients blew into the inhaler ( %) times and inadequately inhaled or failed to hold breath ( %). overall, ( %) had an error either in timing or technique. none of these irregularities were documented in the drug prescription sheet. in conclusion, administration of inhalers should be directly supervised by staff, documented and an action plan for patients that are unable to use inhalers be drawn up. results: patients participated in the audit. % knew the names of their respiratory medication, and % knew the general indication for their respiratory medication. % understood the specific indication for their preventer inhaler, % for their reliever inhaler, and % for the combination inhaler. % of patients knew the correct frequency of use of their inhaler, with % of patients demonstrating adequate inhaler technique. % of participants had previously being reviewed and educated by a respiratory nurse. conclusion: a significant percentage of respiratory patients lack adequate knowledge of their respiratory medication; this is despite a majority having previously been educated on this medication. recommendations: ongoing education and regular assessment of respiratory patients needs to occur. ir j med sci ( ) hcws are a cohort at risk of mycobacterium tb infection. qft-g, a lab based assay, is free of the bias and errors of tst placement or reading with the need for - h follow-up for interpretation eliminated. . % of our cohort had a false positive tst, which calls the sensitivity of this test into question. qft-g has been proven to approach % sensitivity [ ] and % specificity [ ] and is therefore a suitable replacement for tst in hcw screening. while there has been an increased recognition of non-tuberculous mycobacteria (ntm) as a clinical problem, much of this experience has come from specialised population such as cystic fibrosis patients. we evaluated our experience in a general respiratory service. positive non tuberculous mycobacterial culture results in st. vincent's university hospital from january to july were reviewed. patients with a known diagnosis of cystic fibrosis were excluded. fifty-six patients were identified with positive cultures for nontuberculous mycobacteria. thirty-eight isolates were from the respiratory tract, of which fourteen samples were sputum samples, thirteen samples were from both bronchial lavage and sputum and nine samples were bronchial lavage. the medical records of thirteen patients (seven female, six male) with probable disease were reviewed. the most frequent isolated ntm in our institution are mycobacterium avium (n = ). two patients had mycobacterium szulgai. mean age was . ± . years; all except one patient had underlying respiratory disease. five of the thirteen patients received some treatment for ntm but only three completed a full course due to intolerability to the medications and also side-effects. our studies confirm that ntm primarily affects patients with chronic lung disease and that the treatment for this disorder is poorly tolerated. lymphopenia in active mycobacterium tuberculosis (mtb) infection is a common and well-documented finding. rather than being an epiphenomenon, this effect likely contributes to pathogen persistence in the host and the lack of a meaningful response during chronic mtb infection. our study was designed to determine the baseline and post-treatment values of total lymphocyte count and its subsets in hiv-negative patients diagnosed with active pulmonary mtb. we prospectively recruited hiv-negative patients diagnosed with pulmonary mtb infection over a -month period. pre and post treatment analysis of total lymphocyte count and its subsets were performed at baseline and after months of tb chemotherapy. a control group comprising of patients with community acquired pneumonia also had pre-treatment lymphocyte counts performed. ten patients with active mtb infection and seven comparable controls were recruited over a -month period. baseline total lymphocyte count was lower in the study group ( . ± . ) compared to control ( . ± . ). treatment was associated with significant improvements in total lymphocyte, b-cells, cd , cd (p \ . ) and nk cell (p \ . ) counts. recovery of total lymphocyte count in the control group was not significant (p = . ). our study demonstrates treatment of active mtb in hiv-negative patients is associated with significant improvements in total lymphocyte count and its major subsets. pleural tuberculosis is a diagnostic challenge. ada is a biomarker that has been proposed to diagnose tuberculous pleurisy but not routinely used [ ] . we aim to evaluate the sensitivity and specificity of ada in the diagnosis of tuberculous effusions and to improve current practice. we prospectively examined ada levels from patients with pleural effusions and followed the clinical course to establish the final diagnosis via culture, histology and clinical diagnosis. data were analysed using mann-whitney u test. there were cases of tuberculous effusions with mean ada levels of ± . iu/l (ci . - iu/l) while the mean ada of non-tuberculous effusions were . ± iu/l (ci . - . iu/l, p value = . *). true positive rate was / and true negative rate was / . false positive rate was / while false negative rate / . if iu/l is taken as cut value, the specificity is % and the sensitivity is %. we describe four cases of tb occurring during pregnancy and post partum. in all cases the women were non-nationals with a mean age of years. in two cases the tb presented as vertebral osteomyelitis, in one case tb lymphadenitis and in one case as miliary pulmonary tb. the diagnosis and treatment of tb in pregnancy presents many challenges. the cases discussed highlight some of the complexities which we encountered. these included dealing with language and cultural barriers, multi-disciplinary management of tb osteomyelitis in a pregnant woman; involving close collaboration with the obstetric and orthopaedic teams and managing adverse effects of anti-tuberculous medications in the pregnant patient. most samples tested showed no evidence of mycobacteria, indicating need for improved case selection prior to testing. median time to zn testing is as recommended by guidelines, though there is room for improvement. in an unselected population, likelihood of negative results is high after weeks of negative cultures. however, clinical suspicion should remain high until culture negativity is declared at weeks, particularly when there is a high clinical probability of mycobacterial disease. background: a number of patients with bronchiectasis have a middle lobe/lingula predominant radiological pattern. other than an association with non-tuberculous mycobacteria there is a paucity of published data on this subgroup of patients. methods: we retrospectively analysed data from all patients with non-cf bronchiectasis who underwent bronchoscopy with bal in a university hospital over a month period. radiological features, demographic data and microbiology were reviewed. results: patients with bronchiectasis were assessed. ( %) had predominant middle lobe/lingular bronchiectasis. in this group ( %) patients were females compared to ( %) (p = . ) of other patients and mean age was ± compared to ± years (p = . ). bal microbiology in the middle lobe/lingular group revealed no growth in ( %), h influenzae in ( %), s aureus in ( %), mac in ( %) and other ( %). conclusion: middle lobe/lingula predominant bronchiectasis is a common radiological pattern particularly in females and only a minority have ntm infection. cystic fibrosis (cf) is characterised by neutrophil-dominated airway inflammation, in part attributable to the potent chemotactic agent leukotriene b (ltb ). the aim of this study was to investigate the ability of exogenous alpha- antitrypsin (aat) to inhibit ltb signaling. the biological consequence of the described aat induced inhibition was investigated at the level of neutrophil released proteolytic enzymes. circulating neutrophils isolated from healthy control volunteers (n = ) were stimulated with ltb ( - nm/ ) in the presence and absence of aat ( . - . lm) for increasing increments of time ( , , and min). the level of degranulated proteins in surrounding supernatants was determined by western blot analysis. the ability of aat to bind ltb was assessed specrophometrically with uv spectra recorded on a jenway spectrophotometer at °c. our in vitro data has shown that levels of degranulated mpo, ll- and mmp- (markers of primary, secondary and tertiary granule release, respectively) were significantly decreased in the presence of aat (p \ . ). the mechanism of inhibition involved direct binding of aat to ltb as reduced vibrational fine structure of the ltb / aat uv absorbance spectrum indicated complexation of the two molecules. the results of this study indicate that aat can inhibit ltb signaling thereby reducing the proteolytic activity of neutrophils and propose aat aerosolized augmentation therapy as an effective treatment for ltb associated pulmonary diseases including cystic fibrosis and severe asthma. the modified-shuttle-walk-test (mswt) is increasingly used in cystic fibrosis (cf) patients. however, few studies have correlated mswt with severity of disease or assessed the prognostic value of these tests. the aim of this study was to see if a correlation existed between mswt and forced expiratory volume in -s (fev ) and/or cf-able score. a total of mswt assessments were analysed. correlations (spearman) among fev , cf-able-score, percentage predicted distance travelled and percentage predicted distance travelled to desaturation were calculated. nine out of mswt showed desaturation. the mean distance travelled was , m; . % of predicted, and mean distance to desaturation was . m; . % predicted. there was a significant correlation between distance travelled and fev (r = . /p \ . ) ir j med sci ( ) (suppl ):s -s and inverse correlation with cf-able-score (r = - . /p \ . ). there was a significant but poor correlation between distance to desaturation with fev (r = . /p \ . ) and cf-able-score (r = - . /p = . ). however, the presence of desaturation during testing did not correlate with fev (r = - . /p = . ) or correlate significantly with cf-able-score (r = . /p = . ). in conclusion there is significant correlation between total distance walked and both fev and cf-able-score, however, the absence of a correlation with the presence of desaturation during testing highlights the usefulness of mswt as a possible independent predictive measure, with further study needed. prolonged antibiotic therapy for cystic fibrosis (cf) exacerbations leads to increased picc (peripheral inserted central catheter) use. consequently incidence of venous thromboembolism (vte) has risen. rates of picc induced thrombosis in adults are . % [ ] . we aimed to ascertain prevalence of picc induced thrombosis in adult cf patients. a retrospective review of radiology was conducted on patients who had picc insertion for antibiotics for cf exacerbations from january to december . we analyzed patients with confirmed vte on doppler ultrasound and recorded patient demographics, size of picc and site of insertion. piccs were inserted, ( . %) had vte. ( . %) were female and ( . %) were male with symptomatic vte, presenting with arm swelling and pain. further complications were ( . %) with superior vena-cava syndrome, ( . %) with pulmonary embolism. of these, were treated with months anticoagulation therapy, and were anticoagulated for months once repeat doppler ultrasound confirmed no thrombosis. our rate of vte was . %, lower than in existing studies. piccinduced thrombosis depends on the population studied, as well as acquired thrombophilia secondary to inflammation, or deficiencies of anticoagulant proteins (protein c and s) due to vitamin k deficiency and/or liver dysfunction. studies have documented very poor real-life adherence to nebulised antibiotic therapies [ ] . no data exists on real-life experience with inhaled antibiotics. consecutive adult cf patients commencing inhaled antibiotic therapy (tip) were recruited over a -month period. a questionnaire recording safety, efficacy, lung function and adherence at time of recruitment, assessed traditional nebulised treatment (tis) versus new inhaled therapy (tip) at , and months. wilcoxons rank test and paired sample t-tests were employed for statistical analysis. patients have been enrolled to date. patient died (unrelated to the drug). patient received a lung transplant. / ( %) discontinued tip; due to cough/bronchospasm and due to refractory oral candidiasis. / ( %) were intolerant of tis prior to enrolment, with / ( %) subsequently tolerating tip. there was a significant increase in mean adherence score from . in the tis group to . in the tip group (p value . ). there was no significant difference in cough, lung function, or adverse events between the groups. in a real-life clinical setting with new inhaled antibiotic therapy (tip) we demonstrate, improved tolerability, adherence, lower discontinuation rates and stable clinical phenotype. also subgroup analysis supports a trial of this in those who failed traditional nebulised treatment. aim to assess the clinical utility of a hand-held nno analyser to differentiate between pcd, respiratory disease and healthy subjects. clinically stable patients were recruited over a -month period. each subject completed compatible pcd phenotype proforma, nno analysis (niox mino Ò ), and one nasal brushing for electron microscopy (em) analysis. nno was measured using passive sampling at a flow rate of ml/s during tidal breathing. em images will be reviewed internally and externally at an international centre of excellence (unc chapel hill). independent t-tests were used to compare mean nno values between groups. subjects were recruited (n = pcd, n = cf, n = non-cf/ non-pcd bronchiectasis, n = copd, n = healthy subjects). mean nno levels (ppb ± sd) were ± . (pcd), ± (cf), ± (non-cf/non-pcd bronchiectasis), ± (copd) and ± (healthy control). although nno levels were reduced in pcd when compared to copd (p = . ) and healthy subjects (p \ . ), there was no statistically significant difference between nno levels in pcd and cf (p value . ). results of em analysis are pending. in this study, the hand-held niox mino Ò nno analyser distinguished patients with pcd and cf from patients with copd and healthy subjects but not cf from pcd. ir j med sci ( ) studies suggest that incorrect usage of inhalers impacts negatively on asthma control. the aim of this study was to evaluate inhaler technique and symptom control in patients with severe asthma. patients referred to a newly established clinic in cork university hospital were consecutively recruited over a month period. inhaler technique was assessed using a validated scoring system and instruction on correct usage given if scores were suboptimal. patients completed a validated asthma control questionnaire (acq) and asthma quality of life questionnaire (aqlq). at a follow-up clinic months later technique was reassessed and acq repeated. results at baseline and follow-up were compared using standard statistical methods. patients were recruited (female = %), and / were followed up. mean[sd] fev % predicted at baseline = . % ( . ). % of patients were classified as incorrect inhaler users initially, decreasing to % at follow up, indicating a significant improvement in inhaler usage post-training (p = . ). acq scores improved significantly from median (range) . ( . - . ) to . ( - . ), p = . . the aqlq results indicated that patients' qol is moderately affected by asthma; median (range) score of . ( . - . ). this study demonstrates the importance of formally assessing inhaler technique in patients with severe, long-standing asthma as part of their clinical review. asthma is a chronic airway disease characterized by airway inflammation, bronchial hyperresponsiveness and airflow obstruction. patients with persistent symptoms despite maximum treatment as per gina guidelines are considered to have severe persistent asthma. omalizumab is a recombinant humanized monoclonal antibody licensed as an add-on therapy in these patients. the aim of this study is to assess the clinical benefit amongst responders to omalizumab therapy at a tertiary referral centre. this was a retrospective audit assessing the effects on asthma control, frequency of exacerbation and hospitalisation rates over months before and after therapy. the study included responders ( females). there was a reduction in exacerbation and hospitalization rates following initiation of omalizumab, and %, respectively (p value . ). the number of exacerbations decreased from . ± . to . ± . and the mean number of admissions from . ± . to . ± . over the study duration (p \ . ). there was % reduction in the weekly need for rescue salbutamol with mean of . ± . puffs to . ± . puffs after omalizumab (p \ . ). seventy-nine percent of patients were able to reduce their maintenance oral corticosteroid. in summary, responders to omalizumab therapy are less likely to experience an asthma exacerbation and hospitalisation. they were also more likely to reduce maintenance corticosteroid therapy as well as the need for rescue reliever therapy. these data suggest that omalizumab has proven effective in improving health outcomes for a cohort of carefully selected patients with severe allergic asthma in ireland. bronchial thermoplasty (bt) is a bronchoscopic procedure aimed at reducing the mass of airway smooth muscle and attenuating bronchoconstriction in severe asthmatic patients failing medical therapy. we report our experience with the first four patients treated with bt. between december and august , four patients with severe asthma per gina guidelines, underwent three sessions of bronchial thermoplasty, weeks apart. stringent entry criteria were required, including ongoing symptoms despite optimal medical management with the use of ics and laba's. two patients had a limited response to omalizumab. thus far, four patients met study entry criteria. three females and male. the mean age was years (sd . ). the frequency of severe asthma exacerbations was - per year. the mean fev and fev /fvc prior to procedure was . and . %, respectively. the mean fev and fev /fvc after the procedure was . and . %, respectively. patients reported a subjective strong improvement in quality of life post bt with more symptom-free days and less use of rescue inhalers. this emerging data relating to bt in an irish population is consistent with international data sets. bronchial thermoplasty is an additional treatment option for patients with severe asthma. approximately - % of patients with asthma have gastrooesophageal reflux (gor) and it has been postulated that this may worsen asthma severity. this study was undertaken to examine the incidence of gor in an irish steroid-dependent severe asthma cohort. patients with severe asthma were recruited into this descriptive study from the severe asthma clinic in cork university hospital. our cohorts mean age was years. the mean (sd) fev was . ( . ) l ( % predicted). the mean time from asthma diagnosis was . ( . ) years with the patients being steroid dependent on oral steroid therapy for mean . ( . ) years with a mean dose of . mg prednisolone. ( %) reported symptoms of gor; with being concomitantly treated with proton pump inhibitor. ten patients had undergone a barium swallow with five demonstrating gor radiological evidence. a further patient previously had undergone fundoplicative surgery. there was no association between gor and cumulative systemic steroid dose or fev in a subgroup analysis. in our study of steroid dependent asthmatics, % of those formally assessed were found to have evidence of gor on barium swallow, which is consistent with reported research [ ] . the incidence of gor did not depend on cumulative steroid exposure or fev . introduction: incorrect inhaler usage is a significant problem in asthma management, resulting in poor control of asthma symptoms. the ability of patients to correctly use their inhaler might be directly linked to inhaler technique education. education may result in better inhalation technique, improved compliance and asthma control. the economic burden of asthma is very substantial and is one of the highest among chronic diseases. in the united states of america, approximately - billion dollars is wasted because of inhaler misuse per year (fink, ) . research question: ''what is the impact of a nurse-led education programme in promoting compliance with inhaler use in patients with asthma''. methodology: this is a quantitative study engaging a quasi-experimental pre-test and post-test design. a cohort of patients who met the inclusion criteria were recruited from the out-patient department over a period of six months. during each stage, the patient was asked to demonstrate how they take their inhaler. any errors in technique were identified and rectified. their demonstration was measured through observation and the use of an inhaler proficiency schedule (ips). the participant was also asked a series of specific questions in relation to their condition, confidence level with self-administration of their inhaler, and adherence to prescribed frequency of use. the findings in this study show that inhaler education improves technique, promotes compliance and increases participant confidence levels in taking an inhaler, and as a result asthma symptoms improve. it also emerged that participants believed they were taking their inhaler correctly and so assumed that education drives were not targeted at them. % ( ) felt that the service provider had assisted in their success with therapy. overall, respondents use their devices as prescribed, keep in contact with their hospital department and service provider, and most feel their quality of life has improved as a result of starting treatment with cpap. obstructive sleep apnoea syndrome (osas) is characterized by repetitive upper airway (ua) obstruction during sleep. alcohol consumption increases osas severity by diminishing ua muscle tone, aggravating snoring and osas-related daytime symptoms. we hypothesized that behavioural adaptation could lead to reduced alcohol consumption in subjects with more severe osas. the influence of anthropometric, social and demographic variables, along with osas severity on alcohol consumption among subjects undergoing inpatient sleep studies was examined. regression analyses were utilised to identify independent predictors of alcohol consumption, and generate odds ratios (aor) for excessive alcohol consumption by osas severity. subjects were assessed; . % were female, . % in paid employment, and . % married. . % had no osas [apnoeahypopnoea index (ahi) \ ] and . % severe osas (ahi [ ). alcohol consumption was . (± . ) u/week, with . % exceeding recommended limits. stepwise regression revealed male gender and employment status, but not ahi, as independent predictors of increased alcohol use. no difference in adjusted mean alcohol intake by osas severity class was observed. severe osas patients tended towards increased odds of excess alcohol consumption compared to those without (aor . ; % ci . - . ; p = . ). increasing osas severity is not associated with lower alcohol consumption; rather, the reverse may be more likely. in our sleep clinic, ess is a poor predictor of ahi, sacs did not perform as expected, and a combined measure is of limited utility. following polysomnography diagnosis, untreated osas cases were assessed. cpap compliant subjects were re-assessed * weeks later. body composition was assessed by bio-electrical impedence analysis. sensewear armband Ò (swa) measured free-living ee. swa data was included if average weartime was [ %. subjects ( male) (mean age, . years) were included. restrained-eating score was inversely associated with osas severity ( . , . , . in mild, moderate and severe, respectively). conversely, both uncontrolled eating score ( . , . , . ) and emotional eating score ( . , . , . ) were positively associated with osas severity. bmi (p = . ) and fat % (p = . ) were significantly higher in severe versus mild osas. cognitive-restraint was inversely associated with bmi and fat %, whereas both uncontrolledand emotional-eating were positively associated with these parameters. among this sample, more severe disease was associated with adverse eating behaviors. nutritional counseling targeting specific eating behaviors may be beneficial in osas. significant osa (ahi [ ) was present in % of the clinical group and % of the screened group. no correlation of clinical significance was proven between ahi and ess in either group. ess provides useful information on subjective sleepiness but this study might suggest that it is not a reliable predictor of the presence of osa or its severity. decreased energy expenditure (ee) contributes to overweight. we investigated free-living ee and body composition in obstructive sleep apnoea syndrome (osas). following polysomnography (psg) diagnosis, untreated osas cases wore the sensewear armband Ò (swa) for * days, including weekend days. swa quantifies free-living ee and physical activity (pa). data was included if weartime was [ %. body composition was assessed with bio-electrical impedance analysis. upper airway muscle dysfunction is implicated in the pathophysiology of obstructive sleep apnoea syndrome (osas). pharyngeal dilator muscle inotropes may serve as adjunct therapies. we hypothesized that tempol, a superoxide scavenger, would increase sternohyoid muscle power under conditions of oxidative stress (hypoxia). excised sternohyoid muscles from adult male wistar rats, were connected to a dual-mode force transducer, between stimulating electrodes, in a bath of krebs solution at °c, in either high oxygen (control) or low oxygen (hypoxia) ± mm tempol. stress and shortening were measured in muscles contracting from zero up to isometric load under tetanic conditions. peak power was determined. sternohyoid peak power was . ± . and . ± . w/cm in control and hypoxic conditions (drug-free), respectively, and . ± . and . ± . w/cm in control and hypoxic conditions (+tempol), respectively. two-way anova revealed that hypoxia (p \ . ) and tempol (p = . ) were significant factors without drug-gas interaction. tempol increased the power-load relationship over the early ( - %) portion of the load step test and this was significant under hypoxic conditions. we conclude that tempol increases sternohyoid muscle power under control and hypoxic conditions. our results suggest that antioxidant therapy may be useful in the treatment of osas and other muscle weakness disorders. r. lee obstructive sleep apnoea syndrome (osas) is reported as common among ipf patients [ ] . we determined the prevalence of the disorder in a cohort of ipf patients not on long term oxygen therapy and medically stable, excluding patients with active coronary disease and diabetes mellitus. patients with ipf patients attending a specialized clinic underwent overnight polysomnography following a night of acclimatization. a quality of life questionnaire (sf- ) and epworth sleepiness score (ess) were also completed. statistical analysis was by student-t and man-whitney u-testing. of the patients were male and mean age was . ± . (sd). % were current or ex-smoker. only % of the patients received steroids at some time in their treatment. patients had significant sleep-disordered breathing (sdb) based on the standard definition of ahi c /h but only were sleepy (ess c ), thus having osas. bmi correlated positively with ahi (r = . , p = . ). bmi was . ± . kg/m but higher in the osas/sdb group (p = . ). no difference in quality of life was evident between those with or without sdb or osas. we conclude that sdb and osas are as prevalent in ipf as a similar general population and bmi is the principal predictor of ahi in these patients. studies to date reveal wide variability ( - %) in the prevalence of fungus in the cf airway using culture-based methods. this study profiles the fungal microbiota of the cf airway using high-throughput-sequencing, and correlates this with standard culture-based methods and clinical phenotype. clinically stable adult cf patients were prospectively recruited, donating one or more sputum samples. culture-based methods were employed at time of sampling. high-throughput bar-coded sequencing targeting the internal transcribed spacer (its) and small sub-unit (ssu) regions was used to profile the fungal microbiota, with subsequent sequencing on a genome sequencer flx platform. baseline fev % predicted, genotype, gender, bmi and pseudomonas status, were recorded by retrospective review of medical notes. in a total of samples, culture-based methods detected fungus (aspergillus spp. and candida spp. only) in patients. highthroughput-sequencing identified rich fungal communities in greater than % of the patient sputum samples, with over % of the species found not detected by culture. fungi detected included c. albicans, c. dubliniensis saccharomyces cerevisiae, malassezia spp., fuscoporia ferrea, fusarium culmorum, acremonium strictum, thanatephorus cucumeris and cladosporium spp. a comparison of patient status with diversity and species richness of fungal microbiota identified that lower fungal diversity associates with decreased lung function. aim: to identify common anaerobes and their proteases and assess their ability to cleave natural host innate human antiproteases such as alpha one antitrypsin (aat). method: we prospectively recruited patients at our site in beaumont hospital. we obtained both sputum and bronchoalveolar lavage fluid (balf) at both stable and pre and post exacerbation timepoints. all samples were processed using both anaerobic bacteriologic techniques and s r rna sequencing methods. supernatants from p. melaninogenica were cultured in luria-bertani broth (lb) broth, (sigma l - tab) and basal anaerobic media (bam) broth under strict anaerobic conditions in an anaerobic cabinet (davidson & hardy). protease production was measured using sensolyte red protease assay (anaspec). this assay measures matrix metalloproteinase (mmp) activity in broth. the days with highest protease production were recorded. native aat was incubated for selected time points with supernatant and cleavage products visualised by sds-page electrophoresis and western blotting analysis using specific antibodies raised against the antiproteases. results: using sputum and broncheoalvelar lavage from patients with cf, prevotella species accounts for % of anaerobic samples identified from our group and p melaninogenica is the most common anaerobe grown from this group. the sensolyte red protease assay showed p. melaninogenica cultures produced the highest levels of active proteases on day , and . the western blot analysis demonstrated that when day and supernatants were incubated with aat, this antiprotease was degraded to give a distinct cleavage pattern. conclusion: this study is examining for the first time the pathogenicity of anaerobic bacteria found in cf lung and shows that the proteases produced by anaerobic bacteria are destroying host defense mechanisms and that this may impact other natural host innate antiproteases in the cf lung and play a role in inflammation. cf is a genetic disease with a high prevalence in ireland. in cf lungs chronic bacterial infection contributes to progressive respiratory failure. in particular, pseudomonas aeruginosa (pa), forms biofilms in the lungs which significantly contributes to antibiotic resistance. we have previously published on the importance of mif as a key inflammatory mediator in cf [ , ] . building on this work, we hypothesised that mif enhances biofilm formation in the cf lung contributing to enhanced antibiotic resistance. using in vitro biofilm formation methods and qpcr we examined the effects of mif ( ng/ml) on the growth, antibiotic resistance and gene expression of pa (strain pao ). our results to date have shown that mif significantly enhances biofilm formation of the pao strain of pa (p \ . ). in addition we have found a significant earlier induction of specific quorum sensing genes in response to mif. mif in pa cultures is associated with significantly less bacterial killing following antibiotic treatment. this raises the possibility of mif as an adjunct therapy with antibiotics by significantly this supports our hypothesis of mif inhibitors as an adjunct therapy improving the antibacterial effectiveness of antibiotics. macrophage migration inhibitory factor (mif) was one of the first cytokines to be discovered. mif is produced by a wide variety of tumours and is thought to play an important role in tumour progression. mif possesses a unique enzymatic activity linked to this role in cancer. to investigate this further we designed and evaluated a panel of small molecular weight inhibitors of mif and looked at their ability to block mif activity in vitro and in vivo. the small molecules were found to specifically inhibit the enzyme activity of mif when co-incubated with recombinant mif and its substrate. the inhibitors also significantly reduced cellular proliferation induced by treatment with recombinant mif (proliferation reduced by [ %, p \ . ) and significantly inhibited lpsinduced tnf-a production (tnf-a reduced by [ %, p \ . ). in vivo, the inhibitors were found to reduce tumour growth in a subcutaneous model of lewis cell carcinoma (tumour volume reduced by [ %, p \ . ). here we present data describing a number of novel small molecular weight inhibitors of mif found to be effective in vitro and in vivo. these inhibitors have the potential to be developed for therapeutic use in a cancer setting. idiopathic pulmonary fibrosis (ipf) is a progressive disease characterized by fibrosis. il- is a proinflammatory cytokine that has been shown to play a role in many fibrotic diseases including ipf. il- also induces the expression of, and binds to, one of its receptors, il- ra , which has been thought to function as a non-signaling decoy receptor. the cxc chemokine receptor (cxcr ) and its ligands-cxcl , cxcl , and cxcl -have been implicated in vascular remodeling and fibroblast motility during the development of the disease. in this study, cultured pulmonary fibroblasts from wild type and cxcr -deficient mice were treated with various cytokines, and the expression levels of il- ra and cxcr were measured. we demonstrate for the first time the expression of cxcr in cultured pulmonary fibroblasts from mice. also, il- was shown to downregulate basal and ligand-induced cxcr expression in fibroblasts. using wild-type and cxcr -deficient animals, cxcr was found to be necessary for the il- mediated upregulation of il- ra , and blocking cxcr significantly reduced the basal expression of il- ra . manipulation of the cxcr -mediated regulation of il- ra or the il- mediated downregulation of cxcr may represent novel therapeutic modalities in cases of acute lung injury or chronic inflammation that may progress to fibrosis. epithelial cell to mesenchymal transition (emt), whereby epithelial cells undergo transition to a mesenchymal phenotype, giving rise to fibroblasts and myofibroblasts has been implicated in the pathogenesis of idiopathic pulmonary fibrosis (ipf). alveolar epithelial cells (aec) are recognised to undergo emt in response to various stimuli including transforming growth factor-b (tgf-b ). comparison of gene expression, migration and chemokine secretion in normal and transitioned aec with primary pulmonary fibroblasts derived from normal and ipf patients was performed. a cells underwent h (h) serum starvation followed by h treatment with tgf-b ng/ml. total rna was extracted from a cells and primary human pulmonary normal and ipf fibroblasts. changes in expression of a panel of tgf-b target genes was determined by real time polymerase chain reaction array with subsequent validation. migration studies of the various cell types in response to serum and enzyme-linked immunosorbent assay (elisa) of cxcl , cxcl and il- levels in cell supernatants were performed. transitioned aec assumed a mesenchymal phenotype, exhibiting a marked reduction in differential gene expression when compared to fibroblasts. migration in response to serum by transitioned aec was increased significantly compared to normal or ipf fibroblasts as was production of cxcl and cxcl . background: aatd disease is a hereditary disorder leading to the development of emphysema. our group has published first evidence of upr activation within the endoplasmic reticulum (er) of zz monocytes. here we study mirna regulation of upr in healthy and emphysematous zz monocytes. method: monocytes mirnas were profiled using nanostring technologies. mirdip portal and kegg database identified mirna targets and gene networks. transfections with nm anti-mir were performed using siport-neofx. mrna, mirna and protein were measured by qrt-pcr, taqman mirna assay and western blotting. results: sixty mirnas were differentially expressed in zz versus mm monocytes. mir- a- p is overexpressed by [ -fold and predicted to target multiple genes which are enriched for pathways in the er stress response. emphysematous versus healthy zz patients have decreased mir- a- p expression. mir- a- p inhibition increased expression of two arms of the upr; grp and atf . conclusion: mirnas are differentially expressed in zz monocytes and may play a role in the upr. mir- a- p, predicted to target upr genes, is overexpressed in healthy zz monocytes, and negatively regulates the upr. emphysematous zz patients may have lost this protective mirna regulation leading to increased er stress in monocytes, contributing to the inflammatory milieu of aatd lung disease. . alpha- antitrypsin augmentation therapy is associated with decreased neutrophil adam- activity, plasma tnf-a levels and normalisation of neutrophil apoptosis alpha- antitrypsin deficiency (aatd) is characterised by neutrophil driven lung destruction and early emphysema in a low alpha- antitrypsin (aat) and high neutrophil elastase (ne) environment in the lungs of affected individuals. timely and effective neutrophil programmed cell death is essential for the resolution of inflammation and we have previously shown that neutrophils apoptosis is accelerated in aatd individuals. endoplasmic reticulum (er) stress is associated with the release of the pro-apoptotic cytokine tnf-a and, on the cell surface the activity of the sheddase adam- leads to the release of tnf-a from its membrane bound to its soluble form. the aim of our study was to determine if aat augmentation therapy can normalise the accelerated neutrophil apoptosis seen in aatd through inhibition of adam- activity and resultant tnf-a release. neutrophils were isolated from aatd individuals receiving aat augmentation therapy pre and post treatment. the kinetics of apoptosis were measured by caspase- cleavage utilising western blotting and cd b expression by facs analysis. adam- activity measured using a fluorogenic peptide substrate. plasma tnf-a levels were measured by elisa. er stress was determined using the er stress marker grp- . adam- activity was increased in individuals with aatd. in addition, adam- activity, plasma tnf-a levels and caspase- cleavage were reduced after augmentation therapy (p \ . ). cd b expression was increased after therapy indicating normalisation of apoptosis. grp- expression was unchanged. from our data we have demonstrated that aat augmentation therapy can normalise neutrophil apoptosis by ameliorating adam- activity and resultant tnf-a release. the observed normalisation of neutrophil apoptosis may lead to reduced inflammation and a reduction in recurrent infections which characterises patients with aatd. to identify lung-selective mirnas, extracted rna was probed to mirna microarrays (mra- ; , human mirnas), and results confirmed by taqman analysis. in silico analysis using targetscan and microrna.org identified genes targeted by identified mirnas. using a subtractive mirna strategy, lung-selective hypoxic responsive mirnas were identified (anova p \ . ); including mir- a- p and mir- . in silico analysis predicted that mir- a- p targets erythropoietin, which has a well-documented role to play in endothelial repair and angiogenesis. furthermore, mir- targets cullin , which has previously been shown to stabilize hypoxia-inducible factor-a and promote angiogenesis. we conclude that hypoxia, typical of that encountered in pulmonary disease, causes lung-selective alterations in mirna expression. mir- a- p and mir- may play important roles in pulmonary vascular remodelling and angiogenesis. further studies of these mirnas may uncover novel treatment strategies for hypoxic lung disease. this research project is funded by science foundation ireland. to assess whether mal plays a role in killing of intracellular mtb, we infected murine wild-type and mal knockout macrophages with virulent (h rv) mtb. we found that mal deficient cells were unable to kill mycobacteria. human macrophage cell lines transfected with sirna against mal showed the same deficiency in killing mycobacteria. we then proceeded to evaluate key macrophage mechanisms of killing mycobacteria. we found that phagolysosomal maturation and autophagy were mal-dependent in murine and human macrophages. pro-inflammatory cytokine production was also mal dependent. we then sought to determine the effect of the common mal s l polymorphism on macrophage responses to mtb. primary bone marrow derived macrophages from mice with the sl and ll polymorphisms displayed impaired mycobactericidal activity and phagolysosomal maturation. mal plays a critical role in determining macrophage responses to mtb through a pathway culminating in phagolysosomal maturation and killing of intracellular bacteria. asthma has been linked to the vitamin d deficient (vdd) state. we investigated whether vdd was associated with impaired lung function and inflammation. patients with respiratory symptoms (asthmatic and non-asthmatic) underwent spirometry and had serum analyzed for total immunoglobulin e (ige), high sensitive c-reactive protein (hscrp), eosinophil cationic protein (ecp), and -hydroxyvitamin d we examined caucasians (mean age years; mean bmi kg/m , mean fev = . % predicted). mean (oh)d was . nmol/l. % of recruits were vdd, % were insufficient, while only % were vitamin d sufficient. vitamin d levels were positively associated with fev (r = . , p = . ). % of patients with airway obstruction (fev \ % predicted) were vdd. ecp, hscrp and ige were non-significantly elevated in the vdd state compared to sufficiency. however, all patients with ige doctors' education about inhaled respiratory medication is extremely important in management of copd and asthma. while exercise-induced oxygen desaturation is a widely used clinical measure in ipf, data on sleep-related desaturation are lacking. we compared gas exchange during sleep and exercise in a cohort of ipf patients attending a specialized clinic not on long term oxygen therapy and medically stable, excluding patients with active coronary disease and diabetes mellitus. ipf patients underwent overnight polysomnography, including transcutaneous carbon dioxide (p tc co ) measurement, after a night of acclimatization. cardiopulmonary exercise testing was performed by incremental cycle ergometer. pulmonary function and awake arterial blood gases were also measured. statistical analysis included student-t and man-whitney u-testing. patients had significant sleep-disordered breathing (sdb) based on an apnoea-hypopnoea index (ahi) [ . fev was . ± . % (sd) and diffusion (dlco) . ± . % predicted. pao was . ± . kpa and paco . ± . kpa. p tc co rose by . ± . kpa during sleep (p \ . ) consistent with hypoventilation. the minimum oxygen saturation during sleep was lower than exercise ( ± . vs. . ± %), p = . and the fall in oxygen saturation was also greater during sleep ( . ± . vs. . ± . , p \ . ). we conclude that ipf patients desaturate more during sleep than exercise and suggest that nocturnal oxymetry be considered part of the clinical assessment of such patients. diabetes mellitus (t dm) causes increased risk of cardiovascular death, while glycosylated hemoglobin (hba c) level predicts longterm cardiovascular mortality in non-diabetics. while obstructive sleep apnoea syndrome (osas) is associated with adverse cardiometabolic outcomes, it remains unclear if this effect is independent of obesity and other confounders. we examined the relationship of osas severity with t dm prevalence and hba c levels in a large european population. subjects attending university-affiliated sleep laboratories across countries were prospectively assessed. all underwent overnight sleep studies, with bloods drawn to assess glycaemic health. the relationship of osas severity with t dm prevalence, and hba c levels in non-diabetics was examined with regression models adjusting for confounding factors, including obesity. , subjects were assessed, . % male, . % obese, and % with an apnoea-hypopnoea index (ahi)[ events/h. following adjustment for confounding factors, moderate and severe osas remained significant predictors of t dm (adjusted odds ratio . ; %ci . - . ; p = . ). in non-diabetics ahi (standardized b . ; p \ . ), and mean spo (standardized b - . ; p \ . ) were significant independent predictors of elevated hba c levels. osas severity and nocturnal hypoxaemia predict both prevalent t dm and hba c levels even after rigorous adjustment for confounding variables including obesity, which may contribute to excess mortality in osas populations. background: portable devices that determine tst may act as an adjunct to level diagnostic tests for osa. the swa is such and measures tst using a proprietary algorithm. calculation of tst could improve the accuracy of a level diagnostic device. aim: correlation of tst by swa and npsg, in a population with and without sleep apnoea. consecutive patients undergoing npsg because of a suspicion of osa wore an swa on the same night. patients were stratified by the presence and severity of osa. correlation coefficient for tst were determined between swa and npsg for all subjects and in the osa subgroups. results: the prevalence of a normal psg, mild moderate and severe osa was ( . %), ( . %), ( . %) and ( . %) of subjects. and the respective correlation coefficients were r = . , . , . and . . clinically important differences are presented with bland-altman plots (figs. , ) . correlation of tst between the two methods was weakest in those with severe osa. conclusion: the determination of tst by swa in a population with severe osa is likely to be unreliable. npsg remains the gold standard for determination of tst. the relationship between lung cancer and pulmonary fibrosis remains poorly understood. the aim of this study was to conduct a descriptive analysis of clinical data collected from a cuh cohort of patients with both ild and lung cancer. a database of patients with a histological diagnosis of lung cancer between august and december was reviewed. patients with established ild on ct scan were identified. data from clinical notes and radiology patterns were reviewed and analysed. the male to female ratio was . : . all were smokers. % of carcinomas in these patients were non-small cell lung cancer (nsclc). % of patients had usual interstitial pneumonia pattern, % had non-specific fibrosis, and % had asbestosis. the overall median survival was months (sem . ; % ci . to . ). median survival for patients with early stage disease who underwent surgery (n = ) was months, followed by those who received chemo-radiotherapy ( months), those who received no intervention ( months), and those who received radiotherapy alone ( months). survival for patients with lung cancer and ild was lower than published figures for patients with lung cancer alone. surgical candidates had the best survival though the survival benefit was very modest, while patients who received no intervention or radiotherapy alone faired very poorly. pleural ultrasound has a number of advantages over traditional imaging modalities with regard to visualisation of pleural pathology, in particular, pleural effusions. these include portability, the absence of radiation, dynamic imaging as well as increased sensitivity versus computed tomography scans in terms of differentiating between pleural fluid, thickening and masses [ , ] . we present a case series of patients who underwent pleural ultrasound under the care of respiratory physicians trained in this technique in our hospital from january to august . in total, ultrasound scans were carried out in the month period on a total of patients using a portable ultrasound machine. the average patient age was . years (range - years) and % were male. based on ultrasound findings, the physician proceeded directly to aspiration on occasions ( %) and a total of chest drains were inserted ( %). of those that were aspirated, the vast majority were exudative in nature (n = , . %). ( %) of the aspirates were due to malignant effusions. no procedure-related complications occurred. this case series highlights that imaging at the bedside is a feasible and, with the proper training, very safe method for managing pleural effusions. this audit shows that the vast majority of patients with mesothelioma are male with a poor prognosis regardless of therapeutic approach. approximately % die in the hospital/hospice setting. finally, more patients with mesothelioma should be considered for clinical trials. aat deficiency (aatd) results from mutations in the serpina gene, classically presenting with copd and liver disease. the most common mutation causing aatd is the z mutation, with the s mutation weakly associated with lung disease. aat deficiency is under-diagnosed and prolonged delays in diagnosis are common. ats/ers guidelines advocate screening all copd, poorly-controlled asthma, and cryptogenic liver disease patients, as well as relatives of known aatd individuals. over , individuals have been screened following ats/ers guidelines as part of the national aatd targeted detection programme. rare and novel mutations were identified by dna sequencing of the serpina gene. a number of rare serpina mutations including i, f, x christchurch , z bristol , and m malton were identified. the i mutation (arg cys) was present at a relatively high frequency ( . ) with over cases identified. the f mutation (arg cys) was found in cases. in addition, novel null mutations were identified, q dublin and q cork. current testing of suspected aatd cases is often limited and can miss rare and novel clinically significant serpina mutations. our findings underline the need for a comprehensive diagnostic work up of all patients with low aat levels including phenotyping, genotyping and if necessary, dna sequencing of the serpina gene. we previously observed that weaning-failure patients experience increased intensity of dyspnea (ajrccm ; :a ). we also observed that patients reported different qualitative sensations suggesting that more than one mechanism may contribute to dyspnea. the purpose of this study is to determine whether dyspnea experienced in weaning-failure patients is related to changes in pco or increase in respiratory effort or both. methods: tracheostomized patients who were being weaned from prolonged mechanical ventilation at a specialized facility were enrolled. dyspnea, transdiaphragmatic pressure-time product (ptpdi), minute ventilation, and transcutaneous pco (ptcco ) were measured during a -h trial of spontaneous breathing. patients who developed respiratory distress during the trial were considered weaning failures. patients who tolerated the trial and continued to breathe unassisted for at least h after the trial without signs of distress were considered weaning successes. results: patients were studied; were women; age, + (se) years; duration of ventilation before the study, + days. fourteen patients were weaning successes; patients were weaning failures. in the failures, dyspnea score increased from . + . at the start to . + . at the end of the trial (p \ . ). the increase in dyspnea in the failures was accompanied by increases in minute ventilation (p \ . ) and ptcco (p \ . ); ptpdi, an index of patient effort, remained unchanged during the trial. in the successes, dyspnea, minute ventilation and ptcco did not increase during the trial; ptpdi, however, decreased from the start to the end of the trial (p = . ). these findings suggest that an increase in pco , a major driver of minute ventilation, contributes to an increase in dyspnea during weaning failure. that the increase in dyspnea in the failures was not accompanied by an increase in ptpdi together with the successes exhibiting a decrease in ptpdi without any change in dyspnea suggests that effort is not a major determinant of dyspnea during weaning failure. conclusion: dyspnea increases in weaning-failure patients but not in weaning-success patients and the increase in dyspnea is accompanied by increase in pco and minute ventilation but not by an increase in respiratory effort. background: respiratory disease constitutes one of ireland's greatest public health challenges. patients with respiratory disease are often undiagnosed despite symptoms and risk factors for lung disease. the purpose of this study was to determine the prevalence of respiratory symptoms and disease in a targeted population screening program. study design: subjects were asked to complete a questionnaire on respiratory symptoms and risk factors as part of well-publicised free spirometry testing on world spirometry day. multiple linear regression analysis was performed to identify factors contributing to variation in population fev . logistic regression was used to identify predictors of airflow obstruction (fev /fvc \ %) followed by predictive model development and roc curve analysis to determine model diagnostic accuracy. results: ten centers throughout ireland participated in the study. analysis was limited to an initial discovery cohort of patients ( % female; age = years (range - ); fev = % predicted(range - %). factors associated with reduced population ir j med sci ( ) (suppl ):s -s fev (% predicted) were smoking history, male gender, lower educational status and history of existing lung disease. in those with no history of lung disease (n = ), % had abnormal spirometry with % demonstrating airflow obstruction. predictors of airflow obstruction were age, presence of cough and number of pack-years of smoking. presence of cough, age [ years and exposure [ pack years were associated with highest sensitivity and specificity for identifying airflow obstruction although predictive ability was only fair (roc auc = . ). conclusions: demographic and socioeconomic factors influence lung health in ireland. undiagnosed respiratory disease is common, particularly airflow obstruction and targeted screening is justified to identify patients with respiratory disease early. bronchiolitis affects one-third of babies in their first year of life. half of those hospitalised will have persistent cough and wheeze. to map this epidemic, we investigated all bronchiolitis admissions to tallaght hospital in the last years. this will aid future planning of the service and provide an insight into the epidemic in the irish population. from until , , children were admitted to tallaght hospital due to bronchiolitis. we analysed these on the basis of time of year of admission, length of stay, gender and age and compared them to national and international data. the busiest month was december, with . % of admissions. however, there was a significant increase in the incidence of bronchiolitis in the early spring of and (more than doubled) compared to previous years. the average length of stay is . days, male sex had % dominance and average age was . weeks, in keeping with international data. there has been in a significant shift in the timing and incidence of bronchiolitis in tallaght hospital in the last years. we explored the reasons for this, with special attention to rsv incidence, possible climate causes, vaccine programs and exposure risk. we identified children, males and females. mean weight was . kg (range . - kg). mean age was . months (range days- months). stridor was the commonest presenting symptom %. diagnosis was confirmed by micro-laryngobroncoscopy and supplemented by ct in %. % had complete tracheal ring stenosis and % had concurrent cardiac anomalies. two patients had bronchus suis. extracorporeal life support (ecls) was utilized in one patient preoperatively. cardio pulmonary bypass (cpb) or ecls was utilised for the repair. laryngeal release was required in / patients. patients underwent end-end anastomosis, slide and double slide tracheoplasty. a polydiaxanone suture was used for all anastomosis. mean (cpb) time was . min (range - min). mean cross clamp time was . min (range - min). mean length of ventilation was days (range . - days). mean icu length of stay was . days (range - days). there were two hospital mortalities. one patient only required re-intervention with balloon dilation. % were symptom free on a mean follow up of . months (range weeks- years). distal tracheal stenosis can be managed effectively utilizing cpb that also allows concurrent correction of congenital heart anomalies. mayo general hospital, midlands regional hospital background and aim: attempting to reduce unnecessary attendances of well patients at outpatient clinics is prudent. this study evaluated the asthma control test (act)t and respiratory proforma, with feedback through mobile texts, in children with asthma, to determine attendance at clinic or not. methods: patients between and years with a diagnosis of asthma were eligible for inclusion. the parent was surveyed, by post, weeks prior to the clinic date and asked to complete the asthma control test (act) and a respiratory proforma which assessed uacs symptoms, medication usage inclusive of intensification episodes and medical concerns. mobile telephone numbers were requested. parents mailed their responses in a supplied stamped envelope supplied. respondents were divided into two categories (a) act score greater than and a non concerning respiratory proforma, who were texted not to attend the clinic but supplied with another outpatient appointment and (b) the remainder were texted to attend the clinic. results: over clinics the parents of eligible children were surveyed. one hundred and forty-one ( %) replied of whom ( %) were well and did not attend the clinic but rebooked. of who attended, had new symptoms of uacs and had pneumonia. of who did not reply, forgot to reply, came to clinic with completed questionnaires, had good control. thirty-five did not attend the clinic of whom were discharged to the family doctor. conclusion: asthma care through postal survey with mobile text feedback is an option in the outpatient setting. background and aims: asthma is common in paediatrics with the most difficult to manage being those less than years. this study evaluated the impact of a nurse delivered education program developed for parents of children under years in terms of knowledge gained and parental empowerment. methods: twenty parents of children age - years were invited to attend five h educational sessions which related to asthma pathophysiology, signs and symptoms, clinical assessment and medication use. a specific educational program was developed. prior to enrollment each parent was administered two surveys; ( ) a previously tested asthma questionnaire containing statements, and ( ) a survey of parental concerns related to asthma. one month after the program was completed parents asthma knowledge and perceptions of empowerment were reassessed. results: while parents were enrolled data sets for were available for analysis. the pre-intervention mean knowledge level was . ( %) (range - ) and post knowledge level was mean . ( %) (range - , paired t test 
). the parental survey identified asthma recognition and poor coping skills as major themes which the educational program addressed. conclusion: a targeted asthma educational program improves parental knowledge and enhances parental empowerment. written action plans (w.a.p.) are recommended in international guidelines for the management of asthma [ ] . despite this, uptake remains poor [ ] . a qualitative prospective study of parents of children attending the paediatric asthma out-patient clinic at cork university hospital was performed to examine if; ( ) written action plans are valued by parents. ( ) they assist in recognition of symptoms. ( ) parents commence appropriate treatment at home and identify when to seek medical advice as a result of w.a.p. ( ) parents feel assured by possession of w.a.p. thirty parents of children aged - years were interviewed by the paediatric asthma nurse specialist to assess level of asthma control, knowledge of treatment and level of concern. parents were provided with a colour coded w.a.p. and all aspects of treatment were discussed. a follow up telephone interview was performed months later. in the pre intervention group only / felt they had enough information to manage their child's asthma; this increased to / post intervention (p \ . ). / knew the location of their w.a.p.s. there were no incorrect responses regarding dose/frequency of medication. / subjects had dropped a level of concern regarding their child's asthma (p \ . ). with sufficient written information and education, the anxiety and concern that many parents undergo while managing a child with asthma, can be reduced. eight patients ( male) underwent respiratory (ecls). there were -preterm, -term neonates, -infant and -child. indications included, congenital diaphragmatic hernia- , bronchiolitis- , primary pulmonary hypertension- , pertussis- and complete tracheal ring stenosis- . % of patients were transferred to sweden or uk. eight children ( males) underwent (ecpr) runs, with a mean age of . years (range weeks- years). / had underlying congenital heart disease, of which had univentricular pathology. mean conventional (cpr) time before initiation of (ecpr) was min (range - min). in the respiratory (ecls) cohort mortality was . %. the only survivor was treated in ireland. in the (ecpr) cohort our survival rate of % exceeded the international extracorporeal life support organization published results of %. all ecpr patients were treated in ireland. currently there is no funding for pediatric respiratory (ecls) in ireland. patients are being treated abroad at significant expense, family inconvenience and mortality. these results would suggest a change in health policy is overdue! recent evidence has confirmed a high prevalence of bronchiectasis and impaired lung function in school aged children with cf despite little in the way of symptoms of lung disease in this group in preschool years. if we are to significantly improve long term outcomes in cf we must gain a greater understanding of lung disease in the preschool years and intervene earlier with disease modifying treatments before irreversible lung disease occurs. the key to understanding early lung disease in greater detail lies in the design of robust, comprehensive, well powered longitudinal studies. shield cf was established in with these requirements in mind and is a framework through which we can start to answer some important questions. shield cf is centred around the annual cf bal surveillance programmes in our institutions. currently the shield cf programme includes: • bal-immediately processed, aliquoted and biobanked • whole blood-immediately processed, aliquoted and biobanked • oropharyngeal swab-processed for rna extraction • clinical information-baseline and ongoing information related to lung health entered onto online database from individual centres. in the future we plan to include: • lung function measured by lung clearance index (lci) • lung structure determined by chest ct to date patients have been recruited with a total of samples (n = cf, n = control). shield cf has contributed samples to different international multicentre studies. table below summarises key baseline findings within shield cf to date. within the next year shield cf will incorporate preschool children between the three centres. aim of our study was to audit hospitalization for copd exacerbations with respect to patient characteristics, diagnosis and standards of care. all patients admitted to roscommon hospital with a diagnosis of aecopd from july st to december st were included. medical notes were reviewed for data collection. patients were included in the study. there was a frequent failure to objectively confirm the diagnosis of copd by spirometry. only ( . %) patients had spirometry performed at any stage. patients were current smokers. inhaler technique was assessed in only patients. ( %) patients received chest physiotherapy. out of current smokers had documented smoking cessation advice, and received smoking cessation pharmacotherapy. ( %) patients were treated with antibiotics. management of aecopd in our hospital is frequently suboptimal, and may be managed better with respiratory physician involvement. there should be more frequent spirometric confirmation of diagnosis, more conservative use of antibiotics, better screening for ltot and improvement in smoking cessation service. many copd patients return for review at the respiratory outpatient department when clinically stable. they are often reviewed by less experienced nchds who may lack the knowledge and confidence to discharge them. furthermore many beneficial clinical and lifestyle interventions are not commenced. through a series of pdsas, a checklist was developed and implemented to ensure that copd patients received appropriate interventions and highlight which patients could be safely discharged to the care of their general practitioner. this combined a checklist of criteria for optimisation of copd patient management devised in the respiratory department as well as both the validated copd assessment test (cat) and modified medical research council dyspnoea scale. discharged patients had a cat score of b and no significant outstanding treatment modifications. the checklist was completed in copd patients of whom ( %) were suitable for discharge. interventions such as optimised pharmacological therapy, assessment of inhaler technique and vaccination education were not instituted in , and % of patients, respectively. we conclude that an opd discharge checklist is an appropriate intervention to improve quality of care for patients with copd and facilitate the discharge of stable patients from a respiratory opd. pulmonary rehabilitation (pr) is a multidisciplinary approach to improving the exercise capacity and symptoms of people with copd and ild. however, compliance is often suboptimal. this study investigated whether the education and literacy level of patients may affect attendance and completion of pr. patients were divided into two groups based on diagnosis; copd or ild. nine factors were studied: sex, age, baseline activity level, education, literacy, social isolation, transport to programme, oxygen requirements and anxiety and depression scores. completion of pr was defined as attending [ % of the classes. our findings demonstrated that % of copd patients failed the literacy test compared to % of ild patients. % of copd patients had only primary level education in contrast to % of ild patients. % of copd patients completed third level education compared to % of ild patients. % of copd patients travelled to pr in their own car in contrast to % of ild patients. % of copd patients got public transport to pr compared to % of ild patients. % of copd patients and % of ild patients completed pr. although there were significant differences in educational achievements between groups, this did not affect their compliance in completing pr. osteoporosis has not been fully evaluated in copd patients. the development of osteoporosis among copd patients is multifactorial. the objectives of this study were: ( ) to explore the prevalence of osteoporosis among copd patients, ( ) to observe any correlations between t-scores and different disease related variables. copd patients attending respiratory clinics were randomly assigned for dexa scanning. pts were excluded because of the coexistence asthma, age [ years and early menopause. the mean age of the studied patients was (range - ) years, and % were female. mean fev of these patients was %. seventy-two percent had osteoporosis, and % had osteopenia. mean t-score was - . (male - . , female - . ). t-score was noted to have positive correlation with age (r = . , p = . ), but no correlation with bmi (r = . , p = . ) and fev (r = - . , p = . ) was noted. statistical difference in t-score was observed between patients with normal/reduced mobility vs. poor mobility (p = . ) but no difference was observed among patients with steroids inhalers alone (over the last years) or in combinations with oral steroids (p = . ). very high prevalence of osteoporosis was noted among our cohort of copd patients. surprisingly, there was no association of bmd with fev , bmi and corticosteroid exposure. the aim of this study was to determine the benefits of standardised reassessment of long term oxygen therapy (ltot) patients. long-term oxygen therapy (ltot) is the treatment proven to improve survival in chronic obstructive pulmonary disease (copd) patients with chronic respiratory failure. this study was prompted by an absence of any formal or regular assessment of ltot after initial prescription. the patient's oxygen requirements were assessed carrying out abg analysis after the patient had been taken off oxygen for thirty minutes. the patient then participated in a six minute walk test ( mwt) to determine the need for ambulatory oxygen. of the patients contacted attended for ltot reassessment. % patients no longer met the criteria for ltot i.e. pao [ . kpa. % required a decrease in their static oxygen requirements. . % required an increase in their ambulatory oxygen requirements. . % needed a prescription for ambulatory oxygen. % had a sub therapeutic oxygen prescription. in total % of participants required a change to their oxygen prescription. current procedures for the assessment of ltot result in a large proportion of recipients not having appropriate prescription. there is a need for the initiation of standardised regular reassessment of all ltot patients. with increased ambulatory treatment of copd exacerbation, there is a need for opd assessment of blood gases and ph. we looked at the correlation between arterial blood gas (abg) and capillary blood gas (cbg) in a stable population of opd patients with copd. patients attending for oxygen assessment had a capillary blood sample taken from the fingertip pulp. this was analysed using the epoc Ò point of care analysis system. an arterial blood sample was obtained from the radial artery and analysed using a radiometer blood analyser. patients attended for oxygen assessment. we used pearson's correlation to compare the results of abg and cbg. it showed a moderately high correlation of pco at % (p = . ). a correlation of % with po (p = . ). the hco and base excess correlations were extremely high at % (p = . ) and % (p = . ), respectively. independent sample t tests were used to look at the agreement between abg and cbg values. it showed that cbg could be useful in predicting ph, hco and base excess but not very useful clinically in predicting pco and po . cbg could be used in the opd setting to monitor blood ph and may be useful in copd outreach assessments. identifying lung disease early is very important and can be done with spirometry testing. early detection of these diseases can greatly improve outcomes and quality of life for patients. members of the public were given the opportunity to have their lung function tested for free, as part of the world spirometry day campaign. spirometry was performed by respiratory scientists. access to smoking cessation advice, inhaler technique and the benefits of exercise to maintain healthy lungs were also provided. patients were tested. % (n = ) were male and % (n = ) were female. % (n = ) were under years. % (n = ) were [ years. % (n = ) reported that they had a previous lung function test. % (n = ) reported they never had a lung function test performed. % (n = ) did not answer. % (n = ) of those previously tested reported a history of known lung disease. % (n = ) who were never tested reported a history of lung disease. % (n = ) were non-smokers, % (n = ) were current smokers, % (n = ) were ex-smokers and % (n = ) unknown smoking status. % (n = ) achieved normal spirometry. % (n = ) results were abnormal. % (n = ) results were unreliable. of the abnormal results; % (n = ) demonstrated obstructive lung disease, % (n = ) restrictive lung disease & % (n = ) mixed lung disease. implementing and evaluating palliative care responses for patients with advanced respiratory disease. this multi-site action research project used mixed methods data collection strategies including qualitative interviews with patients and families, expert focus groups and quantitative methods such as education surveys, evaluation and chart audits. study findings demonstrate that palliative care interventions can be implemented within respiratory services for those patients with advanced disease. the study methodology of action research ensured that all key stakeholders in the service delivery across several sites contributed to sustainable organisational change which delivered measurable care improvements for patients throughout the research process. interventions that have developed include; shared training and education across sites, multi-disciplinary team meetings, pulmonary rehabilitation session on coping, death reviews and the development of a respiratory palliative care pathway for patients. palliative care interventions are feasible within care delivery models for patients with advanced respiratory disease. referral links and a care pathway between the hospital and hospice settings are at the cornerstone of this care delivery model. half of all patients admitted with copd in ireland are either dead ( %) or re-admitted to hospital ( %) within days [ ] . variation in the management of copd patients may contribute to this. implementation of care pathways has been suggested to improve outcomes such as mortality, admission rates and length of stay. the acmb was introduced as a sticker in the healthcare record in feb . a cross-sectional audit reviewed staff practice prebundle implementation, post-bundle and following an educational drive. % of patients in the pre-bundle group received nebulised bronchodilators within min of presentation, in comparison to[ % in the post-education group. prescription of oral corticosteroids improved with a corresponding decrease in patients receiving none. there is ongoing use of intravenous corticosteroids ([ %). the use of intravenous antibiotics was unchanged at approximately % although over % of patients received an antibiotic recommended in the acmb. % of pre-bundle patients received an abg, % within min; following the educational drive this increased to % with % within the timeframe. further education may be required to decrease the frequency of intravenous medications along with examination of barriers to managing patients within the acmb timeframe. the recent ers audit of irish patients with exacerbations of copd was the first nationwide assessment of survival and readmission rates for this patient cohort. it showed an average length of stay of days, a day readmission rate of % and mortality rate of . %. our copd outreach provides supported or pre-emptive discharge as an alternative to hospital treatment for copd exacerbations. we undertook an audit of patients treated by the outreach team over years to compare rates of these values with those from the ers audit. among patients who died in this period ( %) died in the day period from discharge and ( %) were readmitted. of those that died, % were readmitted within days and % died in hospital within a short period of readmission. of overall readmissions ( ) % were from early discharge programme, ( %) assisted and ( %) prevent readmissions. of note % of prevent readmission patients died within days. the median length of stay was days. these data indicate that survival and readmission rates are the same whether patients are treated in hospital or by outreach teams, however, with shorter lengths of stay the later is associated with substantively lower costs. future research will need to focus on identifying the factors that contribute to the high readmission rates. the central purpose of pulmonary rehabilitation is to reduce morbidity by improving functional capacity through exercise. it is still unknown if improvements in functional capacity are maintained in the long-term and lead to increased physical activity levels. the hypothesis of this study was that pulmonary rehabilitation would lead to a sustained increase in standard outcome measures and in daily physical activity. a prospective study of subjects with copd was performed, registered at clinicaltrials.gov (clinical trial number nct ). the primary outcome was a maintained improvement in standard outcome measures with a secondary aim of an increase in daily physical activity. a convenient sample of the cohort (n = ) was re-evaluated at a third time point at year. a weeks hospital based outpatient pulmonary rehabilitation programme led to a significant reduction in total energy expenditure (p \ . ) and breathlessness (borg, p \ . ) and improved exer- these findings show that while pulmonary rehabilitation increased exercise capacity this was not transmitted into increased daily physical activity. alternative methods to alter/affect behavioural change may need to be addressed. the national clinical programme for chronic obstructive pulmonary disease (copd) aims to improve quality, access and cost of care for patients with copd. pulmonary rehabilitation (pr) has been proven to meet these aims. the purpose of this study was to audit pr throughout ireland. hospitals and all local health areas (lha) were surveyed about prp in their catchment areas -ongoing programmes, length of and numbers on waiting lists, and enrolments in prp in the first months of . those without access to prp were asked about barriers to setting up such programmes. descriptive statistics were used. all hospitals (n = ) and lha (n = ) responded re access. % of hospitals (n = ) and % of lha (n = ) have access to pr. hospital settings have mean waiting lists . months( , ), mean numbers waiting ( , ) and mean number enrolled ( , ), (respondents = ). respondents (n = ) from the community showed waiting lists of and months, numbers waiting and and numbers enrolled and . 'black spots' with no access were identified. barriers that may be amenable to intervention include increased support for primary care teams, facilitation of appropriate referrals and the development of spirometry services in the community. patients were selected as per gold guidelines. the duration of the study was weeks. four primary care centres were selected, one each in longford, athlone, tullamore and mountmellick. one spirometry clinic was held every week on a rotational basis with the intention of accommodating patients per clinic. it was free service and intended for patients who had not previously undergone spirometry testing. the gp practise booked patients directly into the spirometry clinic. a total of patients were booked across the spirometry clinics. of the patients booked, % did not attend and % cancelled their appointment. out of the clinics utilized all available slots with one clinic utilizing only % of available slots. a total of patients were tested. out of these, had normal spirometry, had gold stage mild copd, had stage moderate copd, had stage severe copd and had stage very severe copd, had possible restrictive lung disease and unreliable data. success and efficiency of this type of service is heavily dependent on spirometry clinics being gp driven. a number of advantages, disadvantages and recommendations arose out of this study. . an audit of steroid and antibiotic therapy for acute exacerbations of copd in a cork hospital sought to determine compliance with these guidelines in the mercy university hospital, cork. a retrospective review was conducted on patients admitted with exacerbations of copd from st june to st august . forty-six patients attended the ed with exacerbations of copd. thirty-three charts were available for review. of the patients, ( . %) were prescribed iv hydrocortisone, despite being able to take oral prednisolone, ( . %) were prescribed oral prednisolone and ( . %) were not prescribed steroids. eight patients were prescribed co-amoxiclav alone, patient was prescribed clarithromycin alone and no patients were prescribed doxycycline alone. four were treated with piperacillin/tazobactam, patient with piperacillin/tazobactam and linezolid, patients with co-amoxiclav and clarithromycin, one patient with moxifloxacin, patients with ciproxin and for patients, antibiotics were not prescribed. of the patients prescribed co-amoxiclav and clarithromycin, had infiltrates on cxr. the prescription of antibiotics and steroids in the muh in patients with acute exacerbations of copd did not meet guidelines as per the national copd acute management bundle. though niv significantly improves outcomes in acute copd patient care, there is no compulsory niv training programme for nchds. we assessed nchd's knowledge of the use of niv in copd using a questionnaire, based on bts guidelines, with reliability assessment in a subset of nchds. experience level, knowledge of niv contraindications and settings were examined. questionnaires were completed. inter-rater agreement was good (kappa . , se . , % ci . - . ). % had previously worked in respiratory medicine. % had commenced patients on niv and/or titrated settings on call. % had received training in the use of niv. % adjusted niv settings incorrectly for hypercapneic acidemia. % used epap incorrectly. those with respiratory work experience had greater niv titration experience (p = . ) and superior knowledge of niv settings (p = . ). though % of interns had previously titrated settings, their confidence tended to be lower (p = . ) and their knowledge of niv settings was significantly inferior to more experienced doctors (p = . ). though niv is widely used by nchds of all grades, the present study shows training and knowledge deficiencies, especially among interns and those not in a respiratory post. there is a need for structured training in this key skillset among nchds. table . conclusions: approximately one-third of the patients in who presented to the ralc were classified as asymptomatic. approximately / of asymptomatic and only / of symptomatic patients had early stage cancer ( and ) which was a statistically significant difference. there was no difference in smoking history gender, tissue type and ecog status at presentation between symptomatic and asymptomatic patients. lung cancer is the most common cause of cancer death in ireland. a recent large screening trial demonstrated a % survival advantage with low-dose ct over chest x-ray [ ] . however, the false positive rate of . % for screening detected nodules is a major drawback. a lung cancer biomarker would lead to improved specificity, reduced costs and a reduction in unnecessary procedures for patients with ct-detected pulmonary nodules. biomarkers would also be useful for monitoring response to therapy or disease progression and may reveal the molecular mechanisms underlying cancer development. proteomics represents an important tool for identifying novel cancer biomarkers. recent advances in mass spectrometry allow rapid and accurate analysis of several thousand proteins in a single study [ ] . we prospectively recruited patients presenting to beaumont hospital rapid access lung clinic between april and july . paired bronchoalveolar lavage (bal) and serum samples were obtained. patients were subsequently grouped after clinical and mdt follow-up into ( ) benign, ( ) possible (for surveillance), and ( ) confirmed lung cancer. samples were then analysed by orbitrap mass spectrometry and candidate lung cancer biomarkers identified based on the clinical and histological characterisation. principal components analysis (pca) of the peptides found to be differentially expressed between control bal and cancer bal was performed to determine any outliers in the data and also to identify group clustering as per diagnosis. leave-one-out cross validation (loocv) of a protein plasma combination demonstrated an accuracy of * . % (auc: . ) for distinguishing benign conditions of the lung from cancer (sclc/ nsclc) (fig. ) . further analysis and validation is underway. trapped lung after malignant pleural fluid drainage is a contra-indication to talc pleurodesis. vats identifying patients amenable to talc may be prohibited by co-morbidities. initial experience with a miniinvasive alternative is described in three patients, two transferred with debilitating dyspnoea and previous multiple admissions for drainage procedures. ultrasound was performed and pleurx Ó insertion under la (single in patient, bilateral in ), with palliation of symptoms facilitating discharge in all three. a rapid access lung cancer clinic (rac) with radiological support was recently introduced aiming to both decrease the time to diagnosis of patients, whether negative or positive, and also to decide the most appropriate investigation for each patient with on-site radiologist support. in this observational study, we used a historical cohort of the last fifty red flag patients assessed at the respiratory clinic before the introduction of the rac, and compared it with the first thirty-five patients seen at the rac. time to diagnosis and the number of invasive investigations [bronchoscopy/fine needle aspiration (fna)] were compared as outcome measures. continuous variables were compared using mann-whitney u test and categorical variables using fischer's exact test. patients were similar in terms of demographics. there was a statistically significant reduction in the time to diagnosis (p \ . , mann-whitney u), whether negative or positive, following the introduction of the rac (fig. ) . there was also a statistically significant reduction in the number of bronchoscopies (p \ . , fischer's exact test) carried out after the introduction of the rac. these results demonstrate that the rac with radiological support decreases both the time to diagnosis and the number of invasive investigations that may not have yielded a diagnosis. tbna has been widely available for sampling mediastinal lymph nodes (ln) for over two decades. unfortunately, blind tbna has low sensitivity and limited access to only certain ln stations. ebus-tbna has revolutionised ln sampling demonstrated in many prospective multicentre trails. over a -month period, patients with evidence of lymphadenopathy on chest ct, underwent ebus-tbna. procedures were performed on patients ( males, mean age of . years). diagnostic yield, and sensitivity were calculated by reviewing clinical notes, radiological imaging, cytology, transbronchial/endobronchial biopsy, bal, and mediastinoscopy reports, and redo ebus-tbna reports from another centre. in % of procedures, ln were sampled. . % of ebus-tbna samples were diagnostic ( cases for sarcoid, and for lung cancer). diagnostic yield was compared in st . -month period versus nd and returned versus . %. sensitivities for sarcoidosis and lung cancer were calculated at and . %, respectively. review of current data shows diagnostic yield and sensitivities varies significantly, however, our results were below current published standards. radiologically guided lung biopsy is a relatively safe procedure to reach a histological diagnosis for suspicious lung lesions. we audited the performance of university hospital galway against the bts guidelines. this was a cross-sectional study. all patients who had radiologically guided percutaneous lung biopsies between january and october were included. primary outcome was the ability to reach a histological diagnosis. secondary outcome was development of pneumothorax or other complications. biopsies were performed. were males and were females. mean age was . years. mean lesion size was . ± . cm. the procedure was done under ct-guidance in patients ( . %), fluoroscopy in patients ( . %) and ultrasound in patients ( . %). the overall diagnostic rate for benign and malignant causes was . %. malignancy was diagnosed on biopsies ( %). sensitivity for detection of malignancy for lesions [ cm in size was ( . %). the procedure was complicated by pneumothorax in patients ( . %). only patients ( . %) required chest tube insertion. we achieved a higher diagnostic rate than the level set by the bts but pneumothorax rate was slightly higher. this could be because the majority of our samples were taken using large bore cutting needles. sarcoidosis is a systemic granulomatous disease of unknown aetiology that primarily affects the lung. several reports have suggested that analysis of cd +/cd + lymphocytes can be used to differentiate sarcoidosis from other causes of interstitial lung disease. the aim of this study was to evaluate the diagnostic utility of bal fluid cd /cd ratio in diagnosing pulmonary sarcoidosis. this was a retrospective cohort study. study population included all patients who had bal fluid obtained during fibre-optic bronchoscopy in university hospital galway between november and june . outcome variable was cd +/cd + ratio as calculated on flow-cytometry performed on bal fluid. patients got bal fluid analysed. ( . %) were found suitable for analysis by flow-cytometry. had a transbronchial biopsy performed. out of patients with histological evidence of sarcoidosis, only patients had bal fluid suitable for analysis. ( . %) of them had a cd /cd ratio higher than . . sensitivity of cd /cd ratio [ . in diagnosing pulmonary sarcoidosis was % with a specificity of %. positive predictive value was % and a negative predictive value was . %. the distribution of cd /cd ratios in patients with biopsy-proven sarcoidosis suggests that substitution of bronchoalveolar lavage cellular analysis for transbronchial biopsy is not advisable. we previously reported that smoking cessation (sc) services are available but lacked uniformity or consistency countrywide [ ] . we found that ( %) of service providers (sp) were collecting and analysing data on pregnancy status but % did not analyse it and % did not collect any data on pregnancy. we aimed to look at outcomes of sc in pregnancy, provide evidence based data to improve services for this vulnerable population and aid their evaluation and effectiveness. using a census of all known smoking cessation programmes throughout ireland [ ] , sps were asked to pilot a treatment database for a month period. many different data were entered including pregnancy status and treatment outcomes. the data were returned to tfri for analysis using a statistical package spss. a database was piloted over a month period by sps. a convenience sample of , patients was recruited while attending sc service throughout ireland and their data were entered into the database. a total of pregnant women attended the smoking cessation services during this period which represents . % of the females treated. they achieved a quit rate of . % at weeks and . % at months compared with . and . % of the rest of the female population treated in the same time period. the poor outcomes may be a result of the paucity of services in ireland for this population group. the findings will facilitate planning and delivery of effective sc programmes to pregnant women ensuring equity in service provision. maternal smoking in pregnancy is an important risk factor for low birth weight (lbw) (\ , g) and prematurity (\ weeks gestation) [ ] . the purpose of this study was to examine smoking rates and prevalence of associated adverse birth outcomes in the coombe women and infants university hospital, dublin over a year period - . a cross-sectional observational study was conducted using routinely collected data from the euroking k maternity system from january -december (n = , ). smoking prevalence declined significantly from . to . % over the period. rates in teenage mothers remained very high ( . % in ). smoking prevalence was almost twice as high in mothers of lbw compared to normal birthweight babies, one and a half times higher in mothers of preterm babies compared to full term and more than twice as high in mothers of small for gestational age (sga) babies compared to non sga. a statistically significant decline was seen in the prevalence of sga babies in the period. no statistically significant change was seen in the prevalence of lbw or preterm babies. prevalence rates in pregnancy are high in ireland compared with other developed countries. increased focussed efforts are needed to reduce smoking rates. smoking-related diseases account for over , admissions per year in ireland. % of all smokers will die of smoking-related disease, and smokers on average die years younger than non-smokers. the aim of this project was to assess attitudes and beliefs in smokers and ex-smokers. patients who were smokers or ex-smokers were interviewed using a standardised questionnaire. candidates were recruited from respiratory clinics and general-inpatient wards in beaumont hospital. data regarding underlying medical history was acquired from medical records. patients were included, ex-smokers and smokers. there were no differences in gender or medical history. ex-smokers had a mean age of . years compared to . years in smokers (p = . ). smokers had longer smoking history; . years compared to . years (p = . ). smokers reported lower expectations regarding the benefits of smoking-cessation than the exsmokers; only % believed there would be short-term health benefit and only % believed quitting was worthwhile compared to . and . %, respectively, in the ex-smoking group (p = . /p = . ) there is significant variation amongst smokers and ex-smokers regarding attitudes to smoking-cessation; this is despite receiving the same smoking-cessation advice and having low fagerstrom-scores. of note current-smokers were younger but had longer smoking histories and smoked from an earlier age. results: a total of patients have been referred, . % (n = ) male and . % (n = ) females. the mean age at referral was . years. . % of patients admitted to being current smokers, of these . % were male and . % were female. . % had a previous history of smoking . % of patients were referred from their gp, . % were referred from another consultant based with the mwrh and . % from another centre. a total of patients referred to the clinic subsequently had a diagnosis of cancer. patients had a diagnosis of lung cancer (adenocarcinoma = , scc = , other nsclc = and small cell = ). patients were diagnosed with a malignancy other then lung cancer, the most common being lymphoma, or metastatic lung disease. male patients accounted for . % (n = ) and female . % (n = ) of those diagnosed with cancer, with a mean age across both genders of . years. conclusions: the results of the audit would suggest that the ralc clinic is in line with national trends as regards smoking prevalence and age. the referral pathway needs to be the focus for the future facilitated by early referral from gp's. this will enable the ralc clinic to prioritise prompt investigations and treatments to optimise survival. sarcoidosis. we aimed to assess the diagnostic accuracy of ebus- [ ] . twenty ipf patients attending a specialized clinic were recruited. their blood samples were collected. full pulmonary function and awake arterial blood gas, high resolution computed tomography of chest (hrct) were performed. ccl was quantified using a enzyme-linked immunosorbent assay. ccl levels are presented as median ± interquartile range. correlations were analysed using pearson and simple regression. median concentration of ccl was higher in ipf patients [ , . pg/ml ( , . - , . )] compared to healthy controls [ , pg/ml ( , - , ), p = . ] [ ] . ccl levels were inversely correlated with diffusing capacity for carbon monoxide (dlco) (r = - . , p = . )* and awake carbon dioxide (co ) tension (r = - . , p = . *). positive correlations were observed between a-a gradient and ccl concentration (r = . , p = . *) and co rise during sleep (r = . , p = . *) but no relationship between ccl and fibrosis score, mean reticulation score or mean ground glass score on hrct. ccl levels correlate with physiological marker of fibrosis. we found significant correlation between ccl and markers of daytime hyperventilation and nocturnal hypoventilation. ccl may be a useful marker of disease activity in ipf. were reviewed. patients with normal cxr who had ctpa performed were included in study. in patients who had no pe but incidental findings (n = ), further review was done to see if these findings would account for presentation. in patients with normal cxr and negative ctpa, an alternative diagnosis directed by incidental findings was able to account for presentation in . % (n = ) of cases. of these, respiratory causes accounted for % (n = ), with pneumonia being the commonest overall cause at . %. other causes included atelectasis %, emphysema %, effusion %, collapse %, lesion % and pneumothorax %. ctpa is able to offer an alternative diagnosis in patients who had initial normal cxr and negative ct pa. our study is suggestive of high incidence of pneumonia in patients scanned for suspected pe. ctpa is the investigation of choice for suspected pulmonary embolism (pe). determining pretest probability for risk of pe using risk assessment scores and d-dimer is an important step in diagnosis. to establish positive predictive value of clinical and lab-based risk assessment for diagnosis of pe and to determine whether or not there was an overuse of ctpa in our service. a retrospective audit identified patients (n = ) who had ctpa performed from january -march . patients were classified as being low, intermediate or high risk for pe, based on wells criteria [ ] . cases were reviewed to establish if pretest assessments were used correctly in predicting probability of pe and need for ctpa. in high risk group (wells score [ ) (n = ), there were diagnosed pes (ppv . %). in intermediate risk group (wells score c b ) (n = ), there were pes (ppv . %). in low risk group (wells score b ) (n = ) there were pes (npv . %). in our sample, wells scores had reasonable predictive value for diagnosis of pe in high risk patients. positive predictive value in intermediate group was significantly lower and ctpa may be overused in this group. negative predictive value for low risk group was very high. therapeutic thoracentesis: the role of ultrasound and pleural manometry ultrasound-guided thoracentesis the utilization of endobronchial ultrasound for sampling of primary lung we performed a retrospective audit of mesothelioma patients diagnosed in the whsct between and and compared our practice against guidelines. patients ( male, female) were diagnosed-mean age . years, range - years. asbestos exposure was documented in patients ( . %). patients ( %) had right-sided chest disease with ( %) having left-sided disease /hospice. patients are still alive. all patients were known to a lung cancer specialist nurse pilcher alfred hospital intensive care, melbourne, australia we examined the use of bronchoscopy in a bed icu/hdu over a month period. our aim was to establish the number of procedures done, the indications and complications. we also performed an audit of procedure documentation and set-up. procedures were identified over the period in question. % patients were male and ages ranged from to with a mean of years. various indications were documented with infection ( %), tracheostomy insertion ( %) and difficulties with oxygenation ( %) being the most common interstitial lung disease and pulmonary vascular disease chairs d. o'callaghan, mater misericordiae university hospital we now characterize potential mechanisms associated this b cell phenotype in sarcoidosis. serum was collected from treatment-naive, sarcoidosis patients and control patients. b cell activating factor (baff; r&d systems) and soluble (s) cd (ebioscience) levels were measured by elisa. expression of b cells in sarcoidosis granulomas were assessed using standard immunohistochemistry. all subjects signed an informed consent prior to participation. b cells were detected in sarcoid granulomas, but using serial sections no cd positive b cells were identified with respect to reduced cd b cells in sarcoidosis, we found no evidence that these cells are sequestered in sarcoid granulomas and that the key critical b cell cytokine, baff is appropriately elevated. scd is increased raising the possibility that the phenotype in this population reflects shedding of cd from the surface of memory b cells the diagnosis of sarcoidosis required the presence of non-caseating granulomata with negative ziehl-neelson stain and fungal stain plus negative culture for mycobacterium tuberculosis (tb), other bacteria and fungi. results: patients were tested. / ( . %) had positive tblb. / had negative tblb ( . %). of the negative tblb group, / ( %) had positive ebb. tb cultures on all tblb biopsy samples were negative and bal was negative for bacterial and fungal growth in all cases. no patient suffered complications secondary to the procedure. conclusion: tblb remains a useful diagnostic test in the diagnosis of sarcoidosis serum fibroblastic growth factor- in acute sarcoidosis p other serum biochemical markers measured included calcium, phosphate, h urinary calcium, parathyroid hormone (ipth) and -hydoroxy vitamin d . results: subjects were male and were female. mean (sd) ipth was . ( ) ng/l, serum calcium . ( . ) mmol/l, serum phosphate . ( . ) mmol/l, serum -hydroxy vitamin d ( . ) nmol/l, and h urinary calcium excretion was . ( . , . ) mmol/l. fgf- was detectible only in those patients who also had hypercalciuria and was elevated in all those with hypercalcaemia. after adjusting for covariates using stepwise multivariate linear regression fgf- was independently associated with serum calcium conclusions: this study describes the distribution and determinants of serum fgf- in acute sarcoidosis for the first time. evidence is accumulating that fgf- may have a pathogenic role in adverse cardiovascular outcome, whether this applies to patients with sarcoidosis and normal kidney function merits further investigation convex probe endoscopic and endobronchial ultrasound (eus/ebus) for the diagnosis of sarcoidosis ebus and eus guided lymph node aspiration is a minimally invasive procedure widely used for diagnosis and staging of lung cancer. there has been increasing interest in utilising these modalities for the diagnosis of benign conditions including pirfenidone is an emerging therapy for limited ipf mcnicholas department of respiratory medicine, st. vincent's university hospital, dublin idiopathic pulmonary fibrosis (ipf) patients have reduced exercise capacity [ ], which correlates with parameters of pulmonary function and arterial oxygen tension resting pulmonary function testing and arterial blood gases were recorded. statistical analyses included student-t and mann-whitney u testing. maximal work load was reduced at . ± . % predicted corrected for sex, age and height. vo max was moderately reduced at . ± . % predicted. mean pre and post exercise borg score was and . a positive correlation was observed between vo max and fvc (r = exercise testing in the evaluation of diffuse interstitial lung disease pathophysiology of activity limitation in patients with interstitial lung disease diagnostic serum biomarkers to distinguish idiopathic pulmonary fibrosis from scleroderma-associated lung disease and healthy controls b. kennedy , p. branagan cork idiopathic pulmonary fibrosis (ipf) may be difficult to differentiate from scleroderma-associated interstitial lung disease potential biomarkers were measured by elisa or biochip immunoassay. differences between groups were calculated by unpaired t-tests. data are presented as mean ± sem. mean serum levels of kl- ( ± vs. . ± ng/ml elevated serum sp-d may help differentiate ipf from ssc-ild and healthy controls. the elevated serum sp-d in ipf compared to ssc-ild may reflect increased leakage from pulmonary capillaries arising from more extensive alveolar injury bone marrow and peripheral blood derived cd + cells as agents of tissue remodelling in idiopathic pulmonary fibrosis b cd + cells originate in bone marrow, circulate and then migrate to tissue where they may differentiate into macrophages. we investigated extrapulmonary cd + cells as a source of mediators of tissue remodelling in ipf. peripheral blood (pb) and bone marrow (bm) were obtained from /ml, p = . ) cd + cells. ipfs and controls did not differ significantly in ccl , ccl , tgf-b , ccl , mmp , mmp or timp expression in either pb or bm cd + cells. ipfs and controls do not demonstrate any quantitative differences in the expression of mediators of tissue remodelling in pb or bm cd + cells. nevertheless ccl as an indicator of pulmonary fibrotic activity in idiopathic interstitial pneumonias and systemic sclerosis circulating levels of the chemokine ccl but not cxcl are elevated and correlate with disease activity in rheumatoid arthritis diffusing capacity of carbon monoxide (dlco) are the physiologic characteristics mostly correlated with hrct findings. high fibrosis score and extent of the reticulation and honeycombing on ct are associated with increased the risk of death [ ]. we aim to investigate the correlations between radiological and physiological features of ipf. patients with ipf were recruited from our database. full pulmonary function testing and awake arterial blood gas were performed. survival data were collected after a period of follow up. hrct was scored by a core radiologist on-site. data was analysed using linear regression and spearman correlation high-resolution computed tomography in idiopathic pulmonary fibrosis: diagnosis and prognosis ct features of lung disease in patients with systemic sclerosis: comparison with idiopathic pulmonary fibrosis and nonspecific interstitial pneumonia incidental abnormalities found on negative ct pulmonary angiograms performed on patients for suspected acute pulmonary embolism and with normal chest x-ray primary chest wall tumours and lung cancer invasion of the chest wall are the usual indications for chest wall resection and reconstruction. we evaluated all patients who underwent chest wall resection ± reconstruction in our unit from february to july . patients were identified. reconstruction was completed using either a composite of marlex mesh and methyl-metacrylate or a goretex sheet. reconstruction of the chest wall prevents post operative complications and restores the respiratory dynamics by avoiding paradoxical or harmful movements. in the majority of cases, it was possible to approximate the soft tissue over the reconstruction. in selected cases, our plastic surgical colleagues used a variety of flaps to approximate the defect.we looked at mean length of stay, histological types, morbidity and survival. there were no intra-operative mortalities. day mortality was . %.chest wall resection is not a common procedure but may be performed in high volume centres with low morbidity and mortality. in those with primary chest wall tumours, a wide resection margin is associated with low recurrence rates. in patients with nsclc (t ) involving the chest wall, en bloc lung and chest wall resection has a proven curative benefit with excellent year survival. fibreoptic bronchoscopy is considered a safe diagnostic tool [ ] . it is suggested, however, that post-bronchoscopy complication rate increases with age [ ] . we decided to study the complication rate and the outcomes of bronchoscopy in patients over years in our institution. a retrospective review of case notes of patients over years who underwent bronchoscopy between september and november was performed. data on complications experienced during and after bronchoscopy and the influence of the results on subsequent management were collated and analysed.ninety-six patients were included. mean age was . years (sd . ). thirty subjects ( . %) had a documented lung disease. fifty-nine patients ( . %) were current or ex-smokers. indications for bronchoscopy were; to evaluate for malignancy ( . %) and to evaluate for tb ( . %). post bronchoscopy complications were noted in eight ( . %) cases including hypoxia ( . %), infection ( . %), tachycardia ( %) haemoptysis ( %) and pneumothorax ( %). six patients required post bronchoscopy treatment for complications. malignancy was diagnosed in twenty cases ( . %) and infection was detected in six ( . %). as a result of bronchoscopy, management was altered in fifty-one patients.in conclusion, bronchoscopy is relatively safe and has good diagnostic utility in patients aged more than eighty years. the introduction of an ebus-tbna program more than halved the numbers of endobronchial brushings without a statistically significant change in the number of combined bals and washings or biopsies. we plan to investigate the impact of ebus-tbna on the diagnostic yield of brushings biopsies bal and washings. the use of fibreoptic bronchoscopy in an intensive care unit tbna and eus-fna in patients with suspected sarcoidosis after its implementation at a university hospital. methods: we retrospectively analysed data on all patients with suspected sarcoidosis who underwent ebus/eus since the start of the service. sensitivity and diagnostic yield were calculated based on cytology results and further invasive diagnostics for negative samples. resuts: over months patients ( males females) with a mean age of ± were assessed. % had stage i disease. underwent ebus and eus. lymph nodes (lns) were sampled in total with a mean of . /patient. diagnostic yield was . % with patients diagnosed with sarcoidosis and patient with tuberculosis. there were false negatives yielding a sensitivity for detecting sarcoidosis of %. tumour necrosis factor alpha (tnf-a) inhibitors have had a huge impact on the treatment of inflammatory arthritis, inflammatory bowel disease and psoriasis. there is also much interest in the use of tnf-a inhibitors in the treatment of refractory sarcoidosis [ ] . paradoxically sarcoidosis in response to tnf-a inhibitors is increasingly recognised with over cases reported to date [ ] . we report a series of three cases of sarcoidosis that developed on tnf-a inhibitors.a year old lady with a history of severe crohn's disease developed a right upper lobe consolidation and respiratory failure following two doses of adalimumab. investigations for tuberculosis were negative. a ct guided biopsy of a persistent right upper lobe infiltrate confirmed non caseating granulomas consistent with sarcoidosis.a year old gentleman on etanercept for ankylosing spondylitis presented with dyspnoea and a dry cough. cxr showed diffuse fibrotic change. ct findings and a transbronchial biopsy showing multinucleated giant cells led to a diagnosis of sarcoidosis.a year old man on adalimumab for rheumatoid arthritis was admitted with cough and purulent sputum. cxr and ct thorax confirmed mediastinal and hilar adenopathy. investigations were negative for tuberculosis. endobronchial ultrasound guided needle aspiration showed non caseating granulomas consistent with sarcoidosis.sarcoidosis in response to tnf-a inhibitors is a rare but increasingly recognised condition. following exclusion of tuberculosis a high index of clinical suspicion is needed to prevent a delay in diagnosis. the distribution of cd /cd ratios in patients with biopsy-proven sarcoidosis suggests that substitution of bronchoalveolar lavage cellular analysis for transbronchial biopsy is not advisable. pirfenidone has been approved for the treatment of mild to moderate ipf in europe. pirfenidone regulates the activity of tgf-b and tnfa. we evaluated a single centre experience with pirfenidone.a retrospective cohort design was used to study ipf patients prescribed pirfenidone. a titrating dose of pirfenidone was commenced on patients with an fvc[ % predicted and dlco[ %. primary outcome was change in percentage predicted forced vital capacity (fvc). secondary outcome was change in percentage predicted transfer factor (dlco). symptomatic patients were prescribed pirfendione. the mean age was . years. patient died due to an exacerbation of ipf, others discontinued pirfenidone secondary to adverse-events. patients reached target dose. subjects continued pirfenidone at a reduced dose. participants reported side effects likely related to pirfenidone. the most commonly reported side effects were gastrointestinal disturbance and photosensitivity. no significant decline in fvc or dlco was noted in patients who continued pirfenidone in . weeks follow up. key: cord- - jodunj authors: nan title: paediatric sig: poster session date: - - journal: respirology doi: . /j. - . . _ .x sha: doc_id: cord_uid: jodunj nan patients with non-eosinophilic asthma (nea) or copd have increased numbers of neutrophils in the airways. we have shown a similar defect in the ability of alveolar macrophages (am) to phagocytose apoptotic cells, in sputum from patients with nea and copd. we have also shown that bal-derived am from patients with copd have reduced expression of key macrophage phagocytic recognition molecules. the aim of this pilot study was to investigate the expression of these macrophage markers in induced sputum from patients with eosinophilic asthma (ea, n = ), nea (n = ), copd (n = ) and controls (n = ). methods participants underwent clinical assessment, skin allergy test, hypertonic saline challenge and sputum induction. macrophage phagocytosis of apoptotic cells, expression of mannose receptor (mr), hspr (cd ) and pcam (cd ) was determined using fl ow cytometry. results phagocytosis was signifi cantly impaired in patients with nea and copd. expression of mr, cd and cd were decreased in patients with nea or copd, but not signifi cantly changed in ea conclusion impaired sputum-macrophage phagocytosis of apoptotic cells in nea is associated with reduced expression of key macrophage recognition molecules. this defect may contribute to the chronic infl ammation and persistent airway neutrophilia that characterizes this asthma subtype. the use of induced sputum as a surrogate for the more-invasive bronchoscopic sampling may provide a tool for investigating the mechanisms for the effect of therapies including azithromycin in lung disease. supported by nhmrc. neutrophilic asthma (na) has been associated with increased bacterial colonization of the airways and increased expression of innate immune factors in the lung. this suggests that infection may play an important role in the pathogenesis of na. na is an important health issue as sufferers are resistant to steroid treatment, which is the mainstay of asthma therapy and effective therapies are urgently required. using mouse models of chlamydia and haemophilus infl uenzae lung infection and ovalbumin (ova)-induced allergic airway disease (aad), we have shown how infection may be linked to na. both infections suppressed eosinophilic infl ammation and t-helper (th) type responses but increase neutrophilic infl ammation and innate and th and/or th responses in aad. in the current study, the effectiveness of steroid treatment for the suppression of infection-induced neutrophilic aad was assessed by treating infected ovasensitized mice intranasally with dexamethasone during ova challenge. whilst dexamethasone treatment suppressed th -mediated, eosinophilic aad in uninfected, ova-sensitized groups, chlamydia and haemophilus-induced neutrophilic aad were shown to be steroid-resistant. our fi ndings correlate with clinical observations which show associations between infection, neutrophilic infl ammation and steroid resistance in asthmatics. these models will be utilized to examine the effectiveness of a number of novel therapies for infection-induced neutrophilic aad and to develop improved treatment strategies for steroid-resistant asthma. supported by nhmrc, asthma foundation of nsw, hmri. kj baines , , jl simp s on , , rj scott , lg wood , , pg gibson , priority research centre's for asthma and respiratory disease, and information based medicine, the university of newcastle, nsw, australia, and respiratory & sleep medicine, hmri, john hunter hospital, nsw, australia rationale four infl ammatory phenotypes of asthma have been identifi ed including eosinophilic, neutrophilic, mixed granulocytic and paucigranulocytic asthma, based on the presence or absence of sputum granulocytes. the involvement of systemic infl ammation in the pathogenesis of infl ammatory phenotypes of asthma remains unknown. objective this study investigates differences in the whole genome gene expression profi le of peripheral blood in infl ammatory phenotypes of asthma. methods induced sputum and peripheral blood were collected from participants with asthma (n = ). infl ammatory cell counts were performed and infl ammatory phenotype assigned based on the eosinophil and neutrophil cutoffs of % and %, respectively. rna was extracted from whole blood, gene expression profi les were generated (illumina humanref- v ) and analysed using genespring gx . results participants with eosinophilic asthma had signifi cantly higher rates of atopy and levels of exhaled nitric oxide. there were genes classifi ed as differentially expressed between the asthma phenotypes including the α-defensins (defa) , b, and , neutrophil proteases cathepsin g (ctsg) and elastase (ela ), and the monocyte/macrophage serine esterase, carboxylesterase (ces ). expressions of defa , b, , , ctsg and ela were signifi cantly higher in neutrophilic asthma and expression of ces was significantly higher in mixed granulocytic asthma. microarray results of the α-defensins and neutrophil proteases were successfully validated using realtime pcr. conclusions there is systemic up-regulation of α-defensins and neutrophil proteases in neutrophilic asthma, and these molecules play an important role in neutrophil activation and migration. systemic activation of neutrophils is an important feature involved in the pathogenesis of neutrophilic asthma, which is signifi cantly different to other asthma phenotypes. supported by hmri and xstrata coal; the university of newcastle. confl ict of interest no. airway mucus hypersecretion is an important cause of morbidity and mortality in asthmatic patients. increases in goblet cell number and their secretions are likely to contribute to airfl ow obstruction in asthma. here, we take advantage of an established sheep model of asthma to investigate the association between allergen exposure and goblet cell activity. methods eight allergic sheep (high house dust mite (hdm)-specifi c serum ige) received weekly intra-lung challenges of hdm to the right caudal lobe, and weekly intra-lung challenges of hdm followed by weeks without allergen exposure to the left caudal lobe, with the right medial lobe serving as an untreated internal control. a separate group of sheep were also used as untreated controls. biopsy samples of segmental bronchi tissue were collected from the different lung lobes for histological analysis at and days post-hdm challenge. results the percentage of goblet cells, with respect to epithelial cells, signifi cantly increases following chronic challenge with hdm ( % hdm vs. % control p < . ). goblet cell numbers did not decline in lung lobes after a -week cessation of allergen challenges. goblet cell degranulation is significantly increased day following challenge with allergen, but returns to control levels by days post-allergen challenge ( % day vs. % control p < . ). furthermore, degranulation is increased in both the rested and internal control lobes day following allergen challenge of the right caudal lobe. conclusions in this sheep model of chronic asthma, repeated allergen challenges induces goblet cell hyperplasia which persists even after long-term withdrawal of allergen. additionally, exposure to allergen in one lobe induces goblet cell degranulation in both challenged and unchallenged lobes, suggesting neural mechanisms may be operating in this model. confl ict of interest no. the thickness of the airway smooth muscle (asm) layer is related to severity but not duration of asthma or age (james erj; : ) . it is unknown if the constituents of the asm layer change with age. aim to investigate the relation of mean asm cell volume (v c ), total number of cells per mm of airway (n l ) and fractions of asm (f asm ) and extracellular matrix (f ecm ) within the asm layer with age and age at onset of asthma. methods post-mortem tissues from control subjects (c n = ); non-fatal (nfa n = ) and fatal (fa n = ) cases of asthma were used. the volume density (n v ) of asm cell nuclei was estimated on μm transverse airway sections (haematoxylin) and mean cell volume (v c = /n v ) was calculated, correcting for the volume fraction of asm within the asm layer. f asm and f ecm were estimated on . -μm thick sections of the same airway (masson's trichrome). effects of age on asm cell parameters and tissue volume fractions were tested using general linear models, correcting for sex and study centre and by comparing age at onset of asthma (< vs. > years). results table shows assessment of airway smooth muscle (asm) cell size and number requires estimates of cell volume density (n v ), volume fraction of muscle (f asm ) within the asm layer and the volume of asm per length of airway. stereological techniques have now become the accepted standard for assessing asm cell parameters, but sources of variation remain unclear. aim to assess sources of variability in the estimation of asm cell parameters and volume fractions within the asm layer. methods large and small airways from subjects with and without asthma were examined. transverse airway sections were cut at . μm and μm (masson's trichrome technique), and μm (haematoxylin) and used to estimate asm cell number and volume, and the volume fraction of muscle (f asm ) within the layer of asm. stereological assessments of the possible sources of variation in these asm layer parameters were assessed. results increased section thickness overestimated f asm by < % ( . μm), % ( μm) and % ( μm). stable variation of < % in n v occurred if high-power fi elds (hpf) were used to estimate n v . variation in the depth of muscle in thick sections of the asm layer caused up to % overestimation of n v . although the absolute area of the asm layer varied by up to %, variation of f asm was < % around the airway circumference and along the airway length. f asm differed signifi cantly between large and small airways. conclusion these results suggest that partial thickness hpfs need to be excluded and that ≥ hpf should be used to estimate asm volume density, that a single . μm section of airway can be used to estimate f asm and that asm parameters should be compared separately in large and small airways. grants nhmrc # . nominations nil. confl ict of interest nil. no signifi cant correlation was seen with age for any asm cell parameters or tissue fractions. results were similar for medium and small airways. conclusion size and number of asm cells and the volume fractions of asm and ecm within the layer of asm are not related to age. support nhmrc australia (grants # ; # ). nomination nil. . ± . . ± . . ± . . ± . fa > . ± . . ± . . ± . . ± . background asthma is characterized by excessive airway narrowing to contractile stimuli, termed airway hyper-responsiveness (ahr). changes in airway smooth muscle (asm) protein expression or mass are possible contributing mechanisms underlying ahr and have been examined using cell culture techniques. however, how these cellular changes to asm relate to airway narrowing at the level of the whole airway is unclear. we describe a new method to track changes in airway narrowing (responsiveness) in culture. methods whole airway segments (generation - ) from sheep lungs were studied prior to (fresh) and after and hours in culture in dulbecco's modifi ed eagle medium with % bovine serum albumin, % l-glutamine and antibiotics. airway narrowing was measured from the % decrease in airway volume under a fi xed transmural pressure, using a servo-controlled syringe pump and organ bath apparatus. cumulative acetylcholine dose-response curves (ach, − m − × − m) were performed to determine maximal response (e max ) and sensitivity (pd , negative log of ec ). results fresh airway segments narrowed strongly and approached closure with an e max of . % ± . (±sem) and pd of . ± . . airway narrowing responses were preserved in culture, with no signifi cant difference in maximal response or sensitivity to ach after either (e max . % ± . , pd . ± . ) or hours in culture (e max . % ± . , pd . ± . ). conclusions the present study has validated a new method allowing changes occurring at the cellular level in culture to be related to changes in airway responsiveness at the whole airway level. future studies will assess the effects of chronic infl ammation in disease on airway responsiveness. background deep inspiration (di) produces a bronchodilator response in healthy humans, but this response is impaired in asthma. reduced airway compliance in disease could impair the response to di by limiting the stretch of smooth muscle. aim to show that isolated human bronchi dilate to di in an amplitudedependent manner and that the stretch caused by di depends on airway compliance. methods bronchi were obtained following lung resection from cancer patients who had normal spirometry (n = ). lumen narrowing was measured using a servo-control system which set transmural pressure and simulated breathing movements. bronchi were contracted to carbachol (cch × − m) during tidal breathing (from to cmh o, i.e. Δ cmh o transmural pressure, . hz) and infl ated to three different amplitudes of di (Δ , or cmh o) applied following contraction. results in cch-contracted airways, all three di amplitudes produced a transient bronchodilation. increasing the di amplitude caused a greater increase in luminal volume during the di and a greater bronchodilation following the di (p < . ). cch itself cause approximately a % fall in specifi c compliance (p < . ), which was reversed by di (p < . ). for each di amplitude, the change in lumen volume during the di was positively correlated to the specifi c compliance of the bronchi before di (r > . , p < . ). conclusions isolated human bronchi show a bronchodilation response to di that is proportional to the expansion of the airway caused by the di. the amount of stretch produced by a di depends on airway wall compliance suggesting that increased airway stiffness in disease could suppress the di response by limiting the stretch of bronchi during lung infl ation. confl ict of interest none. ja douglass , , , ea yu , , br thompson , , , gg king , , mj abramson , introduction increasing asthma prevalence and changes in environmental exposure suggest that there may be a relationship between asthma and dietary intake. however, to date, few studies have examined how dietary intakes of asthmatics differ from a healthy population. aim to measure and compare the dietary intakes of adults with stable asthma and healthy controls. methods in a cross-sectional study, dietary intakes calculated from a item food frequency questionnaire (ffq) of adults with stable asthma (n = , age years ± (sd)) were compared with intakes of healthy controls (n = , age years ± (sd)) matched for age and body mass index (bmi). spirometry, airway responsiveness to hypertonic saline, and induced sputum cell counts were also measured. results subjects with severe persistent asthma (n = ) had signifi cantly higher total fat intake than healthy controls ( ± (sem) versus ± (sem) g/day p = . ) and signifi cantly lower fi bre intakes ( ± (sem) versus ± (sem) g/day p = . ). lower fi bre intake in asthmatic subjects (n = ) was associated with lower %predicted fev (r = . , p = . ), %fvc (r = . , p = . ) and fev /fvc (r = . , p = . ). higher fat intake and lower fi bre intake were associated with higher absolute concentrations of sputum eosinophils (r = . , p = < . , n = ). conclusions subjects with severe persistent asthma have an eating pattern of lower diet quality with higher intakes of fat and lower intakes of fi bre than healthy controls, which is related to lower lung function and increased airway infl ammation. factors leading to altered dietary intake in severe asthma require further investigation. methods a randomized, placebo-controlled, single-blinded trial of tailored asthma education including device technique and utilizing pact to address patients' concerns versus brochure-only information for asthma patients over age . measurements of lung function, asthma control (acq), asthma related quality of life (aqol), medication use and adherence score (adh) were obtained at baseline, and months using standard, validated questionnaires. results sixty-fi ve participants ( f m, mean age ± . ) were randomized to the intervention group and ( f m, mean age ± . ) to the control. there were no statistically signifi cant differences between the groups' demographics or baseline measurements. a wilcoxon signed ranks test used to compare median pair ranking at baseline and months post-intervention revealed a signifi cant improvement in the active, but not the brochure-only information group at months in: acq mean ± sd = . ± . vs. . ± . (p = . ). aqol mean ± sd = . ± . vs. . ± . (p = . ). adh mean ± sd = . ± . vs. . ± . (p < . ). conclusion an educational intervention including device technique and addressing the concerns of older people with asthma signifi cantly improved acq, aqol and adh scores at months post-intervention. introduction greater exposure to ultraviolet radiation (uv) may increase the risk of allergic disease, but this association has not been investigated using estimates of time spent outdoors by individuals. the aim of this study was to investigate the relationship between self-reported doctor-diagnosed asthma and/or hayfever, and time spent outdoors. methods this analysis was based on cross-sectional baseline data from a subsample of the australian and up study, comprising men and women aged - years, living in new south wales. participants were randomly selected from the australian universal health insurance database. diagnoses of asthma and/or hayfever and the number of hours spent outdoors were derived by questionnaire. in general, the odds of a diagnosis of asthma and/or hayfever decreased with increasing time spent outdoors for both women and men. for example, in women, the adjusted odds ratios for asthma with hayfever were . ( % ci: . - . ), . ( . - . ), . ( . - . ) and . ( . - . ) for - , - , - and > hours spent outdoors on weekends, respectively, compared with < hour (p trend < . ). time spent outdoors was not associated with a diagnosis of asthma alone in men. conclusions there were statistically signifi cant inverse associations between time spent outdoors and diagnoses of asthma, hayfever or asthma with hayfever, in a large population of older australians. exposure to uv may protect against the development of allergic diseases, such as asthma and hayfever. no. background allergic rhinitis (ar) and eczema are highly prevalent and females are more commonly affected than males in adulthood. although there have been extensive studies on ar and eczema in females, little is known about the effect of reproductive factors and the development of late-onset ar/ eczema. we examined potential associations between reproductive factors and ar and eczema using the tasmanian longitudinal health study (tahs) data. methods the tahs is a population-based cohort study of respiratory disease. two thousand seven hundred sixty-four ( . %) females from the original tahs participants were surveyed in using postal questionnaire which collected information on reproductive factors such as ever pregnancy, age at fi rst child birth, use of oral contraceptive pills (ocp) and age of starting using the ocp. logistic regression was used to assess the predictors of ar and eczema and all analyses were mutually adjusted. of the participants, . % (n = ) had late-onset ar and . % (n = ) had late-onset eczema. maternal and paternal atopy were signifi cantly associated with ar (p < . ). the risk of developing eczema was decreased signifi cantly with increasing age at fi rst menstruation (or: . , % ci: . - . ) and the increased age at birth of fi rst child ( . , . - . ). a decreased risk in ar was observed with the increasing number of pregnancies ( . , . - . ). however, the associations between age of starting using ocp and ar/eczema were not signifi cant. conclusion later age at start of menses and later age at fi rst pregnancy were associated with a reduced risk of eczema which may be related to hormonal dysregulation. tp- airway responsiveness at and years is associated with asthma at years introduction asthma is the most common chronic childhood disease in australia. increased airway responsiveness (ar) is associated with asthma but not all individuals with increased ar have asthma. the perth infant asthma follow-up study recruited a birth cohort of individuals who have undergone longitudinal assessments of many factors associated with childhood ar. our previous work reported an association between increased ar in infancy and asthma at and years. aim to look at the relationship of increased ar and asthma in early adulthood at different time points from birth. methods individuals were recruited from among expectant parents attending an antenatal clinic at a local metropolitan clinic. at ages , and months and again at , and years, participants underwent an assessment that included a respiratory questionnaire and determination of ar (as evidenced by dose-response slope (drs) to histamine using the rapid technique). results children were initially recruited and studied in infancy. two hundred three, , , , and children subsequently had ar assessed at , and months, , and years, respectively. there was a signifi cant relationship between drs at and years and for both asthma at years (p = . and p < . , respectively) and 'wheeze in the past year' at years (p = . and p = . , respectively). there was no significant relationship between drs in infancy and asthma at . conclusion ar at and years is associated with asthma at years. in this study, there was no signifi cant relationship between ar in infancy and asthma at years. the pcaas has found that . % of children with acute asthma presenting to the princess margaret hospital for children emergency department (pmh ed) had hrv, of which % were hrv group c. furthermore, hrvc was associated with more severe attacks. however, the prevalence of hrvc in the community is unknown. aim to test the hypothesis that hrvc would be found more often in children requiring emergency treatment for an ari than sibling controls and determine the impact of days since symptoms began on the prevalence of hrv detection in children with an acute respiratory illness (ari) and sibling controls (sibs). methods ari (n = ) had nasal samples collected on presentation to the pmh ed and sibs with symptoms of a cold (n = ), within week of ari recruitment. viral rna was extracted and reverse transcribed. a two-step pcr of the hrv ' utr was used for detection, followed by dna sequencing for typing. results ari and sibs were % and % male, % and % asthmatic, with mean ages of . and . years, respectively. hrv +ve ari (n = , mean ± sd days of symptoms = . ± . ), hrv -ve ari (n = , . ± . ), hrv +ve sibs (n = , . ± . ) and hrv -ve sibs (n = , . ± . ). of the and hrv +ve ari and sibs, % and % had hrvc. conclusions hrvc is as common in children who have hrv but do/do not require hospital treatment. detection of hrv is more likely when the nasal sample is collected soon after the appearance of cold symptoms. support nhmrc program grant. nomination nil. introduction upper airway dysfunction may make asthma more diffi cult to control and should be suspected in asthmatics refractory to prescribed medical therapy. aim a novel imaging technique, dynamic -slice computerized tomography (ct), was used to examine laryngeal behaviour in healthy and asthmatic individuals. method vocal cord movement was imaged using -slice ct larynx. healthy volunteers were studied to develop and validate an analysis algorithm for quantifi cation of normal vocal cord function. further studies were then conducted in patients with diffi cult-to-treat asthma. in eight severe asthmatics with abnormal vocal cord movement, asthma outcomes were measured after speech therapy. results vocal cord movement was quantifi ed over the breathing cycle by ct using the ratio of vocal cord diameter to tracheal diameter. normal limits were calculated, validated and applied to evaluate diffi cult-to-treat asthma. vocal cord movement was abnormal with excessive narrowing in of ( %) asthmatics and severe in nine ( %) patients (abnormal > % of inspiration or expiration time). after speech therapy in a small subgroup, asthma symptoms and morbidity improved. conclusion non-invasive ct larynx quantifi cation of vocal cord movement was achieved. this new approach has identifi ed frequent upper airway dysfunction in asthma with potential implications for disease control and treatment. aim to investigate the characteristics and mechanisms of chronic cough (cc) following acute respiratory illness from laboratory-confi rmed h n infl uenza. methods subjects who had current symptoms and had been tested for h n infl uenza by pcr assay participated in this study. twenty-one of those continued onto clinical testing. investigations to assess cough included symptom questionnaires, hypertonic saline challenge and cough monitoring. results of the participants, % tested positive for h n and % tested negative for h n . h n -infected participants were younger and predominantly female. the prevalence of post-h n cc was . %, and for non-h n infection, . %. objectively measured cough frequency was times greater; there was a -fold increase in cough refl ex sensitivity, and greater quality-of-life impairment in the participants with chronic post-infectious cough than the non-cough participants. conclusions cc was found to be relatively common, mild in severity and tending to resolution with time. the characteristics of post-h n cc were similar to other post-infectious cough and were associated with cough refl ex hypersensitivity. aim upper airway dysfunction may accompany acute severe asthma, but this has not been investigated. a novel imaging technique, dynamic -slice computerized tomography (ct), was used to examine laryngeal behaviour in acute asthma exacerbation. methods patients were studied in the emergency department or as acute inpatients following admission for an acute exacerbation of asthma. vocal cord movement was imaged by -slice ct larynx and compared to normal vocal cord movement in a healthy cohort. results vocal cord movement was abnormal with excessive narrowing during either inspiration, expiration or both in of cases ( . %) with acute severe asthma. imaging again revealed that laryngeal dysfunction characterized the movement abnormality, rather than isolated vocal cord dysfunction. radiation exposure was low and generally < milli-sievert. conclusion non-invasive ct larynx quantifi cation of vocal cord movement was effectively achieved in acute severe asthma. we identifi ed frequent upper airway dysfunction in acute severe asthma suggesting that treatment of upper airway obstruction (e.g. using bipap) may be merited during asthma exacerbation. aim to determine whether eicosanoids could alter the deposition of extracellular matrix (ecm) proteins and cytokine release from human airway cells. methods airway smooth muscle cells (asm), fi broblasts and epithelial cells were stimulated with leukotrienes b , c , d , e and the prostaglandins e , d , f α and the pgi analogue mre- . after hours, culture medium was collected and il- and il- production and cell deposited ecm proteins tenascin c, fi bronectin and perlecan were assessed by elisa. to determine whether eicosanoids infl uenced cell proliferation, manual counting of cells in the experiments were carried out before and after stimulation. results neither leukotrienes or prostanoids altered cell proliferation after days of stimulation (n > ). leukotrienes had no effect on ecm protein deposition or cytokine release from asm or fi broblasts (n > ). leukotrienes did not alter either parameters in epithelial cells except leukotriene d , which increased tenascin c deposition (n = , p < . ). prostanoids induced il- and il- and other various changes in asm and fi broblasts (n > , p < . ) (see below). introduction the function of asthmatic airway epithelium is disrupted facilitating immune and infl ammatory responses resulting in epithelial damage. human rhinovirus (hrv) causes asthma exacerbations in children; however, paucity exists on how it affects barrier function. this study assessed how hrv infection affects epithelial barrier function and integrity in healthy and asthmatic epithelium. methods adult balb/c mice were intranasally infected with hrv- b and followed for days. tight junction (tj) expression was assessed using immunohistochemistry (ihc) and western blot analysis. primary airway epithelial cells from healthy and asthmatic children were assessed for tj gene and protein expression by qpcr and ihc, respectively. results occludin and zonal occludin- (zo- ) expression was lost and sustained in mice infected with hrv- b however was not observed in shaminjected mice. asthmatic airway epithelial cells were found to exhibit elevated basal gene expression levels of tjs (zo- , occludin and plakophilin- (pkp- )) but markedly lower corresponding protein levels. conclusion hrv- b compromises barrier function in vivo through sustained loss of tj proteins. the marked decreased expression of tj proteins in paediatric asthmatic epithelium may contribute towards increased susceptibility to viral infections. disparity between gene and protein tj expression could indicate either post-transcriptional regulation or compensatory effects by other tj proteins and requires further study. supported by asthma foundation wa; nhmrc. confl ict of interest none. conclusion leukotrienes alone did not affect the ecm proteins and cytokines assessed in this study. prostanoids decreased ecm protein deposition whilst increasing cytokine release without affecting cell proliferation. this study shows that prostanoids may have a more pronounced role on direct ecm remodelling than leukotrienes in airway cells. supported by merck. background toll-like receptor (tlr) is an innate immune receptor involved in the initial detection of pathogen-associated molecular patterns. the effect of ageing and chronic obstructive pulmonary disease (copd) on tlr responses and the impact of these innate immune responses in copd pathogenesis remain unclear. hypothesis expression and activity of tlr on peripheral blood mononuclear cells (pbmcs) is increased with healthy ageing and further increased in copd. methods pbmcs from healthy controls < years and > years; and participants with copd (n = per group) were cultured with or without pam c ys k (tlr agonist). cells and supernatants were collected at hours and protein (cytometric bead array or fl ow cytometry) and gene (real time pcr) expression was examined. results tlr activation led to increased release of interleukin (il)- , , β, and tumor necrosis factor (tnf)-α. tlr gene expression was increased with stimulation; however, cell surface receptor levels were unchanged. there was no difference in the level of tlr between the groups. in older people, tlr activation resulted in less il- β and tnf-α release, but similar release of il- and il- . similar results were seen in copd. at baseline in copd, there was up-regulation of tnf-α gene expression compared to the older healthy group; however, the tlr cytokine response did not differ between the groups. conclusion healthy ageing is characterized by an impaired systemic proinfl ammatory cytokine response to tlr -mediated innate immune activation. this effect persists in copd and is selective in the cytokine pathways involved. these altered infl ammatory mechanisms may affect responses to infection and injury impacting disease pathogenesis and warrant further evaluation. aim to investigate whether the inhibition of matrix metalloproteinase- (mmp- ) by a non-selective mmp inhibitor (doxycycline) and the specifi c mmp- inhibitor i (olic acid) can regulate cellular migration of tsc -null mouse embryonic fi broblasts (mefs), which act as a model for lymphangioleiomyomatosis (lam) cells, as compared to wild-type mefs. methods wild-type (tsc -positive) and tsc -null mefs were treated with diluent, doxycycline ( . pg/ml- μg/ml) or olic acid ( . - μm) for hours. mmp- levels were assessed by zymography and elisa. cell migration for hours was measured using a transwell migration assay. results under basal conditions, mmp- release and cellular migration was . -fold and . -fold higher, respectively, in tsc -null mefs compared to tsc -positive mefs (mmp- release, tsc -null (n = ) and tsc -positive (n = ), p < . ; cell migration, tsc -null (n = ) and tsc -positive (n = ), p < . ). mmp- release was reduced in tsc -null mefs after -hour treatment with doxycycline ( and μg/ml, n = , p < . ) and with olic acid ( - μm, n = , p < . ). treatment with doxycycline ( pg/ml- μg/ml, n = , p < . ) or olic acid ( - μm, n = , p < . ) also signifi cantly reduced cell migration of tsc -null mefs. copd is a leading cause of death worldwide. treatments are limited and restricted to symptomatic care. there is an urgent need for new treatment options targeting the infl ammation. tissue damage in copd is thought to result from an inability of the normal repair processes with accumulation of apoptotic material and impaired clearance of this material by macrophages in the airways. lung infl ammation and macrophage function involves the bioactive sphingolipid sphingosine -phosphate (s p). multiple studies have showed the involvement of these components in infl ammation. methods we investigated lung tissue samples from patients (copd or non copd controls) undergoing curative lobectomy for lung cancer. we analysed the mrna expression profi le, the sphingosine-kinase (sphk) protein activity and the localization and expression of individual proteins. results we show in this study for the fi rst time a comprehensive expression profi le of all synthesizing enzymes, receptors and degrading enzymes in the human lung. correlations between receptor subtypes, degrading enzymes and between s p receptor subtype were detected. multivariance anova showed that in copd, the relative mrna expression of s p receptor subtype was reduced. conclusion the correlations between receptors and enzymes involved in the sphingosine kinase signalling system in the lung suggest common regulatory mechanisms. s pr is expressed on dendritic and nk cells which are reduced under conditions of copd. therefore, our fi ndings of reduced s pr in copd may provide a novel target for pharmacotherapy. lung cancer is responsible for more cancer-related deaths than colon, breast and prostate cancers combined. in patients with copd and/or lung cancer, we have shown a reduction in lung and airway macrophage function, evident by a reduced ability to phagocytose apoptotic airway epithelial cells and neutrophils. the potential for lung cancer cells to directly inhibit this function (a potential immune evasion mechanism) has not been investigated. background kinins have been implicated in airway lung diseases such as asthma and lung cancer by regulating infl ammation, cell proliferation and migration. the effect of kinins is mediated through the binding of two receptors, kinin b and b receptors (b r and b r). a novel b r splice variant (sv) resulting in a shorter ' untranslated region (utr) was identifi ed in cultured airway epithelial and fi broblasts as well as in lung carcinoma tissue and leukocytes. this study aims to characterize the functional role of the novel b r sv in mrna stability, translation effi ciency and receptor expression in cultured airway epithelial cells. methods stability of b r sv was determined by measuring b r mrna levels over time in h cells after actinomycin d treatment. translational effi ciency of wt and sv 'utr was determined by measuring luciferase activity in transfected h cells. expression of wt and sv transcripts through q-rtpcr were compared in cells treated with a b r-specifi c agonist dakd. cell-surface receptor expression post-agonist stimulation was quantifi ed using facs. results mrna stability studies indicated that b r sv was ≈ % less stable than the wt transcript in h cells suggesting a stabilizing element 'utr. translation effi ciency of sv was no different to wt b r. dakd stimulation increased both wt and sv transcripts early in the time course, although the peak expression of wt and sv differed at hours and hours, respectively. dakd stimulated cells showed two phases of receptor expression, ( ) decrease of cell surface receptor up to . hours post-stimulation; ( ) increase in cell surface b r after . hours. conclusion this study has identifi ed a novel regulatory mechanism of b r expression through the production of a sv that alters the 'utr. the translation effi ciency of b r is not affected, but the sv was less stable than the wt in h cells and may play a role in allowing quicker changes in transcription. agonist-induced up-regulation of transcripts in a time-dependent manner may be important in maintaining a chronic response during infl ammation. circulating lymphocytes are increasingly used as a surrogate cell type to refl ect changes in adrβ density elsewhere in the body, particularly the respiratory system. however, adrβ density is non-uniform among lymphocyte subsets and it is unclear if, and the degree to which, adrβ density varies between individuals. aim to assess the extent of variability in adrβ density on human peripheral blood mononuclear cells (pbmc) including lymphocytes and monocytes. method pbmc were isolated from blood of healthy subjects by density gradient centrifugation with ficoll-paque. cell surface and total adrβ of intact and permeabilized lymphocytes (cd +) and monocytes (cd +) were measured using anti-adrβ via facs. geometric mean fl uorescence (gmf) was used as the indices for adrβ density per cell. result surface adrβ -gmf increased by . -and . -folds over negative controls for lymphocytes and monocytes, respectively. magnitude of foldchange was not signifi cantly different between these cells (p = . ), but the distribution of gmf intensity between samples suggests greater variability in adrβ density in lymphocytes versus monocytes (p = . ). proportion of cells-stained adrβ -positive was signifi cantly higher in monocytes versus lymphocytes ( . ± . % vs. . ± . %, p = . ). total adrβ -gmf increased by . ± . and . ± . -folds for lymphocytes and monocytes, respectively (p > . ). proportion of adrβ -positively stained cells were similar between samples (lymphocytes %, monocytes %, p = . ), but greater variability was observed for lymphocytes (range - %) versus monocytes ( - %). conclusions despite similarities in surface and total adrβ density, lymphocytes display greater inter-subject variability compared with monocytes. this will have implication in experimental designs and interpretation of changes in adrβ density in studies using human pbmc as an alternative to primary cells from the organ of interest. confl ict of interest no. pge plays a protective role in asthma by inhibiting airway infl ammation. it is predominantly produced by epithelial cells in response to pro-infl ammatory stimuli and acts as an autocrine and paracrine mediator. on the contrary, il- β is a highly potent cytokine that induces many pro-infl ammatory effects in the human airway including activation of the human lung epithelium which promotes production of pro-infl ammatory cytokines and chemokines. airway epithelial cells express all four known pge (e prostanoid (ep) receptors, but mechanisms underlying the regulation of expression of ep receptors in human lung epithelial cells have remained elusive. therefore, we investigated whether pge , an endogenous protective mechanism of the airways, can modulate il- β infl uence on ep receptor expression in human epithelial cells. methods ep receptor mrna and protein expression was quantifi ed in -hbe cells at basal levels and following stimulation with il- β or pge alone, or simultaneously, using real time rt pcr and facs analysis, respectively. results pge up-regulates all four ep receptors at mrna level, while il- β up-regulates ep , ep and ep and does not infl uence expression of ep . at protein level, preliminary results show transient increase of ep receptors in the presence of pge , while il- β down-regulates this receptor. ep and ep are up-regulated following stimulation with both stimuli. importantly, antiinfl ammatory ep receptor is up-regulated only in the presence of pge . conclusion we show for the fi rst time that pge may infl uence expression of its own receptors and oppose the effect of il- β in human lung epithelial cells. this may in turn alter pge production and autocrine activation with potential implication on the function of epithelial cells, which is important in modulation of immune response in asthma and lung infl ammatory diseases. nomination nil. confl ict of interest no. the burden of obstructive lung disease (bold) study is an international study designed to measure the prevalence, risk factors and burden of copd. data collection using the bold protocol has been undertaken at eight sites with inclusion of urban, rural, coastal and inland regions of australia. methods a random sample of adults aged ≥ years was identifi ed. information on respiratory symptoms and diagnosed copd were collected by questionnaire. post-bronchodilator fev and fvc were used to defi ne gold stage. the (un-weighted) prevalence rates are presented by age groups and sex. results s timmins , , , , g king , , , , c salome , , , r schoeffel , , , c walsh , , the extent of emphysema could increase ventilation heterogeneity independently of its effects on airway narrowing. the aim of this study was to examine the relationship between emphysema extent on computed tomography scans (ct), and airway narrowing and ventilation distribution in copd. methods subjects with copd underwent ct scanning, spirometry, dlco and nitrogen washout by single and multiple breath techniques. closing capacity (cc/tlc%), slope of phase iii (Δphase iii ) and indices of ventilation distribution conductive (scond) and diffusion-dependent airways (sacin) were derived from washouts. helical ct scans were performed at tlc. emphysema extent was measured as low attenuation areas < − hu using osirix program, expressed as % of ct total lung volume. results subjects were of mean (range) age years ( - ), bmi . ( . - . ), fev of ( - %) %predicted and dlco of ( - ) %predicted. emphysema extent was . % ( . - . ). geometric mean (ci) Δphase iii was . ( . - . ), sacin was increased at . l − ( . - . ) and cc/tlc% was % ( - ). emphysema extent correlated with fev / fvc (r = − . , p = . ), dlco (r = − . , p < . ), bmi (r = . , p = . ), Δphase iii (r = . , p = . ), and sacin (r = . p = . ). in multiple regression analysis, emphysema extent was predicted by fev /fvc and Δphase iii (model r = . , p = . ). conclusions the extent of emphysema increases the heterogeneity of ventilation independently of any effects on overall airway narrowing. supported by australian lung foundation webster memorial award, crcaa. conclusions self-reported wheeze in the last months is very common in adults over years. in the younger age group ( - years), many people with wheeze did not have airfl ow obstruction or reversible spirometry at the time of test. aim to determine whether there is any association between change in fev among copd patients and ambient ultrafi ne particle number concentrations in melbourne. methods participants with mild to moderate copd were asked to measure their fev using a portable electronic spirometer (piko) two times a day (morning and evening) for consecutive days. the same procedure was repeated on average months later. ambient ultrafi ne (diameter < . μm) particle number concentrations were measured for the same period using an ultrafi ne condensation particle counter and micro-orifi ce uniform deposit impactor. results aim to examine the implementation of, and barriers and enablers to, six high-evidence recommendations for copd management, in copd hospital inpatients. method observational, mixed methods study in consecutive copd patients admitted to a tertiary hospital. demographic, disease and admission characteristics are recorded. implementation (or not) of smoking cessation, pulmonary rehabilitation, long-term oxygen use if hypoxaemic, medication use, vaccinations and plans for future exacerbations are determined from medical records and patient interviews. interviews with medical offi cers examine their perspectives on recommendation implementation. of pilot data in copd patients (mean (sd) age ( ) years, length of stay ( ) days), were current smokers and had severe copd ( moderate). highest levels of implementation were fl u vaccination (completed by gps, n = ), medication (but not spacer) use, and oxygen use if hypoxaemic (investigated and implemented in all suitable, n = ). pulmonary rehabilitation was discussed with half of the patients, but only severe patients with long length of stay accepted further rehabilitation. exacerbation plans were in place for patient, and newly initiated in patients. doctor interviews (n = ) confi rmed pulmonary rehabilitation was considered mostly for severely unwell patients, and use of exacerbation plans was inconsistent. conclusion pilot data suggest pulmonary rehabilitation is offered and accepted by a small subset of copd patients. findings from this pilot will inform planned larger observational studies, and in turn, experimental studies to improve copd care. high-and extreme high-risk interventions were found by panel ( - . % extreme and . - . % high-risk interventions) and patients' respiratory physicians ( % extreme and % high-risk interventions). additionally, clinical pharmacist involvement was associated with many benefi ts such as: improvement in medication compliance, high level of patient satisfaction and identifi cation of patients with issues in medication knowledge. conclusion clinical pharmacist interventions were estimated to prevent extreme and high risks that might happen due to drug-related problems. clinical pharmacy consultation was associated with positive impact on other important measured outcomes. aerobic exercise training in the form of supervised -minute walks ( mw) reduces exertional dyspnoea in patients with copd. mw goal ( mwg) distances, aiming for a training effect, are generated from a baseline submaximal test ( -minute walk ( mwd), where wg = . × mwd/ × . aim to compare mwg with actual initial mw achieved and to examine the predictors of mwg achievers (ga). methods retrospective review of patients, % male, age ± years (mean ± sd), fev ± %predicted, who completed pulmonary rehabilitation (pr). patients were assessed at baseline and post-completion of pr. initial mwg was calculated from the best of two mwd at initial assessment and ga were defi ned as patients who achieved their mwg at their fi rst visit to pr. results for the group, there was a statistically signifi cant but not clinically signifi cant difference between mwg and actual mw achieved ( ± m vs. ± m, p < . , paired t-test). the patients ( %) who achieved their mwg exceeded the goal by ± m, whereas the patients who did not achieve their mwg fell short by ± m. there was no signifi cant difference between ga and non-ga in age or lung function, but ga had a higher initial mwd, with fewer rests, lower dyspnoea score and lower hr at start and fi nish (p < . , unpaired t-test). ga were also more likely to have a clinically signifi cant response to pr, measured by mwd, compared with non-ga (mean change m vs. m, p < . , chi-square). conclusion mw goals as currently calculated either signifi cantly underestimate or overestimate actual mw achieved. it may be that in non-ga, the mwd is functioning as a true maximal test and these are a group of patients who are truly ventilatory-limited, rather than deconditioned. the receptor for advanced glycation end products (rage) is a key candidate for promoting a self-perpetuating cycle of infl ammation and thereby is a major contributor to numerous chronic disease states. the potential of rage to function as a switch converting a transient infl ammatory response such as one generated by cigarette smoke to sustained cellular dysfunction allows it to act as a mediator for ongoing infl ammation in chronic obstructive pulmonary disease (copd). although the molecular mechanisms regulating rage expression have not been fully elucidated, altered rage activity arises from polymorphisms within the rage gene and its promoter. three polymorphisms in the rage promoter (− t/a, − t/c and a bp deletion from − to − ) increase transcriptional activity and rage expression. the rage g s allele results in an increased ligand-binding affi nity and activation of the infl ammatory mediators with subsequent up-regulation of infl ammatory response. the aim of this pilot cross-sectional study was to investigate the relationship between three known rage polymorphisms (− t/a, bp deletion, g s) and copd and disease severity. methods genomic dna was isolated from peripheral blood lymphocytes. pcr and taqman assays were used to genotype the three rage polymorphisms in copd patients, healthy non-smokers and healthy smokers. fev was measured in all subjects. disease severity was defi ned using gold guidelines. results there was no statistically signifi cant association between bp deletion and copd (p = . ), − t > a and copd (p = . ), g s and copd (p = . ). conclusion no association was found between the − t > a, bp deletion and g s polymorphisms and copd, disease severity or fev introduction the receptor for advanced glycation end products (rage) mediates neutrophil traffi cking and is implicated in the pathogenesis of chronic airways disease. we determined whether changes in airway and systemic levels of soluble rage (which acts as a receptor decoy to limit rage activation) and rage ligands are related to neutrophilic infl ammation in asthma and copd. methods bronchial lavage (bl) fl uid from subjects with moderate-severe persistent asthma or copd, and healthy controls were analysed for neutrophils, total srage (cleaved and secreted), secreted srage (esrage) and the rage ligands hmgb and serum amyloid a (saa). systemic levels srage and esrage were also determined in asthmatic and copd subjects. aims increased numbers of neutrophils are found in the lungs of copd patients, which contribute to airway infl ammation. while cigarette smoke exposure is the major risk factor for copd, it is unclear how cigarette smoke modifi es neutrophil function and activity. this study aimed to assess the effect of cigarette smoke extract (cse) on neutrophils in an in vitro model. methods neutrophils were isolated from peripheral blood donated by volunteers using percoll density gradient centrifugation. neutrophils were seeded in well plates ( cells/well), exposed to different concentrations of cse ( %, %) and monitored at , and hours. at each time point, viability of neutrophils was measured by trypan blue exclusion and supernatant was collected for measurement of cxcl release by elisa (r&d systems conclusions in neutrophils exposed to cse, viability is maintained and cxcl release increases with increasing dose of cse. we conclude that cigarette smoke stimulates an infl ammatory response by neutrophils, which would contribute to the infl ammatory burden in the airways in copd. introduction factor viii (f ) and collagen iv (c ) antibodies are used for quantifying vessels in tissue sections. we compared these two antibodies for vessels staining in bronchial biopsies (bb) in copd. methods bb from healthy non-smokers (h-n) and copd subjects were stained for both antibodies. number, area and mean vascular size (mvs) (surface area/vessel number) of vessels in the lamina propria (lp) to the depth of μm were measured and compared between the two antibodies and are reported as median (range). results number of vessels was not signifi cantly different between the two methods of staining. in copd and h-n, vascular area (μm /μm of lp × ) stained with f was less than that with c ( . ( . - ) vs. ( - . ), p < . and . ( . - . ) vs. . ( . - . ), p < . introduction previous studies have shown that c-reactive protein levels increase at the onset of some copd exacerbations; however, there is limited data on the normal fl uctuation in crp levels in stable patients. aim to investigate within patient variation in crp levels to determine the magnitude of normal day-to-day fl uctuations in stable patients and the correlation with patients' perception of symptom severity. methods early morning crp levels were measured on days , and from patients from the melbourne copd cohort (gold category ii-iv) who identifi ed themselves as stable. patients recorded daily symptom scores including: borg dyspnoea scale at rest, severity of wheeze, cough, dyspnoea, change in sputum colour or volume, night-time waking and the presence of viral symptoms. crp levels were measured by the clinical pathology service and using a point-of care device. variation in crp levels in stable copd and correlation between change in crp levels and symptoms were analysed. aim patient-completed diaries monitoring changes in key symptoms in copd are often used to recognize acute exacerbations (ae) both to prompt additional treatment and monitor treatment effi cacy. we assessed diary compliance and the predictive value of major symptoms of aes which required hospital attendance. methods inpatients recruited during an ae of copd completed daily paper or web-based diaries for months, recording changes from their stable state for: breathlessness, cough, sputum, subjective 'wellness', physical activity and use of reliever ( -point scale, mid-pt = no change). the predictive value of current and lagged symptom scores was compared for each and between symptoms. diagnostic accuracy was assessed by area under the curve (auc) and at specifi c cut-points. in participants ( m, f) with mean age ± and mean fev % predicted ± , there were such aes involving patients. duration of diary keeping was shorter with lower education attainment (p = . ), but compliance did not vary for other demographic or clinical factors. daily compliance while diaries were being kept was %. excluding the current day, the best predictor was the distributed lag score over days, sputum changes giving the strongest signal; relative risk . ( % ci . to . ) with most of the signal in the days prior to the ae. little was gained by combining symptoms. the predictive value was moderate auc = . . conclusions compliance with symptom diaries in severe copd is surprisingly good. however, with only a weak signal for an impending ae requiring hospital attendance up to hours before and for lagged symptom scores over days before, with low positive predictive values, the utility of keeping daily symptom diaries for raising alerts for impending severe aes in copd is questionable. results seven studies with inpatient participants were identifi ed; published as abstracts for which data were not available did not contribute to meta-analyses. no study specifi ed diagnostic criteria for copd and only one specifi ed ae criteria. short course treatment varied between - days and longer duration - days; studies used oral prednisolone (dose mg, studies, tapered dose) and studies used intravenous scs treatment. mean ages of participants ranged from to years. primary outcomes: likelihood of treatment failure did not differ by duration of treatment (odds ratio . ; % ci . to . ) ( studies, n = ). fev did not differ signifi cantly when measured up to days (mean difference (md) − . l; % ci − . to . ) or after days (md − . l; % ci − . to . ) ( studies, n = ). secondary outcomes: limited data ( study) precluded meta-analysis for readmission or mortality. the likelihood of an adverse event ( studies, n = ) was not signifi cantly lower for shorter scs (or . ; % ci . to . ). conclusions we found no signifi cant differences between short (≤ days) and longer (> days) corticosteroid therapy for ae of copd. this has implications for clinical practice and may reduce adverse effects for patients, shorten hospital admissions and reduce costs, but more studies are needed to confi rm these fi ndings. aim to explore factors which infl uence the self-management of exacerbations in patients with copd. methods a pilot cross-sectional study was undertaken to assess patients' compliance with their action plan and their action taken prior to an admission. patients were interviewed during an admission to hospital for exacerbation of copd. the effect of pulmonary rehabilitation on patients' knowledge of copd was also assessed. results % of patients were provided with a written action plan, and % with a verbal action plan. in response to an exacerbation, more than % of the patients stated that they used their action plan. however, where action plans were not adequately utilized, patients delayed seeking medical attention and failed to initiate oral prednisolone and antibiotics during an exacerbation despite being prescribed an emergency supply of these medications. pulmonary rehabilitation had a positive outcome towards enhancing the patients' knowledge of copd. clinical pharmacists have limited involvement in terms of copd and smoking cessation education. conclusion the need to offer a thorough self-management program along with providing a more comprehensive written action plan will encourage patients to start early treatment and follow their action plans. encouraging collaboration between the hcp and patients encourages self-management through discussing and agreeing on goals of treatment and developing a personalized written action plan. context dyspnoea is a common symptom in copd and increases during exacerbations. when respiratory failure supervenes, and assisted ventilation is required, non-invasive ventilation (niv) is the treatment of choice. objective to determine if niv relieves dyspnoea in inpatients with acute respiratory failure due to exacerbations of copd. data sources english language randomized controlled trials (rcts) published prior to august were identifi ed using medline, embase, cinahl, psychinfo and pubmed. additional studies were identifi ed by reviewing the reference list of included studies. search terms included niv, nippv, nppv, bilevel cpap, bipap, artifi cial ventilation, copd and randomized controlled trial. study selection rcts comparing usual medical care (umc) to umc plus niv and measuring dyspnoea at relevant time points were included. abstracts for potentially relevant articles were extracted by one author. these were assessed by a second author to ensure inclusion criteria were met. articles were reviewed to determine if dyspnoea was measured and appropriate statistical analysis reported. the search yielded individual articles. four articles met the review criteria. three articles fi nd that niv relieved dyspnoea to a statistically signifi cant level and two suggested that the relief of dyspnoea is clinically signifi cant. discussion in spite of the common use of niv to relieve dyspnoea, little work has analysed effi cacy in terms of this patient-reported outcome. while our results may suggest niv relieves dyspnoea, reporting or methodological fl aws in several articles limit the strength of the conclusions that may be drawn. these limitations make the conclusion that niv relieves dyspnoea contentious. conclusion despite over two decades of studies investigating niv, the therapeutic impact on breathlessness is poorly described. understanding the impact of niv on patient-reported outcomes is of critical importance in clinical care. confl ict of interest none. introduction in mice, the most direct lung dosing method delivers the agents directly into the trachea. for our cystic fi brosis gene-therapy studies, we deliver fl uids -an airway pretreatment followed by a lentiviral vector -directly into the mouse trachea to target conducting airways. despite using standardized delivery techniques, we see substantial variability in the amount and location of gene transfer. aim the aim of this experiment was to use synchrotron x-ray imaging to track the dynamics of fl uid doses delivered into the live mouse trachea. methods four nembutal anaesthetized c bl/ mice were imaged on the bl b beamline at the spring- synchrotron. mice were intubated and ventilated at br/min with image captured per breath. after minute of baseline, a -μl sample of iodine-based contrast fl uid (a surrogate for our airway pretreatment or gene-vector) was delivered over seconds. following minutes of data collection, an additional μl bolus was delivered over . seconds. image capture continued for a further minutes. frame differencing was used to reveal fl uid motion. results substantial dose losses may occur upon delivery into mouse trachea via immediate retrograde fl uid motion. the speed of bolus delivery into lung may also infl uence the relative targeting of conducting airways and deep lung. introduction use of effi cient nebulizers can enhance the quality of life of cf patients by reducing the treatment time and improving drug delivery effi ciency. the aim of this study was to determine which commonly recommended nebulizer was optimal for delivery of the most commonly used therapies to cf. methods seventeen children with cf ( - years) were recruited. delivery of three commonly used cf therapies ( % hypertonic saline ( ml, . g/ ml), tobramycin ( ml, mg/ml) and pulmozyme ( . ml, mg/ml)) by two vibrating membrane nebulizers, the eflow rapid and the aeroneb go, and a jet nebulizer lc sprint junior with pariboy sx ( . l/min) were tested. for each drug-nebulizer combination (in random order), each child was asked to inhale through an inspiratory fi lter, and drug delivery to the fi lter was measured. pulmozyme was quantifi ed using an enzymatic activity assay, tobramycin was measured using hplc and hypertonic saline was measured using conductivity. total nebulization time was recorded. the results showed that there was no difference in the amount of drug delivered to patients when the nebulizers were compared for all three therapies (p > . ). however, the nebulization time for the eflow rapid was signifi cantly shorter than that for the aeroneb go and lc sprint junior. similarly, the nebulization time for aeroneb go was shorter than that for the lc sprint junior (p > . ) for all therapies). conclusion overall, there were no signifi cant differences between nebulizers in delivered dose for three forms of cf therapy, due to inter-patient variability. despite this, both vibrating membrane nebulizers had shorter nebulization times than the lc sprint junior, with the eflow rapid delivering drug in the shortest time. confl ict of interest nil. introduction as the life expectancy of patients with cystic fi brosis (cf) increases, treatment-related morbidity is increasingly recognized. totally implantable venous access devices (tivads) offer reliable long-term central venous access but are associated with recognized complications including venous thrombosis. superior vena cava syndrome (svcs) however has been rarely reported in this setting. we report a single cf centre's experience of svcs associated with tivads. methods retrospective review of episodes of svcs in patients with cf and a tivad attending the adult cf centre, prince charles hospital, queensland. results between february and december , fi ve episodes of svcs occurred in patients with tivads from a clinic population of patients. all of the affected patients were female, with moderately severe lung disease (mean fev predicted . %). no patients had a recognized thrombophilia. four tivads were inserted at a centre different to our own, three were on oestrogen-based contraception, and two suffered with dehydration at presentation. svcs treatment consisted of anticoagulation ( ), line removal ( ), angioplasty ( ), thrombolysis ( ) noninvasive bioluminescence imaging has allowed for rapid in vivo quantifi cation of long-lasting gene transfer in experimental animals. we are testing the longevity of a single nasal delivery of our lentiviral (lv) gene transfer system in mouse airways. methods normal (c bl/ ) and cystic fi brosis (cf) mice received a nasal bolus of lysophosphatidylcholine (lpc) or a control (pbs) pretreatment hour prior to delivery of a lv vector containing the reporter-gene luciferase (lv-luc). another control group received lpc hour prior to an empty vector (lv-mt). bioluminescence was measured at week, , , , , , , , and months post-lv dosing to assess gene transfer. results normal mice: mice that received lpc/lv-luc treatment had significantly greater gene transfer compared to the two control groups at all time points (p < . , rm anova). no luminescence was detected in mice treated with lpc/lv-mt. unexpectedly, luciferase activity was also detected in the lung. there was no difference in lung luminescence between the lpc and pbs pretreated mice that received lv-luc. cf mice: a statistically signifi cant increase in nasal luminescence persisted for up to months following lpc/ lv-luc (p < . , rm anova). similar to normal mice, there was no statistical difference in lung luminescence between mice that received lpc and pbs lv-luc. conclusions lentiviral luciferase gene expression was signifi cantly improved in mouse nasal airways using lpc pretreatment in both strains. however, the longevity of transduction was reduced in cf mice, which may, in part, be due to reduced animal numbers at the later time points tested. supported by nh&mrc. background the nintendo-wii® facilitates exercise-based programs that may be considered novel, fun and potentially motivating. objective exercise outcomes using the wii have yet to be reported in the cystic fi brosis (cf) adult population. aim to investigate nintendo-wii® exercise training compared with standard exercise in adult cf patients whilst hospitalized for treatment of a pulmonary exacerbation. methods a within-subjects, randomized cross-over study. adult cf participants received two -minute exercise treatment sessions within a -hour period, at least day apart, during the last days of hospitalization. wii exercise consisted interval training with games such as boxing, dancing and track exercises. standard exercise consisted of interval training on treadmill or cycle ergometer at - % of heart rate maximum. results participants completed the study (mean (sd) age ( ) years, % females), with a mean fev % of ( )%. during exercise, no difference was found between groups in average heart rate (p = . ), oxygen desaturation (p = . ), borg rate of perceived exertion (p = . ) or modifi ed borg for dyspnoea (p = . ). on vas ( - ), participants reported the wii program to be more enjoyable (p < . ) and less fatiguing (p = . ). participants rated both exercise sessions as equally effective (p = . ). conclusions this study suggests that a nintendo-wii® exercise session provides an equivalent cardiovascular demand to a standard exercise session in an inpatient adult cf population. greater enjoyment levels and lower fatigue levels reported during nintendo-wii® training may have a positive infl uence on adherence to exercise. further study into the long-term effects of nintendo-wii® training needs to be undertaken. confl ict of interest nil. introduction ion transport is important to maintain the airway epithelial surface, as shown by the disease cystic fi brosis (cf) which is characterized by decreased clsecretion and increased na + absorption. we have previously shown that the cf airway can develop clresponses when the surface is nominally calcium free (middleton et al. ajrccm ; : - . aim to determine the effects of citrate on the nasal potential difference (npd) with and without amiloride pretreatment, and to compare these effects with other clinically relevant calcium chelators and dicarboxylic acids. methods npd was measured using standard techniques (erj ; : ) in cf and non-cf subjects. the nasal pd response to citrate, oxalate, malate, succinate and fumarate (all mm) was compared with the calcium chelators edta and egta. results citrate decreased the basal npd by ∼ mv, but in the presence of amiloride, citrate increased the pd by ∼ mv. with amiloride/low clpretreatment, citrate increased npd by - mv, which suggests that citrate increased clsecretion. in contrast, the other dicarboxylic acids and calcium chelators exhibited little response. conclusion the combination of these responses suggests that citrate exerts complex effects on airway ion transport, most likely dual effects of decreased na + absorption and increased clsecretion. aim to assess the validity of the international physical activity questionnaire (ipaq) in cf adults by comparing energy expenditure measured by the ipaq versus the accelerometer. methods with ethics approval, suitable successive adult patients with cf attending the alfred cf outpatient clinic were recruited. all participants wore an accelerometer (actigraph gt m) around the waist for days of awake time, at the end of which, they completed the ipaq. criterion validity of the ipaq was assessed by comparing the ipaq weekly energy expenditure (ee) in kilocalories (kcal) with weekly ee (kcal) from the accelerometer using spearman correlations and bland-altman procedures. results thirty participants ( % females) completed the assessment: mean (sd); age = ( ) years, fev %predicted = ( ) the median (range) ee: ipaq = ( , ) kcal, gt m = ( , ) kcal. spearman correlations of fev %predicted with ee were gt m ee r = . , p < . ; ipaq ee r = . , p > . . correlation of the ipaq ee with accelerometer ee was moderate (r = . , p = . ). there was a trend towards higher ee measured by the ipaq than measured by the accelerometer (wilcoxon signed ranks test: z = − . , p = . ). conclusion the ipaq underestimates physical activity for patients with lower energy expenditure activities and overestimates for those with higher energy expenditure activities in adults with cf. the ipaq would be a useful screening tool for exercise prescription and monitoring of physical activity longitudinally, but more quantifi able methods for assessment such as the accelerometer should be used in research. confl ict of interest none. infectious endometritis associated with pseudomonas aeruginosa (pa) is an important equine disease resulting in reduced fertility and decreased foal drop. previous typing studies of equine pa report clonal heterogeneity, suggestive of sporadic acquisition, and small clusters of indistinguishable strains. aim we performed molecular typing of a large sample of genital pa isolates from horses in s-e qld. methods thoroughbred genital tract pa isolates submitted to uq vet diagnostic lab during - (screening or infection suspected) were studied. eric-pcr fi ngerprint analysis was performed. isolates producing indistinguishable fi ngerprints were allocated to the same eric-pcr type. mlst was performed on a subset of isolates. results overall, genital (clitoral or uterine) swabs from mares and urethral fossa swabs from stallions located on stud farms were processed. pa was identifi ed in genital cultures from of the ( . %) mares but from none of the stallions. six clusters involving ≥ mares were detected. cluster-a was observed amongst isolates collected from ( %) mares from studs and each year. cluster-b isolates were present in mares from studs during - . clusters c-to-f each contained isolates from mares from or studs. conclusions overall, % of mares harbouring pa had clonally related strains. however, we found no evidence of horizontal transmission between stallions. these data raise the possibility of transmission via environmental or other sources. alternatively, specifi c strains may have trophism for the reproductive tract of horses. the fi nding of a dominant strain amongst thoroughbred mares in a geographic region has interesting parallels with recent evidence of the spread of highly prevalent clonal strains in cystic fi brosis clinics. aim to investigate the prevalence and impact of incontinence in adult men with cystic fi brosis (cf) as compared with age-and sex matched control subjects. methods men with cf were recruited through outpatient clinics and control subjects through advertisements to complete standardized questionnaires relating to respiratory symptoms, bladder and bowel function, mood and physical activity levels. demographic data were collected from medical records for the cf group. results seventy-four men with cf participated (mean (sd) age . ( . ) years). forty-nine men volunteered as controls ( . ( ) years), and were well matched in terms of physical activity levels. / ( %) in the cf group and / ( %) in the control group had reported episodes of urine leakage. in the men with cf, there was no difference in lung function between men with episodes of leak and those with no history of leak (fev % predicted ( )% vs. ( )%, p = . ). anxiety levels were higher in men from both groups with episodes of leak compared to those with no history of leak (hospital anxiety and depression anxiety score . ( . ) vs. . ( . ), p < . ). depression scores were also higher in men with episodes of leak compared to those with no history of leak ( . ( . ) vs. . ( . ), p < . ). conclusions urinary incontinence in men with cf is not associated with disease severity, as measured by lung function. anxiety and depression levels were higher in men with leakage of urine. confl ict of interest no. aim to investigate the bone mineral status of children and adolescents with cf and to explore the relationship between bone mineral density (bmd) and anthropometric and clinical parameters including height, body mass index (bmi), lung function tests and vitamin d levels ( -hydroxyvitamin d) in the cf centre at starship children's hospital, new zealand. methods bmd of the lumbar spine was assessed by dual x-ray absortiometry between january and december . the results of subjects with cf ( males) with a mean age of . years (range - . years) were collected. anthropometric data (height, bmi), forced expiratory volume in second as percent predicted (%fev ) and vitamin levels were assessed and related to bmd. results bmd in our subjects was low in . % and very low in . % when adjusted for age, sex and height (difference in bmd g/cm in the lumbar spine l -l ). there was a strong positive relationship between the lumbar areal bmd (abmd) and bmi z scores (p < . ), abmd and % fev z scores (p < . ), and abmd z scores and vitamin d levels (p < . ). conclusions bmd was normal in the younger and well-nourished subjects with normal or mild reduction of fev . low bmd appeared to evolve during adolescence with decreasing bmi and reduction in lung function. this will lead to ongoing bone disease in early adulthood. it is a further indication to maintain optimal nutritional status and maximize lung health. malnutrition in cf is associated with poorer pulmonary function and is an independent risk factor of survival. aim to compare the nutritional status of the adults attending an adult cf centre in with . method retrospective audit of patients ( excluded, incomplete data) including demographics, nutritional status, pancreatic enzyme replacement therapy (pert) usage, glucose tolerance and dietetic review. results the mean age of the clinic population increased from . to . years. mean (sd) bmi increased from ( . ± . kg/m ) to ( . ± . ) (p = . ). in , % of the clinic population was taking pert with a mean dose of ± iu lipase/kg/day. the proportion of patients with abnormal glucose tolerance has increased from % to % (p = . ). oral supplement use has increased from % to %, yet enteral feeding remained stable ( % − , % − ). this occurred during period of increased annual dietetic review of the patients attending the clinic from % in to % in (p = . ). discussion over a -year period, an improvement in mean bmi refl ects improvement in nutritional status. prevalence of abnormal glucose tolerance has increased; this is likely due to commencing a screening program ( ). use of oral supplements has increased and is higher than identifi ed in the recent daa survey of nutrition practices of cf dietitians ( %). annual review by the cf dietitian has increased despite a twofold increase in the cf population may be attributable to a stable and experienced workforce. current service provision of . a abbott , e cheung , l morgan aim to characterize the microbial colonization of a group of stable adults with non-cf bronchiectasis using an extended culture protocol. methods sputum was collected over an -month period from clinically stable patients. standard semi-quantitative bacterial culture was extended to days with the addition of fungal and mycobacterial culture as routine. results specimens of spontaneously expectorated sputum were collected from patients; mean age years ( - years); mean (sd) fev / fvc ratio % ( %); / never smokers; / on inhaled or oral corticosteroids. the bacteria identifi ed were p. aeruginosa ( % of specimens), h. infl uenzae ( %), h. parainfl uenzae ( %), acinetobacter baumanii ( %), enterobacteriaceae ( %). commensals only were identifi ed in % of specimens. fungi included candida species ( %), aspergillus fumigatus ( %) and penicillium species ( %). non-tuberculous mycobacteria (ntmb) were grown in % of specimens: m. gordonae ( %), m. intracellulare ( %) and m. lentifl avum ( %). the ntm identifi ed were all considered non-pathogenic. only the mycobacteria were identifi ed after day . conclusion microorganisms with potential pathogenicity are frequently identifi ed in adult patients with non-cystic fi brosis bronchiectasis who are not experiencing an acute exacerbation. all these organisms were identifi ed using a standard short culture protocol. the extended regimen, which was costly, did not identify any unusual or unexpected pathogens. it was rare for patients to be colonized with fungi. this study suggests there is limited value in requesting extended culture for bacterial pathogens, including looking for fungi or nmtb in this stable patient group as this adds little to the empiric antibiotic choice for infective exacerbations. confl ict of interest none. s stelzer-braid , , h alsubie , a neilsen , h johal , a steller , er tovey , k mckay , p van asperen , wd rawlinson , introduction respiratory infections are of fundamental importance in determining the morbidity and mortality associated with cystic fi brosis (cf) as such infections can lead to progressive and fatal obstructive lung disease. using polymerase chain reaction (pcr) to detect such infections has advantages over previous studies that used relatively insensitive traditional detection methods and could have underestimated viral prevalence. methods viral and bacterial multiplex pcrs were developed for detection of respiratory pathogens important for children with cf. nasal brush samples were collected from cf patients who were symptomatic or asymptomatic for acute respiratory illness (n = ). sputum and exhaled bioaerosols via a novel mask sampler were collected from a subset (n = ). results as expected, almost all ( %) sputum samples were positive for bacteria. detection of bacteria in the upper respiratory tract was lower ( . %). data from nasal samples indicated strong association of viral pathogen presence, particularly rhinovirus, with exacerbation of disease. results also showed good evidence for rhinovirus infection in the lower respiratory tract. the novel mask sampler is promising as a non-invasive sampling tool. conclusions our results demonstrate the importance of pathogens in exacerbations. early detection and understanding the development of bacterial and viral infections in cf patients is important in clinical decision-making as more and better antiviral and antibiotic agents become available. aim to determine the factors affecting microbiological yield from bronchoalveolar lavage (bal) in patients with suspected pulmonary infection and haematological malignancy or following stem cell transplantation at a tertiary bone marrow transplant centre. methods a retrospective -month audit of patients with pulmonary infi ltrates or febrile neutropenia with haematological malignancy or post-stem cell transplant who underwent bal for microbiological diagnosis. data were obtained on microbiological yield, radiographic appearances, current antimicrobial therapy, the presence and duration of neutropenia and complication rate. of the bal procedures performed, a clinically signifi cant microbiological result was obtained in % of cases ( / ). of these positive results, % ( / ) were exclusively viral pathogens, % ( / ) were fungal, % ( / ) were bacterial and polymicrobial infection was observed in % ( / ) of cases. a high proportion of patients had commenced anti-microbial treatment empirically, with % ( / ) receiving broad spectrum antibacterial treatment and % ( / ) receiving treatment doses of antifungal agents prior to bronchoscopy. in % ( / ), the results of the bal changed the patients therapy. the presence and duration of neutropenia or radiological appearances were not reliable discriminators of specifi c infective aetiologies. complication rates were low and included fevers in % ( / ), hypoxia % ( / ), small volume haemoptysis in % ( / ), atrial fi brillation in % ( / ) and pneumothorax in % ( / ). conclusion whilst bal remains a safe and important tool in establishing a microbiological diagnosis in immunosuppressed patients with pulmonary infi ltrates, a clinically signifi cant yield and changes to patient treatment occur in the minority of cases. clinicians should have a high degree of suspicion of viral infective aetiology when treating this population of patients. aim to examine the outcomes and complications of intercostal catheter (icc) treatment of pneumothoraces (primary (pp) and secondary (sp)) and effusions (malignant (me) and parapneumonic (pe)). methods retrospective review of all iccs in admitted patients in a respiratory unit over months. data collected included type of pneumothorax or effusion, icc type, insertion details, complications (major and minor) and outcome (success defi ned as resolution of pneumothorax or effusion with single tube insertion). results patients required icc treatment. forty-six iccs were used in patients with pneumothorax: pp ; sp ; iatrogenic ; hydropneumothorax . complication rate was % ( % major) and was signifi cantly less in pp ( %) compared with sp ( %), p < . , chi-square. success rate for pneumothorax icc drainage was % (signifi cantly higher for pp ( %) compared with sp ( %), p < . ). fifty-eight iccs were used in patients with pleural effusions: me , pe , other . complication rate was % ( % major) and was signifi cantly higher in me ( %) compared with pe ( %), p < . . success rate for effusion icc drainage was % (signifi cantly less in me ( %) compared with pe ( %), p < . ). small bore iccs (gauge < fr) were used for % of pneumothoraces and % of effusions. tube size did not signifi cantly infl uence complication or success rate for either pneumothoraces or effusions. conclusions compared with pp, icc treatment of sp was less successful and more likely to be associated with complications. similarly, compared with pe, intervention for me with icc was less successful and had a higher complication rate. we conclude that icc intervention is most successful for pp and pe, and speculate that sp and me should have early surgical intervention. introduction spontaneous pneumothorax is a common condition. current management guidelines recommend large pneumothoraces are managed by primary intercostal catheter insertion. we report a single centre's experience in the management of large spontaneous pneumothorax. methods retrospective audit of cases of spontaneous pneumothoraces managed at the prince charles hospital between january and december . patient demographics, co-morbidities, presenting symptoms, examination fi ndings, radiology, management and complications were reviewed. results forty-two patients ( male, female) experienced episodes of spontaneous pneumothorax. chest pain and dyspnoea were the most commonly reported symptoms ( ) %. there were forty-two ( %) episodes of large pneumothorax (≥ % of hemithorax). management of large pneumothoraces consisted of: observation, ( ) seldinger icc ( ) and large bore icc ( ). complications occurred in three patients with seldinger icc ( vasovagal, hydro-pneumothorax) compared to none with large bore icc. outcomes were similar for patients managed by observation compared to icc insertion. all recurrent cases ( %) were referred for consideration of surgical pleurodesis. conclusion patients with large pneumothorax managed by observation recovered similarly to those treated with icc, suggesting a higher threshold for icc insertion should be considered in the future. grant support nil. aim a pilot study of an instrument of pleural ultrasound training in thoracic physicians after a pleural ultrasound course. the instrument was tested for inter-observer agreement and also its ability to be used in a patient compared to a dedicated manikin. methods all chest physicians ( ) were novices in ultrasound and underwent a dedicated -day training course in pleural ultrasound at the australian institute of ultrasound. they were assessed months later by radiologists and one senior ultrasonographer using a specially designed pleural ultrasound training assessment tool (usgt-sat) on both a subject with pleural effusion and a dedicated ultrasound manikin. the mean scores, out of a maximum of , obtained by the each of the participants for the manikin were . , . , . and . , respectively, while the scores for the patient was . , . , . and . , respectively. the mean scores of the participants as a group for manikin were ± . and for the patient as . ± . . there was general agreement between the examiners with mean combined participant scores of . , . and . in the manikin, respectively, and mean score of . , . and . in the patient. conclusions this pilot study shows ranges of scores for design of future validation studies of the usgt-sat. test performance by the chest physicians after a short course in pleural ultrasound was generally good and results for the use of the manikin as an alternative to patients in pleural ultrasound training are encouraging. further studies with larger sample size are required. supported by nil. nomination nil. confl ict of interest no. since the fi rst commercial availability in , fl exible bronchoscopy has evolved from a simple 'look see' procedure to a more complex multifaceted one. today, fl exible bronchoscopy is a tool used for diagnostic procedures, surveillance, delivery of therapy and clinical trials. increasingly, it involves utilizing expensive purpose built equipment in complex diagnostic procedures. this evolution requires a specifi c knowledge base and skill set to safely perform the procedure and care for the equipment. this now mandates additional training by nursing and medical staff to develop and maintain the required skills. medical staff now rely on their nurses to assist in the full range of procedures. thus, the nurses must keep abreast of modern trends and techniques. the modern bronchoscopy suites team is an integrated one, with specifi c roles, defi ned to each member. the procedures performed will refl ect local needs and expertise. just as bronchoscopy has evolved into the speciality of interventional pulmonology, so must bronchoscopy suite nursing be accepted as a specialized area of nursing with a credentialed 'special interest group' to promote, educate and develop the subject as more therapeutic and diagnostic procedures evolve. this will allow nurses involved in bronchoscopy to be respected, recognized and accepted for their unique knowledge and abilities. confl ict of interest nil. background transthoracic pneumostomy (tp) is a novel treatment for patients with severe emphysema that aims to defl ate the lung and improve function. aim to assess the effect of unilateral tp on the volume of each lung and mechanical properties of the lungs. methods subjects were recruited for a multicentre trial of tp (see actrn ). in parallel with the main protocol, we measured ( ) in the six subjects recruited, compared to plethysmography, lung volume was overestimated by cxr (mean difference + . %, range − . to + . ) and underestimated but more closely correlated by ct (mean difference − . %, range − . to − . ). based on ct, the volume of the treated lung decreased in all patients after tp (mean − . %, range − . to − . ) whilst that of the untreated lung did not change (mean − . %, range − . to + . ). in patients with available data, tp reduced dynamic hyperinfl ation during exercise (mean − ml, − . % of ic, range + . % to − . %). lung mechanics were performed in patients. low lung elastic recoil prior to tp and an increase in elastic recoil after tp were associated with greater reductions in lung volume and greater improvements in exercise tolerance. conclusions supine chest ct provided reasonably accurate estimates of plethysmographic lung volume. unilateral tp defl ated the lung and there was no evidence of signifi cant compensatory hyperinfl ation of the contralateral lung. tp also reduced dynamic hyperinfl ation. measurement of lung elastic recoil may help select patients who are likely to benefi t from tp. support and confl ict of interest nil. methods we performed a retrospective chart review of all adult patients who had an icc over a -month period within a tertiary hospital respiratory service. we noted patient demographics, details surrounding chest drain insertion including image guidance and subsequent inpatient events. results over a -month period, there were small-bore icc insertions, of which were image-guided. mean patient age was years, males comprised / . forty drains were inserted for pneumothoraces, for malignant effusions, for parapneumonic effusions, for transudates and for undiagnosed exudative effusions. mean duration of drainage was . days. there were no life-threatening complications. three of the chest drains fell out and became blocked. six pneumothoraces were noted, all following insertion without direct image guidance; none required further intervention. local infection occurred in patient. insertion details were not documented in patients. conclusion insertion of small-bore iccs via the seldinger technique appears to be a safe method of draining pneumothoraces and pleural effusions. image guidance may reduce complication rate of this procedure. documentation of drain insertions could be improved. confl ict of interest nil. rationale pleural effusions are frequently encountered in clinical practice, and often require aspiration for diagnostic and/or therapeutic purposes. use of radiological guidance varies, despite current guidelines recommending routine use of ultrasound. furthermore, concerns exist regarding the downskilling of thoracic medicine trainees due to the increased use of interventional radiology. as a precursor to developing a procedural pleural ultrasound service, we performed a retrospective case review of our current practice. methods patients who had pleural fl uid sent to pathology between january and december were identifi ed on an existing database. patient records were reviewed and details regarding the drainage procedure and outcomes were recorded. information on patient location, method of procedure and performing clinician were also collected. results to date, pleural fl uid aspirations in patients have been identifi ed. overall, % of aspirations were carried out on the ward and % in the radiology department. two procedures occurred in the endoscopy suite on outpatients, and one in the emergency department. fifty percent of procedures were performed using an intravenous cannula for drainage and % utilized a pigtail catheter. all procedures occurring in the radiology department were performed under ultrasound guidance by a radiologist or radiology registrar. of the remaining procedures, % were performed by medical registrars and % were performed with ultrasound marking. six complications occurred following procedures: pneumothoraces, vasovagal and tube blockage. there were signifi cantly more pneumothoraces in patients who did not have an ultrasound marking ( of without marking, of with marking, p = . ). none of the complications required further intervention. conclusion these preliminary data suggest ultrasound marking signifi cantly reduces pneumothorax incidence, supporting the establishment of a pleural ultrasound service. this is likely to have the added benefi t of improved training for thoracic medicine trainees. aim to investigate differences between semi-recumbent and supine posture in terms of cough rate, degree of oxygen desaturation, oxygen supplementation, increase in pulse rate and sedative use during the initial phase of bronchoscopy. methods consecutive patients (n = ) undergoing diagnostic bronchoscopy at an endoscopy unit were recruited for this observational cohort study. the posture was determined by the bronchoscopist's usual practice. patient age, gender, % predicted fev and fvc, indication, pulse and oxygen saturation were recorded. the initial phase was defi ned as the time from bronchoscopy insertion to visualization plus lignocaine instillation of both distal main bronchi. cough rate, peak pulse, nadir oxygen saturation (spo ), range of oxygen supplementation and sedation use during the initial phase were recorded. a post-procedure questionnaire was administered to the patient and the attending nurse. results patients had bronchoscopy in the semi-recumbent posture and in the supine posture. three of bronchoscopists performed in both postures. there were no signifi cant differences in age, gender, smoking status and spirometry between the two groups. the semi-recumbent postures resulted in signifi cantly less cough rate (mean (sd) . ( . ) vs. . ( . ) coughs/min, p = . ) and less fentanyl use ( ( ) vs. ( ) mcg, p = . ) in the initial phase. there were no signifi cant differences in the nadir spo , fall in spo , oxygen supplementation or increase in pulse rate between the two groups. nurse perception of patient discomfort was lower in the semirecumbent position ( ( ) vs. ( ) mm on mm visual analogue scale, p = . ), and there was a trend towards less patient-perceived cough during the procedure in the semi-recumbent group ( ( ) introduction pulmonary infi ltrates in immunocompromised patients with haematological malignancy have a diverse aetiology and are a major source of morbidity. a specifi c diagnosis and targeted therapy may optimize outcomes and reduce the cost of treatment. the diagnostic value of fi breoptic bronchoscopy (fob) and the infl uence of timing of the procedure are unclear. aim to determine the yield of fob, its impact on antibiotic therapy and the infl uence of early vs late timing in this patient population. methods we conducted a retrospective review of immunosuppressed patients with underlying haematological malignancy and new pulmonary infi ltrates who underwent fob over a -month period. the outcomes of early (eb, ≤ days from initial respiratory consultation) and late (lb, ≥ days) fob were compared using fisher's exact test. results thirty-eight fobs, including bronchial or transbronchial biopsies, were performed in patients (males ). there were patients who received eb and who received lb. a specifi c diagnosis was obtained from procedures ( %), including infections ( in eb vs. in lb, p = . ) and non-infective diagnoses ( eb vs. lb, p = . ) based on histology. fob fi ndings from procedures ( %) ( eb vs. lb, p = . ) resulted in modifi cation of antibiotic therapy. there were no procedure-related severe complications. conclusions fob is a useful diagnostic procedure which infl uences diagnostic and therapeutic decisions in this patient group. although early procedures tended to be more likely to change antibiotic therapy than late procedures, the difference was not signifi cant. confl ict of interest none. capsule endoscopy is increasingly performed in gastroenterology to investigate possible small intestinal bleeding. the capsule endoscope is swallowed and then takes photographs every seconds for hours during its transit through the gastrointestinal tract. the images are downloaded by a radio link and the capsule is then passed normally and disposed of. in the present case, the capsule endoscope was inhaled and lodged in the bronchus intermedius. this was only recognized when the images from the capsule download were examined. removal of the capsule was effected with a fi breoptic bronchoscope using an ercp balloon and roth basket. this is believed the only capsule bronchoscopy so far reported. capsule endoscopes are large ( mm × mm diameter) and smooth. this case report shows the images from the capsule endoscope and describes the methods necessary to remove this unusual foreign body from the lung. support nil. background bronchoscopy with endobronchial biopsy (eb) is now an integral component of the research evaluation of airway diseases. there are no published safety data for eb in adult non-cf bronchiectasis. methods a subgroup of subjects enrolled in the bronchiectasis and low dose erythromycin study (bless) a randomized controlled trial of long-term prophylactic erythromycin (anzctrn ) underwent bronchoscopy with bronchoalveolar lavage (bal) and eb performed by a single operator. results ninety-nine bronchoscopies were performed (bal alone in ) in subjects. of procedures with eb, ( . %) were associated with very signifi cant bleeding (> ml either at time of eb or several days post-procedure) and a further ( . %) with immediate moderate bleeding ( - ml). one subject had a history of prior signifi cant haemoptysis. in the four subjects with very signifi cant bleeding, immediate bleeding of > ml occurred in subjects, ml in one subject and ml in one. immediate bleeding was controlled uneventfully. three of the subjects subsequently developed signifi cant haemoptysis (> ml) to days post-bronchoscopy without intervening haemoptysis, with one subject developing massive haemoptysis (> ml) on day post-bronchoscopy. further research ebs were ceased. in one of the subjects with 'delayed rebleeding', repeat bronchoscopy confi rmed the biopsied lobe as the bleeding site. haemoptysis settled in all subjects within hours with simple conservative measures. conclusions in contrast to the experience in asthma and copd, research eb in adults with non-cf bronchiectasis is associated with a signifi cant risk of bleeding, of potentially life-threatening magnitude in . % of cases. of particular concern was the observation of sudden onset delayed rebleeding developing up to days post-eb in spite of early local control. histopathological evaluation will clarify the potential contributions of airway wall vascularity and infl ammation to these events. malignant mesothelioma (mm) is an aggressive cancer which is often associated with exposure to asbestos and sv . this disease has a high latency period and a low survival rate. therefore, new strategies for therapeutic intervention must be developed. recent studies have shown that developmental pathways including the hedgehog (hh) pathway are associated with various types of cancers. the aberrant activation of key hedgehog pathway proteins has been shown to contribute to cancer progression. however, the role of this pathway in mm has yet to be explored. we hypothesize that aberrant activation of the hh pathway is a contributing factor for the development of mm. the mrna expression of hh pathway genes; sonic hedgehog (shh), patched - (ptch- ), smoothened (smo) and gli- were examined in mm cell lines and tumour tissues by rt-pcr and qrt-pcr. hh pathway proteins and mrna expression and distribution were then observed in the tumours by immunochistochemistry and in situ hybridization. we used real-time superarrays to examine the change in expression of a panel of key hh pathway genes by activating and inhibiting the pathway. we showed that the key hh pathway genes are expressed in both the cell lines and tissue samples. upon stimulation with the ligand shh, there was an increase in expression of indian hedgehog (ihh) and shh in most of the mouse and human cell lines that we looked at. interestingly, for the transcription factor gli- , there was a significant decrease in both mouse and human cell lines. inhibiting this pathway increased the expression of ptch in the mouse and human cell lines. the expression and up-regulation of key hh pathway components in mm at baseline and following stimulation suggests a role for the pathway in mm. methods incident cases were obtained from the australian and wa mesothelioma and cancer registries and death registries. exposure was calculated using measures of dustiness in the industry and the town for the period of employment or residence of each case. latency (time from fi rst exposure to diagnosis) by sex, age, smoking status, exposure variables and worker or resident status was estimated. multivariate linear regression modelling examined the determinants of latency. results the mean latency periods of . (sd = . ) years for lc and . (sd = . ) years for mm have increased linearly. increased duration of exposure was associated with reduced latency for mm after adjustment for age at fi rst exposure and age at diagnosis but not signifi cantly for lc. age at diagnosis was strongly associated with latency length for both lc and mm (p < . ). smoking, sex, cumulative exposure (log f/ml-year) and status at wittenoom were not related to latency. latency for lc with increasing age at fi rst exposure declined faster than for mm. conclusions age at diagnosis is associated with reduced shorter latency of mm and lc. duration of exposure is associated with shorter latency of mm. supported by nhmrc australia. confl ict of interest no. aim to assess overall survival of patients following resection for stage nsclc at a centre that has substantially greater resection rates than the nsw average. methods a retrospective audit of those patients who underwent lung resection for stage nsclc at nepean hospital between january and february . results patients ( m: f), mean age (range - ) underwent resection. there were pneumonectomies, bilobectomies and segmentectomies, one involving chest wall resection. the remaining procedures were lobectomies. there was one perioperative death from respiratory failure. actuarial overall survival at months was %, at months, % and at years %. survival was not infl uenced by histology or age. conclusion in our institution, we have an agreed aggressive approach to resection of stage nsclc and our resection rate is %. this pro-surgical policy is associated with good perioperative and long-term overall survival. confl ict of interest no. introduction malignant pleural effusions (mpes) are common, although their management varies widely. providing ambulatory care to minimize hospitalization is a key goal for patients with mpes. indwelling pleural catheters (ipcs) are a new treatment strategy that allows outpatient fl uid drainage. we hypothesized that mpe patients managed with ipcs require fewer hospital admissions. methods a prospective, multicentre, non-randomized study involving all three major respiratory centres in western australia. patients diagnosed to have mpes were prospectively followed, and admissions were recorded. in the absence of accepted guidelines for ipc use, the choice of treatments (thoracentesis, ipc, pleurodesis) was decided by clinicians in-charge. all complications were recorded. bacterial cultures of pleural fl uid were performed monthly for patients with ipcs. hm gallagher , ee duhig , ia yang , rv bowman , be clark , hm marshall , km fong aim to determine the concordance of histological subtyping of nsclc in diagnostic samples to the gold-standard lung resection specimens. methods we have so far evaluated consecutive subjects who underwent curative surgery for primary nsclc at the prince charles hospital between the years and . many of these had workup at other institutions. one hundred forty-seven had queensland health electronic record of positive preoperative diagnostic sampling. we correlated the fi nal nsclc who histological subtype with the subtypes diagnosed by samples prior to surgery including sputum, fi beroptic bronchoscopy (fob) and trans-thoracic needle aspiration (ttna). the resection subtype was set as the reference standard, and concordance was compared. results of the cases of resected nsclc, had malignancy on diagnostic sampling pre-resection, as shown in the results patients were included: median age years (range - ); % male; % living in major cities versus % in regional areas; % rightsided mpm; % epithelial subtype. median time from asbestos exposure to diagnosis was years (range - ). median time from fi rst symptoms or investigations to diagnosis was weeks (range - ). all patients had at least one chest x-ray and ct scan and % had pet scan. a variety of procedures led to the diagnosis: % thoracoscopy, % thoracotomy, % radiology-guided, % chest wall biopsy and % medical pleuroscopy, with % having had cytology alone. median number of diagnostic immunohistochemical stains used was (range - ), with calretinin ( %) the most commonly used mesothelial marker and carcinoembryonic antigen (cea; %) the most common carcinoma marker. median os for the cohort was . months ( % ci: . - . ), with no statistical difference in os between major city and regional patients ( vs. . months, respectively, p = . ). conclusions mpm appeared to affect mainly the elderly, and thoracoscopy was the most common diagnostic procedure. os did not differ between australian major city and regional patients and was comparable to the largest phase iii trial in mpm. aw musk , , p aboagye-scarfo , a reid , a miller, s ruwanpura, l mcleod, p bardin, n watkins, bj jenkins rationale lung cancer is the leading cause of cancer death worldwide. it is well established that cigarette smoking is linked to emphysema and lung cancer, and smokers with emphysema are at an increased risk of developing lung cancer. notably, recent epidemiological studies have indicated that emphysema can predispose to lung cancer irrespective of pack-year smoking history. although infl ammation has been proposed as a common mechanism linking these two diametrically opposed diseases, the conceptual inter-relationship between infl ammation, emphysema and lung cancer has been poorly investigated because existing experimentally induced and genetically modifi ed animal models for lung cancer occur in the absence of emphysema. method we have utilized a newly identifi ed mouse model (gp f/f ) of spontaneous lung infl ammation and emphysema in two well-established lung cancer models. the gp f/f mouse is characterized by deregulated cytokine signalling via gp , the critical co-receptor for the interleukin (il)- cytokine family, leading to hyper-activation of stat , a potent pro-infl ammatory and oncogenic latent transcription factor. in separate studies, we exposed gp f/f mice to a cigarette-derived carcinogen (nnk), and crossed them with the genetically susceptible kras(g d) strain of mice. results in both nnk-and kras(g d)-induced lung cancer models, the lungs of gp f/f mice were highly predisposed to hyperplasia and tumour formation. increased levels of cellular proliferation were observed in hyperplastic and tumour lesions, as well as surrounding areas, of these mice. these observations were verifi ed at the molecular level by gene expression profi ling of tumour-bearing lung tissue. conclusions these studies provide unique insights into the importance of interactions between the gp signalling axis and factors that predispose to lung tumourigenesis in emphysema. support nhmrc. aim to assess the preparedness of hospitals with respect to protecting health-care workers (hcws) during a pandemic. methods a self-administered questionnaire was performed between november and january , and a scoring system was developed to provide a quantifi able measure of preparedness. results a total of hospitals in nsw, australia, were approached -six regional hospitals (rhs) and six tertiary referral centres (trcs). the study was extended to assess three hospitals in england, allowing a limited comparison between the hospitals in australia that had faced the initial wave of the h n ('swine fl u') pandemic and the hospitals in the uk that had more time to prepare for the outbreak. response rates were % from the trcs, % from the rhs and % from the english hospitals. the overall preparedness scores were relatively high, with a median total score (adjusted) of . out of . the demographic that scored the highest total was tertiary referral centres in sydney. all english hospitals scored below the median. however, the range of scores across hospitals was quite narrow ( . - . adjusted). scores were generally high for the areas of preparedness, infection control, education and training. scores for vaccination were more variable. the category that consistently demonstrated the lowest scores was that of psychosocial welfare and assistance, despite this found in previous research to be an integral part of that which hcws have identifi ed as important. conclusions given their integral role in pandemic response, protecting hcws must be a priority as part of any pandemic preparedness plan. this goes beyond protection from infection, extending into aspects of physical and psychological wellbeing. identifying these issues and addressing them is the key to maximizing staff support and morale, and minimizing staff absenteeism at such a crucial time. aim to describe the relationship of respiratory and refl ux symptoms within the general population and relate this to the possible confounding factors of body mass index (bmi) and obstructive sleep apnoea (osa). methods data from a cross-sectional health survey, performed in bussleton, west australia in - , were used to examine the relative effects of bmi and osa on the relationship between respiratory and refl ux symptoms. questionnaire data included information on asthma, cough, wheeze, dyspnoea and gord symptoms. gord symptoms were categorized as never, monthly or less often and weekly or more often. bmi, risk of osa defi ned according to the berlin questionnaire, spirometry and airway hyperresponsiveness to methacholine were also recorded. logistic regression models obtained odds ratios for the associations between each gord symptoms, various respiratory symptoms, bmi and osa. results average age was years and recent wheeze was reported in % and cough and phlegm in %. twelve percent were current smokers. ahr was present in % and osa in %. gord symptoms occured in % and frequent symptoms (weekly or more often) were present in - %. there were strong positive associations between gord symptoms and cough/phlegm, breathlessness, chest tightness and wheeze in the last months. odds ratios increased with increasing frequency of refl ux p ≤ . . there was no effect of obesity or osa on the relationship between respiratory and gord. conclusion cough and phlegm, breathlessness, chest tightness and wheeze (ever or recent) are all strongly associated with symptoms of gord. this relationship is amplifi ed with increasing frequency of gord symptoms indicating a dose-response relationship between refl ux and respiratory symptoms. obesity and osa do not affect the association between gord and respiratory symptoms. introduction diesel exhaust particles (dep) make up the bulk of particulate matter in urban areas. high ambient levels of particulate matter are associated with increased hospitalization due to respiratory disease. we aimed to determine if exposure to dep exacerbates responses to acute viral infection. methods adult female balb/c mice were inoculated with μg dep or control . days after infection with . plaque forming units (pfu) of infl uenza a/mem (or control). six hours after dep inoculation, lung volume (tgv) and lung mechanics were measured by plethysmography and the forced oscillation technique, respectively. bronchoalveolar lavage fl uid was collected to assess cellular infl ammation and cytokine levels. results viral titre was signifi cantly higher in infl uenza-infected mice exposed to dep compared to those exposed to infl uenza alone (p = . ). both dep (p = . ) and infl uenza infection (p < . ) alone signifi cantly increased cellular infl ammation; however, there was no difference between mice exposed to both dep and infl uenza compared to those exposed to infl uenza alone (p = . ). a similar pattern was found in levels of cytokines in the bronchoalveolar lavage (tnf-α, mcp- , il- , ifn-γ). specifi c airway resistance, specifi c tissue damping, specifi c tissue elastance and hysteresivity were signifi cantly increased in infl uenza infected mice (p < . in all cases). none of these parameters were infl uenced by dep exposure alone (p > . in all cases) and there was no additive effect of dep on lung function (p > . in all cases) in infl uenza-infected mice. conclusions dep increases viral titre but is not suffi cient to physiologically exacerbate pre-existing respiratory disease caused by infl uenza infection in mice. supported by nhmrc. confl ict of interest no. introduction lack of treatments for post-transplant obliterative bronchiolitis (ob) is mainly due to the poor understanding of its pathogenesis and lack of small airway models. epithelial-mesenchymal transition (emt) may play a central role and could be crucial to developing treatment drugs. we hypothesize that emt induction may be prevented by pharmacologically available compounds. methods primary cultures of small and large airway epithelial cells (saec and laec) were established and emt induced by adding tgfβ ( ng/ml) (n = ). azithromycin ( - μm), mycophenolate ( . - mg/l) and rad ( . - ng/l) were then added and expression of epithelial (zo- , ck- ) and mesenchymal markers (eda-fn, vim) measured via western blot as well as mmp and activity via zymography. results signifi cantly lower increase in mesenchymal markers and lower decrease in epithelial markers, compared to controls was noted for azithromycin and mycophenolate indicating suppression of emt. mmp and activity increase was also signifi cantly suppressed. azithromycin suppressed emt to a greater extent compared to mycophenolate, but was equally effective in both small and large airway epithelia. rad appeared to have no effect. conclusions azithromycin and mycophenolate are both effective in preventing emt and thus have potential for the clinical treatment of ob. supported by abn foundation. confl ict of interest none. journal compilation © asian pacifi c society of respirology tp- g hodge , , s hodge , , c-l liew , , t-cell pro-infl ammatory cytokines are associated with acute lung transplant rejection. we have previously shown compartmentalization of production of these cytokines in bronchial intraepithelial t cells (iet) obtained by bronchial brushings from stable lung transplant patients. during acute rejection episodes, no signifi cant differences in iet cytokines were observed between stable and rejecting patients due to broad cytokine variability between patient groups. to overcome this limitation, we hypothesized that there would be increased graft pro-infl ammatory iet cytokines compared with native lung or trachea during acute rejection. methods cell cultures from stable patients, patients with evidence of acute rejection and bos and healthy controls were stimulated and intracellular cytokines determined using multiparameter fl ow cytometry. results there was a signifi cant increase in graft iet-cell ifnγ and tnfα in the lungs of patients with acute rejection compared with iet cells obtained from the native lung or trachea, but no changes were noted between other patient groups. there was a signifi cant correlation between increased graft iet-cell tnfα compared with trachea and lungs and acute rejection grade. conclusions differential expression of pro-infl ammatory cytokines by iet cells from graft, trachea or native lung distinguishes severity of acute rejection. improved monitoring response using this assay or therapeutic targeting of these pro-infl ammatory cytokines may reduce acute lung transplant rejection. supported by nhmrc. aim to determine the prevalence of reduced carbon monoxide transfer factor (dlco ≤ % predicted) in subjects undergoing pulmonary function testing (pfts) and to determine whether a cause has been identifi ed. methods a clinical audit of all subjects undergoing pfts at royal melbourne hospital from august to august who have a dlco ≤ % in the setting of normal spirometry. medical records and investigations including transthoracic echocardiogram (tte), high-resolution commuted tomography (hrct), ventilation/perfusion (v/q) scans were reviewed to determine whether a cause for the reduced dlco was established. where a cause was not clear, subjects were invited to participate in a telephone interview to evaluate symptoms and to undergo repeat pfts. subjects with a persistently reduced dlco were invited to undergo further investigation with tte, hrct and v/q scan. preliminary results pft results from subjects were reviewed. subjects with fev /fvc < , fev < % predicted and fvc < % predicted were excluded. three hundred seventy subjects ( %) had an isolated reduction in dlco. / ( %) of these subjects underwent tte with / ( %) demonstrating an elevated right ventricular systolic pressure (rvsp). in all cases where there was an elevated rvsp an identifi able cause was found. / ( %) of these subjects subsequently identifi ed as having pulmonary arterial hypertension (pah) and commenced appropriate therapy and / ( %) identifi ed as having pah where treatment was not commenced. there were / ( %) of subjects who appeared not to have undergone a tte. further evaluation of medical records of subjects who had not undergone tte and those with normal tte is continuing. review of subjects hrct, v/q scans and right heart catheterizations is currently proceeding. conclusions preliminary results suggest that a signifi cant proportion of subjects with isolated reduction of dlco on pfts do not undergo tte which is an important investigation in determining the cause for the reduced dlco. when a tte is performed and demonstrates an elevated rvsp, a cause for the elevated rvsp is identifi ed. sponsor actelion pharmaceuticals australia pty ltd. g hodge , , s hodge , , c-l liew , , , pn reynolds , , m holmes , , background t-cell pro-infl ammatory mediators are associated with acute lung transplant rejection. we have previously shown that bos was associated with lack of immunosuppression of t-cell pro-infl ammatory cytokines and increased t-cell granzyme b in peripheral blood. recently, we also showed that nkt-like cells are a major source of pro-infl ammatory cytokines and granzymes in the blood of stable lung transplant patients. we hypothesized that bos may be associated with lack of immunosuppression of these proinfl ammatory mediators in blood nk and nkt-like cells. method granzyme/perforin profi les from stable patients, patients with evidence of bos and healthy controls were determined and blood cultures stimulated and intracellular cytokines determined using multiparameter fl ow cytometry. results there was a signifi cant increase in the percentage of nk cells expressing granzymes and perforin in bos patients compared with stable patients and controls. there was an increase in the percentage of t, nk and nkt-like cells producing ifnγ and tnfα in bos compared with stable patients. there was a signifi cant correlation between increased nk ifnγ and tnfα and fev . conclusions bos is associated with increased peripheral blood nkt-like and nk cell granzymes, perforin and th pro-infl ammatory cytokines. therapeutic targeting of these pro-infl ammatory mediators and monitoring response using this assay may reduce bos. supported by nhmrc. confl ict of interest nil. rationale pulmonary embolism (pe) is the leading cause of maternal mortality in the developed world. consequently accurate diagnosis of pe is critical. this must be tempered by the potential radiation risk of investigations to the mother and foetus. we performed a retrospective case review to determine the incidence of pe in pregnant patients investigated for this condition. demographic information, the diagnostic algorithm utilized and the diagnostic yield of investigations were obtained. method pregnant women who underwent ventilation perfusion (vq) scanning or computed tomography pulmonary angiogram (ctpa) at our institution between january and january were identifi ed by an internal database audit. in addition to demographic data, information about the diagnostic pathway and fi nal diagnosis were collected. in cases where pe was not diagnosed, the medical records were reviewed for any subsequent events up until the date of delivery. results during the fi ve-year period, vq scans and ctpas were performed on pregnant women. the average gestation at investigation was weeks. only one patient had a previous history of venous thrombo-embolism. % underwent doppler ultrasound of the lower limbs prior to vq or ctpa. overall the incidence of pe was %, diagnosed by vq scan. otherwise the vq scans were normal in %, low probability in % and non-diagnostic in % cases. ctpa was non-diagnostic in % of cases. all other ctpa studies demonstrated no emboli. almost % of scans were done after hours ( % vq and % ctpa). no patients without pe were felt to have had the pe missed up to the time of delivery. conclusions the overall incidence of pe in patients being investigated was extremely low at %. during this study period slightly more vq studies were performed than ctpas, with each test having similar diagnostic rates. only % of patients had undergone venous doppler prior to undergoing radiationexposing investigations. nomination nil. introduction anti-ro- antibodies have been associated with idiopathic interstitial pneumonia (iip) in one small series (n = ). we hypothesize that ro- antibodies, just like myositis antibodies, can serve as a marker of undifferentiated connective tissue disease (ctd) with interstitial pneumonia as the primary phenotypic manifestation. the aim of this study was to examine the characteristics of patients with ro- and iip. methods retrospective study identifying patients with iip and ro- positivity, but negative for ctd and/or myositis antibodies, presenting between june and june . data relating to demographics, diagnosis, pulmonary function tests, length of follow-up and outcome were obtained. all hrct images were reviewed by an independent expert radiologist (dm). results / ro- positive subjects fulfi lled criteria ( male, median age ( - ), european, never smoked). / had ro- titers above and in the intermediate ( - ) range. three patients had raynauds phenomenon; there were no other ctd features. / patients had hrct diagnosis of nsip and / organizing pneumonia; / had extensive fi brosis. mean (sd) % predicted baseline fvc ( ), dlco ( ). median length of follow-up was months. all patients were treated and were considered overall stable at last follow-up, one had declined and one died of respiratory failure. conclusion this study confi rms an association between ro- positivity and interstitial pneumonia in the absence of defi ned connective tissue disease, suggesting an autoimmune basis for the interstitial lung disease in this group of patients. a larger cohort is required to determine the true signifi cance of this observation. background community acquired respiratory viral (carv) infections are believed to contribute to morbidity and mortality after lung transplantation, but previous studies have not conclusively established the evidence base in this area. patients and methods a prospective cohort study was performed at a single centre from august to march (n = lung transplant recipients). carv infection (human metapneumovirus (hmpv), respiratory syncytial virus (rsv), infl uenza a (flu a), infl uenza b (flu b), adenovirus and parainfl uenza virus (piv)) was confi rmed using polymerase chain reaction (pcr) of upper (nasopharangeal swab) and/or lower (bronchoalveolar lavage) respiratory tract secretions. carv infection and bos were included as segmented time-dependent covariates in a cox proportional hazards model with death as the outcome variable. results patients ( % of the total cohort) had a total of separate carv episodes: piv, hmpv, rsv, flu a, flu b, and adenovirus. infection with either rsv or hmpv was associated with an increased risk of death (p < . hr . , % confi dence interval, . - . ), and the effect persisted after multivariate analysis. bos was also a risk factor for acquiring hmpv or rsv infection (p = . or . , % confi dence interval, . - . ). conclusions infections with hmpv and rsv, but not other carvs, are associated with an increased likelihood of death. the presence of bos is a risk factor for symptomatic infection with hmpv and rsv. ns harun , k sanders , a stuart , cl steinfort department of respiratory medicine, barwon health, vic., australia, and department of clinical and biomedical sciences, barwon health, vic., australia aims nebulized colistin is used to treat recurrent exacerbations of bronchiectasis due to pseudomonas aeruginosa, a major pathogen regarded as diffi cult to eradicate. this case-control study aimed to establish if long-term colistin use could clear p. aeruginosa from the sputum of adults with non-cystic fi brosis bronchiectasis, and if so, whether colistin could be ceased in these patients. secondary outcomes included effects of colistin on quality of life (qol), symptom control, admission rates, lung function and tolerability. methods ( ) sputum was collected in bronchiectasis patients with p. aeruginosa. clearance rates in those on colistin were compared with a control group not on colistin. ( ) colistin patients cleared of p. aeruginosa ceased treatment. sputum was re-cultured at day and to detect recurrence. ( ) a questionnaire assessing qol, symptom control, and admission rates was performed on patients. outcomes were compared before and after colistin use. long-term colistin side-effects and lung function were also assessed. results ( ) % (n = / ) of colistin patients cleared p. aeruginosa from sputum compared with % (n = / ) in the controls (p = . ). ( ) % (n = / ) of patients ceasing colistin remained free of p. aeruginosa at day . ( ) there was no difference in frequency of breathlessness, sputum production or qol scores between the groups (p > . ). the colistin group had lower fvc ( . vs. . l, p = . ) and higher admission rates ( % vs. %, p = . ). on colistin, % of patients reported reduction in sputum frequency, breathlessness and improvement in qol. fifty percent reported decreased admission rates. there were no colistin side effects. conclusions clearance of p. aeruginosa in sputum is possible. clearance rates were similar in those with more severe bronchiectasis treated with colistin compared with stable patients not on colistin, and may suggest suppression of p. aeruginosa by colistin in this severe group. there are benefi ts of colistin on qol, symptom control and admission rates. continued sputum clearance after colistin cessation is achievable in some patients. nebulized colistin use is well tolerated. nomination janet elder travel award. confl ict of interest no. however, use of such agents is suboptimal in hospital patients. this study aims to determine whether a dedicated multidisciplinary education and reinforcement program improves the use of appropriate vte prophylaxis. methods prior to the education programme, we audited a bed general thoracic medical ward including patients with general medical conditions, lung cancer, chronic obstructive pulmonary disease, lung transplant and cystic fibrosis. our multidisciplinary research team developed and implemented an education program over months, using posters, leafl ets and oral presentations to increase awareness and promote adherence to vte prophylaxis guidelines for health care staff involved in direct patient management. following completion of the program, we reaudited the same bed ward. results prior to the education program, a total of patients (mean age ± ) were identifi ed as appropriate for vte prophylaxis. of these ( %) were on appropriate vte prophylaxis. the post education audit showed out of ( %) patients were on appropriate vte prophylaxis. (p = . ). conclusion an effective multi-faceted educational program can improve delivery of appropriate vte prophylaxis, leading to improved outcomes in hospitalized patients. supported by sanofi aventis. confl ict of interest nil. the anti-rheumatic anti-infl ammatory biological agents in clinical use are abatacept, anakinra, adalimumab, etanercept, infl iximab and rituximab. a variety of pulmonary side-effects have recently been reported for these agents and the purpose of this review is to compile the various reported pulmonary toxicities and their prevalence methods we performed a search of databases ovid medline® and embase of the english literature up to august using the mesh terms of abatacept, anakinra, rituximab, adalimumab, etanercept, infl iximab and respiratory tract disease with limits to include only human studies or case reports. in addition case reports of respiratory adverse effects reported to the australian drug reaction advisory committee (adrac) were obtained in order to identify the most common pulmonary reactions reported with each individual agent. results using the search criteria defi ned above and articles were identifi ed in the ovid medline and embase database respectively. the majority of adrac reports were associated with rituximab (n = ) and infliximab (n = ), followed by adalimumab (n = ) and etanercept (n = ). various pulmonary side-effects including interstitial lung disease associated with anti-infl ammatory agents were identifi ed. discussion from the articles reviewed, details about the duration between onset of treatment and incidence of pulmonary side effects, diagnosis, treatment options and outcome of patients were extracted and are presented here. conclusion this comprehensive systematic review hopes to improve the awareness about the serious and potentially life-threatening pulmonary sideeffects of this group of agents. confl ict of interest no. sj simpson , pd sly , p franklin , e lombardi , c calogero , m palumbo , gl hall , introduction the forced oscillation technique (fot) is effort independent and thus ideal for young children. the area under the reactance curve (ax) has been proposed to amplify clinically relevant signal by taking advantage of any shape change in the reactance (xrs) curve below the resonant frequency. this study aimed to develop reference values for resistance (rrs), xrs and ax in a large healthy population of children, and determine if ax conferred any additional clinical benefi t when examining disease in children born preterm. methods impedance spectra were obtained in healthy children ( male), aged less than years and with height less than cm using a commercial device (i m, chess medical, belgium). ax was calculated in of these children between hz and the resonant frequency. backwards stepwise linear regressions identifi ed the best predictors of ax, and xrs and rrs at hz (xrs , rrs ), and z scores were generated. z scores were calculated for children born preterm, of which received a neonatal diagnosis of bronchopulmonary dysplasia (bpd). chi squared tests examined the difference in proportion of children born preterm (with and without bpd) with abnormal z scores for each fot variable. results all fot variables were predicted by height (p < . ) and sex. mean (sd) z scores for preterm children with and without bpd for rrs ( . ( . ); . ( . )), xrs ( . ( . ); . ( . )) and ax ( . ( . ); . ( . )) were all signifi cantly different (p < . ) from the healthy population. the number of children born preterm with abnormal z scores was not significantly different when comparing ax, rrs and xrs . conclusions while ax is able to detect respiratory disease in preterm children with and without bpd, it is no more sensitive than xrs or rrs. supported by pmh foundation, nhmrc, asthma foundation wa, carivit, ngo 'solidarietà e servizio' viterbo. confl ict of interest no. introduction survivors of preterm birth born with bronchopulmonary dysplasia (bpd) in the pre-surfactant era of neonatal care (classical bpd) have a reduced pulmonary gas transfer capacity. there is, however, little data to describe gas transfer in preterm infants with bpd in the post-surfactant era (new bpd). objective assess gas transfer using carbon monoxide diffusing capacity (dl co ) and its components, pulmonary capillary blood volume (vc) and pulmonary membrane diffusion (d m ), in contemporary survivors of preterm birth. method gas transfer was assessed using single-breath dl co in children aged to years and born < weeks gestation with bpd (pb, n = ) and without bpd (pt, n = ), and in term born controls (tc, n = ). dl co z scores were calculated. d m and vc were determined in pb, pt and tc children. the mean (sd) dl co z score for the pb group was − . ( . ) differing signifi cantly from (p = . ) while the pt and tc groups ( . ( . ) and − . ( . ), respectively) did not (p > . ). d m was lower in the pb group than the pt and tc groups, with no difference between pt and tc groups. differences in d m were not signifi cant after adjusting for lung size. there were no differences in vc between groups. conclusion gas transfer is reduced in survivors of preterm birth with new bpd. the tendency for reduced d m and not vc in children with new bpd suggests that impaired gas transfer may be a result of alterations in the alveolar membrane rather than pulmonary vascular function. background bronchiectasis is common in indigenous populations such as alaska natives, australian aboriginal, and new zealand maori and pacifi ca. as part of an international collaborative interventional study, we sought the participation of maori and pacifi ca families -groups diffi cult to engage in research in the past. aim to engage, enrol and retain children from maori and pacifi ca families from auckland in a -year research study. methods a randomized controlled trial to determine whether azithromycin is superior to placebo in reducing exacerbations seeking to enrol children aged months to years with bronchiectasis. the enrolment procedure was modifi ed to a process deemed more appropriate to these cultures: ( ) request to defer the decision of enrolment until the process had been completed. ( ) a minimum of meetings; initial invitation, discussion in the home with the extended family, invitation to the extended family to participate in the day of enrolment. ( ) appointment of a 'whanau worker' (family worker) to sit with the family and empower them to get all the information they seek prior to enrolment. results of families approached, ( %) children (median age . years, range . - . years) enrolled with % samoan, % tongan, % maori and % mixed maori/pacifi ca heritage. after -year retention was ( %) with exiting the study after month with new non-pulmonary disease, and exiting after year, moving outside study area. conclusions these are high enrolment and retention fi gures reported in this population. we believe that following a prolonged procedure for enrolment, involving the extended family and appointing a worker to sit 'alongside' the family will improve their understanding of a research project and allow them to feel more comfortable about participating. aim bronchiolitis is the most common reason for hospital admission for infants globally ( ) . the use of macrolides for treating bronchiolitis in nonaffl uent settings remains controversial but potentially benefi cial. in our region readmission with lower respiratory illness in young children (particularly indigenous children) remains high. this rct aims to determine if a single dose of azithromycin reduces the morbidity of young children with bronchiolitis. methods double blinded rct. young children ≤ months admitted to royal darwin hospital (rdh) diagnosed with bronchiolitis are eligible. children are given a single dose ( mg/kg) of either azithromycin/placebo. primary outcome is length of stay for respiratory disease. secondary outcomes are duration of oxygen use and readmission for respiratory illness in -month period. respiratory viral infections often lead to exacerbations of chronic respiratory diseases such as asthma and copd though there is no similar data in noncystic fi brosis (cf) bronchiectasis. the objectives of our study were to ( ) determine the point prevalence and identify viruses associated with exacerbations and ( ) evaluate clinical and investigational differences between viral infection positive and negative exacerbations in children with non-cf bronchiectasis. methods a cohort of children (median age years; boys) with non-cf bronchiectasis was prospectively followed for child-months. polymerase chain reaction for respiratory viruses was performed on nasopharyngeal aspirates collected during paediatric pulmonologist defi ned exacerbations. data on clinical, parent cough-specifi c quality of life (pc-qol), systemic markers (crp, il , procalcitonin, amyloid-a, fi brinogen) and lung function parameters were also collected. results respiratory viruses were detected during ( %) exacerbations: picornavirus in episodes [human-rhinovirus (hrv) in , enterovirus in ]; human bocavirus in ; adenovirus, human meta-pneumovirus, infl uenza a, respiratory syncytial virus, parainfl uenza and in two each; coronavirus and parainfl uenza and in one each. viral co-detections occurred in ( %) exacerbations. among genotyped hrv's, more hrv-a's (n = ) were identifi ed than hrv-c's (n = ). children with proven viral infections were more likely to have fever (or . , % ci . - . ), wheeze and/or crackles (or . , % ci . - . ) and raised crp (or . , % ci . - . ) when compared with virus negative exacerbations. there were no other statistically signifi cant differences. conclusions respiratory viruses are commonly found during pulmonary exacerbations in children with non-cf bronchiectasis. hrv-a is the most frequently detected virus. time sequenced cohort studies during stable state, exacerbations and recovery periods are needed to determine the importance of viral infections and their possible interaction with bacteria. supported by anz trustees scholarship. confl ict of interest none. nominations none. to date children enrolled, % rsv+ve. median age . months. fifty percent have had at least one co-morbidity. readmission rate = %. conclusion co-morbidities are high in this population. antibiotics have the potential to help reduce the impact of additional respiratory burden. foundation. introduction foreign body inhalation is a relatively common presentation in young children, especially less than years of age. early recognition remains a critical factor in the treatment of foreign body inhalation in children. inhaled foreign bodies in children are most often organic material, with seeds and peanuts being the most common items. on review of the literature, there are very few case reports of inhaled metal screws. we report two unusual cases of inhaled metal screws that presented to our service. case presentation both cases presented to our emergency department with wheeze, respiratory distress and fever. foreign body inhalation was not considered as a cause for their symptoms until the object was identifi ed on chest x-ray. both foreign bodies were removed successfully but one child required invasive ventilation in our intensive care unit post removal. both children made a full recovery. interestingly, both metal screws came from fl at pack furniture purchased from a well known international home products store. conclusion foreign body inhalation must always be considered as a cause of respiratory distress in a child. with the increase in the number of fl at pack furniture in australian home's, we believe parents must be warned of the potential danger of loose metal screws to young children. supported by none. cough in children is a common symptom. data on causes of chronic cough in young children have previously been published by our units. however, differences in underlying diagnosis by age at presentation have not been assessed. we present the 'time to cessation' of cough in our multicentre rct using a standardized management algorithm in newly referred children with chronic cough (> weeks) from australian centres. methods parents completed validated cough diary and cough specifi c qol (pc-qol) at recruitment and at cessation of cough. the diagnosis made by the treating physician was based on tsanz position statement. results the median (range) age of the children recruited was . years ( . - . ); ( %) were boys. median (iqr) pc-qol post treatment of . ( . , . ) improved signifi cantly (p = . ) from . ( . , . ) at enrolment. the median (iqr) duration of cough at recruitment was weeks ( . , . ) and 'time to cessation' of cough after application of the management algorithm was weeks ( . , . ). there was no signifi cant difference (p = . ) in median (iqr) 'time to cessation' of cough among the three age cohorts: < years (n = , . %) was . weeks ( . , . ); - years (n = , . %) was weeks ( . , . ); and > years (n = , . %) was weeks ( . , . ). there was also no signifi cant difference in the fi nal primary diagnosis among the three age cohorts (p = . ). the most common diagnoses were protracted bacterial bronchitis (n = , %), asthma/reactive airways disease (n = , . %), tracheobronchomalacia (n = , . %) and bronchiectasis (n = , . %). children ( . %) had more than one diagnosis. conclusions the aetiology and 'time to cessation' of chronic cough in children managed in accordance to a standardized pathway were similar among the three age groups. it is likely that our previous fi ndings in very young children are also applicable to older children. supported by nhmrc grant number . confl ict of interest none. aim to determine the role of fl exible bronchoscopy with bronchial alveolar lavage (bal) in the management of patients with febrile neutropenia. methods a retrospective analysis was made of the number of patients admitted with febrile neutropenia at a single institution who underwent bronchoscopy plus bal from years to . computer database plus patient case notes were reviewed to establish clinical symptoms and signs, radiological fi ndings, antimicrobial treatment and mean duration to bronchoscopy following admission. results a total of episodes of febrile neutropenia were recorded years to . seven patients ( males and females) were referred for bronchoscopy plus bal. the mean age was . years (age range - years) and all had been diagnosed with acute lymphoblastic leukemia. all patients had at least cough as a clinical symptom along with radiological fi ndings. all patients had been on broad spectrum antibiotics at the time of bronchoscopy. the mean duration from admission to time of bronchoscopy was hours ( days) with a standard deviation of hours. of the seven patients one patient yielded a positive result on bal. this did not result in a change in management as the patient improved clinically before the result of the bal was confi rmed. conclusion in this retrospective case series the diagnostic yield of fl exible bronchoscopy plus bal in children with febrile neutropenia was low. prospective studies plus early timing towards bronchoscopy and bal should be conducted to further defi ne its role in the management of febrile neutropenic patients. confl ict of interest nil. methods prospective cohort study involving monthly follow-up with caregivers. two years post enrolment, children undergo clinical and lung function assessment (fot). presence of bronchiectasis is determined by physician review and radiological confi rmation (when indicated). the frequency of pbb episodes is recorded over the study period. of children recruited to the cohort study to date, % ( / ) were male. the median age at recruitment was months (iqr , ). % of children had recurrent pbb. of the children who have had -year clinical follow-up, were able to perform fot and % ( / ) showed abnormalities (reactance above normal range.) % ( / ) with pbb have had subsequent physician diagnosis of bronchiectasis or csld. conclusion the burden of cough in children with pbb years after diagnosis remains high. ongoing clinical follow-up of this cohort of children with pbb should provide further insight into the likelihood of progression from pbb to csld and bronchiectasis. support financial markets foundation for children (for project), allen & hanburys and qcmri (for dw), nhmrc (for ju and ac). introduction national streptococcus pneumoniae (sp) serotype surveillance reports only culture positive cases from sterile sites but the yield from culture is low. polymerase chain reaction (pcr) is more sensitive in detecting sp in culture negative samples. aim to determine whether enhanced molecular surveillance in childhood empyema provides additional sp serotype information compared to national surveillance methods. methods pleural fl uid from children with empyema underwent culture and pcr to identify sp-targeting autolysin (lyta) and multiplex pcr to identify sp serotypes. national surveillance data were obtained from the national notifiable diseases surveillance system (nndss) for the same time period and age groups. results empyema: children, male, median age . (range . - . ) were recruited from april for months. sp was cultured in / ( . %) in blood and / ( . %) in pleural fl uid. sp was identifi ed by pcr in / ( . %). serotypes: , n = ( . %); , n = ( . %); a, n = ( . %); f a, n = ( . %); v/ a, n = ( . %); f/ a, n = ( . %); non-typeable, n = ( . %). one subject had serotypes and in a serotype could not be established. nndss: sp culture positive cases were reported. serotypes: , n = ( . %); , n = ( . %); a, n = ( . %); f a, n = ( . %); v/ a, n = ( . %); f/ a, n = ( . %); non-typeable, n = ( . %). other serotypes were reported in sp positive cases. signifi cant differences between empyema and nsdss data were identifi ed for serotypes (p < . ) and (p < . ). conclusions the proportion of serotypes and were signifi cantly higher in empyema fl uid using pcr. this disease model provides additional serotype information to national surveillance data. this has important implications in monitoring replacement serotypes following the introduction of new vaccines. funded by glaxosmithkline, belgium. h giddings , l seccombe , p rogers , a corbett , e veitch recent theories on the pathophysiology of parkinson's disease (pd) emphasize early brainstem involvement. furthermore various respiratory function abnormalities have been reported without consistent pattern. we sought to study the effects of idiopathic pd on respiratory function and ventilatory response to hypercapnoea and hypoxia. methods patients with a diagnosis of pd but no known respiratory disease were recruited. subjects underwent lung function testing including respiratory muscle strength, ventilatory response to hypercapnoea (with central respiratory drive (p )) and a hypoxic simulation (fio % cough is the most common symptom presenting to doctors. paediatric cough is associated with signifi cant morbidity for both children and their parents. the symptom of cough is associated with airway hyper-reactivity and is a dominant symptom of airway infl ammation. inhaled corticosteroids (ics) can reduce airway infl ammation and hyper-reactivity. the objective of this review was to evaluate evidence for the effi cacy of ics in reducing the severity of cough in children with sub-acute cough (defi ned as cough duration of - weeks). methods search was conducted by the cochrane airways group using cochrane methodology. all randomized controlled trials (rcts) comparing ics with a control group for treatment of sub-acute cough in children were considered for inclusion. search results were analysed using pre-determined criteria for inclusion. results two studies were eligible for inclusion in the review, however there were limitations in that the participants of both these studies were infants, post acute bronchiolitis illness, and cough duration at start of study treatment was ill-defi ned. children were included in the meta-analysis. there was no signifi cant difference between groups in proportion of children 'not cured' (primary outcome measure), with a pooled or of . ( % ci . , . ) (using intention to treat analysis). conclusions there is currently no evidence to support the use of ics in sub-acute cough in children. however, this systematic review is limited by the small number of studies available for analysis and the quality and design of these studies. further well-designed rcts are required to support or refute the effi cacy of treatment with ics in children with sub-acute cough. once obstructive sleep apnoea (osa) is diagnosed, a cpap implementation sleep study is traditionally performed to determine the pressure required to control the upper airway. however, since modern cpap machines store sophisticated control data we reasoned it may equally be possible to commence cpap via a 'best guess' iterative approach without compromising osa control or compliance. aim to compare the outcomes at months of patients commencing cpap after best guess with those commencing cpap after a cpap implementation sleep study. methods we retrospectively reviewed the records of all patients referred by respiratory physicians to our cpap clinic between march and march , and the two methods of starting cpap were compared. data collected included age, sex, bmi, respiratory disturbance index (rdi), cpap pressure commenced, fi nal pressure at months, cpap usage data and cpap clinic contacts. results patients were identifi ed, aged ± years, %male, bmi . ± . , with severe osa, rdi ± . commenced cpap via best guess and after a cpap sleep study. the starting pressures in both groups were similar, . ± . versus . ± . cmh o. in those patients continuing to use cpap at months, there were no differences between the groups for fi nal pressure, numbers of patients changing pressure, control of osa with cpap, and hours cpap used per day. in the best guess group however, signifi cantly more patients were continuing to use cpap at months, % versus % (p = . ). conclusion this study demonstrates that it may no longer be necessary to perform cpap implementation sleep studies routinely and this will save hospital bed days. confl ict of interest nil. six required intubation and the rest were managed with non-invasive ventilation in icu. the average length of stay in icu was . days. polysomnographic data will be described. conclusions obesity hypoventilation as a cause of respiratory failure is likely to increase in frequency as the incidence of obesity increases. increased awareness by the lay public, as well as clinical suspicion and recognition of the condition by all clinicians at an earlier stage, is likely to prevent progression to the point of needing intensive care. it is hoped that this case series may provide a springboard for further study into why these patients presented at such a late stage of their disease process. supported by none. confl ict of interest none. although sa and sleepiness often co-exist, the commonest cause of sleepiness in a general community is depression, with sa being the th most common cause. in order to assist recognition of depression in a snoring population attending a sleep clinic, we introduced a simple two question 'beyond blue questionnaire(bbq)' into our routine assessment. aims to ( ) background indices of ventilation distribution in diffusion (s acin ) and convection (s cond ) dependent airways derived from multiple breath nitrogen washout (mbnw) may vary between interpreters because of differences in calculation of phase iii slopes (Δphase iii ). aims to compare s cond and s acin results of interpreters from a single mbnw in copd subjects. methods subjects with copd underwent mbnw. three washouts were analysed independently by experienced and novice interpreters using custom software for automated breath identifi cation. Δphase iii was fi tted automatically by least squares fi t between predetermined points, and then adjusted manually. s cond was the linear slope of Δphase iii plotted against lung turnover (cumulative expired volume/frc), between turnovers . - . s acin was the Δphase iii of the fi rst breath minus the s cond component. differences expressed as icc and cov, were examined by repeated measures anova. results mean ± sd age was ± years. fev was ± % predicted. s cond was greater while s acin was lower from the experienced introduction β-blockers may cause bronchoconstriction and mask the effect of β -adrenergic agonists. this has implications for the interpretation of routine diagnostic spirometry and bronchodilator response. this study examined this issue in a routine lung function laboratory, and whether it applied to both cardio-selective (c) and non-selective (nc) preparations. method all patients attending the lung function laboratory, royal adelaide hospital over a -month period were asked whether they were currently taking a β-blocker and to identify the drug. spirometry results were analysed to assess airfl ow obstruction and reversibility. results patients completed the survey and patients ( %) were taking β -blockers. the table shows the results of the patients who could be assessed for reversibility in spirometry. of the patients in this group patients ( %) were taking (c) and ( %) (nc) agents. fifty-three patients were unsure whether they were taking a β -blocker. no signifi cant differences were found in the percentage of patients with airfl ow obstruction or reversibility between the groups. aim to examine patterns of adult lung function in terms of airfl ow obstruction, hyperinfl ation and/or reduced diffusing capacity (d l co). this can then be related to the life-time history of risk factors such as smoking, asthma and infections. methods using the population-based tasmanian longitudinal health study (tahs) cohort followed since , an asthma-enriched sub-sample was selected consisting of % ever with asthma, of whom half reported current asthma. measurement of spirometry, d l co (uncorrected for haemoglobin) and lung volumes was performed, then lung function data were analysed using the mean predicted values. airfl ow obstruction was defi ned as post-bronchodilator fev /fvc (post-b.d. fer) < . , hyperinfl ation as total lung capacity (tlc) > % predicted, and reduced d l co as < % predicted. aim to examine the gender-specifi c differences in adult spirometry, d l co and lung volumes, with a view to relating them to life-time respiratory risk factors. methods using the population-based tasmanian longitudinal health study (tahs) followed since , an asthma-enriched sub-sample was selected consisting of % ever with asthma, of whom half reported current asthma. measurement of spirometry, d l co (corrected for haemoglobin) and lung volumes were performed. data were analysed using the statistical upper and lower limits of normal of reference equations by nhanes iii, roca et al and quanjer et al. of the caucasian adults ( females), % completed all tests. mean age . years (range - ). elevated rates of airfl ow obstruction and hyperinfl ation were seen. signifi cantly higher proportions of females than males had reduced d l co and d l co/v a (p < . ). only . % (n = ) of females had a low d l co with low fev /fvc ratio, and . % (n = ) had a reduced tlc overall. there were no signifi cant gender differences in v a , tlc, or ever and current active smoking. males and females averaged over kg more than the mediterranean adults described by roca et al., however weight is not relevant to d l co in males. conclusion a higher percentage of middle aged females have a reduced d l co and/or d l co /v a, compared to males, with an increased rate overall. grant support nhmrc, australian postgraduate association. d chapman , , , j kermode , , , n brown , , , n berend , , , g king , , , background during bronchoconstriction, a deep inspiration (di) dilates the airways, which then re-narrow once tidal breathing is resumed. re-narrowing occurs faster in asthmatic subjects and may be due reduced airway distensibility. aim to determine the association between baseline airway distensibility and the rate of re-narrowing after di. methods eleven asthmatic and fi ve non-asthmatic subjects had baseline airway distensibility measured by forced oscillation technique (fot). after methacholine challenge, respiratory system resistance (rrs) was measured during min of tidal breathing, followed by di to total lung capacity (tlc) and passive return to normal tidal breathing. dilatation was measured as the decrease in rrs between end tidal inspiration and tlc, and re-narrowing as end-expiratory rrs immediately after di, as per cent rrs at end-tidal expiration before the di. distensibility is presented as geometric mean ± %ci and re-narrowing as mean ± % ci. results airway distensibility was reduced in asthmatic compared to healthy subjects ( . s − .cmh o − ( . - . ) vs. . s − .cmh o − ( . - . ), p = . ). dilatation did not differ between groups (p = . ) but re-narrowing was increased in asthmatic compared to healthy subjects ( ± % vs. ± %, p = . ). airway distensibility did not correlate with airway re-narrowing (r s = - . , p = . ). conclusion the increased re-narrowing after di in asthmatic subjects is not due to reduced baseline airway distensibility and may be due to increased shortening velocity of airway smooth muscle or reduced elastic recoil. supported by the nhmrc and the crc for asthma and airways. nomination nil. confl ict of interest no. c ng , , , s jenkins , , , n cecins , , p eastwood , , aim to evaluate the measurement properties of two accelerometers: the activpal and the stepwatch activity monitor (sam) in people with copd. methods the activpal and sam were attached to the anterior right midthigh and the right ankle, respectively (as per device recommendations). each participant performed walking tasks; at a self-selected slow speed and at a self-selected normal speed. at each speed, one walk was performed with a -wheeled walker (ww) and the other without. results participants aged ( ) years (fev = ( ) % pred; males) completed the study. the slow and normal speeds were ( ) m·min − and ( ) m·min − , respectively. agreement between steps recorded by the sam with steps counted during observation did not differ with speed or ww use (p = . ). the mean difference was steps·min − and the limit of agreement (loa) was steps·min − . agreement between steps recorded by the activpal with steps counted was worse at slow speeds (mean difference steps·min − with loa of steps·min − ) compared with normal speeds (mean difference steps·min − with loa of steps·min - ) (p = . ), but was not affected by ww use. both accelerometers detected the small difference in walk speed irrespective of ww use (p < . ). conclusions neither the accuracy nor responsiveness of either accelerometer was affected by ww use. in contrast to the activpal, sam was accurate at both speeds and therefore can be used to detect steps in people who walk very slowly during daily life. breathing and sleep, heidelberg vic., eastern health, melbourne vic., northern health, epping vic., and monash university, clayton vic. aim to document the care and pathways patients with copd travel at three metropolitan health services. methods data were extracted from data sets for patients attending the emergency department of the three hospitals with a diagnosis of copd over year. the three hospitals included a city-based tertiary/quaternary hospital and two smaller community hospitals. analysis was completed on similarities and differences in admission and referral rates, average length of stay, and discharge destination, standardized by age, sex and mode of transport to the emergency department. results there were inpatient separations and emergency department presentations for patients with copd. discharge patterns related to the designated role of the hospital, with the community hospitals discharging to % of patients directly home and the more specialized city hospital discharging % to other hospitals and % home. there were signifi cant differences in the admission rates for category and patients among the hospitals. we found unexplained variation in the acute average lengths of stay of . , . and . days. conclusions the analysis confi rmed some expected patterns based on the type of hospital, but also identifi ed unexplained variation that suggests that factors other than patient characteristics may be contributing to the variation in care pathways. aims to: ( ) determine which tests of exercise capacity relate to average daily energy expenditure (dee) and; ( ) quantify the intensity at which activities of daily living (adl) are undertaken in people with chronic obstructive pulmonary disease (copd). methods a study was undertaken in subjects with stable copd (mean, sd) aged ( ) years with an fev of ( ) % predicted ( males). measures were collected of distance walked during the six-minute walk test ( mwd) and incremental shuttle walk test (iswd) and peak rate of oxygen uptake during a cycle ergometry test (vo peak ). the sensewear armband® was worn during the waking hours for . ( . ) days to measure dee. the intensity at which activities of daily living were undertaken was expressed as a percentage of vo peak . results dee was associated with mwd (r = . ; p = . ), iswd (r = . ; p = . ) but not vo peak (r = . ; p = . ). stronger associations were observed between dee and the body weight-walking product for mwd (r = . ; p < . ) and iswd (r = . ; p < . ). the average intensity of adl was equal to ( %) of vo peak (range to %). conclusions mwd and iswd, but not vo peak were related to dee. as adl were performed at a high percentage of vo peak it may be more realistic to increase dee by increasing the frequency or duration, rather than the intensity of physical activity. in patients with copd, two mwts are recommended prior to commencing a pulmonary rehabilitation program (prp) to allow for a learning effect. aim to determine the characteristics of patients with copd in whom -minute walk distance ( mwd) did not increase on a second test. methods patients ( males) with stable copd (aged , to years) naïve to the mwt performed two tests ( minutes apart) prior to commencing a prp. patients were categorized according to their change in mwd with test repetition. results mwd was the same or decreased on the second test in patients ( %) (table) . in the remaining patients ( %), mwd increased by m ( %) ( % ci to m, to %). logistic regression analysis identifi ed fev (l) as the only signifi cant variable (p < . ) that predicted the absence of a learning effect in mwd with test repetition. conclusions some patients with severe copd may not require a practice mwt to achieve their maximum performance at a prp baseline assessment. ( ) years, with stable ipf were evaluated in this study. demographic data and measures of pulmonary function (spirometry, diffusing capacity for carbon monoxide, (dl co )), dyspnoea (baseline dyspnoea index, bdi), peripheral muscle force (isometric quadriceps force (qf) and handgrip force (hf)), functional exercise capacity ( -minute walk distance, mwd), limitation in daily activities (activities of daily living (adl) score), and health status (sf- ) were assessed. relationships between mwd and mrc grade, pulmonary function, qf, bdi and adl score were examined. results the number of subjects in mrc grades , , and was ( %), ( %), ( %) and ( %), respectively. pulmonary function, bdi, qf, hf, mwd, adl score, and sf- decreased signifi cantly with increasing mrc grade (all p < . ). moderate to strong correlations were found between mwd and mrc grade (r = − . ), dl co (r = . ), qf (r = . ), bdi (r = . ) and adl score (r = . ) (all p < . ). conclusions these fi ndings suggest that the mrc dyspnoea scale can be used to discriminate and classify subjects with ipf according to the severity of impairment and disability. ( ) year (mean, sd) completed two assessment sessions on separate days. on one day, they exercised twice to symptom limitation (tlim) on a treadmill. on the other day, they exercised twice to tlim on a cycle ergometer. the order of exercise modality was randomized between days. on both days, the only difference between the exercise tests was that bipap, titrated to patient comfort, was used during the second test. measures were made of; ) tlim and, ( ) the difference in dyspnoea, using borg scores, at tlim during the fi rst test and the equivalent exercise time during the second test (i.e. iso-time). results bipap increased tlim on the treadmill ( ( ) seconds; p = . ) but not the bike ( ( ) seconds; p = . ). the reduction in dyspnoea at iso-time on the treadmill and bike was similar being, ( ) and ( ), respectively (p = . ). conclusions bipap may confer greater benefi t in exercise tolerance exercising on a treadmill compared with a cycle ergometer in patients awaiting lung or heart-lung transplant. infection with rhinovirus (rv) is known to trigger acute exacerbations in subjects with asthma and these subjects also have increased susceptibility to the effects of rv. the mechanisms remain poorly understood, but appear to involve a host innate immune defect in the airway epithelium. aim we sought to determine in bronchial epithelial cells (becs) if oxidative stress in the form of exposure to cigarette smoke extract (cse), hydrogen peroxide (h o ) and eosinophil peroxidise (epo) results in impaired mitochondrial function and if this directly impairs signalling of rv infection through mda and alters the release of type i and type iii interferons (ifns). methods pbecs were grown to confl uence. cells were then exposed to cse ( %, no fi lter) or h o ( . mm) or epo. cells were then infected with rv -b (moi = ). virus replication was measured by cell titration assay. following infection, il- , cxcl- , cxcl- was measured using cytometric bead array and fl ow cytometry. supernatants and whole cell lysates were collected for ifn-β, bax and mda detection by western blot. ifn-λ and cytochrome-c was measured using conventional elisa. cell viability was assessed by annexin v-pe staining and fl ow cytometry. results rv infection alone induced cxcl- , il- , cxcl- and ifn-λ. pbecs treated with each of the oxidative stressors had increased cytochromec release and increased apoptosis. this mitochondrial dysfunction led to degradation of mda expression and resulted in specifi c suppression of cxcl- and ifn-λ. conclusions exposure of becs to an oxidative stress results in mitochondrial dysfunction in airway epithelial cells. this leads to defective antiviral signalling in the airway epithelium after infection with rv. introduction pleural infection is associated with high morbidity. prompt drainage is key, but pus is often loculated and thick making drainage diffi cult. based on promising animal studies, we hypothesize that intrapleural therapy with t-pa and dnase, which lyse adhesions and reduce fl uid viscosity respectively, can signifi cantly improve pus evacuation in pleural infection. methods consecutive patients with pleural infection were treated with standard antibiotics and intercostal chest tube (ict) drainage. additionally, t-pa mg and dnase mg (each in ml of . % nacl) were instilled intrapleurally via an ict twice daily for up to six doses. the ict was clamped for minutes after each instillation. patients were followed clinically and with serial cxr. opacity from pleural effusion was quantifi ed on chest radiographs. results eleven patients ( male; mean age ) were treated. nine effusions were associated with community acquired pneumonia, of these, eight were visibly purulent, fi ve were culture positive and the mean fl uid ph was . (range . - . ). ten patients ( %) were successfully managed conservatively and one patient required surgery. median hospital stay from fi rst intrapleural treatment dose to discharge was days (range - ). the median amount of fl uid drained in the hours preceding t-pa/dnase treatment was ml (range - ), and improved signifi cantly to ml (range - ) following two doses of treatment. this was paralleled by a signifi cant reduction in radiographic opacity by a mean value of % of the hemithorax (range - %). four patients showed an initial rise in crp following t-pa/dnase, but all patients had resolution of sepsis and signifi cant reduction in crp. there were no major complications. pleuritic chest pain requiring opioid analgesia developed in three patients. methods clinical data were collected using a standardized form for aboriginal children aged days -< months hospitalized with alri and enrolled in a rct of vitamin a/zinc supplementation were matched with data collected during a population-based study of who-defi ned primary endpoint pneumonia (who-p). sensitivities, specifi cities, positive and negative predictive values (ppv, npv) for these signs were compared between who-p cases and lobar pneumonia assigned by a respiratory paediatrician. in episodes of hospitalized alri, who-p was diagnosed in ( . %); the respiratory paediatrician classifi ed ( . %) as lobar pneumonia. the sensitivities of clinical signs ranged from a high of % for tachypnoea to % for fever + tachypnoea + chest-indrawing; the ppv range was % to %, respectively. higher ppvs were observed against the paediatric respiratory physicians diagnosis compared to who-p. conclusions clinical signs on admission are not useful in predicting who-p in this population, presenting challenges for future pneumonia research in this population. who-p may underestimate alveolar consolidation in a clinical context and its use in clinical practice or in research designed to inform clinical management in this population should be avoided. the incidence of tb in the non-indigenous australian population is uncommon at . cases per population . in this paper, we report three cases of pulmonary tuberculosis in young australian born, non-indigenous adults in the hunter new england area where marijuana possibly was a signifi cant risk factor in transmission and severity of disease. all three cases had severe cavitating disease at time of presentation. contact tracing from the fi rst case, a regular heavy marijuana user, identifi ed mantoux positive contacts, one of whom developed active pulmonary tuberculosis. all contacts, mainly young adult males, denied sharing marijuana with the index case. contact tracing from the second case identifi ed mantoux positive contacts, of whom use marijuana regularly and shared bongs (water pipes) with the index case. there were positive mantoux contacts of the third case, one of whom shared bongs with the index case. health professionals need to remain aware of the possibility of tuberculosis in groups with historically low incidence rates. marijuana bong smoking is possibly associated with transmission and severity of tuberculosis . introduction in , these previously well women survived and made a good recovery from severe pneumonia and acute lung injury after retrieval on ecmo. streptococcus pyogenes is an unusual cause of pneumonia in adults. case a -year-old veterinarian with a history of mild asthma presented with days of fever and respiratory symptoms. the diagnosis was confi rmed by a fourfold rise in the anti-streptococcal antibody. this was complicated by respiratory failure, septic shock, acute renal failure, severe pulmonary hypertension and bilateral parapneumonic effusions. despite maximal interventions she deteriorated. femoral venous-venous ecmo was initiated on day at the calvary mater hospital in newcastle by a retrieval team from royal prince alfred hospital (rpa), sydney. she was transferred kms on ecmo in a large multipurpose ambulance. she developed lung abscesses and recurrent pneumothoraces and she required a pleurodesis. she required days of ventilation and days of ecmo. three months later she was asymptomatic, with mildly restrictive spirometry and minor cxr change. case a -year-old offi ce worker with s pyogenes bacteraemia made a similar presentation to our institution. she was ventilated for days, ecmo was initiated by the retrieval team and continued for days. three months later she was asymptomatic with a normal cxr and pulmonary function tests. introduction the urinary pneumococcal antigen (upa) test has been shown to have superior sensitivity to other investigations in determining the aetiology of community-acquired pneumonia (cap), but there is very limited data on its performance in local populations. the aims of this study are to establish the prevalence of positive upa testing in patients admitted to hospital with cap, and determine its utility. secondary aims are to identify associations with positive testing, as well as to determine if a positive test infl uences clinical outcomes. methods the study is a prospective, single-centre study that is still recruiting. adult patients are included upon admission to hospital if they have the diagnosis of cap, as defi ned by new infi ltrates on chest radiograph along with consistent clinical features. clinical data including curb- score of severity, current and prior antibiotics, co-morbidities, mortality and length of hospital stay are recorded. results preliminary results show a positive test prevalence of / ( . %, % ci . - . %) amongst patients admitted with cap. overall prevalence of pneumococcal pneumonia is / ( . %, ci . - . %). patients with a positive upa result have a higher mean curb- score of . compared with . in those with a negative result (p = . ). . % of patients with a positive result were admitted to the intensive care unit, compared with . % those with a negative result (p = . ). conclusions the overall prevalence of positive upa testing in patients admitted to hospital with cap is low. preliminary data suggests that patients with positive results are more likely to have greater severity pneumonia and to require intensive care support. comparative data on length of stay, mortality, previous antibiotic use and specifi c co-morbidities has not revealed any statistically signifi cant differences between positive and negative groups. confl ict of interests no. s herath , c lewis , m nisbet , respiratory department, auckland city hospital, auckland, new zealand, and infectious diseases department, auckland city hospital, auckland, new zealand rhodococcus equi (r. equi), previously known as corynebacterium equi is a gram positive bacillus that is found in soil and causes infection in grazing livestock. it is infrequently isolated from clinical specimens. it is usually associated with human disease in immunocompromised patients and is an uncommon cause of infection in immunocompetent patients. infection is usually acquired by the airborne route with pneumonia being the most common manifestation but it can also be acquired orally or by direct inoculation. we present a case of pneumonia caused by r. equi infection in a year old male builder who presented with cough, dyspnoea and night sweats. r. equi was cultured from a transbronchial aspirate from a subcarinal lymph node. despite extensive investigation, no contributing host immune defect was identifi ed. the patient recovered after three months of antibiotic treatment, initially with intravenous vancomycin and meropenem followed by oral clarithromycin and rifampicin. although infections due to r. equi have been increasingly reported in immunocompromised patients, since there have only been cases described in patients where no associated host immune defect was reported. in this cohort, the median age at presentation was years (range - ) and ( %) patients were male. ten ( %) of these cases had pulmonary infection. two ( %) patients died and the remainder were successfully treated with prolonged antibiotics. r. equi is an uncommon cause of infection in humans and rarely occurs in patients where a host immune defect cannot be identifi ed. introduction recognition of pulmonary involvement in extra pulmonary tuberculosis (ep-tb) may be an important public health issue, as it has been estimated that patients with smear negative pulmonary tb (ptb) are responsible for % of new infections. usually, all patients with ep-tb have a chest x-ray but sputum cultures are requested only if there is an abnormality. methods in this retrospective clinical audit, we aimed to evaluate the percentage of ep-tb patients with ptb despite a normal chest x ray (cxr), and to explore any clinical characteristics of this group. clinical notes, microbiology and cxr reports were reviewed from consecutive patients presenting with ep-tb between and . results of patients with ep-tb, % were male and the mean age was (range to ). most patients were of asian ethnicity (n = , %). the commonest presentation of ep-tb was lymphadenopathy (n = , %), followed by pleural (n = %) and bone (n = , . %) disease. ep-tb was diagnosed by biopsy/excision of the ep site in the majority (n = , . %), and by sputum testing alone in ( . %). sputum cultures were performed in n = , ( %) overall, with n = ( %) being positive. there was higher infl ammatory markers in the sputum culture positive group (esr . vs. . , p = . and crp . vs. . , p = . ). the majority had cxr abnormalities (n = , %). in the group with normal cxr (n = ), ( %) had sputum cultures performed. of these, were culture positive and of these also + smear positive ( on immunosuppression, with cough). conclusion a small number of patients with ep-tb and normal cxr had pulmonary tb, of whom were smear positive. thus, induced sputum testing should be considered in patients with ep-tb even if cxr is normal. this may aid diagnosis and determine infectivity. ntm are normal inhabitants of environmental reservoirs including water. disease due to ntm has been increasing in qld. aim to document the presence of ntm in potable water in brisbane, to compare the species isolated during summer and winter and to relate this to the geographic distribution of patients with ntm. methods water samples ( l) were collected from routine collection sites in winter and sites in summer . samples were processed in triplicate as previously described. h subcultures were taken from positive specimens, dna extracted, followed by s rrna sequencing. patient addresses were obtained from the qld tb control centre database. aim to gauge the full impact of pandemic h n infl uenza across demographic groups in the northern territory, particularly indigenous and remoteliving individuals. methods we performed two cross-sectional serological surveys on specimens from residents of the northern territory, with specimens obtained from january to may (pre-pandemic) and specimens from september (post-pandemic). specimens were selected from among serum tubes collected from ambulatory outpatients. antibody titres were measured by haemagglutination inhibition against the a/california/ / reference virus. all specimens had available data for gender, age, and address, with indigenous status determined in . % of cases. results protective antibody levels, defi ned as a titre of or greater, were present in . % of pre-pandemic specimens and . % of post-pandemic specimens. the pre-pandemic proportion immune was greater with increasing age, but did not differ by other demographic characteristics. the post-pandemic proportion immune was greater among aboriginal and torres strait islanders and in younger age groups, but did not differ by gender or socio-economic index for area. however, the proportion immune was geographically heterogeneous, particularly among remote-living and indigenous groups. the northern territory-wide attack rate adjusted to age, region and indigenous status was . %. conclusions pandemic infl uenza disproportionately affected children and indigenous australians in the northern territory in . the proportion of specimens demonstrating post-pandemic immunity was particularly variable among indigenous and remote-living individuals. the kormp found asymptomatic aboriginal children (ac) had more hrv than asymptomatic non-aboriginal children (non-ac) in a longitudinal communitybased cohort study where infants had nasopharyngeal aspirates (npa) collected regularly from birth to years of age. aim to compare the frequency of hrv groups in asymptomatic ac and non-ac in the kormp. methods npa positive for hrv (n = ) from the npa previously tested for respiratory viruses, had viral rna extracted and reverse transcribed. hrv was detected and typed using a two-step pcr of the hrv ' utr, followed by dna sequencing for typing. chi-square analyses were used. results hrv was detected and typed in npa (from children; ac and non-ac), could not be typed and were not positive for hrv. ac had more hrv in summer and autumn than non-ac and were more likely to be co-infected with at least / bacterial species identifi ed. hrva, b & c were found in . , . and . % of hrv detected. hrvb & c were increased in infants exposed than not exposed to tobacco smoke in utero (hrvb; . vs. . %, p = . and hrvc; . vs. . %, p = . ). of the npa, hrv-a was detected more often in npa from ac than non-ac ( . vs. . %, p = . ), particularly at - months of age (p = . ) and during summer (p < . ). hrvb was detected more often in npa from ac than non-ac in autumn (p < . ). hrvc was detected as often in ac as non-ac in each season except summer. aim to determine whether interferon-gamma release assay (igra) can be effectively used for diagnosis of latent tuberculosis infection in a remote location. methods subjects were enrolled from the darwin centre for disease control tuberculosis clinic and were eligible if a tuberculin skin test (tst) of mm or greater had been recorded for any indication. igras were performed using quantiferon®-tb gold whole blood in-tube assay according to manufacturer's instructions. specimens were incubated and centrifuged at the local laboratory before refrigeration for transport. interferon assay was performed at the reference laboratory, over km away. results igras were performed, with patients ( %) recording negative results, ( %) positive and only one result ( %) indeterminate. negative, and therefore discordant, test results were more common in bcg vaccinated individuals. this effect was not limited to those with tst results of - mm, but was seen primarily in those with results of mm and above. conclusions these results are broadly comparable to fi ndings for igra use in less remote settings. in particular, our low rate of indeterminate results suggests that igra testing is feasible at a remote site after local processing. this approach could be considered for use in the northern territory tuberculosis control program. inhaled medications form the mainstay of drug treatment for patients with airways disease. effectiveness of therapy is dependent on the appropriate selection and prescription of drug and device, correct supply and adherence to therapy with an effective technique. patients frequently admit to acute medical wards both with acute exacerbations and for other co-morbidities eg heart failure or pneumonia. inpatient episodes provide an opportunity to review inhaled therapy however anecdotally add to patient confusion and introduce complexity (rational or ad hoc changes to inhaled drug, device, strength, dose or frequency). aim identify prescribing accuracy and effectiveness of patients' inhaler technique. describe any discrepancies between inhaled therapy: ( ) used prior to admission, ( ) prescribed for inpatient use, ( ) available at the bedside and ( ) administered, prior to and after implementation of an inhaler prescribing and administration guide. methods a single day audit of all inpatients on general medical wards was conducted october (review of medication charts and inhalers in patients' bedside lockers, brief questioning and direct observation of patients' inhaler technique. results compared to post implement of the 'prescribing and administering inhalers' tool (audit in december ). results from ( %) patients had inhalers prescribed, (mean: . prescriptions per patient). % of prescriptions were accurate ( % patient had no errors). discrepancies between used prior to admission and inpatient prescriptions were found in ( %) patients while those between inpatient prescriptions and available at the bedside were found in %. self-administration ('s') was noted on medication charts of ( %) patients, of whom had an ineffective inhaler technique. / patients has a spacer at the bedside with a further r prescribed metered aerosol inhalers. post-intervention differences in prescribing, supply, administration and technique errors will be discussed. conclusions a combination of errors and prescription discrepancies reduce the effectiveness of inhaled therapy for inpatients. confl ict of interest no. males (n (%) % ci) females (n (%) % ci) adm and bed days bmi, body mass index hrqol, health related quality of life chronic respiratory disease questionnaire; adm, admissions, mean (sd) uberculosis notifi cations in australia a cluster of tuberculosis associated with use of a marijuana water pipe the prince charles hospital foundation cc dobler , , gb marks , woolcock institute of medical research, the university of sydney, nsw, and department of respiratory medicine, liverpool hospital, sydney, nsw aim to determine the incidence rate and nature of adverse events in patients taking treatment for latent tuberculosis infection (ltbi). methods records of all patients who received treatment for ltbi at the chest clinic of a large tertiary hospital between / and / were reviewed. an adverse event was defi ned as any change in health status or side effect that led to treatment interruption or cessation. liver function tests were not performed routinely during follow-up, except when the patient was considered to be at an increased risk of developing hepatitis. results of patients in whom treatment for ltbi was initiated ( %) received isoniazid for months, ( %) received a combination of isoniazid and rifampicin for months, and the remainder were treated with different regimens. their mean (sd) age was ( ) years and % were male. nineteen patients ( . %) experienced an adverse event. seven patients developed a rash, four had lethargy and/or mood disorders, three had subclinical hepatitis, four experienced severe nausea, vomiting and/or other gastrointestinal symptoms and three had features of peripheral neuropathy. in eight patients who experienced an adverse event medication was temporarily ceased and then re-started without change; in four the treatment regimen was changed; and in seven the treatment was ceased completely. the risk of adverse events was not signifi cantly related to age, sex, drug regimen (single drug versus combination therapy) or baseline transaminase levels. conclusions in this cohort almost in patients on treatment for ltbi experienced an adverse event. although the adverse events were generally mild to moderate, this risk has to be taken into account when deciding whether to advise treatment for ltbi. introduction human rhinovirus (hrv) is the commonest cause of asthma exacerbations in children. pernasal aspirate (pna) is the gold standard for microbiological sampling but is invasive and distressing for children. studies have showed that less invasive swabs may be just as effi cacious. aim to test the hypothesis that hrv detection is as effi cient using nasal fl ocked swabs or washes and more comfortable, compared with pna in children with respiratory illnesses. methods children were recruited on presentation to the emergency department with respiratory symptoms. pna was collected from one nostril of all children recruited and nasal fl ocked swab (n = ) or wash (n = ) collected from the other nostril alternately. subjects rated the comfort of each sampling method to (least to most). viral rna was extracted and reverse transcribed. a two-step pcr of the hrv ' utr was used for detection, followed by sequencing for typing. results to date, children ( % male, mean age of . years) had paired samples taken. of these children, % (n = ) presented with a diagnosis of viral induced wheeze and % (n = ) had a hrv positive sample. compared with pnas, nasal fl ocked swabs were % ( of pna positive) effective in detecting hrv, whilst nasal washes showed % ( of pna positive) effi cacy. of the successfully typed samples, had hrva and had hrvc. nasal washes had a better comfort rating (mean . , n = ) than fl ocked swabs (mean . , n = ) and pnas (mean . , n = ). conclusion our fi ndings suggest that whilst nasal fl ocked swabs are an effective sampling method for hrv detection, nasal washes were more effective, being as effective as pnas and were the most comfortable. support nhmrc, pmh foundation. nomination nil. aim to describe the inpatients treated by a dedicated niv service. methods a retrospective audit of inpatients treated by the alfred niv service between january and june . the defi nition of niv included patients treated with cpap and bilevel positive pressure ventilation. results patients (age: ± years (mean ± sd), gender: % male) were treated with niv on occasions (repeat admissions patients). commonest indications for niv were osa (n = , %), acute exacerbations (ae) of copd (n = , %), acute cardiogenic pulmonary oedema (acpo) (n = , %) and post-lung transplantation (n = , %). treatment was delivered primarily in the respiratory ward (n = , %), cardiac ward (n = , %), icu (n = , %) and general medical ward (n = , %). episodes of cpap (mean pressure ± cmh o), osa and acpo made up % of those treated. seventy-two episodes of bilevel pap (mean ipap ± cmh o and epap ± cmh o), aecopd and weaning post-mechanical ventilation made up % of those treated. outcome data was available in a subgroup of patients with acpo (n = ) andaecopd (n = ). in the acpo group, patients ( %) improved and niv was ceased. three patients ( %) deteriorated and were intubated and patients ( %) were palliated. in the aecopd group, patients ( %) improved andniv was ceased or they were discharged on therapy. patients either deteriorated on niv or could not tolerate therapy, of these ( %) continued ward management and ( %) were palliated. conclusion the alfred niv service model has managed a large number of referrals across a range of diseases in a variety of wards. this is likely to have reduced demand on icu, hdu and respiratory ward beds. compared to the published literature, theoutcomes for acpo are worse than expected but comparable for aecopd. this may be explained by local referral patterns for acpo. we believe that our service model provides a viable means of administering niv to an ever expanding referral base. transitional & community service, the university of south australia, adelaide, sa , the university of adelaide, adelaide, sa, , the mary potter hospice, north adelaide, sa, , thoracic medicine, the royal adelaide hospital, adelaide, sa, , the royal district nursing service, wayville, sa , and the palliative care council of sa eastwood, sa introduction: the adelaide health service is in the process of developing a new and innovative model of copd community based care. a number of initiatives have informed this development including a recent research project examining the experiences of participants with end stage copd and their carers. a growing body of evidence indicates the importance of a palliative approach, however this often takes the form of referral to a palliative care service rather than a broader application of palliative principles in both specialist and primary care. methods: fifteen participants were interviewed twice at monthly intervals to explore their needs and the services they accessed. a series of focus groups with key service providers in sa was also undertaken. data were analysed to identify how hospital, specialist palliative care units and primary care services currently interface to meet identifi ed patient and carer needs. results: the current service model is episodic and reactive with services activated through the acute care system. our research has shown that, as copd advances, current models of care do not address the importance of supporting quality of life (including a focus on adls) and carers in their ongoing role. also emphasised was the lack of co-ordination of care, collaboration between service providers and communication -the basics of chronic disease management. conclusions the outcomes of this study will inform the development of a proactive, multidisciplinary model of care which is no longer reliant on tertiary care, but places primary care at the centre of the model. greater collaboration between respiratory, palliative and primary care services will provide an integrated approach, focusing on the needs of the patient and carer. aim long term conditions are prevalent in south auckland and impact on the individual, the community and the health system. as nurses living within this community, and employed by counties manakau district health board, our aim was to explore funding opportunities available through the pacifi c health team. lotumoui was established to improve health outcomes/behaviours for pacifi c populations. the church we attend has wide cultural diversity and had no knowledge of the programme and the support provided to make healthy changes within our community. methods firstly a health committee was formed within the church, having 'sold' our vision to the parish council. we launched the group by undertaking free blood pressure checks, followed by a 'walk the talk' project for the days leading into easter. baseline observations were taken and pedometers issued. results the parishioners who attend regular exercise sessions are reporting improved quality of life, exercise tolerance and reducing waist lines. bp parameters are also reducing. conclusions a dedicated health committee within a parish community, supported by the district health board can impact on changes in lifestyle by simple interventions. the investment by the pacifi c team will reap benefi ts for the individual and the health sector. confl ict of interest no. key: cord- -bqlf fe authors: rydell-törmänen, kristina; johnson, jill r. title: the applicability of mouse models to the study of human disease date: - - journal: mouse cell culture doi: . / - - - - _ sha: doc_id: cord_uid: bqlf fe the laboratory mouse mus musculus has long been used as a model organism to test hypotheses and treatments related to understanding the mechanisms of disease in humans; however, for these experiments to be relevant, it is important to know the complex ways in which mice are similar to humans and, crucially, the ways in which they differ. in this chapter, an in-depth analysis of these similarities and differences is provided to allow researchers to use mouse models of human disease and primary cells derived from these animal models under the most appropriate and meaningful conditions. although there are considerable differences between mice and humans, particularly regarding genetics, physiology, and immunology, a more thorough understanding of these differences and their effects on the function of the whole organism will provide deeper insights into relevant disease mechanisms and potential drug targets for further clinical investigation. using specific examples of mouse models of human lung disease, i.e., asthma, chronic obstructive pulmonary disease, and pulmonary fibrosis, this chapter explores the most salient features of mouse models of human disease and provides a full assessment of the advantages and limitations of these models, focusing on the relevance of disease induction and their ability to replicate critical features of human disease pathophysiology and response to treatment. the chapter concludes with a discussion on the future of using mice in medical research with regard to ethical and technological considerations. although the genetic lineages of mice and humans diverged around million years ago, these two species have evolved to live together, particularly since the development of agriculture. for millennia, mice (mus musculus) were considered to be pests due to their propensity to ravenously consume stored foodstuff (mush in ancient sanskrit means "to steal" [ ] ) and their ability to adapt to a wide range of environmental conditions. since the s, domesticated mice have been bred and kept as companion animals, and in victorian england, "fancy" mice were prized for their variations in coat color and comportment; these mouse strains were the forerunners to the strains used in the laboratory today. robert hooke performed the first recorded inquiry-driven experiments on mice in , when he investigated the effects of changes in air pressure on respiratory function [ ] . more recently, with data from the human genome project and sequencing of the mus musculus genome showing remarkable genetic homology between these species, as well as the advent of biotechnology and the development of myriad knockout and transgenic mouse strains, it is clear why the mouse has become the most ubiquitous model organism used to study human disease. in addition, their small size, rapid breeding, and ease of handling are all important advantages to scientists for practical and financial reasons. however, keeping in mind that mice are fellow vertebrates and mammals, there are ethical issues inherent to using these animals in medical research. this chapter will provide an overview of the important similarities and differences between mus musculus and homo sapiens and their relevance to the use of the mouse as a model organism and provide specific examples of the quality of mouse models used to investigate the mechanisms, pathology, and treatment of human lung diseases. we will then conclude with an assessment of the future of mice in medical research considering ethical and technological advances. as a model organism used to test hypotheses and treatments related to human disease, it is important to understand the complex ways in which mice are similar to humans, and crucially, the ways in which they differ. a clear understanding of these aspects will allow researchers to use mouse models of human disease and primary cells derived from mice under the most appropriate and meaningful conditions. in , the encyclopedia of dna elements (encode) program published a comparative analysis of the genomes of homo sapiens and mus musculus [ ] , as well as an in-depth analysis of the differences in the regulatory landscape of the genomes of these species [ ] . encode, a follow-up to the human genome project, was implemented by the national human genome research institute (nhgri) at the national institutes of health in order to develop a comprehensive catalog of protein-encoding and nonproteincoding genes and the regulatory elements that control gene expression in a number of species. this was achieved using a number of genomic approaches (e.g., rna-seq, dnase-seq, and chip-seq) to assess gene expression in over mouse cell types and tissues; the data were then compared with the human genome. overall, these studies showed that although gene expression is fairly similar between mice and humans, considerable differences were observed in the regulatory networks controlling the activity of the immune system, metabolic functions, and responses to stress, all of which have important implications when using mice to model human disease. in essence, mice and humans demonstrate genetic similarity with regulatory divergence. specifically, there is a high degree of similarity in transcription factor networks but a great deal of divergence in the cis-regulatory elements that control gene transcription in the mouse and human genomes. moreover, the chromatin landscape in cell types of similar lineages in mouse and human is both developmentally stable and evolutionarily conserved [ ] . of particular relevance regarding modeling human diseases involving the immune system, in its assessment of transcription factor networks, the mouse encode consortium revealed potentially important differences in the activity of ets in the mouse and human genome. although conserved between the two species, divergence in ets regulation may be responsible for discrepancies in the function of the immune system in mouse and human [ ] . certainly, the biological consequences of these differences in gene expression and regulation between human and mouse invite further investigation. the anatomical and physiological differences between model organisms and humans can have profound impacts on interpreting experimental results. virtually every biological process under investigation in experimental studies involves at least one anatomical structure. to aid in interpretation, many anatomy compendia have been developed for model organisms; the most useful organize anatomical entities into hierarchies representing the structure of the human body, e.g., the foundational model of anatomy developed by the structural informatics group at the university of washington [ ] . although an analysis of the myriad differences between mouse and human anatomy is beyond the scope of this chapter, a few of the most critical issues that have an impact on the interpretation of data from mouse experiments should be mentioned. the most obvious difference between mice and humans is size; the human body is about times larger than that of the mouse. size influences many aspects of biology, particularly the metabolic rate, which is correlated to body size in placental mammals through the relationship bmr ¼ Â mass ( . ), where bmr is the basal metabolic rate (in kcal/day). thus, the mouse bmr is roughly seven times faster than that of an average-sized human [ ] . this higher bmr has effects on thermoregulation, nutrient demand, and nutrient supply. as such, mice have greater amounts of metabolically active tissues (e.g., liver and kidney) and more extensive deposits of brown fat [ ] . furthermore, mice more readily produce reactive oxygen species than do humans, which is an important consideration when modeling human diseases involving the induction of oxidative stress (i.e., aging, inflammation, and neurodegeneration) [ ] . the lung provides an excellent example of the similarities and differences between human and mouse anatomy. similar to the human organ, the mouse lung is subdivided into lobes of lung parenchyma containing a branching bronchial tree and is vascularized by the pulmonary circulation originating from the right ventricle. there are a number of subtle variations in this general structure between species, i.e., the number of lobes on the right and left, the branching pattern, and the distribution of cartilage rings around the large airways, but the most important differences between the mouse and human lung are related to the organism's size (airway diameter and alveolar size are naturally much smaller in the mouse) and respiratory rate. moreover, there are important differences in the blood supply of the large airways in humans versus mice [ ] . specifically, the bronchial circulation (a branch of the high-pressure systemic circulation that arises from the aorta and intercostal arteries) supplies a miniscule proportion of the pulmonary tissue in mice (the trachea and bronchi) compared to humans; the majority of the lung parenchyma is supplied by the low-pressure, high-flow pulmonary circulation. in the mouse, these systemic blood vessels do not penetrate into the intraparenchymal airways, as they do in larger species [ ] . this difference, although subtle, has important ramifications regarding the vascular supply of lung tumors which, in humans, is primarily derived from the systemic circulation [ ] . these differences may also have profound consequences when modeling human diseases involving the lung vasculature. the adaptive immune system evolved in jawed fish about million years ago, well before the evolution of mammals and the divergence of mouse and human ancestral species [ ] . many features of the adaptive immune system, including antigen recognition, clonal selection, antibody production, and immunological tolerance, have been maintained since they first arose in early vertebrates. however, the finer details of the mouse and human immune systems differ considerably, which is not surprising since these species diverged million years ago [ ] . while some have claimed that these differences mean that research into immunological phenomena in mice is not transferable to humans, as long as these differences are understood and acknowledged, the study of mouse immune responses can continue to be relevant. research on mice has been vital to the discovery of key features of both innate and adaptive immune responses; for example, the first descriptions of the major histocompatibility complex, the t cell receptor, and antibody synthesis were derived from experiments performed on mice [ ] . the general structure of the immune system is similar in mice and humans, with similar mediators and cell types involved in rapid, innate immune responses (complement, macrophages, neutrophils, and natural killer cells) as well as adaptive immune responses informed by antigen-presenting dendritic cells and executed by b and t cells. however, due to the anatomical and physiological differences between these species as described above, divergence in key features of the immune system, such as the maintenance of memory t cells (related to the life span of the organism) and the commensal microbiota (related to the lifestyle of the organism), has arisen [ ] . similar to what has been discovered regarding the genetics of mice and humans, i.e., broad similarities in structure but considerable differences in regulation, there are a number of known discrepancies in the regulation of innate and adaptive immunity in mouse models of human disease mice versus humans, including the balance of leukocyte subsets, t cell activation and costimulation, antibody subtypes and cellular responses to antibody, th /th differentiation, and responses to pathogens (described in detail in table ). in addition to these differences in immune cell functions, the expression of specific genes involved in immune responses also differs, particularly those for toll-like receptors, defensins, nk inhibitory receptors, thy- , and many components of chemokine and cytokine signaling; additionally, differences between mouse strains are known to exist for many of these mediators [ ] . another important consideration when using mice to perform immunological research (with a view to translating these findings to human medicine) is the availability of hundreds of strains of genetically modified mice that have enabled exquisitely detailed studies on immune cell function, regulation, and trafficking. many of these strains involve the expression of inducible cre or cas that allow for targeted knockdown or overexpression of key immune function-related genes in specific cell types at specific moments in time. however, it is important to note that drift between mouse colonies has long been known to occur. in fact, a recent report described the fortuitous discovery of a point mutation in the natural cytotoxicity receptor (ncr ) gene in the c /bl cd . mouse strain, resulting in absent ncr expression. this mutation was found to have profound effects on the response of mice to viral infection, i.e., the mice were resistant to cytomegalovirus infection but more susceptible to influenza virus [ ] . this cautionary tale highlights the importance of understanding the genetic evolution of laboratory strains of mice, the effect of these genetic and immunological changes on mouse biology, and the impact on the translation of these results to human medicine. in addition to the differences between mouse and human genetics, physiology, and immunology highlighted above, several factors must also be taken into account when performing in vitro assays using isolated mouse cells and applying these findings to our understanding of human disease. particularly with regard to stem cell research, it should be noted that the telomeres of mouse cells are five-to tenfold longer than human telomeres, resulting in greater replicative capacity [ ] . there are also important differences in the regulation of pluripotency and stem cell differentiation pathways in humans and mice [ ] . moreover, there are considerable species differences in the longevity of cultured cells; for example, mouse fibroblasts are capable of spontaneous immortalization in vitro, whereas human fibroblasts become senescent and ultimately fail to thrive in culture [ ] . in summary, although there are considerable differences between mice and humans, constant improvement in the analytical techniques used to delineate these differences and their effects on whole organism and cell function have provided vital information and contributed to our understanding of both murine and human biology. experimentation employing mouse models of human disease will continue to provide key insights into relevant disease mechanisms and potential drug targets for further clinical investigation. however, several important considerations must be taken into account when selecting a mouse model of human disease, as described in the following section, using mouse models of human lung disease to illustrate this point. the two most salient features of a mouse model of human disease are the accuracy of its etiology (it employs a physiologically relevant method of disease induction) and its presentation (its ability to recapitulate the features of human disease). the relevance of any given mouse model can be judged on the basis of these two criteria, and there is considerable variation within mouse models of human disease in this regard. as a full assessment of the advantages and limitations of all currently available mouse models of human disease would be prohibitively long and complex, here we have elected to assess the accuracy of currently available models of human lung diseases, i.e., asthma, chronic obstructive pulmonary disease, and pulmonary fibrosis, focusing on the relevance of disease induction in these models and their ability to replicate critical features of human disease pathophysiology and response to treatment. the first and foremost notion when modeling human disease in mice is to acknowledge the species differences, which are significant [ ] . as described above, genetics, anatomy, physiology, and immunology differ between mice and humans, but despite these differences, mouse models of human disease are useful and necessary, as long as data interpretation is performed appropriately. an elegant example of differences between mice and humans that must be considered when designing a mouse model of human inflammatory lung disease is the key effector cell type in human asthma, i.e., mast cells. these leukocytes differ in granule composition as well as localization in the mouse and human airways [ ] . mice mostly lack mast cells in the peripheral lung [ ] , whereas humans have numerous mast cells of multiple subpopulations in the alveolar parenchyma [ ] . another example is anatomy: in contrast to humans, mice lack an extensive pulmonary circulation, which may have significant effects on leukocyte adhesion and migration, and subsequently inflammation [ ] . still, as long as these differences are taken into consideration, mouse models can be powerful tools in the discovery and exploitation of new targets for the treatment of human disease. the world health organization (who) defines asthma as a chronic disease characterized by recurrent attacks of breathlessness and wheezing, which may vary in severity and frequency from person to person. the disease is characterized by airway hyperresponsiveness, airway smooth muscle thickening, increased mucus secretion and collagen deposition, as well as prominent inflammation affecting both large and small airways [ ] . nowadays, it is recognized that asthma is not a single homogenous disease but rather several different phenotypes united by similar clinical symptoms [ , ] . only a few animal species develop asthma naturally, including cats and horses [ , ] , whereas mice do not [ ] . however, mice can be manipulated to develop a type of allergic airway inflammation, which is similar in many ways to the human disease, in response to different aeroallergens [ ] . importantly, these models are capable of recapitulating only the allergic type of human asthma and have less relevance for other types of asthma (i.e., endotypes induced by medication, obesity, and air pollution). as with many human diseases, asthma has a complex and multifaceted etiology, where environmental factors, genetic susceptibility, and microbial colonization all contribute; thus, it is important to take strain differences into consideration. generations of inbreeding have created mouse strains that differ not only in coat color and disposition but also from a physiological, immunological, and genetic perspective. different strains may be more susceptible to allergic airway inflammation or pulmonary fibrosis, whereas others are more or less resistant. choosing the right strain to model a specific disease or pathologic event is thus essential. the most widely used strains for models of allergic airway inflammation are balb/c and c bl/ . these strains differ regarding the type of immune response mounted to an inhaled allergen: c bl/ is generally considered a t h -skewed strain, whereas balb/c is regarded as a t h -skewed strain [ ] . due to their strong t h response, and subsequent development of robust asthmatic responses, balb/c has been commonly used to model asthma [ ] . however, most humans do not express such a strongly t h -skewed immune system, suggesting this strain may not be the best model of human disease; instead, c bl/ may be more suitable as immune responses in this strain are more similar to those of atopic human subjects [ ] . furthermore, as c bl/ is the most commonly used strain for the development of genetically manipulated mice, using these mice allows for very specific investigations into disease pathology; thus, this strain is increasingly used in models of human lung disease. besides the genetic differences in the mouse strains used in these models, the etiology (the method of disease induction) of commonly used models of asthma is highly variable. in humans with allergic asthma, environmental allergen exposure occurs at the airway mucosa; the immune response is coordinated in the bronchopulmonary lymph nodes, and the t cells, macrophages, and eosinophils recruited as part of this response travel to the lung where they mediate the cardinal features of asthma: airway inflammation, structural remodeling of the airway wall, and airway hyperreactivity [ ] . ideally, these features should be found in a physiologically relevant mouse model of asthma. however, for the sake of cost and convenience, early mouse models of asthma used the surrogate protein ovalbumin (ova) [ ] rather than an environmental allergen to induce an immune response, which also requires the use of a powerful t h -polarizing adjuvant such as alum delivered via the intraperitoneal route, followed by ova nebulization-a clear divergence from the etiology of human asthma [ ] . in terms of disease presentation, mice develop some hallmarks of asthma, including airway eosinophilic inflammation, goblet cell metaplasia, and increased airway smooth muscle density [ ] . after the cessation of ova exposure, most of the remodeling resolves, although some structural alterations remain up to month after the last challenge [ ] . based on these attributes, the ova model is primarily a model to investigate the initiation of inflammation, rather than the chronic progression and maintenance of inflammation [ ] . a clear advantage with the ova model is the number of studies where it is used; both the pros and cons are familiar. it is easy to find a suitable protocol, and the model is readily accessible and flexible regarding the number of sensitizations and allergen doses. the model is relatively easy to reproduce, as ova and different adjuvants are easily obtained. however, the resolution of remodeling following the cessation of allergen provocations is a disadvantage, as is the practical problem with the nebulization of an allergen-it ends up in the mouse's coat and is ingested during grooming, potentially resulting in systemic exposure (this is particularly relevant in models employing systemic, intraperitoneal sensitization). in addition, concerns have been raised against the use of adjuvants to induce the immunological response, as well as the clinical relevance of ova as an allergen, which have driven the development of more clinically relevant allergens and models [ ] . the common environmental aeroallergen house dust mite (hdm) extract is increasingly used to initiate disease in mouse models of allergic airway inflammation, as it is a common human allergen (around % of asthmatics are sensitized to hdm [ ] ) that evokes asthma attacks and other allergic responses in susceptible individuals. in addition, hdm has inherent allergenic properties, likely due to components with protease activity [ ] , so there is no need to use an adjuvant, thus improving the etiological similarity of these models with the clinical situation [ ] . in contrast to ova, prolonged exposure of hdm (up to weeks) induces asthma-like severe airway inflammation with prominent eosinophilia, severe hyperreactivity to methacholine, and robust remodeling of the airway wall [ ] , i.e., the presentation of chronic respiratory hdm exposure in mice effectively recapitulates the key features of human allergic asthma. importantly, the airway structural changes induced by chronic hdm exposure, such as increased collagen deposition, airway smooth muscle thickening, and microvascular alterations, persist for at least weeks after the cessation of hdm exposure [ ] , another commonality with human asthma in which airway remodeling is currently considered to be irreversible. thus, the advantages of using hdm as the allergen in mouse models of asthma are the clinical relevance of the allergen [ ] and the route of delivery via the respiratory tract. moreover, studies have shown that the type of inflammation and characteristics of tissue remodeling are relatively similar to those seen in human asthmatics [ , , ] . one disadvantage is the complexity of hdm extract; as a consequence of this complexity, variations exist in some components between batches, particularly regarding the content of lipopolysaccharide, so reproducibility in these studies may be problematic. with similarity to hdm, these models were developed to be as clinically relevant as possible, as many patients suffer from allergy toward cockroach allergen, molds, and other environmental irritants. a common feature of these allergens is their complex nature, as they commonly consist of a mix of different allergic epitopes and fragments. this complexity is most likely why the immunological reaction in mice is relatively similar to that seen in asthmatics [ ] . cockroach allergen (cra) is a common allergen, known to induce asthma in susceptible individuals; thus, it shares with hdm the advantage of being highly clinically relevant [ ] . cra induces peribronchial inflammation with significant eosinophilic inflammation and transient airway hyperresponsiveness, both of which can be increased by repeated administrations of the allergen [ ] . colonization of the airways with aspergillus fumigatus is the cause of allergic bronchopulmonary aspergillosis (abpa), a disease where the lungs are colonized by the fungus, but allergens from aspergillus fumigatus can also induce asthma similar to other allergens [ ] . the reaction to aspergillus allergens is robust, and often no adjuvants are needed to elicit inflammation [ ] . in addition to aspergillus, other fungi such as penicillium and alternaria can also induce asthma in humans and have been used to model disease in mice [ ] . a common difficulty with these allergens is the method of administration, as the physiological route is believed to be the inhalation of dry allergens; mimicking this route with a nebulizer introduces the risk of the animals ingesting the allergen and thus causing systemic responses [ ] . exacerbations of asthma are defined as the worsening of symptoms, prompting an adjustment in treatment, and are believed to be associated with increased inflammation in the distal airways. clinically, exacerbations are believed to be induced by infections (most common), allergen exposure, or pollutants, which can be modeled in different ways [ , ] : . infections with viruses and bacteria or exposure to proteins/ dna/rna derived from these microbes. . administration of a high dose of allergen in a previously sensitized animal. . exposure to environmental pollutants, such as diesel exhaust or ozone. modeling exacerbations adds a layer of complexity, as robust ongoing allergic airway inflammation needs to be established first, before challenge with the exacerbating agent. both the ova and hdm models are used in this respect, and in both cases chronic protocols extending for several weeks before triggering an exacerbation have been used [ ] . chronic obstructive pulmonary disease (copd) is characterized by chronic airway obstruction, in contrast to asthma where the obstruction is reversible (particularly in response to bronchodilator treatment). clinically, in copd, chronic bronchitis and emphysema can occur either separately or in combination. copd is almost always associated with either first-or secondhand tobacco smoking or in rare cases with a deficiency in the production of α antitrypsin (a serpin that prevents elastin breakdown as a result of neutrophil degranulation) [ ] . the etiology of copd is highly complex and is believed to develop after many years of smoking in combination with other known factors such as genetic susceptibility or environmental factors [ ] . in similarity to asthma, inflammation is a major component in copd, but the leukocyte profile is very different: the most prominent players in copd-related inflammation are neutrophils and, to some degree, macrophages [ ] . due to the complex etiology of copd, it is difficult to recapitulate all aspects of this disease in a single model, so in most cases, the aim is to induce copd-like lesions by exposing mice to tissue-damaging substances (usually cigarette smoke) or to mimic emphysema by the administration of tissue-degrading enzymes [ , ] . clearly, mice do not smoke cigarettes on their own, so to model copd by cigarette smoke (cs) inhalation, the mice need to be exposed to unfiltered cs in an induction chamber; moreover, in an attempt to better model the chronic aspects of copd, this needs to be performed for a prolonged period of time. mice are very tolerant to cs, but eventually (over a period of several weeks), cs induces pulmonary neutrophilic inflammation that is associated with some degree of tissue degradation and destruction [ ] . an important advantage of this model is the fact that cs is the actual irritant responsible for disease in humans, and mice develop several features similar to the clinical disease, making this model highly clinically relevant [ ] . a significant drawback is the self-limitation of the model-the pathological changes do not progress after the cessation of cs exposure [ ] . furthermore, the exposure time needed for mice to develop copd-like pathology is extensive, i.e., studies have shown that an exposure protocol of days per week for a minimum of months is needed to generate robust structural changes to the lung [ ]. the pathological image in copd is complex and varies greatly between patients, commonly encompassing chronic bronchitis and bronchiolitis, emphysema, fibrosis, and airway obstruction. although mice develop some of these symptoms when exposed to cs, they do not develop all the symptoms of human disease; thus, cs has advantages as a model but fails to mimic the complexity of the clinical situation and disease presentation [ ] . other models of copd rely on the administration of proteases (protein-degrading enzymes) that are believed to be involved in the pathology of this disease in a subset of patients, such as elastindegrading elastase. this approach mimics the emphysematous changes seen in copd, but the pathological process underlying tissue destruction is likely very different compared to the clinical situation [ ] , as very few patients show evidence of elastase dysregulation [ ] . however, if the aim of the study is to investigate the general effect of protease-induced tissue destruction and regeneration, then this is a highly relevant method [ ] . some studies on copd have also used genetically modified animals, such as mice overexpressing collagenase, which results in tissue destruction without inflammation or fibrosis with an end result fairly similar to the type of emphysema observed in copd [ ] . pulmonary fibrosis, the accumulation of fibrotic tissue within the alveolar parenchyma, is merely a symptom of disease, and the etiology of this pathology in humans varies greatly [ ] . the most enigmatic class is perhaps the idiopathic interstitial pneumonias, especially idiopathic pulmonary fibrosis (ipf). ipf is a debilitating and progressive disease with a grave prognosis, characterized by progressive fibrosis believed to reflect aberrant tissue regeneration [ ] . as the reason behind this defective repair is unknown, although a combination of immunological, genetic, and environmental factors are suspected, it is very difficult to model disease in a clinically relevant fashion [ ] . the most common method used to model pulmonary fibrosis in mice is administration of the chemotherapeutic agent bleomycin; this agent is known to cause pulmonary fibrosis in humans as well, but this may not accurately reflect the true etiology of most cases of human disease. the strain of choice is c bl/ , as it is prone to developing pulmonary fibrosis, whereas balb/c is relatively resistant, a feature believed to reflect the cytokine response following cellular stress and damage [ ] . bleomycin administration can be performed locally or systemically, producing very different results. the most common model of pulmonary fibrosis is a single intranasal or intratracheal administration of bleomycin, with analysis to weeks later. during this time, the drug causes acute tissue damage in a restricted area of the lung (where the solution ends up during administration), followed by intense inflammation in this area and subsequent fibrosis, which gradually resolves within weeks. however, if older mice are used, the fibrosis will persist longer than in younger mice, which is in accordance with clinical ipf, where the majority of the patients are years of age or older [ , ] . a great advantage of this model is how well-characterized it is. in addition, local administration is labor-effective, as only one administration is required and the result is highly reproducible. the fibrosis is robust, only affects the lungs, and the accumulation of extracellular matrix can be easily measured using standard techniques [ ] . furthermore, as it is used throughout the world, studies performed in different labs and by different groups can be compared relatively easily. unfortunately, the intense pulmonary inflammation may be lethal, and fatalities are to be expected with this model [ ] , representing an important ethical limitation. furthermore, fibrosis is heterogeneous-it develops where the bleomycin solution is deposited. the solution usually deposits within the central lung, a localization that is not in agreement with the clinical situation where fibrosis is located in the more distal regions of the lung parenchyma. in addition, the fibrosis that develops as a result of severe tissue damage is self-limiting and reversible, unlike what is observed clinically [ ] . the severe degree of tissue damage induced by bleomycin may in fact be more relevant for modeling acute lung injury (ali) or acute respiratory distress syndrome (ards). bleomycin can also be administered systemically, through intravenous or subcutaneous injection. in contrast to local administration, this route requires multiple administrations and is thus more laborintensive [ ] . some studies have described the usage of osmotic mini-pumps, where bleomycin is slowly administered over a short period of time, and then fibrosis continues to develop over subsequent weeks [ ] . irrespective of the route of delivery, systemic administration results in more homogenous fibrosis, affecting the entire lung through the pulmonary endothelium and persisting much longer than following local administration [ ] . the main advantages of systemic administration are that inflammation is limited, while the fibrosis is more apparent and displays a more distal pattern, all of which mimics the clinical situation relatively well. the multiple administrations allow for lower doses with each injection; this is less stressful to the animals and results in little to no mortality [ ] and is thus more ethically acceptable. a major disadvantage with this model is that it takes time for fibrosis to develop [ ] , which may be the reason it is used relatively scarcely, and thus the pathological development is less well-understood. in addition, as ipf is a local disease, local administration of the etiologic agent may better mimic the clinical reality [ ] . the administration of fluorescein isothiocyanate (fitc) induces focal inflammation, primarily involving mononuclear cells and neutrophils, and localizes in areas where the fitc solution is deposited [ ] . antibodies against fitc can be detected after week, and the fibrosis persists for up to months after instillation [ ] . the benefits of this model are mainly related to the persistent fibrosis that does not appear to be self-limiting, thus reflecting the clinical situation, and it is also very easy to determine which part of the lung has been exposed to fitc, as the molecule is fluorescent [ ] . it is also an advantage that both c bl/ and balb/c mice are susceptible and develop fibrosis following fitc administration [ ] . the disadvantages of this model include profound variability due to differences between batches of fitc, as well as in the method used to prepare the solution before instillation. importantly, given the characteristics of the etiologic agent used to induce this model of ipf, this model is considered a very artificial system with limited clinical relevance [ ] . adenovirus vectors have been used to overexpress the pro-fibrotic cytokine transforming growth factor (tgf)-β, which results in pulmonary fibrosis. as tgf-β overexpression in the lungs is known to be crucial in the development of fibrosis in humans [ ] , this model mimics an important feature of disease etiology. however, the delivery system has some drawbacks, as the virus itself initiates an immune response. moreover, adenoviruses display significant tropism for epithelial cells and rarely infect other cell types such as fibroblasts [ ] , which are the cells meant to be targeted in this model. as tgf-β has major effects on fibroblast biology, the main feature of this model is the effect of epitheliumderived tgf-β on fibroblasts and myofibroblasts, resulting in the deposition of ecm proteins and areas of dense fibrosis [ ] . an advantage of this model is the relatively low degree of inflammation, as well as what appears to be a direct effect on fibroblasts/ myofibroblasts [ ] , which is in accordance with the clinical situation (as we understand it today). silica administration induces a similar pathology in mouse lungs as in humans exposed to silica, and as is also observed in human silicainduced fibrosis, structural remodeling persists when administration is halted [ ] . following the administration of silica particles, fibrotic nodules develop in mouse lungs, with considerable resemblance to the human lesions that develop after exposure to mineral fibers [ ] . the fibrotic response is accompanied by a limited inflammatory response, and different pro-fibrotic cytokines such as tgf-β, platelet-derived growth factor, and il- are involved in disease development, which is in accordance with the clinical situation [ ] . another advantage is that nodules develop around silica fibers, and these fibers are easy to identify by light microscopy. the response in this model is strain-dependent, with c bl/ mice being the most susceptible. the main drawbacks are the time required to establish disease, i.e., - days, and the need for special equipment to aerosolize the silica particles. however, since the route of administration, the driving etiologic agent, and the resulting pathobiology are all similar to the characteristics of this subtype of pulmonary fibrosis [ , ] , the silica exposure model can be considered to have very good clinical relevance. what does the future hold for mouse models of human disease? medical research using experimental animals (not only mice but other animals including rats, guinea pigs, zebrafish, and fruit flies) has greatly contributed to many important scientific and medical advances in the past century and will continue to do so into the near future. these advances have contributed to the development of new medicines and treatments for human disease and have therefore played a vital role in increasing the human life span and improving quality of life. despite the acknowledged benefits of performing research using experimental animals, a number of considerations must be made before embarking on this type of research. of course, the financial aspects of conducting this type of work are an important limitation, as the costs of purchasing and housing mice can be prohibitive, especially when genetically modified mice and colony maintenance are required for the study. the practicalities of working with animals such as mice may also be an issue, as this type of work requires specialized facilities, equipment, and staff to ensure studies are carried out in a manner that is safe for both the researchers and the animals. moreover, as discussed in detail in this chapter, the relevance of the selected animal model to human disease must be carefully evaluated to ensure that these experiments provide robust results that are translatable to human health and disease. another important and demanding aspect of biomedical research using animals is the ethics of imposing pain and suffering on live animals. although there has been a considerable reduction in the numbers of animals used in research in the last years, animal research remains a vital part of biomedical research. however, no responsible scientist wants to cause unnecessary suffering in experimental animals if it can be avoided, so scientists have accepted controls on the use of animals for medical research. in the uk, this ethical framework has been enshrined in law, i.e., the animals (scientific procedures) act . this legislation requires that applications for a project license to perform research involving the use of "protected" animals (including all vertebrates and cephalopods) must be fully assessed with regard to any harm imposed on the animals. this involves a detailed examination of the proposed procedures and experiments, and the numbers and types of animal used, with robust statistical calculations to support these numbers. the planned studies are then considered in light of the potential benefits of the project. both within and outside the uk, approval for a study involving protected animals also requires an internal ethical review process, usually conducted by the research institution where the work is taking place, with the aim of promoting animal welfare by ensuring the work will be carried out in an ethical manner and that the use of animals is justified. additionally, the uk has a national animal use reduction strategy supported by the national centre for the replacement, refinement and reduction of animals in research (nc rs; london, uk). this consortium was established in to promote and develop high-quality research that takes the principles of replacement, refinement, and reduction (the rs) into account. replacement strategies often involve the use of alternative, non-protected species (e.g., zebrafish, fruit flies, flatworms) and in vitro correlates (two-dimensional cell culture or threedimensional organoids containing multiple cell types) to test hypotheses and assess the effects of therapeutic interventions. the main obstacle with studies on non-protected animals is the difficulty of accurately mimicking the complex physiological systems involved in human health and disease, as described in detail above. for example, the fruit fly drosophila melanogaster is an excellent model organism for studies on genetic diseases, aging, and pathogen-borne illnesses but may be less relevant for studies on complex lung diseases. importantly, model organisms such as fruit flies, zebrafish, and flatworms do not possess lungs, which somewhat limits the translatability of research on these animals in the field of respiratory disease. as such, it is likely that rodents will remain the model organism of choice for studies into lung disease for some time to come. there has been considerable progress recently in imitating single organs such as the liver, lung, and brain in vitro using multiple cell types and a physical scaffold. as an important advantage, these in vitro tests have replaced a large number of rodents in initial drug discovery experiments, while also speeding up the process [ ] . these studies still require further refinement and validation to establish them as suitable models for an entire organ; importantly, these in vitro organoids cannot take into account interactions between organ systems in complex, multisystem diseases such as copd. refinement involves selecting the most clinically relevant model for the disease available, informed by the discussion above on closely recapitulating the etiologic agent and disease pathobiology associated with clinical cases. another important factor is refining the management of pain. an assessment of the procedures used and the effects of the substance on the animal, as well as the degree of handling, restraint, and analgesia, are other important aspects of refinement. this standard of animal care is achieved through strict regulations and controls on how personnel are trained to carry out experiments on live animals. adequate training is an important aspect of refinement and should be reviewed and improved on an ongoing basis. moreover, refinement can be achieved by improving animal housing by environmental enrichment, e.g., providing a place for mice to hide in the cage and housing social animals such as mice in appropriate-sized groups. these simple changes can improve the physiological and behavioral status of research animals; this not only increases animal well-being but also contributes to the quality of the experimental results by reducing stress levels. the rs aspect of reduction focuses on the statistical power of experiments and by following the animal research: reporting of in vivo experiments (arrive) guidelines, originally published in plos biology in . these guidelines provide a framework to improve the reporting of research performed on live animals by maximizing the quality of the scientific data and by minimizing unnecessary studies. the arrive guidelines provide a checklist of aspects that must be considered in good quality research using live animals. the guidelines are most appropriate for comparative studies involving two or more groups of experimental animals with at least one control group, but they also apply to studies involving drug dosing in which a single animal is used as its own control (within-subject experiments). the guidelines provide recommendations on what should be considered when preparing to report on the results of experiments involving live animals, i.e., by providing a concise but thorough background on the scientific theory and why and how animals were used to test a hypothesis, a statement on ethical approvals and study design including power and sample size calculations, a clear description of the methods used to ensure repeatability, objective measurements of outcomes and adverse effects, and interpretation of the results in light of the available literature and the limitations of the study. in addition to the positive impact of the arrive guidelines on reducing the number of animals used in experiments, this checklist provides an easy-tofollow roadmap on what is required for good quality reporting of experimental results. in conclusion, the use of animals in research will continue to be an important aspect of medical research, and these procedures can be ethically justified provided the proper controls are in place. the benefits of animal research have been vital to the progress of medical science; abandoning these studies would have severe negative consequences on human health. by considering aspects such as the rs and the arrive guidelines in planning experiments involving live animals, the number of animals used and suffering of these animals for the benefit of human health can be minimized. this requires a strong regulatory framework such as that found in the uk and many other countries, as well an ongoing public debate on the advantages and limitations of animal experimentation. use of house mice in biomedical research the laboratory mouse a comparative encyclopedia of dna elements in the mouse genome principles of regulatory information conservation between mouse and human of mice and men: aligning mouse and human anatomies mouse models of human disease: an evolutionary perspective structure and composition of pulmonary arteries, capillaries, and veins angiogenesis in the mouse lung lung cancer perfusion: can we measure pulmonary and bronchial circulation simultaneously? origin and evolution of the adaptive immune system: genetic events and selective pressures the evolutionary basis for differences between the immune systems of man, mouse, pig and ruminants of mice and not men: differences between mouse and 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transforming growth factor-beta induces prolonged severe fibrosis in rat lung the ethics of animal research. talking point on the use of animals in scientific research key: cord- -ye wuwgd authors: moeser, a.; lange, c.; von lilienfeld-toal, m.; welte, t.; pletz, m. title: pneumonien bei immunsupprimierten patienten date: - - journal: pneumologe (berl) doi: . /s - - -x sha: doc_id: cord_uid: ye wuwgd pneumonia occurs frequently in immunocompromised patients and often shows a complicated course of disease when compared to immunocompetent persons. the type of pathogen involved is directly associated with the type of immunosuppression and includes a wide variety of pathogens. congenital and primary immunodeficiencies often appear during childhood. acquired immunodeficiencies are most commonly caused by immunosuppressive medication. the concept of immunosuppression can be extended to patients with copd or elderly patients because the variety of pathogens and specific features regarding frequency and course of the disease are similar to immunosuppressed patients. computed tomography can provide an indication of the pathogen and is superior to the chest x‑ray in this respect. blood cultures, antigen and pcr tests are non-invasive diagnostic tools for pathogen diagnostics. invasive tests include fiberoptic bronchoscopy and complete the diagnostic methods of identifying the causative pathogen. primäre oder angeborene immundefekte stellen eine heterogene gruppe genetischer erkrankungen durch eine oder mehrere defizienzen des immunsystems dar. das spektrum reicht von milden bis hin zu schweren formen der immundefizienz. zusätzlich zu rezidivierenden und chronischen infektionen leiden die patienten auch unter einem erhöhten risiko für autoimmunerkrankungen sowie für lymphoproliferative und maligne erkrankungen [ ] . neben einer positiven familienanamnese sowie gedeihstörungen im säuglingsalter kann man sich die wichtigsten merkmale der pathologischen infektanfälligkeit unter dem akronym "elvis" merken (. tab. ; [ , ] ). neben der infektanfälligkeit sind störungen der immunregulation charakteristisch für primäre immundefekte. diese lassen sich unter dem akronym "garfield" (granulome, autoimmunität, rezidivierendes fieber, ekzeme, lymphoproliferation, darmentzündung) zusammenfassen [ ] . angeborene immundefekte der t-zellen und kombinierte t/b-zell-immundefekte manifestieren sich bereits im säuglingsalter durch das auftreten schwerer infektionskrankheiten, z. b. opportunistische pneumonien (pneumocystis-jirovecii-pneumonie, pjp, . abb. ; cmv). isolierte immundefekte der b-zellen hingegen manifestieren sich durch den antikörper-nestschutz der mutter erst im kleinkindalter. einige dieser erkrankungen, z. b. "common variable immunodeficiency" (cvid), verlaufen sehr variabel und können auch erst im erwachsenenalter diagnostiziert werden. betroffene personen sind vor allem in den wintermonaten anfällig gegenüber bekapselten mikroorganismen (pneumokokken, haemophilus spp.). weitere angeborene immundefekte betreffen: granulozyten und makrophagen → pulmonale infektionen durch staphylokokken, aspergillus spp., salmonella spp. und burkholderia cepacia il- /ifn-γ-achse → vulnerabilität gegenüber mykobakteriellen erregern komplementsystem → infektionen mit bekapselten bakterien, z. b. streptococcus pneumoniae cme tab. in der klinischen praxis stellen erworbene immundefekte häufiger ein risiko für das auftreten von pneumonien bei erwachsenen dar als eine angeborene immundefizienz. zu den erworbenen risikofaktoren gehören die therapie mit immunsuppressiven medikamenten, hämatologische neoplasien, asplenie und splenektomie sowie die hiv-infektion. unter den immunsuppressiven medikamenten für die therapie der rheumatoiden arthritis und kollagenosen ist das risiko für hospitalisationen aufgrund von infektionen unter cyclophosphamid-therapie (rr , ) gegenüber azathioprin (rr ca. , ) und mtx (rr , ) deutlich erhöht [ ] . für kortikosteroide ist das risiko für hospitalisationen aufgrund einer pneumonie dosisabhängig bereits ab einer tagesdosis von mg erhöht, bei > - mg mehr als verdoppelt [ ] . zusätzlich ist im rahmen rheumatologischer grunderkrankungen unabhängig von der therapie eine prädisposition für infektiöse komplikationen, insbesondere der lunge, zu beobachten. bei hiv-patienten treten ambulant erworbene pneumonien unabhängig von der anzahl zirkulierender cd +t-zellen relevant häufiger auf. laut einem aktuellen review wird das risiko für eine bakterielle pneumonie durch eine hiv-infektion ca. um den faktor erhöht. bakterielle patienten mit copd sowie ältere patienten leiden häufiger unter pneumonien mit einem teilweise veränderten erregerspektrum, sie sind jedoch nicht von typischen opportunistischen infektionen betroffen. copd-patienten haben ein deutlich erhöhtes pneumonierisiko, hauptsächlich aufgrund struktureller parenchymveränderungen sowie aufgrund reduzierter lokaler und systemischer immunabwehr. frühere studien wiesen auch auf eine bedeutung einer therapie mit inhalativen steroiden hin, deren dosis allerdings in den letzten jahren deutlich reduziert wurde [ ] . s. pneumoniae ist der häufigste cap-erreger. pseudomonas aeruginosa tritt u. a. häufiger bei patienten mit langzeitsauerstofftherapie, chronischer lebererkrankung und systemischer langzeitsteroidtherapie auf [ ] . darüber hinaus stellt die copd einen möglichen risikofaktor für die invasive pulmonale aspergillose (ipa, . abb. ) dar. hierbei spielen sowohl die lokal beeinträchtigte immunabwehr als auch systemische risikofaktoren wie langzeitsteroidtherapie, malnutrition sowie wiederholte antibiotikatherapien eine rolle [ ] . weiterhin erhöht die inhalative steroidtherapie das risiko für infektionen mit ntm (or , ; [ ] ). Ältere patienten haben ein erhöhtes risiko für pneumonien, was auf eine reihe von ursachen zurückzuführen ist: neben einer bisher schlecht definierten altersassoziierten immunsuppression leiden viele ältere menschen an begleiterkrankungen bis hin zu einem pflegebedürftigen allgemein-und ernährungszustand. zudem sind aspirationspneumonien besonders häufig [ ] . die alterung des gesamten körpers (inklusive der epithelzellen der atmungsorgane und der zellen des immunsystems) prädisponiert zusätzlich für altersabhängige erkrankungen wie die copd oder die idiopathische lungenfibrose, die beide mit einer erhöhten infektionsrate einhergehen [ ] . dabei sind die kriterien für die gesicherte ipa mit eindeutigem histologischem oder zytopathologischem nachweis eines invasiven pilzwachstums im gewebe auch für andere grunderkrankungen zutreffend. die definition der wahrscheinlichen ("probable"/"putative") bzw. möglichen ("possible") ipa basiert auf der kombination von wirts-, klinischen und mikrobiologischen faktoren. dabei sind die o. g. eortc/msg-kriterien nicht auf kritisch kranke patienten auf der intensivstation bzw. copd-patienten übertragbar. für copd-patienten wurden adaptierte kriterien von bulpa et al. vorgeschlagen [ ] , für patienten auf der intensivstation sind die kriterien nach vandewoude hilfreich ( [ ] ; . tab. ). bei copd-patienten mit positiver aspergilluskultur aus den unteren atemwegen ohne exazerbation, bronchospasmus oder neue pulmonale infiltrate liegt eine kolonisation vor [ ] . der β-d-glukan-assay ist geeignet, ipa bei hochrisikopatienten zu diagnostizieren, ist jedoch nicht spezifisch für aspergillus (candida spp., fusaria spp, pjp) und nicht in jedem labor verfügbar. serum-und bal-galaktomannan sind bei bestimmten patientengruppen (hämatologische neoplasien, stammzelltransplantation) empfehlenswert, v. a. in form von serienscreenings (z. b. -wöchentlich) bei patienten ohne prophylaxe. sie werden jedoch nicht zum routinescreening bei patienten nach organtransplantationen oder chronischen granulomatösen erkrankungen empfohlen. die sensitivität von galaktomannan in der bal ist > % verglichen mit kulturellen methoden [ ] . ergänzend zu den o. g. methoden können pcr-assays aus blut oder bal hilfreich sein. allerdings wird der routinemäßige klinische einsatz noch nicht empfohlen, da nur wenige assays standardisiert und validiert sind. in blut und bal ist die sensitivität deutlich höher als bei der kultur, insbesondere in respiratorischen proben kann jedoch nicht zwischen kolonisation und erkrankung unterschieden werden. jedoch kann der hohe negative prädiktive wert der bal-pcr die diagnosesicherung der ipa orientiert sich für patienten mit schwerer immunsuppression an den eortc/msg-kriterien cme tab. kriterien für wahrscheinliche ("probable") bzw. mögliche ("possible") invasiven pulmonalen aspergillose (ipa) bei patienten mit chronischer obstruktiver lungenerkrankung (copd) oder kritisch kranken patienten auf der intensivstation (its) wirtsfaktoren a) patienten mit copd im funktionellen stadium iii oder iv nach gold-kriterien b) kortikosteroidtherapie ohne strikte angabe von gebrauch, dosis oder dauer a) neutropenie (< , × neutrophile/l) vor oder während des aufenthalts auf der its b) hämatologische oder onkologische neoplasie unter therapie mit zytostatika c) glukokortikoidtherapie (> mg/ tag clinical features of invasive bronchial-pulmonary aspergillosis ind critically ill patients with chronic obstructive respiratory diseases: a prospective study chronic respiratory disease, inhaled corticosteroids and risk of non-tuberculous mycobacteriosis pneumonia in the elderly (geriatric) population the impacts of cellular senescence in elderly pneumonia and in age-related lung diseases that increase the risk of respiratory infections severe pneumonia in the elderly: a multivariate analysis of risk factors pneumonia in immunocompromised patients pneumonien bei immunsuppression. radiol up date early detection of pneumonia in febrile neutropenic patients: use of thin-section ct community acquired respiratory virus infections in cancer patients -guideline on diagnosis and management by the infectious diseases working party of the german society for haematology and medical oncology ecil guidelines for the diagnosis of pneumocystis jirovecii pneumonia in patients with haematological malignancies and stem cell transplant recipients updated international consensus guidelines on the management of cytomegalovirus in solid-organ transplantation cytomegalovirus infection in the bone marrow transplant patient cytomegalovirus (cmv) dna quantitation in bronchoalveolar lavage fluid from hematopoetic stem cell transplant recipients with cmv pneumonia pulmonary infiltrates in non-hiv immunocompromised patients: a diagnostic approach using non-invasive and bronchoscopic procedures practice guidelines for the diagnosis and management of aspergillosis: update by the infectious diseases society of america revised definitions of invasive fungal disease from the european organization for research and treatment of cancer/ invasive fungal infections cooperative group and the national institute of allergy and infectious diseases mycoses study group (eortc/msg) consensus group invasive pulmonary aspergillosis in patients with chronic obstructive pulmonary disease clinical relevance of aspergillus isolation from respiratory tract samples in criticalle ill patients diagnostic value of bronchoscopy in patients with hematologic malignancy and pulmonary infiltrates diagnostic efficacy and safety of computed tomography-guided transthoracic needle biopsy in patients with hematologic malignancies ecil guidelines for treatment of pneumocystis jirovecii pneumonia in non-hiv-infected haematology patients key: cord- -d h a authors: provost, karin; desai, himanshu; sethi, sanjay title: infectious mechanisms regulating susceptibility to acute exacerbations of copd date: - - journal: smoking and lung inflammation doi: . / - - - - _ sha: doc_id: cord_uid: d h a acute exacerbations of copd (aecopd) are defined by clinical criteria, outlined in the global initiative for chronic obstructive lung disease (gold) guidelines [ ]. these include an acute increase in one or more of the following cardinal symptoms, beyond day to day variability: dyspnea, increased frequency or severity of cough and increased volume or change in character of sputum, which represent an acute increase in airway inflammation. the role of infection in the pathogenesis of copd, acute exacerbation and disease progression has been a clinical and research question for many years, and the pendulum has swung from infection as a major cause of acute exacerbation and copd (british hypothesis) [ ], to infection as an unrelated epiphomenon in acute exacerbation [ – ], and back again to infection as integral in the development of aecopd and likely an important contributor to copd progression [ – ]. upwards of % of aecopd are driven by infectious stimuli, with – % associated with bacterial infection and – % associated with acute viral infection, with some exacerbations having dual bacterial and viral causation [ ]. much of the advancement in our understanding of the role of infection is aecopd is due to the advancement of clinical and research tools that have allowed researchers to accurately characterize the microbial pathogens, and better understand the host-pathogen interactions (table ). acute exacerbations of copd (aecopd) are defi ned by clinical criteria, outlined in the global initiative for chronic obstructive lung disease (gold) guidelines [ ] . these include an acute increase in one or more of the following cardinal symptoms, beyond day to day variability: dyspnea, increased frequency or severity of cough and increased volume or change in character of sputum, which represent an acute increase in airway infl ammation. the role of infection in the pathogenesis of copd, acute exacerbation and disease progression has been a clinical and research question for many years, and the pendulum has swung from infection as a major cause of acute exacerbation and copd (british hypothesis) [ ] , to infection as an unrelated epiphomenon in acute exacerbation [ - ] , and back again to infection as integral in the development of aecopd and likely an important contributor to copd progression [ - ] . upwards of % of aecopd are driven by infectious stimuli, with - % associated with bacterial infection and - % associated with acute viral infection, with some exacerbations having dual bacterial and viral causation [ ] . much of the advancement in our understanding of the role of infection is aecopd is due to the advancement of clinical and research tools that have allowed researchers to accurately characterize the microbial pathogens, and better understand the host-pathogen interactions (table ) . with the more recent scientifi c acceptance of infectious organisms, both viral and bacterial, as signifi cant players in aecopd, the host response in patients with copd must also be questioned. the airways of patients with copd have significant infi ltration of infl ammatory cells (polymorphonuclear cells and cd + t lymphocytes) and much higher numbers of alveolar macrophages than are seen in healthy persons [ - ] . the nature of the infl ammatory infi ltrate suggests and supports the fi ndings of both viral and bacterial infections, with recruitment of immune cells pertinent to both the innate and adaptive immune response. despite the recruitment of appropriate effector immune cells, in many patients with advanced stage copd (gold iii-iv), there is persistent presence of pathogens in the airway, rather than eradication [ , ] , suggesting an impaired host response to infection. numerous studies have delineated impaired macrophage phagocytosis and cytokine secretion [ - ] , impaired humoral immune response to infection [ - ] and impaired t-lymphocyte responses [ ] . the mechanisms of this impaired responsiveness of both innate and adaptive immune cells to infection has not been clearly delineated, and remains a target of investigation. although the temporal association of bacterial presence in the airway and copd exacerbation was fi rst recognized in the early s, there was divergence away from bacterial causation of aecopd during the s and s related to several observations. there were no differences observed in sputum bacterial isolation rates (at a species level) in between stable state and exacerbations, and studies of immune response studies to bacterial pathogens and placebo controlled antibiotic trials showed inconsistent and contradictory results [ , ] . beginning in , multiple investigators began to recognize an effect of bacterial infection and colonization in stable copd [ , , , - ] , but a direct association with aecopd was not initially recognized. the bacterial isolation in these early studies was done predominantly by sputum culture, and as such, most pathogens isolated can be nasopharyngeal commensals in healthy adults, raising the issue of specimen contamination. in addition, the older studies could not differentiate among strains of a pathogenic species, assuming that all strains isolated from sputum over time were identical. advancing diagnostic techniques of bronchoscopy with protected specimen brushes and bronchoalveolar lavage, as well as molecular bacterial typing allowed identifi cation of bacteria ( streptococcus pneumoniae , haemophilus infl uenzae , moraxella catarrhalis , and pseudomonas aeruginosa and others at potentially pathogenic concentrations) in the distal airways in stable copd [ , , , , , - ] , with more severe gold stage disease being associated with identifi cation of pseudomonas. subsequent studies went on to associate colonization with more severe spirometric airfl ow obstruction [ ] . expanding on the recognition of bacterial colonization during stable copd, it was recognized that the prevalence of bacteria in the lower respiratory tract increased signifi cantly during aecopd as compared to stable copd, when sampled by bronchoscopy [ , - , ] . scientifi c advancement led to the recognition that changes in the overall numbers of potentially pathogenic bacteria in the airways between periods of colonization and acute exacerbation mattered less than the acquisition of a new strain of bacteria [ , - , , ] . acquisition of a new strain of bacteria ( h. infl uenzae, m. catarrhalis, s. pneumoniae or p. aeruginosa ) was associated with a greater likelihood of symptoms of an exacerbation, increased infl ammatory markers both locally and systemically (tnf-α, il- , il- , crp, neutrophil elastase) and development of a specifi c host immune response to the infecting pathogen [ , , , , , ] . although some authors have described a link between the presence of chlamydia penumoniae, mycoplasma pneumoniae and legionella infection and aecopd [ - ] , these studies measured single serologic titers rather than serologic conversion, and an additional respiratory pathogen was often identifi ed. studies using serologic conversion as a diagnostic criterion or molecular detection to identify the presence of atypical bacterial dna in sputa [ ] during aecopd indicate only a minor role of these bacteria in exacerbations, often with co-infection with typical bacterial pathogens ( table ) . the signifi cant role of bacteria in both pathogenesis of copd and aecopd, combined with recent data from improved microbiological detection techniques that the normal lung is not sterile, has led to recent research focused on understanding the microbiome of the lung in stable copd and during exacerbations. two groups recently published data using phylochip microarray analysis and quantitative pcr and pyrosequencing of the variable regions of the s rdna. the fi rst study identifi ed the bacterial diversity seen during severe aecopd requiring intubation in eight patients [ ] , noting signifi cant bacterial richness (as defi ned by the number of bacterial taxa detected) that waned with prolonged intubation. the common 'core' of bacterial taxa representing classifi ed bacterial families was identifi ed in all patients studied. this group included members of the pseudomonadaceae, enterobacteriaceae, campylobacteraceae and helicobacteraceae families, among others. the majority of the bacteria belonged to the proteobacteria phylum, with smaller contributions from firmicutes and bacteroidetes. the second study addressed the effects of cigarette smoke on the bacterial diversity in comparing healthy smokers to smokers with copd to non-smokers [ ] . the investigators demonstrated lung resident bacteria in all groups, and the dominant phyla were proteobacteria, firmicutes and bacteroidetes, as noted in the fi rst study. there was heterogeneity in the bacterial communities in the non-smoker, healthy smoker and mild copd patients, which was lost in the patients with moderate and severe copd. within each patient, geographic differences in bacterial heterogeneity were also noted, suggesting micro-anatomic differences in bacterial communities within the lung. whether the micro-anatomic, spatially distinct bacterial communities within the lung or the overall airway bacterial diversity represent mechanisms of disease progression or contribute to aecopd remains to be determined. respiratory tract viral infections have long been suspected as capable of inciting infl ammation suffi cient to generate an acute exacerbation of copd. the diagnosis of viral infection was initially done by cell culture and serologic methods, with more recent studies detecting viral infection by pcr in either sputa, bal or nasopharyngeal swabs, with the greatest recovery seen in sputa as compared to nasopharyngeal swabs [ , ] . the most commonly recovered viruses (varying in prevalence in various studies) in aecopd using the more sensitive pcr detection methods were infl uenza, rhinovirus, respiratory synctial virus (rsv), parainfl uenza, with the majority of infections due to rhinovirus. these viruses were also found in stable copd, and it is not clear if those fi ndings were subclinical infection or colonization, as there were no symptoms of active infection in the preceding days [ , , - ] . therefore, the presence of viruses in respiratory samples detected by sensitive techniques such as pcr may not always correlate with an acute infection and should be interpreted in its clinical context. though there are studies that suggest viral exacerbations are more severe or protracted than non-viral exacerbations [ , , ] , these studies did not study bacterial infection concurrently. virally-induced aecopd were associated with higher airway levels of il- as compared to aecopd in which virus was not detected [ , , ] . the presence of eosinophils in sputa samples recovered from aecopd of viral etiology also differs from the infl ammatory cells present during bacterial or non-infectious aecopd [ ] . in studies that have examined viral and bacterial infection simultaneously, presence of dual infections are associated with increased clinical severity of exacerbation [ ] . copd is now recognized as a state of chronic infl ammation, with periods of exacerbation marking acute increases in this infl ammation, both locally and systemically. both pathogenic and host factors determine the outcome of the acquisition of a bacterial strain. approximately half of the acquisitions of pathogenic bacteria lead to an exacerbation. pathogen virulence is likely to also play a role in determining which acquisitions lead to acute exacerbations. strains of nontypeable h. infl uenzae (nthi) that are associated with exacerbations have more effective adherence to airway epithelium and result in increased il- and il- secretion in in vitro and mouse models, as compared to those strains associated with colonization [ , , ] , and demonstrated higher levels of neutrophil recruitment to the airway [ , , ] . there are also signifi cant differences in the host response to different pathogens. patients with copd are able to eradicate moraxella catarrhalis and streptococcus pneumoniae from the airway quite well following exacerbations, most likely related to an effective immune response [ , ] . however, though antibody responses develop to nthi or pseudomonas following exacerbations, effective clearance is often not seen with these pathogens. the innate immune response is the most immediately responsive immune defense to the invading pathogen, and both anatomic and functional barriers (mucociliary clearance, epithelial tight junctions), as well as cellular immunity (recognition of invading pathogens via germline encoded pathogen recognition receptors (tlr, nod)) and soluble mediators (slpi, lysozyme, collectins). this initial innate response is multifaceted, including epithelial cells of the upper and lower airways, airway resident macrophages, dendritic cells and recruited polymorphonuclear cells. multiple authors have demonstrated an association between increased infl ammatory cytokines present in the airways of patients with copd and bacterial infection and colonization of the lower airway [ , , , ] . the dominant cytokines involved, il- , il- , tnf-α are also seen in aecopd due to infection, and suggest a common innate immune response at the time of exacerbation. the source of these cytokines may be from either the airway epithelium, after adhesion and invasion by bacterial or viral pathogens, or from the alveolar macrophage after recognition of pathogen associated molecular patterns (pamp's) and activation of toll like receptors (tlr). alveolar macrophages are also less able to phagocytose bacteria in patients with copd [ , , ] and have a less robust response to bacterial proteins, specifi cally omp and los of nthi [ ] , and are less able to clear apoptotic cells from the airway [ ] . both disease and cigarette smoke exposure contribute to this relative hypo-responsiveness, as alveolar macrophages from smokers who had ceased smoking have better phagocytic ability than those who continue to smoke [ , ] , and both were reduced relative to healthy controls. the ongoing presence of apoptotic cells in the airway may function as a source of endogenous ligand for inappropriate self-directed immune responses. normal mucociliary clearance (mcc) maintains the sterility of the tracheobronchial tree by effectively trapping and clearing inhaled and micro-aspirated particles, including infectious pathogens [ , ] smoking disrupts mcc by inducing structural abnormalities in the ciliary apparatus [ ] . other investigators have shown that impairment of mcc is universal, though variable in moderate-to-heavy smokers [ ] . development of chronic bronchitis and airway obstruction in smokers is associated with further deterioration in mcc [ , , ] . infi ltrating neutrophils likely contribute to mcc impairment, probably mediated by increased mucus production (mediated through proteolytic cleavage of tgfα and increased egf receptor (egfr) binding), reduced ciliary beating and reduced viscoelastic properties of mucus [ ] . tobacco smoke also has effects on airway levels of soluble iga. the literature has demonstrated confl icting results [ - ] , and though these trials were quite heterogenous, they supported the issue of the importance of secreted airway immunity. the more recent trials support geographic changes in the structural integrity of the lung, demonstrating localized areas of iga defi ciency associated with altered epithelial cell integrity, and reduced pigr expression (polymeric igg receptor), which is required for trancytosis of the structural components of the iga molecule from the basolateral to the apical surface of the epithelial cell. the reduction in expression of the iga transport system was supported by fi ndings of reduced total iga in the bal of patients with copd [ , ] . in contrast, the systemic iga response elicited in the bronchial mucosa seems preserved in copd, as demonstrated in copd patients with chlamydia pneumoniae infection [ ] . an increasing number of polypeptides with antimicrobial activity have been identifi ed in the airway surface fl uid that may play an important role in host defense in the respiratory tract [ - ] . one major group of these peptides is cationic polypeptides. these include lysozyme, which is lytic to many bacterial membranes; lactoferrin, which excludes iron from bacterial metabolism; defensins, which are released from leukocytes and respiratory epithelial cells; and the cathelicidin family of proteins, (of which only ll- is found in humans), which are present in specifi c granules of neutrophils and airway epithelial cells [ - ] . defi ciency in salivary lysozyme and sputum secretory leukocyte protease inhibitor (slpi) has been related to more frequent exacerbations [ , - ] . in patients with normal baseline slpi levels, these levels drop signifi cantly at the time of infective exacerbations, which return to normal after resolution of the exacerbation [ ] . lower levels of lysozyme and lactoferrin are noted with both colonization and infective exacerbations with nthi and moraxella catarrhalis , as compared to pre-acquisition levels [ ] . in contrast, ll- levels have been shown to increase in the presence of airway bacteria, both in states of colonization as well as infection, with greater increases during infective exacerbation, as compared to colonization [ ] . the divergent responses of the airway anti-microbial peptides during infective exacerbation underscores the fundamental importance of host-pathogen interactions. lower levels may be related to consumption in the face of infection, or a mechanism of bacterial evasion of immune clearance. the role of tobacco smoke specifi cally on the antimicrobial peptides has not been well studied, though murine models suggest that at least with regards to slpi, the presence of tobacco smoke was deleterious to the protease inhibitory activity [ ] . another important group of antimicrobial polypeptides are the collectins. surfactant protein-a (sp-a) and surfactant protein-d (sp-d) are collectins with broad spectrum antimicrobial activity that also promote phagocytosis of particulates by alveolar macrophages [ ] . concentrations of sp-a and sp-d are decreased in smokers, and are further decreased in association with emphysema [ , ] , a fi nding noted in both human and animal models [ ] . mannose binding lectin (mbl) defi ciency has been strongly implicated in infection and copd exacerbations, with an odds ratio of . for infective exacerbations, as compared to normal mbl levels [ ] . though considerable progress has been made in understanding the basic biology of these polypeptides, their role in response to respiratory infections and in the pathogenesis of copd is still poorly understood. pattern recognition receptors, of which the transmembrane toll-like receptors (tlr) and cytosolic nucleotide-binding oligomerization domain (nod) like receptors (nlr) and rig-i-like receptors predominate, are germline encoded receptors that recognize conserved sequences present on mutiple infectious organisms (pathogen associated molecular patterns, pamp). this non-specifi c recognition provides an immediate immune response (innate), without the initial requirement for effector memory responses (table ) . recent evidence suggests that tlr signaling is not restricted to microorganism particles but that tlrs recognize a wide variety of signals such as heat shock proteins [ ] , hyaluronan fragments [ ] , oxidative stress [ ] , and neutrophil [ , ] . this non-classical activation (or damage-associated molecular pattern (damp) activation), may explain the pro-infl ammatory state seen in cigarette smoking healthy controls. recent data defi nes a direct effect of cigarette smoke induced mmp and cxcl- secretion from epithelial cells that is mediated by activation of tlr [ - ] , and independent of lps present in the extract. this was neutralized by the addition of anti-oxidants, suggesting an oxidant stress induced activation of tlr . the classical pattern-recognition role for toll-like receptors through pamp recognition, are affected by both tobacco smoke as well as the development of copd, both on antigen presenting cells (dendritic cells and alveolar macrophages) as well as the airway epithelium. decreased levels of tlr and tlr on both airway epithelial cells as well as alveolar macrophages have been demonstrated in the presence of cigarette smoke as well as in patients with established copd [ - ] . it has been presumed in the past that lower levels of these tlr's contribute to impaired immune responses to pathogenic bacteria, but in the face of newer data demonstrating activation by reactive oxygen species present in cigarette smoke, these may as yet represent downregulation in an attempt to curb detrimental infl ammatory processes, though this has yet to be investigated. the presence of soluble forms of both tlr and tlr , as well as cd are an emerging fi eld of study, and how levels of these proteins factor into the lower levels of cell surface expression is not yet defi ned. natural killer cells are classifi ed as lymphocytes based on their morphology, their lack of antigen specifi c receptors puts their responses within the realm of the innate immune response [ ] . these cells have been found within the airways as well as the lung parenchyma, and act as cytolytic effector lymphocytes, inducing cell death in infected and structural cells in the lung [ , ] through secretion of perforins and granzyme b. increased numbers of cd -cd + nk cells and nkt cells (cd + cd + ) have been noted in the induced sputum of patients with copd as compared to healthy smokers or normal controls [ ] . the cd + cells of patients with copd expressed greater cytolytic activity, which inversely correlated with fev [ ] . dendritic cells are the canonical antigen presenting cells that link the innate and adaptive immune responses. dendritic cells act both locally upon antigen recognition (cytokine secretion) and in the lymphoid follicle, after migration from the primary site. dendritic cells function primarily by promoting differentiation of the cd + t helper lymphocytes, as well as cd + cytotoxicity [ ] . tobacco smoke has been associated with an expansion of dendritic cell populations in the lung. both cd a langerhans-like dendritic cells (subepithelial and bal) and myeloid dendritic cells are selectively recruited into the airways [ - ] , and demonstrate increased expression of co-stimulatory markers (cd , cd ) in smokers as compared to non-smokers [ ] . in patients with copd, all dendritic cell subsets (myeloid and plasmacytoid) demonstrated increased co-stimulatory molecule expression (cd , cd and cd ) that correlated with copd severity and was not explained by smoking alone [ ] . lung dendritic cells coordinate and co-localize with cd + t lymphocytes, and induce th and th responses [ , ] . the increased number and advanced maturation state of both myeloid and plasmacytoid dendritic cells in the airways of patients with progressive gold stage copd, suggests an enhanced antigen presenting capacity that develops with more severe disease. whether this develops in response to bacterial colonization and more frequent antigen recognition, leads to self antigen presentation (anti-elastin and anti-endothelin) and progressive auto-immunity or whether these mature dendritic cells are engendering a state of tolerance (via ctla- interaction with t lymphocytes) has not been defi ned. both the innate and adaptive immune responses are altered in copd and smoking. antigen specifi c effector memory responses, of both cell mediated and humoral arms of the adaptive immune response, are required to effectively clear established infection. these effector memory responses respond more slowly than the innate immune response, but are highly specifi c for the pathogens involved. the airways of patients with copd have been noted to retain signifi cant numbers of infl ammatory cells of both the innate and adaptive immune responses. of the adaptive immune response, effector lymphocytes of both cd + and cd + lineages have been documented in the airways, and subepithelial spaces, with a predominant cd + presence [ , , ] . numbers and cytolytic activity of the cd + cells increases substantially in patients with copd and progressive gold stage disease [ , ] . elevated levels of interferon gamma have been found in both the bal and intracellular staining of these lymphocytes, suggesting a th or tc effector phenotype. of the cd + lymphocytes found in the airways of patients with copd, there have been two sub-types identifi ed, both th and th cells [ - ] . lung lymphocytes of the th cd + lineage increase with severity of copd and emphysema and secrete more interferon gamma than control smokers [ ] . th cells are a newly recognized cd + lymphocyte subset and regulate tissue infl ammation by producing il- a and il- f [ ] . th cells regulate immunity to extracellular pathogens, but have also been associated with auto-immunity [ ] . il- a and il- f act on the airway epithelial cells to induce anti-microbial peptides, g-csf, gm-csf and chemokine secretion. recent data may support a geographically restricted role for the two forms of il- , with il- a localized to the infl ammatory hematopoietic cells in the sub-epithelium of small airways, and il- f localized to the lymphoid follicles and epithelial cells [ ] . b cells have been shown to be present in increased numbers in the large and small airways of patients with copd, organized into lymphoid follicles around the airways and in the parenchyma of patients with copd with advanced gold stage disease [ - ] . these follicles contain memory and naïve b cells, t cells, dendritic cells and follicular dendritic cells, which allow for t and b cell priming and clonal expansion [ , ] . the b and t cells in the balt are oligoclonal suggesting antigen specifi c immunity [ , ] . the antigens involved in this response have not been identifi ed, but leading candidates include microbial antigens, cigarette smoke-derived antigens, damage-associated antigens from apoptosis or extracellular matrix degradation and auto-antigens. despite recruitment of the appropriate effector cell populations, patients with advanced copd are not able to effectively clear bacterial infection and bacterial colonization results. whether the breakdown is solely at the level of the innate immune response, at the interface between the innate and adaptive immune response or due to derangements in the adaptive immune response alone, is not clear. it is likely that that with disease progression, there is progressive dysregulation of the immune response to invading pathogens, and downward spiral of infl ammation, infection, altered immune response, infl ammation and and tissue 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airway bacterial colonization in chronic bronchitis predisposing factors to bacterial colonization in chronic obstructive pulmonary disease bacterial colonization: pathogenesis and clinical signifi cance persistent colonization by haemophilus infl uenzae in chronic obstructive pulmonary disease bacterial infection in chronic obstructive pulmonary disease. a study of stable and exacerbated outpatients using the protected specimen brush new strains of bacteria and exacerbations of chronic obstructive pulmonary disease bacterial infection and the pathogenesis of copd moraxella catarrhalis, a human respiratory tract pathogen pseudomonas aeruginosa population biology in chronic obstructive pulmonary disease pseudomonas aeruginosa in chronic obstructive pulmonary disease relationship between airway colonization, infl ammation and exacerbation frequency in copd serological evidence of mycoplasma pneumoniae infection in acute exacerbation of copd serological evidence of legionella species infection in acute exacerbation of copd chlamydia pneumoniae infection in acute exacerbations of copd the role of atypical respiratory pathogens in exacerbations of chronic obstructive pulmonary disease a persistent and diverse airway microbiota present during chronic obstructive pulmonary disease exacerbations analysis of the lung microbiome in the "healthy" smoker and in copd respiratory viruses in exacerbations of chronic obstructive pulmonary disease requiring hospitalisation: a case-control study respiratory viral infections in patients with chronic, obstructive pulmonary disease infl ammatory response in acute viral exacerbations of copd role of viruses in exacerbations of chronic obstructive pulmonary disease detection of rhinovirus in induced sputum at exacerbation of chronic obstructive pulmonary disease acute exacerbations of chronic obstructive pulmonary disease are accompanied by elevations of plasma fi brinogen and serum il- levels haemophilus infl uenzae from patients with chronic obstructive pulmonary disease exacerbation induce more infl ammation than colonizers persisting haemophilus infl uenzae strains induce lower levels of interleukin- and interleukin- in h lung epithelial cells than nonpersisting strains bronchial microbial patterns in severe exacerbations of chronic obstructive pulmonary disease (copd) requiring mechanical ventilation outer membrane protein p of nontypeable haemophilus infl uenzae is a potent and selective inducer of human macrophage proinfl ammatory cytokines alveolar macrophages from subjects with chronic obstructive pulmonary disease are defi cient in their ability to phagocytose apoptotic airway epithelial cells mucus clearance as a primary innate defense mechanism for mammalian airways mucociliary clearance in the airways ciliary abnormalities in bronchial epithelium of smokers, ex-smokers, and nonsmokers mucociliary clearance in smokers regional impairment of mucociliary clearance in chronic obstructive pulmonary disease in vitro restructuring effect of human airway immunoglobulins a and lysozyme on airway secretions the elevation of serum iga in emphysema serum iga and secretory iga levels in bronchial lavages from patients with a variety of respiratory diseases chlamydia pneumoniae infection in patients with chronic obstructive pulmonary disease reduced epithelial expression of secretory component in small airways correlates with airfl ow obstruction in chronic obstructive pulmonary disease mucosal immunity in asthma and chronic obstructive pulmonary disease: a role for immunoglobulin a? bronchial secretory immunoglobulin a defi ciency correlates with airway infl ammation and progression of chronic obstructive pulmonary disease secretory iga and copd: a new kid on the block? innate immunity in the lung: how epithelial cells fi ght against respiratory pathogens collectins and pulmonary host defense antimicrobial polypeptides defensins: antimicrobial peptides of vertebrates cd -dependent lipopolysaccharide-induced beta-defensin- expression in human tracheobronchial epithelium effects of bacterial infection on airway antimicrobial peptides and proteins in chronic obstructive pulmonary disease the human cathelicidin ll- : a multifunctional peptide involved in infection and infl ammation in the lung cathelicidins, multifunctional peptides of the innate immunity activity of abundant antimicrobials of the human airway lysozyme secretion by submucosal glands protects the airway from bacterial infection killing of gram-negative bacteria by lactoferrin and lysozyme human neutrophil elastase inhibitors in innate and adaptive immunity anti-neutrophil elastase defense of the normal human respiratory epithelial surface provided by the secretory leukoprotease inhibitor changes in bronchial infl ammation during acute exacerbations of chronic bronchitis a possible role for lysozyme in determining acute exacerbation in chronic bronchitis evidence for excessive bronchial infl ammation during an acute exacerbation of chronic obstructive pulmonary disease in patients with alpha( )-antitrypsin defi ciency (piz) human slpi inactivation after cigarette smoke exposure in a new in vivo model of pulmonary oxidative stress structure, biologic properties, and expression of surfactant protein d (sp-d) effects of ageing and smoking on sp-a and sp-d levels in bronchoalveolar lavage fl uid decreased contents of surfactant proteins a and d in bal fl uids of healthy smokers alteration of pulmonary surfactant proteins in rats chronically exposed to cigarette smoke mannose-binding lectin gene polymorphism predicts hospital admissions for copd infections cutting edge: heat shock protein is a putative endogenous ligand of the toll-like receptor- complex hyaluronan in tissue injury and repair role of tlr- in the activation of nuclear factor kap-pab by oxidative stress in cardiac myocytes neutrophil elastase up-regulates cathepsin b and matrix metalloprotease- expression cigarette smokeinduced pulmonary infl ammation is tlr /myd and il- r /myd signaling dependent tlr protein contributes to cigarette smokeinduced matrix metalloproteinase- (mmp- ) expression in chronic obstructive pulmonary disease cigarette smoke regulates the expression of tlr and il- production by human macrophages toll-like receptor- mediates cigarette smoke-induced cytokine production by human macrophages expression of tolllike receptor is up-regulated in monocytes from patients with chronic obstructive pulmonary disease toll-like receptor expression is decreased on alveolar macrophages in cigarette smokers and copd patients epithelial expression of tlr is modulated in copd and by steroids, salmeterol and cigarette smoke innate or adaptive immunity? the example of natural killer cells immunologic aspects of chronic obstructive pulmonary disease enhanced effector function of cytotoxic cells in the induced sputum of copd patients the role of dendritic and epithelial cells as master regulators of allergic airway infl ammation acute effects of tobacco smoke on human airway dendritic cells in vivo lung dendritic cell expression of maturation molecules increases with worsening chronic obstructive pulmonary disease accumulation of dendritic cells and increased ccl levels in the airways of patients with chronic obstructive pulmonary disease dendritic cell subsets in primary and secondary t cell responses at body surfaces lung myeloid dendritic cells coordinately induce th and th responses in human emphysema t-lymphocytes in peripheral airways of smokers with chronic obstructive pulmonary disease cd (+) t cell subsets and chronic obstructive pulmonary disease t helper type -related cytokine expression is increased in the bronchial mucosa of stable chronic obstructive pulmonary disease patients identifi cation of cells expressing il- a and il- f in the lungs of patients with copd th cells in asthma and copd an immune basis for lung parenchymal destruction in chronic obstructive pulmonary disease and emphysema interleukin- and type helper t cells the nature of small-airway obstruction in chronic obstructive pulmonary disease cigarette smoke-induced emphysema: a role for the b cell? lymphoid follicles in (very) severe copd: benefi cial or harmful? bronchus-associated lymphoid tissue (balt) structure and function bronchus associated lymphoid tissue (balt) in human lung: its distribution in smokers and nonsmokers oligoclonal cd + t cells in the lungs of patients with severe emphysema key: cord- -qfnukav authors: nan title: irish thoracic society annual scientific meeting, ramada hotel, belfast: th– th november date: - - journal: ir j med sci doi: . /s - - -y sha: doc_id: cord_uid: qfnukav nan welcome to the irish thoracic society annual scientific meeting . we are delighted that the meeting has made a return to belfast this year and in honour of this we've put together a programme that we feel sure will make for a highly interesting and worthwhile experience. a central feature will be the presentation of original research in both oral and poster form, showcasing the wide range of important and innovative work being carried out throughout the island. the focus of this year's symposium is lung cancer and we are delighted to welcome a panel of leading international speakers who will share their knowledge and insights on this important topic. additional guest lectures on ciliary dyskinesia and asthma by distinguished specialists in both fields complete a varied and, we hope, highly stimulating programme. it is my pleasure to welcome you to the irish thoracic society annual scientific meeting . on behalf of the irish thoracic society i wish to thank dr. jackie rendall for her outstanding work in conjunction with the its office in organising this year's programme. thanks to her sterling efforts we look forward to a rewarding and stimulating meeting. has been a busy year for the irish thoracic society and i would like to take this opportunity to reflect on some of the highlights. february saw the publication of the inhale report, nd edition (ireland needs healthier airways and lungs -the evidence). compiled by the its in conjunction with dr neil brennan and dr terry o'connor, the report underlines the serious resource deficits that still exist in respiratory health-care. clearly a lot more work is needed in this area and the society will continue advocating for a respiratory strategy to tackle the imbalance. throughout the year the society has made representations on a broad range of issues including copd, tuberculosis, critical care services and lung cancer. with respect to the latter, the irish thoracic society lung cancer sub-committee has been working with the national cancer control programme towards the development of improved services for lung cancer care. the society has also been represented on the national copd strategy group and the national tb advisory committee and we look forward to the respective reports on this work. significant headway has been made in the area of education and research. the irish thoracic society boehringer ingelheim research fellowship, launched last year, has recently been awarded for a second time, promising valuable contributions to respiratory research from two very worthy projects in the coming years. our ability to communicate with members has improved dramatically thanks to a radical upgrade of the irish thoracic society website -www.irishthoracicsociety.com. this provides information on the society's activities and other relevant issues. many delegates will have become familiar with its facilities for on-line registration and submission of abstracts in the lead-up to the meeting and we trust they have proven convenient and user-friendly. password protected members areas are designed for more specialist interest content and we encourage members to help us develop these areas further as a resource for sharing information and discussion of issues. we recognise the important role our members continue to play in all these activities. in order to sustain our efforts, the continued support of members and the expansion of our membership base is vital. i would also like to take this opportunity to thank our partners in the pharmaceutical and medical equipment sectors. their support over the years has been central to the society's development and is now more important than ever -we look forward to continued collaboration in and beyond. dr. jj gilmartin, president, the irish thoracic society patient's with copd are known to have decreased levels of activity. this study looks at free-living activities as measured by the sense-ware armband to determine if there was a relationship with standard exercise field tests for this patient population. thirty one patients with copd were recruited: men (n = ), female (n = ). ethical approval and written consent was obtained. the senseware Ò armband was worn for seven consecutive days and distance on the shuttle walk test was measured. pearson's correlations were undertaken using spss version . the mean age of the study population was . yrs (± . ) with a mean fev % (± ). the shuttle walk test (swt) was m (± ). free-living activities as measured by; physical activity level (pal) of . patients low levels of activities in daily life as measured by the senseware Ò armband parameters correlates with the shuttle walk test making it a reliable outcome measure. the shuttle walk test can provide us with valuable insight into the patient's free-living activities and sleep pattern. international literature points to inequity in the provision of palliation in favour of patients with cancer despite the high mortality associated with copd. chronicity is associated with biographical disruption, loss and shifting relationships with healthcare professionals all of which may influence the nature of palliative care in advanced copd. a three phased project is underway aimed at developing palliative care for patients with copd. the purpose of phase one is to identify palliative care needs of these patients. a mixed method research design was employed for phase one involving health status measurement and qualitative interviews. inclusion criteria were those patients who were hospitalised for exacerbation of copd. the patient sample was mainly derived from one hospital over a one year period with a primary diagnosis of copd. gatekeepers were in place to protect confidentiality. data was collected using the st george's respiratory questionnaire(sgrq), hospital anxiety and depression scale (hads), and the medical research council (mrc) dyspnoea scale. in a nd round of interviews, the questions are open and semi-structured. interviews were undertaken in patients' homes. an integrated analysis is underway of data represented in different forms using spss and nvivo software. twenty six patients were interviewed. ages ranged from - yrs (mean = ). anxiety and depression scores averaged . and . respectively. scores of [ indicating moderate and severe levels were found in cases for anxiety and for depression. average sgrq scores = . indicating significant impact on quality of life. themes from qualitative data include a catastrophic diagnostic event along the illness trajectory, ambivalence towards opd visits and rigid daily routine to control breathlessness. issues emerged regarding recruitment, the construing of palliative care in copd and articulation of experiences of quality of care. conclusion: preliminary findings suggest significant disability and lay expertise; isolation; anxiety; impact on relationships and poorly articulated fears of the future. unmet palliative care needs are evident and challenge nursing to find appropriate ways of construing palliative care in copd. patients with severe copd are likely to have repeated exacerbations and early mortality. in ventilated patients herpes simplex virus- (hsv- ) is frequently identified and is associated with an increased mortality. we determined the frequency of hsv- in copd patients (stable and exacerbated) and if it was associated with disease severity and mortality. methods: stable and exacerbated copd patients were recruited. spirometry was performed. sputum was obtained and lysed by ddt. nucleic acids were extracted and specimens were tested for hsv- and gapdh using real-time pcr. results: one hundred and thirty six patients with exacerbations of copd and stable patients were recruited. hsv- was detected in % of copd patients during an exacerbation and % of stable copd patients. no significant differences in hsv- copy numbers were seen on comparison of these groups. detection of hsv- was associated with increasing copd disease severity, p \ . . the presence of hsv- during exacerbations was associated with increased mortality, p \ . , predominantly from respiratory causes, p = . . conclusion: hsv- is frequently detected in the sputum of copd patients. it is more commonly found in patients with severe airways disease and its presence during exacerbations is associated with increased mortality. pulmonary rehabilitation (pr) is associated with symptomatic and physiologic improvements in patients with copd. however, biologic effects on systemic inflammatory and profibrotic cytokines are unproven. thirty two patients with moderate or severe copd (age . ± . y, fev ± . % predicted) were recruited to a pr programme. cardiopulmonary exercise testing was performed before and after the programme. serum c-reactive protein (crp), tumour necrosis factor-alpha (tnf-a), interleukin- (il- ), transforming growth factor-beta (tgf-b) and oxidative burst were measured before exercise, at peak exercise and at recovery. there were statistically significant improvements in all domains of the st georges respiratory questionnaire, chronic respiratory disease questionnaire and hospital anxiety and depression questionnaire. there were no significant changes in crp or tnf-a associated with exercise or pulmonary rehabilitation. exercise was associated with a surge in oxidative burst. endurance exercise was associated with an increase in il- (p = . ) that was attenuated by pulmonary rehabilitation (p = . ). incremental exercise was associated with an increase in tgf-b (p = . ) that was attenuated by pulmonary rehabilitation (p = . ). demonstrating biological effects of pr has proved elusive to date. this is the first study to demonstrate modulation of both circulating inflammatory and profibrotic cytokines by pr in patients with copd. queen's university, royal victoria hospital, belfast city hospital, n. ireland beta cryptoxanthin is a pro-vitamin a carotenoid which is reported to be a good biomarker of fruit and vegetable intake. we hypothesised that levels of serum beta cryptoxanthin would be related to fev . in , men aged to years were recruited into the belfast arm of the prospective epidemiological study of myocardial infarction (prime). we describe the cross-sectional analysis of the men who had a valid spirometry trace and plasma sample at year follow-up. beta cryptoxanthin levels were measured using hplc analysis. fev values at years were modelled using simple linear regression, and adjusted for covariates. serum beta cryptoxanthin levels were positively correlated with fev (r = . , p \ . ). for each nanomole per litre increment in serum beta cryptoxanthin levels, fev was . mls greater. following adjustment for the covariates, for each nanomole per litre increment in serum beta cryptoxanthin levels, fev was . mls greater ( %ci . to . , p \ . ). serum beta cryptoxanthin levels are positively correlated with fev . this suggests that in this population a moderate increase in serum beta cryptoxanthin levels (achievable by a modest increase in dietary intake of fruit and vegetables) may have a protective effect on lung function. the study was undertaken to evaluate organ utilization in the republic of ireland. a retrospective review of potential donors from january to august was performed. donors organ were selected according to criteria set by the international society of heart and lung transplantation (ishlt), abo group compatibility and predicted tlc. this included a donor age \ years old, a satisfactory history, a normal chest radiogram, arterial blood gases (abg) of [ kpa ( mmhg) (fio of % and a peep of ). potential offers for organ donation occurred. the median donor age was years (range - ), the mean period of mechanical ventilation was days (range [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . sixty percent ( offers) were declined on the basis of ishlt criteria, % were declined because of age, % due to poor blood gases, % due to abnormal chest x-ray and % because of chest trauma. sixty-three offers were evaluated at the donor site. five percent ( offers) were excluded because of size and hla crossmatch constraints, these were offered to uk transplant. lungs ( . %) were successfully transplanted. organ donation in republic of ireland is high ( per million population), however lung utilisation is low. the pathway to increase number of lung transplantation may include a framework for optimising donor physiology. the use of endoscopic ultrasound with fine-needle aspiration (eus-fna) is well established in diagnosing and staging non-small cell lung cancer with positron emission tomography (pet) positive posterior mediastinal lymph nodes. the sensitivity of eus-fna ranges between and %. it is less invasive and has lower complication rates when compared to surgical staging of mediastinal nodes. this study aims to describe our initial experience of eus-fna in lung cancer. eus-fna was used prospectively for the assessment of pet positive mediastinal lymph nodes between january and july . when eus-fna did not show malignant invasion, a confirmatory mediastinoscopy was done. endpoints were performance of eus-fna, morbidity and length of hospital stay. patients underwent eus-fna during the study period for both diagnosis and staging. patients had positive lymph node invasion and had no evidence of malignant invasion on eus-fna. negative cytology on the latter was confirmed on mediastinoscopy giving eus-fna a sensitivity of % for the study period. it upstaged the disease in patients. eus-fna is reliable, non-surgical tool for mediastinal staging. it reduces the need for surgical staging procedures in lung cancer patients with suspected mediastinal involvement. the limitation of this study is the poor documentation of the lymph node stations that were sampled. the role played by the innate immune system in determining survival in non-small-cell lung cancer (nsclc) is unclear. the aim of this study was to investigate the prognostic significance of cytotoxic t-lymphoctye infiltration in nsclc. immunohistochemistry was used to detect cd + t-lymphocytes in the tumor islets and tumor stroma in patients with surgically resected nsclc. quantification of immune infiltration was performed using a novel automated image analysis algorithm. univariate cox regression analysis, kaplan-meier analysis and the log-rank test were used to illustrate differences in overall survival according to the expression of tumour to stroma lymphocyte infiltration ratio. lymphocytes were detected in both the tumour islets and stroma in all patients. we used the median of tumor:stroma cd + infiltration ratio as a threshold to dichotomise patients to either high or low infiltration rate. results showed that those with a higher intratumoral lymphocyte infiltration had a significantly better survival compared to those with a low tumour/stroma infiltration ratio (p \ . ). microlocalization of infiltrating cytotoxic t-lymphocytes is a powerful predictor of outcome from surgically resected nsclc. the biologic explanation for this and its implications for the use of adjunctive treatment require further evaluation. . ebus-tbna for lung cancer -initial irish experience accurate mediastinal staging is essential in lung cancer patients under consideration for surgical resection. compared to mediastinoscopy or l anterior mediastinotomy (the gold standard), ebus-tbna is less invasive and may be carried out during diagnostic bronchoscopy, offering the potential for one-stop diagnosis and staging. ebus commenced in sjh in mid . we retrospectively analysed the first cases, ( %) of whom had tbna. patients with known or suspected lung cancer had ebus-tbna of n glands. cytology was positive for malignancy in / ( %). in the patients where cytology was negative, had no further follow up. of the other , only were proven node positive, but were confirmed node negative at mediastinoscopy/surgery and had resolution of nodes at repeat ct. therefore, in these patients ebus-tbna had a negative predictive value of %, sensitivity % and overall accuracy %. in patients with primary paratracheal mass, ebus-tbna was positive in all . of a total lung cancer cases where ebus-tbna was positive, this was the only positive sample in ( %). in % of patients ebus-tbna obviated the need for more invasive sampling of the mediastinum-this is one-stop diagnosis and staging. the national patient safety agency (npsa) (may ) highlights the role of ultrasound guidance for pleural drain procedures. we review our practice from a district general hospital. pleural studies were identified from the hospital pas and the radiology database. case notes of those who had their effusions drained by catheter were studied. patients (m:f : ; age - [mean . ]) had drains placed in the period august through july . were in patients; electively admitted for the procedure and remained an outpatient. ( %) drains were sited under ultrasound guidance, ( %) placed on ward ( of these marked in ultrasound) and ( %) sited in ct. patients had single drain placement, had drains; had drains and patient had drains. ( %) drains were placed by career radiology staff, ( %) by ward based staff. consent was documented on ( %) occasions. ( %) drains were flushed regularly as instructed by radiologist. average time in situ was days (range - days). ( %) patients were discharged home with drains in situ. patients died with drains in place. drain removal was performed by hospital ward staff. we conclude that most drain placements conform to npsa recommendations. consent is poorly documented. this will be addressed by implementation of a chest drain management chart. protocol for the care of pleural-sited catheters has been written. ultrasound is more sensitive than clinical examination or chest x-ray for determining the presence of pleural fluid and helps guide thoracentesis. we report our initial experience with chest ultrasound examinations performed at the bedside by the respiratory consult service for assessment of pleural effusion. ( %) of referrals were from the oncology/haematology service, ( %) from other medical teams and patients from general surgery. on ( %) of ultrasound examinations pleural fluid was detected and drainage was performed. in / ( %) fluid was drained by aspiration alone and in the remaining ( %) a seldinger chest drain was placed. patients ( %) had malignant or paramalignant exudative effusions ( with lung primary; with metastatic cancer from other sites and with lymphoma), ( %) had parapneumonic effusions and there were transudates, hemothorax and unexplained exudates. the procedure was well tolerated by all patients. one patient had a small post-aspiration pneumothorax on chest x-ray that required no further intervention and there was one drain misplacement. ultrasound is safe, portable and sensitive for detection of pleural fluid. it can be used at the bedside by respiratory physicians to guide management of pleural effusion. in an effort to standardise treatment of primary spontaneous pneumothorax (psp) and secondary spontaneous pneumothorax (ssp), the british thoracic society (bts), in , published the first evidence based guidelines for management of this condition. the objective of this audit was to assess compliance with the bts guidelines in amnch. retrospective hipe data, chart and radiology review of all spontaneous pneumothoraces admitted to amnch during . there were spontaneous pneumothoraces admitted to hospital in the year studied ( psp's and ssp's). of the psp's: mean age was . years; male:female ratio was : ; were classified as large and as small; attempted aspiration; intercostal drains were inserted with an average drain time in situ of days; mean drain calibre was fr. of the ssp's: mean age was . years; male:female ratio was : ; underlying pulmonary disease was copd in and cystic fibrosis in ( patients); were classified as large and as small; none were aspirated; intercostal drains were inserted with an average drain time in situ of days; mean drain calibre was fr. conclusion: bts guidelines are not being adhered to in amnch. in particular, aspiration, which is the recommended first line treatment in psp, is an underutilised therapeutic procedure. on average, the calibre of intercostals drain used was too large and not in keeping with the guidelines which recommend initial placement of small calibre ( - fr) drains. it is important to note that our data reflects patients admitted to hospital, and does not include patients managed and discharged from the emergency department. penetrated chest trauma is potentially fatal if not promptly addressed. we aim to review the incidence, demographics and the outcome of patients with napct who attended a single level-iii trauma centre. we conducted a retrospective study of all napct's presented to cork university hospital between - .our definition of napct is non accidental injury of chest involving sharp objects penetrating skin and muscular layers with or without injury to deep structure above the level of the diaphragm requiring hospital admission. patients with napct wounds were admitted to c.u.h from january to december . there were females ( . %) and males ( . %) with a median age of years (range - ). the average length of stay in hospital was days.the highest incidence was . / population (n = ), which was in . there was a decreasing trend in the following nine years. the incidence in was . injuries / population (n = patients). the incidence of napct's was low and the annual incidence is decreasing over the last years. young men were the commonest victims. pleural infection is a difficult management issue with approximately % patients requiring surgical intervention and a % mortality rate. early diagnosis and appropriate therapy is vital to reducing morbidity, mortality and health care costs. this is an audit of the management of pleural infection in the ulster hospital from february to april as per bts guidelines. pleural infection was diagnosed as pleural fluid with ph \ . , ldh [ iu/l, glucose \ . mmol/l. eight patients were identified, ( . %) male with a mean (sd) age (± ) years. all patients had pleural fluid sampling within hours of suspected infection. all patients had chest drains inserted with median (iq range) duration of drainage ( - ) days. positive bacterial culture from pleural fluid was obtained in ( %) patients (haemophilus influenzae, enterococcus) and from sputum in ( . %) patients (h.influenzae, coliforms, klebsiella). antibiotic therapy was as per bts guidelines. median (iq range) hospital stay was ( - ) days while surgical intervention was required in ( . %) patients. one patient died at day from a non-respiratory complication. this audit demonstrates appropriate management of pleural infection but shows that pleural infection remains a difficult management problem with significant morbidity and mortality. twenty-two patients died awaiting lung transplantation. the highest mortality rate was among those patients with idiopathic pulmonary fibrosis n = . the mode of death was acute exacerbations of ipf. cf patients, emphysema patients and sarcoid patient, patient with bronchiectasis died awaiting lung transplantation. these data indicate that the mortality rate of patients awaiting lung transplantation is highest amongst patients with idiopathic pulmonary fibrosis suggesting that early referral on the basis of a gas transfer less that % predicted as per international guidelines should be considered. approximately lung cancers are diagnosed annually in northern ireland, however despite recent advances in the management of this disease little impact has been made on survival rates . the short interval from diagnosis to death and the complex problems that are a reality for many of these patients make it imperative that health care professionals gain a greater understanding of the experiences of those living with this disease. this qualitative study aimed to explore the experiences of patients and carers living with a lung cancer diagnosis within a northern ireland context. a secondary aim was to describe participants' experiences of service delivery in order to identify any areas for improvement. a semi-structured in depth interview process was used and a purposive sample of participants was identified, comprising patients with advanced lung cancer and carers. the central emerging theme of ''living with dying'' highlighted the struggle of dealing with a poor prognosis and the pervasive uncertainty associated with an unpredictable disease trajectory, whilst trying to maintain some quality of life and positivity. the findings confirm the need for effective support and information pathways that provide timely and responsive services which embrace the holistic needs of patients and carers. the total number of patients was and complete data was available on ( %) patients. the mean age was ( - ). there were ( %) male and ( %) female patients. the mean duration from first radiological investigation suspicious for lung cancer to first procedure, first diagnostic procedure and first treatment regardless of modality were , and days respectively. the mean interval from first procedure to first diagnostic procedure, and mean interval from first diagnostic procedure to first treatment were and days respectively. there were ( %) patients with confirmed cancer diagnosis and ( %) of them went for curative surgery. in conclusion, our practice in management of lung cancer is consistent with the bts guidelines. transbronchial needle aspiration (tbna) is a bronchoscopic technique that enhances the diagnosis and staging of patients with thoracic cancers and other diseases. while endobronchial ultrasound guided-tbna (eus-tbna) is the gold standard, many units do not have access to the technology and expertise required. this study explored the clinical utility of tbna in the diagnosis and staging of patients with thoracic cancer in a university hospital. we studied the yield of tbna in patients diagnosed with thoracic cancers in our institution from september st to august st . from patients with thoracic cancer, patients had tbna performed. eleven specimens ( %) were diagnostic ( from hilar nodes and from subcarinal nodes) and of the ( %) were the only positive diagnostic specimen, avoiding the need for further diagnostic procedures such as transthoracic needle biopsy and mediastinoscopy in these patients. three of the eleven cases were small cell lung carcinoma, were squamous cell carcinoma and were adenocarcinoma. while eus-tbna is the gold standard for the diagnosis and staging of patients with thoracic cancer, tbna provides a clinically useful alternative in units that are not equipped to provide this service. however, dedicated training in the use of tbna should preclude the routine use of this procedure in bronchoscopy units. types of cancers in our study are as follow: poorly differentiated small cell cancer (all smokers), squamouss cell cancer (all smokers), nonsmall cell ca ( nonsmokers), adenocarcinoma (all were smokers), nonclassified , wide spread metastasis , carcinoid tumour .and one patient presented with mesothelioma transformed to sarcomatous changes. among nonsmokers had nonsmall cell cancer, mesthelioma, metastatic lung cancer, was unclassified. patients underwent bronchoscopy, bronchoscopic biopsies, bronchial washings sent, patientst under went ct guided biopsies, had mediastinoscopy and lymph node biopsy to confirm diagnosis. patients were given chemotherapy and got radiotherapy. at the time of diagnosis patient were referred for surgery, among them had lobectomies, pneumonectomies, wedge resection, deemed unresectable perioperatively. patients were given chemotherapy and got radiotherapy. patients deemed unsuitable for treatment. majority of these patients referred by general practitioners and the early diagnosis determined the final out come of the patients. there needs to be high index suspicion for early patients refrall in the presence of risk factors for lung cancer. . audit of lung mass/nodule service regional hospital department of respiratory medicine, midland regional hospital mullingar a lung mass/nodule service was established in . service was provided by consultant respiratory physician and respiratory nurse specialist. we performed a retrospective audit on this service and held regular weekly mdt meetings involved oncology service in tullamore and st james's lung cancer service to monitor the progress of all possible lung cancers. aims of study: aim of the service is to provide prompt access to the patients, their investigations, management and proper follow up. in last five years patients were reviewed. ( %) were male. average age was (range - ). number of patients evaluated each year was in , in , in , in , and in (jan-aug). more detailed analysis was performed of a subgroup this population; all patients who presented from jan-june . total number of patients was . ( %) presented with lung mass, ( %) with pulmonary nodule, ( %) had associated pulmonary infiltrates, ( %) haemoptysis, ( %) enlarged mediastinal lymph nodes. ( %) had bronchoscopy, ( %) ct/us guided biopsy, ( %) thoracentesis, deemed unsuitable for further evaluation. ( %) were diagnosed with bronchogenic carcinoma ( non small cell cancer %, ( squamous cell cancer . %, adenocarcinoma . %, undifferentiated . %), small cell cancer . %, sarcoidosis ( . %), and had either an initial nondiagnostic evaluation or assigned to follow-up ct scan protocol (as per fleischner society guidelines ). of the lung cancer patients, ( %) were referred for chemotherapy/radiotherapy, ( %) for surgery, ( %) for palliative management. of the ( %) assigned to the follow-up protocol, was subsequently diagnosed with cancer. lung mass/nodule service facilitates early diagnosis of lung cancer and subsequent assignment to appropriate therapy; it also provides a coordinated careful follow-up of lung nodules. many patients with lung cancer are symptomatic from diagnosis, and quality of life (qol) may be maximised through use of specialist palliative care in parallel with other treatments. patients are at increased risk of psychological disorders such as depression and anxiety. this study explored anxiety, depression and qol of a small group of patients (n = ), predominantly male ( . %), mean age years, using the marie curie ''breathing space'' outpatient clinic over a four week period. ''breathing space'' is a nurse led multidisciplinary clinic using integrative, person-centred care to maximise qol of patients with lung cancer through weekly assessments and interventions to enhance breathing, stamina, relaxation, mood, independence and well-being. a prospective survey design incorporated qualitative and quantitative approaches using semi structured interviews at baseline and after four weeks. qualitative data explored patient expectations and experiences of clinic attendance. most reported preconceived fears about the clinic due to poor information which were later dispelled. anxiety, depression and quality of life scores improved for this small sample. the core elements of ''breathing space'' may contribute to improve qol for patients with lung cancer. further work is needed on a larger sample to confirm the effect on anxiety and depression. we performed a retrospective analysis of procedures done in the endoscopy/bronchoscopy unit in a dublin teaching hospital from to . since , all data in the unit has been entered live to an electronic patient record, replacing hand written reports. this excludes procedures carried out in areas other than the endoscopy unit, such as icu, hdu, bone marrow transplant unit etc. a total of procedures were carried out, which consisted of upper gi endoscopy , ( %), colonoscopy , ( %), bronchoscopy , ( . %), cystoscopy %, ercp %, sigmoidoscopy . %, trus biopsy . %, ileoscopy . %. during bronchoscopy, the following procedures were performed; tbbx ( %), endobronchial bx ( . %), tbna of mediastinal glands or peripheral lesions ( %). indications for bronchoscopy were; mass on the chest radiograph %, haemoptysis %, consolidation %, persistent symptoms with normal chest radiograph . %, pleural effusion %, recurrent infections %, hoarseness . %, stridor . %, others %. focal endobronchial tumours were present in ( %) cases, the vast majority of which were cancer. excessive haemorrhage occurred in ( . %), which was controlled in all cases with standard measures. the incidence of pneumothorax post transbronchial biopsy was \ %. mortality was zero. an electronic database provides a useful tool for audit of clinical practice. bronchoscopy is the third most common procedure performed in an endoscopy unit of a major teaching hospital in dublin. the most common pathological diagnosis in this unit is lung cancer. the workplace smoking ban protects adults from secondhand smoke (shs/ets) but there is now concern about the protection of children from (shs) in the home or in cars. we evaluated the levels of shs/ ets that might be experienced by a child in the back of a car, where the driver is smoking. a particle was located in the back of a car at the height of a child's car seat. measurements were recorded prior, during, and minutes after smoking had stopped. this was repeated with the drivers window open, and with it closed. these results show that particulate levels rise significantly with active smoking. the levels are significantly higher when the driver's window is closed during smoking, however even with the window open the levels are significantly elevated. post smoking levels are higher than the levels during smoking with the window open. these results are comparable with those reported from the us. children in the back seat of cars with the driver smoking are subject to very high levels of ets, which persist even after the smoking has stopped. having the driver's window open reduces the exposure, but it is still significantly higher than background levels. cells (gift from dieter c. gruenert, usf) were pretreated ± % cse and then stimulated with lps; cytomix (tnf-a, il- b, lps) or cytomix (tnf-a, il- b, ifn-c) and il- release measured. exposure to cse significantly reduced the stimulated il- release in all cases in the cfbe o-cells (cytomix : . ± . pg/ml, +cse . ± . pg/ml; cytomix : ± . pg/ml, +cse ± . pg/ml; lps-pa lg/ml . ± . pg/ml, +cse . ± . pg/ml; all p \ . ). however, il- release from hbe o-cells was only significantly inhibited basally and after stimulation with cytomix (cytomix ; ± . pg/ml, +cse ± . pg/ml; p \ . ). these data indicate that the response of the cf cell line to cse differs from that of the normal cell line. cse inhibits via tlr in a cells causing a reduction in both basal and lps stimulated il- release. this would provide a rationale for reduced responses to cytomix or lps. further studies will examine the effect of cse on tlr in our cell lines. previous studies have demonstrated improved lung health in bar workers, and reduction in cardiac morbidity following such bans. we sought to evaluate medical admissions before & following implementation of the ban, to assess for any impact on respiratory and cardiovascular admissions. data were obtained for all medical emergency admissions to our institution in the -month periods from january -december , and january -december using the hospital in-patient enquiry system. data were examined for trends in respiratory and cardiovascular disease between the study periods. medical admissions increased over the study period ( / n = ; / n = ). however, there was a decrease in the proportion of admissions due to pneumonia (rr . ), asthma (rr . ), spontaneous pneumothorax (rr . ), stroke (rr . ), and unstable angina (rr . ). admissions with copd increased (rr . ). these changes were seen in smokers & non-smokers. no significant mortality impact was observed. the proportion of medical admissions for respiratory and cardiovascular disease decreased in the years following the implementation of the smoking ban. any impact on chronic diseases may take many more years to become apparent. the ban on smoking in public places came into force in northern ireland on the th april . the objective was to look at the impact of the smoking ban on smoking prevalence in diabetic patients a year before and a year after the smoking ban. a retrospective analysis of smoking habit data held on a computerised data base (the diamond system) a year before and a year after the introduction of the smoking ban. the data of diabetic patients was analysed. there were % male and % female. type diabetics were % and % of the patients had type diabetes mellitus. a year before the smoking ban, ( %) were smokers- % male, % female. the prevalence of smoking in type male diabetic was % and in type female diabetic %. the prevalence of smoking in type male diabetics was % and in females %. one year after the smoking ban ( %) were smoking- % male and % female (p [ . ). to date, there has been no statistical difference in the number of patients with diabetes mellitus who smoke since the introduction of the smoking ban. the ban on smoking in public places came into force in northern ireland on the th april . our objective was to look at the impact of the smoking ban on blood pressure control in a group of patients with diabetes mellitus. a retrospective analysis of smoking habit data held on a computerised data base (the diamond system) was performed, one year before and one year after the introduction of smoking ban. the data of diabetic patients was analysed, % male and % female. type diabetics were % and % of the patients had type diabetes mellitus. mean blood pressure of the non-smokers was / mmhg before the smoking ban and / mmhg one year after the introduction of smoking ban. the mean blood pressure of smokers was / mmhg before and / mmhg a year after the ban (p [ . ). there was a small improvement in the blood pressure control of nonsmoking diabetic patients a year after the ban, however it was not statistically significant. overall, blood pressure control was at target. the law prohibiting workplace smoking improved the respiratory health of dublin bar workers. however, non-smoking bar workers living with a smoker are exposed to cigarette smoke at home. ( ) . for this study barworkers were studied. current smokers (n = ), and asthmatics (n = ) were excluded from analysis. ( %) lived with a smoker, and ( %) did not. all barworkers had similar baseline co levels, but those without exposure at home had a more significant reduction yr post ban. breathing symptoms in those without home exposure were lower at baseline, while ent symptoms were similar in both groups. fev remained constant in those not exposed to cigarette smoke at home, while it declined (not significantly) in those with home exposure. exposure to cigarette smoke in the home continues to put nonsmokers at increased risk of significant respiratory symptoms. smokefree homes would bring improved health. smoking adversely affects the health of patients with cf. study aims: to determine active and passive smoking exposure among adult irish cf patients. methods: cf patients attending cuh completed a questionnaire relating to personal smoking and second-hand smoke (shs) exposure, correlated with pulmonary function and exacerbation-rate data. results: patients ( male) completed the questionnaire (table ) . . % were currently smokers. . % admitted to having tried smoking at some time. in the never-smoked group (n = ), % were currently exposed to shs; mean duration of exposure was . pack-years ( %ci: . - . ), while % had previous shs exposure; mean duration of exposure was . pack-years. % were never exposed to shs. in those currently exposed, the source was from a parent in . % and a sibling in . %. anthropometric data and exacerbation rates were similar between groups, but smokers showed a trend towards better lung function. a large level of exposure to shs exists among irish cf patients, with a clinically relevant proportion actively smoking. this study identifies a need for more aggressive smoking cessation strategies for both patients and caregivers. supported by cfai. a non-probability sampling of self-identified glc was recruited using electronic and print media advertisements between december and march . , respondents completed the questionnaires. otc data for the same period was analysed (n = , respondents). appropriate statistical analyses were performed to compare the mean differences in smoking rates between these two surveyed populations across age, gender and socio-economic groups (ses). adjusted current rates in glc were % and . % in general population (p = . ) and ''heavy'' smoking prevalence was . % in glc and . % in general population (p = . ). upper ses glcs are ''heavy'' smokers compared to general population of similar ses group (p = . ). glcs (\ years) were ''heavy'' smokers compared to general population of same age-groups (p = . ). no significant gender differences were observed. more glc were ''heavy'' smokers than the general irish population, but current smoking rates among the glc in ireland were not significantly different from the general population. a sampling frame of post-primary schools was used to randomly select schools for the issac study. , children ( - years) completed the isaac questionnaire. smoking prevalence was based on children's self-reported answer to the question ''if you travel by car does anyone smoke cigarettes in the car [yes/no]? for part , we used ''upgreen counters'' for vantage points: a shopping car park (saturday - pm); near a school (monday - pm); a busy sub-traffic junction (monday - pm), and ''moving cameras'' for the th vantage point, the civic offices (monday - am). smoking prevalence in cars was . % in ireland. for the four vantage locations, the prevalence rates were: . % (n = / ), . % (n = / ), . % (n = / ), and . % (n = / ), respectively. smoking in cars is a public-health policy issue. our findings show that children are regularly exposed to second-hand-smoke in cars in ireland and this demands legislation. in march we performed a pilot study to determine the feasibility of a pulmonary outreach programme in the midlands area. there are currently two similar programmes in ireland, but this was the first in a rural setting. our programme has two pathways of care: patients discharged \ h received home visits on consecutive days and were followed up for days (early discharge programme, edp); if discharged [ h due to unsuitability for the edp, they were reviewed for the first two weeks by specialist respiratory support within the community (outreach programme op). all patients were subsequently enrolled into pulmonary rehab. to date, patients have been enrolled to pop. % were male; mean age years; majority had severe disease ( . % stage ii, . iii, . % iv). . % required ltot, % home-nppv. . % were active smokers. . % were readmitted within the first weeks. the mean length of inpatient stay was . d for the edp, and . d for op; the average los nationally is . days. overall there were substantial financial savings. thus, rural pulmonary outreach programmes are feasible as they lead to a reduction in hospital los, improved patient knowledge of their disease, and are cost effective. the physical and psychological symptom burden associated with patients with advanced copd has been compared to that of patients dying with cancer. traditionally palliative care services have focussed on people with cancer, however recently the american thoracic society have endorsed the concept that palliative care should be available to patients at all stages of their illness [ ] endorsing the who palliative care definition [ ] . the irish hospice foundation and hse undertook a study in examining how all levels of palliative care can be extended to people with copd. challenges identified for introducing palliative care for people with copd include the uncertainty of the copd disease trajectory, the tension between delivering hope and planning for the inevitable, the lack of comprehensive respiratory services and the need for further education and research. the development of a model of care for patients with stage iii / iv copd providing a clear pathway of access to all levels of palliative care, the production of information and educational material, the requirement that all palliative care services are accessible to copd patients as required and the need for further collaboration between respiratory and palliative care services are key recommendations in the report of the study. school of pharmacy, queen's university , and mater hospital , belfast introduction: self-management plans for copd is derived from success in asthma. patients may benefit from the early intervention following selfmanagement plan . methods: patients ( y; % females) with mod-severe copd, were randomly assigned to an intervention group ( ) and usual care ( ). a pharmacist delivered an education program on disease state, medications, home exercise and breathing techniques. a booklet and a customised action plan for acute exacerbations (antibiotics and steroids) were given. follow up was at three months by telephone and a six months scheduled visit. the eq- d health status and sgrq were administered to all patients. outcomes included admissions, a/e visits and quality of life. results: at months the intervention group had reduction in both admissions [ ( %) vs ( %); p = . ], and a/e visits [ ( %) vs s ( %); p \ . ]. on the sgrq there was improvement in the symptom (- . ; p = . ), impact (- . ; p = ). and total score (- . ; p = . ). physical activity scores did not improve. the difference in the eq- d scores improved both vas scale [ . vs . ; p = . ], and utility scale [ . vs . ; p = . ]. this ongoing study indicates that a clinical pharmacy led management programme can reduce the need for hospital care in patients with moderate-to-severe copd and improve aspects of their health related quality of life. copd is a leading cause of morbidity and mortality worldwide. exacerbations of copd result in frequent hospitalisation and account for % of the costs associated with the disease. our objective was to identify risk factors which predict relapse requiring readmission following an exacerbation of copd. from to , consecutive exacerbations of copd admitted to hospital were prospectively studied. baseline demographics, number of hospitalisations in the previous year, oxygen use and smoking history were assessed. breathlessness and quality of life scores were recorded and oxygen saturations and spirometry measured. rehospitalisation data was collected at day , weeks and months. during the follow up period, patients ( %) were readmitted by day , ( %) were admitted by six weeks and ( %) were admitted by three months. logistic regression analysis identified hospitalisation in previous months (p = . , or . , ci . - . ) and borg score or higher (p = . , or . , ci . - . ) predicted readmission in % of patients at day . home oxygen use (p = . , or . , ci . - . ), pack year [ (p = . , or . , ci . - . ) and borg score [ (p = . , or . , ci . - . ) predicted week admission in . %. admission in the previous year and borg score of c predict early relapse, while home oxygen use, pack-year history c and borg score of c predict later relapse following an acute exacerbation of moderate copd. aecopd is an inflammatory lung disease associated with systemic consequences. a systematic analysis was undertaken of alpha- antitrypsin (a at), c-reactive protein (crp) and procalcitonin (pct) in the serum of patients with aecopd and matched inflammatory controls (cellulitis), pre-and post-antibiotic therapy. a at and crp are acute phase proteins. pct, a serum calcitonin precursor, is also raised in bacterial infections. venous samples from patients were analysed in this prospective study. amongst the aecopd and controls (cellulitis), were males and females (aged to ). crp(mg/l) levels were elevated in cellulitis (mean ± std error, . ± . ) and aecopd ( . ± . ) patients prior to treatment. a at(lmol/l) levels were also significantly elevated in cellulitis ( . ± . ) and aecopd ( . ± . ) patients. following intravenous antibiotic therapy, crp levels fell in cellulitis ( . ± . ) and copd ( . ± . ) patients. similarly, a at values fell in cellulitis ( . ± . ) and in aecopd ( . ± . ) patients. pct (ng/ml) levels were not elevated in all individuals with either cellulitis ( / ) or aecopd ( / ), but did decrease significantly in those that were elevated following antibiotic therapy. crp and a at levels are significantly elevated during aecopd and cellulitis. both levels fell significantly post antibiotic treatment (p = . for crp and p = . for a at). pct levels, when elevated, were reduced post antibiotic therapy. these data suggest that aecopd elicits a systemic response similar to a non-respiratory infection and this response to treatment can be monitored using biomarkers. in copd there is a cytotoxic t-cell infiltrate in the airway mucosa. it has been suggested that a virus may be a co-factor. we have recently shown high levels of ebv in severe disease . we wanted to establish if it was present in early disease. we recruited smoking ( pack y) subjects ( y) with early copd with mean fev . ( %) and smoking ( pack y) unobstructed smokers ( y) with mean fev . ( %). none of the subjects had used inhaled or oral steroids. nose and throat swabs were taken. induced sputum was obtained using hypertonic saline. total nucleic acids were extracted, and ebv dna was detected using taqman quantitative pcr. results: ebv was detected more often in the copd ( / swabs and / sputum) than the control ( / swabs and / sputum). p = . and . for swabs and sputum respectively (fisher's exact test). there was a wide range of copy numbers which were not different among those who were positive. conclusion: ebv is present more frequently in early copd than in unobstructed smoking controls. ebv is known to be a cyclical herpes virus which comes and goes. it may have a role in the pathogenesis of copd. background and method: niv is a valuable treatment for hypercapnic respiratory failure. [ ] transcutaneous co monitors(tosca) has provided novel approach to monitor these patients.. we assessed niv service and the use of transcutaneous co monitors in our tertiary care center. charts of patients attended from july to dec were retrospectively evaluated. data was retrievable on from total of patients. there mean age was ± yrs. were female. copd was in %, decompensated obesity/hypoventilation was % and neuromuscular/chest wall deformity was %. fev (mean) was . % - . %. % had type and ( %) had type respiratory failure. their average-ph was ( . - . ). mean pco was ( . - . ). only % of patients had repeat blood gas analysis at - hour, tosca was used to monitor non-invasive ventilation in ( %) of patients. the average number of use per patient was . - . . there length of stay(avg) was . days. their mean ipap and epap were . and respectively. ( %) patients were commenced niv in hdu. ( %) died due to respiratory failure. conclusion: % of patients were successfully monitored with tosca. we conclude that tosca is a valuable tool for monitoring patients at ward level. respiratory assessment unit, crest directorate, st. james's hospital, dublin as part of its transformation programme, the hse established a group in september to develop a national strategy for the management of copd. the aim of this survey was to capture information regarding the availability and range of physiotherapy services for persons with copd in ireland and thus inform the report of the national copd strategy group. the survey was emailed to physiotherapy managers across care settings in november . the survey sought information relating to the range of physiotherapy services for persons with copd provided at each site, as well as perceived service deficits and existing/potential innovations in practice. data were analysed using descriptive statistics. fifty-seven sites responded to the survey. no formal joint services between acute hospitals and pccc were reported. pulmonary rehabilitation programmes (prps) were available in sites only. service deficits reported related to lack of appropriate treatment space, lack of specialised respiratory staff, the absence of prps, and lack of interaction between acute hospitals and community services. physiotherapy services for persons with copd vary greatly across sites and settings. prps are not widely available and are primarily hospital based. there is a need for wider availability of joint hospital/ community based initiatives such as copd outreach and prps. pulmonary rehabilitation has established efficacy, but patients often require follow-up care or maintenance. there are few studies that explore the patients' experience of pulmonary rehabilitation and maintenance. also, there are no guidelines for health professionals as to what constitutes effective maintenance for clients who complete pulmonary rehabilitation. the study aim was to explore patients' perceptions of pulmonary rehabilitation and the maintenance options provided to them. a qualitative, exploratory descriptive design used focus groups to collect data. the purposive sample (n = ), had a diagnosis of either copd or bronchiectasis, and had attended a pulmonary rehabilitation programme within the last year. a focus group schedule using open ended questions and prompts was designed. discussions were transcribed verbatim and burnard's ( ) thematic content analysis was used to guide data analysis. the dynamics of group participation and peer support were identified as important incentives for patients. increased confidence and personal achievement were described as outcomes. the reasons for non-participation in maintenance were also elucidated by patients. this study provides an important contribution in relation to the experience of patients and the findings enhance current quantitative studies. patients' experience of outcomes and expectations has the potential to influence future services. following recommendations from the hse transformation programme , a multidisciplinary committee was established to develop a national strategy for the management of copd. as a member of the committee representing anail, the author conducted a survey to establish the range of inpatient and outpatient services provided by respiratory nurses for persons with copd. a questionnaire was devised to gather information regarding the provision of services such as inhaler technique, oxygen assessments, copd outreach programmes, pulmonary rehabilitation programmes (prp's) and palliative care services for persons with end stage copd. thirty-five members of anail were surveyed in october . data were analysed using descriptive statistics. a response rate of % was achieved. inpatient and outpatient services such as respiratory nurse reviews, oxygen assessments, self management plans were provided by more than % of respondents. of those who replied % provided inhaler technique education, % can refer persons with copd for prp, % run an outreach programme and % providing limited palliative care services. a number of current innovations and deficits within the services provided by respiratory nurses were highlighted. the contribution made by specialist nurses to the acute and chronic respiratory service is reflected by this survey. the inspiratory fraction-inspiratory-to-total-lung capacity (ic/ tlc) is an independent risk factor for mortality in chronic obstructive pulmonary disease (copd) . ic/tlc b %predicted is associated with significantly shorter survival. little data exists about the effect of pulmonary rehabilitation (pr) on survival in copd . the purpose of this study is to examine the effect of pr on ic/tlc. patients (mean age . ± . ), with clinical evidence of copd (mean fev . ± %predicted, mean ic/tlc . ± . %predicted) were enrolled in an week pr programme, consisting of twice-weekly sessions of exercise and education. assessments/re-assessments consisted of lung function (spirometry, diffusion, sniff nasal inspiratory pressure, capacity), exercise tests (shuttle, treadmill) and quality-of life-questionnaires (qol). patients, re-assessed at months, demonstrated improvements in exercise and qol compared to baseline (p \ . ). these patients were divided into groups-group ic/tlc b % predicted (n = ), group ic/tlc [ % predicted (n = ) at baseline. there were no between-group differences in improvements in exercise or qol at months. group ic/tlc improved at / from baseline . % predicted to . % predicted, and group from . to . % predicted (not significant). although the results are not significant there appears to be a trend in improved ic/tlc following pr. this study should be repeated with a larger sample size. department of medicine, midland regional hospital, mullingar, ireland primary objective was to assess the appropriateness of our hospital admissions for copd exacerbations as per nice guidelines. we also assessed the quality of their outpatient copd medical care. all copd related admissions mar-may were prospectively reviewed. variables as per nice guidelines were considered with one point for each variable. a score of zero was considered an inappropriate admission while c was appropriate. patients were included. mean age was ( - ), ( %) were male. ( %) patients were admitted as per guidelines, ( %) patient met no criteria. commonest variables present were: poor level of activity ( %), significant co morbidities ( %), inability to cope at home ( %). least common variables were: impaired level of consciousness ( %), cyanosis ( %), acute confusion ( %). ( %) received antibiotics. ( %) had spirometry performed for diagnosis. out of smokers ( %) were offered cessation advice. ( %) were appropriately on inhaled steroids. out of an eligible ( %) were enrolled in pulmonary rehab. mean los was . days, and there was linear relationship between length of stay and guideline score. there was excellent compliance with nice guidelines for copd admissions. quality of outpatient care was good in the domains evaluated. up to % of copd hospital inpatients will be readmitted within weeks of discharged. specific predictive markers of readmission are not currently in routine clinical practice. in this study, we assessed a remote monitoring system for continuous readout of patients' pulse rate and o saturation (biancamed, ireland). a cohort of normal volunteers (n = ) and copd patients (n = ) were enrolled and full remote monitoring and psychological profiling (via a modified hospital anxiety and depression score (hads)) of patients' well being was performed. in controls and patients, mean percentage of recording time was % (range: %- %) and % (range: %- %) respectively. principal reasons for loss of recording were a) patients moving out of range of monitor, b) non-compliance due to impracticality and/or discomfort while wearing the device, and c) accidental slippage of the oximeter probe. analysis of time of o saturation below %, %, % and % per hour revealed significant improvement over time in % of patients. one patient subsequently readmitted showed a significant deterioration prior to admission. in conclusion, this system shows potential in the early identification of copd patients who clinically deteriorate at home. in , % of respiratory inpatient discharges related to copd. information on hospital services for copd patients was required for the development of a national strategy. a survey on relevant staffing, wards and diagnostic units, policies and practice and access to specialist services was distributed to acute hse hospitals via hospital networks. hospitals responded ( %). written policies are in place for management of copd ( %), non invasive ventilation (niv) ( %) and long term oxygen therapy ( %). niv is provided in the emergency department (ed) ( . %), medical assessment unit (mau) ( . %), icu ( . %), hdu ( . %), respiratory ward ( . %), all medical wards ( . %). in almost two thirds of hospitals, all inpatients with copd can access respiratory nurse specialists, smoking cessation officers and palliative care services. access by ed/mau patients is possible in %, % and % of hospitals respectively and by gp referral in %, % and %. ten hospitals have pulmonary rehabilitation programmes ( %), five have onward referral mechanisms and four were planning a programme. the waiting time for programmes is up to one year. three hospitals have outreach programmes in place. this survey highlights the variation in hospital based services for copd patients and opportunities for service development. in the health services executive established a steering group to develop a national strategy for the management of copd. this study aims to describe the range of services available to copd patients and ease of access from the primary care perspective. a postal survey was distributed to a random sample of gps by the icgp. data was analysed using excel. valid questionnaires were returned (response rate . %) from practices in counties. . % have access to spirometry within their own practice. a practice nurse usually conducts the test ( %) and a gp interprets the results ( %). patients are unable to access patient support groups ( . %), pulmonary rehabilitation ( . %), rapid access respiratory clinics ( . %) or community options for management of an exacerbation-home based ( . %) or local community unit/district hospital ( . %). waiting times are up to six months for physiotherapy and pulmonary function testing and up to one year for respiratory consultant review, long term oxygen therapy assessment and pulmonary rehabilitation. this survey highlights geographical variation and gaps to be addressed for a shift to occur towards a community-based, responsive, flexible service for copd patients. oxygen therapy is an important treatment option for patients with severe copd, as long term continuous therapy (ltot). information on relevant community resources for ltot was required for the development of a national copd strategy. a survey was distributed by e-mail via each local health office (lho) manager ( ), covering activity and costs of aids and appliances, policy and procedure. data was analysed using excel. twenty two responses were received from local health areas ( %). there were wide population differences in the rate of ltot between areas, from - / , . home oxygen can be prescribed by hospital consultant, gp, respiratory nurse specialist or physiotherapist. arrangements for follow-up of patients on long term home oxygen vary considerably. half of respondents have difficulty with the level of detail provided on home oxygen prescriptions. % have a policy on provision of portable oxygen cylinders. % are aware of arrangements for ongoing maintenance of oxygen appliances. cost of ltot in was estimated to be in excess of € million. long term oxygen is an important copd therapy but is costly and has potential for harm. standardised practices are required for its use in the community. spirometry is the gold standard for diagnosis of copd. additional pulmonary function tests (pfts) can also assist in management. details of respiratory diagnostic resources in ireland were required to inform the national copd strategy. a questionnaire was developed in conjunction with the irish association of respiratory scientists and circulated to members via email. questions focused on staffing, workload, waiting times, tests available, referral sources and educational activities. ten laboratories responded ( %). pft activity ranged from , to , . minimum waiting times ranged from days to weeks and maximum from four days to eight weeks. laboratories accepted referrals for basic pfts from respiratory consultants (all), other hospital consultants (all), respiratory nurse specialists ( %), emergency departments ( %), medical assessments units ( %) and gps ( %). tests confined to respiratory team/other consultant referrals included bronchial provocation, minute walk, long term oxygen therapy and fitness to fly assessments. five hospitals participated in training relevant to copd in the hospital and two in the community. additional copd services included participation in pulmonary rehabilitation and outreach programmes. respiratory diagnostic laboratories are predominantly resourced for hospital referrals. examples are provided where scientists also provide a service to the community, for diagnostic tests and education. patients with copd have higher blood levels of markers of inflammation such as tumour necorsis factor (tnf-a), interleukin (il- ) interleukin (il- ) and c-reactive protein (crp). these are independent risk factors for decreased lung function and are associated with increased symptoms such as shortness of breath and respiratory rate. recently, tools to measure activity have been developed which continuously record patient free living activity and sleep. we hypothesized that there may be a relationship between levels of systemic inflammation and measures of free-living activities. thirty one patients were recruited: men (n = ), female (n = ). ethical approval and written consent was obtained. venous blood samples were taken (il- , il- , tnf-a and crp which were logged for normal distribution). a senseware Ò activity monitor was worn for consecutive days and the st.george's respiratory questionnaire were measured. pearson's correlations were undertaken using spss version s mean age of . yrs (+/- . ) with an fev or (+/- ) and a mean smoke pack history of (+/- ). a medium negative correlation was found between lgcrp and physical activity duration [r = - . , n = , p = . ]. a large correlation was found between the lgcrp and the st. georges respiratory questionnaire [r = . , n , p = . ]. this was also reflected in the impact section of the questionnaire [r = . , n = , p = . ]. c-reactive protein blood levels appear to be inversely correlated to free-living activities and quality of life. these data suggest that the measure of crp may be an important factor to include in the assessment of the severity of copd. during the months of july and august , in a prospective study, patients were transferred from the adelaide and meath hospital within days of their acute admission with copd, to peamount hospital for airc. patients were enrolled: males with a mean age of . yrs and a mean fev of . l ( %). the mean length of stay (los) in the acute hospital was . days and the mean los in peamount hospital was . days, with a total mean hospital stay of days. we hypothesise that this extended hospital stay and targeted respiratory care will improve patients overall quality of life, breathlessness, and exercise capacity, and reduce their dependency on the acute hospital service and re-admission rates. these patients will be followed up over the next year as a continuation of this study. the miners' disability score (mds), developed during the compensation process for uk miners, utilises a ten-point scale. the medical research council(mrc) dyspnoea scale, previously validated using the incremental shuttle walking test(iswt), utilises a five-point scale which may be less discriminating. we aimed to validate the mds as a score of respiratory disability in copd patients. patient data (mds/iswt/endurance shuttle walking test(eswt)) from our pulmonary rehabilitation programme were initially analysed (n = ; median fev = . l; mean age = yrs). subsequently, inpatients (median fev = . l; mean age = . yrs) had baseline mrc dyspnoea grade, mds, and manchester respiratory activities of daily living score (mradl) determined. degree of association between variables was assessed using the spearman rank correlation. mds correlated well with iswt (rs = - . , %ci - . to - . ), but not with eswt. fev was not associated with mds grade. mds correlated well with mrc dyspnoea grade (rs = . , %ci . to . ). mrc grade and mds correlated well with mradl (mrc rs = .- . , %ci - . to - . ; mds rs = - . , %ci - . to - . ) score. the mds showed a more favourable association. the mds is a valid measure of respiratory disability that could be used to complement fev and may provide an accurate reflection of performance status and disability in patients with copd. copd is an unremitting disease that impacts negatively on quality of life. the aim of this study was to compare functional capacity (fc); a measure of weight distance over six minutes, with standard tools used in the assessment of patients with stable copd. forty one patients with severe copd: fev % ± % predicted were recruited: men (n = ), women (n = ). senseware Ò armbands were worn for seven days to quantify their average daily steps. ethical approval and written consent were obtained. pearson's and spearman's correlations were performed using spss version . functional capacity was significantly associated with mean daily steps: men (r = . , p = . ) women (r = . , p = . ), shuttle walk test: men (r = . , p = . ) women (r = . , p = . ) and fev in men only (r = . , p = . ). there was no relationship between fc and borg: men (r = . , p = . ) women (r = . , p = . ) or the saint-george respiratory questionnaire: men (r = - . , p = . ) women (r = . , p = . ). we found that quantifying ''free-living'' measures is an important dimension of functional status not ordinarily captured and that functional capacity is a reliable outcome measure for assessing stable copd. the only gender difference identified was in male fev . patients (n = , mean age ) admitted to castle hill hospital with acute exacerbation of copd were studied. patients were either treated with standard therapy plus mg erdosteine bd (n = ) or standard therapy alone. (n = ) and followed up at day five and day ten. there was no significant improvement in subjective measures of breathlessness. at day subjective cough frequency was reduced by % in the +erd group as compared with deterioration in the -erd group. fev increased by ml -erd group and ml in the +erd group. hacc hour recordings on nine patients revealed coughs on day one falling to coughs by day five. there was a % reduction in cough frequency on the +erd group and % reduction in the -erd group. cough counting may be a useful objective marker to judge the success or failure of treatment strategies in acute exacerbation. chronic obstructive pulmonary disease is a lung disease characterized by chronic airflow obstruction that is not fully reversible measured using spirometry. the aim of this audit was to assess use of spirometry in diagnosis of copd in primary care. two hundred questionnaires were sent to primary care practices, seventy nine were completed. questionnaires identified which practices used spirometry. information was obtained on who performed spirometry within the practice, what training had been received, what criteria for screening for copd was utilised and general information on management of copd. we found % of practices had a spirometer. the most common reasons for not were cost involved ( %) and lack of confidence in interpreting results ( %). spirometry was performed most commonly by practice nurses ( %), interpretation of results was largely done by general practitioners ( %). only % had received recognised training in spirometry. the largest group of patients screened were symptomatic smokers over years old, however only % of patients screened had spirometry performed. these data indicate that we need to promote training in the use of spirometry for the diagnosis and management of copd in primary care in ireland. physiological responses to pulmonary rehabilitation (pr) are measured using a variety of clinical exercise tests. we compared incremental with endurance cardiopulmonary exercise testing (cpet) in a series of patients attending a pr programme. thirty two patients with moderate or severe copd (age . ± . y, fev ± . % predicted) were recruited to an -week pr programme. exercise capacity was assessed using incremental cpet before and after pr in patients and endurance cpet (at % of the peak incremental cpet workload) before and after pr in patients. among the incremental exercise group, there were no significant differences in vo max (mls/min) (p = . ), vo max (mls/kg/min) (p = . ), vco max (mls/min) (p = . ) or maximum workload achieved (watts) (p = . ) before and after pr. among the endurance exercise group, there was a significant difference (p = . ) in exercise duration ( vs seconds), but no differences in vo max (mls/min) (p = . ), vo max (mls/kg/min) (p = . ) or vco max (p = . ) (mls/min) before and after pr. incremental cpet is a poor tool to measure physiological changes in exercise capacity associated with pr. endurance cpet is the more ideal test, demonstrating significant increases in endurance time associated with pr despite unchanged peak oxygen consumption and carbon dioxide production. cardiopulmonary exercise testing (cpet) provides a global assessment of the integrative exercise responses involving the pulmonary, cardiovascular, haematopoietic, neuropsychological, and skeletal muscle systems, which are not adequately reflected through the measurement of individual organ system function. this case report looks at how cpet makes the initial diagnosis of mcardle's syndrome. a year old man initially presented to the cardiologists complaining of muscle fatigue after a short period of sustained exertion. all his cardiac investigations were normal. deconditioning would have explained the young mans symptoms adequately. as such, he was sent for cardiopulmonary exercise testing (cpet) to differentiate between poor aerobic conditioning and a possible pathological aetiology. the patient managed to exercise for six minutes and the test was limited by muscle fatigue. there was early failure in the aerobic metabolic pathway with a significantly reduced vo max (oxygen uptake-aerobic metabolism) and the absence of a corresponding rise in the vco signalling a concurrent failure of the anaerobic pathway. these results pointed towards a rare muscle enzyme deficiency. diagnosis was confirmed in the conventional way using a muscle biopsy. this case represents a unique and non invasive way of diagnosing a rare and often under diagnosed enzyme deficiency and underlines the versatility and diagnostic value of cpet. non-invasive ventilation (niv) is increasingly provided at ward level with implications for skills and practice development, support and inter-professional decision-making. despite recommendations by the british thoracic society ( ) that niv can be provided outside of the intensive care unit, use of niv at ward level remains problematic, presenting particular contextual challenges to care. a qualitative research study was undertaken, involving focus group interviews with nursing staff (n = ) and individual semistructured interviews with doctors (n = ) from specialised (respiratory) and non-specialised units in a regional teaching hospital. a number of support issues were identified. niv was considered a time-consuming procedure, with a perception of inadequate staffing levels at ward level. access to experienced medical and nursing support was viewed as an integral part of niv service provision. knowledge gaps exist at local level specifically in relation to inadequate education and training. clinical practice guidelines for niv were recommended to guide practice. this research study sought to inform practice development, specifically the greater acceptance and use of niv at ward level, through examining care issues. the themes expressed in the findings point s towards the need for review of present service provision, particularly in the areas of education, training and guideline development. pulmonary function laboratories interface with all medical disciplines. there is anecdotal evidence that pulmonary function tests (pfts) are often requested inappropriately. an audit was undertaken in the pulmonary function laboratory, belfast city hospital to determine how many referrals were appropriate, the origin of each referral and the designation of the referrer. the audit randomly considered requests over a six-month period. requests were reviewed by a clinical scientist and a consultant chest physician. a request was deemed inappropriate if tests unlikely to contribute to the patient's management were sought, or if tests were omitted that should have been requested. the requests originated from the following main specialities: respiratory medicine ( %), general surgery ( %), general medicine ( %) and haematology ( %). sixty-seven percent of referrals were made by junior doctors (junior or senior house officers) and % of these were appropriate. thirteen percent of requests were made by consultants of which % were appropriate. only % of respiratory referrals were appropriate. overall % of requests were considered appropriate, however there was significant variability among disciplines ( %- %). the results indicate that many pft requests are inappropriate. additionally, the quality of respiratory referrals is not better than nonrespiratory referrals. consultant requesting does not guarantee correct referral. the findings have both resource and educational implications. a phenomenological approach enabled the researcher to gain an insight into the participants lived experiences and uncover their stories. the researcher is a respiratory nurse specialist and therefore has a particular interest in this area. a husserlian phenomenological approach with bracketing of preconceived ideas underpinned the chosen methodology. a total of seven interviews were transcribed by the researcher in this study. the participants were patients on long term non invasive ventilation. data was generated using unstructured interviews, which were tape-recorded. data was analysed using colaizzi's framework. beginning the therapy, process of adjustment to the therapy and gaining a new independence were the major themes identified within the study. this study is small however; the findings have implications for nursing practice, education and management locally and highlighted areas that require further research. dysregulation of pulmonary inflammation has been proposed as contributing to airways disease in cystic fibrosis (cf). the aim of this project was to compare two t helper- cytokines (interleukin (il)- and il- ) for their relative stability, activity and interaction with glycosaminoglycans (gags) which are highly abundant in the cf lung. bronchoalveolar lavage fluid (balf), serum and sputum pre-and post-nebulised hypertonic saline (hts) were collected from cf patients and compared to balf and serum from non-cf controls. western blots and elisas were used to visualize and quantify cytokine levels respectively. il- was undetectable within cf balf and was shown to be degraded by neutrophil elastase. as a biological consequence significantly reduced levels of il- were secreted by jurkat t lymphocytes (p = . ). il- was competitively displaced from gags by il- , which binds gags via electrostatic interactions. exposure of cf balf to hts or treatment of cf patients with hts displaced il- from gag matrices rendering the chemokine susceptible to proteolytic cleavage and reducing the chemoattractant capacity of cf sputum. in conclusion, gags possess the ability to influence the cytokine profile of the cf lung promoting a neutrophil dominated immune response and hts treatment may improve resolution of this inflammation. human cathelicidin, ll- , a amino acid antimicrobial peptide produced by neutrophils and respiratory epithelium has been shown to have antimicrobial activity as well as possess immunomodulatory properties. we have investigated this potential immunomodulatory effect of ll- using lps stimulated thp- monocytes. effects of ll- on the lps signalling pathway were investigated using western blot and elisa. ll- was shown to inhibit the degradation of ijba and ijbb during lps stimulation, whilst preventing the phosphorylation of ijba, ikk, stat- , akt, c-jun and atf- . cytokine data showed a partial reduction in lps induced il- and tnf-a with lg/ml ll- . further investigation revealed that lps induced cytokine production could be reduced to control levels when ng and ng of lps was used to challenge cells in the presence of lg/ml of ll- . washing of cells following pretreatment with ll- abolished ll- 's inhibitory effects on lps-induced il- production when compared to unwashed samples. results suggest that ll- is exerting its anti-inflammatory effect primarily by neutralising lps activity as nearly all these effects can be inhibited by higher ll- :lps ratios. exposure of bacteria such as p. aeruginosa, growing within a biofilm in the lungs of cf patients, to antibiotics during treatment of recurring pulmonary exacerbations, may result in the development of antibiotic resistance. the aim of this study was to compare biofilm formation and antibiotic susceptibility of matched p. aeruginosa isolates cultured from cf sputum before and after antibiotic treatment of an acute exacerbation of pulmonary infection. biofilm formation ( hours) by matched pairs of p. aeruginosa isolates, cultured from sputum samples prior to commencing and at the end of antibiotic treatment, was assessed by total viable count using the calgary biofilm device. all isolates formed biofilms with no differences in biofilm formation apparent between any of the matched pairs of isolates. prior to commencing antibiotic treatment, p. aeruginosa isolates from (caz), (tob), (pip/taz) and (mer) patients were susceptible. following antibiotic treatment, the susceptibility status of isolates changed from sensitive to resistant for (caz), (tob), (pip/taz) and (mer) patients. these results indicate that antibiotic treatment had no effect on the ability of p. aeruginosa isolates to form bacterial biofilms but in some patients resulted in the development of antibiotic resistance. cause of death. paradoxically, neutrophils are recruited into the lungs but fail to clear infections. the question that this project will address is; are cf neutrophils intrinsically abnormal? within this study we shall focus on neutrophil membrane proteins and present the first proteome study on normal and cf membranes. a pure neutrophil membrane fraction was prepared by sucrosedensity ultracentrifugation. the solubilizing power of nonionic and zwitterionic detergents as membrane protein solubilizers for twodimensional electrophoresis was investigated. ief was performed with immobilized ph gradients. optimized solubilization of membrane proteins was achieved by combining the zwitterionic detergent chaps ( %) or sb - ( %) with the nonionic detergent triton x- ( %). excellent reproducibility of protein-spots was observed on ph linear gradient strips ( - and - ), allowing for comparative studies. with our now optimized protocol we propose to screen circulating neutrophils from cf patients during periods of exacerbation, and to look for quantitative changes in membrane protein expression (up-regulation, down-regulation or post-translational changes) using a stable-isotope labeling approach. data arising from this project will identify candidate proteins that could be used as biomarkers and/or contribute to a better understanding of disease progression in cf. neutrophil dominated inflammation characterises acute lung injury, pneumonia, copd, cystic fibrosis and bronchiectasis. factors modulating neutrophil mediated inflammation may have important therapeutic potential in these conditions. the anti-inflammatory protein, secretory leukoprotease inhibitor (slpi), is a non-glycosylated molecule produced by epithelial cells, macrophages and neutrophils. this study aims to enhance our knowledge of the anti-inflammatory effects of slpi and to investigate the relationship between slpi and the human neutrophil. neutrophils were purified from whole blood and subcellular fractionation performed employing sucrose gradients and ultracentrifugation techniques. translocation of slpi to the outside of the cell post pma( ng/ml) or fmlp( - m) activation was assessed by western blot analysis. our experimental results confirm the findings of sallenave et al [ ] and demonstrate that slpi resides within the neutrophil cytosol. however, contrary to previously published data we have found that slpi does not co-localise with lactoferrin in the secondary granules [ ] (figure ). cytosolic spli migrated as a dimer on sds-page and upon cell activation translocated to the outside of the cell in predominantly monomeric form. our results may support the concept that slpi orchestrates diverse effects within the neutrophil, with monomer and dimer forms of the molecule possessing distinct anti-inflammatory modes of action. the primary cause of morbidity and mortality is infection by gramnegative bacteria such as pseudomonas aeruginosa, resulting in chronic airway inflammation characterized by release of interleukin (il)- . to avoid the innate immune system, p. aeruginosa can undergo genetic changes [ ] , such as modification of the lipid a component of the lipopolysaccharide (lps) structure [ ] . the aim of this study was to compare the pro-inflammatory response of various types of purified lps isolated from cf patients with that of commercially available lps. human (hte) and cf (cfte) tracheal epithelial cells at * % confluency were serum starved ( h), then stimulated with lps from sigma (laboratory stain) or isolates that differed in their lipid a structure: pak (mild cf), se (severe cf), se (infant cf), bronc (bronchiectasis) and il- release measured. in order to achieve similar il- release, sigma lps was required at -fold higher concentrations than cf lps isolates (ug/ml vs. ng/ml). there was a differential response to lps between hte and cfte cells: se and pak strains induce a higher response in cfte cells when compared to hte. in conclusion, the inflammatory response to p. aeruginosa is dependent upon strain and environment, which may be due to changing lipid a structures. we investigated the ability of secreted bacterial proteinases from three pathogens (burkholderia multivorans, burkholderia cenocepacia, and pseudomonas aeruginosa) involved in chronic bacterial infections in cystic fibrosis to degrade various host defence-related molecules. these included secretory leukocyte proteinase inhibitor (rhslpi), alpha- antitrypsin (aat), secretory iga (siga), igg, lactoferrin and lysozyme. host defence-related molecules were co-incubated with cell-free bacterial supernatants from hour biofilm cultures from all three pathogens under investigation. no degradation of aat, siga, igg, and lactoferrin was observed for any of the organisms. only one out of isolates tested demonstrated the ability to degrade lysozyme. all isolates of b. multivorans (n = ) and p. aeruginosa (n = ) were able to degrade rhslpi however, out of five bacterial isolates tested for b. cenocepacia only two demonstrated a limited ability to degrade the molecule with [ % of the protein band still remaining intact at the end of the experiment. this study demonstrates that the majority of the host defence molecules investigated are resistant to degradation by bacterial proteinases from b. multivorans, b.cenocepacia and p. aeruginosa when grown as a biofilm. however, rhslpi was vulnerable to significant degradation which could result in aberrant serine proteolysis in regions of the lungs containing biofilm growth. children are ten times more sensitive to radiation-induced cancer than adults. we aimed to determine the cumulative radiation exposure associated with imaging in a paediatric population with cf, to identify contributing factors and to suggest ways of reducing their lifetime radiation exposure. medical and radiology records were reviewed. effective radiation dose (msv) and cumulative lifetime radiation doses were calculated for each patient using national radiological protection board (uk)data files. patients, mean age . ( - . ) years with a total follow up time of person years, had chest radiographs, abdominal radiographs and computerized tomography (ct) scans, including thoracic ct scans. average cumulative radiation exposure per patient was . ( . - ) msv. radiation exposure increased with age (p = . ) and with increasing numbers of cts (p = . ). radiation dose was significantly increased in the subgroup who presented with meconium ileus (p = . , independent of age).radiation dose was not significantly related to lung disease severity (measured as forced expiratory volume in second (fev ). radiation exposure in our cf population compares favourably with other tertiary centres worldwide. radiation dose can be minimised by reducing frequency of scans and altering scanning technique. a number of mirna expression profiling studies have shown mir- to be highly expressed in rat and human lung. tom a predicted target of mir- has been shown to interact with tollip and proposed as a negative regulator of il- b and tnf-a signalling pathways. the aim of this study was to validate tom as a target of mir- and elucidate its role in tlr and il- signalling pathways in cystic fibrosis (cf) versus non-cf airway epithelial cells. expression of mir- and tom were evaluated by qpcr. overexpression of premir- was performed by reverse transfection and tom was subsequently detected by western blot. mir- was found to be down-regulated (p = . ) and tom mrna significantly up-regulated (p = . ) in cf bronchial cells when compared to their non-cf counterparts. overexpression of mir in cf cells led to a decrease in tom protein production. this data shows that mirna is differentially regulated in cf airway epithelial cells and that tom is a target of mir- and may have an important role in regulating innate immune responses in the cf lung. case : y.o. male with recurrent infective exacerbations was noted to experience more severe and longer exacerbations compared to other similar patients. common variable immunodeficiency (cvid) was diagnosed based on low iga, igm, igg , igg and lack of antibody response to pneumovax. treatment with ivig has commenced. case : y.o. male who experienced severe anxiety during transition to adult cf care. obsessive compulsive disorder was recognized as exemplified by patient using alcohol wipes weekly to clean himself. he has responded well to cognitive behavioural psychotherapy. we conclude that physicians should appreciate the spectrum of coexisting conditions that are separate to a diagnosis of cf and can contribute to morbidity and mortality. cfrd adversely affects pulmonary function however diabetic control did not significantly impact function any further. this finding warrants larger prospective studies to confirm that a diagnosis of cfrd impacts pulmonary function but that diabetic control may not. with improving cf survival, fertility issues emerge. this descriptive study assesses knowledge & approaches to fertility information provision in cf care. prospective anonymous questionnaires were mailed to a male cf cohort (n = ). sections included demographics, fertility knowledge, investigation & personal relationships. response rate was % (n = ). mean age years (range - , sd . ). all knew that cf affected fertility but only . % (n = ) were able to provide explanations. of this group, . % (n = ) provided the correct explanation. % (n = ) have discussed fertility with a healthcare professional and half (n = ) selfinitiated this. mean discussion age was . years (range - , sd . ). one third stated preference for earlier discussion. . % (n = ) who had discussions were satisfied with information provided. commonest first source where patients heard of infertility was written material ( . %, n = ). three-quarters of respondents (n = ) requested further fertility information. the preferred source was written material ( . %, n = ). . % (n = ) have had semen analysis & all remaining (n = ) would accept an opportunity for this if offered. all respondents were aware of infertility however most unaware of explanation. few have formally discussed fertility. the majority want further information (preferred method written material) & an opportunity for semen analysis. this study identifies significant gaps existing in sex education during provision of cf care. a. sahadevan, s.h. chotirmall, a.k. mann, p. branagan, c. gunaratnam, n.g. mcelvaney discovering predictors of mortality in cf within ireland has therapeutic implications. we aim to determine factors predicting mortality in an irish cf cohort. a retrospective analysis of clinical, microbiological and radiological parameters in deceased cf patients over an -year period ( - ) was conducted (n = ). this was age matched to a living cf cohort. spss version . was used-chi-squared and independent student t-testing applied. mean age . years (sd +/- . , range - ) [deceased group] and . years (sd +/- . , range - ) [living group]. % (n = ) and . % (n = ) were female in the deceased and living groups respectively. within the deceased cohort, . % (n = ) had abnormal liver function (p = . ), . % (n = ) grew pseudomonas (p = . ) and . % (n = ) had candida in sputum (p = . ). correspondingly, in the living cohort . % (n = ) had abnormal liver tests, . % (n = ) and . % (n = ) respectively grew sputum pseudomonas and candida species. the deceased had poorer lung function (p \ . ), weight (p \ . ) and bmi (p \ . ). mean fev was . litres and mean weight . kilograms less than that of the living cohort. poor pulmonary function (fev , fvc), abnormal liver function, sputum culture of pseudomonas and candida spp and suboptimal nutrition (weight, bmi) were all predictors of mortality in our cohort. abnormal lfts are common in cf. we aim to determine any relationship between abnormal lfts & pulmonary function in a cf cohort. cf patients were included during the -month study ( - ). serum bilirubin, alanine aminotransferase (alt), alkaline phosphatase (alkp) & international normalised ratio (inr) were obtained in the outpatient clinic when exacerbation free. lung function (fev ) was concurrently determined. spearman (nonparametric) correlation was applied where appropriate. mean bilirubin was . umol/l (range . - umol/l) and mean alt . iu/l (range - iu/l). . % (n = ) had both above average bilirubin and alt of which ( . %) and ( . %) respectively in the bilirubin and alt groups had fev abnormal liver function did not impact fev however inr showed negative correlation. this may relate to malabsorption of fat soluble vitamins or be explained by a residual coagulopathic state following recurrent pulmonary exacerbations. osteoporosis & vitamin malabsorption contribute to poor nutritional status in cf. we aim to determine the effect of vitamin d deficiency and bone fragility on pulmonary function. systematic random sampling of an outpatient cf cohort was studied. pulmonary function (fev ), vitamin d status (serum) and bone fragility (z-score on dexa) was determined. chi squared analysis was applied to results (spss version . ). patients were included in the study (age - ). . % (n = ) exhibited vitamin d deficiency. of these, a single patient had normal lung function (fev [ % predicted), reduced function (fev - % predicted), markedly reduced function (fev - % predicted) and patient fev \ % predicted (p = . ). vitamin d deficiency was commoner in males (n = ). within the cohort, patients had normal bmd (z-score [ - ), had osteopenia (z-score - - . ) & had osteoporosis (all male) (z-score [ - . ) (n = ). in those with vitamin d deficiency (n = ), patient had osteoporosis & a further osteopenia ( . %) (p = . ). vitamin d deficiency is characterized by lower fev & bmd (osteopenia) however osteoporosis was present in cases of normal vitamin d levels. our study suggests the role bone health plays in the cf ''gender gap'' may be overestimated. biopsy showed nodular glomerulosclerosis (ngs) occurring in the absence of diabetes mellitus, amyloidosis and any other known cause of ngs. a recent paper has suggested that the pathogenesis of ngs in normoglycaemic, non-diabetic cf patients is similar to that of classic diabetes induced ngs and may be mediated by the development of advanced glycosylation end products (age). in cf, chronic pulmonary infection/inflammation, in combination with reduced glutathione levels contribute to an oxidative state and increased levels of age and to s /calgranulin. it is postulated these ligands interacting with rage resulting in the formation of nodular glomerulosclerosis in patients with cystic fibrosis. we conclude that increasing life spans of cf patients may lead to an increased identification of proteinuric renal disease, the aetiology of which may include this newly described pathological process. this is the first case described in a european cystic fibrosis population and the fourth case worldwide. nebulised hypertonic saline is an effective and safe therapy for cf lung disease. however reports show over % of patients cannot tolerate this treatment, and up to % of patients are totally noncompliant when using standard nebuliser units. positive expiratory pressure nebulizer devices splint open the airways and have a more controlled rate of nebulisation. we tested if patients who had failed hypertonic saline via standard nebuliser units could tolerate this therapy via a pep nebulizer. we prospectively recruited adult cf patients over a month period, who had previously failed hypertonic saline trials and commenced them on hypertonic saline via a pep nebulizer. patients completed a questionnaire on tolerability of the new device. notes were examined retrospectively on mean time to intravenous antibiotic usage pre and post therapy and mean time to next exacerbations. there was a subjective reduction of over [ % noted in coughing, chest tightness and bad taste using the pep nebulizer, with all patients tolerating this form of treatment. in this small study we found an absolute reduction in antibiotic usage of % post hypertonic saline usage and a fold increase in time to next exacerbation post nebulized pep treatment. hypertonic saline administered via a pep nebulizer may be a novel therapeutic strategy for patients who cannot tolerate hypertonic saline through a standard nebulizer. chronic lung infection with p. aeruginosa is responsible for most of the morbidity and mortality in patients with cf. cross infection involving the epidemic strains liverpool (les), manchester (mes), midlands (mid ) and clone c has been documented. regular genotyping is recommended to assess distribution of genotypes. genotyping is not currently performed in the belfast trust. the aim of this study is to perform molecular typing of isolates. the results will inform future strategies for laboratory screening, and infection control. p.aeruginosa isolates collected during routine clinics were typed using pulsed field gel electrophoresis (pfge), restriction patterns were analysed using bionumerics. a multiplex pcr ( ) was used to type isolates. samples were typed by both methods and results compared. % of isolates were defined by pfge as the les genotype. . % of adult isolates were defined as clone c. no mes or mid isolates were reported. there was . % correlation between pfge and pcr results. this study reports prevalence of the les strain in the ni cf population. it is recommended that patients with cf infected by p.aeruginosa have all isolates of varying phenotypes genotyped. pcr detection of les isolates will be a useful tool for screening. having successfully derived a method to culture nasal epithelial cells (necs) from cystic fibrosis (cf) and non-cf subjects, the aim of this study was to characterise the electrophysiological responses of these cells. cells from f del/f del patients and non-cf controls were used for patch-clamp investigation. cultured cells were separated and plated on glass coverslips chambers. culture medium was replaced with standard external solution (ses) before establishing whole-cell configuration. membrane ion currents were recorded using patchclamp. once a stable current was achieved, amiloride and forskolin were applied to the cells to elicit their responses. the f del/ f del cells responded to amiloride by rapid reduction in wholecell current, when forskolin was added to the bath it had little or no effect on the cell current amplitude in the cf cells (n = ). in the non-cf cells however, there was a response to the addition of forskolin. these responses to both amiloride and forskolin were as expected and demonstrate that this cell model of nasal epithelial cells obtained from nasal brushings proves to be a very feasible model for future studies of cf and can be used as an ideal model for research into the nature of action of numerous cf drugs. it has been shown that females with cystic fibrosis (cf) have worse lung function compared with cf males. gender and bmi have been correlated with lung function in adults. we aimed to show a similar trend in a paediatric population. we studied children aged years and older attending our cf unit. fev , height and weight were measured at the clinic when patients were at their baseline. of patients, were males ( %) and were females ( %). of the males had fev [ % ( %), had fev - % ( %) and with fev \ % ( %). within the female subgroup, had fev [ % ( . %), had fev - % ( . %) and had fev \ % ( . %) (p = . ). bmi was divided into groups; \ th percentile indicating poor nutrition that may affect lung function and [ th percentile (table ) . no statistical difference was found (p = . ). there was no statistical difference between genders with regards to lung function although there was a trend in favour of males. in our group of well nourished patients, there was no correlation between bmi and fev . this is in contrast to adult data in a similar study. piperacillin-tazobactam induced fever is well documented in patients with cystic fibrosis. here, we report adverse reactions which occurred in three patients treated with piperacillin-tazobactam over a three month period. setting: tertiary care, academic medical centre (beaumont hospital, dublin, ireland). patients and methods: three patients were evaluated retrospectively for piperacillin-tazobactam induced fever and evidence of bone marrow suppression. results: two of our series had evidence of drug induced fever (using criteria by young et al.). both patients had a mean duration of piperacillin-tazobactam exposure of . days with an average temperature of . c. fever resolved in both patients within hours of discontinuation of the antibiotic. neither had evidence of a septic focus (determined by cxr, blood cultures, ivc tip analysis or msu). two of our series developed bone marrow suppression, one becoming pancytopenic requiring bone marrow biopsy, the other becoming transiently neutropenic. both recovered within hours of cessation of offending agent. components of the new iv piperacillin-tazobactam preparation (ph buffers or stabilising agents) may be involved in the development of these late reactions. objectives: cystic fibrosis patients suffer from chronic bacterial colonisation and repeated exacerbations. one of the most challenging elements of treating these patients is that they develop antibiotic resistance. the aim of this study was to assess if changes in antibiotic sensitivity were related to the number of exacerbations (noe). we compared the noe requiring intravenous antibiotics with respiratory cultures at the time. the sensitivities of pseudomonas to antibiotics were analysed from to . we correlated the changes in sensitivities with the noe they had in this period. a univarious analysis was performed using a non-parametric test. noe was used as a dependent variable. thirty-two patients were included. in the piperacillin/tazobactam group, % became resistant with a mean noe of . . (p = . ) no resistance developed with colomycin. % of patients developed resistance to gentamicin. % of patients developed resistance to ceftazidime with average noe of . . (p = . ) only % of patients developed resistance to ciprofloxacin. the findings of this study showed considerable variations with antibiotic sensitivities. twenty-one patients demonstrated some change in sensitivities, and eleven with none. those with antibiotics resistance had a higher noe compared to those with constant sensitivities. slpi is an anti-inflammatory antiprotease that negatively regulates tlr , , and . we examined the effect of the viral rna mimic polyic on cytokine production by evaluating responses it induced in airway epithelial cells; we then evaluated slpi's effect on these responses. we performed selective inhibition studies to identify the receptor by which polyic induces its effects. rna was isolated from cystic fibrosis (cf) and non-cf bronchial epithelial cells and used in quantitative rtpcr reactions with gene- fev \ % ( %) ( %) s specific primers to each receptor. cells were stimulated with polyic in time course and dose response experiments and il- and interferon (ifn)-beta production quantified by elisa. the effect of pre-treatment with slpi or receptor inhibitors was evaluated. polyic induced il- but not ifn beta production. il- production was inhibited by pretreatment with slpi but not by inhibitors to pkr, rig , or mda . further rtpcr experiments demonstrated deficiency of phosphatase shp- , important for interferon production. polyic induces expression of the proinflammatory cytokine il- via a mechanism involving tlr . slpi inhibits this effect. polyic does not induce ifn beta production in airway cells. shp- deficiency demonstrated is a proposed mechanism for this effect. objective: in cystic fibrosis the mechanisms that lead to initial bacterial colonization, the development of a sustained and predominantly neutrophilic inflammatory response, and the ultimate destruction of the lung over decades remains unclear. here we investigate whether humoral autoimmunity could play a role in pathogenesis of cystic fibrosis. circulating autoantibodies in plasma of cystic fibrosis patients (n = ) and of healthy controls (n = ) were studied using immunofluorescense using hep cells as a substrate. selected samples were studied using immunofluorescense on primary bronchial epithelial cells. eight out of cf patients presented igg autoantibodies against hep epithelial cell line and against primary bronchial epithelial cells. there was no apparent correlation between fluorescence intensity and autoantibody titers and the disease intensity. the fluorescence pattern was in all cases mixed (speckled and nucleolar). igg autoantibodies with avidity for bronchial epithelium are present in some patients with cystic fibrosis. this suggest that autoreactive adaptive responses directed against bronchial epithelium may be important in aetiology of the disease and warrant further investigations. the role of pulmonary rehabilitation (pr) has not been widely investigated in patients with diagnoses other than copd. the aim of this study was to investigate the effects of an week pr programme in patients with bronchiectasis. seventeen patients with a diagnosis of bronchiectasis were recruited from respiratory consultant clinics. all patients underwent an -week programme ( supervised sessions) of exercise training and education. subjects were assessed at baseline and on programme completion on measures of exercise capacity and quality of life. data were analysed using minitab version . thirteen patients ( female, male) completed the programmemean age . (sd = . ) years, mean %predicted fev . % (sd = . ). after eight weeks, there was a significant increase (p = . ) in the incremental shuttle walk test distance of . metres ( % ci: . to . m). there was a trend toward a statistically significant improvement (p = . ) in the st george's respiratory questionnaire impacts subscale although there was no statistically significant improvement in the overall score (p = . ). results of this observational study support the potential role of pr in patients with bronchiectasis. robust trials are necessary to assess the effect of such programmes on a range of outcomes, as well as the efficacy of individual programme components. pkcd genetically depleted mice had baseline capillary filtration coefficient (kfc) compared to their wild type counterparts. there was no difference between these groups.similarly, there was no difference between wet-to-dry ratio's at baseline or in response to hydrostatic challenge.however, pkcd knockout mice experienced a significant protective effect when challenged with lps for hours injected intraperitoneally compared to their wild type. this correlated with reduction in neutrophil recruitment to the lung as well as significant attenuation of histological evidence of lung injury. however, there was no significant difference in the respective cytokine profiles. pkcd plays a central role the development of acute lung injury following exposure to lps and may represent a potential therapeutic target in attenuating acute lung injury. the precise mechanisms remains to be elucidated, however it is likely mediated through impaired neutrophil response. mycobacterium tuberculosis (mtb) is responsible for almost million deaths annually (who). the success of the bacillus is largely due to its ability to evade the host immune response. mycobacteria survive s within macrophages by blocking fusion of phagosomes and lysosomes, thus avoiding exposure to antimicrobial peptides and enzymes present in lysosomes. il- inhibits the progression of phagosome maturation in murine macrophages, however little is known about the role of il- on phagosome maturation in human macrophages. pma-differentiated thp- cells were seeded at . x cells/ml on glass coverslips. monocyte derived macrophages (mdms) were isolated from buffy coats obtained from the irish blood transfusion board. cells were treated with anti-il- monoclonal or isotype control antibody, infected with live or killed gfp-bcg and pkh green-labeled m. tuberculosis h ra, and incubated with lamp- antibody and alexa fluorescent stain. the colocalisation of mycobacteria-containing phagosomes with lysosomes, as identified by lamp- , was determined by confocal microscopy. colocalisation of mycobacteria-containing phagosomes with acidified lysosomes was infrequent in untreated thp- cells, % ± . . however colocalisation increased when killed mycobacteria were internalised ( . % ± . ). similarly in cells treated with anti-il- colocalisation increased to % ± . . mdms treated with anti-il- and infected with gfp-bcg showed a significant increase in phagosome maturation compared to untreated mdms. this data suggests il- suppresses the ability of macrophages to proceed with phagosome maturation, favouring survival of mycobacteria within the host. the prevalence of tuberculosis (tb) in ireland is not decreasing and management is becoming more complex with a multi-cultural population and increased drug resistance. there are new presentations (e.g. tb associated with biological agents). shorter rotations for junior doctors may be associated with less familiarity with tb management. we reviewed the appropriateness of our practice by examining the management of randomly selected patients attending our clinic. there was an equal gender balance and % were non-nationals. forty-two percent had pulmonary tb. significant deficiencies in management and documentation were identified. bcg status was not recorded in cases. incomplete data was available on the patients' hiv status. while all patients received pyridoxine prophylaxis, % of patients receiving ethambutol did not have an ophthalmology review. only % of patients received ethambutol. one patient (with multi-drug resistant tb) was transferred to another centre for negative pressure isolation. of the patients who were treated, one did not complete their treatment. this review indicated a need for improved documentation of bcg, hiv status and attention to issues such as ophthalmology review. to achieve this we have developed a clinical care pathway for management of tb in our clinic. background: northern ireland has consistently had a low tb prevalence ( . / , ). however, there has been an increase in cases of mdr-tb admitted to the rvh since . retrospective chart review of mdrtb cases. six patients were admitted between - . five were suspected to have mdr-tb on admission based on epidemiological risks; two had prior tb treatment; one was a contact of mdrtb; two were from countries of high mdr prevalence. four patients had primary mdrtb. the rifampicin resistance probe was positive in all cases. susceptibility testing showed isolates to be resistant to a median of drugs. all were susceptible to second line injectable agents, and / were susceptible to quinolones. one patient was hiv co-infected. patients converted their sputum to culture negative in a median of weeks (range - ) and were considered for discharge when they had negative cultures month apart. hospital admissions were prolonged due to drug toxicities and/or social issues (median hospital stay months, range - ). discussion: due to globalisation, even countries with low tb prevalence need to manage mdrtb. management of these patients is complex, and significant toxicities were seen. prolonged isolation also has significant resource implications. a year old male was admitted from the local psychiatric unit with apparent pneumonia. a chronic schizophrenic and heavy smoker, he had spent some years in institutional care in various facilities. he was treated with high flow humidified oxygen and nebulised bronchodilators. hours later he was found to be sputum smear positive for aafb. he was isolated and the infection control team mobilised. he turned out to have a fully sensitive m.tb organism and responded well to treatment. bts tb guidelines were followed and all staff and patients in the same ward bay as the patient were informed and letters sent to all gps. one patient contact had oesophageal carcinoma and was a chronic alcoholic. he developed post operative pleural effusion (tb culture positive) some months post exposure. a second contact (also alcoholic) was investigated as possible lung cancer some months after exposure and was smear positive for aafb. both patients died on treatment for their tb. all tb isolates were identical. the index case is alive and well. this highlights the danger of even short delays in diagnosis and appropriate isolation of tb patients. streptococcus pneumonia is a leading cause of invasive diseases which will pose an important health problem in ireland. efficacy of pneumovax is between and % (ref ). the vaccination would prevent severe pneumococcal infections (ref ). the purpose of the audit was to determine the rate of update of pneumovax among the chronic respiratory group and to identify reasons why the vaccination may not have been administered. subsequently, address ways of improving current policy. patients who attended the respiratory outpatient clinic in st. james's hospital from july till jan were questioned whether they have the pneumovax given at any stage of the life and ever receive booster dose; and reasons why if they had not been vaccinated. a total of patients were interviewed. . % were male and . % were female. mean age of male was . and mean age of female was . . approx % of patient has obstructive airflow diseases. % has received pneumovax at some stage while % never received pneumovax. the main reason ( . %) is poor awareness of the importance of the vaccine. the main implication from the audit is to raise awareness of pneumovax via campaign, reminding gp; and the funded pneumovax clinic. nursing home acquired pneumonia (nhap) is an important subset of healthcare associated pneumonia. we have prospectively compared three different pneumonia severity scores: pneumonia severity index (psi), modified bts score and naughton score and several inflammatory markers including procalcitonin levels to determine their ability to predict fatality in nhap. this study was carried out on fifty patients presenting to our hospital over a two year period, july to june inclusive. the case fatality rate was %. the modified bts score most accurately identified fatal outcome ( n = ; n = ; n = ). psi and naughton scores were poor predictors with % of deaths characterized as psi category or . procalcitonin levels co-related well with disease severity as measured by the psi and modified bts scores. none of the inflammatory markers accurately predicted patients at low risk of death from nhap. we conclude that the different pneumonia severity scores and several commonly used inflammatory markers fail to accurately predict patients at low risk of death from nhap. the adelaide and meath hospital, tallaght opened in and celebrates its th anniversary this year. we sought to assess changes in the incidence, demographic characteristics, and microbiological profile of tb infection in our institution over this period. patients diagnosed with active tb in the years & were included. patients were identified using laboratory, public health, and hipe records. demographic, clinical, and microbiological data were obtained by retrospective chart review. there was marked growth in the incidence of tb over this period our data emphasizes the re-emergence of tb as a major public health issue in ireland, and highlights immigration as a major contributing factor. the emergence of resistant infection has not to date been seen in our institution, but can be anticipated in the near future. we report a case of a -year-old white male who presented with one month history of pleuritic chest pain. chest radiograph demonstrated left upper lobe cavitation. bronchoalveolar lavage was smear positive for acid-fast bacilli and culture grew pan-sensitive mycobacterium tuberculosis complex. standard anti-tuberculous treatment with rifater and ethambutol was instituted; however the patient developed a severe cutaneous reaction after weeks. skin biopsy demonstrated findings consistent with allergic dermatitis. the rash resolved after discontinuation of therapy; however it recurred after sequential re-exposure to rifampicin, ethambutol, isoniazid and moxifloxacin. the patient underwent desensitization to rifampicin; ethambutol and isoniazid using modified penicillin protocols. titration to target dosing with each individual drug was achieved allowing reinstitution of standard therapy with rifater and ethambutol. the sequential desensitisation processes were each complicated by the reoccurrence of a mild rash, which was controlled by oral prednisolone. to our knowledge this is the first reported case of hypersensitivity to four anti-tuberculosis agents with a favourable response to a strategy of sequential rapid oral desensitisation. introduction: tb is a major infectious disease. in n.ireland the incidence remains low but is increasing. in cases were notified, from the southern trust. a tb nurse was appointed in september . this audit was undertaken to review the tb clinic and optimise the service provided. a retrospective month case note audit. all aspects of the service were reviewed; nationality of those attending, use of interpreter services, the problem of missed appointments and the reason for failure to attend. contact tracing and mantoux testing were assessed as this is a new role for the tb nurse. compliance with treatment in the light of mdrtb cases. results: patients attended the tb clinic in the month period. ( . %) were not native of n.ireland. there have been cases of mdrtb in the trust in the last year which has posed particular operational problems. tb remains an active problem in the southern trust. patient attendance at the clinic may be optimized by having appointment letters in the patients own language and introducing services at peripheral sites. lack of negative pressure ventilation facilities is an ongoing problem. pharmacy dispensing of full treatment course has improved compliance. we sought to analyze differences between patients with latent, pleural and pulmonary tuberculosis (tb) attending a dedicated tb clinic in the mercy university hospital, cork from july to june . two hundred and sixty nine patients were referred to the clinic. one hundred twenty eight ( %) had active tuberculosis, ( %) had latent tuberculosis infection (ltbi), ( %) had an alternative diagnosis and ( %) had atypical mycobacterial infection. among those with active tuberculosis, ( %) had pulmonary tb and had extra pulmonary tb, of whom had pleural tb ( %). in this group of patients with tb infection, female sex and foreignborn status were more frequent in those with ltbi compared with those with pulmonary tb. in contrast, smoking was more prevalent in patients with pulmonary tb. % of patients with pulmonary tb were asymptomatic. mantoux induration was less in those with pleural tb compared with those with pulmonary tb and ltbi. directly observed therapy was implemented predominantly in patients with pulmonary tb and at a rate considerably short of world health organisation recommendations across all groups. the purpose of this study was to determine if the lysophospholipids sphingosine -phosphate (s p) and lysophosphatidic acid (lpa), which have been implicated in allergy, induce up-regulation of adhesion molecules and eosinophil chemoattractants in an in vitro cholinergic nerve cell model, imr- cells. s p and lpa act mainly via g-protein coupled receptors s p - and lpa - respectively. eosinophils accumulate at innervating cholinergic nerves in fatal asthma and in animal models of asthma and adhere to nerve cells in culture via intercellular adhesion molecule- (icam- ). the methods used were real-time pcr and western blotting. s p , s p , lpa , lpa and lpa were expressed on imr- cells. both s p and lpa induced erk phosphorylation and erkand g i -dependent up-regulation of icam- expression in imr- cells, with differing time courses. lpa also induced erk-and g i -dependent up-regulation of the eosinophil chemoattractant, ccl- . the eosinophil granule protein eosinophil peroxidase (epo) induced erk-dependent up-regulation of transcription of s p , lpa , lpa and lpa . thus s p and lpa, acting via g i -coupled nerve cell receptors, induce up-regulation of adhesion molecules and chemoattractants which stimulate eosinophil accumulation and adhesion to cholinergic nerve cells. in turn, epo induces up-regulation of s p and lpa receptors, potentially perpetuating s p-and lpa-induced effects. asthma and rhinitis are characterised by eosinophilic inflammation. however, recent studies indicate that eosinophils are not essential for clinical symptoms, but instead exert a remodelling effect on the local tissues. we propose that neural remodelling involving the bmp pathway, enhancing a cholinergic phenotype, is a potential mechanism of airway remodelling in asthma. imr cells behave like cholinergic neurons when cultured with sodium butyrate. we exposed imr cells to eosinophil granule proteins and to bone morphogenetic proteins & and harvested the cells. proteins were separated into fractions and western blot analysis was performed. rna was isolated, converted to copy dna, and analysed using quantitative pcr. we found that major basic protein, but not eosinophil peroxidase, produced a down-regulation of bmpreceptor a (bmpr a) gene expression ( % reduction at hrs, p = . ). mbp decreased bmpr a in membrane protein and increased bmpr a within the nuclear protein. co-incubation of bmp with mbp attenuated expression of the bmp pathway transcription target id and of choline acetyltransferase. co-incubation with bmp & mbp produced increased expression of id and choline acetyltransferase. these results indicate that eosinophil granule proteins change bmp receptor balance, producing a downstream effect on cholinergic gene expression and therefore on the cholinergic phenotype of cells. exercise-induced bronchoconstriction (eib) has a reported prevalence of - %. this study aimed to measure for the first time, the prevalence of eib and asthma in professional rugby players and to demonstrate the utility of a sport specific field-test as a screening tool in field-sport. prospectively a cohort of senior international rugby players underwent spirometry before and after a rugby-specific exercise challenge. exercise intensity levels were also assessed. a fall in forced expiratory volume in one second (fev ) c % from baseline after exercise challenge was considered diagnostic of eib. during analysis, players were divided into two groups: those with airflow obstruction (ao) and those without (nao). ao airflow obstruction, nao no airflow obstruction forty-two players were tested. table summarises the spirometric results. twelve players ( %) had a history of, or were diagnosed with, airflow obstruction (ao group). seven players had a previous diagnosis of asthma and were on inhaled treatment, of these; % (n = ) had eib after exercise despite regular inhaled therapy. five players ( %) were newly diagnosed with eib. eib is more prevalent in professional rugby players than in the general population. a pre-existing diagnosis of asthma with regular inhaled therapy does not preclude eib. sports-specific field-testing is a useful method of screening in players. ulster hospital, dundonald, regional immunology service, royal hospitals, belfast. asthma is a major risk factor of anaphylactic deaths in children with peanut allergy. peanut allergy is a lifelong condition but some children outgrow their coexistent asthma. it is currently not known whether children who have outgrown their asthma symptoms have ongoing eosinophilic airways inflammation. exhaled nitric oxide is recognised as a non-invasive marker of eosinophillic airways inflammation. the aim of our project was to examine the levels of exhaled nitric oxide in peanut allergic children. children with peanut allergy were recruited at the ulster hospital and royal belfast hospital for sick children, northern ireland. exhaled nitric oxide levels (eno) were measured using the niox mino in all children. results: children were enrolled over a month period, age range to years (median years). ( %) had no history of wheeze, ( %) had outgrown asthma, ( %) had current active asthma and ( %) had occasional wheeze within the last year but were not taking any regular asthma medication. levels of eno were significantly elevated in those with outgrown asthma and those with occasional wheeze but no regular asthma medication (p \ . ). exhaled nitric oxide levels were elevated in children with a history of asthma outgrown and those with current 'untreated' asthma. this would suggest ongoing allergic airways inflammation. our study gives a rationale for checking eno in children with peanut allergy. consideration should then be given to starting inhaled corticosteroid therapy in peanut allergic children with elevated exhaled nitric oxide levels. guideline-defined asthma control, physical activity and bmi omalizumab has been shown to be effective in severe persistent allergic. this study describes our local experience in a group of carefully selected asthmatic sufferers. a retrospective audit was performed on patients with severe persistent allergic asthma who fulfilled the criteria for omalizumab therapy. only those who were regarded as omalizumab-responders were included in this analysis (n = ). the primary outcome measures for the study were acute hospital admissions, exacerbation rates, reliever usage and change in fev . these data were analysed for the six month period prior to commencement of omalizumab and for the six months following. the results showed that as a group acute hospital admissions reduced by %, with a corresponding reduction in exacerbation rates of %. mean fev increased by ml and reliever usage was reduced by %.this is consistent with that reported in the literature. omalizumab has proven effective in our local population of carefully selected severe asthmatics. introduction: difficult to treat asthma (dta) is associated with frequent symptoms despite therapy with high dose inhaled corticosteroids (ics). adolescent asthma presents special difficulties given the associated development issues. we sought to determine objective features of dta in this group. methods: all patients ( - yrs) attending the adolescent asthma clinic were reviewed. clinical data was collected at referral. dta was defined as requiring high dose ics (bdp) of [ mcg/day (\ yr) or [ mcg/day ( - yrs). the dta group was compared with remainder on low dose ics. of a total of ( f: m) patients, ( %) had dta with a mean ics of mcg/day. there were no significant differences in steroid rescue, bmi, fev /fvc, serum ig or eosinophil level, dust mite responsiveness, eczema, rhinitis, or smoking. dta patients were more likely to have elevated eno ( vs. ; p = . ) and lower ige level ( vs. ; p = . ). co-existing conditions more likely in dta included grass allergy (p = . ), any food allergy (p = . ), gord (p = . ) and vcd (p = . ). conclusions: dta in adolescents was associated with higher eno and lower ige levels, grass and food allergy, gord and vcd. identification of these features early can potentially facilitate more comprehensive and effective management. omalizumab is a monoclonal ige antibody which reduces asthma exacerbations. it is only cost effective in severe asthmatics with recurrent exacerbations. to assess the outcome of omalizumab treatment in severe asthmatic patients in the respiratory department of connolly hospital. a retrospective chart review of asthmatic patients treated with omalizumab. baseline demographics, omalizumab dose and frequency, other asthma medications, fev , exacerbation rates, and side effects were reviewed. male to female ratio was : . mean age was . years. mean ige level prior to omalizumab was . u/ml. mean fev prior to treatment was . %. mean fev post treatment was . %. prior to omalizumab five patients were on step of gina treatment guidelines, patients were on step . four patients reduced their shortacting beta agonist requirements, one patient was weaned to a lower dose of steroid and patient increased their inhaled steroid dose during the treatment period. patients had recurrent exacerbations prior to treatment. mean number of exacerbations during year of treatment was . . the most common side effect experienced was joint pains. treatment with omalizumab reduced exacerbation rates in these severe poorly controlled asthmatics. airway sensory hyperreactivity (shr) is an important clinical feature in chronic cough and is characterised by bouts of coughing triggered by relatively innocuous stimuli including exposure to aerosols, scents and changes in air temperature. these abnormal sensory responses are often what distress a patient most about their condition . the aim of this study was to determine the prevalence and clinical features of shr in patients with chronic cough. we undertook a retrospective case review of sequential referrals to the belfast city hospital cough clinic. we defined shr + as those individuals reporting cough provoked by one or more of the following; ) change in air temperature (thermoactivation), ) exposure to aerosols, scents, odours (chemoactivation), ) talking, laughing or singing (mechanoactivation). we compared shr + with shr-patients across a range of variables using chi-square and analysis of variance as appropriate. charts were available for review. we identified shr + in ( %) with significantly more females in the shr + ( % versus %, p = . ). no other features including age, cough duration, cough aetiology, atopic status, preceding urti or pc reliably distinguished shr + from shr-patients. these preliminary results suggest shr is a common problem especially among females with chronic cough. omalizumab is a humanized monoclonal antibody to ige which prevents binding to fceri receptor. it is known to increase eosinophilic apoptosis and inhibit the th immune response culminating in a reduction in eosinophil recruitment, activation and tissue migration. omalizumab use in the management of css however has been reported in one case to ameliorate the asthmatic component of the disease and to significantly lower plasma eosinophil counts at three months. our patient, mb, a year old man diagnosed with css years ago manifesting with uncontrolled asthma, severe pan-sinusitis with recurrent nasal polyposis, eosinophilic gastoenteritis histologically confirmed with duodenal biopsy and subacute bowel obstruction. initial eosinophil count was . /l., with an elevated ige level of u/ml. autoantibodies were negative. mb's extrapulmonary symptoms were well contolled with oral steroids and azathioprine. efforts to minimize oral steroid doses were hampered by persistent asthma and rhinosinusitis as well as a relapse of eosinophilic gastroenteritis in . omalizumab was commenced in june . after weeks, apreciable improvements in asthmatic and sinusitis symptomes were noted. average peak flow improved from to l/m and a reduction in peripheral eosinophil count from . to . /l. a paediatric asthma telephone clinic (patc) was set up in our hospital to provide follow up for children with mild asthma. structured telephone interviews with children aged between and and their carers who received detailed asthma education, was conducted and subsequent appropriate clinical action initiated. the aim of this study is to assess the effectiveness of the patc for medical surveillance by the asthma nurse. a retrospective review of case notes of the children referred to the patc was conducted. unscheduled use of health care & use of antibiotics or steroids between time of the patc and the next out patient clinic were recorded. pulmonary function was compared pre and post the patc. descriptive statistics were carried out and a paired t test was used to detect any significant change in lung function. forty one patients were referred to the patc with asthma. only ( %) had an unscheduled visit to the gp and no patient presented to s the emergency department. there was no significant change in pulmonary function. routine follow up of children with mild asthma and their carers by an asthma nurse via a structured telephone consultation can be considered an alternative to face to face follow up. further evaluation comparing the patc to an outpatient clinic and assessment of child/ carer satisfaction could confirm this. approximately , ( . %) patients received inhaled shortacting beta agonists in combination with a regular standard-dose inhaled corticosteroid.. a further , ( . %) patients were also prescribed a regular inhaled long-acting beta agonist (salmeterol or formoterol). patients ( . %) on combination therapy were coprescribed four different asthmatic treatments inclusive of oral prednisolone. approximately ( . %) of the patients prescribed a respiratory drug were co-prescribed nicotine replacement therapy. in total there were , patients prescribed a mucolytic drug in combination with a respiratory drug b) there were significant levels of coprescribing of salbutamol with beta blocking agents at . % ( %ci: , . ). in addition . % ( %ci: . , . ) of the patients prescribed theophylline in were also prescribed ciprofloxacin. c) levels of co-prescribing with antibiotics was %. the antibiotics coprescribed were augmentin, clarithromycin, cephalosporins and ciprofloxacin. assessing changes in asthma control is difficult. peak flow diaries are not completed and history is subject to recall bias. with a view to developing an electronic asthma management system, we attempted to use breath acoustics to assess changes in respiratory status. spirometry and breath sounds were simultaneously recorded in asthmatic subjects during histamine challenge. breath sounds were recorded by a microphone over the trachea. data was collected from seven male and four female subjects with a mean age . yrs. acoustic features were extracted from the breath sounds and evaluated for a correlation with the percentage change in fev . the highest correlation occurred between the duration of exhalation and percentage change in fev (r = - . ). fev showed a correlation with number of wheezing episodes (r = - . ), median wheeze frequency (r = - . ), maximum wheeze duration (r = . ), frequency of maximum duration wheezing group (r = - . ) and mean frequency of the wheezes(r = - . ). using these features together (combined in a linear discriminant classifier) a % drop in fev was detected with a sensitivity of % and specificity of %. the results of this study suggest a strong relationship between duration of exhalation and fev .the study also showed that combining acoustic features can be beneficial in detecting a decrease in fev . the liver disease of alpha- antitrypsin deficiency (aatd) is associated with endoplasmic reticulum(er) stress. seps is a selenoprotein that through a chaperone activity decreases er stress. we aimed to determine the effect of seps on er stress in this condition by measuring activity of the grp promoter and levels of active atf as markers of the unfolded protein response in hepg cells transfected with zaat transgene. we investigated levels of nfjb activity, a marker of the er overload response. to determine the effect of selenium supplementation on the function of seps we investigated glutathione peroxidase activity, grp promoter and nfjb activity. we also investigated the anti-inflammatory effect of selenium through the -deoxy-d , -prostaglandin j pathway( d-pgj ) and checked selenium levels in a population of zz and mm phenotypes for aatd. seps reduced levels of active atf . overexpression of seps also inhibited grp promoter and nfjb activity and this effect was enhanced in the presence of selenium supplementation. increased d-pgj concentrations were found in selenium supplemented cells. we demonstrated serum selenium levels to be in the low normal range in the patients tested. this data demonstrates a role for seps in this conformational disease and suggests a possible therapeutic potential for selenium supplementation. alpha- antitrypsin (a at) is a glycoprotein synthesised chiefly in the liver and functions as the most important antiprotease in the lung and also demonstrates anti inflammatory properties. it has previously been demonstrated that a at is packaged along with neutrophil elastase within the primary granules of these cells [ ] . thus there remains a paradox as to why an enzyme and cognate inhibitor would simultaneously compartmentalize, potentially impeding protease antimicrobial activity. this aim of this study was to reevaluate the localisation of a at within the neutrophil. compartmentalisation of a at within the neutrophil was established by sub-cellular fractionation, western blot analysis and confocal immunofluorescence. our data clearly show that a at is a genuine outer membrane protein of neutrophils associated with cholesterol-and sphingolipidenriched membrane domains called lipid rafts. we have observed that treatment of neutrophil membranes with phosphatidylinositol-specific phospholipase c (piplc) or high nacl concentrations removed a at from the neutrophil membrane indicating that localization of a at in lipid rafts is mediated by electrostatic interactions to a glycosylphosphatidyl-inositol (gpi) linked membrane protein. further studies will address the relevance of neutrophil associated a at and may support the theory that the anti inflammatory effects of a at are not simply related to modulation of serine proteases activity. aat deficiency (aatd) is a hereditary disorder, resulting from mutations in the serpina gene, classically presenting with earlyonset emphysema and liver disease. the most common mutation associated with aat deficiency is the z mutation, with the s mutation also associated with lung disease. aat deficiency is under-diagnosed and prolonged delays in diagnosis are common. world health organisation guidelines advocate screening patients with copd, asthma, cryptogenic liver disease and first degree relatives of known aatd patients. zz aatd patients on the national alpha- registry (n = , . +/- . years, male, female) were compared to a cohort of mm copd patients (n = , . +/- . years, male, female). mean aat levels in the zz group were . +/- . g/l compared to . +/- . g/l in the mm copd cohort. the mean fev for all zz patients was . +/- . % compared to . +/- . % for mm copd patients. however, when zz cases identified by family screening were removed, the mean fev of the zz cohort was lower than the mm group ( +/- . %, p = . , compared to mm group). when mm and zz groups were stratified by smoking status, zz smokers had mean fev of . +/- . % compared to . +/- . % for never smokers, while mm smokers had mean fev of . +/- . % compared to . +/- . % for never smokers. these findings underline the clinical significance of the zz phenotype and smoking in the development of copd. ). in the present study we examined the immunomodulatory activity of aat and investigated whether nadph-oxidase activation via the g-protein coupled n-formyl-methionyl-leucyl-phenylalanine (fmlp) receptor was inhibited by aat. oxygen (o ) consumption was quantified using a clark-type oxygen electrode and o production was determined by superoxide dismutase (sod)-inhibitable reduction of cytochrome c. both the rate of o consumption and o production elicited by fmlp ( - m) was significantly inhibited in the presence of aat ( lm). in addition, inhibition of o production was dose dependent and almost completely inhibited by . lm aat. mechanisms of inhibition were investigated and found to be mediated through a decrease in intracellular camp. levels of camp at seconds post fmlp stimulation were elevated to . ± . pmol/ neutrophils, whilst co-treatment with aat ( . lm) reduced camp levels to . ± . pmol/ cells. in conclusion, the observed inhibition of neutrophil nadphoxidase activity by aat, is further evidence supporting a role for this molecule as an anti-inflammatory mediator. alpha- antitrypsin (aat) is a serum glycoprotein that inhibits proteases, and is produced mainly by hepatocytes. it is particularly important in dampening the action of neutrophil elastase, which can damage the lungs. aat deficiency results from both a qualitative and a quantitative deficiency of the protein which predisposes to the development of emphysema, chronic bronchitis, bronchiectasis, and liver disease. we investigated patients registered on the irish alpha- database as aat deficiency mz phenotype. the information gathered from the database was supplemented with chart reviews for clinical information and pulmonary function tests. mz patients had a mean fev % predicted of . +/- . %. we note that there is a negative correlation between cigarette pack years and fev % predicted (r = . ). the serum level of aat does not necessarily correlate negatively with fev (r = . ). nearly % of mz patients were detected by family screening of known aat deficient patients. it remains uncertain whether mz patients are predisposed to aat deficiency sequelae when compared to the general population. we aim to settle this uncertainty by comprehensively describing the characteristics of this cohort of patients. this may represent a change in the way mz patients are managed and could implicate earlier preventative measures to decrease the likelihood of developing emphysema. alpha- antitrypsin (aat) is produced by hepatocytes, and is the most important antiprotease in the lung. aat deficiency (aatd) is a hereditary disorder resulting from mutations in the aat gene, presenting with emphysema in adults and liver disease in childhood. who guidelines advocate a targeted strategy in screening copd, non-responsive asthma, and cryptogenic liver disease patients and also relatives of known aatd patients. the most common phenotype associated with disease is zz followed by sz. a chart review of aatd patients on the national alpha- registry was performed on zz (n = ) and sz (n = ) patients. the mean age at diagnosis for zz patients was . +/- . years for males and . +/- . years for females. we demonstrate that zz individuals identified as a result of family screening have significantly increased fev ( . +/- . %, . +/- . years) when compared to zz patients identified by targeted symptomatic screening ( . +/- . %, . +/- . , p = . ). zz and sz patients who smoked had significantly decreased lung function compared to nonsmoking zz and sz and that a positive correlation between pack years and fev exists. our results emphasize the need for increased awareness and early detection of asymptomatic aatd. identification of patients from a targeted detection programme should include aggressive family screening and allow the initiation of preventative measures before significant lung disease has occurred. thirty-three females age - mean and males, age - , mean underwent cpx. mean bmi in females was . ( . ) and . ( . ) in males. most tests were done because of unexplained dyspnoea ( ). other reasons for requesting cpx were: assessment for fitness for lung cancer surgery ( ); assessment of fitness in patients with sarcoid ( ); cardiac transplant assessment ( ); pre surgical assessment for other major surgical procedures ( ). the data on the patients who underwent cpx for unexplained dyspnoea was analysed. mean bmi was . . thirty-two of these patients had normal lung function. as a group these patients were extensively investigated before coming for cpx, had ct scans performed, had lung perfusion scanning, had echocardiography. forty-one of the patients had sub maximal tests with no evidence of cardiac or respiratory disease, the test being limited by reconditioning. in conclusion, cpx is a valuable tool in this district general hospital with various reasons for requesting the test. in patients with unexplained dyspnoea, it may be prudent to request cpx at an earlier stage in the investigative journey. sarcoidosis is a multisystemic disease of unknown aetiology. prognostic biomarkers are not part of routine clinical practice. our hypothesis is that enhanced activity for myofibroblast differentiation in sarcoidosis at the initial diagnosis and is associated with an adverse prognosis and the development of pulmonary fibrosis. in addition we investigate the role of tgf-b in this process. fifty patients with biopsy proven sarcoidosis (stage i n = , stageii n = , stage iii n = ) were enrolled. bronchoalveolar lavage (bal) samples were obtained at initial evaluation. primary lung fibroblasts (ccd- lu) were incubated with bal samples and a-smooth muscle actin (asma) mrna expression as a marker of myofibroblast differentiation was assessed via rt-pcr. asma mrna was significantly elevated up to % (above control) in patient's samples. we also found a significant correlation between asma mrna expression and progression of pulmonary disease in sarcoidosis, (p \ . ). to investigate the role of tgf-b contributing to this enhanced myofibroblast differentiation, we coincubated bal samples with saturating concentrations of anti-tgf-b antibody and found a % reduction in this biological activity, (p \ . ). in conclusion we demonstrate firstly enhanced capacity of bal samples to induce myofibroblast differentiation, secondly it is of prognostic significance and finally tgf-b is a significant contributor to this biological activity (fig. ). we present a case of cs seen recently at our hospital and the management undertaken for this yr old, the son of a tuberculosis specialist in south africa. his main symptom was exertional syncope with evidence of conduction abnormality on ecg, poor cardiac function on echocardiogram with normal coronary angiogram. an exercise stress test induced ventricular tachycardia. a dual chamber pacemaker and a defibrillator were placed. he had several hospital admissions over a year with ventricular tachycardia/ ventricular fibrillation. cardiac ablation followed electrophysiological studies. cardiac biopsies confirmed cs. there was no evidence of pulmonary or eye involvement. we discuss diagnostic tests and criteria and also treatment options. corticosteroids are believed to control the inflammation and fibrosis, preventing cardiac dysfunction. we closely follow his progress to assess long term effect of steroid treatment especially on his arrhythmia. idiopathic pulmonary fibrosis (ipf) is a progressive disease frequently associated with terminal respiratory failure. the insight patients with ipf have into their disease process and prognosis is unknown. this may lead to delayed communication regarding end-of-life issues. we studied insight into disease and attitudes towards invasive ventilation (iv) amongst a group of ipf patients and compared these outcomes with copd patients with a comparable severity of disease. ten patients with ipf and eight patients with copd were studied. spirometry, the minute walk test and arterial blood gas were recorded as markers of severity. patient insight into disease and attitudes towards iv were surveyed using a newly developed questionnaire. % of patients with ipf felt they had sufficient information about their illness compared to % of copd patients. % of ipf patients had discussed prognosis with their doctor, versus % with copd. if the need arose, % of ipf patients wanted iv compared with % of copd patients. only one patient felt that the issue of iv should not be discussed. there is a deficiency in knowledge regarding disease process and prognosis among ipf patients. end of life issues and iv should be carefully addressed with these patients. coeliac disease is a gluten sensitive enteropathy that results in a chronic malabsorptive disorder. the disorder is rarely associated with pulmonary conditions though the link between the gut and lung remains obscure. conditions include the rare association with pulmonary haemosiderosis (hamilton lane syndrome) and for the first time to the best of our knowledge, pulmonary alveolar microlithiasis(pam). we also describe a literature review of the pulmonary associations of coeliac disease. pulmonary haemosiderosis is a form of pulmonary haemorrhage syndrome progressing to pulmonary fibrosis. we describe pulmonary haemosiderosis and capillaritis in a year old female coeliac, an association known as hamilton lane syndrome. treatment involved corticosteroids and a gluten free diet with resolution of her symptoms. pam is a rare disease where minute calculi are found in alveoli resulting in progressive pulmonary fibrosis. no association with coeliac disease has previously been published. we describe a case of a year old female coeliac who over years developed pulmonary fibrosis secondary to pam. there is no effective treatment and individuals may progress to transplantation. coeliac disease should be considered in patients presenting with pulmonary haemorrhage/ haemoptysis and in patients with interstitial lung disease where histological findings are consistent with pam. the vdi at and months with pulmonary involvement were significantly higher (p = . , p \ . respectively), but not at month. a vdi [ has been associated with a fold increase in mortality. ( %) with pulmonary involvement had a vdi [ at initial presentation compared to ( %) (p \ . ) without pulmonary involvement. the percentage with vdi [ in the pulmonary patients reduced at and months ( % and % respectively, p = . ). ( %) of patients with pulmonary involvement at presentation had eu-vas criteria for generalised and severe subgroups compared to ( %) without pulmonary involvement (p \ . ). of patients died had pulmonary involvement; one was attributed to vasculitis. we conclude that pulmonary involvement at presentation is highly predictive of severe organ damage (vdi [ ) at initial presentation and year and more extensive disease activity (bvas (all stages) and euvas) in anca-associated vasculitis. background: levels of adenosine can be rapidly increased during settings of inflammation and acute lung injury. these increases in adenosine have been implicated in pathological progression of lung diseases, as well as, protection against acute lung injury. we tested the effects of elevated adenosine levels on endothelial barrier function in vivo and in vitro. methods: intracellular levels of adenosine were elevated in rodents through inhibition of adenosine deaminase with pentostatin, and lung edema was measured in models of acute lung injury caused by a-naphthylthiourea (antu). the degree of antu-induced lung edema, as measured by lung wet to dry weight ratios and filtration coefficients (k f ), was significantly diminished in the rodents given pentostatin either before or after the antu injury. in vitro analyses using pulmonary artery endothelial cells plated on a monolayer demonstrated that adenosine receptor a a and a b agonist, n-ethylcarboxamidoadenosine (neca), improved permeability. while no significant effects were noted with adenosine receptor a , a a , a b , or a inhibitors or adenosine transporter inhibitors alone, we noted a significant attenuation of the adenosineinduced barrier function enhancement in the presence of adenosine receptor a a and a b antagonists, and adenosine transporter inhibitor, nitrobenzylthioinosine (nbti). adenosine enhances the pulmonary endothelial barrier function in acute lung injury through interaction with a a and a b receptors. childhood interstitial lung disease (child) comprises a spectrum of heterogenous disorders characterised by tachypnoea, radiological diffuse pulmonary infiltrates and abnormal histology. pathologies largely unique to children presenting in the first two years of life are now appreciated and up to % of cases may be inborn errors of surfactant metabolism leading to surfactant dysfunction . we report our experience of child in infants presenting to the royal belfast hospital for sick children over years and describe the presentation, investigations and clinical outcome in this group. all children presented with chronic tachypnoea, hypoxaemia, crackles, indrawing and failure to thrive. differential diagnoses of cystic fibrosis, aspiration, immunodeficiency and cardiac disease were considered and excluded in all cases. nine children had a hrct scan, the commonest finding being a 'mosaic' or diffuse interstitial pattern and four underwent lung biopsy, none of which resulted in a definitive diagnosis. eleven children were treated with inhaled corticosteroids and three with additional systemic steroids and all have experienced clinical resolution over time. the recent identification of the genes responsible for surfactant dysfunction disorders may, in future, obviate the need for a lung biopsy and be diagnostic in approximately % of children. screening of patients with contrast echocardiography, thoracic computerised tomography (ct) and cerebral magnetic resonance imaging (mri) has identified patients with definite hht, ( %) of whom had epistaxis, ( %) had telangiectasia and ( %) had a first-degree relative with hht. contrast echocardiography and/or ct were performed in patients, identifying patients ( %) with pulmonary arteriovenous malformations (pavms). nineteen patients with single or multiple pavms had embolization procedures performed, with - pavms embolized per procedure. mri was performed in ( %) patients but no cerebral arteriovenous malformations (cavms) were diagnosed. hht incidence in ireland is thought to be in - , , suggesting that there are many more undiagnosed cases nationally. internationally published data suggest a prevalence of - % for pavms and - % for cavms in patients with hht. while the prevalence of pavms in our group is consistent with these data, the prevalence of cavms is not, suggesting that irish patients with hht may differ genotypically and phenotypically from those in other countries. atrial and c-type natriuretic peptides (anp, cnp) are known vasodilators in many vascular beds. the role of npr-c in natriuretic peptide (np) mediated pulmonary vasodilation remains unknown. furthermore the role of endothelium in mediating vasoactive effects of np is controversial. using isolated ventilated-perfused lungs to monitor pulmonary artery (pa) pressures upon exposure to increasing doses of angiotensin ii in the presence of vehicle or anp, cnp, or the selective npr-c ligand, canf. additionally, using isolated pa rings constricted with phenylephrine, concentration dependent relaxations were measured in response to nps in endothelium intact/denuded vessels. results: anp and cnp but not canf significantly attenuated the vasoconstrictive properties of angiotensin ii in isolated perfused lung. similarly, canf had no vasodilatory effect in constricted pa rings. anp and cnp both vasodilated the pa rings. however, only cnp had endothelium dependent vasodilation at doses higher than - m. the endothelium dependent vasodilation was completely abolished by pretreatment with l-name, no synthase inhibitor, and iberiotoxin, a k + channel blocker. pretreatment with a-glycyrrhetinic acid ( a-ga), a myoendothelial gap junction inhibitor, and indomethacin, a cyclo-oxygenase inhibitor, had no effect on endothelium dependent vasodilation. conclusion: npr-c plays limited role in np mediated pulmonary vasodilation. the endothelium dependent effect of cnp is mediated by no and bkca channels. pulmonary embolism with potential fatal consequences is common amongst acutely ill medical patients. it is recognised that venous thromboembolism (vte) prophylaxis is underutilised in this population. we postulated that an education campaign could increase its usage. we prospectively studied consecutive medical admissions for one month before and after an educational intervention to see if the rate of thromboprophylaxis prescribed increased in patients who warranted such prophylaxis as recommended by the american college of chest physicians (accp) guidelines. prior to an educational intervention, we studied ninety-nine consecutive medical admissions. thirty-six patients in this group met criteria for prophylaxis and had no contraindication to prophylaxis. nineteen ( . %) of these patients received prophylaxis and seventeen ( . %) did not receive prophylaxis. the data were presented to the medical staff and the guidelines were discussed (educational intervention). subsequently, of consecutive medical admissions, met the criteria for prophylaxis. thirty-six ( . %) of these patients received thromboprophylaxis. compliance with the accp guidelines therefore rose from . % to . % (p = . ; fisher's exact test) of those eligible following the educational intervention. our data supports the use of education to increase adherence to guidelines which may improve outcome in acutely ill medical patients. venous thromboembolic disease is a major cause of morbidity and mortality amongst medical inpatients. prophylactic therapy with low molecular weight heparin, unfractionated heparin, and graded compression stockings has been shown to significantly reduce risk of pe & dvt. we sought to assess compliance with current international guidelines in a medical inpatient population, as well as the impact of a simple, prominent educational poster at ward and emergency department level. data was collected using a proforma derived from current accp guidelines. collection was performed on dates, before and one month after intervention. patients were assessed on each date. at baseline, prophylaxis was indicated in % (n = ) of patients. of these % (n = ) received appropriate therapy. compliance was best among specialist disciplines such as stroke medicine. acute s medical teams fared less well. among the post-survey cohort, prophylaxis was indicated in % (n = ), and prescribed in (n = %) (p = . for comparison) of these. vted prophylaxis is under prescribed. our results suggest that simple educational measures can improve compliance with established international guidelines. however, more interactive methods may yield greater benefits. pulmonary arteriorovenous malformation (pavm), a rare cause of hypoxia, are familial in % manifesting as osler weber rendu (owr) syndrome and are associated with embolic stokes in % ( , ) . this report highlights a case of hypoxia secondary to pavm with a family history of embolic strokes not associated with owr. a year old man was admitted with dyspepsia. admission chest x-ray identified a left mid zone mass. he had no medical history. his mother died from a stroke aged and had an ''abnormality in her lung''. his brother died at age from an embolic stroke. shortly after admission, he complained of dyspnoea. physical exam revealed oxygen saturations of %, tachypnea and tachycardia. oxygen saturations improved to % on % oxygen. he had no telangectasia or other signs of owr syndrome. ct pulmonary angiogram displayed a large pavm in left lower lobe. a contrast echo identified a large extracardiac right to left shunt. endoscopy confirmed oesophagitis secondary to excessive alcohol intake. he was discharged on aspirin pending review by cardiothoracic surgery for definitive treatment of his pavm to prevent worsening of his symptomatic hypoxia and reduce his risk of an embolic stroke. it has been hypothesised that fatigue of the genioglossus muscle contributes to collapse of the upper airway in osas. in this study, fatigability of the genioglossus was compared in healthy control subjects (aged - ) and osas patients (aged - ; apnoea/ hypopnoea frequency - /hr) using surface electromyographic (emg) signals recorded with a novel intra-oral electrode. emg signals were recorded during sustained isometric tongue protrusion at % of maximum voluntary contraction. endurance time was the point at which force fell % below the target level. muscle fibre conduction velocity (cv), an index of fatigue, was estimated from two adjacent emg signals and the rate of muscle fibre cv decrease during each contraction was calculated. the mean endurance time was lower in patients ( . ± . secs) than controls ( . ± . secs). in addition, the mean rate of decrease of muscle fibre cv, when normalised to an initial value of one, was greater in patients ( . ± . percent per second) than in controls ( . ± . percent per second). together, these results suggest increased susceptibility to genioglossus fatigue in untreated osas patients. furthermore, this approach provides a means of examining the role of fatigue in the pathophysiology of osas. obstructive sleep aponea (osa) is characterised by recurrent collapse of the airway during sleep leading to reduced or complete cessation of airflow despite respiratory effort, causing fragmented sleep and excessive daytime sleepiness. sleep deprivation is thought to be responsible for up to % of road traffic accidents. we examined data on the occupation of consecutive patients treated for osa with continous positive airway pressure (cpap) in our institution. specifically the numbers driving vehicles as the primary part of their occupation. drivers made up % ( ) of the total. this included taxi drivers ( ), bus drivers ( ) and train drivers, delivery persons ( ) and drivers of other vehicles ( ) . this data is of major importance given that the rate of osa in the populaiton is estimated at - %, whilst drivers making up % of our diagnosed osa polulation. it has major implications for service provision, the safety of all road users and those legislating in this regard. to avoid expensive sleep laboratory diagnosis of osa, we provide a home-based monitoring service with overnight oximetry and/or five channel limited sleep study. we wished to review these studies to assess their usefulness in reaching a diagnosis and to look at practical difficulties that may arise. we reviewed all oximetries and sleep studies, in patients with suspected osa, requested by one consultant in months period in st. john's hospital limerick and the mid-west regional hospital. of the oximetries, . % were suggestive of mild, . % moderate and . % severe osa. % were normal, . % borderline and . % malfunctioned. patients did not attend their first appointment. % of patients were waiting less than weeks. of the limited sleep studies, . % were suggestive of mild, . % moderate and . % severe osa. . % were normal. patients ( . %) had prior non-diagnostic oximetries. there were a large number ( ) of non-attendants for sleep study; we attribute this to longer waiting time and lack of secretarial back-up. there was minimal damage to the equipment. patients were started on long term cpap, to date nearly % are persisting with this. this confirms that home diagnosis of osa is both feasible and practical. both conditions represent a significant burden to the health service in terms of diagnosis, treatment and management. volunteers agreed to undergo a home limited cardiopulmonary sleep study and to interview with questionnaires including the epworth score. studies were manually scored to determine the apnoea hypopnoea index. results: volunteers were recruited, were excluded due to incomplete studies and withdrew consent. subjects ( female) were analysed, mean age: yrs (range - ), mean bmi: (± . ). significant osahs (ahi [ ) was found in females ( %) and male ( %) subjects, % overall. conclusion: osahs is very common in this group of patients without being the primary reason for attendance. this would suggest that osahs remains under-diagnosed particularly in the context of cardiovascular disease. we suggest that there should be routine screening for osahs in this patient group. to assess newly diagnosed patients with osahs for cardiac dysfunction by echocardiography. background: osahs is a common condition occurring in approximately % of men and % of women. it is associated with an increased morbidity and mortality from cardiovascular disease. newly diagnosed patients (ahi [ ) attending the sleep clinic in st. james's hospital were sent for echo to determine evidence of early heart changes in this group. results: patients were scanned ( female). average age: years, (range - yrs) with average weight of kg (+/- ) evidence of diastolic dysfunction was found in female ( %) and of the male subjects ( % the nf-jb inflammatory pathway is selectively activated by intermittent hypoxia in vitro and in patients with obstructive sleep apnoea syndrome (osas). nitric oxide (no) acts as an important signalling molecule in several biological processes including inflammation. we hypothesise that no plays a critical role in regulating the microenvironment of intermittent hypoxia and in modulation of the associated nf-jb response. serum nitrite and nitrate levels were measured in osas patients with no other medical disorder and healthy controls (body mass index-and age-matched). levels in osas patients were remeasured following continuous positive airway pressure (cpap) therapy. we also investigated the effect of no on transcriptional events initiated by intermittent hypoxia in an in vitro model. serum nitrite and nitrate levels did not differ between osas patients and controls (p = . and p = . respectively). nitrite levels in osas patients increased significantly following cpap therapy ( . lm compared to . lm (p = . )), indicating increased endothelial nitric oxide synthase (nos) activity. in our translational in vitro model no increases oxygen bioavailability in hypoxia through mitochondrial inhibition and decreases intermittent hypoxia-induced nf-jb activity. conversely, nos inhibition increases nf-jb activity. the findings support a role for no in regulating the inflammatory response to intermittent hypoxia. continous positive pressure (cpap) is an effective therapy for obstructive sleep aponea (osa). it's efficacy is limited by several factors including variable compliance with therapy. compliance is defined as cpap usage of greater than hours more than % of nights. studies of predictors of compliance have shown conflicting results. data on patients with osa treated with cpap in our institution was examined including aponea-hyponea index (ahi), oxygen desaturation index (odi), minimum oxygen saturation, epworth sleepiness score (ess) and compliance rates. the overall compliance rate was found to be %, with overall compliance at weeks following initiation of therapy . %. this rate compared with compliance of . % at months. this suggests that week compliance rates are a good marker of longer-term compliance. obstructive sleep aponea (osa) is characterised by recurrent collapse of the airway during sleep leading to reduced or complete cessation of airflow despite respiratory effort. this leads to sleep fragmentation through multiple arousals with poor sleep and has been associated with major co-morbidities including impaired cognition, poor quality of life, and increased risk of accidents. evidence is emerging that osa is an independent risk factor for adverse cardiovascular outcomes. we treat over one hunderd patients for osa with continous positive airway pressure (cpap) in our institution. patient data including body mass index, neck circumference, aponea-hyponea index (ahi), oxygen desaturation index (odi), lowest oxygen (o ) saturation, epworth sleepiness score (ess) was collected. neck circumference was correlated with markers of disease severity and found to be a predictor of more severe disease as defined by higher ahi and lowest o saturation. no correlation was found with odi or ess. we propose that this is a useful and easily obtained marker of severity of osa. prompt management of exacerbations is a cornerstone of effective treatment of cystic fibrosis. it is therefore imperative that patients promptly report changes in symptoms to their physician/cf team. we sought to clarify which symptoms patients would report to the clinical team and when they would report them. an anonymous questionnaire was sent to a random sample of stable adult patients with cystic fibrosis ( male and female). predictors of early response were evaluated using logistic regression. % returned questionnaires that were suitable for analysis. for all symptoms a significant number of patients would not contact the medical team before their next routine out-patient appointment or even report it at all (table ). there was a wide variation in the time to alerting the clinical team between and within symptoms. females were significantly more likely to report a change in small volume haemoptysis or cough before their next out-patient appointment. younger patients were more likely to report small and large volume haemoptysis. delayed patient responsiveness to changes in respiratory symptoms is a barrier to prompt management of exacerbations in cf. supported by: health research board, cf association of ireland. bronchoalveolar lavage can be used to investigate pulmonary aspiration in children by measuring pepsin concentration, however, it is invasive. sputum induction is a potential non-invasive way of obtaining samples. we aimed to: ( ) assess safety and feasible of measuring pepsin in inducted sputum in children and ( ) determine whether the sputum induction procedure caused gastro-oesophageal reflux with refluxed pepsin contaminating samples. children with no respiratory or gastroesophageal symptoms were recruited (n = , range - years). following spirometry, sputum induction was carried out and pepsin concentration measured by an 'in house' elisa. spirometry was repeated and any complications noted. only one child (aged ) produced no sample, however two other year olds did complete sputum induction. no adverse effects were reported. one child required a sabutamol nebuliser following a % decrease in fev . of the sputum samples ( %) were positive for pepsin. sputum induction appeared a safe procedure in children. it is well tolerated by children and can be successfully carried out in children as young years of age. however, the analysis of pepsin in sputum obtained by induction is not useful in the investigation of respiratory associated gastroesophageal reflux disease as % asymptomatic children have positive samples. immunodeficiency may result in recurrent pulmonary infection leading to chronic lung damage and bronchiectasis. the aim of our study was to identify immunodeficiency in idiopathic bronchiectasis and the parameters that correlate with disease severity. patients with idiopathic bronchiectasis were assessed. patients were recruited over a one year period from the respiratory out-patient and in-patient service. serum immunoglobulins, igg subclasses and pneumococcal antibody levels were measured. clinical, physiological, microbiologic and radiologic data was obtained. patients with igg subclass deficiency (iggsd) were significantly more likely to be hospitalised with a respiratory exacerbation as compared with the immunocompetent group (p \ . ). iggsd was associated with lower fev (p \ . ), more severe obstructive airways disease (p \ . ) and persistent sputum purulence (p \ . ). iggsd correlated with low pneumococcal antibody levels. there was no significant difference in bronchiectasis severity or lobar involvement on high resolution ct. our findings support the hypothesis that patients with iggsd and documented bronchiectasis suffer more severe exacerbations even in the contaxt of radiologically mild disease. patients with evidence of bronchiectasis radiologically should have serum immunoglobulins and igg subclasses performed. this cohort is high risk for progressive lung damage in the setting of recurrent severe exacerbations and should be identified early to ensure optimal management. macrophages undergo apoptosis after infection with m. tuberculosis (mtb). this macrophage response deprives the bacillus of its niche cell, and supports the host response through better antigen presentation.virulent strains of mtb do not cause apoptosis at low multiplicities of infection (moi) which may contribute to this pathogen's ability to survive long-term in macrophages. we investigated the ability of mtb to cause macrophage cell death at a high moi ( - ) which is likely to represent the high bacillary burden seen in the later stages of infection. the mechanism of cell death was analysed by fluorescent microscopy and nucleosome elisa. macrophages infected with virulent (h rv) mtb displayed several features typical of apoptosis including dna fragmentation and exposure of phosphatidylserine. however, mitochondrial cytochrome c release and nuclear fragmentation were not observed, suggesting that mtb-induced cell death differs from classical apoptosis. cell death was significantly reduced (p \ . ) following treatment with serine protease inhibitors (aebsf and tpck) but was not effected by the caspase inhibitor zvad-fmk. in summary, mtb triggers a novel serine protease-dependent macrophage cell death pathway which may facilitate dissemination in the later stages of infection. a better understanding of this macrophage response may direct new vaccine and treatment options. patients had microbiological confirmation of tb, were culture positive and patients were pcr positive. the mean (sd) age was ( ). male:female ratio : . of the pulmonary cases, bronchoscopy (bronchial washings/ biopsy) was required to make a microbiological diagnosis in cases ( %). of the cases where sensitivity data was available, there were cases ( . %) of drug resistant tb. of these, ( %) were mono-resistant, ( %) were poly-resistant and ( %) were multidrug-resistant tb. various factors including the presence of a resistant organism determined duration of treatment and site of care. six patients had disease in multiple sites the high rate of drug resistant tb in this population has implications not only for the management of index cases but also for the management of contacts and the management of latent tb in the population as a whole. resource limitations have raised interest in portable monitoring systems that can be used to improve access to the diagnosis of obstructive sleep apnoea syndrome (osas). this prospective study compares a combined electrocardiogram and oximetry recorder (holter-oximeter) in an unattended home setting against attended polysomnography for detection of osas. subjects ( male: female) with suspected osas underwent attended polysomnography (psg) in hospital and subsequent unattended evaluation at home with a holter-oximeter (nemon dr +). an algorithm for estimation of the (apnoea-hypopnoea index) ahi using only a single lead of electrocardiograph (ecg) and the oximetry trace had previously been developed using a database of psg recordings. osas was defined as ahi c , non-osas as ahi \ , and b ahi \ as indeterminate. evaluation methodology was in accordance with the recommended american academy of sleep medicine guidelines (flemons et al. ) . sensitivity and specificity were %. positive and negative likelihood ratios were [ and respectively. estimated ahi agreed closely with psg ahi (r = . ; p \ . ). combined holter-oximeter monitoring compares well against polysomnography for identifying osas and is potentially a suitable device for home screening of sleep apnea in a population suspected of having osas. current international guidelines suggest the combined use of pre test probability scores, d dimers and ct pulmonary angiography (ctpa) for the management of suspected pulmonary embolism (pe). our aim was to audit adherance to international guidelines for the management of suspected pe in a teaching hospital. a retrospective audit was performed on all ctpa's carried out in merlin park hospital from the / / to the / / . patients had clinical notes available for analysis. only % of patients had a documented well's or geneva score. ctpa confirmed pe in % of cases overall. when a well's score was calculated in these patients, % were high risk, % were intermediate risk and % were low risk. a third of patients in the low and intermediate risk groups had no d dimers measured. half of patients in the high risk group had an inappropiate d dimers. no patient with a confirmed pulmonary embolism had a normal d-dimers. % of patients had d dimers measured and . % of these of were normal. all ctpa's in this subgroup were negative for pulmonary embolism. when a well's score was calculated, retrospectively, from clinical notes patients were in an low or intermediate risk group where ctpa was not indicated. we conclude that pre test probability scores are underutilised. it confirms that patients with low or intermediate risk of pe and negative ddimers should not require ctpa. it also highllights that d-dimers should be used appropriately in low or intermediate risk groups. common variable immunodeficiency (cvid) is a primary immunodeficiency syndrome characterised by diminished serum immunoglobulin levels and impaired antibody responses. cvid may present as granulomatous disease and masquerade as ''sarcoidosis''. we have previously described four patients referred to us with a diagnosis of sarcoidosis with granulomatous disease on biopsy who in fact had cvid. sarcoidosis is more typically associated with hypergammaglobulinaemia. we have evaluated serum immunoglobulin levels in patients with granulomatous disease on biopsy with clinical and radiological pattern compatible with sarcoidosis. thirty seven ( %) were male. mean age of presentation was . (sd +/- , range - ). % of patients demonstrated hypergammaglobulinaemia (n = ). % (n = ) demonstrated low igm levels. % (n = ) demonstrated an isolated low igg level. a single patient had low igg and igm levels and has been further evaluated for cvid. % of patients had low/ normal iga levels (n = ). in conclusion, hypergammaglobulinaemia was less common than anticipated in this cohort of patients with granulomatous disease believed to be secondary to sarcoidosis. patients with a putative diagnosis of sarcoidosis should have immunoglobulin levels determined to exclude cvid. in chronic asthma, goblet cell hyperplasia and decreased ciliogenesis are characteristic features which may be influenced by th cytokines (eg il- and il- ). in vitro basal mucociliary differentiation and differences in paediatric epithelial cells (normal & asthmatics) exposed to il- were studied. blind non-bronchoscopic bronchial brushings obtained from children were differentiated at air liquid interface for days. cells s were treated with ng/ml il- and ng/ml il- . transepithelial resistance (ter), number of ciliated (anti a -acetylated tubulin antibody) and goblet cells (muc ac + ) were assessed as a measure of tissue differentiation. both asthmatics and normal cell cultures formed well differentiated pseudostratified epithelium (ter [ x/cm ). asthmatic cultures expressed significantly more goblet cells ( . %, sd = . ) when compared with non-asthmatic cultures ( . %, sd = . ) under basal culture conditions (p = . ). significant more goblet cells are seen in asthmatic cultures when chronically exposed to il ( ng/ml and ng/ml) when compared with identically treated nonasthmatic cultures (p \ . ). asthmatic cultures expressed significantly less ciliated cells ( . %, sd = . ) when compared with nonasthmatic cultures ( . %, sd = . ) under basal culture conditions (p = . ). asthmatic cells differentiate at basal conditions with higher proportion of goblet cells and decreased number of ciliated cells when chronically exposed to il- . combining inhaled corticosteroids with long-acting b -agonists results in improved asthma symptom control and fewer asthma exacerbations compared to inhaled corticosteroids alone. however, there are limited data as to whether these beneficial effects are due to enhanced antiinflammatory actions, or whether such combination therapies impact on airway remodeling in asthma. we sought to determine the effects of inhaled budesonide/formoterol combination therapy, versus inhaled budesonide alone or inhaled placebo, on allergen-induced airway responses, airway inflammation and airway remodeling. fourteen asthmatic subjects with dual responses after allergen inhalation were included in this prospective randomized, double-blind, -period cross-over study. outcomes included asthmatic responses, changes in airway responsiveness and sputum eosinophilia, measured before and after allergen challenge, and numbers of airway submucosal myofibroblasts measured before and after study treatment. combination treatment attenuated the maximal early asthmatic responses and also resulted in a -doubling dose attenuation of allergen-induced airway hyperresponsiveness compared to budesonide or placebo treatment (p \ . ). allergen-induced increases in sputum eosinophils and in submucosal tissue myofibroblasts were significantly reduced by combination treatment (p \ . ), but not by budesonide alone when compared to placebo. inhaled budesonide/formoterol combination therapy attenuated allergen-induced airway responses and provided greater anti-inflammatory effects than either budesonide alone or placebo. combination therapy also attenuated the allergen-induced increases in submucosal myofibroblast numbers, suggesting that clinical benefits associated with such combination treatment may relate to effects on airway remodeling. the purpose of this study was to determine the effects of sub-cytotoxic concentrations of eosinophil peroxidase (epo) on expression and sub-cellular localisation of the linked cell growth and cell cycle mediators, focal adhesion kinase (fak), cyclin-dependent kinase inhibitor p kip and the epidermal growth factor receptors egfr and erbb . eosinophils exert many of their inflammatory effects in allergic disorders by degranulation and release of cationic granule proteins including epo. in sub-cytotoxic concentrations, eosinophil granule proteins increase transcriptional expression of various growth factors in airway cells. the methods used were real-time pcr, western blotting of membrane, nuclear and cytoplasmic cell fractions and immunoprecipitation. epo induced a concomitant time-dependent egress of fak and p kip from the cell nucleus to the cytoplasm. immunoprecipitation indicated a physical association between fak and p kip , implying that fak acts as a nuclear-cytoplasmic shuttle for p kip . epo also induced up-regulation of expression of egfr and erbb . our results imply that epo potentially induces cell proliferation, by up-regulating egfr and erbb and cell cycle, by driving p kip from the nucleus. this has implication for the role of eosinophils in tissue remodelling and turnover in conditions from asthma to cancer. alpha- antitrypsin (a at) deficiency predisposes individuals to early onset emphysema and is a debilitating disease in which neutrophils play a central role. it is becoming more evident that a at possess key anti inflammatory properties and the aim of this project was to examine the possible role of a at in modulating neutrophil chemotaxis. western blot and facs analysis was utilised to examine the effect of a at on release of cd b, a key molecule in chemotaxis and adhesion, from the neutrophil membrane. the effect of a at on neutrophil migration using il- ( - ng/ . cells) was quantified employing a multiwall chemotaxis chamber. our experimental results revealed that a at ( . lm) prevented the release of cd b from the neutrophil membrane. inhibition of il- chemotaxis was dose dependent and almost completely inhibited by . lm aat. in addition, neutrophils of a at deficient (zz) individuals displayed decreased levels of cd b. this study highlights the importance of serum levels of a at for modulating neutrophil activity and aims to evaluate whether infused a at possess the ability to bind and govern the activity of circulating neutrophils in vivo. aat deficiency (aatd) is a hereditary disorder, resulting from mutations in the serpina gene, and classically presents with earlyonset emphysema and liver disease. the most common mutation causing aatd is the z mutation, with the s mutation also associated with lung disease. aat deficiency is under-diagnosed and prolonged delays in diagnosis are common. the world health organisation advocates screening copd, poorly-controlled asthma, cryptogenic liver disease patients and first degree relatives of known aatd patients. , individuals with copd, asthma, or cryptogenic liver disease were screened in the national targeted detection programme. , healthy individuals from the tcd biobank were genotyped for s and z alleles. targeted screening identified zz, sz, ss, mz, ms, and mi individuals, yielding gene frequencies of . and . for s and z respectively. biobank screening of , healthy individuals identified ms, mz, sz and a single ss case, yielding gene frequencies of . and . for s and z. the allele frequencies for s and z in ireland were previously estimated at between . - . and . - . ( ). our pilot study shows s and z alleles occur at higher frequencies, suggesting , zz individuals and over , carriers on the island of ireland. the z mutation is more clinically significant with a higher penetrance than s in the groups we have evaluated. inspiratory-to-total lung capacity ratio predicts mortality in patients with chronic obstructive pulmonary disease joint accp/aacvpr evidence-based clinical practice guidelines sarcoidosis: clinical update hereditary hemorrhagic telangiectasia pulmonary arteriovenous malformations: techniques and long-term outcome of embolotherapy obstructive sleep apnoea in a patient with bilateral carotid body tumours, a unique case references obstructive sleep apnea caused by carotid body tumor: case report obstructive sleep apnea due to a carotid body paraganglioma continuous positive airway pressure therapy compliance rates across three sleep centres we present a unique case of a patient who presented with obstructed sleep apnoea (osa) caused by bilateral carotid body tumours.the patient was treated during a year period, during which time he required non-invasive ventilation at night via continuous positive airways pressure (cpap). he also underwent surgical resection of his right and left carotid body tumours sequentially while on cpap. during family screening his daughter was discovered to have a carotid body tumour but without osa.at presentation, his apnoea-hypopnoea index (ahi) was . , and his epworth score was out of possible . after resection of both carotid body tumours, his ahi score fell to . , and he was symptomatically improved and he was able to return to work.this unusual case highlights the need to investigate patients with osa for an underlying treatable cause. to our knowledge, this is the first report of bilateral familial carotid body tumours causing osa; to date osa has only been reported with unilateral carotid body tumours. , to determine long-term compliance rates for patients prescribed continuous positive airway pressure (cpap) therapy from three sleep centres. having 'limited study' devices now in use for - years now, we have the opportunity to compare cpap compliance rates between sleep centres using these, and established centres using full polysomnography (psg).a population-based analysis of patients prescribed cpap therapy over a -year period - , with compliant vs. non-compliant status determined in june .it is possible to achieve long-term compliance rates of [ % with limited study systems and correct follow-up care. however, factors such as patient education and follow up, along with a high level of home service, are vital. . is brain natriuretic peptide a good marker for obstructive sleep apnea and the efficacy of continuous positive airway pressure therapy in obstructive sleep apnea patients? the aim to assess natriuretic peptide levels n-terminal pro b-type and b natriuretic peptide in congestive heart failure (chf) patients with/without obstructive sleep apnea (sa). the effect of cpap on natriuretic peptides in a sleep apnea population was assessed.a blind study in a known population, sleep apnea status was unknown. biosyn triage measured bnp, roche measured nt bnp. both were measured in congestive heart failure patients ( female, male) with obstructive sleep apnea ( female, male) and normal patients ( female, male).bnp is a good marker for chf. nt probnp is a good marker for chf, it could distinguish chf patients from chf osa patients. cpap didn't reduce natriuretic peptide concentrations. aim: to show that osahs is a common feature in patients with metabolic syndrome. background: metabolic syndrome has been described as a constellation of risk factors for cardiovascular disease. the who places the incidence at % of the population. osahs occurs in - % of males and females. key: cord- - h eiihp authors: guan, wei-jie title: giants in chest medicine: professor nan-shan zhong, md date: - - journal: chest doi: . /j.chest. . . sha: doc_id: cord_uid: h eiihp nan professor nan-shan zhong, md wei-jie guan, phd professor nan-shan zhong was born in nanjing in . following graduation from high school, he pursued medical studies at peking medical university. due to excellent physical fitness, he became well known for his competitiveness as an athlete. the spirit of pursuing excellence has underlined his mental strengths in achieving countless breakthroughs in his career. in , he became a resident at the first affiliated hospital of guangzhou medical university. despite hardships such as poor working conditions, he quickly made great strides in the accumulation of medical knowledge, which lent him support in pursuing future progress. in , the significant national burden of chronic bronchitis prompted the central government to establish the group for prevention and management of chronic bronchitis, which in became guangzhou institute of respiratory disease. in recognition of their achievement in investigating the effects of a chinese herb on chronic bronchitis, professor zhong and colleagues were awarded the national prize for scientific advances. in and , he pursued further studies at the royal infirmary, university of edinburgh and at st. bartholomew's hospital, university of london as a research fellow. apart from his brave behavior of inhalation of carbon monoxide to achieve high blood carboxyhemoglobin concentrations, his findings on the effects of carbon monoxide on the hemoglobin dissociation curve dramatically reshaped scientists' contemporary understanding. in , he was appointed director of the guangzhou institute of respiratory disease (which is currently called guangzhou institute for respiratory health). the development of a hand-squeezed atomizer for performing bronchial provocation tests allowed the exploration of the epidemiology of asthma and the definition of "asymptomatic asthma" (probable asthma) possible in the s and , respectively. the development of a corrected formula for calculating nutritional energy balance in critically ill patients has significantly improved patient health care in icus. in recognition of these achievements, he became an academician of the chinese academy of engineering in . his brave behavior of admitting the most critically ill patients with severe acute respiratory syndrome (sars) and challenging the authoritative opinions about the pathogens of sars made him famous as the "hero of china." he successfully led his team in minimizing the mortality of sars, resulting in the world's lowest record of the disease. his experience was quickly adopted by the central government, leading to the ultimate success of the fight against sars, "the war without gunfire." dedication, innovation, exploration, and collaboration have become the "nan-shan spirit," which remains the famous motto that inspires medical students and staff today. despite enormous achievement in his earlier career, the spirit of pursuing excellence has relentlessly inspired him to make greater strides. the establishment of the state key laboratory of respiratory disease has transformed his visions into an ideal platform for bridging the gap between basic scientific research and clinical practice. he has frequently stated that scientific research should be pursued for the improvement of people's well-being, which has led to copious landmark translational research that has dramatically changed the way medicine should be practiced. the study finding that carbocisteine effectively reduced the annual acute exacerbation rate of copd was awarded "paper of the year " by the lancet editorial board. recognizing challenges of copd management in china, he and colleagues performed the largest epidemiologic investigation on the national disease burden, highlighting that approximately % of patients with copd remained asymptomatic on presentation, that biomass fuel combustion might be the main risk factor for copd in women (particularly in rural areas), and that simple practical approaches (eg, installation of exhaust fans and replacing biomass with biogas) may significantly ameliorate the rate of lung function decline and reduce the incidence of copd. recently, he designed the first multicenter clinical trial proving that early intervention in copd (eg, with tiotropium inhalation) may effectively ameliorate the decline in lung function. his comments on improving air quality to reduce the burden on chronic respiratory diseases have inspired scientists and clinicians to dedicate themselves to the prevention and management of air pollution in china. despite countless awards and prizes, he never ceased his progress in pursuing further research. as stated in a press release, he remains active "post- ." one is never too old to learn, he explained. his open mind, coupled with a laudable drive and physical fitness, have lent him measurable support to pursue further achievement, which will ultimately benefit people worldwide, making him a true giant in chest medicine. physicians and scientists worldwide can benefit considerably by standing on the shoulders of his work. we encourage all to view the interview of professor zhong's words of wisdom (video ). bronchial hyperresponsiveness in young students in china, relation to respiratory symptoms, diagnosed asthma and risk factors is asymptomatic bronchial hyperresponsiveness an indication of potential asthma? using sirna in prophylactic and therapeutic regimens against sars coronavirus in rhesus macaque treatment of sars with glucosteroids: the guangzhou experience what have we learned from sars epidemics in china? biomass fuels are the probable risk factor for chronic obstructive pulmonary disease in rural south china prevalence of chronic obstructive pulmonary disease in china: a large, population-based survey effect of carbocisteine on acute exacerbation of chronic obstructive pulmonary disease (peace study): a randomised placebo-controlled study community based integrated intervention for prevention and management of chronic obstructive pulmonary disease (copd) in guangdong, china: cluster randomised controlled trial clinical findings in cases of influenza a (h n ) virus infection leukotriene d and methacholine bronchial provocation tests for identifying leukotriene-responsiveness subtypes a prospective, multicenter survey on causes of chronic cough in china twice daily n-acetylcysteine mg for exacerbations of chronic obstructive pulmonary disease (pantheon): a randomised, double-blind placebo-controlled trial lung function and incidence of chronic obstructive pulmonary disease after improved cooking fuels and kitchen ventilation: a -year prospective cohort study human infection with a novel avian influenza a(h n ) virus ceftaroline fosamil versus ceftriaxone for the treatment of asian patients with community-acquired pneumonia: a randomised, controlled, double-blind, phase , non-inferiority with nested superiority trial the bronchiectasis severity index and faced score for bronchiectasis prevention and management of copd in china: successes and major challenges impact of air pollution on the burden of chronic respiratory diseases in china: time for urgent action tiotropium in early-stage chronic obstructive pulmonary disease role of sponsors: the sponsor had no role in the design of the study, the collection and analysis of the data, or the preparation of the manuscript. key: cord- -euzvhtax authors: janssens, wim; lehouck, an; decramer, marc; gayan-ramirez, ghislaine title: vitamin d and chronic obstructive pulmonary disease date: - - journal: vitamin d and the lung doi: . / - - - - _ sha: doc_id: cord_uid: euzvhtax vitamin d is an important regulator of calcium and bone homeostasis. it is also involved in the regulation of different genes and cellular functions, particularly in the context of inflammation, regeneration and immune control. conversely, vitamin d deficiency which is often found in chronic, infectious and inflammatory diseases is thought to drive or enhance uncontrolled inflammation. chronic obstructive pulmonary disease (copd) is characterized by chronic inflammation of the airways most often because of cigarette smoking. it has been recognized that repetitive airway infections and systemic consequences or co-morbidities also contribute to the progressive nature of copd. vitamin d deficiency is known to sneak in from the early stages of copd, to become highly prevalent at the more severe stages, and may thereby catalyse airway infection, inflammation and systemic consequences. undoubtedly, vitamin d deficiency enhances bone resorption and osteoporosis in copd for which appropriate vitamin d supplementation is recommended. however, conflicting evidence has emerged on the extra-calcemic effects of vitamin d in copd. a recent intervention trial with high-dose supplementation in copd was only able to reduce exacerbation frequency in the subgroup of patients with lowest baseline vitamin d levels. it confirms that severe vitamin d deficiency is a health hazard but that more clinical and experimental studies are needed to explore how vitamin d deficiency may affect airway biology and systemic effects in the context of smoke-induced lung diseases. over the last years, there is an increasing interest in the role of vitamin d and vitamin d de fi ciency in various chronic diseases. besides the well-known effect of vitamin d de fi ciency on bone loss in adults, accumulating evidence also links a low vitamin d nutritional status to highly prevalent chronic illnesses, including cancers, autoimmune diseases, infectious and cardiovascular diseases [ ] [ ] [ ] . vitamin d is now known to have an important in fl uence on immunoregulation and on the expression of antimicrobial peptides. since patients with chronic obstructive pulmonary disease (copd) often integrate all of these co-morbid diseases in one and given that most of copd exacerbations are triggered by bacterial and viral infection, vitamin d could play a key role in the pathogenesis of this disease. this chapter aims to discuss the prevalence and determinants of vitamin d de fi ciency in copd, the wellknown effect of vitamin d in the development and treatment of copd-associated osteoporosis and its potential role in the uncontrolled in fl ammatory cascade and systemic consequences of the disease. copd is a chronic disease characterized by air fl ow limitation that is progressive, not fully reversible and associated with an abnormal in fl ammatory response of the lungs to noxious particles or gases. in western countries, tobacco smoke is the major cause for copd, accounting for - % of the cases. since only % of smokers develop severe copd, other factors (biological, hereditary, environmental) must be involved [ ] . narrowing of the airways by in fl ammation, mucus production, irreversible remodelling and emphysema results in a limitation of expiratory air fl ow and disturbed gas exchange [ ] . currently, it is estimated that million people suffer from copd worldwide, a number that is still increasing. by , the world health organization predicts that copd will rise from the sixth to the third leading cause of death, next to only cardiovascular disease and cancer [ ] . according to the global obstructive lung disease (gold) de fi nition, diagnosis of copd should be based on spirometry measurements with a post-bronchodilator forced expiratory volume in s over forced vital capacity ratio (fev /fvc) below . . subsequently, copd can be categorized in different stages of severity (gold stages) going from mild, moderate and severe to very severe disease according to fev [ ] . it should be noted, however, that the majority of copd patients, especially in the early stages of the disease, report no complaints, do not perform spirometry and thus are unaware of their disease. treatment for copd focuses on minimizing symptoms and preventing exacerbations. with the exception of smoking cessation, so far, no treatment has clearly proven to signi fi cantly modify copd disease progression. recent data, however, indicate that pharmacological intervention with inhalation therapy may slow down the yearly decline of fev [ ] [ ] [ ] . the pathophysiology of copd is characterized by an increased in fl ammatory response in the airways and parenchyma. besides an increase in number of neutrophils, macrophages and t-lymphocytes, copd is associated with elevated concentrations of various cytokines, including interleukins (il- , il- and il- ), tumour necrosis factor alpha (tnf-a ), oxidative stress and the release of proteolytic enzymes. cigarette smoke is known to cause a direct injury of the airway epithelial cells leading to the release of endogenous intracellular molecules or danger-associated molecular patterns (damps). these signals are recognized by toll-like receptors on epithelial cells which initiate a non-speci fi c in fl ammatory response. as reaction on the release of early cytokines (tnf-a , il- , il- ), macrophages, neutrophils and dendritic cells are recruited to the site of in fl ammation [ ] . proteolytic enzymes and reactive oxygen species are released which may cause further damage to the lung. next, self-antigens and antigens coming from pathogens bound to dendritic cells can activate naive t cells into th cells [ ] and may lead to antibody producing b cells. this adaptive immune response may then further enhance the in fl ammatory cascade. in addition, the observed reduction of regulatory t cells (treg) in copd lungs against the rise of pro-in fl ammatory th cells is pointing towards an impaired immune regulation in copd [ ] . macrophages are believed to play a central role in the pathophysiology of copd [ ] . they are important sources of pro-in fl ammatory mediators but may also protect against infection by phagocytosis. in copd, alveolar macrophages appear to be resistant to the anti-in fl ammatory effects of corticosteroids by the reduced activity of histone deacetylase (hdac ), a nuclear enzyme that switches off in fl ammatory genes activated by the nuclear factor nf-k b [ ] . additionally, taylor and colleagues recently demonstrated that the phagocytotic capacity of macrophages of copd patients is impaired, which may lead to bacterial colonization and increased exacerbation frequency [ ] . overall, the complexity of the pathogenesis of copd with different mechanisms and risk factors is re fl ected in the broad variation of clinical phenotypes. with progression of the disease, as marked by a decline of forced expiratory volume in s (fev ), copd patients become more prone to exacerbations. an exacerbation of copd is an acute worsening of respiratory symptoms which is associated with increased symptoms and worsening of lung function. recent studies have shown that quality of life and health status of patients are mainly determined by the presence and frequency of such exacerbations which, in turn, may lead to a faster decline in fev [ ] . although viral and bacterial infections are assumed to be the major cause of exacerbations, other factors including environmental pollution and allergens have also been identi fi ed [ ] . the exact role of bacterial infection in copd exacerbations is often biased by bacterial colonization of the airways during stable state with the same organisms as those isolated at exacerbations: haemophilus in fl uenzae , streptococcus pneumoniae , moraxella catarrhalis , staphylococcus aureus and pseudomonas aeruginosa . different studies have shown that prevalence and load of organisms increases during an exacerbation [ ] , but recent evidence indicates that the acquisition of a new bacterial strain is likely the main trigger of an exacerbation [ , ] . besides bacterial infections, exacerbations may also be triggered by viral infections, including infections with rhinoviruses , coronavirus , respiratory syncytial virus , in fl uenza , parain fl uenza and adenoviru s. moreover, recently, a frequent exacerbator phenotype has been identi fi ed suggesting that the innate and adaptive immune defence of the host also contributes to exacerbation susceptibility and that individualized therapy may become important in the nearby future [ ] . copd is not restricted to the lungs but also associated with systemic in fl ammation and increased co-morbidities which are now considered as important targets in the therapeutic approach of copd. increased systemic levels of tnf-a , il- and c-reactive protein (crp) are commonly found in patients with copd [ ] . common co-morbidities of copd include lung cancer, cardiovascular disease, osteoporosis, diabetes and skeletal muscle dysfunction [ , ] . whether these co-morbidities are caused by the underlying disease or just co-exist because of common risk factors such as smoking, ageing and inactivity is far from understood. most likely, both mechanisms play together and the attractive hypothesis of in fl ammation in the lung "spilling over" into the systemic circulation and affecting other organs is corroborating this idea [ ] . whatever the mechanism may be, the presence of these co-morbidities clearly contributes to the poor outcome in copd [ , ] . vitamin d is generally obtained by photosynthesis in the skin but can also be derived from nutrition (fatty fi sh, fi sh liver oils and dairy products). ultraviolet light catalyses the fi rst step in the vitamin d biosynthesis, which is the conversion of -dehydrocholesterol into pre-vitamin d. the next step is a hydroxylation in the liver into -ohd, which then circulates in serum with a long half-life of days. next, -ohd is hydroxylated again into the active vitamin d metabolite , (oh) d by ahydroxylase (cyp b ) in the kidney which is controlled by serum levels of calcium and phosphate and regulating hormones such as parathyroid hormone (pth), calcitonin and phosphatonins. , (oh) d also induces the expression of a -hydroxylase (cyp a ) which catabolizes -ohd and , (oh) d into biologically inactive, water-soluble metabolites, thereby serving as its own negative feedback. the majority of -ohd and , (oh) d are bound to plasma proteins, of which more than % to the vitamin d binding protein (dbp), which carry out the delivery to their respective target organs [ ] . , (oh) d may thus bind to the nuclear vitamin d receptor (vdr) in the intestine, bone, kidney and parathyroid gland cells, resulting in the maintenance of normal serum calcium and phosphorus levels and their related effects on mineralization and turnover of bone [ , ] . since a -hydroxylase and the nuclear receptor vdr are widely present in cells of several extrarenal tissues such as skin, bone, prostate and immune cells, local , (oh) d concentrations can also exert different autocrine and paracrine functions. although the enzyme found here is identical to the one that is expressed in the kidney, its expression is regulated by immune signals instead of mediators of bone and calcium homeostasis [ , ] . , (oh) d mediates its effects by binding to the nuclear vdr the vitamin-vdr complex may then activate vitamin d response elements (vdre) on genes involved in different cellular processes. it is estimated that about % of the mouse/human genome is regulated by vitamin d [ ] . directly or indirectly, vitamin d controls many genes that are involved in the regulation of cellular proliferation, differentiation and apoptosis of healthy and pathological cells. because of its long half-life, -ohd is typically used to determine vitamin d status. it re fl ects vitamin d synthesized in the skin as well as that acquired from the diet and vitamin d degradation by catabolizing enzymes. when focusing on the calcemic effects, vitamin d insuf fi ciency is best de fi ned as a -ohd level below ng/ml ( nmol/l) [ , ] . a sensitive parameter to determine vitamin d de fi ciency is serum levels of pth. older data have clearly demonstrated that levels of -ohd below ng/ml are associated with an increase in pth expression [ ] . based on observational studies, several experts have suggested that, for non-calcemic effects, serum levels of at least ng/ml ( nmol/l) are required, but so far, intervention studies to support this are lacking. dietary sources of vitamin d are limited, and food forti fi cation is mostly inadequate or nonexistent. although sunlight is the most important source of vitamin d, several other factors can in fl uence the amount of vitamin d that can be synthesized: season, latitude, clothing, the use of sunscreen, darker skin pigmentation and age. for example, ageing is associated with decreased concentrations of -dehydrocholesterol in the skin, thereby reducing the capacity to synthesize vitamin d. even if regularly exposed to sunlight, elderly people produce % less cutaneous vitamin d than compared to young adults [ ] . due to cultural habits and clothing, even those who live in sunny climates are commonly found to be de fi cient in vitamin d. data from the third national health and nutrition examination survey (nhanes iii) revealed that in us adults, only % of the white population and % of the african americans had levels of vitamin d of at least ng/ml [ ] . according to the current de fi nitions, it is estimated that more than one billion people worldwide have impaired serum levels of vitamin d. as current supplementation regimens with a daily dose of - , iu of vitamin d restore de fi cient serum -ohd levels in a general adult population to concentrations above ng/ml, higher doses are probably required to increase -ohd levels to even higher levels that may be needed for non-calcemic diseases in a population at risk [ , ] . at present, we can only speculate on what such ideal target range of -ohd levels is to maximally exploit these extra-calcemic effects [ ] . we should also acknowledge that an extensive expert analysis of the potential effects of vitamin d supplementation on the health outcome of north-american subjects concluded that there is presently insuf fi cient evidence for extraskeletal bene fi ts of vitamin d therapy and that only new randomized controlled trials will be able to de fi ne such effect [ ] . copd patients should be considered at high risk to become vitamin d de fi cient for a variety of reasons: lower food intake, reduced capacity for vitamin d synthesis of the skin by ageing and smoking, the absence of outdoor activity and sun exposure, impaired activation by renal dysfunction and a lower storage capacity in muscles or fat by wasting may all contribute to a defective vitamin d status in copd [ ] . in , black and colleagues who examined spirometric data from the third national health and nutrition examination survey, a cross-sectional survey on , us civilians over years of age, discovered an important link between vitamin d and spirometric data [ ] . after adjustment for potential confounders, a strong relationship between serum levels of -ohd and pulmonary function, as assessed by fev and fvc, was found. although a signi fi cant correlation with airway obstruction could not be found, the observed dose-response relationship suggested a causal link [ ] . the observation that smoking african-americans more rapidly develop severe air fl ow obstruction as compared to caucasians is also in agreement with the idea that a presumed lower vitamin d status in african-americans correlates with an increased susceptibility to copd [ ] . furthermore, different genetic variants involved in the vitamin d signalling pathway are shown to determine -ohd levels [ ] , and some of these variants have repeatedly been associated with copd. for instance, variants of the dbp gene ( gc ) have been shown to be protective or risk factors for copd [ ] , and a more recent robust candidate gene study in two large data sets identi fi ed the gc genes as susceptibility loci for copd [ ] . in a study of forli and colleagues, vitamin d de fi ciency (< ng/ml) was found in more than % of a cohort waiting for lung transplantation [ ] , but they failed to compare vitamin d serum levels with a matched control group. however, we recently demonstrated in a group of smoking individuals that patients with copd were more likely to suffer from vitamin d de fi ciency than aged and gender-matched healthy control smokers without copd [ ] . in copd patients, we found a signi fi cant association between vitamin d serum levels and severity of disease assessed by fev . the prevalence of vitamin d de fi ciency de fi ned by -ohd levels below ng/ml increased to, respectively, % and % in severe (gold ) and very severe copd patients (gold ) (fig. . ) . interestingly, we also showed that -ohd levels were determined by genetic variants in the vitamin d binding gene ( gc) after correcting for age, gender, smoking history and disease severity and that homozygous carriers of the rs t allele with lowest vitamin d levels exhibited an increased risk for copd. although the risk effect of certain gc alleles may relate to a lower bioavailability of vitamin d, other authors have suggested that protein variants of dbp may directly affect in fl ammation in the airways [ ] . wood and colleagues, for instance, demonstrated that local dbp expression in sputum of copd patients correlates with macrophage phagocytosis capacity [ ] suggesting that the risk effect of dbp may be found in a different activation of macrophages [ ] . a recent population based study in , individuals living in hertfordshire (uk) found reduced vitamin d intake in the copd subgroup of individuals compared to the non-copd subjects but was not able to con fi rm the positive association between -ohd serum levels and fev or fvc [ ] . surprisingly, shaheen et al. found that patients with highest vitamin d levels were more likely to have copd. they concluded that in contrast to a prudent dietary pattern with the intake of high amounts of antioxidants [ ] , vitamin d was not an important determinant for adult pulmonary function and risk of copd. unfortunately, more than % of their population was taking dietary vitamin d supplements for unspeci fi ed reasons, which may have affected their analysis and biased their conclusions. finally, in a small sub-study of the lung health study iii conducted in selected individuals, mean -ohd levels of copd patients with a rapid fev decline were found to be similar to mean -ohd levels of patients with a slow decline, suggesting again that vitamin d de fi ciency does not contribute to copd progression [ ] . together, from these con fl icting data, it is clear that more prospective studies are needed to determine causal relationships between vitamin d de fi ciency and pulmonary function in copd. but even if causality cannot be found for pulmonary function variables, vitamin d de fi ciency may still alter the disease course by affecting other outcomes such as respiratory tract infections or co-morbidities. low levels of vitamin d result in low bioavailability of calcium which stimulates parathyroid glands to increase secretion of pth. in the kidneys, pth reduces the reabsorption of phosphate from the proximal tubule and increases calcium reabsorption in the distal tubule, resulting in a net increase in calcium/phosphate ratio. pth also induces renal a -hydroxylase expression which then leads to an increased production of active , (oh) d. , (oh) d enhances intestinal calcium absorption and acts on the immature osteoblastic cells to stimulate osteoclastogenesis through the rankl/rank regulatory system, with enhanced bone resorption and mobilization of calcium from the bone compartment, causing osteopenia, osteoporosis and increased risk for bone fractures [ ] . this results in higher levels of calcium and , (oh) d with a negative feedback on pth and a subsequent limitation of bone resorption. osteoporosis is a skeletal disorder which is characterized by compromised bone strength resulting in a higher susceptibility to fractures. bone strength is determined by the structural quality of the bone and by bone mineral density, the latter measured by dual x-ray absorptiometry (dxa) and used to de fi ne osteoporosis. osteoporosis is a major health problem as osteoporotic fractures are a frequent cause of signi fi cant and long-lasting morbidity in older individuals. hip fractures and other types of nonvertebral fractures account for most of the burden of osteoporosis, with increased mortality, functional decline, loss of quality of life and need for institutionalization [ ] . female gender, advancing age, a history of fragility fractures, current or former smoking, low body weight or weight loss and the use of systemic glucocorticoids are well-established risk factors for osteoporosis and osteoporotic fractures. as many of these risk factors are present in copd patients, especially at the more severe stages, it should be no surprise that osteoporosis and copd are strongly linked. a recent review of graat-verboom et al. con fi rmed low body mass, disease severity, use of corticosteroids, age and female gender to be independent risk factors for osteoporosis in copd [ ] . the majority of studies have reported an increased risk for osteoporosis with decreasing fev (fig. . ) [ ] [ ] [ ] . the prevalence of osteoporosis in copd varies between % and % depending on the diagnostic methods used, the population studied and the severity of the underlying respiratory disease [ ] . sin and colleagues used the nhanes iii data to demonstrate that air fl ow obstruction is independently associated with reduced bone mineral density [ ] . in their population-based cohort of , non-hispanic white participants, % of all women with severe copd had osteoporosis whereas almost all women with mild airway obstruction had osteopenia. in comparison, men were at lower risk than women but still, in men with severe copd, the prevalence of osteoporosis and osteopenia was % and %, respectively, which was approximately three times higher than expected. most studies looking at prevalence of osteoporosis have used dexa scans which measure bone mineral density but do not evaluate micro-architectural changes of the bone. it is known that these microarchitectural changes may equally cause fragility fractures, even with normal bone density, and should therefore be considered to be osteoporotic as well. when taking dexa measures and vertebral fragility fractures into account, graat-verboom et al. found that prevalence of osteoporosis almost doubled in copd outpatients [ ] . it indicates that prevalence of osteoporosis in copd might be much higher than the current prevalence data suggest [ ] . interesting relationships are also found with emphysema which is associated with reduced bone mineral density and lower body mass index and which may represent a clinical phenotype at risk for osteoporosis [ , ] . visual emphysema as assessed by ct scan was found to be an independent risk factor for osteopenia/osteoporosis [ ] , and different bone turnover markers are increased in copd. recent data also show that osteoprotegerin, which is critically involved in bone turnover by blocking rank-rankl interaction, may become a useful marker for parenchymal lung destruction in copd [ , ] . it is currently not known whether the vitamin d pathway is involved in the speci fi c development of emphysema, but studies in laboratory animals certainly corroborate this idea [ , ] . the consequences of osteoporotic fragility fractures in a copd population may be detrimental. in hip-fracture patients, mortality is close to % within year, and of those who do survive the fracture, again, some % will have to be institutionalized because of its functional consequences [ ] . the exact prevalence of hip fractures in copd patients has not been studied in detail, but it is probable that the impact of such events in disabled copd patients will be even worse. additionally, vertebral compression fractures can lead to back pain, functional impairments, increased kyphosis with reduced rib cage mobility and decline of pulmonary function [ ] [ ] [ ] . the impact of loss of vertebral height on pulmonary deterioration in copd has been demonstrated by leech and colleagues who found that vital capacity and total lung capacity incrementally declined as the number of thoracic vertebral fractures increased [ ] . in the eolo study, a large copd cohort of up to , participants, more than %, had one or more vertebral fractures and the prevalence signi fi cantly correlated with severity of disease [ ] . kyphosis related to osteoporosis may also cause limitation in rib mobility and inspiratory muscle dysfunction and was also correlated with loss of fev and fvc [ ] . there is no doubt that vitamin d protects against osteoporosis and osteoporotic fractures, and therefore, suf fi cient vitamin d supplementation should be encouraged. the fact that the majority of copd patients are of older age, have many common risk factors for osteoporosis and are more likely to be de fi cient in vitamin d supports standard supplementation, especially at the more severe stages of disease. a daily dose of - iu of vitamin d together with an adequate daily calcium intake ( , mg) is probably the best strategy to prevent fractures in older subjects. such supplementation is known to restore low serum -ohd levels in a general adult population to concentrations above the ng/ml ( nmol/l) threshold. patients with copd, particularly those on systemic corticosteroids, should also be considered for a dexa scan and if needed, osteoporosis medication [ ] . even though causality and therapeutic bene fi ts of vitamin d remain to be established for pulmonary in fl ammation and other co-morbidities, prevention of vertebral fractures will positively affect pulmonary function [ ] . along with a progressive loss of pulmonary function, copd patients become more prone to acute copd exacerbations which are an important cause of hospitalization, impaired quality of life and mortality [ ] . appropriate antimicrobial treatment is essential in the treatment of acute bacterial exacerbations whereas in case of colonization, repetitive and long-term antibiotic treatments are still avoided as they contribute to the multi-resistance of colonizing strains. anti-in fl ammatory treatments different from inhaled and systemic corticosteroids are currently validated in copd to reduce exacerbations on top of bronchodilator therapy. pde inhibitors and neo-macrolides are the most promising agents from this perspective and seem to be bene fi cial for a subgroup of patients with repetitive exacerbations [ ] [ ] [ ] . an attractive alternative approach might be the up-regulation of the innate immune defence system with vitamin d, particularly with regard to antimicrobial polypeptides [ ] . wang and colleagues demonstrated that in different cell types such as epithelial cells and white blood cells, the genes encoding for antimicrobial polypeptides such as cathelicidin (ll- ) and b -defensin are driven by vdr elements containing promoters [ ] . in human monocytes, tlr activation up-regulates expression of the vdr and the -a -hydroxylase genes, leading to induction of ll- and killing of intracellular mycobacterium tuberculosis [ ] . ll- is also found to be very effective in the killing of a number of antibiotic-resistant strains such as pseudomonas and s. aureus , different viruses and chlamydia [ , ] . as ll- is diffusely expressed in the surface epithelia of human airways, in the submucosal glands and in macrophages and neutrophils [ ] , substitution of local vitamin d insuf fi ciency may reduce bacterial load and concomitant airway in fl ammation [ ] . apart from its potential bene fi t on bacterial eradication, vitamin d may also down-regulate the complex in fl ammatory cascade at several levels. in vitro vitamin d can reduce the expression of tlrs which are critical in the induction of the early immune response [ ] . high levels of vitamin d also inhibit dendritic cell maturation with lower expression of mhc class ii molecules, down-regulation of co-stimulatory molecules and lower production of pro-in fl ammatory cytokines such as il- , il- , ifn-g and il- [ , ] . in several mouse models, vitamin d also leads to a switch from a th /th responses towards a th and regulatory t cell answer [ , [ ] [ ] [ ] . low serum levels of vitamin d have also been correlated with a decreased phagocytic activity of macrophages in patients with rickets [ ] whereas antimicrobial activity of macrophages against m. tuberculosis could be increased by vitamin d supplementation [ ] . overall, the potential of vitamin d in reducing proin fl ammatory processes of the innate and adaptive immune system, together with an increased bacterial eradication by self antimicrobial peptides and enhanced macrophage phagocytosis, may offer great potential in the treatment of exacerbations. indirect clinical evidence for such hypothesis may be found in the observation that exacerbations of copd are most common in winter, when -ohd levels are lowest. in addition, data from nhanes iii showed that upper respiratory tract infections were most frequent in patients with lowest vitamin d levels. to further investigate such intriguing hypothesis, a randomized placebo-controlled intervention trial was performed to evaluate the effect of vitamin d supplementation in copd patients, prone to exacerbations [ ] . one hundred and eighty-two patients with moderate to very severe copd and a history of recent exacerbations were supplemented with , iu vitamin d or placebo every weeks over one year. because of high-dose supplementation mean, -ohd serum levels increased signi fi cantly in the intervention arm and reached stable mean serum levels of ng/ml, which is in the therapeutic range of the hypothesized extra-calcemic effects [ ] . however, despite effective supplementation, no signi fi cant difference in time to fi rst exacerbation, time to fi rst hospitalization and exacerbation rate could be observed between the intervention and the control group. the absence of a therapeutic effect of vitamin d may relate to the fact that most of the patients presented with severe disease and were on maximal inhalation therapy. as all these treatments are known to reduce exacerbations [ , ] , it is likely that any additional effect of vitamin d on top of regular treatment is more dif fi cult to obtain. intervention within the more early copd stages taking less medications might therefore be more effective which is in line with the idea that such milder stages are also more sensitive to disease modi fi cation [ ] . interestingly, a signi fi cant baseline vitamin level by treatment interaction was observed for exacerbation rates. when performing a post hoc analysis in the subgroup of patients with very de fi cient vitamin d levels at baseline (< ng/ml), a signi fi cant % reduction of the number of exacerbations was observed in the intervention group. as one out of six copd patients in the trial presented with such asymptomatic low baseline -ohd levels which persisted during the entire course of the study, further focus and future studies on this important subgroup may be warranted, eventually resulting in better patient-tailored interventions. recently, a frequent exacerbator phenotype has been indenti fi ed suggesting that individualized therapy-including appropriate vitamin d substitution-may become important [ ] . we also assessed for the presence and load of pathogenic bacteria in cultures of morning sputa during the trial but found no difference in eradication between both study arms. however, monocyte phagocytosis capacity in peripheral blood monocytes of patients receiving vitamin d was signi fi cantly increased compared to the placebo group, an effect which was more pronounced in the subgroup with lowest baseline levels. it is therefore tempting to speculate that the signi fi cant reduction of exacerbations in the vitamin d de fi cient subgroup is explained by an important upregulation of impaired phagocytosis capacity [ ] . so far, hard evidence for this mechanism is lacking. finally, it should be noted that the lack of an overall effect could also relate to local vitamin d insensitivity because of epigenetic modi fi cations. in line with the known corticosteroid resistance in copd [ ] , recent studies in cancer have shown that epigenetic silencing of key enzymes of the vitamin d pathway may occur leaving tumour cells insensitive to vitamin d therapy [ , ] . at least, epigenetic modi fi cations especially in the context of smoking or poor diet may explain why many observations suggest causal relationships between vitamin d de fi ciency and in fl ammatory diseases whilst supplementation later on in the disease cannot reverse this process [ ] . skeletal muscle weakness is common in moderate to severe copd and is an independent predictor of respiratory failure and death [ ] . although the underlying mechanisms of skeletal muscle dysfunction in copd are not entirely understood, it is generally accepted that the combination of disuse because of respiratory limitation, with elevated oxidative stress, systemic in fl ammation, hypoxia and frequent steroid intake, is the main cause of deterioration [ ] . rehabilitation programmes in copd are proven successful, but there is still a large variability in training effectivity [ , ] . since muscle weakness is a prominent feature in rickets and chronic renal failure, and epidemiological studies found a positive association between -ohd levels and lower extremity function in older persons, vitamin d could be an important factor in muscle health [ ] . in elderly individuals, vitamin d status predicts physical performance and consequent decline during long-term follow-up [ ] . several double-blind randomized controlled trials demonstrated that vitamin d supplementation increased muscle strength and balance and reduced the risk of falling in elderly [ ] . although a recent meta-analysis looking at the effect of vitamin d supplementation on muscle strength was negative, positive effects were still found in very de fi cient patients [ ] . moreover, the cross-sectional analysis from nhanes indicated that muscle strength continued to increase throughout -ohd serum levels of - ng/ml, indicating that for obtaining bene fi cial effects on the muscle, higher dose supplementation might be necessary [ ] . on the pathological level, adults with vitamin d de fi ciency show predominantly type ii muscle fi bre atrophy [ ] with several muscle abnormalities such as enlarged inter fi brillar spaces, in fi ltration of fat, fi brosis and glycogen granules [ ] . conversely, increase in relative fi bre composition and type ii fi bre dimensions has been reported in elderly after treatment with vitamin d [ ] . these type ii fi bres are also the fi rst to be recruited to prevent falling [ ] , which may explain why vitamin d supplementation is shown to reduce falling [ ] . in copd, limb muscle adaptation leads to a decrease of the proportion of slow oxidative type i fi bres with a relative increase towards glycolytic type ii fi bres [ , ] , those fi bres that are preferentially affected by vitamin d de fi ciency. therefore, vitamin d de fi ciency may be of particular concern in copd patients with muscle weakness and dysfunction. the exact mechanisms by which vitamin d affect muscle function are not fully understood. however, , (oh) d may impair muscle function by altering calcium regulation. in particular, , (oh) d is responsible for the active calcium transportation into the sarcoplasmic reticulum by ca-atpase. it is known to regulate ca-atpase by phosphorylation of proteins in the sarcoplasmic reticulum membrane; it can increase phosphate transport across the membrane and interacts with calmodulin [ , ] . interestingly, calmodulin is highly sensitive to oxidative stress [ ] , a typical feature of copd, and , (oh) d may yield antioxidant properties. thus, both vitamin d de fi ciency and increased oxidative stress through, e.g. smoking may act synergistically impairing calmodulin function, muscle structure and contractility. , (oh) d has also an important role in protein synthesis in the muscle cell, mediated through nuclear receptor-mediated gene transcription [ ] . for example, it can affect actin and troponin c content, two major contractile proteins in skeletal muscle [ ] , or may up-regulate gene expression of muscular growth factors, for instance, igf-i [ ] . although it is tempting to extrapolate these vitamin d-mediated actions in skeletal muscles of healthy or elderly subjects [ , ] to a speci fi c population of copd patients, it is still to be shown that vitamin d de fi ciency contributes to the observed muscle weakness in copd. at present, there is no direct evidence for such causal relationship but the observation that vdr genotypes may in fl uence quadriceps strength in copd patients is in line with this assumption [ ] . recent data also show that vitamin d de fi cient copd patients referred for rehabilitation have a higher risk for dropout and reduced bene fi t on walking endurance [ ] . in a post hoc analysis in moderate to severe copd, we also found a signi fi cant effect of high-dose vitamin d supplementation on top of months of rehabilitation in terms of improved exercise capacity [ ] . therefore, randomized controlled trials investigating if supplementation of vitamin d de fi ciency may positively affect muscle force, muscle function and general copd outcomes are urgently needed. in the last years, many clinical studies have associated low vitamin d levels to prevalence and incidence of cancer, including lung cancer [ , ] . several studies associate vitamin d de fi ciency with autoimmune diseases like type i diabetes, multiple sclerosis and rheumatoid arthritis [ ] [ ] [ ] . de fi cient vitamin d levels have been linked to chronic infections such as tuberculosis and acute viral infections like in fl uenza or upper tract respiratory infections [ ] [ ] [ ] [ ] . similar data are also available which link vitamin d de fi ciency to cardiovascular diseases, arterial hypertension and even all cause mortality [ ] . it is beyond the scope of this book chapter to review all evidence on vitamin d in these different chronic diseases, but it is striking that many of them are currently considered to be co-morbid conditions of copd and accepted as important determinants of copd outcome and prognosis [ , ] . tackling vitamin d-mediated effects in these co-morbid conditions may therefore indirectly improve copd status [ ] . it should be stressed, however, that the above mentioned relationships between vitamin d de fi ciency and different chronic diseases are speculative and most often rely on cross-sectional and retrospective observations or on evidence of in vitro and animal research. in humans, placebo-controlled intervention studies and observational studies with prospective long-term follow-up speci fi cally designed to demonstrate causal relationships are often lacking. moreover, recent intervention studies with vitamin d supplementation in multiple sclerosis, diabetes, in fl uenza and tuberculosis have reported disappointing results, most often by their limitation of statistical power or insuf fi cient supplementation [ ] [ ] [ ] [ ] . recent expert analysis therefore concluded that there is yet insuf fi cient evidence for extra-calcemic bene fi ts of vitamin d therapy and that more randomized placebo-controlled interventions trials are needed to de fi ne such effects [ ] . for copd in particular, intervention studies targeting co-morbid conditions to improve copd-speci fi c outcomes will be needed and in analogy with the ongoing trial on statins in copd patients ( www.clinicaltrials.gov ), one may think about a large intervention study with vitamin d supplements. indirectly or directly, vitamin d is also believed to regulate extracellular matrix homeostasis in other tissues than bone, within particular lung and skin tissue via the control of transforming growth factor-b , matrix metalloproteinase and plasminogen activator systems [ ] [ ] [ ] [ ] . there is compelling evidence that vitamin d plays a key role in foetal lung growth, development and maturation [ , ] . although . (oh) d toxicity in klotho-null mice results in a phenotype of skin atrophy, osteoporosis and emphysema [ ] , recent data in mice show that severe vitamin d de fi ciency from early life also results in a impaired lung function by differences in lung volume and growth [ ] . evidence from human epidemiological studies also suggests that higher prenatal uptake of vitamin d protects against childhood wheezing [ ] . as impaired lung growth and childhood asthma are known risk factors for copd at later age [ , ] , the causal link between vitamin d de fi ciency and copd may therefore already exist from early childhood on. again, recent evidence from animal studies corroborates this idea. vdr knockout mice develop emphysematous airspace enlargement which is associated with the up-regulation of matrix metalloproteinases in the lung, an increased in fl ux of in fl ammatory cells and the development of typical lymphoid aggregates around the peripheral airways [ ] . the evidence that the vitamin d pathway plays a pivotal role in the biology of healthy and diseased lungs is compelling. as with many chronic diseases, vitamin d de fi ciency is highly prevalent in copd and occurs more frequently with increasing disease severity. such de fi ciency may not only enhance local airway in fl ammation but may also induce or accelerate ongoing co-morbid diseases and subsequently impair the general prognosis of the disease (fig. . ). so far, there is only hard evidence for a causal role of vitamin d de fi ciency in the pathogenesis of copdrelated osteoporosis. for extra-calcemic effects, a recent randomized controlled trial demonstrated no overall effect of high-dose supplementation on exacerbations but was supportive for an important effect in a limited subgroup of patients highly de fi cient for vitamin d. before embarking on new intervention trials with vitamin d in copd targeting subgroups, more fundamental research is needed to learn how vitamin d and its de fi ciency interact with smoking in the development of copd. only then we will be able to understand why so far most intervention trials with vitamin d have failed to yield important health bene fi ts in chronic diseases including copd. vitamin d and health: perspectives from mice and man vitamin d de fi ciency vitamin d and human health: lessons from vitamin d receptor null mice gene-environment interactions in chronic obstructive pulmonary disease chronic obstructive pulmonary disease projections of global mortality and burden of disease from to global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: gold executive summary effect of pharmacotherapy on rate of decline of lung function in chronic obstructive pulmonary disease: results from the torch study effect of tiotropium on outcomes in patients with moderate chronic obstructive pulmonary disease (uplift): a prespeci fi ed subgroup analysis of a randomised controlled trial tiotropium as a fi rst maintenance drug in copd: secondary analysis of the uplift trial chronic obstructive pulmonary disease: molecular and cellular mechanisms antielastin autoimmunity in tobacco smoking-induced emphysema phenotypic characterisation of t-lymphocytes in copd: abnormal cd +cd + regulatory t-lymphocyte response to tobacco smoking alveolar macrophages as orchestrators of copd role of hdac in the pathophysiology of copd schematic representation of potential relationship between vitamin d and copd defective macrophage phagocytosis of bacteria in copd relationship between exacerbation frequency and lung function decline in chronic obstructive pulmonary disease copd exacerbations: de fi ning their cause and prevention effect of interactions between lower airway bacterial and rhinoviral infection in exacerbations of copd new strains of bacteria and exacerbations of chronic obstructive pulmonary disease airway bacterial concentrations and exacerbations of chronic obstructive pulmonary disease susceptibility to exacerbation in chronic obstructive pulmonary disease copd as a systemic disease systemic effects of copd copd as a lung disease with systemic consequences-clinical impact, mechanisms, and potential for early intervention from copd to chronic systemic in fl ammatory syndrome? mortality in copd: role of comorbidities prevalence and outcomes of diabetes, hypertension and cardiovascular disease in copd biological and clinical aspects of the vitamin d binding protein (gc-globulin) and its polymorphism vitamin d physiology overview of general physiologic features and functions of vitamin d identi fi cation and immune regulation of -hydroxyvitamin d- -alpha-hydroxylase in murine macrophages immunoregulation by , -dihydroxyvitamin d : basic concepts genetics and biology of vitamin d receptor polymorphisms th workshop consensus for vitamin d nutritional guidelines vitamin d de fi ciency and secondary hyperparathyroidism in the elderly: consequences for bone loss and fractures and therapeutic implications demographic differences and trends of vitamin d insuf fi ciency in the us population estimation of optimal serum concentrations of -hydroxyvitamin d for multiple health outcomes vitamin d toxicity, policy, and science vitamin d beyond bones in chronic obstructive pulmonary disease: time to act iom report sets new dietary intake levels for calcium and vitamin d to maintain health and avoid risks associated with excess relationship between serum -hydroxyvitamin d and pulmonary function in the third national health and nutrition examination survey make no bones about it: increasing epidemiologic evidence links vitamin d to pulmonary function and copd smoking patterns in african americans and whites with advanced copd common genetic determinants of vitamin d insuf fi ciency: a genome-wide association study vitamin d binding protein variants and the risk of copd candidate genes for copd in two large data sets vitamin d de fi ciency, bone mineral density and weight in patients with advanced pulmonary disease vitamin d de fi ciency is highly prevalent in copd and correlates with variants in the vitamin d binding gene the vitamin d axis in the lung: a key role for vitamin d-binding protein vitamin d-binding protein contributes to copd by activation of alveolar macrophages relationship of vitamin d status to adult lung function and copd the relationship of dietary patterns with adult lung function and copd vitamin d status and longitudinal lung function decline in the lung health study modulation of osteoclast differentiation and function by the new members of the tumor necrosis factor receptor and ligand families meta-analysis: excess mortality after hip fracture among older women and men current status of research on osteoporosis in copd: a systematic review the risk of osteoporosis in caucasian men and women with obstructive airways disease low bone mineral density in copd patients related to worse lung function, low weight and decreased fat-free mass low bone mineral density is related to severity of chronic obstructive pulmonary disease osteoporosis in copd outpatients based on bone mineral density and vertebral fractures correlates of osteoporosis in chronic obstructive pulmonary disease: an underestimated systemic component characterisation of phenotypes based on severity of emphysema in chronic obstructive pulmonary disease relationship between pulmonary emphysema and osteoporosis assessed by ct in patients with copd radiographic emphysema predicts low bone mineral density in a tobacco-exposed cohort relationship between osteoporosis and adipose tissue leptin and osteoprotegerin in patients with chronic obstructive pulmonary disease osteoprotegerin in sputum is a potential biomarker in copd vitamin d de fi ciency causes de fi cits in lung function and alters lung structure deletion of vitamin d receptor leads to premature emphysema/copd by increased matrix metalloproteinases and lymphoid aggregates formation a prospective study on socioeconomic aspects of fracture of the proximal femur relationship of lung function to severity of osteoporosis in women association of osteoporotic vertebral compression fractures with impaired functional status the association of radiographically detected vertebral fractures with back pain and function: a prospective study vertebral fractures in patients with chronic obstructive pulmonary disease: the eolo study reduced pulmonary function in patients with spinal osteoporotic fractures the impact of severe exacerbations on quality of life and the clinical course of chronic obstructive pulmonary disease reduction of exacerbations by the pde inhibitor ro fl umilast-the importance of de fi ning different subsets of patients with copd azithromycin for prevention of exacerbations of copd ro fl umilast in moderate-to-severe chronic obstructive pulmonary disease treated with longacting bronchodilators: two randomised clinical trials antimicrobial peptides of multicellular organisms cutting edge: , -dihydroxyvitamin d is a direct inducer of antimicrobial peptide gene expression toll-like receptor triggering of a vitamin d-mediated human antimicrobial response human cathelicidin (ll- ), a multifunctional peptide, is expressed by ocular surface epithelia and has potent antibacterial and antiviral activity activities of ll- , a cathelin-associated antimicrobial peptide of human neutrophils the peptide antibiotic ll- /hcap- is expressed in epithelia of the human lung where it has broad antimicrobial activity at the airway surface fighting infections with vitamin d vitamin d down-regulates monocyte tlr expression and triggers hyporesponsiveness to pathogen-associated molecular patterns vitamin d signaling in immunemediated disorders: evolving insights and therapeutic opportunities prevention of autoimmune diabetes in nod mice by , dihydroxyvitamin d the coming of age of , -dihydroxyvitamin d( ) analogs as immunomodulatory agents immune modulatory treatment of trinitrobenzene sulfonic acid colitis with calcitriol is associated with a change of a t helper (th) /th to a th and regulatory t cell pro fi le evaluation of phagocytosis in rickets control of mycobacterium tuberculosis through mammalian toll-like receptors high doses of vitamin d to reduce exacerbations in copd: a randomized trial a -year trial of tiotropium in chronic obstructive pulmonary disease combined salmeterol and fl uticasone in the treatment of chronic obstructive pulmonary disease: a randomised controlled trial treatment of copd: the sooner the better? decreased histone deacetylase activity in chronic obstructive pulmonary disease vdr microrna expression and epigenetic silencing of vitamin d signaling in melanoma cells dna methylation-related vitamin d receptor insensitivity in breast cancer vitamin d and susceptibility of chronic lung diseases: role of epigenetics peripheral muscle weakness contributes to exercise limitation in copd pulmonary rehabilitation in chronic obstructive pulmonary disease exercise training in copd: how to distinguish responders from nonresponders higher -hydroxyvitamin d concentrations are associated with better lower-extremity function in both active and inactive persons aged > or = vitamin d status predicts physical performance and its decline in older persons effect of vitamin d on falls: a metaanalysis effect of vitamin d supplementation on muscle strength: a systematic review and meta-analysis role of vitamin d in skeletal muscle function osteomalacic myopathy low-dose vitamin d prevents muscular atrophy and reduces falls and hip fractures in women after stroke: a randomized controlled trial vitamin d and its role in skeletal muscle fall prevention with supplemental and active forms of vitamin d: a meta-analysis of randomised controlled trials oxidative capacity of the skeletal muscle and lactic acid kinetics during exercise in normal subjects and in patients with copd muscle fi ber type iix atrophy is involved in the loss of fat-free mass in chronic obstructive pulmonary disease induction of speci fi c proteins in cultured skeletal muscle cells by , -dihydroxyvitamin d- analysis of the oxidative damage-induced conformational changes of apo-and holocalmodulin by dose-dependent protein oxidative surface mapping the effect of cholecalciferol in vivo on proteins and lipids of skeletal muscle from rachitic chicks vitamin d and human skeletal muscle the effects of whole-body vibration training and vitamin d supplementation on muscle strength, muscle mass, and bone density in institutionalized elderly women: a -month randomized, controlled trial vitamin d receptor genotypes in fl uence quadriceps strength in chronic obstructive pulmonary disease vitamin d status in patients with chronic obstructive pulmonary disease who participate in pulmonary rehabilitation vitamin d supplementation during rehabilitation in patients with chronic obstructive pulmonary disease: an intervention study prospective study of predictors of vitamin d status and cancer incidence and mortality in men vitamin d and calcium supplementation reduces cancer risk: results of a randomized trial vitamin d intake is inversely associated with rheumatoid arthritis: results from the iowa women's health study serum -hydroxyvitamin d levels and risk of multiple sclerosis serum -hydroxyvitamin d, diabetes, and ethnicity in the third national health and nutrition examination survey association between serum -hydroxyvitamin d level and upper respiratory tract infection in the third national health and nutrition examination survey low serum vitamin d levels and tuberculosis: a systematic review and meta-analysis epidemic in fl uenza and vitamin d serum -hydroxyvitamin d and the incidence of acute viral respiratory tract infections in healthy adults vitamin d de fi ciency an important, common, and easily treatable cardiovascular risk factor? treating the systemic effects of chronic obstructive pulmonary disease a phase i/ii dose-escalation trial of vitamin d and calcium in multiple sclerosis randomized trial of vitamin d supplementation to prevent seasonal in fl uenza a in schoolchildren vitamin d supplementation reduces insulin resistance in south asian women living in new zealand who are insulin resistant and vitamin d de fi cient-a randomised, placebo-controlled trial vitamin d as supplementary treatment for tuberculosis: a double-blind, randomized, placebo-controlled trial -dihydroxyvitamin d and its analogues down-regulate cell invasion-associated proteases in cultured malignant cells (oh) d is an autocrine regulator of extracellular matrix turnover and growth factor release via erp activated matrix vesicle metalloproteinases sputum matrix metalloproteases: comparison between chronic obstructive pulmonary disease and asthma upregulation of mmp- production by tnfalpha in keratinocytes and its attenuation by vitamin d childhood asthma may be a consequence of vitamin d de fi ciency the in utero effects of maternal vitamin d de fi ciency: how it results in asthma and other chronic diseases premature aging-like phenotype in fi broblast growth factor null mice is a vitamin d-mediated process maternal vitamin d intake during pregnancy and early childhood wheezing early life origins of chronic obstructive pulmonary disease risk factors for chronic obstructive pulmonary disease in a european cohort of young adults vitamin d de fi ciency and chronic obstructive pulmonary disease: a vicious circle key: cord- -vw c wt authors: jain, kewal k. title: biomarkers of pulmonary diseases date: - - journal: the handbook of biomarkers doi: . / - - - - _ sha: doc_id: cord_uid: vw c wt lungs and airways are affected by several pathologies, the most important of which are inflammation, infection and cancer. some of the biomarkers of these pathologies are similar to those found in involvement of other organs. this chapter will briefly discuss general issues of biomarkers of pulmonary disorders listed in table . . biomarkers of lung cancer are described in chapter . lungs and airways are affected by several pathologies, the most important of which are inflammation, infection and cancer. some of the biomarkers of these pathologies are similar to those found in involvement of other organs. this chapter will briefly discuss general issues of biomarkers of pulmonary disorders listed in table . . biomarkers of lung cancer are described in chapter . low lung function is associated with increased morbidity and mortality. it is therefore of interest to identify biomarkers that are associated with impaired lung function. lung function (fev and fvc) and a panel of inflammatory biomarkers (including cytokines, chemokines, adhesion molecules, crp and wbc count) from blood samples were analysed subjects aged years (kuhlmann et al. ) . wbc count, crp and vcam- were found to relate to poorer lung function. a doserelated association was found for the combination wbc count and crp towards fev and wbc and vcam- towards fvc. this indicates that combination of two biomarkers yielded more information than assessing them one by one when analysing the association between systemic inflammation and lung function. oxidative stress is the hallmark of various chronic inflammatory lung diseases. increased concentrations of ros in the lungs of such patients are reflected by elevated concentrations of oxidative stress markers in the breath, airways, lung tissue and blood. traditionally, the measurement of these biomarkers has involved invasive procedures to procure the samples or to examine the affected compartments, to the patient's discomfort. non-invasive approaches to measure oxidative stress have been investigated. the collection of exhaled breath condensate (ebc) is a noninvasive sampling method for real-time analysis and evaluation of oxidative stress biomarkers in the lower respiratory tract airways. the biomarkers of oxidative stress such as h o , f -isoprostanes, malondialdehyde, -hydroxy- -nonenal, antioxidants, glutathione and nitrosative stress such as nitrate/nitrite and nitrosated species can be measured in ebc. oxidative stress biomarkers also have been measured for various antioxidants in disease prognosis. ebc is currently used as a research and diagnostic tool in free radical research, yielding information on redox disturbance and the degree and type of inflammation in the lung. it is expected that ebc can be exploited to detect specific levels of biomarkers and monitor disease severity in response to treatment. community-acquired pneumonia (cap) is one of the most common reasons for emergency department. despite its prevalence, there are many challenges to proper diagnosis and management of pneumonia. there is no accurate and timely gold standard to differentiate bacterial from viral disease, and there are limitations in precise risk stratification of patients to ensure appropriate site-of-care decisions. clinical risk scores such as pneumonia severity index (psi) and curb- (confusion, urea, respiratory rate, blood pressure, age > years), and blood biomarkers of different physiopathological pathways are used in predicting longterm survival in patients with cap. in a prospective study, patients admitted with cap were followed for years and cox regression models as well as area under the receiver operating characteristics curve (auc) were used to investigate associations between initial risk assessment and all-cause mortality (alan et al. ) . initial psi and curb- scores both had excellent long-term prognostic accuracy, with a step-wise increase in mortality per risk class. the addition of inflammatory (pro-adrenomedullin) and cardiac (pro-atrial natriuretic peptide) blood biomarkers measured upon hospital admission further improved the prognostic capabilities of the psi. pathological changes in severe acute respiratory syndrome (sars) suggest that sars sequelae are associated with dysregulation of cytokine and chemokine production. a study from taiwan showed that cytokine or chemokine profiles in patients with sars differ markedly from those in patients with community-acquired pneumonia (cap) and control groups (chien et al. ) . serum levels of three cytokines were significantly elevated in sars patients versus the cap: interferon-γ-inducible protein- (ip- ), interleukin (il)- , and il- . cytokine levels began to rise before the development of chest involvement and peaked earlier than did lung injury assessed by chest x-ray. conversely, in cap patients but not sars patients or controls, levels of interferon-γ, il- , and il- were elevated, and rose in tandem with radiographic changes. a further difference between groups was the ratio of il- to il- , at . in sars patients versus . in cap patients. however, in both sets of patients, levels of il- correlated strongly with the severity of lung injury. the early induction of ip- and il- , as well as the subsequent overproduction of il- and lack of il- , probably contribute to the main immunopathological processes involved in sars lung injury and may be early biomarkers of lung injury. these findings differ from those observed in subjects with cap. plasma biomarkers related to inflammation − il- and enhanced neutrophil recruitment to the lung (icam- ) − are independently associated with increased mortality in patients with ali. higher levels of il- and icam- independently predicted death (mcclintock et al. ). in addition, lower levels of the coagulation marker protein c were independently associated with an increased risk of death. the association of lower protein c levels with non-survivors continues to support the role for disordered coagulation in ali/ards. these associations exist despite consistent use of lung protective ventilation and persist even when controlling for clinical factors that also impact upon outcomes. the two biomarkers with an independent association with mortality, il- and icam- , need to be be studied further for their potential value in stratifying patients in clinical trials. acute respiratory distress syndrome (ards) is the rapid onset of respiratory failure − the inability to adequately oxygenate the blood − that often occurs in the critically ill. acute lung injury (ali) precedes ards as severe respiratory illnesses progress. both conditions can be life-threatening. in a large-scale, multicenter trial of patients with ards or ali, higher levels of nitric oxide (no) in urine were strongly associated with improved survival, more ventilator-free days, and decreased rates of organ failure (mcclintock et al. ). the authors speculated that no has a beneficial effect on ali since it scavenges oxygen free radicals that are generated during oxidative stress. since no increases microcirculation, it helps to better perfuse tissue beds in the lungs. the investigators offered an alternative hypothesis to explain their findings: no created inside the body may have a beneficial effect on organs other than the lung during ali. it might help prevent further tissue damage by improving oxygen and nutrient delivery to the tissues, while helping to decrease the amount of toxic oxygen species. the authors also speculated that no might have antibacterial effects that could be important in infectious conditions that predispose patients to ali. pulmonary surfactant, a complex of lipids and proteins, functions to keep alveoli from collapsing at expiration. surfactant proteins a (sp-a) and d (sp-d) belong to the collectin family and play pivotal roles in the innate immunity of the lung. pulmonary collectins directly bind with broad specificities to a variety of microorganism and possess antimicrobial effects. these proteins also exhibit both inflammatory and antiinflammatory functions. the collectins enhance phagocytosis of microbes by macrophages through opsonic and/or non-opsonic activities. the proteins stimulate cell surface expression of phagocytic receptors including scavenger receptor a and mannose receptor. since the expression of sp-a and sp-d is abundant and restricted within the lung, the proteins are now clinically used as biomarkers for lung diseases. the levels of sp-a and sp-d in bronchoalveolar lavage fluids, amniotic fluids, tracheal aspirates and pleural effusions reflect alterations in alveolar compartments and epithelium, and lung maturity. the determination of sp-a and sp-d in sera is a noninvasive and useful tool for understanding some pathological changes of the lung in the diseases, including pulmonary fibrosis, collagen vascular diseases complicated with interstitial lung disease, pulmonary alveolar proteinosis, acute respiratory distress syndrome and radiation pneumonitis (takahashi et al. ) . interstitial lung disease (ild) is defined as restrictive lung function impairment with radiographic signs of ild. kl- , a mucinous high-molecular weight glycoprotein, is expressed on type ii pneumonocytes and is a potential biomarker of ild. a retrospective, cross-sectional analysis caucasian patients with polymyositis (pm) or dermatomyositis (dm) and ild were shown to have elevated serum levels of kl- compared to patients without ild (fathi et al. ) . at a cut-off level of u/ml, the sensitivity and specificity for diagnosis of ild was % and %, respectively. the level of serum kl- may serve as measure of ild in patients with pm/dm, and is a promising biomarker for use in clinical practice to assess response to treatment. chronic obstructive pulmonary disease (copd) consists of two main forms − chronic bronchitis and emphysema − and sufferers usually have a combination of these conditions. there has been increasing interest in using pulmonary biomarkers to understand and monitor the inflammation in the respiratory tract of patients with copd. bronchial biopsies and bronchoalveolar lavage provide valuable information about inflammatory cells and mediators, but these procedures are invasive, so that repeated measurements are limited. sputum provides considerable information about the inflammatory process, including mediators and proteinases in copd, but samples usually represent proximal airways and may not reflect inflammatory processes in distal bronchi. analysis of exhaled breath is a noninvasive procedure so that repeated measurements are possible, but the variability is high for some assays. there is relatively little information about how any of these biomarkers relate to other clinical outcomes, such as progression of the disease, severity of disease, clinical subtypes or response to therapy. more information is also needed about the variability in these measurements. in the future pulmonary biomarkers may be useful in predicting disease progression, indicating disease instability and in predicting response to current therapies and novel therapies, many of which are now in development. the copd foundation biomarker qualification consortium (cbqc) is a unique public-private partnership established in between the copd foundation, the pharmaceutical industry, and academic copd experts with advisors from the us national heart lung & blood institute and fda (miller et al. ) . the initial intent of the cbqc was to integrate data collected in and submit a dossier for the qualification. this led to the fda qualification of plasma fibrinogen as a prognostic or enrichment biomarker for all-cause mortality and copd exacerbations in . it is the first biomarker drug development tool qualified for use in copd under the fda's drug development tool qualification program. alpha -antitrypsin (aat) is a plasma glycoprotein that inhibits neutrophil elastase, and individuals who inherit altered aat genes resulting in deficiency of the protein are at high risk for copd and liver cirrhosis. this deficiency can be detected by serum protein pattern studies. in the past, testing for the deficiency has been done retrospectively in patients with copd or liver disease, but the introduction of a home-administered finger-stick blood spot test for aat genotype enables affected families to construct pedigrees to enable them to identify children who are at risk for developing copd in later life and should avoid exposure to dust and smoke. extracellular matrix (ecm) remodeling of the lung tissue releases protein fragments into the blood, where they may be detected as serologic surrogate biomarkers of disease activity in copd. association of ecm turnover with severity and outcome of copd has been assessed in a prospective, observational, multicenter study, global initiative for chronic obstructive lung disease grades ii to iv, and serum samples were analyzed at stable state, during exacerbation as well as weeks after exacerbation (stolz et al. ) . results showed that patients with the lowest levels of pro-forms of collagen type iii (pro-c ) and type vi (pro-c ) had more severe airflow limitation, hyperinflation, air trapping, and emphysema. collagen type iii (c m) and collagen type vi (c m) were associated with dyspnea. in conclusion, serum biomarkers of ecm turnover were significantly associated with disease severity and clinically relevant outcomes in patients with copd. lung ecm remodeling in healthy controls and copd patients was investigated in the copdgene study. the data suggest that type vi collagen turnover and elastin degradation by neutrophil elastase are associated with copd-induced inflammation (eosinophil-bronchitis) and emphysema (bihlet et al. ) . serological assessment of type vi collagen and elastin turnover may assist in identification of phenotypes likely to be associated with progression and amenable to precision medicine for clinical trials. lung failure, also termed "lung attack", is the most common organ failure seen in the intensive care unit. lung attacks, which effect individuals with copd are among the leading cause of visits to emergency rooms among chronic disease sufferers. other causes are neuromuscular impairment, pulmonary edema, pneumonia, and vascular diseases such as acute or chronic pulmonary embolism. when a patient is admitted into the hospital with a severe lung failure, it usually takes > months to get to % of his or her baseline health. if the patient's health is poor to start with, the new attack can be devastating or even fatal. a test that could more accurately present a patient's disease could make it easier to predict and treat copd progression to lung failure. there is need for a test that could be performed in any clinical lab and could be used far more widely than the current lung function tests, which are performed in certain centers by specially trained personnel. in , canada's prevention of organ failure (proof) center of excellence in vancouver received funding from genome british columbia to develop a biomarkerbased test for determining a copd patient's risk for having a lung attack. genes and protein biomarker sets that have been discovered at proof center could have the ability to predict copd-caused lung attacks and need to be validated. circulating bnp levels were evaluated as a parameter for the presence and severity of pulmonary hypertension (ph) in patients with chronic lung disease (leuchte et al. ) . during a follow-up time of approximately year, significant pulmonary hypertension (mean pulmonary artery pressure > mm hg) was diagnosed in more than one-fourth of patients and led to decreased exercise tolerance and life expectancy. elevated bnp concentrations identified significant pulmonary hypertension with a sensitivity of . and specificity of . and predicted mortality. moreover, bnp served as a risk factor of death independent of lung functional impairment or hypoxemia. it is concluded that plasma bnp facilitates noninvasive detection of significant ph with high accuracy and can be used as a screening test for the presence of ph. in addition, bnp enables an assessment of the relevance of ph and could serve as a useful prognostic parameter in chronic lung disease. a study has revealed that serum levels of the neuroendocrine activity biomarker chromagranin a (cga) are increased in male smokers with impaired lung function, and are associated with both respiratory symptoms and the degree of airway obstruction (sorhaug et al. ) . the subgroup of airway epithelial cells belonging to the diffuse neuroendocrine system, termed pulmonary neuroendocrine cells, may represent a putative regulatory function of cga as a prohormone. they are considered to control growth and development of the fetal lung and regulation of ventilation and circulation, but may also have a role in the pathogenesis of smoking-induced airway disease. the findings indicate that neuroendocrine activation may be important in smoking-related airway inflammation and remodeling, and raise the possibility that cga could be of predictive value as a biomarker of prognosis in smoking-associated diseases. measurements of c-reactive protein (crp), a biomarker of inflammation, provide incremental prognostic information beyond that achieved by traditional biomarkers in patients with mild to moderate copd, and may enable more accurate detection of patients at a high risk of mortality. lung function decline is significantly related to crp levels, with an average predicted change in fev of − . % in the highest and . % in the lowest quintile. however, respiratory causes of mortality are not significantly related to crp levels. genome-wide expression profiling of peripheral blood samples from subjects with significant airflow obstruction was performed to find non-invasive gene expression biomarkers for copd (bhattacharya et al. ) . correlation of gene expression with lung function measurements identified a set of genes. a total of biomarkers showed evidence of significant correlation with quantitative traits and differential expression between cases and controls. further comparison of these peripheral gene expression biomarkers with those previously identified from lung tissue of the same cohort revealed that two genes, rp and nape-pld, were decreased in copd cases compared to controls in both lung tissue and blood. these results contribute to our understanding of gene expression changes in the peripheral blood of patients with copd and may provide insight into potential mechanisms involved in the disease. patients with copd are often at high risk of early death and identification of prognostic biomarkers may aid in improving their survival by providing early intensive therapy for high-risk patients. a study has investigated the prognostic role of hyperuricemia at baseline on the prognosis of patients with copd by retrospective evaluation of data . hyperuricemia was found to be not associated with other baseline characteristics in patients with copd. kaplan-meier survival curve showed that patients with copd with hyperuricemia had higher risk of mortality compared with patients with normouricemia. thus, hyperuricemia is a promising biomarker of early mortality in patients with copd. decreased expression of vascular endothelial growth factor (vegf) and its receptor has been implicated in the pathogenesis of copd. levels of placenta growth factor (plgf), another angiogenic factor, are increased in the serum and bronchoalveolar lavage (bal) fluid of patients with copd and are inversely correlated with fev (cheng et al. ) . serum levels of plgf in patients with copd were more than double those in smokers and nonsmokers without copd. these findings suggest that bronchial epithelial cells can express plgf, which may contribute to the pathogenesis of copd. both plgf and vegf expression levels were increased in cultured bronchial epithelial cells exposed to pro-inflammatory cytokines such as tnfα and il- . although the mechanisms underlying the observed detrimental effects of plgf remain to be clarified, persistent plgf expression might have adverse effects on lung parenchyma by down-regulating angiogenesis. although the aim of management of patients with asthma is to control their symptoms and prevent exacerbations and morbidity of the disease, optimal management may require assessment and monitoring of biomarkers, i.e., objective measures of lung dysfunction and inflammation. clinical observations suggest that rhinovirus infection induces a specific inflammatory response in predisposed individuals that results in worsened asthmatic symptoms and increased airway inflammation. a study has shown that ifn-γinduced protein (ip)- is specifically released in acute virus-induced asthma, and can be measured in the serum to predict a viral trigger of acute exacerbations (wark et al. ) . primary bronchial epithelial cell models of rhinovirus infection were used to identify mediators of rhinovirus infection and responded to infection with rhinovirus- by releasing high levels of ip- , rantes, and il- , as well as smaller amounts of il- and tnf-α. ip- , perhaps in combination with tnf-α, might be a useful clinical marker to identify rhinovirus and other virus-induced acute asthma. additional findings suggest that ip- or cxcr (an ip- receptor that is highly expressed in activated t cells) might have a role in worsening of airflow obstruction and airway inflammation, and may therefore be potential therapeutic targets. international guidelines on the management of asthma support the early introduction of corticosteroids to control symptoms and to improve lung function by reducing airway inflammation. however, not all individuals respond to corticosteroids to the same extent and it would be an desirable to be able to predict the response to corticosteroid treatment. several biomarkers have been assessed following treatment with corticosteroids including measures of lung function, peripheral blood and sputum indices of inflammation, exhaled gases and breath condensates. the most widely examined measures in predicting a response to corticosteroids are airway hyperresponsiveness, exhaled no (eno) and induced sputum. of these, sputum eosinophilia has been demonstrated to be the best predictor of a short-term response to corticosteroids. more importantly, directing treatment at normalizing the sputum eosinophil count can substantially reduce severe exacerbations. the widespread utilization of sputum induction is hampered because the procedure is relatively labor intensive. the measurement of eno is simpler, but incorporating the assessment of no in an asthma management strategy has not led to a reduction in exacerbation rates. the challenge now is to either simplify the measurement of a sputum eosinophilia or to identify another inflammatory marker with a similar efficacy as the sputum eosinophil count in predicting both the short-and long-term responses to corticosteroids. airway inflammation is associated with an increased expression and release of inflammatory reactants that regulate processes of cell migration, activation and degranulation. one study was done to quantify bronchial lavage (bal) fluid and serum levels of il- , secretory leukocyte protease inhibitor (slpi), soluble intracellular adhesion molecules- (sicam- ) and scd , as surrogate markers of inflammatory and immune response in asthma and copd patients with similar disease duration time (hollander et al. ). biomarkers were measured using commercially available elisa kits. the findings show that of four measured biomarkers, only the bal il- was higher in copd patients when compared to asthma. severe asthma is characterized by elevated levels of proinflammatory cytokines and neutrophilic inflammation in the airways. blood cytokines, biomarkers of systemic inflammation, may be a feature of increased inflammation in severe asthma. one study found that il- and tnf-α levels were higher in severe asthmatics than in mild-moderate asthmatics or in controls and, in conjunction with augmented circulating neutrophils, suggest the involvement of neutrophil-derived cytokine pattern (silvestri et al. ) . furthermore, in patients with severe asthma, tnf-α levels were positively correlated with both exhaled nitric oxide and circulating neutrophil counts. cytokine levels were elevated even though the patients were on high-dose inhaled steroids. this finding might reflect the inability of these drugs to significantly suppress production of this cytokine by airway cellular sources including epithelial cells and inflammatory cells. in patients with severe asthma there may be an imbalance between il- production and the blocking capacity of il- autoantibodies. the findings of this study may be clinically relevant and suggest that drugs that block tnf-α release or activity might represent a new treatment option in severe asthma. airway hyperresponsiveness is the main feature of asthma and is defined as an increase in the ease and degree of airway narrowing in response to brochoconstrictor stimuli. inflammation plays a central role in the pathogenesis of asthma and much of it can be attributed to helper t cell type cytokine activation, the degree of which strongly correlates to disease severity. one of the inflammatory mediators in asthma is nitric oxide (no). the exhaled no level is elevated in asthma, particularly allergic asthma during the pollen season, and can predict asthma exacerbation. it may be clinically more useful to compare exhaled no values with a subject's previous values than to compare them with a population based normal range. cough variant asthma (cva) and atopic cough both present with bronchodilator-resistant non-productive cough but may be differentiated from and other causes of chronic non-productive cough by measuring exhaled no. exhaled no levels in patients with atopic cough are significantly lower than those in patients with cva and bronchial asthma (fujimura et al. ). there are no significant difference in the exhaled no levels between patients with cva and bronchial asthma. a uk study findings show that it is feasible to measure bronchial flux no concentration ( j no) and alveolar no concentration (c alv ) in % of children, with c alv levels potentially reflecting alveolar inflammation in asthma (paraskakis et al. ) . c alv and j no were measured from the fractional exhaled no (feno ) at multiple exhalation flow rates in asthmatic children. although feno and jno give essentially the same information, c alv is higher in asthmatic children than in normal children. this study also highlights the relationship between poor control of asthma and c alv (a biomarker of alveolar inflammation) but further work is needed to confirm the relevance of this. a novel nanosensor can detect a possible asthma attack before it begins. the minute sensor can be fitted into a hand-held device, and when a person blows into the device, it measures the no content of their breath. use of this device would provide asthma sufferers with a simple and cost effective way to monitor their asthma inflammation. an explanation for increased levels of exhaled no is nonenzymatic generation of no from nitrite due to airway acidification in asthmatics. reduced arginine availability may also contribute to lung injury by promoting formation of cytotoxic radicals such as peroxynitrite. as arginine levels decline, nitric oxide synthase (nos) itself can begin to generate superoxide in lieu of no, thereby favoring no consumption via the generation of peroxynitrite that could induce lung injury. this reduction in bioavailability of no via formation of species such as peroxynitrite could be further amplified by the rapid loss of sod activity during the asthmatic response. plasma arginase activity declines significantly with treatment and improvement of symptoms. additional studies are needed to determine whether measurements of plasma arginase activity will provide a useful biomarker for underlying metabolic disorder and efficacy of treatment for this disease. the arginase activity present in serum probably does not accurately reflect whole body arginase activity or that compartmentalized in the lungs, since the arginases are intracellular enzymes. because arginase is induced in monocytes in response to helper t cell type cytokines, it is speculated that these cells are one likely source of the elevated arginase in serum, consistent with the localization of arginase expression within macrophages in the lungs. athough exhaled no is a clinically useful biomarker of eosinophilic airway inflammation in asthma, significant validation and investigation are required before exhaled breath condensate could be utilized for making decisions in clinical practice (simpson and wark ) . endothelins are proinflammatory, profibrotic, broncho-and vasoconstrictive peptides, which play an important role in the development of airway inflammation and remodeling in asthma. a study has evaluated the endothelin- (et- ) levels in exhaled breath condensate (ebc) of asthmatics with different degree in asthma severity (zietkowski et al. ) . et- concentrations in ebc of all asthmatic patients were significantly higher than in healthy volunteers. et- levels were significantly higher in patients with unstable asthma than in the two groups with stable disease. thus, measurements of et- in ebc may provide another useful diagnostic tool for detecting and monitoring inflammation in patients with asthma. the release of et- from bronchial epithelium through the influence of many inflammatory cells essential in asthma and interactions with other cytokines, may play an important role in increase of airway inflammation, which is observed after postexercise bronchoconstriction in asthmatic patients. ige plays a central role in the pathophysiology of asthma. the two essential phases in this pathophysiology are sensitization to allergen and clinical expression of symptoms on reexposure to the sensitizing allergen. omalizumab (xolair, genentech) is a recombinant humanized igg monoclonal anti-ige antibody that binds to circulating ige, regardless of allergen specificity, forming small, biologically inert ige-anti-ige complexes without activating the complement cascade. an - % reduction in free serum ige (i.e., ige not bound to omalizumab) occurs soon after the administration of omalizumab, and low levels persist throughout treatment with appropriate doses. a total serum ige level should be measured in all patients who are being considered for treatment with omalizumab, because the dose of omalizumab is determined on the basis of the ige level and body weight. the dose is based on the estimated amount of the drug that is required to reduce circulating free ige levels to less than iu per milliliter. lebrikizumab (roche) is an injectable humanized mab designed to block il- , which contributes to key features of asthma. lebrikizumab improves lung function in adult asthma patients who are unable to control their disease on inhaled corticosteroids. il- induces bronchial epithelial cells to secrete periostin, a matricellular protein. increased levels of periostin, a biomarker of asthma, can be measured in the blood. in the milly phase ii trial, patients with high pretreatment periostin levels had greater improvement in lung function when treated with lebrikizumab, compared to patients with low periostin levels (corren et al. ) .the primary endpoint of the trial showed that at week , lebrikizumab-treated patients had a . % greater increase in lung function from the baseline compared to placebo. lebrikizumabtreated patients in the high-periostin subgroup experienced an . % relative increase from baseline forced expiratory volume in second (fev ), compared with placebo. in the low-periostin subgroup, those patients on the drug experienced a . % relative increase in fev , compared with placebo. these results support further investigation of lebrikizumab as a personalized medicine for patients who suffer from moderate to severe uncontrolled asthma periostin enables selection of patients who will benefit most from the drug. cystic fibrosis (cf) is the most common serious genetic disease among caucasians in the us. the disease results from a defective gene that affects multiple aspects of cellular function. its most serious symptom is a build-up of thick, sticky mucus in the airways, which can lead to fatal lung infections. the usual method for screening and diagnosis is genotyping of cystic fibrosis transmembrane conductance regulator (cftr) gene mutations. antibody microarrays have been developed as a platform for identifying a cf-specific serum proteomic signature. serum samples from cf patients have been pooled and compared with equivalent pools of control sera in order to identify patterns of protein expression unique to cf. the set of significantly differentially expressed proteins is enriched in protein mediators of inflammation from the nfkappab signaling pathway, and in proteins that may be selectively expressed in cf-affected tissues such as lung and intestine. in several instances, the data from the antibody microarrays can be validated by quantitative analysis with reverse capture protein microarrays. in conclusion, antibody microarray technology is sensitive, quantitative, and robust, and can be useful as a proteomic platform to discriminate between sera from cf and control patients. saliva, because of the noninvasive collection process, shows great potential as a biological fluid for cf monitoring. extensive protein degradation and differentially expressed proteins have been identified in sputum as biomarkers of inflammation relating to pulmonary exacerbations of cf. use of fiber microarrays for measuring significant variations of the levels of six proteins in saliva supernatants -vegf, mmp- , ip- , il- , il- β and egf -as well as the correlations of these levels with clinical assessments, has demonstrated the value of saliva for cf research and monitoring (nie et al. ) . the prohosp study group. clinical risk scores and blood biomarkers as predictors of long-term outcome in patients with community-acquired pneumonia: a -year prospective follow-up study peripheral blood gene expression profiles in copd subjects biomarkers of extracellular matrix turnover are associated with emphysema and eosinophilic-bronchitis in copd increased expression of placenta growth factor in chronic obstructive pulmonary disease temporal changes in cytokine/chemokine profiles and pulmonary involvement in severe acute respiratory syndrome lebrikizumab treatment in adults with asthma kl- : a serological biomarker for interstitial lung disease in patients with polymyositis and dermatomyositis exhaled nitric oxide levels in patients with atopic cough and cough variant asthma serum and bronchial lavage fluid concentrations of il- , slpi, scd and sicam- in patients with copd and asthma association of biomarkers of inflammation and cell adhesion with lung function in the elderly: a population-based study brain natriuretic peptide is a prognostic parameter in chronic lung disease higher urine nitric oxide is associated with improved outcomes in patients with acute lung injury biomarkers of inflammation, coagulation and fibrinolysis predict mortality in acute lung injury plasma fibrinogen qualification as a drug development tool in chronic obstructive pulmonary disease. perspective of the chronic obstructive pulmonary disease biomarker qualification consortium correlations of salivary biomarkers with clinical assessments in patients with cystic fibrosis measurement of bronchial and alveolar nitric oxide production in normal children and children with asthma parathyroid hormone as a novel biomarker for chronic obstructive pulmonary disease: korean national health and nutrition examination survey high serum levels of tumour necrosis factor-α and interleukin- in severe asthma: markers of systemic inflammation? the role of exhaled nitric oxide and exhaled breath condensates in evaluating airway inflammation in asthma increased serum levels of chromogranin a in male smokers with airway obstruction systemic biomarkers of collagen and elastin turnover are associated with clinically relevant outcomes in copd pulmonary surfactant proteins a and d: innate immune functions and biomarkers for lung diseases ifn-gamma-induced protein is a novel biomarker of rhinovirus-induced asthma exacerbations hyperuricemia is a biomarker of early mortality in patients with chronic obstructive pulmonary disease endothelin- in exhaled breath condensate of stable and unstable asthma patients key: cord- -tf dpo authors: enes, sara rolandsson; uriarte, juan j.; pouliot, robert a.; weiss, daniel j. title: clinical application of stem/stromal cells in copd date: - - journal: stem cell-based therapy for lung disease doi: . / - - - - _ sha: doc_id: cord_uid: tf dpo chronic obstructive pulmonary disease (copd) is a progressive life-threatening disease that is significantly increasing in prevalence and is predicted to become the third leading cause of death worldwide by . at present, there are no true curative treatments that can stop the progression of the disease, and new therapeutic strategies are desperately needed. advances in cell-based therapies provide a platform for the development of new therapeutic approaches in severe lung diseases such as copd. at present, a lot of focus is on mesenchymal stem (stromal) cell (msc)-based therapies, mainly due to their immunomodulatory properties. despite increasing number of preclinical studies demonstrating that systemic msc administration can prevent or treat experimental copd and emphysema, clinical studies have not been able to reproduce the preclinical results and to date no efficacy or significantly improved lung function or quality of life has been observed in copd patients. importantly, the completed appropriately conducted clinical trials uniformly demonstrate that msc treatment in copd patients is well tolerated and no toxicities have been observed. all clinical trials performed so far, have been phase i/ii studies, underpowered for the detection of potential efficacy. there are several challenges ahead for this field such as standardized isolation and culture procedures to obtain a cell product with high quality and reproducibility, administration strategies, improvement of methods to measure outcomes, and development of potency assays. moreover, copd is a complex pathology with a diverse spectrum of clinical phenotypes, and therefore it is essential to develop methods to select the subpopulation of patients that is most likely to potentially respond to msc administration. in this chapter, we will discuss the current state of the art of msc-based cell therapy for copd and the hurdles that need to be overcome. chronic obstructive pulmonary disease (copd) is a progressive life-threatening disease that is significantly increasing in prevalence. the world health organization (who) predicts that copd will become the third leading cause of death worldwide by [ ] [ ] [ ] . there is currently no cure for this disease, and smoking cessation remains the most prominent intervention [ ] . because of the lack of effective curative pharmaceutical options and the increase in prevalence, extensive efforts have been devoted to the development of new strategies for cell replacement and tissue remodeling in copd. so far, most focus has been on mesenchymal stromal cell (msc) therapy. msc are theoretically ideal candidates for cell therapeutic approaches because of their low or absent constitutive hla class i and ii expression, allowing allogeneic administration of mscs obtained from normal healthy volunteers, and their immunosuppressive and antibacterial properties [ , ] . in this chapter, we will examine in detail the biological rationale for use of mscs in copd, clinical trials, and the current challenges for implementing this approach as a potential therapy for copd. copd is a progressive lower respiratory condition, which has a massive impact on public health worldwide. increasing in prevalence, copd is currently responsible for over , us deaths annually and is expected to become the third leading cause of death globally in the next few years [ ] . copd is most often associated with longterm smokers over the age of and is thought to be driven by abnormal tissue response(s) to inhaled toxic particles over time. the life expectancy of continuous cigarette smokers is at least years shorter than nonsmokers and the absolute risk of developing copd among this population has been estimated to be - % [ ] ; however, there is evidence for significant underdiagnosis [ , ] . the most common symptoms of copd are chronic bronchitis (persistent cough with chronic mucus production), dyspnea (shortness-of-breath), wheezing, and chest tightness. as a progressive disease, these symptoms get worse over time. current treatments, most importantly smoking cessation, are part of a delay strategy to slow down the physiological disease progression. these physiologic changes all contribute to the impairment of efficient breathing and include: the gradual loss-of-elasticity of the lung tissue leading to collapse of airway and alveolar sacs, weakening-to-rupture of alveolar septal walls, enlargement of segmented airspace, loss of gasexchange surface area, increased mucus production, airway plugging, and airway narrowing driven by swelling and fibrosis ( fig. . ). copd is a complex pathology with a diverse spectrum of clinical phenotypes, comorbidities, and treatment profiles [ , ] . the gold criteria have been widely utilized to help standardize the copd definitions and treatment guidelines; however, they do not fully encompass the diversity of copd phenotypes [ , ] . the treatments available to patients diagnosed with copd are not curative and cannot completely stop disease progression; however, indicate alveolar space (side-to-side alveolar wall distance). scale bars at × magnification represent μm and at × magnification μm they are key to slowing disease progression and importantly to improve quality of life. the most important intervention at any stage is the cessation of smoking and/or limitation of exposure to other identified environmental risk factors. symptomatic treatment throughout disease progression often relies on bronchodilators, which are inhaled beta-agonists or muscarinic antagonists. early-stage individuals will most often be treated with short-acting bronchodilator therapies (saba/sama); however, as the disease progresses treatment will need to incorporate long-acting drugs that affect these receptors (laba/lama). unfortunately, bronchodilators can only partially resolve lung hyperinflation in emphysema [ ] , becomingly increasingly less effective as the disease progresses. inhaled corticosteroids (ics), often used to treat acute respiratory exacerbations, work by interfering with the transcription pathways of key inflammation genes; however, this treatment does not always work and unfortunately can have little to no longterm benefits [ ] . in addition to direct toxic effects of cigarette smoke on lung epithelial cells, there is increasing appreciation that altered or aberrant immune cell signaling significantly contributes to much of the irreparable tissue damage. smokers with undiagnosed copd normally experience lowlevel infiltration of inflammatory cells into the large airways and peripheral lung parenchyma and have what is increasingly recognized as early disease. in individuals with diagnosed copd, the inflammatory process is amplified and prolonged leading to many of the tissue-remodeling events associated with chronic bronchitis and emphysema; hallmarks of copd [ ] . for example, in smoking-induced emphysema, chronically activated macrophages have been found to express upregulated levels of several proteinases and matrix metalloproteinases (mmps) in both human smokers and in mouse models of cigarette exposure [ ] . macrophages also play a crucial role in triggering the initial immune response in responding to smoking induced inflammation. alveolar macrophages are usually in a quiescent state and actually work to suppress the adaptive immune system in the healthy lung; however, in chronic inflammatory situations alveolar macrophages are the main source of proinflammatory amplification and play a significant role in causing an influx of other immune cells [ ] . ultimately, the disease progresses to a point where gas exchange is limited by the tissue damage and extent of hyperinflation. in many cases invasive surgical interventions are the only option; these include endobronchial valve insertion, bullectomy, lung volume reduction surgery, and lung transplantation [ ] . lung volume reduction surgeries can successfully address some issues with hyperinflation in selected patients by returning some of the mechanical advantage of normal breathing. however, invasive surgeries are associated with high morbidity and operative mortality [ ] [ ] [ ] , especially in late-stage copd patients who are often poor targets for surgical intervention. for some patients with end-stage copd, lung transplantation is the only option. however, this approach offers its own unique challenges including rejection risk, requirement for immunosuppression, and the limited supply of donor lungs. while transplanted lungs can certainly facilitate better gas exchange than severe copd lungs, the benefits are balanced by the risks, as the years survival of transplant recipients is only around % [ ] [ ] [ ] [ ] . at present, there are no true curative treatments that can stop the progression of copd, thus new therapeutic strategies are needed. advances in cell-based therapies provide a platform for development of new therapeutic approaches in copd. at this moment, much focus has been given to msc cell-based therapies, mainly because of their immunomodulatory properties. the promising results in animal models have translated into clinical trials for treatment of copd and emphysema. searching on the clinicaltrials.gov database for trials listed through november , using the keywords "copd" and "stromal cell"; "copd" and "mesenchymal stromal cell"; "copd" and "mesenchymal stem cell"; "emphysema" and "stromal cell"; "emphysema" and "mesenchymal stromal cell"; and "emphysema" and "mesenchymal stem cell", identified studies of human clinical trials. so far, four of the studies have been completed and had their results published in the pubmed database, four are still in the process of recruiting patients, three of them are active but not recruiting patients, three have an unknown status, and four of them have been withdrawn [ ] . this section will be focusing on the clinical studies that have been completed and for which results have been published (table . ). in , ribeiro-paes et al. conducted the first clinical investigation evaluating the safety of using bone marrow-derived mononuclear cells (bmmc) in four patients with advanced-stage copd (nct ). autologous bmmc were collected after days of granulocyte colony stimulating factor (g-csf) stimulation, and bmmc were isolated using ficoll-hypaque premium™. the cells were further resuspended in albumin saline solution (ass) at a final concentration of × mononuclear cells/ml, and intravenously administered directly to the patients without freezing or in vitro culture procedures. the patients were evaluated by several pulmonary function tests, including forced vital capacity (fvc), forced expiratory volume in s (fev ), and partial pressure of carbon dioxide (paco ). [ ] importantly, due to the small size of this study, lack of controls, and the lack of statistical analysis no clear conclusions can be drawn from these results. furthermore, the cells used in this study were heterogeneous mononuclear cells isolated from bone marrow aspirates, and not mscs, and therefore this study cannot be considered as the first msc study for treatment of copd patients. in , weiss et al. performed a prospective, randomized, double-blind, placebo-controlled industry-sponsored trial evaluating the safety and the efficacy of intravenous allogeneic mscs (nct ). the study enrolled patients ( - years of age), from six different centers, with moderate-to-severe copd (gold ii or iii). the patients were randomized into two groups, where the first group received non-hlamatched allogeneic mscs and the second group the infusions were well tolerated and no severe or fatal adverse events were observed during the msc or vehicle administration. no significant differences in fev , fvc, and total lung capacity were seen between the groups. nor were differences in -min walk test or dyspnea assessment observed between the two groups. for most of the circulating inflammatory cytokines no significant differences were seen between the msctreated patients and the vehicle group. however, a decrease in the crp level in patients treated with msc compared to their baseline crp levels was observed. the most important finding in this study was that msc administration was safe in an older population of patients with moderate-tosevere copd [ ] . stolk et al. performed a phase i, prospective, open-label study (nct ) where they aimed to assess the safety and feasibility of intravenously infused bone marrow-derived mscs for ten patients with severe emphysema that had serial lung volume reduction surgeries (lvrs). during the first lvrs bone marrow was aspirated. mscs were isolated from the bone marrow aspirates and expanded in vitro (passage - ) followed by cryopreservation. at three and four weeks prior to the second lvrs, mscs were intravenously administered to the patients at two different occasions. spirometry, gas transfer, lung volumes, and lung densitometry were evaluated at baseline and at the months follow-up. seven patients completed the full protocol. three patients were withdrawn from the study due to problem aspirating bone marrow, no msc growth, or persistent air leak after the first lvrs. no toxicity after the msc infusions was observed and the patients did not report any symptoms that were considered related to the treatment. at months follow-up, a significant increase in fev and body weight was observed compared to baseline levels. however, if changes in fev and body weight was due to msc administration or to the surgeries remain unknown, since this study protocol did not include a control group. importantly, no signs of increased pulmonary fibrosis were observed when lung tissue was evaluated by both histology and ct-derived lung density [ ] . de oliveira et al. combined msc administration with one-way endobronchial valve (ebv) insertion [ ] . this study was a prospective, patient-blinded, placebo (vehicle)-controlled, phase i study on ten patients with advanced heterogeneous emphysema (nct ). de oliveira et al. aimed to investigate the safety of combining ebv insertion with intrabronchial msc administration. the authors hypothesized that combining intrabronchial msc administration with ebv would reduce the inflammation, a common side effect of ebv placement. this study, however, was not designed to investigate msc as a treatment for copd, but rather specifically to investigate if msc treatment would enhance ebv placement by reducing the underlying inflammation. therefore, the secondary aim was to investigate if msc administration reduced the systemic inflammation. mononuclear cells (mncs) were isolated from ml bone marrow aspirate collected from the iliac crest of a single healthy donor using density-gradient centrifugation. mncs were cultured at a density of × cells per cm in iscove's modified dulbecco's medium supplemented with % fetal bovine serum, penicillin, and streptomycin at °c, % co for generation of mscs. mscs were immunophenotyped and samples were taken for microbiological and cytogenetic testing. mscs were harvested at passage three or four, diluted in saline solution, and placed in infusion bags. right before ebv insertion mscs (in ml saline) were administered to five of ten patients using a video bronchoscope with a . -mm instrument channel. the patients in the vehicle group received saline. in both groups, the infusions were performed in the region where the ebvs were supposed to be placed (the segmental or subsegmental bronchus of all branches of the target lobe). immediately after the msc administration or vehicle administration and ebv insertion, a chest radiograph was performed to confirm the ebv placement. for the following days, the patients were evaluated for body temperature, blood pressure, oxygen saturation, heart, and respiratory rates. arterial blood gas, complete blood count, urea, creatinine, glucose, and electrolytes were evaluated at day , , , , and . chest ct scans were performed at day , , and . circulating levels of inflammatory cytokines were assessed in serial blood samples obtained throughout the study period. efficacy was evaluated as improvement from baseline in fev , fvc, fev /fvc, total lung capacity, single-breath carbon monoxide diffusing capacity, the body mass index, airway obstruction, dyspnea, exercise index, and health-related quality of life (st. george's respiratory questionnaire). all ten patients completed the full protocol. the msc administration was well tolerated and all patients tolerated the ebv insertion but one, who developed pneumonia, pneumothorax, empyema, and respiratory failure. no severe adverse events were seen in the group receiving msc, but % in the msc group and % in the placebo group experienced adverse events during the study period, and importantly none of the adverse events was reported to be related to the msc administration. no difference in toxicological or lung function parameters such as fev , fvc, and total lung capacity were observed between the groups. in accordance with data reported by weiss et al. [ ] the msc treated group had significantly reduced levels in crp at day and post administration. patients receiving msc infusions were reported to have a significant decrease in the st. george's respiratory questionnaire scores compared to the placebo group at day post administration. the authors concluded that intrabronchial msc administration in combination with ebv insertion appears to be safe in patients with severe heterogeneous emphysema. furthermore, in this study msc administration tended towards decreased circulating crp levels; however, due to the low number of recruited patients and the limited follow-up period it was not possible to evaluate if msc treatment altered the efficiency of the ebv placement or the subsequent clinical copd course. [ ] . finally, armitage et al. recently published a single site, phase i study that was not listed at the nih clinicaltrials.gov database, rather only in the australian clinical trials registry (number ), which aimed to investigate the distribution of intravenously infused mscs into copd patients. nine patients with mild-tosevere copd (gold i-iv) received infusion of low passage allogenic bone marrow-derived mscs radiolabeled with indium- , followed by a second infusion of unlabeled mscs one week post the first administration. in similarity with the other clinical trials, all patients tolerated the msc infusions well and no infusional or short-term adverse effects were reported. following the first infusion, labeled mscs were detected in the lungs within min by computed tomography (ct) scan, and remained detectible h after the infusion. after h, indium- was detected in spleen, liver, and bone marrow up to days after infusion. moreover, h after the first infusion the patients were assessed by single-photon emission computed tomography (spect) to evaluate msc localization within the lungs. furthermore, the amount of indium- positively correlated with the baseline fev and the diffusing capacity of the lung for carbon monoxide. in addition, this study further aimed to investigate systemic inflammation following the msc infusion. the authors were not able to detect il- beta, il- , il- p , or il- a; however, increased circulating levels of crp were detected at h and up to days after msc administration. interestingly, this study suggests that msc infusion shifted the balance towards a more anti-inflammatory profile, as the number of circulating regulatory t-cells were increased days after msc administration and the proportion of dendritic cells were altered, favoring plasmacytoid dendritic cells [ ] . current clinical trials that aimed to evaluate the effect of msc administration in copd patients differ in a wide range of factors such as routes of administration, number of msc administered, number of administrations, use of fresh mscs or culture-expanded mscs. furthermore, all the investigations discussed above, were phase i-ii studies that were underpowered in order to detect potential efficacy and no improved pulmonary function or respiratory quality of life was observed. although the primary end-point was safety and all studies reported that msc administration was well tolerated and no toxicity was observed, further studies, both clinical and preclinical, are needed to better understand potential therapeutic efficacy of mscs in copd. despite increasing number of preclinical studies demonstrating that msc administration could prevent or treat experimental copd and emphysema [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] , clinical studies have not been able to reproduce the preclinical results, and to date no efficacy or significantly improved pulmonary function in copd patients have been observed. in this section, we will be discussing some of the challenges in the field and the hurdles that need to be overcome in order to improve the efficacy of msc therapy in copd [ ] . mscs are known to be a heterogeneous cell population [ , ] , containing subpopulations that have been demonstrated to be functionally different from each other [ , ] . many of the phenotypic and functional differences depend on differences in culture conditions, individual donors, the harvest site, and the tissue source [ ] [ ] [ ] [ ] . this makes it difficult to compare results between different studies, both preclinical and clinical, and importantly it hinders progression in the field. efforts should therefore be concentrated on developing standardized msc isolation methods and culture conditions. in , the international society for cellular therapy published a position paper in order to address this issue. in this article, they defined minimal suggested criteria for cultured human mscs [ ] . since this position paper by dominici et al. was published it has been updated once in [ ] , but the msc field has advanced and today mscs are isolated from different organs and tissues and therefore these minimal criteria urgently need to be modified and updated. to date, bone marrow-derived mscs are the most widely investigated, but preclinical studies have demonstrated that mscs with immuneregulatory and regenerative properties can be isolated from other tissues such as adipose tissue, umbilical cord, and lung [ , [ ] [ ] [ ] [ ] [ ] [ ] . a large body of data demonstrates that mscs execute their therapeutic effects through a spectrum of paracrine activities, and interestingly preclinical data suggest that mscs isolated from different tissues have different secretome profiles [ , ] . it is also important to realize that primary mscs change phenotype when they are isolated from their native tissue and plated on a plastic culture dish [ ] . the bona-fide msc, which are thought to be small and quiescent, noncycling cells in vivo, changes phenotype into a spindle-shaped and active proliferating and secretory cell in culture [ , ] . at early passages, mscs have a high proliferation rate but as their time in culture progresses their proliferation rate declines and they finally enter a senescence stage [ ] [ ] [ ] . also the morphology is changed during culture expansion, mscs in early passages have a thin spindle-shaped morphology, but at higher passages mscs tend to become larger and more flattened cells with an irregular shape [ , ] . moreover, mscs have been reported to accumulate dna damage during in vitro expansion, which could potentially lead to tumorigenesis upon implantation [ , ] . importantly, tumor development was not observed in any of the clinical studies using msc as treatment for copd and/or emphysema patients, although longer follow-up is necessary [ ] [ ] [ ] [ ] . furthermore, the biological properties of mscs can also be strongly influenced by the cell culture medium. cell culture media are often supplemented with serum, and most often fetal bovine serum (fbs) is used. the use of fbs has several disadvantages, especially in clinical settings. first, the possibility of contamination with pathogens such as prions and viruses and the potential immune reaction to bovine proteins. second, lot-to-lot variation between different fbs batches might induce differences in msc behavior such as proliferation rates and differentiation potential, and make it difficult to standardize methods and reproducibility of results [ , , ] . human platelet lysate (hpl) is as an alternative to fbs in clinical settings. hpl has the advantages of containing non-animal products and therefore no risk of xenogeneic infections and immune rejection. on the other hand, hpl is a human product and has the potential to transmit human diseases such as hepatitis b and c, and human immune deficiency virus (hiv). in similarity with fbs, hpl also brings the disadvantage of having lot-to-lot variation [ , ] . a third option would be to use serum-free cell or synthetic culture media. these media are highly promising, but more studies are needed in order to have evaluate their utility for producing clinical grade-mscs. recently, lensch et al. demonstrated that mscs had a higher proliferation rate when growing in xeno-free medium which resulted in a greater viable cell yield compared to standard fbs containing culture medium [ ] . nevertheless, further studies are needed in order to evaluate if the in vivo biological properties of msc are altered when expanded in the in vitro setting. another factor that may influence the biological function of mscs is the freezing and thawing of cells before administrated to patients. the current model for allogeneic msc use is to expand cells on plastic culture dishes following harvest and isolation from bone marrow or other source and cryopreserve the cells until usage. when it is time for administration, cells are thawed, washed, and directly administered to the patients most commonly through intravenous infusions [ ] . however, a number of studies have demonstrated that mscs that have been freeze-thawed have impaired functional properties. francois et al. reported that cryopreserved mscs had impaired immunosuppressive properties [ ] . in accordance with these results, moll et al. published an article where they demonstrated that freezethawed mscs had a reduced responsiveness to proinflammatory stimuli and an impaired production of anti-inflammatory mediators [ ] . minor effects on gene expression of freeze-thawed mscs compared to continuously cultured mscs have been observed. however, the alterations in gene expression between different donors were larger than the effects of cryopreservation [ ] . although there is a practical need for expanding and cryo-banking cells for therapeutic use [ ] , most preclinical studies have been performed using log phase of growth msc. there are studies, some of them discussed above, which demonstrated that freeze-thawing procedure alters the biological properties of msc. francois et al. found that during the thawing process a heat-shock stress response was initiated that was associated with the impaired immunosuppressive properties of msc. interestingly, this response was reversible and cells were recovered after h of culture [ ] . these results imply that cryopreservation and banking of cells might be possible, as long as the cells are allowed to recover in culture before use. the study by cruz et al. further supports the potential of using freeze-thawed cells for clinical trials. in this study, the authors compared the therapeutic effect of continuously cultured versus freshly thawed bone marrow-derived mscs in an aspergillus hyphal extract (ahe) exposed asthma mouse model, and found no difference in therapeutic effect between the two groups [ ] . utilizing plastic culture dishes are by far the most traditional way of cultivating and expanding msc; however, alternative culture systems have been developed that might mimic the in vivo situation more compared to the more traditional d cultivation on plastic. the use of alternative threedimensional cell culture systems can hopefully contribute to narrowing the gap between preclinical and clinical research. different groups have studied the possibility to grow mscs on plastic culture dishes coated with extracellular matrix molecules (ecm) such as collagen and fibronectin [ , ] . ecm is a three-dimensional network composed of noncellular structures that play an important role within the lung, not only by providing structural support and adding stability but also as a bioactive environment that can influence cellular responses [ ] . engler et al. demonstrated that changing the elasticity of the ecm that mscs were grown on significantly affected the msc phenotype. mscs grown on a stiffer ecm differentiated towards the osteoblast lineage, whereas mscs grown on a softer ecm differentiated towards the adipocyte lineage [ ] . the msc differentiation potential could also be altered by changing the cross-linking of the collagen fibers [ ] . in addition, modifications of the geometric shape, cell density, and cell size have been implicated in the differentiation potential of msc [ , ] . interestingly, mcmurray et al. developed a nanoscale surface that maintained the phenotype and multilineage potential of longterm cultured mscs [ ] . how the ecm environment affects the msc therapeutic behavior, especially in a fibrotic or emphysematous copd lung, is currently a largely untouched area that will most likely play a pivotal role in the development of successful msc-based therapies. a different approach of the three-dimensional cultures is the usage of the hanging drop model. in conformity with primary mscs, culturing mscs using the hanging drop method resulted in nondividing cells [ ] , but an increased potential to differentiate towards osteoblast and adipocyte lineages was also demonstrated [ ] . another strategy that has been used for msc expansion relies on culturing mscs in d scaffolds (decellularized lung tissue or synthetic scaffolds) [ ] [ ] [ ] . in this system, cultivation on a plastic surface could be avoided, but a perfusion-based bioreactor system is required [ ] . studies have shown that mscs cultured in lung ecm hydrogels have enhanced viability and increased expression of sox and oct compared to cells grown on plastic [ ] . furthermore, changes in secretion of cytokines including il- ra, vegf, g-csf, fgf, and hgf have been demonstrated in mscs grown in d culture compared to d [ , ] . taken together, the traditional way of cultivating mscs as monolayer on a plastic surface may result in mscs with a different phenotype compared to mscs expanded in three-dimensional culture systems. however, whether cultivating mscs on ecm coating, in scaffolds, or in hanging drops increases the beneficial effects when used for clinical settings remains to be evaluated and further studies are needed. it is well known that oxygen levels can affect cell functions, such as differentiation, cytokine production, and proliferation [ ] [ ] [ ] [ ] . furthermore, it is also known that different adult tissues experience a wide range of oxygen levels [ ] and that severe pathological inflammation can cause hypoxia, reduced ph, and oxidative stress [ , ] . nevertheless, mscs tend to be cultured at atmospheric oxygen levels ( - % o ) which do not reflect the microenvironment they normally reside in, or the microenvironment they will encounter when administered into the diseased lung [ ] . culturing mscs at oxygen levels that more closely represent their in vivo situation have a huge impact on msc behaviors. lennon et al. observed that mscs grown at lower oxygen levels had a greater number of colony-forming cells and proliferated at a higher rate compared to mscs grown at higher oxygen levels. also, lennon et al. demonstrated that mscs cultured at % oxygen formed more bone structures in vivo, compared to mscs grown in % oxygen [ ] . moreover, adipose-derived mscs grown at low oxygen levels, secreted higher levels of cytokines such as vegf and fgf compared to cells cultured at % oxygen [ ] . combining the low oxygen condition with growing the mscs in d cultures has been shown to increase the expression of pluripotent genes such as oct- , sox- , nanog, and rex- compared to control [ , ] . beegle et al. reported that mscs pretreated with hypoxia before administration enhanced survival rate and cell retention compared to cell grown at % oxygen. taken together, these studies emphasize the importance of understanding the effects of differences in protocols, culture conditions, and oxygen levels in the context of culturing mscs for clinical trials for copd where you have gasexchange impairment, active immune response, and inflammation. despite an enormous interest in using mscs for clinical settings, the exact in vivo function is not understood, especially not within the lung. a compelling amount of data now points towards that mscs act by paracrine mechanisms rather than through engraftment [ , [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . tracking studies of intravenous injected mscs reveal that most of the injected cells disappear after h [ , , , ] , and since mscs do not engraft it is unlikely that mscs can remodel injured tissue by differentiating into other cell types. the mechanisms by which mscs are the most likely to be involved in copd and emphysema are discussed below. immunomodulation through paracrine actions is one of the main mechanisms of actions of mscs and involves both the innate and the adaptive immune system [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] (fig. . ) . these effects include inhibition of t-cell [ , ] and b-cell proliferation [ ] , macrophage polarization [ ] , and differentiation of t-cells towards t-regulatory cells [ ] [ ] [ ] . the paracrine actions have been associated with several mediators such as hepatocyte growth factor (hgf), transforming growth factor beta (tgfβ), prostaglandin (pge ), il- , ifn-gamma, tnf-stimulated gene (tsg ), and indoleamine , -dioxygenase (ido) [ , , , , ] . in addition to the paracrine immunomodulatory effects, mscs might activate the immune system by recognition of the immune cells. as mentioned, mscs are rapidly cleared from the lung after infusion, which was recently demonstrated to be mainly through phagocytosis by monocytes [ ] . the recognition of mscs by monocytes results in a polarization of monocytes/macrophages towards an immuno- suppressive phenotype that results in an immunomodulatory response [ , ] . similar results have also been demonstrated with heatinactivated mscs, suggesting that mscs also can act in a passive immunomodulatory manner [ ] . however the potency of apoptotic mscs are controversial, apoptotic mscs have been demonstrated to be completely ineffective when injected intravenously in mice [ ] . msc are also known to secrete antimicrobial proteins and polypeptides that are molecules responsible for bacterial killing. mscs secrete the antimicrobial peptide, ll- , following eschericia coli. stimulation, which was subsequently found to be responsible for the antimicrobial activity in a model of e. coli pneumonia [ ] . in addition to its antimicrobial activities, ll- can also play an important role in inflammatory and immune modulatory actions [ , ] . a growing body of data suggests that mscs can form links with other cells, and that they have the potential to transfer components such as mitochondria [ ] [ ] [ ] [ ] . through mitochondrial transfer msc have been demonstrated to be able to rescue epithelial cells with defective mitochondria [ ] . the mitochondria transfer is thought to be via direct transfer by microtubules and tunneling nanotubes (tnt) [ , ] . mscs can also transfer mitochondria to macrophages resulting in an increased phagocytic activity [ ] . mitochondrial biogenesis is regulated by extracellular stimuli [ ] and several lung diseases are associated with impaired mitochondrial biogenesis and dysfunctional mitochondria [ , ] . however, beyond the mitochondria-derived reactive oxygen species (ros), the contribution of mitochondria in the development of copd is still under investigation [ ] . in addition to mitochondria transfer through microtubules and tnt, mitochondria can also be transported via extracellular vesicles (ev) [ , [ ] [ ] [ ] . it is also becoming increasingly clear that msc-derived evs can influence the behavior of surrounding inflammatory and structural cells. for example, evs released from mscs can stimulate bronchial epithelial cells and alveolar cells to secrete proinflammatory cytokines [ , ] . furthermore, msc-derived evs suppress the potential of lung fibroblasts to differentiate towards myofibroblasts [ ] . it is not only mitochondria that could be transferred by msc-derived evs, also other components such as microrna, proteins, lipids, dna, and mrna [ , ] . evs are taken up by other cells, and evs derived from mscs have been demonstrated to impact immune cells. evs isolated from il-beta pretreated mscs induced macrophage polarization towards the anti-inflammatory phenotype (m ) [ ] . mscderived evs have also been associated with inhibition of t-cell proliferation, inducing apoptosis of activated t-cells and promotion of regulatory t-cells [ ] . msc-derived evs have been tested in experimental copd models, but further studies are needed [ ] . it is now widely accepted that, following in vivo delivery, culture-derived mscs respond to the microenvironment they encounter, which in copd and emphysema could encompass everything from massive inflammatory environment to emphysematous tissue destruction. therefore, it is important to consider several important aspects of the msc preparation and administration used today. the route by which mscs are delivered into the patients most likely plays an important role in the msc potential function. despite the fact that several clinical trials has been performed using mscs for severe lung disorders [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] , the best route of administration have not been determined. in preclinical studies, two main administration routes have been evaluated: systemic administration [ , , , , , , , , ] and local administration [ , - , , ] . copd is a systemic disease and therefore systemic administration might be better suitable for these patients. in addition, systemic administration is less invasive and has less contamination risks compared to local administration [ ] . not only has the route of administration been different in the different studies conducted to date but also the number of cells administered with each injection and whether single or multiple injections were administered during the trial. according to antunes et al. a wide range of msc doses in preclinical settings have been used, from up to × [ ] . so far, bone marrow-derived mscs are the most frequently used cell source for msc-treatments, especially when used in human clinical trials. however, mscs derived from other sources such as adipose-derived, umbilical cord-derived, lungderived, and amniotic fluid-derived mscs have been evaluated for treatment of copd/emphysema models [ , , , ] . since it is known that the environment affects msc function and viability, several preconditioning strategies have been tested. some researchers have been focusing on the effect of the inflammatory environment and the cytokines that may be encountered in the diseased lung [ , [ ] [ ] [ ] [ ] [ ] [ ] [ ] . krampera et al. reported that mscs stimulated with ifn-gamma, increased the levels of ido produced and secreted by mscs, leading to an increased suppressive effect on t-lymphocyte proliferation. moreover, the authors were able to demonstrate that the inhibitory effects of mscs on t-lymphocyte proliferation were completely abolished when adding an ifn-gamma blocking antibody to the culture system [ ] . in an ifngamma knock out mouse model, polchert et al. were able to demonstrate that endogenous ifngamma was required to initiate msc efficacy. however, after pretreatment of mscs with high doses of ifn-gamma they immediately became active [ ] . also pre-stimulating mscs with a combination of inflammatory cytokines has been explored [ , ] . another interesting approach to mimic the microenvironment is to utilize patient samples such as serum and bronchoalveolar lavage (bal) fluid from patients and pre-stimulate cells with such prior to the administration [ , ] . moreover, attempts to improve the beneficial effects of mscs have utilized treatment with the toll-like receptor- ligand (poly(i:c)). the authors found that mscs pretreated with poly(i:c) had improved immunosuppressive properties, an effect that was inhibited by addition of the microrna mir- [ ] . in addition to the inflammatory environ-ment, others have studied the effect of pretreating mscs with hypoxia and nutrient deficiency. during culture under hypoxic conditions, mscs have been shown to have decreased expression of senescence-associated beta-galactosidase and an increase in the expression of anti-apoptotic proteins such as bcl- and bcl-xl [ , ] . by exposing mscs to hypoxia the hypothesis is that the cells will adapt to the ischemic environment with oxidative stress, an environment they likely will encounter in the copd lung. this might potentially enhance the time that mscs can survive and exert their therapeutic paracrine actions in the recipient lung. a different way of increasing the therapeutic effect by mscs is to genetically manipulate the cells prior to administration [ ] [ ] [ ] . for example, jiang et al. demonstrated that after co-overexpressing the genes ang- and akt in mscs, an increased cell survival and improved angiomyogenesis was observed in an experimental model of acute myocardial infarction [ ] . in lung, mscs overexpressing ang- have been demonstrated to more potently decrease lpsinduced pulmonary inflammation and proinflammatory cytokine release into the bal fluid [ ] . in another study by mcginley et al., overexpression of heat shock protein (hsp ) in mscs led to decreased apoptosis and improved cardiac function [ ] . overexpression of manganese superoxide dismutase in adipose-derived mscs, a gene strongly upregulated during hypoxia, increased the time that the mscs were detectable in a matrigel plug implanted into a mouse model [ ] . moreover, he et al. transduced mscs with angiotensin-converting enzyme (ace ), an enzyme that degrades angiotensin ii and had previously been demonstrated to have a protective role against acute lung injury. the ace transduced mscs were demonstrated to reduce pulmonary vascular permeability, normalize the expression of enos, and improve the endothelial barrier integrity, when infused into an ali-mouse model. furthermore, the ace overexpressing mscs also displayed an improvement in the suppression of the inflammatory response [ ] . combination of different treatments could be another approach to enhance msc efficacy. this approach was used in two of the clinical trials discussed above. stolk et al. combined msc treatment with lung volume reduction surgery and de oliveira et al. with a one-way endobronchial valve insertion [ , ] . an alternative could be to pretreat the recipient tissue with pharmacological drugs in order to make the recipient site more accessible to the infused cells [ , [ ] [ ] [ ] . in a cardiac disease model, pharmacological pretreatment of a vasodilator drug in the recipient site of transplantation resulted in an enhanced delivery of mscs [ ] . in a clinical trial using mscs for treatment of chronic heart failure, the administration site was treated with a shock wave prior to the administration of the cells. in the group receiving both the shock wave pretreatment and the msc infusion, the overall occurrence of major adverse cardiac events were significantly decreased compared to the control groups [ ] .these are all important observations for potential cell-based therapies for lung diseases and should be investigated further. the lack of translating the encouraging preclinical data into clinically relevant effects in patients with copd and emphysema brings up the following question: is copd the most suitable pulmonary disease for msc-based treatment? the animal models of copd and emphysema used in the preclinical studies were optimized to detect the maximum therapeutic effects [ ] , and might therefore not reflect the in vivo situation that mscs encounter when infused into patients with copd and/or emphysema. copd is characterized by tissue damage, structural changes, and inflammation, and as mentioned it is a heterogeneous disease with different degrees of fibrosis and emphysema [ ] . copd patients with different phenotypes might respond differently to msc administration [ ] , and choosing patients that are more likely to respond to the treatment could be one way to improve the clinical outcome. another possible way to improve the outcome could be the timing of the treatment. in animal studies, mscs are frequently administered to the animals in close proximity to the induction of the disease [ , , , ] or even at the same time or prior to the disease induction [ , ] . based on these preclinical findings, mscs might be more beneficial earlier in the disease than in later stages of the disease. however, copd patients tend not to seek medical attention in early stage of the disease [ ] . one way to foresee which patients would most likely respond to the treatment could be to develop in vitro potency assays. even if it is widely accepted that the therapeutic effect of mscs is mainly mediated by paracrine effects, the exact mechanism of action is not determined. this makes it difficult to develop one single analytic or biological assay, and most likely, a combination of evaluating different mechanisms would be needed [ , ] . another potential way would be to develop biomarkers to indicate which patients have an active disease and therefore might benefit more from a msc-based therapy. to date, several potential biomarkers, including circulating fragments of ecm proteins, have been shown to be increased in copd patients with an active disease e.g. in relation to acute exacerbations [ ] [ ] [ ] . finally, broekman et al. suggested that in addition to the optimization of msc-treatment and potency assays, challenges such as improved outcome parameters needs to be addressed [ ] . in parallel with the growing interest of cellbased therapies for copd and other lung diseases, an increased market for commercial stem cell therapies has developed both in the usa and globally [ ] . this very unfortunate and problematic outcome might partly be due to an increased visibility to desperate patients through the internet and open social media channels [ ] . these unproven and often unsafe stem cell treatments can create a situation in which desperate patients easily can be misled into participating in very expensive treatments, which are not covered by insurance. furthermore, the providers at the stem cell clinics often fail to prove safety and efficacy of their treatments failing to fulfill recognized biological and medical standards, exposing the patients to unnecessary risks and leaving the patient and their family with dashed hopes [ , ] . these stem cell clinics have the potential to harm even more patients and their families, as well as bring the field into disrepute and hamper the progression of safe and effective msc-based therapies. therefore, organizations such as the international society for stem cell research (isscr) and the international society for cell and gene therapies (isct) have taken stances against these unethical cell-therapy clinics. also, the food and drug administration (fda) is beginning to take actions against the stem cell tourism [ , ] . in a review by dominici et al., the authors discuss the importance of having proper communication between different players such as medical doctors, industry, patient organizations, and patients, in order to enhance credibility and patient welfare [ ] . in an attempt to begin proactively addressing this issue, the american thoracic society (ats) respiratory cell and molecular biology assembly stem cell working group posted a statement online and several other related publications [ , [ ] [ ] [ ] [ ] . this statement will help to translate new scientific findings into patient education in an unbiased way and to make the public aware of the limitations and potential risks associated with such therapeutic approaches [ , ] . however, it is not only the patients that need education, many pulmonologists are also not familiar with the stem cell field, and the ats respiratory cell and molecular biology assembly stem cell working group has developed educational resources for this audience also [ ] . msc-based therapy for treatment of copd and emphysema has demonstrated promising results in animal models; however, this has not translated into clinically relevant effects in patients to date. current clinical trials have failed to demonstrate efficacy and improved lung function, but importantly they have uniformly demonstrated the msc administration to be safe. the challenges ahead for this field are to standardize the isolation and culture conditions in order to have a cell product with high quality and reproducibility, to select the proper subpopulation of patients that is most likely to respond to the cell treatment, to develop appropriate potency assays, and to improve or develop new methods to measure outcomes. furthermore, the usage of cell-free products such as evs and conditioned medium, or pretreating mscs prior to administration has demonstrated promising results. however, there is still a long way to go and many challenges are ahead before we have an optimal msc-based 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expression, and repair of elastase-injured lung autologous lung-derived mesenchymal stem cell transplantation in experimental emphysema mesenchymal stem cells alleviate airway inflammation and emphysema in copd through down-regulation of cyclooxygenase- via p and erk mapk pathways cell therapy with bone marrow mononuclear cells in elastase-induced pulmonary emphysema effects of different mesenchymal stromal cell sources and delivery routes in experimental emphysema paracrine factors of multipotent stromal cells ameliorate lung injury in an elastase-induced emphysema model intravenous and intratracheal mesenchymal stromal cell injection in a mouse model of pulmonary emphysema mesenchymal stem cell-based hsp promoter-driven vegfa induction by resveratrol alleviates elastase-induced emphysema in a mouse model the therapeutic effects of optimal dose of mesenchymal stem cells in a murine model of an elastase induced-emphysema tracking intravenous adipose-derived mesenchymal stem cells in a model of elastase-induced emphysema mesenchymal stem cells transplantation protects against rat pulmonary emphysema mesenchymal stem cell transplantation increases expression of vascular endothelial growth factor in papain-induced emphysematous lungs and inhibits apoptosis of lung cells lung tissue engineering technique with adipose stromal cells improves surgical outcome for pulmonary emphysema autologous transplantation of adipose tissue-derived stromal cells ameliorates pulmonary emphysema mesenchymal stromal cell therapy in copd: from bench to bedside flexible and dynamic organization of bone marrow stromal compartment bone marrow stromal stem cells: nature, biology, and potential applications isolation of functionally distinct mesenchymal stem cell subsets using antibodies against cd , cd , and mesenchymal stem cell antigen- characterization of bone marrowderived mesenchymal stromal cells (msc) based on gene expression profiling of functionally defined msc subsets a relativity concept in mesenchymal stromal cell manufacturing quantitative proteomic characterization of lung-msc and bone marrow-msc using dia-mass spectrometry msc from fetal and adult lungs possess lung-specific properties compared to bone marrow-derived msc primary mesenchymal stem cells in human transplanted lungs are cd / cd perivascularly located tissue-resident cells minimal criteria for defining multipotent mesenchymal stromal cells. the international society for cellular therapy position statement wharton's jelly-derived cells are a primitive stromal cell population human umbilical cord mesenchymal stem cells: a new era for stem cell therapy multilineage cells from human adipose tissue: implications for cell-based therapies mesenchymal stem cells derived from human adipose tissue mesenchymal stem cells in human secondtrimester bone marrow, liver, lung, and spleen exhibit a similar immunophenotype but a heterogeneous multilineage differentiation potential evidence for tissue-resident mesenchymal stem cells in human adult lung from studies of transplanted allografts unveiling the differences of secretome of human bone marrow mesenchymal stem cells, adipose tissue-derived stem cells, and human umbilical cord perivascular cells: a proteomic analysis low/negative expression of pdgfralpha identifies the candidate primary mesenchymal stromal cells in adult human bone marrow different facets of aging in human mesenchymal stem cells donor variation and loss of multipotency during in vitro expansion of human mesenchymal stem cells for bone tissue engineering human mesenchymal stem cell-replicative senescence and oxidative stress are closely linked to aneuploidy from cytogenomic to epigenomic profiles: monitoring the biologic behavior of in vitro cultured human bone marrow mesenchymal stem cells a link between the accumulation of dna damage and loss of multipotency of human mesenchymal stromal cells serumfree human msc medium supports consistency in human but not in equine adipose-derived multipotent mesenchymal stromal cell culture comparison of human bone marrow stromal cells cultured in human platelet growth factors and fetal bovine serum impact of individual platelet lysates on isolation and growth of human mesenchymal stromal cells comparison of synthetic media designed for expansion of adipose-derived mesenchymal stromal cells cryopreserved mesenchymal stromal cells display impaired immunosuppressive properties as a result of heat-shock response and impaired interferon-gamma licensing do cryopreserved mesenchymal stromal cells display impaired immunomodulatory and therapeutic properties? effects of freeze-thawing and intravenous infusion on mesenchymal stromal cell gene expression freshly thawed and continuously cultured human bone marrow-derived mesenchymal stromal cells comparably ameliorate allergic airways inflammation in immunocompetent mice attachment, growth, and detachment of human mesenchymal stem cells in a chemically defined medium collagen promotes higher adhesion, survival and proliferation of mesenchymal stem cells the extracellular matrixthe under-recognized element in lung disease? matrix elasticity directs stem cell lineage specification extracellular-matrix tethering regulates stem-cell fate geometric cues for directing the differentiation of mesenchymal stem cells cell shape, cytoskeletal tension, and rhoa regulate stem cell lineage commitment nanoscale surfaces for the long-term maintenance of mesenchymal stem cell phenotype and multipotency hematopoietic stem and progenitor cell expansion in contact with mesenchymal stromal cells in a hanging drop model uncovers disadvantages of d culture enhanced differentiation of mesenchymal stromal cells by three-dimensional culture and azacitidine preparation of decellularized lung matrices for cell culture and protein analysis residual detergent detection method for nondestructive cytocompatibility evaluation of decellularized whole lung scaffolds enhanced human bone marrow mesenchymal stromal cell adhesion on scaffolds promotes cell survival and bone formation tunable hydrogels from pulmonary extracellular matrix for d cell culture changes in the secretome of tri-dimensional spheroid-cultured human mesenchymal stem cells in vitro by interleukin- priming combination of msc spheroids wrapped within autologous composite sheet dually protects against immune rejection and enhances stem cell transplantation efficacy in situ normoxia enhances survival and proliferation rate of human adipose tissue-derived stromal cells without increasing the risk of tumourigenesis impact of low oxygen tension on stemness, proliferation and differentiation potential of human adiposederived stem cells critical effect of oxygen tension on rate of growth of animal cells in continuous suspended culture primitive human hpcs are better maintained and expanded in vitro at percent oxygen than at percent effect of hypoxia on human adipose-derived mesenchymal stem cells and its potential clinical applications regulation of immunity and inflammation by hypoxia in immunological niches challenges and strategies for improving the regenerative effects of mesenchymal stromal cell-based therapies cultivation of rat marrow-derived mesenchymal stem cells in reduced oxygen tension: effects on in vitro and in vivo osteochondrogenesis effects of hypoxia on human mesenchymal stem cell expansion and plasticity in d constructs concise review: current status of stem cells and regenerative medicine in lung biology and diseases limited engraftment capacity of bone marrow-derived mesenchymal cells following t-cell-depleted hematopoietic stem cell transplantation plasticity of mesenchymal stem cells in immunomodulation: pathological and therapeutic implications analysis of tissues following mesenchymal stromal cell therapy in humans indicates limited long-term engraftment and no ectopic tissue formation administered mesenchymal stem cells protect against ischemic acute renal failure through differentiation-independent mechanisms evolving paradigms for repair of tissues by adult stem/progenitor cells (mscs) intravenous hmscs improve myocardial infarction in mice because cells embolized in lung are activated to secrete the anti-inflammatory protein tsg- hepatocyte growth factor mediates mesenchymal stem cell-induced recovery in multiple sclerosis models mesenchymal stromal cells: sensors and switchers of inflammation network analysis of transcriptional responses induced by mesenchymal stem cell treatment of experimental sepsis prevention of endotoxin-induced systemic response by bone marrow-derived mesenchymal stem cells in mice multipotent mesenchymal stromal cells and the innate immune system mesenchymal stromal cells and hematopoietic stem cell transplantation human bone marrow stromal cells suppress t-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli mesenchymal stem cells inhibit and stimulate mixed lymphocyte cultures and mitogenic responses independently of the major histocompatibility complex bone marrow mesenchymal stem cells inhibit the response of naive and memory antigen-specific t cells to their cognate peptide bone marrow mesenchymal stem cells induce division arrest anergy of activated t cells role for interferon-gamma in the immunomodulatory activity of human bone marrow mesenchymal stem cells mesenchymal stem cells inhibit human th cell differentiation and function and induce a t regulatory cell phenotype reciprocal interactions between human mesenchymal stem cells and gammadelta t cells or invariant natural killer t cells human mesenchymal stem cells modulate b-cell functions mesenchymal stem cell-natural killer cell interactions: evidence that activated nk cells are capable of killing mscs, whereas mscs can inhibit il- -induced nk-cell proliferation mesenchymal stem cells inhibit dendritic cell differentiation and function by preventing entry into the cell cycle human mesenchymal stem cells inhibit neutrophil apoptosis: a model for neutrophil preservation in the bone marrow niche a new mesenchymal stem cell (msc) paradigm: polarization into a pro-inflammatory msc or an immunosuppressive msc phenotype mesenchymal-stem-cell-induced immunoregulation involves fas-ligand-/fas-mediated t cell apoptosis interaction of human mesenchymal stem cells with cells involved in alloantigen-specific immune response favors the differentiation of cd + t-cell subsets expressing a regulatory/suppressive phenotype cell contact, prostaglandin e( ) and transforming growth factor beta play non-redundant roles in human mesenchymal stem cell induction of cd +cd (high) forkhead box p + regulatory t cells bone marrow stromal cells attenuate sepsis via prostaglandin e( )-dependent reprogramming of host macrophages to increase their interleukin- production anti-inflammatory protein tsg- secreted by activated mscs attenuates zymosan-induced mouse peritonitis by decreasing tlr /nf-kappab signaling in resident macrophages immunomodulation by therapeutic mesenchymal stromal cells (msc) is triggered through phagocytosis of msc by monocytic cells mesenchymal stem cells induce suppressive macrophages through phagocytosis in a mouse model of asthma inactivated mesenchymal stem cells maintain immunomodulatory capacity mesenchymal stromal cells: clinical challenges and therapeutic opportunities antibacterial effect of human mesenchymal stem cells is mediated in part from secretion of the antimicrobial peptide ll- antimicrobial cathelicidin peptide ll- inhibits the lps/atp-induced pyroptosis of macrophages by dual mechanism stem cells, cell therapies, and bioengineering in lung biology and diseases. comprehensive review of the recent literature - mitochondrial transfer between cells can rescue aerobic respiration cell-tocell cross-talk between mesenchymal stem cells and cardiomyocytes in co-culture mechanisms of mesenchymal stem/stromal cell function characterization of intercellular communication and mitochondrial donation by mesenchymal stromal cells derived from the human lung mitochondrial transfer via tunneling nanotubes is an important mechanism by which mesenchymal stem cells enhance macrophage phagocytosis in the in vitro and in vivo models of ards mitochondria in mesenchymal stem cell biology and cell therapy: from cellular differentiation to mitochondrial transfer mitochondrial dysfunction increases allergic airway inflammation association between mitochondrial dysfunction and severity and outcome of septic shock mitochondria in lung diseases intra-and intercellular quality control mechanisms of mitochondria mitochondrial transfer from bone-marrow-derived stromal cells to pulmonary alveoli protects against acute lung injury mesenchymal stem cells use extracellular vesicles to outsource mitophagy and shuttle micrornas monocyte/macrophage-derived microparticles up-regulate inflammatory mediator synthesis by human airway epithelial cells cd -mediated adhesion is required for the induction of a proinflammatory phenotype in lung epithelial cells by mononuclear cell-derived extracellular vesicles thy- dependent uptake of mesenchymal stem cell-derived extracellular vesicles blocks myofibroblastic differentiation extracellular vesicle-shuttled mrna in mesenchymal stem cell communication biological properties of extracellular vesicles and their physiological functions exosomal mir- a contributes to the enhanced therapeutic efficacy of interleukin- beta-primed mesenchymal stem cells against sepsis microvesicles derived from mesenchymal stem cells: potent organelles for induction of tolerogenic signaling adipose stem cell-derived nanovesicles inhibit emphysema primarily via an fgf -dependent pathway treatment with allogeneic mesenchymal stromal cells for moderate to severe acute respiratory distress syndrome (start study): a randomised phase a safety trial a prospective, non-randomized, no placebo-controlled, phase ib clinical trial to study the safety of the adipose derived stromal cells-stromal vascular fraction in idiopathic pulmonary fibrosis a phase b study of placentaderived mesenchymal stromal cells in patients with idiopathic pulmonary fibrosis treatment of acute respiratory distress syndrome with allogeneic adipose-derived mesenchymal stem cells: a randomized, placebo-controlled pilot study autologous mesenchymal stromal cell infusion as adjunct treatment in patients with multidrug and extensively drug-resistant tuberculosis: an open-label phase safety trial mitochondrial transfer of induced pluripotent stem cell-derived mesenchymal stem cells to airway epithelial cells attenuates cigarette smokeinduced damage bone marrow mesenchymal stem cell transplantation for treatment of emphysemic rats mesenchymal stem cells protect cigarette smoke-damaged lung and pulmonary function partly via vegf-vegf receptors therapeutic effects of amniotic fluid-derived mesenchymal stromal cells on lung injury in rats with emphysema ifn-gamma activation of mesenchymal stem cells for treatment and prevention of graft versus host disease species variation in the mechanisms of mesenchymal stem cell-mediated immunosuppression cytokine modulation of tlr expression and activation in mesenchymal stromal cells leads to a proinflammatory phenotype impaired function of bone marrow mesenchymal stem cells from immune thrombocytopenia patients in inducing regulatory dendritic cell differentiation through the notch- /jagged- signaling pathway human msc suppression correlates with cytokine induction of indoleamine , -dioxygenase and bystander m macrophage differentiation mesenchymal stromal cells cross-present soluble exogenous antigens as part of their antigen-presenting cell properties antigen-presenting property of mesenchymal stem cells occurs during a narrow window at low levels of interferon-gamma activation of human mesenchymal stem cells impacts their therapeutic abilities in lung injury by increasing interleukin (il)- and il- rn levels serum from asthmatic mice potentiates the therapeutic effects of mesenchymal stromal cells in experimental allergic asthma the toll-like receptor ligand, poly(i:c), improves immunosuppressive function and therapeutic effect of mesenchymal stem cells on sepsis via inhibiting mir- transplantation of hypoxia-preconditioned mesenchymal stem cells improves infarcted heart function via enhanced survival of implanted cells and angiogenesis reduced oxygen tension attenuates differentiation capacity of human mesenchymal stem cells and prolongs their lifespan mesenchymal stem cells modified with akt prevent remodeling and restore performance of infarcted hearts hepatocyte growth factor-modified mesenchymal stem cells improve ischemia/reperfusioninduced acute lung injury in rats transfection of mesenchymal stem cells with the fgf- gene improves their survival under hypoxic conditions supportive interaction between cell survival signaling and angiocompetent factors enhances donor cell survival and promotes angiomyogenesis for cardiac repair prevention of lps-induced acute lung injury in mice by mesenchymal stem cells overexpressing angiopoietin mesenchymal stem cell survival in the infarcted heart is enhanced by lentivirus vector-mediated heat shock protein expression promotion of survival and engraftment of transplanted adipose tissue-derived stromal and vascular cells by overexpression of manganese superoxide dismutase mesenchymal stem cells overexpressing angiotensin-converting enzyme rescue lipopolysaccharide-induced lung injury prostacyclin improves transcoronary myocardial delivery of adipose tissue-derived stromal cells effect of shock wave-facilitated intracoronary cell therapy on lvef in patients with chronic heart failure: the cellwave randomized clinical trial angiogenic pretreatment improves the efficacy of cellular cardiomyoplasty performed with fetal cardiomyocyte implantation mesenchymal stromal cells: a novel therapy for the treatment of chronic obstructive pulmonary disease? thorax extracellular matrix remodelling in copd understanding copd: a vision on phenotypes, comorbidities and treatment approach copd: early diagnosis and treatment to slow disease progression international society for cellular therapy perspective on immune functional assays for mesenchymal stromal cells as potency release criterion for advanced phase clinical trials the challenge of defining mesenchymal stromal cell potency assays and their potential use as release criteria characterization of serological neo-epitope biomarkers reflecting collagen remodeling in clinically stable chronic obstructive pulmonary disease high levels of biomarkers of collagen remodeling are associated with increased mortality in copd -results from the eclipse study accelerated extracellular matrix turnover during exacerbations of copd positioning a scientific community on unproven cellular therapies: the international society for cellular therapy perspective science, ethics and communication remain essential for the success of cell-based therapies unproven stem cell treatments for lung disease-an emerging public health problem balancing safety and innovation for cell-based regenerative medicine statement on unproven stem cell interventions for lung diseases medical societies, patient education initiatives, public debate and marketing of unproven stem cell interventions co-opting of clinicaltrials. gov by patient-funded studies the global emergence of unregulated stem cell treatments for respiratory diseases. professional societies need to act key: cord- - cl gk authors: humphreys, hilary; winter, bob; paul, mical title: lower respiratory tract infections date: - - journal: infections in the adult intensive care unit doi: . / - - - - _ sha: doc_id: cord_uid: cl gk lower respiratory tract infections are common and are important in the critical care setting either because they precipitate admission to the critical care unit, e.g. severe viral pneumonia or because they complicate the course of a patient with significant underlying disease or following major surgery, e.g. after multiple trauma. furthermore, respiratory failure requiring artifical ventialtion is a well recognised reason for critical care support but it can be difficult to determine if this is due to an underlying non-infectious condition such as chronic obstructive pulmonary disease (copd), infection or a combination of both. the early diagnosis and management of respiratory infection combined with appropriate ventilatory support aids prognosis and the efficient use of critical care facilities given the number of patients affected. lower respiratory tract infections are common and are important in the intensive care setting either because they precipitate admission to the intensive care unit, e.g. severe viral pneumonia or because they complicate the course of a patient with signi fi cant underlying disease or following major surgery, e.g. after multiple trauma. furthermore, respiratory failure requiring arti fi cal ventialtion is a well recognised reason for intensive care support but it can be dif fi cult to determine if this is due to an underlying non-infectious condition such as chronic obstructive pulmonary disease (copd), infection or a combination of both. the early diagnosis and management of respiratory infection combined with appropriate ventilatory support aids prognosis and the ef fi cient use of intensive care facilities given the number of patients affected. community acquired pneumonia (cap) is common with an estimated incidence of - cases/ , population annually [ ] representing . % of uk icu admissions [ ] . community acquired pneumonia requiring icu admission has a high mortality (icu). in a study of , cases of cap admitted to uk intensive care units, icu mortality was . % and ultimate hospital mortality . %. mortality was . % in those admitted to the icu within days of hospital admission rising to . % in those admitted at - days and . % in those admitted after days following hospital admission [ ] . at presentation many patients with severe cap will already be developing multiple organ failure. identi fi cation of the critically ill pneumonia patient is essential to the early and effective management of this condition. severity-of-illness scores, such as the curb- (confusion, uremia, respiratory rate, low blood pressure, age years or greater), or prognostic models, such as the pneumonia severity index (psi), can be used to identify patients with cap who might bene fi t from icu admission. in some studies, signi fi cant numbers of patients with cap are transferred to the icu in the fi rst - h after admission. mortality and morbidity among these patients appears to be greater than those among patients admitted directly to the icu. the most recent modi fi cation of the british thoracic society (bts) criteria includes fi ve easily measurable factors [ ] . multivariate analysis of , patients identi fi ed the following factors as indicators of increased mortality: confusion (based on a speci fi c mental test or disorientation to person, place, or time), bun level mmol/l ( mg/dl), respiratory rate breaths/min, low blood pressure (systolic, < mmhg; or diastolic, mmhg), and age years. this gave rise to the original acronym curb- . in the derivation and validation cohorts, the -day mortality among patients with , , or factors was . , . , and . %, respectively. mortality was higher when , , or factors were present and was reported as . , , and %, respectively. the authors suggested that patients with a curb- score of - be treated as outpatients, those with a score of be admitted to the wards, and that patients with a score of often required icu care. direct admission to an icu is required for patients with septic shock requiring vasopressors or with acute respiratory failure requiring immediate intubation and mechanical ventilation. decisions on direct admission to an icu or high-level monitoring unit should be based on a number of parameters and is recommended for patients with three or more of the following a relatively small number of pathogens account for the majority of cases of cap with streptococcus pneumoniae consistently shown to be the commonest pathogen in europe and north america although in at least one third of cases no de fi nite causative organism is isolated [ ] . a survey of studies of severe cap found the following pathogens: s. pneumoniae - %; legionella spp., - %; staphylococcus aureus - %; and gram negative enteric bacilli - % [ ] . historically, cap was divided into so-called 'typical' and 'atypical' and was said to produce different presentations. 'typical' pneumonia was caused by pneumococci and was said to present with fever of greater than °c, pleuritic chest pain, lobar consolidation, and a left shift of granulocytes. 'atypical' pneumonia had a more gradual onset with diffuse interstitial or alveolar pattern on the plain chest x-ray. studies, however, have shown that clinical overlap between the different pathogens is great and that symptoms and plain chest radiology can not reliably differentiate between the different pathogens [ ] . in severe cap the situation is even more dif fi cult. in the uk intensive care national audit and research centre ( www.icnarc. org ) case mix database viral pneumonia accounted for % of cases admitted to critical care units with cap accounting for % of cases. however, no organism was isolated in % of cases where the primary admission diagnosis was pneumonia. the bts recommends the following investigations for all severe cases of cap [ ] : • blood cultures • sputum or lower respiratory tract sample for gram stain, routine culture, and antibiotic susceptibility tests • pleural fl uid analysis , if a pleural effusion/empyema is present • pneumococcal antigen test on sputum, blood, or urine • investigations for legionella including urine for legionella antigen -sputum or lower respiratory tract samples for legionella culture and direct immuno fl uorescence initial and follow up legionella serology -• direct immuno fl uorescence on appropriate samples, e.g. bronchoscopy sample or equivalent for respiratory viruses (e.g. in fl uenza in season, adenovirus, respiratory synctial virus, etc), chlamydia species, and possibly pneumocystis jirovecii ( carinii ) • initial and follow up serology for pathogens dif fi cult to culture such as however, there is no good evidence that this strategy alters the outcome of severe cap and studies disagree about the impact of microbiological testing on outcome [ ] . the american thoracic society recommendations for inpatient, icu antibiotic treatment are a beta-lactam (cefotaxime, ceftriaxone, or ampicillin-sulbactam) plus either azithromycin or a fl uoroquinolone. for penicillin-allergic patients, a respiratory fl uoroquinolone and aztreonam are recommended. for community-acquired methicillin-resistant staphylococcus aureus infection, vancomycin or linezolid are suggested [ ] . the bts guidelines recommend the combination of amoxicillin/clavulanate with clarithromycin and the optional addition of rifampicin, which provides additional cover, especially against staphylococcus aureus and legionella spp. patients with hypoxemia or respiratory distress should receive a cautious trial of non-invasive ventilation (niv) unless they require immediate intubation because of severe hypoxemia (arterial oxygen pressure/fraction of inspired oxygen [pao /fio ] ratio, < mmhg or kpa) and bilateral alveolar in fi ltrates [ ] . patients with underlying copd are most likely to bene fi t from niv [ ] . patients with cap who were randomized to receive niv had more than a % absolute risk reduction for intubation [ ] . inability to cough may limit the use of niv, but intermittent application of niv may allow for its use in patients with productive cough without excessive sputum production. prompt recognition of a failed niv trial is important, as patients who require intubation after a prolonged niv trial have a worse outcome. within the fi rst - h of niv, failure to improve respiratory rate and oxygenation or failure to decrease carbon dioxide partial pressure (pco ) in patients with initial hypercarbia predicts niv failure and warrants prompt intubation. niv provides no bene fi t for patients with adult respiratory distress syndrome (ards), which may be indistinguishable from cap among patients with bilateral alveolar in fi ltrates. patients with cap who have severe hypoxemia (pao /fio ratio, < ) are also poor candidates for niv [ ] . the optimal ventilator strategy for patients with severe cap has not been established. both volume controlled and pressure controlled modes have been used with varying levels of positive end expiratory pressure (peep). although there is a signi fi cant incidence of ards in patients with cap it is unclear whether the ardsnet lung protective strategy should be applied in all patients [ ] . in patients with cap who fail to respond to initial treatment, broncho-alveolar lavage identi fi es pathogens in - %. although the yield is relatively low, it is recommended that bronchoscopy is performed in severe cap where the diagnosis is not established or where treatment is failing [ ] . once the patient is intubated and ventilated this is relatively easy to perform although often associated with transient deterioration in oxygenation. the diagnosis should be reviewed and other conditions presenting with x-ray in fi ltrates such as cardiac failure and pulmonary infarction excluded. culture results may be available by this stage and may necessitate a change in therapy. the possibility of immunosuppression should be considered with the consequent possibility of an opportunist pathogen, e.g. pneumocystis jirovecii ( carinii ) and a history of recent foreign travel excluded which might impact on the choice of empirical antibiotic therapy. pathogens may vary from country to country and tuberculosis does occasionally present as severe cap. therefore this diagnosis should be considered in the relevant settings or geographical areas. most cases of in fl uenza are self-limiting and are characterized by the sudden abrupt onset of fever, malaise, headache and a non-productive cough. this syndrome is usually easily distinguishable from the common cold caused by coronaviruses, rhinoviruses, para-in fl uenza viruses, etc. the elderly and those with chronic underlying diseases such as ischemic heart disease are more at risk of complications from in fl uenza, including death. however, when a pandemic occurs, as in with h n , other groups of patients were at risk of more severe disease as they had not been exposed to a radically new virus, different to those viral strains that circulated previously. early diagnosis is important and the threshold for suspicion should fall during the in fl uenza season or during a pandemic. then every patient requiring critical care support with respiratory failure should have a throat swab in viral transport medium or nasopharyngeal aspirate, and a good quality lower respiratory sample, e.g. broncholaveloar lavage (bal) or equivalent, sent for viral studies, i.e. immuno fl uorescence or the polymerase chain reaction (pcr). in fl uenza-related pneumonia is similar to other forms of viral pneumonia although the recent pandemic h n strain originating from mexico had some different features. the australasian experience was published by the australia new zealand intensive care society group [ ] . a total of patients with con fi rmed infection with h n infection ( . cases per million inhabitants; % con fi dence interval [ci], . - . ) required admission to an icu in australia or new zealand. of the , . % were under and . % were pregnant. the obese were also adversely affected; . % of icu patients had a body-mass index of more than . the median icu stay was . days, . % required mechanical ventilation for a median of days and . % had died within a month of presentation. higher numbers than usual for viral pneumonia received treatment with extracorporeal membrane oxygenation (ecmo). of patients who required mechanical ventilation, . % were subsequently treated with ecmo. this parallels the situation in uk (richard firmin, personal communication). a recent paper [ ] matched patients referred for ecmo in the uk with patients from a pool of , patients from the icnarc casemix program using three different techniques and found a mortality of around % in patients who were referred for ecmo and around % for the matched controls. during the - h n in fl uenza a pandemic, the united states centers for disease control and prevention and other agencies around the world released guidelines for the use of antivirals for patients with con fi rmed or suspected infection [ ] . for most patients a neuraminidase inhibitor (e.g. oseltamivir) is recommended and this should be started as soon as possible to improve patient outcome and assist in reducing transmission. healthcare-associated pneumonia is de fi ned as new onset of pneumonia more than h after admission to a healthcare facility and may occur in either the open ward environment or in association with mechanical ventilation, i.e. associated pneumonia (vap). infection acquired in an acute hospital compared to that acquired in a long stay institution is more likely to be antibiotic-resistant and due cognisance needs to be taken of this when treating empirically. vap was historically associated with the overgrowth of aerobic gram negative bacilli but is now increasingly characterized by infection with gram positive organisms such as staph aureus including methicillin-resistant staphylococcus aureus (mrsa) as well as resistant strains of acinetobacter spp and enterobacteriaceae resistant to extended-spectrum beta-lactam agents such as third generation cephalosporins. there is a lack of a clear and clinically accepted de fi nition for vap. there is also a difference between research de fi nitions including the need for invasive lung sampling such as protected specimen brushing (psb) or bal, and clinical de fi nitions stressing increased oxygen requirements, new in fi ltrates on chest x-ray, purulent tracheal aspirates etc. the presence of new chest x-ray in fi ltrates plus one of the three clinical variables (fever, i.e. ³ °c, leucocytosis or leucopenia and purulent secretions) is useful for clinical screening and has high sensitivity but should where possible be followed by invasive respiratory sampling ideally before commencing antibiotics. protected specimen brushing with a threshold on quantitative culture of cfu/ml, or bronchoalveolar lavage with threshold of cfu/ml have been said to be equivalent for the diagnosis of ventilator associated pneumonia [ ] . however, - % of patients meeting the above clinical criteria for vap will not have the diagnosis con fi rmed by alternate objective methods such as quantitative cultures of psb or bal samples [ ] . in some studies vap appears to be an independent risk factor for death, with a doubling of the mortality rate directly attributable to vap [ ] . this is, however, dependent on the patient population and the infecting organism [ ] . critical care length of stay is increased by a mean of . days, and the excess costs can be as high as $ , per patient with vap [ ] . recent attempts to limit vap include the use of ventilator care bundles which include a number of the following, avoidance of endotracheal intubation and reintubation, a preference for niv, semi-recumbent positioning, continuous aspiration of subglottic secretions and oral decontamination [ ] . these interventions have been shown to reduce ventilator days and length of stay in a number of studies such as that by crunden and colleagues [ ] . despite showing a reduction in mortality in some studies and critical care unitacquired respiratory infections in many others, selective decontamination of the digestive tract (sdd) has failed to make the jump into mainstream practise outside the netherlands [ , ] . this is partly due to the perceived additional costs of the topical regimens and microbiological surveillance (although offset by the reduced need for therapeutic antibiotics to treat infections) and concerns about antibiotic resistance. many of the larger studies have taken place in the netherlands, a country characterized by admirably low levels of antibiotic consumption and antibiotic resis-tance, e.g. mrsa but in settings where antibiotic resistance is more common, there is understandable concern about the long-term implications on the spread and dissemination of dif fi cult to treat pathogens. sdd is also discussed in chaps. and . prompt initiation of appropriate antibiotic therapy is the cornerstone of vap management and requires knowledge of the local likely fl ora and antibiotic resistance patterns. iregui et al. found a higher mortality rate in patients in whom administration of adequate antibiotic therapy was delayed by approximately h ( . % vs. . % mortality, p < . ) after meeting criteria for the diagnosis of vap [ ] . because of the importance of adequate initial antibiotic therapy in reducing the mortality from vap, especially when patients are at risk from drug resistant organisms, initial therapy should be broad and known to be effective against pathogens such as pseudomonas aeruginosa and mrsa, and tailored using local knowledge. recent north american guidelines suggest that the use of three antibiotics: two drugs of different classes active against pseudomonas, and a third for mrsa [ ] . as previously mentioned copd is a signi fi cant complicating factor in cap. copd is one of the most frequent comorbidities in patients admitted to hospital for cap with respiratory failure [ ] . a prospective study of cap in patients in intensive care units in spain showed that copd was the most frequent comorbidity encountered [ ] . copd patients also fare badly compared with non-copd patients [ ] . another spanish study compared copd patients with non-copd patients and showed that icu mortality (odds ratio (or) . ; % con fi dence interval (ci) . - . ) and mechanical ventilation (or . ; % ci . - . ) rates were higher than in non-copd patients. the icu mortality was % for copd patients initially intubated and % for those who failed non-invasive ventilation [ ] . copd patients also present more frequently with organisms such as pseudomonas aeruginosa and strains of moraxella catarrhalis resistant to fi rst-line therapy, e.g. co-amoxycalv, and empiric antibiotic therapy may need to account for this. noninvasive ventilation (fig. . ) is routinely used in the management of hypercarbic respiratory failure in copd and guidance was produced by the royal college of physicians (uk) in conjunction with the bts and the intensive care society recently [ ] . niv in a number of settings has been shown in a number of randomized controlled trials to reduce the rate of intubation and mortality in copd patients with decompensated respiratory acidosis (ph < . and paco > kpa) despite maximal medical therapy. all units admitting such patients should have local protocols and training in place to offer niv to patients presenting in respiratory failure in the context of copd. infection of the paranasal sinuses is more common in critically ill patients than often realised by clinicians working in the area. it occurs in - % of all critically ill patients and - % of endotracheally intubated patients may develop sinusitis, the variation largely being accounted for by differences in diagnostic criteria [ ] . nasotracheal rather than orotracheal intubation appears to be a risk factor although nasogastric intubation may be a confounding factor. plain radiographs of adequate diagnostic quality are often dif fi cult to obtain in critical care patients and ct scanning is often required to make a radiological diagnosis which should be supplemented with microbiological samples to con fi rm the aetiology [ ] . nosocomial sinusitis is usually caused by gram-negative bacilli or is polymicrobial. pseudomonas aeruginosa represents . % of isolates, with the most common gram-positive isolate being staph. aureus ( . %); fungi represent . % of isolates [ ] . treatment usually involves a combination of appropriate antibiotics, removal of intranasal foreign bodies and drainage [ ] . . if he has severe community-acquired pneumonia by any criteria, he has an estimated mortality of - % depending on the results of further investigations. he is highly likely to require intensive care admission. . bacterial pneumonia is the most common and the pneumococcus accounts for - % of cases in most series but a substantial proportion will have no organism isolated . if he is known or suspected of having copd then niv may reduce the morbidity and mortality associated with intubation. its place in routine pneumonia management is less well de fi ned. severe community-acquired pneumonia community-acquired pneumonia on the intensive care unit: secondary analysis of , cases in the icnarc case mix programme database de fi ning community acquired pneumonia severity on presentation to hospital: an international derivation and validation study community-acquired pneumonia a fi ve-year study of severe community-acquired pneumonia with emphasis on prognosis in patients admitted to an intensive care unit infectious diseases society of america. guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia noninvasive ventilation in severe hypoxemic respiratory failure: a randomized clinical trial noninvasive ventilation for acute exacerbations of chronic obstructive pulmonary disease acute respiratory failure in patients with severe communityacquired pneumonia: a prospective randomized evaluation of noninvasive ventilation predictors of failure of noninvasive positive pressure ventilation in patients with acute hypoxemic respiratory failure: a multi-center study the acute respiratory distress syndrome network. ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome utility of fi beroptic bronchoscopy in nonresolving pneumonia critical care services and h n in fl uenza in australia and new zealand referral to an extracorporeal membrane oxygenation center and mortality among patients with severe in fl uenza a(h n ) updated interim recommendations for the use of antiviral medications in the treatment and prevention of in fl uenza for the - season ventilator-associated pneumonia in a surgical intensive care unit: epidemiology, etiology and comparison of three bronchoscopic methods for microbiological specimen sampling role of quantitative cultures of endotracheal aspirates in the diagnosis of nosocomial pneumonia clinical and economic consequences of ventilatorassociated pneumonia: a systematic review the attributable morbidity and mortality of ventilatorassociated pneumonia in the critically ill patient oral decontamination with chlorhexidine reduces the incidence of ventilator-associated pneumonia an evaluation of the impact of the ventilator care bundle selective decontamination of the digestive tract clinical evidence in intensive care antibiotic prophylaxis to reduce respiratory tract infections and mortality in adults receiving intensive care clinical importance of delays in the initiation of appropriate antibiotic therapy high prevalence of obstructive airways disease in hospitalized patients with community-acquired pneumonia: comparison of four etiologies antibiotic prescription for community-acquired pneumonia in the intensive care unit. impact of adherence to idsa guidelines on survival for the capuci study investigators, et al. implications of copd in patients admitted to the intensive care unit by community acquired pneumonia chronic obstructive pulmonary disease: non-invasive ventilation with bi-phasic positive airways pressure in the management of patients with actute type respiratory failure. concise guidance to good practice series hospital-acquired sinusitis is a common cause of fever of unknown origin in orotracheally intubated critically ill patients acute pranasal sinusitis in critically ill patients: guidelines for prevention, diagnosis and treatment key: cord- -qa bcsbu authors: starkel, julie l.; stapke, christina; stanley-o’malley, abigail; noland, diana title: respiratory date: - - journal: integrative and functional medical nutrition therapy doi: . / - - - - _ sha: doc_id: cord_uid: qa bcsbu lung disease rivals the position for the top cause of death worldwide. causes and pathology of the myriad lung diseases are varied, yet nutrition can either affect the outcome or support treatment in the majority of cases. this chapter explores the modifiable risk factors, from lifestyle changes to dietary intake to specific nutrients, anti-nutrients, and toxins helpful for the nutritionist or dietitian working with lung disease patients. general lung health is discussed, and three major disease states are explored in detail, including alpha- antitrypsin deficiency, asthma, and idiopathic pulmonary fibrosis. although all lung diseases have diverse causes, many integrative and functional medical nutrition therapies are available and are not being utilized in practice today. this chapter begins the path toward better nutrition education for the integrative and functional medicine professional. anti nutrients and inhibitors of lung physiology - lung disease is far more prevalent worldwide than commonly thought. in fact, death from chronic lung disease is increasing, and as of , chronic obstructive pulmonary disease (copd) has become the third leading cause of death in the united states in the past decade, disproportionately affecting the elderly [ ] . another lung disease, asthma, affects in , or about million americans, according to the centers for disease control and prevention and the national center for health statistics [ ] . this is . % of adults, more women than men, and . % of children. asthma is the leading chronic disease in children [ ] . this disease has been increasing since the early s in all age, sex, and racial groups. in europe, lung disease represents % of all deaths -the fourth leading cause. according to the world health organization (who), in , . million people died from acute or chronic lung disease, representing one sixth of the global total deaths [ ] . worldwide, four respiratory disease categories appear in the top ten leading causes of death in [ ] . specifically, copd was the third leading cause of death, followed by lower respiratory infections as the fourth, lung cancer as the fifth, and tuberculosis as the tenth [ ] . the major risk factor is smoking, leading to % of all lung disease-related deaths in europe, where smoking is more prevalent ( % prevalence) than in the united states ( % prevalence) by nearly twofold [ , ] . lung cancer, particularly non-small-cell lung cancer (nsclc) subtype, is the leading cause of cancer-related death worldwide [ ] . added together, lung disease rivals the position for the top cause of death. throughout the life cycle, diet and lifestyle are important modifiable risk factors in the development, progression, and management of obstructive lung diseases, such as asthma and copd [ ] , as well as restrictive lung diseases such as pulmonary fibrosis and sarcoidosis. inflammation, in particular, seems to be the leading contributor toward the progression of lung diseases. as with many diseases, maintaining a healthy lifestyle, including sufficient sleep, low stress, regular exercise, a whole foods diet rich in phytonutrients from plants (fruits and vegetables), and potential anti-inflammatory supplements, is beneficial in supporting the body during these difficult diseases. inflammation, in particular, seems to be the leading contributor toward the progression of lung diseases. high inflammatory foods should be avoided, such as fried foods and foods disproportionately high in carbohydrates, sugar, alcohol, and excessive protein. a healthier suggestion would be a diet with more than half of all food consumed as vegetables, about one third as protein, and the remainder (one sixth) as other foods, such as fruits, dairy, grains, or starches. some dietary supplements may also be recommended for their anti-inflammatory benefits, which will be discussed later in the chapter. as human life expectancy increases, we can expect to see more chronic disease. the world health organization estimates that by , chronic lung disease will account for % (one fifth) of all deaths [ ] , up from one sixth in . despite these growing numbers, relatively little human nutrition research exists for respiratory health, compared to other, less prevalent, diseases. investigators in the areas of aging and lung biology suggest some hope, using genetics and animal models, as well as epidemiological research, to further the general medical approach to lung disease. the pulmonary system is composed of the upper and lower respiratory tracts. air flows in through the nose or mouth, past the frontal and maxillary sinuses, down the pharynx (throat), past the larynx (voice box), and then down the trachea. this makes up the upper respiratory tract. once past the trachea, the air divides into the left and right bronchi, which supply the left and right lungs, each divided into five sections called lobes. the bronchi then divide into smaller bronchioles, at the end of which are air sacs called the alveoli. this makes up the lower respiratory tract [ ] (. fig. . ). the diaphragm is the central muscle that is used for breathing. the intercostal muscles, located between the ribs, and the abdominal muscles are helpful for breathing out when the breath becomes labored, such as during exercise. the neck muscles and the muscles in the collarbone area help with breathing when the other muscles are compromised or impaired. in some neurological diseases, such as amyotrophic lateral sclerosis (als) [see chap. , newton], nerve damage from the brain to breathing muscles can result in impaired movement of these muscles and thus impaired breathing. in certain cases, such as in lung cancer when a lobectomy, removal of part of the lung, is required, there is an expected decrease in short-and long-term pulmonary function and oxygenation. however, respiratory muscle strength may be preserved [ ] . in a pneumonectomy, removal of the entire lung, dramatic changes in thoracic anatomy take place, such as elevation of the hemidiaphragm, hyperinflation of the remaining lung, and influx of fluid into the postpneumonectomy space [ , ] . there are phagocytic macrophages on the cellular surface of the alveoli, type i epithelial cells and type ii epithelial cells. phagocytic macrophages destroy inhaled bacteria and serve an important role in suppressing or activating the immune response to antigens and pathogens, similar to dendritic cells discussed below. macrophage function has been shown to be inhibited by cigarette smoke [ ] . alveolar macrophages also secrete enzymes, arachidonic acid metabolites, growth factors, immune response components, cytokines, and lymphocytes [ ] . type i cells are responsible for maintaining the structure of the alveolar wall, whereas type ii cells and clara cells are responsible for the production of pulmonary surfactant (composed of - % lipid and - % protein as lecithin and myelin), which is essential for lung function. the surfactant reduces surface tension, facilitating easier stretching and collapsing of alveoli during respiration [ ] . diseases associated with inadequate surfactant production are acute/adult respiratory distress syndrome (ards) and infant respiratory distress syndrome (irds) [ ] . irds is seen in premature babies born prior to weeks of gestation due to immature development of pulmonary surfactant, which only begins to develop around the th week of gestation [ ] . dipalmitoylphosphatidylcholine, phosphatidylglycerol, and cholesterol compose the lipid portion of the surfactant, where apoproteins and proteins found in blood plasma compose the protein portion [ , ] . the importance of cholesterol is minimized in today's medical community. those with higher levels of cholesterol tend to have more in their fatty cell membranes which resist pathogenesis at a cellular level. low cholesterol predicts a greater risk of dying from gastrointestinal, neoplastic, or respiratory diseases. it occupies - % of our cell membranes, enhances the mechanical strength of the membrane, and reduces permeability [ ] . it suppresses main-phase transition of the lipid bilayer [ ] . collagen, a fibrous protein, along with elastin and proteoglycans, is a fundamental component of the connective tissue that composes the lungs, and collagen is present in the blood vessels, bronchi, and alveolar interstitium [ ] . connective tissue in the lung is key for the passive diffusion of oxygen and carbon dioxide that characterizes alveolar-capillary gas [ ] . collagen homeostasis is vital to maintaining respiratory function, where collagen production and degradation are balanced. dysregulated collagen homeostasis that favors collagen production over degradation can lead to pulmonary fibrosis and compromised lung function [ ] . some key nutrients to consider for collagen synthesis and crosslinking to maintain connective tissue integrity are vitamin c, vitamin b , iron, copper, zinc [ ] , riboflavin, thiamin, and pantothenic acid [ ] . the airways of the respiratory system (with the exception of parts of the nose and mouth) have cilia, special hairs coated with mucus that trap pathogens and other particles that enter with the air that is inhaled. cilia are responsible for triggering this mucus upward toward the pharynx where these particles or bacteria can be coughed out or swallowed. mucus present in the lungs can also trap inhaled particles such as viruses, bacteria, and smoke particulates [ , ] . along the lining of the respiratory tract, there are several types of cells that are involved in immune response, such as secretory cells (i.e., goblet cells and clara cells) and mast cells. ciliated epithelium and mucus secreted by glands present on airways, goblet cells, and the secretory products of clara cells serve an important mechanism for lung protection. however, excessive goblet cells or hypertrophy of mucous glands may result in increased viscosity of mucus seen in pathologies like bronchitis [ ] . ciliary function is also impaired by cigarette smoke [ ] . dendritic cells are also found in the airway lining from the trachea to the alveoli. immature dendritic cells phagocytize bacteria or other antigens, where they then mature and travel to lymphoid tissues to communicate with the immune system. this delivery of antigens can promote tolerance of the antigen by releasing anti-inflammatory cytokines. conversely, this delivery can also trigger the opposite response if the antigen is recognized as a pathogen, where t lymphocytes are activated and inflammatory cytokines are released [ ] . one potential cause of infections in the upper respiratory tract or bronchial tubes, such as bronchitis, or deep in the lungs, such as pneumonia, is when cilia become damaged and do not trap inhaled germs and particles as effectively. in diseases such as cystic fibrosis, thick mucus secretions can accumulate in the airways and lungs, making it hard to clear and thus increasing risk for infection. in asthma, specific inhaled particles can trigger a reaction causing the airways to narrow, restricting breathing [ ] . surface enzymes and factors can also be found in the lining of the airways that compose the majority of the innate immune system of the respiratory tract. these include: lysozymes: found in leukocytes with bactericidal properties lactoferrin: a bacteriostatic agent (inhibits bacterial reproduction) synthesized by lymphocytes and glandular mucosal cells alpha- antitrypsin: an antiprotease to protect lung tissue from excessive enzymatic activity interferon: an antiviral substance that may be produced by lymphocytes and macrophages complement: participates as a cofactor in antigenantibody reactions [ ] gas exchange takes place in the alveoli so oxygen can enter the body to support metabolic function and the carbon dioxide product from these functions can be removed. this is accomplished through millions of capillaries in the alveoli. these capillaries in the alveoli then connect to arteries and veins that move blood throughout the body. the pulmonary artery supplies carbon dioxide-rich blood to these capillaries within the alveoli to remove carbon dioxide, and the oxygen-rich blood then gets delivered to the heart through the pulmonary vein. the lungs also serve the vital function of maintaining acid-base balance through changes in minute ventilation. these changes affect the ph of the blood by either retaining or excreting carbon dioxide [ ] . poor physiologic management of co and bicarbonate can lead to the conditions of respiratory acidosis and respiratory alkalosis. respiratory acidosis is characterized by higher blood concentrations of co and h + , caused by hypoventilation or decreased rate of breathing. hypoventilation can have acute or chronic etiologies, resulting from copd, interstitial lung diseases, respiratory muscle fatigue (i.e., extended asthma attack), or mechanical abnormalities (i.e., deformities). respiratory alkalosis is characterized by lower blood concentrations of co and h + due to hyperventilation, or increased rate of breathing. possible causes of hyperventilation can also be chronic or acute, such as pneumonia and fever, increased stress and anxiety, liver disease, stroke or meningitis, pregnancy, overuse of aspirin and/or caffeine, excessive mechanical ventilation, or increases in altitude [ ] . a pulse oximeter tool can be used to measure the percentage of oxygenated hemoglobin in an individual's blood to determine their overall respiratory status. typically, oxygen saturations of % or less are indicative of central hypoxia [ ] . pulse oximetry is especially useful for assessing individuals with asthma and copd [ ] . oral health must also be considered as a contributing factor to respiratory health [ ] . for example, in patients affected with periodontal disease, mm of dental plaque could contain around of bacteria. one potential mechanism of this connection is aspiration of bacteria from the oropharynx into the upper or lower respiratory tracts, leading to their adherence to the alveolar and bronchial lining, potentially colonizing respiratory ducts and causing respiratory infections. in addition, cytokines and enzymes associated with inflammation of periodontal tissues can be transferred into the lungs, potentially triggering or exacerbating lung infections [ ] (. fig. . a systematic review done in examined oral health in the elderly and its association with risk of aspiration pneumonia. this review suggested that maintaining oral health, such as brushing after each meal, cleaning dentures once per day, and professional oral healthcare, potentially reduced the amount of potential respiratory pathogens that resulted in lower incidence of aspiration pneumonia [ ] . several other systematic reviews have found that adequate oral hygiene plays an important role in preventing pneumonia, particularly in clinical settings where there is increased risk for hospital-acquired pneumonia (hap) and ventilatorassociated pneumonia (vap), as well as in older populations [ ] . in addition, associations have been made between copd and the risk of periodontitis, although systematic reviews have established that these associations are preliminary and further studies are needed [ ] . another important consideration in respiratory health is orofacial development and structure. anatomical obstructions at the level of the nose and pharynx, such as those caused by allergic rhinitis and hypertrophy of the tonsils, pose an increased risk for obstructive sleep apnea syndrome and respiratory infections due to lack of airflow through the upper respiratory system [ ] . it has been established that the lung has a microbiome of its own that may have a large impact on health and disease [ ] . the fungal microbiome, or mycobiome, may also have a significant impact on respiratory health, although more research is needed to determine definitive associations [ ] . dysbiosis may occur in the lungs with a bacterial infection. a few specific bacterial strains have been studied, and one, in particular, pseudomonas aeruginosa, seems to grow in inflammatory conditions. it then seems to encode inflammatory components causing further inflammation. anti-inflammatory nutrients could help stop the cycle, and vitamin d use has some research supporting this. recurrent bacterial respiratory infections may damage lungs and lead to worse outcomes in future lung disease [ ] . an increased interest in research of the relationship of the airway and gut microbiome is indicating potentially positive results regarding the use of probiotics in pediatric populations that may aid in asthma prevention and intervention [ , ] . the gut-lung axis has also been established, where the microbiomes of the lung and gut have been immunologically linked and are thought to have an impact on respiratory disease [ , ] . the autophagy mechanism within our microenvironment provides a constant "cleanup" system to recycle cell debris from microscopic biowaste generated by dynamic cellular biochemistry [ ] . enzymes such as neutrophil elastase function like garbage disposals recycling waste molecules. alpha- antitrypsin is a thermostat-like control factor that signals the proteolytic enzymes to stop and protect healthy tissue from being affected. antiproteases in the lung, such as alpha- antitrypsin, are required to prevent the overactivity of neutrophil elastase to prevent the degradation of healthy lung tissue. those with the genetic mutations of a at deficiency are at disadvantage, and subsequent lung tissue damage can occur promoting lung diseases like copd, asthma, bronchitis, and emphysema. key components of lung structure are elastin and collagen, which provide support for the bronchioles and clusters of alveoli (acini). the key enzyme present in these cells is neutrophil elastase, which is responsible for the destruction of respiratory bacteria. protease and antiprotease imbalance in the lung resulting in emphysema can be caused by alpha- antitrypsin deficiency and nicotine in cigarette smoke or polluted inhalant exposure [ ] . ifmnt approaches to the a at-deficient patient assess for nutrient insufficiencies for some of the important connective tissue, collagen, and elastin system key nutrients: vitamin c, vitamin d, biotin, balanced fatty acids, and gut microbiome. when insufficiencies or deficiencies are identified, appropriate food and dietary supplementation interventions can be recommended. it should be noted that if an individual is identified with a at deficiency genotype, the status of liver health should also be assessed, as a at pathophysiology can express in liver cirrhosis. more recent studies of respiratory disease [ ] have revealed the relationship with bacterial or viral infections exacerbating the individual's genotype eliciting expression of the associated diseases. one of the most recognized inherited conditions of altered autophagy mechanisms is alpha- antitrypsin deficiency, with - genetic variants affecting severity of lung expression. low levels of circulating a at allow potentially harmful enzymes like neutrophil elastase to remain in the lungs unchecked. low levels of a at, and the consequent proliferation of neutrophil elastase, leave lung tissue vulnerable to destruction, resulting in a decline in lung function. there are several categories of lung disease and many diseases within those categories (. table . ). some micronutrients and phytonutrients have important antioxidant and methyl-donating properties important for the lungs and therefore have great role in a nutritional approach to lung health. iron's interaction with the lungs is essential. it carries oxygen from the lungs to the peripheral parts of the body, as well as carbon dioxide back to the lungs to be exhaled. however, too little or too much iron can pose a problem for the lungs. before iron administration, it is important to rule out hemochromatosis, or iron overload, for an individual. iron-deficiency anemia often presents in many chronic diseases including those of the lung, such as copd, lung cancer, and ipf [ ] . increased mortality, decreased quality of life, increased hospital admissions, and cost of treatment have been reported for those with chronic disease and low iron [ ] . anemia of chronic disease (acd) is usually at the root of this. acd is often the result of inflammation. inflammatory proteins, including il- , stimulate the production of hepcidin in the liver, which inhibits absorption and increases storage of iron resulting in a functional iron deficiency. typical iron markers, such as transferrin saturation, total iron binding capacity (tibc), and ferritin, are also affected by inflammation and are less useful markers in chronic disease. soluble transferrin receptor (stfr) seems to be a lesser known marker that is less affected by inflammation [ ] . because of the difficulty with iron absorption, intravenous iron is often used to replete deficiencies. as iron is a pro-oxidant, researchers studied any negative repercussions. there does not seem to be any increased oxidative stress with intravenous iron, but glutathione, the body's endogenous super antioxidant, does seem to decrease, likely in response to the pro-oxidative activity of iron. in a recent study, administration with vitamin e was seen to eliminate these negative effects [ ] . excessive iron can also be problematic for lung health for those with the genetic mutation for hemochromatosis (hfe). disorders of iron overload are increasingly being recognized as risk factors for most of the chronic diseases like cardiovascular, alzheimer's, and cancer [ ] . high iron can catalyze the formation of highly reactive hydroxyl radicals, oxidative stress, and programmed cell death. in the instance of lung cancer and other cancers affecting the lungs, tumors sequester iron for their own growth, usually leaving the patient with iron-deficiency anemia. in fact, % of cancer patients undergoing chemotherapy are iron deficient. inflammation also plays a role in iron homeostasis. the pro-inflammatory cytokines cascade down to affect the proteins that regulate . chronic obstructive pulmonary disease (copd) disease that restricts airflow through either inflammation of the lining of the bronchial tubes or destruction of alveoli increased risk of emphysema if genetic variant of alpha- antitrypsin deficiency and smoking or exposed to high levels of air pollution [ ] bronchiectasis a disorder of the airways that leads to airway dilation and destruction, chronic sputum production, and a tendency toward recurrent infection [ ] bronchiolitis airway injury that can be caused by infections, irritants, toxic fumes, drug exposures, pneumonitis (typically viral), organ transplants, connective tissue disorders, vasculitis, or other insults [ ] dyspnea shortness of breath or difficulty breathing [ ] emphysema thinning and destruction of the alveoli, resulting in decreased oxygen transfer into the bloodstream and shortness of breath. increased risk of emphysema if genetic variant of alpha- antitrypsin deficiency and smoking or exposed to high levels of air pollution [ ] alpha- antitrypsin deficiency a deficiency of a at, a protein produced in the liver that protects the lungs from excessive neutrophil elastase, an autophagic enzyme. a at may also accumulate in liver and cause liver disease [ ] obstructive asbestosis fibrotic lung disease resulting from extensive inhalation of asbestos fibers [ ] desquamative interstitial pneumonitis (dip) form of idiopathic interstitial pneumonia that is more common in cigarette smokers but may be seen in nonsmokers, in patients with underlying connective tissue diseases or those exposed to inorganic dust/particles [ ] sarcoidosis immune-mediated systemic disorder that is characterized by granuloma formation of the lung parenchyma and the skin [ ] restrictive pathophysiologyneuromuscular weakness amyotrophic lateral sclerosis (als) progressive neurological disease that affects the motor neurons of the nervous system [ ] guillain-barre syndrome progressive immune system attack on the peripheral nerves, usually following an infectious illness such as a respiratory infection. may eventually cause respiratory distress syndrome [ ] restrictive pathophysiologychest wall/pleural disease kyphoscoliosis kyphoscoliosis: a deformity of the thoracic cage that results in restriction of the lungs and impairs pulmonary function [ ] ankylosing spondylitis autoimmune inflammatory disorder characterized by inflammation of the axial skeleton and peripheral joints [ ] chronic pleural effusions chronic accumulation of fluid between the two outer membranes surrounding the lungs [ ] pulmonary vascular disease pulmonary embolism blood clot that typically originates from thrombi in the deep venous system of the legs and travels to the lungs pulmonary arterial hypertension (pah) progressive disorder of primary pulmonary arterial vasculopathy characterized by a mean pulmonary arterial pressure > mm hg at rest (> mmhg during exercise) [ ] iron homeostasis [ ] . iron can also impair cytokine secretion, which can leave those with an iron overload much more susceptible to infection, increasing the morbidity and mortality of infectious diseases, including those of the lung [ ] . oxidative stress may contribute to injury of lung tissue, causing further fibrosing in those lung diseases with that characteristic. allele variants in the genes associated with iron homeostasis (c y, s c, and h d hfe) are significantly more common in those with idiopathic pulmonary fibrosis (ipf) than those without ipf ( . % ipf patients vs . % non-ipf) and are associated with higher irondependent oxygen radical generation [ ] . iron is implicated in lung pathology. monitoring iron status and using supplements or diet to aid the body in increasing or decreasing the iron load are imperative for the nutritionist working with lung disease patients. choosing a good non-constipating form of iron is important, such as iron glycinate. the b vitamins are also important to monitor for lung health. vitamin b and its bioactive form, p- -p, are typically known to protect dna from mutation or damage [ ] . however, there is mixed evidence on its role for lung cancer. some research has shown that it is helpful for lung cancer patients as it is important for apoptosis when using chemotherapy, because it sensitizes cancer cells to apoptosis [ ] . however, research in showed that adult male smokers taking greater than mg vitamin b /day for long periods tended to have a greater risk for lung cancer. many variables, including genetic variants, form of b , and the status of other co-nutrients may be at play [ ] . other studies showed that men in the top quintile of vitamin b serum concentration had about one half the risk of lung cancer, and specifically, vitamin b and folate were inversely associated with risk of lung cancer [ ] . . squamous cell (epidermoid) carcinoma about - % of all lung cancers. these start in early versions of squamous cells, which are flat cells that line the inside of the airways in the lungs. often linked to a history of smoking and tend to be found in the central part of the lungs, near the bronchus [ ] large cell (undifferentiated) carcinoma about - % of lung cancers. it can appear in any part of the lung and tends to grow and spread quickly. a subtype of large cell carcinoma, known as large cell neuroendocrine carcinoma, is a fast-growing cancer that is very similar to small-cell lung cancer [ ] small-cell lung cancer (sclc) about - % of lung cancers are sclc. typically start in the cells lining the bronchi and parts of the lung such as the bronchioles or alveoli [ ] infectious diseases pneumonia inflammation of the lungs, usually caused by bacteria, viruses, or fungi [ ] bronchitis inflammation and eventual scarring of the lining of the bronchial tubes accompanied by restricted airflow, excessive mucus production, and persistent cough [ ] tracheitis bacterial infection that can develop in the trachea [ ] infant respiratory distress syndrome also known as hyaline membrane disease (hmd) or respiratory distress syndrome, this condition affects the alveolar ducts and terminal bronchioles in which the hyaline membrane is a fibrinous material composed of blood and cellular debris, caused by the absence of proper surfactant production due to an immature or poorly developed lung [ ] upper respiratory infection (uri) acute infections involving the nose, sinuses, pharynx, larynx, trachea, and bronchi, referred to as the common cold [ ] bronchopulmonary dysplasia (bpd) chronic lung disorder which may affect infants who have been exposed to high levels of oxygen therapy and ventilator support [ ] other cystic fibrosis disease characterized by abnormally thick mucus secretions from the epithelial surfaces of many organ systems, including the respiratory tract, the gastrointestinal tract, the liver, the genitourinary system, and the sweat glands [ ] acute lung injury clinical and radiographic changes in lung function associated with critical illness (acute respiratory distress syndrome is most severe form) [ ] respiratory because of disagreement in research, particularly with smokers or former smokers, using food first for b vitamins may be a prudent way forward. good sources of vitamin b are fish, chickpeas, chicken, potatoes, turkey, bananas, ground beef, and winter squash. pyridoxal kinase (pdxk) is the enzyme that converts pyridoxine and other vitamin b precursors to its bioactive form of p- -p. dysfunction of this enzyme is a good prognostic for lung cancer and other lung diseases. mthfr aa genotype is associated with a higher risk of lung cancer in women but not in men. the mthfr tt genotype was associated with a significantly decreased risk of lung cancer in women but not in men. in contrast, the mthfr c t and a c polymorphisms interacted with smoking status in men but not in women [ ] . methylation gene testing is imperative to understand the patient's status. some studies suggest that a higher intake of riboflavin (vitamin b ) may protect against lung cancer in smokers [ ] . folate deficiency was also associated with asthma and attacks of shortness of breath [ ] . correcting acidosis may preserve muscle mass in diseases where wasting is an issue, such as copd or ipf. for those receiving chemotherapy, a higher ph (more alkaline status) is helpful for muscle mass protection. high alkaline diets contain more fruits and vegetables, and those supply more magnesium, which is needed to activate vitamin d. as discussed below, vitamin d is extremely helpful for lung health. sleep quality involves maintaining adequate - hours with good sleep hygiene (see chap. ). good rem cycling, feeling refreshed upon awakening, and other characteristics of good sleep play significant roles in maintaining healthy acid-base balance. dietary intake of the minerals magnesium, potassium, sodium, chloride, and calcium promotes the balance of acidbase microenvironment. after exposure and tissue retention of toxic minerals and metals, these substances can contribute to perturbations in the acid-base metabolic milieu. some conditions reduce oxygen intake and should be addressed. one of the most common oxygen-impairing conditions is sleep apnea, altered sleep with random halting of breathing during sleep that is often accompanied by snoring. other limiting conditions are respiratory diseases like copd, a at deficiency, asthma, cystic fibrosis, etc. vitamin a is an important antioxidant and a general umbrella term for several fat-soluble retinoids, including retinol, retinal, and retinyl esters. there are also other substances that are provitamin a carotenoids or precursors to vitamin a. two forms are found in foods, the preformed forms of retinol or retinyl esters, which are found in dairy, fish, caviar, and meats (especially liver), and the provitamin a carotenoids, including the most important and common provitamin a carotenoid, beta-carotene, as well as others including alpha-carotenes and cryptoxanthin, which are found in plant-based foods. our bodies must convert these two forms within our cells to retinal and retinoic acid, the active forms of vitamin a in the body. new studies of the gene, β-carotene , ′-monooxygenase (bcmo ), which is responsible for the enzymatic conversion of β-carotene to vitamin a, are revealing that individuals with heterozygous or homozygous bcmo snps have - % less efficient conversion than those with normal gene function (see chap. ) [ ] . other carotenoids found in food, such as lycopene, lutein, and zeaxanthin, are not converted to vitamin a but have other antioxidant benefits in the body. most vitamin a is stored in the liver as retinyl esters, and deficiency is not visible until these stores are nearly depleted. vitamin a's role as an antioxidant helps the lungs in several ways, including maintaining alveolar epithelium cells and preventing development of respiratory tract infections. most of the developed world's population does not have a risk of deficiency due to sufficient vitamin a intake. however, most people with cystic fibrosis have pancreatic insufficiency, which reduces the ability to absorb fat and therefore the fat-soluble vitamins a, d, e, and k. according to a study in , between % and % of people with cystic fibrosis had a vitamin d deficiency, also a fat-soluble vitamin. with the addition of pancreatic replacement treatments, better nutrition, and vitamin a supplementation, deficiency has become rare. however, improved vitamin a status has not been thoroughly studied as of , and therefore it is largely unknown if an improved vitamin a status has any effect on cystic fibrosis [ ] . vitamin a deficiency has been shown to be associated with emphysema in rats. smoke exposure significantly decreases vitamin a concentration in lung tissue, significantly more in those with copd [ ] . retinoic acid seems to play a beneficial role in the treatment of ipf. a review showed that in all studies, retinoic acid decreased fibrosing, the formation of collagen, and reduced the expression of alpha-smooth muscle actin (alpha-sma), all hallmarks of ipf [ ] . it is important to not take large doses of vitamin a if one is in a malnourished state as it can cause toxicity and should be monitored with blood testing of vitamin a retinol. nourish the body with all foods and all nutrients slowly. the non-provitamin a carotenoids have also shown some benefit. lycopene, found in high amounts in guavas, watermelon, tomatoes, papaya, grapefruit, sweet red peppers, asparagus, purple cabbage, mangos, and carrots, slowed forced expiratory volume (fev) decline in former smokers [ ] . vitamin d's importance with lung health cannot be understated. vitamin d deficiency, or even insufficiency, is linked to accelerated decline in lung function, increased inflammation, and reduced immunity in chronic lung diseases. vitamin d has a role in the regulation of inflammation, immunity, cellular proliferation, senescence, differentiation, and apoptosis. sufficient vitamin d levels are correlated with better asthma control, better immune response related to respiratory infections, and reduced severity of exacerbations with copd and asthma when exposed to inflammation-causing pathogenic activity [ ] . vitamin d is obtained through sunlight on the skin (without sunscreen) and very few dietary sources. therefore, supplementation is generally recommended. higher vitamin d levels are shown to be protective in many lung disease states. sufficient levels improve treatment response with medications and reduce asthma severity [ ] . with infectious diseases of the lung, higher vitamin d concentrations are shown to have a protective action [ ] . vitamin d has a protective effect on lungs of smokers, and higher levels of vitamin d inhibit the pro-fibrotic phenotype of lung fibroblasts and epithelial cells. current data suggest an inverse association between serum vitamin d and lung cancer risk, and vitamin d deficiency at - weeks' gestation is associated with impaired lung function and asthma at years of age [ ] . lower levels of vitamin d are associated with an increased risk for respiratory infections, cystic fibrosis, chronic obstructive pulmonary disease, and interstitial lung disease [ ] . vitamin c is an important antioxidant that helps decrease oxidative damage in the body, including in lung tissue. it is also essential for lipid metabolism. it is present in the airway surface liquid and creates an interface between the epithelial cells and the external environment. vitamin c is a cofactor in collagen synthesis, which can aid in repair of bronchial and alveolar tissue when damaged. it also provides beneficial control of lipid peroxidation of cellular membranes, including those surrounding as well as those within intracellular organelles. vitamin c has some of the best lung protective capabilities, according to current research. vitamin c may also diminish oxidative attack on nonlipid nuclear material and is an antioxidant component of plasma and extracellular fluids surrounding the lungs. it is an antioxidant that not only fights oxidative stress but also reduces oxidized vitamin e and glutathione, allowing them to become active as antioxidants again. vitamin c is antiinflammatory and is helpful in all inflammatory states of the lung, even allergies. there are many ways in which vitamin c, along with its antioxidant partners, glutathione, vitamin e, vitamin a, and plant-based phytonutrients, affects lung health. it is well established that increased levels of vitamin c in the diet improve health outcomes for smokers and their offspring, as smoking depletes vitamin c [ , ] . vitamin c is also helpful in fighting infectious diseases such as respiratory infections and pneumonia, copd regardless of smoking status, asthma, and lung cancer [ ] . specifically, in certain lung cancers, vitamin c, along with other nutrients such as lysine, proline, epigallocatechin gallate, and zinc, can inhibit the proliferation of certain carcinoma lines and induce apoptosis, as well as inhibit lung cancer metastasis [ ] . even in lung transplants, vitamin c is helpful against oxidative stress by reducing glutathione and lowering lipid peroxidation, along with vitamins a and e [ , ] . the literature suggests these benefits can be achieved at - mg/day. check iron status before administering vitamin c supplementation as vitamin c doubles iron absorption from foods. vitamin e's primary role is as an antioxidant, breaking free radical chain damage and preventing peroxidation of lipid molecules. this vitamin also is promising with regard to beneficial effects on lung function preservation. oxidative stress and inflammation are key features in many lung diseases; therefore nutrients with antioxidant capacity can be useful. a few studies suggest that alpha-tocopherol found in sunflower and olive oils has a beneficial effect on fev (forced expiratory volume), whereas gamma-tocopherol found in canola, soybean, and corn oils has a negative effect on fev [ ] . however, from these authors' perspective, this is likely due to the source and type of the oils, which can be inflammatory, rather than the form of vitamin e. for example, a recent study showed that gamma-tocopherol was protective in allergic asthma [ ] . in addition, sufficient levels of vitamin e, in the alpha-tocopherol form, were found to reduce susceptibility of the elderly to acquiring pneumonia. some of the positive effects of vitamin e are synergistic with vitamin c [ ] . phytonutrients have been found to have two effects with respect to lung disease: one is a symptom-improving pattern, and the other is a rate-reducing pattern [ ] . idiopathic pulmonary fibrosis (ipf) is largely characterized by reduced antioxidant and increased inflammatory action. recent literature is showing the ability of certain flavonoids, in particular quercetin, to reduce inflammation and act as a strong antioxidant countering the pro-oxidant environment of ipf. quercetin is recognized as the most potent ros scavenger. taken together with glutathione, the impact is even greater, and it seems to help improve the antioxidant and inflammatory status more for those with ipf than non-diseased controls [ ] . curcumin has been shown to slow or limit fibrosing in murine studies related to lung, liver, or kidney fibrosing [ ] [ ] [ ] [ ] . it has also been shown to attenuate metastatic melanoma in the lungs when delivered in a nanoparticle [ ] . the potential for curcumin is interesting and hopeful. fisetin and fenugreek have also been studied as useful phytonutrients that help combat inflammation in lungs [ , ] . fisetin is found in apples, strawberries, persimmons, cucumbers, and onions, among many other fruits and vegetables. fenugreek is a plant used frequently in south and central asian cooking, where both the seeds and leaves are used. there are now supplements available for both of these phytonutrients. this is a reminder to eat a primarily plantbased diet when combating inflammation and to broaden our palates to include healthy foods and ingredients from other cultures than our own. lastly, the powerful antioxidant cannabidiol (cbd), from the cannabis and closely related hemp plants, is a powerful shield against oxidative stress, prevalent in lung disease [ ] . the research is not robust regarding lung function and minerals, and most has been done with regard to cystic fibrosis where bone density is associated with general nutritional status, including minerals. there have also been many studies trying to determine a correlation between mineral status and copd, where, again, the research shows that mineral status is not predictive but overall nutrient status may fall if not monitored. in contrast, one study in japan showed an inverse association between dietary calcium and the risk for copd [ ] . in an nih-aarp diet and health study, magnesium, iron, selenium, zinc, and copper intakes, both dietary and supplemental, were studied with respect to lung cancer. mineral supplementation did not affect lung cancer risk, yet dietary intake of calcium, along with vitamin d, and iron reduced the risk, and dietary intake of magnesium increased risk [ ] . boron has been shown to be protective against lung cancer, along with other nutrients, at levels of mg/day [ ] . there is some research showing that selenium is helpful, particularly for smokers, for improved fev. higher magnesium status is correlated to better fev but is not yet seen as an association. this may be due to magnesium's role as the vitamin d activator. there have been a few studies showing increased copper levels are related to decreased fev. some recent research has also shown that dietary zinc and iron are associated with reduced lung cancer, but the same was not seen with calcium, copper, magnesium, or selenium [ ] . low mineral bone density is prevalent at a higher rate among cystic fibrosis patients, and therefore supplementation with vitamin d, vitamin k , magnesium, calcium, and the trace minerals can be helpful [ ] . alpha-lipoic acid (ala) is a powerful antioxidant endogenously produced in the human body from foods such as yeast, organ meats, spinach, broccoli, and potatoes and is both water-and fat-soluble. ala, along with n-acetyl cysteine (nac), glycine, and vitamin c, is an important precursor to glutathione, which is a powerful endogenous antioxidant and the primary antioxidant in the lungs. ala has been shown to be anti-inflammatory in lung tissue in those with acute lung injury, and the proposed action is via inhibition of the nf-kappab signaling pathway [ ] . ala has also been shown to downregulate some cancerpromoting actions prevalent in lung cancer, likely by this same pathway [ ] . it also may alleviate nicotine-induced lung oxidative stress [ ] . n-acetyl cysteine (nac), another precursor to glutathione, is a powerful antioxidant on its own as well. in relation to the lungs, nac helps the clearance of mucus in the lungs by pulmonary cilia. this has been shown to be effective at - mg/day in divided doses [ ] . there is significant research on nac and lung health, showing improvement with nearly all lung issues, including nearly studies showing improvement for bronchitis [ ] , infectious diseases by reducing the bacterial count [ ] , smokers, and people with asthma and copd, through both its antioxidant effects and by reducing the viscosity of sputum and mucus. at an oral dose of mg/day, the mean glutathione concentration in lung tissue increased by % on one study [ ] . there are additional studies showing improvement for those with copd, asthma, cystic fibrosis, pulmonary fibrosis, and symptoms related to allergies or other infections. the dose that has been studied and has been shown to be most useful is mg twice daily and more effective if nebulized [ , ] . both ala and nac supplementation should be accompanied by vitamin b and the complex of b vitamins to prevent an elevation in liver enzymes (. fig. . ). there are several specialty labs that conduct micronutrient analysis and functional testing, such as genova diagnostics and spectracell. these tests can be useful for evaluating levels of individual nutrients as they function in the body, rather than just in serum, which is not an accurate indicator of tissue or functional status. patients suffering from copd, interstitial lung disease, and other diseases tend to have muscle and weight loss related to respiratory acidosis, and increasing weight and muscle mass helps with quality of life. respiratory acidosis occurs with co buildup where the lungs are no longer able to effectively exchange o and co . nutritional supplementation should attempt to reduce metabolic co production. fat metabolism produces less co than carbohydrate metabolism, so emphasizing a higher fat, lower carbohydrate diet can be helpful [ ] . in general, a high intake of omega- fatty acids is associated with poorer forced expiratory volume (fev) in patients with lung disease because of their pro-inflammatory nature. however, a complete fatty acid panel or a red blood cell membrane fatty acid test would reveal more details about the status of an individual's omega- pathway. certain omega- s and the work of their corresponding metabolizing enzymes such as elongase and delta- or delta- -desaturase may allow healthful omega- s (linoleic (la), gamma-linolenic (gla), lipoxins [ ] , prostaglandin series metabolites) to flow down an anti-inflammatory pathway instead. important cofactors for this pathway are vitamin b , vitamin b , vitamin b , vitamin b , biotin, vitamin c, zinc, and magnesium. lipid metabolism dysregulation is understood to be part of the pathogenesis of idiopathic pulmonary fibrosis. in ipf, free fatty acids play a role in the proliferation of fibroblasts. certain fats, in particular palmitic acid, oleic acid, and linoleic acid, are elevated in the lungs of those with ipf, whereas stearic acid is low. stearic acid is found in meat, poultry, fish, grain products, and milk and milk products. the palmitic, oleic, and linoleic acids enhance the tgf-ß -induced expression of α-smooth muscle actin (sma) and collagen type in mrc- cells, which can lead to fibrosis. stearic acid inhibits the levels of these fibrosing cells. stearic acid also improves the thrombogenic and atherogenic risk factor profiles [ ] . in one study on patients with copd, omega- fatty acids were found to reduce inflammation in bacterial infections of the lungs without suppressing the ability to clear the bacteria. those taking epa, dha, ala, and gla had improved exercise capacity and had lower risk of developing copd [ ] . although results have been mixed over the years possibly due to doses used in studies, a recent prospective study showed that pufas (omega- s) from fish help prevent lung cancer and can be part of treatment during lung cancer. in general, the strongest evidence for improved lung function and slowing decline is with the epa and dha forms of omega- fatty acids [ ] . because of toxicity issues in fish, increasing quality supplements vs fish intake may be more prudent. protein is essential for all lung conditions, and lack of it can result in poorer pulmonary function, decreased exercise capacity, and increased risk exacerbations. since many lung diseases have oxidative stress as a characteristic, it can cause protein carbonylation which may negatively affect dna expression and lipid membranes. nutritional supplementation with added protein and healthy carbohydrates can increase body weight and muscle strength and improve quality of life. those with copd, interstitial lung diseases, and others that affect oxygen absorption and co exhalation have greater levels of hypoxia and sometimes respiratory acidosis, which exacerbates the loss of muscle through oxidative stress and inflammation. supplementation of free essential amino acids versus complete proteins has been shown to help prevent muscle wasting among copd patients. muscle-building exercise is often prescribed for those with copd and interstitial lung diseases [ ] . supplemental l-carnitine at - g/day for - weeks increased the capacity of copd patients to rehabilitate and build muscle and helped inspiratory muscle strength. carbohydrates should be monitored for sufficient but not excessive levels. more co is produced with the utilization of carbs versus fats for energy. therefore, with gas exchange being an issue with most lung disorders, a slightly higher fat and lower carbohydrate diet may be indicated. it is worth mentioning fiber for a moment, as it is mostly delivered in carbohydrate-rich foods. there is evidence that consuming whole fruits and vegetables higher in dietary fiber is associated with reduced severity of asthma and copd [ ] . a diet that derives its carbohydrates from vegetables and fruits rather than from processed carbohydrates such as grains, breads, pasta, or added sugars will deliver fewer carbohydrate grams. glutathione (gsh), a tripeptide composed of cysteine, glutamine, and glycine and produced from methionine, is in every cell in the body. it is the most powerful and abundant endogenous antioxidant in the airway epithelial lining and is responsible for detoxification of electrophilic compounds, the scavenging of free radicals, and modulation of cellular processes such as dna synthesis and repair, differentiation, apoptosis, and immune function [ ] . it is also a heavy metal chelator. it is more effective than some other antioxidants because it is intracellular and extracellular. in isolated type ii alveolar epithelial cells, extracellular glutathione inhibits hyperoxia-induced injury, inhibits pro-inflammatory cytokine release, and promotes cell growth. it is obviously very important to maintaining lung function as this is the inflammatory process that begins lung cell or tissue damage, as mentioned above. the highest levels of glutathione concentrations in the body are in the lungs, liver, and brain. gsh depletion leads to activation of nf-kb (pro-inflammatory signaling) and increased pro-inflammatory gene transcription and cytokine release from histone deacetylase suppression in epithelial cells. total and reduced gsh concentrations are much lower in people with ards, pulmonary fibrosis, and hypersensitivity pneumonitis than observed in healthy adults. alterations in alveolar and lung gsh metabolism are widely recognized as a central feature of many inflammatory lung diseases such as idiopathic pulmonary fibrosis, acute respiratory distress syndrome, cystic fibrosis, and asthma [ ] . we make glutathione in the body with cysteine and methionine, and it is difficult to take exogenously because digestion can destroy it. the precursors of cysteine (essential), glutamine, and glycine and cofactors (vitamin c, vitamin e, vitamins b , b , b , and b , folate (b ), minerals selenium, magnesium, and zinc, and alpha-lipoic acid, see below) are therefore recommended so that the body can produce it on its own. the two enzymes necessary to produce it, gamma-glutamylcysteine synthetase and glutathione synthetase, must also be functioning well. we also recycle glutathione if the precursors and cofactors are available. cysteine is usually the most rate-limiting precursor, and many people supplement with n-acetylcysteine to provide the body with this nutrient. although glutathione is produced in every cell of the body, the greatest production is in the liver, so focusing on liver health is important to maintain good glutathione production. production declines with age and with lung disease, as well as other conditions. there are very few foods containing glutathione; they are raw or very rare meat, especially liver, unpasteurized milk and other unpasteurized dairy products, and freshly picked fruits and vegetables, such as avocado and asparagus. however, as mentioned earlier, it may be destroyed during digestion. glutathione contains sulfur molecules, which may be why foods high in sulfur help to boost its natural production in the body. these foods include: cruciferous vegetables, such as broccoli, cauliflower, brussels sprouts, and bok choy allium vegetables, such as garlic and onions eggs nuts legumes lean protein, such as fish and chicken other foods and herbs that help to naturally boost glutathione levels include: milk thistle (a liver-regenerating herb) flaxseed guso seaweed whey glutathione is also negatively affected by insomnia. getting enough rest on a regular basis can help increase levels. addressing a drop in glutathione for lung health involves maintaining good levels of the precursors and cofactors mentioned above. a good way to bring in the less abundant amino acid cysteine is to take n-acetylcysteine (nac). doses of - mg were more effective than placebo in reducing symptoms [ ] . supplemental selenium can also help with glutathione production. glutathione supplementation has also become more effective. there are several forms, from capsules to topical liposomal, which have shown good absorption. inhaled gsh has good research for use in cystic fibrosis (cf), chronic otitis media with effusion (ome), hiv seropositive individuals, idiopathic pulmonary fibrosis (ipf), and chronic rhinitis. it is not recommended for asthma due to significant side effects, and additional evidence is needed to determine if use with emphysema is recommended although theoretically it should be useful. it is also not recommended to use inhaled gsh during cancer chemotherapy treatment as it may interfere with the medication's actions. the mechanism of action of inhaled glutathione is limited to the upper airways and lungs and does not seem to affect serum levels. before considering inhaled gsh treatment, the patient should undergo urine sulfite sensitivity testing using a readily available special test strip called "em-quant sulfite test. " if positive, inhaled gsh should not be used as bronchoconstriction may occur. the recommended dose is - mg per day, depending on response, and whether inhaled gsh is considered safe. efficacy should be tested using a baseline pulmonary function test and a follow-up test after a prescribed time later [ ] (. fig. . , box . ). there are also serum tests for glutathione levels. these cofactors are vitamin c; vitamin e; vitamins b , b , b , and b ; folate (b ); minerals selenium, magnesium, and zinc; and alpha-lipoic acid. what do the glutathione cofactors do that makes them so important? direct cysteine toward glutathione production and increase cellular uptake of cysteine help form the glutathione molecule out of the three precursor amino acids help recycle glutathione from its oxidized gssg form back to its reduced (active) gsh form help maintain glutathione levels and keep the gssg-gsh ratio balanced recycle each other, improving overall antioxidant activity stimulate the activity of the whole glutathione enzymatic system co is a fat-soluble compound produced endogenously and also available through food and supplementation. it is required in the production of atp, is a powerful antioxidant, and therefore is helpful against oxidative stress, an important issue in lung disease. coq achieves its strong effects through a set of different mechanisms. it influences genes through its epigenetic effect to reduce inflammation, helps with the immune system, and even reduces aging by reducing systemic oxidative stress and mitochondrial aging [ ] . lungs are the most susceptible organ to oxidant damage because they interact directly with oxygen. therefore, it makes sense that antioxidants, and those that especially affect the lungs, are helpful in tissue and lung cell preservation [ ] . coq levels are significantly lower in those with copd and asthma with insignificant amounts of research on the levels of coq with other lung issues. it has been shown that supplementing patients with coq resulted in measurable benefits. in one study, patients with copd using steroids to reduce inflammation were able to reduce their steroid dosage when using coq [ ] . in another study, benefits were shown for copd patients during exercise, measuring performance, tissue oxygenation, and heart rate at a low dosage of mg/day [ ] . the levels of coq in the blood have been shown to indicate the degree of systemic oxidative stress, which implies it could be used as a marker to assess copd [ ] . several studies confirm the beneficial role of coq in decreasing oxidative stress, cardiovascular risk, and modulating inflammation during aging. dosage levels of mg/ day of coq have been shown to be therapeutic. however, in the reduced, more absorbable form, ubiquinol, mg/ day, was shown to be as effective. there is a wide range of toxins and anti-nutrients that can significantly impact the respiratory system. this can occur through acute or chronic exposure to these agents. the earth's air is the source of oxygen, and the lungs provide access to that oxygen to support life. the human need for oxygen is precarious because humans can only survive for about minutes without the precious gas. from about to sometime between and in europe and the united states, the ramp-up of new industrial revolution manufacturing processes opened a new era of increasing chemical and heavy metal atmospheric contamination. these pollutants can enter the body through breathing the polluted air. the more concentrated atmospheric pollutant densities cluster around areas of dense population. the dirty air provides a serious direct threat to those with respiratory diseases. an integrative and functional approach to assessing an individual with respiratory disease needs to include consideration of potential environmental contributors to the etiology of a condition. . table . lists environmental pollutants that are known to promote lung pathology. a study published in the canadian respiratory journal examined exhaled fractional nitric oxide (feno)an indicator of inflammation in the lungs -in school children at three different schools located three different distances from a large steel mill [ ] . steel processing is known to be a source of ambient iron, nickel, lead, copper, vanadium, and zinc. the study found statistically significant differences in feno between the two closer schools compared to the farthest school from the mill, indicating potential increased lung inflammation caused by heavy metals and/or air pollutants [ ] . although acute metal toxicity is possible, chronic, low-grade exposure is more common and may contribute to respiratory complications and disease. an individual's ability to vitamin c -as an antioxidant, it assists glutathione in this function and has been shown scientifically to raise glutathione levels short term; it is recycled by glutathione from its oxidized state back to its active state, thus strengthening antioxidant defenses; vitamin c also recycles vitamin e and alpha-lipoic acid vitamin e -as an antioxidant it also assists glutathione in eliminating free radicals much like vitamin c; it is also required for the proper functioning of glutathione enzymes; it recycles vitamin c and alpha-lipoic acid b vitamins -vitamins b and b maintain glutathione and its enzymes in their active forms; vitamin b participates in the formation of a glutathione molecule; vitamin b influences glutathione synthesis indirectly as it is important for the proper functioning of amino acids including gsh precursors; vitamin b increases the amount of magnesium (a vital cofactor) that can enter cells; folate (b ) pushes cysteine toward glutathione production rather than homocysteine production; folate and vitamin b work together in amino acid metabolism and protein synthesis. you can read more vitamin b deficiency and its effect on immune health at http://www. immunehealthscience. com/vitamin-b -deficiency. html selenium -part of the enzyme glutathione peroxidase (gpx). glutathione peroxidases, also known as selenoproteins, are a family of antioxidant enzymes that speed up the reaction between glutathione and free radicals magnesium -required for the proper functioning of the enzyme gamma-glutamyl transpeptidase (ggt) involved in the synthesis of glutathione zinc -zinc deficiency reduces glutathione levels, especially in red blood cells. however, zinc levels above normal have pro-oxidant properties and reduce glutathione too alpha-lipoic acid -an antioxidant produced by the body; it has been scientifically proven to enhance and maintain glutathione levels by stimulating enzymes involved in the synthesis of glutathione; it also helps increase the cellular uptake of cysteine, the crucial building block of glutathione; in addition, alpha-lipoic acid recycles vitamins c and e based on data from ref. [ ] eliminate these metals via detoxification in conjunction with gastrointestinal health and other factors can serve as important factors in whether or not these metals accumulate in the body. chronic arsenic exposure may be linked to respiratory complications [ ] . chronic arsenic ingestion via contaminated drinking water may be connected to respiratory symptoms such as chronic cough, shortness of breath, blood in sputum, and abnormal breath sounds [ ] . arsenic can also be ingested through foods such as rice and rice products, shellfish, and seaweeds, which have been shown to have high levels of inorganic arsenic (more toxic than organic arsenic found in fish) [ ] . however, ingested inorganic arsenic is typically biotransformed and excreted in the urine [ ] . that said, altered biotransformation has been observed depending on an individual's age, gender, nutritional status, and genetic polymorphisms responsible for the biotransformation of inorganic arsenic [ ] . chronic inhalation versus ingestion may result in irritation of the throat and respiratory tract [ ] . individuals most affected by arsenic exposure are children, nursing children, and infants of exposed pregnant mothers [ ] . acute inhalation of cadmium may lead to dyspnea and coughing [ ] . long-term exposure to cadmium has been reported to contribute to emphysema, dyspnea, and inflammation of the nose, pharynx, and larynx [ ] . individuals most affected by cadmium toxicity are those with occupations with cadmium exposure, such as those who work in certain types of factories, women, due to higher intestinal absorption because of low iron stores, and residents of asia due to high intake of rice grown in contaminated soil [ ] . the us national health and nutrition examination survey (nhanes) demonstrated an association between obstructive lung disease and serum lead and cadmium concentrations in the blood, where cadmium was shown to partially mediate the association between smoking and obstructive lung disease [ ] . in the korean nhanes, obstructive lung function was found to be associated with higher serum blood levels of cadmium and lead as well [ ] . the specific mechanism of heavy metal burden and its effects on respiratory health must be further investigated. although testing and treatment of heavy metal burden have its limitations, it is worth considering as heavy metal accumulation can wreak havoc on the body. an example of heavy metal testing that can be used in practice is urine provocation testing with a chelating agent, such as fda-approved dmsa. eliminating heavy metals from the body can be potentially harmful and requires careful monitoring and guidance by an experienced healthcare professional. air pollutants that are used as indicators of air quality are carbon monoxide, lead, nitrogen dioxide, ozone, particles, and sulfur dioxide [ ] . air pollution has been shown to have adverse effects on human health [ ] . a systematic review and meta-analysis done in china showed an association between respiratory disease and ambient nitrogen dioxide, which is increased through fuel combustion, industrial production, and fuel exhaust [ ] . diesel exhaust particles in particular have been associated with an increase in cytokines such as il- , il- , and ige in nasal mucosa [ ] . nitrogen dioxide in particular can potentially contribute to respiratory disease as it is a free radical that is highly reactive and poorly water-soluble and can be deposited in the lungs when inhaled [ ] . in another study performed in england, air concentration of nitrogen dioxide was significantly associated with respiratory hospital admissions [ ] . other pollutants, such as fine particulate matter and ozone, have been shown to significantly affect respiratory function in copd patients [ ] . increased ozone exposure has also been associated with increased airway inflammation and respiratory symptoms along with decreased respiratory function in children [ ] . optimization of nutrition and antioxidant status is essential to combating the potential health effects of air pollutants. . [ ] . it would be reasonable to assume having adequate stores and ability to utilize these nutrients may protect against other insults to the respiratory system as discussed in this section through their anti-inflammatory properties. acute and chronic exposure to certain chemicals can also pose a risk to respiratory health. obtaining a full occupational and social history when assessing individuals is important in order to identify any potential exposure to chemicals. one of the most well-known and common toxic chemical exposures that affects respiratory health is cigarette smoke. smoking cigarettes has been identified as a main cause of copd [ ] . increased oxidative stress from inhaling cigarette smoke appears to activate the nf-kb inflammatory pathway, increasing the production of pro-inflammatory cytokines such as interleukin (il)- , il- , and il- and tumor necrosis factor-ɑ (tnf-ɑ) [ ] . it also appears to reduce anti-inflammatory cytokines such as il- [ ] . electronic cigarettes, or e-cigs, have been increasing in popularity in recent years and are marketed as a better alternative to tobacco cigarettes. however, recent evidence suggests that the vapor and associated chemicals produced by e-cigs may be harmful to the respiratory system, although further research is needed to determine the mechanism [ , ] . exposure to metalworking fluid aerosols has been associated with asthma, hypersensitivity pneumonitis, impaired lung function, allergic alveolitis, and sinusitis [ ] . a review also identified an association between occupational exposure to pesticides and increased risk of asthma and chronic bronchitis [ ] . there are many chemicals that are toxic when inhaled. for example, inhalation of chlorine is toxic to the lungs, where low doses can cause airway injury and high doses can cause both airway and alveolar injury [ ] . these injuries can manifest as dyspnea, hypoxemia, pulmonary edema, and pneumonitis [ ] . high doses of carbon dioxide, such as that released from dry ice, can also induce respiratory failure. stress may also play a role in respiratory health and the body's ability to combat insults imposed on the respiratory system. from a physiological standpoint, it is worth noting that acute stress via activation of the sympathetic nervous system increases ventilation through the production of glucocorticoids [ ] . repeated acute stress may also affect growth and repair mechanisms [ ] . chronic biological stress in the form of infections can also be inflammatory and negatively affect the immune system and may affect an individual's susceptibility to respiratory complications. see the chronic infections and respiratory health section on page # below for further information on this association. however, appropriate amounts of physical stress, such as in the form of exercise, can be beneficial to respiratory health. some research has indicated a benefit of aerobic exercise to respiratory muscle strength in cystic fibrosis patients [ ] . chronic stress can be defined as recurrent acute stress or inability to moderate acute stress responses [ ] . this can be in the form of physical or emotional stress. chronic stress and negative emotions such as depression, anxiety, and anger may be linked to endocrine and immune processes [ ] . immunoglobulin e (ige) and cytokine production, as well as respiratory inflammation, are markers that characterize the asthma response and have been shown to respond to stress in some capacity [ ] . it has been hypothesized that increased stress may increase susceptibility to air pollution given its effects on the inflammatory response [ ] . another connection between emotions and respiratory health is acknowledged in east asian medicine, noting the association between the lungs and feelings of sadness, grief, and anxiety [ ] (. table . ). asthma is a chronic inflammatory lung disease, triggered by either an ige allergic reaction or nonallergic factors, and results in reversible airway obstruction and inflammation of the airway [ ] . it is characterized by recurrent episodes of wheezing, breathlessness, coughing, and chest tightness [ ] . severe asthma or asthma that is chronic or poorly controlled may lead to airway and lung remodeling that involves deposition of fibrotic tissue which leads to constriction of the bronchi [ ] . although the exact mechanisms have not yet been identified, compromised nutritional status, such as deficiencies in selenium, zinc, and vitamins a, c, d, and e, has been connected to asthma [ ] . the pathophysiology of asthma, nutrition considerations, genotypic characteristics, and lifestyle influences will be discussed in this section. there are numerous potential triggers to the development and/or exacerbation of asthma which can be summarized in box . . the various causes of asthma have led to the classification of several different subtypes and endotypes of asthma in hopes of choosing more targeted treatments. the pathophysiology of asthma is complex and not fully understood, due in part to its heterogeneous nature, which necessitates its organization into individual phenotypes and endotypes. this organization is important to be able to utilize targeted treatments by identifying the root causes of the symptoms. however, more research is needed to more clearly identify the specific pathological mechanisms of each phenotype and particular treatment responses [ ] . two of the most common asthma phenotypes are allergic and nonallergic asthma [ ] ; allergic is characterized by increased th immunity (th high) and nonallergic defined by varying mechanisms depending on the trigger (th low) [ ] (see also chap. ) . allergic asthma involves the ingestion of typically harmless environmental triggers (listed in . table . ) by antigenpresenting cells in the bronchi, which interact with immature helper t cells that, in turn, trigger an unwarranted allergic response [ ] . this reaction occurs from repeated exposure to a trigger and is referred to as the type hypersensitivity response [ ] . this increased th immunity upregulates eosinophilic inflammation, tissue damage, airway hyperresponsiveness, and bronchoconstriction [ ] . mast cell activation disorders, which is characterized by diseases and conditions related to mast cell mediators and the activation of mast cells, must also be considered when addressing allergic asthma [ ] . in contrast, nonallergic asthma can be caused by other factors such as anxiety, exercise, stress, dry air, cold air, viruses, hyperventilation, smoke, or other irritants [ ] . . inhaled cadmium (cd) is deposited in the alveoli where it is then absorbed into the bloodstream cd is transported to erythrocytes or bound to albumin, where it is then taken up by the liver to form a complex with metallothionein (mt) cd interferes with the absorption of zinc and competes for the same enzyme binding sites enzymatic activity of zinc-dependent enzymes reduces preferential binding of cd to mt can cause zinc deficiency altered biotransformation and excretion of ingested arsenic via contaminated water are linked to respiratory complications chronic inhalation of arsenic may result in irritation of respiratory tract diesel exhaust particles in particular have been associated with increase in cytokines such as il- , il- , and ige in nasal mucosa [ ] nitrogen dioxide is a free radical that is highly reactive and poorly water-soluble and can be deposited in the lungs when inhaled [ ] rising pollen and mold counts [ ] increasing ozone [ ] chemicals increased oxidative stress from inhaling cigarette smoke may activate the nf-kb inflammatory pathway, increasing the production of pro-inflammatory cytokines such as interleukin (il)- , il- , il- , tumor necrosis factor-ɑ(tnf-ɑ) cigarette smoke may reduce anti-inflammatory cytokines such as il- [ ] stress repeated acute stress may also affect growth and repair mechanisms [ ] ige and cytokine production, as well as respiratory inflammation, are markers that characterize the asthma response and have been shown to respond to stress in some capacity [ ] increased stress may increase susceptibility to air pollution given its effects on the inflammatory response [ ] ( individuals suffering from nonallergic asthma will tend to be less responsive to th -targeted treatments due to a differing immune response at play [ ] . some of the additional proposed phenotypes are eosinophilic, exacerbation-prone, exercise-induced, fixed obstruction/airflow limitation, poorly steroid-responsive, and adult-onset obesity-related [ ] . several of the proposed endotypes are summarized in . the american partnership for eosinophilic disorders defines eosinophilic asthma as a type of asthma characterized by especially high levels of eosinophils, more commonly developed later in adulthood, although may occur in some children [ ] . many with eosinophilic asthma do not have underlying allergies or history of allergic conditions such as eczema, food allergy, and hay fever, which are thought to be seen more in people with allergic asthma [ ] . in contrast to allergic asthma, the cause of eosinophilic asthma is still unknown. histamine intolerance must also be considered in assessing the root cause of asthma. ingesting histamine-rich foods and beverages such as bananas, grapes, strawberries, citrus fruits, tomatoes, nuts, chocolate, pineapples, fish, spinach, fermented foods, and beverages [ ] has been shown to provoke a histamine response that may result in asthma exacerbations, among many other potential signs and symptoms [ ] . disruptions in redox, or oxidation/reduction, reactions in addition to hindered antioxidant defense have been . usually not responsive to glucocorticoids [ ] based on data from ref. [ ] found to be a risk factor for asthma severity and development [ ] . the levels of glutathione, one of the lung's most predominant antioxidants in both reduced and unreduced forms, are thought to be important for lung homeostasis and tied to asthma [ ] . more research is needed to determine the exact differences in the pathophysiologies of the various subtypes of asthma in order to develop more targeted treatments. minerals such as zinc, selenium, copper, and manganese may serve as cofactors to major enzymes with antioxidant activity in the lung, such as superoxide dismutase, catalase, and glutathione peroxidase [ ] . asthma has been associated with decreased activity of these enzymes [ ] . low selenium intake has been associated with multiple chronic diseases including asthma [ ] . selenium serves as a cofactor to glutathione peroxidase, an enzyme with antioxidant activity in the lung that is responsible for maintaining gsh/gssg redox balance [ ] . imbalance between oxidants and antioxidants seems to serve an important role in asthma. levels of nonenzymatic antioxidants glutathione, ascorbic acid, alpha-tocopherol, lycopene, and beta-carotene, in addition to antioxidant enzymes superoxide dismutase (sod) and glutathione peroxidase, were significantly lower in asthmatic children compared to healthy controls [ ] . the amino acids glycine and glutamine, which are important in glutathione synthesis, were also found to be significantly lower in children with asthma [ ] . dha has also been found to be abundant in airway mucosa, where it is decreased in individuals with asthma and cystic fibrosis [ ] . magnesium is known to elicit the relaxation of bronchial smooth muscle, decrease responsiveness to histamine, have an anti-inflammatory effect, and decrease the susceptibility of animals to developing anaphylactic reactions [ ] . it is estimated that two-thirds of the population in the western world is not consuming the recommended daily allowance of magnesium [ ] . magnesium can be used intravenously as an effective treatment of acute asthma attacks. one double-blind controlled trial that used . g of magnesium sulfate when patients did not respond to treatment with beta-agonists found decreased likelihood of hospitalization and improved lung function [ ] . magnesium sulfate as an adjunct therapy with bronchodilators and steroids has also been shown to have a benefit in children with moderate to severe asthma [ ] . although the exact mechanism is not yet known, magnesium is thought to increase glutathione concentrations in the lung [ ] . more research is needed to determine additional associations between specific nutrients and asthma. however, optimization of the nutrients discussed in this section has the potential to reduce the severity and/or progression of asthma (. fig. . ) . asthma has a strong genetic component, with more than genes associated with it in varying degrees across many populations [ ] . more recent potential genetic associations include filaggrin, which encodes for the epithelial barrier; ormdl , which encodes transmembrane protein; beta- adrenergic receptor gene, expressed throughout smooth muscle and epithelial cells of the lung; and interleukin- receptor gene, which has a variant associated with elevated ige [ ] . a systematic review and meta-analysis showed that deficiencies in selenium, zinc, vitamins a, c, d, and e, and low fruit and vegetable intake could be associated with the development of asthma [ ] . although this data is tenuous due to lack of randomized controlled trials, it does give some indication of the relationship between nutrition status and dietary patterns with respect to asthma development. more research needs to be done to isolate the impact of these nutrients and dietary patterns on asthma prevention and development. a review conducted by berthon and wood noted the protective effects of the mediterranean diet for allergic respiratory diseases as evidenced by epidemiological studies. this diet emphasizes minimally processed plant foods in the form of fruit, vegetables, cereals, beans, breads, nuts, seeds, and olive oil and low to moderate intake of dairy, poultry, fish, and wine, as well as low intake of red meat [ ] . this association was the strongest in children, where the mediterranean diet had a protective effect on atopy, wheezing, and asthma symptoms [ ] . however, there is less data available to support this pattern in adults. the same review noted an association between the "western" diet, which emphasizes refined grains, red and cured meats, french fries, sweets and desserts, and highfat dairy products and increased risk of asthma in children [ ] . a meta-analysis and systematic review done in showed a reduction of risk in childhood wheezing with high fruit and vegetable intake and also showed negative association between fruit and vegetable intake and asthma risk in adults and children [ ] . in contrast, food allergy has been especially linked with allergic asthma in children [ ] . a study examining food allergy in asthmatic children identified higher serum levels of ige in asthmatic children compared to healthy controls, where all asthmatic children in the study were also identified as having a positive skin prick test (spt) to various food allergens [ ] . a study done on children under the age of diagnosed with asthma, with or without allergic rhinitis, was placed on a meat-based formula of carrots, beef, broccoli, and apricots for weeks. it was found that % had nearly complete resolution of symptoms [ ] . this same study also found that the most common food triggers were milk, egg, chocolate, soy, legumes, and grains [ ] . while food allergy as a cause of asthma is more common in children, hidden food allergy has been reported to be the root cause of asthma in around % of adults [ ] . improvement in respiratory symptoms was also seen in a small study of adults given an antigen-free elemental diet in a hospital setting [ ] . removal of food triggers has also been linked to improvement in exercise-induced asthma [ ] . identifying food allergies can be a complicated process because many of the testing methodologies such as skin prick tests (spts) and blood tests can yield false-positive results for up to - % of cases, according to the food allergy research & education organization [ ] . a food elimination diet and/or oral food challenge can be a powerful tool in determining food allergy specific to asthma symptoms, where a dietitian or nutritionist in conjunction with physician and/or allergist can serve an important role through this process to support the individual. oxidative stress may play a key role in the development of asthma, which can also be true for the development of chronic diseases such as cardiovascular disease, diabetes, and cancer [ ] . it has been shown that obesity may be a risk factor for people with and without allergy and may worsen pre-existing asthma [ ] . individuals with asthma are twice as likely to have gastroesophageal reflux disease (gerd) than people who do not have asthma, especially those resistant to treatment [ ] . celiac disease and asthma have also been linked. an italian cohort study was done that showed a significant association between treated asthma and celiac disease, where antibiotic exposure in the first year of life was controlled for and not found to contribute to this association [ ] . it has also been found that individuals with celiac disease following a glutenfree diet experienced improvement in asthma symptoms [ ] . it is well-known that toxic exposure to particulate matter, airborne pollutants, or cigarette smoke can trigger asthma symptoms [ ] . more specifically, a dose-dependent relationship between cigarette smoke exposure and rates of asthma has been shown [ ] . traffic density and asthma exacerbations have also been clearly demonstrated [ ] . certain medications may also serve as triggers to asthma. aspirin-exacerbated respiratory disease (aerd) is considered another asthma subtype caused by nonsteroidal anti-inflammatory drugs (nsaids) and is characterized by asthma, chronic rhinosinusitis, and acute respiratory reactions [ ] . in addition, overuse of antibiotics in childhood has been linked to asthma [ ] , indicating a connection between the microbiome and asthma development. allergic bronchopulmonary mycosis (abpm) noted in . table . is caused by a hypersensitivity reaction to fungal colonization of the airways [ ] . this is typically caused by the fungus aspergillus fumigatus. without treatment, this may lead to fixed airflow obstruction and bronchiectasis [ ] . the progression of asthma is complex and multifaceted, from preconception through childhood and adulthood. research suggests that early life events are largely predictive for regulatory mechanisms within the pulmonary immune system [ ] . for example, prenatal exposure to a farming environment, one rich in microbial compounds, is thought to influence innate immune patterning in the mother which may affect the development of the neonatal immune system [ ] . this influence in immune patterning can be seen through higher expression of toll-like receptors and and cd on peripheral blood cells, which implies possible desensitization to allergens in children [ ] . t regulatory cells, which serve an important role in immune regulation and are thought to play an important role in asthma by suppressing the th inflammatory response to harmless air particles, have been shown to be impaired in the cord blood of neonates at hereditary risk for allergy [ ] . in the study performed by singh et al. looking at serum ige and cutaneous sensitivity to food allergens in asthmatic children here was a negative correlation of total ige and duration of breastfeeding, indicating a connection between breastfeeding and the immune response [ ] . additionally, reduced maternal intake of vitamins d and e and zinc during pregnancy has been associated with increased asthma symptoms in children [ , ] . vitamin d has been associated with the maintenance and/or development of the t regulatory cells stated earlier in mice; however more research is needed to determine a definitive association in humans [ ] . a clinical trial performed on non-smoking asthmatic patients showed higher vitamin d levels were associated with greater lung function; furthermore, supplementation with vitamin d showed improved treatment response to glucocorticoids [ ] . vitamin d may also directly increase the antiinflammatory cytokine, interleukin (il)- and also enhance steroid-induced il- production (see . fig. . ) [ ] . more research is needed to determine the exact mechanism of vitamin d in asthma and respiratory disease. beta-agonists, combined with corticosteroids, serve as the primary conventional therapy [ ] . typically, a short-acting beta-agonist will first be prescribed to manage symptoms as needed, where low-dose inhaled corticosteroids may also be prescribed [ ] . if symptoms persist, it is recommended to evaluate problems such as adherence to use, inhaler technique, or persistent allergen exposure and comorbidities [ ] . once these are ruled out, the step-up treatment is a combination of an inhaled corticosteroid with a long-acting beta-agonist [ ] . a summary of other conventional treatments and their mechanisms can be found in . table . below. unfortunately, conventional methods for the treatment of asthma may have harmful side effects. for example, the use of . fig. . effect of asthma treatments on regulatory pathways. (reprinted from lloyd and hawrylowicz [ ] . with permission from elsevier) systemic glucocorticoids may lead to immunosuppression, cataracts, and osteoporosis, where long-acting beta-agonists have the potential of increasing asthma exacerbation risk and death [ ] . beta-agonist desensitization is thought to be one of the reasons for increasing asthma exacerbation risk and death [ ] . related to several subtypes of asthma and their differing pathophysiologies, it is important to first determine the subtype before deciding on treatment. for example, in an individual with allergic asthma, this could be a potentially simple fix once the allergen that exacerbates symptoms is identified. a more conventional approach may involve starting the individual on an inhaled corticosteroid or an ige antagonist (i.e., omalizumab) [ ] , rather than identifying the root cause of the patient's symptoms. while medications may be warranted until the trigger is identified, finding the underlying causes may not be common practice in many conventional settings. in contrast, the ifmnt assessment takes a much deeper dive into identifying triggers and any nutrient insufficiencies, inflammation or immune dysregulation, biochemical individuality, lifestyle, energy dysfunction, toxic load, sleep, and stress issues are taken into account. with this information, the practitioner can make more targeted dietary, lifestyle, and supplement recommendations to obtain sustained resolution of symptoms by treating the root cause (. table a -year-old female presented with a complaint of reactive airway disease, which was diagnosed as asthma and had been prescribed inhalers. she reported that she felt like she had difficulty breathing most of her life, especially when exercising. however, her condition was not severe enough to seek help until she was years of age. she reported a lot of stress during this time related to applying for a postgraduate training position. she also reported year prior to diagnosis developing new allergic symptoms. her past medical history was significant for conditions related to airways, including chronic sinus infections, strep throat, bronchitis, and recurrent pneumonia. she could not remember the last time she felt well but assumed it was sometime as a young child. her nutrition and health goals were to breathe better and to not have to rely on inhalers. the following data was collected on her initial visit. . methyl xanthine found in tea used less commonly due to side effects relaxes airways due to inhibition of phosphodiesterases; acts as a functional antagonist in airway smooth muscle [ ] based on data from ref. [ ] . table . summary of an integrative and functional medical nutrition therapy assessment adequacy of nutrient-dense foods to begin to assess nutritional status organic or nonorganic to assess toxic load and nutrient intake food preparation and processing to assess nutrient content and identify potential contaminants (e.g., plastic endocrine disruptors) assess food sensitivities or intolerances to identify potential triggers microbiome status: assess comprehensive digestive stool analysis for microbiology and fermented food intake; history of antibiotics or microbiota agonists (medications, toxins, stress, etc.) toxin intake via plastics or inhalation and skin absorption which may affect immune response assess flavonoids intake as they are antioxidant and anti-inflammatory compounds with mast cell inhibitory action; adequacy may reduce airway reactivity consider celiac disease and gluten intake as potential inflammatory antigens mineral assess and restore zinc, selenium, magnesium, manganese, iron, and iodine status to normal reference. caution to not supplement or intake of food sources higher than reference antioxidants assess and restore antioxidant balance; vitamins a, c, d, and e and glutathione assess quercetin intake (leafy vegetables, broccoli, red onions, peppers, apples, grapes, black and green tea, red wine) as it may act as mast-cell stabilizing agent inhibiting release of histamine, tnf-alpha release, formation of prostaglandin d , reducing interleukin production consider supplementation of quercetin if quercetin intake is low [ ] protein status assess and restore to support connective tissue and immune status ensure adequate glutamine and glycine intake oils/lipid/fatty acids assess fatty acid balance as dha important in lung tissue integrity assess adequate serum cholesterol and fat intake to support lipid bilayer important for cellular function in lung (epithelial cells, surfactant production, etc.) methylation assess methylation status and detoxification capacity of toxins related to asthma exacerbation; important assessment biomarkers suggested: mcv/mch, homocysteine, methylmalonic acid, rbc folate, genomic methylation snps inflammation/immune dysregulation assess asthma biomarkers to help identify root cause (see . fig. extreme exhaustion, depression, add, anxiety (accompanied by panic attacks), constipation, pain in legs, neuropathy in feet (numbness and tingling), rapid heartbeat, and a very severe rash on feet known as chilblains. utis -recurrent as a child. poor immune function (frequent infections). antibiotic use (very frequent from childhood into adulthood). sinus infections, strep throat, and bronchitis -she had recurrent sinus infections and strep throat about once a year every year and often this would lead to bronchitis, she could not remember if she had these issues before middle school. depression, anxiety, add. acne. peptic ulcers. yeast infections -multiple throughout college. eczema. two recent episodes of pneumonia the last episode resulted in her asthma diagnosis. asthma. evaluate exposure to fungus to identify allergic bronchopulmonary mycosis assess individual's medication history, considering short-and long-term use of conventional treatments evaluate exposure to particulate matter, airborne pollutants, cigarette smoke, or toxic metals such as cadmium and arsenic sleep and stress assess sleep adequacy ( - hours with -hour rem sleep) and quality (good sleep hygiene with little light/ sound/emf disturbance) to support detoxification of toxins that may worsen respiratory status and aid in repair of damaged lung tissue . periostin plays a role in the pathogenesis of allergic diseases, including asthma, as it is associated as a downstream molecule of the cytokine, il- . periostin is used as a biomarker for type immunity and can be used to determine the potential effectiveness of medications used to treat asthma, such as anti-ige antibodies and anti-il- antibodies. asthmatic patients with high serum periostin tend to be aspirin intolerant, eosinophilic, late asthma onset, and have a high nitric oxide fraction. high periostin can also indicate a reduced response to inhaled corticosteroids [ , ] . periostin in the right panel is stained brown and is localized in the thickened basement membrane in asthmatic patients. (reprinted from izuhara et al. [ ] . with permission from the korean academy of asthma, allergy and clinical immunology) for several weeks, led to being immobile for almost weeks th- th grade: was often sick (strep, sinus infections, bronchitis); described it as being constantly sick from fall through winter every year; also developed eating disorder during this time; had severe menstrual cramps (induced vomiting) accompanied by acne, which led to being put on birth control at age as a precursor to accutane (never prescribed); chronic constipation starting during this time university freshman -sophomore year: eating disorder was most severe during this time. first semester of freshman year: developed digestion issues, after eating certain foods (especially mexican or salsas), stomach would become distended, experienced pain, and often would result in vomiting. pain so severe during finals week she was admitted to er with no diagnosis. ct scan revealed possible peptic ulcers. junior-senior year: depression, anxiety, and inability to focus were most severe during this time which resulted in missing a lot of class and struggling as a student; suffered multiple panic attacks; gained a lot of weight (from to lb); end of senior year became engaged to be married -moved to dallas, tx. lived in dallas for months, continued to experience depression and anxiety and weight gain, and moved back to home state initially started running (~ miles a day) and experiencing inability to breathe, diagnosed with pneumonia, prescribed inhaler to help with running; other symptoms: eczema around the eyes and neck (after running outside), pain in calves, numbness and poor circulation in feet (pulse not detected by several health professionals), and development of chilblain rash (very painful, itching, lasts about - weeks from development to resolution); increased running -ran a half-marathon. visited pcp and several specialists for help with chilblain rash with no resolution or diagnosis; lost a lot of weight (from to lb). ongoing increased depression, anxiety, and inability to focus; pcp rx cymbalta (depression and anxiety); cymbalta discontinued after ~ months (did not tolerate side effects), continued psychological therapy for several months; chilblain rash continued. stopped running long distances. gained weight back (from to lb); subsequently saw blog for integrative rd and followed suggestion to eliminate gluten and focusing on whole foods diet. chilblains and eczema began to resolve while following integrative rd recommendations of gluten-free diet with some improvements. however, difficulty breathing got worse, and diagnosis of asthma was made with fast-acting inhaler used for exercise; as time progressed, breathing continued to worsen, led to daily inhaler use. weight at this time is still at around lb. high dairy diet (consumed dairy products at most meals and snacks), consumed three smaller meals with three snacks in between meals and snacks balanced with protein, fat, and carbs, with carbs coming from fruits and vegetables and fat mainly from full fat cheese, greek yogurt, and butter mostly nonorganic produce and commercially raised meats digestion, assimilation, and elimination hx of peptic ulcers and chronic constipation (bm ~ - times a month) bms currently at about × per week on encounter utilization, cellular, and molecular (mapdom) hx of likely gluten sensitivity. presented symptoms of possible dairy sensitivity (bloating, acne, asthma). evidence for compromised intestinal barrier. minerals: infrequent bms could indicate low fiber or low mineral status (mg); when bms do occur, they are hard and dry (low mg); severe menstrual cramps (low mg); labs showed low k and na, on yaz birth control (low zinc and low b vitamins). antioxidants: consumed adequate fruits and vegetables each day. protein: has some evidence of poor/slowed wound healing as evidenced by sore on leg that has not completely healed after a year; cuts that take months to heal. d and fat-soluble a, e, and k vitamins -hx of poor immune function (low d), vdr +/+ (low d and possibly a). oils/fatty acids: high omega- /omega- ratio, higher intake of damaged fats, very low intake of omega- . methylation: symptoms of depression, anxiety, add combined with mthfr c t snp and on yaz (low b and folate). eicosanoid fatty acids status -suspect issues with pge series pathway to control inflammation due to following signs and symptoms: allergies, autoimmune condition (asthma), peptic ulcers, eczema, and severe menstrual cramps immune function -suspect gut dysbiosis due to following s&s: poor immune function, yeast infections, hx frequent antibiotic use, cyst, and constipation body composition genetic makeup that indicated prone to gluten and dairy sensitivity, low vitamin d status, and impairment in methylation broad spectrum probiotic + fermented foods bioactive b complex (includes mg p p b and mcg thf) mg gla evening primrose oil and zinc . aim to eat three larger meals a day, allowing space in between of ~ hours; increase omega- intake by adding in small fatty fish, such as sardines or anchovies, once per week and taking fish oil; decrease omega- intake, switch from conventionally raised meats to organic, pasture-raised; and replace fat in diet from dairy with coconut sources, more nuts, and avocados. patient presented ~ months after the initial visit (september ). her breathing had improved immensely. she was able to stop taking her albuterol inhaler before exercise, recently stopped daily inhaler. after dairy-free diet for months, reintroduced dairy (cheese, butter, yogurt). asthmatic symptoms returned about - days after the addition of each. noticed the more dairy consumed, the worse her symptoms became. at time of appointment, diet whole foods, gluten-free, and dairy-free. weight loss lb within the first month of going dairy-free, continued to lose some weight. when reintroduced dairy symptoms of bloating and increase in weight, which resolved returning to dairyfree diet. bms are regular now at ~ × daily. this patient case followed some common patterns in the development of chronic disease and the comorbidities that are common, especially autoimmune conditions like asthma. the first is the genetic susceptibility of the individual; several snps are prone to dairy sensitivity. second, significant evidence for gut dysbiosis, promoted compromised gut barrier, can contribute to the development of dairy sensitivity. third is the exposure to dairy protein antigen. diet history evidenced trigger for asthmatic condition. additionally, inflammation, immune dysfunction, and methylation issues present. signs and symptoms significant for decrease in pge series anti-inflammatory pathways. low dietary omega- s potential contributor to asthma. immune dysfunction evidenced by extensive history of infection-antibiotic use. genomic snp mthfr c t gene, which indicated a greater need for folate. the use of yaz birth control and symptoms of depression, anxiety, and add known further to deplete b and folate. the diet and supplements recommended targeted control of inflammation, restore gut ecology, promote proper methylation, and replete nutrient insufficiencies. results from -month follow-up showed successful outcome in helping improve breathing and wean her off of inhalers. this case is an example of the ifmnt approach able to address the complexity of the whole patient story and bring the metabolic priorities into a manageable intervention program for the individual. one study found that the composition of the nasopharyngeal microbiota in children was linked to the frequency of upper respiratory tract infections and acute sinusitis [ ] . a study that intranasally inoculated mice with lactobacillus fermentum reduced the amount of s. pneumoniae in the respiratory tract and increased the number of macrophages in the lung and lymphocytes in the trachea [ ] . these findings may indicate a benefit of manipulating the upper respiratory tract microbiota with orally or nasally administered probiotics in the prevention and/or treatment of upper respiratory tract infections. allergic bronchopulmonary mycosis (abpm) is caused by a hypersensitivity reaction to fungal colonization of the airways. this is typically caused by the fungus aspergillus fumigatus. without treatment this may lead to fixed airflow obstruction and bronchiectasis [ ] . guillain-barre syndrome (gbs) is a rare neurological disorder in which the body's immune system attacks the peripheral nervous system, known as the network of nerves located outside of the brain and spinal cord [ ] . it is often preceded by a bacterial or viral infection. there are several potential mechanisms in which these infections trigger gbs. if an individual contracts a campylobacter jejuni bacterial infection, antibodies made to fight this infection can attack axons in motor nerves, which can potentially cause paralysis and respiratory failure [ ] . campylobacter can be ingested via contaminated food or other exposures [ ] . pérez-guzmán states that hypocholesterolemia is common among tuberculosis patients and suggests that cholesterol should be used as a complementary measure in antitubercular treatment [ ] . alpha- antitrypsin (a at) deficiency is an underrecognized disease in the united states, with around documented , people suffering from it, according to the alpha- foundation. this deficiency is inherited through autosomal codominant transmission, meaning affected individuals have inherited an abnormal aat gene from each parent [ ] . individuals with this deficient allele present with aat levels at less than % to low-end normal levels [ ] . however, it is also possible for individuals with a variant of this allele to be asymptomatic given different environmental conditions or lifestyle factors, such as refraining from smoking to reduce lung disease development risk [ ] ( box . ). a at deficiency most often manifests in the lungs as chronic obstructive pulmonary disease (copd) (i.e., emphysema or bronchiectasis or "genetic copd"). a at deficiency is often undiagnosed because people with genetic copd experience the same symptoms as people with copd, such as [ ] : shortness of breath wheezing the only way you will know for sure if you have genetic copd due to alpha- is to get tested. ________ a at deficiency can manifest in the liver as cirrhosis. symptoms related to the liver unexplained liver disease or elevated liver enzymes eyes and skin turning yellow (jaundice) swelling of the abdomen (ascites) or legs vomiting blood (from enlarged veins in the esophagus or stomach) a at expresses sometimes in the skin as panniculitis [ ] . panniculitis typically appears as raised red spots on the skin, which may break down and give off an oily discharge. while panniculitis spots (called nodules) may appear anywhere on the body, the most common places are the thighs, buttocks, and areas subject to injury or pressure. normal genotype m m most common abnormal genes are called s and z abnormal variant combinations: zz (highest risk) sz (lower risk increasing if smoker, inhalant pollutants) mz (lower risk of carrying an a at gene variant; considered "carriers") alpha- is the most commonly known genetic risk factor for emphysema up to % of all people diagnosed with copd may have undetected alpha- alpha- can also lead to liver disease. the most serious liver diseases are cirrhosis and liver cancer the world health organization (who), american thoracic society (ats), and the european respiratory society (ers) recommend that everyone with copd be tested for alpha- alpha- is a progressive disease that benefits from early detection. it can cause serious lung diseases, such as copd and emphysema when undiagnosed. in some cases, alpha- can also cause liver disease [ ] symptoms related to the lung [ ] : shortness of breath wheezing chronic bronchitis, which is cough and sputum (phlegm) production that lasts for a long time recurring chest colds less exercise tolerance year-round allergies bronchiectasis the alpha- antitrypsin (a at) protein protects the body, especially fragile lung tissues, from the damaging effects of a powerful enzyme called neutrophil elastase that is released from white blood cells. in a at deficiency, a genetic mutation reduces levels of the protective protein in the bloodstream. a at deficiency can lead to chronic obstructive pulmonary disease (copd), specifically emphysema, and liver disease. smoking, which can inhibit what little a at protein an affected person does have, increases the risk of lung disease. alpha- antitrypsin deficiency is completely determined by mutations in a single gene. the severity of symptoms is mostly a function of which mutations a person has and how many copies. however, smoking can greatly increase the risk of lung disease due to aat mutations. andme reports data only for the pi * m, pi * s, and pi * z versions of the gene that encodes aat. keep in mind that it is possible to have another mutation that causes this condition that is not included in this report [ ] . a at deficiency is a genetic disorder that reduces circulating levels of a protein that protects the lungs by trapping a at in the liver, where the protein is produced, and prevents a at from entering circulation. a at deficiency can lead to chronic obstructive pulmonary disease (copd), specifically emphysema, and liver disease. when a disease-causing mutation is fairly common, as the pi * s and pi * z mutations are in europeans, it suggests that the mutation actually conferred an evolutionary advantage at one time. some researchers have suggested that several thousand years ago when the pi * z and pi * s mutations first arose, these versions of the gene for a at gave people a survival advantage by creating an environment in their lungs that helped fight off infections. the scientists theorize that the antimicrobial benefits of the aat mutations outweighed the cost of an increased risk of copd and liver disease in the era before antibiotics were available [ ] . in contrast to lung disease, manifestation of liver disease related to a at can be referred to as a "toxic gain of function, " due to accumulation of mutant a at protein rather than protease deficiency within the liver [ ] . when taken together, fibrotic lung diseases are the leading cause of mortality worldwide. under the umbrella of interstitial lung disease (ild), pulmonary fibrosis (pf) is the most common. any ild that involves scarring of the lungs falls in the pulmonary fibrosis category. pulmonary fibrosis is the scarring of lungs, which destroys tissue over time, making it impossible to transfer oxygen from inhaled air into the bloodstream. there are more than different diseases under the pulmonary fibrosis umbrella. because pf is often misdiagnosed or goes undiagnosed, there is not an accurate count of those with these diseases. however, it is estimated that as many as in adults over , or , people in the united states, are affected [ ] . there are more than , deaths from ipf every year in the united states. more people die each year from idiopathic pulmonary fibrosis than from breast cancer [ ] . there are other forms of interstitial lung disease including the newly identified pleuroparenchymal fibroelastosis, cryptogenic organizing pneumonia (cop), desquamative interstitial pneumonitis, nonspecific interstitial pneumonitis, hypersensitivity pneumonitis, acute interstitial pneumonitis, interstitial pneumonia, sarcoidosis, and asbestosis [ ] . symptoms include cough and dyspnea, restrictive pulmonary function tests with impaired gas exchange, and progressive lung scarring. the disease progresses with an initiation of inflammation. fibrosing starts with the action of transforming growth factor-β (tgf-β)-dependent differentiation of fibroblasts to myofibroblasts, which then express α-sma (smooth muscle actin) [ ] . after the tgf-β-dependent differentiation of fibroblasts to myofibroblasts, which express α-sma, there is sustained, excessive deposition of collagen by the myofibroblasts in the lung interstitium leading to the progressive lung damage in patients with pf [ ] . research published in supported the idea that dysfunctional type ii aecs (alveolar epithelial cells) facilitate lung fibrosis through increased susceptibility to injury, leading to excessive and dysregulated remodeling [ ] . the disease seems to progress in steps, and inflammation is not typically present continuously, except during certain periodic episodes of deterioration (. fig. . ). there are five main categories of pf causes: drug-induced, radiation-induced, environmental, autoimmune, and occupational. of these five, four have identifiable causes. some of the autoimmune diseases that can lead to pf are rheumatoid arthritis, scleroderma, sjogren's syndrome, polymyositis, dermatomyositis, and antisynthetase syndrome. idiopathic pulmonary fibrosis (ilp) is defined as pf with an unknown cause, including a genetic cause for some families [see . fig. . ]. the symptoms of ilp are a dry, hacking cough, shortness of breath, fatigue, chest discomfort, loss of appetite, and unexplained weight loss, all caused by the fibrosing of the lungs. diagnosis can be difficult, and pf is often misdiagnosed as copd or other more common lung diseases. in addition, in the recent past, path to a true diagnosis was invasive. since damage to the lungs, even through a diagnostic biopsy, can trigger further lung damage or a period of fibrosis, many physicians or patients are cautious with a biopsy approach to diagnosis. since the current treatments are limited, one must evaluate whether defining the exact form of pf is necessary for treatment and follow-up. difficulty breathing, crackling sounds while breathing, and low oxygen levels are the first indicators. clubbed fingernails may also be a symptom. high-resolution ct scans are performed, which can show scarring. the pulmonologist will ask many questions and order more blood tests to try to distinguish between the forms of pf. the future is pointing to molecular endotyping as a more accurate way to diagnose. molecular endotyping includes genetic, metabolic, transcriptional, and environmental factors to help determine the pathophysiology [ ] . genetic research has been progressing for a couple decades with illuminating results. there are more than a dozen genetic variants that have been associated with this family of diseases. researchers now believe at least % of idiopathic pulmonary fibrosis (ipf) patients with multiple family members suffering from ipf have some common familial genetic variants, which may allow researchers to eventually drop the term idiopathic and further define various forms or categories, with differing progression or outcome. the name given to this version of interstitial pneumonias is familial interstitial pneumonia (fip) [ ] [see . currently two categories of genetic focus have been defined: those genes related to telomere biology (shorter telomeres) and those related to surfactant protein processing. the genes related to shorter telomeres are tert, terc, htr, dkc , and rtel . more mutations have been found in the tert gene, which encodes the protein component of telomerase, than any other gene. further research may allow targeted therapies to affect the genetic expression associated with the development of ipf [ , ] . a common variant within the promoter of the muc b gene is the most replicated single-nucleotide polymorphism related to familial and sporadic forms of ipf as well as early radiographic findings of ipf [ ] (. figs. . and . ). wound contraction and re-epithelialization . fig. . the cellular and molecular mechanisms of fibrosis in multiple organs. the cellular and molecular mechanisms of fibrosis in multiple organs. once an injury occurs in an organ, epithelial and/or endothelial cells are impaired, which results in the release of chemokines and growth factors, including il- and tgf-b . macrophages and monocytes are recruited and activated, both of which further release cytokines and chemokines and further induce fibroblast activation. activated fibroblasts transform into a-sma-expressing myofibroblasts and migrate into the wound along the fibrin lattice. ecm is excessively accumulated, and some parenchymal cells (hepatic stellate cells in the liver, tubular epithelial cells in the kidney, alveolar epithelial cells in the lung, or cardiomyocytes in the heart) are further differentiated into myofibroblasts or fibroblasts by the stimulation of cytokines and chemokines, especially for tgf-b . after the inflammatory phase, two events occur. one is the regeneration of injured tissues followed by wound contraction and reepithelialization. in contrast, once chronic injury, inflammation, and necrosis occur, myofibroblasts are perpetually activated, and excessive ecm is deposited, finally resulting in fibrosis formation. ctgf, connective tissue growth factor; ecm, extracellular matrix; egf, epidermal growth factor; emt, epithelial-mesenchymal transition; hsc, hepatic stellate cell; il, interleukin; mmp, matrix metalloproteinase; tgf, transforming growth factor; timp, tissue inhibitors of metalloproteinase. (reprinted from chen et al. [ ] . with permission from elsevier) conventional treatment is typically palliative. the american thoracic society recognizes that supplemental oxygen and transplantation are the only suggested treatments for ipf. supplemental oxygen is prescribed, and the need for oxygen increases over the progression of the disease. keeping the oxygen saturation level over % (normal is in the upper s) is ideal and is how healthcare providers determine the level of supplemental oxygen to be used. cardiovascular exercise, in this case called pulmonary rehabilitation, is recommended to maintain as much use of the lungs as possible. infrequently, nutrition and counseling are recommended and are placed into the category of symptom management. nutrition can have a significant role in the management of this disease, but little implementation exists in some of the proposed protocols. there are currently two medications available in the united states with minor impact on the disease progression: nintedanib (commonly called ofev) and pirfenidone (esbriet). histopathological quantification showed similar amounts of dense collagen fibrosis, fibroblast foci, and alveolar macrophages in untreated or pirfenidone-or nintedanibtreated ipf patients [ ] . both have significant side effects, including fatigue and gi issues, and patients may have to evaluate their quality of life versus length of life. other antiinflammatories or immune-suppressing medications used are corticosteroids, mycophenolate mofetil/mycophenolic acid (cellcept®), or azathioprine (imuran®). immunesuppressing drugs may be harmful for those with short telomeres, and researchers are exploring this potentially contradictory recommendation [ ] . lung transplantation is a final effort. about is half of all transplants. with the prevalence of this disease closer to , , this is a small fraction of those with the disease. some of those with the transplant go on to live productive lives, while others develop pf again, in the transplanted lungs. overall, there is a shorter life expectancy in those with pf, because of telomere shortening. bone marrow or immune response abnormalities have been found in some ipf cases before and after lung transplantation, which increases the associated morbidity. as stated above, inflammation occurs at the beginning and throughout the progression of all fibrosing diseases, including those of the lungs. therefore, reducing inflammation is one wise strategy to slow fibrosing. there are several nutrients that can help slow or reverse the inflammation involved in the fibrosing process. the following two-part diagram shows where in the fibrosing pathogenesis each phytonutrient acts [ ] (. fig. . ). a few of those compounds are discussed in more detail here. curcumin, the active constituent in the common spice turmeric, has been shown to reduce fibrotic activity in several studies. in mice, curcumin inhibited collagen secretion of ipf fibroblasts. it affects the signaling of tgf-β, in a dosespecific manner, resulting in reduced expression of α-sma, which is responsible for inappropriate fibrosing. this was shown in vitro and in vivo in mice, with intraperitoneal, but not oral, administration. at the time of the study, oral ingestion of curcumin was not adequately absorbed into plasma, and there was greater than ten times plasma concentration of curcumin following an intraperitoneal injection [ ] . however, some new oral products on the market are showing greater absorption. the results of this study suggest more research into curcumin, including improved delivery into patients. for example, some delivery options may include nebulized curcumin directly into the lungs, binding it to highly absorbable agents for oral use or liposome-encapsulated curcumin suitable for intravenous use (already shown to be effective in an animal model). according to manufacturers of curcumin products, some are more readily absorbed than others. one study on fibrosing suggested that a dose of around mg curcumin split into three doses taken with meals including pepper (bioperine) achieved doses that were sufficient to exert the desired therapeutic effect. research into using quercetin also has some promising results in slowing the progression of ipf. quercetin reversed lung fibrosing in mice and reversed the disease progression normally caused by typical pulmonary senescence markers [ ] . it is worth mentioning that n-acetylcysteine (nac), a long-used therapeutic agent for breaking down mucus in the lungs, has not been found to be effective in those with ipf. in fact, due to its acidic nature, it has even been shown to be harmful when used in the inhaled form [ ] . several of the drugs being developed have a natural product as a model or foundation. until a drug or gene therapy is developed that stops or reverses this disease, it may make sense for the patient to focus on anti-inflammation and reducing myofibroblast activation, the extracellular matrix (ecm) accumulation, and the epithelial-mesenchymal transition (emt) process. the phytochemicals listed in . fig. . would be good ones to investigate. with the recent identification of genes associated with ild, a call for gene-related therapies both related to telomere lengthening and connective tissue disease has been initiated, and this type of therapy, as with any disease, could be personalized [ ] . one recent study looked at various biomarker values as a more precise way of diagnosing. the biomarker molecules were classified according to their involvement into alveolar epithelial cell injury, fibroproliferation, and matrix remodeling as well as immune regulation. furthermore, genetic variants of tollip, muc- b, and other genes associated with a differential response to treatment and with the development and/or the prognosis of ipf were identified. research into personalized medicine for treatment is starting [ ] . although controversial, because of the lack of research on interpretation of the results, telomere length testing is available directly to consumers and through healthcare . fig. . antifibrosis therapy. the molecular mechanisms and therapeutic targets of natural products against fibrosis. a tgf-b exerts a profibrotic effect through smad-dependent [target ( )] and smadindependent pathways [target ( ) ]. in the smad-dependent pathway, tgf-b directly phosphorylates and activates the downstream mediator smad and smad through tgf-b receptor i, and then smad and smad bind smad , which forms a complex that moves into the nucleus and initiates gene transcription. smad , transcribed by smad , is a negative regulator of tgf-b/smad signaling, and the imbalance between smad and smad contributes to fibrosis. pi k, erk, and p mapk are downstream mediators of the smad-independent tgf-b pathway. pparg [target ( )] could inhibit tgf-b to reduce fibrosis, while ctgf [target ( )], a matricellular protein, contributes to wound healing and virtually all fibrotic pathology. additionally, gas contributes to fibrosis through the tam receptor, which further activates the pi k/akt pathway. similarly, lpa triggers fibrosis through the lpa receptor [target ( ) ] that stimulates b-catenin to induce fibrogenesis. the activation of the hedgehog pathway [target ( ) ] induces the transcriptional activity of gli to express target genes, which have an important role in interstitial fibrosis, undergoing myofibroblast transformation and proliferation. il pathway [target ( ) ] stimulates nf-kb [target ( ) ] to activate tgf-b to induce fibrogenesis, while nrf [target ( ) ] antagonizes nf-kb activity to protect against fibrosis. b the chemical structures of isolated compounds and their therapeutic targets are presented. ctgf, connective tissue growth factor; il, interleukin; lrp, low-density lipoprotein receptor-related protein; ri, transforming growth factor-b receptor i; rii, transforming growth factor-b receptor ii; sara, smad anchor for receptor activation; stat, signal transducer and activator of transcription; tcf, t-cell factor; tgf, transforming growth factor. (reprinted from chen et al. [ ] practitioners. there are a few different methods: quantitative polymerase chain reaction, or qpcr, which has a % variability rate, and flow cytometry and fluorescent in situ hybridization, or flow-fish, which has a % variability rate. most research labs use flow-fish for research. telomere length is a hot topic in research, the antiaging industry, and with popular health blogs. shorter-thanaverage telomeres have also been linked to heart disease and heart failure [ , , ] , cancer [ ] , diabetes [ ] , and osteoporosis [ ] . research has shown ways to slow telomere shortening. some include reducing stress, meditation, practicing loving kindness (a technique encouraging compassion) [ ] , reducing exposure to air pollution and toxins [ ] , cardiovascular exercise [ ] , and a healthy fat and high vegetable diet [ , ] . one study showed that minutes of cardiovascular exercise three times per week resulted in longer telomeres representing years of biological age, similar to those of marathon runners, compared to those who didn't exercise much or at all [ ] . intermittent fasting, which reduces oxidative stress and keeps weight in check, has exploded in the scientific literature as a way to increase longevity and slow telomere shortening [ , ] . nicotinamide adenine dinucleotide (nad+) supplements may also help maintain telomere length by activating sirtuins, the antiaging enzymes; parps, which are involved in dna repair; and cd , which plays a role in insulin production. another supplement, cycloastragenol, derived from the herb astragalus, has also been shown to activate telomerase in mice. an ingredient called ta- has been derived and is used in supplements [ ] . overall, a healthy lifestyle and diet seem to delay the shortening of telomeres. with relation to pf, the gene mutations involved in telomere shortening may or may not be influenced by the above interventions. more research is needed for this. pulmonary fibrosis is a devastating disease with no management or a known cure. the integrative and functional medicine nutritionist can help her/his patient by managing weight, encouraging a healthy diet full of anti-inflammatory foods and encouraging a healthy lifestyle with exercise and stress reduction. there is some promising research into natural supplement use to target the different areas of progression within the disease process and some ongoing drug and gene therapy development to follow. the prevalence of lung disease in the united states and worldwide is growing and will continue to grow rapidly with the deterioration of earth's atmosphere, which is caused by pollutants such as industrial and construction toxins and volcanic and wildfire particulates. poor maternal, childhood, and adult nutrition from micronutrient-poor diets resulting in nutrient insufficiencies, not necessarily nutrient deficiencies, is also contributing to increased lung disease diagnoses or poorer results during treatment [ , ] . lifestyle choices and habits also play a role in the development of many of the lung diseases in today's world, such as smoking or vaping, which uses chemicals that are poorly studied to date. other lung diseases have their roots in genetics. some key processes drive many lung diseases, with the inflammatory process being the most important, according to current literature. nutrition can be of great help with inflammation, using a diet rich in whole foods providing micronutrients and phytonutrients. understanding genetics is also key to unraveling the causes and potential future treatments for many lung diseases. those patients with both genetic and environmental determinants, such as in those who smoke and have genes associated with copd, are at the greatest risk [ ] . despite the prevalence of lung disease, there is a general lack of nutrition knowledge among practitioners, including familiarity with the research about the use of nutrition for prevention, slowing disease progression, or as a treatment of lung disease. historically, nutrition has been used in a supportive role, primarily monitoring macronutrients to prevent weight loss, muscle atrophy, and acid/alkaline balance. although this is extremely important, more attention needs to be directed toward emphasizing micronutrients and phytonutrients. research is strong regarding the benefits of vitamins, minerals, and pre-and probiotics, and indeed, some integrative and functional practitioners are using vitamin and mineral nutritional therapy in oral, intramuscular, and intravenous applications, when allowed, in practice. a newer area of research is around nutraceuticals, including targeted vitamins, minerals, and plantderived constituents concentrated to therapeutic doses. some exciting research around the use of curcumin and quercetin, for example, has been shown to dampen inflammation to the point of disrupting the disease process (see above). the expanding knowledge of the microbiome is identifying the importance of the lung 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antitrypsin deficiency diagnosis assessment of quality of life in children suffered from asthma identifying maternal conditions affecting altered embryologic development. neonatal advanced practice nursing: a case-based learning approach susceptibility for cigarette smoke-induced damp release and damp-induced inflammation in copd key: cord- - r fpmlb authors: foccillo, giampiero title: the infections causing acute respiratory failure in elderly patients date: - - journal: ventilatory support and oxygen therapy in elder, palliative and end-of-life care patients doi: . / - - - - _ sha: doc_id: cord_uid: r fpmlb the immune system of older individuals declines with advancing age (“immunosenescence”) increasing susceptibility to infection, as well as to an increased risk of a worse outcome. severe community-acquired pneumonia and acute exacerbations of chronic obstructive pulmonary disease (aecopd) are causes of acute respiratory failure (arf) in elderly patients. non-invasive mechanical ventilation (niv) is effective in the treatment of patients with arf, above all in case of aecopd. aging is accompanied by profound morphological and physiological alterations. in particular, the immune system undergoes a complex series of remodeling/restructuring events, involving almost all compartments, both cell-mediated immunity and humoral immune responses. this process termed immunosenescence or immune dysregulation, together changes in lung function who occur with advancing age, play a critical role in the manifestation of age-related pulmonary diseases such as infections (i.e., pneumonia), chronic obstructive pulmonary disease (copd), and increased the risk for develop sepsis [ ] . respiratory failure is not a disease per se but a consequence of the problems that interfere with the ability to breathe. the term refers to the inability to perform adequately the fundamental functions of respiration: to deliver oxygen to the blood and to eliminate carbon dioxide from it. respiratory failure has many causes and can come on abruptly (acute respiratory failure), when the underlying cause progresses rapidly, or slowly (chronic respiratory failure), when it is associated over months or even years with a progressive underlying process. triggering causes of arf in advanced aged patients are especially acute heart decompensation, severe community-acquired pneumonia (cap), acute exacerbations of copd (aecopd), and pulmonary embolism. pneumothorax, lung cancer, severe sepsis, and acute asthma were less frequent (< %) [ ] . acute respiratory failure is a condition in which the respiratory system fails in one or both of its gas functions, i.e., oxygenation (pao < mmhg) of and/or elimination of carbon dioxide (arterial carbon dioxide tension (paco ) > mmhg). in practice, it may be classified as either hypoxemic or hypercapnic. hypoxemic respiratory failure (type i) is characterized by an arterial oxygen tension (pao ) lower than mm hg with a normal or low arterial carbon dioxide tension (paco ). this is the most common form of respiratory failure, and it can be associated with virtually all acute diseases of the lung, which generally involve fluid filling or collapse of alveolar units. the four pathophysiological mechanisms related to hypoxemic arf are [ , ] : . ventilation/perfusion inequality which is the main mechanisms in an emergency setting (congestive heart failure or pneumonia) . increased shunt (acute respiratory distress syndrome) . alveolar hypoventilation (chronic obstructive pulmonary disease) . diffusion impairment (pulmonary fibrosis) hypercapnic respiratory failure (type ii) is characterized by a paco higher than mmhg. hypoxemia is common in patients with hypercapnic respiratory failure who are breathing room air. common etiologies include drug overdose, neuromuscular disease, chest wall abnormalities, and severe airway disorders (e.g., chronic obstructive pulmonary disease). in case of a copd exacerbation, an acute inflammation in the airways increases resistance to air flow with consequent air trapping. increased resistance and elastic load due to air trapping place respiratory muscles at a mechanical disadvantage and increases the work of breathing and leads to arf. infectious factor such as pneumonia with/without sepsis caused by a variety of pathogens, including bacteria, viruses, malaria, and fungal is the medical condition that is most commonly associated with acute respiratory distress syndrome (ards). sepsis due to nonpulmonary infections, aspiration of gastric contents, and major trauma with shock also commonly precipitate the injury [ ] . since the same kinds of immune cells and immune proteins, including immunoglobulins and complements, are observed in the pathologic lesions of pneumonia, ards, and other organ-specific pathologic lesions, it may be a reasonable assumption that sepsis and ards have similar underlying mechanisms, characterized by inflammation and endothelial dysfunction [ ] . ards is a heterogeneous syndrome characterized by increased permeability of pulmonary capillary endothelial cells and alveolar epithelial cells, leading to hypoxemia that is refractory to usual oxygen therapy [ ] . the severity of ards is associated with poor prognosis and higher mortality, and, by the berlin definition, diagnostic hypoxemia is defined as decreased arterial pao /fio ratio with parameters of - mmhg for mild ards, - mmhg for moderate ards, and < mmhg for severe ards [ ] . considering the immunopathogenesis of pneumonia, sepsis, and ards, early and appropriate antimicrobial therapy is critical to reduce the number of pathogens and pathogen-originated substances, thereby inducing early recovery from the disease and better outcome. similarly, although the knowledge about the effectiveness of antibiotics in the management of acute exacerbations of copd remains limited by the lack of strong evidence, studies show that early antibiotic administration is associated with improved outcomes among patients hospitalized for acute exacerbations of copd [ ] . furthermore inadequate antibiotic therapy, which through incomplete resolution of the initial exacerbation and persistent bacterial infection, is likely to influence the risk of relapse. exacerbations of chronic obstructive pulmonary disease (copd) are defined as sustained worsening of a patient's condition beyond normal day-to-day variations that is acute in onset, and that may also require a change in medication and/or hospitalization [ ] . an acute copd exacerbation can be viewed as an acute inflammatory event superimposed on chronic inflammation associated with copd. most aecopd may be due to viral infection or bacterial infection ( %), but irritants such as smoke or environmental factors such as low temperature and air pollution account for - % of exacerbations [ ] . in patients with mild disease, streptococcus pneumoniae, haemophilus influenzae, and moraxella catarrhalis are the predominant microorganisms, whereas in patients with severe copd, requiring mechanical ventilation, levels of these bacteria are reduced and other microorganism such as haemophilus parainfluenzae and pseudomonas aeruginosa predominate. it has also been observed that the severity of lung function, measured by fev , has an impact on the microbiology of exacerbation [ ] . patients with increased airway obstruction and frequent exacerbations, the microbiology of the exacerbations is often more complex, with a predominance of enterobacteriaceae and pseudomonas aeruginosa. the role of atypical microorganisms is the subject of debate. according to some authors, there is no association between the presence of organisms such as chlamydia pneumoniae, legionella spp., mycoplasma pneumoniae, and aecopd [ ] . however, in aecb, several older studies and a few recent studies have implicated atypical bacteria in only - % of episodes [ ] . although it is difficult to define precisely the proportion of exacerbations caused by viruses, they are often implicated in aecopd (up to % of cases) [ ] . the most common viruses associated with exacerbations of copd are rhinoviruses, but in more severe exacerbations requiring hospitalization, influenza virus is more common. viral infection may, also, facilitate subsequent bacterial infection or increase the number of bacteria already present in the lower airways. the use of antibiotics in exacerbations copd remains controversial; therefore, in the era of antibiotic resistance, the identification of clinical characteristics that identify patients with aecopd that can be safely treated without antibiotics is extremely important. there is evidence supporting the use antibiotics in exacerbations when patients have clinical signs of a bacterial infection, e.g., increased sputum purulence, especially when there are changes in the color of sputum [ ] . antibiotics are also recommended for patients with exacerbations requiring mechanical ventilation, as this has been shown significantly to reduce mortality and the risk of secondary pneumonia. in summary, antibiotics should be given to patients with exacerbations of copd who have three cardinal symptoms: increase in dyspnea, sputum volume, and sputum purulence; have two of the cardinal symptoms if increased purulence of sputum is one of the two symptoms; or require mechanical ventilation (invasive or non-invasive) [ ] . (table . after the decision to initiate empirical antibiotic therapy, the choice of empirical antibiotic regimen most appropriate for treating an episode of aecopd should be based on the following: . the severity of copd, established by fev and the history of more than three exacerbations in the previous months. . the patients age (≥ or < years). . significant comorbidity (diabetes mellitus, liver cirrhosis, chronic renal failure, or heart disease). . the risk of infection due to p. aeruginosa, which must be considered in the presence of two of the following risk factors: recent hospitalization, frequent (> times/year) or recent (within the previous months) administration of antibiotics, severe disease (fev < %), or the use of oral corticosteroids (> mg of prednisone daily in the previous weeks). between % and % of patients with moderate to severe exacerbations do not respond to initial empirical therapy and require a change of antibiotic. in these cases, the infection can be caused by staphylococcus aureus, p. aeruginosa, or some atypical microorganism not covered by the initial regimen or because of resistant organisms (such as s. pneumoniae); hence, a microbiological assessment would help to adjust the antibiotic treatment of second choice [ ] . there are not enough data concerning the role of antiviral therapy in respiratory failure due to copd. there are no standard procedures that determine the dose and duration of antibiotic treatment in patients with aecopd. therefore, several studies demonstrate that short-term antibiotic use is associated with very important advantages such as reduction of exposure that will result in decreased bacterial resistance, enhanced compliance, and decreased side effects. the recommended length of antibiotics therapy is - days [ ]. the incidence of community-acquired pneumonia increases with age, reaching - cases per inhabitants/year in the population over the age of years, up to four times that of younger patients [ ] . elderly patients are more predisposed to pneumonia because of their impaired gag reflex, decreased mucociliary function, waning immunity, impaired febrile response, and chronic disease (diabetes mellitus, chronic obstructive pulmonary disease, chronic heart failure, cancer and chronic renal insufficiency). furthermore, central nervous system disorders and/or an impaired gag reflex predispose elderly patients to aspiration pneumonia. with respect to the youngest population, pneumonia in the elderly subjects is more severe, requires often hospitalization, and is characterized by a longer length of stay and by greater mortality, particularly in patients with comorbidities [ ] . it is important to remember that clinical presentation of pneumonia in the elderly may be subtle and may be afebrile. altered mental status, a sudden decline in functional capacity, worsening of underlying diseases, and falls may be the only findings. as stated by sir william osler [ ] "in old age, pneumonia may be latent, coming on without chill, the cough and expectoration are slight, the physical signs ill defined and changeable, and the constitutional symptoms out of all proportion." as with any infectious disease, identifying the causative agent in cap can be extremely useful in guiding antimicrobial therapy. unfortunately, despite the use of more sensitive and specific diagnostic methods to define an etiologic pathogen in community-acquired pneumonia requiring hospitalization, in the majority of patients, a microbiologic diagnosis cannot be made [ ] . in most cases, the microbiologic patterns observed in the elderly do not differ significantly from those observed in younger populations although with a different age-related distribution. streptococcus pneumoniae is still the most important pathogen in younger as well as older adults and the incidence of pneumococcal pneumonia generally increases with age. haemophilus influenzae is relatively more common in elderly patients than in non-elderly adults and are the second most frequently identified microorganisms, while moraxella catarrhalis is of particular importance as a cause of community-acquired pneumonia in patients with chronic bronchitis. the most discernible differences between the two groups were gram-negatives, especially enterobacteriaceae were found more frequently in the elderly, whereas certain atypical pathogens (legionella pneumophila, mycoplasma pneumoniae, and coxiella burnetii) were more frequent in younger patient [ ] . among the atypical bacteria, chlamydophila pneumoniae is the most common agent, while mycoplasma pneumoniae is less frequently associated with cap in this age group. although uncommon, legionella pneumophila should be considered in elderly adults presenting with atypical symptoms (e.g., headache, weakness, altered mental status, gastrointestinal disturbances, or bradycardia in the setting of a paucity of respiratory symptoms) or those with severe pneumonia. gram-negative organisms are an uncommon cause of cap. however, in severely debilitated or chronically ill elderly patients from the community, a high index of suspicion for gram-negative bacilli may be warranted, especially in those who fail to improve on standard therapy. the probability of mrsa in patients hospitalized in conventional wards is low being more frequent in severe cap understood as the need for admission in an intensive care unit (icu). thus, in the presence of less than two factors of multiresistance (severe pneumonia, hospitalization in the previous days, living in a residence, severe basal dependence for basic daily life activities, immunodepression, or the taking of antibiotics in the previous months) coverage against mrsa should be included if the patient presents severe disease. pseudomonas aeruginosa is not a frequent pathogen in cap; factors increasing the likelihood for pseudomonas infection are structural lung disease such as bronchiectasis or severe copd with fev < %, severe pneumonia requiring icu admission, frequent or recent use of antibiotics, recent hospital admission and steroid use. aspiration pneumonia refers to an infection that develops after the entrance of pathologic oropharyngeal microbes into the lung. major risk factors for aspiration include depressed consciousness, compromised airway defenses, dysphagia, gastroesophageal reflux disease, and recurrent vomiting. most patients with communityacquired aspiration pneumonia have a mixed infection with anaerobic and aerobic bacteria, whereas those with hospital-acquired pneumonia will more likely have gram-negative infections, including pseudomonas aeruginosa [ ] . in regard to viral etiology, the influenza virus and respiratory syncytial virus are most important cause of pneumonia in the elderly, often within the context of epidemic outbreaks and may cause both viral primary pneumonias such as bacterial superinfection by s. pneumoniae, s. aureus, and haemophilus influenzae. (table . antimicrobials are the cornerstone of therapy for cap in any population, but limited data are available regarding the specific treatments for elderly patients. the only guidelines for the management of community-acquired pneumonia in the elderly patient are published in the year in spanish [ ] . initial antibiotic selection for cap is often empirical, as the causative pathogen cannot be predicted from clinical laboratory or radiological findings and therapy must be started swiftly as rapid antibiotic delivery is associated with a better outcome [ ] . empirical antimicrobial therapy must include coverage for the most prevalent pathogens and should be based on several aspects such as the severity of diseases, local patterns of antimicrobial resistances, multi-drug-resistant risk factors, and drug allergies. international guidelines agree that patients hospitalized with non-severe cap should be started on empirical combination therapy using a β-lactam plus a macrolide or a respiratory fluoroquinolone alone (levofloxacin, moxifloxacin, and gatifloxacin). the respiratory quinolones are quinolones that are highly active against both the typical and atypical respiratory pathogens causing cap. because ciprofloxacin is relatively inactive against streptococcus pneumoniae, even though it is active against the atypical pathogens, it is not termed a "respiratory quinolone." in patients with severe community-acquired pneumonia (admission in icu or intermediate care), the guidelines recommend a minimum of a β-lactam plus either a macrolide or a quinolone. the combination treatment offers an advantage over monotherapy by expanding the antimicrobial coverage and probably by immunomodulation (macrolides, quinolones). in severe patients with risk factors for mrsa vancomycin or linezolid should be added. cap patients with risk factors for p. aeruginosa should receive empirical combination therapy as an antipneumococcal anti-pseudomonal β-lactam plus either ciprofloxacin or high-dose levofloxacin or the above β-lactam plus an aminoglycoside and azithromycin is an appropriate regimen. in patients with risk factors of aspiration, an antibiotic should be used which should also cover s. pneumoniae and be effective against anaerobes and enterobacteriaceae since these may be the causal microorganisms involved. in most guidelines, β-lactam/β-lactamase inhibitors (amoxicillin-clavulanate, ampicillin/sulbactam/piperacillin/tazobactam) are considered to be the antibiotics of choice. ceftriaxone plus clindamycin or metronidazole and respiratory fluoroquinolone are the alternative. for patients at the increasing rise of resistances of enterobacteriaceae ertapenem this therapeutic option is valid mainly for its sensitivity versus anaerobes, s. pneumoniae, and all the enterobacteriaceae, including extended-spectrum β-lactamase-producing (esbl). antibiotic agents with specific anaerobic activity (metronidazole or clindamycin) are not routinely warranted and may be indicated only in patients with severe periodontal disease, putrid sputum, or evidence of necrotizing pneumonia or lung abscess on radiographs of the chest. antiviral treatment is recommended as early as possible for any patient with confirmed or suspected influenza pneumonia and should not be delayed by confirmatory laboratory testing results. neuraminidase inhibitors, oseltamivir and zanamivir, are the agents of choice. the usual dosing of oseltamivir for the treatment of influenza is mg orally twice daily and of zanamivir is mg ( inhalations) twice daily. the recommended duration for antiviral treatment is days. the optimal duration of antibiotic therapy is not yet known. bts guidelines [ ] propose - days treatment for most patients with severe cap, whereas european guidelines [ ] suggest that the duration of treatment should generally not exceed days in a patient who responds to initial therapy. the use of biomarkers such as procalcitonin or the c-reactive protein may be useful to shorten the duration of antibiotic treatment [ ] . the duration of antibiotic treatment may be prolonged in patients receiving initial inadequate antibiotic therapy, patients with extrapulmonary infection (e.g., endocarditis, meningitis), patients infected with multi-drugresistant organism (e.g., s. aureus) and patients with necrotizing pneumonia. regarding the dosing (table . ), there are many considerations to be made when caring for elderly patients: multiple comorbidities, polypharmacy potentially resulting in drug interactions, pharmacokinetic and pharmacodynamic changes that can result in altered drug metabolism and subsequent toxic effects of drug accumulation [ ] . despite the complexity of all of these changes, however, the singular impairment that most significantly influences the medical management of infection in older patients is the decline in renal function commonly observed in this group. in patients with impaired renal function, antibiotics should always be started at full initial doses and then adjusted based on renal function. lower respiratory tract infections, including pneumonia and exacerbation of chronic obstructive pulmonary disease, are among the most common causes of arf in elderly people and the most important cause of hospitalization. moreover pulmonary infection is also the most frequent single cause of ards. in the management of respiratory failure, it is mandatory reversing and/or preventing tissue hypoxia through conventional oxygen therapy or invasive or non-invasive mechanical ventilation. besides, early administration of appropriate antimicrobials has been postulated as a key strategy in the survival of patients with very severe infections requiring intensive care unit admission taking into account the most risk of adverse events of an antimicrobial in a frail elderly patient. . acute respiratory failure is a frequent complication in elderly patients. . infections (cap and aecopd) are among the most frequent triggering causes of arf in advanced aged patients. . antimicrobials are the cornerstone of therapy for cap and in copd exacerbations when patients have clinical signs of a bacterial infection. . antibiotic duration should be as shorter as possible, based on the pathogen, clinical response, and presence of complications. . a judicious use of antibiotic therapy in the respiratory tract infections is critical in the era of antibiotic resistance. the impact of immunosenescence on pulmonary disease acute respiratory failure in the elderly: etiology, emergency diagnosis and prognosis respiratory failure acute respiratory failure in the elderly: diagnosis and prognosis acute respiratory distress syndrome, and early immune-modulator therapy the acute respiratory distress syndrome acute respiratory distress syndrome acute respiratory distress syndrome: the berlin definition antibiotic therapy and treatment failure in patients hospitalized for acute exacerbations of chronic obstructive pulmonary disease global initiative for chronic obstructive lung diseases. global strategy for the diagnosis, management and prevention of chronic obstructive pulmonary disease infection in the pathogenesis and course of chronic obstructive pulmonary disease infective exacerbations of chronic bronchitis: relation between bacteriologic etiology and lung function the role of atypical pathogens in exacerbations of chronic obstructive pulmonary disease infectious etiology of acute exacerbations of chronic bronchitis prevalence of viral infection detected by pcr and rt-pcr in patients with acute exacerbation of copd: a systematic review sputum colour and bacteria in chronic bronchitis exacerbations: a pooled analysis pathogen-directed therapy in acute exacerbations of copd pneumonia in the very old community-acquired pneumonia in very elderly patients: causative organisms, clinical characteristics, and outcomes bacterial pneumonia in the elderly: the observations of sir william osler in retrospect community-acquired pneumonia requiring hospitalization among u.s. adults pneumonia in the elderly: a review of the epidemiology, pathogenesis, microbiology, and clinical features aspiration-related pulmonary syndromes guidelines for the management of community-acquired pneumonia in the elderly patient infectious diseases society of america/ american thoracic society consensus guidelines on the management of community-acquired pneumonia in adults guidelines for the management of communityacquired pneumonia in adults: update guidelines for the management of adult lower respiratory tract infections blood biomarkers for personalized treatment and patient management decisions in community-acquired pneumonia antibacterial agents in the elderly key: cord- - gzh lw authors: gillissen, adrian; zielen, stefan title: bronchitis, bronchiolitis und lungenemphysem date: journal: medizinische therapie | doi: . / - - - _ sha: doc_id: cord_uid: gzh lw nan die akute bronchitis ist pathophysiologisch durch eine tracheobronchiale entzündung charakterisiert, die meistens mit einer infektion der oberen und/oder unteren atemwege einher geht. sie tritt gehäuft in den wintermonaten auf und wird durch viren einschließlich influenza-, adeno-, rs-("respiratory syncytial"), rhino-und coronaviren, aber auch durch bakterien, wie mykoplasmen, chlamydien und bordetella pertussis hervorgerufen. sekundärinfektionen mit haemophilus influenzae und streptokokken kommen vor. klinisch imponiert ein oft als sehr unangenehm empfundener husten, der zu beginn unproduktiv ist, später aber durchaus putride werden kann. weitere von den patienten beschriebene symptome sind retrosternales brennen und thoraxschmerzen als zeichen einer bestehenden tracheitis. bei der diagnostik der akuten bronchitis imponieren lediglich in der auskultation grobblasige rasselgeräusche. unauffällig sind die lungenfunktionsprüfung, die blutgasanalyse sowie das röntgenthoraxbild. die meisten fälle müssen daher nicht oder allenfalls vorübergehend mit antitussiva behandelt werden. in deutschland sind die in tabelle . - genannten antitussiva verfügbar. codein, dextromethorphan, noscapin, eprazinon, levodropropizin und clobutinol sind in der lage, die hustenintensität und -frequenz zu senken und werden daher zumindest partiell von der n e g n u l h e fe p m e e i p a r e h t r e d z n e d i v ev v d a r g z n e d i v ev v -s g n u l h e fe p m e e k r ä t s z n e r a k n e g r e l l a b -i b g n u r e i s i l i b i s n e s o p y hy y a -i b β a k i t e m i m o k i h t a p m y s -) e m a s k r i w g n a l d n u z r u k ( a -i a n i l l yl l hy y p o e h t a -i b l i m o r c o d e n , e r u ä s n i c i l g o m o r c b -i c n e t s i n o g a t n a r o t p e z e r n e i r t o k u e l a -i b e d i o k i t r o k o k u l g e v i t a l a h n i a -i a e t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t tab a t tab ab b b b b t t t t t t t t t t t t t t t t t b b b a tab ab ab ab b b b b b a a a a t t t t t t t t t t t t t t t t t b b b b ab ab ab ab ab ab ab ab ab ab ab ab abe e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e el l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l ll l l l l l le . - . schweregradle . . l le . . le . . e . . e . . . . . . . l l l l l l l l l le . - . le . - . le . - . le . - . le . - . le . - . le . - . le . - . le . - . le . - . le . - . le . - . le . - . einteilung (nach den empfehlungen der deutschen atemwegsliga) ab ab ab ab ab ab ab ab ab ab ab ab ab american college of chest physicians zur unspezifischen antitussiven therapie empfohlen. im gegensatz dazu gibt es kaum oder gar keine kontrollierten untersuchungen, die den einsatz von pentoxyverin, menadioldiphosphat, pipacetat, benproperin sowie von pflanzlichen oder homöopathischen präparaten rechtfertigen könnten, obwohl diese als auch salben, riechlösungen etc. zur externen anwendung zur verfügung stehen und von den patienten oft als angenehm empfunden werden (tabelle . - ). substanzen wie antihistaminika (z. b. diphenhydramin), inhalativ zu applizierende β -adrenergika, parasympatholytika oder lokal wirksame lokalanästhetika (z. b. während der bronchoskopie) werden ebenfalls antitussive effekte zugesprochen. auch die chronische bronchitis wird klinisch definiert. die gebräuchlichste definition der chronischen bronchitis wurde von der who formuliert: "die chronische bronchitis ist eine erkrankung, die gekennzeichnet ist durch übermäßige schleimproduktion im bronchialbaum und die sich manifestiert mit andauerndem oder immer wieder auftretendem husten, mit oder ohne auswurf an den meisten tagen von mindestens drei aufeinander folgenden monaten während mindestens zwei aufeinander folgender jahre". die chronische bronchitis wird nahezu immer durch inhalative agenzien ausgelöst. pathophysiologisch ist an erster stelle der langjährige chronische zigarettenabusus zu nennen. weitere häufige auslöser sind t b b b a tab ab ab ab b b b b b a ab ab ab ab ab ab ab ab ab ab ab ab abe e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e el l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l lle . . l le . . le . . l l l le . - . Übersicht über . l le . . le . . e . . e . . . . . . . l l l l l l l l l le . organismen (z. b. viren, bakterien) oder stäube (z. b. kohlemischstäube bei bergleuten). ca. % aller raucher reagieren mit einer zunehmenden lungenfunktionsverschlechterung (fev = einsekundenkapazität). t b b b a tab ab ab ab b b b b b a kausaler und damit effektivster therapeutischer ansatz in der therapie der chronischen bronchitis ist die elimination des auslösenden agens. patienten mit einer bronchitis von der notwendigkeit der zigarettenabstinenz zu überzeugen, ist schwierig, denn selbst in der lung-health-studie gaben trotz eines intensiven trainings nur ca. % das zigarettenrauchen auf. neuere untersuchungen zeigen einen gegenüber plazebo und nikotinpflaster signifikant besseren therapieerfolg mit bupropion ( -mal mg an tag - , danach -mal mg über monate; abstinenzraten: plazebo , %, nikotinpflaster , %, bupropion , %; p< , ). allerdings sind die nebenwirkungen von bupropion zu beachten (z. b. zerebrale krampfanfälle). nationale und internationale therapieempfehlungen zur behandlung der chronischen obstruktiven bronchitis äußern sich sehr zurückhaltend zum einsatz von mukoregulanzien, da es widersprüchliche studienergebnisse zur effektivität dieser substanzgruppe gibt. die tabelle . - gibt eine Übersicht über die auf dem markt befindlichen präparate. am meisten sind n-acetylcystein, carbocystein, ambroxol und bromhexin untersucht, während es von präparaten, die auf pflanzlicher basis beruhen, keine gesicherten studien gibt (ausnahme: cineole). eine prophylaktische gabe z. b. von n-acetylcystein über die wintermonate wird mangels gesicherter daten nicht empfohlen. eine kurzfristige applikation (wochen) wird oft von den patienten, die über einen schlecht abhustbaren und zähen bronchialschleim klagen, als angenehm empfunden, z. b. ambroxol bis zu -mal mg/tag; bromhexin -mal mg/tag, n-acetylcystein -mal mg/ tag, carbocystein -mal mg/tag, cineol -mal mg/ tag. als antioxidans wird lediglich n-acetylcystein zur therapie der paracetamol-/paraquatintoxikation eingesetzt (s. dort). in der von den national institutes of health (nih) und der who ins leben gerufenen gold-initiative (global initiative for chronic obstructive lung disease) definiert sich die copd als erkrankung, die durch eine nicht voll reversible atemflusslimitierung charakterisiert ist. diese atemflusslimitation nimmt meist über jahre/jahrzehnte zu, und basiert auf einen durch inhalative noxen (partikel und gase) verursachten entzündungsprozess in den atemwegen. die atemwegsobstruktion wird in vier schweregrade eingeteilt (tabelle . - .), ist i. d. r. progressiv, im gegensatz zum asthma bronchiale wenig variabel und nach inhalativer gabe eines kurzwirksamen β -agonisten (fev -veränderung < % soll und < ml) wenig reversibel. außerdem gehören folgende symptome zu diesem krankheitsbild: chronischer husten, auswurf sowie verschiedene ausprägungsgrade einer chronischen luftnotsymptomatik, deren basis eine über jahre zunehmende reduktion des exspirativen atemflusses ist. weitere charakteristika dieser erkrankung sind die Überblähung der lunge, eine reduktion der diffusionskapazität oder eine bronchiale Überempfindlichkeit, die einzeln oder zusammen vorliegen können. in der behandlung der copd muss zwischen der pharmakotherapie der stabilen erkrankung und der notfallsituation unterschieden werden. zudem sollten die medikamentöse, die nichtmedikamentöse konventionelle und die operative therapie voneinander differenziert werden. medikamentöse therapie der stabilen copd für die medikamentöse therapie der copd stehen kurz-und langwirksame β -rezeptoragonisten, theophyllin, anticholinergika und kortikosteroide zur verfügung, die entsprechend der erkrankungsschwere kombiniert eingesetzt werden (abb. . - ). tabelle . - gibt eine Übersicht der gebräuchlichsten substanzen und deren dosierungen. kokortikosteroide müssen aufgrund kürzlich publizierter langzeitstudien wegen der hohen nonresponderrate von - % als grundsätzlich ungeeignet zur therapie der stabilen copd angesehen werden. um in der praxis responder von nonrespondern und copd-patienten mit einer asthmakomponente, bei denen ein klinischer nutzen zu erwarten ist, besser voneinander differenzieren und den therapieerfolg dokumentieren zu können, wurde der in abb. . - abgebildete vorschlag zur therapieevaluation formuliert. demnach erscheinen der therapieversuch bei mittleren und schweren erkrankungsformen (definition s. tabelle . - ) sowie vierteljährliche kontrollen sinnvoll. leichte erkrankungsformen haben keinen benefit von einer steroidtherapie (s. abb. . - ). bei schweren formen können inhalative steroide in der langzeittherapie die copd-exazerbationsrate senken. feste kombinationspräparate zur inhalativen therapie (salmeterol/ fluticason, formoterol/budenosid) scheinen den jeweiligen monopräparaten überlegen zu sein. exazerbation muss bei folgenden symptomen ("winnipeg-kriterien") angenommen werden:  zunahme der dyspnoe,  zunahme des auswurfvolumens,  zunahme der purulenz des auswurfs. die lungenfunktions-und blutgasanalyse (quantifizierung der atemwegsobstruktion und der Überblähung der lunge, diagnostik der respiratorischen insuffizienz) helfen neben der klinik, die schwere der exazerbation einzuschätzen. labor-, bakteriologische und radiologische untersuchungen unterstützen die identifizierung einer akuten entzündung sowie die detektion von "problemkeimen" und grenzen wichtige differentialdiagnosen von der copd ab. neben der intensivierung der schon bei der stabilen erkrankungsform genannten medikation (s. tabelle . - ) können im notfall β -rezeptoragonisten, theophyllin und kortikosteroide auch intravenös appliziert werden. tabelle . - gibt eine Übersicht über die substanzen, deren dosierung und die applikationsformen. im gegensatz zur stabilen copd führt bei der exazerbation eine initial hochdosierte kortikosteroidtherapie zu einer beschleunigten verbesserung der fev und zu einer verkürzung der krankenhausaufenthaltsdauer. eine mehrwöchig hochdosierte glukokortikosteroidtherapie (> mg/tag und ausschleichen nach > monaten) erbrachte jedoch im vergleich zu plazebo und zu niedrigeren steroiddosen kein besseres klinisches ergebnis. deswegen sollte auch bei der exazerbation bis auf ausnahmen die therapiedauer von tagen nicht überschritten werden, da nach gegenwärtiger studienlage der nutzen in keiner relation zu den typischen steroidnebenwirkungen steht. nur bei % aller copd-patienten kann eine bakterielle infektion nachgewiesen werden. daher sollte eine kalkulierte antimikrobielle differentialtherapie nur bei patienten, die den o. g. "winnipeg-kriterien" entsprechen oder sich in einem schweren erkrankungsstadium befinden (fev < % soll ), bei schwerer komorbidität, häufigen (≥ ) exazerbationen pro jahr und/oder beim vorliegen einer penicillinresistenz erfolgen. die wahl des antibiotikums richtet sich nach der erkrankungsschwere der akuten exazerbation (abb. . - ). nichtmedikamentöse konventionelle therapie zur nichtmedikamentösen konventionellen therapie der copd werden die sauerstofflangzeittherapie und die nichtinvasiven sowie in-vasiven beatmungsverfahren gezählt. durch eine kontinuierliche sauerstoffgabe konnte eine verbesserung der Überlebensrate der copd-patienten erzielt werden, weshalb diese bei chronisch hypoxischen patienten empfohlen wird. indikationen für eine sauerstofflangzeittherapie sind:  ruhe-pao ≤ mmhg (sao ≤ %),  ruhe pao - mmhg (sao ≥ %) plus cor pulmonale oder globale herzinsuffizienz oder ein hämatokrit > %,  belastungs pao ≤ mmhg oder pao ≤ mmhg während des schlafs. zu den ergänzenden maßnahmen in prophylaxe und therapie der copd gehören außerdem die rehabilitation und physikalische maßnahmen. eine grippeschutzimpfung und die pneumokokkenimpfung werden von der ständigen impfkommission (stiko) bei copd-patienten empfohlen. der impfstoff für die grippeschutzimpfung muss die aktuelle von der who empfohlene antigenkomponente enthalten. beide impfungen können simultan, sollten aber nicht an der gleichen impfstelle erfolgen. die grippeschutzimpfung erfolgt jährlich, am besten im herbst, die pneumokokkenimpfung alle fünf bis sechs jahre. unter einer bronchiolitis wird eine entzündungsreaktion im bereich des bronchialepithels der kleinen knorpelfreien atemwege verstanden. in abhängigkeit vom erkrankungsstadium kann der v . . . . . . . . . k . . . . . . . . . . . . . . . . . . . . . . . . . - . . . - . . . - . . . - . . . - . . . - . . . - . . . - . . . - . . . - . . . - . . . - . . . - unter bronchiektasen versteht man eine abnormale, irreversible erweiterung eines oder mehrerer bronchien. der terminus ist unabhängig vom grund der bronchiektasenentstehung und den pathophysiologischen sowie klinischen veränderungen. reversible formen, wie sie beispielsweise im rahmen von pneumonien auftreten, fallen definitionsgemäß nicht unter diesen begriff. die erkrankung war anfang des jahrhunderts häufig. sie trat vor allem nach pneumonien und zusammen mit keuchhusten-, masern-und influenzaepidemien auf. die entwicklung von antibiotischer therapie einerseits und von impfstoffen andererseits hat zu einer steten abnahme der erkrankungszahlen geführt. zuverlässige epidemiologische daten gibt es gegenwärtig nicht. es wird jedoch davon ausgegangen, dass inzwischen mehr bronchiektasieerkrankungen auf grund kongenitaler störungen als postinfektiöser natur zu beobachten sind. strahlenpneumonitis, aspiration, ards ("adult respiratory distress syndrome") empfehlungen zum strukturierten patiententraining bei obstruktiven atemwegserkrankungen building a national strategy for the prevention and management of and research in chronic obstructive pulmonary disease präoperative identifizierung des pulmonalen risikopatienten vor lungenresektion long-term oxygen therapy long-term effect of inhaled budesonide in mild and moderate chronic obstructive pulmonary disease: a randomised controlled trial empfehlungen der deutschen atemwegsliga zum asthma management bei erwachsenen und bei kindern empfehlungen der deutschen atemwegsliga zur behandlung von patienten mit chronisch obstruktiver bronchitis und lungenemphysem risikofaktoren der copd who report of an expert committee: definition and diagnosis of pulmonary disease with special reference to chronic bronchitis and emphysema prophylaxe und therapie von bronchiale infektionen unter morphologischen gesichtspunkten werden drei haupttypen von bronchiektasien unterschieden: zylindrisch, varikös und sakkulär (zystisch) standards for the diagnosis and care of patients with chronic obstructive pulmonary disease effects of smoking intervention and the use of an inhaled anticholinergic bronchodilator on the rate of decline of fev . the lung heath study antibiotic therapy in exacerbations of chronic obstructive pulmonary disease chronic obstructive pulmonary disease inhaled corticosteroids are not beneficial in chronic obstructive pulmonary disease guidelines for the management of chronic obstructive pulmonary disease inhaled corticosteroids are beneficial in chronic obstructive pulmonary disease guidelines for the assessment and management of chronic obstructive pulmonary disease oral corticosteroids in patients admitted to hospital with exacerbations of chronic obstructive pulmonary disease: a prospective randomised controlled trial lung transplant waiting list: differential outcome of type of end-stage lung disease, one year after registration empfehlungen zur sauerstoff-langzeit-therapie bei schwerer chronischer hyoxämie chronic obstructive pulmonary disease international guidelines the natural history of chronic airway obstruction adenovirusinfektionen als ursache schwerer pulmonaler erkrankungen im kindesalter inhalierbare kortikosteroide in der langzeittherapie der copd. stellungnahme eines expertengremiums sinn und unsinn von antitussiva managing cough as a defense mechanism and as a symptom. a consensus panel report of the a controlled trial of sustained-release bupropion, a nicotine patch, or both for smoking cessation chronisch persistierender husten (cph): therapie an evidence-based approach to noninvasive ventilation in acute respiratory failure long term domiciliary oxygen therapy in chronic hypoxic cor pulmonale complicating chronic bronchitis and emphysema effect of systemic glucocorticoids on exacerbations of chronic obstructive pulmonary disease continuous or nocturnal oxygen therapy in hypoxemic chronic obstructive lung disease long-term treatment with inhaled budesonide in persons with mild chronic obstructive pulmonary disease who continue smoking ribavirin therapy of respiratory syncytial virus initial: mg/kg über min i.v., fortsetzung , - , mg/kg/h (perfusor/infusion) = (bei kg) - mg/tag glukokortikosteroide prednisolon -mal - mg/tag oral, -mal mg/tag i.v., nach tagen reduzieren und, je nach befund, nach tagen absetzen ab ab ab ab ab ab ab ab ab ab ab ab abe e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e el l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l lle . . l le . . le . . l l l l l s . l le . . le . . e . . e . . . . . . . l l l l l l l l l le . - . le . - . le . - . le . - . le . - . le . - . le . - . le . - . le . - . le . - . le . - . le . - . le . - . ubstanzen und deren dosierung zur therapie der copd t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t tab a t tab ab t t t b b b b t t t t t t t t t t t t t t t t t t t t t t t b b b t tab ab ab ab t t t t t t ein schlüssiges und allgemein akzeptiertes behandlungskonzept bei der organtransplantationsassoziierten bronchiolitis existiert nicht, obwohl oft glukokortikosteroide und andere immunsuppressiva eingesetzt werden. bei bronchiolitiden, die bei patienten mit systemerkrankungen auftreten, wird primär die grundkrankheit behandelt. ansonsten beschränkt sich die insgesamt wenig etablierte therapie dieser und der idiopathischen bronchiolitisformen meist auf die gabe hochdosierter glukokortikosteroide (s. oben) und die behandlung der begleitsymptome. das lungenemphysem ist pathologisch-anatomisch definiert. es ist charakterisiert durch eine dauerhafte und irreversible Überblähung der atemwege distal der bronchioli terminales, begleitet von einer destruktion der alveolarwände ohne wesentliche fibrose. die diagnostik ist intra vitam, insbesondere bei leichten erkrankungsformen, schwierig. sie umfasst die klinische untersuchung (charakteristischerweise hypersonorer klopfschall, leises atemgeräusch und leise herztöne), die lungenfunktion mit zeichen der irreversiblen Überblähung und die bildgebenden verfahren (z. b. röntgenthorax, computertomographie des thorax).da es sich beim lungenemphysem um ein irreversibles krankheitsbild handelt, stehen lediglich operative verfahren für deren beseitigung zur verfügung. die bedeutung präventiver maßnahmen (elimination der inhalationsnoxe, substitution von α -antitrypsin beim α -antitrypsin-mangelpatienten) ist daher besonders hervorzuheben. indikationen zur bullektomie, bei der einzelne empyhsemblasen operativ entfernt werden, sind atemnot, rezidivierende pneumothoraces, infektion der bulla (spiegelbildung), perforation, hämoptysen und nicht zuletzt die abklärung maligner verdachtsdiagnosen. der eingriff kann thorakoskopisch oder offen erfolgen.lungenvolumenreduktion (lvr) und lungentransplantation (ltx) sind weitere invasive verfahren, die eine strenge patientenselektion erfordern. probleme bei der lvr sind postoperativ auftretende leckagen und trotz operation eine sich nach monaten und wenigen (z. b. drei) jahren sich wieder verschlechternde lungenfunktion. bisherige erfahrungen bei der ltx zeigen, dass bei copd-patienten primär zwar die lebensqualität, nicht jedoch die statistische lebenserwartung zu verbessern ist. key: cord- - avevzya authors: losada, liliana; ghedin, elodie; morris, alison; chu, hong wei; nierman, william c. title: the human lung microbiome date: - - journal: metagenomics of the human body doi: . / - - - - _ sha: doc_id: cord_uid: avevzya the human lower respiratory tract is considered sterile in normal healthy individuals (flanagan et al., ; speert, ) despite the fact that every day we breathe in multiple microorganisms present in the air and aspirate thousands of organisms from the mouth and nasopharynx. this apparent sterility is maintained by numerous interrelated components of the lung physical structures such as the mucociliary elevator and components of the innate and adaptive immune systems (discussed below) (reviewed in (diamond et al., ; gerritsen, )). however, it is possible that the observed sterility might be a result of the laboratory practices applied to study the flora of the lungs. historically, researchers faced with a set of diseases characterized by a changing and largely cryptic lung microbiome have lacked tools to study lung ecology as a whole and have concentrated on familiar, cultivatable candidate pathogens. the human lower respiratory tract is considered sterile in normal healthy individuals (flanagan et al., ; speert, ) despite the fact that every day we breathe in multiple microorganisms present in the air and aspirate thousands of organisms from the mouth and nasopharynx. this apparent sterility is maintained by numerous interrelated components of the lung physical structures such as the mucociliary elevator and components of the innate and adaptive immune systems (discussed below) (reviewed in (diamond et al., ; gerritsen, ) ). however, it is possible that the observed sterility might be a result of the laboratory practices applied to study the flora of the lungs. historically, researchers faced with a set of diseases characterized by a changing and largely cryptic lung microbiome have lacked tools to study lung ecology as a whole and have concentrated on familiar, cultivatable candidate pathogens. with the availability of new technologies for cultivation-independent analysis of microbial populations, it is now possible to follow individuals by sampling their lung microbiome sequentially during episodes of disease and recovery in order to identify associations between the lung microbiome and health and disease. any respired contaminating particles or pathogens that evade the lung's physical and immune barriers are usually eliminated by dendritic cells and alveolar macrophages that deliver them into local draining lymph nodes. macrophages kill invading microorganisms while en route to the draining lymph nodes, and in some cases at the nodes themselves (bozza et al., ; kirby et al., ) . thus, it is not unusual to isolate viable bacteria or fungi from "normal" lung tissue (lass-florl et al., ) , and the term "sterile" should be applied with caution. it is perhaps more accurate to say that there is no resident flora that permanently colonizes normal lungs. even normal healthy lungs are not microbe free all the time. lower airway infections by bacteria, viruses, or fungi are among the most prevalent causes of transmissible disease in humans, with two to three million community-acquired (non-hospital-acquired) cases per year in the united states (segreti et al., ) . in , the number of deaths attributed to pneumonia (bacterial and viral) and influenza in the united states was , (gao et al., ) www.cdc.gov/ nchs/fastats/deaths.htm). in , nearly . million new cases of tuberculosis were reported around the world (http://www.who.int/mediacentre/factsheets/ fs /en/index.html). with proper treatment, the lungs of individuals with these infectious diseases will revert to their normal "sterile" state. little is known about the composition of the microbial population of the upper and lower airways in health or disease. it is likely, given the multiple microorganisms already implicated in chronic lung diseases such as chronic obstructive pulmonary disease (copd) , that there are other undetected organisms and that there are complex relationships between multiple pathogens involved that are not currently understood. a few studies have examined microbial species in limited numbers of normal subjects and patients with various respiratory disorders. one study using s rdna clone libraries and microarrays did not detect any bacteria in the lungs of patients without respiratory disease who were briefly intubated for surgery (flanagan et al., ) . the same study reported that all patients intubated for longer periods had detectable s rdna and that the bacterial diversity present decreased during antibiotic usage. another study used s rdna amplification to identify bacterial species in patients with ventilator-associated pneumonia (bahrani-mougeot et al., ) . this study identified bacterial pathogens not seen using conventional culture techniques, especially anaerobes, and found that oral bacteria could be detected in the lung. in one study, sputum samples from cystic fibrosis (cf) patients were analyzed using s gene profiling and the authors identified an average of . species present per subject (bittar et al., ) . viruses have also been examined in nasal lavages in both asthmatic and normal subjects with cold symptoms using the virochip microarray (kistler et al., ) . the microarray technology identified more viruses than conventional culture methods and had excellent sensitivity and specificity compared with pathogen-specific polymerase chain reaction (pcr). an unexpected diversity of human coronavirus and rhinovirus strains was discovered in the subjects. so if the lung is generally sterile, why do some individuals become chronically colonized? what organisms colonize the lungs? those with physically compromised airways or immune system deficiencies are subject to chronic microbial colonization of their airways and to high-frequency episodes of viral, bacterial, or fungal lower respiratory infections. perhaps in no other body site is the direct relationship between disease and microbiome more explicit than in the lungs where there is a distinct and obvious microbial difference between normal and diseased individuals. the lower respiratory tract, composed of the trachea and lungs, is quite different in structure and function from the upper respiratory tract, which is highly colonized by microorganisms. the lungs themselves are divided into different sections according to their function and structures: the bronchi, bronchioles, and alveoli. bronchi and bronchioles are primarily conductive airways surrounded by thick cartilage that allow easy airflow into the parenchyma (or alveolar tissue) of the lungs, where gas exchange occurs. conductive airways are covered in ciliated epithelium interspersed with different types of secretory cells that release mucins, immunomodulatory proteins, surfactants, and proteases. together, the physical and chemical barriers protect against physical and biological damage by establishing a mucociliary elevator, which brings about an upward transport of a mucus stream for the lungs (fraser, ) . the secretory cells decrease in proportion from to % in the trachea to less than % in the distal and alveolar parts of the lungs. in addition to the physicochemical protection provided by cilia and mucus, the epithelium is also protected by several immune cells, including dendritic, langerhans, t lymphocytes, and mast cells, that respond to inhaled antigens establishing a robust immunity (fraser, ) . it is thought that in conjunction with the physical barriers provided by the nose and upper respiratory mucosa, these defenses are enough to maintain sterility in the lower respiratory tract. the vast majority of the lung surface epithelium, however, is alveolar. it is estimated that % of the total volume of the lungs is alveolar, with only % of this being tissue and the remainder gas (stone et al., ) . the primary role of this tissue is to carry out gas exchange. the epithelium is mostly a continuous single layer of cells overlying a thin interstitium, which contains numerous capillaries that supply ample blood for gas exchange (fraser, ; stone et al., ) . unlike the epithelium in the conducting airways, the respiratory epithelium is not ciliated or protected by mucus. instead, it is covered by surfactant proteins that maintain the surface tension for efficient gas exchange. the lack of mucus or secretory cells is compensated by the presence of alveolar macrophages, mast cells, lymphocytes, dendritic cells, and other monocyte-like cells that protect the epithelium from potential pathogens and help maintain sterility. recent world health organisation (who) figures rank lower respiratory diseases second in an assessment of the burden of disease worldwide (http://www.who.int/ respiratory/en/). in , , people died in the us due to chronic lower respiratory disease (www.cdc.gov/nchs/fastats/deaths.htm). chronic respiratory diseases include: asthma, copd, cf, and bronchiectasis. these diseases generally lead to impaired clearance and function of the mucociliary elevator and/or the immune protection of the lung. in addition, immune deficiency such as that caused by the human immunodeficiency virus (hiv) also disrupts the typical immune homeostasis in the lungs. without the normal protective barriers, the lungs fall victim to persistent and severe colonization that can ultimately lead to death, particularly for cf patients. as discussed below, the lung microbiome in each of these diseases is very different from normal individuals. the data discussed in the following sections demonstrate a clear link between microbial colonization and severity of disease symptoms. it is unclear, however, what exact role these different microbial populations play in initiating and enhancing the progress of such chronic respiratory diseases. lastly, in some cases, the data hint that some population structures might actually be protective against further decline, but much more research needs to be conducted in this area to make a definitive claim. this chapter discusses the methods for sampling and characterizing the microbiome of the lungs. in addition, it reviews the current status of our understanding of the lung microbiome in asthma, idiopathic bronchiectasis, cf, copd, and during immune deficiency due to hiv infection. several procedures have been developed for sampling the microbial population of the human lung econiche. in order of increasing invasiveness they are sputum induction, bronchoalveolar lavage (bal), bronchial brushing, endobronchial biopsy, and transbronchial biopsy. sputum induction by inhalation of hypertonic saline is a noninvasive method to obtain samples from the lower respiratory tract for cell and microbial analysis (bickerman et al., ) . the quality of samples varies and can be scored on the volume of the obtained sputum plugs and the level of salivary contamination as measured by squamous cells observed by microscopy. bal is a procedure in which a bronchoscope is passed through the mouth or nose into the lungs and saline is instilled into a segment of the lung and then recollected for examination (henderson, ; reynolds and chretien, ) . bal is most commonly used to diagnose infections in both immunocompetent and immunosuppressed patients. bal is the most common procedure for sampling the lower respiratory system microbial colonization/infection status, to sample the components of the epithelial lining fluid, and to determine the protein composition of the airways. it is often used in evaluating the patient's lung immunological status by sampling cells and pathogen levels. bal is an invasive procedure and thus is less ideal for research purposes. bronchial brushing provides access to cells and microbes that are adherent to the luminal surfaces of the lower airways. in this procedure, a flexible fiber optic bronchoscope is used for brushing a targeted lesion or site (fennessy, ; zavala et al., ) , where induced sputum and bal procedures will allow sampling of cells and microbes that can be washed from the lumen surface, brushing will recover adherent cells (e.g., bronchial epithelial cells) and microbes. recently, brushing techniques have been developed to sample distal lung (i.e., small airway) epithelial cells and associated microbes (ammous et al., ) . this technique will enable investigators to further study the microbiome in lung diseases such as copd. endobronchial biopsy involves using the fiber optic bronchoscope to identify appropriate target sites in the lung and obtain large airway tissue samples using inserted alligator forceps, cup forceps, or curette passed through the endoscope's central channel. this procedure poses a higher risk than bal but allows sampling the invasive microbes within the airway tissue (scott et al., ; trulock et al., ) . transbronchial biopsy, the most invasive of these sampling procedures, is routinely performed for clinical care and allows clinicians and researchers to obtain distal (small) airway tissues as well as alveolar tissues. this procedure has been safely done by several research groups (balzar et al., ) and will likely further our understanding of the microbiome in human distal lung tissues, but carries a significant risk of complications. standard microbiological and virologic methods detect only a small proportion of the bacteria and viruses present in various body sites because the great majority of these organisms are uncharacterized or uncultivable. to understand the real diversity, culture-independent methods, such as sequencing, are thus a necessity. sequenced-based identification of microbial species is facilitated by decreased costs of sequencing, and the availability of next-generation sequencing technologies, further enhances the capacity to generate large amounts of data. for the identification of bacterial species within an environment, the amplification of s rrna genes (or s rdna) using universal primers are useful for diversity characterization because this genetic locus is present in all bacterial species (relman et al., ) . the nine hypervariable regions of the s rdna can be used for bacterial species identification (chakravorty et al., ; rokas et al., ) with some regions having better discriminatory value than others. the sequencing and phylogenetic analysis of bacterial s rrna derived from microbiome samples has been the primary method used to investigate bacterial diversity in the human body (bik et al., ; dekio et al., ; eckburg et al., ; gao et al., ; hugenholtz et al., ; hyman et al., ; zhang et al., ) . these studies have revealed a far higher level of diversity than conventional culture techniques (aly et al., ; bik et al., ; dekio et al., ; kazor et al., ; korting et al., ; kroes et al., ; paster et al., ) . these studies revealed that the majority of bacterial sequences correspond to uncultivated species and novel organisms. there was significant intersubject variability and variability between stool and mucosal microbial populations. for example, recent studies by blaser and colleagues at new york university have demonstrated substantial changes in the ratio of the genus streptococcus to propionibacterium in skin samples from healthy persons and in normal skin of patients with psoriasis (ratio = . ; n = , clones), and from psoriatic lesion samples (ratio = . ; n = , clones; p = . ) (gao et al., ) . in a lung study, bacterial diversity was analyzed in the endotrachael aspirates from seven intubated patients colonized with pseudomonas aeruginosa using both sequencing from s rrna clone libraries and an oligonucleotide microarray termed as the phylochip (flanagan et al., ) . controls were subjects briefly intubated for elective surgery. bacteria were not detected by either method in samples from the controls. sequencing from the clone libraries detected the presence of many orally, nasally, and gastrointestinal associated bacteria including known pathogens. the phylochip detected the same organisms and many additional bacterial groups present at low abundance. following antibiotic therapy, the bacterial populations' diversity decreased and was dominated by a single respiratory pathogen. in six of the seven patients, the dominant species was p. aeruginosa in spite of targeting this organism with antibiotics to which it was reportedly sensitive. the authors hypothesize that the loss of population diversity may directly contribute to pathogenicity, persistence, and development of pneumonia. similarly, amplification of regions from the s and internal transcribed spacer (its) regions of the rrna, a conserved fungal gene, allows discrimination of fungal species (fujita et al., ; makimura, ) . a preliminary study was undertaken to examine the efficacy of a community sequencing method to identify the fungal species in bal lung samples from human subjects. the fungal its - . s-its region was amplified and the results showed that of patients ( %) had fungal dna levels that could be reproducibly detected by pcr. the detected fungi included aspergillus fumigatus, candida tropicalis, and penicillium digitatum, among others (denning, unpublished) . these data agree with a culture-based study that showed that % of their sample population had evidence of pulmonary fungal colonization (lass-florl et al., ) , most commonly with a. fumigatus and other candida species, and also zygomycetes. the results also demonstrate that rrna sequencing is a viable platform for characterization of fungal communities in the human body. although there are no conserved genes that can be targeted for determination of viral diversity, whole genome shotgun of a sample enriched for viruses (such as by filtering) can lead to an effective characterization of viral communities (angly et al., ) . hundreds of viral genome sequences can be completed in a single sequencing reaction run using the gs-flx ( /roche) sequencing platform. using this technology and a random priming-based method, referred to as sequence independent single primer amplification (sispa), near-full-length genomes of rna or dna viruses can be sequenced. sispa can be used to sequence known and unknown viral genomes (djikeng et al., ) . this viral sequencing methodology can potentially be adapted for the determination of viruses within bal by enrichment using nuclease treatment and filtration followed by taking the extracted total rna and dna through the sispa process followed by sequence comparisons to known viruses. the initial studies of small s rrna described above hinted at great diversity within the human microbiome, yet it left important questions unanswered such as the identity of the nondominant community members and their biological roles. the applications of shotgun techniques to the study of the human microbiome (kurokawa et al., ; manichanh et al., ; zhang et al., ) again highlight the extent of microbial diversity associated with the human body while revealing much more of the identity and biology of nonculturable microorganisms. as a result of reduced costs and improved sequencing technologies, it is possible to perform in-depth metagenomic surveys of the human body's microbial diversity beyond the s rrna surveys. metagenomics, a term introduced in , describes the functional and sequence-based analysis of total microbial genomes from environmental samples (handelsman et al., ) . metagenomics uses techniques that resemble the "whole genome shotgun" approach of single genome sequencing, but it is not limited to a single species. human metagenomics has provided insight into the complex composition of the microbiome of these several body sites, and this information has allowed us to draw tentative conclusions about the relationship between specific microbiomes and health. the human microbiome is composed of multiple "ecological niches", including the mouth (kroes et al., ; paster et al., ) , esophagus (zhang et al., ) , stomach (bik et al., ) , intestine , skin (gao et al., ) , and vagina (zhou et al., ) . our understanding of the overlap and the degree of communication between them is rudimentary at best. perhaps the most extensively studied has been the human gut microbiome where the interaction of the gut microflora, independently or through interaction with the genetic makeup of the host plays a role in obesity, crohn's disease, and ulcerative colitis (frank et al., ; gophna et al., ; turnbaugh et al., ) . asthma is a complex disease characterized by chronic inflammation in the lungs and reversible narrowing of the airways. symptoms include dyspnea, coughing, wheezing, airway hyper-reactivity, chronic eosinophilic atopy, and mucus hyper secretion (busse and lemanske, ) . about million people in the us have been diagnosed with asthma; million of them are children. asthma causes , deaths per year in the us and million exacerbations. asthma is caused by environmental and genetic factors (martinez, ) , with asthma attacks resulting from immune responses to inhaled allergens. the majority of asthma exacerbations are caused by viral infections (krishnan et al., ) . atypical bacterial infections have also been associated with asthma exacerbations and with chronic asthma (johnston and martin, ; martin et al., ) . in susceptible individuals, the development of asthma has been associated with bacterial colonization in neonates (bisgaard et al., ) and viral and bacterial infections (wu and chu, ). there is abundant evidence testifying to the importance of microbes to the development and maintenance of asthma. a recent publication using a bacterial gene sequencing method suggests a disordered microbiome in asthmatic airways (hilty et al., ) . in the developed world there has been an increased focus on predisposing factors for asthma due to its rapidly increasing prevalence, now affecting up to a quarter of urban children (lilly, ) . asthma is known to be caused by environmental and genetic factors (martinez, ) . these factors determine asthma severity and how easily it can be treated (martinez, ) . many associations with asthma have been detected including exposure to cigarette smoke (thomson et al., ) , caesarean section birth relative to natural birth (thavagnanam et al., ) , early viral respiratory infections (gold and wright, ; harju et al., ) , early in life antibiotic use (marra et al., ) , and living in the us (gold and wright, ) . one theory for the cause of the increase in asthma incidence is the hygiene hypothesis (strachan, ) , that the rise in prevalence of asthma is a direct consequence of the success of modern hygienic practices in preventing childhood infections. this hypothesis is supported by numerous studies that have shown that children coming from a less hygienic environment have less asthma and other allergenic diseases (ball et al., ; celedon et al., ; jarvis et al., ) . in addition, alterations in innate immune system genes have been shown to be associated with the inception and development of asthma. these genes include the toll-like receptors and other genes such as mbl, mylk, defb , jun, inf-α , and nos a reviewed in wu and chu ( ) . asthma exacerbations have long been associated with viral infections (pattemore et al., ) . more recently, the use of reverse transcriptase pcr has greatly facilitated the identification of the exacerbation-associated virus. studies using this tool have suggested that - % of asthma exacerbations are caused by virus infections (wark et al., ) . rhinovirus (rv) infections during early childhood are associated with the development of asthma, lower respiratory tract infections, and wheezing (jackson et al., ; lemanske et al., ) . they are also associated with hospitalization for asthma in adults (venarske et al., ) . a separate study revealed that patients with allergic asthma infected with rv had increased admissions to hospitals and that dust mite allergen was the primary allergen when these patients were skin tested with a panel of aeroallergens (green et al., ) . respiratory syncytial virus (rsv) in infants causes lower respiratory infection leading to pneumonia and bronchiolitis. rsv bronchiolitis is the leading cause of wheezing in infants and young children, and children infected with rsv resulting in bronchiolitis are more likely to develop wheezing and asthma later in childhood (peebles, ) . similarly, the human metapneumovirus (hmpv) was first isolated from children in and has been found to be associated with asthma exacerbations in both children under years of age and adults (foulongne et al., ; williams et al., ) . mycoplasma pneumoniae and chlamydia pneumoniae are bacteria that attach to airway epithelial cells and cause cell damage. infections by these bacteria have been shown to be associated with asthma exacerbations (johnston and martin, ; lieberman et al., ; martin et al., ) . using a pcr assay, of patients with asthma were positive for either of these bacteria in lung tissue or bal, suggesting that some level of colonization by these bacteria may be common in asthma patients (martin et al., ) . studies in a mouse model suggest that preexisting allergic inflammation impairs the ability to upregulate tlr- and il- in the lungs, leading to decreased clearance of m. pneumoniae and an increase in airway inflammation (kraft et al., ) . evidence is accumulating that infections are associated with the induction and development of asthma. first, long-term cohort studies on the development of asthma show that most childhood asthma begins in infancy. the first episode of wheezing begins before the age of and is frequently associated with lower respiratory tract viral infections, usually rsv, but also rv (gern et al., ; sigurs et al., ) . these infectious episodes and associated wheezing are strong predictors for the development of childhood asthma and atopy (devulapalli et al., ; kusel et al., ; martinez et al., ; singh et al., ) . second, many studies have associated viral infections with asthma prevalence in children (devulapalli et al., ; jackson et al., ; kusel et al., ; papadopoulos and kalobatsou, ; sigurs et al., ; singh et al., ; williams et al., ) . lastly, wu et al. have provided evidence to suggest that viral infections have a causal role in asthma initiation and development where they show that viral infection during the first months of age is strongly correlated with the development of asthma by age (wu et al., ) . only one-third of children with childhood wheezing and asthma, however, will develop persistent asthma symptoms in adulthood (gerritsen, ; taylor et al., ; vonk et al., ) . management of the symptoms with corticosteroid therapy is effective but may not alter the asthma progression (guilbert et al., ) . the role of infections in asthma induction and development will likely be shown to be mediated through the effect of these infections on the chronic inflammatory response in the airways of asthmatics. microbial infections can generate either a th -or a th -biased response that could exacerbate or attenuate asthma, respectively. in asthmatics, a pro-inflammatory th response persists even in the absence of allergens involving cd + th cells, eosinophils, mast cells, and the th cytokines il- , il- , il- , and il- (holgate, ) . bacterial infections have been shown to contribute to asthma development. in a longitudinal prospective birth cohort study of infants born to mothers with current or previous asthma, neonates colonized in the hypopharyngeal regions with streptococcus pneumoniae, haemophilus influenzae, or moraxella catarrhalis or a combination of these organisms were found to be at increased risk for recurrent wheezing in early childhood and asthma at age (bisgaard et al., ) . a protective role for some bacteria has been reported . several studies have found a protective effect of mycobacterial exposure on atopy and airway inflammation (camporota et al., ; shirakawa et al., ; yang et al., ) . these exposures include bacillus calmette-guerin vaccination or heat-killed mycobacterium vaccae. early exposure to bacterial endotoxins may reduce future allergies or asthma (von mutius et al., ) , although endotoxins associated with house dust are associated with more asthma symptoms and worse lung function (dales et al., ; michel et al., ; park et al., ) . thus, the role of bacteria in asthma initiation and development appears to be complex. the causative interaction is likely to prove to be the interaction of bacteria and bacterial components in modulating the th and th innate immune system responses. the characterization of these interactions will be complicated by timing, dose, anatomical site, and duration of the bacterial exposure as well as the host genetic and environmental factors influencing the immune inflammatory response (holt, ) . it has recently been demonstrated that patients with severe asthma who are also atopic or sensitized to environmental fungi may benefit from treatment with the antifungal azole itraconazole . this observation has raised questions about the relationships among asthma severity, fungal sensitization, and fungal exposure. the issue is complicated by more than . million species of fungi that are thought to exist (hawksworth and rossman, ) and more than species of fungi that have been associated with symptoms of airway allergy (horner et al., ) . for one species, a. fumigatus, allergens are thought to participate in human airway allergies (www.allergome.org). determining the clinical relevance of fungal allergens is confounded further by extensive cross-reactivity among fungal allergens (crameri et al., ) . fungal allergens can induce a number of different human bronchopulmonary disorders, each with a distinct immune pathogenesis. in allergic bronchopulmonary aspergillosis (abpa), the respiratory system is chronically colonized typically with a. fumigatus. evidence now suggests that severe asthmatics without abpa are more likely to be atopic to fungi than patients with milder disease. the diagnostic label "severe asthma with fungal sensitization (safs)" has recently been applied to this group . in these patients, the fungal sensitization is most commonly a. fumigatus, candida albicans, and penicillium notatum . the association between severe asthma and fungi has been identified in numerous studies. atopy to environmental fungi has been associated with severe asthma (o'driscoll et al., ) . many population studies have shown an association between local fungal spore counts and medical emergencies due to asthma exacerbations (atkinson et al., ) . furthermore, studies have shown that fungus exposure in fungal-sensitized individuals induces asthma symptoms (malling, ; matheson et al., ; pulimood et al., ; salo et al., ; woodcock et al., ) . treatment of patients with safs with antifungal drugs has generally led to improvement of asthma symptoms concurrent with improvements in several markers of atopy such as reduced ige values, reduced eosinophils counts, and reductions in the level of dose of oral and systemic steroids required (pasqualotto et al., ) . these findings lead to the considerations of the fungal composition of the lung microbiome in asthmatic individuals and indeed in normal individuals. environmental fungi colonize the lungs of otherwise healthy people (lass-florl et al., ; okudaira et al., ) . these studies were dependent on cultivationbased methods for the detection and identification of these fungi. as a cultivationindependent method, gas chromatography/mass spectroscopy on exhaled breath has revealed the presence of fungus specific biomarkers in patients with cf with and without fungal colonization by a. fumigatus (syhre et al., ) . this approach was limited to analyzing for known a. fumigatus markers. the application of sequencing-based approaches for studying the lung microbiome will be essential for revealing the role of fungi in the lung microbiome and the role of the lung microbiome on asthma. cf is the most common inherited lung disease in the world. it is a severe autosomal recessive disease with an incidence of : at birth in populations of northwestern european origin, with a mutant gene carrier frequency of : in these populations. the genetic defect occurs in the cystic fibrosis transmembrane regulator (cftr) protein, which acts to transport chloride across cell membranes. patients with cf are the archetype population with chronic bronchial colonization. symptoms include permanent bacterial colonization of the lower airways, with a formation of a biofilm, fat maldigestion, male infertility, and elevated levels of chloride in the sweat (knowles and durie, ) . the thick pulmonary system mucus in cf patients minimizes the effectiveness of the mucociliary elevator in clearing the lung of mucus-trapped microorganisms and other debris. as a consequence, microbes chronically colonize these patients' lungs and they suffer bouts of infection, requiring frequent hospital admission. cultures reveal a wide range of bacteria, including p. aeruginosa, mycobacteria, a. fumigatus, and sometimes viruses. the precise contributions of different microbes to patient morbidity, and the importance of inter-specific interactions remain largely unclear [reviewed in (harrison, ) ]. the complexity of this ecosystem is difficult to overstate. as an example of this complexity, the lungs of cf patients contain large numbers of neutrophils that migrate to this location in response to microbial colonization. these neutrophils secrete granule antimicrobial proteins called defensins that kill microbes. by analysis of cf sputum samples, the levels of extracellular defensins are sufficiently abundant that they may damage the airway epithelium (soong et al., ) . as another example of this inter-specific complexity, p. aeruginosa in cf lungs produces copious amounts of a tricyclic compound pyocyanin that kills competing microbes and eukaryotic cells. this compound was shown to specifically inactivate a human lung epithelial cell line vacuolar atpase (ran et al., ) . a study of the microbiome of the lungs was conducted to explore the hypothesis that organisms not routinely identified by culture occur in the lungs of cf patient airways and may contribute to disease. to test this hypothesis, s rrna sequence analysis was performed on bal samples from subjects, cf patients, and other disease controls (harris et al., ) . the findings of this analysis were that, for cf subjects, a single rrna type was dominantly represented in the clone libraries prepared from lung microbiome genomic dna. this was not found in the controls. thirteen of the cf subjects' samples contained bacteria not routinely assessed by culture. candidate pathogens were identified in four cf subjects. candidate pathogens were also identified in the controls. this study documented the power of culture-independent molecular techniques to provide a broader view of the airway bacteria than standard clinical culture methods. the cf viral metagenome was explored in a recent study using five cf individuals and five individuals without disease (willner et al., ) . in both cohorts, the overall viral diversity was low. the cf bacteriophage communities were highly similar to each other, whereas the non-cf individual had more distinct phage communities. cf eukaryotic viral communities were dominated by a few viruses, including human herpes viruses and retroviruses. the significance of fastidious or noncultivatable organisms in the airway of cf patients is beginning to be explored. application of specific culture conditions to favor the growth of anaerobes coupled with molecular identification techniques have focused attention in cf on bacteria not routinely detected by standard culture and biochemical identification techniques (harris et al., ; tunney et al., ; worlitzsch et al., ) . direct, culture-independent detection techniques have identified much larger numbers of bacterial species in cf airways and have demonstrated the ability to identify likely pathogenic bacteria occurring during exacerbations when routine cultures are negative (harris et al., ) . these molecular identification and detection methods have identified bacteria with different antibiotic susceptibilities relative to conventional pathogens and will undoubtedly lead to novel antimicrobial intervention trials in cf (worlitzsch et al., ) . similar methodology to detect anaerobes or noncultivatable bacteria has not been applied systematically to patients with idiopathic bronchiectasis. bronchiectasis is characterized by chronic dilation and inflammation of the conducting airways associated with recurring infections (barker, ) . it is the pathologic manifestation of several genetic disorders, including cf and primary ciliary dyskinesia (pcd). however, many patients have no identifiable causes. idiopathic bronchiectasis is estimated to affect approximately , us adults (weycker et al., ) . symptoms include cough and chronic sputum production, recurring airway infection, dyspnea, wheezing, and chest pain (barker, ) . microbial infections are central to the pathogenesis and progression of disease. much of the research characterizing the composition and significance of the lower airway microbial flora has been done in cf and relatively little is known about the microbial contribution to disease pathogenesis in idiopathic bronchiectasis. however, recent observations suggest a link between the lower airway microbial flora and host disease characteristics. for example, the prevalence of idiopathic bronchiectasis associated with nontuberculous mycobacteria (ntm) appears to be increasing (billinger et al., ; marras et al., ) . both familial clustering and a characteristic "tall asthenic" phenotype (scoliosis, pectus excavatum, mitral valve abnormalities) in postmenopausal women with bronchiectasis associated with ntm infection (colombo et al., ; kim et al., ) have been reported. it is unknown whether the age, female sex, and unique body morphotype associations are seen in idiopathic bronchiectasis unassociated with ntm. correlating disease phenotype with microbial flora is dependent upon accurately categorizing the microbial status of the patients. for environmental organisms like ntm, it is important that this categorization include both accurate speciation and determination that the organism likely represents true infection rather than contamination or transient colonization. the american thoracic society and the infectious diseases society of america (ats/idsa) microbiologic diagnostic criteria for pulmonary disease based on sputum specimens call for at least two positive sputum specimens for the same species (kim et al., ) . concomitant recovery of filamentous fungi from airway specimens is also common in bronchiectasis, but the pathophysiologic consequences are not known. a recent study in cf patients found that a. fumigatus, like ntm, was commonly present in older patients: % of patients aged - years and in % of patients over age (valenza et al., ) . amin and colleagues further noted that cf patients who were chronically infected with a. fumigatus (defined as two positive cultures in a given year) had significantly worse airway obstruction as evidenced by a lower forced expiratory volume in one second (fev ) and significantly higher risk of pulmonary exacerbations during subsequent follow-up than patients without a. fumigatus (amin et al., ) . this potential negative impact on the course of bronchiectasis and a possible benefit from antifungal treatment for chronic infection in cf have prompted initiation of a multicenter clinical trial of itraconazole in cf patients in canada (amin et al., ; shoseyov et al., ) . in non-cf bronchiectasis, a recent study suggested that aspergillus is more common in patients infected with ntm than in those without ntm, and that it is commonly associated with fungal lung disease manifestations in ntm-infected patients (kunst et al., ) . however, outside the relatively small numbers of idiopathic bronchiectasis patients with allergic bronchopulmonary aspergillosis (abpa) or chronic necrotizing aspergillosis, the pathologic significance of these fungi has not been systematically explored in large numbers of patients and very few data are available for aspergillus species other than fumigatus or filamentous fungi other than aspergillus (kobashi et al., ; kunst et al., ; raju et al., ) . abpa is well described in association with bronchiectasis occurring in asthmatics and patients with cf (malde and greenberger, ) . the diagnostic criteria rely on an elevated total ige as well as elevated a. fumigatus-specific ige and igg in the setting of episodic bronchial obstruction, pulmonary infiltrates, and central bronchiectasis. kunst and colleagues assessed the prevalence of positive serologic markers for a. fumigatus [ige by radioallergosorbent test (rast) and precipitins] among idiopathic bronchiectasis patients and found these markers to be commonly present especially in the setting of concomitant ntm disease (kunst et al., ) . patients with these serologic markers more commonly had radiographic manifestations suggesting aspergillus-associated disease. while other filamentous fungi such as scedosporium species have been commonly recovered from the airways of both cf and non-cf bronchiectasis patients, the role these fungi play in disease pathogenesis remains controversial (cooley et al., ) . while specific ige antibody rast and precipitin assays can be prepared using allergen prepared from the isolated species and correlated with the clinical presentation of allergic bronchopulmonary mycoses, these assays have not been commonly used to characterize the clinical significance of these fungal species recovered from the lower airway (fedorova et al., ; lake et al., ) . copd is the fourth leading cause of death in the us (petty, ) and is expected to rank third in the world by (lopez and murray, ) . despite efforts aimed at smoking cessation, little impact has been made on copd incidence, and current treatments are ineffective in slowing progression of the disease. copd has been defined by the global initiative for chronic obstructive lung disease (gold) as "a disease state characterized by airflow limitation that is not fully reversible". the diagnosis of copd can also encompass those with chronic obstructive bronchiolitis and emphysema. tissue inflammation in copd is characterized by a predominant neutrophil, cd + lymphocyte, and macrophage infiltration (keatings et al., ; lacoste et al., ; o'shaughnessy et al., ; saetta et al., ) . it has been proposed that the mechanism of tissue damage involves the recruitment and activation of neutrophils, macrophages, and cd + t cells with concomitant upregulation of several cellular proteases and inflammatory cytokines. although smoking is clearly the leading risk factor for copd, not all smokers develop disease (buist and connett, ) . while smoking can stimulate inflammation in the lungs, smokers with copd have an increased inflammatory response than smokers without copd, and inflammation can persist despite smoking cessation (keatings et al., ; lacoste et al., ; o'shaughnessy et al., ; saetta et al., ) . these observations suggest that some other factor or factors contribute to development and perpetuation of the inflammatory response in copd. infection might be one such factor critical in triggering and perpetuating the inflammatory response in copd. the mechanism by which infections might act to promote copd progression has been termed the "vicious circle" hypothesis (sethi, a; sethi and murphy, ) . in this scenario, smoking causes structural remodeling that renders smokers more likely to become colonized and/or less able to clear subclinical infection. defects in mucociliary clearance and surfactant abnormalities caused by smoking also contribute to the tendency to develop chronic infection (finley and ladman, ; honda et al., ; raju et al., ; vastag et al., ; verra et al., ) . once colonization is established, the organism or organisms recruit white blood cells to the lungs, stimulating release of inflammatory cytokines and chemokines as well as proteases. inability to clear the inciting organism perpetuates the cycle, ultimately resulting in tissue destruction, airway thickening, and clinical copd. the most commonly implicated bacteria are h. influenzae, m. catarrhalis, s. pneumoniae, and p. aeruginosa (sethi, ) . viruses that seem to be important in copd include adenovirus, influenzae viruses, rhinovirus, respiratory syncytial virus, and human metapneumovirus (mallia et al., ; martinello et al., ; retamales et al., ; seemungal et al., ) . these pathogens can be found in patients with copd in the stable state and during exacerbations (sethi, ) . the colonization seen in patients with copd is likely playing a role in disease and is not just an innocent bystander. for example, as bacterial load increases, fev falls, and colonization has been associated with greater sputum purulence, increased sputum neutrophils, and increased levels of interleukin (il)- , tumor necrosis factor (tnf)α, and neutrophil elastase (obrian et al., ; patel et al., ; sethi, b; stockley et al., ) . exacerbations associated with viruses are more severe and last longer than those without a viral trigger (papi et al., ; seemungal et al., ) . in addition, exacerbations associated with both bacteria and viruses may be more severe than those associated with single organisms (obrian et al., ) , suggesting the usefulness of metagenomic techniques in this disease. colonization with the fungus pneumocystis jirovecii (pc, formerly pneumocystis carinii f. sp. hominis) has recently been implicated in copd pathogenesis. this organism generally causes acute pneumocystis pneumonia (pcp) in patients with immunosuppression such as those infected with hiv, but colonization with the organism occurs in both hiv + and hiv − individuals and may be important in copd. colonization with pc is increased in hiv patients with copd and correlates with disease severity (morris et al., b; probst et al., ) . animal models also support the role of pc colonization in copd. christensen and colleagues recently reported that in immunocompetent mice, exposure to cigarette smoke and pc colonization resulted in pulmonary function deficits and airspace enlargement characteristic of emphysema (christensen et al., ) . in a model of pc colonization in simian/human-immunodeficiency virus (shiv)-infected nonhuman primates (norris et al., ) , pc-colonized animals developed airway obstruction and radiographic emphysema while animals infected with shiv alone did not develop these changes (shipley et al., ) . although pulmonary infections and neoplasms associated with hiv have decreased since the availability of highly active antiretroviral therapy (haart) (palella et al., ) , some pulmonary conditions may actually be increasing in persons with hiv. diseases such as copd, asthma, and bronchiectasis were reported to be increased in those with hiv before the introduction of antiretroviral therapy, and a similar decrease in these conditions as seen in the opportunistic infections has not occurred after antiretroviral treatment of hiv. in fact, in a recent study of hiv + patients, almost % of deaths were due to obstructive airway disease in , a threefold increase from the pre-haart era (louie et al., ) . before the haart era, hiv + subjects were noted to have an accelerated form of emphysema with significant emphysematous disease seen in subjects less than years old (diaz et al., (diaz et al., , . both emphysema and airflow obstruction have been reported in hiv infection. unlike many of the acquired immunodeficiency syndrome (aids)defining opportunistic infections, hiv-associated copd may actually be more common in the current era of hiv as it is frequently reported in those without a history of aids-related pulmonary complications and the now aging hiv + population has a longer exposure to smoking and hiv. given the immunological defects seen with hiv, it is quite possible that hiv + subjects, especially those who smoke, are more prone to develop subclinical pulmonary infections, even if successfully treated with haart. the changes that occur in the lung microbiome have not been studied in hiv, but microbial colonization is a likely factor in the accelerated copd seen in this population. the vicious circle hypothesis of copd could be further worsened in hiv + patients by upregulation of hiv levels in the lung stimulated by pulmonary colonization. several studies have shown that pulmonary infections increase lung levels of hiv. koziel and colleagues reported that hiv rna was detected in % of patients with active lung disease compared to % of asymptomatic subjects, independent of clinical stage of hiv and serum hiv rna levels (koziel et al., ) . the lung appears to be an independent compartment for hiv replication as drug mutations found in bal differ from those in blood (white et al., ) . hiv in the lungs is associated with a lymphocytic alveolitis, particularly in those subjects with cd cell counts between and cells/μl, suggesting that the virus might act independently to stimulate pulmonary inflammation (twigg et al., ) . the relationship of hiv pulmonary viral levels, infections, inflammation, and copd has not been examined. pneumocystis colonization is likely important in the pathogenesis of copd in those with hiv as well as in the hivpopulation. in hiv + subjects, the prevalence of colonization is high, particularly if subjects smoke, and colonization is seen even in patients with high cd cell counts receiving haart (morris et al., a) . anatomic emphysema is also more common in hiv + patients with pc colonization (morris, unpublished data) . it has recently been shown that pneumocystis colonization in hiv + subjects is associated with worse airway obstruction and an increased likelihood of clinical diagnosis of copd, independent of smoking history and cd cell count ). in addition, the shiv-infected nonhuman primates described above serve as a model for the development of copd in the setting of pc colonization and hiv-like immunodeficiency (norris et al., ; shipley et al., in press ). microorganisms including bacteria, fungi, and viruses play a central role in development, exacerbation, and progress of lung diseases. even though normal lungs do not have a permanent resident microbiome, diseased lungs are acutely infected and/or chronically colonized. standard laboratory practices have not properly reflected the entirety of the microbiomes, either in health or in disease, and thus newer sequence-based technologies have begun to reveal the true complexity of the lung microbiomes. much more research still needs to be conducted in order to fully understand the microbial burden of the lungs, and how this burden relates to health and disease. it is apparent that conditions that compromise the physical and immune system barriers to lung colonization by microbes result in chronic colonization and recurrent infections. these conditions include chronic inflammation as seen in hiv, asthma, and bronchiecstasis, or physical obstruction observed in cf and bronchiecstasis. the lung microbiomes in each of these conditions has not been properly explored to date, which limits our ability to make definitive conclusions on how to best manage these diseases. our understanding of the fundamental role of viruses in the initial establishment and progress of asthma underscores how little knowledge exists on the role of viral infection in other chronic respiratory diseases. in addition, the fact that some bacterial populations and/or components seem to be protective against further and severe exacerbations in asthma opens the door to questions about the role of microorganisms in protecting against other diseases. the exact nature of this protection is not clearly understood, and great benefit would come from studies that further clarify these intriguing results. furthermore, if some population structures aid in preventing disease progression, it is likely that other population structures may predispose episodes of acute acerbations and progression of the underlying disease condition. a comprehensive understanding of the dynamics of these microbiome interactions would likely result in better, more efficient therapies for these and other respiratory diseases. our developing 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cystic fibrosis patients evidence of a causal role of winter virus infection during infancy in early childhood asthma role of infections in the induction and development of asthma: genetic and inflammatory drivers mycobacterial infection inhibits established allergic inflammatory responses via alteration of cytokine production and vascular cell adhesion molecule- expression use of the bronchofiberscope for bronchial brush biopsy. diagnostic results and comparison with other brushing techniques signature patterns revealed by microarray analyses of mice infected with influenza virus a and streptococcus pneumoniae characterization of vaginal microbial communities in adult healthy women using cultivation-independent methods key: cord- -h f fpd authors: naughton, matthew t.; tuxen, david v. title: acute exacerbations of chronic obstructive pulmonary disease and asthma date: - - journal: clinical critical care medicine doi: . /b - - - - . - sha: doc_id: cord_uid: h f fpd nan chronic obstructive pulmonary disease (copd) and asthma are conditions characterized by fixed and variable airflow obstruction, respectively. increased use of inhaled steroids and exacerbation management plans have resulted in decreased hospital and intensive care admission rates for asthma. the same is not true for copd. although both can have common overlapping clinical presentations (table . ) and are responsible for significant morbidity and mortality, with a demand on intensive care services, their etiology and management differ. copd is a condition in which permanent airflow obstruction occurs, associated with alveolar destruction (emphysema) and inflammation of the airway walls (chronic bronchitis). asthma is defined by variable airflow obstruction that is reversible, completely or partially, spontaneously or with treatment, and is associated with airway inflammation and increased airway responsiveness to a variety of stimuli. worldwide, it has been estimated that . billion people have copd, a prevalence expected to increase to . billion people by . in the united kingdom, % of men and % of women older than age years report a chronic cough with sputum, with % of men and % of women meeting diagnostic criteria for copd. in the united states, copd is estimated to occur in up to % of the adult community and result in million physician visits and , hospital admissions per year. copd is the fourth most common cause of death worldwide, accounting for % of all deaths-an age-adjusted rate that has risen from to , in comparison with those for cardiovascular disease and stroke, both of which have declined. the mortality of copd patients admitted to the hospital is %, exceeding that for myocardial infarction. risk factors for mortality in copd are low body mass index, degree of airflow obstruction as measured by fev , exercise limitation, and degree of dyspnea. survival can also be predicted by the paco ( fig. . ). asthma is estimated to occur in % of children and % of adults, with % to % of these having poorly controlled disease. life-threatening episodes occur in . % of patients. in the united states, asthma is responsible for . million emergency department visits per year, with in requiring overnight admission. new zealand, australia, and the united kingdom have the greatest prevalence rates. chapter matthew t. naughton and david v. tuxen • hypercapnic chronic obstructive pulmonary disease (copd) patients should be treated with noninvasive ventilation and supplemental oxygen sufficient to overcome hypoxemia but avoid hyperoxia. • intravenous or oral steroids in copd should be limited to to days in most cases. • in acute severe asthma, there is no proof that the intravenous administration of short-acting b-agonists has an advantage over adequate nebulized administration. • in severe asthma, dynamic pulmonary hyperinflation due to mechanical ventilation can result in hypotension, pnemothoraces, and, in very severe asthma, circulatory collapse with pulseless electrical activity (i.e., electromechanical dissociation). this can be acutely relieved with a -second apnea test and thereafter prevented by a slow respiratory rate and a long expiratory time with permissive hypercapnia. • following acute severe exacerbations of copd and asthma, precipitating factors should be sought and avoided or treated. patient-orientated action plans should be instituted to avoid further acute deterioration. ninety-five percent of patients with copd have tobacco smoking as a risk factor. other environmental factors include exposure to secondary tobacco smoke, air pollution, indoor fumes (e.g., indoor cooking with solid biomass fuel), and poor socioeconomic status. host factors are also important but, with the exception of a -antitrypsin deficiency, are poorly understood. although there is a clear familial prevalence of asthma, and several genes have been implicated, no single gene defined could allow for meaningful genetic planning. a number of other risk factors have been proposed, including ( ) inadequate exposure to allergens due to excessive antibiotic use, ( ) excessively clean dust-free environment (i.e., the hygiene hypothesis), ( ) excessive exposure to common allergic (e.g., house dust mite, pollen, and animal dander) or nonallergic triggers (e.g., cold air, exercise, and atmospheric pollutants), and ( ) exposure to medications that modulate airway control (e.g., aspirin and beta blockers). the increasing prevalence of asthma during the past years has been attributed to increasing environmental exposures. exposure to infections such as respiratory syncytial virus and parainfluenza (in children) and chlamydia (in adults) has been implicated as a risk factor. stress and socioeconomic status have also been implicated. in % of patients, no precipitant can be identified. reduction in expiratory airflow occurs because of increased airway resistance and reduced lung elastic recoil. airway resistance increases in the th-to th-generation airways as a result of mucosal inflammation, basement membrane thickening, edema, mucosal hypertrophy, secretions, and bronchospasm. loss of lung elastic recoil is due to destruction of lung elastin and reduction in alveolar surface tension. reduced elastic recoil decreases expiratory airflow by reducing the alveolar pressure driving expiratory airflow. forced expiration increases alveolar driving pressure but also causes dynamic airway compression, resulting in no improvement, or sometimes a reduction, in expiratory airflow. the importance of this factor is a function of the degree of emphysema in each individual patient. hypoxia and vascular wall changes lead to pulmonary vasoconstriction, pulmonary hypertension, cor pulmonale, and ventilation-to-perfusion heterogeneity. most commonly, smoking-related copd results in apical, rather than basal, disease ( fig. . ), whereas a antitrypsin deficiency usually causes basal emphysema. central respiratory drive may also be poorly responsive to the physiological trigger of hypercapnic acidosis, contributing to chronic hypercapnia. this may occur in the setting of sleep (i.e., obstructive sleep apnea), obesity, drugs (sedatives, antiepileptics, and alcohol), or metabolic disturbance (metabolic alkalosis). postmortem studies indicate that small airway narrowing occurs as a result of bronchial wall edema, inflammatory cell infiltrates, smooth muscle hypertrophy and hyperplasia, collagen deposition beneath the basement membrane thickening, and intraluminal secretions of eosinophilic inflammatory cells. eosinophils infiltrate the nerve bundles and release major basic protein, which antagonizes the inhibitory m muscarinic receptor present on parasympathetic nerve endings. the nocturnal (or circadian) exacerbation commonly seen in asthma is due to a combination of factors, including exposure to cool dry air, inhalation of excessive allergens related to bedding, and circadian changes in airway diameter and cortisol. in copd and asthma, pulmonary hyperinflation has both static and dynamic components. the static component is the increase in functional residual capacity (frc) that exists at the end of an exhalation that is long enough for all expiratory airflow to cease (i.e., - sec). this component of hyperinflation is primarily due to airway closure that occurs throughout exhalation. dynamic hyperinflation is the further increase in hyperinflation that occurs because of failure to complete exhalation before beginning the inhalation associated with the next breath. the extent of dynamic hyperinflation depends on the severity of airflow obstruction, the amount inspired (i.e., the tidal volume), and the expiratory time. thus, the degree of hyperinflation may vary with changes in tidal volume and/or respira- tory rate that occur in response to changes in co production (as a function of exercise, diet, fever, or the metabolic response to illness) or changes in dead space, as well as with changes in airflow obstruction that occur during an exacerbation. chest wall hyperinflation puts the inspiratory respiratory muscles at a mechanical disadvantage, increases the work of breathing, and predisposes patients to developing respiratory muscle fatigue. chronic use of corticosteroids, electrolyte disturbances, and/or other medications may also contribute to this problem. in copd, minor reductions in lung function due to infection, cardiac failure, or atelectasis increase the work of breathing by increasing airway resistance, lung stiffness, and/or dead space. this may result in rapid decompensation with ventilatory failure, acute hypercapnia, and respiratory acidosis as the tidal volume falls as a result of the increased volume of trapped gas and diminished respiratory muscle strength. during exhalation, use their accessory respiratory muscles for inhalation, are hyperinflated, and may develop right heart failure but only late in their course. in contrast, patients with a paco greater than mm hg are generally more obese, have depression of their hypoxic and/or hypercarbic ventilatory drives (which can be worsened by excessive oxygen, alcohol, sedatives, or analgesics), have sleep-related hypoventilation, and are more likely to develop right heart failure early. approximately % of patients with an acute exacerbation of copd will be hypercapnic, a portion of them as a result of excessive oxygen administration. acute exacerbations of copd seem to result from respiratory infections (~ %) or cardiac failure (~ %). the remaining % may have retained secretions, air pollution, coexistent medical problems (e.g., pulmonary embolus, gastroesophageal reflux, and medication compliance or side effects) or no cause can be identified (box . ). the most common bacterial isolates are streptococcus pneumoniae, hemophilus influenzae, streptococcus viridans, and moraxella catarrhalis. mycobacterium pneumonia and pseudomonas aeruginosa may also be found. viruses have been isolated in % to % of exacerbations. these include rhinovirus, influenza and parainfluenza viruses, corona viruses, and, occasionally, adenovirus and respiratory syncitial virus have been isolated in % to % of exacerbations. whether these organisms are pathogens or colonizers is often unclear. pneumonia may account for % of those presentations requiring mechanical ventilation. left ventricular systolic failure may result from coexisting ischemic heart disease, fluid overload, or tachyarrhythmias. diastolic dysfunction may occur secondary to right ventricular dilation. many of these patients have high levels of intrinsic positive end-expiratory pressure (peep) (or auto-peep), particularly during acute exacerbations, and this may decrease cardiac output by decreasing venous return. the increased work of breathing related to copd will also contribute to heart failure because blood flow distributed to the respiratory muscles may increase by up to -fold. in the absence of roentgenographic evidence of pulmonary edema, left ventricular failure may be difficult to diagnose. uncontrolled oxygen administration may precipitate acute hypercapnia in patients with acute copd exacerbations as a result of relaxing hypoxic vasoconstriction, thereby allowing increased perfusion to regions with reduced alveolar ventilation. although a reduction in hypercarbic drive was previously thought to account for this problem, the contribution of abnormal drive is limited. an accurate and detailed history is needed to distinguish asthma from other causes of dyspnea. classically, asthmatic patients will have wheeze, cough, and/or dyspnea occurring with exercise, at night, or with exposure to specific triggers. when asthma is mild, there is typically a prompt resolution following inhalation of short-acting b-agonists (sabas). the assessment of asthma severity (table . ) and triage is crucial. most commonly, patients with severe asthma have a history of previous hospitalizations for asthma (some that may be near fatal), low socioeconomic status, female gender, obesity, nighttime symptoms, fev less than % with optimal treatment, continual symptoms, reduced quality of life, use of oral or systemic steroids in the past months, use of more than canister of saba per month, elevated residual volume-tototal lung capacity (rv:tlc) ratio on pulmonary function testing, and a peak expiratory flow rate variability of more than % (i.e., variability-(bestworst)/best reading). a typical pattern is the progression over hours to days, occurring in the setting of a history of recurrent presentations. this form is associated with greater airway inflammation and generally responds poorly, or incompletely, to initial bronchodilator therapy but responds to steroid and bronchodilators over a few hours or days. less commonly, patients can present with hyperacute exacerbations, with the interval between the onset of symptoms and respiratory failure of less than hours. this form of asthma occurs in younger patients, more commonly male, with intervening normal lung function but with highly sensitive bronchial reactivity to triggers, which is attributed to marked bronchial smooth muscle contraction. this form of asthma responds to saba treatment within minutes to hours. physical examination should include assessment of speech (ability to speak in sentences, phrases, or words), oxygen saturation, heart rate, pulsus paradox, use of accessory muscles, chest auscultation, conscious state, and response to immediate inhaled bronchodilators. pulse higher than beats/min, respiratory rate higher than /min, and pulsus paradox more than mm hg indicate severe asthma. auscultatory findings of a silent chest may indicate extremely severe bronchospasm or the presence of pneumothorax. the diagnosis of copd is usually established prior to patient presentation, with respiratory failure based on history, clinical examination, and investigations. patients with copd usually have a history of smoking more than pack-years. in some settings, exposure to indoor solid fuel heating or cooking or a family history of a -antitrypsin deficiency may be causative or contributing factors. they may have a history of chronic cough and sputum production and describe exertional dyspnea and wheeze. in patients with mild, stable disease, an expiratory wheeze on forced expiration and mild exertional dyspnea may be the only findings. in patients with moderate disease, modest to severe exertional dyspnea is associated with clinical signs of hyperinflation and increased work of breathing. in severe but stable disease, marked accessory muscle use is seen in association with tachypnea at rest, pursed lip breathing, hypoxemia, and signs of pulmonary hypertension [right ventricular heave, loud and palpable pulmonary second sound, and elevated "a" wave in jugular venous pressure (jvp)] and cor pulmonale (elevated jvp, hepatomegaly, and ankle swelling). in severe unstable copd, there is marked tachypnea at rest, hypoxemia and tachycardia, and, in some cases, signs of hypercapnia (dilated cutaneous veins, blurred vision, headaches, obtunded mentation, and confusion). clinical examination may also identify associated medical conditions precipitating the exacerbation, such as pulmonary crepitations and bronchial breathing with pneumonia, crepitations and cardiomegaly related to heart failure, or mediastinal shift related to a pneumothorax. the severity of copd is best judged by assessing pulmonary function [i.e., peak expiratory flow rate (pefr)] or fev . the vital capacity (vc) is initially normal and decreases later in the course of the disease but to a lesser degree than the fev . an fev :vc ratio less than % with an fev % to % of predicted without a bronchodilator response usually indicates mild copd. a significant bronchodilator response (i.e., > % or > ml increase in either fev or vc) implies a diagnosis of asthma. an fev % to % predicted indicates moderately severe copd, and an fev less than % predicted indicates severe disease. although the diagnosis may be based on spirometry alone, further lung function testing may be useful to characterize sever-ity. flow volume curves demonstrate reduced expiratory flow rates and show the characteristic "concave" expiratory flow pattern. lung volumes measured either by helium dilution or by plethysmography show elevated tlc, frc, and rv. the rv:tlc ratio is characteristically more than %, representing intrathoracic gas trapping. the diffusion capacity, a measurement of alveolar surface area, is usually less than % predicted and is reduced in proportion to the extent of emphysema. chest x-rays will commonly show hyperinflated lung fields as suggested by flattened diaphragms (best seen on lateral cxr), evidence of emphysematous bullae, and/or a paucity of lung markings. pulmonary hypertension may be suggested by the presence of enlarged proximal pulmonary arteries, attenuated distal vascular markings, and right ventricular enlargement. high-resolution computed tomography (ct) scans show emphysema and can also confirm coexistent bronciectasis. such scans are less sensitive than standard chest ct scans ( -cm slice) for detecting pulmonary lesions (e.g., neoplasms) ( fig. . ). nuclear ventilation-perfusion scans show diffuse, well-matched, nonsegmental ventilation-perfusion abnormalities, with the degree of severity matching what is seen clinically. arterial blood gases are mandatory to assess the degree of hypoxia and hypercapnia and to determine the acid-base status. a serum bicarbonate level more than meq/liter indicates either renal compensation for a chronic respiratory acidosis or a primary metabolic alkalosis (e.g., diuretic therapy, high-dose steroids, or high-volume gastric fluid loss). renal compensation for chronic hypercapnia will increase the serum bicarbonate by approximately meq/liter for each mm hg of chronic paco rise above mm hg in order to return ph to the low normal range. the electrocardiogram (ecg) is commonly normal but may show features of right atrial or right ventricular hypertrophy and strain, including p pulmonale, right axis deviation, dominant r waves in v -v , right bundle branch block, and st depression and t wave flattening or inversion in v -v . these changes may be chronic or may develop acutely if there is a marked increase in pulmonary vascular resistance during the illness. the ecg may also show coexistent ischemic heart disease, tachycardia, and atrial fibrillation. occasionally, continuous ecg monitoring is required to identify transient arrhythmias, which may also precipitate an acute deterioration. as with copd, the diagnosis of asthma is usually apparent from history and examination. tests of airflow obstruction are needed to assess severity. a pefr of less than l/min or an fev of less than liter indicates a life-threatening asthma situation. these should be repeated to assess response to treatment. in mild to moderate asthma, arterial blood gases show a respiratory alkalosis as ventilation generally increases. in severe asthma, hypoxemia is present and can be easily corrected with supplemental oxygen with normal ph and paco . in fulminant disease, hypercapnic respiratory acidosis develops with more severe hypoxemia. the respiratory acidosis may be compounded by lactic acidosis if intravenous sabas (salbutamol, epinephrine, or isoprenaline) are used. occasionally, continuously nebulized salbutamol can produce lactic acidosis. the chest x-ray rarely shows consolidation but should be obtained regardless, seeking evidence of pneumothorax or chapter pneumomediastinum (fig. . ) . importantly, a chest x-ray will also assist in excluding other differential diagnoses, such as left ventricular failure and possibly inhaled foreign bodies. if pulmonary infiltrates are found, the possibility of allergic bronchopulmonary aspergillosis should be considered. serum ige and eosinophil levels can be obtained in the acute setting. if either is elevated, the diagnosis of "extrinsic" asthma is established and even more attention should be paid to seeking out a specific allergen. other causes of "asthma" should always be considered (e.g., inhaled foreign body, aspiration, left ventricular failure, pulmonary embolus, and pneumothorax). a new asthma exacerbation in an already hospitalized patient is more likely to be due to these causes than due to the asthma. oxygen given by low-flow intranasal cannulae ( - l/min) or % to % by venturi mask should be initiated with the goal of achieving an arterial saturation (saco ) of ± % because this will limit o -induced increases in paco (which occur most commonly in patients with initial paco > mm hg and ph < . ). if the rise in paco is excessive (> mm hg), consider reducing the fio to a sao of % or % versus increasing the level of noninvasive positive pressure ventilatory support. although high levels of o should be avoided (sao > %), reversal of hypoxia is important and o should not be withheld in the presence of hypercapnia nor withdrawn if it worsens. inadequate improvement of hypoxia with oxygen suggests that an additional problem is present (e.g., pneumonia, pulmonary edema, pulmonary embolus, or pneumothorax) and the diagnostic investigation should be broadened. while this is occurring, however, additional o should be administered to alleviate the hypoxemia. bronchodilators are routinely given in all exacerbations of copd because a small reversible component of airflow obstruction is common, and bronchodilators may also improve mucociliary clearance of secretions. anticholinergic agents have a similar or greater bronchodilator action than b-agonists in copd, and they also have fewer side effects and are not associated with the development of tachyphylaxis. anticholinergic agents should be used routinely in copd with acute respiratory failure, and many now believe them to be the agent of first choice. ipratropium bromide, . mg in ml, should be given either as a metered-dose inhaler (preferentially) or nebulized initially every hours and then every to hours. chronic use of a long-acting anticholinergic (i.e., tiotropium) reduces the incidence of exacerbations, but this agent should not be used in the intensive care setting. nebulized b-agonists are also effective bronchodilators in copd, although they may cause tachycardia, tremor, mild reductions in potassium and pao (due to pulmonary vasodilatation), and tachyphylaxis. sabas (e.g., salbutamol, terbutaline, or fenoterol) should be given by metered-dose inhaler or nebulizer every to hours in combination with ipratropium. the combination is more effective than either agent alone. con- tinuous inhalation is not recommended because this has been shown to increase side effects without augmenting the response to treatment. parenteral administration is also not recommended. in stable patients, long-term use of b-agonists may improve symptoms of dyspnea, particularly in the subgroup of copd with an objective bronchodilator response. long-acting b-agonists (labas) may also have a beneficial effect on symptoms, quality of life, and exercise capacity. aminophylline is a weak bronchodilator in copd. although studies suggest that it improves diaphragm contractility, stimulates respiratory drive, improves mucociliary transport and right heart function, is anti-inflammatory, and is a weak diuretic, other studies have shown no or small benefits and frequent side effects when given to patients with acute copd exacerbations. accordingly, the literature does not support including this medication in the treatment of acute exacerbations. short-term systemic corticosteroids improve the rate of airflow limitation in patients with acute copd exacerbations. current american thoracic society guidelines and cochrane reviews recommend a maximum dose equivalent to oral prednisolone at . mg/kg body weight for to days. steroids should be avoided if the deterioration is clearly due to bacterial pneumonia without bronchospasm. long-term oral steroids in copd are associated with a number of serious side effects (e.g., osteoporosis, diabetes, peptic ulcer, myopathy, systemic hypertension, fluid retention, and weight gain) that are likely to impair quality of life and precipitate readmission. accordingly, long-term use should be avoided whenever possible. a small group of patients (no more than % of the copd population) may have a more than % improvement in their fev following or weeks of systemic corticosteroids. in these patients, the dose should be tapered to the lowest possible that maintains this improvement, and alternate-day dosing and/or a trial of chronic inhaled steroids can be considered. in the majority of patients, long-term inhaled steroids do not improve lung function or survival (although a trial designed and supported by the pharmaceutical industry suggests they may improve quality of life and reduce hospital admissions). antibiotics have an accepted role in the treatment of infectioninduced exacerbations of copd. amoxicillin is a suitable firstline agent against h. influenzae, s. pneumoniae, and m. catarrahalis. if a chest x-ray suggests a component of pneumonia, then community-acquired pneumonia guidelines should be followed and treatment should include a tetracycline, macrolide, or fluoroquinolone. treatment of associated medical conditions, such as fluid overload (diuretics), left heart failure (digoxin and vasodilators), pneumothorax (intercostal drainage), pulmonary embolus (anticoagulation), and electrolyte correction, should be undertaken as appropriate. respiratory stimulants (e.g., acetazolamide, medroxyprogesterone, naloxone, doxapram, and almitrine) have no role because attempts to increase minute ventilation will increase dynamic hyperinflation and reduce muscle effectiveness and thereby increase work of breathing and fatigue. narcotic-or benzodiazepine-induced respiratory depression is best managed with the appropriate antagonistnaloxone or flumazenil, respectively. excessive carbohydrate calories should be avoided because this increases co production and may worsen respiratory failure. noninvasive ventilation (niv), a technique in which ventilatory support is provided via a nasal, facial, total face, or oral mask (fig. . ) , should be considered in hypercapnic patients. several randomized controlled trials have demonstrated improved respiratory physiology, reduced mortality, reduced iatrogenic complications, reduced need for intubation and mechanical ventilation, and reduced length of stay in hospital (table . and fig. . ) . all studies have shown good tolerance of the technique (~ % of patients) with few side effects and improvements in both oxygenation and paco compared with medically treated control patients. niv unloads the inspiratory respiratory muscles, thereby reducing the work of breathing and the attendant co production. this immediately improves respiratory acidosis, even if alveolar ventilation is unchanged. indications for niv to treat acute exacerbations of copd are acute dyspnea, respiratory rate higher than beats/min, or paco higher than mm hg with a ph less than . despite optimal medical treatment. although these indications include mild to moderate exacerbations, most randomized studies have used these as entry guidelines (table . ). copd patients liberated from invasive ventilatory support may also benefit from niv, although studies have questioned the utility of its use in this setting. side effects of niv include discomfort, intolerance, skin necrosis (fig. . ) , gastric distention, barotrauma, and aspiration. choice of mask is extremely important. face masks are generally preferred in the emergency setting, but if their use is complicated by air leaks, claustrophobia, discomfort, or nasal skin damage, then a larger face (head hood) may be better tolerated or more effective. nasal masks are more suited to long-term support and usually not recommended for an acute exacerbation. invasive ventilatory support may be required if respiratory failure progresses despite the previously discussed measures or if the patient is drowsy, uncooperative, or in extremis. the decision to ventilate requires careful consideration in some patients who may have near end-stage lung disease and whose quality of life may not justify aggressive treatment. obviously, this problem is markedly attenuated if primary care or outpatient specialty physicians appropriately address end-of-life issues with these patients prior to the acute exacerbation. the goals of invasive ventilatory support in copd are to allow respiratory muscles to rest and recover without causing them to atrophy from total inactivity and to minimize dynamic hyperinflation. a variety of approaches can be used, but pressure-support ventilation is frequently employed in milder exacerbations. since auto-peep exists in virtually every patient during an acute exacerbation, however, continuous positive airway pressure (cpap) should always be applied. the level of cpap should be adjusted and readjusted empirically, observing the work of breathing associated with inspiration (or by observing the esophageal pressure trace if this is being monitored). it cannot be adjusted on the basis of the airway pressure trace. pressure support should be titrated to achieve an adequate tidal volume ( - ml), adequate spontaneous rate (< breaths/min), and patient comfort without excessive minute ventilation (< ml/kg/min) or excessive correction of hypercapnia. more severely affected patients need continuous ventilation or synchronized intermittent ventilation; dynamic hyperinflation should be avoided by using a low minute ventilation ( /ml/kg is a guide). this should be achieved by the use of a small tidal volume ( ml/kg) and a ventilator rate less than breaths/min. plateau airway pressure (pplat) should be measured by applying an end-inspiratory pause of . second following a single breath. this maneuver shortens expiratory time, and if it is applied to a series of breaths it will increase dynamic hyperinflation, increase the pplat level, and increase the risk of volutrauma. if pplat exceeds cm h o, the ventilator rate should be reduced. if a higher minute ventilation is required for excessive hypercapnic acidosis, the degree of dynamic hyperinflation and its effects should be assessed using pplat. use of a high inspiratory flow rate is recommended because it results in a shorter inspiratory time and hence a longer expiratory time for a given ven- figure . . a series of arterial blood gases taken from a -yearold man with severe smoking-related copd (fev , ml) over hr who demonstrates acute hyperoxic-induced hypercapnia upon a background of chronic compensated hypercapnia. a reduction in inspired oxygen concentration and noninvasive ventilation prevented intubation and mechanical ventilation. despite presenting with severe hypercapnic acidosis and altered conscious state, the patient was suitable for discharge days later. tilatory rate, which in turn reduces dynamic hyperinflation and alveolar pressure and improves gas exchange. if dynamic hyperinflation is excessive (with attendant circulatory compromise and/or a risk of barotraumas), minute ventilation should be decreased, accepting the resulting hypercapnic acidosis. muscle relaxants should be avoided unless essential. normally, however, spontaneous ventilation should be encouraged to promote ongoing respiratory muscle activity and minimize wasting. flow-by, pressure support, and low-level cpap may all reduce the work of spontaneous breathing and promote a better ventilatory pattern. care must be taken with all these supports because each can increase dynamic hyperinflation by a different mechanism, leading to circulatory compromise or risk of barotrauma. flow-by increases resistance through the expiratory valve, pressure support increases tidal volume and may increase inspiratory time, and cpap increases functional residual capacity. patients who have been invasively ventilated for to days and have failed a trial of extubation with noninvasive ventilatory support may benefit from the insertion of a tracheotomy tube. this may be done via dilational (seldinger) or surgical techniques. generally, the former is more convenient, can be done in the icu, and heals more quickly upon removal. the advantages of a tracheostomy are that dead space is reduced; the endotracheal tube can be removed from the mouth or nose, thus reducing local irritation and sedation; and it facilitates suctioning. the disadvantages include nosocomial infection, local trauma, reduced capacity to cough effectively, and loss of natural humidification. protection of the airway from secretions that accumulate above the tracheostomy is not % even with the tracheostomy cuff inflated. appropriate reduction in time on ventilatory support with an awake cooperative patient, allowing for periods of some respiratory work to maintain muscle strength, is crucial before eventual cessation of ventilatory support and removal of tracheostomy. usually, tracheostomies can be safely removed if suctioning occurs less frequently than every hours and patients are capable of independent ventilation and coughing (i.e., adequate muscle strength and drive) and have no anatomic abnormality that would preclude natural ventilation. response to treatment within the first hours is an important predictor of outcome. the patient should be allowed to sit upright and be given humidified oxygen at flow rates that keep the oxygen saturation higher than %. the development of oxygen-induced hypercapnia may indicate either underlying copd with chronic hypercapnia or deteriorating progressive severe asthma. sabas (salbutamol, albuterol, tertbutaline, and isoprenaline) are the cornerstone of acute asthma management. salbutamol has b selective bronchodilator properties with minimal b mediated cardiac toxicity and is thus the first choice b-agonist. labas such as salmeterol or eformoterol should not be used in acute asthma management. the mode of bronchodilator delivery is an important consideration. multidose inhalers with spacer devices have the greatest penetration of drug into the lungs (~ %), are inexpensive, and should be used in patients with mild to moderate severity who are cooperative. in severe asthma or in uncooperative patients, nebulizers should be used; however, only approximately % of the drug reaches the lungs. nebulizers require to liters per minute gas flow to operate, and this can be achieved with an electric air pump or with pressurized oxygen or air. nebulized particle size ranges from to mm. intravenous delivery of b-agonist has no advantage over the inhaled route. in severe asthma, a standard approach is to initiate nebulized mg salbutamol with l/min oxygen every minutes in severe cases and every to hours in mild to moderate asthma. the volume of salbutamol should be made up to to ml with saline or short-acting anticholinergics. side effects of the b -agonists include tachycardia, arrhythmias, hypertension, hypotension, tremor, hypokalemia, worsening of ventilation-perfusion matching, and hyperglycemia. lactic acidosis (up to - mmol/liter) is a common, doserelated consequence of intravenous saba, appearing in as many as % of patients approximately to hours after initiation of treatment. when stable, sabas should be replaced with labas in combination with inhaled steroid cover. labas should not be used as single treatments in asthma because there have been reported events of increased mortality, particularly in african americans. anticholinergics should be used as an adjunct treatment to a saba rather than a single first-line treatment. again, metered dose inhalers are preferable, but the medication can also be administered via nebulizer (usual dosages are - mg every - hr). blurred vision may occur due to local effects on the eye. anticholinergic preservative-induced bronchospasm has been reported and should be considered in patients with persistent wheeze. systemic corticosteroids reduce hospitalization rates, mortality, and length of hospital stay in patients with asthma. their mode of action is to primarily decrease the inflammatory response and the associated bronchospasm and mucus secretion, with an onset of action to hours after administration. hydrocortisone ( - mg/kg) or methylprednisolone ( . - mg/kg) is given intravenously, or prednisone or prednisolone ( . - . mg/kg) is given orally every hours. these high doses are usually continued for to days or until clear clinical improvement is observed, after which they are tapered and replaced with inhaled steroids. side effects of steroids include hyperglycemia, hypokalemia, hypertension, acute psychosis, myopathy, and gastritis. longer term steroids are associated with additional problems, such as osteoporosis, cataracts, diabetes, oral thrush, and other secondary infections. aminophylline has bronchodilatory and a variety of other antiinflammatory properties due to its ability to inhibit phosphodiesterase. the role of theophylline in acute asthma is not clear due to conflicting results from clinical trials and its narrow chapter therapeutic window, and its side effects include vomiting, tachyarrhythmias, headaches, restlessness, and convulsions. it is a fourth-line agent following sabas, anticholinergics, and steroids. a usual dosage regime is a loading dose of mg/kg and infusion rate of . mg/kg. serum levels need to be monitored. several alternative treatments have been proposed, such as methotrexate, intravenous g-globulin, cyclosporine, colchicines, troleandomycoin, lignocaine, and magnesium sulfate, with either no or marginal effect. helium gas mixture has been used, as has the sedative ketamine, with similar marginal degrees of success. noninvasive ventilatory support has been used infrequently for several years in acute asthma, and only in recent years have reports confirmed its safety and efficacy. in addition to expiratory airway pressure countering the effects of auto-peep, inspiratory positive airway pressure may counter the increased inspiratory resistance. potential complications with noninvasive ventilation are patient-ventilator asynchrony, gas trapping (pulmonary or gastric), and decreased cardiac output from decreased venous return. careful monitoring, similar to that of an intubated patient, is required. this should be considered in patients with severe and lifethreatening asthma (table . ) who have failed medical treatments as listed previously. as in copd, the consequence of delayed expiratory airflow in asthma is that the inspired tidal volume cannot be completely exhaled to functional residual capacity and a proportion of each breath is trapped, impairing the arrival of each new breath. as lung volume increases, expiratory airflow also increases as a result of increasing small airway caliber and increasing elastic recoil pressure. this enables the lungs to inflate to an equilibrium point at which all the tidal volume is able to be exhaled during the expiratory time available. in mild airflow obstruction, this process is adaptive because it enables required minute ventilation to be achieved at a higher lung volume with only moderate loss of inspiratory muscle power. when airflow obstruction is severe, however, the equilibrium point may encroach on total lung capacity. the hyperinflation is the result of both airflow limitation and the increased minute ventilation required to provide a normal paco . complaints of needing ventilatory help, clinical appearance of exhaustion, deteriorating respiratory status, or reduced conscious state are more important indicators of the need for intubation than any specific paco . the first hours after intubation is the period of highest risk for ventilation-induced dynamic hyperinflation because airflow obstruction is often at its worst, co production and dead space are the highest, and hence the minute ventilation requirement is highest. at this time, patient respiratory distress and clinician desire to reduce hypercapnic acidosis can easily lead to a level of ventilation that results in excessive dynamic hyperinflation with risk of hypotension, pneumothoraces, and, uncommonly, circulatory collapse. as in copd, initial minute ventilation should be restricted to ml/kg/min ( liters/min for a -kg lean weight patient) or less, tidal volume ml/kg ( ml for a -kg lean weight patient) or less, and respiratory rate breaths/min or less. this should be delivered with a short inspiratory time (vi ≥ liters/min or ti ≤ . sec) to allow a long expiratory time (te ≤ . sec) to minimize dynamic hyperinflation. either pressure or volume control mode can be used to achieve this. volume control mode is more established, results in more reliable volume delivery, and is preferred by these authors. peep can be used to counter intrinsic peep, but the possibility of increasing lung volume further (as will occur if external peep exceeds intrinsic peep) must be kept in mind. external peep will only be necessary if the patient continues to have spontaneous ventilation and is unable to trigger the ventilation. generally, these patients receive heavy sedation to suppress their normal response to hypercarbia when their bronchospasm is so severe that sufficient alveolar ventilation cannot be accomplished. although some patients may require one or two bolus doses of neuromuscular blocking agents, these agents should be avoided if possible because of the concern for profound, long-term myopathy thought to occur more frequently in patients receiving the combination of neuromuscular blocking agents and corticosteroids. once initial ventilation is established, dynamic hyperinflation should be assessed by measuring pplat and auto-peep and observing the response of central venous pressure and blood pressure to a transient period of reduced respiratory rate or ventilator disconnection. if pplat is more than cm h o or circulatory improvement occurs, respiratory rate should be reduced and ventilation reassessed. if pplat is low (e.g., < - cm h o) and hypercapnia is present, respiratory rate may be increased. once asthma has improved, sedation may be reduced and spontaneous ventilation in cpap mode with pressure support can occur. cpap to cm h o can be introduced to match auto-peep and reduce work of breathing. hypotension can occur as a result of sedation, ventilationinduced dynamic hyperinflation, pneumothorax, hypovolemia, or arrhythmias. pplat is commonly higher than cm h o, but an equally important assessment for hypotension is the response of the blood pressure and central venous pressure to sec of ventilator disconnection ("apnea test"). circulatory arrest with apparent electromechanical dissociation is a recognized complication of severe asthma. it occurs usually within minutes of intubation and can result in severe cerebral ischemic injury and death if not recognized and managed appropriately. most patients can tolerate mechanical ventilation with ml/kg/min ventilation; however, a small number of patients with unusually severe asthma can develop life-threatening levels of dynamic hyperinflation despite this restriction in minute ventilation. in these patients, a -to second apnea test should be undertaken and ventilation resumed at the respiratory rate of to breaths/min. a common pitfall is the insertion of intravenous cannulae into the chest in the belief that this circulatory collapse is due to tension pneumothoraces. these procedures usually result in the complication they are seeking to relieve, and it is often difficult to know if a pneumothorax was initially present. apnea testing should precede intercostal cannulae, and, if possible, incision with blunt insertion technique should be used. pathophysiology of severe asthma. nhbli workshop the nature of small-airway obstruction in chronic obstructive pulmonary disease treatment of oxygen induced hypercapnia (correspondence) glucocorticoid for acute severe asthma in hospitalized patients global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. nhlbi/who global initiative for chronic obstructive lung disease (gold) workshop summary early use of noninvasive ventilation for acute exacerbations of chronic obstructive pulmonary disease on general respiratory wards: a multicentre randomised controlled trial non-invasive positive pressure ventilation for treatment of respiratory failure due to exacerbations of chronic obstructive pulmonary disease. cochrane database systematic rev fda safety alert sleep and sleep disordered breathing in adults with predominantly mild obstructive airway disease a pilot prospective randomized placebo controlled trial of bilevel positive airway pressure in acute asthmatic attacks chapter uncontrolled oxygen administration in copd inadequate use of noninvasive ventilation in copd excessive minute ventilation during mechanical ventilation circulatory collapse soon after intubation in patients with very severe asthma early intercostal cannula insertion during circulatory collapse development of myopathy due to prolonged muscle relaxation and steroids high-resolution ct scans not contiguous and thus may miss pulmonary lesions inadequate post-icu follow-up to recognize and treat precipitating factors etiology of acute exacerbation of copd and asthma dosage and duration of corticosteroids in acute copd and asthma role of noninvasive ventilation and acute exacerbations of asthma role of intravenous short-acting b-agonists development of hyperoxic hypercapnia in copd circulatory failure and pneumothoraces with mechanical ventilation myopathy lactic acidosis micro-macroaspiration of enteral feeds during sleep/supine position acute necrotizing myopathy is characterized by muscle weakness and histological evidence of myonecrosis, muscle cell vacuolization, and type ii muscle atrophy. myopathy ranges in severity from mild limb weakness to functional quadraparesis. diagnosis is made by elevated creatine kinase levels and electromyography. muscle biopsy is usually not required. there are no specific treatments and recovery is usually complete, but in severely affected patients significant weakness may still be present at months. boxes . , . , and . list the pitfalls, complications, and controversies. key: cord- -qyf vymf authors: sica, valentina; izzo, valentina title: pathophysiologic role of autophagy in human airways date: - - journal: autophagy networks in inflammation doi: . / - - - - _ sha: doc_id: cord_uid: qyf vymf lung diseases are among the most common and widespread disorders worldwide. they refer to many different pathological conditions affecting the pulmonary system in acute or chronic forms, such as asthma, chronic obstructive pulmonary disease, infections, cystic fibrosis, lung cancer and many other breath complications. environmental, epigenetic and genetic co-factors are responsible for these pathologies that can lead to respiratory failure, and, even, ultimately death. increasing evidences have highlighted the implication of the autophagic pathways in the pathogenesis of lung diseases and, in some cases, the deregulated molecular mechanisms underlying autophagy may be considered as potential new therapeutic targets. this chapter summarizes recent advances in understanding the pathophysiological functions of autophagy and its possible roles in the causation and/or prevention of human lung diseases. lung diseases are some of the most common medical conditions in the world. the lung has the principal aim to mediate gas exchange [ ] . for this reason, the lung can be subjected to several insults, belonging to the environment (inspiration of foreign matter, particles, smoke), reactive oxygen species (ros) production, biological origins (e.g., viruses, bacteria), changes in o tension, and mechanical stresses (e.g., mechanical ventilation). it is possible to discriminate between diseases affecting: (i) the airways (asthma, chronic obstructive pulmonary disease, chronic bronchitis, emphysema, acute bronchitis and cystic fi brosis); (ii) the interstitium (sarcoidosis, idiopathic pulmonary fi brosis, autoimmune diseases, pneumonias and pulmonary edemas); (iii) the blood vessels (pulmonary embolism and hypertension); the pleura (pleural effusion, pneumothorax and mesothelioma); (iv) the chest wall (obesity hypoventilation syndrome and neuromuscular disorders). the development of lung diseases can be associated to both acute and chronic exposure to such insults. however, in most conditions, a favouring genetic is necessary [ ] . yet, the lung has various inducible defence mechanisms to protect itself. first, constitutive and inducible stress protein and antioxidant defences; second, innate immune responses; third, pro-and anti-apoptotic mechanisms [ , , ] . several studies have recently pinpointed the emerging role of macroautophagy (more often and hereby referred to as autophagy) in lung homeostasis and diseases. autophagy is a catabolic process that involves the sequential sequestration of cytoplasmic material within double-membraned vesicles (autophagosomes), the fusion of autophagosomes with lysosomes, and the degradation of autophagosomal cargoes (as well as of structural autophagosomal components) by lysosomal hydrolases [ ] . autophagy is mediated by a genetically encoded, evolutionary conserved machinery that is connected to most, if not all, major biochemical processes of the cell, including core metabolic circuitries as well as signal transduction pathways initiated by plasma membrane receptors [ ] . basically, autophagy responds to three major organismal needs: ( ) it preserves cellular homeostasis in physiological conditions; ( ) it plays a key role in cellular adaptation to stressful stimuli; and ( ) it participates in the communication of states of the danger to the whole organism [ ] . indeed, autophagy continuously operates to mediate the disposal of potentially dangerous structures that may otherwise accumulate in the cytoplasm as a consequence of normal cellular activities, like old (and damaged) organelles or protein aggregates [ ] . moreover, the autophagic fl ux is highly responsive to situations in which intracellular or extracellular homeostasis is perturbed, which generally involves either an increased offer of autophagic substrates (as it occurs in the course of viral infection) or an increased need for autophagic functions or products (as it occurs in response to nutrient deprivation) [ ] . in both these settings, profi cient autophagic responses are required for the optimal adaptation of cells to stress, as demonstrated in experiments involving pharmacological inhibitors of autophagy or the depletion of essential components of the autophagic machinery [ ] . finally, autophagy is required for cells experiencing so-called "oncogenic stress" (i.e., the boost of cellular functions driven by activating mutations in one oncogene or loss-of-function mutation in one tumor suppressor gene) to become senescent (a cell-intrinsic oncosuppressive mechanism) while secreting immunostimulatory cytokines and expressing on their surface ligands for activatory natural killer (nk)-cell receptors (hence triggering a cell-extrinsic mechanism of tumor suppression) [ ] . along similar lines, cancer cells succumbing to a peculiar form of apoptosis known as "immunogenic cell death" are able to recruit antigen-presenting cells and hence trigger an adaptive immune response only if they secrete atp as they die, a process that requires profi cient autophagic responses [ , ] . it should be noted that autophagy has also been causally implicated in some instances of cell death, especially in lower organisms like drosophila melanogaster [ , ] . however, in mammals autophagy mainly mediates robust cytoprotective functions, and -when cellular homeostasis is irremediably compromised -contributes to the maintenance of organismal homeostasis by playing a role in danger signalling. in line with this notion, defects in the autophagic machinery have been associated with a wide panel of human pathologies, including (but not limited to) malignant diseases, neurodegenerative disorders, as well as cardiovascular, renal and pulmonary conditions [ ] . an accurate description of the autophagy pathway and its role in immunity and infl ammation has been provided in several previous chapters of this book; therefore, here we will focus on the impact of autophagic in the etiology and treatment of human pulmonary diseases. acute lung injury (ali) and the acute respiratory distress syndrome (ards) describe clinical syndromes of acute respiratory failure with substantial morbidity and mortality. ali is characterised by acute infl ammation that causes disruption of the lung endothelial and epithelial barriers. the ali cellular features include loss of alveolar-capillary membrane integrity, excessive transepithelial neutrophil migration, and release of pro-infl ammatory, cytotoxic mediators. the treatment of ali is predominantly based on ventilatory strategies [ ] . however, prolonged exposure to high oxygen therapy (hyperoxia) can result in lung injury [ ] . few studies are present in the literature concerning the role of autophagy in ali, even so these works support the hypothesis that activation of autophagy has a protective role in this disease. it has been demonstrated that prolonged hyperoxia, which causes characteristic lung injury in mice, induced the increase of lc ii expression. moreover, in pulmonary epithelial cells, the genetic depletion of lc sentitizes the cells to hyperoxia-induced cell death suggesting that lc activation confers cytoprotection in oxygen-dependent cytotoxicity [ ] . besides, the involvement of mitophagy has also been identifi ed. the ability to resist hyperoxia is proportional to pten-induced putative kinase (pink ) expression. in fact, the pink −/− mice were more susceptible to hyperoxia when compared to wild-type mice. furthermore, genetic deletion of pink or pink silencing in the lung endothelium cells increased susceptibility to hyperoxia via alterations in autophagy/mitophagy, proteasome activation, apoptosis and oxidant generation [ ] . chronic obstructive pulmonary disease (copd) is a chronic infl ammatory lung disease that causes breathing diffi culty, cough, sputum production and dyspnoea. emphysema and chronic bronchitis can contribute to copd development. emphysema is a condition resulting from a severe damage of air sacs (the alveoli). chronic bronchitis is due to infl ammation of the lining of the bronchial tubes. the lung damage that leads to copd is caused by long-term exposure to irritating gases or particulate matter, most often from cigarette smoke (cs), air pollution or workplace exposure to dust, smoke or fumes. however, a genetic susceptibility to the disease should be considered as an important cofactor. patients with copd present increased risk of developing other pathologies, such as heart disease or lung cancer [ ] . multiple molecular mechanisms, not fully understood, participate to the copd evolution and, among others, the involvement of the autophagic pathway has been pointed out [ , ] . in lung tissue from copd patients, an increase of autophagic vacuoles as well as several autophagy markers (lc , atg , atg / , atg ) expression has been detected [ ] . these evidences are perhaps a result of defective autophagic fl ux. to corroborate this hypothesis, an increased accumulation of p and ubiquitinated proteins and a decreased expression levels of sirtuin (sirt ) have been evaluated in lung homogenates from copd patients [ ] . kuwano and colleagues hypothesize that the insuffi cient autophagic clearance is involved in the accelerated cell senescence observed in copd [ , ] . the cs induces mitochondrial damage, accompanied by increased ros production in vitro . the cs-induced mitophagy was inhibited by pink and park knockdown, resulting in enhanced mitochondrial ros production. moreover, a decreased expression of park in copd lungs compared with non-copd lungs has been detected, suggesting that insuffi cient mitophagy is a part of the pathogenic sequence and cellular senescence of copd [ ] . in addition, a defective xenophagy has been observed in alveolar macrophages of smokers, suggesting that the deregulation of this selective process may contribute to recurrent infections [ ] . in contrast, other fi ndings indicate that autophagy has an opposite role in copd favouring the pathological environment. it has been shown that rtp (also known as redd ) expression is increased in human emphysematous lungs and in lungs of mice exposed to cs, whereas rtp knockout mice were protected against acute cs-induced lung injury. rtp inhibits mammalian target of rapamycin (mtor), by stabilizing the tsc -tsc inhibitory complex. the inhibition of mtor is linked to autophagy induction, but rtp expression enhances oxidative stress-dependent cell death, amplifying the development of cs-induced lung injury [ ] . furthermore, the higher expression of autophagy proteins has been linked to lung epithelial cell death, airway dysfunction and emphysema in response to cs. genetic depletion of lc b in vivo ( map lc b −/− mice) suppressed cell death and emphysematous airspace enlargement during chronic cs exposure compared to the wild type mice [ ] . more recently, the same group demonstrated that mitophagy regulates necroptosis, which contributes to the copd pathogenesis. mice defi cient for pink were protected against mitochondrial dysfunction, airspace enlargement and mucociliary clearance (mcc) disruption during cs exposure [ ] . interestingly, they identifi ed the contribution of a novel selective autophagy-dependent pathway that regulates cilia length, "ciliophagy", in the copd pathophysiological evolution. exposure to cs reduced cilia length and autophagy-impaired ( beclin +/− or map lc b −/− ) mice resisted to the cs-induced cilia shortening via a mechanism involving histone deacetylase (hdac ) [ ] . accordingly, it has been shown that autophagy negatively regulate ciliogenesis by the degradation of the essential ciliary protein ift [ ] . conversely, hedgehog (hh) signalling from primary cilia promotes autophagy [ ] and autophagy promotes ciliogenesis by degrading ofd (oral facial digital syndrome) at centriolar satellites [ ] . further studies are necessary to clarify the dual relationship between these processes [ ] . in conclusion, these studies illustrate that the contribution of autophagy in copd pathophysiology is complex and show a context-specifi c role depending on the cell type and tissue as well as on the different stimuli involved. interstitial lung disease (ild) is a general category that includes all lung diseases affecting the interstitium, the tissue and space that extends throughout both lungs. among them the most common are sarcoidosis and idiopathic pulmonary fi brosis (ipf). sarcoidosis is a systemic infl ammatory disease caused by persistent reaction toward a stimulus (virus or antigens) that continues even when it is physiologically cleared from the body. lung interstitium fi brosis is the fi rst symptom in patients with sarcoidosis. conversely, ipf is characterized by specifi c fi brosis at interstitial level due to the increased extracellular matrix (ecm) protein deposition and hyper activation of myofi broblasts [ ] . recently, reduced lc ii expression and p accumulation has been found in lung tissue from ipf patients [ ] . the reduced expression of the transcription factor foxo a in ipf fi broblasts could be the cause for the reduction in the levels of lc protein as the expression of this latter is positively stimulated by foxo a [ ] . furthermore, in fi broblast of ipf patients, decreased expression in beclin- protein and increased expression of the anti-apoptotic protein bcl- have been found, confi rming a defect in the autophagy pathway at different level [ ] . moreover, fi broblastic foci (ff), that are the starting point for fi brogenesis, are enriched in ubiquitinated proteins and p , confi rming the insuffi cient autophagy at the basis of ipf pathogenesis [ ] . autophagy inhibition is able to induce acceleration of epithelial cell senescence and fi broblast to myofi broblast differentiation (fmd), which have a critical role in ipf development [ ] . transforming growth factor-β (tgf-β ) is one of the essential mediators of fi brosis since it stimulates fi broblasts to produce fi bronectin and the smooth muscle-α actin (α-sma), which is a myofi broblast marker. autophagy has been associated to fi brosis through tgf-β . in fact, genetic deletion of lc or beclin increases tgf-β activity as well as in vivo treatment with rapamycin can protect from fi brosis [ ] . tgf-β expression seems to be dependent on il- a, a proinfl ammatory cytokine involved in chronic infl ammation and autoimmune disease. blocking il- a might reduce the progression of fi brosis promoting the autophagic degradation of collagen [ ] . recently, lacking of matrix metalloproteinases- (mmp- ) has been associated with exacerbated fi brosis in the hyperplastic alveolar epithelium of ipf lungs [ ] . additionally, mmp- -defi cient mice exhibit diminished atg c protein expression, demonstrating a direct correlation between these two pathways [ ] . similar evidences from an independent group corroborate the role of autophagy in promoting fmd. in fact, atg b-defi cient mice exhibited reduction in autophagic activity in lungs, collagen accumulation and increased protein levels of the myofibroblast biomarker α-sma [ ] . pharmacological treatment with the alkaloid barberine has been proposed for ipf monitoring because of its capacity to inhibit the activation of mtor and to increase the expression of lc and beclin in an bleomycin in vivo model of airway-fi brosis [ ] . furthermore, the multiple tyrosine kinase inhibitor nintedanib has recently been approved for the treatment of ips for its anti-fi brotic effect. it has been shown that nintedanib is able to reduce the expression of ecm proteins, fi bronectin and collagen as well as to induce a beclin dependent, atg independent autophagy [ ] . asthma is a chronic respiratory disease affecting million people worldwide. asthma manifests through several symptoms including wheezing, breathlessness, and chest tightness. asthmatic airways are characterized by chronic infl ammation, eosinophil infi ltration, epithelial fi brosis, mucus hyperproduction, and goblet cell hyperplasia [ ] . it is considered as chronic allergic infl ammatory disease, mostly mediated by a th response, but an initial th -type immune response seems to be the trigger for the subsequent th -type response [ ] . thus, th hyperactivation leads to persistent airway infl ammation and the occurring of asthma phenotype [ ] . emerging evidences suggest that activation of autophagy is associated with reduced lung function in asthmatic patients. in particular electron microscopy analysis of fi broblast and epithelial cells from asthmatic patients showed increased autophagic hallmarks "such as double membrane autophagosomes" compared to healthy patients [ ] . unfortunately, at present, the role of autophagy in asthma is still unclear. a recent study demonstrated that two single nucleotide polymorphisms (snps), namely rs and rs were associated with childhood asthma. in particular rs localises at the promoter of atg gene and could increase its expression in nasal epithelium of acute asthmatics compared to stable asthmatics and non-asthmatic patients [ ] . another intronic snp variant (rs ) in atg gene was also shown to be associated with pre-bronchodilator forced expiratory volume in second (fev ) in asthmatic patients [ ] . atg is an essential player in the initiation of autophagy, but its role in asthma pathogenesis is controversial. on one hand atg could help viral elimination through the activation of xenophagy, and on the other hand it negatively regulates the antiviral properties of type i interferon (ifn) inhibiting innate anti-virus immune responses [ , ] . together with these fi ndings, lungs from conditional atg knockout mice manifest hyper-responsiveness to cholinergic stimuli, which is a common sign of asthma and chronic infl ammatory diseases [ ] . asthma severity has been directly correlated with the level of autophagic response in the sputum granulocytes, peripheral blood cells and peripheral blood eosinophils of severe and non-severe asthmatic patients [ ] . autophagy is also involved in the maintenance of intracellular ros homeostasis, and it has been well established that oxidative stress is associated with asthma so that exhaled levels of hydrogen peroxide (h o ) and nitric oxide (no) are currently used as predictors of asthma severity [ ] . chronic asthma is characterized by excessive ecm deposition and proliferation of myofi broblasts, leading to fi brosis in the airway wall [ ] . the accumulation of fi brotic tissue is mostly due to the production of collagen a and fi bronectin by the primary human airway smooth muscle through a mechanism autophagy-dependent that involves the tgfβ . this response is reverted by the silencing of the major key autophagy-inducing gene atg and atg [ ] . as already mentioned, asthma is a pathology mostly driven by th -type cytokines. among them, il- is extensively produced in activated cd + th lymphocytes and is overexpressed in the airway epithelium of asthmatic patients [ ] . here, il- is thought to be responsible for epithelial hypertrophy, mucus hypersecretion, adventitial fi brosis and goblet cell hyperplasia [ ] . it directly induces hypersecretion of mucin ac, oligomeric mucus/gel forming (muc ac) in airway epithelial cell and oxidant stress through a mechanism that is autophagy-dependent, as demonstrated in vitro by depletion of atg or atg in primary human trachealbronchial epithelial cells [ ] . autophagy might be involved in the pathophysiology of alternaria (alt-e)associated asthma. alt-e is an outdoor allergen able to activate autophagy, which in turn stimulates epithelial cells to release il- [ ] . this latter when produced is able to stimulate th differentiation from naïve cd + t-cells and ifn-γ production by th cells. il- level in serum of asthmatic patients might refl ect the degree of disease exacerbation [ ] . cystic fibrosis (cf) is one of the most common lethal genetic diseases in caucasian population. it is an autosomal recessive disease caused by mutation in the cystic fibrosis transmembrane conductance regulator (cftr) gene. approximately out of caucasians are carriers for mutation in this gene. up to date over types of different mutations have been discovered and classifi ed according to the degree of functional cftr protein ( http://www.genet.sickkids.on.ca/statisticspage. html ; [ ] ). among these, the most common one is the f del-cftr. approximately % of cf patients have at least one f del-cftr allele, and about % are homozygous for it. the cftr channel is located at the apical surface of epithelial cells and it is deputized to move out cl − from the cell. na + passes through the membranes passively, increasing the movement of water by osmosis. loss of functional cftr expression is thought to alter this homeostatic balance through the epithelial layer, leading to net volume depletion of mucus, increased viscosity, and ineffective bacterial clearance [ , ] . recurrent pulmonary infections in turn induce an increased infl ammatory response and signalling, thus starting a vicious cycle of mucus retention, infection, and infl ammation. since the cftr is localized in many organs, cf symptoms could go from malabsorption at pancreatic level and gastrointestinal obstruction to male infertility and liver disease. nevertheless, the main cause of death remains persistent and untreatable pulmonary pseudomonas aeruginosa infection. several recent studies have demonstrated an impairment of autophagy in cf. in fact, in epithelial cells, mutated/unfunctional cftr causes increased ros production with consequent increase in tissue transglutaminase type (tg ) levels. tg , in turn, leads to crosslinking of several targets including beclin [ , ] . beclin interactome displaces from the endoplasmic reticulum (er) leading to the sequestration of class iii-phosphoinositide -kinase (pi k) complex, accumulation of p with consequent inhibition of autophagosomes formation. the resulting accumulation of aggresomes leads to proteasome overload and may promote the accumulation of mutated cftr in intracellular aggregates [ ] . restoration of beclin activity, depletion of p by genetic manipulation or treatment with autophagy-stimulatory proteostasis regulators, such as cystamine, functionally rescue the cftr mutated protein at the apical surface of epithelial cells both in vitro and in vivo [ ] . heme oxygenases are enzymes involved in the catabolism of the heme ring to generate carbon monoxide, biliverdin-ixα, and ferrous iron. the inducible isoform heme oxygenase- (ho- ) is activated in response to stress such as oxidative stress, hypoxia, heavy metals exposure and cytokines. ho- , together with its enzymatic products, is able to inhibit apoptosis and related cell death pathways, conferring tissue protection in case of lung or vascular injury [ ] . ho- could represent the link between cf and impaired autophagy since its expression is increased in human bronchial cf cells. this increase has been associated either to the reduction of apoptosis/injury during p. aeruginosa challenge either to the expression of infl ammatory mediators [ ] . other evidences suggesting the cytoprotective role of ho- in cf showed that lipopolysaccharide (lps)-challenged cf macrophages fail to compartmentalize ho- to the cell surface and this mechanism seems to be dependent on the reduction in caveolin- (cav- ) expression [ ] . in fact, when ho- localises at the plasma membrane, is able to form a complex with cav- , which in turn binds and detaches myd from its complex with tlr thus terminating the cell death signal [ ] . autophagic clearance of bacteria (so-called xenophagy) could also be impaired in case of disease, inducing increased bacterial infection that is one of the most frequent injuries in cf patients [ ] . in fact it has been demonstrated that burkholderia cenocepacia has the capacity to survive in f del-cftr macrophages since immediately after the engulfment, the bacteria resides on lc -positive vacuoles that appear as arrested autophagosomes [ ] . this capacity is directly correlated to the levels of p , so that its depletion leads not only to a decreased bacterial survival in macrophages but also to the release of beclin from aggresomes allowing its recruitment to the b. cenocepacia vacuole and bacterial clearance via autophagy [ ] . b. cenocepacia represents a serious threat for cf patients since the infection results in persistent lung infl ammation and the bacteria are resistant to most of all available antibiotics [ ] . similar fi ndings showed that pharmacological or molecular inhibition of autophagy reduces the clearance of intracellular pseudomonas aeruginosa in vitro [ ] . treatment of cf mice with the mtor inhibitor rapamycin decreases bacterial burden in the lungs and drastically reduces signs of lung infl ammation [ ] . in a normal situation, autophagy can help not only removing polyubiquitinated protein but also controlling bacteria clearance; for these reasons novel strategies aimed at restoring autophagy are emerging as promising therapeutic approaches for cf patients [ ] . aatd is a hereditary disorder characterized by a low serum level of alpha- -antitrypsin (aat), a kda serine protease inhibitor, member of the serpin family [ ] . aat is essentially synthetized in the liver and secreted into the bloodstream, where it controls tissue degradation by the enzyme neutrophil elastase. the defi ciency in aat is associated with liver and lung disease due to the loss of anti-infl ammatory and antiproteolytic functions. the majority of patients with aat defi ciency are homozygotes for a missense mutation ("piz mutation": lysine replaces glutamic acid at position ) that alters protein folding. mutant aat molecules polymerize and aggregate in the er of hepatocytes, forming large intrahepatocytic globules, the characteristic features of this disease. the proteasome is responsible for degrading the soluble form of att by means of er-associated degradation while autophagy is involved in disposal of insoluble att polymers and aggregates [ ] . in fact, a signifi cant accumulation of autophagic vacuoles was found in vitro and in vivo in liver cells from aatd patients as well as in piz mouse model [ , ] . whereas in absence of autophagy the degradation of aat was retarded [ ] . moreover, it has been demonstrated that the stimulation of autophagy by carbamazepine or rapamycin treatment or by liver-directed gene transfer of transcription factor eb (tfeb), a gene regulating lysosomal function and autophagy [ ] , reduce the hepatic amount of aat as well as the hepatic fi brosis in mice expressing mutant aat [ , , ] . although these results should be corroborated, altogether indicate that autophagy exerts a protective role in aatd and open a real possibility to treat aatd with pro-autophagic molecules. pulmonary hypertension (ph) was fi rst identifi ed in by ernst von romberg. ph is a severe and progressive disease that consists in increased blood pressure of lung vasculature and, often, can be a complication of chronic lung disease [ ] . since the pathology has been classifi ed, by the world health organization (who), in fi ve groups on the basis of mechanisms underlying the pathogenesis of the multiple types of ph. the role of autophagy in pulmonary hypertension has mainly been described in correlation with pulmonary arterial hypertension (pah), who group i. little is known about the aetiology of ph, one of the most frequent genetic mutations causing idiopathic inherited form of ph is found in the gene encoding bone morphogenetic protein (bmp) receptor type-ii (bmpr ). in pah, the pulmonary artery smooth muscle cells (pasmcs) proliferate excessively and are resistant to apoptosis. chloroquine, a known inhibitor of autophagy fl ux, has been described as a drug preventing experimental pah progression. the induction of pah, by monocrotaline, in rat is associated with increased autophagy and decreased bmpr protein expression. the inhibition of autophagy by chloroquine ameliorates the level of bmpr , inhibits the proliferation and stimulates apoptosis of rat pasmcs [ ] . a recent publication [ ] confi rms that the inhibition of autophagy, by overexpressing mtor, is a promising therapeutic strategy against pah. however, the role of autophagy in ph is still unclear and controversial, in fact, its protective role has been described in the initial phase of the pathogenesis of ph. histochemical analysis of samples obtained from human ph lungs and mouse exposed to chronic hypoxia, showed an increase in the lipidated form of lc and in egr- , which regulates lc expression. moreover, lc −/− or egr- −/− , but not beclin +/− mice are more susceptible to ph and in vitro lc knockdown cells showed an increase of hypoxic cell proliferation, suggesting a role for lc in the adaptation during vascular remodelling under hypoxia [ ] . in most organs, including the lung, autophagy robustly counteracts malignant transformation, i.e. , the conversion of a healthy cell into a (pre-)neoplastic cell, and several mechanisms related to the ability of autophagy to preserve cellular or organismal homeostasis account for such a pronounced oncosuppressive activity [ ] . indeed, besides being required for oncogene-induced senescence and anticancer immunosurveillance (see above) [ ] , autophagy promotes the maintenance of genomic integrity by multiple mechanisms [ ] . first, it mediates the degradation of damaged mitochondria, which are prone to overproduce genotoxic ros and other redox active entities of endogenous and exogenous origin [ ] . second, profi cient autophagic responses appear to be required for optimal dna damage responses [ ] . third, autophagy is involved in the disposal of potentially oncogenic retrotransposons and micronuclei [ ] . moreover, autophagy generally mediates anti-infl ammatory effects, and chronic infl ammation is known to accelerate oncogenesis (at least in some tissues, including the lung) [ ] . finally, it has been proposed that autophagy is required for the preservation of normal tissue architecture, in particular at the level of the stem-cell compartment [ ] . although little is known on the deregulation of stem cells in pulmonary carcinogenesis, it cannot be excluded that autophagic defects may promote malignant transformation in the lung also via this mechanism [ ] . conversely, the ability of autophagy to preserve genomic and redox homeostasis seems very relevant in the context of lung tumorigenesis, which in a signifi cant proportion of cases is associated with tobacco smoking or exposure to environmental nanoparticles like asbestos crystals [ ] . indeed, the oncogenic effects of both smoking and asbestos have been linked to their ability to cause ros overgeneration along with genetic/genomic defects and chronic infl ammatory responses [ ] . all these effects are limited, at least to some extent, by profi cient autophagic responses. irrespective of the precise mechanisms whereby autophagy counteracts malignant transformation in the lung, various genetic interventions aimed at specifi cally disabling autophagy in the lungs have been shown to promote malignant transformation driven by several oncogenes, including mutated b-raf proto-oncogene, serine/threonine kinase ( braf ) [ ] , epidermal growth factor receptor ( egfr ) [ ] , kirsten rat sarcoma viral oncogene homolog ( kras ) [ , ] . intriguingly enough, in one of these models, accelerated oncogenesis caused by the lung-specifi c inactivation of atg was linked to increased tumor-infi ltration by immunosuppressive cd + cd + foxp + regulatory t cells [ ] . moreover, the concomitant bi-allelic inactivation of serine/threonine kinase (stk , best known as lkb ) and phosphatase and tensin homolog (pten), two tumor suppressor genes that inhibit autophagy [ , ] , has been shown to cause the formation of pulmonary squamous cell carcinomas that express high levels of the immunosuppressive molecule cd (best known as pd-l ) [ ] . these latter observations strongly corroborate the notion that autophagy mediates not only cell-intrinsic, but also cell-extrinsic oncosuppression. the capacity of autophagy to preserve cellular homeostasis is benefi cial to healthy cells, but also benefi cial to transformed cells. this implies that autophagy often (but not always) promotes tumor progression, i.e., the growth and evolution of a transformed cells into an ever more malignant cancer [ ] . indeed, malignant cells are often exposed to relatively adverse microenvironmental conditions, including a shortage of nutrients and oxygen (especially in poorly vascularized tumor areas), and autophagy is instrumental for these cells (as it is for their non-transformed counterparts) to cope with stress and proliferate. along similar lines, the ability of autophagy to preserve stemness is benefi cial for the host when it preserves normal tissue architecture, but detrimental when it sustains the malignant stem-cell compartment. finally, autophagy supports the survival of malignant cells in key step of tumor progression, the so-called "epithelial-to-mesenchymal transition" (emt). in this context, epithelial cancer cells "initially growing in situ " physically detach from ecm and become able to colonize surrounding tissues as well as distant organs. the emt is required for all malignancies to become locally and distantly invasive, and critically relies on profi cient autophagic responses [ ] . in the presence of autophagic defects or pharmacological inhibitors of autophagy, indeed, malignant cells undergoing the emt and detaching from the ecm, succumb to a form of regulated cell death often referred to as "anoikis" [ ] . corroborating these observations, the genetic and/or pharmacological inhibition of the autophagic machinery in established tumors has been shown to accelerate disease progression in various models of pulmonary oncogenesis, including (but not limited to) braf -and kras -driven tumorigenesis [ , , ] . autophagy provides malignant cells with an increased resistance to various perturbations of homeostasis, including the lack of nutrient and oxygen that cancer cells normally experience in poorly vascularized tumor areas, as well as the presence of xenobiotics like chemotherapeutic agents and physical stress conditions like irradiation. an abundant amount of literature demonstrates indeed that chemical inhibitors of autophagy as well as genetic interventions that compromise autophagic responses accelerate (rather than inhibit) the demise of malignant cells exposed to a wide panel of chemotherapeutics or to irradiation, both in vitro and in vivo . these observations provided a strong rationale to the development of combinatorial therapeutic strategies involving chemo-or radiotherapy given in combination with an inhibitor of autophagy [ ] . clinical grade highly specifi c chemical inhibitors of autophagy, however, have not yet been developed, and currently available molecules that can be used in the clinic, like chloroquine (a widely employed antimalarial agent) often operate as lysosomal inhibitors, i.e., they target several processes other than autophagy [ ] . moreover, concerns have been raised that inhibiting autophagy at the whole-body level may de facto favor malignant transformation in healthy tissues, refl ecting the prominent oncosuppressive functions of autophagy in physiological conditions [ ] . finally, recent data highlight the differential role of autophagy in cancer therapy in immunocompromised versus immunocompetent hosts [ ] . in this setting, the response to radiotherapy of human non-small cell lung carcinoma (nsclc) or murine colorectal carcinoma (crc) cells xenografted in nude mice was significantly improved when cells were rendered autophagy-defi cient by the stable depletion of atg or beclin [ ] . however, when murine crc cells were implanted in immunocompetent syngeneic mice, the stable knockdown of atg compromised the therapeutic activity of irradiation, a defect that could be restored (at least in part) by the intratumoral administration of a chemical inhibitor of extracellular atpases [ ] . these fi ndings demonstrate that inhibiting autophagy in immunocompetent hosts may prevent the elicitation of a therapeutically relevant immune response against dying cancer cells. in summary, although autophagy generally (but not always) promote the progression of pulmonary malignancies and increases the resistance of lung cancer cells to chemo-and radiotherapeutic regimens, additional experiments are required to understand whether combinatorial treatments involving autophagy inhibitors constitute a clinically viable approach against pulmonary neoplasms. similarly, further work is needed to clarify whether biomarkers of autophagy such as the expres-sion levels of beclin or the lipidation of lc have a positive or negative prognostic/ predictive value in patients with lung cancer, as preliminary results are rather controversial [ , ] . abundant evidences indicate that autophagy actively participates in a wide range of cellular responses to both physiologic-and pathologic-related events in the diverse tissues and cell types that constitute the lung system. nevertheless, much is yet to be learnt about its biological relevance, functional targets, and role in development and disease. as described in this chapter, lungs are the fi rst line of defence against several insults and associated diseases are growing both in number and chronicisation. a clear deregulation of the autophagic machinery has been highlighted in most of the lung diseases, suggesting that this process mainly exerts a defensive role. however, in some pathological contexts, it has been reported that the activation of the autophagic process contributes to damage. as a consequence, a detailed knowledge of the molecular mechanisms at the basis of autophagy in lung pathologies is required for the development of novel diagnostic tools and promising therapeutic strategies. autophagy stimulation by rapamycin suppresses lung infl ammation and infection by burkholderia cenocepacia in a model of cystic fi brosis depletion of the ubiquitin-binding adaptor molecule sqstm /p from macrophages harboring cftr Δf mutation improves the delivery of burkholderia cenocepacia to the autophagic machinery autophagy in the pathogenesis of pulmonary disease regulation of autophagy during ecm detachment is linked to a selective inhibition of mtorc by perk autophagy mechanisms in sputum and peripheral blood cells of patients with severe asthma: a new therapeutic target essential role for the atg b protease and autophagy in bleomycin-induced pulmonary fi brosis oxygen toxicity and tolerance egr- regulates autophagy in cigarette smoke-induced chronic obstructive pulmonary disease autophagy protein microtubule-associated protein light chain- b (lc b) activates extrinsic apoptosis during cigarette smoke-induced emphysema oxidative stress and pulmonary fi brosis berberine inhibits smad and non-smad signaling cascades and enhancesautophagy against pulmonary fi brosis neutralizing tumor-promoting chronic infl ammation: a magic bullet autophagy, not apoptosis, is essential for midgut cell death in drosophila autophagy in infection, infl ammation and immunity il activates autophagy to regulate secretion in airway epithelial cells insuffi cient autophagy promotes bronchial epithelial cell senescence in chronic obstructive pulmonary disease essential versus accessory aspects of cell death: recommendations of the nccd metabolic control of autophagy autophagy in malignant transformation and cancer progression asthma and chronic obstructive pulmonary disease to be or not to be? how selective autophagy and cell death govern cell fate mitochondria and the autophagy-infl ammationcell death axis in organismal aging the bone marrow niche, stem cells, and leukemia: impact of drugs, chemicals, and the environment autophagy suppresses progression of k-ras-induced lung tumors to oncocytomas and maintains lipid homeostasis hallmarks of cancer: the next generation regulation mechanisms and signaling pathways of autophagy cystic fi brosis-associated liver disease an autophagy-enhancing drug promotes degradation of mutant alpha -antitrypsin z and reduces hepatic fi brosis alpha anti-trypsin: one protein, many functions reduced foxo a expression causes low autophagy in idiopathic pulmonary fi brosis fi broblasts on collagen matrices inducible disruption of autophagy in the lung causes airway hyper-responsiveness -mediated mitophagy is involved in regulation of hbec senescence in copd pathogenesis matrix metalloproteinase (mmp)- -defi cient fi broblasts display a profi brotic phenotype lkb modulates lung cancer differentiation and metastasis acute lung injury: epidemiology, pathogenesis, and treatment the atg atg conjugate associates with innate antiviral immune responses autophagy enhances bacterial clearance during p. aeruginosa lung infection autophagy and role in asthma intracellular inclusions containing mutant alpha -antitrypsin z are propagated in the absence of autophagic activity light-chain a autophagic activity and prognostic signifi cance in non-small cell lung carcinomas rapamycin reduces intrahepatic alpha- -antitrypsin mutant z protein polymers and liver injury in a mouse model consensus guidelines for the detection of immunogenic cell death the molecular basis for disease variability in cystic fi brosis autophagy inhibition radiosensitizes in vitro, yet reduces radioresponses in vivo due to defi cient immunogenic signalling immunogenic cell death in cancer therapy autophagy and the integrated stress response direct effects of interleukin- on epithelial cells cause airway hyperreactivity and mucus overproduction in asthma histone deacetylase -mediated selective autophagy regulates copd-associated cilia dysfunction autophagic protein lc b confers resistance against hypoxia-induced pulmonary hypertension mammalian target of rapamycin overexpression antagonizes chronic hypoxia-triggered pulmonary arterial hypertension via the autophagic pathway autophagic and tumour suppressor activity of a novel beclin -binding protein uvrag chloroquine prevents progression of experimental pulmonary hypertension via inhibition of autophagy and lysosomal bone morphogenetic protein type ii receptor degradation global burden of copd defective cftr induces aggresome formation and lung infl ammation in cystic fi brosis through ros-mediated autophagy inhibition autophagy and cellular immune responses the holy grail of cystic fi brosis research: pharmacological repair of the f del-cftr mutation tissue transglutaminase activation modulates infl ammation in cystic fi brosis via ppargamma down-regulation functional variant in the autophagy-related gene promotor is associated with childhood asthma autophagy suppresses tumor progression by limiting chromosomal instability casarett and doull's toxicology: the basic science of poisons blocking il- a promotes the resolution of pulmonary infl ammation and fi brosis via tgf-beta -dependent and -independent mechanisms the ampk signalling pathway coordinates cell growth, autophagy and metabolism mitophagydependent necroptosis contributes to the pathogenesis of copd autophagy: renovation of cells and tissues identifi cation of an autophagy defect in smokers' alveolar macrophages heme oxygenase- , a critical arbitrator of cell death pathways in lung injury and disease alternaria extract activates autophagy that induces il- release from airway epithelial cells hydrogen peroxide content and ph of expired breath condensate from patients with asthma and copd autophagy in cancer stem cells: a potential link between chemoresistance, recurrence, and metastasis functional interaction between autophagy and ciliogenesis gene transfer of master autophagy regulator tfeb results in clearance of toxic protein and correction of hepatic disease in alpha- -anti-trypsin defi ciency autophagy in idiopathic pulmonary fi brosis autophagy inhibition suppresses pulmonary metastasis of hcc in mice via impairing anoikis resistance and colonization of hcc cells autophagic disposal of the aggregation-prone protein that causes liver infl ammation and carcinogenesis in α - -antitrypsin defi ciency genetic and histologic evidence for autophagy in asthma pathogenesis novel mechanisms for the anti-fi brotic action of nintedanib a dual role for autophagy in a murine model of lung cancer cystic fi brosis airway fi brosis in asthma: mechanisms, consequences, and potential for therapeutic intervention autophagic removal of micronuclei decreased expression of autophagic beclin protein in idiopathic pulmonary fi brosisfi broblasts predominant th -like bronchoalveolar t-lymphocyte population in atopic asthma autophagy modulation as a potential therapeutic target for diverse diseases heme oxygenase- /carbon monoxide: from metabolism to molecular therapy autophagy in the lung autophagy in lung disease pathogenesis and therapeutics the biology and clinical relevance of the pten tumor suppressor pathway oxygen sensing, homeostasis, and disease tfeb links autophagy to lysosomal biogenesis organelle-specifi c initiation of autophagy autophagy sustains mitochondrial glutamine metabolism and growth of brafv e-driven lung tumors autophagy induction by sirt through attenuation of insulin-like growth factor signaling is involved in the regulation of human bronchial epithelial cell senescence hyperoxiainduced lc b interacts with the fas apoptotic pathway in epithelial cell death il- might refl ect disease activity in mild and moderate asthma exacerbation autophagy promotes primary ciliogenesis by removing ofd from centriolar satellites fasting in alpha -antitrypsin defi cient liver: constitutive activation of autophagy retention of mutant alpha -antitrypsin z in endoplasmic reticulum is associated with an autophagic response intracellular survival of burkholderia cepacia complex in phagocytic cells the heme oxygenase- /carbon monoxide pathway suppresses tlr signaling by regulating the interaction of tlr with caveolin- egfr-mediated beclin phosphorylation in autophagy suppression, tumor progression, and tumor chemoresistance cytoskeleton: autophagy and ciliogenesis come together loss of lkb and pten leads to lung squamous cell carcinoma with elevated pd-l expression current concepts on oxidative/carbonyl stress, infl ammation and epigenetics in pathogenesis of chronic obstructive pulmonary disease autophagy regulates tgf-beta induced fi brosis in human airway smooth muscle cells rtp , a suppressor of mtor signaling, is an essential mediator of cigarette smoke-induced pulmonary injury and emphysema matrix metalloproteinase- is a key regulator of lung fi brosis in mice and humans reduced caveolin- promotes hyperinfl ammation due to abnormal heme oxygenase- localization in lipopolysaccharide-challenged macrophages with dysfunctional cystic fi brosis transmembrane conductance regulator endothelial pink mediates the protective effects of nlrp defi ciency during lethal oxidant injury heme oxygenase- expression in human lungs with cystic fi brosis and cytoprotective effects against pseudomonas aeruginosa in vitro autophagic protein beclin serves as an independent positive prognostic biomarker for non-small cell lung cancer pulmonary expression of interleukin- causes infl ammation, mucus hypersecretion, subepithelial fi brosis, physiologic abnormalities, and eotaxin production mechanism of action of conventional and targeted anticancer therapies: reinstating immunosurveillance the authors report no confl ict of interest. key: cord- - btpqlxd authors: kato, akane; hanaoka, masayuki title: pathogenesis of copd (persistence of airway inflammation): why does airway inflammation persist after cessation of smoking? date: - - journal: chronic obstructive pulmonary disease doi: . / - - - - _ sha: doc_id: cord_uid: btpqlxd the structural features of airways in patients with copd are airway wall inflammation, fibrosis, muscle hypertrophy, and goblet cell metaplasia. these structural cellular changes contribute to mucus hypersecretion and destruction of the alveolar walls and a decline in forced expiratory volume in one second (fev( )). at the cellular level, macrophages, t lymphocytes, and neutrophils, driven by cytokines including interleukin- (il- ), gather on the airways. the main cause of copd inflammation is cigarette smoke. smoke causes an increase in the secretion of matrix metalloproteinase (mmps) and neutrophilic elastase from epithelial cells and neutrophils, which are responsible for mucin production and destruction of the lung. initially, cigarette smoke influences the expression of pattern recognition receptors (prrs) including toll-like receptors (tlrs), the intracellularly located nucleotide-binding oligomerization domain (nod)-like receptors (nlrs), retinoic acid-inducible gene i (rig-i)-like receptors (rlrs), and receptors for advanced glycation end products (rage) on lung epithelial cells, endothelial cells, and leukocytes in the lung. these actions bring about the production of cytokines and activation of inflammatory cells, leading to production of mmps and neutrophilic elastase. the inflammatory changes persist for several months and years after smoking cessation and are sometimes irreversible. damage-associated molecular patterns (damps) released from dying cells after cigarette smoking increase the number of apoptotic cells, suppress efferocytosis, induce hypoxia and oxidative stress, and prolong the inflammatory changes, even after smoking cessation. viral and bacterial infections of the respiratory tract then fortify these inflammatory responses. exacerbations of copd then worsen the deterioration of copd. global initiative for chronic obstructive lung disease (gold ) states that "smoking cessation is the single most effective and cost-effective intervention in most people to reduce the risk of developing copd and stop its progression (evidence a)." however, once a patient smokes and develops copd, the inflammatory changes persist through the innate and adaptive immune systems, which are commonly activated during infection. in this chapter, we will explain why the pathogenesis of copd progresses, even after smoking cessation, from the point of view of inflammation. the airway inflammation is related not only to the cigarette smoke itself but also viral and bacterial infections occurring before and after smoking cessation. first, the structural and cellular aspects of the inflammatory changes that are also seen with respiratory infection and that occur during copd formation will be described in general. then, the progression of copd after smoking cessation will be discussed. finally, the relationships between latent respiratory infections, copd exacerbations, and copd progressions will be reviewed. clinically, most copd patients are current or former smokers. in this chapter, we will first explain what happens in the airways of patients with copd. at the end of the peripheral airways are the alveoli, which are composed of type and type pneumocytes. bronchiolar patency is stabilized by surfactant secreted from alveoli. small airways adjacent to alveoli are lined by the epithelium. the epithelial cells are composed of two principal cell types-ciliated and secretory cells. secretory cells are further divided into goblet and clara cells [ ] . beneath the epithelium is the basal membrane, and further down the smooth muscle layer ( fig. . ) [ ] . the secretory cells release mucus, which contains mucins or large glycoproteins [ ] . mucins form polymers. two of the polymers, mucin ac (muc ac) and muc b, are highly expressed in the airways [ ] . in patients with copd, the development of airflow obstruction is associated with structural and cellular changes in both the peripheral and central airways. the structural level of peripheral changes involves airway wall inflammation, fibrosis, smooth muscle hypertrophy, goblet cell metaplasia, and lumen occlusion by mucus plugging [ ] . these are all possible causes of airflow limitation ( fig. . ) . however, despite that airway wall fibrosis can be a major contributor to the irreversible component of airflow obstruction in smokers with copd, the presence of a precise characterization of the fibrotic tissue in peripheral airways has never been reported [ ] . goblet cell metaplasia produces an excess of mucus, which can obstruct the lumen and alter the surface tension of the fluid lining the airway, rendering the peripheral airways unstable and facilitating their closure [ ] . mucus hypersecretion from hyperplastic airway goblet cells is a hallmark of copd [ ] . a recent study showed that chronic sputum production was significantly associated with both excess of fev decline and increased risk of subsequent hospitalization [ ] . airway wall inflammatory reaction contributes not only to the mucus hypersecretion described above but also to the destruction of the alveolar walls, allowing the airway wall to deform and narrowing the airway lumen [ ] . activated inflammatory cells are thought to release elastases, which destroy the lung tissue [ ] . the major sources of elastases in the lung are granulocytes and macrophages, and their products include leukocyte elastase, proteinase , mmps, cysteine proteinases, and plasminogen activators [ ] . because anti-elastin antibodies are found in patients with copd, it is thought that copd is also an autoimmune disease of elastin [ ] . mmp gene expression is regulated by numerous stimulatory and suppressive factors, including several cytokines and growth factors such as interleukin- α (il- α), il- , il- , and interferon-γ (ifn-γ) [ ] . mmps bring about not only muc ac accumulation but also the destruction of the lung that leads to emphysema. mmps probably participate in a proteolytic attack on the alveolar wall matrix [ ] . mmp is known as gelatinase b. it has multiple potential substrates including collagens, gelatin, elastin, and pro-mmp and . it is secreted by bronchial epithelial cells, neutrophils, eosinophils, mast cells, and alveolar macrophages. the development of airflow obstruction is associated with an increase of macrophages and t lymphocytes in the airway wall and of neutrophils in the airway lumen [ ] . although the mechanism of neutrophil accumulation in the airway lumen of smokers with copd is not entirely clear, it is possible that an imbalance between pro-and anti-inflammatory cytokines may play a role. for example, il- is a cytokine that promotes neutrophil chemotaxis, and tumor necrosis factor (tnf-α) is a cytokine that activates an increase in adhesion molecules [ ] . there is a shift in the balance of the cd -/cd -positive t lymphocyte ratio in favor of cd -positive ones [ ] . indeed, the cd -positive cytotoxic t lymphocytes infiltrate the central airways [ ] , peripheral airways [ ] , and lung parenchyma [ ] suggesting a consistent inflammatory process along the entire tracheobronchial tree in smokers with copd. inflammatory changes persist for several months after smoking cessation and are sometimes irreversible [ ] . the association observed between smoking and the incidence of copd is more likely to reflect an early interaction between tobacco exposure and genetic or immunologic host characteristics rather than the effect of the cumulative exposure to cigarette smoke [ ] . during cessation of smoking, the number of blood leukocytes immediately falls, goblet cell hyperplasia in the airway declines remarkably, and the number of macrophages and neutrophils in bronchoalveolar lavage fluid (balf) decreases. however, il- , and consequently neutrophils in the airways of ex-smokers, still remains higher than those in nonsmokers [ ] . a recent cross-sectional study in which bronchial inflammation was compared between smokers and ex-smokers in patients with copd [ ] showed that the cd þ, cd þ, and plasma cell numbers were significantly higher in the ex-smokers with copd than current smokers with copd. furthermore, compared with current smokers, the short-term ex-smokers showed significantly higher cd þ and cd þ cell numbers, whereas the long-term ex-smokers showed significantly lower cd þ cell numbers and cd /cd ratios and higher plasma cell numbers [ ] . these results indicate that the inflammation persists in the airways of patients with copd even after smoking cessation [ ] , though the progression of inflammation might attenuate gradually. unfortunately, once mild copd occurs, smoking cessation is not always effective in terminating the progression of copd. the alterations in squamous metaplasia, gland size, smooth muscle mass, and fibrosis after exposure to smoking do not always recover after smoking cessation [ ] , though the situation is much better than not quitting smoking [ ] . the hypersecretion of mucus, formation of emphysema, and fibrosis in copd begin with the inhalation of cigarette smoke, which acts on epithelial cells, macrophages, and t lymphocytes in the airway lumen. activation of epithelial growth factor receptor (egfr) is responsible for mucin production after inhalation of cigarette smoke in the airways [ , , ] . meanwhile, acrolein is one of the main cigarette smoke constituents, which increases muc ac-positive cells, lung mmp transcripts, and egfr/mitogen-activated protein kinase (mapk) signaling. these, in turn, contribute to muc ac accumulation in the airways [ ] . systemic administration of acrolein causes the stress response in the endoplasmic reticulum and lung cell apoptosis, and chronic administration leads to an enlargement of the alveolar air spaces and emphysema in rats [ ] . both the innate and adaptive immune systems are involved during the progression of the pulmonary inflammation that occurs in copd [ ] . lung epithelium is always exposed to external microbes in the air such that the innate and adaptive immune responses play important roles in reacting to those external pathogens [ ] . innate immunity is the first line of defense against foreign pathogens. contrary to adaptive immune responses by which we can obtain protective immunity throughout our lifetime against the same pathogens once we are infected, the innate immune response occurs only once, though it can react to diverse pathogens, including the varied constituents in cigarette smoke. the role of innate immunity in the airways involves detection of pathogen-associated molecular patterns (pamps) or damps by prrs including tlrs and nlrs ( fig. . ) [ ] . cells that are associated with innate immunity in the lung include macrophages, dendritic cells, monocytes, and neutrophils [ ] . the recognition of microbes is first done by prrs expressed in alveolar macrophages, dendritic cells, and epithelial cells. tlrs are a major family of prrs, and humans have ten kinds of tlrs to recognize pathogens. the tlrs associated with copd are tlr and tlr [ , ] . they usually recognize bacteria or viruses, but cigarette smoke can also induce pulmonary inflammation via tlrs [ ] [ ] [ ] . additionally, the interaction between tlrs and egfr increases il- and vascular endothelial growth factor (vegf) [ ] . through tlr stimulation, reactive oxygen species (ros) activate the latent form of tnf-α-converting enzyme (tace), which cleaves the transforming growth factor (tgf)-α proligand that activates egfr. this results in signaling that leads to il- and vegf production [ , ] . indeed, it was reported that cigarette smoke augments tlr , which stimulates il- release and increases total mmp activity in the airways [ ] . il- leads to the recruitment and activation of neutrophils in the airways (see sect. . . . ). nlrs represent a group of key sensors of infections and tissue damage in the lung [ ] . activation of most known nlrs leads to the production and release of proinflammatory cytokines and induction of cell death [ ] . ligand recognition by nod and nod receptors leads to signal transduction through receptorinteracting protein (rip ) kinase, with downstream activation of mapks and transcription factor nuclear factor-kappa b (nf-kb). this then leads to the activation of genes encoding different cytokines and chemokines such as il- [ ] . inflammasomes consisting of one or two nlr proteins serve as platforms for autocatalytic caspase- activation, which in turn critically regulates il- β and il- production, inducing an inflammatory form of cell death called pyroptosis. importantly, the nlr protein (nlrp ) inflammasome responds to a vast range of sterile stimuli particularly damps released by dying cells such as adenosine triphosphate (atp), uric acid metabolites, and biglycan as well as hyaluronan [ ] . experimental studies in mice suggest that activation of nlrps by some of those damps might have important functions in the pathogenesis of acute lung injury/acute respiratory distress syndrome (ali/ards), copd/emphysema, and lung fibrosis [ ] . rlrs, including rig- and melanoma differentiation-associated gene (mda- ), are important pattern recognition receptors for viral elimination [ ] . when viral rna binds to the c-terminal regulatory domain of rig- or mda- , it can initiate a signaling cascade. this cascade leads to activation and nuclear translocation of the transcription factors nf-kb and interferon regulatory transcription (irf- ), which are needed to turn on transcription of interferons (ifns) [ ] . viral infection is a significant cause of copd and acute exacerbations of copd [ ] . up to half of copd exacerbation cases are associated with viral infections [ ] . the top four causes are rhinovirus (rv), coronavirus, influenza virus, and respiratory syncytial virus [ ] . recent studies provide evidence that mda- is responsible for recognizing rv and subsequently activating signaling pathways, causing an exaggerated inflammatory response in patients with copd. these responses include increased levels of il- , il- , cxc-chemokine ligand (cxcl ), tnf-α, il- β, and monocyte chemotactic protein (mcp- ) [ ] . rage are members of an immunoglobulin superfamily of cell surface receptors that function as pattern recognition receptors capable of signal transduction after interaction with diverse ligands [ ] . rage is upregulated wherever its ligands accumulate in chronic conditions such as inflammation, cardiovascular disease, diabetes, cancer, and neurodegeneration [ ] . rage expression increases in the pulmonary epithelium when tobacco smoke is present [ ] . rage engagement activates an inflammatory signaling pathway. smoke-induced rage expression mediates cytokine secretions via ras, a gtpase that influences raf/map kinase, phosphoinositide -kinase (pi k), c-jun n-terminal kinase (jnk)/p , nf-kb [ ] , and the rho proinflammatory pathway [ ] . at minimum, rage signaling orchestrates polymorphonucleocyte recruitment and reservoirs of elastolytic enzymes including mmp and other mediators of emphysema regulated by rage signaling [ ] . recently, both soluble and circulating forms of rage were said to be the useful biomarkers for the presence or progression of emphysema because rage is generated via cleavage of full-length rage from the cell surface by metalloproteinases such as disintegrin, metalloproteinase domain-containing protein (adam ), and mmp [ ] . similar to the importance of the innate immune reaction, the adaptive immune system is also a necessary element in the mechanism of copd formation. animal models of autoimmune emphysema not related to cigarette smoke are known [ , ] . in this model, anti-endothelial cell antibodies (aeca) have been shown to trigger emphysema because of the reduction of the endothelium in the lung. little is known about the role of b cells in the development of copd [ ] . the presence of b cells in lymphoid follicles has been reported in the airways and parenchyma of patients with copd and of mice exposed to cigarette smoke [ ] . in mice, the development of lymphoid follicles was progressive over time and correlated with the increase in airspace enlargement [ ] . the b-cell follicles are surrounded by t cells, with the majority being cd þ [ ] . the b cells are interspaced by follicular dendritic cells that are necessary for antigen presentation and affinity maturation [ ] . follicle formation is associated with increased levels of cytokines including il- , il- , il- , and il- [ ] . these cytokines are essential for the formation and differentiation of germinal centers [ ] . overexpression of il- in mice results in severe emphysema [ ] . the absence of bacterial and viral products in the follicles suggests that oligoclonal b cells arise in response to lung antigens [ ] . nevertheless, viral and bacterial infections could be important in perpetuating the inflammatory process and are regarded as the main cause of the exacerbations in copd. barry et al. [ ] hypothesized that cigarette smoke-induced breakdown products of the extracellular matrix might also be immunogenic and trigger a specific b-cell reaction [ ] . it is likely that antigens from necrotic and apoptotic cells in the lungs of smokers are taken up by dendritic cells and presented as antigens to cd þ t lymphocytes [ ] . activated t cells leave the blood vessels and enter the lung parenchyma. in the lungs of smokers with copd, cd þ and cd þ t cells express the tissuespecific chemokine receptors cxcr , cxcr , and cxcr [ ] . these receptors correlate with the severity of the disease [ ] . in both the airway and alveolar compartments, the cd þ cytotoxic t cell is the predominant t cell in patients with copd and causes tissue injury [ ] . any cell that displays mhc class i can be a target of cd þ cytolytic t cells. after a cytolytic attack, target cells die of apoptosis or necrosis from the damage done by perforin, granulysin, or granzyme a or b (fig. . ) , all of which are proteolytic enzymes released by cd þ t cells [ ] in the lungs of patients with copd. cd þ t cells also play an important role in copd. the cytokine il- is a -kda molecule that is produced in vitro by cd þ and cd þ subsets of t lymphocytes from humans and mice [ ] . il- a signaling appears to be crucial for the formation of cigarette smoking-induced emphysema [ ] . the frequencies of th (cd þ il- þ) and tc (cd þ il- þ) cells in the lungs of smokeexposed mice and smoke-ceased mice are positively correlated with emphysematous lesions [ ] . il- a plays several important roles in copd formation. first, it causes lung destruction. il- induces il- , which is a chemoattractant for neutrophilic migration (fig. . ) . activated neutrophils and macrophages cause lung destruction through the release of oxygen radicals and proteolytic enzymes such as neutrophil elastase and mmps including mmp , mmp , and mmp (macrophage elastase) [ ] . as mentioned above for "the innate immune system," proteolytic enzymes cause cleavage of tgf-α proligands, which bind to egfr and lead to hypersecretion of muc ac [ ] . this results in the destruction of the extracellular matrix, tissue damage, and formation of emphysema. second, il- a leads to mucus hypersecretion. in addition to recruitment and activation of the epithelial cells in the lungs, il- a also induces muc ac expression together with il- β, tnf-α, cxcl , granulocyte colony-stimulating factor (g-csf), and intracellular adhesion molecule- (icam- ) in the lungs, resulting in hypersecretion of mucus [ ] . moreover, there is evidence that both il- and il- mediate muc b expression through the extracellular signal-regulated kinase (erk) signaling pathway [ ] . though the definition of emphysema is "non-fibrotic lesions," fibrosis is said to play an important role in copd, for example, pulmonary hypertension. in a recent study, il- β caused fibrosis in the lung. smad and nf-kb cooperate to mediate il- β and integrin α v β -dependent dendritic cell chemokine ccl expression [ ] . driving ccl expression involves integrin α v β -mediated activation of tgf-β [ ] . dendritic cell depletion or deficiency in the crucial dendritic cell chemokine receptor ccr protects cells from adenoviral il- β-induced adaptive t cell immune responses and fibrosis in the airways of mice [ ] . the average duration of smoking cessation before lung volume reduction surgery is . years [ ] , proving that copd deteriorates for several years after smoking cessation. the immunological changes in the lungs of copd patients during this period are key to understanding the mechanisms involved in this pathologic progression. needless to say, cigarette smoking is not a significant cause of the progression of copd after smoking cessation. before explaining the relationship between copd and infection after smoking cessation, we will first take a look at the mechanism of copd deterioration caused by copd itself. first, damps arise from the direct stimulation of acute exposure to cigarette smoke, but copd itself is a cause of damps. in copd, apoptotic cells are increased because of enhanced induction of apoptosis and deficient phagocytosis of the apoptotic cells by alveolar macrophages. the increased apoptosis of lung parenchyma leads to impaired resolution of inflammation. on the other hand, apoptosis of neutrophils followed by efferocytosis (the process by which dying or dead cells are removed by phagocytic cells) not only prevents damage but also induces an anti-inflammatory macrophage phenotype (m or alternatively activated macrophages). in a murine model of copd, acute cigarette exposure suppresses efferocytosis by alveolar macrophages (fig. . ) [ ] . failed efferocytosis of apoptotic neutrophils leads to secondary necrosis, resulting in the release of damps, neutrophil elastase, and other toxic components into the extracellular space [ ] . all of these might be recognized by prrs initially mediating the inflammatory response, eventually leading to worsening of copd. second, hypoxia is another factor involved in copd deterioration. recently, a close relationship between hypoxia and inflammation was identified [ ] . hypoxia could perpetuate inflammatory changes in copd [ ] . hypoxia seen in copd also promotes prolonged copd deterioration. under hypoxic conditions, hypoxiainducible factor α (hif α) translocates from the cytoplasm to the nucleus, inducing transcription of multiple genes, including those of tlrs and nuclear factor-kb, which are the influential factors in copd progression. hif α also prolongs the life span of neutrophils by inhibiting apoptosis and promoting copd progression [ ] . on the other hand, the decrease of hif α is reported to bring about emphysema or copd by reducing vegf [ ] . more research is necessary to clarify the impact of hif α on copd or emphysema. other factors include oxidative stress, which is discussed in another chapter. while smoking is a very important determinant for adult lung function and copd, there is a wide variation in adult lung function that is not related to smoking [ ] . an association between lower respiratory infections and adult lung function impairment is reasonably well documented (fig. . ) [ ] . viral infection plays an important role. recently, the subject of viral infection and copd was taken up mainly in the topic of copd exacerbation (mainly rhinovirus), but the groundwork of copd could already be set by respiratory viral infections during childhood, and adult lung function could be determined early in life [ ] . the estimates for individual childhood disadvantage factors such as maternal asthma, paternal asthma, childhood asthma, and severe respiratory infection were comparable to or larger than the estimate for smoking - cigarettes daily [ ] . one of the most well-known viruses in relation with copd is adenovirus. latent adenoviral infection may amplify inflammation and predispose to copd [ ] . double-stranded dna viruses have the ability to persist in the airway epithelial cells long after the acute infection has cleared. the expression of the adenoviral trans-activating protein has been demonstrated in the airway epithelium and is associated with an amplification of the cigarette smoke-induced inflammatory response and emphysema. in vitro, human airway epithelial cells with viral genes upregulate the expression of intercellular adhesion molecule (icam- ) and il- in these cells [ ] . human rhinovirus (hrv) is also a main virus of respiratory infection and closely related with copd. il- a synergistically enhances hrv type (hrv- )-induced epithelial production of neutrophil chemoattractant of il- [ ] . bacterial infection is also reported to be the cause of copd. tuberculosis is an important matter. the results of a nationwide survey of adults in south africa suggested that the strongest predictor of copd was a history of pulmonary tuberculosis [ ] , but other pathogenic bacteria are, of course, important. viral infections yield a negative chain of succeeding bacterial infections. preceding rhinovirus infections precipitate secondary bacterial infections in % of copd patients by the production of rhinovirus-induced neutrophil elastase and reductions in antimicrobial molecules [ ] . in copd, impaired innate lung defenses predispose patients copd progression apoptosis↑ phagocytosis↓ efferocytosis↓ hypoxia to microbial colonization and infection of the lower respiratory tract, which causes additional airway epithelial injury. this cyclical sequence of events amplifies chronic inflammation and perpetuates microbial infections. the frequency of chronic bacterial colonization and infection increases progressively with disease severity [ ] . in a study of bacterial colonization of the lower respiratory tract, potentially pathogenic bacteria were recovered in . % of patients with copd compared with . % in ex-smokers without copd and nonsmokers by means of bal culture. neutrophilia and decreases in macrophages were seen among subjects with copd after smoking cessation. additionally, patients with copd demonstrated increased levels of il- in the bal. copd patients also had increased levels of proteinase and proteinase inhibitors, including neutrophil elastase/ antineutrophil elastase (ne-a at) complex, mmp , and tissue inhibitor of matrix metalloproteinase- (timp- ) [ ] . in short, bacterial colonization in the lower respiratory tract is related to il- and neutrophils and could contribute to airway inflammation and progressive airway destruction and obstruction in copd [ ] . on the contrary, copd prolongs bacterial infections. the alveolar macrophage is a key defense against inhaled particulate matter and pathogens. indeed, the phagocytosis of bacteria such as haemophilus influenzae and streptococcus pneumoniae by alveolar macrophages is impaired in copd [ , ] . histone deacetylase (hdac) is a key molecule in the repression of proinflammatory cytokine production in alveolar macrophages, and its expression is diminished in copd patients [ ] . the decreased tlr expression on alveolar macrophages has also been observed in patients with copd, and the decrements in tlr expression in nasal and tracheal epithelium have been noted in severe copd [ ] . additional important factors of attacking infections in copd include the impairment of mucociliary clearance because the airway surface liquid is rich in endogenous antimicrobial polypeptides, including cationic polypeptides and collectins. several of these molecules also have important immunoregulatory functions [ ] . lastly, we look at the relationship between acute exacerbations and subsequent copd progression (fig. . ). there is a considerable new evidence that infection is the predominant cause of exacerbations and likely contributes to the pathogenesis of copd [ ] . viruses can be detected in - % of sputum samples from patients with copd and - % of those with copd exacerbations, depending on the sensitivity of the detection method [ ] . exacerbations of copd result in elevated levels of circulating fragments of structural proteins. this suggests that patients with copd have accelerated extracellular matrix turnover during exacerbations that is related to disease severity [ ] . the worsening of airway obstruction is also caused by viral infection in copd exacerbation. the cd þ t cells of balf from patients with copd showed a mixed th and th cell cytokine phenotype during acute rhinovirus infection [ ] . though th -biased immunity has previously been linked to the immunopathology of copd and emphysema, th as well as th bias is seen in acute exacerbations of copd [ ] . hrv-encoded proteinase a induces strong th and th immune responses from cd þ t cells, implicating this microbial proteinase as an adjuvant factor during respiratory tract infections in patients with copd. th induces the production of cytokines such as il- , il- , ifn-γ, and il- , which causes an asthma-like attack [ ] . this mechanism of the worsening obstruction in acute exacerbations of copd triggered by viral infection could accumulate the inflammatory microbes and particles, such as the bacteria themselves and the related damps and pamps, in the respiratory airways, eventually accelerating copd deterioration. copd deterioration is not just the result of exposure to substances in cigarette smoke. the progression of copd is associated with delayed immunological reactions caused by neutrophils, macrophages, and lymphatic cells and the cytokines secreted by these cells. the viral and bacterial infections accelerate pathological processes in the respiratory tract, even several years after smoking cessation. in view of these, airway inflammation persists after smoking cessation. airway mucus function and dysfunction the nature of small-airway obstruction in chronic obstructive pulmonary disease the impact of smoking cessation on respiratory symptoms, lung function, airway hyperresponsiveness and inflammation cellular and structural bases of chronic obstructive pulmonary disease activation of epidermal growth factor receptors is responsible for mucin synthesis induced by cigarette smoke inhibition of vegf receptors causes lung cell apoptosis and emphysema acrolein-activated matrix metalloproteinase contributes to persistent mucin production series "matrix metalloproteinases in lung health and disease": matrix metalloproteinases in copd airway mucosal inflammation in copd is similar in smokers and ex-smokers: a pooled analysis end-stage chronic obstructive pulmonary disease: the cigarette is burned out but inflammation rages on improving the diagnosis and management of copd cigarette smoke total particulate matter increases mucous secreting cell numbers in vitro: a potential model of goblet cell hyperplasia acrolein induces endoplasmic reticulum stress and causes airspace enlargement critical role of rig-i-like receptors in inflammation in chronic obstructive pulmonary disease new insights into the immunology of chronic obstructive pulmonary disease molecular processes that drive cigarette smokeinduced epithelial cell fate of the lung cigarette smoke-induced pulmonary inflammation is tlr / myd and il- r /myd signaling dependent smoking decreases the response of human lung macrophages to double-stranded rna by reducing tlr expression cigarette smoke augments the expression and responses of toll-like receptor in human macrophages multiple tlrs activate egfr via a signaling cascade to produce innate immune responses in airway epithelium regulation of interleukin- via an airway epithelial signaling cascade autocrine ligands for the epidermal growth factor receptor mediate interleukin- release from bronchial epithelial cells in response to cigarette smoke nod-like receptors in lung diseases conditional overexpression of receptors for advanced glycation end-products in the adult murine lung causes airspace enlargement and induces inflammation circulating soluble receptor for advanced glycation end products(srage) as a biomarker of emphysema and the rage axis in the lung an animal model of autoimmune emphysema immunomodulatory strategies prevent the development of autoimmune emphysema cigarette smoke-induced emphysema: a role for the b cell? immunologic aspects of chronic obstructive pulmonary disease persistence of th /tc cell expression upon smoking cessation in mice with cigarette smoke-induced emphysema stimulation of airway mucin gene expression by interleukin (il)- through il- paracrine/autocrine loop transforming growth factor-β and interleukin- β signaling pathways converge on the chemokine ccl promoter a critical role for dendritic cells in the evolution of il- β-mediated murine airway disease hypoxia and inflammation hypoxia inducible factor- α in human emphysema lung tissue early life origins of chronic obstructive pulmonary disease role of latent viral infections in chronic obstructive pulmonary disease and asthma interleukin- a modulates human airway epithelial responses to human rhinovirus infection rhinovirus infection induces degradation of antimicrobial peptides and secondary bacterial infection in chronic obstructive pulmonary disease airway inflammation and bronchial bacterial colonization in chronic obstructive pulmonary disease infection in the pathogenesis and course of chronic obstructive pulmonary disease decreased histone deacetylase activity in chronic obstructive pulmonary disease accelerated extracellular matrix turnover during exacerbations of copd human rhinovirus proteinase a induces th and th immunity in patients with chronic obstructive pulmonary disease key: cord- -sqr y authors: nan title: paediatric sig: poster session date: - - journal: respirology doi: . /j. - . . _ .x sha: doc_id: cord_uid: sqr y nan increased airway smooth muscle (asm) in asthma may be due to hyperplasia or hypertrophy of asm cells. the contribution of extracellular matrix (ecm) within asm bundles has not previously been accounted for when estimating asm cell volume. aim to estimate the mean asm cell volume in asm bundles in asthma. methods post-mortem tissues from control subjects (c n = ); nonfatal (nfa n = ) and fatal (fa n = ) cases of asthma were studied. on mm transverse airway sections stained with haematoxylin, the volume density (nv) of asm cell nuclei was estimated using an optical disector (¥ ). the mean cell volume (vc = /nv) was calculated, correcting for the volume fraction of asm (fasm) within the asm bundle (corrected vc = /(nv ¥ fasm)). fasm was estimated on . mm thick sections of the same airway stained with masson's trichrome. basement membrane perimeter (pbm) was used to indicate airway size. results table shows mean Ϯ sd. (one-way anova) *p < . for c v fa, nfa v fa. conclusion these data suggest that although asm area is increased in asthma, mean asm cell volume is unchanged. therefore hyperplasia, not hypertrophy, of asm cells is present in both mild and severe asthma. these results were similar for both large and small airways. asthma is characterized by airway inflammation and remodelling which contribute to airway hyperresponsiveness and episodic airflow obstruction. mast cell (mc) densities are higher on the smooth muscle (asm) in asthma so their mediators may modulate other asm functions as well as cause contraction. aim to investigate the effect of mc mediators on chemokine and extracellular matrix (ecm) production by asm cells from donors with and without asthma. methods mc were isolated from the resected lung samples of patients, resuspended at cells/ml in dmem + % fbs and stimulated with ige/anti-ige. supernatants (sn) were collected after and h and the mc lysed. sub-confluent asm cells from donors with and without asthma were serum deprived for h before mc sn/lysates were added in dmem + %fbs for h. il- and eotaxin levels in all asm sn and mc sn/lysates were measured by elisa. fibronectin and collagen iv deposition was measured in situ by immunoassay following asm cell lysis. results in asthmatic and non-asthmatic asm cells all mc sn and lysates reduced eotaxin release by up to % and %, whereas the - h mc sn significantly increased il- release to Ϯ . % (p = . ) and Ϯ % (p = . ) of the fbs control respectively. however, only nonasthmatic asm cell il- release was increased by the mc - h sn ( Ϯ %; p = . ) and cell lysates ( Ϯ %; p = . ). the - h mc sn also increased fibronectin deposition to Ϯ % (p = . ) by asthmatic asm cells only. mc sn and lysates had no effect on collagen iv deposition. conclusions activated mast cell mediators differentially modulated chemokine and ecm secretion by asm cells from donors with and without asthma. thus mast cells may modulate their own recruitment to the smooth muscle and remodelling locally in the airways in asthma. supported by nhmrc. the technique of ige passive sensitization reproduces ige-related allergic responses in vitro and studies have validated this technique for investigations modelling allergic smooth muscle responses. there are no studies investigating effects of ige sensitization on rhinovirus (rv) infection. we hypothesized that rv infection is enhanced by ige sensitization, a consequence of diminished early innate immune responses. methods beas- b epithelial cells and primary culture airway fibroblasts were sensitized with ige h- d prior to infection with rv . samples of tissue culture supernatant and cell lysates were collected over a h period after infection for analysis. viral replication was measured by real-time rt-qpcr and viral titration and type i interferon mrna by rt-qpcr. ige receptor mrna expression was examined using rt-pcr. results initial studies to establish the model used human serum high in ige (> iu/ml), this yielded inconsistent results and it was found that purified ige ( iu/ml) provided more reliable responses. sensitization was established after h ige incubation and was comparable with up to d. rt-pcr detected mrna for the ige low affinity receptor only after sensitization. following rv infection, vrna was increased after h in ige sensitized cells (p < . ), but this effect varied noticeably between and within cell lines. cellular expression of ifn-b mrna increased with viral infection but in cells sensitized with ige lower levels of expression were noted (p < . ). conclusions ige passive sensitization enhanced rv replication in vitro but the model is constrained by significant variability between and within cell lines. the effect of sensitization on rv replication may occur through the low affinity ige receptor. activated mast cells (mc) are present in higher numbers on the airway smooth muscle (asm) in asthma compared with other inflammatory airway diseases. matrix metallo-proteinases (mmps) cleave chemokines and alter chemokine gradients by degrading the extracellular matrix and thus may modulate mc migration to the asm. aim to determine the levels of mmp- , mmp- and their inhibitors, timp- and timp- , secreted by asm cells from donors with and without asthma. method confluent asm cells were washed, serum-starved for h and then stimulated with th (il- , tnf and ifn) or th (il- , il- and il- ) cytokines or left unstimulated. after and h,the sn were collected. the relative amount of pro and active forms of mmp- and mmp- in sn were determined by gelatine zymography. timp- and timp- levels in the sn were measured by elisa. results pro-and active mmp- were not detected. however, pro-mmp- levels were high in sn of asm cells from donors with ( . Ϯ . % positive control/ cells) and without ( . Ϯ . % positive control/ cells) asthma. a trend to increased active mmp- production by asm cells from donors with ( . Ϯ . % positive control/ cells, n = ) compared to without ( . Ϯ . % positive control/ cells, n = ) asthma after h was not significant (p = . ). timp- and timp- levels respectively were high in the sn of cells from donors with ( . Ϯ . and . Ϯ . ng/ cells, n = ) and without ( . Ϯ . and . Ϯ . ng/ cells, n = ) asthma. th and th cytokine stimulation did not affect mmp or timp release. conclusions th and th cytokines did not regulate asm cell production of mmp- , timp- and timp- . altered asm mmp- activity is unlikely to play a role in mc chemotaxis to asm cells from donors with asthma in vitro or their presence on the asm in asthma. there has been a marked increase in the prevalence of asthma and other allergic diseases in the last few decades. one of the explanations for this is the change in our diet. one of the characteristics of the "western diet" is a high intake of both saturated and polyunsaturated fat. this prompted us to compare the effects of high fat and low fat meals on the numbers of circulating eosinophils and other leukocytes. methods we studied volunteers who had allergic rhinitis and/or asthma and a peripheral eosinophil count at baseline of Ն ¥ /l. this was a randomized, crossover trial with participants studied on two different days. on each occasion they arrived fasting and after bloods were drawn consumed a calorie meal. one of the meals was high in saturated fat and refined carbohydrate. the other meal was low in saturated fat and high in fruit and fibre. bloods were drawn postprandially every hour for five hours. results eosinophil counts were highest in the early morning and fell over the course of the day but the decrease was less with the high fat meal (p = . ). over the same period of time the increase in lymphocytes (p = . ) was greater with the high fat meal. the high fat meal was also associated with greater increases in triglycerides (p < . ) and cholesterol ( . ). conclusions in atopic individuals a high fat meal was associated with higher circulating numbers of eosinophils and lymphocytes than an isocaloric meal that was low in fat. further studies of the effect of dietary fat on eosinophilic inflammation are warranted. supported by the university of auckland research committeee. intravenous gamma globulin therapy (ivig), which is therapeutic in a variety of immune diseases, has been reported to be effective on patients with severe steroid-dependent asthma. although fcer are known to play important roles in asthma, there are few reports about the role of fcg?receptors in asthma. fcg receptor iib (fcgriib) is unique inhibitory receptor, which suppresses immune response. in this study, we evaluated the effect of ivig in allergic airway inflammation in ova-challenged mice and the mechanism of the inhibitory effects of ivig and fcgriib. method c bl/ mice (wt) and fcgriib deficient mice (ko) were sensitized with ovalbumin (ova) and alum and subsequently challenged with nebulized ova. before ova challenge rabbit igg was administered intravenously. the airway inflammation and effects of igg were assessed by histology, cell counts of bal fluid and airway hyperresponsiveness. result histology showed that igg treatment ameliorated the inflammation around the airway and the vessels and hypertrophy of goblet cells induced by ova challenge. the migratory activity of dcs is modulated in inflammatory diseases such as asthma. recently, we reported that immature dcs express kinin receptors and that bradykinin (bk) significantly enhances the migration of immature dc in vitro. as kinins mediate many of the pathophysiological effects associated with asthma, we hypothesized that lys-des[arg ]-bk, which is produced during inflammation and acts via the b receptor (b r), would inhibit migration of mature dcs. methods day cultured human monocyte-derived dcs were matured with lps, tnfa +il- b or cd l in the absence or presence of lys-des[arg ]-bk. maturation of dc was analysed by flow cytometry (facs). b r expression was assessed by reverse-transcriptase pcr and quantitative confocal microscopy. migration of mature dc was assessed in transwell chambers with lysdes [arg ]-bk and the chemokine ccl used as chemoattractants. results maturation of dcs was found to result in down-regulation of b r expression to varying degrees depending upon the maturation stimulus used. mature dcs all demonstrated an ability to migrate toward lys-des[arg ]-bk and ccl . however pre-treatment with lys-des[arg ]-bk decreased the migratory ability of all mature dcs to both chemoattractants. conclusions along with chemokines, lys-des[arg ]-bk is likely to play a crucial role in regulating the in vivo migration of mature dc during inflammation. the production of lys-des [arg ]-bk during inflammation potentially immobilizes mature dcs thereby facilitating locally-mediated immune responses within inflamed tissues. supported by the asthma foundation of western australia. introduction alternative or aberrant splicing is a major contributor to protein diversity, in which a single gene can generate structurally and functionally distinct protein isoforms. the role of alternative splicing in asthma pathogenesis has not been previously investigated. we hypothesized that specific alternatively spliced asthma candidate genes contribute to the development of asthma. we chose to use a new and innovative approach involving the use of the genechip (r) exon array system together with real-time quantitative pcr to study asthma candidate genes in human monocyte-derived dendritic cells. asthmatic and non-asthmatic subjects provided ml of blood from which peripheral blood mononuclear cells (pbmc) were isolated by ficoll-paque gradient centrifugation. monocytes were separated from other leukocytes by adherence method, and differentiated into dendritic cells following incubation with defined concentrations of gm-csf and il- . rna was isolated and reverse transcribed for real-time semi-quantitative pcr and densitometry. chi squared test was used to assess associations between alternative splicing and asthma. results data indicate splice variant expression in dendritic cells from asthmatic patients is influenced by asthma severity. conclusion exon expression array analysis has generated a number of asthma candidate genes with alternative splice variants. further studies to validate these data in a replicate data set and establish the functional significance of our findings in asthma are underway. alternative or aberrant splicing occurs in more than % of genes and is a major contributor to protein diversity, in which a single gene can generate structurally and functionally distinct protein isoforms . the role of alternative splicing in asthma pathogenesis has not been previously investigated. we hypothesized that specific alternatively spliced asthma candidate genes contribute to the development of asthma. we chose to study one asthma candidate gene in human stimulated and unstimulated: ( ) monocytes, ( ) monocytederived dendritic cells and ( ) lung smooth muscle cells. methods asthmatic and non-asthmatic subjects provided ml of blood from which peripheral blood mononuclear cells (pbmc) were isolated by ficoll-paque gradient centrifugation. monocytes were separated from other leukocytes by adherence method. up to % of the monocytes were then differentiated into dendritic cells following incubation with defined concentrations of gm-csf and il- . induction experiments used mg/ml lps and cells were stimulated for an optimal period of hrs. rna was isolated and reverse transcribed for real-time semi-quantitative pcr and densitometry. chi squared test was used to assess associations between alternative splicing and asthma. results data from stimulation experiments indicate splice variant production can be regulated by the inflammatory response and that this response is influenced by asthma status. conclusion preliminary experiments have confirmed the presence of an aberrant splice variant for an asthma candidate gene in the primary cells studied. further studies to confirm these data and establish the functional significance of our findings in asthma are underway. exposure to environmental factors, such as environmental tobacco smoke (ets), plays a significant role in modulating pre-existing genetic susceptibilities to diseases including asthma. the glutathione s-transferase enzymes (gsts) play an important role in the detoxification of ets. there are several gst isoforms and gstp codes for the gst pi isoform, which is the primary gst isoform expressed in human lung tissue. two single nucleotide polymorphisms (snps) at positions and have been reported in gstp and associated with asthma and atopy. the aim of this study was to examine the effect of these snps in combination with ets, on asthma phenotypes in a cohort of asthmatic children. children were recruited during an acute episode requiring presentation at an emergency department. genotyping using pcr-rflp was completed on children and ets exposure was determined by parental questionnaire. urinary cotinine was measured in the children and was in agreement with questionnaire responses. statistical analyses were performed using spss. there were no significant associations between the genotypes and asthma severity during acute exacerbations. significant associations were found between the snps and atopy in this population with an odds ratio of . for the aa genotype (p = . ) and or of . for the cc genotype (p = . ). however, when an interaction with ets was included, the odds ratios increased to . for aa (p = . ) and . for cc (p = . ). these results suggest that there is a significant gene/environment interaction impacting on atopy in this cohort. the rage gene encodes the receptor for advanced glycation end-products (rage), a member of the immunoglobulin superfamily. rage activation by ligands, including amphoterin and s /calgranulins, leads to prolonged nf-kb signalling and has been associated with chronic inflammation. despite high levels of rage expression in lung tissue, little research has been undertaken into the role of rage in the chronic inflammatory asthma phenotypes of severe and aspirin-sensitive asthma. objective determine genetic associations between functional polymorphisms in the rage promoter and severe and aspirin-sensitive asthma phenotypes. methods pcr and restriction fragment length polymorphism (rflp) were used to genotype three rage promoter polymorphisms, - t>c, - t>a and a bp deletion from - to - , in a large case-control asthma population phenotyped for asthma severity, atopy and aspirin sensitivity. results no associations were identified between any of the polymorphisms and the occurrence of asthma. however, the - a allele was linked with both severe asthma (p = . ) and aspirin-sensitive asthma (p < . ). likewise, genotypes containing the - a allele were strongly associated with both severe asthma (or . , % ci . - . ) and aspirin-sensitive asthma (or . , % ci . - . ). conclusions the - a allele of the rage gene, previously shown to lead to a -fold increase in promoter activity, is associated with the chronic inflammatory asthma phenotypes of severe and aspirin-sensitive asthma. these results suggest that increased rage expression, with a concomitant increase in nf-kb signalling, may in part contribute to the inflammatory response seen in these conditions. the global prevalence of allergic diseases is rising and australia has one of the highest prevalence rates in the world. the role of early childhood infections in the development of allergic disease remains controversial. objective to examine the association between early childhood infections and the development of allergic diseases in later childhood, in high risk children. methods data were analysed from the melbourne atopic cohort study (macs) of infants with or more first-degree family members with atopic disease. primary risk factors assessed were otitis media, bronchitis and gastroenteritis reported in the first two years of life. outcomes were current asthma, hay fever and eczema at years of age. logistic regression was used to estimate crude and adjusted odds ratios. results asthma was the most common allergic condition ( . %, % ci . - . %), followed by eczema ( . %, % ci . - . %) and hayfever ( . %, % ci . - . %). the most commonly reported infection was otitis media ( . %, % ci . - . %), then gastroenteritis ( . %, % ci . - . %) and then bronchitis ( . %, % ci . [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . %). all types of infection within the first years of life were associated with increased risk of asthma. an increased risk of asthma at years was seen with otitis media (or = . , % ci . - . ), bronchitis (or = . , % ci . - . ) and gastroenteritis (or = . , % ci . - . ). when the frequency of infection was examined, those who reported at least episodes of gastroenteritis had a - -fold increased risk and an almost % absolute increased risk (rd . , % ci . - . ). conclusion these findings appear to contradict the hygiene hypothesis. the findings for gastroenteritis are novel. further examination of these associations and possible underlying mechanisms is warranted. grant support asthma foundation of victoria, nestle. background knowledge about incident cases of asthma in australia is limited because they are not routinely reported. the ability to predict the number of new cases of asthma would be helpful in allocating resources for asthma education, management and care. data on first use of medications for asthma gives an indication of the incidence of asthma. the objective of this study was to estimate the incidence rate of asthma by investigating asthma medication use in individuals. methods pharmaceutical benefits scheme (pbs) records for all prescriptions filled for inhaled corticosteroids (alone or combined formulation), cromones and leukotriene receptor antagonists from july to june were included. using a -year look back window, any persons who had their first prescription for any of these drugs dispensed between july and june were assumed to be incident cases. overall and age-specific incidence rates were calculated per asthma-medication-free individuals. results there were , individuals who had their first asthma medication dispensed between july and june , which equates to an overall incidence rate for asthma of . per . the incidence was higher among children aged - years ( . ) and adults aged years and over ( . ) . conclusions our estimated incidence rates were consistent with those reported by others in the literature. while the pbs database was designed for administrative purposes, it can be used to estimate incidence rates for asthma. support acam is a collaborating unit of the australian institute of health and welfare and is funded by the department of health and ageing (doha). we acknowledge the pharmaceutical pricing and estimates section of doha for provision of pbs data. keywords asthma incidence, pharmaceutical benefits scheme. rosario ampon , guy marks , teresa to , leanne poulos , anne-marie waters australian centre for asthma monitoring (acam), sydney, australia, and hospital for sick children, toronto, canada background the ability to assess individual patterns of asthma medication use would have clinical relevance in targeting effective asthma education and management for this common condition. to describe longitudinal patterns of asthma medication use, we used a population-based prescription database to follow individuals from the first time they filled an asthma prescription. asthma is more commonly listed on death certificates as an associated cause of death, in people whose deaths are attributed to other causes, than as an underlying cause of death. understanding the importance of these associations would contribute towards an overall appreciation of the impact of asthma on mortality. the objective of this analysis was to estimate the prevalence of asthma as an associated cause of death when various other diseases were attributed as the underlying cause of death. background acam currently recommend indicators to measure population-level asthma health and outcomes. we examined correlations among several asthma indicators covering prevalence, morbidity and mortality to try and produce a condensed set of indicators which minimized redundancy. methods seven of the indicators were included in this study: prevalence of ever having doctor diagnosed asthma, prevalence of current asthma, asthma-related general practice (gp) encounters, proportion of people with asthma with an asthma action plan (aap), hospitalizations for asthma, hospital patient days for asthma, and deaths due to asthma. a correlation matrix was created for these indicators by age groups. pearson correlation coefficients Ն . or Յ- . were considered strong. results there were strong positive correlations between prevalence of ever asthma and current asthma (r = . ); gp visits and aap possession (r = . ), hospitalization (r = . ) and patient days (r = . ); and hospitalization and patient days (r = . ) and aap possession (r = . ). recent australian reports have shown that the prevalence of asthma and respiratory symptoms has decreased over the last - years. as part of a larger study investigating child health and air quality we have collected nationwide data from schoolchildren living in act, victoria, queensland, wa and sa. methods schools were selected based on proximity to air quality monitoring stations. classes from years to were randomly selected and all children were invited to participate. parents self completed a questionnaire that included questions about diagnosed asthma and respiratory symptoms. results a total of children provided questionnaires for analysis. the response rate varied between states and territories and ranged from % to %. the sample comprised . % girls and the mean age of children was . years. ever diagnosed asthma . current asthma ('does he/she still have asthma? ') . wheeze in the past months . respiratory symptoms limiting activities . missed school due to asthma or wheezing . conclusions despite the relatively low participation rate, the prevalence estimates for current asthma are similar to those reported in the national health survey - [ ] . there is no evidence of any recent increase in the prevalence of childhood asthma. methods tahs is a longitudinal population-based respiratory study of subjects which commenced in when they were years of age. since the initial study another follow-ups have been conducted, including the most recent follow-up when subjects were years of age. lung function of the total sample was measured at baseline and in sub-samples in subsequent followups. asthma was categorized as persistent, frequent or episodic when participants reported asthma symptoms in at least follow-ups, in follow-ups or in follow-up respectively. results by age years ever asthma prevalence was %. at age , % of those who had not reported asthma by age had asthma symptoms while % of those who reported asthma by age had no asthma symptoms. hence over all only % of the asthma symptoms at age were attributable to asthma developed by age . in contrast, % of the persistent and frequent asthmatics had developed their asthma by age . persistent and frequent asthmatics had more symptoms and poorer lung function at age , and as well as more reversibility at age (p < . ). childhood asthmatics who also had a productive cough by age were more likely to have persistent asthma than those without a cough (p < . ). conclusions although the majority of middle-age asthma is related to postchildhood onset asthma, most severe middle-age asthma has its origin in persistent childhood disease. having productive cough in childhood may identify high risk asthmatics who require especially rigorous management in early life. one third of women experience an improvement in asthma during pregnancy, and symptoms improve in most women in the late third trimester. we hypothesized that the exacerbation rate would be reduced and that symptoms during exacerbations would be less severe in the third trimester compared to the second trimester. methods pregnant women with asthma (n = ) were prospectively followed from recruitment ( . weeks ( sd) ) to delivery at clinic visits ( , , weeks and during exacerbation), and fortnightly phone calls. the asthma control questionnaire (acq) was administered at each contact and exacerbations classified as severe (requiring medical intervention) or mild (selfmanaged). lung function, medication use, fractional exhaled nitric oxide (feno) and full blood counts were assessed. paracetamol is commonly used in infants as an analgesic and antipyretic. it has been hypothesized that frequent paracetamol consumption may result in reduced lung capacity to cope with oxidative stress and increase risk of respiratory disease. to date, no study has examined exposure to paracetamol during infancy, when lungs are still developing, and risk of childhood asthma. method a birth cohort of infants with an atopic family history was recruited. frequency of paracetamol exposure was prospectively documented up to years of age. interviews were conducted at and years to ascertain asthma in the previous months. results paracetamol exposure in infancy was common ( % exposed by two years of age), with some infants receiving paracetamol on up to days. it has been hypothesized that mucosal immune response requires a particular micro-flora milieu in the infant's gastro-intestinal tract, and that early life antibiotic exposure may disrupt this process and increase risk of allergic disease. method a birth cohort of infants with an atopic family history was recruited. exposure to oral antibiotics was prospectively documented up to months of age. interviews were conducted at and years to ascertain asthma in the previous months. results by one year of age, approximately % of infants had received at least one course of oral antibiotics. the prevalence of current asthma in childhood was approximately % ( / ). frequent use of antibiotics (more than days exposure during first year of life) was associated with increased risk of childhood asthma (or = . , % ci = . - . ) when compared to infant who had not been exposed. excluding infants with a diagnosis of asthma within the first two years of life, reduced this association by about % (or = . , % ci = . - . ) and adjustment for gender, parental history of asthma and number of infections in the first year of life further reduced this association (or = . , % ci = . - . ). the increased risk of childhood asthma associated with antibiotic exposure in the first year of life is, at least in part, due to confounding with early life wheeze and infections. if real, the independent effect of antibiotic exposure on risk of childhood asthma is likely to be minimal in this high risk cohort. support dairy australia, crc for asthma and airways, vichealth, nestle. the epidemiological data on asthma suggest a gender difference that varies with age. hormonal effects have been suggested as a possible explanation for these differences. the aim of this study was to examine reproductive factors and risk of asthma among the females of the tasmanian longitudinal health study (tahs). methods the tahs is a longitudinal population-based cohort study of respiratory disease which commenced in when subjects were years of age. four follow-up studies have been conducted including the current most comprehensive follow-up with subjects at years of age. information has now been collected on reproductive factors such as number of pregnancies, age at pregnancies, age at menarche and contraceptive pill use as well as on asthma status. reproductive factors were examined as risk factors for asthma using multiple logistic regression to adjust for all likely confounders. results a total of , women completed the most recent postal survey. of these ( . %) had current asthma, and of these women with current asthma . % ( ) developed asthma after childhood. on average these women were in their mid-twenties when they developed asthma (mean Ϯ sd age = . Ϯ . yrs). we found with increasing age at first birth an approxi-mate~ % reduced risk of current asthma in women who developed their asthma post-childhood (trend p = . ). we did not observe any other associations between reproductive factors and risk of asthma. conclusions our results are consistent with the hypothesis that early pregnancy may promote asthma development by altering the immune response favouring a th pathway. a delay in the age of first pregnancy reduces this risk of asthma. grant support nhmrc, clifford craig foundation, victorian & tasmanian asthma foundations. introduction the association between exposure to pets in early life and subsequent development of sensitization and allergic disease remains controversial. the objective of this analysis was to examine the relationship between cat exposure before birth and development of cat sensitization over time within the melbourne atopic cohort study (macs). methods the macs is a prospective longitudinal cohort study that initially recruited women antenatal in melbourne from february to november . detailed information on cat exposure was collected at recruitment and frequently until two years of age. skin prick test (spt) were conducted at , , months and years. the data were analysed by logistic regression and using generalized estimating equations (gee) for the repeated measures design. results among subjects, ( . %) had a cat before birth. at months, . % (n = ) of subjects were sensitized to cat and by years of age . % (n = ) were sensitized. those who did not have cat before birth belong to a higher social class, and were more likely to have a father with allergic disease than those with a cat. those who developed sensitization to cat were more likely to have a paternal family history of allergic disease and more likely to be sensitized to other allergens. we did not observe any association between exposure to cat before birth and the development of sensitization to cat at months (or = . , % ci . - . ) , months (or = . , . - . ), months (or = . , . - . ) or years (or = . , . - . ) . these crosssectional results were confirmed by the gee analysis. conclusion our results fail to show an association between cat exposure before birth and development of sensitization to cat. furthermore exposure after birth in the first months of life was not associated with an increased or decrease risk of sensitization to cat. our results do not support either a benefit or risk associated with cat ownership and sensitization. introduction peri-natal events influence the development of asthma and atopic diseases in childhood but the current literature is contradictory on the effect of low birth weight, small for gestational age and prematurity on asthma risk. the aim of this study was to assess the relationship between these three exposures and asthma from childhood to adulthood. aim to assess the current prevalence of dda, wheeze (< months), atopy and ahr in children and adults in busselton. methods an age-and sex-stratified random sample of adults, selected from the electoral roll, was invited to complete a questionnaire and attend the local study centre for assessment of atopy (allergen skin tests) and ahr (methacholine). all children from participating primary and secondary schools were also invited to attend. the prevalences of dda, wheeze, atopy, ahr and "current asthma" (wheeze + ahr) were calculated. background asthma is often associated with comorbidity, however few studies have investigated comorbidities among people with this common condition. the objective of this analysis was to describe patterns of non-respiratory comorbidity among adults hospitalized with asthma in australia. methods data on hospitalizations for people aged years and over with a principal diagnosis of asthma (j , j ) were obtained from the australian institute of health and welfare's (aihw) national hospital morbidity database for the period - . patterns of comorbidity were examined by investigating additional diagnoses for non-respiratory disease according to icd- diseasespecific chapters. results among people aged years and over hospitalized in - with a principal diagnosis of asthma ( , hospitalizations; % female; % aged - years), % had at least one non-respiratory comorbidity. median length of stay was higher among those with at least one comorbidity ( days) than among those with no comorbidities ( days). among people aged - years, the most common comorbid condition was endocrine, nutritional and metabolic diseases ( %), while among those aged years and over it was diseases of the circulatory system ( %). conclusions a large proportion of asthma hospitalizations in australia are associated with non-respiratory comorbidity and a longer length of stay. further, the pattern of non-respiratory comorbidity associated with asthma hospitalizations varies by age. given our rapidly ageing population, the level of comorbidity associated with asthma has implications for coordinated health care and demand on health services. support acam is a collaborating unit of the aihw and is funded by the department of health and ageing. keywords comorbidity, hospitalization, asthma. background asthma exacerbations are often triggered by viral respiratory infections, yet the influence of respiratory infections on the morbidity of acute asthma beyond the immediate period is unknown. we examined the influence of nasopharyngeal (npa) respiratory viral, chlamydia and mycoplasma detection on asthma morbidity in children presenting to the emergency department for an acute exacerbation of asthma. methods a subset (n = ) of the children enrolled for a randomized controlled trial (rct) on the efficacy of vs days of oral prednisolone had an npa taken at presentation. npa were examined for chlamydia, mycoplasma and respiratory viruses (enteroviruses, coronaviruses, human metapneumovirus, adenovirus, parainfluenza, influenza, rsv, rhinoviruses) by pcr. enrolled children were aged - years with recurrent wheeze and required Ն ?g (mdi/spacer) or Ն . mg (nebulized) of salbutamol to reduce tachypnoea. parents filled validated diary cards for cough and asthma severity, and completed asthma qol data at enrolment and end of weeks and . results pcr for various viruses was positive in ( . %) children, with no significant difference in the groups the children were randomized into. rhinovirus pcr was positive in the npa of children, rsv in , hmpv in , adenovirus, parainfluenza, influenza a and b in one each. specimens were negative for the other micro-organisms listed above. children with a npa viral positive state were significantly (p = . ) younger than those with a negative state. however, there was no difference in the any of the asthma outcomes of children whose npa was positive or negative for the micro-organisms tested. conclusions in children with an acute asthma exacerbation presenting to emergency health facilities, a respiratory virus could be identified in > % but the presence of a respiratory virus did not influence the morbidity of the asthma exacerbation at presentation or at the end of week- and week- . the university of sydney, nsw , and royal north shore hospital, st leonards, nsw airway wall thickness measured using hrct is reported to be increased in asthmatic compared with control subjects. however, it is unknown whether wall thickness is a fixed structural characteristic of the airways or if it responds to transient changes in bronchomotor tone or airway size. aim to determine the effects of bronchomotor tone and lung volume on airway wall area measured by hrct. methods patients with doctor-diagnosed asthma had partial chest hrct scans, before and after bronchodilator (bd), at frc, tlc and a volume midway between (mid-volume). airway segments were identified between branch points and matched between consecutive lung volumes both before and after bd, and also at constant lung volume before and after bd. mean lumen areas and wall areas for each airway segment at each volume were measured using automated analysis software. paired t-tests were used to determine changes due to bd and lung inflation. results airways were matched before and after bd at frc. absolute airway wall area (wa) was related to airway lumen diameter (di wood smoke air pollution is of concern with respect to respiratory health due to its complex chemical composition and potential to carry air toxics into the lower respiratory system. launceston has a long history of poor winter air quality, primarily due to use of domestic wood heaters. participants in hobart had a similar prevalence of wood heater use, but hobart does not experience the same wood smoke pollution (due to differences in regional geography , asthma control and anxiety and depression were completed at baseline, immediately following ( wks), and mths after the intervention period. results clinically and statistically (p < . ) significant improvements in qol were observed in the exercise group at wks compared to the control group. this difference was not maintained at mths. mwd improved at wks and mths in the exercise group (p < . ), however the difference between groups was not significant. in the exercise group there was a trend towards improved asthma control and a reduction in anxiety and depression that was not observed in the control group. *p < . , change at wks vs baseline; home asthma monitoring is important for measuring day-to-day variation in lung function and symptoms. this approach requires the availability of complete diaries for a comprehensive assessment. we assessed the completeness of written diaries collected as part of a nation wide study of air quality and child health. methods children who had ever been diagnosed with asthma and had respiratory symptoms in the last year were identified from a cross-sectional study. these children were asked to record symptom scores and peak expiratory flows twice daily in diaries for a five week period. the diaries and peak flow devices were explained at a face-to-face meeting with parents and children. each week diaries were mailed back and parents received a phone call to encourage completion. completeness was defined as no missing responses to symptom questions or peak flow measurements in diaries from week two to week five. results data from the first children ( day records) were available for analysis. the sample included ( %) girls, mean age yrs. the overall frequencies for complete records were; morning symptoms %, morning peak flow %, evening symptoms % and evening peak flow %. there was a significant trend for more complete morning peak flow records over the four weeks (cochrane-armitage trend test p < . ). agreement between morning and evening symptom completeness and between morning and evening peak flow completeness was fairly poor (kappa < . ). conclusions the completeness of symptom and peak flow records collected in this study was very high. the comprehensive follow-up protocol implemented is likely to have had an important impact on the completeness of asthma diaries. daily peak expiratory flow (pef) monitoring has been used in epidemiological studies to assess changes in lung function over time. the value of written pef diaries has been questioned because of problems with completeness and validity. this study aimed to compare stored electronic pef data and a written diary record of those data in a panel study in children with weekly reminders to aid adherence. methods children who had ever been diagnosed with asthma and had respiratory symptoms in the last year were identified in a population study. they were given electronic pef devices with a digital readout (miniwright digital, mwd, clement clarke, uk) and written symptom and peak flow diaries and instructed in their use at a meeting with parents and children. each child was asked to complete three pef manoeuvres every morning and evening for five weeks and to record these in the written diary. background previous research suggests that comorbid anxiety is associated with lower asthma-related quality of life (aqol) in adults with asthma. however, research is scant on the role of psychological interventions in these patients. aim to evaluate the effectiveness of a four-session cognitive-behavioural therapy (cbt) intervention, in improving the aqol, in participants with anxiety and asthma. method participants identified with comorbid anxiety and asthma were randomly assigned to the cbt intervention group (n = ) and the asthma monitoring control group (n = ) and evaluated on aqol measures, at various intervals. results nine participants, in the cbt group, completed the study. seven participants showed a clinically significant improvement in asthma-related emotional functioning (ef) and six participants in total aqol scores, at the -week post-intervention assessment. additionally, six participants in the cbt group indicated clinically significant improvement in ef and five participants in total aqol scores, at the -month follow-up assessment. only three participants in the control group completed the study. none of these participants showed any improvement in aqol scores at the -week or -month assessment. conclusion this pilot study suggests that a higher number of participants in the cbt group showed clinically significant improvement in ef and total aqol scores with higher retention rates. further research needs to confirm these findings in a larger group, identifying the elements of a successful cbt intervention and characteristics of participants who respond to the cbt intervention. gastro-oesophageal reflux disease (gord) is a risk factor for uncontrolled asthma. we conducted an update of a systematic review to assess whether treatment of gastro-oesophageal reflux in subjects with asthma improved asthma outcomes. methods randomized controlled trials (rcts) of gord treatment in adults or children that reported asthma health outcomes and had symptomatic gord were included and assessed in accordance with the standard cochrane systematic review process. subjects received pharmacological therapies compared with conservative management. results from potentially relevant studies, rcts were included in the review. when compared to placebo, morning peak expiratory flow did not significantly improve (change from baseline wmd . , % ci: - . to . ) with proton pump inhibitor treatment (n = trials involving participants). asthma exacerbations were not significantly less in the intervention groups compared with the control groups (odds ratio . ; . - . ; n = ). conclusions while some trials reported evidence of asthma improvement with gord therapy, overall there appears to be no statistically significant evidence of a beneficial effect. it is clear that not all persons with gord and asthma will gain improved control over their asthma with gord therapy; this may be due to the heterogeneous pathophysiology of asthma. future large-scale trials would be required to demonstrate an effect on asthma exacerbations. kel and brd were supported by a cochrane airways group scholarship. background the ats/ers task force recommend the use of metered dose inhaler (mdi) and spacer for airflow limitation reversibility testing. salbutamol given via mdi & spacer has been shown to be equivalent to a nebulizer in the clinical setting. this has not been well studied in respiratory laboratory setting. aim to compare the methods of reversibility testing in a laboratory setting. methods we conducted a laboratory based crossover study in a secondary hospital. patients with asthma or copd were eligible. the patients firstly underwent spirometry and reversibility testing following a standard dose of nebulized salbutamol. they were asked to return for a second set of spirometry within the same week and at the same time of day when reversibility with an mdi and spacer was recorded. we used an incremental dose of salbutamol starting from puffs and up to puffs. spirometry parameters were recorded minutes after each intervention. the primary outcome was the percentage change in fev after each intervention. side effects were monitored for. results nine patients with asthma were recruited. the mean percentage change in fev was higher in the nebulizer group than after only puffs via mdi & spacer ( . Ϯ . vs . Ϯ [mean Ϯ sd], p = . ). however, there were no differences between the arms following higher doses of bronchodilator via mdi & spacer. the mean percentage change in fev after , and puffs were . Ϯ . , . Ϯ . , and . Ϯ . respectively (p = . , . and . respectively when compared to the nebulizer group). conclusion using an mdi and spacer for bronchodilator reversibility is equivalent to that of a nebulizer and should be the standard method of testing. the dose of bronchodilator needs to be at least puffs as recommended by the ats/ers; however puffs correlated best with a standard nebulizer route. further increments in bronchodilator dose provided little additional bronchodilatation. the study was limited by the small number of patients. asthma guidelines recommend a stepwise approach to treatment. the role of inhaled corticosteroid (ics) and long-acting beta-agonist (laba) combination therapy in asthma written action plans is not clear. objective to assess the efficacy of adjusting ics/laba combination therapy in a written action plan compared to fixed dosing in people with asthma requiring maintenance ics. methods cochrane systematic review of randomized controlled trials comparing ics/laba combination therapy in a single inhaler that is adjusted up or down according to a written action plan (wap) to comparison : budesonide/ formoterol given as a fixed maintenance dose (fd) (n = ) or comparison : fluticasone/salmeterol fd (n = ). results parallel randomized controlled trials describing interventions met the inclusion criteria. for the trials that compared wap to fd budesonide/ formoterol there were significant reductions for the wap group in exacerbations, (rr ( %ci): . ( . to . )), severe exacerbations (rr ( %ci): . ( . to . )) and study medications (wmd ( %ci): - . (- . to - . )) with no difference in asthma control or adverse events. the results for the two trials reporting wap budesonide/formoterol to fd fluticasone/ salmeterol were discordant and a homogenous pooled result could not be determined. of the australians who died from asthma in , over two thirds were over years of age. this trend resulted in the national asthma council of australia (nac) calling for better management of asthma in the elderly. we designed an educational intervention using evidence based educational strategies to improve the content and style of general practice consultations for older people with asthma. methods randomized controlled trial of a multi-faceted program consisting of a group educational session, a videotaped standardized simulated patient consultation, followed by an academic detailing session. forty-two gps were randomized into an active or a control group. gps provided the names of patients who would be happy to participate in the study and the program was evaluated by patient and gp outcomes. results gps recruited into our program reported improvements in a range of clinical areas. one hundred and ten patients were recruited, their outcomes are under analysis. conclusion gps were overwhelmingly positive about participation in this trial and our intervention successfully improved the capacity and confidence of gp's to deliver care to older people with asthma. our study also developed several tools that would enable dissemination of our findings. supported by an asthma targeted in studies where direct clinical assessment is not possible, urgent health care utilization (hcu) is often used as an indirect measure of asthma control. this study aimed to identify factors predicting urgent hcu and asthma control. methods patients in nsw with a doctor diagnosis of asthma were recruited from community pharmacies, a research volunteer database, and databases of asthma foundation nsw, to complete a questionnaire about asthma. poor asthma control was defined as asthma control questionnaire (acq) score Ն . . urgent hcu was defined as hospitalization, ed visit, or urgent doctor visit due to asthma. multiple logistic regression was used to identify predictors of poor control and urgent hcu. results questionnaires were completed by adults ( % female) with a doctor diagnosis of asthma (pharmacy , woolcock , asthma foundation ). % used inhaled corticosteroid (ics) Ϯ long-acting b -agonist in the last wks. median age was yrs (range - ), and % were current smokers. mean acq score was . ( % ci . - . ), with % of participants having poor asthma control (acq Ն . ). % had urgent hcu for asthma in the previous year. significant independent predictors for poor asthma control were younger age, current smoking, living in more disadvantaged areas, being retired, having only primary education, and holding a concession card. predictors for urgent hcu were younger age, being in full-time employment, having only primary education, and being of non-english speaking background. neither ics use nor possession of a written asthma action plan was associated with lower risk for either poor asthma control or hcu. conclusions poor asthma control is common in nsw even in patients using inhaled corticosteroids. although urgent hcu is often used as an indirect measure of poor asthma control, it is affected by different factors, perhaps because health care utilization represents a more complex balance between need and access. bronchial challenge tests with mannitol, to measure airway hyperresponsiveness, can take up to minutes and require inhalation of up to mg of mannitol. our aim was to determine if positive mannitol challenges can be detected after half the maximal dose ( mg) using the forced oscillation technique (fot) to measure response. methods non-asthmatic subjects and asthmatic subjects underwent standard mannitol challenge, up to mg mannitol. respiratory system conductance (grs) and reactance (xrs) was measured by fot at hz during sec tidal breathing immediately after each dose of mannitol. fev was measured after fot, within sec of mannitol administration. two point dose response slope (drs), was calculated for grs (drsgrs) and xrs (drsxrs) for standard tests, up to mg, and for short tests by excluding data from doses above mg. ability to detect a positive test, defined as pd fev < mg, was determined by the area under the roc curve (auc) and repeatability by intra-class correlation coefficient (icc). results asthmatic and non-asthmatic subjects had positive tests, with pd fev values from . to mg. auc ( %ci) did not differ between standard (std) and short tests for drsgrs (p = . ) or drsxrs ( combined use of inhaled steroids (ics) and long acting beta-agonists (laba) have an important role in asthma management. we used data from a population sample to examine medication use in adults and children. methods all adults ( - years) and children ( - years) from within four discrete zones in northern sydney were eligible for an interview survey, as part of a study investigating health effects associated with traffic-related air pollution. the prevalence of use of short-acting beta-agonists (saba), any ics (alone or combination) and combined formulations of ics/laba in the previous three months was estimated for the study population and those with diagnosed asthma. results there were children [mean (sd) age . ( . ) years and % female] and adults [mean (sd) age . ( . ) years and % female] interviewed in households, representing an overall response rate of %. the prevalence of ever diagnosed asthma was . % in children and . % in adults. medication data were missing for subjects. background asthma affects : adult australians and is a leading cause of rejection for recruitment into the australian defence force (adf). within this diagnosis there is a wide spectrum of disease activity and clinical outcomes. also asthma assessment and management has improved so that many asthmatics are now fully active without any significant disruption or risk to their lives. hypothesis: there is a subgroup of asthmatics who are at very low risk from significant adverse effects from asthma and who could be considered for recruitment to the adf. aims . to identify the subgroup of asthmatics who could be considered for recruitment to the adf. . to develop an assessment process to identify this subgroup (screening). . to develop a process to evaluate the outcomes of any change to the recruitment standard for asthma (evaluation). methods . a literature review of the natural history, assessment, management and response to treatment of mild episodic and mild persistent asthma. . a literature review of asthma in the military. . a clinical review of the outcomes of known asthmatics in the adf. . an expert group to review the above and to develop a screening process and an evaluation of the program. the literature review identified a subgroup of asthmatics, defined as mild episodic and mild persistent, who with appropriate management, have a low risk of significant adverse asthma outcomes. they can be identified by a combination of questionnaire, spirometry and bronchial provocation testing. a screening process has been developed which allows asthmatics to be recruited with a negative mannitol or hypertonic saline challenge on mg/day or less of budesonide (or equivalent) without laba. a methodology to evaluate the impact of these changes on the recruitment standard has also been developed. alexithymia is a personality trait associated with difficulty identifying and communicating emotional and physical feelings. it has been associated with poor control of asthma and near fatal asthma. the primary objectives of this study were to: ( ) identify alexithymia in a cohort of australian asthma patients; ( ) investigate the relationship between alexithymia and asthma control; ( ) investigate the relationship between alexithymia and asthma management. methods cross sectional study of moderate to severe asthma patients recruited from royal adelaide hospital outpatients. participants were either mailed the questionnaire pack or completed it after a clinic appointment. existing validated questionnaires were used. statistical analyses were performed using spss. results male ( %) and female ( %) patients with moderate to severe persistent asthma (mean age years, sd = ) participated. alexithymia scores ranged from . to . (x = . , sd = . ). % (n = ) of participants could be classified high alexithymia, % (n = ) borderline alexithymia and % (n = ) were low alexithymia. alexithymia mean scores were not statistically different across sociodemographic variables. a positive correlation/association was found between alexithymia score and asthma control score (r = . , p < . ), quality of life (r = - . , p < . ), and adherence (p = . ) but not satisfaction with communication (r = - . , p = . ) or number of hospitalizations (p = . ). conclusions this is the first australian study to identify alexithymia among asthma patients and investigate relationship to control as well as management and communication. associations between alexithymia and asthma control were confirmed. a larger sample size is needed to determine impact of alexithymia on self-management and provision of clinical care for asthma. port hedland is impacted by iron-containing dust particles (pm ) that may activate lung cells when inhaled. furthermore, the effects of port hedland pm may differ from the effects of urban pm impacting metropolitan areas. the aim of this study was to assess the effects of port hedland pm on production and release of the inflammatory cytokines, il- and il- , by human airway epithelial (a ) cells, and to compare these with the effects urban pm from metropolitan areas. methods human airway epithelial (a ) cells were exposed to pm collected at port hedland and at urban locations (sydney, perth). a cells were exposed to a range of pm concentrations ( - mg/ml) for h. lipopolysaccharide (lps) and phorbol myristate acetate (pma) were used as positive controls. supernatants from cell cultures were assayed for il- and il- using specific elisa kits. rna was extracted and reverse transcribed to cdna. il- and il- mrna expression was quantified by duplex real-time pcr using taqman primer/probes. results lps stimulated a . -fold increase in il- release and pma stimulated a -fold increase in il- release and a -fold increase in il- release. however, neither port hedland pm nor urban pm stimulated concentration dependent release of il- or il- by a cells. expression of il- or il- mrna was also not altered by port hedland or urban dust. cd + t-cells may cause airway epithelial cell apoptosis via the granzyme pathway. we have reported increased apoptosis of airway epithelial cells and increased bal t-cell expression of granzyme b in copd, and a positive correlation between the two. we hypothesized that the increased granzyme b would also be related to smoking history (pack years -pk/y), age and severity of airflow obstruction (fev %pred) in patients with copd. we further hypothesized that the t-cell granzyme b expression would be higher in the airway than the peripheral blood. methods we investigated t-cell intracellular granzyme b expression in blood from copd subjects ( current and ex-smokers) and never-smoker controls, and bronchoalveolar lavage (bal) and bronchial brushing (intraepithelial t-cells) from a cohort of these subjects using flow cytometry. correlations between granzyme b and pk/y, age or fev were performed using spearman's rank correlation. granzyme b in t-cells from blood, bal and bronchial brushings were compared. results there were significant correlations between fev and granzyme b expression in blood and bal (blood: r - . , p = . ; bal: r - . , p = . ). there was a significant correlation between pk/y and granzyme b expression in blood (r . , p = . ), but not in bal. there were no significant correlations between granzyme b and age. there were no significant differences in granzyme b expression in blood, bal or intra-epithelial compartments. conclusion granzyme b is expressed at similar levels in blood, bal and intra-epithelial compartments, supporting recent opinion that copd is a systemic disease. t-cell granzyme b is related to severity of airflow obstruction and smoking history in patients with copd and may be one mechanism of apoptosis leading to lung injury and airflow obstruction in copd. jc allen , t schlosser, ee ramsay , q ge , aj ammit as development of remodelled airways is correlated with deterioration of lung function, we require therapies that reduce and reverse structural changes in remodelled airways. in asthma, corticosteroids can halt some, but not all, aspects of airway remodelling. therefore, in order to aid future design of efficacious anti-remodelling agents we need a better understanding of the molecular mechanism/s underlying the development of airway remodelling and the effectiveness of corticosteroids. hyperplasia of airway smooth muscle (asm) is a feature of the remodelled airway in asthmatics. in this study we examined the effect of corticosteroids on a key regulator of g progressioncyclin d . asm cells from n = non-asthmatics and n = asthmatics were pretreated for h with vehicle or dexamethasone ( . mm). the temporal kinetics of cyclin d mrna and protein expression were measured up to h after stimulation with the mitogen platelet-derived growth factor-bb (pdgf-bb). pdgf-bb induced a significant increase in cyclin d mrna expression in asm from non-asthmatics ( . Ϯ . -fold) and asthmatics ( . Ϯ . -fold) after h stimulation. in non-asthmatics, the corticosteroid dexamethasone significantly (p < . ) reduced the amount of cyclin d mrna expressed (to . Ϯ . -fold). in contrast, cyclin d expression in asthmatics was relatively resistant to inhibition by dexamethasone; the amount of pdgf-bb-induced cyclin d expression in the absence or presence of dexamethasone was not significantly different ( sphingosine -phosphate (s p), a bioactive sphingolipid found elevated in the airways of asthmatics, modulates myriad airway smooth muscle (asm) functions that promote inflammation and remodelling in asthma. in this study, we uncover the molecular pathway/s underlying s p-induced secretion of il- , and investigate if, and how, corticosteroids inhibit il- secretion. using cultured asm cells from non-asthmatics, we found that s p induces il- secretion from asm cells via cre, but not ap- , c/ebp or nf-kb, transcriptional regulation of il- gene expression. cre-dependence was supported by s p-induced creb phosphorylation. although the corticosteroid dexamethasone reduced s p-induced il- secretion in a dose-dependant manner, this inhibition appeared to occur via a pathway independent of creb/cre, suggesting the existence of a parallel pathway. as we recently discovered that the antiinflammatory actions of corticosteroids in asm can be mediated via the induction of the endogenous mitogen-activated protein kinase (mapk) inhibitor, mapk phosphatase- (mkp- ), we investigated whether mapk represents the parallel pathway targeted by corticosteroids. we found that s p can induce activation of a variety of mapk, however, only p mapk phosphorylation was inhibited by dexamethasone; importantly, the increase in mkp- after corticosteroid treatment appeared to mirror the decrease in s p-induced p mapk phosphorylation. furthermore, exogenous expression of mkp- inhibited s pinduced il- secretion. taken together, these results suggest that parallel pathways exist to induce il- secretion (transcriptional via creb/cre and possibly post-transcriptional via p mapk) and serve to underscore the importance of mkp- upregulation as a mechanism of action of corticocosteroids in asm. angiogenesis is a hallmark feature of asthma. angiogenic promoters, such as vegf and tgfb are reported to be increased in airways of asthmatics. tumstatin, an endogenous angiogenic inhibitor, is the non-collagenous domain- (nc ) of the alpha chain of collagen iv. decreased levels of collagen iv have been reported in the airways of asthmatics. we investigated the presence of tumstatin in the airway of asthmatics and its potential role as an angiogenic inhibitor. we detected the six a chain nc domains of col iv and the s domain of the a chain using immunohistochemistry. the level of tumstatin in serum and bal-f was measured by dot blot. western blots were used to identify the association with the rest of the collagen iv molecule. a tube formation assay using primary pulmonary endothelial cells (ppec) was performed to evaluate the role of tumstatin in the airway. the effect of intranasal tumstatin on airway hyperresponsiveness and angiogenesis was studied in an ovalbumin mouse model. tumstatin was absent in the airways of asthmatics (n = ) while the remaining six collagen iv a chains were present. the s domain of the a chain was present in the asthmatic airway (n = ). tumstatin was detected in both serum and bal-f samples from asthmatic volunteers (n = ), however the level of expression was not significantly different from that in nonasthmatics (n = ). in asthmatic serum tumstatin was part of the whole collagen iv a chain. tumstatin was able to inhibit ppec tube formation in a dose related manner. tumstatin inhibited angiogenesis in the mice airways and was associated with an improvement in ahr. the fact that tumstatin is absent from asthmatic airways and inhibited airway hyperresponsiveness and angiogenesis may indicate potential for therapeutic intervention in airway remodelling. this work was supported by the crc for asthma and airways and nh&mrc. introduction epithelial egfr (epidermal growth factor receptor) expression correlates with disease severity and neutrophil infiltration in asthmatic airways. acute exacerbations of asthma and copd are also associated with steroid refractory neutrophilic inflammation, with rhinoviruses being the most common trigger. . mg/l and il- : . vs. . ng/l). since il- stimulates the acute phase response, we correlated its levels with the other markers. only crp was strongly correlated with il- (spearman r = . , p < . ), suggesting differential regulation of saa and ip . saa discriminated between non-pathogen (n = ) vs. pathogen-associated (n = ) events (saa: . vs. . mg/l p = . ), whereas no significant change was observed in the other markers (ip- : . vs. . ng/l, crp: vs. mg/l, il- : . vs. . ng/ l). however when aecopd marker levels were stratified on the basis of pathogen type (viral = , bacterial = , viral and bacterial = ), none of the markers were significantly altered. conclusions ip- is significantly elevated during an aecopd, however only saa differentiated non-pathogen from pathogen associated events. background severe persistent asthma is characterized by structural changes in the airways-airway remodelling. airway smooth muscle (asm) cells have the potential to play a key role in these processes through the release of growth factors, cytokines and extracellular matrix (ecm) proteins. we have previously studied the effects of budesonide and formoterol individually however, the effect of their combination on these characteristics of asm cells is not known. methods asm cells from asthmatic (n = ) and nonasthmatic (n = ) individuals were stimulated with transforming growth factor ß (tgfß) ( ng/ml) with or without budesonide ( - m) and formoterol ( - and - m) and fibronectin levels and interleukin- (il- ) release were measured by elisa. bronchial rings from nonasthmatic individuals (n = ) were incubated with tgfß with or without the drugs and ecm protein expression (fibronectin and collagen i) measured using immunohistochemistry. results in nonasthmatic cells, budesonide alone induced fibronectin deposition whether tgfß was present or not. formoterol decreased fibronectin induced by tgfß and, when combined with budesonide, reversed the increase in fibronectin. a similar pattern was observed in asthmatic cells, except that budesonide did not further increase the tgfß mediated fibronectin release. as before [ ] , il- was induced by formoterol but inhibited by budesonide. tgfßinduced il- was inhibited by both drugs and their combination in both cell types. in bronchial rings the presence of either drug did not affect tgfßinduced fibronectin or collagen i. severe combined immune deficiency (scid) spontaneous mutation specifically impairs differentiation of stem cells into mature lymphocytes. nod-cb prkd scid (known as nod-scid) lacked nk cells, hence is commonly used in cell transfer experiments for transferring tissue and haematological xenografts. the aim of this study was to establish lung inflamamtory model in nod-scid strain. methods balb/c and nod-scid balb/c mice (n = ) were exposed to cigarette smoke for days, and weeks ( cigarettes/day; days/week). bronchoalveolar lavage fluid (balf) and lung tissue were collected for inflammatory profiling and analysis for cytokines, chemokines and protease expression and/or activity. results nod-scid have significant accumulation of macrophages in lung after days, and weeks smoking as compared to no smoke control (p < . ) that was not different to balb/c (p > . ). nod-scid also have increased neutrophil number after and weeks smoking (p < . ). even though myeloid cell differentiation isn't affected by scid phenotype, nod-scid have one fold less neutrophil than balb/c mice (p < . ) that is also reflected in the reduced expression of matrix metalloproteinase- . consistent with the known lymphopenic phenotype, nod-scid have significant but less lymphocytes recruitment as compared to balb/c mice after weeks smoking (p < . ) despite the enhanced expression of inteferon inducible protein (lymphocytes specific chemokine) in lung. both mouse strains showed the same elevation of net gelatinase and serine protease activity in lung. nodscid mice also demonstrated comparable transcriptional induction of proinflammatory cytokines (tnfa, il- ), growth factors (gm-csf, g-csf) and chemokines (mcp- , mip- ), indicating susceptibility to smoke-induced injury. conclusions nod-scid mice are capable to mount smoke induced inflammatory response. this model may be useful to study localization and role of immunocytes, including adoptively transfer human cells in the pathogenesis of copd. supported by the nhmrc. rhinovirus (rv) is the cause of most common colds and up to % of asthma attacks. in our previous studies, plasminogen activator inhibitor (pai- ) was expressed at high levels and was induced in vivo and in vitro by rv infection. pai- may have antiviral properties suggested by antiviral activity in some models, high pai- expression levels and further upregulation by rv infection. methods to determine whether pai- has antiviral activities following rv infection, o-hela, pai- expression-deficient cells were first transfected with pai- or control genes. this was followed by infection with rv and effects on viral replication were assessed by rt-qpcr for vrna and by viral titration for virus release. ifn expression was assessed by rt-qpcr. results ifn-a and -b mrna expression were induced in response to rv infection and to pai- expression in cells. pai- expression followed by rv infection elicited a synergistic response and pai- over-expression reduced vrna by > fold and viral titre by > log (p < . ). however, this effect was not specific to pai- , as transfection of cells with control genes/plasmids reduced viral titre to a comparableextent. one of the pathological findings in idiopathic pulmonary fibrosis (ipf) is the presence on fibroblastic foci comprising cells which exhibit mesenchymal phenotypic features such as myofibroblast-like morphology, increased asma expression and collagen deposition. currently steroid treatment in ipf has shown limited efficacy. the cellular origins of these mesenchymal cells remain unclear, but evidence from other studies suggests that epithelial cells may undergo a transition to a mesenchymal cell phenotype (emt). transforming growth factor ß has been implicated in promoting this emt. in this study we have induced a morphological change in a cells using tgf-ß and assessed the influence of glucocorticoids, and the changes to the extracellular environment of the cells, on emt. methods a cells were grown on uncoated plastic cultures plates or those coated with monomeric or fibrillar collagen and treated with - pm tgf-ß . the influence of the glucocorticoid, dexamethasone (dex, - nm), or collagen type, on emt was assessed by microscopy, rt-pcr and western blotting for markers of myofibroblast phenotype. results tgf-ß induced an increase in mrna expression of asma ( . fold), collagen ( . fold) and fibronectin ( . fold). dex ( nm) partially inhibited the expression of collagen, but had no effect on asma levels. however, dex ( nm) reduced asma and ctgf protein levels. dex ( nm) also prevented the tgf-ß -induced morphological changes, regardless of ecm matrix. conclusion glucocorticoids appear to control some of the emt phenotype changes induced by tgf-ß . however, the inability to fully inhibit these changes may contribute to the resistance of ipf to glucocorticoids. the extracellular environment may also play a role in the development of fibroblastic foci and their pharmacological responses. defective alveolar macrophage (am) phagocytic function in the airway may perpetuate inflammation via secondary necrosis of uncleared apoptotic cells in copd. we have previously reported that low-dose azithromycin improved macrophage function in vitro, although the mechanisms for this effect were not identified. we explored the possible role of the collectin pathway in the azithromycin-mediated improvement in phagocytosis as well as possible defects in this pathway in copd subjects. methods ( ) mannose binding lectin (mbl), mannose receptor (mr), surfactant protein d (sp-d) were measured in copd subjects and controls. ( ) the in vitro effects of addition of rhmbl, and blocking mr with a specific antibody, on am phagocytic ability were assessed. in vitro effects of azithromycin on am expression of mr were also investigated. ( ) azithromycin ( mg orally ¥ weekly/ weeks) was administered to copd subjects. bronchoscopies were performed prior to and weeks following therapy. ex vivo assessments included am phagocytic ability, levels of mbl, sp-d and mr and apoptosis of bronchial epithelial cells. results am mr expression and levels of mbl and sp-d were significantly reduced in copd subjects vs controls. azithomycin ( ng/ml) increased mr expression by % in vitro. rhmbl induced a dose-dependent increase in am phagocytic ability (up to %). blocking mr significantly decreased am phagocytic ability by %. in copd patients following azithromycin therapy, we observed improved am phagcocytic ability, increased levels of mr and reduced levels of bronchial epithelial cell apoptosis. conclusions these findings strongly implicate the mr in both the defective phagocytic function of am in copd and as a target for the azithromycinmediated improvement in phagocytic ability. obstructive sleep apnea (osa) is associated with hypoxia and increased cardiovascular morbidity. t cells and monocytes play a significant role in atherogenesis via cytokine production. there have been reports of benefits of continuous positive airway pressure (cpap) therapy in osa. the purpose of this study was to characterize leucocyte inflammatory cytokine/chemokine production by t cells and monocytes in a group of osa patients and to investigate the therapeutic effects of cpap therapy. methods a comprehensive range of intracellular t-cell and monocyte proand anti-inflammatory cytokines/chemokines was investigated in peripheral blood from osa patients and aged-matched control subjects (with no evidence of sleep problems) using multiparameter flow cytometry. osa patients were again studied following days of cpap therapy. results in osa patients there was an increase in intracellular t-cell ifng and tnfa production but no change in il- , il- or tgfb compared with control. there was an increase in intracellular monocyte il- a, il- , tnfa, mcp- and mcp- in osa patients but no change in il- or il- . following cpap therapy, t-cell ifng and tnfa production returned to 'normal' levels. however, although intracellular monocyte cytokine/chemokine production was decreased following cpap, levels were significantly elevated compared with control. conclusions osa is associated with increased intracellular proinflammatory cytokine/chemokines, many of which are increased in atherosclerotic plaques. although one week of cpap therapy resulted in amelioration of t-cell pro-inflammatory cytokines, longer cpap use or alternative therapy may be required to reduce monocyte pro-inflammatory mediators associated with atherosclerosis in patients with osa. gp has been associated with the progression of fibrosis especially in patients with idiopathic pulmonary fibrosis (ipf). gp is the common subunit of the receptor complexes for the il- family of cytokines including il- and oncostatin m (osm), where gp -mediated signalling leads to activation of the erk or stat pathways. we have previously demonstrated exaggerated gp -stat signalling to be fundamental to the development of pulmonary fibrosis in a murine model of bleomycin-induced lung fibrosis. the aim of this study was to elucidate the role of the il- cytokine family in the development of pulmonary fibrosis by identifying which il- family cytokines regulate fibrosis in bleomycin treated mice, and determine the effects of these cytokines on cell function. bleomycin ( . u/mouse) or control saline was administered intranasally to wildtype mice (wt), genetically engineered mice containing point mutations to prevent gp erk signalling (gp f ) or gp stat signalling (gp dstat ), and duel il- and il- a-receptor knockout mice (il- -/-;il- ar -/-). the effect of bleomycin on collagen production was examined in lung tissue days post treatment by hplc. there was a significant increase in collagen levels in bleomycin treated wt lungs which was further increased in gp f lungs. the lungs of gp dstat and il- -/-;il- ar -/mice were protected from fibrosis suggesting that gp -stat signalling is important in inducing lung fibrosis which may be mediated through il- and/or il- . cell proliferation was examined in lung fibroblasts isolated from wt, gp dstat and gp f mice. il- , il- and osm were significantly mitogenic for gp dstat cells but not for wt or gp f cells, reflecting different responses to the different signalling pathways. changes in cytokine profiles are currently being examined in lung tissue and serum of control and bleomycin treated mice - days after treatment. in conclusion, il- and il- are likely to play a role in bleomycin-induced fibrosis via the gp -stat-mediated pathway, however this may not be due to regulation of proliferation induced by these cytokines. supported by the nhmrc. mimicking viral infection by application of various toll-like receptor ligands has shown clinical promise in the treatment of persistent viral infections and more recently with malignant tumours. commercially available toll-like receptor ligands (tlr l), such as those of the imidazoquinoline family have been applied clinically for the treatment of a number of conditions including basal cell carcinoma and hpv-induced genital warts. these compounds are known to retard tumour growth indirectly by promoting activation and migration of dcs, leading to a strong th cellular response, and directly via release of proinflammatory cytokines and promotion of tumour cell apoptosis. malignant mesothelioma (mm), an aggressive tumour with a mean survival of months, is highly resistant to chemotherapy, radiotherapy and surgery and is therefore an interesting candidate for immunotherapy in the form of tlr ligand treatment. whilst tlr is known to be selectively expressed in immune cells and its relative expression low amongst other cell and tissue types in mammals, its expression on tumour cells and the consequences of such expression on tumour growth are unknown. here we describe the presence of tlr (mrna and protein) directly in a range of different tumours, including several murine and human mm cell lines. reactive oxygen species (ros) produced during the innate immune response are important agents of anti-pathogen defense but may also cause oxidative lung damage. glutathione peroxidase- (gpx- ) is a detoxifying enzyme that may protect lungs from such damage. methods wild-type (wt) or mice deficient in glutathione peroxidase- (gpx- -/-) were placed in a perspex chamber and exposed to cigarette (cig) smoke generated from cigs per day for days. on the fifth day, mice were killed, the lungs lavaged with pbs and then harvested for proteomic and genomic analysis. results wt mice exposed to cig smoke for days had significantly more macrophages ( . Ϯ . (sem) ¥ ) and neutrophils ( . Ϯ . ¥ ) than sham-exposed mice ( . Ϯ . ¥ and , respectively) (n = , p < . ). however, gpx- mice exposed to cig smoke had significantly greater macrophages ( . Ϯ . ¥ ) and neutrophils ( . Ϯ . ¥ ) than smokeexposed wt mice (n = , p < . ). macrophage and neutrophil numbers in sham-exposed gpx- -/mice ( . Ϯ . ¥ and . Ϯ . ¥ ) were similar to those of sham-exposed wt mice ( . Ϯ . ¥ and ). in addition, we found that balf of gpx -/mice exposed to cig smoke had an increased proteolytic burden compared with smoke-exposed wt mice as assessed by zymography and net gelatinase activity assay. conclusions these data suggest that gpx- protects the lung from cigarette smoke-induced inflammation and that targeting gpx- may have therapeutic utility in inflammatory lung diseases where cigarette smoke plays a role. funded by nhmrc. the becs from subjects with chronic obstructive pulmonary disease (copd) are exposed to frequent infectious and inflammatory stimuli. infection with rv is known to trigger acute exacerbations and subjects with copd are particularly susceptible. we hypothesized that exposure of copd becs to these stimuli would alter their response to rv infection. methods bec were obtained by endobronchial brushing from subjects with gold stage copd (n = , all ex-smokers), subjects with mild persistent asthma (n = ) and healthy controls (hc, n = ). becs were cultured and then treated with tumour necrosis factor (tnf)a ng/ml or lps mg/ml for hrs and then infected with rv- , rv- b. response was measured by release of il- , il- and ip- mrna and by elisa. virus replication measured by cell titration assay. results infection with both rv strains led to increased release of il- and ip- in all groups. exposure of hc and asthma becs to both lps and tnf led to increased release of il- . in these becs there was no increase in release of il- exposed to lps and tnf and then infected with either rv. becs from subjects with copd released significantly less il- in response to all conditions and rv infection compared to hcs and asthma. no differences were seen in rv replication. the aim of this study was to determine opinions and attitudes to exercise from chronic obstructive pulmonary disease (copd) subjects after completion of a -month maintenance exercise program. methods following completion of a -month exercise study, which included a supervised program (intervention, n = ) and control group (control, n = ), copd subjects [mean age (sd): ( ); mean fev (% predicted) = % ( )] were asked to complete a questionnaire. the questionnaire included closedended questions using visual analogue scales ( mm). in copd the minute walk distance ( mwd) is known to increase with test repetition (familiarization) and in response to exercise training. it is unknown whether the magnitudes of these increases are related to the degree of disability of the individual patient. methods mwd was measured twice before and once after an week out-patient exercise program in patients ( males) aged Ϯ . yrs, fev Ϯ % predicted (meanϮsd) with stable copd. the changes in mwd following a familiarization test and following training were compared between patients grouped according to their degree of disability (defined as the pre-training mwd [best of tests] expressed as %predicted mwd). *p < . gp vs gp . conclusions before training, mwd increases following a familiarization test irrespective of the level of disability. the magnitude of this increase is similar in all groups when normalized for their pre-training mwd. following training, the increase in mwd is greatest in patients with the greatest disability (lowest pre-training mwd). in less disabled patients, the relatively smaller increase in mwd following training may reflect an inability to further increase stride length, thereby reducing the responsiveness of the mwt in this group. supported by nhmrc. endotoxin is a stimulant of the innate immune system and is a major component of cigarette smoke. smokers have evidence of increased airway neutrophils and inflammation. we hypothesized that endotoxin levels would be higher in the bronchial lavage (bl) of subjects who were former smokers and subjects with chronic obstructive pulmonary disease (copd). methods subjects were all ex-smokers for at least years (n = , copd, healthy controls) or never smokers (n = , asthma, healthy controls). bl was collected and analysed for cell count and differential, culture for microbiology. the supernatant was analysed for il- by elisa and endotoxin by quantitative kinetic lal assay. results median endotoxin levels were significantly higher in ex-smokers compared to never smokers . u/ml (p < . ). there were no differences between subjects with copd and hs. subjects with copd had higher median endotoxin levels ( u/ml), compared to asthma ( . u/ml) and hc ( . u/ml, p = . ). there was no correlation between endotoxin levels and bl total cell count, neutrophils (%) or fev % predicted. there was a strong correlation with previous packet years smoked and endotoxin levels (r = . , p < . ). conclusions bl endotoxin levels are higher in ex-smokers, including subjects with copd. despite this there is no relationship to increased neutrophilic inflammation. copd is associated with inflammation associated with ineffective repair of the injured epithelium and loss of structural integrity. we have shown that these changes may result from dysregulated 'efferocytosis' (increased apoptosis of bronchial epithelial cells and defective clearance of these cells by alveolar macrophages (am)). we have also reported that azithromycin, at subbactericidal dose, improved am phagocytic function ex vivo. methods we administered azithromycin at low dose ( mg/ twice weekly for weeks) to copd subjects ( male, age: Ϯ yr, current/ ex-smokers, fev : Ϯ % pred, fev /fvc: Ϯ %). the study was openlabel, uncontrolled and primarily focused on objective biological responses obtained from the bronchoscopy samples taken. phagocytic ability of am (from bal), apoptosis of bronchial epithelial cells (from bronchial brushing), markers of inflammation in blood, bal and breath condensate (crp, wcc and inflammatory cytokines), health status (st. george's respiratory questionnaire), ecg and lung function were assessed pre and post-administration of azithromycin. results azithromycin significantly improved phagocytic ability of am (by %) and reduced bronchial epithelial cell apoptosis (by %). antiinflammatory effects of azithromycin included significantly reduced blood wcc and crp. there were non-significant reductions in levels of pro-inflammatory cytokines il- , il- and tnf-a in blood, bal and breath condensate, and a trend for improved health status. conclusions our findings indicate a novel approach to supplement existing therapies in copd that may improve clearance of accumulated apoptotic material and reduce the risk of secondary necrosis and release of toxic cell contents that perpetuate inflammation. background the prevalence of gastro-oesophageal reflux disease (gord) across the disease spectrum in copd and bronchiectasis is not well described. the aim of this study was to determine the prevalence of symptomatic and silent gord in copd and bronchiectasis and its effect on lung function and quality of life (qol ] ) and healthy controls were recruited. the prevalence of gord in bronchiectasis was %; % in copd; % in controls. in copd and bronchiectasis, total nre and ri were increased in those with distal and proximal gord compared to those without gord (all p < . ). there was no difference in extent or severity of bronchiectasis in patients with or without gord (all p > . ). in copd, the relationship between proximal gord and fev was small to moderate (r = . ). sgrq symptom scores were higher in patients with bronchiectasis with increased ri (p = . ). increased proximal nre was associated with reduced physical (p = . ) and mental health (p = . ) in the sf- in copd. conclusions gord is a co-morbidity in patients with copd and bronchiectasis. the impact of gord on disease severity requires further evaluation. funding source nhmrc, the university of melbourne, monash university, physiotherapy research foundation. chronic obstructive pulmonary disease (copd) is prevalent among older people, however little is known about the influence of ageing on airway inflammation. the aim of this study was to compare airway inflammation in older people with obstructive airway disease to groups of older and younger healthy controls. methods participants (> years of age) with stable airway disease and incomplete reversibility (fev % predicted < % and fev /fvc < %; copd n = ) and healthy controls (n = , older > years and younger < years) were recruited from the respiratory ambulatory care clinic or by advertisement. participants underwent a clinical assessment, skin allergy test, hypertonic saline challenge, sputum induction and gas diffusion studies. results participants with copd had moderate airflow obstruction (mean (sd) fev % predicted ( )) and ( %) were current or ex-smokers with a median (iqr) pack year history of ( - ) pack years. ageing was associated with an increase in airway neutrophils (p = . ). compared to older controls, participants with copd had increased airway eosinophils and lymphopenia (p = . , p = . respectively), but no difference in airway neutrophils. conclusion airway neutrophilia is a feature of ageing and is not further increased in the presence of copd. copd is associated increased numbers of airway eosinophils with reduced lymphocytes which may impact on the ability of the immune system to combat infection. supported by nhmrc, the university of newcastle. chronic obstructive pulmonary disease (copd) is third leading cause of death and fourth leading cause of disease burden in australia. mechanisms involved in emphysema severity have not been fully understood. micrornas are noncoding rnas that regulate gene expression. we hypothesize that microrna expression differs between emphysema severity in copd patients. methods mirna profiling was performed using k agilent human oligo mirna microarrays on total rna extracted from non-tumour lung tissue from copd patients undergoing resection for lung cancer. the mirnas were quantile normalized and anova was used to find differentially expressed genes. results demographic characteristics of the copd patients (mean (sd)) were age ( ) years, fev ( ) % predicted and fev /fvc ratio (< %). anova identified mirnas that were differentially expressed when stratified into two classes according to kco % predicted > or < % (t-test, p < . ). discussion this mirna analysis has identified mirnas that may be important in emphysema severity in copd patients. further validation will be performed using qrt-pcr and mirna assays on the training set and an independent set, and target prediction and validation. t-helper type (th ) and type (th ) lymphocyte responses have been well recognized as being important pathways in inflammation. recently another form of inflammatory lymphocyte response has been described, the th pathway. th cells produce cytokines such as il- a to clear extra-cellular bacteria and fungi and have been implicated in autoimmune and chronic inflammatory diseases. the th response in copd is unknown. methods subjects were patients with copd (ex-smokers, fev < % predicted who had not had an exacerbation for at least month) and control subjects (ex-smokers and normal spirometry). serum samples were obtained for measurement of c reactive protein (crp) and il- a, the latter measured using enzyme-linked immunosorbent assay (elisa). production of il- a by t-cell subsets was also identified by intra-cellular cytokine staining and measured by flow cytometry. the mean fev of copd subjects was % predicted ( . sem, n = ) and mean fev of controls was % predicted ( . sem, n = ). the copd group had a higher mean level of crp . mg/l ( . sem) compared to the control group mean level of . mg/l ( . sem). the mean level of the il- in the copd group as measured by elisa was . pg/ml ( . sem, range - ) whilst no il- was measured in any of the control subjects. conclusions the findings of this pilot study suggest that il- may be elevated in association with crp in stable copd. airway obstruction is defined as a fev /fvc ratio below the lower limit of normal. airway obstruction may prolong the forced expiratory time (fet). method spirometry results from patients were categorized as obstructive, restrictive or normal. the mean, range and coefficient of variation were determined for fet in each diagnostic group. receiver operator characteristic (roc) curves were used to determine if fet could predict a low fev /fvc. the number of patients with airway obstruction in five fet groups: < ; ; - ; - ; and > seconds were determined. results the coefficient of variation was high for all groups. pair-wise comparisons showed a difference in mean fet between patients with normal lung function versus those with airway obstruction (p < . ). the best cut-point in the roc analysis of . seconds had a sensitivity of . , specificity . and area under the curve of . for predicting obstruction. the technique of skeletal muscle microbiopsy has previously been validated [ ] and shown to be minimally invasive and well tolerated in participants with stable copd. aim a study was undertaken to determine the feasibility and tolerability of obtaining microbiopsy muscle samples from the patient admitted for acute exacerbation of copd patient. methods written informed consent was obtained to collect the muscle, blood and sputum samples for research purposes. local anaesthetic was injected prior to the insertion of a gauge bard max core disposable biopsy instrument through the associated guide needle. multiple passes (up to ) were obtained. the patient was asked to evaluate the experience by rating it on the modified borg scale - . results to date patients and controls have participated in this study. the gold severity ranged from - and ats exacerbation severity - . the mean age years (range - years), bmi mean . kg m - (range . - . kg m - ) and fat free mass was determined using single frequency bioimpedance. the sample mass obtained ranged from . - . mg, with an increasing yield occurring with increased experience of the operator. the procedure has been well tolerated, the borg scale rating ranged from - / . all patients were ambulant post procedure; no haematoma or bruising was observed in any of the subjects. conclusion the microbiopsy technique allows the collection of muscle tissue with minimal discomfort to the participant. small tissue masses such as these are sufficient to obtain measures of local markers of wasting and may prove to be a useful adjunct to the collection of sputum and blood for the measure of biomarkers in copd research. introduction older people (op) with obstructive airways disease (oad) experience multiple problems that may impact on their quality of life (qol) and disease management. these problems may relate to pathophysiology, symptoms, self management skills, psychological issues, lifestyle or other problems identified as important by the patient. aim the aim of this study was to determine the frequency of clinical problems associated with oad and to determine if a problem based assessment (pba) could adequately identify these problems. methods a multidimensional assessment tool was developed and the content compared to clinical practice guidelines. participants over years with diagnosed oad underwent this assessment. results sixty-one consecutive patients, aged - years, with mean (sd) fev of . ( . ) % predicted were assessed. the assessment tool identified a mean (sd) of . ( . ) current and significant co morbidities with an additional ( . ) clinical problems per patient. qol was increasingly impaired with an increasing number of problems (p < . ). regression modelling identified that the number of identified clinical problems accounted for % of the qol impairment. the model demonstrated that every additional patient problem was associated with a clinically significant change in qol impairment ( . units) . conclusions op with oad experience multiple clinical problems and co morbidities that adversely impact their qol. a pba of op with oad identifies significant problems that may not be addressed in a diagnosis centred approach. there is a need to identify and effectively manage this array of problems in clinical practice. discussion in this diverse group of copd patients, there was a positive correlation between dlco and fev , but not kco and fev . the fev / kco plot identifies substantial numbers of patients with the potential ad and e phenotypes defined above. we intend to study inflammatory biomarkers in these groups. fat free mass index (ffmi) is a marker of morbidity and mortality in copd. measurement of ffm in the out-patient population is commonly undertaken using single frequency bioelectrical impedance analysis (bia). however the formulae to convert measured values to ffm are population dependent. schols et al (am j clin nutr, ) suggested that formula used for the general population may be inappropriate for patients with copd, and derived a specific formula from total body water (tbw) as measured by deuterium dilution. we compare this method of measuring ffm with others, along with tbw and ffm hydration. methods tbw was measured in outpatients with copd by bia and a difference method (weight-(protein+bone mineral+fat+non-bone mineral+ glycogen)) and ffm hydration was calculated. ffmi was measured by skin fold anthropometry (sfa), bia ( separate formulae), dual energy x-ray absorptiometry (dexa) and total body potassium by g-counter (tbk). comparison between methods for tbw and ffmi was made by bland-altman analysis and between methods of calculation of ffm hydration by paired t-test. the two methods of assessment of tbw showed little difference (bias - . , % limits of agreement - . to . ). however there was a significant difference in calculation of hydration of ffm (p = . ). sfa, bia (lukaski), bia (tanita) and tbk underestimated ffmi when compared to bia (schols), with bias of - . , - . , - . and - . respectively. dexa however had a bias of only . and % loa of - . to . . conclusions there are differences between methods of assessment of tbw and ffmi and comparing values between methods must be done with caution. this has implications for assessment of morbidity and mortality in copd. chronic obstructive pulmonary disease (copd) has been identified as a major health problem in australia. recent studies have suggested that respiratory viral infections are the major cause of a worsening of copd; however this has not been studied in australia. aim to characterize pef changes and identify viruses during copd exacerbations. methods a pilot prospective longitudinal cohort study was done. patients had confirmed copd with fev < % predicted and reversibility < % and/or ml. patients recorded daily peak expiratory flow (pef) measurements and daily chest and cold scores over a period of years. sputum samples and nasal aspirates were taken at -month review (control visit) and whenever they had symptoms of an exacerbation (worsening of copd symptoms -seemungal et. al. am j resp crit care med, ). nasal aspirates and sputum samples were obtained and analysed by rt-pcr for rhinovirus (rv). result five patients have finished years of study. a total of exacerbations were reported based on patient symptoms. only exacerbations were associated with significant reductions in pef and only one was linked to increases in nasal cold scores. all samples taken at control visits and nasal aspirates and sputum samples during exacerbations were negative for rv by rt-pcr. positive controls confirmed the accuracy of the assay. conclusion our data suggest that a symptom-based definition of copd exacerbation is not always accompanied by significant reductions in lung function parameters. these 'exacerbations' are also not associated with the commonest reported viral cause. our findings suggest that variability of copd may mimic. bronchiectasis is characterized by hypersecretion of mucus and impaired clearance that results in mucus accumulation, chronic cough, sputum production and recurrent infections. inhaled mannitol ( mg) improves clearance of mucus by increasing the airway hydration and by reducing the viscoelastic and surface properties of mucus. however, the effect of other doses of mannitol on the clearance of mucus in patients with bronchiectasis is unknown. methods fourteen patients, age: . Ϯ . yr, were studied on visits. clearance of mucus was measured using m tc-sulphur colloid and imaging with a gamma camera at baseline and with mannitol ( weight loss and skeletal muscle atrophy are major determinants of morbidity in chronic obstructive pulmonary disease (copd), which are independent of lung function impairment. thus, we examined if a high-fat diet (hfd) protected against the wasting associated with prolonged cigarette smoke exposure (se) in mice. methods male balb/c mice were exposed to the smoke of cigarettes/day, days/week for weeks. sham mice were handled identically without smoke exposure. mice consumed either standard laboratory chow ( . kcal/g, consisting of % fat) or a hfd ( . kcal/g, % consisting of fat). we examined the effect of se and hfd on hind limb skeletal muscles, lung (tissue & bronchoalveolar lavage (balf)) and systemic inflammation in the groups of mice (n = / group). results after weeks of hfd, sham and se mice were and % heavier (respectively, p < . ) than chow fed animals. conversely, se significantly decreased body weight of chow and hfd fed mice by and %, respectively, compared to sham animals (p < . ). the hfd did not protect against the decrease in soleus, tibialis anterior and gastrocnemius skeletal muscle weights induced by se (p < . ). se altered the mrna expression of a number of genes associated with the regulation of skeletal muscle mass including insulin-like growth factor-i (igf-i), atrogin- and interleukin (il)- . the mrna expression of pro-inflammatory cytokines and chemokines was significantly increased by se in the lung, as were the number of inflammatory cells in balf (p < . ). on the other hand, although obesity has been linked to systemic inflammation, the hfd exerted little direct effect on the skeletal muscle and lung parameters measured. se and hfd had no effect on two markers of systemic inflammation, il- and serum amyloid a, whereas se tended to reduce circulating igf-i, an anabolic hormone. conclusions the hfd was not protective against the weight loss and skeletal muscle wasting associated with cigarette smoke exposure. supported by the nhmrc and crc for chronic inflammatory diseases. background patients with copd and bronchiectasis undertake airway clearance therapy (act) and exercise as part of physiotherapy management but it is unknown whether these treatments provoke gastro-oesophageal reflux (gor). this study aimed to determine the impact of positive expiratory pressure (pep) therapy and exercise on gastro-oesophageal function. p. aeruginosa is a significant opportunistic lung pathogen in individuals with cystic fibrosis (cf) and is associated with increased lung disease and morbidity. early intervention is beneficial for the effective clearance of p. aeruginosa and better long-term health outcomes. currently, lung flora of cf patients is monitored by regular culturing of sputum, however, children unable to expectorate are limited to annual bronchoalveolar lavages (bal), which is invasive and requires general anaesthesia. saliva is useful for clinical assays as collection is simple, non-invasive. we are developing a standardized enzymelinked immunosorbent assay (elisa) to detect respiratory infection of p. aeruginosa in cf children who cannot expectorate. methods children ( - years) with cf and recent p. aeruginosa lung infection history and non cf children ( - years) with no previous p. aeruginosa infection history provided saliva as positive, negative controls respectively. saliva was obtained by spitting, or absorbed using cellulose swabs and later extracted. these cell-free supernatant samples were used in an elisa anti-p. aeruginosa iga using commercial antigen. all results were standardized to account for flow using total iga expression. results median value was increased fold in the recent p. aeruginosa lung infection group (mann-whitney test, n = , p Յ . ). there was no significance between mucoid and non mucoid samples, and detection was independent of cfu/ml. discussion early findings support that p. aeruginosa respiratory infection can be detected through specific analysis of salivary iga expression. larger population sampling ( positive, negative) will aid selection of cut-off values for specificity and sensitivity testing in the future to objectively determine the utility of this assay as a means of monitoring for p. aeruginosa and for determining effectiveness of treatment. medical thoracoscopy is utilized widely throughout europe and northern america by thoracic physicians for the management of pleural disease, including the undiagnosed pleural effusion, malignant effusions and less commonly pneumothorax (ptx). australia has limited experience in this modality. we report the success of medical thoracoscopy in both primary and secondary ptx requiring intervention. methods data were collected from to in patients treated with medical thoracoscopy for the treatment of ptx. results patients, male, female. average age (range - ). first episode primary spontaneous (ps) ptx, third episodes of ps, first secondary spontaneous (ss), second ssptx, third ssptx. underlying pulmonary disease in secondary ptx included: chronic obstructive pulmonary disease, lymphangioleiomyomatosis, mesothelioma, metastatic angiosarcoma and was secondary to a motor vehicle accident. had a history of smoking, were former smokers and were current smokers, with a mean pack year history (range - ). ptx were large, moderate. patients had an intercostal catheter (icc) inserted prior to thoracoscopy, had failed pleural aspirate. there was evidence of bronchopleural fistula in patients prior to the procedure. there was a median of days from ptx to thoracoscopy. light sedation was used for the procedure in patients, required a general anaesthesia with a double lumen endotracheal tube due to anxiety. single port entry, dry talc poudrage and a gauge french icc was used for all procedures. icc was removed a mean of days following thoracoscopy and patients discharged on day . pain was the most common complication, requiring narcotic analgesia. one patient died on day , secondary to metastatic angiosarcoma. there has been no recurrence of ptx in any patient. conclusion medical thoracoscopy, performed by thoracic physicians is an effective procedure for the treatment of pneumothorax requiring intervention, including selected patients with evidence of bronchopleural fistula. funding nil. conflict of interest nil. nomination for young investigator award no. background lung cancer incidence and mortality are high in tasmania. australia (aihw ) / / tasmania (cancer registry ) / / aims and objectives (a) to determine patient demographics in southern tasmania, (b) to determine compliance to identified measures of best practice and (c) assess referral rates, clinical utility and potential delay to positron emission tomography (pet) in a regional setting. methods a prospective database collected information on local clinical practice. cases presented at a multidisciplinary lung cancer meeting over a month period (march -april were analysed. data were available for n = / ( %). results are shown as mean Ϯ sd. results primary lung cancer cases were identified. the mean age was Ϯ years. % of patients were male and % were current or ex-smokers. % were non-small cell lung cancers (nsclc). tissue diagnosis % time from diagnosis to surgery ( Ϯ days) % < days macroscopically complete surgical resection ( / ) % pet for stage iiib before radical chemoradiotherapy % % of patients presenting with early or locally advanced disease underwent further staging with pet (n = / ). management was changed in % of cases ( / ). the average time from pet referral to scan was Ϯ days. conclusion a disproportionate number of lung cancers occurred in women. although surgery was performed within recognized timeframes, of patients had incomplete resections. pet influenced management decisions and was performed in a timely fashion. hp chan , , v tran , , c lewis , , p thomas exhaled breath condensate (ebc) is a simple, safe and non-invasive method of sampling breath and has the potential to investigate lung cancer and the associated neoplastic process in the lungs. increased oxidative stress has been implicated in the pathogenesis of lung cancer, and is characterized by elevated hydrogen ions, and hydrogen peroxide (h o ), which is formed from the conversion of superoxide anions by superoxide dismutase. airway ph has already been shown to be decreased in ebc of patients with other respiratory conditions, but not in lung cancer. therefore the concentration of h o and hydrogen ions in the ebc of lung cancer subjects was compared with matched controls. methods six subjects with newly diagnosed lung cancer were recruited and matched with control subjects: non-smokers, ex-smokers and smokers. ebc was collected and h o was then measured by an assay method based on oxidation of , ', , '-tetramethybenzidine by horseradish peroxidase and h o while ph was measured using a ph meter. results there was a significant difference (p = . , anova) in h o concentration between the groups with the lung cancer group having elevated mean h o concentration of . mm ( . (sem) compared to the controls: non-smokers, . mm ( . (sem); ex-smokers, . mm ( . (sem); and smokers, . mm ( . (sem). ph did not differ significantly (p = . , kruskal-wallis test) between the groups. conclusion these preliminary data suggest that there is significant difference in h o concentration between the groups. the demonstration of an elevated h o level in those with lung cancer indicates an increase in oxidative stress which implies that this may be part of the pathogenesis or response to neoplasia. supported by none. conflict of interest none. pro-inflammatory th cytokines produced by t cells and monocytes play an important role in the immune response to malignant cells. however, tumours may escape immune surveillance by inhibiting th response and promoting chronic inflammation at the tumour site. methods to investigate the effect of soluble factors released by lung cancer cells on t cell and monocyte pro-and anti-inflammatory cytokines, culture supernatants from several lung cancer cell lines and a normal epithelial cell line ( hbe) were cultured with whole blood for hours, then for a further hrs with and without stimuli. intracellular cytokine / chemokine production was determined using multiparameter flow cytometry. results in stimulated cultures, there was a significant decrease in t cell th pro-inflammatory cytokines ifng, tnfa and il- and a decrease in monocyte il- a, il- , il- , tnfa, mcp- and mcp- but an increase in antiinflammatory cytokine il- compared with hbe and control media. in non-stimulated blood cultures there was an increase in all monocyte inflammatory cytokines / chemokines in the presence of lung cancer supernatants. conclusions lung cancers secrete soluble factors that inhibit the antitumour pro-inflammatory th response by t cells and monocytes and upregulate monocyte anti-inflammatory cytokine il- following "antigenic challenge". lung cancer cells may also escape immune surveillance by secreting soluble factors that cause newly recruited monocytes to release inflammatory cytokines promoting chronic inflammation at the tumour site. cytotoxic t-cells (ctl's) are important barriers against tumour cells. ctl's induce apoptosis of target cells by mechanisms that include the release of pore-forming perforin and granule associated enzymes, such as granzyme b and granulysin. proteinase inhibitor- (pi- ) is the only known granzyme b inhibitor and its expression has been observed in some cancers. we hypothesized that pi- would be differentially expressed in lung cancer cells and may inhibit granzyme b-induced apoptosis in these cells. methods we investigated pi- , granulysin and granzyme b expression in various lung cancer cell lines ( ( , ( , and normal epithelial cells obtained from bronchial brushing using flow cytometry. peripheral bloodderived t-cells were then incubated with lung cancer cell line supernatants and levels of pi- , granzyme b and t-cell reactive oxygen species (ros) were assessed. results pi- expression was detected in all lung cancer cell lines, ( ( . %), ( . %), ( %), sbc- ( %)), at much higher levels than in normal bronchial epithelial cells ( . %). granzyme b and granulysin levels were undetectable or low in cancer cells ( - . %). increased expression of pi- and reduced levels of granzyme b were observed in cd + t-cells in the presence of all cancer cell supernatants tested (p < . ). interestingly, t-cell ros levels were significantly increased in cd + t-cells after incubation with cancer cell supernatants (p < . ). conclusions high pi- expression in lung cancer cells combined with a reduction in t-cell granzyme b expression and enhanced intracellular t-cell ros levels may be a mechanism of immune evasion of lung cancer cells to granzyme b-induced cytotoxicity. immunotherapy for lung malignancies such as lung cancer and mesothelioma is most likely to be successful it it can be combined with conventional tumour debulking approaches such as chemotherapy and surgery. but they scientific basis of such combinations is yet to be determined. to study this we evaluated ( ) the capacity of different lung chemotherapy drugs to alter tumour antigen cross-presentation and immunogencity, ( ) duration of antigen presentation and responsiveness to immunotherapy after debulking surgery with/without lymphadenectomy, and ( ) the pattern of tlr agonism which best synergized with chemotherapy and surgery. we used the ab -ha murine model of lung malignancy in balb/c mice. results ( ) the antimetabolite drugs gemcitabine and pemetrexed were most immunogenic compared to the cytotoxic antibiotics doxorubicin and mitomycin c and the alkylating agent cisplatin. gemcitabine delived large amounts of tumour antigen into the cross-presentation pathway. ( ) tumour antigen cross-presentation persisted for only days following resection. the optimal window for immunotherapy following cancer surgery is week for effector ctl stimulation and - weeks for memory ctl stimulation. ( ) the viral-like tlr agonists tlr , and were the most effective adjuvant tlr molecules, with tlr agonists generating the strongest systemic anti-tumour responses. conclusion these results help explain previous lung immunotherapy failures and will inform new clinical trials. background mesothelioma is a highly aggressive tumour with an increasing world wide incidence. the serum biomarker mesothelin is elevated in some individuals prior to development of clinical symptoms of the disease and may be useful for screening. we therefore studied the sensitivity and specificity of urinary versus serum levels of mesothelin for mesothelioma patients and evaluated the influence if renal function on the biomarker level. materials and methods concurrent sera and urine samples collected from patients with and control populations. mesothelin concentrations were determined by double-determinant elisa using the mesomark tm assay (fdi, pa). their estimated glomerular filtration rate (egfr) was also calculated. results mesothelin levels correlated between serum and urine samples (pearson's correlation . ; p < . ). mesothelin levels were significantly higher in patients with mesothelioma compared to those with asbestosis and/or pleural plaques in serum ( Ϯ . versus . Ϯ . nm; p < . , respectively), in urine ( . Ϯ . versus . Ϯ . ; p < . ) and in urine following normalization using creatine levels ( . Ϯ . versus . Ϯ . ). age and egfr were significantly associated with mesothelin levels. conclusion the sensitivity and specificity of mesothelin in urine and in serum were comparable. urine mesothelin may prove to be a useful alternative to serum mesothelin for mass screening of asbestos-exposed individuals. patients undergoing ct coronary angiogram (cta) are often former or current smokers with a high incidence of asymptomatic lung disease. overseas reports show a rate of lung abnormalities ranging from . % to %. there are no studies from australia and local factors such as the higher incidence of atypical mycobacteria may influence the rate of benign findings. we are therefore performing a prospective observational study to identify the prevalence and characteristics of incidental lung findings in people undergoing routine cta. methods population: patients undergoing routine cta after informed consent. intervention: radiologist evaluation of lung windows on diagnostic standard workstations. comparator: uncontrolled observational study of consecutive patients. outcomes: primary: prevalence and characteristics of abnormal findings, final diagnosis (clinical judgment, biopsy or long term followup). secondary: number of downstream investigations and costs. results ctas have been studied to date. in / ( %), abnormalities were noted on lung windows. in / ( %), there were lung nodules, in / ( %) there were hilar lymph node abnormalities, in / ( %), there was hemidiaphragm elevation and in / ( %) there were pleural plaques (data collection ongoing with study closure expected in february ). conclusions preliminary data indicate a substantial number of incidental pulmonary findings from cta; full results will be presented. further analysis is required to determine the impact (benefits, costs and harms) that may result from the concurrent examination of lung windows at routine cta. aim increased levels of nitrogen oxides (nox) and inflammatory markers have been found in bronchoalveolar fluid of lung cancer (lc) patients, but have not been investigated in exhaled breath condensate (ebc).the aim of this study was to compare nox and total protein levels in ebc of lc patients with control subjects. methods ebc was collected during tidal breathing through a glass collection device cooled to °c. ebc nox concentrations were measured by a fluorescent modification of the greiss method. total protein in ebc was determined employing the bicinchoninic acid (bca) assay. ebc nox data were log transformed. all data were analysed using anova and expressed as mean Ϯ sem. results a total of control subjects and patients with primary lc were recruited. nox and protein concentrations are shown in table . there was no significant difference in ebc nox levels (p > . ), but in total protein there was a significant difference between lung cancer patients and all control groups (p = . ). conclusion significantly increased ebc total protein levels were found in patients with lung cancer. these data suggest that protein mediator secretion or vascular leak may be present in those with lung cancer. future studies will focus upon the identification of these proteins. methods in this two stage case-control study lung cancer cases and healthy smoker controls were recruited. genetic markers (snps) implicated in lung cancer were screened in our test cohort of smokers and ex-smokers. snps whose genotypes (co-dominant or recessive model) were associated with either the healthy smokers (protective) or lung cancer (susceptibility) phenotype were identified. after genotyping this snp panel in a second cohort of subjects snps were chosen and assigned a simple composite genetic score that was combined with scores for age, history of copd and family history of lung cancer, weighted according to our multivariate regression analysis (n = total subjects). the lung cancer risk score was linearly related to the likelihood of lung cancer with odds ratios (referenced against the lowest score quintile) ranging from to in the highest quintile. on receiver operator curve analyses, the auc was . and the frequency distribution showed bimodal separation between healthy smokers and lung cancer cases. utility of the score was not affected by effects of age, smoking history or lung function. we suggest that genetic data may be combined with other risk variables to define smokers or ex-smokers at risk of lung cancer for targeted interventions such as smoking cessation and early detection of lung cancer. supported by health research council, nz. conflict of interest yes. tp v aiyappan , a graham department of medicine, maroondah hospital, melbourne, australia, and the new disease-modifying anti-rheumatic drug (dmard) leflunomide is being used increasingly to treat inflammatory arthritis. its association with interstitial lung disease needs to be considered before combining it with methotrexate. case report a -year-old male who was known to have rheumatoid arthritis and was on methotrexate was admitted with progressive dyspnoea and malaise. he had been recently started on leflunomide. investigations revealed interstitial lung disease and acute renal failure. he improved on conservative treatment (stoppage of disease modifying drugs (dmard), iv fluids and steroids). review of literature an epidemiological study by suissa et al has suggested that there is increased risk of ild associated with leflunomide in patients with a history of ild or methotrexate use but they attributed this to channelling bias. there has also been a report of leflunomide associated with iga glomerulonephritis.by this presentation we aim to increase the awareness of this entity. we also suggest that any patient who is started on combination dmard (i.e. methotrexate and leflunomide) should have a baseline chest x-ray and be monitored for development of interstitial lung disease. conclusion we are reporting the first ever case of interstitial lung disease and glomerulonephritis (in the same patient), due to usage of leflunomide. this entity needs to be thought about in any patient on combination dmards. background bone morphogenic protein receptor ii (bmpr-ii) mutations are associated with pulmonary artery hypertension. failure of the growth inhibitory effects of bmp may contribute to vascular obliteration and remodelling leading to pulmonary artery hypertension (pah) [ ] . pah has been observed following venous thrombembolic disease (vte), including pulmonary embolism (pe) and deep venous thrombosis (dvt) [ ] . local markers of the pulmonary vascular endothelium rather than traditional markers of thromobophilia are thought to be involved [ ] . methods plasma was collected from age and gender matched participants within hours of diagnosis of vte and prior to commencement of warfarin therapy. plasma samples were hybridized to individual human cytokine antibody arrays, to detect protein levels of bmp , bmp and bmpr-ii. results bmp and bmp levels were higher in patients with dvt than pe. no difference in the bmp level was observed between patients with pe and controls. soluble bmpr-ii receptor was lower in patients with pe than in controls or patients with dvt. conclusion in patients with pulmonary artery stress during the time of a pe the bmpr-ii receptor is reduced, which may predispose patients to vascular remodelling and obliteration. the bmp and levels are reduced at the same time, suggesting a possible overriding regulatory mechanism. the physiological role of bmp's and bmp receptors in patients with vte warrants further investigation. historically, cyclophosphamide has had a variable role in interstitial lung disease (ild), the rationale for its use based on the benefit seen in vasculitis and scleroderma, its rapid effect and low toxicity profile. in patients with severe progressive ild a rapidly effective, well-tolerated agent is desirable. for this reason a treatment protocol for the use of intravenous (iv) cyclophosphamide was implemented at our hospital. aim to review the indications, duration, tolerability and effect of intravenous cyclophosphamide in ild patients following the introduction of a treatment protocol. methods records of patients [dlco was Ϯ % and fvc Ϯ %] completing a course of iv cyclophosphamide during - were reviewed (excluding patients with systemic sclerosis). data covering months prior to and following treatment were collected. comparative analysis of paired pulmonary function data months before and after treatment was performed. % had underlying autoimmune disease. results primary treatment indications included progressive disease(n = ); severe disease (n = ); suspected vasculopathy (n = ); bridging therapy to transplantation (n = ); and accelerated decline (n = ). patients received mg/m [mean dose Ϯ mg, median number of pulses ( - )]. patients with paired pulmonary function data had a difference in median change in dlco% predicted from - . % (- . to . %) before treatment to + . % (- . to . %) following treatment (p < . ). this remained significant with exclusion of vasculitis, or any autoimmune disease, and independent of prior immunosuppression. therapy was well tolerated ( withdrew from treatment, deaths within yr, none directly related to treatment). conclusion iv cyclophosphamide is well tolerated, and associated with functional stability or improvement in the majority of patients. it remains a viable treatment alternative for consideration. pulmonary hypertension is common in interstitial lung disease (ild) and associated with a poor prognosis. as the gold-standard test, right-heart catheterization (rhc) is invasive, and resource-limited, reliable non-invasive measures of ph are needed. methods all ild patients referred for rhc during - were included (n = ; male; age . Ϯ yrs). all patients had concurrent echocardiography (tte) and pulmonary function. the relationship of rhc mean pulmonary artery pressure (mpap) to tte variables, pulmonary function, exercise capacity, as measured by six minute walk testing ( mwt, n = ) and brain natriuretic peptide (bnp, n = ), was examined. case a year old male, non-smoker for years, retired professor of anatomy (had chronic exposure to embalming fluids, formaldehyde, phenol, antifungal and other solvents, for years) presented with chronic cough and phlegm production. these symptoms were worse at night (waking him several times) and early morning. his pulmonary tests were stopped due to persistent cough. a chest x-ray revealed features of longstanding interstitial lung disease. the hrct revealed widespread subpleural interlobular thickening, worse at bases, in keeping with idiopathic pulmonary fibrosis (ipf). there was minimal fibrosis and honeycombing, but no groundglass opacification, large bullae, pleural calcification or pleural plaques. however, there was associated bronchiectasis at the lung bases considered to be due to traction. the ba lavage showed % macrophages, % neutrophils, % lymphocytes, and %, eosinophils and no infection. the patient declined to have a lung biopsy. as per his past x-rays, the duration of his ipf is a little over one year. he maintains that his symptoms started only after starting irbesartan (irb). introduction transbronchial lung biopsy (tbb) has a variable and unpredictable diagnostic yield in sarcoidosis. we hypothesized that the extent and pattern of parenchymal disease on ct would predict the likelihood of a positive tbb. methods data relating to ethnicity, symptoms, pulmonary function and site and results of tbb and bronchoalveolar lavage (bal) from sarcoidosis patients were recorded. all had a ct scan within weeks prior to the tbb procedure. cxr stage was determined from radiology report. ct scans were scored quantitatively for patterns of parenchymal disease (nodular, reticular, consolidation, ground glass and mosaic attenuation) on a lobar basis. results % patients had a positive tbb (total % of cohort had histological confirmation). symptoms, ethnicity, treatment, lung function and cxr stage were not predictors of a positive biopsy. positive biopsy was associated with higher bal lymphocyte count (p < . ) and female gender (p < . ). a reticular pattern (p < . ) and higher total lung score (excluding da) (p < . ) on ct scan predicted a positive biopsy. in those patients with tbb from right lower lobe ( / ) the total rll score on ct was predictive of positive biopsy (p < . ). on multivariate analysis gender, bal lymphocytosis and total lung score were independent predictors of a positive tbb (area under roc . ). pulmonary arterial hypertension has two histological variants; 'arterial-only pulmonary arterial hypertension' (artpah) and 'pulmonary veno-occlusive disease' (pvod). bosentan, a dual endothelin receptor antagonist, has been found to improve haemodynamics, functional capacity and survival in artpah. however, the response to bosentan in clinically diagnosed artpah is often variable. it was hypothesized that a lack of response to bosentan therapy in clinically diagnosed artpah can be explained by misdiagnosed pvod. aims included to: ( ) perform morphometric and qualitative pulmonary vessel analysis on normal controls and cases clinically diagnosed with artpah who had failed bosentan therapy; ( ) ascertain if pvod is present within the case group; ( ) correlate clinical variables and vessel microanatomy to identify the pathologies driving pulmonary pressure elevation. this study reviewed cases of clinically diagnosed artpah (idiopathic n = , associated with scleroderma n = ), who had failed bosentan therapy and had available lung tissue. controls (n = ) were obtained from explanted lungs for other causes and a prior transthoracic echocardiogram excluded pulmonary hypertension. vessel morphometry and qualitative analysis was performed with a novel technique of smooth muscle actin immunohistochemistry counterstained with verhoeff's elastin. baseline clinical data were retrieved. we found % of cases had pathology confirmed pvod. only % of cases had artpah, the original clinical diagnosis. in pvod, significant pathology was present in all vessel types. all vessels had significant smooth muscle hypertrophy. the obstructive, collagenous, pauci-cellular intimal fibrosis of the venules (p < . ) and arterioles (p < . ) was considerably different to the concentric laminar proliferation of smooth muscle observed in the muscular arteries (p < . ) and arterioles (p = . ) in artpah. artpah also had muscular artery smooth muscle hypertrophy (p = . ). the median time to bosentan failure was shorter in pvod than artpah ( vs. days). in conclusion, pvod is an under-diagnosed cause of pulmonary hypertension, is commonly clinically misdiagnosed as artpah and may present with a poor bosentan therapy response. finally, pvod is a vaso-occlusive, not a veno-occlusive disease, and is an independent type of pulmonary hypertension, not a subtype of pulmonary arterial hypertension. cutaneous t cell lymphomas (ctcl) are a heterogenous group of lymphoproliferative disorders. they show various clinical manifestations and diverse morphological, histological and immunological characteristics of the malignant cells. they are caused by clonally derived, skin invasive t cells. peripheral t cell lymphomas (ptcl) are generally more aggressive and have one of the lowest overall and failure-free survival rates. because of the rarity of these disorders, diagnosis and treatment remain challenging. this case report describes a -year-old woman presenting with progressive dyspnoea and cough, together with a distressing generalized pruritic rash. she was initially treated as left ventricular failure with the rash ascribed to a drug reaction as suggested by initial skin biopsies. the diagnosis was made on a third skin biopsy and flow cytometry of lymphocytes obtained by broncho-alveolar lavage months after presentation. despite an initial response to chemotherapy she succumbed to the disease months after diagnosis. clinical pathways to guide the investigation of suspected pulmonary embolism (pe) have been increasingly adopted by emergency departments (ed) worldwide. compliance with these diagnostic algorithms is critical in ensuring good patient outcomes. this study evaluated the compliance to the clinical pathway used in our ed that combines risk assessment (wells scoring system) with d-dimer test, vq scan or ctpa. the main objectives of this study were to identify those factors which contributed to compliance and to assess patient outcomes. methods a prospective observational study of consecutive patients who underwent investigation for pe in our ed. patient demographics, pathway parameters and patient outcomes at -month follow-up were collected. case we report the case of a year old woman who presented to the emergency department with a three day history of dry cough and dyspnoea. the patient was in her third pregnancy at weeks gestation. she had no fever, chest pain or coryzal symptoms. the patient had presented with a right sided spontaneous pneumothorax seven months prior to the current presentation. her past medical history included placental abruption, complicating her previous two pregnancies. her second pregnancy was complicated by placental abruption at weeks and the foetus had not survived. her first pregnancy was complicated by placental abruption at weeks with successful delivery of the foetus. at presentation, significant findings included tachycardia, hypoxemia, tachypnoea and reduced breath sounds over the right side of the chest. chest x-ray demonstrated a large right pneumothorax. a right intercostal catheter was inserted resulting in right lung re-expansion. the catheter was removed three days later. the patient returned to hospital twenty four hours after catheter removal with a recurrent right sided pneumothorax. the patient agreed to surgical intervention involving video-assisted thoracotomy and talc pleurodesis. the patient had no further complications with the pregnancy. she delivered a healthy baby at weeks gestation. discussion spontaneous pneumothorax in pregnancy is rare and there is little evidence to provide guidelines for the management of recurrent pneumothorax in high risk pregnancy. our case illustrates a successful outcome for mother and foetus with surgical intervention at weeks gestation. folfox is currently the standard adjuvant treatment for locally advanced (stage iii) colon cancer and increases disease free survival. its toxicity is well tolerated with common adverse effects being paraesthesia, bone marrow suppression and gastrointestinal disturbance. pulmonary toxicity has rarely been reported. three clinical cases of acute dyspnoea following folfox therapy ( ) ( ) ( ) for stage iii colon cancer are reported. all had an anterior resection followed by - cycles of folfox. each developed rapidly progressive dyspnoea requiring hospital admission within one week of their last cycle. one patient required invasive ventilation in icu. high resolution computed tomography (hrct) showed bilateral widespread honeycomb pattern with associated ground glass opacification consistent with pulmonary fibrosis. they had reduced lung volumes and gas transfer. transbronchial biopsy and bronchoalveolar lavage in one patient showed an acute eosinophilic pneumonitis. other causes of interstitial lung disease were carefully excluded. all three patients received high dose corticosteroids with one receiving additional cyclophosphamide. the first patient showed complete recovery following an eight week course of corticosteroids, with resolution of the hrct changes and improvement in lung function. the second had symptomatic improvement of dyspnoea, but a persistent moderate reduction in gas transfer. the final patient had persisting radiographic changes and a reduced gas transfer. he remained dependant on ambulatory oxygen months after his initial presentation. these patients' interstitial lung disease appears due to folfox with oxaliplatin being the most likely causative agent. the use of oxaliplatin chemotherapy has increased markedly over the last years and although rare, physicians should be aware of its potential for lung toxicity. lung function testing at baseline, during and towards the end of oxaliplatin treatment should be undertaken and may allow early detection and intervention in cases of pulmonary toxicity. the forced oscillation technique (fot) with broadband signals has been employed relatively rarely in the studies on respiratory mechanics. recent work from our laboratory [ ] indicated that the cheek support and the neck angle have minor influence on the impedance spectra around the first antiresonance (far, ), which makes the use of the broadband fot especially attractive in young children. methods we studied healthy children (c; female: ) and children with bronchopulmonary dysplasia (bpd; female: ), using multiple-frequency fot between and hz superimposed on spontaneous breathing. results groups c and bpd did not differ in age ( lung function impairment is common in children with cardiac defects associated with increases in pulmonary blood flow/pressure. to investigate the development of bronchial hyperreactivity (bhr), an aorto-caval shunt was created in a model of precapillary pulmonary hypertension. surgical shunt repair was performed to assess the reversibility of bhr. methods rats were divided into groups: group c (n = ) with sham surgery, group s (n = ) where an aorto-caval shunt was created (follow-up wks), group r (n = ) with aorto-caval shunt but surgical correction of the shunt at wks (follow-up wks). in all animals, respiratory input impedance (zrs) was measured at baseline and following increasing doses of methacholine (mch , , , mcg/kg). airway resistance (raw), inertance, tissue damping (g) and elastance were estimated from the zrs spectra by model fitting. measurements were repeated in all animals at wks and at wks for groups r and c. results there was a significant increase in raw and g in group s and rat wks at baseline and following mch ( fig.) which was reversed after surgery. to characterize the factors contributing to lung function impairment following cardiopulmonary bypass (cpb), functional residual capacity (frc), lung clearance index (lci) and respiratory mechanics were measured in children with pulmonary hypoperfusion (tetralogy of fallot, tof n = ) and hyperperfusion (ventricular septal defect, vsd n = ) undergoing surgical repair of congenital heart disease. methods frc and lci were measured using a sf washout technique and respiratory mechanics using a low frequency oscillation technique in the perioperative period. results while chest opening led to a significant improvement of lung volumes and respiratory mechanics in all patients (p < . ), a reduction in pulmonary blood flow during cpb decreased lung volumes and airway resistance in parallel but significantly more in children with tof compared with those with vsd. re-establishing pulmonary blood flow during cpb improved respiratory function particularly in children with tof ( figure) . conclusions sternotomy had a great impact on lung function with parallel improvement in alveolar recruitment, ventilation inhomogeneity and airway resistance. in contrast, onset of cpb led to lung function impairment with a significant drop in frc especially in children with pre-existing hypoperfused lungs. this suggest that pulmonary blood flow enhances alveolar stability through a tethering effect on the alveolar walls. children with advanced lung disease being considered for lung transplantation are likely to spend disproportionately longer periods on transplant waiting lists before appropriately sized donor organs become available. these longer waiting times reflect the lower organ donation rates seen in children; rates that are significantly lower than those reported in the adult population. we describe two children with advanced lung disease who deteriorated whilst on the waiting list for lung transplantation, and in the absence of appropriately sized donor lungs, underwent lobar lung transplantation. methods we describe the clinical course of two children, aged and years old, with advanced lung disease secondary to post-mycoplasma obliterative bronchiolitis and cystic fibrosis-associated bronchiectasis, respectively. results both children received a "cutdown" bilateral lobar transplant from two oversized adult brain-dead organ donors. in both cases the transplant operation involved implantation of the right middle and upper lobes, and of the left upper lobe from the donor. conclusion given the low organ donation rates in children, and in the absence of appropriately sized donor lungs, novel strategies such as lobar transplantation must be considered, particularly when children continue to clinically deteriorate whilst on the lung transplant waiting list. data from the west australian adult outcomes of extreme preterm birth study suggest that adult survivors of bronchopulmonary dysplasia (bpd) may be left with functional and structural pulmonary abnormalities, most notably emphysema. animal data suggest that the antenatal administration of corticosteroids may adversely affect lung development. we therefore sought to determine if maternal variables, including administration of corticosteroid, could predict emphysema severity in adulthood. methods bpd subjects (birthweight < g and oxygen dependence at weeks post-menstrual age) born prior to were identified and recruited prospectively via the statewide neonatal follow up program as previously described. pulmonary function tests and thin selective inspiratory and expiratory computerised (ct) images were acquired and scored for emphysema severity (voxel index (%)). the obstetric history was obtained from retrospective review of case notes. results adults ( females, aged - ) were studied, declined ct. all subjects had abnormal ct findings. fifteen ( %) had areas of emphysema. emphysema score and fev were not influenced by the administration of antenatal corticosteroids, indication for delivery, maternal age or presence or absence of chorioamnionitis. conclusion maternal factors, including the administration of antenatal corticosteroids, do not predict the long term respiratory outcome of bpd. the factors determining the severity of emphysema in this group remain unknown. the prevalence of childhood asthma is high in the torres strait. children have generally more severe asthma and asthma knowledge is poor. however, there is no culturally appropriate asthma education program for these children. we are conducting a randomized controlled trial to examine the additional benefits of an education intervention by indigenous health care workers (hcw) on asthma outcomes. we describe the study's objectives, design and baseline measurements. methods children with wheeze were reviewed by two paediatric respiratory physicians using a standardized protocol; children with asthma were eligible. after obtaining informed consent children were randomly allocated to: ( ) three additional asthma education sessions with a hcw; or ( ) no additional education from a hcw. trained hcws carried out the education sessions using culturally appropriate tools. primary outcome was the number of unscheduled hospital/doctor visits due to asthma exacerbation. all children were re-assessed at months. results we enrolled children aged to years, % were torres strait islanders and % aboriginal and torres strait islanders. the clinical spectrum of asthma was: % infrequent episodic asthma, % frequent episodic asthma and % chronic asthma. eighteen percent of the children knew what a written asthma action plan was; . % had one. carers' assessment of knowledge of medications showed that % could not name any asthma medication used by their child, % could not explain dosage, and % could not explain how beta agonists worked. conclusions asthma knowledge and possession of asthma action plans in this cohort is poor at baseline. there is substantial room for improvement and additional asthma education by hcws potentially has significant benefits. impulse oscillometry system (ios) measures respiratory function during normal breathing by transmitting mixed frequency rectangular pressure impulses down the airways and measuring reflected pressure. computer analysis calculates respiratory impedance and its components, airways resistance and reactance, at a range of frequencies from . hz to hz. no previous australian normative data exists. the ios software generates predictive normal values for each of the parameters measured including total airway resistance (r ), the proximal airway resistance (r ) as well as peripheral capacitive reactance (x ). however, they are based on german data. methods cross-sectional study of community dwelling adults, with males and females per -year cohort. inclusion criteria: age range - years, apparently good respiratory health. exclusion criteria: smokers, asthmatics and others with acute or chronic respiratory disease. both ios and spirometry were conducted on all participants. results australian predictive normal equations have been generated and compared to the current published equations. the ios parameters have been correlated with the spirometric data. results have been analysed by gender, age, height and weight and compared with the predictive normal values for each parameter provided by the german manufacturer of the ios instrument. analysis includes calculation of mean range, and lower limit of normal. conclusions a preliminary set of australian predictive equations have now been produced for the ios. these have been compared with international equations. ios has potential application in a range of respiratory disease states and in population screening for occupational health (e.g. mining, & high dust load environments). supported by phc red. rationale although clinical practice guidelines for both asthma and copd recommend spirometry for diagnosis and monitoring, beneficial effects on the management of chronic respiratory diseases in general practice have not been established. we hypothesized that spirometry would improve health outcomes compared to usual care. methods we are conducting a single masked rct with arms: group a receive monthly spirometry and followup, group b receive spirometry before and after the trial and group c usual care. general practices were recruited though divisions of general practice in melbourne. invitations were mailed by of these practices to patients who had been prescribed inhaled medications during the previous months. participants returned respiratory and generic quality of life questionnaires and an asthma score card. groups a and b were tested on a micromedical turbine spirometer following ats/ers guidelines. results eligible patients ( adults, children aged - and youths aged - years) entered the trial. were randomized to group a, to group b and to group c. the mean (sd) age of adult participants was . ( . ), children . ( . ) and youths ( . ) years. there were males and females. the adults were highly symptomatic in the previous months: % reporting wheeze, % chest tightness on waking, % shortness of breath on exertion, % nocturnal cough, % morning cough and % sputum. symptoms of chronic bronchitis were reported by % of adults and a diagnosis of copd by %. asthma was reported by %, confirmed by a doctor in % and % had experienced an attack in the last months. only % had a written asthma action plan. % of adults had ever visited a hospital ed and % had been admitted. conclusion it is possible to recruit asthma and copd patients from general practice and to randomize them to spirometry or usual care. whether spirometry is associated with fewer symptoms, changes in medication, uptake of action plans or improvement in lung function or quality of life requires further followup. supported by nhmrc. s shah , jk roydhouse , b toelle , s sawyer , c jenkins for the pace australia management committee university of sydney, woolcock institute of medical research, sydney, nsw , and royal children's hospital, melbourne, vic it is widely held that recruitment of general practitioners for research can be challenging. in this paper, we discuss the recruitment experience from a current study evaluating the impact of an educational asthma intervention on patient outcomes. our aim is to describe the two different strategies utilized to date: ( ) in-house through an academic department of gp and ( ) outsourced to a private gp organization. methods initial interest was generated through faxes, presentations at gp divisional meetings and newsletter advertisements. gps who expressed interest were visited by project staff to discuss the study further. a major difference was recruiting one gp per practice in the first strategy versus multiple gps per practice in the second strategy. to assess the strategies, we examined participant characteristics, number of gps recruited and number retained. results participant characteristics: under both strategies, % of recruits had trained in asia and % were women. the first strategy recruited more gps who spoke at least two languages at home ( % vs %) and the second strategy recruited more recently graduated gps ( % vs %). recruitment: the first strategy recruited gps over months and the second recruited gps over months. retention: gps ( %) from the first strategy stayed in, compared to ( %) from the second. conclusions whilst absolute numbers of gps recruited were similar, retention was much higher under the second strategy. recruitment in primary care is difficult and requires a range of approaches which need to be re-evaluated and adapted as necessary during the course of the study. supported by the australian government department of health and ageing. bronchiectasis is a heterogeneous condition with a large number of causative factors and range of symptoms. the classification of this condition is often confusing and hard to remember. the aim of this study was to classify non-cf bronchiectasis into different clinical phenotypes. methods consecutive patients with non-cf bronchiectasis confirmed on high resolution ct scanning had a detailed clinical, spirometric and laboratory assessment performed by a respiratory physician (pk/mf/pw) and were then followed up for an average of Ϯ years (mean and sd) for a total of over reviews. results of the patients ( %) could be classified as belonging to phenotypic groups; ) bronchiectasis arising in childhood, ) bronchiectasis occurring in smokers and ) bronchiectasis occurring in the elderly. each group had different features which are listed in the there are few data on the long term outcomes of treatment for tuberculosis (tb) by directly observed therapy (dot) in low-incidence settings. the aim of this study was to assess the incidence of recurrent tb in nsw. methods data linkage was performed within the nsw department of health tb notifications database to identify cases that had more than one tb notification between and . recurrent tuberculosis was defined to include all patients with two or more culture positive episodes at least months apart, where patients had received at least six months treatment for the initial episode. in cases where data contained within the notification details was not sufficient to allow us to distinguish between true cases of recurrent disease, duplication notification for the same episode or persistent disease after incomplete treatment, additional information was obtained from the area tb coordinator. results there were tb notifications between and with being culture positive. cases of recurrent culture positive disease after completed treatment for the first episode were identified (recurrence rate: . %). conclusions in a population with a low tb incidence, treatment of active tuberculosis with dot results in a very low rate of disease recurrence over a long period of follow-up. support nhmrc ccre in respiratory and sleep medicine. introduction rhinoviruses (rvs) are the major cause of viral-induced exacerbation of asthma. to date, the molecular mechanisms of rv pathogenesis are not understood. recent findings suggest that rv pathology may involve host cell nucleocytoplasmic trafficking, inhibiting key cell functions such as transcription and translation. the study aims to investigate the mechanism of rv c protease nuclear trafficking. methods hela cells were infected with rv or transfected with plasmids and cellular localization of c analysed at various times thereafter using immunofluorescent confocal microscopy and western blotting with specific antibodies. results c protease was predominantly present in nuclei of rv infected cells up to hours after infection, becoming increasingly cytoplasmic thereafter. the nuclear membrane of infected cells became progressively indistinct with time. using a specific inhibitor we also found that c utilizes the crm- nuclear export pathway. c was predominantly in the form of cd in both cytoplasm and nucleus of infected cells; mature c protease was also detected from hours after infection. deletion analysis indicats that the nuclear localization domain and a nuclear export signal are most likely to be present within the n terminal amino acids. the nuclear export signal is inhibited in the full length protein, via an unknown mechanism. conclusion our data suggest that c and cd proteins localize to the nucleus in infected cells where they may play a key role in rv pathogenesis by disrupting cellular transcription and the nuclear transport machinery. chronic necrotizing pulmonary aspergillosis (cnpa) is a relatively uncommon, sub-acute, locally destructive process due to aspergillus invasion of the lung. the incidence and prognosis of cnpa are poorly described. case report we present a case of cnpa in a patient on intermittent low dose steroid therapy and recurrent refractory exacerbations of chronic obstructive pulmonary disease (copd).the patient presented with worsening shortness of breath and productive cough requiring recurrent inpatient admissions. human influenza virus is found to bind preferentially to saa , gal receptors found in the upper respiratory tract, while avian viruses bind to saa , gal receptors expressed in lower airways. this is thought to affect the ability of transmission to humans. our aim was to study the ability of avian and human influenza strains to infect bronchial epithelial cells and relate this to levels of the sialic acid receptor expression. methods calu- cells were used as a proximal airway cell and a were used as distal airway cell. human primary bronchial epithelial cells (pbecs) were obtained from healthy, asthmatic, and copd volunteers by endobronchial brushing. epithelial cells were stained with sambucus nigra lectin that binds saa , gal receptor, and maackia amurensis lectin ii that binds to saa , gal. the cells was analysed by flow cytometry. human influenza a/h n /wellington strain and low pathogenic avian influenza a/h n /sandpiper were chosen and were used at an moi of . to infect cells. the supernatants were harvested at hr post infection, of which was then analysed by plaque assay for virus replication. results the calu- showed greater expression of saa , gal linkage than saa , gal linkage, and a displayed slightly higher expression of both receptors compared to pbecs. despite this human and avian influenza virus replicated to similar titre at , pfu/ml in both cell lines, but showed low replication in pbecs. background treatment of community-acquired pneumonia remains based on 'best guess' empiric algorithms because of the poor utility of current pathogen tests. furthermore our ability to stratify patients into risk groups is crude at best, relying on scores such as the pneumonia severity index or the curb- have major limitations. we have been slowly improving real-time pcr assays for pneumococcus as a clinical tool in patients with pneumonia. methods building on previous research we assesed two targets in the autolysin (lyta) gene and the pneumolysin (ply) gene of s.pneumoniae using the lightcycler instrument and fluorescence resonance energy transfer (fret) probes. all common s. pneumoniae serotypes were detected while other bacteria and viruses were not. the lyta target had the best sensitivity with a detection range between ng to fg. both assays were then applied to whole blood samples from adult patients with community-acquired pneumonia, all of whom had blood cultures prior to antibiotic administration and urinary antigen testing for s.pneumoniae. the lyta pcr had the best performance characteristics with a sensitivity more than twice that of blood cultures in the clinical samples. most pcr+ve/culture -ve patients had positive urinary antigen tests. there was clinical evidence that urinary antigen +ve/ pcr -ve patients were false +ves. most significantly there was a strong correlation between quantitative bacterial count and clinical outcome. conclusions real-time quantitative pcr for pneumococcus has significant potential as both a diagnostic and therapeutic tool in patients with pneumonia. the pitjantjatjara lands are situated in the north-western corner of south australia, occupying an area of over square kilometres with a population of approximately . the population lives in small communities or homelands, and there is a high level of mobility between this region and other aboriginal communities in south australia and the northern territory. nganampa health council provides all health care services to the region. specialized support for tb control comes from both the south australia tb service based at royal adelaide hospital as well as a centre for disease control in alice springs. the prevalence of tuberculosis (tb) in this predominantly indigenous community is thought to be significantly higher than the national rate. there are considerable challenges in detecting and managing tuberculosis, relating to the community's geographical remoteness, migration of populations and access to health services. the aims of this study are to quantify the prevalence of tuberculosis in the pitjantjatjara lands, and describe the significant barriers to tb diagnosis and treatment. methods a retrospective study of all diagnoses of tuberculosis within the pitjantjatjara lands in the period - . outcomes include measures of tuberculosis diagnosis, the rates of completed tb treatment and rates of tuberculosis drug resistance. the study will draw conclusions about the reasons for high levels of tb prevalence in this community and identify barriers to effective tuberculosis treatment. conflict of interest no. patients admitted to hospital with a diagnosis of community-acquired pneumonia (cap) are usually treated with intravenous (iv) antibiotics irrespective of pneumonia severity. available guidelines vary in recommended timing and indications for switching to oral antibiotics. aim to examine the patterns of antibiotic choice and delivery method (iv, oral and time to switch) in patients admitted with cap. methods a retrospective chart review of admissions to the respiratory unit over a -month period with a diagnostic-related group (drg) coding of pneumonia. charts were reviewed. data collected included patient demographics, clinical features at presentation (temperature, pulse rate, respiratory rate, bp, oxygenation), initial investigations, initial antibiotic regime, time to change (iv to oral), subsequent antibiotic regime and duration, time to defervescence, length of stay and outcome. pneumonia severity was calculated using the revised british thoracic society system (curb- ), score Ն = severe. results patients were excluded due to incorrect coding. of the patients, age was Ϯ (mean Ϯ sd) yrs and ( %) were male. patients ( %) were febrile at presentation and the median curb- score was (range - ). patients ( %) received iv antibiotics. the curb- score was or (non-severe) in patients and of these patients received a combination of iv ceftriaxone and a macrolide. time to defervescence was . Ϯ . days. time from defervescence to switching to oral therapy was . Ϯ . days. in non-febrile patients, time to switch was . Ϯ . days. length of stay was . Ϯ . days. conclusions the time between defervescence and switch to an oral regime was relatively long, possibly contributing to an increased length of stay. many patients received ceftriaxone even with a curb- severity rating of or . implementing local guideline-based treatment protocols may reduce length of stay. ultrasonic flow sensors can determine flow, volume and molar mass (mm) of the gas flow simultaneously. during tidal breathing the expired molar mass curve can be used to compute co over expired volume and a capnography index (cpi) can be computed. the relationship between cpi and copd classification according to gold was investigated. methods prospective, controlled trial. consecutive patients who underwent routine lung function were enrolled to participate in a tidal breathing test using an ultrasonic flow sensor. each test consisted of three tidal breathing recordings of sec. flow, volume and molar mass were measured at hz and data were acquired using prototype wbreath data acquisition software. mean expirograms (mm over volume) were computed and the measurements were analyzed to determine the slope of exhaled phase ii (s ), the slope of phase iii (s ) and the relationship between s and s (cpi = s /s ). gold stages were determined from the lung function results and the ers predicted values. results volunteers participated in the study with a mean age of (sd ), were male, mean bmi (sd ), had never smoked. the mean pack/year smoking history was . there was a clear relationship between gold stage and cpi: gold stage 'normal' had a mean cpi of . (sd . , n = ), stage 'severe' had a mean cpi of . (sd = . , n = ). conclusion computation of cpi based on tidal breathing analysis using an ultrasonic flow and mm sensor correlates well with gold stages. it may therefore be possible to use a simple tidal breathing test to determine the severity of airways disease. background osa is common in tetraplegia and appears within weeks of injury. although cpap treatment is efficacious in able-bodied subjects, case series suggest that cpap is poorly tolerated in tetraplegia. no prospective study has examined cpap efficacy or adherence in tetraplegia. aim to determine the feasibility of cpap use to treat osa following acute tetraplegia. methods all acute admissions who consented and fulfilled the inclusion and exclusion criteria underwent full, portable polysomnography. those found to have an apnoea hypopnoea index of > events per hour (osa) were offered cpap, delivered via an auto-titrating device. results to date, patients have been admitted ( excluded, refused consent). no significant, adverse events have been observed. two patients did not have osa. of the nine with osa, four are mid-study, two had incomplete follow-up ( returned to uk and refused month assessment), two adhered with cpap and one did not due to severe, pre-existing nasal obstruction. preliminary analyses suggest that those who adhered to cpap had a marked reduction ( % compared with - %) in sleepiness and a greater reduction in the functional outcomes of sleepiness compared to either those without osa or who were unable to use cpap. patient accrual, recruitment and completion rates are consistent with our initial estimates. study recruitment will be completed by end-october . conclusion initial data suggest that auto-titrating cpap is a feasible treatment for osa in acute tetraplegia. these data will be used to finalize planning for a multi-national, multi-centre randomized controlled of therapy. this research was supported by the transport accident commission. visual recognition of cyanosis is an important clinical activity. cyanosis recognition is affected by lighting colour and there is anecdotal evidence that people with significant colour vision deficiencies (cvds) have particular difficulty. studies to date have centred on the colour change with oxygenation of isolated blood but it is not clear how this extrapolates to cyanotic patients in vivo. methods ten patients known to be chronically hypoxaemic and showing signs of cyanosis were recruited from the chronic respiratory program. ten normal subjects were recruited as controls. the spectral reflectances of their lips, nail beds and palm creases were measured using a topcon sr- telespectroradiometer. the patients were measured at rest and after exercise to lower their saturation by - %. the chromaticities were calculated and plotted. results both groups showed a spread of colours but they fell into two distinct ranges. the colour difference between the groups lies very close to the colour confusions made by congenital cvds. within the cyanosed group, the colour shift was not tightly related to decreasing oxygen saturation. this is most likely due to interpersonal factors such as pigmentation and vascular perfusion that affect colour and the difficulties in measuring the colour of heterogeneous anatomical features. conclusions these results quantify the anecdotal difficulties in detecting cyanosis and suggest that observers with cvd would have problems recognizing the condition. the photographs obtained from this study will be used to compare the ability of subjects with and without cvd to detect cyanosis. supported by the nsw ambulance service. baroreflex sensitivity is depressed in osa patients during sleep but effects during wakefulness are less clear. we have now examined relationships between awake brs and severity of sleep disordered breathing (sdb). methods immediately prior to overnight polysomnography, continuous ( min) beat-to-beat arterial blood pressure was measured via finger plethysmography (portapres) and heart rate via ecg in , supine, normotensive, untreated osa patients ( males; age: Ϯ years (mean Ϯ sd); bmi: Ϯ kg/m ). spontaneous baroreflex sensitivity (brs) was calculated using the sequence technique. sdb was characterized as apnoea hyponoea index (events/hour) and arousal index (ai). data were analysed via mathematical modelling and unpaired t test. results brs fell with increasing ahi. patients with ahi > events/hour (n = ) had a significantly lower brs ( . Ϯ . ms/mmhg) than those with ahi < events/hour ( . Ϯ . ms/mmhg, p < . ). brs was negatively related to both ahi and ai via fitted exponential functions (r = . and . , respectively). it is hypothesized that the analysis of morphology of the ecg waveform in combination with the heart rate patterns could lead to the possibility of detection of the start and duration of apnoea/hypopnoea events and consequently estimation of the apnoea-hypopnoea index (ahi). to the authors' knowledge the published ecg based algorithms for detecting sleep disordered breathing are only capable of minute by minute analysis rather than detection of individual respiratory events. methods changes to ecg parameters were investigated during respiratory events with no distinction made between apnoea and hypopnoea events. isolated respiratory events and controls of identical duration were obtained from polysomnographic studies, using a randomized procedure. features such as the r wave amplitude, t wave amplitude, qrs area and the r-r interval were extracted from the lead ecg. a number of physiological predictors based on these features were generated. a logistic regression model was used to investigate the association between the predictors and true events, using the statistical software, stata. results univariate and multivariate analyses were performed. three multivariate models were developed; heart parameters only, ecg waveform morphology parameters only and the combinations of the two. the area under the receiver operator characteristic curves (auc) for these models were compared. the best results were obtained with the combination of morphology and heart rate parameters (auc = . ( . (sd))) compared to the morphology (auc = . ( . (sd))) and heart rate (auc = . ( . (sd))) models. the multivariate analysis has shown encouraging results indicating that an algorithm using a combination of heart rate and ecg morphological parameters could potentially be constructed that would enable the determination of individual respiratory events and subsequently an ahi. supported by the arc. introduction sacin and scond are measures of ventilation heterogeneity in acinar and conducting airways, derived from analysis of mbnw. maintaining tidal volumes of l at - breaths/minute (bpm) is impossible for some. our aim was to examine the effect of different tidal volumes on sacin and scond in normals and asthmatics. methods normals ( - yrs) and asthmatics ( - yrs) underwent mbnw at tidal volumes of ml at - bpm, l at - bpm, and l at - bpm. scond and sacin, were determined from the normalized phase iii slopes of breaths between turnovers (cumulative ventilation/frc) . & . results the mean Ϯ sd %predicted fev was . Ϯ % in normals and Ϯ % in asthmatics. in normals, sacin at tv of . , and l were . Ϯ . l - , . Ϯ . l - and . Ϯ . l - , respectively (p = . , anova), while scond were . Ϯ . l - , . Ϯ . l - and . Ϯ . l - (p = . ), respectively. in asthmatics, sacin were . Ϯ . l - , . Ϯ . l - and . Ϯ . l - , respectively (p < . ), while scond were . Ϯ . l - , . Ϯ . l - and . Ϯ . l - , respectively (p < . ). conclusion increasing tidal volume while maintaining the same minute ventilation during mbnw led to large decreases in scond and sacin in both asthmatics and normals. this may be due to reduced inter-regional differences in specific ventilation with greater tv. the log-log relationship between sacin and tv allows an adjustment to be made for variations in tidal volume. funding crc for asthma and airways and nhmrc project grant # . dj smith , k bowden , t lloyd , j coucher , l garske respiratory medicine, and radiology, princess alexandra hospital, brisbane, australia introduction we have shown diaphragmatic flattening and decreased diaphragmatic excursion qualitatively assessed on ultrasound is strongly predictive of dyspnea severity and lower lung inflation in patients with pleural effusion. we sought to quantitatively measure diaphragm length and movement and determine how closely these are related to dyspnea severity and lung inflation. methods patients with unilateral pleural effusions had ct imaging of their diaphragm during a measured inspiratory capacity manoeuvre. maximal sagittal length was measured at tlc, and frc. patients had a baseline dyspnea index (bdi: - ) and respiratory function measured. results patients with unilateral effusion (all right side; malignant mesothelioma, inflammatory) had a mean (sd) bdi of . ( . ), and tlc of % ( . ) predicted. the right diaphragm on the side of the effusion tended to be shorter than the left at frc (p = . ), and had a trend to reduced shortening with inspiration (p = . ). conclusions the right diaphragm is known to be longer than the left in health. the strong trend to a shorter and less mobile right diaphragm associated with effusion suggests this is a potential mechanism for dyspnea. further recruitment will enable correlation between bdi, tlc and diaphragm length and mobility. ) ) that was slightly worse than an able bodied, control population ( . ( . )), but better than an able-bodied population with untreated osa ( . ( . )). the mapi predicted that % of the sample were likely to have osa. these data will be complimented by full sleep studies to be performed at the participants' homes in late , early . conclusion our interim data suggest that the rate of subjective sleep complaints are not substantially different in the population with tetraplegia compared with the able-bodied. this research was supported by the victorian neurotrauma initiative. it has long been assumed that the ventilation heterogeneity associated with lung disease could in itself affect the measurement of carbon monoxide transfer factor. the aim of this study was to investigate the potential estimation errors of carbon monoxide diffusing capacity (tlco) measurement that are specifically due to conductive ventilation heterogeneity. we induced conductive airway ventilation heterogeneity in never-smoker normal subjects by histamine provocation, and related the resulting changes in ventilation heterogeneity (derived from the multiple breath washout test) to corresponding changes in diffusing capacity, alveolar volume and inspired vital capacity (derived from the single breath tlco method). average conductive ventilation heterogeneity doubled (p < . ), while tlco decreased by % (p < . ), with no correlation between individual data (p > . ). when dividing diffusing capacity by alveolar volume, the resulting transfer coefficient was not significantly different pre versus post histamine (p = . ). these findings can be brought in agreement with recent modelling work, where specific ventilation heterogeneity resulting from different distributions of either inspired volume or end-expiratory lung volume have been shown to affect tlco estimation errors in opposite ways. the combination of these errors appears to largely cancel out in our experimental situation of induced ventilation heterogeneity comparable to that observed in lung disease. we conclude that conductive ventilation heterogeneity per se has a negligible effect on diffusing capacity measurement. an important determinant of airway function in humans is vagal-mediated cholinergic tone in airway smooth muscle (asm). this airway tone may be altered in disease states. the use of mouse models for the study of airway diseases, including asthma, pulmonary fibrosis and copd is well established. however, it is not known whether mice actually possess basal asm tone or, if it does exist, how this tone changes in disease models. this study was undertaken to determine whether mice have detectable asm tone in vivo. methods respiratory system impedance (zrs) was measured in female adult balb/c mice using a wave-tube modification of the forced oscillation technique. zrs was measured during slow (~ s) inflation-deflation manoeuvres between the transrespiratory pressures of and cmh o. baseline lung mechanics and thoracic lung volumes (tgv) were measured before and after each mouse was allocated to one of four treatment groups: 'saline' mice received an i.p injection of saline, 'atropine' mice received i.p. atropine sulphate, 'vagotomy' mice had their left and right cervical vagus nerves isolated by blunt dissection and cut, and 'sham' mice had the area of the vagus nerves exposed but the nerves were not cut. results there were no post-treatment changes in tgv, airway resistance, tissue damping, tissue elastance, inertance or tissue hysteresivity in any of the four groups. conclusions the lack of change in lung mechanics post-atropine or postvagotomy in balb/c mice suggests that, unlike humans and many other species, the airways of mice have no baseline asm tone. supported by nhmrc grant# . nomination none. conflict of interest none. both male gender and increased mandibular enclosure volume predict more severe sleep disordered breathing in obstructive sleep apnoea patients. we now examine gender/body size/mandibular enclosure volume relationships for normal subjects stepwise multiple linear regression analysis was used to model body size/enclosure volume interactions. results for the whole group, mv was . Ϯ . ml (mean Ϯ se) while rmv was . Ϯ . ml. head circumference (positive) and forehead height (negative) were both independent predictors for mv and rmv (both p < . ), while hip circumference was an additional positive predictive factor for rmv (p < . ). after adjusting for these parameters, male mv and rmv were larger than for females conclusion these findings suggest that mandibular enclosure volumes are relatively larger in males, even after adjusting for body size/cranial dimension. differing body size/mandibular enclosure volume interactions may contribute to gender influences on the severity of sleep disordered breathing. supported by nhmrc of australia nomination john read prize for sleep and physiological research tp audit of ctpa in a regional hospital y raje, s vincent, g simpson department of thoracic medicine, cairns base hospital, cairns, qld since the introduction of computerized tomographic pulmonary angiograms (ctpa) at our institution the number of requests for this investigation at our institution has grown at an alarming rate. the purpose of this study was to evaluate the clinical assessment of suspected pulmonary embolism (pe). methods ctpa were reviewed. results female, male. mean age yrs (range - ). ctpa requests came from department of medicine, from emergency department, from surgical teams and from oncology outpatients. patients presented with chest pain (pleuritic in cases), had dyspnea, presented with collapse. patients had haemoptysis. hypoxaemia was recorded in . none were clinically shocked and only one had a recorded tachycardia. d-dimer requested in patients and was elevated in . arterial blood gases performed in only patients ( %). patients had prior chest x-ray which was normal in ( %). patients had consolidation on chest x-ray, pleural effusions, atelectasis and fractured ribs. recorded risk factors included patients with previous dvt or pe, patients with malignancy and patients were immediately post-operative. only ctpas ( %) demonstrated evidence of pe. of these had recent dvt and were post-operative. had a history of bowel cancer. there was no formal record of pre-test clinical probability of pe (eg wells' score) for any of the cases. retrospective calculation of the cases of pe, had a wells' score of . and of with the remaining patient with wells' score of under . only patients (one with clinically probable pe) had received fractionated heparin prior to the ctpa. conclusion ( ) ctpas performed at our institution have a low yield ( %).( ) pre-investigation clinical assessment was poor and there was poor adherence to published guidelines, ( ) this results in many unnecessary ctpa examinations generating increased work and expense for the medical imaging department and exposes many patients to unnecessary and potentially harmful radiation exposure. the evaluation and management of hereditary hemorrhagic telangiectasia involves a multidisciplinary approach according to international guidelines. the aim of this audit was to compare the assessment process in one centre with that of the international recommendations. methods retrospective comparison was made by medical chart review of all patients with a diagnosis of hht between the years to . demographic along with clinical data with diagnostic investigations, complications, treatment and genetic evaluation, including family screening was collected. the proportion of patients evaluated and managed as per the international recommendations was determined. results the audit identified patients with the diagnosis of hht, with the mean age years. diagnostic criteria were met in % of the cohort. of the known clinical features, % had a family history, and % epistaxis. cutaneous telangiectasia was present in % and visceral involvement in %. pulmonary arterio-venous malformations (pavm) were seen in patients, cerebral avm in , gastrointestinal telangiectasia was documented in . one patient had a spinal (cervical) avm, and another had pulmonary hypertension in association with this condition. only patients underwent diagnostic or screening investigations in accordance with the international recommendations. furthermore, one patient was referred for a genetic evaluation. conclusions this clinical audit found that % of patients referred to this centre were evaluated in accordance with the international recommendations. genetic assessment was lacking. the study supports the need for a coordinated, multidisciplinary approach to the evaluation and management of hht in this centre. lm young , n good , d milne , w fergusson , i zeng , j kolbe , ml wilsher background while airflow limitation is the most common physiological impairment in sarcoidosis, there are limited data on airway hyperresponsiveness (ahr). understanding the role of ahr in sarcoidosis, if any, may help to identify individuals who might benefit from inhaled therapies. aims ( ) to determine the prevalence of ahr in sarcoidosis. ( ) to determine the correlation between responses to direct (using histamine) and indirect (using hypertonic saline) bronchial challenge. ( ) to determine the clinical, physiological and radiological predictors of ahr. methods subjects with a diagnosis of sarcoidosis based on typical clinical presentation and compatible hrct features and/or tissue biopsy and with a baseline fev > % predicted were recruited. subjects underwent standard hypertonic ( % fall in fev ) and histamine ( % fall in fev ) challenge (> day but < days apart), lung function testing and high resolution computed tomography (hrct) of the chest. results the subjects ( Ϯ years, % female, % european, % stage i, % stage ii, % stage iii, % stage iv) had well preserved lung function overall (fev = . l Ϯ . . % predicted). ahr was detected in / ( %) to hypertonic saline and / ( %) to histamine challenge. on univariate analysis, response to histamine challenge was predicted by conglomerate fibrosis (p = . ) and reticular pattern (p = . ) on hrct. the baseline % predicted fev was significantly associated with ahr on univariate (p = . ), and multivariate analysis (p = . ) when adjusted by hrct patterns. conclusions there is a high prevalence of ahr using histamine challenge in this study of sarcoidosis subjects. ahr most strongly associates with baseline % predicted fev but also conglomerate fibrosis and reticular pattern on hrct. these findings may reflect the consequence of airway remodelling following inflammation. further studies are warranted to confirm these findings. background upper airway shunt represents a significant source of measurement artefact in the use of the forced oscillation technique (fot), with increasing importance in young children. changes in respiratory system admittance, ars (or zrs - ), are theoretically independent of the upper airway shunt. this study examines the possible clinical benefit of ars in preschool children by assessing any increased ability to differentiate responses to bronchial challenges in the routine clinical setting. we hypothesized the use of ars would provide improved sensitivity to clinically relevant obstruction, bronchodilator responsiveness (bdr) and airway hyper-responsiveness (ahr) in young children with respiratory disease. method previous fot measurements were re-analysed and ars calculated to derive: ( ) ars reference equations in healthy young children (n = ); ( ) bdr in ars, respiratory system resistance (rrs) and reactance (xrs) in healthy children (n = ), children with cystic fibrosis (n = ), neonatal chronic lung disease (n = ), asthma (n = ) and wheeze (n = ); ( ) ahr to inhaled adenosine- ′-monosphate (amp) in children. fisher's exact tests were used to assess changes in diagnostic outcomes between ars and conventional fot outcomes (rrs and xrs). results ars was no more sensitive to bronchodilator induced changes than conventional fot outcomes. amp challenges resulted in equivalent responses measured by relative changes in rrs and ars while absolute changes in ars were the least sensitive variable. conclusion this study does not support a clinical advantage in using ars in measuring responses to either inhaled bronchodilator or amp. c hollier , , c menadue , , d flunt , , aj piper , department of respiratory and sleep medicine, royal prince alfred hospital, nsw , and woolcock institute of medical research, nsw serial measurement of arterial carbon dioxide (paco ), ph and bicarbonate (hco -) is essential in the management of patients with hypercapnic respiratory failure (hrf). this information is usually obtained from a sample of arterial blood (abg). the procedure can be painful and distressing for patients, and is sometimes technically difficult due to obesity or contractures. our aim was to determine the validity and feasibility of arterialized venous blood (av) sampling as an alternative to abgs in measuring paco , ph and hco levels in patients with chronic hrf. method eighteen patients completed the study. venous blood was arterialized by heating forearm skin to a temperature of - °c with an electric heating pad. an av sample was taken from a cannula positioned in a vein of the heated forearm simultaneously with an abg. in addition, the reliability of av sampling within the recommended temperature range ( - °c) was investigated in ten healthy volunteers placed on volume cycled ventilation in order to maintain constant ventilation. av samples were taken at . °c temperature intervals from . - °c results the table below summarizes results for validation of av sampling: based on the evidence that cardiovascular dynamics are altered due to obstructive sleep apnea, this study aims to identify the onset and termination of each apnea event using power spectral density (psd) and morphological features of single lead ecg signal over second period. methods ecgs from patients overnight sleep studies were examined for location of the pre-scored apnea events. onset (n = ), maximum (n = ) and termination (n = ) of each apnea event and normal events (n = ) were annotated on second windows. features extracted were psd, amplitudes of r and t wave of second ecgs. receiver operating characteristics (roc) analysis was used to gauge the event recognition ability of all features. weight loss causes an improvement in the severity of osa, however substantial weight loss is very difficult for obese patients. the very low caloric diet (vlcd) has been shown to be successful in causing significant weight loss in obese patients. this is a pilot study on the use of a formal screening protocol to identify osa patients who are potentially eligible for the supervised vlcd program offered by the endocrinology department at auckland city hospital. method consecutive patients who attended the sleep laboratory at ach between june to december were screened using the protocol. patients who are eligible to be considered for the vlcd program are identified as having a combination of obesity (bmi > ), osa (ahi > on sleep study) and being residents within the auckland district healthboard region. results / patients screened did not fulfil the inclusion criteria: lived outside the adhb region; had bmi < ; patients did not have osa (ahi < ). patients fulfilled the inclusion criteria. / patients ( %) were excluded due to medical or psychiatric contraindications to vlcd. patients ( %) who did not have contraindications to vlcd were contacted. patients were contacted successfully. patients were either unavailable to phone contacts on separate days or were disconnected. / patients consented to being referred ( %). / patients declined referral ( %). conclusion this pilot study is the first study using a formal comprehensive screening protocol in the recruitment of obese osa patients into a medically supervised vlcd program. only a small proportion ( %) of patients proceeded to being referred to the vlcd program. key: cord- - gdfo vd authors: nan title: tsanz oral abstracts date: - - journal: respirology doi: . /j. - . . .x sha: doc_id: cord_uid: gdfo vd nan introduction very little is known about adult health of survivors of extreme preterm birth. the aim of this study was to assess the burden of respiratory symptoms in a cohort of young adults born prematurely compared to sibling controls. method one hundred and fifty six children born prematurely ( - weeks gestation) at the mater hospital brisbane between [ ] [ ] were mailed questionnaires to assess their respiratory symptoms using a modified version of the european community health survey. term-born siblings were invited to act as controls. results thirty six responses were received ( %). the studied cohort consisted of cases ( % female) and controls ( % female). the median age was years ( - ) in the cases and years ( - ) in the control group (p = ns). shortness of breath (sob) was reported in % of the preterm cases, but nil in the control group (p = . ). there was a higher incidence of day/night cough ( % vs. %, p = . ) and morning cough ( % vs. %, p = . ) in the preterm cases compared to controls. the preterm cases were also more likely to experience a chest infection before the age of five ( % vs. % of controls, p = . ). sob was unrelated to a history of asthma, atopy, exposure to smoke or domestic animals as there was no difference between controls and cases. conclusion a higher incidence of sob was reported in young adults who were born prematurely compared to sibling matched controls, and this appears to be unrelated to asthma and atopy. further subjects will be enrolled interstate to assess predictors of respiratory symptoms in early adulthood. background currently all protocols for checking patient readiness for oral intake post fibre optic bronchoscopy (fob) are non-evidence based. there is a need to establish the shortest safe time to implement resumption of oral intake following administration of local anaesthesia for various reasons. we examined return times for the gag reflex and swallow response. method a prospective study of consecutive patients presenting for a fob, age - , were assessed for optimum time to check the gag and swallow reflex. the gag was checked pre and post fob by the touch method (tickle back of throat), swallow was checked post fob with a sip of water at various times. results after hour % and % of patients had a gag reflex (n = ) and swallow response (n = ) respectively. this increased to % and % at ½ hours, % and % at hours, % and % at ½ hours. the amount of sedation or length of procedure did not correlate with the return of the gag reflex or swallow response. none of the patients who swallowed with the gag still absent coughed or aspirated. eighteen patients did not have a gag reflex pre fob. conclusion the gag reflex and swallow response are separate. data shows it is possible to swallow safely without a gag reflex. the time to safe swallow is much shorter than recommended in current protocols. however, we consider it safer to allow oral intake when both reflexes are present, if the gag is present pre fob. otherwise the patient should wait for ½ hours post fob as % have a returned gag reflex, if swallow response is also back. nomination none. introduction home monitoring in copd may identify acute exacerbations earlier, enabling prompt treatment, thus improving morbidity and mortality. reactance (x rs ), measured by forced oscillation technique has a potential role in home monitoring. the aim of this study was to determine within-and between-day repeatability of resistance (r rs ), x rs , and spirometry in stable copd subjects. methods ten copd subjects underwent seven consecutive home visits consisting of three measures of fot ( minute recording) and spirometry before and after mcg ventolin via spacer. results subject characteristics mean (sd) -age . years ( . ), smoking history . pack years ( . ), post-bd (post-bronchodilator) fev . % predicted ( . ), fev /fvc ratio . ( . ). repeatability measures are reported as intra-class correlation coefficient (icc) and sd of within subject variance (sw). introduction chronic obstructive pulmonary disease (copd) is the single most important risk factor for lung cancer (affecting - % of those diagnosed). considerable overlap exists between smokers who develop copd and/or lung cancer, suggesting involvement of shared pathogenic pathways (inflammation, matrix remodeling and cell death). in a prospective study of high and low risk smokers we have combined snps from gwas and candidate gene studies to develop a susceptibility score for lung cancer (lcss). methods seven hundred and twenty eight high risk individuals (chronic smokers, > years old, > pack years, spirometric confirmed copd), and smokers without copd were recruited and followed for a mean of years. cohorts were matched for smoking history, ethnicity, gender and age, thereby excluding confounding from these variables. all volunteers completed spirometry, modified ats respiratory questionnaire and gave blood for dna. iplex and taqman systems were used to genotype the snp panel. cases are in the high risk (copd) cohort ( % over years, mean score = . ) and ( %) from the low risk cohort, normal lung function ( % over years, mean score . ). the healthy unaffected smokers' mean score was . . this prospective study confirms the risk status assigned by the lcss with ( %) vs. ( %) lung cancers over the year follow up (or = . (%% ci . - . , p = . ).the performance characteristics of the lcss reported here, confirm its utility, in correctly identifying smokers at greatest lung cancer risk. conclusion in this prospective study, we show that the lcss identifies those at greatest risk of lung cancer who might benefit from aggressive preventive strategies such as cessation and chemoprevention. the author is not aware of any conflict of interest. malignant mesothelioma (mm) remains an incurable cancer and its global incidence is rising rapidly. alternative therapeutic strategies are therefore required. bacterial products have been trialled in an effort to enhance local immunity and have demonstrated tumouricidal activity. staphylococcal enterotoxins (se) are classic models of superantigens that have potent mitogenic activity on t cells and demonstrated anti-tumour effects in several cancer models. intrapleural delivery of staphylococcal enterotoxin c (sec) has been used in china for many years as a pleurodesing agent. however, it is unknown whether sec actually kills cancer cells. in this study, we examined the efficacy of sec in the treatment of mm. sec was added at various concentrations ( - ng/ml) to several human and murine mm cell lines and a human benign mesothelial cell line in vitro. dose dependant cytotoxicity was observed in all cell lines resulting in a significant reduction in viability at higher doses ( ng/ml) when using trypan blue exclusion and wst- assays ( . < p < . ). in an effort to elucidate the mechanism of action of sec, annexin v staining and flow cytometry were used to measure apoptosis. results demonstrated a significant increase in apoptosis in mm cells when treated with sec compared to untreated controls ( . < p < . ). on the contrary, benign mesothelial cells appeared to be resistant to the apoptotic effects of sec at equivalent concentrations (p > . ). elisa based assays were used to examine cytokine profiles in culture supernatants of sec treated mm cells and benign mesothelial cells. levels of the pro-inflammatory cytokine il- decreased in sec treated mm cells ( . < p < . ) compared to a significant increase in levels observed in benign mesothelial cells ( . < p < . ). these results suggest that sec kills mm cells in vitro with some specificity and its activity against mm in vivo warrants investigation. conflict of interest no. purpose we examined age trends in the distribution of stage at diagnosis in patients presenting with non-small cell lung cancer (nsclc) at tertiary hospitals. methods we used the queensland integrated lung cancer outcomes project (qilcop), a clinical registry which collects information on about % of all lung cancer patients in queensland, to analyse the distribution of clinical (tnm) stage among , patients diagnosed with nsclc between and . differences in stage distribution across age were analysed using tests of proportions and multivariable logistic regression with stage as the dependent variable and other demographic characteristics as covariates. results the median age at diagnosis of patients in the study was years (range - ) and % were males. the overall proportions of stages i, ii, iii, and iv were, respectively, %, %, %, and %. the percentage of stage i disease increased with age (p < . ), from % in those younger than years to %, %, and % in those aged - , - , and years or older, respectively. age differences in stage distribution remained significant in multivariable analysis controlling for gender, rural residence, and socioeconomic status. among the other characteristics, only gender differences in stage was significant, with stage i cancer being more common in women compared to men ( % vs. %, p = . ). australia has the world's highest incidence of mesothelioma, a disease which has no proven effective therapy. the median survival of less than months and five year survival of % have not changed in two decades. radical resection has a high attrition rate with most cases recurring locally, and few patients have durable responses to chemotherapy. symptoms are related to local disease which compresses the lung and causes severe chest pain from enlarging tumour masses. aim to improve local control of mesothelioma by high dose radiotherapy using advanced technologies that precisely define the active tumour and reduce toxicity to normal tissues. methods all patients had fdg pet scans co-registered with a simulation ct scan to define the target volume, and follow-up pet scans were analysed to assess the residual total glycolytic volumes (tgv) after radiotherapy. acute and long term toxicities were assessed. results between and thirty patients with incompletely resected pleural mesothelioma were treated with radiation doses of to gy to part or all of one hemithorax. all patients who received chemotherapy had progressed prior to radiotherapy. in we introduced a program using a new technique called intensity-modulated radiotherapy (imrt). tgvs reduced by % after radiotherapy, median survival was extended to months and there were no major radiation toxicities, the most common being grade two pneumonitis. relapses were frequent on extended follow-up, the majority in areas outside the radiotherapy field. conclusions imrt is effective in maximising local control in mesothelioma patients who have had extrapleural pneumonectomies, and for selected patients with an intact lung. toxicities are manageable and locoregional control is very good. high dose radiotherapy is recommended for most mesothelioma patients for long term palliation and control of locoregional progression. introduction mortality benefits for ldct screening are not yet known. the queensland lung cancer screening study is screening up to high risk volunteers based on the nlst/acrin protocol. aims observational cohort study to assess: disease detection rate; lung nodule work-up; cost; quality of life issues; smoking cessation; biomarker collection feasibility. methods recruitment via local advertisement and press release. major inclusion criteria: age - years; smoking history ‡ pack years; fit for surgery. volunteers have one prevalence and two incidence scans and follow-up for three more years. ldct parameters: phillips brilliance slice multidetector scanner; low-dose protocol; . mm slice width. scan reporting: two radiologists independently; independent cad reading (phillips brilliance software); final report is agreed by consensus. results see table -to be updated. magnetic resonance imaging (mri) is a useful modality for assessing chronic thromboembolic pulmonary hypertension (cteph) before pulmonary endarterectomy (pea). cardiac mri provides more accurate right ventricular (rv) data than echocardiography. mr angiography demonstrates vascular changes reliably to a segmental level and mr perfusion shows disease distribution. aim to examine the relationship between changes in mri parameters with clinical and haemodynamic outcomes post-pea. methods rv end-diastolic volume (rvedv), rv ejection fraction (rvef), vessel abnormalities and lobar perfusion defects were determined with mri before and after peas performed during [ ] [ ] [ ] [ ] . changes in new york heart association (nyha) functional class, six minute walk distance ( mwd), mean pulmonary artery pressure (mpap) and cardiac output (co) were collected retrospectively from patient charts. results nineteen patients assessed pre-pea were of mean ± sd age ± years, nyha class . ± . , mwd ± metre and mpap ± mmhg. immediately post-pea, mpap fell by ± mmhg which was related to changes in rvedv of ± % (r = . , p = . ). at - months post-pea, mwd improvement ( ± metre) was related to changes in rvef of ± % (r = . , p = . ) but angiographic changes had a weak relationship with nyha class shift (r = . , p = . ). perfusion generally improved after pea relating weakly with rvedv (r = . , p = . ) but not clinical outcomes. conclusions this study shows that improvements in mri parameters (rv data more than angiographic findings) after pea correspond to clinical and haemodynamic outcomes. we have demonstrated a useful imaging test for monitoring patients post-pea with no radiation exposure. purpose allergic reactions to antibiotics are very common in cystic fibrosis (cf) patients and can complicate treatment in patients with multi-or pan-resistant bacterial species. we hypothesised that post-transplant immunosuppression may reduce the requirement for desensitisation. methods and materials a retrospective review was performed in june to detect prescribing practices and any changes in allergy patterns before and following lung transplantation in cf. since antibiotic desensitisation has not been used post-transplant at our institution, our aim was to review our experience with antibiotic rechallenge, without desensitisation, in the post-transplant setting. results fifty eight cf patients, ( %) female, aged years, range - years, heart-lung, heart-lung liver have undergone transplantation at our institution. ( %) had a pre-transplant history of ige (angioedema - %) or non-ige (e.g. rash, nausea, arthralgia or liver dysfunction - %) mediated reactions to at least one antibiotic ( % penicillin, % cephalosporin, % carbapenem, % aztreonam and % others). desensitization to antibiotics with non ige mediated reaction was attempted in out of the patients pre-transplant and successful on all occasions. in other patients, alternative antibiotics were selected and desensitisation was not required. after transplantation, ( %) patients with non ige mediated reactions were rechallenged without desensitisation on occasions. no life-threatening reactions were observed. only two episodes required antibiotic cessation and both recovered without incident. new onset of adverse reaction to iv colistin and voriconazole occurred in two patients following transplantation. conclusions cautious antibiotic rechallenge can be successfully achieved without desensitisation in the majority of patients who have had non ige mediated allergic phenomena to the same compound prior to transplantation. idiopathic pulmonary fibrosis (ipf) is characterised by marked collagen deposition. the receptor subunit gp has been associated with the progression of fibrosis. the interleukin (il)- family of cytokines all require gp to initiate signal transduction to activate either the extracellular regulated kinase (erk) or signal transducer and activator of transcription (stat) pathways. the il- family of cytokines consist of il- , il- , oncostatin m (osm), leukaemia inhibitory factor (lif), cardiotrophin- (ct- ), ciliary neurotrophic factor (cntf), il- and il- . previous studies performed in our laboratory have demonstrated that exaggerated gp -stat signalling is fundamental to the development of bleomycin-induced lung fibrosis in a murine model. we hypothesise that pulmonary fibrosis is mediated by il- family cytokine/gp -stat / signalling. the aim of the current study was to identify which of the il- family cytokines are important in the development of bleomycin-induced pulmonary fibrosis. bleomycin or control saline was administered intranasally to individual il- knockout (il- -/-) mice and dual il- and il- a-receptor knockout (il- -/-;il- ar -/-) mice. collagen production was examined by histology and hplc in lung tissue days post treatment. no significant increase in collagen was observed in bleomycin treated il- -/or il- -/-;il- ar -/mice implicating a role for il- in the development of pulmonary fibrosis. interestingly, the histology of il- -/-;il- ar -/mice displayed marked emphysema which was not observed in individual il- -/mice suggesting this is an il- -mediated response. the role of il- family cytokines in proliferation, myofibroblast differentiation and collagen expression were examined using fibroblasts isolated from wildtype (wt) and genetically engineered mice containing point mutations to prevent gp -erk / signalling (gp f ) or gp -stat / signalling (gp stat ). overall, there was no significant increase in proliferation hours post cytokine stimulation as assessed by wst- reagent. il- and il- did not stimulate a-sma or collagen expression above control, measured by real time pcr. in conclusion, increasing evidence suggests that il- plays an important role in the development of bleomycininduced pulmonary fibrosis but this does not appear to be induced by direct effects of il- on fibroblast proliferation, differentiation or collagen production. mannose binding lectin (mbl) is a key mediator of innate immunity and efferocytosis (clearance of apoptotic cells) and is thus important in protecting against tissue damage. reduced mbl is implicated in airways disease including infection, copd and bos, however, 'normal' plasma levels of mbl are highly variable due genetic polymorphisms complicating correlation with disease processes. we have previously shown reduced mbl and defective efferocytosis in bal from patients with post-transplant bos, but there are conflicting reports of the link between low plasma mbl levels, increased complement activation and graft rejection. to compare mbl levels in the peripheral blood and bal compartments, we investigated mbl in paired plasma and bal from lung transplant recipients ( stable; stable with infection, with lymphocytic bronchiolitis and with bos) and in plasma from and bal from controls. in plasma, mbl levels were highly variable. no significant differences were noted among the transplant groups although levels were significantly reduced in all transplant patients vs. controls. there was no correlation between mbl and time post-transplant or pre-transplant diagnosis. in bal, mbl levels were less variable and significantly reduced in patients with bos (mbl ng/ml: controls: . ± ; stable . ± . ; stable infected . ± . ; bos . ± . ). interestingly, in all patients with lb, mbl levels were very low in both plasma (mean . ng/ml) and bal ( ng/ml). low levels of mbl in the airway may play a role in reduced efferocytosis, leading to tissue damage and airways disease post-transplant. in normal subjects, external dead space with exercise is associated with a slower deeper breathing pattern compared at the same ventilation. with simulated lung restriction and constant intensity exercise, we tested the hypothesis that dead space combined with reduced exercise intensity to match ventilation, would alter pattern of breathing, reduce inspiratory reserve volume (irv) and thus increase dyspnea. methods eleven healthy male subjects, aged ( ) (sd) years completed separate visits with (a) no restriction and (b) chest wall strapping to reduce fvc by ( ) introduction glossopharyngeal breathing (gpb) is used by competitive breath-hold divers to increase lung gas content above tlc to improve performance. this occurs by both lung expansion and gas compression. whilst gpb is known to induce hypotension and tachycardia, little is known about the changes that occur to both the pulmonary circulation and the structural integrity of the thorax. the aim of this study was to investigate these changes within an elite cohort. methods six male breath-hold divers were studied. exhaled vc was measured before and after gpb. subjects were studied in the supine position at baseline tlc and after maximal gpb above tlc at least hours apart. tc m labelled macro aggregated albumin was injected and a computed tomography (ct) of the thorax was performed during breath-hold. dynamic and single photon emission ct (spect) images were generated and analysed by two blinded nuclear medicine physicians for perfusion intensity (wilcoxon signed rank test) and dynamic regional blood flow. a paired t-test was used to assess physiological parameters. registered ct images were used to determine structural change in the thorax. results five subjects increased exhaled vc with gpb [mean (sd)] by . ( . ) l (p < . ). there was a reduction in perfusion intensity following gpb in the anterior (p < . ) and inferior (p < . ) lung segments. there was no change in the timing of blood flow. % of the increase in expired lung volume above baseline tlc was via thoracic expansion ( . ( . ) l (p < . )) with a caudal displacement of the diaphragm. one subject who was not proficient at gpb had no change in exhaled volume, ct appearance or lung perfusion. background we have developed a sensitive method to determine conductance-lung volume (conductance profile) and distensibility-lung volume (distensibility profile) relationships using the forced oscillation technique (fot). using this method, we aimed to assess the effect of a short-acting bronchodilator (bd) on these profiles in asthma. methods twenty two asthmatics and healthy controls completed distensibility measurements (fot) and lung function tests before and after bd. the conductance and distensibility profiles were described continuously and determined at specific lung volumes, residual volume (rv), frc, tlc and midway between frc and tlc (mid). results following administration of bd: the conductance profile in the asthma group was shifted upwards, and the distensibility profile was altered such that significant increases in distensibility were observed at rv (p < . ) and frc (p < . ), but not at mid or tlc. in contrast, no changes were seen in the conductance or distensibility profiles in the control group. post-bd distensibility in asthma remained reduced compared to controls. conclusion using a sensitive method for determining conductance and distensibility profiles, we found that both conductance and distensibility are reduced in asthma across a range from low to high lung volumes. both these profiles are altered in asthma after bd but not in controls. we propose that in asthma the remaining deficit in distensibility after bd will provide unique insight into to altered airway mechanical function due to airway remodelling. cigarette smoke exposure is a major risk factor in susceptibility to serious respiratory infections, particularly in children. although smoke exposure is known to alter immunity to infection, the underlying molecular mechanisms are not well understood. aim identify regulatory mechanisms that drive impaired macrophage function. methods the mh-s alveolar macrophage cell line was exposed to a short minute pulse of cigarette smoke extract (cse) prior to challenge with lps or fitc-e.coli. results cse blocked phagocytosis of e.coli and inhibited lps activation of canonical and alternative tlr pathways. both nfjb translocation and transactivation pathways were compromised as cse inhibited ijba degradation and p phosphorylation. cse also blocked ap- activity by inhibiting p , but not jnk or erk / . we next excluded lps tolerance mechanisms involving receptor internalisation or induction of negative regulators. as free radical species are abundant in cse we investigated their role using the potent scavenger, reduced glutathione (gsh). since gsh restored all responses, we screened a panel of oxidative/nitrosative stress markers and identified carbonylation as the only cse inducible marker. oxyblot analysis confirmed that cse potently introduced carbonyl groups to many proteins ( - kda range) in a dose and time dependent manner that inversely correlated with tnf-a expression. cse treated macrophages also displayed heavily carbonylated pseudopodia that was reversed by gsh as determined by immunocytochemistry (icc). conclusion macrophage sensing and ingestion of pathogen is compromised by protein carbonylation of the outer membrane where phagocytic receptors cluster and also penetrates cytoplasmic regions where signalling moieties reside. therefore, targeting single pathways will not restore macrophage function due to the global nature of cse mediated carbonylation. support nhmrc. background asthma shows varying levels of resistance to effective treatment by glucocorticoids. in studies on tgfb-induced epithelial mesenchymal cell transition (emt) using the a type ii human epithelial cell line, the regulatory effect of the glucocorticoid, dexamethasone (dex, . - nm) on interleukin- a (il- a)-induced interleukin- (il- ) generation was markedly reduced in the presence of tgf-b pm (n = ; p < . ). aim our studies were designed to characterise the mechanism of the glucocorticoid resistance. results the resistance induced by tgf-b was: concentration dependent ( - pm); a glucocorticoid class effect as it also occurred with budesonide; independent of emt: it was observed within hours, whereas emt requires days; also observed in the central airway epithelial cell line, beas- b and passaged, primary bronchial epithelial (nhbe) cells. treatment of a cells with sb , a tgfb receptor type i kinase inhibitor, restored the dex inhibitory effect on il- release (from control ± % to ± %, inhibition in sb lm, n = ; p < . ). in a cells transfected with a glucocorticoid response element (gre)-driven reporter gene, tgfb ( pm) inhibited the gre response to dex ( . - nm) by more than %. in addition, tgf-b impaired dex regulation of the gre-dependent gene, ijb. pge plays a protective role in asthma by inhibiting airway inflammation. it is predominantly produced by epithelial cells in response to pro-inflammatory stimuli and acts as an autocrine and paracrine mediator. prostanoids have been shown to regulate expression of enzymes involved in their metabolism, as well as expression of their receptors and that regulation is tissue-and cell-specific. despite its importance, however, mechanisms underlying the regulation of expression of enzymes involved in pge metabolism and its receptors in human lung epithelial cells have remained elusive. therefore, we hypothesised that pge regulates expression of pge synthase (pges ) and its receptors (e prostanoid (ep) - ) in human airway epithelial cells. methods real time rt pcr and facs analysis were used to assess mrna and protein expression, respectively in human airway epithelial cells hbe before and after pge stimulation. results pge up-regulates pges in time and concentration dependant manner. in addition, ep receptors (ep , ep and ep ) were up-regulated following pge stimulation at mrna level. however, these receptors show different dynamics in expression. while ep reaches peak in mrna expression at hour, peak expression for ep and ep is at hour post stimulation. monocyte derived dendritic cells (dcs) have been recognised for their potential role in immune responses and their functional relevance with regard to adaptive immune responses although more detailed knowledge of dc biology in human airways is required. the objective of this study was to modify the monocyte derived dcs from peripheral blood and direct the cells via exposure to pro-inflammatory conditions as seen in copd, with a view to identifying novel targets for cellular therapy. we characterised monocyte-derived dcs in culture and evaluated the effects of human rhinovirus infected bronchial epithelial cells, pi:c (polyinosine-polycytidytic acid) and bc (bacterial extract) on directing dc differentiation and maturation in culture. we found an impaired adaptive immune response, and in particular, an impaired cd effector cell function in copd patients. our dc culture results showed that both mhc-i and mhc-ii expression on dcs from copd were significantly down regulated compare to healthy controls, which could affect mhc restricted ag presentation, and lead to a failure to activate responder t cells. furthermore, we tested the capability of monocyte-precursors to differentiate into functional dcs. only a very small percentage of cultured monocytes from patients with copd was capable of differentiating into mature dcs, compared with healthy controls. during dc activation, there was up-regulation of co-stimulatory (cd / ) and maturation markers (mhcs), enabling dc to activate naïve t cells in mixed lymphocyte culture both in copd patients and healthy controls. our preliminary data indicated that this activation leads to the generation of effector t cells, further study is needed. defective dc activation of t cells may underlie poor t cell responsiveness in copd in response to inflammation and may, in part, determine the response to therapy. our data suggest a promising role in vitro for pharmacologic treatment as a means of generating functional dcs and will further stimulate speculation regarding their potential clinical application. support nhmrc australia. anxiety and depression are the two most common and the least treated comorbidities associated with chronic obstructive pulmonary disease (copd). they have been found to have a statistically significant and independent adverse association with mortality, longer length of hospital stay, persistent smoking and worse physical and social function. evidence for various interventions to overcome these symptoms in copd is limited or inconclusive. methods this is a cochrane review. all randomised controlled trials (rcts) and cross over trials (cots) dealing with pharmacological and/or psychological interventions for anxiety and/or depression in adults with copd were considered. search was performed via various medical search engines and cochrane database register. duration of follow-up in the studies was generalised as short-term ( - months), medium-term ( - months) and long-term ( - months). the data was analysed using the fixed effect model and difference in symptom control by interventions as mean difference (md) or the standardised mean difference (smd) depending upon the heterogeneity of various scales used. results eight rcts/cots were included. pharmacotherapy showed nil significant effect to control anxiety (smd of - . , p value . , n = ), however, showed significant benefit in controlling depression symptoms (smd - . , p value . , n = ) in copd over short-term. on the other hand, cbt was found to be beneficial in controlling both anxiety (md - . , p value . , n = ) as well as depression (md - . , p value . , n = ) in copd over short term. conclusion cbt is superior as compared to pharmacotherapy over short-term to control anxiety and depression in copd. background the emergence of clonal pa and associated risk of cross-infection is a major cause for concern in cf centres in several countries, including australia. two clonal pa strains (aes and aes ) have been detected in several eastern australian cf centres, but the overall prevalence of these and other strains throughout australia remains unknown. methods a cross-sectional study involving cf centres ( paediatric, adult, combined) was performed. in total, sputum-producing children and adults with documented pa infection provided two sputum samples, months apart, and pa isolates from each sample were genotyped by reppcr-based cluster analysis. results collectively, aes and/or aes strains were identified in % of pa infected cf patients and found in all participating cf centres. several other minor clonal strains were also identified in many centres. only % of patients were infected with unique (non-clonal) pa strains and % of patients were infected with more than one clonal strain. conclusion clonal pa strains are common in australian patients with cf. there is marked variation in prevalence of both major and minor clonal strains between cf centres and within states. longitudinal analysis of the clinical impact of clonal pa infection is urgently required so as to allow an evidence-based approach to patient management and infection control. reduced glutathione (gsh), a major component of anti-oxidant defence, is transported into the lung via cftr. gsh protects against myeloperoxidase (mpo)-induced oxidative stress by undergoing oxidation to gssg and gsa. excess mpo induces chlorination of tyrosine ( -cl-tyr) via the production of hypochlorous acid. we undertook a cross-sectional survey of young children with cf participating in our early surveillance program that includes annual bronchoalveolar lavage (bal) and chest ct scan. markers of neutrophilic inflammation and of the gsh system were determined in bal and the presence of bronchiectasis (b) and air trapping (at) determined on chest ct. samples from children with cf (mean age . years) and nine samples from children without cf (mean age . years) undergoing investigation for chronic respiratory symptoms (ncf) were studied. cf samples had more neutrophils that ncf samples (geometric mean . vs. . · /ml fluid retrieved), more mpo ( . vs. . ng/ml, p < . ), lower levels of gsh ( . vs. . nm, p < . ) and a trend for a lower gsh:gssg ( . vs. . , p = . ). within the cf samples levels of mpo correlated with gssg (p = . ), and gsa (p < . ) and -cl-try correlated with gssg (p = . ) and gsa (p < . ) indicating neutrophilic inflammation exceeding anti-oxidant defence capability. however, after controlling for age and the presence of free neutrophil elastase, there were no relationships between gsh, gssg or gsa and either b or at. while our data demonstrate gsh deficiency and defective anti-oxidant defence, these are not related to structural lung disease. longitudinal studies will be required to determine the impact of gsh deficiency in the initiation and progression of lung disease in cf. support cfft, inc (usa); nhmrc, acfrt, mcri and pmh foundation (aust). introduction there are no australasian guidelines for the detection and eradication of pseudomonas aeruginosa in preschool children with cf. the optimal eradication regimen for preschool children remains uncertain. aims to develop australasian guidelines for p. aeruginosa detection and eradication in preschool children with cf based on a national multi-centre randomized control trial. methods an electronic web-based questionnaire was sent to every tertiary paediatric cf centre in australasia to determine current detection and eradication practices. results all eleven centres completed the survey. a combination of positive oropharyngeal culture (opc) and confirmatory bronchoalveolar lavage (bal) culture was the most common method of p. aeruginosa detection ( %), with surveillance frequencies varying; annually (n = , %), every clinic visit ( , %) and clinically indicated ( , . %). eradication treatment was instigated on one positive culture (opc n = , bal culture n = centres) for p. aeruginosa at any bacterial density ( %) or bacterial density ‡ cfu/ml ( % of centres). eradication regimens varied between centres with most ( %) using intravenous antibiotics either alone (n = - ); in combination with - months nebulised antibiotics (n = ); or with - months nebulised and oral antibiotics (n = ). choice of regimen was influenced by clinical status in three centres. two centres used combinations of inhaled and oral antibiotics alone. failure to eradicate resulted in a change in treatment in % of centres. inhaled tobramycin mg ( days and months) was considered the least acceptable regimen for preschool children in terms of efficacy and burden of care with most favouring more aggressive iv treatments. conclusion this survey supports a call for evidenced based australasian guidelines for the detection and eradication of p. aeruginosa in preschool children. comparative trials of the most favoured eradication regimens would enhance this process. pseudomonas aeruginosa is the most important respiratory pathogen in cystic fibrosis (cf). although unproven, it is generally thought to be acquired from the environment. however, molecular typing studies indicate person-to-person transmission by some clonal strains may also occur. clonal p.aeruginosa strains have not been compared previously with isolates collected from non-cf patients, animals or the environment. aim to determine sequence-based clonality of p.aeruginosa isolates collected from several different ecological niches. methods mlst and sequence type (st) analysis was performed on isolates collected from cf patients (n = ), non-cf patients (n = ), animals (n = ), and the natural environment (n = ). cf isolates included each of the major and minor clonal australian strains and a range of unique strains isolated from patients residing in se qld. non-cf, animal and environmental isolates were collected from the same region. results of the individual strains detected, ( . %) were found in more than one niche. overall, unique and minor clonal cf strains were detected in at least one other niche; including cf strains found in the environment. to date, none of the three major qld cf clonal strains have been detected in another niche. conclusions in cf, environmental exposure to p aeruginosa seems important for acquiring unique and minor clonal strains. finding that the three major clonal strains were confined to cf patients further suggests person-to-person transmission is occurring and/or strain associated adaptation to the cf lung. support nhmrc, acfrt, tpch foundation. background clostridium difficile colitis remains a rare but potentially life threatening complication in cf patients particularly in the post lung transplant setting. aim ( ) to review the incidence of c. difficile colitis among non-transplant and post-lung transplant cf patients attending our centre. ( ) to identify the clinical features in cf patients presenting with cdad. method retrospective study on c. difficile toxin status in all fecal samples collected in cf patients between to was reviewed. patients with positive c. difficile toxin were identified as index cases, those with negative samples were selected as control cases. results two hundred and twenty-three fecal samples were collected from cf patients. nineteen cdad cases were identified in patients including non-transplant and two post-transplant patients. thirteen had mild colitis and two had fulminant colitis. incidence density of cdad in non-transplanted cf patients ( . / patient-days) is comparable to the transplanted group (two episodes/ patient-days). time to diagnose cdad among post-transplant patients is shorter than non-transplant patients ( vs. days). a significantly proportion in the cdad group had recent ciprofloxacin when comparied to controls ( . % vs. %, p-value: . .). a significantly higher proportion of patients in the cdad group are currently on gastric suppression therapy than control ( % vs. %, p-value: . ). conclusion the incidence density of cdad is comparable between pre and post transplant cf patients. cdad is more common among patients with prolonged ciprofloxacin treatment and concurrent gastric acid suppression. improving patient awareness by optimising patient education particularly during prescription of ciprofloxacin or gastric acid suppression treatment can prompt early presentation and management of cdad. conflict of interest no. g karmakar , d milne , m wilsher green lane respiratory services, and department of radiology, auckland city hospital, auckland, new zealand introduction major (massive or submissive) pulmonary embolism (pe) is a potentially lethal condition particularly if associated with cardiogenic shock. thrombolysis is accepted as standard treatment for massive pe with hypotension, but it carries substantial risk of bleeding and risk may outweigh the benefit in sub-massive pe. the objective of this study was to examine risk factors for and the outcome of major pe in this institution. methods we collected data retrospectively from all patients with mpe requiring icu admission in auckland city hospital (ach) over a year period. the primary outcome variable was mortality with secondary variables including precipitating factors and morbidity. results twenty-eight subjects ( massive pe) were identified. eight of with massive pe were thrombolysed and four were treated conservatively with day mortality of % and % respectively. twelve of patients with sub-massive pe received thrombolysis with no mortality. significant bleeding complications were reported in four of thrombolysed patients. prior surgery without dvt prophylaxis was identified as a precipitant in patients. conclusions massive pe carries significant mortality irrespective of thrombolysis but such treatment appears safe in sub-massive pe. in spite of evidence of efficacy, failure to offer prophylaxis of dvt in the perioperative setting appears an ongoing risk factor for major pe. introduction there is a need to improve general understanding of the epidemiology, pathophysiology, outcome and therapies for rare (orphan) lung diseases. aims ) to establish an electronic reporting registry of orphan lung diseases in australasia. ) to provide a useful resource for physicians and patients. methods a website (www.arnold.org.au) was developed containing information on orphan lung diseases, useful links and an on-line patient discussion forum. tsanz members were invited to participate in reporting cases electronically by a quarterly email reminder. the following data were entered: first two letters of given and family name, date of birth, postcode and whether the patient was new or old to the physician. results ethical approval in new zealand is still awaited. results twenty-three h n cases of mean ± sd age . ± years were confirmed from known lt recipients (incidence . %). cases peaked in new south wales (n = ) and queensland (n = ) consistent with epidemiology in the general community. clinical manifestations included allograft dysfunction in of ( . %), upper respiratory tract symptoms only . %, fever . %, myalgias . %, hypoxia . % and radiological infiltrates . %. mean hospitalisation was ± . days. cases were diagnosed in the hospital setting (n = ) and in the community (n = ). other risk factors included obesity n = , diabetes n = and malignancy n = . treatment consisted of oseltamivir mg bd initially for days in all cases, extension beyond days n = (mean ± . days) due to ongoing symptoms, steroid therapy n = , mechanical ventilation n = and noninvasive support n = . patients ( . %) have not returned to baseline lung function and there were four deaths (bos grade three n = and grade n = prior to diagnosis). conclusions the incidence of h n in the australian lt population was less than that estimated for the broader community but mirrored the geographical distribution. the majority experienced allograft dysfunction with most deaths recorded in those with preexisting bos grade . we recommend h n vaccine (panvax, csl) for all lt recipients. as the only commonly transplanted organ exposed to the atmosphere, the lung allograft may be uniquely susceptible to iga deficiency. since igg deficiency is common after transplantation, we hypothesised that iga production may be similarly affected and may contribute to bos pathogenesis. methods we conducted a cross-sectional evaluation of our transplant cohort. total iga, igm, igg, and igg subclasses were measured in serum using elisa. demographic data, immunosuppression and bos status were recorded. results one hundred and twenty three patients ( % of the total cohort, aged . years (range . - . ), % female, % cf, % copd) were evaluated. the median iga level was . g/l (normal range - g/l). patients ( %) were iga deficient, and ( %) of these were pan-hypogammaglobulinaemic. iga levels were lower in patients with bos (median, iq range; . , . - . vs. . , . - . , p = . ). iga deficiency was not associated with age, sex, diagnosis, transplant type or time post-transplant. the median igg level was . g/l (normal range - g/l) and patients ( %) were deficient. igg levels were lower in bos (median, iq range; . , . - . vs. . , . - . , p = . ) and igg deficiency was more common in copd ( %, p = . ). igg levels were negatively correlated with age (r = . , p = . ). multivariate logistic regression models identified iga deficiency as independently associated with bos (p = . ), while the association of igg deficiency with bos was explained by interaction between bos, age and copd. igm deficiency was present in patients ( %) and was more common in males ( %, p < . ), but was not significantly different in bos. igg, iga and igm levels were not associated with immunosuppression or the use of basiliximab induction conclusions serum iga deficiency is common after transplantation and is independently associated with bos. impaired defence of mucosal surfaces because of iga deficiency may contribute to bos pathogenesis. results rv infection alone led to induction of, pstat- , cxcl and release of ifn-k sirna, knockdown of mda- reduced cxcl , ifn-b and pstat- and also reduced ifn-k. silencing of tlr- and rig-i alone had no effect. when combined both sirna for tlr- and mda- had no additional effect. treatment of becs with bx inhibited the production of type i ifn but only partially inhibited ifn-k release. blockade of p mapk however led to substantial blocking of ifn-k release and also led to a marked reduction in the typeiifn response. conclusion we found that following infection with rv, becs type i ifn responses, pstat- induction as well as release of ifn-k was dependent on mda- . blockade of tbk- /ikk by bx reduced type i ifn response, but ifn-k release was only partially inhibited blockade of p mapk resulted in suppression of both ifn-k and type ifn, suggesting this pathway is crucial in the antiviral response to rv infection. conflict of interest none. introduction pregnant women have increased susceptibility to respiratory virus infection. human rhinovirus (hrv) and influenza are the most common respiratory viruses isolated during severe exacerbations in pregnant asthmatics and are high risk factor for respiratory-related maternal and neonatal morbidity and mortality. understanding the innate and adaptive immunological processes underlying respiratory virus infection in pregnancy will lead to improved treatments, resulting in better health outcomes for both mother and baby. methods cross-sectional study of pregnant asthmatics, pregnant non-asthmatics, non-pregnant asthmatics and healthy non-pregnant women. blood mononuclear cells were cultured with hrv (rv or rv b), influenza a (h n ), phytohaemagglutinin or tlr and tlr agonists, polyinosinic:polycytidylic acid and imiquimod, respectively. protein concentrations of ifn-a, ifn-k ifn-c, il- and il- were quantified from culture supernatant by elisa and cba. results pregnant asthmatics had significantly increased il- a and il- (median . pg/ml and . pg/ml, respectively) compared to healthy women (median pg/ml and . pg/ml, respectively, p < . ). ifn-c was significantly reduced in pregnant asthmatics (median . pg/ml) compared to healthy women ( . pg/ml, p = . ). ifn-a and ifn-k were induced by hrv and influenza in response to rv , pregnant women had decreased ifn-a production ( . pg/ml) compared to healthy controls ( . pg/ml, p = . ) whilst ifn-k production was significantly reduced in both pregnant asthmatics ( . pg/ml, p = . ) and pregnant non-asthmatics ( pg/ml p < . ). conclusion increased il- and il- production and reduced ifn-c, ifn-a and ifn-k are important inflammatory and anti-viral alterations during pregnancy and asthma; providing important insight into why pregnant women are more susceptible to respiratory virus infections. support nhmrc. conflict of interest no. nomination nil. the incidence of ntmld is increasing markedly in australia. it is not known why patients with ntmld are susceptible to these organisms, as most patients do not have identifiable risk factors or a documented immune defect. as cell-mediated immunity is crucial for control of mycobacterial disease, we assessed whether ntmld is associated with diminished th immune responses. methods our study cohort consisted of patients with ntmld at different stages of treatment, offspring of patients and unrelated healthy controls. plasma levels of cxcl and il- were assayed on all subjects by cytometric bead array or elisa. in a subset of subjects, pbmc were assessed for production of ifng, il- , il- and il- in response to stimulation with mitogen (seb) and purified protein derivative (ppd). all data was analysed using non-parametric statistical tests. results plasma levels of both cxcl and il- were higher in ntm patients compared with unrelated controls and/or offspring (p < . ). cxcl levels were lower in patients who responded well to treatment compared to those who responded poorly (p = . ). compared with healthy controls, pbmc from ntm patients produced similar levels of ifng, il- and il- , less il- (p < . ) in response to seb, but more il- in response to ppd (p < . ). conclusions ntmld is not associated with diminished th responses. elevated levels of cxcl indicate ongoing ifng release in vivo. ntm patients may have a bias towards il- production in response to mycobacterial antigens and/or harbour an intrinsic defect in th immunity. paracetamol is commonly used in infants as an analgesic and antipyretic. cross sectional studies have reported an association between frequent paracetamol consumption in early life and risk of childhood asthma. to date, no study has controlled for indication for use of paracetamol, or confounders such as history of respiratory infections, which is independently associated with asthma. aim to examine, in a prospective cohort study, whether frequent paracetamol exposure during early life increases the risk of childhood asthma. method six hundred and twenty infants with an atopic family history were recruited. paracetamol exposure was prospectively documented on occasions to years of age, including the number of days and the indication for use. an interviewer-administered questionnaire was used at and years to ascertain asthma in the previous months. results exposure to paracetamol occurred in % of participants by two years of age. increasing frequency of use of paracetamol was associated with increased risk of childhood asthma (or = . , %ci . - . per doubling of days of use). adjustment for frequency of respiratory infections substantially reduced the strength of these associations (aor = . , . - . ). paracetamol use for non-respiratory tract infections and injury was not associated with asthma (or = . , . - . ). conclusions in children with a family history of allergic disease, we found no association between early paracetamol use and risk of subsequent allergic disease when adjusted for respiratory infections, or when only paracetamol use for non-respiratory tract infections was examined. these findings do not support suggestions that paracetamol use up to age two years increases the risk of asthma. support nhmrc. aim to determine whether a water-based exercise program was effective in improving exercise capacity and quality of life in people with copd with physical co-morbidities compared to a land-based exercise program or no exercise. methods participants with copd referred to pulmonary rehabilitation and who had a physical co-morbidity were randomly allocated to one of three groups: land-based exercise, water-based exercise or a control group of no exercise. the two exercise groups trained for eight weeks, three exercise sessions per week. participants underwent measurements of respiratory function, exercise capacity and quality of life by a blinded investigator at baseline and following intervention. results of participants (mean (sd) age ( ) knowledge of airway dimensions is critical for bronchoscopists assessing airway stenoses requiring interventions. it is also important for evaluating phenotypic features of obstructive lung diseases (old). however, real-time quantification of airway dimensions during bronchoscopy is lacking. inserted into the airways via a bronchoscope, anatomical optical coherence tomography (aoct) is a light-based imaging technique with the unique capacity to obtain such measurements. we describe the validation, research and clinical applications of bronchoscopic aoct. methods (study ) aoct was validated in a phantom model, excised porcine airways and in human subjects. (study ) airway compliance curves were constructed and compared from aoct-based measurements in volunteers with and without old during bronchoscopy. (study ) stenosis dimensions (length, calibre) were measured compared in patients with symptomatic airway stenosis using pre-procedure computed tomography (ct) and intra-procedure aoct (bland altman analysis) to determine interventional strategy. results in phantom and porcine airways, aoct measurements were accurate and reliable. mean ct-aoct diameter measurements differed by . ± . mm. ( ) airway compliance was increased in copd (n = ) relative to control (n = ) and asthma ( ) subjects, which were similar. ( ) in patients, the mean difference between ct and aoct-based stenosis measurements was . ± . mm. aoct proved more reliable when ct image quality was poor or where a delay occurred between ct and bronchoscopy. conclusions aoct provides real-time measurements of airway dimensions which are accurate and reliable and can be used for research and clinical applications. nomination ann woolcock young investigator award. support nhmrc. disclosure to declare yes. a notable feature of allergic asthma is the infiltration of mast cells into human airway smooth muscle (hasm) bundles. thus, mast cells and hasm can likely exhibit mutual functional modulation via direct cell-cell contact or through released factors. to examine this possibility, we have used a human mast cell line (hmc- ) to evaluate mast cell modulation of hasm cell function. methods hmc- cells were transfected with human fcria, and fcri expressing cells were flow sorted. the functional activity of these cells (hmc- a) was examined by measurement of released cytokines via ige/antigen stimulation. hasm cells were co-cultured with hmc- a cells, or with conditioned media derived from hmc- a cells, to examine the impact on cytokine release. methods hmc- a cells were activated by ige/antigen to release il- . the co-culture of hasm cells with hmc- a cells, induced both il- (n = , p < . ) and eotaxin (n = , p < . ) production from hasm cells and this effect was greatly amplified when hmc- a cells were antigen-activated. the effect of hmc- a co-culture could be reproduced by addition of conditioned media derived from activated hmc- a cells. a bio-plexÔ cytokine array showed release of mcp- and mip- b was strongly induced from hmc- a cells upon ige/antigen stimulation. however, treatment of hasm cells with these cytokines did not elicit il- release. conclusions our study provides further evidence that the release of soluble mediators from activated mast cells can induce cytokine production from hasm cells. further work is currently ongoing to identify the factor/s responsible for this effect. we have previously demonstrated that gp -mediated stat signaling is required for bleomycin-induced lung fibrosis in mice. to determine the role of phosphorylated stat (pstat ) in the development of human lung fibrosis we examined stat and the regulation of stat expression in lung tissue from idiopathic pulmonary fibrosis (ipf) patients. immunohistochemistry revealed nuclear localization of pstat in fibroblastic cells within fibrotic foci. suppressor of cytokine signaling- (socs ) is a known negative regulator of gp -induced stat activation. we tested the hypothesis that reduced socs expression may account for elevated pstat in cells within the fibroblastic foci of ipf lungs. rt pcr profiler analysis of the jak/stat pathway demonstrated that il- up-regulated socs mrna in both ipf and hlf. western blot analysis confirmed that socs expression was not aberrant in these cells, although a trend towards reduced socs expression was evident. our analysis identified six jak-stat pathway associated genes that were significantly altered in ipf cells following il- exposure for minutes but of those, only il- was up-regulated. examination of other known regulators of stat signaling including socs , socs , socs , socs , pias , pias and protein tyrosine phosphatase non-receptor type (ptpn ) was performed but only socs expression was reduced in ipf. in summary, dysregulation of socs does not appear to cause high stat levels in ipf tissue but the potential regulation by socs is the subject of ongoing investigations. the phosphoinositide kinase (pi k) signal transduction pathway contributes to the airway remodelling associated with asthma; however, the precise roles of the specific pi k isoforms are currently unknown. in this study, we investigated the roles of the class ia pi k isoforms p a, p b and p d in airway smooth muscle (asm) cells derived from asthmatic subjects and asm cells and lung fibroblasts from non-asthmatic subjects. methods cells were stimulated with transforming growth factorb (tgfb; ng/ml) and/or % fbs in the presence or absence of specific pi k inhibitors pik (p a), tgx (p b) or ic (p d) (all . - lm) or vehicle control (dmso). fibronectin deposition, vegf and il- secretion were measured using elisa, mitochondrial activity was assessed by mtt assay and proliferation by bromodeoxyuridine (brdu) incorporation assay. results in non-asthmatic asm cells inhibition of p a and p b decreased vegf and il- secretion and cell proliferation (n = ; p < . ), whereas in asthmatic asm cells, only inhibition of p a (n = - , p < . ) but not p b (n = - , p > . ) had an effect. furthermore, we demonstrated isoform specific roles with p a (n = , p < . ) but not p b (n = - ) or p d (n = - ) modulating fibronectin deposition in asm cells and lung fibroblasts. conclusion specific pi k isoforms have distinct roles in the regulation of inflammatory cytokines (il- ), growth factors (vegf) and extracellular matrix proteins (fibronectin) associated with airway remodelling. intrinsic differences exist in the roles of the pi k isoforms in asthmatic asm. acute respiratory distress syndrome is characterized by inflammation and fibrosis. cellular therapies potentially restore pneumocytes and reduce inflammation. aims we evaluated the role of term human umbilical cord mesenchymal stem cells derived from wharton's jelly (umscs) and human amnion epithelial cells (haecs) in treating a bleomycin-induced model of lung injury. methods cells were administered systemically into a mouse model of acute lung injury hours following intra-nasal administered bleomycin. results both haecs and umscs reduced inflammation with decreased tnf-a, il- , il- and tgf-b. collagen in the lung was significantly reduced by both umscs and haecs as a possible consequence of increased degradation by matrix metalloproteinase- (mmp- ) and down-regulation of their endogenous inhibitors the tissue inhibitors of matrix metalloproteinases (timps) - and - . umscs were detected in the lung at weeks postinjection, vs. weeks for haecs. in addition, umscs did not demonstrate lung differentiation while haecs developed an alveolar phenotype. conclusions both umscs and haecs, have anti-inflammatory properties and reduce fibrosis in lung injury but haecs adopt a lung phenotype support small grant monash university. nomination nil. background with improvement in clinical care and longer survival of patients with cystic fibrosis, pregnancy has become commonplace. however the impact of cystic fibrosis on maternal health and foetal outcomes requires ongoing review. methods a retrospective study of pregnancies from women with cystic fibrosis during the period - was performed. changes in lung function, body mass index, and development of gestational diabetes were recorded. foetal outcomes and maternal survival were examined and the influence of pre-pregnancy parameters on outcomes were evaluated. results mean age of pregnancy was . years with a mean pre-pregnancy fev of . % predicted. eleven out of twenty pregnancies had a pre-pregnancy fev < % predicted. during pregnancy, fev fell by . % (ci . - . ), but recovered to baseline within months post-partum. mothers gained a mean weight of . kg and gestational diabetes developed in . % of women. all women delivered live births apart from one therapeutic abortion. five infants were preterm and three had low birthweight for age. four mothers either died or required lung transplantation after pregnancy on follow up. fev < % predicted and body mass index < kg/m were significant predictors of foetal complications. background carrier screening for cf has been available for many years but there is no national program for population-based screening in australia. knowledge of australian cf healthcare professionals' attitudes towards carrier screening would provide useful information about how a program could be implemented. the aim of this study was to investigate the attitudes of cf respiratory physicians and cf clinic coordinators in australia towards population-based carrier screening for cf. method a purposed designed questionnaire assessing knowledge and attitudes towards cf carrier screening was distributed to respiratory physicians and cf clinic coordinators throughout australia. results there were respiratory physicians registered with the cf special interest group of tsanz and cf clinic nurses identified through the cf coordinators network. seventy-five responded, respiratory physicians ( . %) and coordinators ( %). forty-two ( %) respondents were in favour of population-based carrier screening for cf. sixty-four ( %) rated raising a child with cf as difficult/very difficult, ( %) rated the shortened life span as a significant concern and ( %) the daily treatment regimen as a significant concern. disadvantages of screening were perceived anxiety amongst carriers (n = , %) and discrimination of carriers (n = , %). respondents rated the following barriers as most important: limitations of predicting clinical outcomes (n = , %) and insufficient time and resources for providers (n = , %). fifty-four ( %) of respondents believed they had a role in the development of a cf carrier screening program. adherence to medication regimens in patients with cystic fibrosis (cf) vary substantially. direct measures of adherence using electronic monitors attached to medication bottles enable the precise recording of usage. the macrolide antibiotic, azithromycin has demonstrated clinical benefit when used in cf patients with moderate to severe impairment of lung function. aim this study compares the adherence levels of cf patients randomised to two different treatment regimens of azithromycin, measured by electronic monitoring. methods patients were prescribed the medication once ( mg) or three times ( mg) a week. data were collected over weeks using electronic monitoring devices. adherence measures were defined as: total adherence (total amount of medication taken divided by total medication prescribed) and total number of days adhered (number of days where prescribed doses were taken divided by number of days monitored). results the study recruited participants ( % male; mean age = . sd = years, mean fev % = . , sd = . ). total adherence in patients prescribed the weekly regimen (m = . , sd = . %) were significantly different compared to the three times a week regimen (m = . , sd = . %, p < . ). no significant difference was observed in total number of days adhered. fev % predicted negatively correlated with adherence to medication (total adherence r = - . , p< . , days adhered r = - . , p < . ) and to bmi (r = . ,p < . ). positive correlation was observed between age of the participant and adherence to medication (total adherence r = . , p < . , days adhered r = . , p < . ). conclusion participants adhered better to a once weekly regimen than a three times a week regimen. preclinical studies in non-human primates (nhp) are essential to estimate effectiveness and safety in developing gene transfer protocols to treat cystic fibrosis (cf) airway disease prior to clinical trials. lentiviral (lv) vectors can provide in vivo gene expression and persistence suited to long lasting cf airway correction in mice. we have begun examination of lv gene transfer in lungs of marmosets (callithrix jacchus), a small non-human primate with lung anatomy and physiology similar to humans. methods lysophosphatidylcholine (lpc, . %) pre-treatment was followed by a lv vector encoding the lacz (lv-lacz) reporter gene, pseudotyped with the vsv-g surface protein. doses were delivered into the trachea of four intubated marmosets. trachea and lungs in two animals were examined after week; blood taken daily was tested for presence of vector particles. results epithelial cell lacz gene expression was present primarily in conducting airways in a patchy distribution. a transient o desaturation was noted in some animals after lpc administration; behavioural and physiological indices were normal postoperatively. limited patches of haemorrhage and neutrophil / mononuclear cell infiltration were deemed unremarkable by a veterinary pathologist. serum p lv capsid protein levels that appeared after dosing were absent after day two. conclusions these first studies indicate lpc/lv dosing procedures are well tolerated and can induce target-cell gene expression. further histological and immunological analyses are in progress. the remaining two animals will undergo longer-term assessment of the success of lentiviral lung gene transfer. background bronchiectasis and air trapping are important features of cystic fibrosis (cf) structural lung damage, however data on disease progression in young children are lacking. aim to assess longitudinal changes in ct-detected early structural lung damage in. methods subjects included children (age range . to . years) who underwent annual ct scans, with paired scans. each ct scan consisted of three slices at endinspiration and three slices at end-expiration. the left and right upper, middle and lower zones were assessed for the presence and extent (none, less than %, more than %) of bronchiectasis and air trapping using previously described methods. infection and inflammation were assessed using bronchoalveolar lavage at the time of ct scan. results bronchiectasis was present in % of initial scans, persisting in % of subsequent scans. median extent increased from initial to subsequent scan (p = . ). previous psa infection and neutrophilic inflammation was associated with increased prevalence of bronchiectasis at subsequent scan (or = . ). air trapping was present in % of initial scans, persisting in % of subsequent scans. median extent increased from initial to subsequent scan (p = . ). infection and inflammation did not increase risk of air trapping, but air trapping was more common in girls (or = . ). bronchiectasis and air trapping commonly occurred together. the minute walk test ( mwt) and incremental shuttle walk test (iswt) are commonly used to assess functional exercise capacity, prescribe the training intensity and measure the efficacy of pulmonary rehabilitation. no studies have compared these tests in patients with non-cf bronchiectasis. aims to compare peak dyspnea and heart rate (hr), and nadir oxygen saturation (spo ) during the mwt and iswt in subjects with non-cf bronchiectasis. methods twenty-seven participants (aged ± year, fev ± %pred, fvc ± %pred) with non-cf bronchiectasis enrolled in a trial of pulmonary rehabilitation, completed two mwts and two iswts in random order. results the minute walk distance ( mwd) and the incremental shuttle walk distance (iswd) were significantly greater on the nd test (both p < . ). the mean ( % ci) increase in the mwd was m ( to m); % ( to %) and in the iswd was m ( to m); % ( to %). the greatest mwd and iswd was ± m and ± m respectively. there was a strong relationship between the mwd and iswd (r = . , p < . ). peak dyspnoea was higher for the iswt ( . ± . vs. . ± . , p = . ) but there was no difference in peak hr ( ± vs. ± % age pred maximal hr, p = . ) or nadir spo ( . vs. . %, p = . ). conclusion although peak hr was similar, the externally paced, incremental nature of the iswt may account for the higher dyspnea scores in these subjects with non-cf bronchiectasis. future research will determine the responsiveness of the iswt and mwt following pulmonary rehabilitation in this population. the six minute walk test ( mwt) is extensively used in clinical practice. however, the role of this test in people with dust-related lung disease remains unclear. aim the aims of the study were to investigate the relationships between exercise capacity measured by the mwt and the incremental peak and endurance cycle tests, the mwt and health-related quality of life, and the mwt and activity levels in people with dust-related lung disease. methods thirty male participants with asbestos related pleural disease, asbestosis or silicosis performed two mwts separated by minutes with the better of the tests used for analysis. during the rest period, participants completed the st george's respiratory questionnaire (sgrq). on a separate day, participants performed spirometry, lung volumes, dlco and a peak and endurance cycle test. participants wore an activity monitor (sense-wear pro ) for a period of seven days. results mean (sd) age of participants was ( ) there was a significant correlation between mwt distance and peak watts (r = . , p < . ) but not with endurance cycle time. there were significant correlations between the mwt and all components of the sgrq, the strongest correlation being with the 'activity' domain (r = - . , p < . ) and significant correlations between mwt and average daily steps (r = . , p = . ) and average mets (r = . , p < . ). conclusion findings suggest the mwt may be a useful measure of exercise capacity and may reflect daily activity in people with dust-related lung disease. the minute walk test ( mwt) is used to assess prognosis and evaluate exercise capacity in interstitial lung disease (ild), however the physiological load imposed by the mwt is unknown. this study compared cardiorespiratory responses to mwt and cardiopulmonary exercise testing (cpet) in ild. methods fifteen participants with ild (nine ipf), mean age (standard deviation ) years and tlco ( ) %predicted undertook cpet and mwt on the same day in random order. pulmonary oxygen uptake (vo ), ventilation (ve), carbon dioxide production (vco ), oxyhaemoglobin saturation (spo ) and heart rate were compared between the tests using a portable metabolic cart. relationships between minute walk distance ( mwd) and peak cardiorespiratory responses on cpet were evaluated using correlations. results peak vo measured during the mwt was lower than during cpet ( . ( . ) vs . ( . ) ml.kg/min, p = . ). oxygen consumption during mwt reached a mean of % of vo peak achieved on cpet ( % confidence interval - %vo peak). peak ventilation, carbon dioxide production and peak heart rate were significantly lower during mwt, but there was no difference in nadir spo ( ( )% vs. ( )% on mwt and cpet respectively, p = . ). a higher mwd was associated with a higher peak work rate (r = . , p < . ) but there were no relationships between mwd and peak cardiorespiratory responses on cpet. conclusions the mwt elicits a high but submaximal oxygen uptake in people with ild. given the poor relationship between mwd and peak cardiorespiratory responses elicited by cpet, the prognostic value of the mwt may be related to the degree of oxygen desaturation elicited by this test. results there were no differences between groups at baseline for age, gender, body mass index or respiratory function. after twelve months both groups had similar improvement in fef - %(mean . l/sec, % confidence interval . - . l/sec). there was no significant effect on fev or fvc due to either treatment allocation or time. both groups demonstrated significant improvements in all domains of both the sgrq and lcq but there was no difference between groups. conclusion the inhalation of both isotonic ( . %) and hypertonic ( %) saline improved small airways function and improved quality of life over months, however both treatments were equally effective. introduction this project aimed to develop, implement and evaluate an innovative primary care model in community pharmacy for screening, monitoring and education of people with or at risk of sleep disorders (sd). methods a randomised control trial comparing two approaches was conducted: ) risk assessment only (rao) or ) risk assessment plus overnight nasal flow monitoring using the flowwizardÒ device (ra+). the risk assessment tool collected data on lifestyle, medical conditions, medications and included validated instruments for detecting sd. twentythree pharmacies ( rao/ ra+) recruited patients during a month period. patients at significant risk for a sd were provided with information and referred to a gp. results patients were recruited (rao n = , ra+ n = ). of these, . % (rao %, ra+ %) had an increased risk of daytime sleepiness, . % (rao %, ra+ %) were at risk of significant insomnia, . % (rao %, ra+ %) at risk of obstructive sleep apnea, and . % (rao %, ra+ %) at risk of restless legs syndrome (rls). pharmacists recorded a total of interventions and patients were referred to their gp ( of screened). preliminary results showed that patients (rao, n = , ra+, n = ) have completed the follow-up questionnaire with gp referrals being taken up and seven sd diagnosed ( % of those who took up a referral, rao, n = , ra+, n = ). nine patients ( %) received a diagnosis other than a sd and patients reported still awaiting sleep specialist assessment or testing. conclusion the results of this study indicate that community pharmacy is a potential site for sd screening. support the pharmacy guild of australia, investigator initiated grants. nomination nil. conflict of interest nil. jm foster , l smith , sz bosnic-anticevich , t usherwood , sm sawyer , cs rand , hk reddel university of sydney, australia, royal childrens hospital melbourne, australia, and johns hopkins university, baltimore, usa aim to identify beliefs and behaviours associated with poor adherence which could be used to guide tailored interventions in primary care. methods patients aged ‡ years with doctor-diagnosed asthma and a current ics/laba prescription completed questionnaires on beliefs and behaviours, side-effects, asthma control (acq), and underwent spirometry. adherence with ics/laba was measured over weeks by smartinhalers which electronically recorded the time and date of each actuation. univariate and multivariate analyses of questionnaire items identified predictors of adherence. results ninety-nine of patients completed the study ( female; mean ± sd fev % predicted ± ; acq . ± . ). mean adherence was % ± (n = ). thirty one beliefs or behaviours were significantly associated with poor adherence (p < . ). factor analysis of these items identified themes: f . perceived necessity; f . safety concerns; f . acceptance of asthma chronicity and ics/laba effectiveness; f . advice from friends/family; f . motivation/routine; f . ease of use; and f . satisfaction with asthma management. regression analysis demonstrated that items in themes independently predicted poor adherence (model adj. r sq. = . ; p < . ) including 'my preventer is necessary to keep my asthma under control'(f ), 'i get side effects from my steroid inhaler'(f ), 'i think i will have asthma for a long time'(f ), 'my family/ friends tell me i should use my preventer inhaler more often'(f ), 'i have a fixed daily routine for taking my asthma medications'(f ). adherence was lower for patients who attributed dental deterioration or dry eyes to their ics, but not for hoarseness. conclusions this study identified key beliefs or behaviours associated with poor adherence which may be amenable to change in patient-specific primary care interventions. support asthma foundation nsw, glaxosmithkline (medications investigation of pulmonary embolism with ctpa is often performed despite low clinical risk and results in unnecessary exposure to radiation and radiocontrast as well as inefficient use of medical resources. risk stratification with a validated prediction tool (wells score) complements clinical decision making and rationalises the use of ctpa to appropriate patient groups. methods prospective assignment of wells score by requesting clinicians on a formal algorithm form was instituted in . all patients being investigated for pulmonary embolism were required to have the form filled prior to performance of ctpa. patients stratified low clinical risk (wells £ ) did not proceed to ctpa unless a senior physician override was applied. intermediate risk patients (wells - ) proceeded to d-dimer measurement and if above the laboratory cutoff ( . ) proceeded to imaging. all high risk patients (wells > ) proceeded to ctpa directly. ctpa outcomes, d-dimer levels, request locations and dates were recorded. data were collected from february to august . results a total of patients were investigated with ctpa in this period. patients ( %) did not have the wells score assigned but patients ( %) had complete data. ( %) request originated from the emergency department, ( %) from inpatient wards and ( %) and ( %) from icu and outpatients respectively. the prevalence of pulmonary embolism in our study population was % similar to data from wells and others. ( %) patients were stratified to low risk, ( %) to intermediate risk and ( %) to high risk. the prevalences of pulmonary embolism were %, % and % respectively in these risk groups, comparable with published data. when evaluated against the same period in , there was an absolute reduction of ( %) ctpas performed. conclusion institutional implementation of a formal clinical prediction tool into the decision making process is feasible and yields significant reduction in ctpas performed, with substantial cost savings and patient benefits. aim to conduct an rct to measure the impact of the practitioner asthma communication and education program (pace) on general practitioner (gp) management of paediatric asthma. methods gps recruited through local practice networks identified patients aged - with diagnosed asthma. gps received two hour interactive workshops. results outcome data were collected from intervention and control gps, and intervention and control families. a significantly higher percent of intervention gps than control gps reported frequently providing a written asthma action plan ( . %, p = . , nnt = . ).intervention gps reported higher rates of giving written instructions to adjust medication ( . %, p = . , nnt = . ) and of providing spacers ( . %, p = . , nnt = . ). a significantly higher percent of intervention group children had received a written asthma action plan in the last year ( . %, p = . , nnt = . ). fewer intervention group children with infrequent intermittent symptoms were using regular ics ( . %, p = . , nnt = . ). intervention gps had higher improvements in confidence ( . %, p = . ), helpfulness ( . %, p = . ) and frequency of using the taught communication strategies ( . %, p = . ). conclusion the pace program is the most robustly evaluated program of gp asthma education in australia. our results provide high level evidence that paediatric asthma management is improved by pace. pace may be useful for educating other health professionals involved in chronic disease management. support australian government department of health and ageing. nomination nil. conflict of interest nil. vincent siaw, karmen yai, anand rose department of respiratory medicine, flinders medical centre, bedford park, south australia, australia pulmonary embolism is a common cause for presentation to the emergency departments of tertiary hospitals. if undiagnosed it has a % mortality. the diagnostic algorithm includes a clinical assessment, d'dimer assays and imaging in the appropriate patient. the preferred tool in our institution for confirming a diagnosis of a pulmonary embolism is the ct pulmonary angiogram (ctpa). we decided to audit our practise of doing a clinical assessment using a standardised risk score (eg.wells score) prior to requesting a ctpa. aim to audit the use of standardised clinical risk assessments prior to requesting a ctpa when a pulmonary embolism is suspected. methods ctpa requests from the emergency department from february and march were retrieved. cases notes were screened for mention of the wells or geneva scores. individual symptoms were also studied in attempt to reconstruct the score from the notes. results of the ct pulmonary angiograms performed - requests were from the emergency department. of these requests . % ( patients) were positive studies. systematic clinical risk assessment had been used in . % ( cases). when a systematic clinical score was performed . % of the ctpa studies were positive. this was greater than when no risk score was performed ( % of ctpa studies returned positive). we aimed to compare gp and parent reports of asthma management styles from an rct of practitioner asthma communication and education (pace). methods gps recruited through local networks identified patients aged - with diagnosed asthma. intervention gps participated in two hour workshops of patient education and communication techniques. results at months, gps ( intervention, control) and parents ( intervention, control) provided data. more intervention gps ( . %) reported checking device use (vs. . %; diff = . %, p = . ). intervention parents ( . %) reported that gps checked their device use more frequently (vs. . %; diff = . %, p = . ). more intervention gps ( . %) reported providing educational messages (vs. . %; diff = . %, p = . ). however, more control parents ( . %) (vs. . %; diff = - . %, p = . ) reported receiving messages. more control gps ( . %) said they asked patients about new medication fears (vs. . %; diff = - . %, p = . ), but more intervention parents ( . %) reported being asked about this (vs. . %; diff = . %, p = . ). conclusions gp and parental reports of device use checking were consistent. reports of educational messages and communication were less consistent, though these may have been provided or used but not recognised by parents. these findings highlight that parents and their gps can have very different perceptions of some aspects of a child's asthma management. care should be taken when selecting outcome measures for clinical trials. support australian government department of health and ageing. nomination nil. conflict of interest nil. to background smoking cessation interventions in outpatient settings has been clearly demonstrated to be one of the most cost effective strategies available in reducing disease burden. given the evidence of superior benefits with over nicotine replacement therapy, we aimed to evaluate its benefit in the inpatient setting for smokers admitted with acute smoking related events. methods adult patients (n = , - years) recruited from the respiratory, cardiology, neurology, vascular and general medical wards of the queen elizabeth hospital, lyell mcewin health service and the royal adelaide hospital were randomised to receive either vt (varenicline tartrate) plus quit sa counselling (n = ) or quit sa counselling alone, (n = ). results preliminary analysis shows that after three months of follow-up, smoking abstinence was achieved by . % in the control and . % in the intervention group, (p = . ). preliminary subgroup analysis indicates that cardiac patients, (n = ) have gained the most benefit with . % obtaining continuous abstinence. conclusion whilst a beneficial smoking cessation trend is evident at three months, these are only preliminary results. our recruitment target sample size is likely to provide sufficient power to identify significant differences in abstinence rates between treatment and control groups, and permit sub-group analyses of treatment effect based upon inpatient characteristics. support nil. nomination nil. introduction cigarette smoking prevalence has been in decline in australia over many decades but prevalence remains high in lower socioeconomic groups. hospital employees span the socioeconomic spectrum but there are few data on smoking prevalence from these sites. the visibility of smoking on campus conflicts with the health message that hospitals should promote but cessation services are often not provided. the queen elizabeth hospital (tqeh) has had an ongoing stop smoking service (using cost-price nrt and counselling) provided by tej since and -yearly surveys are conducted to assess benefits and ongoing need. methods employees of three metropolitan teaching hospitals (royal adelaide -rah, flinders medical centre -fmc and tqeh) and the alice springs hospital (ash) were sent a single page questionnaire asking about smoking status and views about smoking on campus. returns were voluntary but encouraged via a small monetary prize. tqeh was surveyed thrice ( , and ) , the other hospitals were surveyed once (late / early ) . results almost all employees reported knowing smoking is a health hazard. most employees (smokers & non-smokers) at all hospitals, thought smoking in public view was unacceptable but support for a total ban was less than for suitable areas where smoking was allowed. tqeh smoking prevalence is much lower than the comparator hospitals where prevalence is similar to national prevalence ( introduction interleukin- a is a cytokine released from t helper (th ) cells which induces and mediates various pro-inflammatory responses. as a result, il- a has been linked to many immune/autoimmune related diseases but its role in copd has not been explored. in the present study we investigated whether il- a regulates cigarette smoke (cs)-induced lung inflammation. methods wild-type (wt) or mice deficient in il- a (il- a -/-) were placed in a perspex chamber and exposed to cs generated from nine cigs per day for days. in separate experiments, cs-exposed wt mice were treated with anti-il- a antibody. on the fifth day, mice were killed, the lungs lavaged with pbs and then harvested for genomic analysis. results wt mice exposed to cs for days had significantly more balf macrophages ( . ± . (sem) · ) and neutrophils ( . ± . · ) than sham-exposed mice ( . ± . · and , respectively) (n = - , p < . ). however, cs-exposed il- a -/mice had significantly fewer macrophages ( . ± . · ) and neutrophils ( . ± . · ) than cs-exposed wt mice (n = - , p < . ). macrophage and neutrophil numbers in sham-exposed il- a -/mice ( . ± . · and . ± . · ) were similar to those of sham-exposed wt mice. gene expression analysis by qpcr showed that cs-exposed il- a -/mice had markedly reduced mcp- , tnfa, il- a, il- and mmp- expression compared to cs-exposed wt mice. treatment of cs-exposed mice with anti-il- a antibody significantly reduced cs-exposed balf macrophages and neutrophils (n = , p < . ). in addition, we found that lungs of nod-scid mice deficient in t & b lymphocytes expressed il- a in response to cs. conclusions these data show that il- a regulates cs-induced lung inflammation and that targeting il- a may have therapeutic utility in inflammatory lung diseases where cs plays a role. introduction in utero exposure to tobacco constituents may contribute to respiratory health problems later in childhood. glutathione s-transferases (gsts) are important in detoxification of xenobiotics. a reduction in the mother and fetus's detoxification ability due to genetic variation in gsts could expose the fetus to higher levels of toxins. objective to investigate the interactive effects of maternal smoking during pregnancy with maternal and infant gst genotypes on airway responsiveness (ar) and lung function in infancy at , and months and longitudinally throughout the first year. methods gstt , gstp and gstm were genotyped in infants and mothers using pcr. in utero exposure to maternal smoke was evaluated by questionnaire, ar was assessed by histamine challenge and v'maxfrc was measured using the rapid thoracoabdominal compression technique. results gstt non-null in infants, mothers or both was associated with reduced ar at months and throughout the first year and increased v'maxfrc at months. maternal gstp val/val or ile/val was associated with increased v'maxfrc at months. in infants exposed to in utero smoke, gstt non-null infants, mothers or both was associated with reduced ar at month and throughout the first year and increased v'maxfrc throughout the first year. there were no significant associations with gstm . conclusion gst genes may be especially important during fetal development as they may modify, through proficient detoxification, the effects of in utero maternal smoke exposure on ar and lung function in infants. funding nhmrc. conflict of interest no. introduction there are few birth cohort studies in which frequent, contemporary measures of tobacco smoke exposure have been related to lung function and airway responsiveness in later childhood. aim to examine the effects of in utero and post natal exposure to ets on lung function and airway responsiveness at age years. methods children with a family history of asthma were recruited antenatally into a randomized trial of house dust mite avoidance and dietary modification results a total of subjects were enrolled ( indigenous australians, indonesians). in the indigenous australian setting the sgrq total score was independently associated with exacerbation frequency and lung function (% predicted fev ) whilst the symptom score was associated more strongly with ae frequency and activity score with lung function. in indonesians with ptb the total sgrq score correlated with treatment response over time as well as lung function (% predicted fvc), exercise tolerance ( mwt) and the extent of involvement on cxr. conclusions in an indigenous australian and indonesia, setting respiratory-related qol using a modified sgrq correlates with lung function, exercise performance, disease activity and treatment. these tools should be a useful addition to evaluating interventions in this setting. background epithelial mesenchymal transition is a process in which airway epithelial cells disaggregate and then migrate through the reticular basement membrane (rbm) into the lamina propria to become myofibroblasts. the aim of this study was to identify if emt is active in the airways in smokers, and whether relevant to copd. methods endobronchial biopsies (ebb) from current smokers with copd (cs; n = ) and ex-smokers with copd (es; n = ), smokers with normal lung function (ns; n = ) and never-smoking controls (nc; n = ) were stained for emt markers, s a a fibroblast protein, epidermal growth factor receptor (egfr) and matrix metalloproteinase- (mmp- ). computer-assisted image analysis was used to quantify the expression of markers in biopsies and slides were counted by an observer blinded to subject and diagnosis. we used non-parametric statistics. results compared to nc, there was significant fragmentation of the rbm in cs, es and ns groups (p < . ), which was especially marked in cs and was positively related to pack years in copd subjects (r = . , p = . ). cs, ns and es demonstrated increased staining for: basal epithelial s a (p < . ), epithelial egfr (p < . ) and mmp- (p < . ) for cells in rbm 'clefts', and rbm cell s a (p < . ) compared to nc. there was increased rbm cell s a staining in cs vs. es and ns (p < . ). basal epithelial cells staining for s a correlated negatively with airflow limitation (r = - . , p = . ) in cs, and dual staining revealed that basal s a positive cells co-stained with vimentin (an additional mesenchymal marker). conclusions our findings suggest that emt is active in smokers, and is most evident in current smokers with copd, suggesting a role in copd pathogenesis. pulmonary emphysema is a major component of the chronic obstructive pulmonary disease (copd), and also predisposes affected individuals to lung cancer. emphysema can be a familial or acquired disease, with the great variation in development of disease in atrisk populations reflecting the influence of other susceptibility determinants. in this regard, the il- cytokine family has been linked with emphysema pathogenesis. however, studies into the definitive mechanisms by which these cytokines cause emphysema have been hampered by the absence of informative animal disease models. to address this issue, we have utilized a sophisticated animal model (gp f/f mice) with a subtle mutation in the il- cytokine family receptor gp which, as a consequence of abolishing binding of both shp and socs , simultaneously mediates stat / hyper-activation and impaired shp -mapk and -pi k activation. the gp f/f mice spontaneously develop emphysema by months of age characterized by increased static compliance. lung stereology has further confirmed emphysematous changes, revealing increases in volumes of airspace and lung. among the il- cytokine family, il- expression is significantly up-regulated in the lungs of gp f/f mice, and genetic ablation of il- in gp f/f mice prevents the development of emphysema. notably, an increased apoptosis of alveolar cells has been identified as the underlying cellular mechanism associated with the emphysema in gp f/f mice. collectively, our observations identify for the first time that deregulated gp signalling by il- cause's alveolar cells to undergo apoptosis, which coincide with the pathogenesis of emphysema. furthermore, this mouse model has the enormous potential to allow us to explore common mechanistic links between copd and lung cancer. supported by the nhmrc, australia. conflict of interest no. introduction despite smoking cessation, susceptible copd patients continue to decline in lung function. understanding biological pathways and their gene ontologies would help to develop better treatments and diagnostic methods for copd. the aims of this study were to identify gene ontologies associated with mild and moderate copd by (i) profiling mrna and (ii) mirnas and their predicted targets. methods profiling was performed on total rna extracted from lung tissue of copd patients undergoing resection for lung cancer. microarray platforms (operon v and agilent g v ) were used to characterise mrnas and mirnas respectively. analysis was performed using brb array tools v . and gsea. results the patients were caucasian former smokers with mean (sd) age ( ), fev ( ) % predicted, kco ( )% predicted and pack years ( ). we identified authentic candidate genes (p < . ) that predicted copd progression with % accuracy in in-house and public datasets. genes involved in cell cycle, proliferation, development and growth were identified. increasing expression of mir- c, a candidate mirna for emphysema progression, on lung fibroblast and epithelial cells downregulated predicted mrna targets with potential biological role in copd. conclusions we have identified multiple gene ontologies associated with copd severity. these targets have promising biological roles in copd and can be further developed as biomarkers or therapeutic targets. cigarette smoke (cs)-induced oxidative stress is known to drive the pathogenesis of copd. the antioxidant glutathione (gsh) is essential for efficient macrophage functions including phagocytosis of apoptotic cells (efferocytosis) which we have shown to be defective in copd. gsh synthesis is controlled by a cd /xct cysteine transporter pathway. cd is also a ligand for galectin- (gal- ), a lectin important for macrophage phagocytosis and gsh synthesis. we hypothesised that targeting oxidative stress in copd by increasing gsh would increase gal- levels and improve efferocytosis. we investigated (a) ex vivo: oxidative stress markers ( -isoprostane; mmp ), gsh and gal- in bal from controls and current-and ex-smoker copd subjects (b) in vitro: the effects of cs on alveolar macrophage production of gal- and gsh (c) in vivo: the effects of treatment with a gsh precursor, procysteine, on efferocytosis, gal- and gsh in smokeexposed mice. procysteine was administered in semi-solid mouse feed. efferocytosis was investigated in lung tissue and bal macrophages. -isoprostane and mmp were significantly increased in bal in current-and ex-smokers with copd. gsh and gal- were decreased in copd (gal- , ng/ml: current . ± . , ex-smoker . ± . vs. controls . ± . ). in vitro cs treatment decreased gal- expression. in vivo, cs caused decreased efferocytosis that was significantly improved by procysteine (control; smokeexposed; procysteine + smoke-exposed: bal . %; . %; . %; tissue . %; . %; . %). gsh and gal- were also significantly increased by procysteine (gal- , ng/ml: control . ± . ; smoke-exposed . ± . ; procysteine + smoke-exposed . ± . ng/ml). targeting oxidative stress is a viable approach to improve macrophage dysfunction in copd. support nhmrc, arc. introduction our knowledge about the effects of inhaled corticosteroids (ics) on airway remodelling in chronic obstructive pulmonary disease (copd) is limited. we have previously reported that in bronchial biopsies (bb) from copd subjects the reticular basement membrane (rbm) is fragmented and hypervascular. in this study we have examined the effects of ics on these airway remodelling changes in copd. methods in a double blind and randomised study we compared the effects of months of fluticasone propionate (fp, . mg/twice daily) with placebo. bb were stained with collagen iv antibody to mark vessel endothelial basement membrane. the length of rbm splits and the number and area of vessels in the rbm were compared before and after treatment. results copd subjects were randomized : to receive either fp (n = ) or placebo (n = ). there were no differences between the groups before treatment. introduction copd is a complex disease characterised by fixed airflow obstruction and neutrophilic airway inflammation. markers of systemic inflammation such as serum amyloid a (saa) are elevated in copd. however, little is known about the relationship between airway and systemic inflammation. this study tested the hypothesis that systemic inflammation is associated with airway neutrophils in copd. methods participants with copd (n = , > years, with fev /fvc < and fev % predicted < ) and healthy controls (hc; with normal lung function n = > years) underwent clinical assessment, spirometry, blood collection for saa, il- and crp and sputum induction. sputum was processed for differential cell count and mediators. results airway proportions of neutrophils and eosinophils, levels of il- , total mmp- and gene expression of il- were increased in participants with copd. serum il- (median q -q ; ( . ( . - . )) vs. asbestos-related lung cancers (arlc) account for - % of all lung cancer, and are difficult to distinguish from non-asbestos related tumours (narlc) by clinical and histological criteria. we hypothesised that whole genome array comparative genomic hybridization (acgh) profiling could identify regions of gain and loss common and specific to asbestos-related lung cancer. methods the acgh profiling by agilent cgh b arrays was performed on primary non-small cell lung cancers obtained from the prince charles hospital (tpch) lung tumour bank. lung cancers occurring in individuals with >= asbestos bodies/gram wet weight (ab/gww) of lung tissue were defined arlc and individuals with ab/gww were defined narlc. genome breakpoints were called using the circular binary segmentation algorithm implemented in dnacopy. recurrent regions of amplification and deletion were identified using the genomic identification of significant targets in cancer (gistic) algorithm developed by the broad institute, controlling for false discovery rates (q < . ). results gistic identified recurrent copy number gains in q and narlc at q < . but none for arlc at the same threshold. to introduction the relationship between asbestos exposure and asbestos related diseases (ard) such as asbestosis, lung cancer and mesothelioma are well established. less is known about asbestos exposure and non-ard respiratory diseases. aim to investigate respiratory symptoms and lung function in former workers and residents from wittenoom who have not developed an ard. methods an annual review, which includes lung function, plain chest x-ray and respiratory questionnaire, is conducted on a cohort of ex-workers and ex-residents from wittenoom. only those who had been reviewed within the previous years and had not developed an ard, nor had plain chest radiographic evidence of asbestosis, were included in the analyses. the prevalence of respiratory symptoms was determined and standardised lung function z-scores calculated. predictors of symptoms and lung function were assessed using both multiple logistic and linear regression. results questionnaire data was available for subjects ( women, ex-workers; mean age . ± . years), while acceptable lung function data was available for subjects ( women, ex-workers). the prevalence of reported symptoms ranged between and % for wheeze, cough, sputum, shortness of breath and bronchitis. pack years of smoking and/or being an ex-worker were the main risk factors for symptoms. standardised lung function scores ( %ci) for the total group were - . (- . -- . ), - . (- . -- . ) and . ( . - . ) for fev, fvc and fev/fvc respectively. both pack-years and cumulative asbestos exposure were independently associated with reduced fev and fvc. conclusions people previously exposed to asbestos, particularly ex-workers, have high rates of respiratory symptoms which are mostly related to smoking. reduced lung function in the cohort was associated with both smoking and cumulative asbestos exposure. conflict of interest none. introduction malignant mesothelioma (mm) is an aggressive cancer with a very poor prognosis. interactions of the components of the extracellular matrix (ecm) are now known to be important for the growth and regulation of cancer cells. tgfb is an important regulator of the ecm and in particular collagen. previous data in our laboratory has shown that blocking tgfb signaling by using tgfb antibodies inhibits collagen production and mm growth. aim to determine the signaling pathways downstream of tgfb that are important in the regulation of collagen expression in mm. methods components of the tgfb pathway were inhibited by use of chemical inhibitors and overexpression of the endogenous inhibitor smad in control and mm cell lines. collagen levels were measured by realtime pcr. results collagen regulation is thought to occur through the classic smad / signaling pathway. our data show that smad overexpression inhibits tgfb-induced collagen production in normal mesothelial cells and the mesothelial cell line met- a but not in the mm cell lines investigated. therefore, the smad / pathway for collagen regulation appears to be altered in malignant mesothelioma. it was shown that smad / are expressed, phosphorylated and activated by tgfb in the mm cell lines. our results indicate that nuclear import of smad , which is responsible for the nuclear import of smad / , is altered in mm. aim to characterise impedance variability at hz in asthma and its relationship to asthma severity. methods a school-based cohort of non-asthmatic children, aged (mean (sd)) . ( . ) years (uptech feasibility study) were tested on two occasions weeks apart. an asthma camp cohort of asthmatics, aged . ( . ) years, were tested daily for days. mean resistance (rrs ) and reactance (xrs ) of at least three technically acceptable one minute recordings were reported. medications were not withheld. variability was assessed by intraclass correlation coefficient (icc) and within-subject standard deviation (sd w ) using first and last testing day data, and all days of data for sd w severity comparison amongst asthmatics. results repeat fot measures at hz were obtained in / non-asthmatic children. mean (sd) rrs and xrs was . ( . ) and - . ( . ) for the uptech cohort, and . ( . ) and - . ( . ) cmh o/l/s in the asthma camp cohort respectively. rrs variability was increased in asthmatics. rrs variability tended to be higher in persistent vs. intermittent asthmatics but did not reach statistical significance (p = . ). non asthmatic (n = ) introduction our cochrane review examining the efficacy of using feno to tailor the dose of inhaled corticosteroid showed that feno cannot be routinely recommended for clinical practice at this stage and remains uncertain. however all the studies used a single feno cut-off. in this rct we determined if asthma monitoring using feno (using two different cut-offs dependent on atopy) is better than control (symptoms and fev ) in preventing asthma exacerbations in children on inhaled corticosteroids. methods over -months, children underwent spirometry, feno, qol and asthma/ cough diary during every visit. treatment for asthma was adjusted according to pre-determined criteria taking into account atopy status and dependent on allocation group (feno or control). results about children were randomised-feno group (n = , median age . , iqr . ), or control group (n = , median age . , iqr . ). significantly fewer children in the feno group had asthma exacerbations compared to the control group ( vs. ; p = . ) over -months. number needed to treat (nnt) to prevent one child from having any exacerbation in months = ( %ci , ). parental qol improved in feno group at final visit in comparison to the qol in control group (p = . ). fev increased in both groups over the duration of the study but there was no difference between the groups when measured at baseline (p = . ) and at final (p = . ). conclusion tailoring of asthma medications in accordance to feno levels (compared to usual management), taking into account atopy status, reduces asthma exacerbations and improves asthma qol. however both strategies equally improved fev . background inhaled corticosteroids have a modest effect on improving symptom control in preschool asthmatic children. delivery of inhaled steroids with pmdi-spacers are influenced by children's proficiency in spacer technique, and adherence to prescribed medication. aim to investigate the influence of an incentive spacer (funhaler), on spacer technique, adherence to treatment, and asthma control in preschool asthmatic children. methods about children aged - years, and being prescribed regular inhaled steroids in the community were randomised to receive regular inhaled fluticasone through either an aerochamber plus Ò , of a funhaler Ò . subjects were followed up three monthly for a year. proficiency in spacer technique was measured at each visit by measuring the amount of salbutamol inhaled from spacer onto a filter interposed between subject and spacer. adherence was monitored by smartinhaler Ò electronic devices. symptoms were recorded on diary cards for a week before each study visit. results there was no difference between the funhaler group and the aerochamber group in terms of adherence to medication or measures of asthma control (p > . ). spacer technique was significantly better in the funhaler group in subjects younger than years of age at time of randomisation (p < . ). there was large inter subject variation in drug dose inhaled on filter, ranging from - % (drug dose recovered from filter, as percentage of total dose recovered), and mean adherence over each month period ranging from - %. discussion the funhaler Ò does not improve clinical outcome, but improves spacer technique in children younger than years of age. the large variability in adherence and drug delivery should encourage both efforts to improve adherence, and efforts to standardise inhaled drug delivery in preschool children. - and - . about % of ob cases were notified within year of arrival. of the australianborn cases were close household contacts of an adult tb case. about cases had culture confirmed disease ( fully sensitive to first line drugs, one multidrug resistant). % had pulmonary and % had lymph node tb. about cases completed the treatment, two were lost to follow-up and one died. compared to adult tb cases, children were more likely to be refugees (or . (ci . - . )), diagnosed on contact screening (or . ( . - . )), have lymphatic tb (or . (ci . - . )), and less likely to be culture-confirmed (or . (ci . -. )). the png child visitors' cases diagnosed in queensland had a higher level of severe and culture-confirmed disease. conclusion queensland has a very low burden of childhood tb, indicating low levels of tb transmission in the community. hrgm children, especially refugees, will remain at risk due to infection acquired overseas. contact screening is an important method of diagnosing early tb, and refugee screening and preventive treatment may play a role in protecting this group. funding support nil. conflicts of interest nil. introduction in response to injury, normal and efficient epithelial repair is essential in order to maintain barrier integrity and immune function. however, aberrant repair has been suggested as a contributor to disease progression in asthma. many studies have only included subjects with atopic asthma and thus any intrinsic epithelial abnormality common to all asthmatic phenotypes is difficult to isolate. this study aimed to assess whether epithelial repair is dysregulated in asthmatic subjects and if this is common to the disease or is phenotype specific. the regulatory mechanisms promoting the cellular proliferation and migratory aspects of the repair process were also assessed. methods paediatric airway epithelial cells (paec) of atopic and non-atopic healthy and asthmatic subjects were isolated by non-bronchoscopic bronchial brushings. culture monolayers were wounded using an in-house wounding device, and the percentage of wound closure determined daily. proliferation and migration were also assessed over the course of repair using western blot. results paecs from healthy non-atopic (paec hna ) and healthy atopic (paec ha ) subjects successfully achieved full wound closure between - days. in contrast, atopic asthmatic (paec aa ) and non atopic asthmatic (paec naa ) subjects failed to fully repair and only achieved % wound closure by days. protein analysis showed a -fold increase in proliferation and -fold increase in migratory markers during repair in paec hna . however, reduced proliferation and no migration activity were seen in paec aa. conclusion atopic and non-atopic asthmatic epithelial cells possess dysfunctional repair profiles in response to mechanical wounding. results suggest dysregulated repair is an intrinsic epithelial abnormality in asthma and this appears to be independent of phenotypic criteria or atopy. introduction refractory chronic cough is associated with increased cough sensitivity. speech pathology intervention has been shown to be an effective intervention for refractory cough but the mechanism behind the improvement is not known. this study provides objective measures of the mechanism and the number of treatments required to effect a response. methods adults with chronic cough (n = ) were assessed before, during and after speech pathology intervention. the primary outcome measures were capsaicin cough reflex sensitivity, automated cough frequency detection and cough-related quality of life. results participants responded to the treatment with a significant improvement in coughrelated quality of life, p = . , cough reflex sensitivity, c : mean ± sd . ± . vs. c : . ± . lmol/l, p = . , cough frequency cf: . ± . vs. ± . coughs/hr, p = . , cough threshold ct: . ± . vs. . ± . lmol/l, p = . , and urge-to-cough utc: median (iqr), ( ) vs. ( ), p = . . conclusion speech pathology management is an effective treatment for refractory chronic cough. the mechanism behind the improvement is due to reduced laryngeal irritation which results in decreased cough sensitivity, improvement in cough symptoms, laryngeal symptoms, and cough quality of life. introduction airway hyperresponsiveness (ahr) is a characteristic feature of asthma. in young asthmatics, severity of ahr is related to exhaled nitric oxide (eno), a marker of eosinophilic airway inflammation, and ventilation heterogeneity in the conducting airways (scond). with increasing age, eosinophilic inflammation decreases and ventilation heterogeneity in the very peripheral, acinar, airways worsens. aim to determine if the predictors of ahr differ in young and older asthmatics. methods about young ( - ) and older ( - ) asthmatic subjects underwent baseline spirometry, body plethysmography, eno, multiple breath nitrogen washout (mbnw), and methacholine (mch) challenge. ahr was expressed as dose response slope (drs = %fall fev /lmol mch). ventilation heterogeneity of the conducting (scond) and acinar (sacin) airways were calculated from the mbnw. predictors of ahr in each group were determined by multiple linear regression. results compared to younger asthmatics, older asthmatics had lower values of eno, less severe ahr, worse acinar heterogeneity; however there were no differences in scond values. in younger asthmatics, ahr was predicted by fev /fvc (partial r = . ), eno (partial r = . ) and scond (partial r = . ) (overall r = . , p < . ). in older asthmatics, ahr was predicted by rv % predicted (partial r = . ), sacin (partial r = . ) and fev % predicted (partial r = . ) (overall r = . , p < . ). conclusions the predictors of ahr are different in young and old asthmatics. in older asthmatics, eno is not a significant predictor of ahr, which may reflect the changing inflammatory profile associated with aging. the association between ahr and both rv and sacin suggests that ahr in older asthmatics is determined by abnormalities in very peripheral airways. introduction in this systematic review and meta-analysis, we sought to establish if maternal asthma is associated with an increased risk of adverse perinatal outcomes associated with size at birth and timing of birth. methods electronic databases were searched for the following terms: (asthma or wheeze) and (pregnan* or perinat* or obstet*). cohort studies published between and march were considered for inclusion. articles were identified, and publications involving , , subjects met the inclusion criteria, by reporting at least one perinatal outcome in pregnant women with and without asthma. meta-analysis was conducted with subgroup analyses by study design and active asthma management. results maternal asthma was associated with an increased risk of low birth weight (relative risk [rr] . , % confidence interval [ci] . , . ), small for gestational age (sga, rr . , ci . , . ), very sga (rr . , ci . , . ), significantly reduced mean birth weight (weighted mean difference - g, ci - , - g), and reduced risk of high birth weight (rr . , ci . , . ). maternal asthma was associated with an increased risk of preterm labor (rr . , ci . , . ), early preterm labor (rr . , ci . , . ) and preterm delivery (rr . , ci . , . ). the risk for preterm labor and delivery was reduced to a non-significant level in those studies reporting active management of asthma during pregnancy (rr . , ci . , . ; rr . , ci . , . ). conclusion pregnant women with asthma are at increased risk of perinatal complications which affect the baby's size and timing at birth. active asthma management may reduce the risk of preterm labor and delivery. with threats of new pandemic strains of influenza a virus and resistance to anti-virals there is a need for novel therapeutics that reduce viral replication and lung pathology. the pathology arising from pandemic influenza is due to an excessive host response characterised by a rapid, massive infiltration of inflammatory cells of the innate immune system into the airways leading to excessive reactive oxygen species (ros) production. thus, we investigated the primary enzymatic source of inflammatory cell ros, nox -containing nadph oxidase, as a novel target against lung inflammation and pathology caused by influenza a viruses of varying virulence. wt and nox -/--mice were pfu/mouse) or high virulence following infection with x- , lungs of nox -/-mice displayed a significant reduction in viral titre (~ - %), macrophages, peribronchial inflammation and mcp- compared to virusinfected wt mice. lung levels of il- b were approximately -fold higher in nox -/-mice. balf macrophages, neutrophils, and t lymphocytes of nox -/-mice produced minimal superoxide compared to controls. the magnitude of balf and spleen influenza-specific dbnp + and dbpa + cd + t cells were similar in wt and nox -/-mice indicating that the major mechanisms of the adaptive immune response that effectively clear influenza a virus are preserved in nox -/-mice. in vivo administration of the nox inhibitor apocynin ( mg/kg/day) significantly suppressed viral titre, airways inflammation and inflammatory cell superoxide following infection with x- or pr/ strains. in conclusion, nox inhibition should be considered for seasonal and pandemic control of the mortality/ morbidity induced by influenza a virus, irrespective of the strain department of respiratory medicine australia, cooperative research centre for asthma and airways, new south wales, australia, and department of respiratory medicine therefore the aim, of this study was to examine the impact of a standard, -week exercise-based pr program on pal. methods about subjects ( ( ) years) with copd (fev % predicted = ( )) completed pr where they undertook twice weekly exercise classes consisting of one hour of upper and lower limb strengthening exercise and aerobic exercise. pal was estimated using a multi-sensor device (sensewear, healthware bodymedia) worn for a day period. an index of pal was derived by dividing total daily energy expenditure in metabolic equivalents (mets) by whole night sleeping energy expenditure (average of nights sleeping). pal was measured in the week immediately prior and in the immediately following pr. results despite a significant increase in six minute walk distance ( mwd), pr resulted in no change in pal copd patients failed to increase their pal. while changes in pal may take longer to elicit i.e. the change in pal may be delayed following pr, it is possible that the current focus of pr on increasing outcomes such as mwd may be too narrow to elicit changes in pal little is known regarding the use of acts in patients admitted with aecopd in australia. this survey aimed to identify current practice and opinion of australian hospital physiotherapists concerning acts. methods paper-based surveys were distributed to physiotherapists of 'large' and 'principal referral' australian public hospitals (identified via a government health report). a response rate of % (n = hospitals) yielded surveys for analysis. results most physiotherapists ( %) prescribe acts for - % of patients with ae-copd, with % of act treatments lasting - minutes. the techniques most frequently used for airway clearance were physical exercise ( %) and the active cycle of breathing technique ( %). the main influences on choice of act were precautions or contraindications to individual techniques ( %) and the degree of patient dyspnoea ( %). many physiotherapists ( %) prescribe acts with the aim of enhancing a patient's recovery from aecopd and % perceive airway clearance to be fairly or very important to the overall management of aecopd. there was mixed awareness of the evidence for acts in aecopd, with % of physiotherapists citing it as supportive conclusion australian physiotherapists frequently use acts for patients with aecopd and perceive their role to be important. physical exercise is the present modality of choice to achieve airway clearance acknowledgements nh&mrc, cure cf foundation sa. conflict of interest no. aim to examine the health outcomes of , children first exposed to blue asbestos at wittenoom when they were less than years of age. methods standardised mortality ratios (smr's) calculated to compare wittenoom children's mortality with the western australian population. results about , females and , males were children at wittenoom, mean age of arrival years (sd years); ( %) were born there or moved there soon after birth. median duration of residence was months (iqr - months). there were deaths ( females and males) between and end of . deaths were from malignant mesothelioma ( % of all deaths - females, males, - pleural, peritoneal). among males, there was excess mortality from all causes (smr = . ), all cancers (smr = . ), mm (smr = ), accidents, injuries and poisonings (smr = . ) and circulatory disease (smr = . ). mortality from suicide and transport accidents were also in excess but not statistically significantly increased. among females there was excess mortality from all causes (smr = . ), and all cancers (smr = . ) and mm (smr = ). conclusion former children of wittenoom experience high cancer mortality. support nhmrc. nomination nil. conflict of interest nil. introduction blue asbestos (crocidolite) was mined and milled at wittenoom between and . tailings from the mine were distributed and used extensively throughout the town. exposure to children also occurred from the laundering of workers clothes at home. earlier work has shown a lower risk of malignant mesothelioma (mm) in children from wittenoom than in those exposed to blue asbestos as adults.a case report of a year old ex-forestry worker with an pack year smoking history is presented. he was referred with two distinct periods of hemoptysis, one months prior to referral for which he declined investigation or follow up, and another three weeks prior to referral. on each occasion, he described two tablespoons of hemoptysis daily lasting approximately month. he lives on an acreage at mt kilcoy, km north of brisbane, with his wife, one goat, three dogs, one cat, deer and wild birds. emphysema manifesting as gradually worsening exertional dyspnoea with wheeze, had been diagnosed years ago by his local doctor. he described symptoms of obstructive sleep apnoea including witnessed apnoea, choking arousals and loud snoring. he also reported intermittent diarrhoea for years but denied weight loss or rectal blood or mucous. a ct chest showed multiple bilateral nodules of varying size the largest being . cm, and multiple low density liver lesions. the provisional diagnosis was metastatic colorectal cancer. bronchoscopy with ebus guidance did not yield the diagnosis which was eventually made by trans-thoracic needle aspiration without complication. echinococcus serology performed post procedure was > , consistent with echinococcus infection. this case of echinococcus disease is presented and the vectors discussed. echinococcus disease was previously prevalent in australia and new zealand, with a reduction in incidence from improved animal husbandry. with an increasing deer population in south east queensland and subsequent rising human contact, clinical awareness is necessary to avoid potential complications from biopsy and ensure cases are promptly treated rather than mistakenly diagnosed as incurable disease. introduction community-acquired pneumonia (cap) is a leading cause of mortality, morbidity and hospital admission places strain on our healthcare system. procalcitonin (pct) is a biomarker of bacterial infection which may help gauge the severity and prognosis of patients with cap. aim to examine the role of pct measurement in reducing hospital admissions, length of stay (los), and antibiotic (ab) usage in patients with cap. methods prospective, single-blinded, externally controlled study of consenting adult patients admitted with cap. pct levels were obtained on day and day (if indicated). the investigator evaluated clinical parameters and the pct values to determine the timing of oral ab switch and discharge. this process was used to compare with standard practice but was not actually implemented for the purpose of this study. results sixty patients were included in the study. the mean age was . ± . y and . % were male. the average psi was ± (class iv) and the median curb- was . the mean los for this cohort was . ± . d and the calculated los using pct guidance pathway was . ± . d. (p = . ) a multivariate analysis will be presented. conclusions our study supports the hypothesis that the incorporation of pct levels can reduce the requirement for hospital admission and los in patients with cap. a randomised prospective clinical trial is planned to help clarify these findings. support nil. introduction children in the highlands of papua new guinea (png) suffer on average . acute lower respiratory infections (alris) before age months, / of which are moderate or severe. while streptococcus pneumoniae and haemophilus influenzae are the primary bacterial cause of alri in png, the role of viruses in the aetiology of alri is uncertain. aim determine identification rates of respiratory viruses in nasal samples collected from children with moderate/severe alri and healthy children aged < months in png. methods as part of a neonatal pneumococcal conjugate vaccine trial in the png highlands, we collected pernasal swabs from children with moderate/severe alri (n = ) and at routine follow-up (n = ). rt-pcr methods were used to identify a broad range of respiratory viruses. the frequency of viral detection was compared between groups of samples collected during an alri and routinely using chi-square analysis. results several viruses were detected more frequently in alri than routine samples: adenoviruses . / . (% of alri samples positive/% of routine samples positive) p = . , influenza viruses . / . p = . and respiratory syncytial virus (rsv) . / . p = . . human metapneumovirus and parainfluenza viruses were detected in four and three samples, with no difference between groups. human coronaviruses and human rhinoviruses (hrv) were less commonly detected in alri than in routine samples ( . / . p = . and . / . p = . , respectively). a total of different hrv strains were identified. conclusion in young children in png, viral identification rates are high, with rsv, adenoviruses and influenza viruses associated with moderate/severe alri and a large amount of genetic diversity of rhinoviruses in both sick and healthy children. introduction to increase the documentation and documented provision of an electronic asthma action plan (e-aap) to children discharged with asthma from the emergency department (ed) at chw. methods an electronic aap (e-aap) was introduced in april by a multidisciplinary team comprising representatives. at chw, aaps were available to be printed off by the intranet. to be entered into the electronic medical record (emr), the medical officer had to photocopy the completed plan which would then be scanned into the emr. evidence suggested that busy doctors, particularly in the ed, were either not providing patients with aaps on discharge or not photocopying them for the medical record. the evaluation of the e-aap consisted of a review of the documented provision of asthma action plans in the hospital wide emr (powerchart) for a year pre & post the introduction of the e-aap, a review of patients discharged from the ed with a diagnosis of asthma for similar six month periods pre and post intervention and a medical staff satisfaction survey. results the total number of plans recorded in emr increased by %, from - to - . the number of plans recorded for ed discharges increased significantly from % to % [p < . ]. the number of patients recorded as leaving the ed with a plan increased significantly from % to % (p < . ). the use of the e-aap in the ed is now standard of care and this is also being adopted hospital wide as more staff became familiar with its usefulness.conclusion the e-aap significantly increased the number of recorded aaps and patients discharged with a recorded aap. support nil. nomination asthma/allergy. conflict of interest no. lisa wood , , manohar garg , amber wood , , peter gibson , centre for asthma and respiratory diseases, university of newcastle, new south wales, australia, and nutraceuticals research group, university of newcastle, new south wales, australiaintroduction dietary fat activates innate immune responses, leading to an increase in systemic inflammation. however, the effect of dietary fat on airway inflammation has not been investigated. we hypothesised that a high fat intake may lead to increased airway neutrophilia in asthma. the aim of this study was to examine the effect of a high fat versus low fat food challenge on airway inflammation in asthma. methods non-obese subjects with asthma were randomized to receive a high fat/ high energy (hf) (n = ) or low fat/ low energy (lf) (n = ) food challenge. obese subjects also received a hf challenge. subjects on the hf challenge consumed a meal containing kj, including % of energy ( g) from fat. subjects on the lf challenge consumed a meal containing kj, including % of energy ( g) from fat. at baseline, hypertonic saline challenge and clinical assessment were performed. induced sputum samples were collected at baseline and at hours. airway inflammatory markers included induced sputum total and differential cell counts, il- and neutrophil elastase, measured by commercial assay. tlr mrna expression from sputum cells was measured using rt-pcr. results at hours after the food challenge, subjects on the hf challenge, had a significantly higher increase in %sputum neutrophils ( . ( . (sem)) % vs. . ( . ) %, p = . ) and higher fold increase in tlr mrna expression ( . ( . - . (iqr)) vs. . ( . - . ), p = . ), compared to the lf challenge. subjects on the hf challenge also had an impaired bronchodilator response, with a lower increase in fev /fvc% at hours compared to the lf challenge ( . (- . - . (iqr)) % vs. . ( . - . ) %, p = . ). there were no differences in the responses of obese vs. non-obese asthmatics to the hf challenge. conclusions a high fat/ high energy challenge causes an increase in airway inflammation and suppresses bronchodilator response in asthma. strategies aimed at reducing dietary fat intake may be useful in reducing inflammation in asthma. support nhmrc project grant. introduction longitudinal fev data in children with non-cystic fibrosis (non-cf) bronchiectasis is contradictory and there is no multi-factor data on the evolution of lung function and growth in this group. we longitudinally reviewed lung function and growth in children with non-cf bronchiectasis and explored biologically plausible factors associated with changes in these parameters over time.methods fifty-two children with ‡ years of lung function data were retrospectively reviewed. changes in annual anthropometry and spirometry at year- and year- from baseline were analysed. the impact of gender, age, aetiology, baseline fev , exacerbation frequency, radiological extent and period of diagnosis was evaluated. results over years, the group mean fef - %predicted and bmi z-score improved by . (p = . , %ci . - . ) and . (p = . , %ci . - . ) per annum, respectively. fev %predicted, fvc %predicted and height z-score all showed non-significant improvement. over years, there was improvement in fvc %predicted (slope . , p = . ) annually but only minor improvement in other parameters. children with immunodeficiency and those with low baseline fev had significantly lower bmi at diagnosis. frequency of hospitalized exacerbation and low baseline fev were the only significant predictors of change in fev over years. decline in fev %predicted was large (but nonsignificant) for each additional year in age of diagnosis. conclusions spirometric and anthropometric parameters in children with non-cf bronchiectasis remain stable over - year follow-up period once appropriate therapy is instituted. severe exacerbations result in accelerated lung function decline. increased medical cognizance of children with chronic moist cough is needed for early diagnosis, better management and improving overall outcome in bronchiectasis. introduction it is well established that many survivors of very low birth weight (vlbw; < g at birth) have impaired lung function. the aim of this study was to determine whether abnormal lung function at years of age is established in childhood. a second aim was to see if abnormal lung function at years of age tracks through the period of normal lung development to predict impaired maximal lung function and may be a precursor to copd in adult years. methods a cohort of vlbw (n = ) and normal birth weight (nbw; > g at birth; n = ) has been followed for years. very low birthweight participants completed spirometry and lung volumes at , , , and years of age and nbw at , and years of age. restricted maximum likelihood modeling was used for longitudinal fev z-score as it allows for analysis of data from different time points that are not necessarily evenly spaced, without being affected by missing data. results about vlbw children completed lung function testing at years of age, ( . %) had abnormal fev z-scores (defined as > sd's below the mean). vlbw survivors showed minimal 'catch-up' in fev z-score over the years of the study; those without (bronchopulmonary dysplasia) fev improved . (p = . ) z-scores, those with bpd fev improved . (p = . ) z-scores. vlbw with bpd survivors did not return to within normal limits. conclusions the reduced lung function in adult survivors of low birth weight is established in early childhood. while there is some improvement in growth of those with abnormal fev z-scores in early childhood, those with bpd remain below two sd's from the mean, and at the age of have a reduced peak lung function. introduction bronchopulmonary dysplasia (bpd) is a common complication of preterm birth. although there is evidence that individuals with a history of bpd have respiratory abnormalities in childhood, there remains a paucity of evidence regarding the outcome of the disease in adulthood. in a pilot study we recently described high resolution computed tomography (hrct) appearances of emphysema in young adults with a history of bpd. aims to describe the structural pulmonary sequelae of bronchopulmonary dysplasia in adulthood and to evaluate a scoring system originally designed for paediatric subjects. methods about adult survivors of bpd underwent hrct of the chest, along with lung function testing (spirometry, lung volumes and diffusing capacity) and a respiratory health survey. the ct studies were scored by two thoracic radiologists blinded to the patient's clinical details, using a previously described system developed for children and adolescents who were born prematurely using parameters. results abnormal findings were seen in all scans, the most common findings were subpleural triangular opacities ( %), linear opacities ( %), air trapping ( %) and emphysema ( %). agreement between the two observers for total score and common abnormalities varied with a linear weighted kappa value of . for linear opacities, . for triangular opacities, . for air trapping, and . for emphysema. conclusions linear and sub-triangular opacities on hrct chest are almost universal in young adults with a history of bpd. findings of emphysema and gas trapping are common and there is good interobservor agreement for these abnormalities. introduction pulmonary surfactant (ps) is synthesised by alveolar type ii epithelial cells to regulate the surface tension at the air-liquid interface of the air breathing lung. developmental maturation of ps is controlled by many factors including oxygen, glucose, catecholamines and cortisol. the intrauterine growth restricted (iugr) fetus is hypoxemic and hypoglycaemic, with elevated plasma catecholamines and cortisol. aim to determine the impact of iugr induced by chronic placental restriction via the carunclectomy model on ps maturation. methods we investigated the expression of surfactant protein (sp) -a, -b and -c and their genes in lung tissue of fetal sheep at days and days gestation (term, ± days) from control and carunclectomised merino ewes. results placentally restricted (pr) fetuses had a body weight < sd from the mean of control fetuses and a mean gestational pao < mmhg. pr fetuses had a reduced absolute, but not relative lung weight, decreased plasma glucose and increased plasma cortisol concentration. lung sp-a, -b and -c protein and mrna expression were reduced in pr compared with control fetuses at both ages. sp-b and -c, but not sp-a mrna expression and sp-a, but not sp-b or -c protein expression increased with gestational age. mean gestational pao was positively correlated with sp-a, -b and -c protein and sp-a and -c mrna expression. sp-a and -b gene expression were inversely related to plasma cortisol concentration. conclusion chronic placental restriction and hypoxemia results in an inhibition of ps maturation and thus iugr fetuses are at risk of lung complications, especially if born prematurely. support by the arc & nhmrc. nomination nil. conflict of interest nil. to sue jenkins , , , nola cecins , , sir charles gairdner hospital, perth, western australia, australia, curtin university of technology, perth, western australia, australia, and lung institute of western australia, perth, western australia, australiaintroduction the mwt is widely used to assess patients with chronic lung disease (cld). anecdotal reports and studies in small numbers of patients suggest that adverse events associated with the mwt are rare in patients with cld. this study reports observed adverse events and predictors of oxygen desaturation during the mwt in patients with stable cld referred to an out-patient pulmonary rehabilitation service. methods about consecutive patients completed the mwt in accordance with a standardised protocol that included continuous monitoring of oxygen saturation (spo ) and heart rate (hr, polar). the respiratory diagnoses of the patients were chronic obstructive pulmonary disease (copd), n = ( %); interstitial lung disease (ild), n = ( %); bronchiectasis, n = ( %) and asthma n = ( %). results observed adverse events occurred in tests ( %). one test was terminated when the patient reported chest pain and one patient developed persistent tachycardia (hr > bpm) immediately following the test. in tests ( %), the tester instructed the patient to stop walking due to profound oxygen desaturation (spo < %). six patients prematurely terminated the mwt due to intolerable symptoms. forty-seven per cent (n = ) of patients demonstrated oxygen desaturation, defined as a decrease in spo ‡ % to < % during the test. pre-exercise spo was a significant predictor of desaturation in the copd ( . , . to . , adjusted odds ratio [or], % confidence intervals) and ild (or . , . to . ) cohorts with fev also a predictor in patients with copd (or . , . to . ). conclusions profound oxygen desaturation is the commonest adverse event observed during the mwt in patients with stable cld. this finding questions the american thoracic society guidelines for the mwt which state that oximetry is optional. introduction there is weak support for use of opiates in palliation of refractory dyspnea; respiratory depression is perceived as a major risk. we evaluated the effect of i.v. morphine on dyspnea in controlled conditions and related this to concomitant respiratory depression. methods with ethical approval, healthy subjects received . mg/kg morphine sulphate or saline on separate days in a randomised controlled design. before and for hours after administration, subjects performed (i) dyspnea responses (measured with a visual analog scale) to increasing p et co with ventilation () constrained at resting levels (ii) unconstrainedresponses to increasing p et co to assess respiratory drive. results pre morphine with constrained , all subjects tolerated an elevated p et co of - mmhg; mean dyspnea rating was % ( (sem)). post morphine, at the same p et co , mean dyspnea rating fell to % ( , p < . , paired t). all subjects reported reduced dyspnea at minutes and this was sustained for hours. no changes in dyspnea scores were seen following saline. with unconstrained, at equivalent levels of p et co , morphine, but not saline, was associated with a lower in each subject for up to hours; mean fell from ( ) to ( ) l/min (p < . ). to assess if respiratory depression could account for reduced dyspnea, scores were compared at the different p et co levels that induced equivalent unconstrainedlevels with and without morphine; mean dyspnea scores were not different ( ( ) vs. ( ) %). conclusion a clinically moderate dose of morphine results in substantial and sustained relief of laboratory dyspnea in a small group of healthy subjects consistent with the associated degree of respiratory depression. support breathlessness research charitable trust uk; nih, usa. nomination nil. introduction pulmonary rehabilitation (pr) is a cornerstone of management for patients with chronic obstructive pulmonary disease (copd) and its efficacy is supported with level evidence. despite the known benefits of pr, up to one third of those people with copd who are referred to pr choose not to participate. there is little information regarding perceived barriers to attendance in an australian health care context. methods nineteen people with copd ( women and nine men, gold stage i-iv, age range - years) who had declined to take part in an outpatient pr program at a metropolitan teaching hospital participated in a qualitative study. semi-structured interviews were used to establish reasons for failing to attend the pr program. these interviews were transcribed verbatim and analysed using the principles of grounded theory. results three major themes were identified regarding barriers to attendance at pr. the first related to difficulties with getting there, including a lack of available transport and poor mobility. the second theme related to a lack of perceived benefit, including perceptions that pr would not improve their health or that they were currently doing enough exercise. the third major theme involved restrictions imposed by underlying medical conditions and included the influence of comorbidities and pain. minor themes that arose included competing demands, age, fatigue and program timing. conclusions in australia many patients with copd who are invited to attend pr do not perceive the program would be beneficial, feel they are too unwell to attend or have difficulty with access. further support should be offered to pr candidates and alternative methods of delivering pr to enhance uptake should be considered. introduction pulmonary rehabilitation has emerged as recommended standard care for people with chronic lung disease. however potential demand to access these services far exceeds the available resources. this study's aim was to determine if baseline measures of the bode index, dyspnea (modified medical research council questionnaire), minute walk distance ( mwd), physical activity, taunton respiratory quality of life questionnaire (trq), smoking status, and frequency of hospitalisations can predict responders to pulmonary rehabilitation. methods we retrospectively evaluated all participants with a diagnosis of copd, who attended the pulmonary rehabilitation program at the prince charles hospital between and . a participant was considered a responder to pulmonary rehabilitation if benefit was achieved in exercise capacity ( ‡ % increase in mwd) and/or quality of life ( ‡ . sd decrease in trq as described by cohen's effect size). prediction of responders was assessed using chi square cross tabulations and t-tests with significant measures analysed using a binary logistic regression model. results one hundred and forty-two participants ( males, mean age ( sd) years, mean fev . ( . ) %) who completed pulmonary rehabilitation were analysed. sixtyfive ( . %) people were categorised as responders using the above criteria. significant mean differences were: trq . ( . ) for responders vs. . ( . ) for non-responders p < . ; bode index . ( . ) vs. . ( . ) p = . ; mwd ( ) m vs. ( ) m p = . . the binary logistic regression model showed a higher trq score was the only factor that predicted a responder to pulmonary rehabilitation. no other measure added to the predictive power of the model. conclusion higher trq scores may be useful in predicting which participants are most likely to benefit from referral to pulmonary rehabilitation. further study is underway investigating other factors that may improve these findings. support nil. nomination nil. conflict of interest no. key: cord- -ysur sjq authors: nan title: respiratory nurses sig: poster session date: - - journal: respirology doi: . /j. - . . _ .x sha: doc_id: cord_uid: ysur sjq nan patients with non-eosinophilic asthma (nea) or copd have increased numbers of neutrophils in the airways. we have shown a similar defect in the ability of alveolar macrophages (am) to phagocytose apoptotic cells, in sputum from patients with nea and copd. we have also shown that bal-derived am from patients with copd have reduced expression of key macrophage phagocytic recognition molecules. the aim of this pilot study was to investigate the expression of these macrophage markers in induced sputum from patients with eosinophilic asthma (ea, n = ), nea (n = ), copd (n = ) and controls (n = ). methods participants underwent clinical assessment, skin allergy test, hypertonic saline challenge and sputum induction. macrophage phagocytosis of apoptotic cells, expression of mannose receptor (mr), hspr (cd ) and pcam (cd ) was determined using fl ow cytometry. results phagocytosis was signifi cantly impaired in patients with nea and copd. expression of mr, cd and cd were decreased in patients with nea or copd, but not signifi cantly changed in ea conclusion impaired sputum-macrophage phagocytosis of apoptotic cells in nea is associated with reduced expression of key macrophage recognition molecules. this defect may contribute to the chronic infl ammation and persistent airway neutrophilia that characterizes this asthma subtype. the use of induced sputum as a surrogate for the more-invasive bronchoscopic sampling may provide a tool for investigating the mechanisms for the effect of therapies including azithromycin in lung disease. supported by nhmrc. neutrophilic asthma (na) has been associated with increased bacterial colonization of the airways and increased expression of innate immune factors in the lung. this suggests that infection may play an important role in the pathogenesis of na. na is an important health issue as sufferers are resistant to steroid treatment, which is the mainstay of asthma therapy and effective therapies are urgently required. using mouse models of chlamydia and haemophilus infl uenzae lung infection and ovalbumin (ova)-induced allergic airway disease (aad), we have shown how infection may be linked to na. both infections suppressed eosinophilic infl ammation and t-helper (th) type responses but increase neutrophilic infl ammation and innate and th and/or th responses in aad. in the current study, the effectiveness of steroid treatment for the suppression of infection-induced neutrophilic aad was assessed by treating infected ovasensitized mice intranasally with dexamethasone during ova challenge. whilst dexamethasone treatment suppressed th -mediated, eosinophilic aad in uninfected, ova-sensitized groups, chlamydia and haemophilus-induced neutrophilic aad were shown to be steroid-resistant. our fi ndings correlate with clinical observations which show associations between infection, neutrophilic infl ammation and steroid resistance in asthmatics. these models will be utilized to examine the effectiveness of a number of novel therapies for infection-induced neutrophilic aad and to develop improved treatment strategies for steroid-resistant asthma. supported by nhmrc, asthma foundation of nsw, hmri. kj baines , , jl simp s on , , rj scott , lg wood , , pg gibson , priority research centre's for asthma and respiratory disease, and information based medicine, the university of newcastle, nsw, australia, and respiratory & sleep medicine, hmri, john hunter hospital, nsw, australia rationale four infl ammatory phenotypes of asthma have been identifi ed including eosinophilic, neutrophilic, mixed granulocytic and paucigranulocytic asthma, based on the presence or absence of sputum granulocytes. the involvement of systemic infl ammation in the pathogenesis of infl ammatory phenotypes of asthma remains unknown. objective this study investigates differences in the whole genome gene expression profi le of peripheral blood in infl ammatory phenotypes of asthma. methods induced sputum and peripheral blood were collected from participants with asthma (n = ). infl ammatory cell counts were performed and infl ammatory phenotype assigned based on the eosinophil and neutrophil cutoffs of % and %, respectively. rna was extracted from whole blood, gene expression profi les were generated (illumina humanref- v ) and analysed using genespring gx . results participants with eosinophilic asthma had signifi cantly higher rates of atopy and levels of exhaled nitric oxide. there were genes classifi ed as differentially expressed between the asthma phenotypes including the α-defensins (defa) , b, and , neutrophil proteases cathepsin g (ctsg) and elastase (ela ), and the monocyte/macrophage serine esterase, carboxylesterase (ces ). expressions of defa , b, , , ctsg and ela were signifi cantly higher in neutrophilic asthma and expression of ces was significantly higher in mixed granulocytic asthma. microarray results of the α-defensins and neutrophil proteases were successfully validated using realtime pcr. conclusions there is systemic up-regulation of α-defensins and neutrophil proteases in neutrophilic asthma, and these molecules play an important role in neutrophil activation and migration. systemic activation of neutrophils is an important feature involved in the pathogenesis of neutrophilic asthma, which is signifi cantly different to other asthma phenotypes. supported by hmri and xstrata coal; the university of newcastle. confl ict of interest no. airway mucus hypersecretion is an important cause of morbidity and mortality in asthmatic patients. increases in goblet cell number and their secretions are likely to contribute to airfl ow obstruction in asthma. here, we take advantage of an established sheep model of asthma to investigate the association between allergen exposure and goblet cell activity. methods eight allergic sheep (high house dust mite (hdm)-specifi c serum ige) received weekly intra-lung challenges of hdm to the right caudal lobe, and weekly intra-lung challenges of hdm followed by weeks without allergen exposure to the left caudal lobe, with the right medial lobe serving as an untreated internal control. a separate group of sheep were also used as untreated controls. biopsy samples of segmental bronchi tissue were collected from the different lung lobes for histological analysis at and days post-hdm challenge. results the percentage of goblet cells, with respect to epithelial cells, signifi cantly increases following chronic challenge with hdm ( % hdm vs. % control p < . ). goblet cell numbers did not decline in lung lobes after a -week cessation of allergen challenges. goblet cell degranulation is significantly increased day following challenge with allergen, but returns to control levels by days post-allergen challenge ( % day vs. % control p < . ). furthermore, degranulation is increased in both the rested and internal control lobes day following allergen challenge of the right caudal lobe. conclusions in this sheep model of chronic asthma, repeated allergen challenges induces goblet cell hyperplasia which persists even after long-term withdrawal of allergen. additionally, exposure to allergen in one lobe induces goblet cell degranulation in both challenged and unchallenged lobes, suggesting neural mechanisms may be operating in this model. confl ict of interest no. the thickness of the airway smooth muscle (asm) layer is related to severity but not duration of asthma or age (james erj; : ) . it is unknown if the constituents of the asm layer change with age. aim to investigate the relation of mean asm cell volume (v c ), total number of cells per mm of airway (n l ) and fractions of asm (f asm ) and extracellular matrix (f ecm ) within the asm layer with age and age at onset of asthma. methods post-mortem tissues from control subjects (c n = ); non-fatal (nfa n = ) and fatal (fa n = ) cases of asthma were used. the volume density (n v ) of asm cell nuclei was estimated on μm transverse airway sections (haematoxylin) and mean cell volume (v c = /n v ) was calculated, correcting for the volume fraction of asm within the asm layer. f asm and f ecm were estimated on . -μm thick sections of the same airway (masson's trichrome). effects of age on asm cell parameters and tissue volume fractions were tested using general linear models, correcting for sex and study centre and by comparing age at onset of asthma (< vs. > years). results table shows assessment of airway smooth muscle (asm) cell size and number requires estimates of cell volume density (n v ), volume fraction of muscle (f asm ) within the asm layer and the volume of asm per length of airway. stereological techniques have now become the accepted standard for assessing asm cell parameters, but sources of variation remain unclear. aim to assess sources of variability in the estimation of asm cell parameters and volume fractions within the asm layer. methods large and small airways from subjects with and without asthma were examined. transverse airway sections were cut at . μm and μm (masson's trichrome technique), and μm (haematoxylin) and used to estimate asm cell number and volume, and the volume fraction of muscle (f asm ) within the layer of asm. stereological assessments of the possible sources of variation in these asm layer parameters were assessed. results increased section thickness overestimated f asm by < % ( . μm), % ( μm) and % ( μm). stable variation of < % in n v occurred if high-power fi elds (hpf) were used to estimate n v . variation in the depth of muscle in thick sections of the asm layer caused up to % overestimation of n v . although the absolute area of the asm layer varied by up to %, variation of f asm was < % around the airway circumference and along the airway length. f asm differed signifi cantly between large and small airways. conclusion these results suggest that partial thickness hpfs need to be excluded and that ≥ hpf should be used to estimate asm volume density, that a single . μm section of airway can be used to estimate f asm and that asm parameters should be compared separately in large and small airways. grants nhmrc # . nominations nil. confl ict of interest nil. no signifi cant correlation was seen with age for any asm cell parameters or tissue fractions. results were similar for medium and small airways. conclusion size and number of asm cells and the volume fractions of asm and ecm within the layer of asm are not related to age. support nhmrc australia (grants # ; # ). nomination nil. . ± . . ± . . ± . . ± . fa > . ± . . ± . . ± . . ± . background asthma is characterized by excessive airway narrowing to contractile stimuli, termed airway hyper-responsiveness (ahr). changes in airway smooth muscle (asm) protein expression or mass are possible contributing mechanisms underlying ahr and have been examined using cell culture techniques. however, how these cellular changes to asm relate to airway narrowing at the level of the whole airway is unclear. we describe a new method to track changes in airway narrowing (responsiveness) in culture. methods whole airway segments (generation - ) from sheep lungs were studied prior to (fresh) and after and hours in culture in dulbecco's modifi ed eagle medium with % bovine serum albumin, % l-glutamine and antibiotics. airway narrowing was measured from the % decrease in airway volume under a fi xed transmural pressure, using a servo-controlled syringe pump and organ bath apparatus. cumulative acetylcholine dose-response curves (ach, − m − × − m) were performed to determine maximal response (e max ) and sensitivity (pd , negative log of ec ). results fresh airway segments narrowed strongly and approached closure with an e max of . % ± . (±sem) and pd of . ± . . airway narrowing responses were preserved in culture, with no signifi cant difference in maximal response or sensitivity to ach after either (e max . % ± . , pd . ± . ) or hours in culture (e max . % ± . , pd . ± . ). conclusions the present study has validated a new method allowing changes occurring at the cellular level in culture to be related to changes in airway responsiveness at the whole airway level. future studies will assess the effects of chronic infl ammation in disease on airway responsiveness. background deep inspiration (di) produces a bronchodilator response in healthy humans, but this response is impaired in asthma. reduced airway compliance in disease could impair the response to di by limiting the stretch of smooth muscle. aim to show that isolated human bronchi dilate to di in an amplitudedependent manner and that the stretch caused by di depends on airway compliance. methods bronchi were obtained following lung resection from cancer patients who had normal spirometry (n = ). lumen narrowing was measured using a servo-control system which set transmural pressure and simulated breathing movements. bronchi were contracted to carbachol (cch × − m) during tidal breathing (from to cmh o, i.e. Δ cmh o transmural pressure, . hz) and infl ated to three different amplitudes of di (Δ , or cmh o) applied following contraction. results in cch-contracted airways, all three di amplitudes produced a transient bronchodilation. increasing the di amplitude caused a greater increase in luminal volume during the di and a greater bronchodilation following the di (p < . ). cch itself cause approximately a % fall in specifi c compliance (p < . ), which was reversed by di (p < . ). for each di amplitude, the change in lumen volume during the di was positively correlated to the specifi c compliance of the bronchi before di (r > . , p < . ). conclusions isolated human bronchi show a bronchodilation response to di that is proportional to the expansion of the airway caused by the di. the amount of stretch produced by a di depends on airway wall compliance suggesting that increased airway stiffness in disease could suppress the di response by limiting the stretch of bronchi during lung infl ation. confl ict of interest none. ja douglass , , , ea yu , , br thompson , , , gg king , , mj abramson , introduction increasing asthma prevalence and changes in environmental exposure suggest that there may be a relationship between asthma and dietary intake. however, to date, few studies have examined how dietary intakes of asthmatics differ from a healthy population. aim to measure and compare the dietary intakes of adults with stable asthma and healthy controls. methods in a cross-sectional study, dietary intakes calculated from a item food frequency questionnaire (ffq) of adults with stable asthma (n = , age years ± (sd)) were compared with intakes of healthy controls (n = , age years ± (sd)) matched for age and body mass index (bmi). spirometry, airway responsiveness to hypertonic saline, and induced sputum cell counts were also measured. results subjects with severe persistent asthma (n = ) had signifi cantly higher total fat intake than healthy controls ( ± (sem) versus ± (sem) g/day p = . ) and signifi cantly lower fi bre intakes ( ± (sem) versus ± (sem) g/day p = . ). lower fi bre intake in asthmatic subjects (n = ) was associated with lower %predicted fev (r = . , p = . ), %fvc (r = . , p = . ) and fev /fvc (r = . , p = . ). higher fat intake and lower fi bre intake were associated with higher absolute concentrations of sputum eosinophils (r = . , p = < . , n = ). conclusions subjects with severe persistent asthma have an eating pattern of lower diet quality with higher intakes of fat and lower intakes of fi bre than healthy controls, which is related to lower lung function and increased airway infl ammation. factors leading to altered dietary intake in severe asthma require further investigation. methods a randomized, placebo-controlled, single-blinded trial of tailored asthma education including device technique and utilizing pact to address patients' concerns versus brochure-only information for asthma patients over age . measurements of lung function, asthma control (acq), asthma related quality of life (aqol), medication use and adherence score (adh) were obtained at baseline, and months using standard, validated questionnaires. results sixty-fi ve participants ( f m, mean age ± . ) were randomized to the intervention group and ( f m, mean age ± . ) to the control. there were no statistically signifi cant differences between the groups' demographics or baseline measurements. a wilcoxon signed ranks test used to compare median pair ranking at baseline and months post-intervention revealed a signifi cant improvement in the active, but not the brochure-only information group at months in: acq mean ± sd = . ± . vs. . ± . (p = . ). aqol mean ± sd = . ± . vs. . ± . (p = . ). adh mean ± sd = . ± . vs. . ± . (p < . ). conclusion an educational intervention including device technique and addressing the concerns of older people with asthma signifi cantly improved acq, aqol and adh scores at months post-intervention. introduction greater exposure to ultraviolet radiation (uv) may increase the risk of allergic disease, but this association has not been investigated using estimates of time spent outdoors by individuals. the aim of this study was to investigate the relationship between self-reported doctor-diagnosed asthma and/or hayfever, and time spent outdoors. methods this analysis was based on cross-sectional baseline data from a subsample of the australian and up study, comprising men and women aged - years, living in new south wales. participants were randomly selected from the australian universal health insurance database. diagnoses of asthma and/or hayfever and the number of hours spent outdoors were derived by questionnaire. in general, the odds of a diagnosis of asthma and/or hayfever decreased with increasing time spent outdoors for both women and men. for example, in women, the adjusted odds ratios for asthma with hayfever were . ( % ci: . - . ), . ( . - . ), . ( . - . ) and . ( . - . ) for - , - , - and > hours spent outdoors on weekends, respectively, compared with < hour (p trend < . ). time spent outdoors was not associated with a diagnosis of asthma alone in men. conclusions there were statistically signifi cant inverse associations between time spent outdoors and diagnoses of asthma, hayfever or asthma with hayfever, in a large population of older australians. exposure to uv may protect against the development of allergic diseases, such as asthma and hayfever. no. background allergic rhinitis (ar) and eczema are highly prevalent and females are more commonly affected than males in adulthood. although there have been extensive studies on ar and eczema in females, little is known about the effect of reproductive factors and the development of late-onset ar/ eczema. we examined potential associations between reproductive factors and ar and eczema using the tasmanian longitudinal health study (tahs) data. methods the tahs is a population-based cohort study of respiratory disease. two thousand seven hundred sixty-four ( . %) females from the original tahs participants were surveyed in using postal questionnaire which collected information on reproductive factors such as ever pregnancy, age at fi rst child birth, use of oral contraceptive pills (ocp) and age of starting using the ocp. logistic regression was used to assess the predictors of ar and eczema and all analyses were mutually adjusted. of the participants, . % (n = ) had late-onset ar and . % (n = ) had late-onset eczema. maternal and paternal atopy were signifi cantly associated with ar (p < . ). the risk of developing eczema was decreased signifi cantly with increasing age at fi rst menstruation (or: . , % ci: . - . ) and the increased age at birth of fi rst child ( . , . - . ). a decreased risk in ar was observed with the increasing number of pregnancies ( . , . - . ). however, the associations between age of starting using ocp and ar/eczema were not signifi cant. conclusion later age at start of menses and later age at fi rst pregnancy were associated with a reduced risk of eczema which may be related to hormonal dysregulation. tp- airway responsiveness at and years is associated with asthma at years introduction asthma is the most common chronic childhood disease in australia. increased airway responsiveness (ar) is associated with asthma but not all individuals with increased ar have asthma. the perth infant asthma follow-up study recruited a birth cohort of individuals who have undergone longitudinal assessments of many factors associated with childhood ar. our previous work reported an association between increased ar in infancy and asthma at and years. aim to look at the relationship of increased ar and asthma in early adulthood at different time points from birth. methods individuals were recruited from among expectant parents attending an antenatal clinic at a local metropolitan clinic. at ages , and months and again at , and years, participants underwent an assessment that included a respiratory questionnaire and determination of ar (as evidenced by dose-response slope (drs) to histamine using the rapid technique). results children were initially recruited and studied in infancy. two hundred three, , , , and children subsequently had ar assessed at , and months, , and years, respectively. there was a signifi cant relationship between drs at and years and for both asthma at years (p = . and p < . , respectively) and 'wheeze in the past year' at years (p = . and p = . , respectively). there was no significant relationship between drs in infancy and asthma at . conclusion ar at and years is associated with asthma at years. in this study, there was no signifi cant relationship between ar in infancy and asthma at years. the pcaas has found that . % of children with acute asthma presenting to the princess margaret hospital for children emergency department (pmh ed) had hrv, of which % were hrv group c. furthermore, hrvc was associated with more severe attacks. however, the prevalence of hrvc in the community is unknown. aim to test the hypothesis that hrvc would be found more often in children requiring emergency treatment for an ari than sibling controls and determine the impact of days since symptoms began on the prevalence of hrv detection in children with an acute respiratory illness (ari) and sibling controls (sibs). methods ari (n = ) had nasal samples collected on presentation to the pmh ed and sibs with symptoms of a cold (n = ), within week of ari recruitment. viral rna was extracted and reverse transcribed. a two-step pcr of the hrv ' utr was used for detection, followed by dna sequencing for typing. results ari and sibs were % and % male, % and % asthmatic, with mean ages of . and . years, respectively. hrv +ve ari (n = , mean ± sd days of symptoms = . ± . ), hrv -ve ari (n = , . ± . ), hrv +ve sibs (n = , . ± . ) and hrv -ve sibs (n = , . ± . ). of the and hrv +ve ari and sibs, % and % had hrvc. conclusions hrvc is as common in children who have hrv but do/do not require hospital treatment. detection of hrv is more likely when the nasal sample is collected soon after the appearance of cold symptoms. support nhmrc program grant. nomination nil. introduction upper airway dysfunction may make asthma more diffi cult to control and should be suspected in asthmatics refractory to prescribed medical therapy. aim a novel imaging technique, dynamic -slice computerized tomography (ct), was used to examine laryngeal behaviour in healthy and asthmatic individuals. method vocal cord movement was imaged using -slice ct larynx. healthy volunteers were studied to develop and validate an analysis algorithm for quantifi cation of normal vocal cord function. further studies were then conducted in patients with diffi cult-to-treat asthma. in eight severe asthmatics with abnormal vocal cord movement, asthma outcomes were measured after speech therapy. results vocal cord movement was quantifi ed over the breathing cycle by ct using the ratio of vocal cord diameter to tracheal diameter. normal limits were calculated, validated and applied to evaluate diffi cult-to-treat asthma. vocal cord movement was abnormal with excessive narrowing in of ( %) asthmatics and severe in nine ( %) patients (abnormal > % of inspiration or expiration time). after speech therapy in a small subgroup, asthma symptoms and morbidity improved. conclusion non-invasive ct larynx quantifi cation of vocal cord movement was achieved. this new approach has identifi ed frequent upper airway dysfunction in asthma with potential implications for disease control and treatment. aim to investigate the characteristics and mechanisms of chronic cough (cc) following acute respiratory illness from laboratory-confi rmed h n infl uenza. methods subjects who had current symptoms and had been tested for h n infl uenza by pcr assay participated in this study. twenty-one of those continued onto clinical testing. investigations to assess cough included symptom questionnaires, hypertonic saline challenge and cough monitoring. results of the participants, % tested positive for h n and % tested negative for h n . h n -infected participants were younger and predominantly female. the prevalence of post-h n cc was . %, and for non-h n infection, . %. objectively measured cough frequency was times greater; there was a -fold increase in cough refl ex sensitivity, and greater quality-of-life impairment in the participants with chronic post-infectious cough than the non-cough participants. conclusions cc was found to be relatively common, mild in severity and tending to resolution with time. the characteristics of post-h n cc were similar to other post-infectious cough and were associated with cough refl ex hypersensitivity. aim upper airway dysfunction may accompany acute severe asthma, but this has not been investigated. a novel imaging technique, dynamic -slice computerized tomography (ct), was used to examine laryngeal behaviour in acute asthma exacerbation. methods patients were studied in the emergency department or as acute inpatients following admission for an acute exacerbation of asthma. vocal cord movement was imaged by -slice ct larynx and compared to normal vocal cord movement in a healthy cohort. results vocal cord movement was abnormal with excessive narrowing during either inspiration, expiration or both in of cases ( . %) with acute severe asthma. imaging again revealed that laryngeal dysfunction characterized the movement abnormality, rather than isolated vocal cord dysfunction. radiation exposure was low and generally < milli-sievert. conclusion non-invasive ct larynx quantifi cation of vocal cord movement was effectively achieved in acute severe asthma. we identifi ed frequent upper airway dysfunction in acute severe asthma suggesting that treatment of upper airway obstruction (e.g. using bipap) may be merited during asthma exacerbation. aim to determine whether eicosanoids could alter the deposition of extracellular matrix (ecm) proteins and cytokine release from human airway cells. methods airway smooth muscle cells (asm), fi broblasts and epithelial cells were stimulated with leukotrienes b , c , d , e and the prostaglandins e , d , f α and the pgi analogue mre- . after hours, culture medium was collected and il- and il- production and cell deposited ecm proteins tenascin c, fi bronectin and perlecan were assessed by elisa. to determine whether eicosanoids infl uenced cell proliferation, manual counting of cells in the experiments were carried out before and after stimulation. results neither leukotrienes or prostanoids altered cell proliferation after days of stimulation (n > ). leukotrienes had no effect on ecm protein deposition or cytokine release from asm or fi broblasts (n > ). leukotrienes did not alter either parameters in epithelial cells except leukotriene d , which increased tenascin c deposition (n = , p < . ). prostanoids induced il- and il- and other various changes in asm and fi broblasts (n > , p < . ) (see below). introduction the function of asthmatic airway epithelium is disrupted facilitating immune and infl ammatory responses resulting in epithelial damage. human rhinovirus (hrv) causes asthma exacerbations in children; however, paucity exists on how it affects barrier function. this study assessed how hrv infection affects epithelial barrier function and integrity in healthy and asthmatic epithelium. methods adult balb/c mice were intranasally infected with hrv- b and followed for days. tight junction (tj) expression was assessed using immunohistochemistry (ihc) and western blot analysis. primary airway epithelial cells from healthy and asthmatic children were assessed for tj gene and protein expression by qpcr and ihc, respectively. results occludin and zonal occludin- (zo- ) expression was lost and sustained in mice infected with hrv- b however was not observed in shaminjected mice. asthmatic airway epithelial cells were found to exhibit elevated basal gene expression levels of tjs (zo- , occludin and plakophilin- (pkp- )) but markedly lower corresponding protein levels. conclusion hrv- b compromises barrier function in vivo through sustained loss of tj proteins. the marked decreased expression of tj proteins in paediatric asthmatic epithelium may contribute towards increased susceptibility to viral infections. disparity between gene and protein tj expression could indicate either post-transcriptional regulation or compensatory effects by other tj proteins and requires further study. supported by asthma foundation wa; nhmrc. confl ict of interest none. conclusion leukotrienes alone did not affect the ecm proteins and cytokines assessed in this study. prostanoids decreased ecm protein deposition whilst increasing cytokine release without affecting cell proliferation. this study shows that prostanoids may have a more pronounced role on direct ecm remodelling than leukotrienes in airway cells. supported by merck. background toll-like receptor (tlr) is an innate immune receptor involved in the initial detection of pathogen-associated molecular patterns. the effect of ageing and chronic obstructive pulmonary disease (copd) on tlr responses and the impact of these innate immune responses in copd pathogenesis remain unclear. hypothesis expression and activity of tlr on peripheral blood mononuclear cells (pbmcs) is increased with healthy ageing and further increased in copd. methods pbmcs from healthy controls < years and > years; and participants with copd (n = per group) were cultured with or without pam c ys k (tlr agonist). cells and supernatants were collected at hours and protein (cytometric bead array or fl ow cytometry) and gene (real time pcr) expression was examined. results tlr activation led to increased release of interleukin (il)- , , β, and tumor necrosis factor (tnf)-α. tlr gene expression was increased with stimulation; however, cell surface receptor levels were unchanged. there was no difference in the level of tlr between the groups. in older people, tlr activation resulted in less il- β and tnf-α release, but similar release of il- and il- . similar results were seen in copd. at baseline in copd, there was up-regulation of tnf-α gene expression compared to the older healthy group; however, the tlr cytokine response did not differ between the groups. conclusion healthy ageing is characterized by an impaired systemic proinfl ammatory cytokine response to tlr -mediated innate immune activation. this effect persists in copd and is selective in the cytokine pathways involved. these altered infl ammatory mechanisms may affect responses to infection and injury impacting disease pathogenesis and warrant further evaluation. aim to investigate whether the inhibition of matrix metalloproteinase- (mmp- ) by a non-selective mmp inhibitor (doxycycline) and the specifi c mmp- inhibitor i (olic acid) can regulate cellular migration of tsc -null mouse embryonic fi broblasts (mefs), which act as a model for lymphangioleiomyomatosis (lam) cells, as compared to wild-type mefs. methods wild-type (tsc -positive) and tsc -null mefs were treated with diluent, doxycycline ( . pg/ml- μg/ml) or olic acid ( . - μm) for hours. mmp- levels were assessed by zymography and elisa. cell migration for hours was measured using a transwell migration assay. results under basal conditions, mmp- release and cellular migration was . -fold and . -fold higher, respectively, in tsc -null mefs compared to tsc -positive mefs (mmp- release, tsc -null (n = ) and tsc -positive (n = ), p < . ; cell migration, tsc -null (n = ) and tsc -positive (n = ), p < . ). mmp- release was reduced in tsc -null mefs after -hour treatment with doxycycline ( and μg/ml, n = , p < . ) and with olic acid ( - μm, n = , p < . ). treatment with doxycycline ( pg/ml- μg/ml, n = , p < . ) or olic acid ( - μm, n = , p < . ) also signifi cantly reduced cell migration of tsc -null mefs. copd is a leading cause of death worldwide. treatments are limited and restricted to symptomatic care. there is an urgent need for new treatment options targeting the infl ammation. tissue damage in copd is thought to result from an inability of the normal repair processes with accumulation of apoptotic material and impaired clearance of this material by macrophages in the airways. lung infl ammation and macrophage function involves the bioactive sphingolipid sphingosine -phosphate (s p). multiple studies have showed the involvement of these components in infl ammation. methods we investigated lung tissue samples from patients (copd or non copd controls) undergoing curative lobectomy for lung cancer. we analysed the mrna expression profi le, the sphingosine-kinase (sphk) protein activity and the localization and expression of individual proteins. results we show in this study for the fi rst time a comprehensive expression profi le of all synthesizing enzymes, receptors and degrading enzymes in the human lung. correlations between receptor subtypes, degrading enzymes and between s p receptor subtype were detected. multivariance anova showed that in copd, the relative mrna expression of s p receptor subtype was reduced. conclusion the correlations between receptors and enzymes involved in the sphingosine kinase signalling system in the lung suggest common regulatory mechanisms. s pr is expressed on dendritic and nk cells which are reduced under conditions of copd. therefore, our fi ndings of reduced s pr in copd may provide a novel target for pharmacotherapy. lung cancer is responsible for more cancer-related deaths than colon, breast and prostate cancers combined. in patients with copd and/or lung cancer, we have shown a reduction in lung and airway macrophage function, evident by a reduced ability to phagocytose apoptotic airway epithelial cells and neutrophils. the potential for lung cancer cells to directly inhibit this function (a potential immune evasion mechanism) has not been investigated. background kinins have been implicated in airway lung diseases such as asthma and lung cancer by regulating infl ammation, cell proliferation and migration. the effect of kinins is mediated through the binding of two receptors, kinin b and b receptors (b r and b r). a novel b r splice variant (sv) resulting in a shorter ' untranslated region (utr) was identifi ed in cultured airway epithelial and fi broblasts as well as in lung carcinoma tissue and leukocytes. this study aims to characterize the functional role of the novel b r sv in mrna stability, translation effi ciency and receptor expression in cultured airway epithelial cells. methods stability of b r sv was determined by measuring b r mrna levels over time in h cells after actinomycin d treatment. translational effi ciency of wt and sv 'utr was determined by measuring luciferase activity in transfected h cells. expression of wt and sv transcripts through q-rtpcr were compared in cells treated with a b r-specifi c agonist dakd. cell-surface receptor expression post-agonist stimulation was quantifi ed using facs. results mrna stability studies indicated that b r sv was ≈ % less stable than the wt transcript in h cells suggesting a stabilizing element 'utr. translation effi ciency of sv was no different to wt b r. dakd stimulation increased both wt and sv transcripts early in the time course, although the peak expression of wt and sv differed at hours and hours, respectively. dakd stimulated cells showed two phases of receptor expression, ( ) decrease of cell surface receptor up to . hours post-stimulation; ( ) increase in cell surface b r after . hours. conclusion this study has identifi ed a novel regulatory mechanism of b r expression through the production of a sv that alters the 'utr. the translation effi ciency of b r is not affected, but the sv was less stable than the wt in h cells and may play a role in allowing quicker changes in transcription. agonist-induced up-regulation of transcripts in a time-dependent manner may be important in maintaining a chronic response during infl ammation. circulating lymphocytes are increasingly used as a surrogate cell type to refl ect changes in adrβ density elsewhere in the body, particularly the respiratory system. however, adrβ density is non-uniform among lymphocyte subsets and it is unclear if, and the degree to which, adrβ density varies between individuals. aim to assess the extent of variability in adrβ density on human peripheral blood mononuclear cells (pbmc) including lymphocytes and monocytes. method pbmc were isolated from blood of healthy subjects by density gradient centrifugation with ficoll-paque. cell surface and total adrβ of intact and permeabilized lymphocytes (cd +) and monocytes (cd +) were measured using anti-adrβ via facs. geometric mean fl uorescence (gmf) was used as the indices for adrβ density per cell. result surface adrβ -gmf increased by . -and . -folds over negative controls for lymphocytes and monocytes, respectively. magnitude of foldchange was not signifi cantly different between these cells (p = . ), but the distribution of gmf intensity between samples suggests greater variability in adrβ density in lymphocytes versus monocytes (p = . ). proportion of cells-stained adrβ -positive was signifi cantly higher in monocytes versus lymphocytes ( . ± . % vs. . ± . %, p = . ). total adrβ -gmf increased by . ± . and . ± . -folds for lymphocytes and monocytes, respectively (p > . ). proportion of adrβ -positively stained cells were similar between samples (lymphocytes %, monocytes %, p = . ), but greater variability was observed for lymphocytes (range - %) versus monocytes ( - %). conclusions despite similarities in surface and total adrβ density, lymphocytes display greater inter-subject variability compared with monocytes. this will have implication in experimental designs and interpretation of changes in adrβ density in studies using human pbmc as an alternative to primary cells from the organ of interest. confl ict of interest no. pge plays a protective role in asthma by inhibiting airway infl ammation. it is predominantly produced by epithelial cells in response to pro-infl ammatory stimuli and acts as an autocrine and paracrine mediator. on the contrary, il- β is a highly potent cytokine that induces many pro-infl ammatory effects in the human airway including activation of the human lung epithelium which promotes production of pro-infl ammatory cytokines and chemokines. airway epithelial cells express all four known pge (e prostanoid (ep) receptors, but mechanisms underlying the regulation of expression of ep receptors in human lung epithelial cells have remained elusive. therefore, we investigated whether pge , an endogenous protective mechanism of the airways, can modulate il- β infl uence on ep receptor expression in human epithelial cells. methods ep receptor mrna and protein expression was quantifi ed in -hbe cells at basal levels and following stimulation with il- β or pge alone, or simultaneously, using real time rt pcr and facs analysis, respectively. results pge up-regulates all four ep receptors at mrna level, while il- β up-regulates ep , ep and ep and does not infl uence expression of ep . at protein level, preliminary results show transient increase of ep receptors in the presence of pge , while il- β down-regulates this receptor. ep and ep are up-regulated following stimulation with both stimuli. importantly, antiinfl ammatory ep receptor is up-regulated only in the presence of pge . conclusion we show for the fi rst time that pge may infl uence expression of its own receptors and oppose the effect of il- β in human lung epithelial cells. this may in turn alter pge production and autocrine activation with potential implication on the function of epithelial cells, which is important in modulation of immune response in asthma and lung infl ammatory diseases. nomination nil. confl ict of interest no. the burden of obstructive lung disease (bold) study is an international study designed to measure the prevalence, risk factors and burden of copd. data collection using the bold protocol has been undertaken at eight sites with inclusion of urban, rural, coastal and inland regions of australia. methods a random sample of adults aged ≥ years was identifi ed. information on respiratory symptoms and diagnosed copd were collected by questionnaire. post-bronchodilator fev and fvc were used to defi ne gold stage. the (un-weighted) prevalence rates are presented by age groups and sex. results s timmins , , , , g king , , , , c salome , , , r schoeffel , , , c walsh , , the extent of emphysema could increase ventilation heterogeneity independently of its effects on airway narrowing. the aim of this study was to examine the relationship between emphysema extent on computed tomography scans (ct), and airway narrowing and ventilation distribution in copd. methods subjects with copd underwent ct scanning, spirometry, dlco and nitrogen washout by single and multiple breath techniques. closing capacity (cc/tlc%), slope of phase iii (Δphase iii ) and indices of ventilation distribution conductive (scond) and diffusion-dependent airways (sacin) were derived from washouts. helical ct scans were performed at tlc. emphysema extent was measured as low attenuation areas < − hu using osirix program, expressed as % of ct total lung volume. results subjects were of mean (range) age years ( - ), bmi . ( . - . ), fev of ( - %) %predicted and dlco of ( - ) %predicted. emphysema extent was . % ( . - . ). geometric mean (ci) Δphase iii was . ( . - . ), sacin was increased at . l − ( . - . ) and cc/tlc% was % ( - ). emphysema extent correlated with fev / fvc (r = − . , p = . ), dlco (r = − . , p < . ), bmi (r = . , p = . ), Δphase iii (r = . , p = . ), and sacin (r = . p = . ). in multiple regression analysis, emphysema extent was predicted by fev /fvc and Δphase iii (model r = . , p = . ). conclusions the extent of emphysema increases the heterogeneity of ventilation independently of any effects on overall airway narrowing. supported by australian lung foundation webster memorial award, crcaa. conclusions self-reported wheeze in the last months is very common in adults over years. in the younger age group ( - years), many people with wheeze did not have airfl ow obstruction or reversible spirometry at the time of test. aim to determine whether there is any association between change in fev among copd patients and ambient ultrafi ne particle number concentrations in melbourne. methods participants with mild to moderate copd were asked to measure their fev using a portable electronic spirometer (piko) two times a day (morning and evening) for consecutive days. the same procedure was repeated on average months later. ambient ultrafi ne (diameter < . μm) particle number concentrations were measured for the same period using an ultrafi ne condensation particle counter and micro-orifi ce uniform deposit impactor. results aim to examine the implementation of, and barriers and enablers to, six high-evidence recommendations for copd management, in copd hospital inpatients. method observational, mixed methods study in consecutive copd patients admitted to a tertiary hospital. demographic, disease and admission characteristics are recorded. implementation (or not) of smoking cessation, pulmonary rehabilitation, long-term oxygen use if hypoxaemic, medication use, vaccinations and plans for future exacerbations are determined from medical records and patient interviews. interviews with medical offi cers examine their perspectives on recommendation implementation. of pilot data in copd patients (mean (sd) age ( ) years, length of stay ( ) days), were current smokers and had severe copd ( moderate). highest levels of implementation were fl u vaccination (completed by gps, n = ), medication (but not spacer) use, and oxygen use if hypoxaemic (investigated and implemented in all suitable, n = ). pulmonary rehabilitation was discussed with half of the patients, but only severe patients with long length of stay accepted further rehabilitation. exacerbation plans were in place for patient, and newly initiated in patients. doctor interviews (n = ) confi rmed pulmonary rehabilitation was considered mostly for severely unwell patients, and use of exacerbation plans was inconsistent. conclusion pilot data suggest pulmonary rehabilitation is offered and accepted by a small subset of copd patients. findings from this pilot will inform planned larger observational studies, and in turn, experimental studies to improve copd care. high-and extreme high-risk interventions were found by panel ( - . % extreme and . - . % high-risk interventions) and patients' respiratory physicians ( % extreme and % high-risk interventions). additionally, clinical pharmacist involvement was associated with many benefi ts such as: improvement in medication compliance, high level of patient satisfaction and identifi cation of patients with issues in medication knowledge. conclusion clinical pharmacist interventions were estimated to prevent extreme and high risks that might happen due to drug-related problems. clinical pharmacy consultation was associated with positive impact on other important measured outcomes. aerobic exercise training in the form of supervised -minute walks ( mw) reduces exertional dyspnoea in patients with copd. mw goal ( mwg) distances, aiming for a training effect, are generated from a baseline submaximal test ( -minute walk ( mwd), where wg = . × mwd/ × . aim to compare mwg with actual initial mw achieved and to examine the predictors of mwg achievers (ga). methods retrospective review of patients, % male, age ± years (mean ± sd), fev ± %predicted, who completed pulmonary rehabilitation (pr). patients were assessed at baseline and post-completion of pr. initial mwg was calculated from the best of two mwd at initial assessment and ga were defi ned as patients who achieved their mwg at their fi rst visit to pr. results for the group, there was a statistically signifi cant but not clinically signifi cant difference between mwg and actual mw achieved ( ± m vs. ± m, p < . , paired t-test). the patients ( %) who achieved their mwg exceeded the goal by ± m, whereas the patients who did not achieve their mwg fell short by ± m. there was no signifi cant difference between ga and non-ga in age or lung function, but ga had a higher initial mwd, with fewer rests, lower dyspnoea score and lower hr at start and fi nish (p < . , unpaired t-test). ga were also more likely to have a clinically signifi cant response to pr, measured by mwd, compared with non-ga (mean change m vs. m, p < . , chi-square). conclusion mw goals as currently calculated either signifi cantly underestimate or overestimate actual mw achieved. it may be that in non-ga, the mwd is functioning as a true maximal test and these are a group of patients who are truly ventilatory-limited, rather than deconditioned. the receptor for advanced glycation end products (rage) is a key candidate for promoting a self-perpetuating cycle of infl ammation and thereby is a major contributor to numerous chronic disease states. the potential of rage to function as a switch converting a transient infl ammatory response such as one generated by cigarette smoke to sustained cellular dysfunction allows it to act as a mediator for ongoing infl ammation in chronic obstructive pulmonary disease (copd). although the molecular mechanisms regulating rage expression have not been fully elucidated, altered rage activity arises from polymorphisms within the rage gene and its promoter. three polymorphisms in the rage promoter (− t/a, − t/c and a bp deletion from − to − ) increase transcriptional activity and rage expression. the rage g s allele results in an increased ligand-binding affi nity and activation of the infl ammatory mediators with subsequent up-regulation of infl ammatory response. the aim of this pilot cross-sectional study was to investigate the relationship between three known rage polymorphisms (− t/a, bp deletion, g s) and copd and disease severity. methods genomic dna was isolated from peripheral blood lymphocytes. pcr and taqman assays were used to genotype the three rage polymorphisms in copd patients, healthy non-smokers and healthy smokers. fev was measured in all subjects. disease severity was defi ned using gold guidelines. results there was no statistically signifi cant association between bp deletion and copd (p = . ), − t > a and copd (p = . ), g s and copd (p = . ). conclusion no association was found between the − t > a, bp deletion and g s polymorphisms and copd, disease severity or fev introduction the receptor for advanced glycation end products (rage) mediates neutrophil traffi cking and is implicated in the pathogenesis of chronic airways disease. we determined whether changes in airway and systemic levels of soluble rage (which acts as a receptor decoy to limit rage activation) and rage ligands are related to neutrophilic infl ammation in asthma and copd. methods bronchial lavage (bl) fl uid from subjects with moderate-severe persistent asthma or copd, and healthy controls were analysed for neutrophils, total srage (cleaved and secreted), secreted srage (esrage) and the rage ligands hmgb and serum amyloid a (saa). systemic levels srage and esrage were also determined in asthmatic and copd subjects. aims increased numbers of neutrophils are found in the lungs of copd patients, which contribute to airway infl ammation. while cigarette smoke exposure is the major risk factor for copd, it is unclear how cigarette smoke modifi es neutrophil function and activity. this study aimed to assess the effect of cigarette smoke extract (cse) on neutrophils in an in vitro model. methods neutrophils were isolated from peripheral blood donated by volunteers using percoll density gradient centrifugation. neutrophils were seeded in well plates ( cells/well), exposed to different concentrations of cse ( %, %) and monitored at , and hours. at each time point, viability of neutrophils was measured by trypan blue exclusion and supernatant was collected for measurement of cxcl release by elisa (r&d systems conclusions in neutrophils exposed to cse, viability is maintained and cxcl release increases with increasing dose of cse. we conclude that cigarette smoke stimulates an infl ammatory response by neutrophils, which would contribute to the infl ammatory burden in the airways in copd. introduction factor viii (f ) and collagen iv (c ) antibodies are used for quantifying vessels in tissue sections. we compared these two antibodies for vessels staining in bronchial biopsies (bb) in copd. methods bb from healthy non-smokers (h-n) and copd subjects were stained for both antibodies. number, area and mean vascular size (mvs) (surface area/vessel number) of vessels in the lamina propria (lp) to the depth of μm were measured and compared between the two antibodies and are reported as median (range). results number of vessels was not signifi cantly different between the two methods of staining. in copd and h-n, vascular area (μm /μm of lp × ) stained with f was less than that with c ( . ( . - ) vs. ( - . ), p < . and . ( . - . ) vs. . ( . - . ), p < . introduction previous studies have shown that c-reactive protein levels increase at the onset of some copd exacerbations; however, there is limited data on the normal fl uctuation in crp levels in stable patients. aim to investigate within patient variation in crp levels to determine the magnitude of normal day-to-day fl uctuations in stable patients and the correlation with patients' perception of symptom severity. methods early morning crp levels were measured on days , and from patients from the melbourne copd cohort (gold category ii-iv) who identifi ed themselves as stable. patients recorded daily symptom scores including: borg dyspnoea scale at rest, severity of wheeze, cough, dyspnoea, change in sputum colour or volume, night-time waking and the presence of viral symptoms. crp levels were measured by the clinical pathology service and using a point-of care device. variation in crp levels in stable copd and correlation between change in crp levels and symptoms were analysed. aim patient-completed diaries monitoring changes in key symptoms in copd are often used to recognize acute exacerbations (ae) both to prompt additional treatment and monitor treatment effi cacy. we assessed diary compliance and the predictive value of major symptoms of aes which required hospital attendance. methods inpatients recruited during an ae of copd completed daily paper or web-based diaries for months, recording changes from their stable state for: breathlessness, cough, sputum, subjective 'wellness', physical activity and use of reliever ( -point scale, mid-pt = no change). the predictive value of current and lagged symptom scores was compared for each and between symptoms. diagnostic accuracy was assessed by area under the curve (auc) and at specifi c cut-points. in participants ( m, f) with mean age ± and mean fev % predicted ± , there were such aes involving patients. duration of diary keeping was shorter with lower education attainment (p = . ), but compliance did not vary for other demographic or clinical factors. daily compliance while diaries were being kept was %. excluding the current day, the best predictor was the distributed lag score over days, sputum changes giving the strongest signal; relative risk . ( % ci . to . ) with most of the signal in the days prior to the ae. little was gained by combining symptoms. the predictive value was moderate auc = . . conclusions compliance with symptom diaries in severe copd is surprisingly good. however, with only a weak signal for an impending ae requiring hospital attendance up to hours before and for lagged symptom scores over days before, with low positive predictive values, the utility of keeping daily symptom diaries for raising alerts for impending severe aes in copd is questionable. results seven studies with inpatient participants were identifi ed; published as abstracts for which data were not available did not contribute to meta-analyses. no study specifi ed diagnostic criteria for copd and only one specifi ed ae criteria. short course treatment varied between - days and longer duration - days; studies used oral prednisolone (dose mg, studies, tapered dose) and studies used intravenous scs treatment. mean ages of participants ranged from to years. primary outcomes: likelihood of treatment failure did not differ by duration of treatment (odds ratio . ; % ci . to . ) ( studies, n = ). fev did not differ signifi cantly when measured up to days (mean difference (md) − . l; % ci − . to . ) or after days (md − . l; % ci − . to . ) ( studies, n = ). secondary outcomes: limited data ( study) precluded meta-analysis for readmission or mortality. the likelihood of an adverse event ( studies, n = ) was not signifi cantly lower for shorter scs (or . ; % ci . to . ). conclusions we found no signifi cant differences between short (≤ days) and longer (> days) corticosteroid therapy for ae of copd. this has implications for clinical practice and may reduce adverse effects for patients, shorten hospital admissions and reduce costs, but more studies are needed to confi rm these fi ndings. aim to explore factors which infl uence the self-management of exacerbations in patients with copd. methods a pilot cross-sectional study was undertaken to assess patients' compliance with their action plan and their action taken prior to an admission. patients were interviewed during an admission to hospital for exacerbation of copd. the effect of pulmonary rehabilitation on patients' knowledge of copd was also assessed. results % of patients were provided with a written action plan, and % with a verbal action plan. in response to an exacerbation, more than % of the patients stated that they used their action plan. however, where action plans were not adequately utilized, patients delayed seeking medical attention and failed to initiate oral prednisolone and antibiotics during an exacerbation despite being prescribed an emergency supply of these medications. pulmonary rehabilitation had a positive outcome towards enhancing the patients' knowledge of copd. clinical pharmacists have limited involvement in terms of copd and smoking cessation education. conclusion the need to offer a thorough self-management program along with providing a more comprehensive written action plan will encourage patients to start early treatment and follow their action plans. encouraging collaboration between the hcp and patients encourages self-management through discussing and agreeing on goals of treatment and developing a personalized written action plan. context dyspnoea is a common symptom in copd and increases during exacerbations. when respiratory failure supervenes, and assisted ventilation is required, non-invasive ventilation (niv) is the treatment of choice. objective to determine if niv relieves dyspnoea in inpatients with acute respiratory failure due to exacerbations of copd. data sources english language randomized controlled trials (rcts) published prior to august were identifi ed using medline, embase, cinahl, psychinfo and pubmed. additional studies were identifi ed by reviewing the reference list of included studies. search terms included niv, nippv, nppv, bilevel cpap, bipap, artifi cial ventilation, copd and randomized controlled trial. study selection rcts comparing usual medical care (umc) to umc plus niv and measuring dyspnoea at relevant time points were included. abstracts for potentially relevant articles were extracted by one author. these were assessed by a second author to ensure inclusion criteria were met. articles were reviewed to determine if dyspnoea was measured and appropriate statistical analysis reported. the search yielded individual articles. four articles met the review criteria. three articles fi nd that niv relieved dyspnoea to a statistically signifi cant level and two suggested that the relief of dyspnoea is clinically signifi cant. discussion in spite of the common use of niv to relieve dyspnoea, little work has analysed effi cacy in terms of this patient-reported outcome. while our results may suggest niv relieves dyspnoea, reporting or methodological fl aws in several articles limit the strength of the conclusions that may be drawn. these limitations make the conclusion that niv relieves dyspnoea contentious. conclusion despite over two decades of studies investigating niv, the therapeutic impact on breathlessness is poorly described. understanding the impact of niv on patient-reported outcomes is of critical importance in clinical care. confl ict of interest none. introduction in mice, the most direct lung dosing method delivers the agents directly into the trachea. for our cystic fi brosis gene-therapy studies, we deliver fl uids -an airway pretreatment followed by a lentiviral vector -directly into the mouse trachea to target conducting airways. despite using standardized delivery techniques, we see substantial variability in the amount and location of gene transfer. aim the aim of this experiment was to use synchrotron x-ray imaging to track the dynamics of fl uid doses delivered into the live mouse trachea. methods four nembutal anaesthetized c bl/ mice were imaged on the bl b beamline at the spring- synchrotron. mice were intubated and ventilated at br/min with image captured per breath. after minute of baseline, a -μl sample of iodine-based contrast fl uid (a surrogate for our airway pretreatment or gene-vector) was delivered over seconds. following minutes of data collection, an additional μl bolus was delivered over . seconds. image capture continued for a further minutes. frame differencing was used to reveal fl uid motion. results substantial dose losses may occur upon delivery into mouse trachea via immediate retrograde fl uid motion. the speed of bolus delivery into lung may also infl uence the relative targeting of conducting airways and deep lung. introduction use of effi cient nebulizers can enhance the quality of life of cf patients by reducing the treatment time and improving drug delivery effi ciency. the aim of this study was to determine which commonly recommended nebulizer was optimal for delivery of the most commonly used therapies to cf. methods seventeen children with cf ( - years) were recruited. delivery of three commonly used cf therapies ( % hypertonic saline ( ml, . g/ ml), tobramycin ( ml, mg/ml) and pulmozyme ( . ml, mg/ml)) by two vibrating membrane nebulizers, the eflow rapid and the aeroneb go, and a jet nebulizer lc sprint junior with pariboy sx ( . l/min) were tested. for each drug-nebulizer combination (in random order), each child was asked to inhale through an inspiratory fi lter, and drug delivery to the fi lter was measured. pulmozyme was quantifi ed using an enzymatic activity assay, tobramycin was measured using hplc and hypertonic saline was measured using conductivity. total nebulization time was recorded. the results showed that there was no difference in the amount of drug delivered to patients when the nebulizers were compared for all three therapies (p > . ). however, the nebulization time for the eflow rapid was signifi cantly shorter than that for the aeroneb go and lc sprint junior. similarly, the nebulization time for aeroneb go was shorter than that for the lc sprint junior (p > . ) for all therapies). conclusion overall, there were no signifi cant differences between nebulizers in delivered dose for three forms of cf therapy, due to inter-patient variability. despite this, both vibrating membrane nebulizers had shorter nebulization times than the lc sprint junior, with the eflow rapid delivering drug in the shortest time. confl ict of interest nil. introduction as the life expectancy of patients with cystic fi brosis (cf) increases, treatment-related morbidity is increasingly recognized. totally implantable venous access devices (tivads) offer reliable long-term central venous access but are associated with recognized complications including venous thrombosis. superior vena cava syndrome (svcs) however has been rarely reported in this setting. we report a single cf centre's experience of svcs associated with tivads. methods retrospective review of episodes of svcs in patients with cf and a tivad attending the adult cf centre, prince charles hospital, queensland. results between february and december , fi ve episodes of svcs occurred in patients with tivads from a clinic population of patients. all of the affected patients were female, with moderately severe lung disease (mean fev predicted . %). no patients had a recognized thrombophilia. four tivads were inserted at a centre different to our own, three were on oestrogen-based contraception, and two suffered with dehydration at presentation. svcs treatment consisted of anticoagulation ( ), line removal ( ), angioplasty ( ), thrombolysis ( ) noninvasive bioluminescence imaging has allowed for rapid in vivo quantifi cation of long-lasting gene transfer in experimental animals. we are testing the longevity of a single nasal delivery of our lentiviral (lv) gene transfer system in mouse airways. methods normal (c bl/ ) and cystic fi brosis (cf) mice received a nasal bolus of lysophosphatidylcholine (lpc) or a control (pbs) pretreatment hour prior to delivery of a lv vector containing the reporter-gene luciferase (lv-luc). another control group received lpc hour prior to an empty vector (lv-mt). bioluminescence was measured at week, , , , , , , , and months post-lv dosing to assess gene transfer. results normal mice: mice that received lpc/lv-luc treatment had significantly greater gene transfer compared to the two control groups at all time points (p < . , rm anova). no luminescence was detected in mice treated with lpc/lv-mt. unexpectedly, luciferase activity was also detected in the lung. there was no difference in lung luminescence between the lpc and pbs pretreated mice that received lv-luc. cf mice: a statistically signifi cant increase in nasal luminescence persisted for up to months following lpc/ lv-luc (p < . , rm anova). similar to normal mice, there was no statistical difference in lung luminescence between mice that received lpc and pbs lv-luc. conclusions lentiviral luciferase gene expression was signifi cantly improved in mouse nasal airways using lpc pretreatment in both strains. however, the longevity of transduction was reduced in cf mice, which may, in part, be due to reduced animal numbers at the later time points tested. supported by nh&mrc. background the nintendo-wii® facilitates exercise-based programs that may be considered novel, fun and potentially motivating. objective exercise outcomes using the wii have yet to be reported in the cystic fi brosis (cf) adult population. aim to investigate nintendo-wii® exercise training compared with standard exercise in adult cf patients whilst hospitalized for treatment of a pulmonary exacerbation. methods a within-subjects, randomized cross-over study. adult cf participants received two -minute exercise treatment sessions within a -hour period, at least day apart, during the last days of hospitalization. wii exercise consisted interval training with games such as boxing, dancing and track exercises. standard exercise consisted of interval training on treadmill or cycle ergometer at - % of heart rate maximum. results participants completed the study (mean (sd) age ( ) years, % females), with a mean fev % of ( )%. during exercise, no difference was found between groups in average heart rate (p = . ), oxygen desaturation (p = . ), borg rate of perceived exertion (p = . ) or modifi ed borg for dyspnoea (p = . ). on vas ( - ), participants reported the wii program to be more enjoyable (p < . ) and less fatiguing (p = . ). participants rated both exercise sessions as equally effective (p = . ). conclusions this study suggests that a nintendo-wii® exercise session provides an equivalent cardiovascular demand to a standard exercise session in an inpatient adult cf population. greater enjoyment levels and lower fatigue levels reported during nintendo-wii® training may have a positive infl uence on adherence to exercise. further study into the long-term effects of nintendo-wii® training needs to be undertaken. confl ict of interest nil. introduction ion transport is important to maintain the airway epithelial surface, as shown by the disease cystic fi brosis (cf) which is characterized by decreased clsecretion and increased na + absorption. we have previously shown that the cf airway can develop clresponses when the surface is nominally calcium free (middleton et al. ajrccm ; : - . aim to determine the effects of citrate on the nasal potential difference (npd) with and without amiloride pretreatment, and to compare these effects with other clinically relevant calcium chelators and dicarboxylic acids. methods npd was measured using standard techniques (erj ; : ) in cf and non-cf subjects. the nasal pd response to citrate, oxalate, malate, succinate and fumarate (all mm) was compared with the calcium chelators edta and egta. results citrate decreased the basal npd by ∼ mv, but in the presence of amiloride, citrate increased the pd by ∼ mv. with amiloride/low clpretreatment, citrate increased npd by - mv, which suggests that citrate increased clsecretion. in contrast, the other dicarboxylic acids and calcium chelators exhibited little response. conclusion the combination of these responses suggests that citrate exerts complex effects on airway ion transport, most likely dual effects of decreased na + absorption and increased clsecretion. aim to assess the validity of the international physical activity questionnaire (ipaq) in cf adults by comparing energy expenditure measured by the ipaq versus the accelerometer. methods with ethics approval, suitable successive adult patients with cf attending the alfred cf outpatient clinic were recruited. all participants wore an accelerometer (actigraph gt m) around the waist for days of awake time, at the end of which, they completed the ipaq. criterion validity of the ipaq was assessed by comparing the ipaq weekly energy expenditure (ee) in kilocalories (kcal) with weekly ee (kcal) from the accelerometer using spearman correlations and bland-altman procedures. results thirty participants ( % females) completed the assessment: mean (sd); age = ( ) years, fev %predicted = ( ) the median (range) ee: ipaq = ( , ) kcal, gt m = ( , ) kcal. spearman correlations of fev %predicted with ee were gt m ee r = . , p < . ; ipaq ee r = . , p > . . correlation of the ipaq ee with accelerometer ee was moderate (r = . , p = . ). there was a trend towards higher ee measured by the ipaq than measured by the accelerometer (wilcoxon signed ranks test: z = − . , p = . ). conclusion the ipaq underestimates physical activity for patients with lower energy expenditure activities and overestimates for those with higher energy expenditure activities in adults with cf. the ipaq would be a useful screening tool for exercise prescription and monitoring of physical activity longitudinally, but more quantifi able methods for assessment such as the accelerometer should be used in research. confl ict of interest none. infectious endometritis associated with pseudomonas aeruginosa (pa) is an important equine disease resulting in reduced fertility and decreased foal drop. previous typing studies of equine pa report clonal heterogeneity, suggestive of sporadic acquisition, and small clusters of indistinguishable strains. aim we performed molecular typing of a large sample of genital pa isolates from horses in s-e qld. methods thoroughbred genital tract pa isolates submitted to uq vet diagnostic lab during - (screening or infection suspected) were studied. eric-pcr fi ngerprint analysis was performed. isolates producing indistinguishable fi ngerprints were allocated to the same eric-pcr type. mlst was performed on a subset of isolates. results overall, genital (clitoral or uterine) swabs from mares and urethral fossa swabs from stallions located on stud farms were processed. pa was identifi ed in genital cultures from of the ( . %) mares but from none of the stallions. six clusters involving ≥ mares were detected. cluster-a was observed amongst isolates collected from ( %) mares from studs and each year. cluster-b isolates were present in mares from studs during - . clusters c-to-f each contained isolates from mares from or studs. conclusions overall, % of mares harbouring pa had clonally related strains. however, we found no evidence of horizontal transmission between stallions. these data raise the possibility of transmission via environmental or other sources. alternatively, specifi c strains may have trophism for the reproductive tract of horses. the fi nding of a dominant strain amongst thoroughbred mares in a geographic region has interesting parallels with recent evidence of the spread of highly prevalent clonal strains in cystic fi brosis clinics. aim to investigate the prevalence and impact of incontinence in adult men with cystic fi brosis (cf) as compared with age-and sex matched control subjects. methods men with cf were recruited through outpatient clinics and control subjects through advertisements to complete standardized questionnaires relating to respiratory symptoms, bladder and bowel function, mood and physical activity levels. demographic data were collected from medical records for the cf group. results seventy-four men with cf participated (mean (sd) age . ( . ) years). forty-nine men volunteered as controls ( . ( ) years), and were well matched in terms of physical activity levels. / ( %) in the cf group and / ( %) in the control group had reported episodes of urine leakage. in the men with cf, there was no difference in lung function between men with episodes of leak and those with no history of leak (fev % predicted ( )% vs. ( )%, p = . ). anxiety levels were higher in men from both groups with episodes of leak compared to those with no history of leak (hospital anxiety and depression anxiety score . ( . ) vs. . ( . ), p < . ). depression scores were also higher in men with episodes of leak compared to those with no history of leak ( . ( . ) vs. . ( . ), p < . ). conclusions urinary incontinence in men with cf is not associated with disease severity, as measured by lung function. anxiety and depression levels were higher in men with leakage of urine. confl ict of interest no. aim to investigate the bone mineral status of children and adolescents with cf and to explore the relationship between bone mineral density (bmd) and anthropometric and clinical parameters including height, body mass index (bmi), lung function tests and vitamin d levels ( -hydroxyvitamin d) in the cf centre at starship children's hospital, new zealand. methods bmd of the lumbar spine was assessed by dual x-ray absortiometry between january and december . the results of subjects with cf ( males) with a mean age of . years (range - . years) were collected. anthropometric data (height, bmi), forced expiratory volume in second as percent predicted (%fev ) and vitamin levels were assessed and related to bmd. results bmd in our subjects was low in . % and very low in . % when adjusted for age, sex and height (difference in bmd g/cm in the lumbar spine l -l ). there was a strong positive relationship between the lumbar areal bmd (abmd) and bmi z scores (p < . ), abmd and % fev z scores (p < . ), and abmd z scores and vitamin d levels (p < . ). conclusions bmd was normal in the younger and well-nourished subjects with normal or mild reduction of fev . low bmd appeared to evolve during adolescence with decreasing bmi and reduction in lung function. this will lead to ongoing bone disease in early adulthood. it is a further indication to maintain optimal nutritional status and maximize lung health. malnutrition in cf is associated with poorer pulmonary function and is an independent risk factor of survival. aim to compare the nutritional status of the adults attending an adult cf centre in with . method retrospective audit of patients ( excluded, incomplete data) including demographics, nutritional status, pancreatic enzyme replacement therapy (pert) usage, glucose tolerance and dietetic review. results the mean age of the clinic population increased from . to . years. mean (sd) bmi increased from ( . ± . kg/m ) to ( . ± . ) (p = . ). in , % of the clinic population was taking pert with a mean dose of ± iu lipase/kg/day. the proportion of patients with abnormal glucose tolerance has increased from % to % (p = . ). oral supplement use has increased from % to %, yet enteral feeding remained stable ( % − , % − ). this occurred during period of increased annual dietetic review of the patients attending the clinic from % in to % in (p = . ). discussion over a -year period, an improvement in mean bmi refl ects improvement in nutritional status. prevalence of abnormal glucose tolerance has increased; this is likely due to commencing a screening program ( ). use of oral supplements has increased and is higher than identifi ed in the recent daa survey of nutrition practices of cf dietitians ( %). annual review by the cf dietitian has increased despite a twofold increase in the cf population may be attributable to a stable and experienced workforce. current service provision of . a abbott , e cheung , l morgan aim to characterize the microbial colonization of a group of stable adults with non-cf bronchiectasis using an extended culture protocol. methods sputum was collected over an -month period from clinically stable patients. standard semi-quantitative bacterial culture was extended to days with the addition of fungal and mycobacterial culture as routine. results specimens of spontaneously expectorated sputum were collected from patients; mean age years ( - years); mean (sd) fev / fvc ratio % ( %); / never smokers; / on inhaled or oral corticosteroids. the bacteria identifi ed were p. aeruginosa ( % of specimens), h. infl uenzae ( %), h. parainfl uenzae ( %), acinetobacter baumanii ( %), enterobacteriaceae ( %). commensals only were identifi ed in % of specimens. fungi included candida species ( %), aspergillus fumigatus ( %) and penicillium species ( %). non-tuberculous mycobacteria (ntmb) were grown in % of specimens: m. gordonae ( %), m. intracellulare ( %) and m. lentifl avum ( %). the ntm identifi ed were all considered non-pathogenic. only the mycobacteria were identifi ed after day . conclusion microorganisms with potential pathogenicity are frequently identifi ed in adult patients with non-cystic fi brosis bronchiectasis who are not experiencing an acute exacerbation. all these organisms were identifi ed using a standard short culture protocol. the extended regimen, which was costly, did not identify any unusual or unexpected pathogens. it was rare for patients to be colonized with fungi. this study suggests there is limited value in requesting extended culture for bacterial pathogens, including looking for fungi or nmtb in this stable patient group as this adds little to the empiric antibiotic choice for infective exacerbations. confl ict of interest none. s stelzer-braid , , h alsubie , a neilsen , h johal , a steller , er tovey , k mckay , p van asperen , wd rawlinson , introduction respiratory infections are of fundamental importance in determining the morbidity and mortality associated with cystic fi brosis (cf) as such infections can lead to progressive and fatal obstructive lung disease. using polymerase chain reaction (pcr) to detect such infections has advantages over previous studies that used relatively insensitive traditional detection methods and could have underestimated viral prevalence. methods viral and bacterial multiplex pcrs were developed for detection of respiratory pathogens important for children with cf. nasal brush samples were collected from cf patients who were symptomatic or asymptomatic for acute respiratory illness (n = ). sputum and exhaled bioaerosols via a novel mask sampler were collected from a subset (n = ). results as expected, almost all ( %) sputum samples were positive for bacteria. detection of bacteria in the upper respiratory tract was lower ( . %). data from nasal samples indicated strong association of viral pathogen presence, particularly rhinovirus, with exacerbation of disease. results also showed good evidence for rhinovirus infection in the lower respiratory tract. the novel mask sampler is promising as a non-invasive sampling tool. conclusions our results demonstrate the importance of pathogens in exacerbations. early detection and understanding the development of bacterial and viral infections in cf patients is important in clinical decision-making as more and better antiviral and antibiotic agents become available. aim to determine the factors affecting microbiological yield from bronchoalveolar lavage (bal) in patients with suspected pulmonary infection and haematological malignancy or following stem cell transplantation at a tertiary bone marrow transplant centre. methods a retrospective -month audit of patients with pulmonary infi ltrates or febrile neutropenia with haematological malignancy or post-stem cell transplant who underwent bal for microbiological diagnosis. data were obtained on microbiological yield, radiographic appearances, current antimicrobial therapy, the presence and duration of neutropenia and complication rate. of the bal procedures performed, a clinically signifi cant microbiological result was obtained in % of cases ( / ). of these positive results, % ( / ) were exclusively viral pathogens, % ( / ) were fungal, % ( / ) were bacterial and polymicrobial infection was observed in % ( / ) of cases. a high proportion of patients had commenced anti-microbial treatment empirically, with % ( / ) receiving broad spectrum antibacterial treatment and % ( / ) receiving treatment doses of antifungal agents prior to bronchoscopy. in % ( / ), the results of the bal changed the patients therapy. the presence and duration of neutropenia or radiological appearances were not reliable discriminators of specifi c infective aetiologies. complication rates were low and included fevers in % ( / ), hypoxia % ( / ), small volume haemoptysis in % ( / ), atrial fi brillation in % ( / ) and pneumothorax in % ( / ). conclusion whilst bal remains a safe and important tool in establishing a microbiological diagnosis in immunosuppressed patients with pulmonary infi ltrates, a clinically signifi cant yield and changes to patient treatment occur in the minority of cases. clinicians should have a high degree of suspicion of viral infective aetiology when treating this population of patients. aim to examine the outcomes and complications of intercostal catheter (icc) treatment of pneumothoraces (primary (pp) and secondary (sp)) and effusions (malignant (me) and parapneumonic (pe)). methods retrospective review of all iccs in admitted patients in a respiratory unit over months. data collected included type of pneumothorax or effusion, icc type, insertion details, complications (major and minor) and outcome (success defi ned as resolution of pneumothorax or effusion with single tube insertion). results patients required icc treatment. forty-six iccs were used in patients with pneumothorax: pp ; sp ; iatrogenic ; hydropneumothorax . complication rate was % ( % major) and was signifi cantly less in pp ( %) compared with sp ( %), p < . , chi-square. success rate for pneumothorax icc drainage was % (signifi cantly higher for pp ( %) compared with sp ( %), p < . ). fifty-eight iccs were used in patients with pleural effusions: me , pe , other . complication rate was % ( % major) and was signifi cantly higher in me ( %) compared with pe ( %), p < . . success rate for effusion icc drainage was % (signifi cantly less in me ( %) compared with pe ( %), p < . ). small bore iccs (gauge < fr) were used for % of pneumothoraces and % of effusions. tube size did not signifi cantly infl uence complication or success rate for either pneumothoraces or effusions. conclusions compared with pp, icc treatment of sp was less successful and more likely to be associated with complications. similarly, compared with pe, intervention for me with icc was less successful and had a higher complication rate. we conclude that icc intervention is most successful for pp and pe, and speculate that sp and me should have early surgical intervention. introduction spontaneous pneumothorax is a common condition. current management guidelines recommend large pneumothoraces are managed by primary intercostal catheter insertion. we report a single centre's experience in the management of large spontaneous pneumothorax. methods retrospective audit of cases of spontaneous pneumothoraces managed at the prince charles hospital between january and december . patient demographics, co-morbidities, presenting symptoms, examination fi ndings, radiology, management and complications were reviewed. results forty-two patients ( male, female) experienced episodes of spontaneous pneumothorax. chest pain and dyspnoea were the most commonly reported symptoms ( ) %. there were forty-two ( %) episodes of large pneumothorax (≥ % of hemithorax). management of large pneumothoraces consisted of: observation, ( ) seldinger icc ( ) and large bore icc ( ). complications occurred in three patients with seldinger icc ( vasovagal, hydro-pneumothorax) compared to none with large bore icc. outcomes were similar for patients managed by observation compared to icc insertion. all recurrent cases ( %) were referred for consideration of surgical pleurodesis. conclusion patients with large pneumothorax managed by observation recovered similarly to those treated with icc, suggesting a higher threshold for icc insertion should be considered in the future. grant support nil. aim a pilot study of an instrument of pleural ultrasound training in thoracic physicians after a pleural ultrasound course. the instrument was tested for inter-observer agreement and also its ability to be used in a patient compared to a dedicated manikin. methods all chest physicians ( ) were novices in ultrasound and underwent a dedicated -day training course in pleural ultrasound at the australian institute of ultrasound. they were assessed months later by radiologists and one senior ultrasonographer using a specially designed pleural ultrasound training assessment tool (usgt-sat) on both a subject with pleural effusion and a dedicated ultrasound manikin. the mean scores, out of a maximum of , obtained by the each of the participants for the manikin were . , . , . and . , respectively, while the scores for the patient was . , . , . and . , respectively. the mean scores of the participants as a group for manikin were ± . and for the patient as . ± . . there was general agreement between the examiners with mean combined participant scores of . , . and . in the manikin, respectively, and mean score of . , . and . in the patient. conclusions this pilot study shows ranges of scores for design of future validation studies of the usgt-sat. test performance by the chest physicians after a short course in pleural ultrasound was generally good and results for the use of the manikin as an alternative to patients in pleural ultrasound training are encouraging. further studies with larger sample size are required. supported by nil. nomination nil. confl ict of interest no. since the fi rst commercial availability in , fl exible bronchoscopy has evolved from a simple 'look see' procedure to a more complex multifaceted one. today, fl exible bronchoscopy is a tool used for diagnostic procedures, surveillance, delivery of therapy and clinical trials. increasingly, it involves utilizing expensive purpose built equipment in complex diagnostic procedures. this evolution requires a specifi c knowledge base and skill set to safely perform the procedure and care for the equipment. this now mandates additional training by nursing and medical staff to develop and maintain the required skills. medical staff now rely on their nurses to assist in the full range of procedures. thus, the nurses must keep abreast of modern trends and techniques. the modern bronchoscopy suites team is an integrated one, with specifi c roles, defi ned to each member. the procedures performed will refl ect local needs and expertise. just as bronchoscopy has evolved into the speciality of interventional pulmonology, so must bronchoscopy suite nursing be accepted as a specialized area of nursing with a credentialed 'special interest group' to promote, educate and develop the subject as more therapeutic and diagnostic procedures evolve. this will allow nurses involved in bronchoscopy to be respected, recognized and accepted for their unique knowledge and abilities. confl ict of interest nil. background transthoracic pneumostomy (tp) is a novel treatment for patients with severe emphysema that aims to defl ate the lung and improve function. aim to assess the effect of unilateral tp on the volume of each lung and mechanical properties of the lungs. methods subjects were recruited for a multicentre trial of tp (see actrn ). in parallel with the main protocol, we measured ( ) in the six subjects recruited, compared to plethysmography, lung volume was overestimated by cxr (mean difference + . %, range − . to + . ) and underestimated but more closely correlated by ct (mean difference − . %, range − . to − . ). based on ct, the volume of the treated lung decreased in all patients after tp (mean − . %, range − . to − . ) whilst that of the untreated lung did not change (mean − . %, range − . to + . ). in patients with available data, tp reduced dynamic hyperinfl ation during exercise (mean − ml, − . % of ic, range + . % to − . %). lung mechanics were performed in patients. low lung elastic recoil prior to tp and an increase in elastic recoil after tp were associated with greater reductions in lung volume and greater improvements in exercise tolerance. conclusions supine chest ct provided reasonably accurate estimates of plethysmographic lung volume. unilateral tp defl ated the lung and there was no evidence of signifi cant compensatory hyperinfl ation of the contralateral lung. tp also reduced dynamic hyperinfl ation. measurement of lung elastic recoil may help select patients who are likely to benefi t from tp. support and confl ict of interest nil. methods we performed a retrospective chart review of all adult patients who had an icc over a -month period within a tertiary hospital respiratory service. we noted patient demographics, details surrounding chest drain insertion including image guidance and subsequent inpatient events. results over a -month period, there were small-bore icc insertions, of which were image-guided. mean patient age was years, males comprised / . forty drains were inserted for pneumothoraces, for malignant effusions, for parapneumonic effusions, for transudates and for undiagnosed exudative effusions. mean duration of drainage was . days. there were no life-threatening complications. three of the chest drains fell out and became blocked. six pneumothoraces were noted, all following insertion without direct image guidance; none required further intervention. local infection occurred in patient. insertion details were not documented in patients. conclusion insertion of small-bore iccs via the seldinger technique appears to be a safe method of draining pneumothoraces and pleural effusions. image guidance may reduce complication rate of this procedure. documentation of drain insertions could be improved. confl ict of interest nil. rationale pleural effusions are frequently encountered in clinical practice, and often require aspiration for diagnostic and/or therapeutic purposes. use of radiological guidance varies, despite current guidelines recommending routine use of ultrasound. furthermore, concerns exist regarding the downskilling of thoracic medicine trainees due to the increased use of interventional radiology. as a precursor to developing a procedural pleural ultrasound service, we performed a retrospective case review of our current practice. methods patients who had pleural fl uid sent to pathology between january and december were identifi ed on an existing database. patient records were reviewed and details regarding the drainage procedure and outcomes were recorded. information on patient location, method of procedure and performing clinician were also collected. results to date, pleural fl uid aspirations in patients have been identifi ed. overall, % of aspirations were carried out on the ward and % in the radiology department. two procedures occurred in the endoscopy suite on outpatients, and one in the emergency department. fifty percent of procedures were performed using an intravenous cannula for drainage and % utilized a pigtail catheter. all procedures occurring in the radiology department were performed under ultrasound guidance by a radiologist or radiology registrar. of the remaining procedures, % were performed by medical registrars and % were performed with ultrasound marking. six complications occurred following procedures: pneumothoraces, vasovagal and tube blockage. there were signifi cantly more pneumothoraces in patients who did not have an ultrasound marking ( of without marking, of with marking, p = . ). none of the complications required further intervention. conclusion these preliminary data suggest ultrasound marking signifi cantly reduces pneumothorax incidence, supporting the establishment of a pleural ultrasound service. this is likely to have the added benefi t of improved training for thoracic medicine trainees. aim to investigate differences between semi-recumbent and supine posture in terms of cough rate, degree of oxygen desaturation, oxygen supplementation, increase in pulse rate and sedative use during the initial phase of bronchoscopy. methods consecutive patients (n = ) undergoing diagnostic bronchoscopy at an endoscopy unit were recruited for this observational cohort study. the posture was determined by the bronchoscopist's usual practice. patient age, gender, % predicted fev and fvc, indication, pulse and oxygen saturation were recorded. the initial phase was defi ned as the time from bronchoscopy insertion to visualization plus lignocaine instillation of both distal main bronchi. cough rate, peak pulse, nadir oxygen saturation (spo ), range of oxygen supplementation and sedation use during the initial phase were recorded. a post-procedure questionnaire was administered to the patient and the attending nurse. results patients had bronchoscopy in the semi-recumbent posture and in the supine posture. three of bronchoscopists performed in both postures. there were no signifi cant differences in age, gender, smoking status and spirometry between the two groups. the semi-recumbent postures resulted in signifi cantly less cough rate (mean (sd) . ( . ) vs. . ( . ) coughs/min, p = . ) and less fentanyl use ( ( ) vs. ( ) mcg, p = . ) in the initial phase. there were no signifi cant differences in the nadir spo , fall in spo , oxygen supplementation or increase in pulse rate between the two groups. nurse perception of patient discomfort was lower in the semirecumbent position ( ( ) vs. ( ) mm on mm visual analogue scale, p = . ), and there was a trend towards less patient-perceived cough during the procedure in the semi-recumbent group ( ( ) introduction pulmonary infi ltrates in immunocompromised patients with haematological malignancy have a diverse aetiology and are a major source of morbidity. a specifi c diagnosis and targeted therapy may optimize outcomes and reduce the cost of treatment. the diagnostic value of fi breoptic bronchoscopy (fob) and the infl uence of timing of the procedure are unclear. aim to determine the yield of fob, its impact on antibiotic therapy and the infl uence of early vs late timing in this patient population. methods we conducted a retrospective review of immunosuppressed patients with underlying haematological malignancy and new pulmonary infi ltrates who underwent fob over a -month period. the outcomes of early (eb, ≤ days from initial respiratory consultation) and late (lb, ≥ days) fob were compared using fisher's exact test. results thirty-eight fobs, including bronchial or transbronchial biopsies, were performed in patients (males ). there were patients who received eb and who received lb. a specifi c diagnosis was obtained from procedures ( %), including infections ( in eb vs. in lb, p = . ) and non-infective diagnoses ( eb vs. lb, p = . ) based on histology. fob fi ndings from procedures ( %) ( eb vs. lb, p = . ) resulted in modifi cation of antibiotic therapy. there were no procedure-related severe complications. conclusions fob is a useful diagnostic procedure which infl uences diagnostic and therapeutic decisions in this patient group. although early procedures tended to be more likely to change antibiotic therapy than late procedures, the difference was not signifi cant. confl ict of interest none. capsule endoscopy is increasingly performed in gastroenterology to investigate possible small intestinal bleeding. the capsule endoscope is swallowed and then takes photographs every seconds for hours during its transit through the gastrointestinal tract. the images are downloaded by a radio link and the capsule is then passed normally and disposed of. in the present case, the capsule endoscope was inhaled and lodged in the bronchus intermedius. this was only recognized when the images from the capsule download were examined. removal of the capsule was effected with a fi breoptic bronchoscope using an ercp balloon and roth basket. this is believed the only capsule bronchoscopy so far reported. capsule endoscopes are large ( mm × mm diameter) and smooth. this case report shows the images from the capsule endoscope and describes the methods necessary to remove this unusual foreign body from the lung. support nil. background bronchoscopy with endobronchial biopsy (eb) is now an integral component of the research evaluation of airway diseases. there are no published safety data for eb in adult non-cf bronchiectasis. methods a subgroup of subjects enrolled in the bronchiectasis and low dose erythromycin study (bless) a randomized controlled trial of long-term prophylactic erythromycin (anzctrn ) underwent bronchoscopy with bronchoalveolar lavage (bal) and eb performed by a single operator. results ninety-nine bronchoscopies were performed (bal alone in ) in subjects. of procedures with eb, ( . %) were associated with very signifi cant bleeding (> ml either at time of eb or several days post-procedure) and a further ( . %) with immediate moderate bleeding ( - ml). one subject had a history of prior signifi cant haemoptysis. in the four subjects with very signifi cant bleeding, immediate bleeding of > ml occurred in subjects, ml in one subject and ml in one. immediate bleeding was controlled uneventfully. three of the subjects subsequently developed signifi cant haemoptysis (> ml) to days post-bronchoscopy without intervening haemoptysis, with one subject developing massive haemoptysis (> ml) on day post-bronchoscopy. further research ebs were ceased. in one of the subjects with 'delayed rebleeding', repeat bronchoscopy confi rmed the biopsied lobe as the bleeding site. haemoptysis settled in all subjects within hours with simple conservative measures. conclusions in contrast to the experience in asthma and copd, research eb in adults with non-cf bronchiectasis is associated with a signifi cant risk of bleeding, of potentially life-threatening magnitude in . % of cases. of particular concern was the observation of sudden onset delayed rebleeding developing up to days post-eb in spite of early local control. histopathological evaluation will clarify the potential contributions of airway wall vascularity and infl ammation to these events. malignant mesothelioma (mm) is an aggressive cancer which is often associated with exposure to asbestos and sv . this disease has a high latency period and a low survival rate. therefore, new strategies for therapeutic intervention must be developed. recent studies have shown that developmental pathways including the hedgehog (hh) pathway are associated with various types of cancers. the aberrant activation of key hedgehog pathway proteins has been shown to contribute to cancer progression. however, the role of this pathway in mm has yet to be explored. we hypothesize that aberrant activation of the hh pathway is a contributing factor for the development of mm. the mrna expression of hh pathway genes; sonic hedgehog (shh), patched - (ptch- ), smoothened (smo) and gli- were examined in mm cell lines and tumour tissues by rt-pcr and qrt-pcr. hh pathway proteins and mrna expression and distribution were then observed in the tumours by immunochistochemistry and in situ hybridization. we used real-time superarrays to examine the change in expression of a panel of key hh pathway genes by activating and inhibiting the pathway. we showed that the key hh pathway genes are expressed in both the cell lines and tissue samples. upon stimulation with the ligand shh, there was an increase in expression of indian hedgehog (ihh) and shh in most of the mouse and human cell lines that we looked at. interestingly, for the transcription factor gli- , there was a significant decrease in both mouse and human cell lines. inhibiting this pathway increased the expression of ptch in the mouse and human cell lines. the expression and up-regulation of key hh pathway components in mm at baseline and following stimulation suggests a role for the pathway in mm. methods incident cases were obtained from the australian and wa mesothelioma and cancer registries and death registries. exposure was calculated using measures of dustiness in the industry and the town for the period of employment or residence of each case. latency (time from fi rst exposure to diagnosis) by sex, age, smoking status, exposure variables and worker or resident status was estimated. multivariate linear regression modelling examined the determinants of latency. results the mean latency periods of . (sd = . ) years for lc and . (sd = . ) years for mm have increased linearly. increased duration of exposure was associated with reduced latency for mm after adjustment for age at fi rst exposure and age at diagnosis but not signifi cantly for lc. age at diagnosis was strongly associated with latency length for both lc and mm (p < . ). smoking, sex, cumulative exposure (log f/ml-year) and status at wittenoom were not related to latency. latency for lc with increasing age at fi rst exposure declined faster than for mm. conclusions age at diagnosis is associated with reduced shorter latency of mm and lc. duration of exposure is associated with shorter latency of mm. supported by nhmrc australia. confl ict of interest no. aim to assess overall survival of patients following resection for stage nsclc at a centre that has substantially greater resection rates than the nsw average. methods a retrospective audit of those patients who underwent lung resection for stage nsclc at nepean hospital between january and february . results patients ( m: f), mean age (range - ) underwent resection. there were pneumonectomies, bilobectomies and segmentectomies, one involving chest wall resection. the remaining procedures were lobectomies. there was one perioperative death from respiratory failure. actuarial overall survival at months was %, at months, % and at years %. survival was not infl uenced by histology or age. conclusion in our institution, we have an agreed aggressive approach to resection of stage nsclc and our resection rate is %. this pro-surgical policy is associated with good perioperative and long-term overall survival. confl ict of interest no. introduction malignant pleural effusions (mpes) are common, although their management varies widely. providing ambulatory care to minimize hospitalization is a key goal for patients with mpes. indwelling pleural catheters (ipcs) are a new treatment strategy that allows outpatient fl uid drainage. we hypothesized that mpe patients managed with ipcs require fewer hospital admissions. methods a prospective, multicentre, non-randomized study involving all three major respiratory centres in western australia. patients diagnosed to have mpes were prospectively followed, and admissions were recorded. in the absence of accepted guidelines for ipc use, the choice of treatments (thoracentesis, ipc, pleurodesis) was decided by clinicians in-charge. all complications were recorded. bacterial cultures of pleural fl uid were performed monthly for patients with ipcs. hm gallagher , ee duhig , ia yang , rv bowman , be clark , hm marshall , km fong aim to determine the concordance of histological subtyping of nsclc in diagnostic samples to the gold-standard lung resection specimens. methods we have so far evaluated consecutive subjects who underwent curative surgery for primary nsclc at the prince charles hospital between the years and . many of these had workup at other institutions. one hundred forty-seven had queensland health electronic record of positive preoperative diagnostic sampling. we correlated the fi nal nsclc who histological subtype with the subtypes diagnosed by samples prior to surgery including sputum, fi beroptic bronchoscopy (fob) and trans-thoracic needle aspiration (ttna). the resection subtype was set as the reference standard, and concordance was compared. results of the cases of resected nsclc, had malignancy on diagnostic sampling pre-resection, as shown in the results patients were included: median age years (range - ); % male; % living in major cities versus % in regional areas; % rightsided mpm; % epithelial subtype. median time from asbestos exposure to diagnosis was years (range - ). median time from fi rst symptoms or investigations to diagnosis was weeks (range - ). all patients had at least one chest x-ray and ct scan and % had pet scan. a variety of procedures led to the diagnosis: % thoracoscopy, % thoracotomy, % radiology-guided, % chest wall biopsy and % medical pleuroscopy, with % having had cytology alone. median number of diagnostic immunohistochemical stains used was (range - ), with calretinin ( %) the most commonly used mesothelial marker and carcinoembryonic antigen (cea; %) the most common carcinoma marker. median os for the cohort was . months ( % ci: . - . ), with no statistical difference in os between major city and regional patients ( vs. . months, respectively, p = . ). conclusions mpm appeared to affect mainly the elderly, and thoracoscopy was the most common diagnostic procedure. os did not differ between australian major city and regional patients and was comparable to the largest phase iii trial in mpm. aw musk , , p aboagye-scarfo , a reid , a miller, s ruwanpura, l mcleod, p bardin, n watkins, bj jenkins rationale lung cancer is the leading cause of cancer death worldwide. it is well established that cigarette smoking is linked to emphysema and lung cancer, and smokers with emphysema are at an increased risk of developing lung cancer. notably, recent epidemiological studies have indicated that emphysema can predispose to lung cancer irrespective of pack-year smoking history. although infl ammation has been proposed as a common mechanism linking these two diametrically opposed diseases, the conceptual inter-relationship between infl ammation, emphysema and lung cancer has been poorly investigated because existing experimentally induced and genetically modifi ed animal models for lung cancer occur in the absence of emphysema. method we have utilized a newly identifi ed mouse model (gp f/f ) of spontaneous lung infl ammation and emphysema in two well-established lung cancer models. the gp f/f mouse is characterized by deregulated cytokine signalling via gp , the critical co-receptor for the interleukin (il)- cytokine family, leading to hyper-activation of stat , a potent pro-infl ammatory and oncogenic latent transcription factor. in separate studies, we exposed gp f/f mice to a cigarette-derived carcinogen (nnk), and crossed them with the genetically susceptible kras(g d) strain of mice. results in both nnk-and kras(g d)-induced lung cancer models, the lungs of gp f/f mice were highly predisposed to hyperplasia and tumour formation. increased levels of cellular proliferation were observed in hyperplastic and tumour lesions, as well as surrounding areas, of these mice. these observations were verifi ed at the molecular level by gene expression profi ling of tumour-bearing lung tissue. conclusions these studies provide unique insights into the importance of interactions between the gp signalling axis and factors that predispose to lung tumourigenesis in emphysema. support nhmrc. aim to assess the preparedness of hospitals with respect to protecting health-care workers (hcws) during a pandemic. methods a self-administered questionnaire was performed between november and january , and a scoring system was developed to provide a quantifi able measure of preparedness. results a total of hospitals in nsw, australia, were approached -six regional hospitals (rhs) and six tertiary referral centres (trcs). the study was extended to assess three hospitals in england, allowing a limited comparison between the hospitals in australia that had faced the initial wave of the h n ('swine fl u') pandemic and the hospitals in the uk that had more time to prepare for the outbreak. response rates were % from the trcs, % from the rhs and % from the english hospitals. the overall preparedness scores were relatively high, with a median total score (adjusted) of . out of . the demographic that scored the highest total was tertiary referral centres in sydney. all english hospitals scored below the median. however, the range of scores across hospitals was quite narrow ( . - . adjusted). scores were generally high for the areas of preparedness, infection control, education and training. scores for vaccination were more variable. the category that consistently demonstrated the lowest scores was that of psychosocial welfare and assistance, despite this found in previous research to be an integral part of that which hcws have identifi ed as important. conclusions given their integral role in pandemic response, protecting hcws must be a priority as part of any pandemic preparedness plan. this goes beyond protection from infection, extending into aspects of physical and psychological wellbeing. identifying these issues and addressing them is the key to maximizing staff support and morale, and minimizing staff absenteeism at such a crucial time. aim to describe the relationship of respiratory and refl ux symptoms within the general population and relate this to the possible confounding factors of body mass index (bmi) and obstructive sleep apnoea (osa). methods data from a cross-sectional health survey, performed in bussleton, west australia in - , were used to examine the relative effects of bmi and osa on the relationship between respiratory and refl ux symptoms. questionnaire data included information on asthma, cough, wheeze, dyspnoea and gord symptoms. gord symptoms were categorized as never, monthly or less often and weekly or more often. bmi, risk of osa defi ned according to the berlin questionnaire, spirometry and airway hyperresponsiveness to methacholine were also recorded. logistic regression models obtained odds ratios for the associations between each gord symptoms, various respiratory symptoms, bmi and osa. results average age was years and recent wheeze was reported in % and cough and phlegm in %. twelve percent were current smokers. ahr was present in % and osa in %. gord symptoms occured in % and frequent symptoms (weekly or more often) were present in - %. there were strong positive associations between gord symptoms and cough/phlegm, breathlessness, chest tightness and wheeze in the last months. odds ratios increased with increasing frequency of refl ux p ≤ . . there was no effect of obesity or osa on the relationship between respiratory and gord. conclusion cough and phlegm, breathlessness, chest tightness and wheeze (ever or recent) are all strongly associated with symptoms of gord. this relationship is amplifi ed with increasing frequency of gord symptoms indicating a dose-response relationship between refl ux and respiratory symptoms. obesity and osa do not affect the association between gord and respiratory symptoms. introduction diesel exhaust particles (dep) make up the bulk of particulate matter in urban areas. high ambient levels of particulate matter are associated with increased hospitalization due to respiratory disease. we aimed to determine if exposure to dep exacerbates responses to acute viral infection. methods adult female balb/c mice were inoculated with μg dep or control . days after infection with . plaque forming units (pfu) of infl uenza a/mem (or control). six hours after dep inoculation, lung volume (tgv) and lung mechanics were measured by plethysmography and the forced oscillation technique, respectively. bronchoalveolar lavage fl uid was collected to assess cellular infl ammation and cytokine levels. results viral titre was signifi cantly higher in infl uenza-infected mice exposed to dep compared to those exposed to infl uenza alone (p = . ). both dep (p = . ) and infl uenza infection (p < . ) alone signifi cantly increased cellular infl ammation; however, there was no difference between mice exposed to both dep and infl uenza compared to those exposed to infl uenza alone (p = . ). a similar pattern was found in levels of cytokines in the bronchoalveolar lavage (tnf-α, mcp- , il- , ifn-γ). specifi c airway resistance, specifi c tissue damping, specifi c tissue elastance and hysteresivity were signifi cantly increased in infl uenza infected mice (p < . in all cases). none of these parameters were infl uenced by dep exposure alone (p > . in all cases) and there was no additive effect of dep on lung function (p > . in all cases) in infl uenza-infected mice. conclusions dep increases viral titre but is not suffi cient to physiologically exacerbate pre-existing respiratory disease caused by infl uenza infection in mice. supported by nhmrc. confl ict of interest no. introduction lack of treatments for post-transplant obliterative bronchiolitis (ob) is mainly due to the poor understanding of its pathogenesis and lack of small airway models. epithelial-mesenchymal transition (emt) may play a central role and could be crucial to developing treatment drugs. we hypothesize that emt induction may be prevented by pharmacologically available compounds. methods primary cultures of small and large airway epithelial cells (saec and laec) were established and emt induced by adding tgfβ ( ng/ml) (n = ). azithromycin ( - μm), mycophenolate ( . - mg/l) and rad ( . - ng/l) were then added and expression of epithelial (zo- , ck- ) and mesenchymal markers (eda-fn, vim) measured via western blot as well as mmp and activity via zymography. results signifi cantly lower increase in mesenchymal markers and lower decrease in epithelial markers, compared to controls was noted for azithromycin and mycophenolate indicating suppression of emt. mmp and activity increase was also signifi cantly suppressed. azithromycin suppressed emt to a greater extent compared to mycophenolate, but was equally effective in both small and large airway epithelia. rad appeared to have no effect. conclusions azithromycin and mycophenolate are both effective in preventing emt and thus have potential for the clinical treatment of ob. supported by abn foundation. confl ict of interest none. journal compilation © asian pacifi c society of respirology tp- g hodge , , s hodge , , c-l liew , , t-cell pro-infl ammatory cytokines are associated with acute lung transplant rejection. we have previously shown compartmentalization of production of these cytokines in bronchial intraepithelial t cells (iet) obtained by bronchial brushings from stable lung transplant patients. during acute rejection episodes, no signifi cant differences in iet cytokines were observed between stable and rejecting patients due to broad cytokine variability between patient groups. to overcome this limitation, we hypothesized that there would be increased graft pro-infl ammatory iet cytokines compared with native lung or trachea during acute rejection. methods cell cultures from stable patients, patients with evidence of acute rejection and bos and healthy controls were stimulated and intracellular cytokines determined using multiparameter fl ow cytometry. results there was a signifi cant increase in graft iet-cell ifnγ and tnfα in the lungs of patients with acute rejection compared with iet cells obtained from the native lung or trachea, but no changes were noted between other patient groups. there was a signifi cant correlation between increased graft iet-cell tnfα compared with trachea and lungs and acute rejection grade. conclusions differential expression of pro-infl ammatory cytokines by iet cells from graft, trachea or native lung distinguishes severity of acute rejection. improved monitoring response using this assay or therapeutic targeting of these pro-infl ammatory cytokines may reduce acute lung transplant rejection. supported by nhmrc. aim to determine the prevalence of reduced carbon monoxide transfer factor (dlco ≤ % predicted) in subjects undergoing pulmonary function testing (pfts) and to determine whether a cause has been identifi ed. methods a clinical audit of all subjects undergoing pfts at royal melbourne hospital from august to august who have a dlco ≤ % in the setting of normal spirometry. medical records and investigations including transthoracic echocardiogram (tte), high-resolution commuted tomography (hrct), ventilation/perfusion (v/q) scans were reviewed to determine whether a cause for the reduced dlco was established. where a cause was not clear, subjects were invited to participate in a telephone interview to evaluate symptoms and to undergo repeat pfts. subjects with a persistently reduced dlco were invited to undergo further investigation with tte, hrct and v/q scan. preliminary results pft results from subjects were reviewed. subjects with fev /fvc < , fev < % predicted and fvc < % predicted were excluded. three hundred seventy subjects ( %) had an isolated reduction in dlco. / ( %) of these subjects underwent tte with / ( %) demonstrating an elevated right ventricular systolic pressure (rvsp). in all cases where there was an elevated rvsp an identifi able cause was found. / ( %) of these subjects subsequently identifi ed as having pulmonary arterial hypertension (pah) and commenced appropriate therapy and / ( %) identifi ed as having pah where treatment was not commenced. there were / ( %) of subjects who appeared not to have undergone a tte. further evaluation of medical records of subjects who had not undergone tte and those with normal tte is continuing. review of subjects hrct, v/q scans and right heart catheterizations is currently proceeding. conclusions preliminary results suggest that a signifi cant proportion of subjects with isolated reduction of dlco on pfts do not undergo tte which is an important investigation in determining the cause for the reduced dlco. when a tte is performed and demonstrates an elevated rvsp, a cause for the elevated rvsp is identifi ed. sponsor actelion pharmaceuticals australia pty ltd. g hodge , , s hodge , , c-l liew , , , pn reynolds , , m holmes , , background t-cell pro-infl ammatory mediators are associated with acute lung transplant rejection. we have previously shown that bos was associated with lack of immunosuppression of t-cell pro-infl ammatory cytokines and increased t-cell granzyme b in peripheral blood. recently, we also showed that nkt-like cells are a major source of pro-infl ammatory cytokines and granzymes in the blood of stable lung transplant patients. we hypothesized that bos may be associated with lack of immunosuppression of these proinfl ammatory mediators in blood nk and nkt-like cells. method granzyme/perforin profi les from stable patients, patients with evidence of bos and healthy controls were determined and blood cultures stimulated and intracellular cytokines determined using multiparameter fl ow cytometry. results there was a signifi cant increase in the percentage of nk cells expressing granzymes and perforin in bos patients compared with stable patients and controls. there was an increase in the percentage of t, nk and nkt-like cells producing ifnγ and tnfα in bos compared with stable patients. there was a signifi cant correlation between increased nk ifnγ and tnfα and fev . conclusions bos is associated with increased peripheral blood nkt-like and nk cell granzymes, perforin and th pro-infl ammatory cytokines. therapeutic targeting of these pro-infl ammatory mediators and monitoring response using this assay may reduce bos. supported by nhmrc. confl ict of interest nil. rationale pulmonary embolism (pe) is the leading cause of maternal mortality in the developed world. consequently accurate diagnosis of pe is critical. this must be tempered by the potential radiation risk of investigations to the mother and foetus. we performed a retrospective case review to determine the incidence of pe in pregnant patients investigated for this condition. demographic information, the diagnostic algorithm utilized and the diagnostic yield of investigations were obtained. method pregnant women who underwent ventilation perfusion (vq) scanning or computed tomography pulmonary angiogram (ctpa) at our institution between january and january were identifi ed by an internal database audit. in addition to demographic data, information about the diagnostic pathway and fi nal diagnosis were collected. in cases where pe was not diagnosed, the medical records were reviewed for any subsequent events up until the date of delivery. results during the fi ve-year period, vq scans and ctpas were performed on pregnant women. the average gestation at investigation was weeks. only one patient had a previous history of venous thrombo-embolism. % underwent doppler ultrasound of the lower limbs prior to vq or ctpa. overall the incidence of pe was %, diagnosed by vq scan. otherwise the vq scans were normal in %, low probability in % and non-diagnostic in % cases. ctpa was non-diagnostic in % of cases. all other ctpa studies demonstrated no emboli. almost % of scans were done after hours ( % vq and % ctpa). no patients without pe were felt to have had the pe missed up to the time of delivery. conclusions the overall incidence of pe in patients being investigated was extremely low at %. during this study period slightly more vq studies were performed than ctpas, with each test having similar diagnostic rates. only % of patients had undergone venous doppler prior to undergoing radiationexposing investigations. nomination nil. introduction anti-ro- antibodies have been associated with idiopathic interstitial pneumonia (iip) in one small series (n = ). we hypothesize that ro- antibodies, just like myositis antibodies, can serve as a marker of undifferentiated connective tissue disease (ctd) with interstitial pneumonia as the primary phenotypic manifestation. the aim of this study was to examine the characteristics of patients with ro- and iip. methods retrospective study identifying patients with iip and ro- positivity, but negative for ctd and/or myositis antibodies, presenting between june and june . data relating to demographics, diagnosis, pulmonary function tests, length of follow-up and outcome were obtained. all hrct images were reviewed by an independent expert radiologist (dm). results / ro- positive subjects fulfi lled criteria ( male, median age ( - ), european, never smoked). / had ro- titers above and in the intermediate ( - ) range. three patients had raynauds phenomenon; there were no other ctd features. / patients had hrct diagnosis of nsip and / organizing pneumonia; / had extensive fi brosis. mean (sd) % predicted baseline fvc ( ), dlco ( ). median length of follow-up was months. all patients were treated and were considered overall stable at last follow-up, one had declined and one died of respiratory failure. conclusion this study confi rms an association between ro- positivity and interstitial pneumonia in the absence of defi ned connective tissue disease, suggesting an autoimmune basis for the interstitial lung disease in this group of patients. a larger cohort is required to determine the true signifi cance of this observation. background community acquired respiratory viral (carv) infections are believed to contribute to morbidity and mortality after lung transplantation, but previous studies have not conclusively established the evidence base in this area. patients and methods a prospective cohort study was performed at a single centre from august to march (n = lung transplant recipients). carv infection (human metapneumovirus (hmpv), respiratory syncytial virus (rsv), infl uenza a (flu a), infl uenza b (flu b), adenovirus and parainfl uenza virus (piv)) was confi rmed using polymerase chain reaction (pcr) of upper (nasopharangeal swab) and/or lower (bronchoalveolar lavage) respiratory tract secretions. carv infection and bos were included as segmented time-dependent covariates in a cox proportional hazards model with death as the outcome variable. results patients ( % of the total cohort) had a total of separate carv episodes: piv, hmpv, rsv, flu a, flu b, and adenovirus. infection with either rsv or hmpv was associated with an increased risk of death (p < . hr . , % confi dence interval, . - . ), and the effect persisted after multivariate analysis. bos was also a risk factor for acquiring hmpv or rsv infection (p = . or . , % confi dence interval, . - . ). conclusions infections with hmpv and rsv, but not other carvs, are associated with an increased likelihood of death. the presence of bos is a risk factor for symptomatic infection with hmpv and rsv. ns harun , k sanders , a stuart , cl steinfort department of respiratory medicine, barwon health, vic., australia, and department of clinical and biomedical sciences, barwon health, vic., australia aims nebulized colistin is used to treat recurrent exacerbations of bronchiectasis due to pseudomonas aeruginosa, a major pathogen regarded as diffi cult to eradicate. this case-control study aimed to establish if long-term colistin use could clear p. aeruginosa from the sputum of adults with non-cystic fi brosis bronchiectasis, and if so, whether colistin could be ceased in these patients. secondary outcomes included effects of colistin on quality of life (qol), symptom control, admission rates, lung function and tolerability. methods ( ) sputum was collected in bronchiectasis patients with p. aeruginosa. clearance rates in those on colistin were compared with a control group not on colistin. ( ) colistin patients cleared of p. aeruginosa ceased treatment. sputum was re-cultured at day and to detect recurrence. ( ) a questionnaire assessing qol, symptom control, and admission rates was performed on patients. outcomes were compared before and after colistin use. long-term colistin side-effects and lung function were also assessed. results ( ) % (n = / ) of colistin patients cleared p. aeruginosa from sputum compared with % (n = / ) in the controls (p = . ). ( ) % (n = / ) of patients ceasing colistin remained free of p. aeruginosa at day . ( ) there was no difference in frequency of breathlessness, sputum production or qol scores between the groups (p > . ). the colistin group had lower fvc ( . vs. . l, p = . ) and higher admission rates ( % vs. %, p = . ). on colistin, % of patients reported reduction in sputum frequency, breathlessness and improvement in qol. fifty percent reported decreased admission rates. there were no colistin side effects. conclusions clearance of p. aeruginosa in sputum is possible. clearance rates were similar in those with more severe bronchiectasis treated with colistin compared with stable patients not on colistin, and may suggest suppression of p. aeruginosa by colistin in this severe group. there are benefi ts of colistin on qol, symptom control and admission rates. continued sputum clearance after colistin cessation is achievable in some patients. nebulized colistin use is well tolerated. nomination janet elder travel award. confl ict of interest no. however, use of such agents is suboptimal in hospital patients. this study aims to determine whether a dedicated multidisciplinary education and reinforcement program improves the use of appropriate vte prophylaxis. methods prior to the education programme, we audited a bed general thoracic medical ward including patients with general medical conditions, lung cancer, chronic obstructive pulmonary disease, lung transplant and cystic fibrosis. our multidisciplinary research team developed and implemented an education program over months, using posters, leafl ets and oral presentations to increase awareness and promote adherence to vte prophylaxis guidelines for health care staff involved in direct patient management. following completion of the program, we reaudited the same bed ward. results prior to the education program, a total of patients (mean age ± ) were identifi ed as appropriate for vte prophylaxis. of these ( %) were on appropriate vte prophylaxis. the post education audit showed out of ( %) patients were on appropriate vte prophylaxis. (p = . ). conclusion an effective multi-faceted educational program can improve delivery of appropriate vte prophylaxis, leading to improved outcomes in hospitalized patients. supported by sanofi aventis. confl ict of interest nil. the anti-rheumatic anti-infl ammatory biological agents in clinical use are abatacept, anakinra, adalimumab, etanercept, infl iximab and rituximab. a variety of pulmonary side-effects have recently been reported for these agents and the purpose of this review is to compile the various reported pulmonary toxicities and their prevalence methods we performed a search of databases ovid medline® and embase of the english literature up to august using the mesh terms of abatacept, anakinra, rituximab, adalimumab, etanercept, infl iximab and respiratory tract disease with limits to include only human studies or case reports. in addition case reports of respiratory adverse effects reported to the australian drug reaction advisory committee (adrac) were obtained in order to identify the most common pulmonary reactions reported with each individual agent. results using the search criteria defi ned above and articles were identifi ed in the ovid medline and embase database respectively. the majority of adrac reports were associated with rituximab (n = ) and infliximab (n = ), followed by adalimumab (n = ) and etanercept (n = ). various pulmonary side-effects including interstitial lung disease associated with anti-infl ammatory agents were identifi ed. discussion from the articles reviewed, details about the duration between onset of treatment and incidence of pulmonary side effects, diagnosis, treatment options and outcome of patients were extracted and are presented here. conclusion this comprehensive systematic review hopes to improve the awareness about the serious and potentially life-threatening pulmonary sideeffects of this group of agents. confl ict of interest no. sj simpson , pd sly , p franklin , e lombardi , c calogero , m palumbo , gl hall , introduction the forced oscillation technique (fot) is effort independent and thus ideal for young children. the area under the reactance curve (ax) has been proposed to amplify clinically relevant signal by taking advantage of any shape change in the reactance (xrs) curve below the resonant frequency. this study aimed to develop reference values for resistance (rrs), xrs and ax in a large healthy population of children, and determine if ax conferred any additional clinical benefi t when examining disease in children born preterm. methods impedance spectra were obtained in healthy children ( male), aged less than years and with height less than cm using a commercial device (i m, chess medical, belgium). ax was calculated in of these children between hz and the resonant frequency. backwards stepwise linear regressions identifi ed the best predictors of ax, and xrs and rrs at hz (xrs , rrs ), and z scores were generated. z scores were calculated for children born preterm, of which received a neonatal diagnosis of bronchopulmonary dysplasia (bpd). chi squared tests examined the difference in proportion of children born preterm (with and without bpd) with abnormal z scores for each fot variable. results all fot variables were predicted by height (p < . ) and sex. mean (sd) z scores for preterm children with and without bpd for rrs ( . ( . ); . ( . )), xrs ( . ( . ); . ( . )) and ax ( . ( . ); . ( . )) were all signifi cantly different (p < . ) from the healthy population. the number of children born preterm with abnormal z scores was not significantly different when comparing ax, rrs and xrs . conclusions while ax is able to detect respiratory disease in preterm children with and without bpd, it is no more sensitive than xrs or rrs. supported by pmh foundation, nhmrc, asthma foundation wa, carivit, ngo 'solidarietà e servizio' viterbo. confl ict of interest no. introduction survivors of preterm birth born with bronchopulmonary dysplasia (bpd) in the pre-surfactant era of neonatal care (classical bpd) have a reduced pulmonary gas transfer capacity. there is, however, little data to describe gas transfer in preterm infants with bpd in the post-surfactant era (new bpd). objective assess gas transfer using carbon monoxide diffusing capacity (dl co ) and its components, pulmonary capillary blood volume (vc) and pulmonary membrane diffusion (d m ), in contemporary survivors of preterm birth. method gas transfer was assessed using single-breath dl co in children aged to years and born < weeks gestation with bpd (pb, n = ) and without bpd (pt, n = ), and in term born controls (tc, n = ). dl co z scores were calculated. d m and vc were determined in pb, pt and tc children. the mean (sd) dl co z score for the pb group was − . ( . ) differing signifi cantly from (p = . ) while the pt and tc groups ( . ( . ) and − . ( . ), respectively) did not (p > . ). d m was lower in the pb group than the pt and tc groups, with no difference between pt and tc groups. differences in d m were not signifi cant after adjusting for lung size. there were no differences in vc between groups. conclusion gas transfer is reduced in survivors of preterm birth with new bpd. the tendency for reduced d m and not vc in children with new bpd suggests that impaired gas transfer may be a result of alterations in the alveolar membrane rather than pulmonary vascular function. background bronchiectasis is common in indigenous populations such as alaska natives, australian aboriginal, and new zealand maori and pacifi ca. as part of an international collaborative interventional study, we sought the participation of maori and pacifi ca families -groups diffi cult to engage in research in the past. aim to engage, enrol and retain children from maori and pacifi ca families from auckland in a -year research study. methods a randomized controlled trial to determine whether azithromycin is superior to placebo in reducing exacerbations seeking to enrol children aged months to years with bronchiectasis. the enrolment procedure was modifi ed to a process deemed more appropriate to these cultures: ( ) request to defer the decision of enrolment until the process had been completed. ( ) a minimum of meetings; initial invitation, discussion in the home with the extended family, invitation to the extended family to participate in the day of enrolment. ( ) appointment of a 'whanau worker' (family worker) to sit with the family and empower them to get all the information they seek prior to enrolment. results of families approached, ( %) children (median age . years, range . - . years) enrolled with % samoan, % tongan, % maori and % mixed maori/pacifi ca heritage. after -year retention was ( %) with exiting the study after month with new non-pulmonary disease, and exiting after year, moving outside study area. conclusions these are high enrolment and retention fi gures reported in this population. we believe that following a prolonged procedure for enrolment, involving the extended family and appointing a worker to sit 'alongside' the family will improve their understanding of a research project and allow them to feel more comfortable about participating. aim bronchiolitis is the most common reason for hospital admission for infants globally ( ) . the use of macrolides for treating bronchiolitis in nonaffl uent settings remains controversial but potentially benefi cial. in our region readmission with lower respiratory illness in young children (particularly indigenous children) remains high. this rct aims to determine if a single dose of azithromycin reduces the morbidity of young children with bronchiolitis. methods double blinded rct. young children ≤ months admitted to royal darwin hospital (rdh) diagnosed with bronchiolitis are eligible. children are given a single dose ( mg/kg) of either azithromycin/placebo. primary outcome is length of stay for respiratory disease. secondary outcomes are duration of oxygen use and readmission for respiratory illness in -month period. respiratory viral infections often lead to exacerbations of chronic respiratory diseases such as asthma and copd though there is no similar data in noncystic fi brosis (cf) bronchiectasis. the objectives of our study were to ( ) determine the point prevalence and identify viruses associated with exacerbations and ( ) evaluate clinical and investigational differences between viral infection positive and negative exacerbations in children with non-cf bronchiectasis. methods a cohort of children (median age years; boys) with non-cf bronchiectasis was prospectively followed for child-months. polymerase chain reaction for respiratory viruses was performed on nasopharyngeal aspirates collected during paediatric pulmonologist defi ned exacerbations. data on clinical, parent cough-specifi c quality of life (pc-qol), systemic markers (crp, il , procalcitonin, amyloid-a, fi brinogen) and lung function parameters were also collected. results respiratory viruses were detected during ( %) exacerbations: picornavirus in episodes [human-rhinovirus (hrv) in , enterovirus in ]; human bocavirus in ; adenovirus, human meta-pneumovirus, infl uenza a, respiratory syncytial virus, parainfl uenza and in two each; coronavirus and parainfl uenza and in one each. viral co-detections occurred in ( %) exacerbations. among genotyped hrv's, more hrv-a's (n = ) were identifi ed than hrv-c's (n = ). children with proven viral infections were more likely to have fever (or . , % ci . - . ), wheeze and/or crackles (or . , % ci . - . ) and raised crp (or . , % ci . - . ) when compared with virus negative exacerbations. there were no other statistically signifi cant differences. conclusions respiratory viruses are commonly found during pulmonary exacerbations in children with non-cf bronchiectasis. hrv-a is the most frequently detected virus. time sequenced cohort studies during stable state, exacerbations and recovery periods are needed to determine the importance of viral infections and their possible interaction with bacteria. supported by anz trustees scholarship. confl ict of interest none. nominations none. to date children enrolled, % rsv+ve. median age . months. fifty percent have had at least one co-morbidity. readmission rate = %. conclusion co-morbidities are high in this population. antibiotics have the potential to help reduce the impact of additional respiratory burden. foundation. introduction foreign body inhalation is a relatively common presentation in young children, especially less than years of age. early recognition remains a critical factor in the treatment of foreign body inhalation in children. inhaled foreign bodies in children are most often organic material, with seeds and peanuts being the most common items. on review of the literature, there are very few case reports of inhaled metal screws. we report two unusual cases of inhaled metal screws that presented to our service. case presentation both cases presented to our emergency department with wheeze, respiratory distress and fever. foreign body inhalation was not considered as a cause for their symptoms until the object was identifi ed on chest x-ray. both foreign bodies were removed successfully but one child required invasive ventilation in our intensive care unit post removal. both children made a full recovery. interestingly, both metal screws came from fl at pack furniture purchased from a well known international home products store. conclusion foreign body inhalation must always be considered as a cause of respiratory distress in a child. with the increase in the number of fl at pack furniture in australian home's, we believe parents must be warned of the potential danger of loose metal screws to young children. supported by none. cough in children is a common symptom. data on causes of chronic cough in young children have previously been published by our units. however, differences in underlying diagnosis by age at presentation have not been assessed. we present the 'time to cessation' of cough in our multicentre rct using a standardized management algorithm in newly referred children with chronic cough (> weeks) from australian centres. methods parents completed validated cough diary and cough specifi c qol (pc-qol) at recruitment and at cessation of cough. the diagnosis made by the treating physician was based on tsanz position statement. results the median (range) age of the children recruited was . years ( . - . ); ( %) were boys. median (iqr) pc-qol post treatment of . ( . , . ) improved signifi cantly (p = . ) from . ( . , . ) at enrolment. the median (iqr) duration of cough at recruitment was weeks ( . , . ) and 'time to cessation' of cough after application of the management algorithm was weeks ( . , . ). there was no signifi cant difference (p = . ) in median (iqr) 'time to cessation' of cough among the three age cohorts: < years (n = , . %) was . weeks ( . , . ); - years (n = , . %) was weeks ( . , . ); and > years (n = , . %) was weeks ( . , . ). there was also no signifi cant difference in the fi nal primary diagnosis among the three age cohorts (p = . ). the most common diagnoses were protracted bacterial bronchitis (n = , %), asthma/reactive airways disease (n = , . %), tracheobronchomalacia (n = , . %) and bronchiectasis (n = , . %). children ( . %) had more than one diagnosis. conclusions the aetiology and 'time to cessation' of chronic cough in children managed in accordance to a standardized pathway were similar among the three age groups. it is likely that our previous fi ndings in very young children are also applicable to older children. supported by nhmrc grant number . confl ict of interest none. aim to determine the role of fl exible bronchoscopy with bronchial alveolar lavage (bal) in the management of patients with febrile neutropenia. methods a retrospective analysis was made of the number of patients admitted with febrile neutropenia at a single institution who underwent bronchoscopy plus bal from years to . computer database plus patient case notes were reviewed to establish clinical symptoms and signs, radiological fi ndings, antimicrobial treatment and mean duration to bronchoscopy following admission. results a total of episodes of febrile neutropenia were recorded years to . seven patients ( males and females) were referred for bronchoscopy plus bal. the mean age was . years (age range - years) and all had been diagnosed with acute lymphoblastic leukemia. all patients had at least cough as a clinical symptom along with radiological fi ndings. all patients had been on broad spectrum antibiotics at the time of bronchoscopy. the mean duration from admission to time of bronchoscopy was hours ( days) with a standard deviation of hours. of the seven patients one patient yielded a positive result on bal. this did not result in a change in management as the patient improved clinically before the result of the bal was confi rmed. conclusion in this retrospective case series the diagnostic yield of fl exible bronchoscopy plus bal in children with febrile neutropenia was low. prospective studies plus early timing towards bronchoscopy and bal should be conducted to further defi ne its role in the management of febrile neutropenic patients. confl ict of interest nil. methods prospective cohort study involving monthly follow-up with caregivers. two years post enrolment, children undergo clinical and lung function assessment (fot). presence of bronchiectasis is determined by physician review and radiological confi rmation (when indicated). the frequency of pbb episodes is recorded over the study period. of children recruited to the cohort study to date, % ( / ) were male. the median age at recruitment was months (iqr , ). % of children had recurrent pbb. of the children who have had -year clinical follow-up, were able to perform fot and % ( / ) showed abnormalities (reactance above normal range.) % ( / ) with pbb have had subsequent physician diagnosis of bronchiectasis or csld. conclusion the burden of cough in children with pbb years after diagnosis remains high. ongoing clinical follow-up of this cohort of children with pbb should provide further insight into the likelihood of progression from pbb to csld and bronchiectasis. support financial markets foundation for children (for project), allen & hanburys and qcmri (for dw), nhmrc (for ju and ac). introduction national streptococcus pneumoniae (sp) serotype surveillance reports only culture positive cases from sterile sites but the yield from culture is low. polymerase chain reaction (pcr) is more sensitive in detecting sp in culture negative samples. aim to determine whether enhanced molecular surveillance in childhood empyema provides additional sp serotype information compared to national surveillance methods. methods pleural fl uid from children with empyema underwent culture and pcr to identify sp-targeting autolysin (lyta) and multiplex pcr to identify sp serotypes. national surveillance data were obtained from the national notifiable diseases surveillance system (nndss) for the same time period and age groups. results empyema: children, male, median age . (range . - . ) were recruited from april for months. sp was cultured in / ( . %) in blood and / ( . %) in pleural fl uid. sp was identifi ed by pcr in / ( . %). serotypes: , n = ( . %); , n = ( . %); a, n = ( . %); f a, n = ( . %); v/ a, n = ( . %); f/ a, n = ( . %); non-typeable, n = ( . %). one subject had serotypes and in a serotype could not be established. nndss: sp culture positive cases were reported. serotypes: , n = ( . %); , n = ( . %); a, n = ( . %); f a, n = ( . %); v/ a, n = ( . %); f/ a, n = ( . %); non-typeable, n = ( . %). other serotypes were reported in sp positive cases. signifi cant differences between empyema and nsdss data were identifi ed for serotypes (p < . ) and (p < . ). conclusions the proportion of serotypes and were signifi cantly higher in empyema fl uid using pcr. this disease model provides additional serotype information to national surveillance data. this has important implications in monitoring replacement serotypes following the introduction of new vaccines. funded by glaxosmithkline, belgium. h giddings , l seccombe , p rogers , a corbett , e veitch recent theories on the pathophysiology of parkinson's disease (pd) emphasize early brainstem involvement. furthermore various respiratory function abnormalities have been reported without consistent pattern. we sought to study the effects of idiopathic pd on respiratory function and ventilatory response to hypercapnoea and hypoxia. methods patients with a diagnosis of pd but no known respiratory disease were recruited. subjects underwent lung function testing including respiratory muscle strength, ventilatory response to hypercapnoea (with central respiratory drive (p )) and a hypoxic simulation (fio % cough is the most common symptom presenting to doctors. paediatric cough is associated with signifi cant morbidity for both children and their parents. the symptom of cough is associated with airway hyper-reactivity and is a dominant symptom of airway infl ammation. inhaled corticosteroids (ics) can reduce airway infl ammation and hyper-reactivity. the objective of this review was to evaluate evidence for the effi cacy of ics in reducing the severity of cough in children with sub-acute cough (defi ned as cough duration of - weeks). methods search was conducted by the cochrane airways group using cochrane methodology. all randomized controlled trials (rcts) comparing ics with a control group for treatment of sub-acute cough in children were considered for inclusion. search results were analysed using pre-determined criteria for inclusion. results two studies were eligible for inclusion in the review, however there were limitations in that the participants of both these studies were infants, post acute bronchiolitis illness, and cough duration at start of study treatment was ill-defi ned. children were included in the meta-analysis. there was no signifi cant difference between groups in proportion of children 'not cured' (primary outcome measure), with a pooled or of . ( % ci . , . ) (using intention to treat analysis). conclusions there is currently no evidence to support the use of ics in sub-acute cough in children. however, this systematic review is limited by the small number of studies available for analysis and the quality and design of these studies. further well-designed rcts are required to support or refute the effi cacy of treatment with ics in children with sub-acute cough. once obstructive sleep apnoea (osa) is diagnosed, a cpap implementation sleep study is traditionally performed to determine the pressure required to control the upper airway. however, since modern cpap machines store sophisticated control data we reasoned it may equally be possible to commence cpap via a 'best guess' iterative approach without compromising osa control or compliance. aim to compare the outcomes at months of patients commencing cpap after best guess with those commencing cpap after a cpap implementation sleep study. methods we retrospectively reviewed the records of all patients referred by respiratory physicians to our cpap clinic between march and march , and the two methods of starting cpap were compared. data collected included age, sex, bmi, respiratory disturbance index (rdi), cpap pressure commenced, fi nal pressure at months, cpap usage data and cpap clinic contacts. results patients were identifi ed, aged ± years, %male, bmi . ± . , with severe osa, rdi ± . commenced cpap via best guess and after a cpap sleep study. the starting pressures in both groups were similar, . ± . versus . ± . cmh o. in those patients continuing to use cpap at months, there were no differences between the groups for fi nal pressure, numbers of patients changing pressure, control of osa with cpap, and hours cpap used per day. in the best guess group however, signifi cantly more patients were continuing to use cpap at months, % versus % (p = . ). conclusion this study demonstrates that it may no longer be necessary to perform cpap implementation sleep studies routinely and this will save hospital bed days. confl ict of interest nil. six required intubation and the rest were managed with non-invasive ventilation in icu. the average length of stay in icu was . days. polysomnographic data will be described. conclusions obesity hypoventilation as a cause of respiratory failure is likely to increase in frequency as the incidence of obesity increases. increased awareness by the lay public, as well as clinical suspicion and recognition of the condition by all clinicians at an earlier stage, is likely to prevent progression to the point of needing intensive care. it is hoped that this case series may provide a springboard for further study into why these patients presented at such a late stage of their disease process. supported by none. confl ict of interest none. although sa and sleepiness often co-exist, the commonest cause of sleepiness in a general community is depression, with sa being the th most common cause. in order to assist recognition of depression in a snoring population attending a sleep clinic, we introduced a simple two question 'beyond blue questionnaire(bbq)' into our routine assessment. aims to ( ) background indices of ventilation distribution in diffusion (s acin ) and convection (s cond ) dependent airways derived from multiple breath nitrogen washout (mbnw) may vary between interpreters because of differences in calculation of phase iii slopes (Δphase iii ). aims to compare s cond and s acin results of interpreters from a single mbnw in copd subjects. methods subjects with copd underwent mbnw. three washouts were analysed independently by experienced and novice interpreters using custom software for automated breath identifi cation. Δphase iii was fi tted automatically by least squares fi t between predetermined points, and then adjusted manually. s cond was the linear slope of Δphase iii plotted against lung turnover (cumulative expired volume/frc), between turnovers . - . s acin was the Δphase iii of the fi rst breath minus the s cond component. differences expressed as icc and cov, were examined by repeated measures anova. results mean ± sd age was ± years. fev was ± % predicted. s cond was greater while s acin was lower from the experienced introduction β-blockers may cause bronchoconstriction and mask the effect of β -adrenergic agonists. this has implications for the interpretation of routine diagnostic spirometry and bronchodilator response. this study examined this issue in a routine lung function laboratory, and whether it applied to both cardio-selective (c) and non-selective (nc) preparations. method all patients attending the lung function laboratory, royal adelaide hospital over a -month period were asked whether they were currently taking a β-blocker and to identify the drug. spirometry results were analysed to assess airfl ow obstruction and reversibility. results patients completed the survey and patients ( %) were taking β -blockers. the table shows the results of the patients who could be assessed for reversibility in spirometry. of the patients in this group patients ( %) were taking (c) and ( %) (nc) agents. fifty-three patients were unsure whether they were taking a β -blocker. no signifi cant differences were found in the percentage of patients with airfl ow obstruction or reversibility between the groups. aim to examine patterns of adult lung function in terms of airfl ow obstruction, hyperinfl ation and/or reduced diffusing capacity (d l co). this can then be related to the life-time history of risk factors such as smoking, asthma and infections. methods using the population-based tasmanian longitudinal health study (tahs) cohort followed since , an asthma-enriched sub-sample was selected consisting of % ever with asthma, of whom half reported current asthma. measurement of spirometry, d l co (uncorrected for haemoglobin) and lung volumes was performed, then lung function data were analysed using the mean predicted values. airfl ow obstruction was defi ned as post-bronchodilator fev /fvc (post-b.d. fer) < . , hyperinfl ation as total lung capacity (tlc) > % predicted, and reduced d l co as < % predicted. aim to examine the gender-specifi c differences in adult spirometry, d l co and lung volumes, with a view to relating them to life-time respiratory risk factors. methods using the population-based tasmanian longitudinal health study (tahs) followed since , an asthma-enriched sub-sample was selected consisting of % ever with asthma, of whom half reported current asthma. measurement of spirometry, d l co (corrected for haemoglobin) and lung volumes were performed. data were analysed using the statistical upper and lower limits of normal of reference equations by nhanes iii, roca et al and quanjer et al. of the caucasian adults ( females), % completed all tests. mean age . years (range - ). elevated rates of airfl ow obstruction and hyperinfl ation were seen. signifi cantly higher proportions of females than males had reduced d l co and d l co/v a (p < . ). only . % (n = ) of females had a low d l co with low fev /fvc ratio, and . % (n = ) had a reduced tlc overall. there were no signifi cant gender differences in v a , tlc, or ever and current active smoking. males and females averaged over kg more than the mediterranean adults described by roca et al., however weight is not relevant to d l co in males. conclusion a higher percentage of middle aged females have a reduced d l co and/or d l co /v a, compared to males, with an increased rate overall. grant support nhmrc, australian postgraduate association. d chapman , , , j kermode , , , n brown , , , n berend , , , g king , , , background during bronchoconstriction, a deep inspiration (di) dilates the airways, which then re-narrow once tidal breathing is resumed. re-narrowing occurs faster in asthmatic subjects and may be due reduced airway distensibility. aim to determine the association between baseline airway distensibility and the rate of re-narrowing after di. methods eleven asthmatic and fi ve non-asthmatic subjects had baseline airway distensibility measured by forced oscillation technique (fot). after methacholine challenge, respiratory system resistance (rrs) was measured during min of tidal breathing, followed by di to total lung capacity (tlc) and passive return to normal tidal breathing. dilatation was measured as the decrease in rrs between end tidal inspiration and tlc, and re-narrowing as end-expiratory rrs immediately after di, as per cent rrs at end-tidal expiration before the di. distensibility is presented as geometric mean ± %ci and re-narrowing as mean ± % ci. results airway distensibility was reduced in asthmatic compared to healthy subjects ( . s − .cmh o − ( . - . ) vs. . s − .cmh o − ( . - . ), p = . ). dilatation did not differ between groups (p = . ) but re-narrowing was increased in asthmatic compared to healthy subjects ( ± % vs. ± %, p = . ). airway distensibility did not correlate with airway re-narrowing (r s = - . , p = . ). conclusion the increased re-narrowing after di in asthmatic subjects is not due to reduced baseline airway distensibility and may be due to increased shortening velocity of airway smooth muscle or reduced elastic recoil. supported by the nhmrc and the crc for asthma and airways. nomination nil. confl ict of interest no. c ng , , , s jenkins , , , n cecins , , p eastwood , , aim to evaluate the measurement properties of two accelerometers: the activpal and the stepwatch activity monitor (sam) in people with copd. methods the activpal and sam were attached to the anterior right midthigh and the right ankle, respectively (as per device recommendations). each participant performed walking tasks; at a self-selected slow speed and at a self-selected normal speed. at each speed, one walk was performed with a -wheeled walker (ww) and the other without. results participants aged ( ) years (fev = ( ) % pred; males) completed the study. the slow and normal speeds were ( ) m·min − and ( ) m·min − , respectively. agreement between steps recorded by the sam with steps counted during observation did not differ with speed or ww use (p = . ). the mean difference was steps·min − and the limit of agreement (loa) was steps·min − . agreement between steps recorded by the activpal with steps counted was worse at slow speeds (mean difference steps·min − with loa of steps·min − ) compared with normal speeds (mean difference steps·min − with loa of steps·min - ) (p = . ), but was not affected by ww use. both accelerometers detected the small difference in walk speed irrespective of ww use (p < . ). conclusions neither the accuracy nor responsiveness of either accelerometer was affected by ww use. in contrast to the activpal, sam was accurate at both speeds and therefore can be used to detect steps in people who walk very slowly during daily life. breathing and sleep, heidelberg vic., eastern health, melbourne vic., northern health, epping vic., and monash university, clayton vic. aim to document the care and pathways patients with copd travel at three metropolitan health services. methods data were extracted from data sets for patients attending the emergency department of the three hospitals with a diagnosis of copd over year. the three hospitals included a city-based tertiary/quaternary hospital and two smaller community hospitals. analysis was completed on similarities and differences in admission and referral rates, average length of stay, and discharge destination, standardized by age, sex and mode of transport to the emergency department. results there were inpatient separations and emergency department presentations for patients with copd. discharge patterns related to the designated role of the hospital, with the community hospitals discharging to % of patients directly home and the more specialized city hospital discharging % to other hospitals and % home. there were signifi cant differences in the admission rates for category and patients among the hospitals. we found unexplained variation in the acute average lengths of stay of . , . and . days. conclusions the analysis confi rmed some expected patterns based on the type of hospital, but also identifi ed unexplained variation that suggests that factors other than patient characteristics may be contributing to the variation in care pathways. aims to: ( ) determine which tests of exercise capacity relate to average daily energy expenditure (dee) and; ( ) quantify the intensity at which activities of daily living (adl) are undertaken in people with chronic obstructive pulmonary disease (copd). methods a study was undertaken in subjects with stable copd (mean, sd) aged ( ) years with an fev of ( ) % predicted ( males). measures were collected of distance walked during the six-minute walk test ( mwd) and incremental shuttle walk test (iswd) and peak rate of oxygen uptake during a cycle ergometry test (vo peak ). the sensewear armband® was worn during the waking hours for . ( . ) days to measure dee. the intensity at which activities of daily living were undertaken was expressed as a percentage of vo peak . results dee was associated with mwd (r = . ; p = . ), iswd (r = . ; p = . ) but not vo peak (r = . ; p = . ). stronger associations were observed between dee and the body weight-walking product for mwd (r = . ; p < . ) and iswd (r = . ; p < . ). the average intensity of adl was equal to ( %) of vo peak (range to %). conclusions mwd and iswd, but not vo peak were related to dee. as adl were performed at a high percentage of vo peak it may be more realistic to increase dee by increasing the frequency or duration, rather than the intensity of physical activity. in patients with copd, two mwts are recommended prior to commencing a pulmonary rehabilitation program (prp) to allow for a learning effect. aim to determine the characteristics of patients with copd in whom -minute walk distance ( mwd) did not increase on a second test. methods patients ( males) with stable copd (aged , to years) naïve to the mwt performed two tests ( minutes apart) prior to commencing a prp. patients were categorized according to their change in mwd with test repetition. results mwd was the same or decreased on the second test in patients ( %) (table) . in the remaining patients ( %), mwd increased by m ( %) ( % ci to m, to %). logistic regression analysis identifi ed fev (l) as the only signifi cant variable (p < . ) that predicted the absence of a learning effect in mwd with test repetition. conclusions some patients with severe copd may not require a practice mwt to achieve their maximum performance at a prp baseline assessment. ( ) years, with stable ipf were evaluated in this study. demographic data and measures of pulmonary function (spirometry, diffusing capacity for carbon monoxide, (dl co )), dyspnoea (baseline dyspnoea index, bdi), peripheral muscle force (isometric quadriceps force (qf) and handgrip force (hf)), functional exercise capacity ( -minute walk distance, mwd), limitation in daily activities (activities of daily living (adl) score), and health status (sf- ) were assessed. relationships between mwd and mrc grade, pulmonary function, qf, bdi and adl score were examined. results the number of subjects in mrc grades , , and was ( %), ( %), ( %) and ( %), respectively. pulmonary function, bdi, qf, hf, mwd, adl score, and sf- decreased signifi cantly with increasing mrc grade (all p < . ). moderate to strong correlations were found between mwd and mrc grade (r = − . ), dl co (r = . ), qf (r = . ), bdi (r = . ) and adl score (r = . ) (all p < . ). conclusions these fi ndings suggest that the mrc dyspnoea scale can be used to discriminate and classify subjects with ipf according to the severity of impairment and disability. ( ) year (mean, sd) completed two assessment sessions on separate days. on one day, they exercised twice to symptom limitation (tlim) on a treadmill. on the other day, they exercised twice to tlim on a cycle ergometer. the order of exercise modality was randomized between days. on both days, the only difference between the exercise tests was that bipap, titrated to patient comfort, was used during the second test. measures were made of; ) tlim and, ( ) the difference in dyspnoea, using borg scores, at tlim during the fi rst test and the equivalent exercise time during the second test (i.e. iso-time). results bipap increased tlim on the treadmill ( ( ) seconds; p = . ) but not the bike ( ( ) seconds; p = . ). the reduction in dyspnoea at iso-time on the treadmill and bike was similar being, ( ) and ( ), respectively (p = . ). conclusions bipap may confer greater benefi t in exercise tolerance exercising on a treadmill compared with a cycle ergometer in patients awaiting lung or heart-lung transplant. infection with rhinovirus (rv) is known to trigger acute exacerbations in subjects with asthma and these subjects also have increased susceptibility to the effects of rv. the mechanisms remain poorly understood, but appear to involve a host innate immune defect in the airway epithelium. aim we sought to determine in bronchial epithelial cells (becs) if oxidative stress in the form of exposure to cigarette smoke extract (cse), hydrogen peroxide (h o ) and eosinophil peroxidise (epo) results in impaired mitochondrial function and if this directly impairs signalling of rv infection through mda and alters the release of type i and type iii interferons (ifns). methods pbecs were grown to confl uence. cells were then exposed to cse ( %, no fi lter) or h o ( . mm) or epo. cells were then infected with rv -b (moi = ). virus replication was measured by cell titration assay. following infection, il- , cxcl- , cxcl- was measured using cytometric bead array and fl ow cytometry. supernatants and whole cell lysates were collected for ifn-β, bax and mda detection by western blot. ifn-λ and cytochrome-c was measured using conventional elisa. cell viability was assessed by annexin v-pe staining and fl ow cytometry. results rv infection alone induced cxcl- , il- , cxcl- and ifn-λ. pbecs treated with each of the oxidative stressors had increased cytochromec release and increased apoptosis. this mitochondrial dysfunction led to degradation of mda expression and resulted in specifi c suppression of cxcl- and ifn-λ. conclusions exposure of becs to an oxidative stress results in mitochondrial dysfunction in airway epithelial cells. this leads to defective antiviral signalling in the airway epithelium after infection with rv. introduction pleural infection is associated with high morbidity. prompt drainage is key, but pus is often loculated and thick making drainage diffi cult. based on promising animal studies, we hypothesize that intrapleural therapy with t-pa and dnase, which lyse adhesions and reduce fl uid viscosity respectively, can signifi cantly improve pus evacuation in pleural infection. methods consecutive patients with pleural infection were treated with standard antibiotics and intercostal chest tube (ict) drainage. additionally, t-pa mg and dnase mg (each in ml of . % nacl) were instilled intrapleurally via an ict twice daily for up to six doses. the ict was clamped for minutes after each instillation. patients were followed clinically and with serial cxr. opacity from pleural effusion was quantifi ed on chest radiographs. results eleven patients ( male; mean age ) were treated. nine effusions were associated with community acquired pneumonia, of these, eight were visibly purulent, fi ve were culture positive and the mean fl uid ph was . (range . - . ). ten patients ( %) were successfully managed conservatively and one patient required surgery. median hospital stay from fi rst intrapleural treatment dose to discharge was days (range - ). the median amount of fl uid drained in the hours preceding t-pa/dnase treatment was ml (range - ), and improved signifi cantly to ml (range - ) following two doses of treatment. this was paralleled by a signifi cant reduction in radiographic opacity by a mean value of % of the hemithorax (range - %). four patients showed an initial rise in crp following t-pa/dnase, but all patients had resolution of sepsis and signifi cant reduction in crp. there were no major complications. pleuritic chest pain requiring opioid analgesia developed in three patients. methods clinical data were collected using a standardized form for aboriginal children aged days -< months hospitalized with alri and enrolled in a rct of vitamin a/zinc supplementation were matched with data collected during a population-based study of who-defi ned primary endpoint pneumonia (who-p). sensitivities, specifi cities, positive and negative predictive values (ppv, npv) for these signs were compared between who-p cases and lobar pneumonia assigned by a respiratory paediatrician. in episodes of hospitalized alri, who-p was diagnosed in ( . %); the respiratory paediatrician classifi ed ( . %) as lobar pneumonia. the sensitivities of clinical signs ranged from a high of % for tachypnoea to % for fever + tachypnoea + chest-indrawing; the ppv range was % to %, respectively. higher ppvs were observed against the paediatric respiratory physicians diagnosis compared to who-p. conclusions clinical signs on admission are not useful in predicting who-p in this population, presenting challenges for future pneumonia research in this population. who-p may underestimate alveolar consolidation in a clinical context and its use in clinical practice or in research designed to inform clinical management in this population should be avoided. the incidence of tb in the non-indigenous australian population is uncommon at . cases per population . in this paper, we report three cases of pulmonary tuberculosis in young australian born, non-indigenous adults in the hunter new england area where marijuana possibly was a signifi cant risk factor in transmission and severity of disease. all three cases had severe cavitating disease at time of presentation. contact tracing from the fi rst case, a regular heavy marijuana user, identifi ed mantoux positive contacts, one of whom developed active pulmonary tuberculosis. all contacts, mainly young adult males, denied sharing marijuana with the index case. contact tracing from the second case identifi ed mantoux positive contacts, of whom use marijuana regularly and shared bongs (water pipes) with the index case. there were positive mantoux contacts of the third case, one of whom shared bongs with the index case. health professionals need to remain aware of the possibility of tuberculosis in groups with historically low incidence rates. marijuana bong smoking is possibly associated with transmission and severity of tuberculosis . introduction in , these previously well women survived and made a good recovery from severe pneumonia and acute lung injury after retrieval on ecmo. streptococcus pyogenes is an unusual cause of pneumonia in adults. case a -year-old veterinarian with a history of mild asthma presented with days of fever and respiratory symptoms. the diagnosis was confi rmed by a fourfold rise in the anti-streptococcal antibody. this was complicated by respiratory failure, septic shock, acute renal failure, severe pulmonary hypertension and bilateral parapneumonic effusions. despite maximal interventions she deteriorated. femoral venous-venous ecmo was initiated on day at the calvary mater hospital in newcastle by a retrieval team from royal prince alfred hospital (rpa), sydney. she was transferred kms on ecmo in a large multipurpose ambulance. she developed lung abscesses and recurrent pneumothoraces and she required a pleurodesis. she required days of ventilation and days of ecmo. three months later she was asymptomatic, with mildly restrictive spirometry and minor cxr change. case a -year-old offi ce worker with s pyogenes bacteraemia made a similar presentation to our institution. she was ventilated for days, ecmo was initiated by the retrieval team and continued for days. three months later she was asymptomatic with a normal cxr and pulmonary function tests. introduction the urinary pneumococcal antigen (upa) test has been shown to have superior sensitivity to other investigations in determining the aetiology of community-acquired pneumonia (cap), but there is very limited data on its performance in local populations. the aims of this study are to establish the prevalence of positive upa testing in patients admitted to hospital with cap, and determine its utility. secondary aims are to identify associations with positive testing, as well as to determine if a positive test infl uences clinical outcomes. methods the study is a prospective, single-centre study that is still recruiting. adult patients are included upon admission to hospital if they have the diagnosis of cap, as defi ned by new infi ltrates on chest radiograph along with consistent clinical features. clinical data including curb- score of severity, current and prior antibiotics, co-morbidities, mortality and length of hospital stay are recorded. results preliminary results show a positive test prevalence of / ( . %, % ci . - . %) amongst patients admitted with cap. overall prevalence of pneumococcal pneumonia is / ( . %, ci . - . %). patients with a positive upa result have a higher mean curb- score of . compared with . in those with a negative result (p = . ). . % of patients with a positive result were admitted to the intensive care unit, compared with . % those with a negative result (p = . ). conclusions the overall prevalence of positive upa testing in patients admitted to hospital with cap is low. preliminary data suggests that patients with positive results are more likely to have greater severity pneumonia and to require intensive care support. comparative data on length of stay, mortality, previous antibiotic use and specifi c co-morbidities has not revealed any statistically signifi cant differences between positive and negative groups. confl ict of interests no. s herath , c lewis , m nisbet , respiratory department, auckland city hospital, auckland, new zealand, and infectious diseases department, auckland city hospital, auckland, new zealand rhodococcus equi (r. equi), previously known as corynebacterium equi is a gram positive bacillus that is found in soil and causes infection in grazing livestock. it is infrequently isolated from clinical specimens. it is usually associated with human disease in immunocompromised patients and is an uncommon cause of infection in immunocompetent patients. infection is usually acquired by the airborne route with pneumonia being the most common manifestation but it can also be acquired orally or by direct inoculation. we present a case of pneumonia caused by r. equi infection in a year old male builder who presented with cough, dyspnoea and night sweats. r. equi was cultured from a transbronchial aspirate from a subcarinal lymph node. despite extensive investigation, no contributing host immune defect was identifi ed. the patient recovered after three months of antibiotic treatment, initially with intravenous vancomycin and meropenem followed by oral clarithromycin and rifampicin. although infections due to r. equi have been increasingly reported in immunocompromised patients, since there have only been cases described in patients where no associated host immune defect was reported. in this cohort, the median age at presentation was years (range - ) and ( %) patients were male. ten ( %) of these cases had pulmonary infection. two ( %) patients died and the remainder were successfully treated with prolonged antibiotics. r. equi is an uncommon cause of infection in humans and rarely occurs in patients where a host immune defect cannot be identifi ed. introduction recognition of pulmonary involvement in extra pulmonary tuberculosis (ep-tb) may be an important public health issue, as it has been estimated that patients with smear negative pulmonary tb (ptb) are responsible for % of new infections. usually, all patients with ep-tb have a chest x-ray but sputum cultures are requested only if there is an abnormality. methods in this retrospective clinical audit, we aimed to evaluate the percentage of ep-tb patients with ptb despite a normal chest x ray (cxr), and to explore any clinical characteristics of this group. clinical notes, microbiology and cxr reports were reviewed from consecutive patients presenting with ep-tb between and . results of patients with ep-tb, % were male and the mean age was (range to ). most patients were of asian ethnicity (n = , %). the commonest presentation of ep-tb was lymphadenopathy (n = , %), followed by pleural (n = %) and bone (n = , . %) disease. ep-tb was diagnosed by biopsy/excision of the ep site in the majority (n = , . %), and by sputum testing alone in ( . %). sputum cultures were performed in n = , ( %) overall, with n = ( %) being positive. there was higher infl ammatory markers in the sputum culture positive group (esr . vs. . , p = . and crp . vs. . , p = . ). the majority had cxr abnormalities (n = , %). in the group with normal cxr (n = ), ( %) had sputum cultures performed. of these, were culture positive and of these also + smear positive ( on immunosuppression, with cough). conclusion a small number of patients with ep-tb and normal cxr had pulmonary tb, of whom were smear positive. thus, induced sputum testing should be considered in patients with ep-tb even if cxr is normal. this may aid diagnosis and determine infectivity. ntm are normal inhabitants of environmental reservoirs including water. disease due to ntm has been increasing in qld. aim to document the presence of ntm in potable water in brisbane, to compare the species isolated during summer and winter and to relate this to the geographic distribution of patients with ntm. methods water samples ( l) were collected from routine collection sites in winter and sites in summer . samples were processed in triplicate as previously described. h subcultures were taken from positive specimens, dna extracted, followed by s rrna sequencing. patient addresses were obtained from the qld tb control centre database. aim to gauge the full impact of pandemic h n infl uenza across demographic groups in the northern territory, particularly indigenous and remoteliving individuals. methods we performed two cross-sectional serological surveys on specimens from residents of the northern territory, with specimens obtained from january to may (pre-pandemic) and specimens from september (post-pandemic). specimens were selected from among serum tubes collected from ambulatory outpatients. antibody titres were measured by haemagglutination inhibition against the a/california/ / reference virus. all specimens had available data for gender, age, and address, with indigenous status determined in . % of cases. results protective antibody levels, defi ned as a titre of or greater, were present in . % of pre-pandemic specimens and . % of post-pandemic specimens. the pre-pandemic proportion immune was greater with increasing age, but did not differ by other demographic characteristics. the post-pandemic proportion immune was greater among aboriginal and torres strait islanders and in younger age groups, but did not differ by gender or socio-economic index for area. however, the proportion immune was geographically heterogeneous, particularly among remote-living and indigenous groups. the northern territory-wide attack rate adjusted to age, region and indigenous status was . %. conclusions pandemic infl uenza disproportionately affected children and indigenous australians in the northern territory in . the proportion of specimens demonstrating post-pandemic immunity was particularly variable among indigenous and remote-living individuals. the kormp found asymptomatic aboriginal children (ac) had more hrv than asymptomatic non-aboriginal children (non-ac) in a longitudinal communitybased cohort study where infants had nasopharyngeal aspirates (npa) collected regularly from birth to years of age. aim to compare the frequency of hrv groups in asymptomatic ac and non-ac in the kormp. methods npa positive for hrv (n = ) from the npa previously tested for respiratory viruses, had viral rna extracted and reverse transcribed. hrv was detected and typed using a two-step pcr of the hrv ' utr, followed by dna sequencing for typing. chi-square analyses were used. results hrv was detected and typed in npa (from children; ac and non-ac), could not be typed and were not positive for hrv. ac had more hrv in summer and autumn than non-ac and were more likely to be co-infected with at least / bacterial species identifi ed. hrva, b & c were found in . , . and . % of hrv detected. hrvb & c were increased in infants exposed than not exposed to tobacco smoke in utero (hrvb; . vs. . %, p = . and hrvc; . vs. . %, p = . ). of the npa, hrv-a was detected more often in npa from ac than non-ac ( . vs. . %, p = . ), particularly at - months of age (p = . ) and during summer (p < . ). hrvb was detected more often in npa from ac than non-ac in autumn (p < . ). hrvc was detected as often in ac as non-ac in each season except summer. aim to determine whether interferon-gamma release assay (igra) can be effectively used for diagnosis of latent tuberculosis infection in a remote location. methods subjects were enrolled from the darwin centre for disease control tuberculosis clinic and were eligible if a tuberculin skin test (tst) of mm or greater had been recorded for any indication. igras were performed using quantiferon®-tb gold whole blood in-tube assay according to manufacturer's instructions. specimens were incubated and centrifuged at the local laboratory before refrigeration for transport. interferon assay was performed at the reference laboratory, over km away. results igras were performed, with patients ( %) recording negative results, ( %) positive and only one result ( %) indeterminate. negative, and therefore discordant, test results were more common in bcg vaccinated individuals. this effect was not limited to those with tst results of - mm, but was seen primarily in those with results of mm and above. conclusions these results are broadly comparable to fi ndings for igra use in less remote settings. in particular, our low rate of indeterminate results suggests that igra testing is feasible at a remote site after local processing. this approach could be considered for use in the northern territory tuberculosis control program. inhaled medications form the mainstay of drug treatment for patients with airways disease. effectiveness of therapy is dependent on the appropriate selection and prescription of drug and device, correct supply and adherence to therapy with an effective technique. patients frequently admit to acute medical wards both with acute exacerbations and for other co-morbidities eg heart failure or pneumonia. inpatient episodes provide an opportunity to review inhaled therapy however anecdotally add to patient confusion and introduce complexity (rational or ad hoc changes to inhaled drug, device, strength, dose or frequency). aim identify prescribing accuracy and effectiveness of patients' inhaler technique. describe any discrepancies between inhaled therapy: ( ) used prior to admission, ( ) prescribed for inpatient use, ( ) available at the bedside and ( ) administered, prior to and after implementation of an inhaler prescribing and administration guide. methods a single day audit of all inpatients on general medical wards was conducted october (review of medication charts and inhalers in patients' bedside lockers, brief questioning and direct observation of patients' inhaler technique. results compared to post implement of the 'prescribing and administering inhalers' tool (audit in december ). results from ( %) patients had inhalers prescribed, (mean: . prescriptions per patient). % of prescriptions were accurate ( % patient had no errors). discrepancies between used prior to admission and inpatient prescriptions were found in ( %) patients while those between inpatient prescriptions and available at the bedside were found in %. self-administration ('s') was noted on medication charts of ( %) patients, of whom had an ineffective inhaler technique. / patients has a spacer at the bedside with a further r prescribed metered aerosol inhalers. post-intervention differences in prescribing, supply, administration and technique errors will be discussed. conclusions a combination of errors and prescription discrepancies reduce the effectiveness of inhaled therapy for inpatients. confl ict of interest no. males (n (%) % ci) females (n (%) % ci) adm and bed days bmi, body mass index hrqol, health related quality of life chronic respiratory disease questionnaire; adm, admissions, mean (sd) uberculosis notifi cations in australia a cluster of tuberculosis associated with use of a marijuana water pipe the prince charles hospital foundation cc dobler , , gb marks , woolcock institute of medical research, the university of sydney, nsw, and department of respiratory medicine, liverpool hospital, sydney, nsw aim to determine the incidence rate and nature of adverse events in patients taking treatment for latent tuberculosis infection (ltbi). methods records of all patients who received treatment for ltbi at the chest clinic of a large tertiary hospital between / and / were reviewed. an adverse event was defi ned as any change in health status or side effect that led to treatment interruption or cessation. liver function tests were not performed routinely during follow-up, except when the patient was considered to be at an increased risk of developing hepatitis. results of patients in whom treatment for ltbi was initiated ( %) received isoniazid for months, ( %) received a combination of isoniazid and rifampicin for months, and the remainder were treated with different regimens. their mean (sd) age was ( ) years and % were male. nineteen patients ( . %) experienced an adverse event. seven patients developed a rash, four had lethargy and/or mood disorders, three had subclinical hepatitis, four experienced severe nausea, vomiting and/or other gastrointestinal symptoms and three had features of peripheral neuropathy. in eight patients who experienced an adverse event medication was temporarily ceased and then re-started without change; in four the treatment regimen was changed; and in seven the treatment was ceased completely. the risk of adverse events was not signifi cantly related to age, sex, drug regimen (single drug versus combination therapy) or baseline transaminase levels. conclusions in this cohort almost in patients on treatment for ltbi experienced an adverse event. although the adverse events were generally mild to moderate, this risk has to be taken into account when deciding whether to advise treatment for ltbi. introduction human rhinovirus (hrv) is the commonest cause of asthma exacerbations in children. pernasal aspirate (pna) is the gold standard for microbiological sampling but is invasive and distressing for children. studies have showed that less invasive swabs may be just as effi cacious. aim to test the hypothesis that hrv detection is as effi cient using nasal fl ocked swabs or washes and more comfortable, compared with pna in children with respiratory illnesses. methods children were recruited on presentation to the emergency department with respiratory symptoms. pna was collected from one nostril of all children recruited and nasal fl ocked swab (n = ) or wash (n = ) collected from the other nostril alternately. subjects rated the comfort of each sampling method to (least to most). viral rna was extracted and reverse transcribed. a two-step pcr of the hrv ' utr was used for detection, followed by sequencing for typing. results to date, children ( % male, mean age of . years) had paired samples taken. of these children, % (n = ) presented with a diagnosis of viral induced wheeze and % (n = ) had a hrv positive sample. compared with pnas, nasal fl ocked swabs were % ( of pna positive) effective in detecting hrv, whilst nasal washes showed % ( of pna positive) effi cacy. of the successfully typed samples, had hrva and had hrvc. nasal washes had a better comfort rating (mean . , n = ) than fl ocked swabs (mean . , n = ) and pnas (mean . , n = ). conclusion our fi ndings suggest that whilst nasal fl ocked swabs are an effective sampling method for hrv detection, nasal washes were more effective, being as effective as pnas and were the most comfortable. support nhmrc, pmh foundation. nomination nil. aim to describe the inpatients treated by a dedicated niv service. methods a retrospective audit of inpatients treated by the alfred niv service between january and june . the defi nition of niv included patients treated with cpap and bilevel positive pressure ventilation. results patients (age: ± years (mean ± sd), gender: % male) were treated with niv on occasions (repeat admissions patients). commonest indications for niv were osa (n = , %), acute exacerbations (ae) of copd (n = , %), acute cardiogenic pulmonary oedema (acpo) (n = , %) and post-lung transplantation (n = , %). treatment was delivered primarily in the respiratory ward (n = , %), cardiac ward (n = , %), icu (n = , %) and general medical ward (n = , %). episodes of cpap (mean pressure ± cmh o), osa and acpo made up % of those treated. seventy-two episodes of bilevel pap (mean ipap ± cmh o and epap ± cmh o), aecopd and weaning post-mechanical ventilation made up % of those treated. outcome data was available in a subgroup of patients with acpo (n = ) andaecopd (n = ). in the acpo group, patients ( %) improved and niv was ceased. three patients ( %) deteriorated and were intubated and patients ( %) were palliated. in the aecopd group, patients ( %) improved andniv was ceased or they were discharged on therapy. patients either deteriorated on niv or could not tolerate therapy, of these ( %) continued ward management and ( %) were palliated. conclusion the alfred niv service model has managed a large number of referrals across a range of diseases in a variety of wards. this is likely to have reduced demand on icu, hdu and respiratory ward beds. compared to the published literature, theoutcomes for acpo are worse than expected but comparable for aecopd. this may be explained by local referral patterns for acpo. we believe that our service model provides a viable means of administering niv to an ever expanding referral base. transitional & community service, the university of south australia, adelaide, sa , the university of adelaide, adelaide, sa, , the mary potter hospice, north adelaide, sa, , thoracic medicine, the royal adelaide hospital, adelaide, sa, , the royal district nursing service, wayville, sa , and the palliative care council of sa eastwood, sa introduction: the adelaide health service is in the process of developing a new and innovative model of copd community based care. a number of initiatives have informed this development including a recent research project examining the experiences of participants with end stage copd and their carers. a growing body of evidence indicates the importance of a palliative approach, however this often takes the form of referral to a palliative care service rather than a broader application of palliative principles in both specialist and primary care. methods: fifteen participants were interviewed twice at monthly intervals to explore their needs and the services they accessed. a series of focus groups with key service providers in sa was also undertaken. data were analysed to identify how hospital, specialist palliative care units and primary care services currently interface to meet identifi ed patient and carer needs. results: the current service model is episodic and reactive with services activated through the acute care system. our research has shown that, as copd advances, current models of care do not address the importance of supporting quality of life (including a focus on adls) and carers in their ongoing role. also emphasised was the lack of co-ordination of care, collaboration between service providers and communication -the basics of chronic disease management. conclusions the outcomes of this study will inform the development of a proactive, multidisciplinary model of care which is no longer reliant on tertiary care, but places primary care at the centre of the model. greater collaboration between respiratory, palliative and primary care services will provide an integrated approach, focusing on the needs of the patient and carer. aim long term conditions are prevalent in south auckland and impact on the individual, the community and the health system. as nurses living within this community, and employed by counties manakau district health board, our aim was to explore funding opportunities available through the pacifi c health team. lotumoui was established to improve health outcomes/behaviours for pacifi c populations. the church we attend has wide cultural diversity and had no knowledge of the programme and the support provided to make healthy changes within our community. methods firstly a health committee was formed within the church, having 'sold' our vision to the parish council. we launched the group by undertaking free blood pressure checks, followed by a 'walk the talk' project for the days leading into easter. baseline observations were taken and pedometers issued. results the parishioners who attend regular exercise sessions are reporting improved quality of life, exercise tolerance and reducing waist lines. bp parameters are also reducing. conclusions a dedicated health committee within a parish community, supported by the district health board can impact on changes in lifestyle by simple interventions. the investment by the pacifi c team will reap benefi ts for the individual and the health sector. confl ict of interest no. key: cord- -klhg x z authors: tan, dingyu; walline, joseph harold; ling, bingyu; xu, yan; sun, jiayan; wang, bingxia; shan, xueqin; wang, yunyun; cao, peng; zhu, qingcheng; geng, ping; xu, jun title: high-flow nasal cannula oxygen therapy versus non-invasive ventilation for chronic obstructive pulmonary disease patients after extubation: a multicenter, randomized controlled trial date: - - journal: crit care doi: . /s - - - sha: doc_id: cord_uid: klhg x z background: high-flow nasal cannula (hfnc) oxygen therapy is being increasingly used to prevent post-extubation hypoxemic respiratory failure and reintubation. however, evidence to support the use of hfnc in chronic obstructive pulmonary disease (copd) patients with hypercapnic respiratory failure after extubation is limited. this study was conducted to test if hfnc is non-inferior to non-invasive ventilation (niv) in preventing post-extubation treatment failure in copd patients previously intubated for hypercapnic respiratory failure. methods: copd patients with hypercapnic respiratory failure who were already receiving invasive ventilation were randomized to hfnc or niv at extubation at two large tertiary academic teaching hospitals. the primary endpoint was treatment failure, defined as either resumption of invasive ventilation or switching to the other study treatment modality (niv for patients in the nfnc group or vice versa). results: ninety-six patients were randomly assigned to the hfnc group or niv group. after secondary exclusion, patients in the hfnc group and patients in the niv group were included in the analysis. the treatment failure rate in the hfnc group was . % and . % in the niv group—risk difference of − . % ( % ci, − . – . %, p = . ), which was significantly lower than the non-inferior margin of %. analysis of the causes of treatment failure showed that treatment intolerance in the hfnc group was significantly lower than that in the niv group, with a risk difference of − . % ( % ci, − . to − . %, p = . ). one hour after extubation, the mean respiratory rates of both groups were faster than their baseline levels before extubation (p < . ). twenty-four hours after extubation, the respiratory rate of the hfnc group had returned to baseline, but the niv group was still higher than the baseline. forty-eight hours after extubation, the respiratory rates of both groups were not significantly different from the baseline. the average number of daily airway care interventions in the niv group was ( – . ), which was significantly higher than ( – ) times in the hfnc group (p = . ). the comfort score and incidence of nasal and facial skin breakdown of the hfnc group was also significantly better than that of the niv group [ ( – ) vs ( – ), p < . ] and [ vs . %, p = . ], respectively. conclusion: among copd patients with severe hypercapnic respiratory failure who received invasive ventilation, the use of hfnc after extubation did not result in increased rates of treatment failure compared with niv. hfnc also had better tolerance and comfort than niv. trial registration: chictr.org (chictr ). registered on september , http://www.chictr.org.cn/usercenter.aspx chronic obstructive pulmonary disease (copd) is one of the leading causes of death worldwide. acute hypercapnic respiratory failure is a common serious complication of copd, and invasive mechanical ventilation is often required for severe cases. longer durations of invasive mechanical ventilation will increase the incidence of ventilator-associated pneumonia and difficulty weaning off ventilation [ , ] . multiple studies have shown that a sequential strategy with non-invasive ventilation (niv) using a pulmonary infection control (pic) window as the switching point can reduce the duration of invasive ventilation in copd patients and significantly improve prognosis [ , ] . the success of niv is closely related to the experience and abilities of the treating medical staff, the level of education and compliance of patients, and the performance of the niv device [ , ] . due primarily to poor patient tolerance, niv fails in approximately to % of patients, potentially leading to endotracheal intubation [ ] [ ] [ ] . for post-extubation patients with copd who cannot tolerate niv or have contraindications to niv, alternative respiratory support methods are urgently needed. high-flow nasal cannula (hfnc) oxygen therapy is a new type of respiratory support system which can supply high flow mixed gases through special nasal prongs at a sufficient temperature and humidity for patient comfort. many studies have confirmed that the comfort and tolerance of hfnc is significantly higher than that of niv [ ] [ ] [ ] . as an alternative to niv, hfnc has been shown to be as efficacious as niv in preventing post-extubation respiratory failure or re-intubation in patients with hypoxemic respiratory failure [ , ] . however, the postextubation application of hfnc in copd patients with hypercapnic respiratory failure has not been widely studied. in a pilot study, hfnc was reported to maintain similar patient vital signs and arterial blood gases as niv in post-extubated hypercapnic copd patients [ ] . this trial was conducted to test the hypothesis that hfnc immediately after extubation is non-inferior to niv in reducing treatment failure in copd patients previously intubated for hypercapnic respiratory failure. this was a multicenter, unblinded, non-inferiority, randomized controlled trial, registered at chictr.org (chictr ). from january to february , the study was performed in the intensive care units (icus) of two large tertiary-care hospitals. this study was approved by the human subjects ethics committees of the two hospitals involved ( ky- and ), and informed consent was obtained from all enrolled patients or their relatives. copd patients with hypercapnic respiratory failure who received invasive ventilation were screened for enrollment. the diagnosis of copd was established according to the gold criteria [ ] . other inclusion criteria included patients who were ≤ years of age, able to care for themselves within the past year, respiratory failure induced by broncho-pulmonary infection, and meeting criteria of the pic window. exclusion criteria were age less than years; lacking informed consent; contraindications to niv (oral or facial trauma, poor sputum excretion ability, hemodynamic instability); poor shortterm prognosis (high risk of death within days or receiving palliative treatment); heart, brain, liver, or kidney failure; tracheotomy; or a weak cough ability during the pic window. the following types of patients were secondarily excluded: withdrawn informed consent, loss to followup, uncertain -day survival, discharge from hospital within h after enrollment, and patients who refused to use their assigned device. the settings of the enrolled patients' invasive mechanical ventilation were adjusted by the attending physician according to the patient's ventilation status and blood gas analysis. the patients were randomly divided into the hfnc group and the niv group when the pic window appeared. randomization was performed using a computer-generated random number generator, and allocation was concealed through an opaque envelope. these envelopes were kept in permuted blocks of ten, five each for niv and hfnc, to ensure an even distribution of subject numbers in both groups at both centers. all subjects receiving niv (philips v or bipap vision) were set in s/t mode with a standard oral-nasal (full-face) mask (rt ). niv settings were adjusted with an adaptive method: the initial expiratory pressure airway pressure was set to cmh o, and the pressure level was gradually increased to ensure that the patient could trigger the niv device with each inhalation. the inspiratory airway pressure was initially set to cmh o and gradually increased to achieve a satisfactory tidal volume with acceptable tolerance. the pressure level and the fraction of inspiration oxygen (fio ) were adjusted to maintain a respiratory rate ≤ /min, a pulse oxygen saturation (spo ) of - %, and a partial pressure of arterial carbon dioxide (paco ) of either - mmhg or the last paco level recorded prior to extubation. subjects randomized to the hfnc group (airvo™ , fisher & paykel healthcare, auckland, new zealand) were given suitable large-bore nasal prongs selected according to the size of the patients' nostrils. the initial airflow was set at l/min and adjusted according to patient tolerance. the hfnc was set to an absolute humidity of mg h o/l, temperature was set to °c, and fio was adjusted to maintain an spo of - %. the patient's initial respiratory support was targeted to last at least h and then continued as needed. nasal cannula oxygen was administered during any interruptions to niv. niv or hfnc were discontinued when the total daily treatment duration was less than h and could be reused if needed. treatment success was defined as no need for respiratory support within h after stopping niv or hfnc. the primary outcome was treatment failure, defined as a return to invasive mechanical ventilation, or a switch in respiratory support modality (i.e., changing from hfnc to niv or from niv to hfnc). secondary outcomes included arterial blood gas analysis [ph, pao (partial pressure of oxygen in arterial blood), paco , and fio ] and vital signs such as respiratory rate, heart rate, and blood pressure at , , and h after extubation, as well as the total duration of respiratory support after extubation, the daily number of nursing airway care interventions, the patients' comfort score, the patients' dyspnea score, the incidence of nasofacial skin breakdown, -day mortality, and total icu and hospital lengths of stay. airway care interventions were defined as the need for nursing staff to correct unplanned device displacement due to intolerance, discomfort, or another reason, or the need for nursing staff to assist in the removal or fixation of the device due to sputum, eating, or drinking. the patient's comfort score was assessed using a modified -cm visual analog scale, in which meant very uncomfortable and meant very comfortable [ ] . the patients' dyspnea was evaluated with a borg rating scale [ ] . the criteria for reintubation in this study were [ , ] cardiac arrest or obvious hemodynamic instability, refractory hypoxemia (pao < mmhg with sufficient oxygen therapy), significant hypercapnia with ph ≤ . , severe disturbances of consciousness such as coma, respiratory depression (respiratory frequency < /min), or severe dyspnea (respiratory frequency > /min). based on previous studies [ , ] , we estimated that niv would fail in % patients (either intubation or intolerance) of included copd patients, and the absolute difference of treatment failure rates between hfnc and niv was likely to fall between and % [ ] . after discussions with three senior pulmonologists, we set the non-inferiority cutoff at %. to assess non-inferiority using an α = . , β = . , and -sided testing, subjects were needed in each group ( total). for the primary outcome, analysis was performed both on an intention-to-treat and on a per-protocol basis. the kaplan-meier method was used to draw the cumulative survival and failure curves. the kolmogorov-smirnov test was used to test the normal distribution for measurement data. normally distributed data were expressed as means ± standard deviation, and the skewed distributed data was reported as medians with interquartile ( th- th) percentiles. the two groups were compared using t tests or mann-whitney u tests. numeric data were expressed as a percentage (%), using χ or fisher's exact probability tests. the comparison of vital signs and blood gas analyses at multiple time points was performed by repeated measures analysis of variance, or non-parametric test of multiple correlated samples (friedman test for heterogeneity of variance or the skewed distributed data), in which the significance level was adjusted using the bonferroni correction method. all data analysis was conducted using spss . (ibm corporation, armonk, ny, usa). among copd patients who received invasive ventilation in our enrolling centers during the study period, ( . %) patients were randomized to the niv or hfnc groups after patients were excluded for various reasons (see fig. ). six patients in the niv group and four patients in the hfnc group were secondarily excluded. finally, patients in the niv group and patients in the hfnc group were included in the analysis. demographic, relevant comorbidities, smoking history, copd medications, respiratory therapy at home, available pulmonary function tests, the simplified acute physiology score ii (saps ii), and the acute physiological and chronic health status score ii (apache ii) at admission in the two groups were similar (see table ). seventeen ( . %) patients in the hfnc group and ( . %) in the niv group initially received niv or hfnc after admission before invasive ventilation, and the remaining patients received invasive ventilation directly. there were also no significant differences in respiratory parameters, blood gas analyses, and vital signs between the two groups at the time of enrollment (pic window before extubation). the stable fio after extubation in the hfnc group was . ( . - . ), which was not significantly different from . ( . - . ) in the niv group. treatment failure occurred in patients ( . %) in the hfnc group and patients ( . %) in the niv group (risk difference, − . %; % ci, − . to . %; see table ). additionally, kaplan-meier curves showed no statistical difference in cumulative failure rates between the two groups (log-rank test . , p = . , see fig. ). among the patients with treatment failure, the intubation rate in the hfnc group was similar to that of the niv group (− . %; % ci, − . to . %), and the treatment switch rate was lower than that in the niv group (− . %; % ci, − . to . %). however, there were no significant differences between the two groups in intubation or treatment switch rate. analysis of the causes of treatment failure showed that treatment intolerance was significantly lower in the hfnc group than in the niv group, with a risk difference of − . % ( % ci, − . to − . %, p = . , see table ). there was no significant difference between the two groups in exacerbated respiratory distress, hypoxemia, or carbon dioxide retention. the causes for six intolerances in the niv group were feelings of data are shown as means ± standard deviation, number (%) patients, or median (interquartile range) hfnc high-flow nasal cannula oxygen therapy, niv non-invasive ventilation, copd chronic obstructive pulmonary disease, nco nasal cannula oxygen, icu intensive care unit, apache ii acute physiology and chronic health evaluation ii, saps ii simplified acute physiology score ii, imv invasive mechanical ventilation, pic pulmonary infection control, peep positive end expiratory pressure, paco partial pressure of arterial carbon dioxide, pao partial pressure of arterial oxygen, fio fraction of inspiration oxygen *twenty-five cases in the hfnc group and cases in the niv group claustrophobia (n = ), excessive air flow or pressure (n = ), breathlessness (n = ), and headache (n = ). heart rate and mean arterial pressure within h after extubation in the two groups were not significantly different from baseline levels before extubation. respiratory rate in both groups was faster than before extubation at h after extubation (p < . , see table ). the respiratory rate h after extubation in the hfnc group had decreased to its baseline and was lower than the respiratory rate in the niv group [ ( . - . )/min vs . ( - )/min, p < . ]. the niv group's respiratory rate was also higher than its baseline level. there was no significant difference in respiratory rate between the two groups at h after extubation. arterial blood gas analyses showed that the pao /fio and ph values in the hfnc group were lower than their baseline levels, while paco was higher than the baseline level h after extubation (all p < . , see table ). the pao /fio , ph, and paco in the hfnc and niv groups h and h after extubation were not statistically different from the baseline levels. there were no significant differences in the duration of post-extubation respiratory support, dyspnea scores, icu, or hospital total lengths of stay between the two groups (all p < . , see table ). the -day mortality in the hfnc group was . %, which was not significantly different from the . % in the niv group (logrank test . , p = . , see fig. ). the number of daily airway care interventions was significantly lower in the hfnc group than in the niv group [ ( - ) vs ( - . ), p = . ]. the comfort score in the hfnc group was also significantly higher than that in the niv group [ ( - ) vs ( - ), p < . ], whereas the incidence of nasofacial skin breakdown was significantly lower in the hfnc group than in the niv group ( vs . %, p = . ). this multicenter, randomized controlled trial showed that hfnc was not inferior to niv at preventing postextubation treatment failure and re-intubation for copd patients recently extubated after hypercapnic respiratory failure. compared with niv, hfnc was more comfortable and better tolerated. the number of airway care interventions and the incidence of nasofacial skin breakdown associated with hfnc were significantly lower than in niv. hfnc appears to be an effective means of respiratory support for copd patients extubated after severe hypercapnic respiratory failure. invasive ventilation is sometimes necessary to rescue copd patients with severe hypercapnic respiratory failure. weaning strategies which include niv are recommended as the standard treatment to reduce rates of ventilator-associated pneumonia and mortality without increasing the risk of re-intubation or weaning failure [ ] . however, niv intolerance appears in more than % patients due to various reasons, which increases the risk of treatment failure and re-intubation [ , ] . like in this study, many others have found that hfnc is often better tolerated than niv, but data on copd patients so far has been limited. hfnc has been increasingly suggested for use in patients with copd with acute hypercapnic respiratory failure. bräunlich et al. reported that in patients with an acute exacerbation of copd and a ph of less than . , hfnc increased the ph by . and reduced carbon dioxide by . mmhg [ ] . in a prospective observational study involving patients with moderate hypercapnic respiratory failure who were intolerant to niv, patients' ph improved and respiratory rate decreased with hfnc treatment, and the non-response rate to hfnc was only . % [ ] . subsequently, two cohort studies with larger samples showed that for copd patients with acute moderate hypercapnic respiratory failure, similar tracheal intubation and mortality rates were observed between hfnc and niv, while hfnc was better tolerated [ , ] . other efforts to observe the efficacy of hfnc in copd patients after invasive ventilation have been limited. in a cross-over study comparing hfnc to conventional low-flow oxygen therapy, hfnc was found to significantly decrease post-extubation work of breathing and neuroventilatory drive in copd patients recovering from acute hypercapnic respiratory failure [ ] . in a small randomized controlled trial, hypercapnic copd patients received either hfnc or niv immediately after extubation [ ] . at and h after extubation, the ph in the hfnc group was higher than niv group. no significant differences of vital signs and arterial blood gases were found at h after extubation. unlike in the above study, the respiratory rate in both groups of our study increased at h after extubation, which may be related to the relatively lower intensity of respiratory support after extubation. the respiratory rate in the hfnc group decreased to its baseline level h after extubation, while the respiratory rate in the niv group was still high at h. this can be explained by the relatively poor tolerance of niv and the increase in effective alveolar ventilation caused by the washout effect of dead space in hfnc. one hour after extubation, the ph in the hfnc group of this study decreased and the paco increased, while the niv group had no significant change from its baseline level. the difference between the two groups may be because hfnc does not have the added pressure support of niv, resulting in decreased ventilation and oxygenation. however, the excellent tolerance and increased effective alveolar ventilation gradually made up for the above deficiencies, so that there was no significant difference in blood gas values between the two groups at and h after extubation. to the best of our knowledge, this is the first randomized controlled trial to compare the failure rate of hfnc and niv in patients with copd after invasive ventilation. treatment failure in this study was defined as reintubation or switch to the other treatment modality. although the latter criterion added an element of patient subjectivity to the definition, this composite end-point reflects the pragmatic application of hfnc or niv in everyday clinical practice [ ] . analysis of the causes of treatment failure in this study showed that treatment intolerance was significantly higher in the niv group than in the hfnc group, suggesting that poor tolerance is an important reason for the failure of niv treatment. doshi et al. also found that % of niv failures were attributed to treatment intolerance, which was significantly higher than the % rate of hfnc [ ] . hfnc's design does not lead to a sense of claustrophobia, which significantly improves compliance. at the same time, the heating and humidifying function of hfnc enables the gas delivered to reach an absolute humidity of mg h o/l and a temperature of °c, which effectively promotes the discharge of secretions while avoiding side effects such as dry mucous membranes [ ] . because of these characteristics, patients can easily tolerate a gas flow rate of up to - l/min. the better tolerance of hfnc over niv is clearly seen in comparing the comfort scores between the two groups. the number of airway care interventions and cases of nasofacial skin breakdown in the hfnc group were also significantly lower than those in the niv group, which was related to the hfnc nasal plug design and better comfort. due to intolerance, drinking and eating, sputum clearance, communication, discomfort, or displacement of the niv mask, niv patients frequently remove their masks and significantly increase the nursing workload [ ] . patients in the hfnc group were not restricted by respiratory support in eating, drinking, and communicating. the incidence of skin breakdown and displacement of nasal prongs was extremely low. there were some limitations to this study. first, the primary endpoint of this study was a composite of reintubation rate and switching to the other treatment modality, which has potential limitations described above. as for the re-intubation rate, the possibility of obtaining a positive result by increasing the sample size cannot be ruled out. second, the settings for the hfnc gas flow in this study were based on each patient's tolerance level, which is subjective. in subsequent studies, the hfnc gas flow could be titrated through diaphragmatic potential or ultrasound assessment of diaphragmatic muscle movement for better standardization. finally, attending physicians could not be blinded to the study group since the devices were clearly different. however, investigators were excluded from clinical decisions and randomization was employed to help reduce bias. among copd patients with severe hypercapnic respiratory failure who received invasive ventilation, the use of hfnc as compared with niv after extubation did not result in increased rates of treatment failure, while hfnc had better tolerance and comfort. these findings support the use of hfnc in such patients, especially for those who cannot tolerate niv. abbreviations copd: chronic obstructive pulmonary disease; niv: non-invasive ventilation; hfnc: high-flow nasal cannula oxygen therapy; pic: pulmonary infection control; icu: intensive care unit; apache ii: acute physiological and chronic health status score ii; saps ii: simplified acute physiology score ii; paco : partial pressure of arterial carbon dioxide; pao : partial pressure of arterial oxygen; fio : fraction of inspired oxygen weaning from mechanical ventilation the attributable morbidity and mortality of ventilator-associated pneumonia in the critically ill patient. the canadian critical trials group efficacy of two noninvasive weaning strategies in intubated patients with chronic obstructive pulmonary disease: a meta-analysis and indirect treatment comparison pulmonary infection control window as a switching point for sequential ventilation in the treatment of copd patients: a metaanalysis practical insight to monitor home niv in copd patients causes of failure of noninvasive mechanical ventilation evolution of mechanical ventilation in response to clinical research complications of noninvasive ventilation in acute care a multicenter randomized trial assessing the efficacy of helium/oxygen in severe exacerbations of chronic obstructive pulmonary disease high-flow oxygen through nasal cannula in acute hypoxemic respiratory failure nasal highflow improves ventilation in patients with copd high-flow oxygen therapy after noninvasive ventilation interruption in patients recovering from hypercapnic acute respiratory failure: a physiological crossover trial can high-flow nasal cannula reduce the rate of reintubation in adult patients after extubation? a meta-analysis effect of postextubation high-flow nasal cannula vs noninvasive ventilation on reintubation and postextubation respiratory failure in high-risk patients: a randomized clinical trial comparison of high flow nasal cannula with noninvasive ventilation in chronic obstructive pulmonary disease patients with hypercapnia in preventing postextubation respiratory failure: a pilot randomized controlled trial clinical guideline highlights for the hospitalist: the gold and nice guidelines for the management of copd perceived exertion as an indicator of somatic stress what determines immediate use of invasive ventilation in patients with copd? global strategy for the diagnosis, management, and prevention of chronic obstructive lung disease report. gold executive summary non-invasive positive pressure ventilation to treat respiratory failure resulting from exacerbations of chronic obstructive pulmonary disease: cochrane systematic review and meta-analysis collaborating research group for noninvasive mechanical ventilation of chinese respiratory, s. pulmonary infection control window in treatment of severe respiratory failure of chronic obstructive pulmonary diseases: a prospective, randomized controlled, multi-centred study non-invasive ventilation for the management of acute hypercapnic respiratory failure due to exacerbation of chronic obstructive pulmonary disease noninvasive ventilation intolerance: characteristics, predictors, and outcomes treatment of acute hypoxemic nonhypercapnic respiratory insufficiency with continuous positive airway pressure delivered by a face mask: a randomized controlled trial nasal high-flow in acute hypercapnic exacerbation of copd efficacy and safety of high-flow nasal cannula oxygen therapy in moderate acute hypercapnic respiratory failure. rev bras ter intensiva high flow nasal cannulae oxygen therapy in acute-moderate hypercapnic respiratory failure high flow nasal cannula oxygen therapy versus non-invasive ventilation for chronic obstructive pulmonary disease with acute-moderate hypercapnic respiratory failure: an observational cohort study high-flow nasal cannula oxygen therapy decreases postextubation neuroventilatory drive and work of breathing in patients with chronic obstructive pulmonary disease high-flow nasal oxygen vs noninvasive positive airway pressure in hypoxemic patients after cardiothoracic surgery: a randomized clinical trial high-velocity nasal insufflation in the treatment of respiratory failure: a randomized clinical trial high-flow nasal cannula oxygen therapy in adults: physiological benefits, indication, clinical benefits, and adverse effects publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations none. the datasets used and analyzed during the current study are available from the corresponding author in response to reasonable requests. this study was approved by the human subjects ethics committees of the two hospitals involved ( ky- and ), and informed consent was obtained from all enrolled patients or their relatives. not applicable. the authors declare that they have no competing interests. key: cord- -fxus mp authors: nan title: lung cancer/bronchology sigs: combined poster session date: - - journal: respirology doi: . /j. - . . _ .x sha: doc_id: cord_uid: fxus mp nan increased airway smooth muscle (asm) in asthma may be due to hyperplasia or hypertrophy of asm cells. the contribution of extracellular matrix (ecm) within asm bundles has not previously been accounted for when estimating asm cell volume. aim to estimate the mean asm cell volume in asm bundles in asthma. methods post-mortem tissues from control subjects (c n = ); nonfatal (nfa n = ) and fatal (fa n = ) cases of asthma were studied. on mm transverse airway sections stained with haematoxylin, the volume density (nv) of asm cell nuclei was estimated using an optical disector (¥ ). the mean cell volume (vc = /nv) was calculated, correcting for the volume fraction of asm (fasm) within the asm bundle (corrected vc = /(nv ¥ fasm)). fasm was estimated on . mm thick sections of the same airway stained with masson's trichrome. basement membrane perimeter (pbm) was used to indicate airway size. results table shows mean Ϯ sd. (one-way anova) *p < . for c v fa, nfa v fa. conclusion these data suggest that although asm area is increased in asthma, mean asm cell volume is unchanged. therefore hyperplasia, not hypertrophy, of asm cells is present in both mild and severe asthma. these results were similar for both large and small airways. asthma is characterized by airway inflammation and remodelling which contribute to airway hyperresponsiveness and episodic airflow obstruction. mast cell (mc) densities are higher on the smooth muscle (asm) in asthma so their mediators may modulate other asm functions as well as cause contraction. aim to investigate the effect of mc mediators on chemokine and extracellular matrix (ecm) production by asm cells from donors with and without asthma. methods mc were isolated from the resected lung samples of patients, resuspended at cells/ml in dmem + % fbs and stimulated with ige/anti-ige. supernatants (sn) were collected after and h and the mc lysed. sub-confluent asm cells from donors with and without asthma were serum deprived for h before mc sn/lysates were added in dmem + %fbs for h. il- and eotaxin levels in all asm sn and mc sn/lysates were measured by elisa. fibronectin and collagen iv deposition was measured in situ by immunoassay following asm cell lysis. results in asthmatic and non-asthmatic asm cells all mc sn and lysates reduced eotaxin release by up to % and %, whereas the - h mc sn significantly increased il- release to Ϯ . % (p = . ) and Ϯ % (p = . ) of the fbs control respectively. however, only nonasthmatic asm cell il- release was increased by the mc - h sn ( Ϯ %; p = . ) and cell lysates ( Ϯ %; p = . ). the - h mc sn also increased fibronectin deposition to Ϯ % (p = . ) by asthmatic asm cells only. mc sn and lysates had no effect on collagen iv deposition. conclusions activated mast cell mediators differentially modulated chemokine and ecm secretion by asm cells from donors with and without asthma. thus mast cells may modulate their own recruitment to the smooth muscle and remodelling locally in the airways in asthma. supported by nhmrc. the technique of ige passive sensitization reproduces ige-related allergic responses in vitro and studies have validated this technique for investigations modelling allergic smooth muscle responses. there are no studies investigating effects of ige sensitization on rhinovirus (rv) infection. we hypothesized that rv infection is enhanced by ige sensitization, a consequence of diminished early innate immune responses. methods beas- b epithelial cells and primary culture airway fibroblasts were sensitized with ige h- d prior to infection with rv . samples of tissue culture supernatant and cell lysates were collected over a h period after infection for analysis. viral replication was measured by real-time rt-qpcr and viral titration and type i interferon mrna by rt-qpcr. ige receptor mrna expression was examined using rt-pcr. results initial studies to establish the model used human serum high in ige (> iu/ml), this yielded inconsistent results and it was found that purified ige ( iu/ml) provided more reliable responses. sensitization was established after h ige incubation and was comparable with up to d. rt-pcr detected mrna for the ige low affinity receptor only after sensitization. following rv infection, vrna was increased after h in ige sensitized cells (p < . ), but this effect varied noticeably between and within cell lines. cellular expression of ifn-b mrna increased with viral infection but in cells sensitized with ige lower levels of expression were noted (p < . ). conclusions ige passive sensitization enhanced rv replication in vitro but the model is constrained by significant variability between and within cell lines. the effect of sensitization on rv replication may occur through the low affinity ige receptor. activated mast cells (mc) are present in higher numbers on the airway smooth muscle (asm) in asthma compared with other inflammatory airway diseases. matrix metallo-proteinases (mmps) cleave chemokines and alter chemokine gradients by degrading the extracellular matrix and thus may modulate mc migration to the asm. aim to determine the levels of mmp- , mmp- and their inhibitors, timp- and timp- , secreted by asm cells from donors with and without asthma. method confluent asm cells were washed, serum-starved for h and then stimulated with th (il- , tnf and ifn) or th (il- , il- and il- ) cytokines or left unstimulated. after and h,the sn were collected. the relative amount of pro and active forms of mmp- and mmp- in sn were determined by gelatine zymography. timp- and timp- levels in the sn were measured by elisa. results pro-and active mmp- were not detected. however, pro-mmp- levels were high in sn of asm cells from donors with ( . Ϯ . % positive control/ cells) and without ( . Ϯ . % positive control/ cells) asthma. a trend to increased active mmp- production by asm cells from donors with ( . Ϯ . % positive control/ cells, n = ) compared to without ( . Ϯ . % positive control/ cells, n = ) asthma after h was not significant (p = . ). timp- and timp- levels respectively were high in the sn of cells from donors with ( . Ϯ . and . Ϯ . ng/ cells, n = ) and without ( . Ϯ . and . Ϯ . ng/ cells, n = ) asthma. th and th cytokine stimulation did not affect mmp or timp release. conclusions th and th cytokines did not regulate asm cell production of mmp- , timp- and timp- . altered asm mmp- activity is unlikely to play a role in mc chemotaxis to asm cells from donors with asthma in vitro or their presence on the asm in asthma. there has been a marked increase in the prevalence of asthma and other allergic diseases in the last few decades. one of the explanations for this is the change in our diet. one of the characteristics of the "western diet" is a high intake of both saturated and polyunsaturated fat. this prompted us to compare the effects of high fat and low fat meals on the numbers of circulating eosinophils and other leukocytes. methods we studied volunteers who had allergic rhinitis and/or asthma and a peripheral eosinophil count at baseline of Ն ¥ /l. this was a randomized, crossover trial with participants studied on two different days. on each occasion they arrived fasting and after bloods were drawn consumed a calorie meal. one of the meals was high in saturated fat and refined carbohydrate. the other meal was low in saturated fat and high in fruit and fibre. bloods were drawn postprandially every hour for five hours. results eosinophil counts were highest in the early morning and fell over the course of the day but the decrease was less with the high fat meal (p = . ). over the same period of time the increase in lymphocytes (p = . ) was greater with the high fat meal. the high fat meal was also associated with greater increases in triglycerides (p < . ) and cholesterol ( . ). conclusions in atopic individuals a high fat meal was associated with higher circulating numbers of eosinophils and lymphocytes than an isocaloric meal that was low in fat. further studies of the effect of dietary fat on eosinophilic inflammation are warranted. supported by the university of auckland research committeee. intravenous gamma globulin therapy (ivig), which is therapeutic in a variety of immune diseases, has been reported to be effective on patients with severe steroid-dependent asthma. although fcer are known to play important roles in asthma, there are few reports about the role of fcg?receptors in asthma. fcg receptor iib (fcgriib) is unique inhibitory receptor, which suppresses immune response. in this study, we evaluated the effect of ivig in allergic airway inflammation in ova-challenged mice and the mechanism of the inhibitory effects of ivig and fcgriib. method c bl/ mice (wt) and fcgriib deficient mice (ko) were sensitized with ovalbumin (ova) and alum and subsequently challenged with nebulized ova. before ova challenge rabbit igg was administered intravenously. the airway inflammation and effects of igg were assessed by histology, cell counts of bal fluid and airway hyperresponsiveness. result histology showed that igg treatment ameliorated the inflammation around the airway and the vessels and hypertrophy of goblet cells induced by ova challenge. the migratory activity of dcs is modulated in inflammatory diseases such as asthma. recently, we reported that immature dcs express kinin receptors and that bradykinin (bk) significantly enhances the migration of immature dc in vitro. as kinins mediate many of the pathophysiological effects associated with asthma, we hypothesized that lys-des[arg ]-bk, which is produced during inflammation and acts via the b receptor (b r), would inhibit migration of mature dcs. methods day cultured human monocyte-derived dcs were matured with lps, tnfa +il- b or cd l in the absence or presence of lys-des[arg ]-bk. maturation of dc was analysed by flow cytometry (facs). b r expression was assessed by reverse-transcriptase pcr and quantitative confocal microscopy. migration of mature dc was assessed in transwell chambers with lysdes [arg ]-bk and the chemokine ccl used as chemoattractants. results maturation of dcs was found to result in down-regulation of b r expression to varying degrees depending upon the maturation stimulus used. mature dcs all demonstrated an ability to migrate toward lys-des[arg ]-bk and ccl . however pre-treatment with lys-des[arg ]-bk decreased the migratory ability of all mature dcs to both chemoattractants. conclusions along with chemokines, lys-des[arg ]-bk is likely to play a crucial role in regulating the in vivo migration of mature dc during inflammation. the production of lys-des [arg ]-bk during inflammation potentially immobilizes mature dcs thereby facilitating locally-mediated immune responses within inflamed tissues. supported by the asthma foundation of western australia. introduction alternative or aberrant splicing is a major contributor to protein diversity, in which a single gene can generate structurally and functionally distinct protein isoforms. the role of alternative splicing in asthma pathogenesis has not been previously investigated. we hypothesized that specific alternatively spliced asthma candidate genes contribute to the development of asthma. we chose to use a new and innovative approach involving the use of the genechip (r) exon array system together with real-time quantitative pcr to study asthma candidate genes in human monocyte-derived dendritic cells. asthmatic and non-asthmatic subjects provided ml of blood from which peripheral blood mononuclear cells (pbmc) were isolated by ficoll-paque gradient centrifugation. monocytes were separated from other leukocytes by adherence method, and differentiated into dendritic cells following incubation with defined concentrations of gm-csf and il- . rna was isolated and reverse transcribed for real-time semi-quantitative pcr and densitometry. chi squared test was used to assess associations between alternative splicing and asthma. results data indicate splice variant expression in dendritic cells from asthmatic patients is influenced by asthma severity. conclusion exon expression array analysis has generated a number of asthma candidate genes with alternative splice variants. further studies to validate these data in a replicate data set and establish the functional significance of our findings in asthma are underway. alternative or aberrant splicing occurs in more than % of genes and is a major contributor to protein diversity, in which a single gene can generate structurally and functionally distinct protein isoforms . the role of alternative splicing in asthma pathogenesis has not been previously investigated. we hypothesized that specific alternatively spliced asthma candidate genes contribute to the development of asthma. we chose to study one asthma candidate gene in human stimulated and unstimulated: ( ) monocytes, ( ) monocytederived dendritic cells and ( ) lung smooth muscle cells. methods asthmatic and non-asthmatic subjects provided ml of blood from which peripheral blood mononuclear cells (pbmc) were isolated by ficoll-paque gradient centrifugation. monocytes were separated from other leukocytes by adherence method. up to % of the monocytes were then differentiated into dendritic cells following incubation with defined concentrations of gm-csf and il- . induction experiments used mg/ml lps and cells were stimulated for an optimal period of hrs. rna was isolated and reverse transcribed for real-time semi-quantitative pcr and densitometry. chi squared test was used to assess associations between alternative splicing and asthma. results data from stimulation experiments indicate splice variant production can be regulated by the inflammatory response and that this response is influenced by asthma status. conclusion preliminary experiments have confirmed the presence of an aberrant splice variant for an asthma candidate gene in the primary cells studied. further studies to confirm these data and establish the functional significance of our findings in asthma are underway. exposure to environmental factors, such as environmental tobacco smoke (ets), plays a significant role in modulating pre-existing genetic susceptibilities to diseases including asthma. the glutathione s-transferase enzymes (gsts) play an important role in the detoxification of ets. there are several gst isoforms and gstp codes for the gst pi isoform, which is the primary gst isoform expressed in human lung tissue. two single nucleotide polymorphisms (snps) at positions and have been reported in gstp and associated with asthma and atopy. the aim of this study was to examine the effect of these snps in combination with ets, on asthma phenotypes in a cohort of asthmatic children. children were recruited during an acute episode requiring presentation at an emergency department. genotyping using pcr-rflp was completed on children and ets exposure was determined by parental questionnaire. urinary cotinine was measured in the children and was in agreement with questionnaire responses. statistical analyses were performed using spss. there were no significant associations between the genotypes and asthma severity during acute exacerbations. significant associations were found between the snps and atopy in this population with an odds ratio of . for the aa genotype (p = . ) and or of . for the cc genotype (p = . ). however, when an interaction with ets was included, the odds ratios increased to . for aa (p = . ) and . for cc (p = . ). these results suggest that there is a significant gene/environment interaction impacting on atopy in this cohort. the rage gene encodes the receptor for advanced glycation end-products (rage), a member of the immunoglobulin superfamily. rage activation by ligands, including amphoterin and s /calgranulins, leads to prolonged nf-kb signalling and has been associated with chronic inflammation. despite high levels of rage expression in lung tissue, little research has been undertaken into the role of rage in the chronic inflammatory asthma phenotypes of severe and aspirin-sensitive asthma. objective determine genetic associations between functional polymorphisms in the rage promoter and severe and aspirin-sensitive asthma phenotypes. methods pcr and restriction fragment length polymorphism (rflp) were used to genotype three rage promoter polymorphisms, - t>c, - t>a and a bp deletion from - to - , in a large case-control asthma population phenotyped for asthma severity, atopy and aspirin sensitivity. results no associations were identified between any of the polymorphisms and the occurrence of asthma. however, the - a allele was linked with both severe asthma (p = . ) and aspirin-sensitive asthma (p < . ). likewise, genotypes containing the - a allele were strongly associated with both severe asthma (or . , % ci . - . ) and aspirin-sensitive asthma (or . , % ci . - . ). conclusions the - a allele of the rage gene, previously shown to lead to a -fold increase in promoter activity, is associated with the chronic inflammatory asthma phenotypes of severe and aspirin-sensitive asthma. these results suggest that increased rage expression, with a concomitant increase in nf-kb signalling, may in part contribute to the inflammatory response seen in these conditions. the global prevalence of allergic diseases is rising and australia has one of the highest prevalence rates in the world. the role of early childhood infections in the development of allergic disease remains controversial. objective to examine the association between early childhood infections and the development of allergic diseases in later childhood, in high risk children. methods data were analysed from the melbourne atopic cohort study (macs) of infants with or more first-degree family members with atopic disease. primary risk factors assessed were otitis media, bronchitis and gastroenteritis reported in the first two years of life. outcomes were current asthma, hay fever and eczema at years of age. logistic regression was used to estimate crude and adjusted odds ratios. results asthma was the most common allergic condition ( . %, % ci . - . %), followed by eczema ( . %, % ci . - . %) and hayfever ( . %, % ci . - . %). the most commonly reported infection was otitis media ( . %, % ci . - . %), then gastroenteritis ( . %, % ci . - . %) and then bronchitis ( . %, % ci . [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . %). all types of infection within the first years of life were associated with increased risk of asthma. an increased risk of asthma at years was seen with otitis media (or = . , % ci . - . ), bronchitis (or = . , % ci . - . ) and gastroenteritis (or = . , % ci . - . ). when the frequency of infection was examined, those who reported at least episodes of gastroenteritis had a - -fold increased risk and an almost % absolute increased risk (rd . , % ci . - . ). conclusion these findings appear to contradict the hygiene hypothesis. the findings for gastroenteritis are novel. further examination of these associations and possible underlying mechanisms is warranted. grant support asthma foundation of victoria, nestle. background knowledge about incident cases of asthma in australia is limited because they are not routinely reported. the ability to predict the number of new cases of asthma would be helpful in allocating resources for asthma education, management and care. data on first use of medications for asthma gives an indication of the incidence of asthma. the objective of this study was to estimate the incidence rate of asthma by investigating asthma medication use in individuals. methods pharmaceutical benefits scheme (pbs) records for all prescriptions filled for inhaled corticosteroids (alone or combined formulation), cromones and leukotriene receptor antagonists from july to june were included. using a -year look back window, any persons who had their first prescription for any of these drugs dispensed between july and june were assumed to be incident cases. overall and age-specific incidence rates were calculated per asthma-medication-free individuals. results there were , individuals who had their first asthma medication dispensed between july and june , which equates to an overall incidence rate for asthma of . per . the incidence was higher among children aged - years ( . ) and adults aged years and over ( . ) . conclusions our estimated incidence rates were consistent with those reported by others in the literature. while the pbs database was designed for administrative purposes, it can be used to estimate incidence rates for asthma. support acam is a collaborating unit of the australian institute of health and welfare and is funded by the department of health and ageing (doha). we acknowledge the pharmaceutical pricing and estimates section of doha for provision of pbs data. keywords asthma incidence, pharmaceutical benefits scheme. rosario ampon , guy marks , teresa to , leanne poulos , anne-marie waters australian centre for asthma monitoring (acam), sydney, australia, and hospital for sick children, toronto, canada background the ability to assess individual patterns of asthma medication use would have clinical relevance in targeting effective asthma education and management for this common condition. to describe longitudinal patterns of asthma medication use, we used a population-based prescription database to follow individuals from the first time they filled an asthma prescription. asthma is more commonly listed on death certificates as an associated cause of death, in people whose deaths are attributed to other causes, than as an underlying cause of death. understanding the importance of these associations would contribute towards an overall appreciation of the impact of asthma on mortality. the objective of this analysis was to estimate the prevalence of asthma as an associated cause of death when various other diseases were attributed as the underlying cause of death. background acam currently recommend indicators to measure population-level asthma health and outcomes. we examined correlations among several asthma indicators covering prevalence, morbidity and mortality to try and produce a condensed set of indicators which minimized redundancy. methods seven of the indicators were included in this study: prevalence of ever having doctor diagnosed asthma, prevalence of current asthma, asthma-related general practice (gp) encounters, proportion of people with asthma with an asthma action plan (aap), hospitalizations for asthma, hospital patient days for asthma, and deaths due to asthma. a correlation matrix was created for these indicators by age groups. pearson correlation coefficients Ն . or Յ- . were considered strong. results there were strong positive correlations between prevalence of ever asthma and current asthma (r = . ); gp visits and aap possession (r = . ), hospitalization (r = . ) and patient days (r = . ); and hospitalization and patient days (r = . ) and aap possession (r = . ). recent australian reports have shown that the prevalence of asthma and respiratory symptoms has decreased over the last - years. as part of a larger study investigating child health and air quality we have collected nationwide data from schoolchildren living in act, victoria, queensland, wa and sa. methods schools were selected based on proximity to air quality monitoring stations. classes from years to were randomly selected and all children were invited to participate. parents self completed a questionnaire that included questions about diagnosed asthma and respiratory symptoms. results a total of children provided questionnaires for analysis. the response rate varied between states and territories and ranged from % to %. the sample comprised . % girls and the mean age of children was . years. ever diagnosed asthma . current asthma ('does he/she still have asthma? ') . wheeze in the past months . respiratory symptoms limiting activities . missed school due to asthma or wheezing . conclusions despite the relatively low participation rate, the prevalence estimates for current asthma are similar to those reported in the national health survey - [ ] . there is no evidence of any recent increase in the prevalence of childhood asthma. methods tahs is a longitudinal population-based respiratory study of subjects which commenced in when they were years of age. since the initial study another follow-ups have been conducted, including the most recent follow-up when subjects were years of age. lung function of the total sample was measured at baseline and in sub-samples in subsequent followups. asthma was categorized as persistent, frequent or episodic when participants reported asthma symptoms in at least follow-ups, in follow-ups or in follow-up respectively. results by age years ever asthma prevalence was %. at age , % of those who had not reported asthma by age had asthma symptoms while % of those who reported asthma by age had no asthma symptoms. hence over all only % of the asthma symptoms at age were attributable to asthma developed by age . in contrast, % of the persistent and frequent asthmatics had developed their asthma by age . persistent and frequent asthmatics had more symptoms and poorer lung function at age , and as well as more reversibility at age (p < . ). childhood asthmatics who also had a productive cough by age were more likely to have persistent asthma than those without a cough (p < . ). conclusions although the majority of middle-age asthma is related to postchildhood onset asthma, most severe middle-age asthma has its origin in persistent childhood disease. having productive cough in childhood may identify high risk asthmatics who require especially rigorous management in early life. one third of women experience an improvement in asthma during pregnancy, and symptoms improve in most women in the late third trimester. we hypothesized that the exacerbation rate would be reduced and that symptoms during exacerbations would be less severe in the third trimester compared to the second trimester. methods pregnant women with asthma (n = ) were prospectively followed from recruitment ( . weeks ( sd) ) to delivery at clinic visits ( , , weeks and during exacerbation), and fortnightly phone calls. the asthma control questionnaire (acq) was administered at each contact and exacerbations classified as severe (requiring medical intervention) or mild (selfmanaged). lung function, medication use, fractional exhaled nitric oxide (feno) and full blood counts were assessed. paracetamol is commonly used in infants as an analgesic and antipyretic. it has been hypothesized that frequent paracetamol consumption may result in reduced lung capacity to cope with oxidative stress and increase risk of respiratory disease. to date, no study has examined exposure to paracetamol during infancy, when lungs are still developing, and risk of childhood asthma. method a birth cohort of infants with an atopic family history was recruited. frequency of paracetamol exposure was prospectively documented up to years of age. interviews were conducted at and years to ascertain asthma in the previous months. results paracetamol exposure in infancy was common ( % exposed by two years of age), with some infants receiving paracetamol on up to days. it has been hypothesized that mucosal immune response requires a particular micro-flora milieu in the infant's gastro-intestinal tract, and that early life antibiotic exposure may disrupt this process and increase risk of allergic disease. method a birth cohort of infants with an atopic family history was recruited. exposure to oral antibiotics was prospectively documented up to months of age. interviews were conducted at and years to ascertain asthma in the previous months. results by one year of age, approximately % of infants had received at least one course of oral antibiotics. the prevalence of current asthma in childhood was approximately % ( / ). frequent use of antibiotics (more than days exposure during first year of life) was associated with increased risk of childhood asthma (or = . , % ci = . - . ) when compared to infant who had not been exposed. excluding infants with a diagnosis of asthma within the first two years of life, reduced this association by about % (or = . , % ci = . - . ) and adjustment for gender, parental history of asthma and number of infections in the first year of life further reduced this association (or = . , % ci = . - . ). the increased risk of childhood asthma associated with antibiotic exposure in the first year of life is, at least in part, due to confounding with early life wheeze and infections. if real, the independent effect of antibiotic exposure on risk of childhood asthma is likely to be minimal in this high risk cohort. support dairy australia, crc for asthma and airways, vichealth, nestle. the epidemiological data on asthma suggest a gender difference that varies with age. hormonal effects have been suggested as a possible explanation for these differences. the aim of this study was to examine reproductive factors and risk of asthma among the females of the tasmanian longitudinal health study (tahs). methods the tahs is a longitudinal population-based cohort study of respiratory disease which commenced in when subjects were years of age. four follow-up studies have been conducted including the current most comprehensive follow-up with subjects at years of age. information has now been collected on reproductive factors such as number of pregnancies, age at pregnancies, age at menarche and contraceptive pill use as well as on asthma status. reproductive factors were examined as risk factors for asthma using multiple logistic regression to adjust for all likely confounders. results a total of , women completed the most recent postal survey. of these ( . %) had current asthma, and of these women with current asthma . % ( ) developed asthma after childhood. on average these women were in their mid-twenties when they developed asthma (mean Ϯ sd age = . Ϯ . yrs). we found with increasing age at first birth an approxi-mate~ % reduced risk of current asthma in women who developed their asthma post-childhood (trend p = . ). we did not observe any other associations between reproductive factors and risk of asthma. conclusions our results are consistent with the hypothesis that early pregnancy may promote asthma development by altering the immune response favouring a th pathway. a delay in the age of first pregnancy reduces this risk of asthma. grant support nhmrc, clifford craig foundation, victorian & tasmanian asthma foundations. introduction the association between exposure to pets in early life and subsequent development of sensitization and allergic disease remains controversial. the objective of this analysis was to examine the relationship between cat exposure before birth and development of cat sensitization over time within the melbourne atopic cohort study (macs). methods the macs is a prospective longitudinal cohort study that initially recruited women antenatal in melbourne from february to november . detailed information on cat exposure was collected at recruitment and frequently until two years of age. skin prick test (spt) were conducted at , , months and years. the data were analysed by logistic regression and using generalized estimating equations (gee) for the repeated measures design. results among subjects, ( . %) had a cat before birth. at months, . % (n = ) of subjects were sensitized to cat and by years of age . % (n = ) were sensitized. those who did not have cat before birth belong to a higher social class, and were more likely to have a father with allergic disease than those with a cat. those who developed sensitization to cat were more likely to have a paternal family history of allergic disease and more likely to be sensitized to other allergens. we did not observe any association between exposure to cat before birth and the development of sensitization to cat at months (or = . , % ci . - . ) , months (or = . , . - . ), months (or = . , . - . ) or years (or = . , . - . ) . these crosssectional results were confirmed by the gee analysis. conclusion our results fail to show an association between cat exposure before birth and development of sensitization to cat. furthermore exposure after birth in the first months of life was not associated with an increased or decrease risk of sensitization to cat. our results do not support either a benefit or risk associated with cat ownership and sensitization. introduction peri-natal events influence the development of asthma and atopic diseases in childhood but the current literature is contradictory on the effect of low birth weight, small for gestational age and prematurity on asthma risk. the aim of this study was to assess the relationship between these three exposures and asthma from childhood to adulthood. aim to assess the current prevalence of dda, wheeze (< months), atopy and ahr in children and adults in busselton. methods an age-and sex-stratified random sample of adults, selected from the electoral roll, was invited to complete a questionnaire and attend the local study centre for assessment of atopy (allergen skin tests) and ahr (methacholine). all children from participating primary and secondary schools were also invited to attend. the prevalences of dda, wheeze, atopy, ahr and "current asthma" (wheeze + ahr) were calculated. background asthma is often associated with comorbidity, however few studies have investigated comorbidities among people with this common condition. the objective of this analysis was to describe patterns of non-respiratory comorbidity among adults hospitalized with asthma in australia. methods data on hospitalizations for people aged years and over with a principal diagnosis of asthma (j , j ) were obtained from the australian institute of health and welfare's (aihw) national hospital morbidity database for the period - . patterns of comorbidity were examined by investigating additional diagnoses for non-respiratory disease according to icd- diseasespecific chapters. results among people aged years and over hospitalized in - with a principal diagnosis of asthma ( , hospitalizations; % female; % aged - years), % had at least one non-respiratory comorbidity. median length of stay was higher among those with at least one comorbidity ( days) than among those with no comorbidities ( days). among people aged - years, the most common comorbid condition was endocrine, nutritional and metabolic diseases ( %), while among those aged years and over it was diseases of the circulatory system ( %). conclusions a large proportion of asthma hospitalizations in australia are associated with non-respiratory comorbidity and a longer length of stay. further, the pattern of non-respiratory comorbidity associated with asthma hospitalizations varies by age. given our rapidly ageing population, the level of comorbidity associated with asthma has implications for coordinated health care and demand on health services. support acam is a collaborating unit of the aihw and is funded by the department of health and ageing. keywords comorbidity, hospitalization, asthma. background asthma exacerbations are often triggered by viral respiratory infections, yet the influence of respiratory infections on the morbidity of acute asthma beyond the immediate period is unknown. we examined the influence of nasopharyngeal (npa) respiratory viral, chlamydia and mycoplasma detection on asthma morbidity in children presenting to the emergency department for an acute exacerbation of asthma. methods a subset (n = ) of the children enrolled for a randomized controlled trial (rct) on the efficacy of vs days of oral prednisolone had an npa taken at presentation. npa were examined for chlamydia, mycoplasma and respiratory viruses (enteroviruses, coronaviruses, human metapneumovirus, adenovirus, parainfluenza, influenza, rsv, rhinoviruses) by pcr. enrolled children were aged - years with recurrent wheeze and required Ն ?g (mdi/spacer) or Ն . mg (nebulized) of salbutamol to reduce tachypnoea. parents filled validated diary cards for cough and asthma severity, and completed asthma qol data at enrolment and end of weeks and . results pcr for various viruses was positive in ( . %) children, with no significant difference in the groups the children were randomized into. rhinovirus pcr was positive in the npa of children, rsv in , hmpv in , adenovirus, parainfluenza, influenza a and b in one each. specimens were negative for the other micro-organisms listed above. children with a npa viral positive state were significantly (p = . ) younger than those with a negative state. however, there was no difference in the any of the asthma outcomes of children whose npa was positive or negative for the micro-organisms tested. conclusions in children with an acute asthma exacerbation presenting to emergency health facilities, a respiratory virus could be identified in > % but the presence of a respiratory virus did not influence the morbidity of the asthma exacerbation at presentation or at the end of week- and week- . the university of sydney, nsw , and royal north shore hospital, st leonards, nsw airway wall thickness measured using hrct is reported to be increased in asthmatic compared with control subjects. however, it is unknown whether wall thickness is a fixed structural characteristic of the airways or if it responds to transient changes in bronchomotor tone or airway size. aim to determine the effects of bronchomotor tone and lung volume on airway wall area measured by hrct. methods patients with doctor-diagnosed asthma had partial chest hrct scans, before and after bronchodilator (bd), at frc, tlc and a volume midway between (mid-volume). airway segments were identified between branch points and matched between consecutive lung volumes both before and after bd, and also at constant lung volume before and after bd. mean lumen areas and wall areas for each airway segment at each volume were measured using automated analysis software. paired t-tests were used to determine changes due to bd and lung inflation. results airways were matched before and after bd at frc. absolute airway wall area (wa) was related to airway lumen diameter (di wood smoke air pollution is of concern with respect to respiratory health due to its complex chemical composition and potential to carry air toxics into the lower respiratory system. launceston has a long history of poor winter air quality, primarily due to use of domestic wood heaters. participants in hobart had a similar prevalence of wood heater use, but hobart does not experience the same wood smoke pollution (due to differences in regional geography , asthma control and anxiety and depression were completed at baseline, immediately following ( wks), and mths after the intervention period. results clinically and statistically (p < . ) significant improvements in qol were observed in the exercise group at wks compared to the control group. this difference was not maintained at mths. mwd improved at wks and mths in the exercise group (p < . ), however the difference between groups was not significant. in the exercise group there was a trend towards improved asthma control and a reduction in anxiety and depression that was not observed in the control group. *p < . , change at wks vs baseline; home asthma monitoring is important for measuring day-to-day variation in lung function and symptoms. this approach requires the availability of complete diaries for a comprehensive assessment. we assessed the completeness of written diaries collected as part of a nation wide study of air quality and child health. methods children who had ever been diagnosed with asthma and had respiratory symptoms in the last year were identified from a cross-sectional study. these children were asked to record symptom scores and peak expiratory flows twice daily in diaries for a five week period. the diaries and peak flow devices were explained at a face-to-face meeting with parents and children. each week diaries were mailed back and parents received a phone call to encourage completion. completeness was defined as no missing responses to symptom questions or peak flow measurements in diaries from week two to week five. results data from the first children ( day records) were available for analysis. the sample included ( %) girls, mean age yrs. the overall frequencies for complete records were; morning symptoms %, morning peak flow %, evening symptoms % and evening peak flow %. there was a significant trend for more complete morning peak flow records over the four weeks (cochrane-armitage trend test p < . ). agreement between morning and evening symptom completeness and between morning and evening peak flow completeness was fairly poor (kappa < . ). conclusions the completeness of symptom and peak flow records collected in this study was very high. the comprehensive follow-up protocol implemented is likely to have had an important impact on the completeness of asthma diaries. daily peak expiratory flow (pef) monitoring has been used in epidemiological studies to assess changes in lung function over time. the value of written pef diaries has been questioned because of problems with completeness and validity. this study aimed to compare stored electronic pef data and a written diary record of those data in a panel study in children with weekly reminders to aid adherence. methods children who had ever been diagnosed with asthma and had respiratory symptoms in the last year were identified in a population study. they were given electronic pef devices with a digital readout (miniwright digital, mwd, clement clarke, uk) and written symptom and peak flow diaries and instructed in their use at a meeting with parents and children. each child was asked to complete three pef manoeuvres every morning and evening for five weeks and to record these in the written diary. background previous research suggests that comorbid anxiety is associated with lower asthma-related quality of life (aqol) in adults with asthma. however, research is scant on the role of psychological interventions in these patients. aim to evaluate the effectiveness of a four-session cognitive-behavioural therapy (cbt) intervention, in improving the aqol, in participants with anxiety and asthma. method participants identified with comorbid anxiety and asthma were randomly assigned to the cbt intervention group (n = ) and the asthma monitoring control group (n = ) and evaluated on aqol measures, at various intervals. results nine participants, in the cbt group, completed the study. seven participants showed a clinically significant improvement in asthma-related emotional functioning (ef) and six participants in total aqol scores, at the -week post-intervention assessment. additionally, six participants in the cbt group indicated clinically significant improvement in ef and five participants in total aqol scores, at the -month follow-up assessment. only three participants in the control group completed the study. none of these participants showed any improvement in aqol scores at the -week or -month assessment. conclusion this pilot study suggests that a higher number of participants in the cbt group showed clinically significant improvement in ef and total aqol scores with higher retention rates. further research needs to confirm these findings in a larger group, identifying the elements of a successful cbt intervention and characteristics of participants who respond to the cbt intervention. gastro-oesophageal reflux disease (gord) is a risk factor for uncontrolled asthma. we conducted an update of a systematic review to assess whether treatment of gastro-oesophageal reflux in subjects with asthma improved asthma outcomes. methods randomized controlled trials (rcts) of gord treatment in adults or children that reported asthma health outcomes and had symptomatic gord were included and assessed in accordance with the standard cochrane systematic review process. subjects received pharmacological therapies compared with conservative management. results from potentially relevant studies, rcts were included in the review. when compared to placebo, morning peak expiratory flow did not significantly improve (change from baseline wmd . , % ci: - . to . ) with proton pump inhibitor treatment (n = trials involving participants). asthma exacerbations were not significantly less in the intervention groups compared with the control groups (odds ratio . ; . - . ; n = ). conclusions while some trials reported evidence of asthma improvement with gord therapy, overall there appears to be no statistically significant evidence of a beneficial effect. it is clear that not all persons with gord and asthma will gain improved control over their asthma with gord therapy; this may be due to the heterogeneous pathophysiology of asthma. future large-scale trials would be required to demonstrate an effect on asthma exacerbations. kel and brd were supported by a cochrane airways group scholarship. background the ats/ers task force recommend the use of metered dose inhaler (mdi) and spacer for airflow limitation reversibility testing. salbutamol given via mdi & spacer has been shown to be equivalent to a nebulizer in the clinical setting. this has not been well studied in respiratory laboratory setting. aim to compare the methods of reversibility testing in a laboratory setting. methods we conducted a laboratory based crossover study in a secondary hospital. patients with asthma or copd were eligible. the patients firstly underwent spirometry and reversibility testing following a standard dose of nebulized salbutamol. they were asked to return for a second set of spirometry within the same week and at the same time of day when reversibility with an mdi and spacer was recorded. we used an incremental dose of salbutamol starting from puffs and up to puffs. spirometry parameters were recorded minutes after each intervention. the primary outcome was the percentage change in fev after each intervention. side effects were monitored for. results nine patients with asthma were recruited. the mean percentage change in fev was higher in the nebulizer group than after only puffs via mdi & spacer ( . Ϯ . vs . Ϯ [mean Ϯ sd], p = . ). however, there were no differences between the arms following higher doses of bronchodilator via mdi & spacer. the mean percentage change in fev after , and puffs were . Ϯ . , . Ϯ . , and . Ϯ . respectively (p = . , . and . respectively when compared to the nebulizer group). conclusion using an mdi and spacer for bronchodilator reversibility is equivalent to that of a nebulizer and should be the standard method of testing. the dose of bronchodilator needs to be at least puffs as recommended by the ats/ers; however puffs correlated best with a standard nebulizer route. further increments in bronchodilator dose provided little additional bronchodilatation. the study was limited by the small number of patients. asthma guidelines recommend a stepwise approach to treatment. the role of inhaled corticosteroid (ics) and long-acting beta-agonist (laba) combination therapy in asthma written action plans is not clear. objective to assess the efficacy of adjusting ics/laba combination therapy in a written action plan compared to fixed dosing in people with asthma requiring maintenance ics. methods cochrane systematic review of randomized controlled trials comparing ics/laba combination therapy in a single inhaler that is adjusted up or down according to a written action plan (wap) to comparison : budesonide/ formoterol given as a fixed maintenance dose (fd) (n = ) or comparison : fluticasone/salmeterol fd (n = ). results parallel randomized controlled trials describing interventions met the inclusion criteria. for the trials that compared wap to fd budesonide/ formoterol there were significant reductions for the wap group in exacerbations, (rr ( %ci): . ( . to . )), severe exacerbations (rr ( %ci): . ( . to . )) and study medications (wmd ( %ci): - . (- . to - . )) with no difference in asthma control or adverse events. the results for the two trials reporting wap budesonide/formoterol to fd fluticasone/ salmeterol were discordant and a homogenous pooled result could not be determined. of the australians who died from asthma in , over two thirds were over years of age. this trend resulted in the national asthma council of australia (nac) calling for better management of asthma in the elderly. we designed an educational intervention using evidence based educational strategies to improve the content and style of general practice consultations for older people with asthma. methods randomized controlled trial of a multi-faceted program consisting of a group educational session, a videotaped standardized simulated patient consultation, followed by an academic detailing session. forty-two gps were randomized into an active or a control group. gps provided the names of patients who would be happy to participate in the study and the program was evaluated by patient and gp outcomes. results gps recruited into our program reported improvements in a range of clinical areas. one hundred and ten patients were recruited, their outcomes are under analysis. conclusion gps were overwhelmingly positive about participation in this trial and our intervention successfully improved the capacity and confidence of gp's to deliver care to older people with asthma. our study also developed several tools that would enable dissemination of our findings. supported by an asthma targeted in studies where direct clinical assessment is not possible, urgent health care utilization (hcu) is often used as an indirect measure of asthma control. this study aimed to identify factors predicting urgent hcu and asthma control. methods patients in nsw with a doctor diagnosis of asthma were recruited from community pharmacies, a research volunteer database, and databases of asthma foundation nsw, to complete a questionnaire about asthma. poor asthma control was defined as asthma control questionnaire (acq) score Ն . . urgent hcu was defined as hospitalization, ed visit, or urgent doctor visit due to asthma. multiple logistic regression was used to identify predictors of poor control and urgent hcu. results questionnaires were completed by adults ( % female) with a doctor diagnosis of asthma (pharmacy , woolcock , asthma foundation ). % used inhaled corticosteroid (ics) Ϯ long-acting b -agonist in the last wks. median age was yrs (range - ), and % were current smokers. mean acq score was . ( % ci . - . ), with % of participants having poor asthma control (acq Ն . ). % had urgent hcu for asthma in the previous year. significant independent predictors for poor asthma control were younger age, current smoking, living in more disadvantaged areas, being retired, having only primary education, and holding a concession card. predictors for urgent hcu were younger age, being in full-time employment, having only primary education, and being of non-english speaking background. neither ics use nor possession of a written asthma action plan was associated with lower risk for either poor asthma control or hcu. conclusions poor asthma control is common in nsw even in patients using inhaled corticosteroids. although urgent hcu is often used as an indirect measure of poor asthma control, it is affected by different factors, perhaps because health care utilization represents a more complex balance between need and access. bronchial challenge tests with mannitol, to measure airway hyperresponsiveness, can take up to minutes and require inhalation of up to mg of mannitol. our aim was to determine if positive mannitol challenges can be detected after half the maximal dose ( mg) using the forced oscillation technique (fot) to measure response. methods non-asthmatic subjects and asthmatic subjects underwent standard mannitol challenge, up to mg mannitol. respiratory system conductance (grs) and reactance (xrs) was measured by fot at hz during sec tidal breathing immediately after each dose of mannitol. fev was measured after fot, within sec of mannitol administration. two point dose response slope (drs), was calculated for grs (drsgrs) and xrs (drsxrs) for standard tests, up to mg, and for short tests by excluding data from doses above mg. ability to detect a positive test, defined as pd fev < mg, was determined by the area under the roc curve (auc) and repeatability by intra-class correlation coefficient (icc). results asthmatic and non-asthmatic subjects had positive tests, with pd fev values from . to mg. auc ( %ci) did not differ between standard (std) and short tests for drsgrs (p = . ) or drsxrs ( combined use of inhaled steroids (ics) and long acting beta-agonists (laba) have an important role in asthma management. we used data from a population sample to examine medication use in adults and children. methods all adults ( - years) and children ( - years) from within four discrete zones in northern sydney were eligible for an interview survey, as part of a study investigating health effects associated with traffic-related air pollution. the prevalence of use of short-acting beta-agonists (saba), any ics (alone or combination) and combined formulations of ics/laba in the previous three months was estimated for the study population and those with diagnosed asthma. results there were children [mean (sd) age . ( . ) years and % female] and adults [mean (sd) age . ( . ) years and % female] interviewed in households, representing an overall response rate of %. the prevalence of ever diagnosed asthma was . % in children and . % in adults. medication data were missing for subjects. background asthma affects : adult australians and is a leading cause of rejection for recruitment into the australian defence force (adf). within this diagnosis there is a wide spectrum of disease activity and clinical outcomes. also asthma assessment and management has improved so that many asthmatics are now fully active without any significant disruption or risk to their lives. hypothesis: there is a subgroup of asthmatics who are at very low risk from significant adverse effects from asthma and who could be considered for recruitment to the adf. aims . to identify the subgroup of asthmatics who could be considered for recruitment to the adf. . to develop an assessment process to identify this subgroup (screening). . to develop a process to evaluate the outcomes of any change to the recruitment standard for asthma (evaluation). methods . a literature review of the natural history, assessment, management and response to treatment of mild episodic and mild persistent asthma. . a literature review of asthma in the military. . a clinical review of the outcomes of known asthmatics in the adf. . an expert group to review the above and to develop a screening process and an evaluation of the program. the literature review identified a subgroup of asthmatics, defined as mild episodic and mild persistent, who with appropriate management, have a low risk of significant adverse asthma outcomes. they can be identified by a combination of questionnaire, spirometry and bronchial provocation testing. a screening process has been developed which allows asthmatics to be recruited with a negative mannitol or hypertonic saline challenge on mg/day or less of budesonide (or equivalent) without laba. a methodology to evaluate the impact of these changes on the recruitment standard has also been developed. alexithymia is a personality trait associated with difficulty identifying and communicating emotional and physical feelings. it has been associated with poor control of asthma and near fatal asthma. the primary objectives of this study were to: ( ) identify alexithymia in a cohort of australian asthma patients; ( ) investigate the relationship between alexithymia and asthma control; ( ) investigate the relationship between alexithymia and asthma management. methods cross sectional study of moderate to severe asthma patients recruited from royal adelaide hospital outpatients. participants were either mailed the questionnaire pack or completed it after a clinic appointment. existing validated questionnaires were used. statistical analyses were performed using spss. results male ( %) and female ( %) patients with moderate to severe persistent asthma (mean age years, sd = ) participated. alexithymia scores ranged from . to . (x = . , sd = . ). % (n = ) of participants could be classified high alexithymia, % (n = ) borderline alexithymia and % (n = ) were low alexithymia. alexithymia mean scores were not statistically different across sociodemographic variables. a positive correlation/association was found between alexithymia score and asthma control score (r = . , p < . ), quality of life (r = - . , p < . ), and adherence (p = . ) but not satisfaction with communication (r = - . , p = . ) or number of hospitalizations (p = . ). conclusions this is the first australian study to identify alexithymia among asthma patients and investigate relationship to control as well as management and communication. associations between alexithymia and asthma control were confirmed. a larger sample size is needed to determine impact of alexithymia on self-management and provision of clinical care for asthma. port hedland is impacted by iron-containing dust particles (pm ) that may activate lung cells when inhaled. furthermore, the effects of port hedland pm may differ from the effects of urban pm impacting metropolitan areas. the aim of this study was to assess the effects of port hedland pm on production and release of the inflammatory cytokines, il- and il- , by human airway epithelial (a ) cells, and to compare these with the effects urban pm from metropolitan areas. methods human airway epithelial (a ) cells were exposed to pm collected at port hedland and at urban locations (sydney, perth). a cells were exposed to a range of pm concentrations ( - mg/ml) for h. lipopolysaccharide (lps) and phorbol myristate acetate (pma) were used as positive controls. supernatants from cell cultures were assayed for il- and il- using specific elisa kits. rna was extracted and reverse transcribed to cdna. il- and il- mrna expression was quantified by duplex real-time pcr using taqman primer/probes. results lps stimulated a . -fold increase in il- release and pma stimulated a -fold increase in il- release and a -fold increase in il- release. however, neither port hedland pm nor urban pm stimulated concentration dependent release of il- or il- by a cells. expression of il- or il- mrna was also not altered by port hedland or urban dust. cd + t-cells may cause airway epithelial cell apoptosis via the granzyme pathway. we have reported increased apoptosis of airway epithelial cells and increased bal t-cell expression of granzyme b in copd, and a positive correlation between the two. we hypothesized that the increased granzyme b would also be related to smoking history (pack years -pk/y), age and severity of airflow obstruction (fev %pred) in patients with copd. we further hypothesized that the t-cell granzyme b expression would be higher in the airway than the peripheral blood. methods we investigated t-cell intracellular granzyme b expression in blood from copd subjects ( current and ex-smokers) and never-smoker controls, and bronchoalveolar lavage (bal) and bronchial brushing (intraepithelial t-cells) from a cohort of these subjects using flow cytometry. correlations between granzyme b and pk/y, age or fev were performed using spearman's rank correlation. granzyme b in t-cells from blood, bal and bronchial brushings were compared. results there were significant correlations between fev and granzyme b expression in blood and bal (blood: r - . , p = . ; bal: r - . , p = . ). there was a significant correlation between pk/y and granzyme b expression in blood (r . , p = . ), but not in bal. there were no significant correlations between granzyme b and age. there were no significant differences in granzyme b expression in blood, bal or intra-epithelial compartments. conclusion granzyme b is expressed at similar levels in blood, bal and intra-epithelial compartments, supporting recent opinion that copd is a systemic disease. t-cell granzyme b is related to severity of airflow obstruction and smoking history in patients with copd and may be one mechanism of apoptosis leading to lung injury and airflow obstruction in copd. jc allen , t schlosser, ee ramsay , q ge , aj ammit as development of remodelled airways is correlated with deterioration of lung function, we require therapies that reduce and reverse structural changes in remodelled airways. in asthma, corticosteroids can halt some, but not all, aspects of airway remodelling. therefore, in order to aid future design of efficacious anti-remodelling agents we need a better understanding of the molecular mechanism/s underlying the development of airway remodelling and the effectiveness of corticosteroids. hyperplasia of airway smooth muscle (asm) is a feature of the remodelled airway in asthmatics. in this study we examined the effect of corticosteroids on a key regulator of g progressioncyclin d . asm cells from n = non-asthmatics and n = asthmatics were pretreated for h with vehicle or dexamethasone ( . mm). the temporal kinetics of cyclin d mrna and protein expression were measured up to h after stimulation with the mitogen platelet-derived growth factor-bb (pdgf-bb). pdgf-bb induced a significant increase in cyclin d mrna expression in asm from non-asthmatics ( . Ϯ . -fold) and asthmatics ( . Ϯ . -fold) after h stimulation. in non-asthmatics, the corticosteroid dexamethasone significantly (p < . ) reduced the amount of cyclin d mrna expressed (to . Ϯ . -fold). in contrast, cyclin d expression in asthmatics was relatively resistant to inhibition by dexamethasone; the amount of pdgf-bb-induced cyclin d expression in the absence or presence of dexamethasone was not significantly different ( sphingosine -phosphate (s p), a bioactive sphingolipid found elevated in the airways of asthmatics, modulates myriad airway smooth muscle (asm) functions that promote inflammation and remodelling in asthma. in this study, we uncover the molecular pathway/s underlying s p-induced secretion of il- , and investigate if, and how, corticosteroids inhibit il- secretion. using cultured asm cells from non-asthmatics, we found that s p induces il- secretion from asm cells via cre, but not ap- , c/ebp or nf-kb, transcriptional regulation of il- gene expression. cre-dependence was supported by s p-induced creb phosphorylation. although the corticosteroid dexamethasone reduced s p-induced il- secretion in a dose-dependant manner, this inhibition appeared to occur via a pathway independent of creb/cre, suggesting the existence of a parallel pathway. as we recently discovered that the antiinflammatory actions of corticosteroids in asm can be mediated via the induction of the endogenous mitogen-activated protein kinase (mapk) inhibitor, mapk phosphatase- (mkp- ), we investigated whether mapk represents the parallel pathway targeted by corticosteroids. we found that s p can induce activation of a variety of mapk, however, only p mapk phosphorylation was inhibited by dexamethasone; importantly, the increase in mkp- after corticosteroid treatment appeared to mirror the decrease in s p-induced p mapk phosphorylation. furthermore, exogenous expression of mkp- inhibited s pinduced il- secretion. taken together, these results suggest that parallel pathways exist to induce il- secretion (transcriptional via creb/cre and possibly post-transcriptional via p mapk) and serve to underscore the importance of mkp- upregulation as a mechanism of action of corticocosteroids in asm. angiogenesis is a hallmark feature of asthma. angiogenic promoters, such as vegf and tgfb are reported to be increased in airways of asthmatics. tumstatin, an endogenous angiogenic inhibitor, is the non-collagenous domain- (nc ) of the alpha chain of collagen iv. decreased levels of collagen iv have been reported in the airways of asthmatics. we investigated the presence of tumstatin in the airway of asthmatics and its potential role as an angiogenic inhibitor. we detected the six a chain nc domains of col iv and the s domain of the a chain using immunohistochemistry. the level of tumstatin in serum and bal-f was measured by dot blot. western blots were used to identify the association with the rest of the collagen iv molecule. a tube formation assay using primary pulmonary endothelial cells (ppec) was performed to evaluate the role of tumstatin in the airway. the effect of intranasal tumstatin on airway hyperresponsiveness and angiogenesis was studied in an ovalbumin mouse model. tumstatin was absent in the airways of asthmatics (n = ) while the remaining six collagen iv a chains were present. the s domain of the a chain was present in the asthmatic airway (n = ). tumstatin was detected in both serum and bal-f samples from asthmatic volunteers (n = ), however the level of expression was not significantly different from that in nonasthmatics (n = ). in asthmatic serum tumstatin was part of the whole collagen iv a chain. tumstatin was able to inhibit ppec tube formation in a dose related manner. tumstatin inhibited angiogenesis in the mice airways and was associated with an improvement in ahr. the fact that tumstatin is absent from asthmatic airways and inhibited airway hyperresponsiveness and angiogenesis may indicate potential for therapeutic intervention in airway remodelling. this work was supported by the crc for asthma and airways and nh&mrc. introduction epithelial egfr (epidermal growth factor receptor) expression correlates with disease severity and neutrophil infiltration in asthmatic airways. acute exacerbations of asthma and copd are also associated with steroid refractory neutrophilic inflammation, with rhinoviruses being the most common trigger. . mg/l and il- : . vs. . ng/l). since il- stimulates the acute phase response, we correlated its levels with the other markers. only crp was strongly correlated with il- (spearman r = . , p < . ), suggesting differential regulation of saa and ip . saa discriminated between non-pathogen (n = ) vs. pathogen-associated (n = ) events (saa: . vs. . mg/l p = . ), whereas no significant change was observed in the other markers (ip- : . vs. . ng/l, crp: vs. mg/l, il- : . vs. . ng/ l). however when aecopd marker levels were stratified on the basis of pathogen type (viral = , bacterial = , viral and bacterial = ), none of the markers were significantly altered. conclusions ip- is significantly elevated during an aecopd, however only saa differentiated non-pathogen from pathogen associated events. background severe persistent asthma is characterized by structural changes in the airways-airway remodelling. airway smooth muscle (asm) cells have the potential to play a key role in these processes through the release of growth factors, cytokines and extracellular matrix (ecm) proteins. we have previously studied the effects of budesonide and formoterol individually however, the effect of their combination on these characteristics of asm cells is not known. methods asm cells from asthmatic (n = ) and nonasthmatic (n = ) individuals were stimulated with transforming growth factor ß (tgfß) ( ng/ml) with or without budesonide ( - m) and formoterol ( - and - m) and fibronectin levels and interleukin- (il- ) release were measured by elisa. bronchial rings from nonasthmatic individuals (n = ) were incubated with tgfß with or without the drugs and ecm protein expression (fibronectin and collagen i) measured using immunohistochemistry. results in nonasthmatic cells, budesonide alone induced fibronectin deposition whether tgfß was present or not. formoterol decreased fibronectin induced by tgfß and, when combined with budesonide, reversed the increase in fibronectin. a similar pattern was observed in asthmatic cells, except that budesonide did not further increase the tgfß mediated fibronectin release. as before [ ] , il- was induced by formoterol but inhibited by budesonide. tgfßinduced il- was inhibited by both drugs and their combination in both cell types. in bronchial rings the presence of either drug did not affect tgfßinduced fibronectin or collagen i. severe combined immune deficiency (scid) spontaneous mutation specifically impairs differentiation of stem cells into mature lymphocytes. nod-cb prkd scid (known as nod-scid) lacked nk cells, hence is commonly used in cell transfer experiments for transferring tissue and haematological xenografts. the aim of this study was to establish lung inflamamtory model in nod-scid strain. methods balb/c and nod-scid balb/c mice (n = ) were exposed to cigarette smoke for days, and weeks ( cigarettes/day; days/week). bronchoalveolar lavage fluid (balf) and lung tissue were collected for inflammatory profiling and analysis for cytokines, chemokines and protease expression and/or activity. results nod-scid have significant accumulation of macrophages in lung after days, and weeks smoking as compared to no smoke control (p < . ) that was not different to balb/c (p > . ). nod-scid also have increased neutrophil number after and weeks smoking (p < . ). even though myeloid cell differentiation isn't affected by scid phenotype, nod-scid have one fold less neutrophil than balb/c mice (p < . ) that is also reflected in the reduced expression of matrix metalloproteinase- . consistent with the known lymphopenic phenotype, nod-scid have significant but less lymphocytes recruitment as compared to balb/c mice after weeks smoking (p < . ) despite the enhanced expression of inteferon inducible protein (lymphocytes specific chemokine) in lung. both mouse strains showed the same elevation of net gelatinase and serine protease activity in lung. nodscid mice also demonstrated comparable transcriptional induction of proinflammatory cytokines (tnfa, il- ), growth factors (gm-csf, g-csf) and chemokines (mcp- , mip- ), indicating susceptibility to smoke-induced injury. conclusions nod-scid mice are capable to mount smoke induced inflammatory response. this model may be useful to study localization and role of immunocytes, including adoptively transfer human cells in the pathogenesis of copd. supported by the nhmrc. rhinovirus (rv) is the cause of most common colds and up to % of asthma attacks. in our previous studies, plasminogen activator inhibitor (pai- ) was expressed at high levels and was induced in vivo and in vitro by rv infection. pai- may have antiviral properties suggested by antiviral activity in some models, high pai- expression levels and further upregulation by rv infection. methods to determine whether pai- has antiviral activities following rv infection, o-hela, pai- expression-deficient cells were first transfected with pai- or control genes. this was followed by infection with rv and effects on viral replication were assessed by rt-qpcr for vrna and by viral titration for virus release. ifn expression was assessed by rt-qpcr. results ifn-a and -b mrna expression were induced in response to rv infection and to pai- expression in cells. pai- expression followed by rv infection elicited a synergistic response and pai- over-expression reduced vrna by > fold and viral titre by > log (p < . ). however, this effect was not specific to pai- , as transfection of cells with control genes/plasmids reduced viral titre to a comparableextent. one of the pathological findings in idiopathic pulmonary fibrosis (ipf) is the presence on fibroblastic foci comprising cells which exhibit mesenchymal phenotypic features such as myofibroblast-like morphology, increased asma expression and collagen deposition. currently steroid treatment in ipf has shown limited efficacy. the cellular origins of these mesenchymal cells remain unclear, but evidence from other studies suggests that epithelial cells may undergo a transition to a mesenchymal cell phenotype (emt). transforming growth factor ß has been implicated in promoting this emt. in this study we have induced a morphological change in a cells using tgf-ß and assessed the influence of glucocorticoids, and the changes to the extracellular environment of the cells, on emt. methods a cells were grown on uncoated plastic cultures plates or those coated with monomeric or fibrillar collagen and treated with - pm tgf-ß . the influence of the glucocorticoid, dexamethasone (dex, - nm), or collagen type, on emt was assessed by microscopy, rt-pcr and western blotting for markers of myofibroblast phenotype. results tgf-ß induced an increase in mrna expression of asma ( . fold), collagen ( . fold) and fibronectin ( . fold). dex ( nm) partially inhibited the expression of collagen, but had no effect on asma levels. however, dex ( nm) reduced asma and ctgf protein levels. dex ( nm) also prevented the tgf-ß -induced morphological changes, regardless of ecm matrix. conclusion glucocorticoids appear to control some of the emt phenotype changes induced by tgf-ß . however, the inability to fully inhibit these changes may contribute to the resistance of ipf to glucocorticoids. the extracellular environment may also play a role in the development of fibroblastic foci and their pharmacological responses. defective alveolar macrophage (am) phagocytic function in the airway may perpetuate inflammation via secondary necrosis of uncleared apoptotic cells in copd. we have previously reported that low-dose azithromycin improved macrophage function in vitro, although the mechanisms for this effect were not identified. we explored the possible role of the collectin pathway in the azithromycin-mediated improvement in phagocytosis as well as possible defects in this pathway in copd subjects. methods ( ) mannose binding lectin (mbl), mannose receptor (mr), surfactant protein d (sp-d) were measured in copd subjects and controls. ( ) the in vitro effects of addition of rhmbl, and blocking mr with a specific antibody, on am phagocytic ability were assessed. in vitro effects of azithromycin on am expression of mr were also investigated. ( ) azithromycin ( mg orally ¥ weekly/ weeks) was administered to copd subjects. bronchoscopies were performed prior to and weeks following therapy. ex vivo assessments included am phagocytic ability, levels of mbl, sp-d and mr and apoptosis of bronchial epithelial cells. results am mr expression and levels of mbl and sp-d were significantly reduced in copd subjects vs controls. azithomycin ( ng/ml) increased mr expression by % in vitro. rhmbl induced a dose-dependent increase in am phagocytic ability (up to %). blocking mr significantly decreased am phagocytic ability by %. in copd patients following azithromycin therapy, we observed improved am phagcocytic ability, increased levels of mr and reduced levels of bronchial epithelial cell apoptosis. conclusions these findings strongly implicate the mr in both the defective phagocytic function of am in copd and as a target for the azithromycinmediated improvement in phagocytic ability. obstructive sleep apnea (osa) is associated with hypoxia and increased cardiovascular morbidity. t cells and monocytes play a significant role in atherogenesis via cytokine production. there have been reports of benefits of continuous positive airway pressure (cpap) therapy in osa. the purpose of this study was to characterize leucocyte inflammatory cytokine/chemokine production by t cells and monocytes in a group of osa patients and to investigate the therapeutic effects of cpap therapy. methods a comprehensive range of intracellular t-cell and monocyte proand anti-inflammatory cytokines/chemokines was investigated in peripheral blood from osa patients and aged-matched control subjects (with no evidence of sleep problems) using multiparameter flow cytometry. osa patients were again studied following days of cpap therapy. results in osa patients there was an increase in intracellular t-cell ifng and tnfa production but no change in il- , il- or tgfb compared with control. there was an increase in intracellular monocyte il- a, il- , tnfa, mcp- and mcp- in osa patients but no change in il- or il- . following cpap therapy, t-cell ifng and tnfa production returned to 'normal' levels. however, although intracellular monocyte cytokine/chemokine production was decreased following cpap, levels were significantly elevated compared with control. conclusions osa is associated with increased intracellular proinflammatory cytokine/chemokines, many of which are increased in atherosclerotic plaques. although one week of cpap therapy resulted in amelioration of t-cell pro-inflammatory cytokines, longer cpap use or alternative therapy may be required to reduce monocyte pro-inflammatory mediators associated with atherosclerosis in patients with osa. gp has been associated with the progression of fibrosis especially in patients with idiopathic pulmonary fibrosis (ipf). gp is the common subunit of the receptor complexes for the il- family of cytokines including il- and oncostatin m (osm), where gp -mediated signalling leads to activation of the erk or stat pathways. we have previously demonstrated exaggerated gp -stat signalling to be fundamental to the development of pulmonary fibrosis in a murine model of bleomycin-induced lung fibrosis. the aim of this study was to elucidate the role of the il- cytokine family in the development of pulmonary fibrosis by identifying which il- family cytokines regulate fibrosis in bleomycin treated mice, and determine the effects of these cytokines on cell function. bleomycin ( . u/mouse) or control saline was administered intranasally to wildtype mice (wt), genetically engineered mice containing point mutations to prevent gp erk signalling (gp f ) or gp stat signalling (gp dstat ), and duel il- and il- a-receptor knockout mice (il- -/-;il- ar -/-). the effect of bleomycin on collagen production was examined in lung tissue days post treatment by hplc. there was a significant increase in collagen levels in bleomycin treated wt lungs which was further increased in gp f lungs. the lungs of gp dstat and il- -/-;il- ar -/mice were protected from fibrosis suggesting that gp -stat signalling is important in inducing lung fibrosis which may be mediated through il- and/or il- . cell proliferation was examined in lung fibroblasts isolated from wt, gp dstat and gp f mice. il- , il- and osm were significantly mitogenic for gp dstat cells but not for wt or gp f cells, reflecting different responses to the different signalling pathways. changes in cytokine profiles are currently being examined in lung tissue and serum of control and bleomycin treated mice - days after treatment. in conclusion, il- and il- are likely to play a role in bleomycin-induced fibrosis via the gp -stat-mediated pathway, however this may not be due to regulation of proliferation induced by these cytokines. supported by the nhmrc. mimicking viral infection by application of various toll-like receptor ligands has shown clinical promise in the treatment of persistent viral infections and more recently with malignant tumours. commercially available toll-like receptor ligands (tlr l), such as those of the imidazoquinoline family have been applied clinically for the treatment of a number of conditions including basal cell carcinoma and hpv-induced genital warts. these compounds are known to retard tumour growth indirectly by promoting activation and migration of dcs, leading to a strong th cellular response, and directly via release of proinflammatory cytokines and promotion of tumour cell apoptosis. malignant mesothelioma (mm), an aggressive tumour with a mean survival of months, is highly resistant to chemotherapy, radiotherapy and surgery and is therefore an interesting candidate for immunotherapy in the form of tlr ligand treatment. whilst tlr is known to be selectively expressed in immune cells and its relative expression low amongst other cell and tissue types in mammals, its expression on tumour cells and the consequences of such expression on tumour growth are unknown. here we describe the presence of tlr (mrna and protein) directly in a range of different tumours, including several murine and human mm cell lines. reactive oxygen species (ros) produced during the innate immune response are important agents of anti-pathogen defense but may also cause oxidative lung damage. glutathione peroxidase- (gpx- ) is a detoxifying enzyme that may protect lungs from such damage. methods wild-type (wt) or mice deficient in glutathione peroxidase- (gpx- -/-) were placed in a perspex chamber and exposed to cigarette (cig) smoke generated from cigs per day for days. on the fifth day, mice were killed, the lungs lavaged with pbs and then harvested for proteomic and genomic analysis. results wt mice exposed to cig smoke for days had significantly more macrophages ( . Ϯ . (sem) ¥ ) and neutrophils ( . Ϯ . ¥ ) than sham-exposed mice ( . Ϯ . ¥ and , respectively) (n = , p < . ). however, gpx- mice exposed to cig smoke had significantly greater macrophages ( . Ϯ . ¥ ) and neutrophils ( . Ϯ . ¥ ) than smokeexposed wt mice (n = , p < . ). macrophage and neutrophil numbers in sham-exposed gpx- -/mice ( . Ϯ . ¥ and . Ϯ . ¥ ) were similar to those of sham-exposed wt mice ( . Ϯ . ¥ and ). in addition, we found that balf of gpx -/mice exposed to cig smoke had an increased proteolytic burden compared with smoke-exposed wt mice as assessed by zymography and net gelatinase activity assay. conclusions these data suggest that gpx- protects the lung from cigarette smoke-induced inflammation and that targeting gpx- may have therapeutic utility in inflammatory lung diseases where cigarette smoke plays a role. funded by nhmrc. the becs from subjects with chronic obstructive pulmonary disease (copd) are exposed to frequent infectious and inflammatory stimuli. infection with rv is known to trigger acute exacerbations and subjects with copd are particularly susceptible. we hypothesized that exposure of copd becs to these stimuli would alter their response to rv infection. methods bec were obtained by endobronchial brushing from subjects with gold stage copd (n = , all ex-smokers), subjects with mild persistent asthma (n = ) and healthy controls (hc, n = ). becs were cultured and then treated with tumour necrosis factor (tnf)a ng/ml or lps mg/ml for hrs and then infected with rv- , rv- b. response was measured by release of il- , il- and ip- mrna and by elisa. virus replication measured by cell titration assay. results infection with both rv strains led to increased release of il- and ip- in all groups. exposure of hc and asthma becs to both lps and tnf led to increased release of il- . in these becs there was no increase in release of il- exposed to lps and tnf and then infected with either rv. becs from subjects with copd released significantly less il- in response to all conditions and rv infection compared to hcs and asthma. no differences were seen in rv replication. the aim of this study was to determine opinions and attitudes to exercise from chronic obstructive pulmonary disease (copd) subjects after completion of a -month maintenance exercise program. methods following completion of a -month exercise study, which included a supervised program (intervention, n = ) and control group (control, n = ), copd subjects [mean age (sd): ( ); mean fev (% predicted) = % ( )] were asked to complete a questionnaire. the questionnaire included closedended questions using visual analogue scales ( mm). in copd the minute walk distance ( mwd) is known to increase with test repetition (familiarization) and in response to exercise training. it is unknown whether the magnitudes of these increases are related to the degree of disability of the individual patient. methods mwd was measured twice before and once after an week out-patient exercise program in patients ( males) aged Ϯ . yrs, fev Ϯ % predicted (meanϮsd) with stable copd. the changes in mwd following a familiarization test and following training were compared between patients grouped according to their degree of disability (defined as the pre-training mwd [best of tests] expressed as %predicted mwd). *p < . gp vs gp . conclusions before training, mwd increases following a familiarization test irrespective of the level of disability. the magnitude of this increase is similar in all groups when normalized for their pre-training mwd. following training, the increase in mwd is greatest in patients with the greatest disability (lowest pre-training mwd). in less disabled patients, the relatively smaller increase in mwd following training may reflect an inability to further increase stride length, thereby reducing the responsiveness of the mwt in this group. supported by nhmrc. endotoxin is a stimulant of the innate immune system and is a major component of cigarette smoke. smokers have evidence of increased airway neutrophils and inflammation. we hypothesized that endotoxin levels would be higher in the bronchial lavage (bl) of subjects who were former smokers and subjects with chronic obstructive pulmonary disease (copd). methods subjects were all ex-smokers for at least years (n = , copd, healthy controls) or never smokers (n = , asthma, healthy controls). bl was collected and analysed for cell count and differential, culture for microbiology. the supernatant was analysed for il- by elisa and endotoxin by quantitative kinetic lal assay. results median endotoxin levels were significantly higher in ex-smokers compared to never smokers . u/ml (p < . ). there were no differences between subjects with copd and hs. subjects with copd had higher median endotoxin levels ( u/ml), compared to asthma ( . u/ml) and hc ( . u/ml, p = . ). there was no correlation between endotoxin levels and bl total cell count, neutrophils (%) or fev % predicted. there was a strong correlation with previous packet years smoked and endotoxin levels (r = . , p < . ). conclusions bl endotoxin levels are higher in ex-smokers, including subjects with copd. despite this there is no relationship to increased neutrophilic inflammation. copd is associated with inflammation associated with ineffective repair of the injured epithelium and loss of structural integrity. we have shown that these changes may result from dysregulated 'efferocytosis' (increased apoptosis of bronchial epithelial cells and defective clearance of these cells by alveolar macrophages (am)). we have also reported that azithromycin, at subbactericidal dose, improved am phagocytic function ex vivo. methods we administered azithromycin at low dose ( mg/ twice weekly for weeks) to copd subjects ( male, age: Ϯ yr, current/ ex-smokers, fev : Ϯ % pred, fev /fvc: Ϯ %). the study was openlabel, uncontrolled and primarily focused on objective biological responses obtained from the bronchoscopy samples taken. phagocytic ability of am (from bal), apoptosis of bronchial epithelial cells (from bronchial brushing), markers of inflammation in blood, bal and breath condensate (crp, wcc and inflammatory cytokines), health status (st. george's respiratory questionnaire), ecg and lung function were assessed pre and post-administration of azithromycin. results azithromycin significantly improved phagocytic ability of am (by %) and reduced bronchial epithelial cell apoptosis (by %). antiinflammatory effects of azithromycin included significantly reduced blood wcc and crp. there were non-significant reductions in levels of pro-inflammatory cytokines il- , il- and tnf-a in blood, bal and breath condensate, and a trend for improved health status. conclusions our findings indicate a novel approach to supplement existing therapies in copd that may improve clearance of accumulated apoptotic material and reduce the risk of secondary necrosis and release of toxic cell contents that perpetuate inflammation. background the prevalence of gastro-oesophageal reflux disease (gord) across the disease spectrum in copd and bronchiectasis is not well described. the aim of this study was to determine the prevalence of symptomatic and silent gord in copd and bronchiectasis and its effect on lung function and quality of life (qol ] ) and healthy controls were recruited. the prevalence of gord in bronchiectasis was %; % in copd; % in controls. in copd and bronchiectasis, total nre and ri were increased in those with distal and proximal gord compared to those without gord (all p < . ). there was no difference in extent or severity of bronchiectasis in patients with or without gord (all p > . ). in copd, the relationship between proximal gord and fev was small to moderate (r = . ). sgrq symptom scores were higher in patients with bronchiectasis with increased ri (p = . ). increased proximal nre was associated with reduced physical (p = . ) and mental health (p = . ) in the sf- in copd. conclusions gord is a co-morbidity in patients with copd and bronchiectasis. the impact of gord on disease severity requires further evaluation. funding source nhmrc, the university of melbourne, monash university, physiotherapy research foundation. chronic obstructive pulmonary disease (copd) is prevalent among older people, however little is known about the influence of ageing on airway inflammation. the aim of this study was to compare airway inflammation in older people with obstructive airway disease to groups of older and younger healthy controls. methods participants (> years of age) with stable airway disease and incomplete reversibility (fev % predicted < % and fev /fvc < %; copd n = ) and healthy controls (n = , older > years and younger < years) were recruited from the respiratory ambulatory care clinic or by advertisement. participants underwent a clinical assessment, skin allergy test, hypertonic saline challenge, sputum induction and gas diffusion studies. results participants with copd had moderate airflow obstruction (mean (sd) fev % predicted ( )) and ( %) were current or ex-smokers with a median (iqr) pack year history of ( - ) pack years. ageing was associated with an increase in airway neutrophils (p = . ). compared to older controls, participants with copd had increased airway eosinophils and lymphopenia (p = . , p = . respectively), but no difference in airway neutrophils. conclusion airway neutrophilia is a feature of ageing and is not further increased in the presence of copd. copd is associated increased numbers of airway eosinophils with reduced lymphocytes which may impact on the ability of the immune system to combat infection. supported by nhmrc, the university of newcastle. chronic obstructive pulmonary disease (copd) is third leading cause of death and fourth leading cause of disease burden in australia. mechanisms involved in emphysema severity have not been fully understood. micrornas are noncoding rnas that regulate gene expression. we hypothesize that microrna expression differs between emphysema severity in copd patients. methods mirna profiling was performed using k agilent human oligo mirna microarrays on total rna extracted from non-tumour lung tissue from copd patients undergoing resection for lung cancer. the mirnas were quantile normalized and anova was used to find differentially expressed genes. results demographic characteristics of the copd patients (mean (sd)) were age ( ) years, fev ( ) % predicted and fev /fvc ratio (< %). anova identified mirnas that were differentially expressed when stratified into two classes according to kco % predicted > or < % (t-test, p < . ). discussion this mirna analysis has identified mirnas that may be important in emphysema severity in copd patients. further validation will be performed using qrt-pcr and mirna assays on the training set and an independent set, and target prediction and validation. t-helper type (th ) and type (th ) lymphocyte responses have been well recognized as being important pathways in inflammation. recently another form of inflammatory lymphocyte response has been described, the th pathway. th cells produce cytokines such as il- a to clear extra-cellular bacteria and fungi and have been implicated in autoimmune and chronic inflammatory diseases. the th response in copd is unknown. methods subjects were patients with copd (ex-smokers, fev < % predicted who had not had an exacerbation for at least month) and control subjects (ex-smokers and normal spirometry). serum samples were obtained for measurement of c reactive protein (crp) and il- a, the latter measured using enzyme-linked immunosorbent assay (elisa). production of il- a by t-cell subsets was also identified by intra-cellular cytokine staining and measured by flow cytometry. the mean fev of copd subjects was % predicted ( . sem, n = ) and mean fev of controls was % predicted ( . sem, n = ). the copd group had a higher mean level of crp . mg/l ( . sem) compared to the control group mean level of . mg/l ( . sem). the mean level of the il- in the copd group as measured by elisa was . pg/ml ( . sem, range - ) whilst no il- was measured in any of the control subjects. conclusions the findings of this pilot study suggest that il- may be elevated in association with crp in stable copd. airway obstruction is defined as a fev /fvc ratio below the lower limit of normal. airway obstruction may prolong the forced expiratory time (fet). method spirometry results from patients were categorized as obstructive, restrictive or normal. the mean, range and coefficient of variation were determined for fet in each diagnostic group. receiver operator characteristic (roc) curves were used to determine if fet could predict a low fev /fvc. the number of patients with airway obstruction in five fet groups: < ; ; - ; - ; and > seconds were determined. results the coefficient of variation was high for all groups. pair-wise comparisons showed a difference in mean fet between patients with normal lung function versus those with airway obstruction (p < . ). the best cut-point in the roc analysis of . seconds had a sensitivity of . , specificity . and area under the curve of . for predicting obstruction. the technique of skeletal muscle microbiopsy has previously been validated [ ] and shown to be minimally invasive and well tolerated in participants with stable copd. aim a study was undertaken to determine the feasibility and tolerability of obtaining microbiopsy muscle samples from the patient admitted for acute exacerbation of copd patient. methods written informed consent was obtained to collect the muscle, blood and sputum samples for research purposes. local anaesthetic was injected prior to the insertion of a gauge bard max core disposable biopsy instrument through the associated guide needle. multiple passes (up to ) were obtained. the patient was asked to evaluate the experience by rating it on the modified borg scale - . results to date patients and controls have participated in this study. the gold severity ranged from - and ats exacerbation severity - . the mean age years (range - years), bmi mean . kg m - (range . - . kg m - ) and fat free mass was determined using single frequency bioimpedance. the sample mass obtained ranged from . - . mg, with an increasing yield occurring with increased experience of the operator. the procedure has been well tolerated, the borg scale rating ranged from - / . all patients were ambulant post procedure; no haematoma or bruising was observed in any of the subjects. conclusion the microbiopsy technique allows the collection of muscle tissue with minimal discomfort to the participant. small tissue masses such as these are sufficient to obtain measures of local markers of wasting and may prove to be a useful adjunct to the collection of sputum and blood for the measure of biomarkers in copd research. introduction older people (op) with obstructive airways disease (oad) experience multiple problems that may impact on their quality of life (qol) and disease management. these problems may relate to pathophysiology, symptoms, self management skills, psychological issues, lifestyle or other problems identified as important by the patient. aim the aim of this study was to determine the frequency of clinical problems associated with oad and to determine if a problem based assessment (pba) could adequately identify these problems. methods a multidimensional assessment tool was developed and the content compared to clinical practice guidelines. participants over years with diagnosed oad underwent this assessment. results sixty-one consecutive patients, aged - years, with mean (sd) fev of . ( . ) % predicted were assessed. the assessment tool identified a mean (sd) of . ( . ) current and significant co morbidities with an additional ( . ) clinical problems per patient. qol was increasingly impaired with an increasing number of problems (p < . ). regression modelling identified that the number of identified clinical problems accounted for % of the qol impairment. the model demonstrated that every additional patient problem was associated with a clinically significant change in qol impairment ( . units) . conclusions op with oad experience multiple clinical problems and co morbidities that adversely impact their qol. a pba of op with oad identifies significant problems that may not be addressed in a diagnosis centred approach. there is a need to identify and effectively manage this array of problems in clinical practice. discussion in this diverse group of copd patients, there was a positive correlation between dlco and fev , but not kco and fev . the fev / kco plot identifies substantial numbers of patients with the potential ad and e phenotypes defined above. we intend to study inflammatory biomarkers in these groups. fat free mass index (ffmi) is a marker of morbidity and mortality in copd. measurement of ffm in the out-patient population is commonly undertaken using single frequency bioelectrical impedance analysis (bia). however the formulae to convert measured values to ffm are population dependent. schols et al (am j clin nutr, ) suggested that formula used for the general population may be inappropriate for patients with copd, and derived a specific formula from total body water (tbw) as measured by deuterium dilution. we compare this method of measuring ffm with others, along with tbw and ffm hydration. methods tbw was measured in outpatients with copd by bia and a difference method (weight-(protein+bone mineral+fat+non-bone mineral+ glycogen)) and ffm hydration was calculated. ffmi was measured by skin fold anthropometry (sfa), bia ( separate formulae), dual energy x-ray absorptiometry (dexa) and total body potassium by g-counter (tbk). comparison between methods for tbw and ffmi was made by bland-altman analysis and between methods of calculation of ffm hydration by paired t-test. the two methods of assessment of tbw showed little difference (bias - . , % limits of agreement - . to . ). however there was a significant difference in calculation of hydration of ffm (p = . ). sfa, bia (lukaski), bia (tanita) and tbk underestimated ffmi when compared to bia (schols), with bias of - . , - . , - . and - . respectively. dexa however had a bias of only . and % loa of - . to . . conclusions there are differences between methods of assessment of tbw and ffmi and comparing values between methods must be done with caution. this has implications for assessment of morbidity and mortality in copd. chronic obstructive pulmonary disease (copd) has been identified as a major health problem in australia. recent studies have suggested that respiratory viral infections are the major cause of a worsening of copd; however this has not been studied in australia. aim to characterize pef changes and identify viruses during copd exacerbations. methods a pilot prospective longitudinal cohort study was done. patients had confirmed copd with fev < % predicted and reversibility < % and/or ml. patients recorded daily peak expiratory flow (pef) measurements and daily chest and cold scores over a period of years. sputum samples and nasal aspirates were taken at -month review (control visit) and whenever they had symptoms of an exacerbation (worsening of copd symptoms -seemungal et. al. am j resp crit care med, ). nasal aspirates and sputum samples were obtained and analysed by rt-pcr for rhinovirus (rv). result five patients have finished years of study. a total of exacerbations were reported based on patient symptoms. only exacerbations were associated with significant reductions in pef and only one was linked to increases in nasal cold scores. all samples taken at control visits and nasal aspirates and sputum samples during exacerbations were negative for rv by rt-pcr. positive controls confirmed the accuracy of the assay. conclusion our data suggest that a symptom-based definition of copd exacerbation is not always accompanied by significant reductions in lung function parameters. these 'exacerbations' are also not associated with the commonest reported viral cause. our findings suggest that variability of copd may mimic. bronchiectasis is characterized by hypersecretion of mucus and impaired clearance that results in mucus accumulation, chronic cough, sputum production and recurrent infections. inhaled mannitol ( mg) improves clearance of mucus by increasing the airway hydration and by reducing the viscoelastic and surface properties of mucus. however, the effect of other doses of mannitol on the clearance of mucus in patients with bronchiectasis is unknown. methods fourteen patients, age: . Ϯ . yr, were studied on visits. clearance of mucus was measured using m tc-sulphur colloid and imaging with a gamma camera at baseline and with mannitol ( weight loss and skeletal muscle atrophy are major determinants of morbidity in chronic obstructive pulmonary disease (copd), which are independent of lung function impairment. thus, we examined if a high-fat diet (hfd) protected against the wasting associated with prolonged cigarette smoke exposure (se) in mice. methods male balb/c mice were exposed to the smoke of cigarettes/day, days/week for weeks. sham mice were handled identically without smoke exposure. mice consumed either standard laboratory chow ( . kcal/g, consisting of % fat) or a hfd ( . kcal/g, % consisting of fat). we examined the effect of se and hfd on hind limb skeletal muscles, lung (tissue & bronchoalveolar lavage (balf)) and systemic inflammation in the groups of mice (n = / group). results after weeks of hfd, sham and se mice were and % heavier (respectively, p < . ) than chow fed animals. conversely, se significantly decreased body weight of chow and hfd fed mice by and %, respectively, compared to sham animals (p < . ). the hfd did not protect against the decrease in soleus, tibialis anterior and gastrocnemius skeletal muscle weights induced by se (p < . ). se altered the mrna expression of a number of genes associated with the regulation of skeletal muscle mass including insulin-like growth factor-i (igf-i), atrogin- and interleukin (il)- . the mrna expression of pro-inflammatory cytokines and chemokines was significantly increased by se in the lung, as were the number of inflammatory cells in balf (p < . ). on the other hand, although obesity has been linked to systemic inflammation, the hfd exerted little direct effect on the skeletal muscle and lung parameters measured. se and hfd had no effect on two markers of systemic inflammation, il- and serum amyloid a, whereas se tended to reduce circulating igf-i, an anabolic hormone. conclusions the hfd was not protective against the weight loss and skeletal muscle wasting associated with cigarette smoke exposure. supported by the nhmrc and crc for chronic inflammatory diseases. background patients with copd and bronchiectasis undertake airway clearance therapy (act) and exercise as part of physiotherapy management but it is unknown whether these treatments provoke gastro-oesophageal reflux (gor). this study aimed to determine the impact of positive expiratory pressure (pep) therapy and exercise on gastro-oesophageal function. p. aeruginosa is a significant opportunistic lung pathogen in individuals with cystic fibrosis (cf) and is associated with increased lung disease and morbidity. early intervention is beneficial for the effective clearance of p. aeruginosa and better long-term health outcomes. currently, lung flora of cf patients is monitored by regular culturing of sputum, however, children unable to expectorate are limited to annual bronchoalveolar lavages (bal), which is invasive and requires general anaesthesia. saliva is useful for clinical assays as collection is simple, non-invasive. we are developing a standardized enzymelinked immunosorbent assay (elisa) to detect respiratory infection of p. aeruginosa in cf children who cannot expectorate. methods children ( - years) with cf and recent p. aeruginosa lung infection history and non cf children ( - years) with no previous p. aeruginosa infection history provided saliva as positive, negative controls respectively. saliva was obtained by spitting, or absorbed using cellulose swabs and later extracted. these cell-free supernatant samples were used in an elisa anti-p. aeruginosa iga using commercial antigen. all results were standardized to account for flow using total iga expression. results median value was increased fold in the recent p. aeruginosa lung infection group (mann-whitney test, n = , p Յ . ). there was no significance between mucoid and non mucoid samples, and detection was independent of cfu/ml. discussion early findings support that p. aeruginosa respiratory infection can be detected through specific analysis of salivary iga expression. larger population sampling ( positive, negative) will aid selection of cut-off values for specificity and sensitivity testing in the future to objectively determine the utility of this assay as a means of monitoring for p. aeruginosa and for determining effectiveness of treatment. medical thoracoscopy is utilized widely throughout europe and northern america by thoracic physicians for the management of pleural disease, including the undiagnosed pleural effusion, malignant effusions and less commonly pneumothorax (ptx). australia has limited experience in this modality. we report the success of medical thoracoscopy in both primary and secondary ptx requiring intervention. methods data were collected from to in patients treated with medical thoracoscopy for the treatment of ptx. results patients, male, female. average age (range - ). first episode primary spontaneous (ps) ptx, third episodes of ps, first secondary spontaneous (ss), second ssptx, third ssptx. underlying pulmonary disease in secondary ptx included: chronic obstructive pulmonary disease, lymphangioleiomyomatosis, mesothelioma, metastatic angiosarcoma and was secondary to a motor vehicle accident. had a history of smoking, were former smokers and were current smokers, with a mean pack year history (range - ). ptx were large, moderate. patients had an intercostal catheter (icc) inserted prior to thoracoscopy, had failed pleural aspirate. there was evidence of bronchopleural fistula in patients prior to the procedure. there was a median of days from ptx to thoracoscopy. light sedation was used for the procedure in patients, required a general anaesthesia with a double lumen endotracheal tube due to anxiety. single port entry, dry talc poudrage and a gauge french icc was used for all procedures. icc was removed a mean of days following thoracoscopy and patients discharged on day . pain was the most common complication, requiring narcotic analgesia. one patient died on day , secondary to metastatic angiosarcoma. there has been no recurrence of ptx in any patient. conclusion medical thoracoscopy, performed by thoracic physicians is an effective procedure for the treatment of pneumothorax requiring intervention, including selected patients with evidence of bronchopleural fistula. funding nil. conflict of interest nil. nomination for young investigator award no. background lung cancer incidence and mortality are high in tasmania. australia (aihw ) / / tasmania (cancer registry ) / / aims and objectives (a) to determine patient demographics in southern tasmania, (b) to determine compliance to identified measures of best practice and (c) assess referral rates, clinical utility and potential delay to positron emission tomography (pet) in a regional setting. methods a prospective database collected information on local clinical practice. cases presented at a multidisciplinary lung cancer meeting over a month period (march -april were analysed. data were available for n = / ( %). results are shown as mean Ϯ sd. results primary lung cancer cases were identified. the mean age was Ϯ years. % of patients were male and % were current or ex-smokers. % were non-small cell lung cancers (nsclc). tissue diagnosis % time from diagnosis to surgery ( Ϯ days) % < days macroscopically complete surgical resection ( / ) % pet for stage iiib before radical chemoradiotherapy % % of patients presenting with early or locally advanced disease underwent further staging with pet (n = / ). management was changed in % of cases ( / ). the average time from pet referral to scan was Ϯ days. conclusion a disproportionate number of lung cancers occurred in women. although surgery was performed within recognized timeframes, of patients had incomplete resections. pet influenced management decisions and was performed in a timely fashion. hp chan , , v tran , , c lewis , , p thomas exhaled breath condensate (ebc) is a simple, safe and non-invasive method of sampling breath and has the potential to investigate lung cancer and the associated neoplastic process in the lungs. increased oxidative stress has been implicated in the pathogenesis of lung cancer, and is characterized by elevated hydrogen ions, and hydrogen peroxide (h o ), which is formed from the conversion of superoxide anions by superoxide dismutase. airway ph has already been shown to be decreased in ebc of patients with other respiratory conditions, but not in lung cancer. therefore the concentration of h o and hydrogen ions in the ebc of lung cancer subjects was compared with matched controls. methods six subjects with newly diagnosed lung cancer were recruited and matched with control subjects: non-smokers, ex-smokers and smokers. ebc was collected and h o was then measured by an assay method based on oxidation of , ', , '-tetramethybenzidine by horseradish peroxidase and h o while ph was measured using a ph meter. results there was a significant difference (p = . , anova) in h o concentration between the groups with the lung cancer group having elevated mean h o concentration of . mm ( . (sem) compared to the controls: non-smokers, . mm ( . (sem); ex-smokers, . mm ( . (sem); and smokers, . mm ( . (sem). ph did not differ significantly (p = . , kruskal-wallis test) between the groups. conclusion these preliminary data suggest that there is significant difference in h o concentration between the groups. the demonstration of an elevated h o level in those with lung cancer indicates an increase in oxidative stress which implies that this may be part of the pathogenesis or response to neoplasia. supported by none. conflict of interest none. pro-inflammatory th cytokines produced by t cells and monocytes play an important role in the immune response to malignant cells. however, tumours may escape immune surveillance by inhibiting th response and promoting chronic inflammation at the tumour site. methods to investigate the effect of soluble factors released by lung cancer cells on t cell and monocyte pro-and anti-inflammatory cytokines, culture supernatants from several lung cancer cell lines and a normal epithelial cell line ( hbe) were cultured with whole blood for hours, then for a further hrs with and without stimuli. intracellular cytokine / chemokine production was determined using multiparameter flow cytometry. results in stimulated cultures, there was a significant decrease in t cell th pro-inflammatory cytokines ifng, tnfa and il- and a decrease in monocyte il- a, il- , il- , tnfa, mcp- and mcp- but an increase in antiinflammatory cytokine il- compared with hbe and control media. in non-stimulated blood cultures there was an increase in all monocyte inflammatory cytokines / chemokines in the presence of lung cancer supernatants. conclusions lung cancers secrete soluble factors that inhibit the antitumour pro-inflammatory th response by t cells and monocytes and upregulate monocyte anti-inflammatory cytokine il- following "antigenic challenge". lung cancer cells may also escape immune surveillance by secreting soluble factors that cause newly recruited monocytes to release inflammatory cytokines promoting chronic inflammation at the tumour site. cytotoxic t-cells (ctl's) are important barriers against tumour cells. ctl's induce apoptosis of target cells by mechanisms that include the release of pore-forming perforin and granule associated enzymes, such as granzyme b and granulysin. proteinase inhibitor- (pi- ) is the only known granzyme b inhibitor and its expression has been observed in some cancers. we hypothesized that pi- would be differentially expressed in lung cancer cells and may inhibit granzyme b-induced apoptosis in these cells. methods we investigated pi- , granulysin and granzyme b expression in various lung cancer cell lines ( ( , ( , and normal epithelial cells obtained from bronchial brushing using flow cytometry. peripheral bloodderived t-cells were then incubated with lung cancer cell line supernatants and levels of pi- , granzyme b and t-cell reactive oxygen species (ros) were assessed. results pi- expression was detected in all lung cancer cell lines, ( ( . %), ( . %), ( %), sbc- ( %)), at much higher levels than in normal bronchial epithelial cells ( . %). granzyme b and granulysin levels were undetectable or low in cancer cells ( - . %). increased expression of pi- and reduced levels of granzyme b were observed in cd + t-cells in the presence of all cancer cell supernatants tested (p < . ). interestingly, t-cell ros levels were significantly increased in cd + t-cells after incubation with cancer cell supernatants (p < . ). conclusions high pi- expression in lung cancer cells combined with a reduction in t-cell granzyme b expression and enhanced intracellular t-cell ros levels may be a mechanism of immune evasion of lung cancer cells to granzyme b-induced cytotoxicity. immunotherapy for lung malignancies such as lung cancer and mesothelioma is most likely to be successful it it can be combined with conventional tumour debulking approaches such as chemotherapy and surgery. but they scientific basis of such combinations is yet to be determined. to study this we evaluated ( ) the capacity of different lung chemotherapy drugs to alter tumour antigen cross-presentation and immunogencity, ( ) duration of antigen presentation and responsiveness to immunotherapy after debulking surgery with/without lymphadenectomy, and ( ) the pattern of tlr agonism which best synergized with chemotherapy and surgery. we used the ab -ha murine model of lung malignancy in balb/c mice. results ( ) the antimetabolite drugs gemcitabine and pemetrexed were most immunogenic compared to the cytotoxic antibiotics doxorubicin and mitomycin c and the alkylating agent cisplatin. gemcitabine delived large amounts of tumour antigen into the cross-presentation pathway. ( ) tumour antigen cross-presentation persisted for only days following resection. the optimal window for immunotherapy following cancer surgery is week for effector ctl stimulation and - weeks for memory ctl stimulation. ( ) the viral-like tlr agonists tlr , and were the most effective adjuvant tlr molecules, with tlr agonists generating the strongest systemic anti-tumour responses. conclusion these results help explain previous lung immunotherapy failures and will inform new clinical trials. background mesothelioma is a highly aggressive tumour with an increasing world wide incidence. the serum biomarker mesothelin is elevated in some individuals prior to development of clinical symptoms of the disease and may be useful for screening. we therefore studied the sensitivity and specificity of urinary versus serum levels of mesothelin for mesothelioma patients and evaluated the influence if renal function on the biomarker level. materials and methods concurrent sera and urine samples collected from patients with and control populations. mesothelin concentrations were determined by double-determinant elisa using the mesomark tm assay (fdi, pa). their estimated glomerular filtration rate (egfr) was also calculated. results mesothelin levels correlated between serum and urine samples (pearson's correlation . ; p < . ). mesothelin levels were significantly higher in patients with mesothelioma compared to those with asbestosis and/or pleural plaques in serum ( Ϯ . versus . Ϯ . nm; p < . , respectively), in urine ( . Ϯ . versus . Ϯ . ; p < . ) and in urine following normalization using creatine levels ( . Ϯ . versus . Ϯ . ). age and egfr were significantly associated with mesothelin levels. conclusion the sensitivity and specificity of mesothelin in urine and in serum were comparable. urine mesothelin may prove to be a useful alternative to serum mesothelin for mass screening of asbestos-exposed individuals. patients undergoing ct coronary angiogram (cta) are often former or current smokers with a high incidence of asymptomatic lung disease. overseas reports show a rate of lung abnormalities ranging from . % to %. there are no studies from australia and local factors such as the higher incidence of atypical mycobacteria may influence the rate of benign findings. we are therefore performing a prospective observational study to identify the prevalence and characteristics of incidental lung findings in people undergoing routine cta. methods population: patients undergoing routine cta after informed consent. intervention: radiologist evaluation of lung windows on diagnostic standard workstations. comparator: uncontrolled observational study of consecutive patients. outcomes: primary: prevalence and characteristics of abnormal findings, final diagnosis (clinical judgment, biopsy or long term followup). secondary: number of downstream investigations and costs. results ctas have been studied to date. in / ( %), abnormalities were noted on lung windows. in / ( %), there were lung nodules, in / ( %) there were hilar lymph node abnormalities, in / ( %), there was hemidiaphragm elevation and in / ( %) there were pleural plaques (data collection ongoing with study closure expected in february ). conclusions preliminary data indicate a substantial number of incidental pulmonary findings from cta; full results will be presented. further analysis is required to determine the impact (benefits, costs and harms) that may result from the concurrent examination of lung windows at routine cta. aim increased levels of nitrogen oxides (nox) and inflammatory markers have been found in bronchoalveolar fluid of lung cancer (lc) patients, but have not been investigated in exhaled breath condensate (ebc).the aim of this study was to compare nox and total protein levels in ebc of lc patients with control subjects. methods ebc was collected during tidal breathing through a glass collection device cooled to °c. ebc nox concentrations were measured by a fluorescent modification of the greiss method. total protein in ebc was determined employing the bicinchoninic acid (bca) assay. ebc nox data were log transformed. all data were analysed using anova and expressed as mean Ϯ sem. results a total of control subjects and patients with primary lc were recruited. nox and protein concentrations are shown in table . there was no significant difference in ebc nox levels (p > . ), but in total protein there was a significant difference between lung cancer patients and all control groups (p = . ). conclusion significantly increased ebc total protein levels were found in patients with lung cancer. these data suggest that protein mediator secretion or vascular leak may be present in those with lung cancer. future studies will focus upon the identification of these proteins. methods in this two stage case-control study lung cancer cases and healthy smoker controls were recruited. genetic markers (snps) implicated in lung cancer were screened in our test cohort of smokers and ex-smokers. snps whose genotypes (co-dominant or recessive model) were associated with either the healthy smokers (protective) or lung cancer (susceptibility) phenotype were identified. after genotyping this snp panel in a second cohort of subjects snps were chosen and assigned a simple composite genetic score that was combined with scores for age, history of copd and family history of lung cancer, weighted according to our multivariate regression analysis (n = total subjects). the lung cancer risk score was linearly related to the likelihood of lung cancer with odds ratios (referenced against the lowest score quintile) ranging from to in the highest quintile. on receiver operator curve analyses, the auc was . and the frequency distribution showed bimodal separation between healthy smokers and lung cancer cases. utility of the score was not affected by effects of age, smoking history or lung function. we suggest that genetic data may be combined with other risk variables to define smokers or ex-smokers at risk of lung cancer for targeted interventions such as smoking cessation and early detection of lung cancer. supported by health research council, nz. conflict of interest yes. tp v aiyappan , a graham department of medicine, maroondah hospital, melbourne, australia, and the new disease-modifying anti-rheumatic drug (dmard) leflunomide is being used increasingly to treat inflammatory arthritis. its association with interstitial lung disease needs to be considered before combining it with methotrexate. case report a -year-old male who was known to have rheumatoid arthritis and was on methotrexate was admitted with progressive dyspnoea and malaise. he had been recently started on leflunomide. investigations revealed interstitial lung disease and acute renal failure. he improved on conservative treatment (stoppage of disease modifying drugs (dmard), iv fluids and steroids). review of literature an epidemiological study by suissa et al has suggested that there is increased risk of ild associated with leflunomide in patients with a history of ild or methotrexate use but they attributed this to channelling bias. there has also been a report of leflunomide associated with iga glomerulonephritis.by this presentation we aim to increase the awareness of this entity. we also suggest that any patient who is started on combination dmard (i.e. methotrexate and leflunomide) should have a baseline chest x-ray and be monitored for development of interstitial lung disease. conclusion we are reporting the first ever case of interstitial lung disease and glomerulonephritis (in the same patient), due to usage of leflunomide. this entity needs to be thought about in any patient on combination dmards. background bone morphogenic protein receptor ii (bmpr-ii) mutations are associated with pulmonary artery hypertension. failure of the growth inhibitory effects of bmp may contribute to vascular obliteration and remodelling leading to pulmonary artery hypertension (pah) [ ] . pah has been observed following venous thrombembolic disease (vte), including pulmonary embolism (pe) and deep venous thrombosis (dvt) [ ] . local markers of the pulmonary vascular endothelium rather than traditional markers of thromobophilia are thought to be involved [ ] . methods plasma was collected from age and gender matched participants within hours of diagnosis of vte and prior to commencement of warfarin therapy. plasma samples were hybridized to individual human cytokine antibody arrays, to detect protein levels of bmp , bmp and bmpr-ii. results bmp and bmp levels were higher in patients with dvt than pe. no difference in the bmp level was observed between patients with pe and controls. soluble bmpr-ii receptor was lower in patients with pe than in controls or patients with dvt. conclusion in patients with pulmonary artery stress during the time of a pe the bmpr-ii receptor is reduced, which may predispose patients to vascular remodelling and obliteration. the bmp and levels are reduced at the same time, suggesting a possible overriding regulatory mechanism. the physiological role of bmp's and bmp receptors in patients with vte warrants further investigation. historically, cyclophosphamide has had a variable role in interstitial lung disease (ild), the rationale for its use based on the benefit seen in vasculitis and scleroderma, its rapid effect and low toxicity profile. in patients with severe progressive ild a rapidly effective, well-tolerated agent is desirable. for this reason a treatment protocol for the use of intravenous (iv) cyclophosphamide was implemented at our hospital. aim to review the indications, duration, tolerability and effect of intravenous cyclophosphamide in ild patients following the introduction of a treatment protocol. methods records of patients [dlco was Ϯ % and fvc Ϯ %] completing a course of iv cyclophosphamide during - were reviewed (excluding patients with systemic sclerosis). data covering months prior to and following treatment were collected. comparative analysis of paired pulmonary function data months before and after treatment was performed. % had underlying autoimmune disease. results primary treatment indications included progressive disease(n = ); severe disease (n = ); suspected vasculopathy (n = ); bridging therapy to transplantation (n = ); and accelerated decline (n = ). patients received mg/m [mean dose Ϯ mg, median number of pulses ( - )]. patients with paired pulmonary function data had a difference in median change in dlco% predicted from - . % (- . to . %) before treatment to + . % (- . to . %) following treatment (p < . ). this remained significant with exclusion of vasculitis, or any autoimmune disease, and independent of prior immunosuppression. therapy was well tolerated ( withdrew from treatment, deaths within yr, none directly related to treatment). conclusion iv cyclophosphamide is well tolerated, and associated with functional stability or improvement in the majority of patients. it remains a viable treatment alternative for consideration. pulmonary hypertension is common in interstitial lung disease (ild) and associated with a poor prognosis. as the gold-standard test, right-heart catheterization (rhc) is invasive, and resource-limited, reliable non-invasive measures of ph are needed. methods all ild patients referred for rhc during - were included (n = ; male; age . Ϯ yrs). all patients had concurrent echocardiography (tte) and pulmonary function. the relationship of rhc mean pulmonary artery pressure (mpap) to tte variables, pulmonary function, exercise capacity, as measured by six minute walk testing ( mwt, n = ) and brain natriuretic peptide (bnp, n = ), was examined. case a year old male, non-smoker for years, retired professor of anatomy (had chronic exposure to embalming fluids, formaldehyde, phenol, antifungal and other solvents, for years) presented with chronic cough and phlegm production. these symptoms were worse at night (waking him several times) and early morning. his pulmonary tests were stopped due to persistent cough. a chest x-ray revealed features of longstanding interstitial lung disease. the hrct revealed widespread subpleural interlobular thickening, worse at bases, in keeping with idiopathic pulmonary fibrosis (ipf). there was minimal fibrosis and honeycombing, but no groundglass opacification, large bullae, pleural calcification or pleural plaques. however, there was associated bronchiectasis at the lung bases considered to be due to traction. the ba lavage showed % macrophages, % neutrophils, % lymphocytes, and %, eosinophils and no infection. the patient declined to have a lung biopsy. as per his past x-rays, the duration of his ipf is a little over one year. he maintains that his symptoms started only after starting irbesartan (irb). introduction transbronchial lung biopsy (tbb) has a variable and unpredictable diagnostic yield in sarcoidosis. we hypothesized that the extent and pattern of parenchymal disease on ct would predict the likelihood of a positive tbb. methods data relating to ethnicity, symptoms, pulmonary function and site and results of tbb and bronchoalveolar lavage (bal) from sarcoidosis patients were recorded. all had a ct scan within weeks prior to the tbb procedure. cxr stage was determined from radiology report. ct scans were scored quantitatively for patterns of parenchymal disease (nodular, reticular, consolidation, ground glass and mosaic attenuation) on a lobar basis. results % patients had a positive tbb (total % of cohort had histological confirmation). symptoms, ethnicity, treatment, lung function and cxr stage were not predictors of a positive biopsy. positive biopsy was associated with higher bal lymphocyte count (p < . ) and female gender (p < . ). a reticular pattern (p < . ) and higher total lung score (excluding da) (p < . ) on ct scan predicted a positive biopsy. in those patients with tbb from right lower lobe ( / ) the total rll score on ct was predictive of positive biopsy (p < . ). on multivariate analysis gender, bal lymphocytosis and total lung score were independent predictors of a positive tbb (area under roc . ). pulmonary arterial hypertension has two histological variants; 'arterial-only pulmonary arterial hypertension' (artpah) and 'pulmonary veno-occlusive disease' (pvod). bosentan, a dual endothelin receptor antagonist, has been found to improve haemodynamics, functional capacity and survival in artpah. however, the response to bosentan in clinically diagnosed artpah is often variable. it was hypothesized that a lack of response to bosentan therapy in clinically diagnosed artpah can be explained by misdiagnosed pvod. aims included to: ( ) perform morphometric and qualitative pulmonary vessel analysis on normal controls and cases clinically diagnosed with artpah who had failed bosentan therapy; ( ) ascertain if pvod is present within the case group; ( ) correlate clinical variables and vessel microanatomy to identify the pathologies driving pulmonary pressure elevation. this study reviewed cases of clinically diagnosed artpah (idiopathic n = , associated with scleroderma n = ), who had failed bosentan therapy and had available lung tissue. controls (n = ) were obtained from explanted lungs for other causes and a prior transthoracic echocardiogram excluded pulmonary hypertension. vessel morphometry and qualitative analysis was performed with a novel technique of smooth muscle actin immunohistochemistry counterstained with verhoeff's elastin. baseline clinical data were retrieved. we found % of cases had pathology confirmed pvod. only % of cases had artpah, the original clinical diagnosis. in pvod, significant pathology was present in all vessel types. all vessels had significant smooth muscle hypertrophy. the obstructive, collagenous, pauci-cellular intimal fibrosis of the venules (p < . ) and arterioles (p < . ) was considerably different to the concentric laminar proliferation of smooth muscle observed in the muscular arteries (p < . ) and arterioles (p = . ) in artpah. artpah also had muscular artery smooth muscle hypertrophy (p = . ). the median time to bosentan failure was shorter in pvod than artpah ( vs. days). in conclusion, pvod is an under-diagnosed cause of pulmonary hypertension, is commonly clinically misdiagnosed as artpah and may present with a poor bosentan therapy response. finally, pvod is a vaso-occlusive, not a veno-occlusive disease, and is an independent type of pulmonary hypertension, not a subtype of pulmonary arterial hypertension. cutaneous t cell lymphomas (ctcl) are a heterogenous group of lymphoproliferative disorders. they show various clinical manifestations and diverse morphological, histological and immunological characteristics of the malignant cells. they are caused by clonally derived, skin invasive t cells. peripheral t cell lymphomas (ptcl) are generally more aggressive and have one of the lowest overall and failure-free survival rates. because of the rarity of these disorders, diagnosis and treatment remain challenging. this case report describes a -year-old woman presenting with progressive dyspnoea and cough, together with a distressing generalized pruritic rash. she was initially treated as left ventricular failure with the rash ascribed to a drug reaction as suggested by initial skin biopsies. the diagnosis was made on a third skin biopsy and flow cytometry of lymphocytes obtained by broncho-alveolar lavage months after presentation. despite an initial response to chemotherapy she succumbed to the disease months after diagnosis. clinical pathways to guide the investigation of suspected pulmonary embolism (pe) have been increasingly adopted by emergency departments (ed) worldwide. compliance with these diagnostic algorithms is critical in ensuring good patient outcomes. this study evaluated the compliance to the clinical pathway used in our ed that combines risk assessment (wells scoring system) with d-dimer test, vq scan or ctpa. the main objectives of this study were to identify those factors which contributed to compliance and to assess patient outcomes. methods a prospective observational study of consecutive patients who underwent investigation for pe in our ed. patient demographics, pathway parameters and patient outcomes at -month follow-up were collected. case we report the case of a year old woman who presented to the emergency department with a three day history of dry cough and dyspnoea. the patient was in her third pregnancy at weeks gestation. she had no fever, chest pain or coryzal symptoms. the patient had presented with a right sided spontaneous pneumothorax seven months prior to the current presentation. her past medical history included placental abruption, complicating her previous two pregnancies. her second pregnancy was complicated by placental abruption at weeks and the foetus had not survived. her first pregnancy was complicated by placental abruption at weeks with successful delivery of the foetus. at presentation, significant findings included tachycardia, hypoxemia, tachypnoea and reduced breath sounds over the right side of the chest. chest x-ray demonstrated a large right pneumothorax. a right intercostal catheter was inserted resulting in right lung re-expansion. the catheter was removed three days later. the patient returned to hospital twenty four hours after catheter removal with a recurrent right sided pneumothorax. the patient agreed to surgical intervention involving video-assisted thoracotomy and talc pleurodesis. the patient had no further complications with the pregnancy. she delivered a healthy baby at weeks gestation. discussion spontaneous pneumothorax in pregnancy is rare and there is little evidence to provide guidelines for the management of recurrent pneumothorax in high risk pregnancy. our case illustrates a successful outcome for mother and foetus with surgical intervention at weeks gestation. folfox is currently the standard adjuvant treatment for locally advanced (stage iii) colon cancer and increases disease free survival. its toxicity is well tolerated with common adverse effects being paraesthesia, bone marrow suppression and gastrointestinal disturbance. pulmonary toxicity has rarely been reported. three clinical cases of acute dyspnoea following folfox therapy ( ) ( ) ( ) for stage iii colon cancer are reported. all had an anterior resection followed by - cycles of folfox. each developed rapidly progressive dyspnoea requiring hospital admission within one week of their last cycle. one patient required invasive ventilation in icu. high resolution computed tomography (hrct) showed bilateral widespread honeycomb pattern with associated ground glass opacification consistent with pulmonary fibrosis. they had reduced lung volumes and gas transfer. transbronchial biopsy and bronchoalveolar lavage in one patient showed an acute eosinophilic pneumonitis. other causes of interstitial lung disease were carefully excluded. all three patients received high dose corticosteroids with one receiving additional cyclophosphamide. the first patient showed complete recovery following an eight week course of corticosteroids, with resolution of the hrct changes and improvement in lung function. the second had symptomatic improvement of dyspnoea, but a persistent moderate reduction in gas transfer. the final patient had persisting radiographic changes and a reduced gas transfer. he remained dependant on ambulatory oxygen months after his initial presentation. these patients' interstitial lung disease appears due to folfox with oxaliplatin being the most likely causative agent. the use of oxaliplatin chemotherapy has increased markedly over the last years and although rare, physicians should be aware of its potential for lung toxicity. lung function testing at baseline, during and towards the end of oxaliplatin treatment should be undertaken and may allow early detection and intervention in cases of pulmonary toxicity. the forced oscillation technique (fot) with broadband signals has been employed relatively rarely in the studies on respiratory mechanics. recent work from our laboratory [ ] indicated that the cheek support and the neck angle have minor influence on the impedance spectra around the first antiresonance (far, ), which makes the use of the broadband fot especially attractive in young children. methods we studied healthy children (c; female: ) and children with bronchopulmonary dysplasia (bpd; female: ), using multiple-frequency fot between and hz superimposed on spontaneous breathing. results groups c and bpd did not differ in age ( lung function impairment is common in children with cardiac defects associated with increases in pulmonary blood flow/pressure. to investigate the development of bronchial hyperreactivity (bhr), an aorto-caval shunt was created in a model of precapillary pulmonary hypertension. surgical shunt repair was performed to assess the reversibility of bhr. methods rats were divided into groups: group c (n = ) with sham surgery, group s (n = ) where an aorto-caval shunt was created (follow-up wks), group r (n = ) with aorto-caval shunt but surgical correction of the shunt at wks (follow-up wks). in all animals, respiratory input impedance (zrs) was measured at baseline and following increasing doses of methacholine (mch , , , mcg/kg). airway resistance (raw), inertance, tissue damping (g) and elastance were estimated from the zrs spectra by model fitting. measurements were repeated in all animals at wks and at wks for groups r and c. results there was a significant increase in raw and g in group s and rat wks at baseline and following mch ( fig.) which was reversed after surgery. to characterize the factors contributing to lung function impairment following cardiopulmonary bypass (cpb), functional residual capacity (frc), lung clearance index (lci) and respiratory mechanics were measured in children with pulmonary hypoperfusion (tetralogy of fallot, tof n = ) and hyperperfusion (ventricular septal defect, vsd n = ) undergoing surgical repair of congenital heart disease. methods frc and lci were measured using a sf washout technique and respiratory mechanics using a low frequency oscillation technique in the perioperative period. results while chest opening led to a significant improvement of lung volumes and respiratory mechanics in all patients (p < . ), a reduction in pulmonary blood flow during cpb decreased lung volumes and airway resistance in parallel but significantly more in children with tof compared with those with vsd. re-establishing pulmonary blood flow during cpb improved respiratory function particularly in children with tof ( figure) . conclusions sternotomy had a great impact on lung function with parallel improvement in alveolar recruitment, ventilation inhomogeneity and airway resistance. in contrast, onset of cpb led to lung function impairment with a significant drop in frc especially in children with pre-existing hypoperfused lungs. this suggest that pulmonary blood flow enhances alveolar stability through a tethering effect on the alveolar walls. children with advanced lung disease being considered for lung transplantation are likely to spend disproportionately longer periods on transplant waiting lists before appropriately sized donor organs become available. these longer waiting times reflect the lower organ donation rates seen in children; rates that are significantly lower than those reported in the adult population. we describe two children with advanced lung disease who deteriorated whilst on the waiting list for lung transplantation, and in the absence of appropriately sized donor lungs, underwent lobar lung transplantation. methods we describe the clinical course of two children, aged and years old, with advanced lung disease secondary to post-mycoplasma obliterative bronchiolitis and cystic fibrosis-associated bronchiectasis, respectively. results both children received a "cutdown" bilateral lobar transplant from two oversized adult brain-dead organ donors. in both cases the transplant operation involved implantation of the right middle and upper lobes, and of the left upper lobe from the donor. conclusion given the low organ donation rates in children, and in the absence of appropriately sized donor lungs, novel strategies such as lobar transplantation must be considered, particularly when children continue to clinically deteriorate whilst on the lung transplant waiting list. data from the west australian adult outcomes of extreme preterm birth study suggest that adult survivors of bronchopulmonary dysplasia (bpd) may be left with functional and structural pulmonary abnormalities, most notably emphysema. animal data suggest that the antenatal administration of corticosteroids may adversely affect lung development. we therefore sought to determine if maternal variables, including administration of corticosteroid, could predict emphysema severity in adulthood. methods bpd subjects (birthweight < g and oxygen dependence at weeks post-menstrual age) born prior to were identified and recruited prospectively via the statewide neonatal follow up program as previously described. pulmonary function tests and thin selective inspiratory and expiratory computerised (ct) images were acquired and scored for emphysema severity (voxel index (%)). the obstetric history was obtained from retrospective review of case notes. results adults ( females, aged - ) were studied, declined ct. all subjects had abnormal ct findings. fifteen ( %) had areas of emphysema. emphysema score and fev were not influenced by the administration of antenatal corticosteroids, indication for delivery, maternal age or presence or absence of chorioamnionitis. conclusion maternal factors, including the administration of antenatal corticosteroids, do not predict the long term respiratory outcome of bpd. the factors determining the severity of emphysema in this group remain unknown. the prevalence of childhood asthma is high in the torres strait. children have generally more severe asthma and asthma knowledge is poor. however, there is no culturally appropriate asthma education program for these children. we are conducting a randomized controlled trial to examine the additional benefits of an education intervention by indigenous health care workers (hcw) on asthma outcomes. we describe the study's objectives, design and baseline measurements. methods children with wheeze were reviewed by two paediatric respiratory physicians using a standardized protocol; children with asthma were eligible. after obtaining informed consent children were randomly allocated to: ( ) three additional asthma education sessions with a hcw; or ( ) no additional education from a hcw. trained hcws carried out the education sessions using culturally appropriate tools. primary outcome was the number of unscheduled hospital/doctor visits due to asthma exacerbation. all children were re-assessed at months. results we enrolled children aged to years, % were torres strait islanders and % aboriginal and torres strait islanders. the clinical spectrum of asthma was: % infrequent episodic asthma, % frequent episodic asthma and % chronic asthma. eighteen percent of the children knew what a written asthma action plan was; . % had one. carers' assessment of knowledge of medications showed that % could not name any asthma medication used by their child, % could not explain dosage, and % could not explain how beta agonists worked. conclusions asthma knowledge and possession of asthma action plans in this cohort is poor at baseline. there is substantial room for improvement and additional asthma education by hcws potentially has significant benefits. impulse oscillometry system (ios) measures respiratory function during normal breathing by transmitting mixed frequency rectangular pressure impulses down the airways and measuring reflected pressure. computer analysis calculates respiratory impedance and its components, airways resistance and reactance, at a range of frequencies from . hz to hz. no previous australian normative data exists. the ios software generates predictive normal values for each of the parameters measured including total airway resistance (r ), the proximal airway resistance (r ) as well as peripheral capacitive reactance (x ). however, they are based on german data. methods cross-sectional study of community dwelling adults, with males and females per -year cohort. inclusion criteria: age range - years, apparently good respiratory health. exclusion criteria: smokers, asthmatics and others with acute or chronic respiratory disease. both ios and spirometry were conducted on all participants. results australian predictive normal equations have been generated and compared to the current published equations. the ios parameters have been correlated with the spirometric data. results have been analysed by gender, age, height and weight and compared with the predictive normal values for each parameter provided by the german manufacturer of the ios instrument. analysis includes calculation of mean range, and lower limit of normal. conclusions a preliminary set of australian predictive equations have now been produced for the ios. these have been compared with international equations. ios has potential application in a range of respiratory disease states and in population screening for occupational health (e.g. mining, & high dust load environments). supported by phc red. rationale although clinical practice guidelines for both asthma and copd recommend spirometry for diagnosis and monitoring, beneficial effects on the management of chronic respiratory diseases in general practice have not been established. we hypothesized that spirometry would improve health outcomes compared to usual care. methods we are conducting a single masked rct with arms: group a receive monthly spirometry and followup, group b receive spirometry before and after the trial and group c usual care. general practices were recruited though divisions of general practice in melbourne. invitations were mailed by of these practices to patients who had been prescribed inhaled medications during the previous months. participants returned respiratory and generic quality of life questionnaires and an asthma score card. groups a and b were tested on a micromedical turbine spirometer following ats/ers guidelines. results eligible patients ( adults, children aged - and youths aged - years) entered the trial. were randomized to group a, to group b and to group c. the mean (sd) age of adult participants was . ( . ), children . ( . ) and youths ( . ) years. there were males and females. the adults were highly symptomatic in the previous months: % reporting wheeze, % chest tightness on waking, % shortness of breath on exertion, % nocturnal cough, % morning cough and % sputum. symptoms of chronic bronchitis were reported by % of adults and a diagnosis of copd by %. asthma was reported by %, confirmed by a doctor in % and % had experienced an attack in the last months. only % had a written asthma action plan. % of adults had ever visited a hospital ed and % had been admitted. conclusion it is possible to recruit asthma and copd patients from general practice and to randomize them to spirometry or usual care. whether spirometry is associated with fewer symptoms, changes in medication, uptake of action plans or improvement in lung function or quality of life requires further followup. supported by nhmrc. s shah , jk roydhouse , b toelle , s sawyer , c jenkins for the pace australia management committee university of sydney, woolcock institute of medical research, sydney, nsw , and royal children's hospital, melbourne, vic it is widely held that recruitment of general practitioners for research can be challenging. in this paper, we discuss the recruitment experience from a current study evaluating the impact of an educational asthma intervention on patient outcomes. our aim is to describe the two different strategies utilized to date: ( ) in-house through an academic department of gp and ( ) outsourced to a private gp organization. methods initial interest was generated through faxes, presentations at gp divisional meetings and newsletter advertisements. gps who expressed interest were visited by project staff to discuss the study further. a major difference was recruiting one gp per practice in the first strategy versus multiple gps per practice in the second strategy. to assess the strategies, we examined participant characteristics, number of gps recruited and number retained. results participant characteristics: under both strategies, % of recruits had trained in asia and % were women. the first strategy recruited more gps who spoke at least two languages at home ( % vs %) and the second strategy recruited more recently graduated gps ( % vs %). recruitment: the first strategy recruited gps over months and the second recruited gps over months. retention: gps ( %) from the first strategy stayed in, compared to ( %) from the second. conclusions whilst absolute numbers of gps recruited were similar, retention was much higher under the second strategy. recruitment in primary care is difficult and requires a range of approaches which need to be re-evaluated and adapted as necessary during the course of the study. supported by the australian government department of health and ageing. bronchiectasis is a heterogeneous condition with a large number of causative factors and range of symptoms. the classification of this condition is often confusing and hard to remember. the aim of this study was to classify non-cf bronchiectasis into different clinical phenotypes. methods consecutive patients with non-cf bronchiectasis confirmed on high resolution ct scanning had a detailed clinical, spirometric and laboratory assessment performed by a respiratory physician (pk/mf/pw) and were then followed up for an average of Ϯ years (mean and sd) for a total of over reviews. results of the patients ( %) could be classified as belonging to phenotypic groups; ) bronchiectasis arising in childhood, ) bronchiectasis occurring in smokers and ) bronchiectasis occurring in the elderly. each group had different features which are listed in the there are few data on the long term outcomes of treatment for tuberculosis (tb) by directly observed therapy (dot) in low-incidence settings. the aim of this study was to assess the incidence of recurrent tb in nsw. methods data linkage was performed within the nsw department of health tb notifications database to identify cases that had more than one tb notification between and . recurrent tuberculosis was defined to include all patients with two or more culture positive episodes at least months apart, where patients had received at least six months treatment for the initial episode. in cases where data contained within the notification details was not sufficient to allow us to distinguish between true cases of recurrent disease, duplication notification for the same episode or persistent disease after incomplete treatment, additional information was obtained from the area tb coordinator. results there were tb notifications between and with being culture positive. cases of recurrent culture positive disease after completed treatment for the first episode were identified (recurrence rate: . %). conclusions in a population with a low tb incidence, treatment of active tuberculosis with dot results in a very low rate of disease recurrence over a long period of follow-up. support nhmrc ccre in respiratory and sleep medicine. introduction rhinoviruses (rvs) are the major cause of viral-induced exacerbation of asthma. to date, the molecular mechanisms of rv pathogenesis are not understood. recent findings suggest that rv pathology may involve host cell nucleocytoplasmic trafficking, inhibiting key cell functions such as transcription and translation. the study aims to investigate the mechanism of rv c protease nuclear trafficking. methods hela cells were infected with rv or transfected with plasmids and cellular localization of c analysed at various times thereafter using immunofluorescent confocal microscopy and western blotting with specific antibodies. results c protease was predominantly present in nuclei of rv infected cells up to hours after infection, becoming increasingly cytoplasmic thereafter. the nuclear membrane of infected cells became progressively indistinct with time. using a specific inhibitor we also found that c utilizes the crm- nuclear export pathway. c was predominantly in the form of cd in both cytoplasm and nucleus of infected cells; mature c protease was also detected from hours after infection. deletion analysis indicats that the nuclear localization domain and a nuclear export signal are most likely to be present within the n terminal amino acids. the nuclear export signal is inhibited in the full length protein, via an unknown mechanism. conclusion our data suggest that c and cd proteins localize to the nucleus in infected cells where they may play a key role in rv pathogenesis by disrupting cellular transcription and the nuclear transport machinery. chronic necrotizing pulmonary aspergillosis (cnpa) is a relatively uncommon, sub-acute, locally destructive process due to aspergillus invasion of the lung. the incidence and prognosis of cnpa are poorly described. case report we present a case of cnpa in a patient on intermittent low dose steroid therapy and recurrent refractory exacerbations of chronic obstructive pulmonary disease (copd).the patient presented with worsening shortness of breath and productive cough requiring recurrent inpatient admissions. human influenza virus is found to bind preferentially to saa , gal receptors found in the upper respiratory tract, while avian viruses bind to saa , gal receptors expressed in lower airways. this is thought to affect the ability of transmission to humans. our aim was to study the ability of avian and human influenza strains to infect bronchial epithelial cells and relate this to levels of the sialic acid receptor expression. methods calu- cells were used as a proximal airway cell and a were used as distal airway cell. human primary bronchial epithelial cells (pbecs) were obtained from healthy, asthmatic, and copd volunteers by endobronchial brushing. epithelial cells were stained with sambucus nigra lectin that binds saa , gal receptor, and maackia amurensis lectin ii that binds to saa , gal. the cells was analysed by flow cytometry. human influenza a/h n /wellington strain and low pathogenic avian influenza a/h n /sandpiper were chosen and were used at an moi of . to infect cells. the supernatants were harvested at hr post infection, of which was then analysed by plaque assay for virus replication. results the calu- showed greater expression of saa , gal linkage than saa , gal linkage, and a displayed slightly higher expression of both receptors compared to pbecs. despite this human and avian influenza virus replicated to similar titre at , pfu/ml in both cell lines, but showed low replication in pbecs. background treatment of community-acquired pneumonia remains based on 'best guess' empiric algorithms because of the poor utility of current pathogen tests. furthermore our ability to stratify patients into risk groups is crude at best, relying on scores such as the pneumonia severity index or the curb- have major limitations. we have been slowly improving real-time pcr assays for pneumococcus as a clinical tool in patients with pneumonia. methods building on previous research we assesed two targets in the autolysin (lyta) gene and the pneumolysin (ply) gene of s.pneumoniae using the lightcycler instrument and fluorescence resonance energy transfer (fret) probes. all common s. pneumoniae serotypes were detected while other bacteria and viruses were not. the lyta target had the best sensitivity with a detection range between ng to fg. both assays were then applied to whole blood samples from adult patients with community-acquired pneumonia, all of whom had blood cultures prior to antibiotic administration and urinary antigen testing for s.pneumoniae. the lyta pcr had the best performance characteristics with a sensitivity more than twice that of blood cultures in the clinical samples. most pcr+ve/culture -ve patients had positive urinary antigen tests. there was clinical evidence that urinary antigen +ve/ pcr -ve patients were false +ves. most significantly there was a strong correlation between quantitative bacterial count and clinical outcome. conclusions real-time quantitative pcr for pneumococcus has significant potential as both a diagnostic and therapeutic tool in patients with pneumonia. the pitjantjatjara lands are situated in the north-western corner of south australia, occupying an area of over square kilometres with a population of approximately . the population lives in small communities or homelands, and there is a high level of mobility between this region and other aboriginal communities in south australia and the northern territory. nganampa health council provides all health care services to the region. specialized support for tb control comes from both the south australia tb service based at royal adelaide hospital as well as a centre for disease control in alice springs. the prevalence of tuberculosis (tb) in this predominantly indigenous community is thought to be significantly higher than the national rate. there are considerable challenges in detecting and managing tuberculosis, relating to the community's geographical remoteness, migration of populations and access to health services. the aims of this study are to quantify the prevalence of tuberculosis in the pitjantjatjara lands, and describe the significant barriers to tb diagnosis and treatment. methods a retrospective study of all diagnoses of tuberculosis within the pitjantjatjara lands in the period - . outcomes include measures of tuberculosis diagnosis, the rates of completed tb treatment and rates of tuberculosis drug resistance. the study will draw conclusions about the reasons for high levels of tb prevalence in this community and identify barriers to effective tuberculosis treatment. conflict of interest no. patients admitted to hospital with a diagnosis of community-acquired pneumonia (cap) are usually treated with intravenous (iv) antibiotics irrespective of pneumonia severity. available guidelines vary in recommended timing and indications for switching to oral antibiotics. aim to examine the patterns of antibiotic choice and delivery method (iv, oral and time to switch) in patients admitted with cap. methods a retrospective chart review of admissions to the respiratory unit over a -month period with a diagnostic-related group (drg) coding of pneumonia. charts were reviewed. data collected included patient demographics, clinical features at presentation (temperature, pulse rate, respiratory rate, bp, oxygenation), initial investigations, initial antibiotic regime, time to change (iv to oral), subsequent antibiotic regime and duration, time to defervescence, length of stay and outcome. pneumonia severity was calculated using the revised british thoracic society system (curb- ), score Ն = severe. results patients were excluded due to incorrect coding. of the patients, age was Ϯ (mean Ϯ sd) yrs and ( %) were male. patients ( %) were febrile at presentation and the median curb- score was (range - ). patients ( %) received iv antibiotics. the curb- score was or (non-severe) in patients and of these patients received a combination of iv ceftriaxone and a macrolide. time to defervescence was . Ϯ . days. time from defervescence to switching to oral therapy was . Ϯ . days. in non-febrile patients, time to switch was . Ϯ . days. length of stay was . Ϯ . days. conclusions the time between defervescence and switch to an oral regime was relatively long, possibly contributing to an increased length of stay. many patients received ceftriaxone even with a curb- severity rating of or . implementing local guideline-based treatment protocols may reduce length of stay. ultrasonic flow sensors can determine flow, volume and molar mass (mm) of the gas flow simultaneously. during tidal breathing the expired molar mass curve can be used to compute co over expired volume and a capnography index (cpi) can be computed. the relationship between cpi and copd classification according to gold was investigated. methods prospective, controlled trial. consecutive patients who underwent routine lung function were enrolled to participate in a tidal breathing test using an ultrasonic flow sensor. each test consisted of three tidal breathing recordings of sec. flow, volume and molar mass were measured at hz and data were acquired using prototype wbreath data acquisition software. mean expirograms (mm over volume) were computed and the measurements were analyzed to determine the slope of exhaled phase ii (s ), the slope of phase iii (s ) and the relationship between s and s (cpi = s /s ). gold stages were determined from the lung function results and the ers predicted values. results volunteers participated in the study with a mean age of (sd ), were male, mean bmi (sd ), had never smoked. the mean pack/year smoking history was . there was a clear relationship between gold stage and cpi: gold stage 'normal' had a mean cpi of . (sd . , n = ), stage 'severe' had a mean cpi of . (sd = . , n = ). conclusion computation of cpi based on tidal breathing analysis using an ultrasonic flow and mm sensor correlates well with gold stages. it may therefore be possible to use a simple tidal breathing test to determine the severity of airways disease. background osa is common in tetraplegia and appears within weeks of injury. although cpap treatment is efficacious in able-bodied subjects, case series suggest that cpap is poorly tolerated in tetraplegia. no prospective study has examined cpap efficacy or adherence in tetraplegia. aim to determine the feasibility of cpap use to treat osa following acute tetraplegia. methods all acute admissions who consented and fulfilled the inclusion and exclusion criteria underwent full, portable polysomnography. those found to have an apnoea hypopnoea index of > events per hour (osa) were offered cpap, delivered via an auto-titrating device. results to date, patients have been admitted ( excluded, refused consent). no significant, adverse events have been observed. two patients did not have osa. of the nine with osa, four are mid-study, two had incomplete follow-up ( returned to uk and refused month assessment), two adhered with cpap and one did not due to severe, pre-existing nasal obstruction. preliminary analyses suggest that those who adhered to cpap had a marked reduction ( % compared with - %) in sleepiness and a greater reduction in the functional outcomes of sleepiness compared to either those without osa or who were unable to use cpap. patient accrual, recruitment and completion rates are consistent with our initial estimates. study recruitment will be completed by end-october . conclusion initial data suggest that auto-titrating cpap is a feasible treatment for osa in acute tetraplegia. these data will be used to finalize planning for a multi-national, multi-centre randomized controlled of therapy. this research was supported by the transport accident commission. visual recognition of cyanosis is an important clinical activity. cyanosis recognition is affected by lighting colour and there is anecdotal evidence that people with significant colour vision deficiencies (cvds) have particular difficulty. studies to date have centred on the colour change with oxygenation of isolated blood but it is not clear how this extrapolates to cyanotic patients in vivo. methods ten patients known to be chronically hypoxaemic and showing signs of cyanosis were recruited from the chronic respiratory program. ten normal subjects were recruited as controls. the spectral reflectances of their lips, nail beds and palm creases were measured using a topcon sr- telespectroradiometer. the patients were measured at rest and after exercise to lower their saturation by - %. the chromaticities were calculated and plotted. results both groups showed a spread of colours but they fell into two distinct ranges. the colour difference between the groups lies very close to the colour confusions made by congenital cvds. within the cyanosed group, the colour shift was not tightly related to decreasing oxygen saturation. this is most likely due to interpersonal factors such as pigmentation and vascular perfusion that affect colour and the difficulties in measuring the colour of heterogeneous anatomical features. conclusions these results quantify the anecdotal difficulties in detecting cyanosis and suggest that observers with cvd would have problems recognizing the condition. the photographs obtained from this study will be used to compare the ability of subjects with and without cvd to detect cyanosis. supported by the nsw ambulance service. baroreflex sensitivity is depressed in osa patients during sleep but effects during wakefulness are less clear. we have now examined relationships between awake brs and severity of sleep disordered breathing (sdb). methods immediately prior to overnight polysomnography, continuous ( min) beat-to-beat arterial blood pressure was measured via finger plethysmography (portapres) and heart rate via ecg in , supine, normotensive, untreated osa patients ( males; age: Ϯ years (mean Ϯ sd); bmi: Ϯ kg/m ). spontaneous baroreflex sensitivity (brs) was calculated using the sequence technique. sdb was characterized as apnoea hyponoea index (events/hour) and arousal index (ai). data were analysed via mathematical modelling and unpaired t test. results brs fell with increasing ahi. patients with ahi > events/hour (n = ) had a significantly lower brs ( . Ϯ . ms/mmhg) than those with ahi < events/hour ( . Ϯ . ms/mmhg, p < . ). brs was negatively related to both ahi and ai via fitted exponential functions (r = . and . , respectively). it is hypothesized that the analysis of morphology of the ecg waveform in combination with the heart rate patterns could lead to the possibility of detection of the start and duration of apnoea/hypopnoea events and consequently estimation of the apnoea-hypopnoea index (ahi). to the authors' knowledge the published ecg based algorithms for detecting sleep disordered breathing are only capable of minute by minute analysis rather than detection of individual respiratory events. methods changes to ecg parameters were investigated during respiratory events with no distinction made between apnoea and hypopnoea events. isolated respiratory events and controls of identical duration were obtained from polysomnographic studies, using a randomized procedure. features such as the r wave amplitude, t wave amplitude, qrs area and the r-r interval were extracted from the lead ecg. a number of physiological predictors based on these features were generated. a logistic regression model was used to investigate the association between the predictors and true events, using the statistical software, stata. results univariate and multivariate analyses were performed. three multivariate models were developed; heart parameters only, ecg waveform morphology parameters only and the combinations of the two. the area under the receiver operator characteristic curves (auc) for these models were compared. the best results were obtained with the combination of morphology and heart rate parameters (auc = . ( . (sd))) compared to the morphology (auc = . ( . (sd))) and heart rate (auc = . ( . (sd))) models. the multivariate analysis has shown encouraging results indicating that an algorithm using a combination of heart rate and ecg morphological parameters could potentially be constructed that would enable the determination of individual respiratory events and subsequently an ahi. supported by the arc. introduction sacin and scond are measures of ventilation heterogeneity in acinar and conducting airways, derived from analysis of mbnw. maintaining tidal volumes of l at - breaths/minute (bpm) is impossible for some. our aim was to examine the effect of different tidal volumes on sacin and scond in normals and asthmatics. methods normals ( - yrs) and asthmatics ( - yrs) underwent mbnw at tidal volumes of ml at - bpm, l at - bpm, and l at - bpm. scond and sacin, were determined from the normalized phase iii slopes of breaths between turnovers (cumulative ventilation/frc) . & . results the mean Ϯ sd %predicted fev was . Ϯ % in normals and Ϯ % in asthmatics. in normals, sacin at tv of . , and l were . Ϯ . l - , . Ϯ . l - and . Ϯ . l - , respectively (p = . , anova), while scond were . Ϯ . l - , . Ϯ . l - and . Ϯ . l - (p = . ), respectively. in asthmatics, sacin were . Ϯ . l - , . Ϯ . l - and . Ϯ . l - , respectively (p < . ), while scond were . Ϯ . l - , . Ϯ . l - and . Ϯ . l - , respectively (p < . ). conclusion increasing tidal volume while maintaining the same minute ventilation during mbnw led to large decreases in scond and sacin in both asthmatics and normals. this may be due to reduced inter-regional differences in specific ventilation with greater tv. the log-log relationship between sacin and tv allows an adjustment to be made for variations in tidal volume. funding crc for asthma and airways and nhmrc project grant # . dj smith , k bowden , t lloyd , j coucher , l garske respiratory medicine, and radiology, princess alexandra hospital, brisbane, australia introduction we have shown diaphragmatic flattening and decreased diaphragmatic excursion qualitatively assessed on ultrasound is strongly predictive of dyspnea severity and lower lung inflation in patients with pleural effusion. we sought to quantitatively measure diaphragm length and movement and determine how closely these are related to dyspnea severity and lung inflation. methods patients with unilateral pleural effusions had ct imaging of their diaphragm during a measured inspiratory capacity manoeuvre. maximal sagittal length was measured at tlc, and frc. patients had a baseline dyspnea index (bdi: - ) and respiratory function measured. results patients with unilateral effusion (all right side; malignant mesothelioma, inflammatory) had a mean (sd) bdi of . ( . ), and tlc of % ( . ) predicted. the right diaphragm on the side of the effusion tended to be shorter than the left at frc (p = . ), and had a trend to reduced shortening with inspiration (p = . ). conclusions the right diaphragm is known to be longer than the left in health. the strong trend to a shorter and less mobile right diaphragm associated with effusion suggests this is a potential mechanism for dyspnea. further recruitment will enable correlation between bdi, tlc and diaphragm length and mobility. ) ) that was slightly worse than an able bodied, control population ( . ( . )), but better than an able-bodied population with untreated osa ( . ( . )). the mapi predicted that % of the sample were likely to have osa. these data will be complimented by full sleep studies to be performed at the participants' homes in late , early . conclusion our interim data suggest that the rate of subjective sleep complaints are not substantially different in the population with tetraplegia compared with the able-bodied. this research was supported by the victorian neurotrauma initiative. it has long been assumed that the ventilation heterogeneity associated with lung disease could in itself affect the measurement of carbon monoxide transfer factor. the aim of this study was to investigate the potential estimation errors of carbon monoxide diffusing capacity (tlco) measurement that are specifically due to conductive ventilation heterogeneity. we induced conductive airway ventilation heterogeneity in never-smoker normal subjects by histamine provocation, and related the resulting changes in ventilation heterogeneity (derived from the multiple breath washout test) to corresponding changes in diffusing capacity, alveolar volume and inspired vital capacity (derived from the single breath tlco method). average conductive ventilation heterogeneity doubled (p < . ), while tlco decreased by % (p < . ), with no correlation between individual data (p > . ). when dividing diffusing capacity by alveolar volume, the resulting transfer coefficient was not significantly different pre versus post histamine (p = . ). these findings can be brought in agreement with recent modelling work, where specific ventilation heterogeneity resulting from different distributions of either inspired volume or end-expiratory lung volume have been shown to affect tlco estimation errors in opposite ways. the combination of these errors appears to largely cancel out in our experimental situation of induced ventilation heterogeneity comparable to that observed in lung disease. we conclude that conductive ventilation heterogeneity per se has a negligible effect on diffusing capacity measurement. an important determinant of airway function in humans is vagal-mediated cholinergic tone in airway smooth muscle (asm). this airway tone may be altered in disease states. the use of mouse models for the study of airway diseases, including asthma, pulmonary fibrosis and copd is well established. however, it is not known whether mice actually possess basal asm tone or, if it does exist, how this tone changes in disease models. this study was undertaken to determine whether mice have detectable asm tone in vivo. methods respiratory system impedance (zrs) was measured in female adult balb/c mice using a wave-tube modification of the forced oscillation technique. zrs was measured during slow (~ s) inflation-deflation manoeuvres between the transrespiratory pressures of and cmh o. baseline lung mechanics and thoracic lung volumes (tgv) were measured before and after each mouse was allocated to one of four treatment groups: 'saline' mice received an i.p injection of saline, 'atropine' mice received i.p. atropine sulphate, 'vagotomy' mice had their left and right cervical vagus nerves isolated by blunt dissection and cut, and 'sham' mice had the area of the vagus nerves exposed but the nerves were not cut. results there were no post-treatment changes in tgv, airway resistance, tissue damping, tissue elastance, inertance or tissue hysteresivity in any of the four groups. conclusions the lack of change in lung mechanics post-atropine or postvagotomy in balb/c mice suggests that, unlike humans and many other species, the airways of mice have no baseline asm tone. supported by nhmrc grant# . nomination none. conflict of interest none. both male gender and increased mandibular enclosure volume predict more severe sleep disordered breathing in obstructive sleep apnoea patients. we now examine gender/body size/mandibular enclosure volume relationships for normal subjects stepwise multiple linear regression analysis was used to model body size/enclosure volume interactions. results for the whole group, mv was . Ϯ . ml (mean Ϯ se) while rmv was . Ϯ . ml. head circumference (positive) and forehead height (negative) were both independent predictors for mv and rmv (both p < . ), while hip circumference was an additional positive predictive factor for rmv (p < . ). after adjusting for these parameters, male mv and rmv were larger than for females conclusion these findings suggest that mandibular enclosure volumes are relatively larger in males, even after adjusting for body size/cranial dimension. differing body size/mandibular enclosure volume interactions may contribute to gender influences on the severity of sleep disordered breathing. supported by nhmrc of australia nomination john read prize for sleep and physiological research tp audit of ctpa in a regional hospital y raje, s vincent, g simpson department of thoracic medicine, cairns base hospital, cairns, qld since the introduction of computerized tomographic pulmonary angiograms (ctpa) at our institution the number of requests for this investigation at our institution has grown at an alarming rate. the purpose of this study was to evaluate the clinical assessment of suspected pulmonary embolism (pe). methods ctpa were reviewed. results female, male. mean age yrs (range - ). ctpa requests came from department of medicine, from emergency department, from surgical teams and from oncology outpatients. patients presented with chest pain (pleuritic in cases), had dyspnea, presented with collapse. patients had haemoptysis. hypoxaemia was recorded in . none were clinically shocked and only one had a recorded tachycardia. d-dimer requested in patients and was elevated in . arterial blood gases performed in only patients ( %). patients had prior chest x-ray which was normal in ( %). patients had consolidation on chest x-ray, pleural effusions, atelectasis and fractured ribs. recorded risk factors included patients with previous dvt or pe, patients with malignancy and patients were immediately post-operative. only ctpas ( %) demonstrated evidence of pe. of these had recent dvt and were post-operative. had a history of bowel cancer. there was no formal record of pre-test clinical probability of pe (eg wells' score) for any of the cases. retrospective calculation of the cases of pe, had a wells' score of . and of with the remaining patient with wells' score of under . only patients (one with clinically probable pe) had received fractionated heparin prior to the ctpa. conclusion ( ) ctpas performed at our institution have a low yield ( %).( ) pre-investigation clinical assessment was poor and there was poor adherence to published guidelines, ( ) this results in many unnecessary ctpa examinations generating increased work and expense for the medical imaging department and exposes many patients to unnecessary and potentially harmful radiation exposure. the evaluation and management of hereditary hemorrhagic telangiectasia involves a multidisciplinary approach according to international guidelines. the aim of this audit was to compare the assessment process in one centre with that of the international recommendations. methods retrospective comparison was made by medical chart review of all patients with a diagnosis of hht between the years to . demographic along with clinical data with diagnostic investigations, complications, treatment and genetic evaluation, including family screening was collected. the proportion of patients evaluated and managed as per the international recommendations was determined. results the audit identified patients with the diagnosis of hht, with the mean age years. diagnostic criteria were met in % of the cohort. of the known clinical features, % had a family history, and % epistaxis. cutaneous telangiectasia was present in % and visceral involvement in %. pulmonary arterio-venous malformations (pavm) were seen in patients, cerebral avm in , gastrointestinal telangiectasia was documented in . one patient had a spinal (cervical) avm, and another had pulmonary hypertension in association with this condition. only patients underwent diagnostic or screening investigations in accordance with the international recommendations. furthermore, one patient was referred for a genetic evaluation. conclusions this clinical audit found that % of patients referred to this centre were evaluated in accordance with the international recommendations. genetic assessment was lacking. the study supports the need for a coordinated, multidisciplinary approach to the evaluation and management of hht in this centre. lm young , n good , d milne , w fergusson , i zeng , j kolbe , ml wilsher background while airflow limitation is the most common physiological impairment in sarcoidosis, there are limited data on airway hyperresponsiveness (ahr). understanding the role of ahr in sarcoidosis, if any, may help to identify individuals who might benefit from inhaled therapies. aims ( ) to determine the prevalence of ahr in sarcoidosis. ( ) to determine the correlation between responses to direct (using histamine) and indirect (using hypertonic saline) bronchial challenge. ( ) to determine the clinical, physiological and radiological predictors of ahr. methods subjects with a diagnosis of sarcoidosis based on typical clinical presentation and compatible hrct features and/or tissue biopsy and with a baseline fev > % predicted were recruited. subjects underwent standard hypertonic ( % fall in fev ) and histamine ( % fall in fev ) challenge (> day but < days apart), lung function testing and high resolution computed tomography (hrct) of the chest. results the subjects ( Ϯ years, % female, % european, % stage i, % stage ii, % stage iii, % stage iv) had well preserved lung function overall (fev = . l Ϯ . . % predicted). ahr was detected in / ( %) to hypertonic saline and / ( %) to histamine challenge. on univariate analysis, response to histamine challenge was predicted by conglomerate fibrosis (p = . ) and reticular pattern (p = . ) on hrct. the baseline % predicted fev was significantly associated with ahr on univariate (p = . ), and multivariate analysis (p = . ) when adjusted by hrct patterns. conclusions there is a high prevalence of ahr using histamine challenge in this study of sarcoidosis subjects. ahr most strongly associates with baseline % predicted fev but also conglomerate fibrosis and reticular pattern on hrct. these findings may reflect the consequence of airway remodelling following inflammation. further studies are warranted to confirm these findings. background upper airway shunt represents a significant source of measurement artefact in the use of the forced oscillation technique (fot), with increasing importance in young children. changes in respiratory system admittance, ars (or zrs - ), are theoretically independent of the upper airway shunt. this study examines the possible clinical benefit of ars in preschool children by assessing any increased ability to differentiate responses to bronchial challenges in the routine clinical setting. we hypothesized the use of ars would provide improved sensitivity to clinically relevant obstruction, bronchodilator responsiveness (bdr) and airway hyper-responsiveness (ahr) in young children with respiratory disease. method previous fot measurements were re-analysed and ars calculated to derive: ( ) ars reference equations in healthy young children (n = ); ( ) bdr in ars, respiratory system resistance (rrs) and reactance (xrs) in healthy children (n = ), children with cystic fibrosis (n = ), neonatal chronic lung disease (n = ), asthma (n = ) and wheeze (n = ); ( ) ahr to inhaled adenosine- ′-monosphate (amp) in children. fisher's exact tests were used to assess changes in diagnostic outcomes between ars and conventional fot outcomes (rrs and xrs). results ars was no more sensitive to bronchodilator induced changes than conventional fot outcomes. amp challenges resulted in equivalent responses measured by relative changes in rrs and ars while absolute changes in ars were the least sensitive variable. conclusion this study does not support a clinical advantage in using ars in measuring responses to either inhaled bronchodilator or amp. c hollier , , c menadue , , d flunt , , aj piper , department of respiratory and sleep medicine, royal prince alfred hospital, nsw , and woolcock institute of medical research, nsw serial measurement of arterial carbon dioxide (paco ), ph and bicarbonate (hco -) is essential in the management of patients with hypercapnic respiratory failure (hrf). this information is usually obtained from a sample of arterial blood (abg). the procedure can be painful and distressing for patients, and is sometimes technically difficult due to obesity or contractures. our aim was to determine the validity and feasibility of arterialized venous blood (av) sampling as an alternative to abgs in measuring paco , ph and hco levels in patients with chronic hrf. method eighteen patients completed the study. venous blood was arterialized by heating forearm skin to a temperature of - °c with an electric heating pad. an av sample was taken from a cannula positioned in a vein of the heated forearm simultaneously with an abg. in addition, the reliability of av sampling within the recommended temperature range ( - °c) was investigated in ten healthy volunteers placed on volume cycled ventilation in order to maintain constant ventilation. av samples were taken at . °c temperature intervals from . - °c results the table below summarizes results for validation of av sampling: based on the evidence that cardiovascular dynamics are altered due to obstructive sleep apnea, this study aims to identify the onset and termination of each apnea event using power spectral density (psd) and morphological features of single lead ecg signal over second period. methods ecgs from patients overnight sleep studies were examined for location of the pre-scored apnea events. onset (n = ), maximum (n = ) and termination (n = ) of each apnea event and normal events (n = ) were annotated on second windows. features extracted were psd, amplitudes of r and t wave of second ecgs. receiver operating characteristics (roc) analysis was used to gauge the event recognition ability of all features. weight loss causes an improvement in the severity of osa, however substantial weight loss is very difficult for obese patients. the very low caloric diet (vlcd) has been shown to be successful in causing significant weight loss in obese patients. this is a pilot study on the use of a formal screening protocol to identify osa patients who are potentially eligible for the supervised vlcd program offered by the endocrinology department at auckland city hospital. method consecutive patients who attended the sleep laboratory at ach between june to december were screened using the protocol. patients who are eligible to be considered for the vlcd program are identified as having a combination of obesity (bmi > ), osa (ahi > on sleep study) and being residents within the auckland district healthboard region. results / patients screened did not fulfil the inclusion criteria: lived outside the adhb region; had bmi < ; patients did not have osa (ahi < ). patients fulfilled the inclusion criteria. / patients ( %) were excluded due to medical or psychiatric contraindications to vlcd. patients ( %) who did not have contraindications to vlcd were contacted. patients were contacted successfully. patients were either unavailable to phone contacts on separate days or were disconnected. / patients consented to being referred ( %). / patients declined referral ( %). conclusion this pilot study is the first study using a formal comprehensive screening protocol in the recruitment of obese osa patients into a medically supervised vlcd program. only a small proportion ( %) of patients proceeded to being referred to the vlcd program. key: cord- -w thois authors: figueira gonçalves, juan marco; golpe, rafael title: clinical challenges in chronic obstructive pulmonary disease in patients who suffered sars-cov- infection() date: - - journal: med clin (engl ed) doi: . /j.medcle. . . sha: doc_id: cord_uid: w thois nan ni el manuscrito ni parte de su contenido han sido publicados previamente por ninguno de los autores, ni están en consideración para su publicación en ninguna otra revista al momento de su presentación. no hay conflicto financiero de interés relacionado con este trabajo. todos los autores han participado en la concepción de este manuscrito. the world health organization (who) has declared sars-cov- (covid- ) a pandemic. although the evidence to date suggests that most cases manifest mildly, up to % of cases may require hospital admission . to date, the relationship between chronic obstructive pulmonary disease (copd) and covid- is not clear. although various studies show that the main comorbidities related to the development of a serious form of the disease are high blood pressure, diabetes mellitus or cardiovascular disease , we know that copd is associated with an increased risk of admission to an intensive care unit, as well as death . many of the most common chronic diseases occur more frequently in patients with copd compared to the general population. up to - % of copd patients develop some comorbidity, an aspect that will contribute to the severity of symptoms and jeopardize patient survival. reported complications of sars-cov- infection, such as extensive pneumonia/acute lung damage or adult acute respiratory distress syndrome, the occurrence of myocarditis/cardiac arrhythmias or the development of thromboembolic / episodes are events that may worsen the baseline condition of the copd patient surviving the process, having to take into account their existence when planning their outpatient follow-up. unfortunately, we do not have information about how the sars-cov- infection will impact our patients in the medium-long term and, for the time being, we must make assumptions based on the knowledge gained from other coronaviruses such as sars-cov- or mers-cov. viral infections cause an intense systemic inflammatory response resulting in an imbalance between the homeostatic pro-coagulant and anticoagulant mechanisms, , therefore, thromboembolic disease is an aspect to analyse. based on the limited evidence we currently have, there is a possibility that sars-cov- infection increases the risk of a venous thromboembolic event . multiple pathogenic mechanisms appear to be involved including endothelial dysfunction, elevation of von willebrand factor, toll-like receptor or tissue factor pathway activation . however, apart from infection, we must be aware that other factors such as strict and prolonged quarantine and, subsequently, immobilization could lead to it. despite what has been described, there is a lack of evidence about the incidence of pulmonary embolism in patients with sars-cov- . , . a study published by cui et al. determined that the incidence of pulmonary thromboembolism in patients admitted to an intensive care unit for a severe sars-cov- infection was %. in the case of sars-cov- , post-mortem studies in infected patients detected thrombi in the pulmonary vascular bed . a study carried out in singapore that included autopsies of confirmed cases of sars-cov- described pulmonary thrombi in patients, deep vein thrombosis in and generalized multiorgan infarctions due to thrombi in two of the patients . although the main scientific societies have formulated positions and consensus related to the diagnosis of covid- and the role of tests such as ct in this procedure, no specific proposals have been made on the indication of ct angiography to diagnose a thromboembolic pulmonary event. despite the lack of sufficient evidence at the moment, the results reported to date and the pathogenic mechanisms plausibly involved, make it advisable to consider this aspect in those patients with copd who, after hospital discharge, develop in the medium to long term an increase in dyspnoea not justified by spirometric parameters. on the other hand, we have to consider the risk of cardiovascular disease development. abnormal biomarkers consistent with heart damage are a prominent feature of sars-cov- infection and are associated with a poorer prognosis . the underlying mechanisms are not well established, but it is likely that it involves the presence of myocardial stress in relation to hypoxemia, or it might be related to a direct effect of the viral infection, with a systemic inflammatory response, or with a combination of the factors. a post-mortem real-time pcr of heart tissue during the sars-cov- epidemic detected the presence of the viral genome in % of those deceased . it is noteworthy that these hearts had a decrease in the expression of angiotensin receptors (an aspect that could highlight the relationship of this receptor in the mediation of the infection) and a greater hypertrophy . myocardial pericytes, which play an important role in maintaining endothelial function, express angiotensin- receptors abundantly . pericyte and endothelial cell dysfunction, either due to direct infection or global inflammation, can lead to coro-j o u r n a l p r e -p r o o f / nary microcirculation disruption with subsequent ischemic consequences, but its possible relationship with sars-cov- infection is pure conjecture for now. we do not know if patients suffering from a sars-cov- -related myocarditis will develop any type of medium to long-term heart failure. other aspects of cardiac involvement to consider in sars-cov- infection are cardiac arrhythmias. such events may arise from severe hypoxemia, from ion disorders, from systemic inflammation, from the use of drugs to combat coronavirus, or from direct damage to the myocardium caused by sars-cov- . furthermore, patients with sars-cov- can develop acute coronary syndromes and acute myocardial infarction, but the incidence of such events is unclear. a priori, the risk of coronary event in these patients may increase due to an increased thrombotic predisposition, as evidenced by the significantly high levels of d-dimer in these patients . underlying this risk are predisposing factors related to inflammation that will have a relevant role in this process, such as endothelial and smooth muscle cell activation, macrophage activation and tissue factor expression, in addition to platelet activation. cardiovascular complications are possible even after recovery from infection. in italy, the development of fulminant myocarditis has been described in a convalescent patient one week after respiratory symptoms had resolved . this suggests that the underlying inflammation may persist and progress "silently" with its complications manifesting in a delayed manner. in the sars-cov- epidemic, some of the survivors developed avascular necrosis, pulmonary fibrosis, and dyslipidaemia after viral infection , , which may have a relevant impact on those patients who already had some underlying respiratory or cardiovascular condition. taking into account the aforementioned, we must carefully evaluate, case by case, the worsening or the de novo onset of cardiovascular comorbidity when planning outpatient follow-up in patients with copd who have suffered a sars-cov- infection, since patients with copd and concomitant heart disease suffer a greater degree of dyspnoea and exercise intolerance and an increased risk of hospitalization. finally, we must evaluate acute lung damage (severe pneumonia/adult acute respiratory distress) and lung function deterioration. similar to that described in the mers-cov and sars-cov- , the most common radiological findings are ground glass opacities with or without consolidation and predominantly in the lung bases with posterior and peripheral location. although considerable information is available on the acute radiological manifestations of the disease, we do not yet have information on its long-term progression, nor on its possible impact on lung function. therefore, at the moment, one can only speculate about whether future changes will be similar to those described in other viral infections. chen et al. conducted a follow-up of patients for h n influenza with the intention of assessing the functional and radiological progression on ct during years after infection. despite the persistence of interstitial changes and fibrosis on imaging tests, the functional parameters of ventilation and diffusion showed a tendency to improve after months. however, after years, a mild-moderate impairment in the diffusing capacity of lung for co (dlco) persisted in % of cases. ong et al. evaluated lung function in patients one year after suffering from a sars-cov- respiratory infection. this study demonstrated that % of the cases had a slight-moderate / reduction in dlco values, while % of patients showed no anomalies in the spirometric parameters. zhang et al. monitored the functional respiratory and radiological progression of sars-cov- infection patients for years. they described how in the first year of follow-up there was a radiological improvement that stabilized in subsequent years. from a functional point of view, patients without interstitial changes on ct showed a more significant improvement in spirometric parameters compared to those with interstitial involvement. if sars-cov- infection behaves similarly to that described by these authors, a radiological and functional improvement is expected in the months following infection, but we do not know whether a certain degree of irreversible deterioration will persist, especially in patients with copd, or if there will be changes in functional decline. nor do we know if the hypothetical functional impact depends on the prevalence of a phenotype of airway or lung parenchyma involvement (emphysema). finally, there is evidence that severe sars-cov- infection cases may develop traction bronchiectasis . the potential impact of this fact in a patient with copd is very great, since the presence of bronchiectasis in these subjects increases the risk of chronic bronchitis and neutrophilic inflammation of the airway and is associated with a greater functional decline, quality of life deterioration and increased risk of exacerbation and death. in conclusion, the sars-cov- pandemic will involve changes in the care of copd patients suffering from the infection. there is sufficient theoretical basis to fear that some of these patients will suffer new comorbidities or the worsening of the existing ones (with special impact on cardiovascular health) and that the infection could have an impact on lung function of uncertain extent. the effect on the symptoms, exacerbations and the vital prognosis of our patients is still an area of uncertainty, and in the coming months we will have to incorporate the information generated regarding the foreseeable modifications that will be made in the monitoring and treatment schedules of the disease. j o u r n a l p r e -p r o o f clinical characteristics of coronavirus disease in china comorbidity and its impact on patients with covid- in china: a nationwide analysis the impact of copd and smoking history on the severity of covid- : a systemic review and meta-analysis procoagulant activity during viral infections abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia acute pulmonary embolism and covid- pneumonia: a random association prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia analysis of deaths during the severe acute respiratory syndrome (sars) epidemic in singapore: challenges in determining a sars association of cardiac injury with mortality in hospitalized patients with covid- in wuhan, china sarscoronavirus modulation of myocardial ace expression and inflammation in patients with sars the ace expression in human heart indicates new potential mechanism of heart injury among patients infected with sars-cov- covid- and the heart clinical course and risk factors for mortality of adult inpatients with covid- in wuhan, china: a retrospective cohort study cardiac involvement in a patient with coronavirus disease (covid- ) altered lipid metabolism in recovered sars patients twelve years after infection thin-section ct in patients with severe acute respiratory syndrome following hospital discharge: preliminary experience long term outcomes in survivors of epidemic influenza a (h n ) virus infection -year pulmonary function and health status in survivors of severe acute respiratory syndrome long-term bone and lung consequences associated with sars relation between chest ct findings and clinical conditions of coronavirus disease (covid- ) pneumonia: a multicenter study key: cord- - lb kho authors: nan title: oliv sig: poster session date: - - journal: respirology doi: . /j. - . . _ .x sha: doc_id: cord_uid: lb kho nan patients with non-eosinophilic asthma (nea) or copd have increased numbers of neutrophils in the airways. we have shown a similar defect in the ability of alveolar macrophages (am) to phagocytose apoptotic cells, in sputum from patients with nea and copd. we have also shown that bal-derived am from patients with copd have reduced expression of key macrophage phagocytic recognition molecules. the aim of this pilot study was to investigate the expression of these macrophage markers in induced sputum from patients with eosinophilic asthma (ea, n = ), nea (n = ), copd (n = ) and controls (n = ). methods participants underwent clinical assessment, skin allergy test, hypertonic saline challenge and sputum induction. macrophage phagocytosis of apoptotic cells, expression of mannose receptor (mr), hspr (cd ) and pcam (cd ) was determined using fl ow cytometry. results phagocytosis was signifi cantly impaired in patients with nea and copd. expression of mr, cd and cd were decreased in patients with nea or copd, but not signifi cantly changed in ea conclusion impaired sputum-macrophage phagocytosis of apoptotic cells in nea is associated with reduced expression of key macrophage recognition molecules. this defect may contribute to the chronic infl ammation and persistent airway neutrophilia that characterizes this asthma subtype. the use of induced sputum as a surrogate for the more-invasive bronchoscopic sampling may provide a tool for investigating the mechanisms for the effect of therapies including azithromycin in lung disease. supported by nhmrc. neutrophilic asthma (na) has been associated with increased bacterial colonization of the airways and increased expression of innate immune factors in the lung. this suggests that infection may play an important role in the pathogenesis of na. na is an important health issue as sufferers are resistant to steroid treatment, which is the mainstay of asthma therapy and effective therapies are urgently required. using mouse models of chlamydia and haemophilus infl uenzae lung infection and ovalbumin (ova)-induced allergic airway disease (aad), we have shown how infection may be linked to na. both infections suppressed eosinophilic infl ammation and t-helper (th) type responses but increase neutrophilic infl ammation and innate and th and/or th responses in aad. in the current study, the effectiveness of steroid treatment for the suppression of infection-induced neutrophilic aad was assessed by treating infected ovasensitized mice intranasally with dexamethasone during ova challenge. whilst dexamethasone treatment suppressed th -mediated, eosinophilic aad in uninfected, ova-sensitized groups, chlamydia and haemophilus-induced neutrophilic aad were shown to be steroid-resistant. our fi ndings correlate with clinical observations which show associations between infection, neutrophilic infl ammation and steroid resistance in asthmatics. these models will be utilized to examine the effectiveness of a number of novel therapies for infection-induced neutrophilic aad and to develop improved treatment strategies for steroid-resistant asthma. supported by nhmrc, asthma foundation of nsw, hmri. kj baines , , jl simp s on , , rj scott , lg wood , , pg gibson , priority research centre's for asthma and respiratory disease, and information based medicine, the university of newcastle, nsw, australia, and respiratory & sleep medicine, hmri, john hunter hospital, nsw, australia rationale four infl ammatory phenotypes of asthma have been identifi ed including eosinophilic, neutrophilic, mixed granulocytic and paucigranulocytic asthma, based on the presence or absence of sputum granulocytes. the involvement of systemic infl ammation in the pathogenesis of infl ammatory phenotypes of asthma remains unknown. objective this study investigates differences in the whole genome gene expression profi le of peripheral blood in infl ammatory phenotypes of asthma. methods induced sputum and peripheral blood were collected from participants with asthma (n = ). infl ammatory cell counts were performed and infl ammatory phenotype assigned based on the eosinophil and neutrophil cutoffs of % and %, respectively. rna was extracted from whole blood, gene expression profi les were generated (illumina humanref- v ) and analysed using genespring gx . results participants with eosinophilic asthma had signifi cantly higher rates of atopy and levels of exhaled nitric oxide. there were genes classifi ed as differentially expressed between the asthma phenotypes including the α-defensins (defa) , b, and , neutrophil proteases cathepsin g (ctsg) and elastase (ela ), and the monocyte/macrophage serine esterase, carboxylesterase (ces ). expressions of defa , b, , , ctsg and ela were signifi cantly higher in neutrophilic asthma and expression of ces was significantly higher in mixed granulocytic asthma. microarray results of the α-defensins and neutrophil proteases were successfully validated using realtime pcr. conclusions there is systemic up-regulation of α-defensins and neutrophil proteases in neutrophilic asthma, and these molecules play an important role in neutrophil activation and migration. systemic activation of neutrophils is an important feature involved in the pathogenesis of neutrophilic asthma, which is signifi cantly different to other asthma phenotypes. supported by hmri and xstrata coal; the university of newcastle. confl ict of interest no. airway mucus hypersecretion is an important cause of morbidity and mortality in asthmatic patients. increases in goblet cell number and their secretions are likely to contribute to airfl ow obstruction in asthma. here, we take advantage of an established sheep model of asthma to investigate the association between allergen exposure and goblet cell activity. methods eight allergic sheep (high house dust mite (hdm)-specifi c serum ige) received weekly intra-lung challenges of hdm to the right caudal lobe, and weekly intra-lung challenges of hdm followed by weeks without allergen exposure to the left caudal lobe, with the right medial lobe serving as an untreated internal control. a separate group of sheep were also used as untreated controls. biopsy samples of segmental bronchi tissue were collected from the different lung lobes for histological analysis at and days post-hdm challenge. results the percentage of goblet cells, with respect to epithelial cells, signifi cantly increases following chronic challenge with hdm ( % hdm vs. % control p < . ). goblet cell numbers did not decline in lung lobes after a -week cessation of allergen challenges. goblet cell degranulation is significantly increased day following challenge with allergen, but returns to control levels by days post-allergen challenge ( % day vs. % control p < . ). furthermore, degranulation is increased in both the rested and internal control lobes day following allergen challenge of the right caudal lobe. conclusions in this sheep model of chronic asthma, repeated allergen challenges induces goblet cell hyperplasia which persists even after long-term withdrawal of allergen. additionally, exposure to allergen in one lobe induces goblet cell degranulation in both challenged and unchallenged lobes, suggesting neural mechanisms may be operating in this model. confl ict of interest no. the thickness of the airway smooth muscle (asm) layer is related to severity but not duration of asthma or age (james erj; : ) . it is unknown if the constituents of the asm layer change with age. aim to investigate the relation of mean asm cell volume (v c ), total number of cells per mm of airway (n l ) and fractions of asm (f asm ) and extracellular matrix (f ecm ) within the asm layer with age and age at onset of asthma. methods post-mortem tissues from control subjects (c n = ); non-fatal (nfa n = ) and fatal (fa n = ) cases of asthma were used. the volume density (n v ) of asm cell nuclei was estimated on μm transverse airway sections (haematoxylin) and mean cell volume (v c = /n v ) was calculated, correcting for the volume fraction of asm within the asm layer. f asm and f ecm were estimated on . -μm thick sections of the same airway (masson's trichrome). effects of age on asm cell parameters and tissue volume fractions were tested using general linear models, correcting for sex and study centre and by comparing age at onset of asthma (< vs. > years). results table shows assessment of airway smooth muscle (asm) cell size and number requires estimates of cell volume density (n v ), volume fraction of muscle (f asm ) within the asm layer and the volume of asm per length of airway. stereological techniques have now become the accepted standard for assessing asm cell parameters, but sources of variation remain unclear. aim to assess sources of variability in the estimation of asm cell parameters and volume fractions within the asm layer. methods large and small airways from subjects with and without asthma were examined. transverse airway sections were cut at . μm and μm (masson's trichrome technique), and μm (haematoxylin) and used to estimate asm cell number and volume, and the volume fraction of muscle (f asm ) within the layer of asm. stereological assessments of the possible sources of variation in these asm layer parameters were assessed. results increased section thickness overestimated f asm by < % ( . μm), % ( μm) and % ( μm). stable variation of < % in n v occurred if high-power fi elds (hpf) were used to estimate n v . variation in the depth of muscle in thick sections of the asm layer caused up to % overestimation of n v . although the absolute area of the asm layer varied by up to %, variation of f asm was < % around the airway circumference and along the airway length. f asm differed signifi cantly between large and small airways. conclusion these results suggest that partial thickness hpfs need to be excluded and that ≥ hpf should be used to estimate asm volume density, that a single . μm section of airway can be used to estimate f asm and that asm parameters should be compared separately in large and small airways. grants nhmrc # . nominations nil. confl ict of interest nil. no signifi cant correlation was seen with age for any asm cell parameters or tissue fractions. results were similar for medium and small airways. conclusion size and number of asm cells and the volume fractions of asm and ecm within the layer of asm are not related to age. support nhmrc australia (grants # ; # ). nomination nil. . ± . . ± . . ± . . ± . fa > . ± . . ± . . ± . . ± . background asthma is characterized by excessive airway narrowing to contractile stimuli, termed airway hyper-responsiveness (ahr). changes in airway smooth muscle (asm) protein expression or mass are possible contributing mechanisms underlying ahr and have been examined using cell culture techniques. however, how these cellular changes to asm relate to airway narrowing at the level of the whole airway is unclear. we describe a new method to track changes in airway narrowing (responsiveness) in culture. methods whole airway segments (generation - ) from sheep lungs were studied prior to (fresh) and after and hours in culture in dulbecco's modifi ed eagle medium with % bovine serum albumin, % l-glutamine and antibiotics. airway narrowing was measured from the % decrease in airway volume under a fi xed transmural pressure, using a servo-controlled syringe pump and organ bath apparatus. cumulative acetylcholine dose-response curves (ach, − m − × − m) were performed to determine maximal response (e max ) and sensitivity (pd , negative log of ec ). results fresh airway segments narrowed strongly and approached closure with an e max of . % ± . (±sem) and pd of . ± . . airway narrowing responses were preserved in culture, with no signifi cant difference in maximal response or sensitivity to ach after either (e max . % ± . , pd . ± . ) or hours in culture (e max . % ± . , pd . ± . ). conclusions the present study has validated a new method allowing changes occurring at the cellular level in culture to be related to changes in airway responsiveness at the whole airway level. future studies will assess the effects of chronic infl ammation in disease on airway responsiveness. background deep inspiration (di) produces a bronchodilator response in healthy humans, but this response is impaired in asthma. reduced airway compliance in disease could impair the response to di by limiting the stretch of smooth muscle. aim to show that isolated human bronchi dilate to di in an amplitudedependent manner and that the stretch caused by di depends on airway compliance. methods bronchi were obtained following lung resection from cancer patients who had normal spirometry (n = ). lumen narrowing was measured using a servo-control system which set transmural pressure and simulated breathing movements. bronchi were contracted to carbachol (cch × − m) during tidal breathing (from to cmh o, i.e. Δ cmh o transmural pressure, . hz) and infl ated to three different amplitudes of di (Δ , or cmh o) applied following contraction. results in cch-contracted airways, all three di amplitudes produced a transient bronchodilation. increasing the di amplitude caused a greater increase in luminal volume during the di and a greater bronchodilation following the di (p < . ). cch itself cause approximately a % fall in specifi c compliance (p < . ), which was reversed by di (p < . ). for each di amplitude, the change in lumen volume during the di was positively correlated to the specifi c compliance of the bronchi before di (r > . , p < . ). conclusions isolated human bronchi show a bronchodilation response to di that is proportional to the expansion of the airway caused by the di. the amount of stretch produced by a di depends on airway wall compliance suggesting that increased airway stiffness in disease could suppress the di response by limiting the stretch of bronchi during lung infl ation. confl ict of interest none. ja douglass , , , ea yu , , br thompson , , , gg king , , mj abramson , introduction increasing asthma prevalence and changes in environmental exposure suggest that there may be a relationship between asthma and dietary intake. however, to date, few studies have examined how dietary intakes of asthmatics differ from a healthy population. aim to measure and compare the dietary intakes of adults with stable asthma and healthy controls. methods in a cross-sectional study, dietary intakes calculated from a item food frequency questionnaire (ffq) of adults with stable asthma (n = , age years ± (sd)) were compared with intakes of healthy controls (n = , age years ± (sd)) matched for age and body mass index (bmi). spirometry, airway responsiveness to hypertonic saline, and induced sputum cell counts were also measured. results subjects with severe persistent asthma (n = ) had signifi cantly higher total fat intake than healthy controls ( ± (sem) versus ± (sem) g/day p = . ) and signifi cantly lower fi bre intakes ( ± (sem) versus ± (sem) g/day p = . ). lower fi bre intake in asthmatic subjects (n = ) was associated with lower %predicted fev (r = . , p = . ), %fvc (r = . , p = . ) and fev /fvc (r = . , p = . ). higher fat intake and lower fi bre intake were associated with higher absolute concentrations of sputum eosinophils (r = . , p = < . , n = ). conclusions subjects with severe persistent asthma have an eating pattern of lower diet quality with higher intakes of fat and lower intakes of fi bre than healthy controls, which is related to lower lung function and increased airway infl ammation. factors leading to altered dietary intake in severe asthma require further investigation. methods a randomized, placebo-controlled, single-blinded trial of tailored asthma education including device technique and utilizing pact to address patients' concerns versus brochure-only information for asthma patients over age . measurements of lung function, asthma control (acq), asthma related quality of life (aqol), medication use and adherence score (adh) were obtained at baseline, and months using standard, validated questionnaires. results sixty-fi ve participants ( f m, mean age ± . ) were randomized to the intervention group and ( f m, mean age ± . ) to the control. there were no statistically signifi cant differences between the groups' demographics or baseline measurements. a wilcoxon signed ranks test used to compare median pair ranking at baseline and months post-intervention revealed a signifi cant improvement in the active, but not the brochure-only information group at months in: acq mean ± sd = . ± . vs. . ± . (p = . ). aqol mean ± sd = . ± . vs. . ± . (p = . ). adh mean ± sd = . ± . vs. . ± . (p < . ). conclusion an educational intervention including device technique and addressing the concerns of older people with asthma signifi cantly improved acq, aqol and adh scores at months post-intervention. introduction greater exposure to ultraviolet radiation (uv) may increase the risk of allergic disease, but this association has not been investigated using estimates of time spent outdoors by individuals. the aim of this study was to investigate the relationship between self-reported doctor-diagnosed asthma and/or hayfever, and time spent outdoors. methods this analysis was based on cross-sectional baseline data from a subsample of the australian and up study, comprising men and women aged - years, living in new south wales. participants were randomly selected from the australian universal health insurance database. diagnoses of asthma and/or hayfever and the number of hours spent outdoors were derived by questionnaire. in general, the odds of a diagnosis of asthma and/or hayfever decreased with increasing time spent outdoors for both women and men. for example, in women, the adjusted odds ratios for asthma with hayfever were . ( % ci: . - . ), . ( . - . ), . ( . - . ) and . ( . - . ) for - , - , - and > hours spent outdoors on weekends, respectively, compared with < hour (p trend < . ). time spent outdoors was not associated with a diagnosis of asthma alone in men. conclusions there were statistically signifi cant inverse associations between time spent outdoors and diagnoses of asthma, hayfever or asthma with hayfever, in a large population of older australians. exposure to uv may protect against the development of allergic diseases, such as asthma and hayfever. no. background allergic rhinitis (ar) and eczema are highly prevalent and females are more commonly affected than males in adulthood. although there have been extensive studies on ar and eczema in females, little is known about the effect of reproductive factors and the development of late-onset ar/ eczema. we examined potential associations between reproductive factors and ar and eczema using the tasmanian longitudinal health study (tahs) data. methods the tahs is a population-based cohort study of respiratory disease. two thousand seven hundred sixty-four ( . %) females from the original tahs participants were surveyed in using postal questionnaire which collected information on reproductive factors such as ever pregnancy, age at fi rst child birth, use of oral contraceptive pills (ocp) and age of starting using the ocp. logistic regression was used to assess the predictors of ar and eczema and all analyses were mutually adjusted. of the participants, . % (n = ) had late-onset ar and . % (n = ) had late-onset eczema. maternal and paternal atopy were signifi cantly associated with ar (p < . ). the risk of developing eczema was decreased signifi cantly with increasing age at fi rst menstruation (or: . , % ci: . - . ) and the increased age at birth of fi rst child ( . , . - . ). a decreased risk in ar was observed with the increasing number of pregnancies ( . , . - . ). however, the associations between age of starting using ocp and ar/eczema were not signifi cant. conclusion later age at start of menses and later age at fi rst pregnancy were associated with a reduced risk of eczema which may be related to hormonal dysregulation. tp- airway responsiveness at and years is associated with asthma at years introduction asthma is the most common chronic childhood disease in australia. increased airway responsiveness (ar) is associated with asthma but not all individuals with increased ar have asthma. the perth infant asthma follow-up study recruited a birth cohort of individuals who have undergone longitudinal assessments of many factors associated with childhood ar. our previous work reported an association between increased ar in infancy and asthma at and years. aim to look at the relationship of increased ar and asthma in early adulthood at different time points from birth. methods individuals were recruited from among expectant parents attending an antenatal clinic at a local metropolitan clinic. at ages , and months and again at , and years, participants underwent an assessment that included a respiratory questionnaire and determination of ar (as evidenced by dose-response slope (drs) to histamine using the rapid technique). results children were initially recruited and studied in infancy. two hundred three, , , , and children subsequently had ar assessed at , and months, , and years, respectively. there was a signifi cant relationship between drs at and years and for both asthma at years (p = . and p < . , respectively) and 'wheeze in the past year' at years (p = . and p = . , respectively). there was no significant relationship between drs in infancy and asthma at . conclusion ar at and years is associated with asthma at years. in this study, there was no signifi cant relationship between ar in infancy and asthma at years. the pcaas has found that . % of children with acute asthma presenting to the princess margaret hospital for children emergency department (pmh ed) had hrv, of which % were hrv group c. furthermore, hrvc was associated with more severe attacks. however, the prevalence of hrvc in the community is unknown. aim to test the hypothesis that hrvc would be found more often in children requiring emergency treatment for an ari than sibling controls and determine the impact of days since symptoms began on the prevalence of hrv detection in children with an acute respiratory illness (ari) and sibling controls (sibs). methods ari (n = ) had nasal samples collected on presentation to the pmh ed and sibs with symptoms of a cold (n = ), within week of ari recruitment. viral rna was extracted and reverse transcribed. a two-step pcr of the hrv ' utr was used for detection, followed by dna sequencing for typing. results ari and sibs were % and % male, % and % asthmatic, with mean ages of . and . years, respectively. hrv +ve ari (n = , mean ± sd days of symptoms = . ± . ), hrv -ve ari (n = , . ± . ), hrv +ve sibs (n = , . ± . ) and hrv -ve sibs (n = , . ± . ). of the and hrv +ve ari and sibs, % and % had hrvc. conclusions hrvc is as common in children who have hrv but do/do not require hospital treatment. detection of hrv is more likely when the nasal sample is collected soon after the appearance of cold symptoms. support nhmrc program grant. nomination nil. introduction upper airway dysfunction may make asthma more diffi cult to control and should be suspected in asthmatics refractory to prescribed medical therapy. aim a novel imaging technique, dynamic -slice computerized tomography (ct), was used to examine laryngeal behaviour in healthy and asthmatic individuals. method vocal cord movement was imaged using -slice ct larynx. healthy volunteers were studied to develop and validate an analysis algorithm for quantifi cation of normal vocal cord function. further studies were then conducted in patients with diffi cult-to-treat asthma. in eight severe asthmatics with abnormal vocal cord movement, asthma outcomes were measured after speech therapy. results vocal cord movement was quantifi ed over the breathing cycle by ct using the ratio of vocal cord diameter to tracheal diameter. normal limits were calculated, validated and applied to evaluate diffi cult-to-treat asthma. vocal cord movement was abnormal with excessive narrowing in of ( %) asthmatics and severe in nine ( %) patients (abnormal > % of inspiration or expiration time). after speech therapy in a small subgroup, asthma symptoms and morbidity improved. conclusion non-invasive ct larynx quantifi cation of vocal cord movement was achieved. this new approach has identifi ed frequent upper airway dysfunction in asthma with potential implications for disease control and treatment. aim to investigate the characteristics and mechanisms of chronic cough (cc) following acute respiratory illness from laboratory-confi rmed h n infl uenza. methods subjects who had current symptoms and had been tested for h n infl uenza by pcr assay participated in this study. twenty-one of those continued onto clinical testing. investigations to assess cough included symptom questionnaires, hypertonic saline challenge and cough monitoring. results of the participants, % tested positive for h n and % tested negative for h n . h n -infected participants were younger and predominantly female. the prevalence of post-h n cc was . %, and for non-h n infection, . %. objectively measured cough frequency was times greater; there was a -fold increase in cough refl ex sensitivity, and greater quality-of-life impairment in the participants with chronic post-infectious cough than the non-cough participants. conclusions cc was found to be relatively common, mild in severity and tending to resolution with time. the characteristics of post-h n cc were similar to other post-infectious cough and were associated with cough refl ex hypersensitivity. aim upper airway dysfunction may accompany acute severe asthma, but this has not been investigated. a novel imaging technique, dynamic -slice computerized tomography (ct), was used to examine laryngeal behaviour in acute asthma exacerbation. methods patients were studied in the emergency department or as acute inpatients following admission for an acute exacerbation of asthma. vocal cord movement was imaged by -slice ct larynx and compared to normal vocal cord movement in a healthy cohort. results vocal cord movement was abnormal with excessive narrowing during either inspiration, expiration or both in of cases ( . %) with acute severe asthma. imaging again revealed that laryngeal dysfunction characterized the movement abnormality, rather than isolated vocal cord dysfunction. radiation exposure was low and generally < milli-sievert. conclusion non-invasive ct larynx quantifi cation of vocal cord movement was effectively achieved in acute severe asthma. we identifi ed frequent upper airway dysfunction in acute severe asthma suggesting that treatment of upper airway obstruction (e.g. using bipap) may be merited during asthma exacerbation. aim to determine whether eicosanoids could alter the deposition of extracellular matrix (ecm) proteins and cytokine release from human airway cells. methods airway smooth muscle cells (asm), fi broblasts and epithelial cells were stimulated with leukotrienes b , c , d , e and the prostaglandins e , d , f α and the pgi analogue mre- . after hours, culture medium was collected and il- and il- production and cell deposited ecm proteins tenascin c, fi bronectin and perlecan were assessed by elisa. to determine whether eicosanoids infl uenced cell proliferation, manual counting of cells in the experiments were carried out before and after stimulation. results neither leukotrienes or prostanoids altered cell proliferation after days of stimulation (n > ). leukotrienes had no effect on ecm protein deposition or cytokine release from asm or fi broblasts (n > ). leukotrienes did not alter either parameters in epithelial cells except leukotriene d , which increased tenascin c deposition (n = , p < . ). prostanoids induced il- and il- and other various changes in asm and fi broblasts (n > , p < . ) (see below). introduction the function of asthmatic airway epithelium is disrupted facilitating immune and infl ammatory responses resulting in epithelial damage. human rhinovirus (hrv) causes asthma exacerbations in children; however, paucity exists on how it affects barrier function. this study assessed how hrv infection affects epithelial barrier function and integrity in healthy and asthmatic epithelium. methods adult balb/c mice were intranasally infected with hrv- b and followed for days. tight junction (tj) expression was assessed using immunohistochemistry (ihc) and western blot analysis. primary airway epithelial cells from healthy and asthmatic children were assessed for tj gene and protein expression by qpcr and ihc, respectively. results occludin and zonal occludin- (zo- ) expression was lost and sustained in mice infected with hrv- b however was not observed in shaminjected mice. asthmatic airway epithelial cells were found to exhibit elevated basal gene expression levels of tjs (zo- , occludin and plakophilin- (pkp- )) but markedly lower corresponding protein levels. conclusion hrv- b compromises barrier function in vivo through sustained loss of tj proteins. the marked decreased expression of tj proteins in paediatric asthmatic epithelium may contribute towards increased susceptibility to viral infections. disparity between gene and protein tj expression could indicate either post-transcriptional regulation or compensatory effects by other tj proteins and requires further study. supported by asthma foundation wa; nhmrc. confl ict of interest none. conclusion leukotrienes alone did not affect the ecm proteins and cytokines assessed in this study. prostanoids decreased ecm protein deposition whilst increasing cytokine release without affecting cell proliferation. this study shows that prostanoids may have a more pronounced role on direct ecm remodelling than leukotrienes in airway cells. supported by merck. background toll-like receptor (tlr) is an innate immune receptor involved in the initial detection of pathogen-associated molecular patterns. the effect of ageing and chronic obstructive pulmonary disease (copd) on tlr responses and the impact of these innate immune responses in copd pathogenesis remain unclear. hypothesis expression and activity of tlr on peripheral blood mononuclear cells (pbmcs) is increased with healthy ageing and further increased in copd. methods pbmcs from healthy controls < years and > years; and participants with copd (n = per group) were cultured with or without pam c ys k (tlr agonist). cells and supernatants were collected at hours and protein (cytometric bead array or fl ow cytometry) and gene (real time pcr) expression was examined. results tlr activation led to increased release of interleukin (il)- , , β, and tumor necrosis factor (tnf)-α. tlr gene expression was increased with stimulation; however, cell surface receptor levels were unchanged. there was no difference in the level of tlr between the groups. in older people, tlr activation resulted in less il- β and tnf-α release, but similar release of il- and il- . similar results were seen in copd. at baseline in copd, there was up-regulation of tnf-α gene expression compared to the older healthy group; however, the tlr cytokine response did not differ between the groups. conclusion healthy ageing is characterized by an impaired systemic proinfl ammatory cytokine response to tlr -mediated innate immune activation. this effect persists in copd and is selective in the cytokine pathways involved. these altered infl ammatory mechanisms may affect responses to infection and injury impacting disease pathogenesis and warrant further evaluation. aim to investigate whether the inhibition of matrix metalloproteinase- (mmp- ) by a non-selective mmp inhibitor (doxycycline) and the specifi c mmp- inhibitor i (olic acid) can regulate cellular migration of tsc -null mouse embryonic fi broblasts (mefs), which act as a model for lymphangioleiomyomatosis (lam) cells, as compared to wild-type mefs. methods wild-type (tsc -positive) and tsc -null mefs were treated with diluent, doxycycline ( . pg/ml- μg/ml) or olic acid ( . - μm) for hours. mmp- levels were assessed by zymography and elisa. cell migration for hours was measured using a transwell migration assay. results under basal conditions, mmp- release and cellular migration was . -fold and . -fold higher, respectively, in tsc -null mefs compared to tsc -positive mefs (mmp- release, tsc -null (n = ) and tsc -positive (n = ), p < . ; cell migration, tsc -null (n = ) and tsc -positive (n = ), p < . ). mmp- release was reduced in tsc -null mefs after -hour treatment with doxycycline ( and μg/ml, n = , p < . ) and with olic acid ( - μm, n = , p < . ). treatment with doxycycline ( pg/ml- μg/ml, n = , p < . ) or olic acid ( - μm, n = , p < . ) also signifi cantly reduced cell migration of tsc -null mefs. copd is a leading cause of death worldwide. treatments are limited and restricted to symptomatic care. there is an urgent need for new treatment options targeting the infl ammation. tissue damage in copd is thought to result from an inability of the normal repair processes with accumulation of apoptotic material and impaired clearance of this material by macrophages in the airways. lung infl ammation and macrophage function involves the bioactive sphingolipid sphingosine -phosphate (s p). multiple studies have showed the involvement of these components in infl ammation. methods we investigated lung tissue samples from patients (copd or non copd controls) undergoing curative lobectomy for lung cancer. we analysed the mrna expression profi le, the sphingosine-kinase (sphk) protein activity and the localization and expression of individual proteins. results we show in this study for the fi rst time a comprehensive expression profi le of all synthesizing enzymes, receptors and degrading enzymes in the human lung. correlations between receptor subtypes, degrading enzymes and between s p receptor subtype were detected. multivariance anova showed that in copd, the relative mrna expression of s p receptor subtype was reduced. conclusion the correlations between receptors and enzymes involved in the sphingosine kinase signalling system in the lung suggest common regulatory mechanisms. s pr is expressed on dendritic and nk cells which are reduced under conditions of copd. therefore, our fi ndings of reduced s pr in copd may provide a novel target for pharmacotherapy. lung cancer is responsible for more cancer-related deaths than colon, breast and prostate cancers combined. in patients with copd and/or lung cancer, we have shown a reduction in lung and airway macrophage function, evident by a reduced ability to phagocytose apoptotic airway epithelial cells and neutrophils. the potential for lung cancer cells to directly inhibit this function (a potential immune evasion mechanism) has not been investigated. background kinins have been implicated in airway lung diseases such as asthma and lung cancer by regulating infl ammation, cell proliferation and migration. the effect of kinins is mediated through the binding of two receptors, kinin b and b receptors (b r and b r). a novel b r splice variant (sv) resulting in a shorter ' untranslated region (utr) was identifi ed in cultured airway epithelial and fi broblasts as well as in lung carcinoma tissue and leukocytes. this study aims to characterize the functional role of the novel b r sv in mrna stability, translation effi ciency and receptor expression in cultured airway epithelial cells. methods stability of b r sv was determined by measuring b r mrna levels over time in h cells after actinomycin d treatment. translational effi ciency of wt and sv 'utr was determined by measuring luciferase activity in transfected h cells. expression of wt and sv transcripts through q-rtpcr were compared in cells treated with a b r-specifi c agonist dakd. cell-surface receptor expression post-agonist stimulation was quantifi ed using facs. results mrna stability studies indicated that b r sv was ≈ % less stable than the wt transcript in h cells suggesting a stabilizing element 'utr. translation effi ciency of sv was no different to wt b r. dakd stimulation increased both wt and sv transcripts early in the time course, although the peak expression of wt and sv differed at hours and hours, respectively. dakd stimulated cells showed two phases of receptor expression, ( ) decrease of cell surface receptor up to . hours post-stimulation; ( ) increase in cell surface b r after . hours. conclusion this study has identifi ed a novel regulatory mechanism of b r expression through the production of a sv that alters the 'utr. the translation effi ciency of b r is not affected, but the sv was less stable than the wt in h cells and may play a role in allowing quicker changes in transcription. agonist-induced up-regulation of transcripts in a time-dependent manner may be important in maintaining a chronic response during infl ammation. circulating lymphocytes are increasingly used as a surrogate cell type to refl ect changes in adrβ density elsewhere in the body, particularly the respiratory system. however, adrβ density is non-uniform among lymphocyte subsets and it is unclear if, and the degree to which, adrβ density varies between individuals. aim to assess the extent of variability in adrβ density on human peripheral blood mononuclear cells (pbmc) including lymphocytes and monocytes. method pbmc were isolated from blood of healthy subjects by density gradient centrifugation with ficoll-paque. cell surface and total adrβ of intact and permeabilized lymphocytes (cd +) and monocytes (cd +) were measured using anti-adrβ via facs. geometric mean fl uorescence (gmf) was used as the indices for adrβ density per cell. result surface adrβ -gmf increased by . -and . -folds over negative controls for lymphocytes and monocytes, respectively. magnitude of foldchange was not signifi cantly different between these cells (p = . ), but the distribution of gmf intensity between samples suggests greater variability in adrβ density in lymphocytes versus monocytes (p = . ). proportion of cells-stained adrβ -positive was signifi cantly higher in monocytes versus lymphocytes ( . ± . % vs. . ± . %, p = . ). total adrβ -gmf increased by . ± . and . ± . -folds for lymphocytes and monocytes, respectively (p > . ). proportion of adrβ -positively stained cells were similar between samples (lymphocytes %, monocytes %, p = . ), but greater variability was observed for lymphocytes (range - %) versus monocytes ( - %). conclusions despite similarities in surface and total adrβ density, lymphocytes display greater inter-subject variability compared with monocytes. this will have implication in experimental designs and interpretation of changes in adrβ density in studies using human pbmc as an alternative to primary cells from the organ of interest. confl ict of interest no. pge plays a protective role in asthma by inhibiting airway infl ammation. it is predominantly produced by epithelial cells in response to pro-infl ammatory stimuli and acts as an autocrine and paracrine mediator. on the contrary, il- β is a highly potent cytokine that induces many pro-infl ammatory effects in the human airway including activation of the human lung epithelium which promotes production of pro-infl ammatory cytokines and chemokines. airway epithelial cells express all four known pge (e prostanoid (ep) receptors, but mechanisms underlying the regulation of expression of ep receptors in human lung epithelial cells have remained elusive. therefore, we investigated whether pge , an endogenous protective mechanism of the airways, can modulate il- β infl uence on ep receptor expression in human epithelial cells. methods ep receptor mrna and protein expression was quantifi ed in -hbe cells at basal levels and following stimulation with il- β or pge alone, or simultaneously, using real time rt pcr and facs analysis, respectively. results pge up-regulates all four ep receptors at mrna level, while il- β up-regulates ep , ep and ep and does not infl uence expression of ep . at protein level, preliminary results show transient increase of ep receptors in the presence of pge , while il- β down-regulates this receptor. ep and ep are up-regulated following stimulation with both stimuli. importantly, antiinfl ammatory ep receptor is up-regulated only in the presence of pge . conclusion we show for the fi rst time that pge may infl uence expression of its own receptors and oppose the effect of il- β in human lung epithelial cells. this may in turn alter pge production and autocrine activation with potential implication on the function of epithelial cells, which is important in modulation of immune response in asthma and lung infl ammatory diseases. nomination nil. confl ict of interest no. the burden of obstructive lung disease (bold) study is an international study designed to measure the prevalence, risk factors and burden of copd. data collection using the bold protocol has been undertaken at eight sites with inclusion of urban, rural, coastal and inland regions of australia. methods a random sample of adults aged ≥ years was identifi ed. information on respiratory symptoms and diagnosed copd were collected by questionnaire. post-bronchodilator fev and fvc were used to defi ne gold stage. the (un-weighted) prevalence rates are presented by age groups and sex. results s timmins , , , , g king , , , , c salome , , , r schoeffel , , , c walsh , , the extent of emphysema could increase ventilation heterogeneity independently of its effects on airway narrowing. the aim of this study was to examine the relationship between emphysema extent on computed tomography scans (ct), and airway narrowing and ventilation distribution in copd. methods subjects with copd underwent ct scanning, spirometry, dlco and nitrogen washout by single and multiple breath techniques. closing capacity (cc/tlc%), slope of phase iii (Δphase iii ) and indices of ventilation distribution conductive (scond) and diffusion-dependent airways (sacin) were derived from washouts. helical ct scans were performed at tlc. emphysema extent was measured as low attenuation areas < − hu using osirix program, expressed as % of ct total lung volume. results subjects were of mean (range) age years ( - ), bmi . ( . - . ), fev of ( - %) %predicted and dlco of ( - ) %predicted. emphysema extent was . % ( . - . ). geometric mean (ci) Δphase iii was . ( . - . ), sacin was increased at . l − ( . - . ) and cc/tlc% was % ( - ). emphysema extent correlated with fev / fvc (r = − . , p = . ), dlco (r = − . , p < . ), bmi (r = . , p = . ), Δphase iii (r = . , p = . ), and sacin (r = . p = . ). in multiple regression analysis, emphysema extent was predicted by fev /fvc and Δphase iii (model r = . , p = . ). conclusions the extent of emphysema increases the heterogeneity of ventilation independently of any effects on overall airway narrowing. supported by australian lung foundation webster memorial award, crcaa. conclusions self-reported wheeze in the last months is very common in adults over years. in the younger age group ( - years), many people with wheeze did not have airfl ow obstruction or reversible spirometry at the time of test. aim to determine whether there is any association between change in fev among copd patients and ambient ultrafi ne particle number concentrations in melbourne. methods participants with mild to moderate copd were asked to measure their fev using a portable electronic spirometer (piko) two times a day (morning and evening) for consecutive days. the same procedure was repeated on average months later. ambient ultrafi ne (diameter < . μm) particle number concentrations were measured for the same period using an ultrafi ne condensation particle counter and micro-orifi ce uniform deposit impactor. results aim to examine the implementation of, and barriers and enablers to, six high-evidence recommendations for copd management, in copd hospital inpatients. method observational, mixed methods study in consecutive copd patients admitted to a tertiary hospital. demographic, disease and admission characteristics are recorded. implementation (or not) of smoking cessation, pulmonary rehabilitation, long-term oxygen use if hypoxaemic, medication use, vaccinations and plans for future exacerbations are determined from medical records and patient interviews. interviews with medical offi cers examine their perspectives on recommendation implementation. of pilot data in copd patients (mean (sd) age ( ) years, length of stay ( ) days), were current smokers and had severe copd ( moderate). highest levels of implementation were fl u vaccination (completed by gps, n = ), medication (but not spacer) use, and oxygen use if hypoxaemic (investigated and implemented in all suitable, n = ). pulmonary rehabilitation was discussed with half of the patients, but only severe patients with long length of stay accepted further rehabilitation. exacerbation plans were in place for patient, and newly initiated in patients. doctor interviews (n = ) confi rmed pulmonary rehabilitation was considered mostly for severely unwell patients, and use of exacerbation plans was inconsistent. conclusion pilot data suggest pulmonary rehabilitation is offered and accepted by a small subset of copd patients. findings from this pilot will inform planned larger observational studies, and in turn, experimental studies to improve copd care. high-and extreme high-risk interventions were found by panel ( - . % extreme and . - . % high-risk interventions) and patients' respiratory physicians ( % extreme and % high-risk interventions). additionally, clinical pharmacist involvement was associated with many benefi ts such as: improvement in medication compliance, high level of patient satisfaction and identifi cation of patients with issues in medication knowledge. conclusion clinical pharmacist interventions were estimated to prevent extreme and high risks that might happen due to drug-related problems. clinical pharmacy consultation was associated with positive impact on other important measured outcomes. aerobic exercise training in the form of supervised -minute walks ( mw) reduces exertional dyspnoea in patients with copd. mw goal ( mwg) distances, aiming for a training effect, are generated from a baseline submaximal test ( -minute walk ( mwd), where wg = . × mwd/ × . aim to compare mwg with actual initial mw achieved and to examine the predictors of mwg achievers (ga). methods retrospective review of patients, % male, age ± years (mean ± sd), fev ± %predicted, who completed pulmonary rehabilitation (pr). patients were assessed at baseline and post-completion of pr. initial mwg was calculated from the best of two mwd at initial assessment and ga were defi ned as patients who achieved their mwg at their fi rst visit to pr. results for the group, there was a statistically signifi cant but not clinically signifi cant difference between mwg and actual mw achieved ( ± m vs. ± m, p < . , paired t-test). the patients ( %) who achieved their mwg exceeded the goal by ± m, whereas the patients who did not achieve their mwg fell short by ± m. there was no signifi cant difference between ga and non-ga in age or lung function, but ga had a higher initial mwd, with fewer rests, lower dyspnoea score and lower hr at start and fi nish (p < . , unpaired t-test). ga were also more likely to have a clinically signifi cant response to pr, measured by mwd, compared with non-ga (mean change m vs. m, p < . , chi-square). conclusion mw goals as currently calculated either signifi cantly underestimate or overestimate actual mw achieved. it may be that in non-ga, the mwd is functioning as a true maximal test and these are a group of patients who are truly ventilatory-limited, rather than deconditioned. the receptor for advanced glycation end products (rage) is a key candidate for promoting a self-perpetuating cycle of infl ammation and thereby is a major contributor to numerous chronic disease states. the potential of rage to function as a switch converting a transient infl ammatory response such as one generated by cigarette smoke to sustained cellular dysfunction allows it to act as a mediator for ongoing infl ammation in chronic obstructive pulmonary disease (copd). although the molecular mechanisms regulating rage expression have not been fully elucidated, altered rage activity arises from polymorphisms within the rage gene and its promoter. three polymorphisms in the rage promoter (− t/a, − t/c and a bp deletion from − to − ) increase transcriptional activity and rage expression. the rage g s allele results in an increased ligand-binding affi nity and activation of the infl ammatory mediators with subsequent up-regulation of infl ammatory response. the aim of this pilot cross-sectional study was to investigate the relationship between three known rage polymorphisms (− t/a, bp deletion, g s) and copd and disease severity. methods genomic dna was isolated from peripheral blood lymphocytes. pcr and taqman assays were used to genotype the three rage polymorphisms in copd patients, healthy non-smokers and healthy smokers. fev was measured in all subjects. disease severity was defi ned using gold guidelines. results there was no statistically signifi cant association between bp deletion and copd (p = . ), − t > a and copd (p = . ), g s and copd (p = . ). conclusion no association was found between the − t > a, bp deletion and g s polymorphisms and copd, disease severity or fev introduction the receptor for advanced glycation end products (rage) mediates neutrophil traffi cking and is implicated in the pathogenesis of chronic airways disease. we determined whether changes in airway and systemic levels of soluble rage (which acts as a receptor decoy to limit rage activation) and rage ligands are related to neutrophilic infl ammation in asthma and copd. methods bronchial lavage (bl) fl uid from subjects with moderate-severe persistent asthma or copd, and healthy controls were analysed for neutrophils, total srage (cleaved and secreted), secreted srage (esrage) and the rage ligands hmgb and serum amyloid a (saa). systemic levels srage and esrage were also determined in asthmatic and copd subjects. aims increased numbers of neutrophils are found in the lungs of copd patients, which contribute to airway infl ammation. while cigarette smoke exposure is the major risk factor for copd, it is unclear how cigarette smoke modifi es neutrophil function and activity. this study aimed to assess the effect of cigarette smoke extract (cse) on neutrophils in an in vitro model. methods neutrophils were isolated from peripheral blood donated by volunteers using percoll density gradient centrifugation. neutrophils were seeded in well plates ( cells/well), exposed to different concentrations of cse ( %, %) and monitored at , and hours. at each time point, viability of neutrophils was measured by trypan blue exclusion and supernatant was collected for measurement of cxcl release by elisa (r&d systems conclusions in neutrophils exposed to cse, viability is maintained and cxcl release increases with increasing dose of cse. we conclude that cigarette smoke stimulates an infl ammatory response by neutrophils, which would contribute to the infl ammatory burden in the airways in copd. introduction factor viii (f ) and collagen iv (c ) antibodies are used for quantifying vessels in tissue sections. we compared these two antibodies for vessels staining in bronchial biopsies (bb) in copd. methods bb from healthy non-smokers (h-n) and copd subjects were stained for both antibodies. number, area and mean vascular size (mvs) (surface area/vessel number) of vessels in the lamina propria (lp) to the depth of μm were measured and compared between the two antibodies and are reported as median (range). results number of vessels was not signifi cantly different between the two methods of staining. in copd and h-n, vascular area (μm /μm of lp × ) stained with f was less than that with c ( . ( . - ) vs. ( - . ), p < . and . ( . - . ) vs. . ( . - . ), p < . introduction previous studies have shown that c-reactive protein levels increase at the onset of some copd exacerbations; however, there is limited data on the normal fl uctuation in crp levels in stable patients. aim to investigate within patient variation in crp levels to determine the magnitude of normal day-to-day fl uctuations in stable patients and the correlation with patients' perception of symptom severity. methods early morning crp levels were measured on days , and from patients from the melbourne copd cohort (gold category ii-iv) who identifi ed themselves as stable. patients recorded daily symptom scores including: borg dyspnoea scale at rest, severity of wheeze, cough, dyspnoea, change in sputum colour or volume, night-time waking and the presence of viral symptoms. crp levels were measured by the clinical pathology service and using a point-of care device. variation in crp levels in stable copd and correlation between change in crp levels and symptoms were analysed. aim patient-completed diaries monitoring changes in key symptoms in copd are often used to recognize acute exacerbations (ae) both to prompt additional treatment and monitor treatment effi cacy. we assessed diary compliance and the predictive value of major symptoms of aes which required hospital attendance. methods inpatients recruited during an ae of copd completed daily paper or web-based diaries for months, recording changes from their stable state for: breathlessness, cough, sputum, subjective 'wellness', physical activity and use of reliever ( -point scale, mid-pt = no change). the predictive value of current and lagged symptom scores was compared for each and between symptoms. diagnostic accuracy was assessed by area under the curve (auc) and at specifi c cut-points. in participants ( m, f) with mean age ± and mean fev % predicted ± , there were such aes involving patients. duration of diary keeping was shorter with lower education attainment (p = . ), but compliance did not vary for other demographic or clinical factors. daily compliance while diaries were being kept was %. excluding the current day, the best predictor was the distributed lag score over days, sputum changes giving the strongest signal; relative risk . ( % ci . to . ) with most of the signal in the days prior to the ae. little was gained by combining symptoms. the predictive value was moderate auc = . . conclusions compliance with symptom diaries in severe copd is surprisingly good. however, with only a weak signal for an impending ae requiring hospital attendance up to hours before and for lagged symptom scores over days before, with low positive predictive values, the utility of keeping daily symptom diaries for raising alerts for impending severe aes in copd is questionable. results seven studies with inpatient participants were identifi ed; published as abstracts for which data were not available did not contribute to meta-analyses. no study specifi ed diagnostic criteria for copd and only one specifi ed ae criteria. short course treatment varied between - days and longer duration - days; studies used oral prednisolone (dose mg, studies, tapered dose) and studies used intravenous scs treatment. mean ages of participants ranged from to years. primary outcomes: likelihood of treatment failure did not differ by duration of treatment (odds ratio . ; % ci . to . ) ( studies, n = ). fev did not differ signifi cantly when measured up to days (mean difference (md) − . l; % ci − . to . ) or after days (md − . l; % ci − . to . ) ( studies, n = ). secondary outcomes: limited data ( study) precluded meta-analysis for readmission or mortality. the likelihood of an adverse event ( studies, n = ) was not signifi cantly lower for shorter scs (or . ; % ci . to . ). conclusions we found no signifi cant differences between short (≤ days) and longer (> days) corticosteroid therapy for ae of copd. this has implications for clinical practice and may reduce adverse effects for patients, shorten hospital admissions and reduce costs, but more studies are needed to confi rm these fi ndings. aim to explore factors which infl uence the self-management of exacerbations in patients with copd. methods a pilot cross-sectional study was undertaken to assess patients' compliance with their action plan and their action taken prior to an admission. patients were interviewed during an admission to hospital for exacerbation of copd. the effect of pulmonary rehabilitation on patients' knowledge of copd was also assessed. results % of patients were provided with a written action plan, and % with a verbal action plan. in response to an exacerbation, more than % of the patients stated that they used their action plan. however, where action plans were not adequately utilized, patients delayed seeking medical attention and failed to initiate oral prednisolone and antibiotics during an exacerbation despite being prescribed an emergency supply of these medications. pulmonary rehabilitation had a positive outcome towards enhancing the patients' knowledge of copd. clinical pharmacists have limited involvement in terms of copd and smoking cessation education. conclusion the need to offer a thorough self-management program along with providing a more comprehensive written action plan will encourage patients to start early treatment and follow their action plans. encouraging collaboration between the hcp and patients encourages self-management through discussing and agreeing on goals of treatment and developing a personalized written action plan. context dyspnoea is a common symptom in copd and increases during exacerbations. when respiratory failure supervenes, and assisted ventilation is required, non-invasive ventilation (niv) is the treatment of choice. objective to determine if niv relieves dyspnoea in inpatients with acute respiratory failure due to exacerbations of copd. data sources english language randomized controlled trials (rcts) published prior to august were identifi ed using medline, embase, cinahl, psychinfo and pubmed. additional studies were identifi ed by reviewing the reference list of included studies. search terms included niv, nippv, nppv, bilevel cpap, bipap, artifi cial ventilation, copd and randomized controlled trial. study selection rcts comparing usual medical care (umc) to umc plus niv and measuring dyspnoea at relevant time points were included. abstracts for potentially relevant articles were extracted by one author. these were assessed by a second author to ensure inclusion criteria were met. articles were reviewed to determine if dyspnoea was measured and appropriate statistical analysis reported. the search yielded individual articles. four articles met the review criteria. three articles fi nd that niv relieved dyspnoea to a statistically signifi cant level and two suggested that the relief of dyspnoea is clinically signifi cant. discussion in spite of the common use of niv to relieve dyspnoea, little work has analysed effi cacy in terms of this patient-reported outcome. while our results may suggest niv relieves dyspnoea, reporting or methodological fl aws in several articles limit the strength of the conclusions that may be drawn. these limitations make the conclusion that niv relieves dyspnoea contentious. conclusion despite over two decades of studies investigating niv, the therapeutic impact on breathlessness is poorly described. understanding the impact of niv on patient-reported outcomes is of critical importance in clinical care. confl ict of interest none. introduction in mice, the most direct lung dosing method delivers the agents directly into the trachea. for our cystic fi brosis gene-therapy studies, we deliver fl uids -an airway pretreatment followed by a lentiviral vector -directly into the mouse trachea to target conducting airways. despite using standardized delivery techniques, we see substantial variability in the amount and location of gene transfer. aim the aim of this experiment was to use synchrotron x-ray imaging to track the dynamics of fl uid doses delivered into the live mouse trachea. methods four nembutal anaesthetized c bl/ mice were imaged on the bl b beamline at the spring- synchrotron. mice were intubated and ventilated at br/min with image captured per breath. after minute of baseline, a -μl sample of iodine-based contrast fl uid (a surrogate for our airway pretreatment or gene-vector) was delivered over seconds. following minutes of data collection, an additional μl bolus was delivered over . seconds. image capture continued for a further minutes. frame differencing was used to reveal fl uid motion. results substantial dose losses may occur upon delivery into mouse trachea via immediate retrograde fl uid motion. the speed of bolus delivery into lung may also infl uence the relative targeting of conducting airways and deep lung. introduction use of effi cient nebulizers can enhance the quality of life of cf patients by reducing the treatment time and improving drug delivery effi ciency. the aim of this study was to determine which commonly recommended nebulizer was optimal for delivery of the most commonly used therapies to cf. methods seventeen children with cf ( - years) were recruited. delivery of three commonly used cf therapies ( % hypertonic saline ( ml, . g/ ml), tobramycin ( ml, mg/ml) and pulmozyme ( . ml, mg/ml)) by two vibrating membrane nebulizers, the eflow rapid and the aeroneb go, and a jet nebulizer lc sprint junior with pariboy sx ( . l/min) were tested. for each drug-nebulizer combination (in random order), each child was asked to inhale through an inspiratory fi lter, and drug delivery to the fi lter was measured. pulmozyme was quantifi ed using an enzymatic activity assay, tobramycin was measured using hplc and hypertonic saline was measured using conductivity. total nebulization time was recorded. the results showed that there was no difference in the amount of drug delivered to patients when the nebulizers were compared for all three therapies (p > . ). however, the nebulization time for the eflow rapid was signifi cantly shorter than that for the aeroneb go and lc sprint junior. similarly, the nebulization time for aeroneb go was shorter than that for the lc sprint junior (p > . ) for all therapies). conclusion overall, there were no signifi cant differences between nebulizers in delivered dose for three forms of cf therapy, due to inter-patient variability. despite this, both vibrating membrane nebulizers had shorter nebulization times than the lc sprint junior, with the eflow rapid delivering drug in the shortest time. confl ict of interest nil. introduction as the life expectancy of patients with cystic fi brosis (cf) increases, treatment-related morbidity is increasingly recognized. totally implantable venous access devices (tivads) offer reliable long-term central venous access but are associated with recognized complications including venous thrombosis. superior vena cava syndrome (svcs) however has been rarely reported in this setting. we report a single cf centre's experience of svcs associated with tivads. methods retrospective review of episodes of svcs in patients with cf and a tivad attending the adult cf centre, prince charles hospital, queensland. results between february and december , fi ve episodes of svcs occurred in patients with tivads from a clinic population of patients. all of the affected patients were female, with moderately severe lung disease (mean fev predicted . %). no patients had a recognized thrombophilia. four tivads were inserted at a centre different to our own, three were on oestrogen-based contraception, and two suffered with dehydration at presentation. svcs treatment consisted of anticoagulation ( ), line removal ( ), angioplasty ( ), thrombolysis ( ) noninvasive bioluminescence imaging has allowed for rapid in vivo quantifi cation of long-lasting gene transfer in experimental animals. we are testing the longevity of a single nasal delivery of our lentiviral (lv) gene transfer system in mouse airways. methods normal (c bl/ ) and cystic fi brosis (cf) mice received a nasal bolus of lysophosphatidylcholine (lpc) or a control (pbs) pretreatment hour prior to delivery of a lv vector containing the reporter-gene luciferase (lv-luc). another control group received lpc hour prior to an empty vector (lv-mt). bioluminescence was measured at week, , , , , , , , and months post-lv dosing to assess gene transfer. results normal mice: mice that received lpc/lv-luc treatment had significantly greater gene transfer compared to the two control groups at all time points (p < . , rm anova). no luminescence was detected in mice treated with lpc/lv-mt. unexpectedly, luciferase activity was also detected in the lung. there was no difference in lung luminescence between the lpc and pbs pretreated mice that received lv-luc. cf mice: a statistically signifi cant increase in nasal luminescence persisted for up to months following lpc/ lv-luc (p < . , rm anova). similar to normal mice, there was no statistical difference in lung luminescence between mice that received lpc and pbs lv-luc. conclusions lentiviral luciferase gene expression was signifi cantly improved in mouse nasal airways using lpc pretreatment in both strains. however, the longevity of transduction was reduced in cf mice, which may, in part, be due to reduced animal numbers at the later time points tested. supported by nh&mrc. background the nintendo-wii® facilitates exercise-based programs that may be considered novel, fun and potentially motivating. objective exercise outcomes using the wii have yet to be reported in the cystic fi brosis (cf) adult population. aim to investigate nintendo-wii® exercise training compared with standard exercise in adult cf patients whilst hospitalized for treatment of a pulmonary exacerbation. methods a within-subjects, randomized cross-over study. adult cf participants received two -minute exercise treatment sessions within a -hour period, at least day apart, during the last days of hospitalization. wii exercise consisted interval training with games such as boxing, dancing and track exercises. standard exercise consisted of interval training on treadmill or cycle ergometer at - % of heart rate maximum. results participants completed the study (mean (sd) age ( ) years, % females), with a mean fev % of ( )%. during exercise, no difference was found between groups in average heart rate (p = . ), oxygen desaturation (p = . ), borg rate of perceived exertion (p = . ) or modifi ed borg for dyspnoea (p = . ). on vas ( - ), participants reported the wii program to be more enjoyable (p < . ) and less fatiguing (p = . ). participants rated both exercise sessions as equally effective (p = . ). conclusions this study suggests that a nintendo-wii® exercise session provides an equivalent cardiovascular demand to a standard exercise session in an inpatient adult cf population. greater enjoyment levels and lower fatigue levels reported during nintendo-wii® training may have a positive infl uence on adherence to exercise. further study into the long-term effects of nintendo-wii® training needs to be undertaken. confl ict of interest nil. introduction ion transport is important to maintain the airway epithelial surface, as shown by the disease cystic fi brosis (cf) which is characterized by decreased clsecretion and increased na + absorption. we have previously shown that the cf airway can develop clresponses when the surface is nominally calcium free (middleton et al. ajrccm ; : - . aim to determine the effects of citrate on the nasal potential difference (npd) with and without amiloride pretreatment, and to compare these effects with other clinically relevant calcium chelators and dicarboxylic acids. methods npd was measured using standard techniques (erj ; : ) in cf and non-cf subjects. the nasal pd response to citrate, oxalate, malate, succinate and fumarate (all mm) was compared with the calcium chelators edta and egta. results citrate decreased the basal npd by ∼ mv, but in the presence of amiloride, citrate increased the pd by ∼ mv. with amiloride/low clpretreatment, citrate increased npd by - mv, which suggests that citrate increased clsecretion. in contrast, the other dicarboxylic acids and calcium chelators exhibited little response. conclusion the combination of these responses suggests that citrate exerts complex effects on airway ion transport, most likely dual effects of decreased na + absorption and increased clsecretion. aim to assess the validity of the international physical activity questionnaire (ipaq) in cf adults by comparing energy expenditure measured by the ipaq versus the accelerometer. methods with ethics approval, suitable successive adult patients with cf attending the alfred cf outpatient clinic were recruited. all participants wore an accelerometer (actigraph gt m) around the waist for days of awake time, at the end of which, they completed the ipaq. criterion validity of the ipaq was assessed by comparing the ipaq weekly energy expenditure (ee) in kilocalories (kcal) with weekly ee (kcal) from the accelerometer using spearman correlations and bland-altman procedures. results thirty participants ( % females) completed the assessment: mean (sd); age = ( ) years, fev %predicted = ( ) the median (range) ee: ipaq = ( , ) kcal, gt m = ( , ) kcal. spearman correlations of fev %predicted with ee were gt m ee r = . , p < . ; ipaq ee r = . , p > . . correlation of the ipaq ee with accelerometer ee was moderate (r = . , p = . ). there was a trend towards higher ee measured by the ipaq than measured by the accelerometer (wilcoxon signed ranks test: z = − . , p = . ). conclusion the ipaq underestimates physical activity for patients with lower energy expenditure activities and overestimates for those with higher energy expenditure activities in adults with cf. the ipaq would be a useful screening tool for exercise prescription and monitoring of physical activity longitudinally, but more quantifi able methods for assessment such as the accelerometer should be used in research. confl ict of interest none. infectious endometritis associated with pseudomonas aeruginosa (pa) is an important equine disease resulting in reduced fertility and decreased foal drop. previous typing studies of equine pa report clonal heterogeneity, suggestive of sporadic acquisition, and small clusters of indistinguishable strains. aim we performed molecular typing of a large sample of genital pa isolates from horses in s-e qld. methods thoroughbred genital tract pa isolates submitted to uq vet diagnostic lab during - (screening or infection suspected) were studied. eric-pcr fi ngerprint analysis was performed. isolates producing indistinguishable fi ngerprints were allocated to the same eric-pcr type. mlst was performed on a subset of isolates. results overall, genital (clitoral or uterine) swabs from mares and urethral fossa swabs from stallions located on stud farms were processed. pa was identifi ed in genital cultures from of the ( . %) mares but from none of the stallions. six clusters involving ≥ mares were detected. cluster-a was observed amongst isolates collected from ( %) mares from studs and each year. cluster-b isolates were present in mares from studs during - . clusters c-to-f each contained isolates from mares from or studs. conclusions overall, % of mares harbouring pa had clonally related strains. however, we found no evidence of horizontal transmission between stallions. these data raise the possibility of transmission via environmental or other sources. alternatively, specifi c strains may have trophism for the reproductive tract of horses. the fi nding of a dominant strain amongst thoroughbred mares in a geographic region has interesting parallels with recent evidence of the spread of highly prevalent clonal strains in cystic fi brosis clinics. aim to investigate the prevalence and impact of incontinence in adult men with cystic fi brosis (cf) as compared with age-and sex matched control subjects. methods men with cf were recruited through outpatient clinics and control subjects through advertisements to complete standardized questionnaires relating to respiratory symptoms, bladder and bowel function, mood and physical activity levels. demographic data were collected from medical records for the cf group. results seventy-four men with cf participated (mean (sd) age . ( . ) years). forty-nine men volunteered as controls ( . ( ) years), and were well matched in terms of physical activity levels. / ( %) in the cf group and / ( %) in the control group had reported episodes of urine leakage. in the men with cf, there was no difference in lung function between men with episodes of leak and those with no history of leak (fev % predicted ( )% vs. ( )%, p = . ). anxiety levels were higher in men from both groups with episodes of leak compared to those with no history of leak (hospital anxiety and depression anxiety score . ( . ) vs. . ( . ), p < . ). depression scores were also higher in men with episodes of leak compared to those with no history of leak ( . ( . ) vs. . ( . ), p < . ). conclusions urinary incontinence in men with cf is not associated with disease severity, as measured by lung function. anxiety and depression levels were higher in men with leakage of urine. confl ict of interest no. aim to investigate the bone mineral status of children and adolescents with cf and to explore the relationship between bone mineral density (bmd) and anthropometric and clinical parameters including height, body mass index (bmi), lung function tests and vitamin d levels ( -hydroxyvitamin d) in the cf centre at starship children's hospital, new zealand. methods bmd of the lumbar spine was assessed by dual x-ray absortiometry between january and december . the results of subjects with cf ( males) with a mean age of . years (range - . years) were collected. anthropometric data (height, bmi), forced expiratory volume in second as percent predicted (%fev ) and vitamin levels were assessed and related to bmd. results bmd in our subjects was low in . % and very low in . % when adjusted for age, sex and height (difference in bmd g/cm in the lumbar spine l -l ). there was a strong positive relationship between the lumbar areal bmd (abmd) and bmi z scores (p < . ), abmd and % fev z scores (p < . ), and abmd z scores and vitamin d levels (p < . ). conclusions bmd was normal in the younger and well-nourished subjects with normal or mild reduction of fev . low bmd appeared to evolve during adolescence with decreasing bmi and reduction in lung function. this will lead to ongoing bone disease in early adulthood. it is a further indication to maintain optimal nutritional status and maximize lung health. malnutrition in cf is associated with poorer pulmonary function and is an independent risk factor of survival. aim to compare the nutritional status of the adults attending an adult cf centre in with . method retrospective audit of patients ( excluded, incomplete data) including demographics, nutritional status, pancreatic enzyme replacement therapy (pert) usage, glucose tolerance and dietetic review. results the mean age of the clinic population increased from . to . years. mean (sd) bmi increased from ( . ± . kg/m ) to ( . ± . ) (p = . ). in , % of the clinic population was taking pert with a mean dose of ± iu lipase/kg/day. the proportion of patients with abnormal glucose tolerance has increased from % to % (p = . ). oral supplement use has increased from % to %, yet enteral feeding remained stable ( % − , % − ). this occurred during period of increased annual dietetic review of the patients attending the clinic from % in to % in (p = . ). discussion over a -year period, an improvement in mean bmi refl ects improvement in nutritional status. prevalence of abnormal glucose tolerance has increased; this is likely due to commencing a screening program ( ). use of oral supplements has increased and is higher than identifi ed in the recent daa survey of nutrition practices of cf dietitians ( %). annual review by the cf dietitian has increased despite a twofold increase in the cf population may be attributable to a stable and experienced workforce. current service provision of . a abbott , e cheung , l morgan aim to characterize the microbial colonization of a group of stable adults with non-cf bronchiectasis using an extended culture protocol. methods sputum was collected over an -month period from clinically stable patients. standard semi-quantitative bacterial culture was extended to days with the addition of fungal and mycobacterial culture as routine. results specimens of spontaneously expectorated sputum were collected from patients; mean age years ( - years); mean (sd) fev / fvc ratio % ( %); / never smokers; / on inhaled or oral corticosteroids. the bacteria identifi ed were p. aeruginosa ( % of specimens), h. infl uenzae ( %), h. parainfl uenzae ( %), acinetobacter baumanii ( %), enterobacteriaceae ( %). commensals only were identifi ed in % of specimens. fungi included candida species ( %), aspergillus fumigatus ( %) and penicillium species ( %). non-tuberculous mycobacteria (ntmb) were grown in % of specimens: m. gordonae ( %), m. intracellulare ( %) and m. lentifl avum ( %). the ntm identifi ed were all considered non-pathogenic. only the mycobacteria were identifi ed after day . conclusion microorganisms with potential pathogenicity are frequently identifi ed in adult patients with non-cystic fi brosis bronchiectasis who are not experiencing an acute exacerbation. all these organisms were identifi ed using a standard short culture protocol. the extended regimen, which was costly, did not identify any unusual or unexpected pathogens. it was rare for patients to be colonized with fungi. this study suggests there is limited value in requesting extended culture for bacterial pathogens, including looking for fungi or nmtb in this stable patient group as this adds little to the empiric antibiotic choice for infective exacerbations. confl ict of interest none. s stelzer-braid , , h alsubie , a neilsen , h johal , a steller , er tovey , k mckay , p van asperen , wd rawlinson , introduction respiratory infections are of fundamental importance in determining the morbidity and mortality associated with cystic fi brosis (cf) as such infections can lead to progressive and fatal obstructive lung disease. using polymerase chain reaction (pcr) to detect such infections has advantages over previous studies that used relatively insensitive traditional detection methods and could have underestimated viral prevalence. methods viral and bacterial multiplex pcrs were developed for detection of respiratory pathogens important for children with cf. nasal brush samples were collected from cf patients who were symptomatic or asymptomatic for acute respiratory illness (n = ). sputum and exhaled bioaerosols via a novel mask sampler were collected from a subset (n = ). results as expected, almost all ( %) sputum samples were positive for bacteria. detection of bacteria in the upper respiratory tract was lower ( . %). data from nasal samples indicated strong association of viral pathogen presence, particularly rhinovirus, with exacerbation of disease. results also showed good evidence for rhinovirus infection in the lower respiratory tract. the novel mask sampler is promising as a non-invasive sampling tool. conclusions our results demonstrate the importance of pathogens in exacerbations. early detection and understanding the development of bacterial and viral infections in cf patients is important in clinical decision-making as more and better antiviral and antibiotic agents become available. aim to determine the factors affecting microbiological yield from bronchoalveolar lavage (bal) in patients with suspected pulmonary infection and haematological malignancy or following stem cell transplantation at a tertiary bone marrow transplant centre. methods a retrospective -month audit of patients with pulmonary infi ltrates or febrile neutropenia with haematological malignancy or post-stem cell transplant who underwent bal for microbiological diagnosis. data were obtained on microbiological yield, radiographic appearances, current antimicrobial therapy, the presence and duration of neutropenia and complication rate. of the bal procedures performed, a clinically signifi cant microbiological result was obtained in % of cases ( / ). of these positive results, % ( / ) were exclusively viral pathogens, % ( / ) were fungal, % ( / ) were bacterial and polymicrobial infection was observed in % ( / ) of cases. a high proportion of patients had commenced anti-microbial treatment empirically, with % ( / ) receiving broad spectrum antibacterial treatment and % ( / ) receiving treatment doses of antifungal agents prior to bronchoscopy. in % ( / ), the results of the bal changed the patients therapy. the presence and duration of neutropenia or radiological appearances were not reliable discriminators of specifi c infective aetiologies. complication rates were low and included fevers in % ( / ), hypoxia % ( / ), small volume haemoptysis in % ( / ), atrial fi brillation in % ( / ) and pneumothorax in % ( / ). conclusion whilst bal remains a safe and important tool in establishing a microbiological diagnosis in immunosuppressed patients with pulmonary infi ltrates, a clinically signifi cant yield and changes to patient treatment occur in the minority of cases. clinicians should have a high degree of suspicion of viral infective aetiology when treating this population of patients. aim to examine the outcomes and complications of intercostal catheter (icc) treatment of pneumothoraces (primary (pp) and secondary (sp)) and effusions (malignant (me) and parapneumonic (pe)). methods retrospective review of all iccs in admitted patients in a respiratory unit over months. data collected included type of pneumothorax or effusion, icc type, insertion details, complications (major and minor) and outcome (success defi ned as resolution of pneumothorax or effusion with single tube insertion). results patients required icc treatment. forty-six iccs were used in patients with pneumothorax: pp ; sp ; iatrogenic ; hydropneumothorax . complication rate was % ( % major) and was signifi cantly less in pp ( %) compared with sp ( %), p < . , chi-square. success rate for pneumothorax icc drainage was % (signifi cantly higher for pp ( %) compared with sp ( %), p < . ). fifty-eight iccs were used in patients with pleural effusions: me , pe , other . complication rate was % ( % major) and was signifi cantly higher in me ( %) compared with pe ( %), p < . . success rate for effusion icc drainage was % (signifi cantly less in me ( %) compared with pe ( %), p < . ). small bore iccs (gauge < fr) were used for % of pneumothoraces and % of effusions. tube size did not signifi cantly infl uence complication or success rate for either pneumothoraces or effusions. conclusions compared with pp, icc treatment of sp was less successful and more likely to be associated with complications. similarly, compared with pe, intervention for me with icc was less successful and had a higher complication rate. we conclude that icc intervention is most successful for pp and pe, and speculate that sp and me should have early surgical intervention. introduction spontaneous pneumothorax is a common condition. current management guidelines recommend large pneumothoraces are managed by primary intercostal catheter insertion. we report a single centre's experience in the management of large spontaneous pneumothorax. methods retrospective audit of cases of spontaneous pneumothoraces managed at the prince charles hospital between january and december . patient demographics, co-morbidities, presenting symptoms, examination fi ndings, radiology, management and complications were reviewed. results forty-two patients ( male, female) experienced episodes of spontaneous pneumothorax. chest pain and dyspnoea were the most commonly reported symptoms ( ) %. there were forty-two ( %) episodes of large pneumothorax (≥ % of hemithorax). management of large pneumothoraces consisted of: observation, ( ) seldinger icc ( ) and large bore icc ( ). complications occurred in three patients with seldinger icc ( vasovagal, hydro-pneumothorax) compared to none with large bore icc. outcomes were similar for patients managed by observation compared to icc insertion. all recurrent cases ( %) were referred for consideration of surgical pleurodesis. conclusion patients with large pneumothorax managed by observation recovered similarly to those treated with icc, suggesting a higher threshold for icc insertion should be considered in the future. grant support nil. aim a pilot study of an instrument of pleural ultrasound training in thoracic physicians after a pleural ultrasound course. the instrument was tested for inter-observer agreement and also its ability to be used in a patient compared to a dedicated manikin. methods all chest physicians ( ) were novices in ultrasound and underwent a dedicated -day training course in pleural ultrasound at the australian institute of ultrasound. they were assessed months later by radiologists and one senior ultrasonographer using a specially designed pleural ultrasound training assessment tool (usgt-sat) on both a subject with pleural effusion and a dedicated ultrasound manikin. the mean scores, out of a maximum of , obtained by the each of the participants for the manikin were . , . , . and . , respectively, while the scores for the patient was . , . , . and . , respectively. the mean scores of the participants as a group for manikin were ± . and for the patient as . ± . . there was general agreement between the examiners with mean combined participant scores of . , . and . in the manikin, respectively, and mean score of . , . and . in the patient. conclusions this pilot study shows ranges of scores for design of future validation studies of the usgt-sat. test performance by the chest physicians after a short course in pleural ultrasound was generally good and results for the use of the manikin as an alternative to patients in pleural ultrasound training are encouraging. further studies with larger sample size are required. supported by nil. nomination nil. confl ict of interest no. since the fi rst commercial availability in , fl exible bronchoscopy has evolved from a simple 'look see' procedure to a more complex multifaceted one. today, fl exible bronchoscopy is a tool used for diagnostic procedures, surveillance, delivery of therapy and clinical trials. increasingly, it involves utilizing expensive purpose built equipment in complex diagnostic procedures. this evolution requires a specifi c knowledge base and skill set to safely perform the procedure and care for the equipment. this now mandates additional training by nursing and medical staff to develop and maintain the required skills. medical staff now rely on their nurses to assist in the full range of procedures. thus, the nurses must keep abreast of modern trends and techniques. the modern bronchoscopy suites team is an integrated one, with specifi c roles, defi ned to each member. the procedures performed will refl ect local needs and expertise. just as bronchoscopy has evolved into the speciality of interventional pulmonology, so must bronchoscopy suite nursing be accepted as a specialized area of nursing with a credentialed 'special interest group' to promote, educate and develop the subject as more therapeutic and diagnostic procedures evolve. this will allow nurses involved in bronchoscopy to be respected, recognized and accepted for their unique knowledge and abilities. confl ict of interest nil. background transthoracic pneumostomy (tp) is a novel treatment for patients with severe emphysema that aims to defl ate the lung and improve function. aim to assess the effect of unilateral tp on the volume of each lung and mechanical properties of the lungs. methods subjects were recruited for a multicentre trial of tp (see actrn ). in parallel with the main protocol, we measured ( ) in the six subjects recruited, compared to plethysmography, lung volume was overestimated by cxr (mean difference + . %, range − . to + . ) and underestimated but more closely correlated by ct (mean difference − . %, range − . to − . ). based on ct, the volume of the treated lung decreased in all patients after tp (mean − . %, range − . to − . ) whilst that of the untreated lung did not change (mean − . %, range − . to + . ). in patients with available data, tp reduced dynamic hyperinfl ation during exercise (mean − ml, − . % of ic, range + . % to − . %). lung mechanics were performed in patients. low lung elastic recoil prior to tp and an increase in elastic recoil after tp were associated with greater reductions in lung volume and greater improvements in exercise tolerance. conclusions supine chest ct provided reasonably accurate estimates of plethysmographic lung volume. unilateral tp defl ated the lung and there was no evidence of signifi cant compensatory hyperinfl ation of the contralateral lung. tp also reduced dynamic hyperinfl ation. measurement of lung elastic recoil may help select patients who are likely to benefi t from tp. support and confl ict of interest nil. methods we performed a retrospective chart review of all adult patients who had an icc over a -month period within a tertiary hospital respiratory service. we noted patient demographics, details surrounding chest drain insertion including image guidance and subsequent inpatient events. results over a -month period, there were small-bore icc insertions, of which were image-guided. mean patient age was years, males comprised / . forty drains were inserted for pneumothoraces, for malignant effusions, for parapneumonic effusions, for transudates and for undiagnosed exudative effusions. mean duration of drainage was . days. there were no life-threatening complications. three of the chest drains fell out and became blocked. six pneumothoraces were noted, all following insertion without direct image guidance; none required further intervention. local infection occurred in patient. insertion details were not documented in patients. conclusion insertion of small-bore iccs via the seldinger technique appears to be a safe method of draining pneumothoraces and pleural effusions. image guidance may reduce complication rate of this procedure. documentation of drain insertions could be improved. confl ict of interest nil. rationale pleural effusions are frequently encountered in clinical practice, and often require aspiration for diagnostic and/or therapeutic purposes. use of radiological guidance varies, despite current guidelines recommending routine use of ultrasound. furthermore, concerns exist regarding the downskilling of thoracic medicine trainees due to the increased use of interventional radiology. as a precursor to developing a procedural pleural ultrasound service, we performed a retrospective case review of our current practice. methods patients who had pleural fl uid sent to pathology between january and december were identifi ed on an existing database. patient records were reviewed and details regarding the drainage procedure and outcomes were recorded. information on patient location, method of procedure and performing clinician were also collected. results to date, pleural fl uid aspirations in patients have been identifi ed. overall, % of aspirations were carried out on the ward and % in the radiology department. two procedures occurred in the endoscopy suite on outpatients, and one in the emergency department. fifty percent of procedures were performed using an intravenous cannula for drainage and % utilized a pigtail catheter. all procedures occurring in the radiology department were performed under ultrasound guidance by a radiologist or radiology registrar. of the remaining procedures, % were performed by medical registrars and % were performed with ultrasound marking. six complications occurred following procedures: pneumothoraces, vasovagal and tube blockage. there were signifi cantly more pneumothoraces in patients who did not have an ultrasound marking ( of without marking, of with marking, p = . ). none of the complications required further intervention. conclusion these preliminary data suggest ultrasound marking signifi cantly reduces pneumothorax incidence, supporting the establishment of a pleural ultrasound service. this is likely to have the added benefi t of improved training for thoracic medicine trainees. aim to investigate differences between semi-recumbent and supine posture in terms of cough rate, degree of oxygen desaturation, oxygen supplementation, increase in pulse rate and sedative use during the initial phase of bronchoscopy. methods consecutive patients (n = ) undergoing diagnostic bronchoscopy at an endoscopy unit were recruited for this observational cohort study. the posture was determined by the bronchoscopist's usual practice. patient age, gender, % predicted fev and fvc, indication, pulse and oxygen saturation were recorded. the initial phase was defi ned as the time from bronchoscopy insertion to visualization plus lignocaine instillation of both distal main bronchi. cough rate, peak pulse, nadir oxygen saturation (spo ), range of oxygen supplementation and sedation use during the initial phase were recorded. a post-procedure questionnaire was administered to the patient and the attending nurse. results patients had bronchoscopy in the semi-recumbent posture and in the supine posture. three of bronchoscopists performed in both postures. there were no signifi cant differences in age, gender, smoking status and spirometry between the two groups. the semi-recumbent postures resulted in signifi cantly less cough rate (mean (sd) . ( . ) vs. . ( . ) coughs/min, p = . ) and less fentanyl use ( ( ) vs. ( ) mcg, p = . ) in the initial phase. there were no signifi cant differences in the nadir spo , fall in spo , oxygen supplementation or increase in pulse rate between the two groups. nurse perception of patient discomfort was lower in the semirecumbent position ( ( ) vs. ( ) mm on mm visual analogue scale, p = . ), and there was a trend towards less patient-perceived cough during the procedure in the semi-recumbent group ( ( ) introduction pulmonary infi ltrates in immunocompromised patients with haematological malignancy have a diverse aetiology and are a major source of morbidity. a specifi c diagnosis and targeted therapy may optimize outcomes and reduce the cost of treatment. the diagnostic value of fi breoptic bronchoscopy (fob) and the infl uence of timing of the procedure are unclear. aim to determine the yield of fob, its impact on antibiotic therapy and the infl uence of early vs late timing in this patient population. methods we conducted a retrospective review of immunosuppressed patients with underlying haematological malignancy and new pulmonary infi ltrates who underwent fob over a -month period. the outcomes of early (eb, ≤ days from initial respiratory consultation) and late (lb, ≥ days) fob were compared using fisher's exact test. results thirty-eight fobs, including bronchial or transbronchial biopsies, were performed in patients (males ). there were patients who received eb and who received lb. a specifi c diagnosis was obtained from procedures ( %), including infections ( in eb vs. in lb, p = . ) and non-infective diagnoses ( eb vs. lb, p = . ) based on histology. fob fi ndings from procedures ( %) ( eb vs. lb, p = . ) resulted in modifi cation of antibiotic therapy. there were no procedure-related severe complications. conclusions fob is a useful diagnostic procedure which infl uences diagnostic and therapeutic decisions in this patient group. although early procedures tended to be more likely to change antibiotic therapy than late procedures, the difference was not signifi cant. confl ict of interest none. capsule endoscopy is increasingly performed in gastroenterology to investigate possible small intestinal bleeding. the capsule endoscope is swallowed and then takes photographs every seconds for hours during its transit through the gastrointestinal tract. the images are downloaded by a radio link and the capsule is then passed normally and disposed of. in the present case, the capsule endoscope was inhaled and lodged in the bronchus intermedius. this was only recognized when the images from the capsule download were examined. removal of the capsule was effected with a fi breoptic bronchoscope using an ercp balloon and roth basket. this is believed the only capsule bronchoscopy so far reported. capsule endoscopes are large ( mm × mm diameter) and smooth. this case report shows the images from the capsule endoscope and describes the methods necessary to remove this unusual foreign body from the lung. support nil. background bronchoscopy with endobronchial biopsy (eb) is now an integral component of the research evaluation of airway diseases. there are no published safety data for eb in adult non-cf bronchiectasis. methods a subgroup of subjects enrolled in the bronchiectasis and low dose erythromycin study (bless) a randomized controlled trial of long-term prophylactic erythromycin (anzctrn ) underwent bronchoscopy with bronchoalveolar lavage (bal) and eb performed by a single operator. results ninety-nine bronchoscopies were performed (bal alone in ) in subjects. of procedures with eb, ( . %) were associated with very signifi cant bleeding (> ml either at time of eb or several days post-procedure) and a further ( . %) with immediate moderate bleeding ( - ml). one subject had a history of prior signifi cant haemoptysis. in the four subjects with very signifi cant bleeding, immediate bleeding of > ml occurred in subjects, ml in one subject and ml in one. immediate bleeding was controlled uneventfully. three of the subjects subsequently developed signifi cant haemoptysis (> ml) to days post-bronchoscopy without intervening haemoptysis, with one subject developing massive haemoptysis (> ml) on day post-bronchoscopy. further research ebs were ceased. in one of the subjects with 'delayed rebleeding', repeat bronchoscopy confi rmed the biopsied lobe as the bleeding site. haemoptysis settled in all subjects within hours with simple conservative measures. conclusions in contrast to the experience in asthma and copd, research eb in adults with non-cf bronchiectasis is associated with a signifi cant risk of bleeding, of potentially life-threatening magnitude in . % of cases. of particular concern was the observation of sudden onset delayed rebleeding developing up to days post-eb in spite of early local control. histopathological evaluation will clarify the potential contributions of airway wall vascularity and infl ammation to these events. malignant mesothelioma (mm) is an aggressive cancer which is often associated with exposure to asbestos and sv . this disease has a high latency period and a low survival rate. therefore, new strategies for therapeutic intervention must be developed. recent studies have shown that developmental pathways including the hedgehog (hh) pathway are associated with various types of cancers. the aberrant activation of key hedgehog pathway proteins has been shown to contribute to cancer progression. however, the role of this pathway in mm has yet to be explored. we hypothesize that aberrant activation of the hh pathway is a contributing factor for the development of mm. the mrna expression of hh pathway genes; sonic hedgehog (shh), patched - (ptch- ), smoothened (smo) and gli- were examined in mm cell lines and tumour tissues by rt-pcr and qrt-pcr. hh pathway proteins and mrna expression and distribution were then observed in the tumours by immunochistochemistry and in situ hybridization. we used real-time superarrays to examine the change in expression of a panel of key hh pathway genes by activating and inhibiting the pathway. we showed that the key hh pathway genes are expressed in both the cell lines and tissue samples. upon stimulation with the ligand shh, there was an increase in expression of indian hedgehog (ihh) and shh in most of the mouse and human cell lines that we looked at. interestingly, for the transcription factor gli- , there was a significant decrease in both mouse and human cell lines. inhibiting this pathway increased the expression of ptch in the mouse and human cell lines. the expression and up-regulation of key hh pathway components in mm at baseline and following stimulation suggests a role for the pathway in mm. methods incident cases were obtained from the australian and wa mesothelioma and cancer registries and death registries. exposure was calculated using measures of dustiness in the industry and the town for the period of employment or residence of each case. latency (time from fi rst exposure to diagnosis) by sex, age, smoking status, exposure variables and worker or resident status was estimated. multivariate linear regression modelling examined the determinants of latency. results the mean latency periods of . (sd = . ) years for lc and . (sd = . ) years for mm have increased linearly. increased duration of exposure was associated with reduced latency for mm after adjustment for age at fi rst exposure and age at diagnosis but not signifi cantly for lc. age at diagnosis was strongly associated with latency length for both lc and mm (p < . ). smoking, sex, cumulative exposure (log f/ml-year) and status at wittenoom were not related to latency. latency for lc with increasing age at fi rst exposure declined faster than for mm. conclusions age at diagnosis is associated with reduced shorter latency of mm and lc. duration of exposure is associated with shorter latency of mm. supported by nhmrc australia. confl ict of interest no. aim to assess overall survival of patients following resection for stage nsclc at a centre that has substantially greater resection rates than the nsw average. methods a retrospective audit of those patients who underwent lung resection for stage nsclc at nepean hospital between january and february . results patients ( m: f), mean age (range - ) underwent resection. there were pneumonectomies, bilobectomies and segmentectomies, one involving chest wall resection. the remaining procedures were lobectomies. there was one perioperative death from respiratory failure. actuarial overall survival at months was %, at months, % and at years %. survival was not infl uenced by histology or age. conclusion in our institution, we have an agreed aggressive approach to resection of stage nsclc and our resection rate is %. this pro-surgical policy is associated with good perioperative and long-term overall survival. confl ict of interest no. introduction malignant pleural effusions (mpes) are common, although their management varies widely. providing ambulatory care to minimize hospitalization is a key goal for patients with mpes. indwelling pleural catheters (ipcs) are a new treatment strategy that allows outpatient fl uid drainage. we hypothesized that mpe patients managed with ipcs require fewer hospital admissions. methods a prospective, multicentre, non-randomized study involving all three major respiratory centres in western australia. patients diagnosed to have mpes were prospectively followed, and admissions were recorded. in the absence of accepted guidelines for ipc use, the choice of treatments (thoracentesis, ipc, pleurodesis) was decided by clinicians in-charge. all complications were recorded. bacterial cultures of pleural fl uid were performed monthly for patients with ipcs. hm gallagher , ee duhig , ia yang , rv bowman , be clark , hm marshall , km fong aim to determine the concordance of histological subtyping of nsclc in diagnostic samples to the gold-standard lung resection specimens. methods we have so far evaluated consecutive subjects who underwent curative surgery for primary nsclc at the prince charles hospital between the years and . many of these had workup at other institutions. one hundred forty-seven had queensland health electronic record of positive preoperative diagnostic sampling. we correlated the fi nal nsclc who histological subtype with the subtypes diagnosed by samples prior to surgery including sputum, fi beroptic bronchoscopy (fob) and trans-thoracic needle aspiration (ttna). the resection subtype was set as the reference standard, and concordance was compared. results of the cases of resected nsclc, had malignancy on diagnostic sampling pre-resection, as shown in the results patients were included: median age years (range - ); % male; % living in major cities versus % in regional areas; % rightsided mpm; % epithelial subtype. median time from asbestos exposure to diagnosis was years (range - ). median time from fi rst symptoms or investigations to diagnosis was weeks (range - ). all patients had at least one chest x-ray and ct scan and % had pet scan. a variety of procedures led to the diagnosis: % thoracoscopy, % thoracotomy, % radiology-guided, % chest wall biopsy and % medical pleuroscopy, with % having had cytology alone. median number of diagnostic immunohistochemical stains used was (range - ), with calretinin ( %) the most commonly used mesothelial marker and carcinoembryonic antigen (cea; %) the most common carcinoma marker. median os for the cohort was . months ( % ci: . - . ), with no statistical difference in os between major city and regional patients ( vs. . months, respectively, p = . ). conclusions mpm appeared to affect mainly the elderly, and thoracoscopy was the most common diagnostic procedure. os did not differ between australian major city and regional patients and was comparable to the largest phase iii trial in mpm. aw musk , , p aboagye-scarfo , a reid , a miller, s ruwanpura, l mcleod, p bardin, n watkins, bj jenkins rationale lung cancer is the leading cause of cancer death worldwide. it is well established that cigarette smoking is linked to emphysema and lung cancer, and smokers with emphysema are at an increased risk of developing lung cancer. notably, recent epidemiological studies have indicated that emphysema can predispose to lung cancer irrespective of pack-year smoking history. although infl ammation has been proposed as a common mechanism linking these two diametrically opposed diseases, the conceptual inter-relationship between infl ammation, emphysema and lung cancer has been poorly investigated because existing experimentally induced and genetically modifi ed animal models for lung cancer occur in the absence of emphysema. method we have utilized a newly identifi ed mouse model (gp f/f ) of spontaneous lung infl ammation and emphysema in two well-established lung cancer models. the gp f/f mouse is characterized by deregulated cytokine signalling via gp , the critical co-receptor for the interleukin (il)- cytokine family, leading to hyper-activation of stat , a potent pro-infl ammatory and oncogenic latent transcription factor. in separate studies, we exposed gp f/f mice to a cigarette-derived carcinogen (nnk), and crossed them with the genetically susceptible kras(g d) strain of mice. results in both nnk-and kras(g d)-induced lung cancer models, the lungs of gp f/f mice were highly predisposed to hyperplasia and tumour formation. increased levels of cellular proliferation were observed in hyperplastic and tumour lesions, as well as surrounding areas, of these mice. these observations were verifi ed at the molecular level by gene expression profi ling of tumour-bearing lung tissue. conclusions these studies provide unique insights into the importance of interactions between the gp signalling axis and factors that predispose to lung tumourigenesis in emphysema. support nhmrc. aim to assess the preparedness of hospitals with respect to protecting health-care workers (hcws) during a pandemic. methods a self-administered questionnaire was performed between november and january , and a scoring system was developed to provide a quantifi able measure of preparedness. results a total of hospitals in nsw, australia, were approached -six regional hospitals (rhs) and six tertiary referral centres (trcs). the study was extended to assess three hospitals in england, allowing a limited comparison between the hospitals in australia that had faced the initial wave of the h n ('swine fl u') pandemic and the hospitals in the uk that had more time to prepare for the outbreak. response rates were % from the trcs, % from the rhs and % from the english hospitals. the overall preparedness scores were relatively high, with a median total score (adjusted) of . out of . the demographic that scored the highest total was tertiary referral centres in sydney. all english hospitals scored below the median. however, the range of scores across hospitals was quite narrow ( . - . adjusted). scores were generally high for the areas of preparedness, infection control, education and training. scores for vaccination were more variable. the category that consistently demonstrated the lowest scores was that of psychosocial welfare and assistance, despite this found in previous research to be an integral part of that which hcws have identifi ed as important. conclusions given their integral role in pandemic response, protecting hcws must be a priority as part of any pandemic preparedness plan. this goes beyond protection from infection, extending into aspects of physical and psychological wellbeing. identifying these issues and addressing them is the key to maximizing staff support and morale, and minimizing staff absenteeism at such a crucial time. aim to describe the relationship of respiratory and refl ux symptoms within the general population and relate this to the possible confounding factors of body mass index (bmi) and obstructive sleep apnoea (osa). methods data from a cross-sectional health survey, performed in bussleton, west australia in - , were used to examine the relative effects of bmi and osa on the relationship between respiratory and refl ux symptoms. questionnaire data included information on asthma, cough, wheeze, dyspnoea and gord symptoms. gord symptoms were categorized as never, monthly or less often and weekly or more often. bmi, risk of osa defi ned according to the berlin questionnaire, spirometry and airway hyperresponsiveness to methacholine were also recorded. logistic regression models obtained odds ratios for the associations between each gord symptoms, various respiratory symptoms, bmi and osa. results average age was years and recent wheeze was reported in % and cough and phlegm in %. twelve percent were current smokers. ahr was present in % and osa in %. gord symptoms occured in % and frequent symptoms (weekly or more often) were present in - %. there were strong positive associations between gord symptoms and cough/phlegm, breathlessness, chest tightness and wheeze in the last months. odds ratios increased with increasing frequency of refl ux p ≤ . . there was no effect of obesity or osa on the relationship between respiratory and gord. conclusion cough and phlegm, breathlessness, chest tightness and wheeze (ever or recent) are all strongly associated with symptoms of gord. this relationship is amplifi ed with increasing frequency of gord symptoms indicating a dose-response relationship between refl ux and respiratory symptoms. obesity and osa do not affect the association between gord and respiratory symptoms. introduction diesel exhaust particles (dep) make up the bulk of particulate matter in urban areas. high ambient levels of particulate matter are associated with increased hospitalization due to respiratory disease. we aimed to determine if exposure to dep exacerbates responses to acute viral infection. methods adult female balb/c mice were inoculated with μg dep or control . days after infection with . plaque forming units (pfu) of infl uenza a/mem (or control). six hours after dep inoculation, lung volume (tgv) and lung mechanics were measured by plethysmography and the forced oscillation technique, respectively. bronchoalveolar lavage fl uid was collected to assess cellular infl ammation and cytokine levels. results viral titre was signifi cantly higher in infl uenza-infected mice exposed to dep compared to those exposed to infl uenza alone (p = . ). both dep (p = . ) and infl uenza infection (p < . ) alone signifi cantly increased cellular infl ammation; however, there was no difference between mice exposed to both dep and infl uenza compared to those exposed to infl uenza alone (p = . ). a similar pattern was found in levels of cytokines in the bronchoalveolar lavage (tnf-α, mcp- , il- , ifn-γ). specifi c airway resistance, specifi c tissue damping, specifi c tissue elastance and hysteresivity were signifi cantly increased in infl uenza infected mice (p < . in all cases). none of these parameters were infl uenced by dep exposure alone (p > . in all cases) and there was no additive effect of dep on lung function (p > . in all cases) in infl uenza-infected mice. conclusions dep increases viral titre but is not suffi cient to physiologically exacerbate pre-existing respiratory disease caused by infl uenza infection in mice. supported by nhmrc. confl ict of interest no. introduction lack of treatments for post-transplant obliterative bronchiolitis (ob) is mainly due to the poor understanding of its pathogenesis and lack of small airway models. epithelial-mesenchymal transition (emt) may play a central role and could be crucial to developing treatment drugs. we hypothesize that emt induction may be prevented by pharmacologically available compounds. methods primary cultures of small and large airway epithelial cells (saec and laec) were established and emt induced by adding tgfβ ( ng/ml) (n = ). azithromycin ( - μm), mycophenolate ( . - mg/l) and rad ( . - ng/l) were then added and expression of epithelial (zo- , ck- ) and mesenchymal markers (eda-fn, vim) measured via western blot as well as mmp and activity via zymography. results signifi cantly lower increase in mesenchymal markers and lower decrease in epithelial markers, compared to controls was noted for azithromycin and mycophenolate indicating suppression of emt. mmp and activity increase was also signifi cantly suppressed. azithromycin suppressed emt to a greater extent compared to mycophenolate, but was equally effective in both small and large airway epithelia. rad appeared to have no effect. conclusions azithromycin and mycophenolate are both effective in preventing emt and thus have potential for the clinical treatment of ob. supported by abn foundation. confl ict of interest none. journal compilation © asian pacifi c society of respirology tp- g hodge , , s hodge , , c-l liew , , t-cell pro-infl ammatory cytokines are associated with acute lung transplant rejection. we have previously shown compartmentalization of production of these cytokines in bronchial intraepithelial t cells (iet) obtained by bronchial brushings from stable lung transplant patients. during acute rejection episodes, no signifi cant differences in iet cytokines were observed between stable and rejecting patients due to broad cytokine variability between patient groups. to overcome this limitation, we hypothesized that there would be increased graft pro-infl ammatory iet cytokines compared with native lung or trachea during acute rejection. methods cell cultures from stable patients, patients with evidence of acute rejection and bos and healthy controls were stimulated and intracellular cytokines determined using multiparameter fl ow cytometry. results there was a signifi cant increase in graft iet-cell ifnγ and tnfα in the lungs of patients with acute rejection compared with iet cells obtained from the native lung or trachea, but no changes were noted between other patient groups. there was a signifi cant correlation between increased graft iet-cell tnfα compared with trachea and lungs and acute rejection grade. conclusions differential expression of pro-infl ammatory cytokines by iet cells from graft, trachea or native lung distinguishes severity of acute rejection. improved monitoring response using this assay or therapeutic targeting of these pro-infl ammatory cytokines may reduce acute lung transplant rejection. supported by nhmrc. aim to determine the prevalence of reduced carbon monoxide transfer factor (dlco ≤ % predicted) in subjects undergoing pulmonary function testing (pfts) and to determine whether a cause has been identifi ed. methods a clinical audit of all subjects undergoing pfts at royal melbourne hospital from august to august who have a dlco ≤ % in the setting of normal spirometry. medical records and investigations including transthoracic echocardiogram (tte), high-resolution commuted tomography (hrct), ventilation/perfusion (v/q) scans were reviewed to determine whether a cause for the reduced dlco was established. where a cause was not clear, subjects were invited to participate in a telephone interview to evaluate symptoms and to undergo repeat pfts. subjects with a persistently reduced dlco were invited to undergo further investigation with tte, hrct and v/q scan. preliminary results pft results from subjects were reviewed. subjects with fev /fvc < , fev < % predicted and fvc < % predicted were excluded. three hundred seventy subjects ( %) had an isolated reduction in dlco. / ( %) of these subjects underwent tte with / ( %) demonstrating an elevated right ventricular systolic pressure (rvsp). in all cases where there was an elevated rvsp an identifi able cause was found. / ( %) of these subjects subsequently identifi ed as having pulmonary arterial hypertension (pah) and commenced appropriate therapy and / ( %) identifi ed as having pah where treatment was not commenced. there were / ( %) of subjects who appeared not to have undergone a tte. further evaluation of medical records of subjects who had not undergone tte and those with normal tte is continuing. review of subjects hrct, v/q scans and right heart catheterizations is currently proceeding. conclusions preliminary results suggest that a signifi cant proportion of subjects with isolated reduction of dlco on pfts do not undergo tte which is an important investigation in determining the cause for the reduced dlco. when a tte is performed and demonstrates an elevated rvsp, a cause for the elevated rvsp is identifi ed. sponsor actelion pharmaceuticals australia pty ltd. g hodge , , s hodge , , c-l liew , , , pn reynolds , , m holmes , , background t-cell pro-infl ammatory mediators are associated with acute lung transplant rejection. we have previously shown that bos was associated with lack of immunosuppression of t-cell pro-infl ammatory cytokines and increased t-cell granzyme b in peripheral blood. recently, we also showed that nkt-like cells are a major source of pro-infl ammatory cytokines and granzymes in the blood of stable lung transplant patients. we hypothesized that bos may be associated with lack of immunosuppression of these proinfl ammatory mediators in blood nk and nkt-like cells. method granzyme/perforin profi les from stable patients, patients with evidence of bos and healthy controls were determined and blood cultures stimulated and intracellular cytokines determined using multiparameter fl ow cytometry. results there was a signifi cant increase in the percentage of nk cells expressing granzymes and perforin in bos patients compared with stable patients and controls. there was an increase in the percentage of t, nk and nkt-like cells producing ifnγ and tnfα in bos compared with stable patients. there was a signifi cant correlation between increased nk ifnγ and tnfα and fev . conclusions bos is associated with increased peripheral blood nkt-like and nk cell granzymes, perforin and th pro-infl ammatory cytokines. therapeutic targeting of these pro-infl ammatory mediators and monitoring response using this assay may reduce bos. supported by nhmrc. confl ict of interest nil. rationale pulmonary embolism (pe) is the leading cause of maternal mortality in the developed world. consequently accurate diagnosis of pe is critical. this must be tempered by the potential radiation risk of investigations to the mother and foetus. we performed a retrospective case review to determine the incidence of pe in pregnant patients investigated for this condition. demographic information, the diagnostic algorithm utilized and the diagnostic yield of investigations were obtained. method pregnant women who underwent ventilation perfusion (vq) scanning or computed tomography pulmonary angiogram (ctpa) at our institution between january and january were identifi ed by an internal database audit. in addition to demographic data, information about the diagnostic pathway and fi nal diagnosis were collected. in cases where pe was not diagnosed, the medical records were reviewed for any subsequent events up until the date of delivery. results during the fi ve-year period, vq scans and ctpas were performed on pregnant women. the average gestation at investigation was weeks. only one patient had a previous history of venous thrombo-embolism. % underwent doppler ultrasound of the lower limbs prior to vq or ctpa. overall the incidence of pe was %, diagnosed by vq scan. otherwise the vq scans were normal in %, low probability in % and non-diagnostic in % cases. ctpa was non-diagnostic in % of cases. all other ctpa studies demonstrated no emboli. almost % of scans were done after hours ( % vq and % ctpa). no patients without pe were felt to have had the pe missed up to the time of delivery. conclusions the overall incidence of pe in patients being investigated was extremely low at %. during this study period slightly more vq studies were performed than ctpas, with each test having similar diagnostic rates. only % of patients had undergone venous doppler prior to undergoing radiationexposing investigations. nomination nil. introduction anti-ro- antibodies have been associated with idiopathic interstitial pneumonia (iip) in one small series (n = ). we hypothesize that ro- antibodies, just like myositis antibodies, can serve as a marker of undifferentiated connective tissue disease (ctd) with interstitial pneumonia as the primary phenotypic manifestation. the aim of this study was to examine the characteristics of patients with ro- and iip. methods retrospective study identifying patients with iip and ro- positivity, but negative for ctd and/or myositis antibodies, presenting between june and june . data relating to demographics, diagnosis, pulmonary function tests, length of follow-up and outcome were obtained. all hrct images were reviewed by an independent expert radiologist (dm). results / ro- positive subjects fulfi lled criteria ( male, median age ( - ), european, never smoked). / had ro- titers above and in the intermediate ( - ) range. three patients had raynauds phenomenon; there were no other ctd features. / patients had hrct diagnosis of nsip and / organizing pneumonia; / had extensive fi brosis. mean (sd) % predicted baseline fvc ( ), dlco ( ). median length of follow-up was months. all patients were treated and were considered overall stable at last follow-up, one had declined and one died of respiratory failure. conclusion this study confi rms an association between ro- positivity and interstitial pneumonia in the absence of defi ned connective tissue disease, suggesting an autoimmune basis for the interstitial lung disease in this group of patients. a larger cohort is required to determine the true signifi cance of this observation. background community acquired respiratory viral (carv) infections are believed to contribute to morbidity and mortality after lung transplantation, but previous studies have not conclusively established the evidence base in this area. patients and methods a prospective cohort study was performed at a single centre from august to march (n = lung transplant recipients). carv infection (human metapneumovirus (hmpv), respiratory syncytial virus (rsv), infl uenza a (flu a), infl uenza b (flu b), adenovirus and parainfl uenza virus (piv)) was confi rmed using polymerase chain reaction (pcr) of upper (nasopharangeal swab) and/or lower (bronchoalveolar lavage) respiratory tract secretions. carv infection and bos were included as segmented time-dependent covariates in a cox proportional hazards model with death as the outcome variable. results patients ( % of the total cohort) had a total of separate carv episodes: piv, hmpv, rsv, flu a, flu b, and adenovirus. infection with either rsv or hmpv was associated with an increased risk of death (p < . hr . , % confi dence interval, . - . ), and the effect persisted after multivariate analysis. bos was also a risk factor for acquiring hmpv or rsv infection (p = . or . , % confi dence interval, . - . ). conclusions infections with hmpv and rsv, but not other carvs, are associated with an increased likelihood of death. the presence of bos is a risk factor for symptomatic infection with hmpv and rsv. ns harun , k sanders , a stuart , cl steinfort department of respiratory medicine, barwon health, vic., australia, and department of clinical and biomedical sciences, barwon health, vic., australia aims nebulized colistin is used to treat recurrent exacerbations of bronchiectasis due to pseudomonas aeruginosa, a major pathogen regarded as diffi cult to eradicate. this case-control study aimed to establish if long-term colistin use could clear p. aeruginosa from the sputum of adults with non-cystic fi brosis bronchiectasis, and if so, whether colistin could be ceased in these patients. secondary outcomes included effects of colistin on quality of life (qol), symptom control, admission rates, lung function and tolerability. methods ( ) sputum was collected in bronchiectasis patients with p. aeruginosa. clearance rates in those on colistin were compared with a control group not on colistin. ( ) colistin patients cleared of p. aeruginosa ceased treatment. sputum was re-cultured at day and to detect recurrence. ( ) a questionnaire assessing qol, symptom control, and admission rates was performed on patients. outcomes were compared before and after colistin use. long-term colistin side-effects and lung function were also assessed. results ( ) % (n = / ) of colistin patients cleared p. aeruginosa from sputum compared with % (n = / ) in the controls (p = . ). ( ) % (n = / ) of patients ceasing colistin remained free of p. aeruginosa at day . ( ) there was no difference in frequency of breathlessness, sputum production or qol scores between the groups (p > . ). the colistin group had lower fvc ( . vs. . l, p = . ) and higher admission rates ( % vs. %, p = . ). on colistin, % of patients reported reduction in sputum frequency, breathlessness and improvement in qol. fifty percent reported decreased admission rates. there were no colistin side effects. conclusions clearance of p. aeruginosa in sputum is possible. clearance rates were similar in those with more severe bronchiectasis treated with colistin compared with stable patients not on colistin, and may suggest suppression of p. aeruginosa by colistin in this severe group. there are benefi ts of colistin on qol, symptom control and admission rates. continued sputum clearance after colistin cessation is achievable in some patients. nebulized colistin use is well tolerated. nomination janet elder travel award. confl ict of interest no. however, use of such agents is suboptimal in hospital patients. this study aims to determine whether a dedicated multidisciplinary education and reinforcement program improves the use of appropriate vte prophylaxis. methods prior to the education programme, we audited a bed general thoracic medical ward including patients with general medical conditions, lung cancer, chronic obstructive pulmonary disease, lung transplant and cystic fibrosis. our multidisciplinary research team developed and implemented an education program over months, using posters, leafl ets and oral presentations to increase awareness and promote adherence to vte prophylaxis guidelines for health care staff involved in direct patient management. following completion of the program, we reaudited the same bed ward. results prior to the education program, a total of patients (mean age ± ) were identifi ed as appropriate for vte prophylaxis. of these ( %) were on appropriate vte prophylaxis. the post education audit showed out of ( %) patients were on appropriate vte prophylaxis. (p = . ). conclusion an effective multi-faceted educational program can improve delivery of appropriate vte prophylaxis, leading to improved outcomes in hospitalized patients. supported by sanofi aventis. confl ict of interest nil. the anti-rheumatic anti-infl ammatory biological agents in clinical use are abatacept, anakinra, adalimumab, etanercept, infl iximab and rituximab. a variety of pulmonary side-effects have recently been reported for these agents and the purpose of this review is to compile the various reported pulmonary toxicities and their prevalence methods we performed a search of databases ovid medline® and embase of the english literature up to august using the mesh terms of abatacept, anakinra, rituximab, adalimumab, etanercept, infl iximab and respiratory tract disease with limits to include only human studies or case reports. in addition case reports of respiratory adverse effects reported to the australian drug reaction advisory committee (adrac) were obtained in order to identify the most common pulmonary reactions reported with each individual agent. results using the search criteria defi ned above and articles were identifi ed in the ovid medline and embase database respectively. the majority of adrac reports were associated with rituximab (n = ) and infliximab (n = ), followed by adalimumab (n = ) and etanercept (n = ). various pulmonary side-effects including interstitial lung disease associated with anti-infl ammatory agents were identifi ed. discussion from the articles reviewed, details about the duration between onset of treatment and incidence of pulmonary side effects, diagnosis, treatment options and outcome of patients were extracted and are presented here. conclusion this comprehensive systematic review hopes to improve the awareness about the serious and potentially life-threatening pulmonary sideeffects of this group of agents. confl ict of interest no. sj simpson , pd sly , p franklin , e lombardi , c calogero , m palumbo , gl hall , introduction the forced oscillation technique (fot) is effort independent and thus ideal for young children. the area under the reactance curve (ax) has been proposed to amplify clinically relevant signal by taking advantage of any shape change in the reactance (xrs) curve below the resonant frequency. this study aimed to develop reference values for resistance (rrs), xrs and ax in a large healthy population of children, and determine if ax conferred any additional clinical benefi t when examining disease in children born preterm. methods impedance spectra were obtained in healthy children ( male), aged less than years and with height less than cm using a commercial device (i m, chess medical, belgium). ax was calculated in of these children between hz and the resonant frequency. backwards stepwise linear regressions identifi ed the best predictors of ax, and xrs and rrs at hz (xrs , rrs ), and z scores were generated. z scores were calculated for children born preterm, of which received a neonatal diagnosis of bronchopulmonary dysplasia (bpd). chi squared tests examined the difference in proportion of children born preterm (with and without bpd) with abnormal z scores for each fot variable. results all fot variables were predicted by height (p < . ) and sex. mean (sd) z scores for preterm children with and without bpd for rrs ( . ( . ); . ( . )), xrs ( . ( . ); . ( . )) and ax ( . ( . ); . ( . )) were all signifi cantly different (p < . ) from the healthy population. the number of children born preterm with abnormal z scores was not significantly different when comparing ax, rrs and xrs . conclusions while ax is able to detect respiratory disease in preterm children with and without bpd, it is no more sensitive than xrs or rrs. supported by pmh foundation, nhmrc, asthma foundation wa, carivit, ngo 'solidarietà e servizio' viterbo. confl ict of interest no. introduction survivors of preterm birth born with bronchopulmonary dysplasia (bpd) in the pre-surfactant era of neonatal care (classical bpd) have a reduced pulmonary gas transfer capacity. there is, however, little data to describe gas transfer in preterm infants with bpd in the post-surfactant era (new bpd). objective assess gas transfer using carbon monoxide diffusing capacity (dl co ) and its components, pulmonary capillary blood volume (vc) and pulmonary membrane diffusion (d m ), in contemporary survivors of preterm birth. method gas transfer was assessed using single-breath dl co in children aged to years and born < weeks gestation with bpd (pb, n = ) and without bpd (pt, n = ), and in term born controls (tc, n = ). dl co z scores were calculated. d m and vc were determined in pb, pt and tc children. the mean (sd) dl co z score for the pb group was − . ( . ) differing signifi cantly from (p = . ) while the pt and tc groups ( . ( . ) and − . ( . ), respectively) did not (p > . ). d m was lower in the pb group than the pt and tc groups, with no difference between pt and tc groups. differences in d m were not signifi cant after adjusting for lung size. there were no differences in vc between groups. conclusion gas transfer is reduced in survivors of preterm birth with new bpd. the tendency for reduced d m and not vc in children with new bpd suggests that impaired gas transfer may be a result of alterations in the alveolar membrane rather than pulmonary vascular function. background bronchiectasis is common in indigenous populations such as alaska natives, australian aboriginal, and new zealand maori and pacifi ca. as part of an international collaborative interventional study, we sought the participation of maori and pacifi ca families -groups diffi cult to engage in research in the past. aim to engage, enrol and retain children from maori and pacifi ca families from auckland in a -year research study. methods a randomized controlled trial to determine whether azithromycin is superior to placebo in reducing exacerbations seeking to enrol children aged months to years with bronchiectasis. the enrolment procedure was modifi ed to a process deemed more appropriate to these cultures: ( ) request to defer the decision of enrolment until the process had been completed. ( ) a minimum of meetings; initial invitation, discussion in the home with the extended family, invitation to the extended family to participate in the day of enrolment. ( ) appointment of a 'whanau worker' (family worker) to sit with the family and empower them to get all the information they seek prior to enrolment. results of families approached, ( %) children (median age . years, range . - . years) enrolled with % samoan, % tongan, % maori and % mixed maori/pacifi ca heritage. after -year retention was ( %) with exiting the study after month with new non-pulmonary disease, and exiting after year, moving outside study area. conclusions these are high enrolment and retention fi gures reported in this population. we believe that following a prolonged procedure for enrolment, involving the extended family and appointing a worker to sit 'alongside' the family will improve their understanding of a research project and allow them to feel more comfortable about participating. aim bronchiolitis is the most common reason for hospital admission for infants globally ( ) . the use of macrolides for treating bronchiolitis in nonaffl uent settings remains controversial but potentially benefi cial. in our region readmission with lower respiratory illness in young children (particularly indigenous children) remains high. this rct aims to determine if a single dose of azithromycin reduces the morbidity of young children with bronchiolitis. methods double blinded rct. young children ≤ months admitted to royal darwin hospital (rdh) diagnosed with bronchiolitis are eligible. children are given a single dose ( mg/kg) of either azithromycin/placebo. primary outcome is length of stay for respiratory disease. secondary outcomes are duration of oxygen use and readmission for respiratory illness in -month period. respiratory viral infections often lead to exacerbations of chronic respiratory diseases such as asthma and copd though there is no similar data in noncystic fi brosis (cf) bronchiectasis. the objectives of our study were to ( ) determine the point prevalence and identify viruses associated with exacerbations and ( ) evaluate clinical and investigational differences between viral infection positive and negative exacerbations in children with non-cf bronchiectasis. methods a cohort of children (median age years; boys) with non-cf bronchiectasis was prospectively followed for child-months. polymerase chain reaction for respiratory viruses was performed on nasopharyngeal aspirates collected during paediatric pulmonologist defi ned exacerbations. data on clinical, parent cough-specifi c quality of life (pc-qol), systemic markers (crp, il , procalcitonin, amyloid-a, fi brinogen) and lung function parameters were also collected. results respiratory viruses were detected during ( %) exacerbations: picornavirus in episodes [human-rhinovirus (hrv) in , enterovirus in ]; human bocavirus in ; adenovirus, human meta-pneumovirus, infl uenza a, respiratory syncytial virus, parainfl uenza and in two each; coronavirus and parainfl uenza and in one each. viral co-detections occurred in ( %) exacerbations. among genotyped hrv's, more hrv-a's (n = ) were identifi ed than hrv-c's (n = ). children with proven viral infections were more likely to have fever (or . , % ci . - . ), wheeze and/or crackles (or . , % ci . - . ) and raised crp (or . , % ci . - . ) when compared with virus negative exacerbations. there were no other statistically signifi cant differences. conclusions respiratory viruses are commonly found during pulmonary exacerbations in children with non-cf bronchiectasis. hrv-a is the most frequently detected virus. time sequenced cohort studies during stable state, exacerbations and recovery periods are needed to determine the importance of viral infections and their possible interaction with bacteria. supported by anz trustees scholarship. confl ict of interest none. nominations none. to date children enrolled, % rsv+ve. median age . months. fifty percent have had at least one co-morbidity. readmission rate = %. conclusion co-morbidities are high in this population. antibiotics have the potential to help reduce the impact of additional respiratory burden. foundation. introduction foreign body inhalation is a relatively common presentation in young children, especially less than years of age. early recognition remains a critical factor in the treatment of foreign body inhalation in children. inhaled foreign bodies in children are most often organic material, with seeds and peanuts being the most common items. on review of the literature, there are very few case reports of inhaled metal screws. we report two unusual cases of inhaled metal screws that presented to our service. case presentation both cases presented to our emergency department with wheeze, respiratory distress and fever. foreign body inhalation was not considered as a cause for their symptoms until the object was identifi ed on chest x-ray. both foreign bodies were removed successfully but one child required invasive ventilation in our intensive care unit post removal. both children made a full recovery. interestingly, both metal screws came from fl at pack furniture purchased from a well known international home products store. conclusion foreign body inhalation must always be considered as a cause of respiratory distress in a child. with the increase in the number of fl at pack furniture in australian home's, we believe parents must be warned of the potential danger of loose metal screws to young children. supported by none. cough in children is a common symptom. data on causes of chronic cough in young children have previously been published by our units. however, differences in underlying diagnosis by age at presentation have not been assessed. we present the 'time to cessation' of cough in our multicentre rct using a standardized management algorithm in newly referred children with chronic cough (> weeks) from australian centres. methods parents completed validated cough diary and cough specifi c qol (pc-qol) at recruitment and at cessation of cough. the diagnosis made by the treating physician was based on tsanz position statement. results the median (range) age of the children recruited was . years ( . - . ); ( %) were boys. median (iqr) pc-qol post treatment of . ( . , . ) improved signifi cantly (p = . ) from . ( . , . ) at enrolment. the median (iqr) duration of cough at recruitment was weeks ( . , . ) and 'time to cessation' of cough after application of the management algorithm was weeks ( . , . ). there was no signifi cant difference (p = . ) in median (iqr) 'time to cessation' of cough among the three age cohorts: < years (n = , . %) was . weeks ( . , . ); - years (n = , . %) was weeks ( . , . ); and > years (n = , . %) was weeks ( . , . ). there was also no signifi cant difference in the fi nal primary diagnosis among the three age cohorts (p = . ). the most common diagnoses were protracted bacterial bronchitis (n = , %), asthma/reactive airways disease (n = , . %), tracheobronchomalacia (n = , . %) and bronchiectasis (n = , . %). children ( . %) had more than one diagnosis. conclusions the aetiology and 'time to cessation' of chronic cough in children managed in accordance to a standardized pathway were similar among the three age groups. it is likely that our previous fi ndings in very young children are also applicable to older children. supported by nhmrc grant number . confl ict of interest none. aim to determine the role of fl exible bronchoscopy with bronchial alveolar lavage (bal) in the management of patients with febrile neutropenia. methods a retrospective analysis was made of the number of patients admitted with febrile neutropenia at a single institution who underwent bronchoscopy plus bal from years to . computer database plus patient case notes were reviewed to establish clinical symptoms and signs, radiological fi ndings, antimicrobial treatment and mean duration to bronchoscopy following admission. results a total of episodes of febrile neutropenia were recorded years to . seven patients ( males and females) were referred for bronchoscopy plus bal. the mean age was . years (age range - years) and all had been diagnosed with acute lymphoblastic leukemia. all patients had at least cough as a clinical symptom along with radiological fi ndings. all patients had been on broad spectrum antibiotics at the time of bronchoscopy. the mean duration from admission to time of bronchoscopy was hours ( days) with a standard deviation of hours. of the seven patients one patient yielded a positive result on bal. this did not result in a change in management as the patient improved clinically before the result of the bal was confi rmed. conclusion in this retrospective case series the diagnostic yield of fl exible bronchoscopy plus bal in children with febrile neutropenia was low. prospective studies plus early timing towards bronchoscopy and bal should be conducted to further defi ne its role in the management of febrile neutropenic patients. confl ict of interest nil. methods prospective cohort study involving monthly follow-up with caregivers. two years post enrolment, children undergo clinical and lung function assessment (fot). presence of bronchiectasis is determined by physician review and radiological confi rmation (when indicated). the frequency of pbb episodes is recorded over the study period. of children recruited to the cohort study to date, % ( / ) were male. the median age at recruitment was months (iqr , ). % of children had recurrent pbb. of the children who have had -year clinical follow-up, were able to perform fot and % ( / ) showed abnormalities (reactance above normal range.) % ( / ) with pbb have had subsequent physician diagnosis of bronchiectasis or csld. conclusion the burden of cough in children with pbb years after diagnosis remains high. ongoing clinical follow-up of this cohort of children with pbb should provide further insight into the likelihood of progression from pbb to csld and bronchiectasis. support financial markets foundation for children (for project), allen & hanburys and qcmri (for dw), nhmrc (for ju and ac). introduction national streptococcus pneumoniae (sp) serotype surveillance reports only culture positive cases from sterile sites but the yield from culture is low. polymerase chain reaction (pcr) is more sensitive in detecting sp in culture negative samples. aim to determine whether enhanced molecular surveillance in childhood empyema provides additional sp serotype information compared to national surveillance methods. methods pleural fl uid from children with empyema underwent culture and pcr to identify sp-targeting autolysin (lyta) and multiplex pcr to identify sp serotypes. national surveillance data were obtained from the national notifiable diseases surveillance system (nndss) for the same time period and age groups. results empyema: children, male, median age . (range . - . ) were recruited from april for months. sp was cultured in / ( . %) in blood and / ( . %) in pleural fl uid. sp was identifi ed by pcr in / ( . %). serotypes: , n = ( . %); , n = ( . %); a, n = ( . %); f a, n = ( . %); v/ a, n = ( . %); f/ a, n = ( . %); non-typeable, n = ( . %). one subject had serotypes and in a serotype could not be established. nndss: sp culture positive cases were reported. serotypes: , n = ( . %); , n = ( . %); a, n = ( . %); f a, n = ( . %); v/ a, n = ( . %); f/ a, n = ( . %); non-typeable, n = ( . %). other serotypes were reported in sp positive cases. signifi cant differences between empyema and nsdss data were identifi ed for serotypes (p < . ) and (p < . ). conclusions the proportion of serotypes and were signifi cantly higher in empyema fl uid using pcr. this disease model provides additional serotype information to national surveillance data. this has important implications in monitoring replacement serotypes following the introduction of new vaccines. funded by glaxosmithkline, belgium. h giddings , l seccombe , p rogers , a corbett , e veitch recent theories on the pathophysiology of parkinson's disease (pd) emphasize early brainstem involvement. furthermore various respiratory function abnormalities have been reported without consistent pattern. we sought to study the effects of idiopathic pd on respiratory function and ventilatory response to hypercapnoea and hypoxia. methods patients with a diagnosis of pd but no known respiratory disease were recruited. subjects underwent lung function testing including respiratory muscle strength, ventilatory response to hypercapnoea (with central respiratory drive (p )) and a hypoxic simulation (fio % cough is the most common symptom presenting to doctors. paediatric cough is associated with signifi cant morbidity for both children and their parents. the symptom of cough is associated with airway hyper-reactivity and is a dominant symptom of airway infl ammation. inhaled corticosteroids (ics) can reduce airway infl ammation and hyper-reactivity. the objective of this review was to evaluate evidence for the effi cacy of ics in reducing the severity of cough in children with sub-acute cough (defi ned as cough duration of - weeks). methods search was conducted by the cochrane airways group using cochrane methodology. all randomized controlled trials (rcts) comparing ics with a control group for treatment of sub-acute cough in children were considered for inclusion. search results were analysed using pre-determined criteria for inclusion. results two studies were eligible for inclusion in the review, however there were limitations in that the participants of both these studies were infants, post acute bronchiolitis illness, and cough duration at start of study treatment was ill-defi ned. children were included in the meta-analysis. there was no signifi cant difference between groups in proportion of children 'not cured' (primary outcome measure), with a pooled or of . ( % ci . , . ) (using intention to treat analysis). conclusions there is currently no evidence to support the use of ics in sub-acute cough in children. however, this systematic review is limited by the small number of studies available for analysis and the quality and design of these studies. further well-designed rcts are required to support or refute the effi cacy of treatment with ics in children with sub-acute cough. once obstructive sleep apnoea (osa) is diagnosed, a cpap implementation sleep study is traditionally performed to determine the pressure required to control the upper airway. however, since modern cpap machines store sophisticated control data we reasoned it may equally be possible to commence cpap via a 'best guess' iterative approach without compromising osa control or compliance. aim to compare the outcomes at months of patients commencing cpap after best guess with those commencing cpap after a cpap implementation sleep study. methods we retrospectively reviewed the records of all patients referred by respiratory physicians to our cpap clinic between march and march , and the two methods of starting cpap were compared. data collected included age, sex, bmi, respiratory disturbance index (rdi), cpap pressure commenced, fi nal pressure at months, cpap usage data and cpap clinic contacts. results patients were identifi ed, aged ± years, %male, bmi . ± . , with severe osa, rdi ± . commenced cpap via best guess and after a cpap sleep study. the starting pressures in both groups were similar, . ± . versus . ± . cmh o. in those patients continuing to use cpap at months, there were no differences between the groups for fi nal pressure, numbers of patients changing pressure, control of osa with cpap, and hours cpap used per day. in the best guess group however, signifi cantly more patients were continuing to use cpap at months, % versus % (p = . ). conclusion this study demonstrates that it may no longer be necessary to perform cpap implementation sleep studies routinely and this will save hospital bed days. confl ict of interest nil. six required intubation and the rest were managed with non-invasive ventilation in icu. the average length of stay in icu was . days. polysomnographic data will be described. conclusions obesity hypoventilation as a cause of respiratory failure is likely to increase in frequency as the incidence of obesity increases. increased awareness by the lay public, as well as clinical suspicion and recognition of the condition by all clinicians at an earlier stage, is likely to prevent progression to the point of needing intensive care. it is hoped that this case series may provide a springboard for further study into why these patients presented at such a late stage of their disease process. supported by none. confl ict of interest none. although sa and sleepiness often co-exist, the commonest cause of sleepiness in a general community is depression, with sa being the th most common cause. in order to assist recognition of depression in a snoring population attending a sleep clinic, we introduced a simple two question 'beyond blue questionnaire(bbq)' into our routine assessment. aims to ( ) background indices of ventilation distribution in diffusion (s acin ) and convection (s cond ) dependent airways derived from multiple breath nitrogen washout (mbnw) may vary between interpreters because of differences in calculation of phase iii slopes (Δphase iii ). aims to compare s cond and s acin results of interpreters from a single mbnw in copd subjects. methods subjects with copd underwent mbnw. three washouts were analysed independently by experienced and novice interpreters using custom software for automated breath identifi cation. Δphase iii was fi tted automatically by least squares fi t between predetermined points, and then adjusted manually. s cond was the linear slope of Δphase iii plotted against lung turnover (cumulative expired volume/frc), between turnovers . - . s acin was the Δphase iii of the fi rst breath minus the s cond component. differences expressed as icc and cov, were examined by repeated measures anova. results mean ± sd age was ± years. fev was ± % predicted. s cond was greater while s acin was lower from the experienced introduction β-blockers may cause bronchoconstriction and mask the effect of β -adrenergic agonists. this has implications for the interpretation of routine diagnostic spirometry and bronchodilator response. this study examined this issue in a routine lung function laboratory, and whether it applied to both cardio-selective (c) and non-selective (nc) preparations. method all patients attending the lung function laboratory, royal adelaide hospital over a -month period were asked whether they were currently taking a β-blocker and to identify the drug. spirometry results were analysed to assess airfl ow obstruction and reversibility. results patients completed the survey and patients ( %) were taking β -blockers. the table shows the results of the patients who could be assessed for reversibility in spirometry. of the patients in this group patients ( %) were taking (c) and ( %) (nc) agents. fifty-three patients were unsure whether they were taking a β -blocker. no signifi cant differences were found in the percentage of patients with airfl ow obstruction or reversibility between the groups. aim to examine patterns of adult lung function in terms of airfl ow obstruction, hyperinfl ation and/or reduced diffusing capacity (d l co). this can then be related to the life-time history of risk factors such as smoking, asthma and infections. methods using the population-based tasmanian longitudinal health study (tahs) cohort followed since , an asthma-enriched sub-sample was selected consisting of % ever with asthma, of whom half reported current asthma. measurement of spirometry, d l co (uncorrected for haemoglobin) and lung volumes was performed, then lung function data were analysed using the mean predicted values. airfl ow obstruction was defi ned as post-bronchodilator fev /fvc (post-b.d. fer) < . , hyperinfl ation as total lung capacity (tlc) > % predicted, and reduced d l co as < % predicted. aim to examine the gender-specifi c differences in adult spirometry, d l co and lung volumes, with a view to relating them to life-time respiratory risk factors. methods using the population-based tasmanian longitudinal health study (tahs) followed since , an asthma-enriched sub-sample was selected consisting of % ever with asthma, of whom half reported current asthma. measurement of spirometry, d l co (corrected for haemoglobin) and lung volumes were performed. data were analysed using the statistical upper and lower limits of normal of reference equations by nhanes iii, roca et al and quanjer et al. of the caucasian adults ( females), % completed all tests. mean age . years (range - ). elevated rates of airfl ow obstruction and hyperinfl ation were seen. signifi cantly higher proportions of females than males had reduced d l co and d l co/v a (p < . ). only . % (n = ) of females had a low d l co with low fev /fvc ratio, and . % (n = ) had a reduced tlc overall. there were no signifi cant gender differences in v a , tlc, or ever and current active smoking. males and females averaged over kg more than the mediterranean adults described by roca et al., however weight is not relevant to d l co in males. conclusion a higher percentage of middle aged females have a reduced d l co and/or d l co /v a, compared to males, with an increased rate overall. grant support nhmrc, australian postgraduate association. d chapman , , , j kermode , , , n brown , , , n berend , , , g king , , , background during bronchoconstriction, a deep inspiration (di) dilates the airways, which then re-narrow once tidal breathing is resumed. re-narrowing occurs faster in asthmatic subjects and may be due reduced airway distensibility. aim to determine the association between baseline airway distensibility and the rate of re-narrowing after di. methods eleven asthmatic and fi ve non-asthmatic subjects had baseline airway distensibility measured by forced oscillation technique (fot). after methacholine challenge, respiratory system resistance (rrs) was measured during min of tidal breathing, followed by di to total lung capacity (tlc) and passive return to normal tidal breathing. dilatation was measured as the decrease in rrs between end tidal inspiration and tlc, and re-narrowing as end-expiratory rrs immediately after di, as per cent rrs at end-tidal expiration before the di. distensibility is presented as geometric mean ± %ci and re-narrowing as mean ± % ci. results airway distensibility was reduced in asthmatic compared to healthy subjects ( . s − .cmh o − ( . - . ) vs. . s − .cmh o − ( . - . ), p = . ). dilatation did not differ between groups (p = . ) but re-narrowing was increased in asthmatic compared to healthy subjects ( ± % vs. ± %, p = . ). airway distensibility did not correlate with airway re-narrowing (r s = - . , p = . ). conclusion the increased re-narrowing after di in asthmatic subjects is not due to reduced baseline airway distensibility and may be due to increased shortening velocity of airway smooth muscle or reduced elastic recoil. supported by the nhmrc and the crc for asthma and airways. nomination nil. confl ict of interest no. c ng , , , s jenkins , , , n cecins , , p eastwood , , aim to evaluate the measurement properties of two accelerometers: the activpal and the stepwatch activity monitor (sam) in people with copd. methods the activpal and sam were attached to the anterior right midthigh and the right ankle, respectively (as per device recommendations). each participant performed walking tasks; at a self-selected slow speed and at a self-selected normal speed. at each speed, one walk was performed with a -wheeled walker (ww) and the other without. results participants aged ( ) years (fev = ( ) % pred; males) completed the study. the slow and normal speeds were ( ) m·min − and ( ) m·min − , respectively. agreement between steps recorded by the sam with steps counted during observation did not differ with speed or ww use (p = . ). the mean difference was steps·min − and the limit of agreement (loa) was steps·min − . agreement between steps recorded by the activpal with steps counted was worse at slow speeds (mean difference steps·min − with loa of steps·min − ) compared with normal speeds (mean difference steps·min − with loa of steps·min - ) (p = . ), but was not affected by ww use. both accelerometers detected the small difference in walk speed irrespective of ww use (p < . ). conclusions neither the accuracy nor responsiveness of either accelerometer was affected by ww use. in contrast to the activpal, sam was accurate at both speeds and therefore can be used to detect steps in people who walk very slowly during daily life. breathing and sleep, heidelberg vic., eastern health, melbourne vic., northern health, epping vic., and monash university, clayton vic. aim to document the care and pathways patients with copd travel at three metropolitan health services. methods data were extracted from data sets for patients attending the emergency department of the three hospitals with a diagnosis of copd over year. the three hospitals included a city-based tertiary/quaternary hospital and two smaller community hospitals. analysis was completed on similarities and differences in admission and referral rates, average length of stay, and discharge destination, standardized by age, sex and mode of transport to the emergency department. results there were inpatient separations and emergency department presentations for patients with copd. discharge patterns related to the designated role of the hospital, with the community hospitals discharging to % of patients directly home and the more specialized city hospital discharging % to other hospitals and % home. there were signifi cant differences in the admission rates for category and patients among the hospitals. we found unexplained variation in the acute average lengths of stay of . , . and . days. conclusions the analysis confi rmed some expected patterns based on the type of hospital, but also identifi ed unexplained variation that suggests that factors other than patient characteristics may be contributing to the variation in care pathways. aims to: ( ) determine which tests of exercise capacity relate to average daily energy expenditure (dee) and; ( ) quantify the intensity at which activities of daily living (adl) are undertaken in people with chronic obstructive pulmonary disease (copd). methods a study was undertaken in subjects with stable copd (mean, sd) aged ( ) years with an fev of ( ) % predicted ( males). measures were collected of distance walked during the six-minute walk test ( mwd) and incremental shuttle walk test (iswd) and peak rate of oxygen uptake during a cycle ergometry test (vo peak ). the sensewear armband® was worn during the waking hours for . ( . ) days to measure dee. the intensity at which activities of daily living were undertaken was expressed as a percentage of vo peak . results dee was associated with mwd (r = . ; p = . ), iswd (r = . ; p = . ) but not vo peak (r = . ; p = . ). stronger associations were observed between dee and the body weight-walking product for mwd (r = . ; p < . ) and iswd (r = . ; p < . ). the average intensity of adl was equal to ( %) of vo peak (range to %). conclusions mwd and iswd, but not vo peak were related to dee. as adl were performed at a high percentage of vo peak it may be more realistic to increase dee by increasing the frequency or duration, rather than the intensity of physical activity. in patients with copd, two mwts are recommended prior to commencing a pulmonary rehabilitation program (prp) to allow for a learning effect. aim to determine the characteristics of patients with copd in whom -minute walk distance ( mwd) did not increase on a second test. methods patients ( males) with stable copd (aged , to years) naïve to the mwt performed two tests ( minutes apart) prior to commencing a prp. patients were categorized according to their change in mwd with test repetition. results mwd was the same or decreased on the second test in patients ( %) (table) . in the remaining patients ( %), mwd increased by m ( %) ( % ci to m, to %). logistic regression analysis identifi ed fev (l) as the only signifi cant variable (p < . ) that predicted the absence of a learning effect in mwd with test repetition. conclusions some patients with severe copd may not require a practice mwt to achieve their maximum performance at a prp baseline assessment. ( ) years, with stable ipf were evaluated in this study. demographic data and measures of pulmonary function (spirometry, diffusing capacity for carbon monoxide, (dl co )), dyspnoea (baseline dyspnoea index, bdi), peripheral muscle force (isometric quadriceps force (qf) and handgrip force (hf)), functional exercise capacity ( -minute walk distance, mwd), limitation in daily activities (activities of daily living (adl) score), and health status (sf- ) were assessed. relationships between mwd and mrc grade, pulmonary function, qf, bdi and adl score were examined. results the number of subjects in mrc grades , , and was ( %), ( %), ( %) and ( %), respectively. pulmonary function, bdi, qf, hf, mwd, adl score, and sf- decreased signifi cantly with increasing mrc grade (all p < . ). moderate to strong correlations were found between mwd and mrc grade (r = − . ), dl co (r = . ), qf (r = . ), bdi (r = . ) and adl score (r = . ) (all p < . ). conclusions these fi ndings suggest that the mrc dyspnoea scale can be used to discriminate and classify subjects with ipf according to the severity of impairment and disability. ( ) year (mean, sd) completed two assessment sessions on separate days. on one day, they exercised twice to symptom limitation (tlim) on a treadmill. on the other day, they exercised twice to tlim on a cycle ergometer. the order of exercise modality was randomized between days. on both days, the only difference between the exercise tests was that bipap, titrated to patient comfort, was used during the second test. measures were made of; ) tlim and, ( ) the difference in dyspnoea, using borg scores, at tlim during the fi rst test and the equivalent exercise time during the second test (i.e. iso-time). results bipap increased tlim on the treadmill ( ( ) seconds; p = . ) but not the bike ( ( ) seconds; p = . ). the reduction in dyspnoea at iso-time on the treadmill and bike was similar being, ( ) and ( ), respectively (p = . ). conclusions bipap may confer greater benefi t in exercise tolerance exercising on a treadmill compared with a cycle ergometer in patients awaiting lung or heart-lung transplant. infection with rhinovirus (rv) is known to trigger acute exacerbations in subjects with asthma and these subjects also have increased susceptibility to the effects of rv. the mechanisms remain poorly understood, but appear to involve a host innate immune defect in the airway epithelium. aim we sought to determine in bronchial epithelial cells (becs) if oxidative stress in the form of exposure to cigarette smoke extract (cse), hydrogen peroxide (h o ) and eosinophil peroxidise (epo) results in impaired mitochondrial function and if this directly impairs signalling of rv infection through mda and alters the release of type i and type iii interferons (ifns). methods pbecs were grown to confl uence. cells were then exposed to cse ( %, no fi lter) or h o ( . mm) or epo. cells were then infected with rv -b (moi = ). virus replication was measured by cell titration assay. following infection, il- , cxcl- , cxcl- was measured using cytometric bead array and fl ow cytometry. supernatants and whole cell lysates were collected for ifn-β, bax and mda detection by western blot. ifn-λ and cytochrome-c was measured using conventional elisa. cell viability was assessed by annexin v-pe staining and fl ow cytometry. results rv infection alone induced cxcl- , il- , cxcl- and ifn-λ. pbecs treated with each of the oxidative stressors had increased cytochromec release and increased apoptosis. this mitochondrial dysfunction led to degradation of mda expression and resulted in specifi c suppression of cxcl- and ifn-λ. conclusions exposure of becs to an oxidative stress results in mitochondrial dysfunction in airway epithelial cells. this leads to defective antiviral signalling in the airway epithelium after infection with rv. introduction pleural infection is associated with high morbidity. prompt drainage is key, but pus is often loculated and thick making drainage diffi cult. based on promising animal studies, we hypothesize that intrapleural therapy with t-pa and dnase, which lyse adhesions and reduce fl uid viscosity respectively, can signifi cantly improve pus evacuation in pleural infection. methods consecutive patients with pleural infection were treated with standard antibiotics and intercostal chest tube (ict) drainage. additionally, t-pa mg and dnase mg (each in ml of . % nacl) were instilled intrapleurally via an ict twice daily for up to six doses. the ict was clamped for minutes after each instillation. patients were followed clinically and with serial cxr. opacity from pleural effusion was quantifi ed on chest radiographs. results eleven patients ( male; mean age ) were treated. nine effusions were associated with community acquired pneumonia, of these, eight were visibly purulent, fi ve were culture positive and the mean fl uid ph was . (range . - . ). ten patients ( %) were successfully managed conservatively and one patient required surgery. median hospital stay from fi rst intrapleural treatment dose to discharge was days (range - ). the median amount of fl uid drained in the hours preceding t-pa/dnase treatment was ml (range - ), and improved signifi cantly to ml (range - ) following two doses of treatment. this was paralleled by a signifi cant reduction in radiographic opacity by a mean value of % of the hemithorax (range - %). four patients showed an initial rise in crp following t-pa/dnase, but all patients had resolution of sepsis and signifi cant reduction in crp. there were no major complications. pleuritic chest pain requiring opioid analgesia developed in three patients. methods clinical data were collected using a standardized form for aboriginal children aged days -< months hospitalized with alri and enrolled in a rct of vitamin a/zinc supplementation were matched with data collected during a population-based study of who-defi ned primary endpoint pneumonia (who-p). sensitivities, specifi cities, positive and negative predictive values (ppv, npv) for these signs were compared between who-p cases and lobar pneumonia assigned by a respiratory paediatrician. in episodes of hospitalized alri, who-p was diagnosed in ( . %); the respiratory paediatrician classifi ed ( . %) as lobar pneumonia. the sensitivities of clinical signs ranged from a high of % for tachypnoea to % for fever + tachypnoea + chest-indrawing; the ppv range was % to %, respectively. higher ppvs were observed against the paediatric respiratory physicians diagnosis compared to who-p. conclusions clinical signs on admission are not useful in predicting who-p in this population, presenting challenges for future pneumonia research in this population. who-p may underestimate alveolar consolidation in a clinical context and its use in clinical practice or in research designed to inform clinical management in this population should be avoided. the incidence of tb in the non-indigenous australian population is uncommon at . cases per population . in this paper, we report three cases of pulmonary tuberculosis in young australian born, non-indigenous adults in the hunter new england area where marijuana possibly was a signifi cant risk factor in transmission and severity of disease. all three cases had severe cavitating disease at time of presentation. contact tracing from the fi rst case, a regular heavy marijuana user, identifi ed mantoux positive contacts, one of whom developed active pulmonary tuberculosis. all contacts, mainly young adult males, denied sharing marijuana with the index case. contact tracing from the second case identifi ed mantoux positive contacts, of whom use marijuana regularly and shared bongs (water pipes) with the index case. there were positive mantoux contacts of the third case, one of whom shared bongs with the index case. health professionals need to remain aware of the possibility of tuberculosis in groups with historically low incidence rates. marijuana bong smoking is possibly associated with transmission and severity of tuberculosis . introduction in , these previously well women survived and made a good recovery from severe pneumonia and acute lung injury after retrieval on ecmo. streptococcus pyogenes is an unusual cause of pneumonia in adults. case a -year-old veterinarian with a history of mild asthma presented with days of fever and respiratory symptoms. the diagnosis was confi rmed by a fourfold rise in the anti-streptococcal antibody. this was complicated by respiratory failure, septic shock, acute renal failure, severe pulmonary hypertension and bilateral parapneumonic effusions. despite maximal interventions she deteriorated. femoral venous-venous ecmo was initiated on day at the calvary mater hospital in newcastle by a retrieval team from royal prince alfred hospital (rpa), sydney. she was transferred kms on ecmo in a large multipurpose ambulance. she developed lung abscesses and recurrent pneumothoraces and she required a pleurodesis. she required days of ventilation and days of ecmo. three months later she was asymptomatic, with mildly restrictive spirometry and minor cxr change. case a -year-old offi ce worker with s pyogenes bacteraemia made a similar presentation to our institution. she was ventilated for days, ecmo was initiated by the retrieval team and continued for days. three months later she was asymptomatic with a normal cxr and pulmonary function tests. introduction the urinary pneumococcal antigen (upa) test has been shown to have superior sensitivity to other investigations in determining the aetiology of community-acquired pneumonia (cap), but there is very limited data on its performance in local populations. the aims of this study are to establish the prevalence of positive upa testing in patients admitted to hospital with cap, and determine its utility. secondary aims are to identify associations with positive testing, as well as to determine if a positive test infl uences clinical outcomes. methods the study is a prospective, single-centre study that is still recruiting. adult patients are included upon admission to hospital if they have the diagnosis of cap, as defi ned by new infi ltrates on chest radiograph along with consistent clinical features. clinical data including curb- score of severity, current and prior antibiotics, co-morbidities, mortality and length of hospital stay are recorded. results preliminary results show a positive test prevalence of / ( . %, % ci . - . %) amongst patients admitted with cap. overall prevalence of pneumococcal pneumonia is / ( . %, ci . - . %). patients with a positive upa result have a higher mean curb- score of . compared with . in those with a negative result (p = . ). . % of patients with a positive result were admitted to the intensive care unit, compared with . % those with a negative result (p = . ). conclusions the overall prevalence of positive upa testing in patients admitted to hospital with cap is low. preliminary data suggests that patients with positive results are more likely to have greater severity pneumonia and to require intensive care support. comparative data on length of stay, mortality, previous antibiotic use and specifi c co-morbidities has not revealed any statistically signifi cant differences between positive and negative groups. confl ict of interests no. s herath , c lewis , m nisbet , respiratory department, auckland city hospital, auckland, new zealand, and infectious diseases department, auckland city hospital, auckland, new zealand rhodococcus equi (r. equi), previously known as corynebacterium equi is a gram positive bacillus that is found in soil and causes infection in grazing livestock. it is infrequently isolated from clinical specimens. it is usually associated with human disease in immunocompromised patients and is an uncommon cause of infection in immunocompetent patients. infection is usually acquired by the airborne route with pneumonia being the most common manifestation but it can also be acquired orally or by direct inoculation. we present a case of pneumonia caused by r. equi infection in a year old male builder who presented with cough, dyspnoea and night sweats. r. equi was cultured from a transbronchial aspirate from a subcarinal lymph node. despite extensive investigation, no contributing host immune defect was identifi ed. the patient recovered after three months of antibiotic treatment, initially with intravenous vancomycin and meropenem followed by oral clarithromycin and rifampicin. although infections due to r. equi have been increasingly reported in immunocompromised patients, since there have only been cases described in patients where no associated host immune defect was reported. in this cohort, the median age at presentation was years (range - ) and ( %) patients were male. ten ( %) of these cases had pulmonary infection. two ( %) patients died and the remainder were successfully treated with prolonged antibiotics. r. equi is an uncommon cause of infection in humans and rarely occurs in patients where a host immune defect cannot be identifi ed. introduction recognition of pulmonary involvement in extra pulmonary tuberculosis (ep-tb) may be an important public health issue, as it has been estimated that patients with smear negative pulmonary tb (ptb) are responsible for % of new infections. usually, all patients with ep-tb have a chest x-ray but sputum cultures are requested only if there is an abnormality. methods in this retrospective clinical audit, we aimed to evaluate the percentage of ep-tb patients with ptb despite a normal chest x ray (cxr), and to explore any clinical characteristics of this group. clinical notes, microbiology and cxr reports were reviewed from consecutive patients presenting with ep-tb between and . results of patients with ep-tb, % were male and the mean age was (range to ). most patients were of asian ethnicity (n = , %). the commonest presentation of ep-tb was lymphadenopathy (n = , %), followed by pleural (n = %) and bone (n = , . %) disease. ep-tb was diagnosed by biopsy/excision of the ep site in the majority (n = , . %), and by sputum testing alone in ( . %). sputum cultures were performed in n = , ( %) overall, with n = ( %) being positive. there was higher infl ammatory markers in the sputum culture positive group (esr . vs. . , p = . and crp . vs. . , p = . ). the majority had cxr abnormalities (n = , %). in the group with normal cxr (n = ), ( %) had sputum cultures performed. of these, were culture positive and of these also + smear positive ( on immunosuppression, with cough). conclusion a small number of patients with ep-tb and normal cxr had pulmonary tb, of whom were smear positive. thus, induced sputum testing should be considered in patients with ep-tb even if cxr is normal. this may aid diagnosis and determine infectivity. ntm are normal inhabitants of environmental reservoirs including water. disease due to ntm has been increasing in qld. aim to document the presence of ntm in potable water in brisbane, to compare the species isolated during summer and winter and to relate this to the geographic distribution of patients with ntm. methods water samples ( l) were collected from routine collection sites in winter and sites in summer . samples were processed in triplicate as previously described. h subcultures were taken from positive specimens, dna extracted, followed by s rrna sequencing. patient addresses were obtained from the qld tb control centre database. aim to gauge the full impact of pandemic h n infl uenza across demographic groups in the northern territory, particularly indigenous and remoteliving individuals. methods we performed two cross-sectional serological surveys on specimens from residents of the northern territory, with specimens obtained from january to may (pre-pandemic) and specimens from september (post-pandemic). specimens were selected from among serum tubes collected from ambulatory outpatients. antibody titres were measured by haemagglutination inhibition against the a/california/ / reference virus. all specimens had available data for gender, age, and address, with indigenous status determined in . % of cases. results protective antibody levels, defi ned as a titre of or greater, were present in . % of pre-pandemic specimens and . % of post-pandemic specimens. the pre-pandemic proportion immune was greater with increasing age, but did not differ by other demographic characteristics. the post-pandemic proportion immune was greater among aboriginal and torres strait islanders and in younger age groups, but did not differ by gender or socio-economic index for area. however, the proportion immune was geographically heterogeneous, particularly among remote-living and indigenous groups. the northern territory-wide attack rate adjusted to age, region and indigenous status was . %. conclusions pandemic infl uenza disproportionately affected children and indigenous australians in the northern territory in . the proportion of specimens demonstrating post-pandemic immunity was particularly variable among indigenous and remote-living individuals. the kormp found asymptomatic aboriginal children (ac) had more hrv than asymptomatic non-aboriginal children (non-ac) in a longitudinal communitybased cohort study where infants had nasopharyngeal aspirates (npa) collected regularly from birth to years of age. aim to compare the frequency of hrv groups in asymptomatic ac and non-ac in the kormp. methods npa positive for hrv (n = ) from the npa previously tested for respiratory viruses, had viral rna extracted and reverse transcribed. hrv was detected and typed using a two-step pcr of the hrv ' utr, followed by dna sequencing for typing. chi-square analyses were used. results hrv was detected and typed in npa (from children; ac and non-ac), could not be typed and were not positive for hrv. ac had more hrv in summer and autumn than non-ac and were more likely to be co-infected with at least / bacterial species identifi ed. hrva, b & c were found in . , . and . % of hrv detected. hrvb & c were increased in infants exposed than not exposed to tobacco smoke in utero (hrvb; . vs. . %, p = . and hrvc; . vs. . %, p = . ). of the npa, hrv-a was detected more often in npa from ac than non-ac ( . vs. . %, p = . ), particularly at - months of age (p = . ) and during summer (p < . ). hrvb was detected more often in npa from ac than non-ac in autumn (p < . ). hrvc was detected as often in ac as non-ac in each season except summer. aim to determine whether interferon-gamma release assay (igra) can be effectively used for diagnosis of latent tuberculosis infection in a remote location. methods subjects were enrolled from the darwin centre for disease control tuberculosis clinic and were eligible if a tuberculin skin test (tst) of mm or greater had been recorded for any indication. igras were performed using quantiferon®-tb gold whole blood in-tube assay according to manufacturer's instructions. specimens were incubated and centrifuged at the local laboratory before refrigeration for transport. interferon assay was performed at the reference laboratory, over km away. results igras were performed, with patients ( %) recording negative results, ( %) positive and only one result ( %) indeterminate. negative, and therefore discordant, test results were more common in bcg vaccinated individuals. this effect was not limited to those with tst results of - mm, but was seen primarily in those with results of mm and above. conclusions these results are broadly comparable to fi ndings for igra use in less remote settings. in particular, our low rate of indeterminate results suggests that igra testing is feasible at a remote site after local processing. this approach could be considered for use in the northern territory tuberculosis control program. inhaled medications form the mainstay of drug treatment for patients with airways disease. effectiveness of therapy is dependent on the appropriate selection and prescription of drug and device, correct supply and adherence to therapy with an effective technique. patients frequently admit to acute medical wards both with acute exacerbations and for other co-morbidities eg heart failure or pneumonia. inpatient episodes provide an opportunity to review inhaled therapy however anecdotally add to patient confusion and introduce complexity (rational or ad hoc changes to inhaled drug, device, strength, dose or frequency). aim identify prescribing accuracy and effectiveness of patients' inhaler technique. describe any discrepancies between inhaled therapy: ( ) used prior to admission, ( ) prescribed for inpatient use, ( ) available at the bedside and ( ) administered, prior to and after implementation of an inhaler prescribing and administration guide. methods a single day audit of all inpatients on general medical wards was conducted october (review of medication charts and inhalers in patients' bedside lockers, brief questioning and direct observation of patients' inhaler technique. results compared to post implement of the 'prescribing and administering inhalers' tool (audit in december ). results from ( %) patients had inhalers prescribed, (mean: . prescriptions per patient). % of prescriptions were accurate ( % patient had no errors). discrepancies between used prior to admission and inpatient prescriptions were found in ( %) patients while those between inpatient prescriptions and available at the bedside were found in %. self-administration ('s') was noted on medication charts of ( %) patients, of whom had an ineffective inhaler technique. / patients has a spacer at the bedside with a further r prescribed metered aerosol inhalers. post-intervention differences in prescribing, supply, administration and technique errors will be discussed. conclusions a combination of errors and prescription discrepancies reduce the effectiveness of inhaled therapy for inpatients. confl ict of interest no. males (n (%) % ci) females (n (%) % ci) adm and bed days bmi, body mass index hrqol, health related quality of life chronic respiratory disease questionnaire; adm, admissions, mean (sd) uberculosis notifi cations in australia a cluster of tuberculosis associated with use of a marijuana water pipe the prince charles hospital foundation cc dobler , , gb marks , woolcock institute of medical research, the university of sydney, nsw, and department of respiratory medicine, liverpool hospital, sydney, nsw aim to determine the incidence rate and nature of adverse events in patients taking treatment for latent tuberculosis infection (ltbi). methods records of all patients who received treatment for ltbi at the chest clinic of a large tertiary hospital between / and / were reviewed. an adverse event was defi ned as any change in health status or side effect that led to treatment interruption or cessation. liver function tests were not performed routinely during follow-up, except when the patient was considered to be at an increased risk of developing hepatitis. results of patients in whom treatment for ltbi was initiated ( %) received isoniazid for months, ( %) received a combination of isoniazid and rifampicin for months, and the remainder were treated with different regimens. their mean (sd) age was ( ) years and % were male. nineteen patients ( . %) experienced an adverse event. seven patients developed a rash, four had lethargy and/or mood disorders, three had subclinical hepatitis, four experienced severe nausea, vomiting and/or other gastrointestinal symptoms and three had features of peripheral neuropathy. in eight patients who experienced an adverse event medication was temporarily ceased and then re-started without change; in four the treatment regimen was changed; and in seven the treatment was ceased completely. the risk of adverse events was not signifi cantly related to age, sex, drug regimen (single drug versus combination therapy) or baseline transaminase levels. conclusions in this cohort almost in patients on treatment for ltbi experienced an adverse event. although the adverse events were generally mild to moderate, this risk has to be taken into account when deciding whether to advise treatment for ltbi. introduction human rhinovirus (hrv) is the commonest cause of asthma exacerbations in children. pernasal aspirate (pna) is the gold standard for microbiological sampling but is invasive and distressing for children. studies have showed that less invasive swabs may be just as effi cacious. aim to test the hypothesis that hrv detection is as effi cient using nasal fl ocked swabs or washes and more comfortable, compared with pna in children with respiratory illnesses. methods children were recruited on presentation to the emergency department with respiratory symptoms. pna was collected from one nostril of all children recruited and nasal fl ocked swab (n = ) or wash (n = ) collected from the other nostril alternately. subjects rated the comfort of each sampling method to (least to most). viral rna was extracted and reverse transcribed. a two-step pcr of the hrv ' utr was used for detection, followed by sequencing for typing. results to date, children ( % male, mean age of . years) had paired samples taken. of these children, % (n = ) presented with a diagnosis of viral induced wheeze and % (n = ) had a hrv positive sample. compared with pnas, nasal fl ocked swabs were % ( of pna positive) effective in detecting hrv, whilst nasal washes showed % ( of pna positive) effi cacy. of the successfully typed samples, had hrva and had hrvc. nasal washes had a better comfort rating (mean . , n = ) than fl ocked swabs (mean . , n = ) and pnas (mean . , n = ). conclusion our fi ndings suggest that whilst nasal fl ocked swabs are an effective sampling method for hrv detection, nasal washes were more effective, being as effective as pnas and were the most comfortable. support nhmrc, pmh foundation. nomination nil. aim to describe the inpatients treated by a dedicated niv service. methods a retrospective audit of inpatients treated by the alfred niv service between january and june . the defi nition of niv included patients treated with cpap and bilevel positive pressure ventilation. results patients (age: ± years (mean ± sd), gender: % male) were treated with niv on occasions (repeat admissions patients). commonest indications for niv were osa (n = , %), acute exacerbations (ae) of copd (n = , %), acute cardiogenic pulmonary oedema (acpo) (n = , %) and post-lung transplantation (n = , %). treatment was delivered primarily in the respiratory ward (n = , %), cardiac ward (n = , %), icu (n = , %) and general medical ward (n = , %). episodes of cpap (mean pressure ± cmh o), osa and acpo made up % of those treated. seventy-two episodes of bilevel pap (mean ipap ± cmh o and epap ± cmh o), aecopd and weaning post-mechanical ventilation made up % of those treated. outcome data was available in a subgroup of patients with acpo (n = ) andaecopd (n = ). in the acpo group, patients ( %) improved and niv was ceased. three patients ( %) deteriorated and were intubated and patients ( %) were palliated. in the aecopd group, patients ( %) improved andniv was ceased or they were discharged on therapy. patients either deteriorated on niv or could not tolerate therapy, of these ( %) continued ward management and ( %) were palliated. conclusion the alfred niv service model has managed a large number of referrals across a range of diseases in a variety of wards. this is likely to have reduced demand on icu, hdu and respiratory ward beds. compared to the published literature, theoutcomes for acpo are worse than expected but comparable for aecopd. this may be explained by local referral patterns for acpo. we believe that our service model provides a viable means of administering niv to an ever expanding referral base. transitional & community service, the university of south australia, adelaide, sa , the university of adelaide, adelaide, sa, , the mary potter hospice, north adelaide, sa, , thoracic medicine, the royal adelaide hospital, adelaide, sa, , the royal district nursing service, wayville, sa , and the palliative care council of sa eastwood, sa introduction: the adelaide health service is in the process of developing a new and innovative model of copd community based care. a number of initiatives have informed this development including a recent research project examining the experiences of participants with end stage copd and their carers. a growing body of evidence indicates the importance of a palliative approach, however this often takes the form of referral to a palliative care service rather than a broader application of palliative principles in both specialist and primary care. methods: fifteen participants were interviewed twice at monthly intervals to explore their needs and the services they accessed. a series of focus groups with key service providers in sa was also undertaken. data were analysed to identify how hospital, specialist palliative care units and primary care services currently interface to meet identifi ed patient and carer needs. results: the current service model is episodic and reactive with services activated through the acute care system. our research has shown that, as copd advances, current models of care do not address the importance of supporting quality of life (including a focus on adls) and carers in their ongoing role. also emphasised was the lack of co-ordination of care, collaboration between service providers and communication -the basics of chronic disease management. conclusions the outcomes of this study will inform the development of a proactive, multidisciplinary model of care which is no longer reliant on tertiary care, but places primary care at the centre of the model. greater collaboration between respiratory, palliative and primary care services will provide an integrated approach, focusing on the needs of the patient and carer. aim long term conditions are prevalent in south auckland and impact on the individual, the community and the health system. as nurses living within this community, and employed by counties manakau district health board, our aim was to explore funding opportunities available through the pacifi c health team. lotumoui was established to improve health outcomes/behaviours for pacifi c populations. the church we attend has wide cultural diversity and had no knowledge of the programme and the support provided to make healthy changes within our community. methods firstly a health committee was formed within the church, having 'sold' our vision to the parish council. we launched the group by undertaking free blood pressure checks, followed by a 'walk the talk' project for the days leading into easter. baseline observations were taken and pedometers issued. results the parishioners who attend regular exercise sessions are reporting improved quality of life, exercise tolerance and reducing waist lines. bp parameters are also reducing. conclusions a dedicated health committee within a parish community, supported by the district health board can impact on changes in lifestyle by simple interventions. the investment by the pacifi c team will reap benefi ts for the individual and the health sector. confl ict of interest no. key: cord- -jrvmgnu authors: nan title: asthma & allergy sig: poster session . physiology, environment, investigation and management date: - - journal: respirology doi: . /j. - . . _ .x sha: doc_id: cord_uid: jrvmgnu nan increased airway smooth muscle (asm) in asthma may be due to hyperplasia or hypertrophy of asm cells. the contribution of extracellular matrix (ecm) within asm bundles has not previously been accounted for when estimating asm cell volume. aim to estimate the mean asm cell volume in asm bundles in asthma. methods post-mortem tissues from control subjects (c n = ); nonfatal (nfa n = ) and fatal (fa n = ) cases of asthma were studied. on mm transverse airway sections stained with haematoxylin, the volume density (nv) of asm cell nuclei was estimated using an optical disector (¥ ). the mean cell volume (vc = /nv) was calculated, correcting for the volume fraction of asm (fasm) within the asm bundle (corrected vc = /(nv ¥ fasm)). fasm was estimated on . mm thick sections of the same airway stained with masson's trichrome. basement membrane perimeter (pbm) was used to indicate airway size. results table shows mean Ϯ sd. (one-way anova) *p < . for c v fa, nfa v fa. conclusion these data suggest that although asm area is increased in asthma, mean asm cell volume is unchanged. therefore hyperplasia, not hypertrophy, of asm cells is present in both mild and severe asthma. these results were similar for both large and small airways. asthma is characterized by airway inflammation and remodelling which contribute to airway hyperresponsiveness and episodic airflow obstruction. mast cell (mc) densities are higher on the smooth muscle (asm) in asthma so their mediators may modulate other asm functions as well as cause contraction. aim to investigate the effect of mc mediators on chemokine and extracellular matrix (ecm) production by asm cells from donors with and without asthma. methods mc were isolated from the resected lung samples of patients, resuspended at cells/ml in dmem + % fbs and stimulated with ige/anti-ige. supernatants (sn) were collected after and h and the mc lysed. sub-confluent asm cells from donors with and without asthma were serum deprived for h before mc sn/lysates were added in dmem + %fbs for h. il- and eotaxin levels in all asm sn and mc sn/lysates were measured by elisa. fibronectin and collagen iv deposition was measured in situ by immunoassay following asm cell lysis. results in asthmatic and non-asthmatic asm cells all mc sn and lysates reduced eotaxin release by up to % and %, whereas the - h mc sn significantly increased il- release to Ϯ . % (p = . ) and Ϯ % (p = . ) of the fbs control respectively. however, only nonasthmatic asm cell il- release was increased by the mc - h sn ( Ϯ %; p = . ) and cell lysates ( Ϯ %; p = . ). the - h mc sn also increased fibronectin deposition to Ϯ % (p = . ) by asthmatic asm cells only. mc sn and lysates had no effect on collagen iv deposition. conclusions activated mast cell mediators differentially modulated chemokine and ecm secretion by asm cells from donors with and without asthma. thus mast cells may modulate their own recruitment to the smooth muscle and remodelling locally in the airways in asthma. supported by nhmrc. the technique of ige passive sensitization reproduces ige-related allergic responses in vitro and studies have validated this technique for investigations modelling allergic smooth muscle responses. there are no studies investigating effects of ige sensitization on rhinovirus (rv) infection. we hypothesized that rv infection is enhanced by ige sensitization, a consequence of diminished early innate immune responses. methods beas- b epithelial cells and primary culture airway fibroblasts were sensitized with ige h- d prior to infection with rv . samples of tissue culture supernatant and cell lysates were collected over a h period after infection for analysis. viral replication was measured by real-time rt-qpcr and viral titration and type i interferon mrna by rt-qpcr. ige receptor mrna expression was examined using rt-pcr. results initial studies to establish the model used human serum high in ige (> iu/ml), this yielded inconsistent results and it was found that purified ige ( iu/ml) provided more reliable responses. sensitization was established after h ige incubation and was comparable with up to d. rt-pcr detected mrna for the ige low affinity receptor only after sensitization. following rv infection, vrna was increased after h in ige sensitized cells (p < . ), but this effect varied noticeably between and within cell lines. cellular expression of ifn-b mrna increased with viral infection but in cells sensitized with ige lower levels of expression were noted (p < . ). conclusions ige passive sensitization enhanced rv replication in vitro but the model is constrained by significant variability between and within cell lines. the effect of sensitization on rv replication may occur through the low affinity ige receptor. activated mast cells (mc) are present in higher numbers on the airway smooth muscle (asm) in asthma compared with other inflammatory airway diseases. matrix metallo-proteinases (mmps) cleave chemokines and alter chemokine gradients by degrading the extracellular matrix and thus may modulate mc migration to the asm. aim to determine the levels of mmp- , mmp- and their inhibitors, timp- and timp- , secreted by asm cells from donors with and without asthma. method confluent asm cells were washed, serum-starved for h and then stimulated with th (il- , tnf and ifn) or th (il- , il- and il- ) cytokines or left unstimulated. after and h,the sn were collected. the relative amount of pro and active forms of mmp- and mmp- in sn were determined by gelatine zymography. timp- and timp- levels in the sn were measured by elisa. results pro-and active mmp- were not detected. however, pro-mmp- levels were high in sn of asm cells from donors with ( . Ϯ . % positive control/ cells) and without ( . Ϯ . % positive control/ cells) asthma. a trend to increased active mmp- production by asm cells from donors with ( . Ϯ . % positive control/ cells, n = ) compared to without ( . Ϯ . % positive control/ cells, n = ) asthma after h was not significant (p = . ). timp- and timp- levels respectively were high in the sn of cells from donors with ( . Ϯ . and . Ϯ . ng/ cells, n = ) and without ( . Ϯ . and . Ϯ . ng/ cells, n = ) asthma. th and th cytokine stimulation did not affect mmp or timp release. conclusions th and th cytokines did not regulate asm cell production of mmp- , timp- and timp- . altered asm mmp- activity is unlikely to play a role in mc chemotaxis to asm cells from donors with asthma in vitro or their presence on the asm in asthma. there has been a marked increase in the prevalence of asthma and other allergic diseases in the last few decades. one of the explanations for this is the change in our diet. one of the characteristics of the "western diet" is a high intake of both saturated and polyunsaturated fat. this prompted us to compare the effects of high fat and low fat meals on the numbers of circulating eosinophils and other leukocytes. methods we studied volunteers who had allergic rhinitis and/or asthma and a peripheral eosinophil count at baseline of Ն ¥ /l. this was a randomized, crossover trial with participants studied on two different days. on each occasion they arrived fasting and after bloods were drawn consumed a calorie meal. one of the meals was high in saturated fat and refined carbohydrate. the other meal was low in saturated fat and high in fruit and fibre. bloods were drawn postprandially every hour for five hours. results eosinophil counts were highest in the early morning and fell over the course of the day but the decrease was less with the high fat meal (p = . ). over the same period of time the increase in lymphocytes (p = . ) was greater with the high fat meal. the high fat meal was also associated with greater increases in triglycerides (p < . ) and cholesterol ( . ). conclusions in atopic individuals a high fat meal was associated with higher circulating numbers of eosinophils and lymphocytes than an isocaloric meal that was low in fat. further studies of the effect of dietary fat on eosinophilic inflammation are warranted. supported by the university of auckland research committeee. intravenous gamma globulin therapy (ivig), which is therapeutic in a variety of immune diseases, has been reported to be effective on patients with severe steroid-dependent asthma. although fcer are known to play important roles in asthma, there are few reports about the role of fcg?receptors in asthma. fcg receptor iib (fcgriib) is unique inhibitory receptor, which suppresses immune response. in this study, we evaluated the effect of ivig in allergic airway inflammation in ova-challenged mice and the mechanism of the inhibitory effects of ivig and fcgriib. method c bl/ mice (wt) and fcgriib deficient mice (ko) were sensitized with ovalbumin (ova) and alum and subsequently challenged with nebulized ova. before ova challenge rabbit igg was administered intravenously. the airway inflammation and effects of igg were assessed by histology, cell counts of bal fluid and airway hyperresponsiveness. result histology showed that igg treatment ameliorated the inflammation around the airway and the vessels and hypertrophy of goblet cells induced by ova challenge. the migratory activity of dcs is modulated in inflammatory diseases such as asthma. recently, we reported that immature dcs express kinin receptors and that bradykinin (bk) significantly enhances the migration of immature dc in vitro. as kinins mediate many of the pathophysiological effects associated with asthma, we hypothesized that lys-des[arg ]-bk, which is produced during inflammation and acts via the b receptor (b r), would inhibit migration of mature dcs. methods day cultured human monocyte-derived dcs were matured with lps, tnfa +il- b or cd l in the absence or presence of lys-des[arg ]-bk. maturation of dc was analysed by flow cytometry (facs). b r expression was assessed by reverse-transcriptase pcr and quantitative confocal microscopy. migration of mature dc was assessed in transwell chambers with lysdes [arg ]-bk and the chemokine ccl used as chemoattractants. results maturation of dcs was found to result in down-regulation of b r expression to varying degrees depending upon the maturation stimulus used. mature dcs all demonstrated an ability to migrate toward lys-des[arg ]-bk and ccl . however pre-treatment with lys-des[arg ]-bk decreased the migratory ability of all mature dcs to both chemoattractants. conclusions along with chemokines, lys-des[arg ]-bk is likely to play a crucial role in regulating the in vivo migration of mature dc during inflammation. the production of lys-des [arg ]-bk during inflammation potentially immobilizes mature dcs thereby facilitating locally-mediated immune responses within inflamed tissues. supported by the asthma foundation of western australia. introduction alternative or aberrant splicing is a major contributor to protein diversity, in which a single gene can generate structurally and functionally distinct protein isoforms. the role of alternative splicing in asthma pathogenesis has not been previously investigated. we hypothesized that specific alternatively spliced asthma candidate genes contribute to the development of asthma. we chose to use a new and innovative approach involving the use of the genechip (r) exon array system together with real-time quantitative pcr to study asthma candidate genes in human monocyte-derived dendritic cells. asthmatic and non-asthmatic subjects provided ml of blood from which peripheral blood mononuclear cells (pbmc) were isolated by ficoll-paque gradient centrifugation. monocytes were separated from other leukocytes by adherence method, and differentiated into dendritic cells following incubation with defined concentrations of gm-csf and il- . rna was isolated and reverse transcribed for real-time semi-quantitative pcr and densitometry. chi squared test was used to assess associations between alternative splicing and asthma. results data indicate splice variant expression in dendritic cells from asthmatic patients is influenced by asthma severity. conclusion exon expression array analysis has generated a number of asthma candidate genes with alternative splice variants. further studies to validate these data in a replicate data set and establish the functional significance of our findings in asthma are underway. alternative or aberrant splicing occurs in more than % of genes and is a major contributor to protein diversity, in which a single gene can generate structurally and functionally distinct protein isoforms . the role of alternative splicing in asthma pathogenesis has not been previously investigated. we hypothesized that specific alternatively spliced asthma candidate genes contribute to the development of asthma. we chose to study one asthma candidate gene in human stimulated and unstimulated: ( ) monocytes, ( ) monocytederived dendritic cells and ( ) lung smooth muscle cells. methods asthmatic and non-asthmatic subjects provided ml of blood from which peripheral blood mononuclear cells (pbmc) were isolated by ficoll-paque gradient centrifugation. monocytes were separated from other leukocytes by adherence method. up to % of the monocytes were then differentiated into dendritic cells following incubation with defined concentrations of gm-csf and il- . induction experiments used mg/ml lps and cells were stimulated for an optimal period of hrs. rna was isolated and reverse transcribed for real-time semi-quantitative pcr and densitometry. chi squared test was used to assess associations between alternative splicing and asthma. results data from stimulation experiments indicate splice variant production can be regulated by the inflammatory response and that this response is influenced by asthma status. conclusion preliminary experiments have confirmed the presence of an aberrant splice variant for an asthma candidate gene in the primary cells studied. further studies to confirm these data and establish the functional significance of our findings in asthma are underway. exposure to environmental factors, such as environmental tobacco smoke (ets), plays a significant role in modulating pre-existing genetic susceptibilities to diseases including asthma. the glutathione s-transferase enzymes (gsts) play an important role in the detoxification of ets. there are several gst isoforms and gstp codes for the gst pi isoform, which is the primary gst isoform expressed in human lung tissue. two single nucleotide polymorphisms (snps) at positions and have been reported in gstp and associated with asthma and atopy. the aim of this study was to examine the effect of these snps in combination with ets, on asthma phenotypes in a cohort of asthmatic children. children were recruited during an acute episode requiring presentation at an emergency department. genotyping using pcr-rflp was completed on children and ets exposure was determined by parental questionnaire. urinary cotinine was measured in the children and was in agreement with questionnaire responses. statistical analyses were performed using spss. there were no significant associations between the genotypes and asthma severity during acute exacerbations. significant associations were found between the snps and atopy in this population with an odds ratio of . for the aa genotype (p = . ) and or of . for the cc genotype (p = . ). however, when an interaction with ets was included, the odds ratios increased to . for aa (p = . ) and . for cc (p = . ). these results suggest that there is a significant gene/environment interaction impacting on atopy in this cohort. the rage gene encodes the receptor for advanced glycation end-products (rage), a member of the immunoglobulin superfamily. rage activation by ligands, including amphoterin and s /calgranulins, leads to prolonged nf-kb signalling and has been associated with chronic inflammation. despite high levels of rage expression in lung tissue, little research has been undertaken into the role of rage in the chronic inflammatory asthma phenotypes of severe and aspirin-sensitive asthma. objective determine genetic associations between functional polymorphisms in the rage promoter and severe and aspirin-sensitive asthma phenotypes. methods pcr and restriction fragment length polymorphism (rflp) were used to genotype three rage promoter polymorphisms, - t>c, - t>a and a bp deletion from - to - , in a large case-control asthma population phenotyped for asthma severity, atopy and aspirin sensitivity. results no associations were identified between any of the polymorphisms and the occurrence of asthma. however, the - a allele was linked with both severe asthma (p = . ) and aspirin-sensitive asthma (p < . ). likewise, genotypes containing the - a allele were strongly associated with both severe asthma (or . , % ci . - . ) and aspirin-sensitive asthma (or . , % ci . - . ). conclusions the - a allele of the rage gene, previously shown to lead to a -fold increase in promoter activity, is associated with the chronic inflammatory asthma phenotypes of severe and aspirin-sensitive asthma. these results suggest that increased rage expression, with a concomitant increase in nf-kb signalling, may in part contribute to the inflammatory response seen in these conditions. the global prevalence of allergic diseases is rising and australia has one of the highest prevalence rates in the world. the role of early childhood infections in the development of allergic disease remains controversial. objective to examine the association between early childhood infections and the development of allergic diseases in later childhood, in high risk children. methods data were analysed from the melbourne atopic cohort study (macs) of infants with or more first-degree family members with atopic disease. primary risk factors assessed were otitis media, bronchitis and gastroenteritis reported in the first two years of life. outcomes were current asthma, hay fever and eczema at years of age. logistic regression was used to estimate crude and adjusted odds ratios. results asthma was the most common allergic condition ( . %, % ci . - . %), followed by eczema ( . %, % ci . - . %) and hayfever ( . %, % ci . - . %). the most commonly reported infection was otitis media ( . %, % ci . - . %), then gastroenteritis ( . %, % ci . - . %) and then bronchitis ( . %, % ci . [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . %). all types of infection within the first years of life were associated with increased risk of asthma. an increased risk of asthma at years was seen with otitis media (or = . , % ci . - . ), bronchitis (or = . , % ci . - . ) and gastroenteritis (or = . , % ci . - . ). when the frequency of infection was examined, those who reported at least episodes of gastroenteritis had a - -fold increased risk and an almost % absolute increased risk (rd . , % ci . - . ). conclusion these findings appear to contradict the hygiene hypothesis. the findings for gastroenteritis are novel. further examination of these associations and possible underlying mechanisms is warranted. grant support asthma foundation of victoria, nestle. background knowledge about incident cases of asthma in australia is limited because they are not routinely reported. the ability to predict the number of new cases of asthma would be helpful in allocating resources for asthma education, management and care. data on first use of medications for asthma gives an indication of the incidence of asthma. the objective of this study was to estimate the incidence rate of asthma by investigating asthma medication use in individuals. methods pharmaceutical benefits scheme (pbs) records for all prescriptions filled for inhaled corticosteroids (alone or combined formulation), cromones and leukotriene receptor antagonists from july to june were included. using a -year look back window, any persons who had their first prescription for any of these drugs dispensed between july and june were assumed to be incident cases. overall and age-specific incidence rates were calculated per asthma-medication-free individuals. results there were , individuals who had their first asthma medication dispensed between july and june , which equates to an overall incidence rate for asthma of . per . the incidence was higher among children aged - years ( . ) and adults aged years and over ( . ) . conclusions our estimated incidence rates were consistent with those reported by others in the literature. while the pbs database was designed for administrative purposes, it can be used to estimate incidence rates for asthma. support acam is a collaborating unit of the australian institute of health and welfare and is funded by the department of health and ageing (doha). we acknowledge the pharmaceutical pricing and estimates section of doha for provision of pbs data. keywords asthma incidence, pharmaceutical benefits scheme. rosario ampon , guy marks , teresa to , leanne poulos , anne-marie waters australian centre for asthma monitoring (acam), sydney, australia, and hospital for sick children, toronto, canada background the ability to assess individual patterns of asthma medication use would have clinical relevance in targeting effective asthma education and management for this common condition. to describe longitudinal patterns of asthma medication use, we used a population-based prescription database to follow individuals from the first time they filled an asthma prescription. asthma is more commonly listed on death certificates as an associated cause of death, in people whose deaths are attributed to other causes, than as an underlying cause of death. understanding the importance of these associations would contribute towards an overall appreciation of the impact of asthma on mortality. the objective of this analysis was to estimate the prevalence of asthma as an associated cause of death when various other diseases were attributed as the underlying cause of death. background acam currently recommend indicators to measure population-level asthma health and outcomes. we examined correlations among several asthma indicators covering prevalence, morbidity and mortality to try and produce a condensed set of indicators which minimized redundancy. methods seven of the indicators were included in this study: prevalence of ever having doctor diagnosed asthma, prevalence of current asthma, asthma-related general practice (gp) encounters, proportion of people with asthma with an asthma action plan (aap), hospitalizations for asthma, hospital patient days for asthma, and deaths due to asthma. a correlation matrix was created for these indicators by age groups. pearson correlation coefficients Ն . or Յ- . were considered strong. results there were strong positive correlations between prevalence of ever asthma and current asthma (r = . ); gp visits and aap possession (r = . ), hospitalization (r = . ) and patient days (r = . ); and hospitalization and patient days (r = . ) and aap possession (r = . ). recent australian reports have shown that the prevalence of asthma and respiratory symptoms has decreased over the last - years. as part of a larger study investigating child health and air quality we have collected nationwide data from schoolchildren living in act, victoria, queensland, wa and sa. methods schools were selected based on proximity to air quality monitoring stations. classes from years to were randomly selected and all children were invited to participate. parents self completed a questionnaire that included questions about diagnosed asthma and respiratory symptoms. results a total of children provided questionnaires for analysis. the response rate varied between states and territories and ranged from % to %. the sample comprised . % girls and the mean age of children was . years. ever diagnosed asthma . current asthma ('does he/she still have asthma? ') . wheeze in the past months . respiratory symptoms limiting activities . missed school due to asthma or wheezing . conclusions despite the relatively low participation rate, the prevalence estimates for current asthma are similar to those reported in the national health survey - [ ] . there is no evidence of any recent increase in the prevalence of childhood asthma. methods tahs is a longitudinal population-based respiratory study of subjects which commenced in when they were years of age. since the initial study another follow-ups have been conducted, including the most recent follow-up when subjects were years of age. lung function of the total sample was measured at baseline and in sub-samples in subsequent followups. asthma was categorized as persistent, frequent or episodic when participants reported asthma symptoms in at least follow-ups, in follow-ups or in follow-up respectively. results by age years ever asthma prevalence was %. at age , % of those who had not reported asthma by age had asthma symptoms while % of those who reported asthma by age had no asthma symptoms. hence over all only % of the asthma symptoms at age were attributable to asthma developed by age . in contrast, % of the persistent and frequent asthmatics had developed their asthma by age . persistent and frequent asthmatics had more symptoms and poorer lung function at age , and as well as more reversibility at age (p < . ). childhood asthmatics who also had a productive cough by age were more likely to have persistent asthma than those without a cough (p < . ). conclusions although the majority of middle-age asthma is related to postchildhood onset asthma, most severe middle-age asthma has its origin in persistent childhood disease. having productive cough in childhood may identify high risk asthmatics who require especially rigorous management in early life. one third of women experience an improvement in asthma during pregnancy, and symptoms improve in most women in the late third trimester. we hypothesized that the exacerbation rate would be reduced and that symptoms during exacerbations would be less severe in the third trimester compared to the second trimester. methods pregnant women with asthma (n = ) were prospectively followed from recruitment ( . weeks ( sd) ) to delivery at clinic visits ( , , weeks and during exacerbation), and fortnightly phone calls. the asthma control questionnaire (acq) was administered at each contact and exacerbations classified as severe (requiring medical intervention) or mild (selfmanaged). lung function, medication use, fractional exhaled nitric oxide (feno) and full blood counts were assessed. paracetamol is commonly used in infants as an analgesic and antipyretic. it has been hypothesized that frequent paracetamol consumption may result in reduced lung capacity to cope with oxidative stress and increase risk of respiratory disease. to date, no study has examined exposure to paracetamol during infancy, when lungs are still developing, and risk of childhood asthma. method a birth cohort of infants with an atopic family history was recruited. frequency of paracetamol exposure was prospectively documented up to years of age. interviews were conducted at and years to ascertain asthma in the previous months. results paracetamol exposure in infancy was common ( % exposed by two years of age), with some infants receiving paracetamol on up to days. it has been hypothesized that mucosal immune response requires a particular micro-flora milieu in the infant's gastro-intestinal tract, and that early life antibiotic exposure may disrupt this process and increase risk of allergic disease. method a birth cohort of infants with an atopic family history was recruited. exposure to oral antibiotics was prospectively documented up to months of age. interviews were conducted at and years to ascertain asthma in the previous months. results by one year of age, approximately % of infants had received at least one course of oral antibiotics. the prevalence of current asthma in childhood was approximately % ( / ). frequent use of antibiotics (more than days exposure during first year of life) was associated with increased risk of childhood asthma (or = . , % ci = . - . ) when compared to infant who had not been exposed. excluding infants with a diagnosis of asthma within the first two years of life, reduced this association by about % (or = . , % ci = . - . ) and adjustment for gender, parental history of asthma and number of infections in the first year of life further reduced this association (or = . , % ci = . - . ). the increased risk of childhood asthma associated with antibiotic exposure in the first year of life is, at least in part, due to confounding with early life wheeze and infections. if real, the independent effect of antibiotic exposure on risk of childhood asthma is likely to be minimal in this high risk cohort. support dairy australia, crc for asthma and airways, vichealth, nestle. the epidemiological data on asthma suggest a gender difference that varies with age. hormonal effects have been suggested as a possible explanation for these differences. the aim of this study was to examine reproductive factors and risk of asthma among the females of the tasmanian longitudinal health study (tahs). methods the tahs is a longitudinal population-based cohort study of respiratory disease which commenced in when subjects were years of age. four follow-up studies have been conducted including the current most comprehensive follow-up with subjects at years of age. information has now been collected on reproductive factors such as number of pregnancies, age at pregnancies, age at menarche and contraceptive pill use as well as on asthma status. reproductive factors were examined as risk factors for asthma using multiple logistic regression to adjust for all likely confounders. results a total of , women completed the most recent postal survey. of these ( . %) had current asthma, and of these women with current asthma . % ( ) developed asthma after childhood. on average these women were in their mid-twenties when they developed asthma (mean Ϯ sd age = . Ϯ . yrs). we found with increasing age at first birth an approxi-mate~ % reduced risk of current asthma in women who developed their asthma post-childhood (trend p = . ). we did not observe any other associations between reproductive factors and risk of asthma. conclusions our results are consistent with the hypothesis that early pregnancy may promote asthma development by altering the immune response favouring a th pathway. a delay in the age of first pregnancy reduces this risk of asthma. grant support nhmrc, clifford craig foundation, victorian & tasmanian asthma foundations. introduction the association between exposure to pets in early life and subsequent development of sensitization and allergic disease remains controversial. the objective of this analysis was to examine the relationship between cat exposure before birth and development of cat sensitization over time within the melbourne atopic cohort study (macs). methods the macs is a prospective longitudinal cohort study that initially recruited women antenatal in melbourne from february to november . detailed information on cat exposure was collected at recruitment and frequently until two years of age. skin prick test (spt) were conducted at , , months and years. the data were analysed by logistic regression and using generalized estimating equations (gee) for the repeated measures design. results among subjects, ( . %) had a cat before birth. at months, . % (n = ) of subjects were sensitized to cat and by years of age . % (n = ) were sensitized. those who did not have cat before birth belong to a higher social class, and were more likely to have a father with allergic disease than those with a cat. those who developed sensitization to cat were more likely to have a paternal family history of allergic disease and more likely to be sensitized to other allergens. we did not observe any association between exposure to cat before birth and the development of sensitization to cat at months (or = . , % ci . - . ) , months (or = . , . - . ), months (or = . , . - . ) or years (or = . , . - . ) . these crosssectional results were confirmed by the gee analysis. conclusion our results fail to show an association between cat exposure before birth and development of sensitization to cat. furthermore exposure after birth in the first months of life was not associated with an increased or decrease risk of sensitization to cat. our results do not support either a benefit or risk associated with cat ownership and sensitization. introduction peri-natal events influence the development of asthma and atopic diseases in childhood but the current literature is contradictory on the effect of low birth weight, small for gestational age and prematurity on asthma risk. the aim of this study was to assess the relationship between these three exposures and asthma from childhood to adulthood. aim to assess the current prevalence of dda, wheeze (< months), atopy and ahr in children and adults in busselton. methods an age-and sex-stratified random sample of adults, selected from the electoral roll, was invited to complete a questionnaire and attend the local study centre for assessment of atopy (allergen skin tests) and ahr (methacholine). all children from participating primary and secondary schools were also invited to attend. the prevalences of dda, wheeze, atopy, ahr and "current asthma" (wheeze + ahr) were calculated. background asthma is often associated with comorbidity, however few studies have investigated comorbidities among people with this common condition. the objective of this analysis was to describe patterns of non-respiratory comorbidity among adults hospitalized with asthma in australia. methods data on hospitalizations for people aged years and over with a principal diagnosis of asthma (j , j ) were obtained from the australian institute of health and welfare's (aihw) national hospital morbidity database for the period - . patterns of comorbidity were examined by investigating additional diagnoses for non-respiratory disease according to icd- diseasespecific chapters. results among people aged years and over hospitalized in - with a principal diagnosis of asthma ( , hospitalizations; % female; % aged - years), % had at least one non-respiratory comorbidity. median length of stay was higher among those with at least one comorbidity ( days) than among those with no comorbidities ( days). among people aged - years, the most common comorbid condition was endocrine, nutritional and metabolic diseases ( %), while among those aged years and over it was diseases of the circulatory system ( %). conclusions a large proportion of asthma hospitalizations in australia are associated with non-respiratory comorbidity and a longer length of stay. further, the pattern of non-respiratory comorbidity associated with asthma hospitalizations varies by age. given our rapidly ageing population, the level of comorbidity associated with asthma has implications for coordinated health care and demand on health services. support acam is a collaborating unit of the aihw and is funded by the department of health and ageing. keywords comorbidity, hospitalization, asthma. background asthma exacerbations are often triggered by viral respiratory infections, yet the influence of respiratory infections on the morbidity of acute asthma beyond the immediate period is unknown. we examined the influence of nasopharyngeal (npa) respiratory viral, chlamydia and mycoplasma detection on asthma morbidity in children presenting to the emergency department for an acute exacerbation of asthma. methods a subset (n = ) of the children enrolled for a randomized controlled trial (rct) on the efficacy of vs days of oral prednisolone had an npa taken at presentation. npa were examined for chlamydia, mycoplasma and respiratory viruses (enteroviruses, coronaviruses, human metapneumovirus, adenovirus, parainfluenza, influenza, rsv, rhinoviruses) by pcr. enrolled children were aged - years with recurrent wheeze and required Ն ?g (mdi/spacer) or Ն . mg (nebulized) of salbutamol to reduce tachypnoea. parents filled validated diary cards for cough and asthma severity, and completed asthma qol data at enrolment and end of weeks and . results pcr for various viruses was positive in ( . %) children, with no significant difference in the groups the children were randomized into. rhinovirus pcr was positive in the npa of children, rsv in , hmpv in , adenovirus, parainfluenza, influenza a and b in one each. specimens were negative for the other micro-organisms listed above. children with a npa viral positive state were significantly (p = . ) younger than those with a negative state. however, there was no difference in the any of the asthma outcomes of children whose npa was positive or negative for the micro-organisms tested. conclusions in children with an acute asthma exacerbation presenting to emergency health facilities, a respiratory virus could be identified in > % but the presence of a respiratory virus did not influence the morbidity of the asthma exacerbation at presentation or at the end of week- and week- . the university of sydney, nsw , and royal north shore hospital, st leonards, nsw airway wall thickness measured using hrct is reported to be increased in asthmatic compared with control subjects. however, it is unknown whether wall thickness is a fixed structural characteristic of the airways or if it responds to transient changes in bronchomotor tone or airway size. aim to determine the effects of bronchomotor tone and lung volume on airway wall area measured by hrct. methods patients with doctor-diagnosed asthma had partial chest hrct scans, before and after bronchodilator (bd), at frc, tlc and a volume midway between (mid-volume). airway segments were identified between branch points and matched between consecutive lung volumes both before and after bd, and also at constant lung volume before and after bd. mean lumen areas and wall areas for each airway segment at each volume were measured using automated analysis software. paired t-tests were used to determine changes due to bd and lung inflation. results airways were matched before and after bd at frc. absolute airway wall area (wa) was related to airway lumen diameter (di wood smoke air pollution is of concern with respect to respiratory health due to its complex chemical composition and potential to carry air toxics into the lower respiratory system. launceston has a long history of poor winter air quality, primarily due to use of domestic wood heaters. participants in hobart had a similar prevalence of wood heater use, but hobart does not experience the same wood smoke pollution (due to differences in regional geography , asthma control and anxiety and depression were completed at baseline, immediately following ( wks), and mths after the intervention period. results clinically and statistically (p < . ) significant improvements in qol were observed in the exercise group at wks compared to the control group. this difference was not maintained at mths. mwd improved at wks and mths in the exercise group (p < . ), however the difference between groups was not significant. in the exercise group there was a trend towards improved asthma control and a reduction in anxiety and depression that was not observed in the control group. *p < . , change at wks vs baseline; home asthma monitoring is important for measuring day-to-day variation in lung function and symptoms. this approach requires the availability of complete diaries for a comprehensive assessment. we assessed the completeness of written diaries collected as part of a nation wide study of air quality and child health. methods children who had ever been diagnosed with asthma and had respiratory symptoms in the last year were identified from a cross-sectional study. these children were asked to record symptom scores and peak expiratory flows twice daily in diaries for a five week period. the diaries and peak flow devices were explained at a face-to-face meeting with parents and children. each week diaries were mailed back and parents received a phone call to encourage completion. completeness was defined as no missing responses to symptom questions or peak flow measurements in diaries from week two to week five. results data from the first children ( day records) were available for analysis. the sample included ( %) girls, mean age yrs. the overall frequencies for complete records were; morning symptoms %, morning peak flow %, evening symptoms % and evening peak flow %. there was a significant trend for more complete morning peak flow records over the four weeks (cochrane-armitage trend test p < . ). agreement between morning and evening symptom completeness and between morning and evening peak flow completeness was fairly poor (kappa < . ). conclusions the completeness of symptom and peak flow records collected in this study was very high. the comprehensive follow-up protocol implemented is likely to have had an important impact on the completeness of asthma diaries. daily peak expiratory flow (pef) monitoring has been used in epidemiological studies to assess changes in lung function over time. the value of written pef diaries has been questioned because of problems with completeness and validity. this study aimed to compare stored electronic pef data and a written diary record of those data in a panel study in children with weekly reminders to aid adherence. methods children who had ever been diagnosed with asthma and had respiratory symptoms in the last year were identified in a population study. they were given electronic pef devices with a digital readout (miniwright digital, mwd, clement clarke, uk) and written symptom and peak flow diaries and instructed in their use at a meeting with parents and children. each child was asked to complete three pef manoeuvres every morning and evening for five weeks and to record these in the written diary. background previous research suggests that comorbid anxiety is associated with lower asthma-related quality of life (aqol) in adults with asthma. however, research is scant on the role of psychological interventions in these patients. aim to evaluate the effectiveness of a four-session cognitive-behavioural therapy (cbt) intervention, in improving the aqol, in participants with anxiety and asthma. method participants identified with comorbid anxiety and asthma were randomly assigned to the cbt intervention group (n = ) and the asthma monitoring control group (n = ) and evaluated on aqol measures, at various intervals. results nine participants, in the cbt group, completed the study. seven participants showed a clinically significant improvement in asthma-related emotional functioning (ef) and six participants in total aqol scores, at the -week post-intervention assessment. additionally, six participants in the cbt group indicated clinically significant improvement in ef and five participants in total aqol scores, at the -month follow-up assessment. only three participants in the control group completed the study. none of these participants showed any improvement in aqol scores at the -week or -month assessment. conclusion this pilot study suggests that a higher number of participants in the cbt group showed clinically significant improvement in ef and total aqol scores with higher retention rates. further research needs to confirm these findings in a larger group, identifying the elements of a successful cbt intervention and characteristics of participants who respond to the cbt intervention. gastro-oesophageal reflux disease (gord) is a risk factor for uncontrolled asthma. we conducted an update of a systematic review to assess whether treatment of gastro-oesophageal reflux in subjects with asthma improved asthma outcomes. methods randomized controlled trials (rcts) of gord treatment in adults or children that reported asthma health outcomes and had symptomatic gord were included and assessed in accordance with the standard cochrane systematic review process. subjects received pharmacological therapies compared with conservative management. results from potentially relevant studies, rcts were included in the review. when compared to placebo, morning peak expiratory flow did not significantly improve (change from baseline wmd . , % ci: - . to . ) with proton pump inhibitor treatment (n = trials involving participants). asthma exacerbations were not significantly less in the intervention groups compared with the control groups (odds ratio . ; . - . ; n = ). conclusions while some trials reported evidence of asthma improvement with gord therapy, overall there appears to be no statistically significant evidence of a beneficial effect. it is clear that not all persons with gord and asthma will gain improved control over their asthma with gord therapy; this may be due to the heterogeneous pathophysiology of asthma. future large-scale trials would be required to demonstrate an effect on asthma exacerbations. kel and brd were supported by a cochrane airways group scholarship. background the ats/ers task force recommend the use of metered dose inhaler (mdi) and spacer for airflow limitation reversibility testing. salbutamol given via mdi & spacer has been shown to be equivalent to a nebulizer in the clinical setting. this has not been well studied in respiratory laboratory setting. aim to compare the methods of reversibility testing in a laboratory setting. methods we conducted a laboratory based crossover study in a secondary hospital. patients with asthma or copd were eligible. the patients firstly underwent spirometry and reversibility testing following a standard dose of nebulized salbutamol. they were asked to return for a second set of spirometry within the same week and at the same time of day when reversibility with an mdi and spacer was recorded. we used an incremental dose of salbutamol starting from puffs and up to puffs. spirometry parameters were recorded minutes after each intervention. the primary outcome was the percentage change in fev after each intervention. side effects were monitored for. results nine patients with asthma were recruited. the mean percentage change in fev was higher in the nebulizer group than after only puffs via mdi & spacer ( . Ϯ . vs . Ϯ [mean Ϯ sd], p = . ). however, there were no differences between the arms following higher doses of bronchodilator via mdi & spacer. the mean percentage change in fev after , and puffs were . Ϯ . , . Ϯ . , and . Ϯ . respectively (p = . , . and . respectively when compared to the nebulizer group). conclusion using an mdi and spacer for bronchodilator reversibility is equivalent to that of a nebulizer and should be the standard method of testing. the dose of bronchodilator needs to be at least puffs as recommended by the ats/ers; however puffs correlated best with a standard nebulizer route. further increments in bronchodilator dose provided little additional bronchodilatation. the study was limited by the small number of patients. asthma guidelines recommend a stepwise approach to treatment. the role of inhaled corticosteroid (ics) and long-acting beta-agonist (laba) combination therapy in asthma written action plans is not clear. objective to assess the efficacy of adjusting ics/laba combination therapy in a written action plan compared to fixed dosing in people with asthma requiring maintenance ics. methods cochrane systematic review of randomized controlled trials comparing ics/laba combination therapy in a single inhaler that is adjusted up or down according to a written action plan (wap) to comparison : budesonide/ formoterol given as a fixed maintenance dose (fd) (n = ) or comparison : fluticasone/salmeterol fd (n = ). results parallel randomized controlled trials describing interventions met the inclusion criteria. for the trials that compared wap to fd budesonide/ formoterol there were significant reductions for the wap group in exacerbations, (rr ( %ci): . ( . to . )), severe exacerbations (rr ( %ci): . ( . to . )) and study medications (wmd ( %ci): - . (- . to - . )) with no difference in asthma control or adverse events. the results for the two trials reporting wap budesonide/formoterol to fd fluticasone/ salmeterol were discordant and a homogenous pooled result could not be determined. of the australians who died from asthma in , over two thirds were over years of age. this trend resulted in the national asthma council of australia (nac) calling for better management of asthma in the elderly. we designed an educational intervention using evidence based educational strategies to improve the content and style of general practice consultations for older people with asthma. methods randomized controlled trial of a multi-faceted program consisting of a group educational session, a videotaped standardized simulated patient consultation, followed by an academic detailing session. forty-two gps were randomized into an active or a control group. gps provided the names of patients who would be happy to participate in the study and the program was evaluated by patient and gp outcomes. results gps recruited into our program reported improvements in a range of clinical areas. one hundred and ten patients were recruited, their outcomes are under analysis. conclusion gps were overwhelmingly positive about participation in this trial and our intervention successfully improved the capacity and confidence of gp's to deliver care to older people with asthma. our study also developed several tools that would enable dissemination of our findings. supported by an asthma targeted in studies where direct clinical assessment is not possible, urgent health care utilization (hcu) is often used as an indirect measure of asthma control. this study aimed to identify factors predicting urgent hcu and asthma control. methods patients in nsw with a doctor diagnosis of asthma were recruited from community pharmacies, a research volunteer database, and databases of asthma foundation nsw, to complete a questionnaire about asthma. poor asthma control was defined as asthma control questionnaire (acq) score Ն . . urgent hcu was defined as hospitalization, ed visit, or urgent doctor visit due to asthma. multiple logistic regression was used to identify predictors of poor control and urgent hcu. results questionnaires were completed by adults ( % female) with a doctor diagnosis of asthma (pharmacy , woolcock , asthma foundation ). % used inhaled corticosteroid (ics) Ϯ long-acting b -agonist in the last wks. median age was yrs (range - ), and % were current smokers. mean acq score was . ( % ci . - . ), with % of participants having poor asthma control (acq Ն . ). % had urgent hcu for asthma in the previous year. significant independent predictors for poor asthma control were younger age, current smoking, living in more disadvantaged areas, being retired, having only primary education, and holding a concession card. predictors for urgent hcu were younger age, being in full-time employment, having only primary education, and being of non-english speaking background. neither ics use nor possession of a written asthma action plan was associated with lower risk for either poor asthma control or hcu. conclusions poor asthma control is common in nsw even in patients using inhaled corticosteroids. although urgent hcu is often used as an indirect measure of poor asthma control, it is affected by different factors, perhaps because health care utilization represents a more complex balance between need and access. bronchial challenge tests with mannitol, to measure airway hyperresponsiveness, can take up to minutes and require inhalation of up to mg of mannitol. our aim was to determine if positive mannitol challenges can be detected after half the maximal dose ( mg) using the forced oscillation technique (fot) to measure response. methods non-asthmatic subjects and asthmatic subjects underwent standard mannitol challenge, up to mg mannitol. respiratory system conductance (grs) and reactance (xrs) was measured by fot at hz during sec tidal breathing immediately after each dose of mannitol. fev was measured after fot, within sec of mannitol administration. two point dose response slope (drs), was calculated for grs (drsgrs) and xrs (drsxrs) for standard tests, up to mg, and for short tests by excluding data from doses above mg. ability to detect a positive test, defined as pd fev < mg, was determined by the area under the roc curve (auc) and repeatability by intra-class correlation coefficient (icc). results asthmatic and non-asthmatic subjects had positive tests, with pd fev values from . to mg. auc ( %ci) did not differ between standard (std) and short tests for drsgrs (p = . ) or drsxrs ( combined use of inhaled steroids (ics) and long acting beta-agonists (laba) have an important role in asthma management. we used data from a population sample to examine medication use in adults and children. methods all adults ( - years) and children ( - years) from within four discrete zones in northern sydney were eligible for an interview survey, as part of a study investigating health effects associated with traffic-related air pollution. the prevalence of use of short-acting beta-agonists (saba), any ics (alone or combination) and combined formulations of ics/laba in the previous three months was estimated for the study population and those with diagnosed asthma. results there were children [mean (sd) age . ( . ) years and % female] and adults [mean (sd) age . ( . ) years and % female] interviewed in households, representing an overall response rate of %. the prevalence of ever diagnosed asthma was . % in children and . % in adults. medication data were missing for subjects. background asthma affects : adult australians and is a leading cause of rejection for recruitment into the australian defence force (adf). within this diagnosis there is a wide spectrum of disease activity and clinical outcomes. also asthma assessment and management has improved so that many asthmatics are now fully active without any significant disruption or risk to their lives. hypothesis: there is a subgroup of asthmatics who are at very low risk from significant adverse effects from asthma and who could be considered for recruitment to the adf. aims . to identify the subgroup of asthmatics who could be considered for recruitment to the adf. . to develop an assessment process to identify this subgroup (screening). . to develop a process to evaluate the outcomes of any change to the recruitment standard for asthma (evaluation). methods . a literature review of the natural history, assessment, management and response to treatment of mild episodic and mild persistent asthma. . a literature review of asthma in the military. . a clinical review of the outcomes of known asthmatics in the adf. . an expert group to review the above and to develop a screening process and an evaluation of the program. the literature review identified a subgroup of asthmatics, defined as mild episodic and mild persistent, who with appropriate management, have a low risk of significant adverse asthma outcomes. they can be identified by a combination of questionnaire, spirometry and bronchial provocation testing. a screening process has been developed which allows asthmatics to be recruited with a negative mannitol or hypertonic saline challenge on mg/day or less of budesonide (or equivalent) without laba. a methodology to evaluate the impact of these changes on the recruitment standard has also been developed. alexithymia is a personality trait associated with difficulty identifying and communicating emotional and physical feelings. it has been associated with poor control of asthma and near fatal asthma. the primary objectives of this study were to: ( ) identify alexithymia in a cohort of australian asthma patients; ( ) investigate the relationship between alexithymia and asthma control; ( ) investigate the relationship between alexithymia and asthma management. methods cross sectional study of moderate to severe asthma patients recruited from royal adelaide hospital outpatients. participants were either mailed the questionnaire pack or completed it after a clinic appointment. existing validated questionnaires were used. statistical analyses were performed using spss. results male ( %) and female ( %) patients with moderate to severe persistent asthma (mean age years, sd = ) participated. alexithymia scores ranged from . to . (x = . , sd = . ). % (n = ) of participants could be classified high alexithymia, % (n = ) borderline alexithymia and % (n = ) were low alexithymia. alexithymia mean scores were not statistically different across sociodemographic variables. a positive correlation/association was found between alexithymia score and asthma control score (r = . , p < . ), quality of life (r = - . , p < . ), and adherence (p = . ) but not satisfaction with communication (r = - . , p = . ) or number of hospitalizations (p = . ). conclusions this is the first australian study to identify alexithymia among asthma patients and investigate relationship to control as well as management and communication. associations between alexithymia and asthma control were confirmed. a larger sample size is needed to determine impact of alexithymia on self-management and provision of clinical care for asthma. port hedland is impacted by iron-containing dust particles (pm ) that may activate lung cells when inhaled. furthermore, the effects of port hedland pm may differ from the effects of urban pm impacting metropolitan areas. the aim of this study was to assess the effects of port hedland pm on production and release of the inflammatory cytokines, il- and il- , by human airway epithelial (a ) cells, and to compare these with the effects urban pm from metropolitan areas. methods human airway epithelial (a ) cells were exposed to pm collected at port hedland and at urban locations (sydney, perth). a cells were exposed to a range of pm concentrations ( - mg/ml) for h. lipopolysaccharide (lps) and phorbol myristate acetate (pma) were used as positive controls. supernatants from cell cultures were assayed for il- and il- using specific elisa kits. rna was extracted and reverse transcribed to cdna. il- and il- mrna expression was quantified by duplex real-time pcr using taqman primer/probes. results lps stimulated a . -fold increase in il- release and pma stimulated a -fold increase in il- release and a -fold increase in il- release. however, neither port hedland pm nor urban pm stimulated concentration dependent release of il- or il- by a cells. expression of il- or il- mrna was also not altered by port hedland or urban dust. cd + t-cells may cause airway epithelial cell apoptosis via the granzyme pathway. we have reported increased apoptosis of airway epithelial cells and increased bal t-cell expression of granzyme b in copd, and a positive correlation between the two. we hypothesized that the increased granzyme b would also be related to smoking history (pack years -pk/y), age and severity of airflow obstruction (fev %pred) in patients with copd. we further hypothesized that the t-cell granzyme b expression would be higher in the airway than the peripheral blood. methods we investigated t-cell intracellular granzyme b expression in blood from copd subjects ( current and ex-smokers) and never-smoker controls, and bronchoalveolar lavage (bal) and bronchial brushing (intraepithelial t-cells) from a cohort of these subjects using flow cytometry. correlations between granzyme b and pk/y, age or fev were performed using spearman's rank correlation. granzyme b in t-cells from blood, bal and bronchial brushings were compared. results there were significant correlations between fev and granzyme b expression in blood and bal (blood: r - . , p = . ; bal: r - . , p = . ). there was a significant correlation between pk/y and granzyme b expression in blood (r . , p = . ), but not in bal. there were no significant correlations between granzyme b and age. there were no significant differences in granzyme b expression in blood, bal or intra-epithelial compartments. conclusion granzyme b is expressed at similar levels in blood, bal and intra-epithelial compartments, supporting recent opinion that copd is a systemic disease. t-cell granzyme b is related to severity of airflow obstruction and smoking history in patients with copd and may be one mechanism of apoptosis leading to lung injury and airflow obstruction in copd. jc allen , t schlosser, ee ramsay , q ge , aj ammit as development of remodelled airways is correlated with deterioration of lung function, we require therapies that reduce and reverse structural changes in remodelled airways. in asthma, corticosteroids can halt some, but not all, aspects of airway remodelling. therefore, in order to aid future design of efficacious anti-remodelling agents we need a better understanding of the molecular mechanism/s underlying the development of airway remodelling and the effectiveness of corticosteroids. hyperplasia of airway smooth muscle (asm) is a feature of the remodelled airway in asthmatics. in this study we examined the effect of corticosteroids on a key regulator of g progressioncyclin d . asm cells from n = non-asthmatics and n = asthmatics were pretreated for h with vehicle or dexamethasone ( . mm). the temporal kinetics of cyclin d mrna and protein expression were measured up to h after stimulation with the mitogen platelet-derived growth factor-bb (pdgf-bb). pdgf-bb induced a significant increase in cyclin d mrna expression in asm from non-asthmatics ( . Ϯ . -fold) and asthmatics ( . Ϯ . -fold) after h stimulation. in non-asthmatics, the corticosteroid dexamethasone significantly (p < . ) reduced the amount of cyclin d mrna expressed (to . Ϯ . -fold). in contrast, cyclin d expression in asthmatics was relatively resistant to inhibition by dexamethasone; the amount of pdgf-bb-induced cyclin d expression in the absence or presence of dexamethasone was not significantly different ( sphingosine -phosphate (s p), a bioactive sphingolipid found elevated in the airways of asthmatics, modulates myriad airway smooth muscle (asm) functions that promote inflammation and remodelling in asthma. in this study, we uncover the molecular pathway/s underlying s p-induced secretion of il- , and investigate if, and how, corticosteroids inhibit il- secretion. using cultured asm cells from non-asthmatics, we found that s p induces il- secretion from asm cells via cre, but not ap- , c/ebp or nf-kb, transcriptional regulation of il- gene expression. cre-dependence was supported by s p-induced creb phosphorylation. although the corticosteroid dexamethasone reduced s p-induced il- secretion in a dose-dependant manner, this inhibition appeared to occur via a pathway independent of creb/cre, suggesting the existence of a parallel pathway. as we recently discovered that the antiinflammatory actions of corticosteroids in asm can be mediated via the induction of the endogenous mitogen-activated protein kinase (mapk) inhibitor, mapk phosphatase- (mkp- ), we investigated whether mapk represents the parallel pathway targeted by corticosteroids. we found that s p can induce activation of a variety of mapk, however, only p mapk phosphorylation was inhibited by dexamethasone; importantly, the increase in mkp- after corticosteroid treatment appeared to mirror the decrease in s p-induced p mapk phosphorylation. furthermore, exogenous expression of mkp- inhibited s pinduced il- secretion. taken together, these results suggest that parallel pathways exist to induce il- secretion (transcriptional via creb/cre and possibly post-transcriptional via p mapk) and serve to underscore the importance of mkp- upregulation as a mechanism of action of corticocosteroids in asm. angiogenesis is a hallmark feature of asthma. angiogenic promoters, such as vegf and tgfb are reported to be increased in airways of asthmatics. tumstatin, an endogenous angiogenic inhibitor, is the non-collagenous domain- (nc ) of the alpha chain of collagen iv. decreased levels of collagen iv have been reported in the airways of asthmatics. we investigated the presence of tumstatin in the airway of asthmatics and its potential role as an angiogenic inhibitor. we detected the six a chain nc domains of col iv and the s domain of the a chain using immunohistochemistry. the level of tumstatin in serum and bal-f was measured by dot blot. western blots were used to identify the association with the rest of the collagen iv molecule. a tube formation assay using primary pulmonary endothelial cells (ppec) was performed to evaluate the role of tumstatin in the airway. the effect of intranasal tumstatin on airway hyperresponsiveness and angiogenesis was studied in an ovalbumin mouse model. tumstatin was absent in the airways of asthmatics (n = ) while the remaining six collagen iv a chains were present. the s domain of the a chain was present in the asthmatic airway (n = ). tumstatin was detected in both serum and bal-f samples from asthmatic volunteers (n = ), however the level of expression was not significantly different from that in nonasthmatics (n = ). in asthmatic serum tumstatin was part of the whole collagen iv a chain. tumstatin was able to inhibit ppec tube formation in a dose related manner. tumstatin inhibited angiogenesis in the mice airways and was associated with an improvement in ahr. the fact that tumstatin is absent from asthmatic airways and inhibited airway hyperresponsiveness and angiogenesis may indicate potential for therapeutic intervention in airway remodelling. this work was supported by the crc for asthma and airways and nh&mrc. introduction epithelial egfr (epidermal growth factor receptor) expression correlates with disease severity and neutrophil infiltration in asthmatic airways. acute exacerbations of asthma and copd are also associated with steroid refractory neutrophilic inflammation, with rhinoviruses being the most common trigger. . mg/l and il- : . vs. . ng/l). since il- stimulates the acute phase response, we correlated its levels with the other markers. only crp was strongly correlated with il- (spearman r = . , p < . ), suggesting differential regulation of saa and ip . saa discriminated between non-pathogen (n = ) vs. pathogen-associated (n = ) events (saa: . vs. . mg/l p = . ), whereas no significant change was observed in the other markers (ip- : . vs. . ng/l, crp: vs. mg/l, il- : . vs. . ng/ l). however when aecopd marker levels were stratified on the basis of pathogen type (viral = , bacterial = , viral and bacterial = ), none of the markers were significantly altered. conclusions ip- is significantly elevated during an aecopd, however only saa differentiated non-pathogen from pathogen associated events. background severe persistent asthma is characterized by structural changes in the airways-airway remodelling. airway smooth muscle (asm) cells have the potential to play a key role in these processes through the release of growth factors, cytokines and extracellular matrix (ecm) proteins. we have previously studied the effects of budesonide and formoterol individually however, the effect of their combination on these characteristics of asm cells is not known. methods asm cells from asthmatic (n = ) and nonasthmatic (n = ) individuals were stimulated with transforming growth factor ß (tgfß) ( ng/ml) with or without budesonide ( - m) and formoterol ( - and - m) and fibronectin levels and interleukin- (il- ) release were measured by elisa. bronchial rings from nonasthmatic individuals (n = ) were incubated with tgfß with or without the drugs and ecm protein expression (fibronectin and collagen i) measured using immunohistochemistry. results in nonasthmatic cells, budesonide alone induced fibronectin deposition whether tgfß was present or not. formoterol decreased fibronectin induced by tgfß and, when combined with budesonide, reversed the increase in fibronectin. a similar pattern was observed in asthmatic cells, except that budesonide did not further increase the tgfß mediated fibronectin release. as before [ ] , il- was induced by formoterol but inhibited by budesonide. tgfßinduced il- was inhibited by both drugs and their combination in both cell types. in bronchial rings the presence of either drug did not affect tgfßinduced fibronectin or collagen i. severe combined immune deficiency (scid) spontaneous mutation specifically impairs differentiation of stem cells into mature lymphocytes. nod-cb prkd scid (known as nod-scid) lacked nk cells, hence is commonly used in cell transfer experiments for transferring tissue and haematological xenografts. the aim of this study was to establish lung inflamamtory model in nod-scid strain. methods balb/c and nod-scid balb/c mice (n = ) were exposed to cigarette smoke for days, and weeks ( cigarettes/day; days/week). bronchoalveolar lavage fluid (balf) and lung tissue were collected for inflammatory profiling and analysis for cytokines, chemokines and protease expression and/or activity. results nod-scid have significant accumulation of macrophages in lung after days, and weeks smoking as compared to no smoke control (p < . ) that was not different to balb/c (p > . ). nod-scid also have increased neutrophil number after and weeks smoking (p < . ). even though myeloid cell differentiation isn't affected by scid phenotype, nod-scid have one fold less neutrophil than balb/c mice (p < . ) that is also reflected in the reduced expression of matrix metalloproteinase- . consistent with the known lymphopenic phenotype, nod-scid have significant but less lymphocytes recruitment as compared to balb/c mice after weeks smoking (p < . ) despite the enhanced expression of inteferon inducible protein (lymphocytes specific chemokine) in lung. both mouse strains showed the same elevation of net gelatinase and serine protease activity in lung. nodscid mice also demonstrated comparable transcriptional induction of proinflammatory cytokines (tnfa, il- ), growth factors (gm-csf, g-csf) and chemokines (mcp- , mip- ), indicating susceptibility to smoke-induced injury. conclusions nod-scid mice are capable to mount smoke induced inflammatory response. this model may be useful to study localization and role of immunocytes, including adoptively transfer human cells in the pathogenesis of copd. supported by the nhmrc. rhinovirus (rv) is the cause of most common colds and up to % of asthma attacks. in our previous studies, plasminogen activator inhibitor (pai- ) was expressed at high levels and was induced in vivo and in vitro by rv infection. pai- may have antiviral properties suggested by antiviral activity in some models, high pai- expression levels and further upregulation by rv infection. methods to determine whether pai- has antiviral activities following rv infection, o-hela, pai- expression-deficient cells were first transfected with pai- or control genes. this was followed by infection with rv and effects on viral replication were assessed by rt-qpcr for vrna and by viral titration for virus release. ifn expression was assessed by rt-qpcr. results ifn-a and -b mrna expression were induced in response to rv infection and to pai- expression in cells. pai- expression followed by rv infection elicited a synergistic response and pai- over-expression reduced vrna by > fold and viral titre by > log (p < . ). however, this effect was not specific to pai- , as transfection of cells with control genes/plasmids reduced viral titre to a comparableextent. one of the pathological findings in idiopathic pulmonary fibrosis (ipf) is the presence on fibroblastic foci comprising cells which exhibit mesenchymal phenotypic features such as myofibroblast-like morphology, increased asma expression and collagen deposition. currently steroid treatment in ipf has shown limited efficacy. the cellular origins of these mesenchymal cells remain unclear, but evidence from other studies suggests that epithelial cells may undergo a transition to a mesenchymal cell phenotype (emt). transforming growth factor ß has been implicated in promoting this emt. in this study we have induced a morphological change in a cells using tgf-ß and assessed the influence of glucocorticoids, and the changes to the extracellular environment of the cells, on emt. methods a cells were grown on uncoated plastic cultures plates or those coated with monomeric or fibrillar collagen and treated with - pm tgf-ß . the influence of the glucocorticoid, dexamethasone (dex, - nm), or collagen type, on emt was assessed by microscopy, rt-pcr and western blotting for markers of myofibroblast phenotype. results tgf-ß induced an increase in mrna expression of asma ( . fold), collagen ( . fold) and fibronectin ( . fold). dex ( nm) partially inhibited the expression of collagen, but had no effect on asma levels. however, dex ( nm) reduced asma and ctgf protein levels. dex ( nm) also prevented the tgf-ß -induced morphological changes, regardless of ecm matrix. conclusion glucocorticoids appear to control some of the emt phenotype changes induced by tgf-ß . however, the inability to fully inhibit these changes may contribute to the resistance of ipf to glucocorticoids. the extracellular environment may also play a role in the development of fibroblastic foci and their pharmacological responses. defective alveolar macrophage (am) phagocytic function in the airway may perpetuate inflammation via secondary necrosis of uncleared apoptotic cells in copd. we have previously reported that low-dose azithromycin improved macrophage function in vitro, although the mechanisms for this effect were not identified. we explored the possible role of the collectin pathway in the azithromycin-mediated improvement in phagocytosis as well as possible defects in this pathway in copd subjects. methods ( ) mannose binding lectin (mbl), mannose receptor (mr), surfactant protein d (sp-d) were measured in copd subjects and controls. ( ) the in vitro effects of addition of rhmbl, and blocking mr with a specific antibody, on am phagocytic ability were assessed. in vitro effects of azithromycin on am expression of mr were also investigated. ( ) azithromycin ( mg orally ¥ weekly/ weeks) was administered to copd subjects. bronchoscopies were performed prior to and weeks following therapy. ex vivo assessments included am phagocytic ability, levels of mbl, sp-d and mr and apoptosis of bronchial epithelial cells. results am mr expression and levels of mbl and sp-d were significantly reduced in copd subjects vs controls. azithomycin ( ng/ml) increased mr expression by % in vitro. rhmbl induced a dose-dependent increase in am phagocytic ability (up to %). blocking mr significantly decreased am phagocytic ability by %. in copd patients following azithromycin therapy, we observed improved am phagcocytic ability, increased levels of mr and reduced levels of bronchial epithelial cell apoptosis. conclusions these findings strongly implicate the mr in both the defective phagocytic function of am in copd and as a target for the azithromycinmediated improvement in phagocytic ability. obstructive sleep apnea (osa) is associated with hypoxia and increased cardiovascular morbidity. t cells and monocytes play a significant role in atherogenesis via cytokine production. there have been reports of benefits of continuous positive airway pressure (cpap) therapy in osa. the purpose of this study was to characterize leucocyte inflammatory cytokine/chemokine production by t cells and monocytes in a group of osa patients and to investigate the therapeutic effects of cpap therapy. methods a comprehensive range of intracellular t-cell and monocyte proand anti-inflammatory cytokines/chemokines was investigated in peripheral blood from osa patients and aged-matched control subjects (with no evidence of sleep problems) using multiparameter flow cytometry. osa patients were again studied following days of cpap therapy. results in osa patients there was an increase in intracellular t-cell ifng and tnfa production but no change in il- , il- or tgfb compared with control. there was an increase in intracellular monocyte il- a, il- , tnfa, mcp- and mcp- in osa patients but no change in il- or il- . following cpap therapy, t-cell ifng and tnfa production returned to 'normal' levels. however, although intracellular monocyte cytokine/chemokine production was decreased following cpap, levels were significantly elevated compared with control. conclusions osa is associated with increased intracellular proinflammatory cytokine/chemokines, many of which are increased in atherosclerotic plaques. although one week of cpap therapy resulted in amelioration of t-cell pro-inflammatory cytokines, longer cpap use or alternative therapy may be required to reduce monocyte pro-inflammatory mediators associated with atherosclerosis in patients with osa. gp has been associated with the progression of fibrosis especially in patients with idiopathic pulmonary fibrosis (ipf). gp is the common subunit of the receptor complexes for the il- family of cytokines including il- and oncostatin m (osm), where gp -mediated signalling leads to activation of the erk or stat pathways. we have previously demonstrated exaggerated gp -stat signalling to be fundamental to the development of pulmonary fibrosis in a murine model of bleomycin-induced lung fibrosis. the aim of this study was to elucidate the role of the il- cytokine family in the development of pulmonary fibrosis by identifying which il- family cytokines regulate fibrosis in bleomycin treated mice, and determine the effects of these cytokines on cell function. bleomycin ( . u/mouse) or control saline was administered intranasally to wildtype mice (wt), genetically engineered mice containing point mutations to prevent gp erk signalling (gp f ) or gp stat signalling (gp dstat ), and duel il- and il- a-receptor knockout mice (il- -/-;il- ar -/-). the effect of bleomycin on collagen production was examined in lung tissue days post treatment by hplc. there was a significant increase in collagen levels in bleomycin treated wt lungs which was further increased in gp f lungs. the lungs of gp dstat and il- -/-;il- ar -/mice were protected from fibrosis suggesting that gp -stat signalling is important in inducing lung fibrosis which may be mediated through il- and/or il- . cell proliferation was examined in lung fibroblasts isolated from wt, gp dstat and gp f mice. il- , il- and osm were significantly mitogenic for gp dstat cells but not for wt or gp f cells, reflecting different responses to the different signalling pathways. changes in cytokine profiles are currently being examined in lung tissue and serum of control and bleomycin treated mice - days after treatment. in conclusion, il- and il- are likely to play a role in bleomycin-induced fibrosis via the gp -stat-mediated pathway, however this may not be due to regulation of proliferation induced by these cytokines. supported by the nhmrc. mimicking viral infection by application of various toll-like receptor ligands has shown clinical promise in the treatment of persistent viral infections and more recently with malignant tumours. commercially available toll-like receptor ligands (tlr l), such as those of the imidazoquinoline family have been applied clinically for the treatment of a number of conditions including basal cell carcinoma and hpv-induced genital warts. these compounds are known to retard tumour growth indirectly by promoting activation and migration of dcs, leading to a strong th cellular response, and directly via release of proinflammatory cytokines and promotion of tumour cell apoptosis. malignant mesothelioma (mm), an aggressive tumour with a mean survival of months, is highly resistant to chemotherapy, radiotherapy and surgery and is therefore an interesting candidate for immunotherapy in the form of tlr ligand treatment. whilst tlr is known to be selectively expressed in immune cells and its relative expression low amongst other cell and tissue types in mammals, its expression on tumour cells and the consequences of such expression on tumour growth are unknown. here we describe the presence of tlr (mrna and protein) directly in a range of different tumours, including several murine and human mm cell lines. reactive oxygen species (ros) produced during the innate immune response are important agents of anti-pathogen defense but may also cause oxidative lung damage. glutathione peroxidase- (gpx- ) is a detoxifying enzyme that may protect lungs from such damage. methods wild-type (wt) or mice deficient in glutathione peroxidase- (gpx- -/-) were placed in a perspex chamber and exposed to cigarette (cig) smoke generated from cigs per day for days. on the fifth day, mice were killed, the lungs lavaged with pbs and then harvested for proteomic and genomic analysis. results wt mice exposed to cig smoke for days had significantly more macrophages ( . Ϯ . (sem) ¥ ) and neutrophils ( . Ϯ . ¥ ) than sham-exposed mice ( . Ϯ . ¥ and , respectively) (n = , p < . ). however, gpx- mice exposed to cig smoke had significantly greater macrophages ( . Ϯ . ¥ ) and neutrophils ( . Ϯ . ¥ ) than smokeexposed wt mice (n = , p < . ). macrophage and neutrophil numbers in sham-exposed gpx- -/mice ( . Ϯ . ¥ and . Ϯ . ¥ ) were similar to those of sham-exposed wt mice ( . Ϯ . ¥ and ). in addition, we found that balf of gpx -/mice exposed to cig smoke had an increased proteolytic burden compared with smoke-exposed wt mice as assessed by zymography and net gelatinase activity assay. conclusions these data suggest that gpx- protects the lung from cigarette smoke-induced inflammation and that targeting gpx- may have therapeutic utility in inflammatory lung diseases where cigarette smoke plays a role. funded by nhmrc. the becs from subjects with chronic obstructive pulmonary disease (copd) are exposed to frequent infectious and inflammatory stimuli. infection with rv is known to trigger acute exacerbations and subjects with copd are particularly susceptible. we hypothesized that exposure of copd becs to these stimuli would alter their response to rv infection. methods bec were obtained by endobronchial brushing from subjects with gold stage copd (n = , all ex-smokers), subjects with mild persistent asthma (n = ) and healthy controls (hc, n = ). becs were cultured and then treated with tumour necrosis factor (tnf)a ng/ml or lps mg/ml for hrs and then infected with rv- , rv- b. response was measured by release of il- , il- and ip- mrna and by elisa. virus replication measured by cell titration assay. results infection with both rv strains led to increased release of il- and ip- in all groups. exposure of hc and asthma becs to both lps and tnf led to increased release of il- . in these becs there was no increase in release of il- exposed to lps and tnf and then infected with either rv. becs from subjects with copd released significantly less il- in response to all conditions and rv infection compared to hcs and asthma. no differences were seen in rv replication. the aim of this study was to determine opinions and attitudes to exercise from chronic obstructive pulmonary disease (copd) subjects after completion of a -month maintenance exercise program. methods following completion of a -month exercise study, which included a supervised program (intervention, n = ) and control group (control, n = ), copd subjects [mean age (sd): ( ); mean fev (% predicted) = % ( )] were asked to complete a questionnaire. the questionnaire included closedended questions using visual analogue scales ( mm). in copd the minute walk distance ( mwd) is known to increase with test repetition (familiarization) and in response to exercise training. it is unknown whether the magnitudes of these increases are related to the degree of disability of the individual patient. methods mwd was measured twice before and once after an week out-patient exercise program in patients ( males) aged Ϯ . yrs, fev Ϯ % predicted (meanϮsd) with stable copd. the changes in mwd following a familiarization test and following training were compared between patients grouped according to their degree of disability (defined as the pre-training mwd [best of tests] expressed as %predicted mwd). *p < . gp vs gp . conclusions before training, mwd increases following a familiarization test irrespective of the level of disability. the magnitude of this increase is similar in all groups when normalized for their pre-training mwd. following training, the increase in mwd is greatest in patients with the greatest disability (lowest pre-training mwd). in less disabled patients, the relatively smaller increase in mwd following training may reflect an inability to further increase stride length, thereby reducing the responsiveness of the mwt in this group. supported by nhmrc. endotoxin is a stimulant of the innate immune system and is a major component of cigarette smoke. smokers have evidence of increased airway neutrophils and inflammation. we hypothesized that endotoxin levels would be higher in the bronchial lavage (bl) of subjects who were former smokers and subjects with chronic obstructive pulmonary disease (copd). methods subjects were all ex-smokers for at least years (n = , copd, healthy controls) or never smokers (n = , asthma, healthy controls). bl was collected and analysed for cell count and differential, culture for microbiology. the supernatant was analysed for il- by elisa and endotoxin by quantitative kinetic lal assay. results median endotoxin levels were significantly higher in ex-smokers compared to never smokers . u/ml (p < . ). there were no differences between subjects with copd and hs. subjects with copd had higher median endotoxin levels ( u/ml), compared to asthma ( . u/ml) and hc ( . u/ml, p = . ). there was no correlation between endotoxin levels and bl total cell count, neutrophils (%) or fev % predicted. there was a strong correlation with previous packet years smoked and endotoxin levels (r = . , p < . ). conclusions bl endotoxin levels are higher in ex-smokers, including subjects with copd. despite this there is no relationship to increased neutrophilic inflammation. copd is associated with inflammation associated with ineffective repair of the injured epithelium and loss of structural integrity. we have shown that these changes may result from dysregulated 'efferocytosis' (increased apoptosis of bronchial epithelial cells and defective clearance of these cells by alveolar macrophages (am)). we have also reported that azithromycin, at subbactericidal dose, improved am phagocytic function ex vivo. methods we administered azithromycin at low dose ( mg/ twice weekly for weeks) to copd subjects ( male, age: Ϯ yr, current/ ex-smokers, fev : Ϯ % pred, fev /fvc: Ϯ %). the study was openlabel, uncontrolled and primarily focused on objective biological responses obtained from the bronchoscopy samples taken. phagocytic ability of am (from bal), apoptosis of bronchial epithelial cells (from bronchial brushing), markers of inflammation in blood, bal and breath condensate (crp, wcc and inflammatory cytokines), health status (st. george's respiratory questionnaire), ecg and lung function were assessed pre and post-administration of azithromycin. results azithromycin significantly improved phagocytic ability of am (by %) and reduced bronchial epithelial cell apoptosis (by %). antiinflammatory effects of azithromycin included significantly reduced blood wcc and crp. there were non-significant reductions in levels of pro-inflammatory cytokines il- , il- and tnf-a in blood, bal and breath condensate, and a trend for improved health status. conclusions our findings indicate a novel approach to supplement existing therapies in copd that may improve clearance of accumulated apoptotic material and reduce the risk of secondary necrosis and release of toxic cell contents that perpetuate inflammation. background the prevalence of gastro-oesophageal reflux disease (gord) across the disease spectrum in copd and bronchiectasis is not well described. the aim of this study was to determine the prevalence of symptomatic and silent gord in copd and bronchiectasis and its effect on lung function and quality of life (qol ] ) and healthy controls were recruited. the prevalence of gord in bronchiectasis was %; % in copd; % in controls. in copd and bronchiectasis, total nre and ri were increased in those with distal and proximal gord compared to those without gord (all p < . ). there was no difference in extent or severity of bronchiectasis in patients with or without gord (all p > . ). in copd, the relationship between proximal gord and fev was small to moderate (r = . ). sgrq symptom scores were higher in patients with bronchiectasis with increased ri (p = . ). increased proximal nre was associated with reduced physical (p = . ) and mental health (p = . ) in the sf- in copd. conclusions gord is a co-morbidity in patients with copd and bronchiectasis. the impact of gord on disease severity requires further evaluation. funding source nhmrc, the university of melbourne, monash university, physiotherapy research foundation. chronic obstructive pulmonary disease (copd) is prevalent among older people, however little is known about the influence of ageing on airway inflammation. the aim of this study was to compare airway inflammation in older people with obstructive airway disease to groups of older and younger healthy controls. methods participants (> years of age) with stable airway disease and incomplete reversibility (fev % predicted < % and fev /fvc < %; copd n = ) and healthy controls (n = , older > years and younger < years) were recruited from the respiratory ambulatory care clinic or by advertisement. participants underwent a clinical assessment, skin allergy test, hypertonic saline challenge, sputum induction and gas diffusion studies. results participants with copd had moderate airflow obstruction (mean (sd) fev % predicted ( )) and ( %) were current or ex-smokers with a median (iqr) pack year history of ( - ) pack years. ageing was associated with an increase in airway neutrophils (p = . ). compared to older controls, participants with copd had increased airway eosinophils and lymphopenia (p = . , p = . respectively), but no difference in airway neutrophils. conclusion airway neutrophilia is a feature of ageing and is not further increased in the presence of copd. copd is associated increased numbers of airway eosinophils with reduced lymphocytes which may impact on the ability of the immune system to combat infection. supported by nhmrc, the university of newcastle. chronic obstructive pulmonary disease (copd) is third leading cause of death and fourth leading cause of disease burden in australia. mechanisms involved in emphysema severity have not been fully understood. micrornas are noncoding rnas that regulate gene expression. we hypothesize that microrna expression differs between emphysema severity in copd patients. methods mirna profiling was performed using k agilent human oligo mirna microarrays on total rna extracted from non-tumour lung tissue from copd patients undergoing resection for lung cancer. the mirnas were quantile normalized and anova was used to find differentially expressed genes. results demographic characteristics of the copd patients (mean (sd)) were age ( ) years, fev ( ) % predicted and fev /fvc ratio (< %). anova identified mirnas that were differentially expressed when stratified into two classes according to kco % predicted > or < % (t-test, p < . ). discussion this mirna analysis has identified mirnas that may be important in emphysema severity in copd patients. further validation will be performed using qrt-pcr and mirna assays on the training set and an independent set, and target prediction and validation. t-helper type (th ) and type (th ) lymphocyte responses have been well recognized as being important pathways in inflammation. recently another form of inflammatory lymphocyte response has been described, the th pathway. th cells produce cytokines such as il- a to clear extra-cellular bacteria and fungi and have been implicated in autoimmune and chronic inflammatory diseases. the th response in copd is unknown. methods subjects were patients with copd (ex-smokers, fev < % predicted who had not had an exacerbation for at least month) and control subjects (ex-smokers and normal spirometry). serum samples were obtained for measurement of c reactive protein (crp) and il- a, the latter measured using enzyme-linked immunosorbent assay (elisa). production of il- a by t-cell subsets was also identified by intra-cellular cytokine staining and measured by flow cytometry. the mean fev of copd subjects was % predicted ( . sem, n = ) and mean fev of controls was % predicted ( . sem, n = ). the copd group had a higher mean level of crp . mg/l ( . sem) compared to the control group mean level of . mg/l ( . sem). the mean level of the il- in the copd group as measured by elisa was . pg/ml ( . sem, range - ) whilst no il- was measured in any of the control subjects. conclusions the findings of this pilot study suggest that il- may be elevated in association with crp in stable copd. airway obstruction is defined as a fev /fvc ratio below the lower limit of normal. airway obstruction may prolong the forced expiratory time (fet). method spirometry results from patients were categorized as obstructive, restrictive or normal. the mean, range and coefficient of variation were determined for fet in each diagnostic group. receiver operator characteristic (roc) curves were used to determine if fet could predict a low fev /fvc. the number of patients with airway obstruction in five fet groups: < ; ; - ; - ; and > seconds were determined. results the coefficient of variation was high for all groups. pair-wise comparisons showed a difference in mean fet between patients with normal lung function versus those with airway obstruction (p < . ). the best cut-point in the roc analysis of . seconds had a sensitivity of . , specificity . and area under the curve of . for predicting obstruction. the technique of skeletal muscle microbiopsy has previously been validated [ ] and shown to be minimally invasive and well tolerated in participants with stable copd. aim a study was undertaken to determine the feasibility and tolerability of obtaining microbiopsy muscle samples from the patient admitted for acute exacerbation of copd patient. methods written informed consent was obtained to collect the muscle, blood and sputum samples for research purposes. local anaesthetic was injected prior to the insertion of a gauge bard max core disposable biopsy instrument through the associated guide needle. multiple passes (up to ) were obtained. the patient was asked to evaluate the experience by rating it on the modified borg scale - . results to date patients and controls have participated in this study. the gold severity ranged from - and ats exacerbation severity - . the mean age years (range - years), bmi mean . kg m - (range . - . kg m - ) and fat free mass was determined using single frequency bioimpedance. the sample mass obtained ranged from . - . mg, with an increasing yield occurring with increased experience of the operator. the procedure has been well tolerated, the borg scale rating ranged from - / . all patients were ambulant post procedure; no haematoma or bruising was observed in any of the subjects. conclusion the microbiopsy technique allows the collection of muscle tissue with minimal discomfort to the participant. small tissue masses such as these are sufficient to obtain measures of local markers of wasting and may prove to be a useful adjunct to the collection of sputum and blood for the measure of biomarkers in copd research. introduction older people (op) with obstructive airways disease (oad) experience multiple problems that may impact on their quality of life (qol) and disease management. these problems may relate to pathophysiology, symptoms, self management skills, psychological issues, lifestyle or other problems identified as important by the patient. aim the aim of this study was to determine the frequency of clinical problems associated with oad and to determine if a problem based assessment (pba) could adequately identify these problems. methods a multidimensional assessment tool was developed and the content compared to clinical practice guidelines. participants over years with diagnosed oad underwent this assessment. results sixty-one consecutive patients, aged - years, with mean (sd) fev of . ( . ) % predicted were assessed. the assessment tool identified a mean (sd) of . ( . ) current and significant co morbidities with an additional ( . ) clinical problems per patient. qol was increasingly impaired with an increasing number of problems (p < . ). regression modelling identified that the number of identified clinical problems accounted for % of the qol impairment. the model demonstrated that every additional patient problem was associated with a clinically significant change in qol impairment ( . units) . conclusions op with oad experience multiple clinical problems and co morbidities that adversely impact their qol. a pba of op with oad identifies significant problems that may not be addressed in a diagnosis centred approach. there is a need to identify and effectively manage this array of problems in clinical practice. discussion in this diverse group of copd patients, there was a positive correlation between dlco and fev , but not kco and fev . the fev / kco plot identifies substantial numbers of patients with the potential ad and e phenotypes defined above. we intend to study inflammatory biomarkers in these groups. fat free mass index (ffmi) is a marker of morbidity and mortality in copd. measurement of ffm in the out-patient population is commonly undertaken using single frequency bioelectrical impedance analysis (bia). however the formulae to convert measured values to ffm are population dependent. schols et al (am j clin nutr, ) suggested that formula used for the general population may be inappropriate for patients with copd, and derived a specific formula from total body water (tbw) as measured by deuterium dilution. we compare this method of measuring ffm with others, along with tbw and ffm hydration. methods tbw was measured in outpatients with copd by bia and a difference method (weight-(protein+bone mineral+fat+non-bone mineral+ glycogen)) and ffm hydration was calculated. ffmi was measured by skin fold anthropometry (sfa), bia ( separate formulae), dual energy x-ray absorptiometry (dexa) and total body potassium by g-counter (tbk). comparison between methods for tbw and ffmi was made by bland-altman analysis and between methods of calculation of ffm hydration by paired t-test. the two methods of assessment of tbw showed little difference (bias - . , % limits of agreement - . to . ). however there was a significant difference in calculation of hydration of ffm (p = . ). sfa, bia (lukaski), bia (tanita) and tbk underestimated ffmi when compared to bia (schols), with bias of - . , - . , - . and - . respectively. dexa however had a bias of only . and % loa of - . to . . conclusions there are differences between methods of assessment of tbw and ffmi and comparing values between methods must be done with caution. this has implications for assessment of morbidity and mortality in copd. chronic obstructive pulmonary disease (copd) has been identified as a major health problem in australia. recent studies have suggested that respiratory viral infections are the major cause of a worsening of copd; however this has not been studied in australia. aim to characterize pef changes and identify viruses during copd exacerbations. methods a pilot prospective longitudinal cohort study was done. patients had confirmed copd with fev < % predicted and reversibility < % and/or ml. patients recorded daily peak expiratory flow (pef) measurements and daily chest and cold scores over a period of years. sputum samples and nasal aspirates were taken at -month review (control visit) and whenever they had symptoms of an exacerbation (worsening of copd symptoms -seemungal et. al. am j resp crit care med, ). nasal aspirates and sputum samples were obtained and analysed by rt-pcr for rhinovirus (rv). result five patients have finished years of study. a total of exacerbations were reported based on patient symptoms. only exacerbations were associated with significant reductions in pef and only one was linked to increases in nasal cold scores. all samples taken at control visits and nasal aspirates and sputum samples during exacerbations were negative for rv by rt-pcr. positive controls confirmed the accuracy of the assay. conclusion our data suggest that a symptom-based definition of copd exacerbation is not always accompanied by significant reductions in lung function parameters. these 'exacerbations' are also not associated with the commonest reported viral cause. our findings suggest that variability of copd may mimic. bronchiectasis is characterized by hypersecretion of mucus and impaired clearance that results in mucus accumulation, chronic cough, sputum production and recurrent infections. inhaled mannitol ( mg) improves clearance of mucus by increasing the airway hydration and by reducing the viscoelastic and surface properties of mucus. however, the effect of other doses of mannitol on the clearance of mucus in patients with bronchiectasis is unknown. methods fourteen patients, age: . Ϯ . yr, were studied on visits. clearance of mucus was measured using m tc-sulphur colloid and imaging with a gamma camera at baseline and with mannitol ( weight loss and skeletal muscle atrophy are major determinants of morbidity in chronic obstructive pulmonary disease (copd), which are independent of lung function impairment. thus, we examined if a high-fat diet (hfd) protected against the wasting associated with prolonged cigarette smoke exposure (se) in mice. methods male balb/c mice were exposed to the smoke of cigarettes/day, days/week for weeks. sham mice were handled identically without smoke exposure. mice consumed either standard laboratory chow ( . kcal/g, consisting of % fat) or a hfd ( . kcal/g, % consisting of fat). we examined the effect of se and hfd on hind limb skeletal muscles, lung (tissue & bronchoalveolar lavage (balf)) and systemic inflammation in the groups of mice (n = / group). results after weeks of hfd, sham and se mice were and % heavier (respectively, p < . ) than chow fed animals. conversely, se significantly decreased body weight of chow and hfd fed mice by and %, respectively, compared to sham animals (p < . ). the hfd did not protect against the decrease in soleus, tibialis anterior and gastrocnemius skeletal muscle weights induced by se (p < . ). se altered the mrna expression of a number of genes associated with the regulation of skeletal muscle mass including insulin-like growth factor-i (igf-i), atrogin- and interleukin (il)- . the mrna expression of pro-inflammatory cytokines and chemokines was significantly increased by se in the lung, as were the number of inflammatory cells in balf (p < . ). on the other hand, although obesity has been linked to systemic inflammation, the hfd exerted little direct effect on the skeletal muscle and lung parameters measured. se and hfd had no effect on two markers of systemic inflammation, il- and serum amyloid a, whereas se tended to reduce circulating igf-i, an anabolic hormone. conclusions the hfd was not protective against the weight loss and skeletal muscle wasting associated with cigarette smoke exposure. supported by the nhmrc and crc for chronic inflammatory diseases. background patients with copd and bronchiectasis undertake airway clearance therapy (act) and exercise as part of physiotherapy management but it is unknown whether these treatments provoke gastro-oesophageal reflux (gor). this study aimed to determine the impact of positive expiratory pressure (pep) therapy and exercise on gastro-oesophageal function. p. aeruginosa is a significant opportunistic lung pathogen in individuals with cystic fibrosis (cf) and is associated with increased lung disease and morbidity. early intervention is beneficial for the effective clearance of p. aeruginosa and better long-term health outcomes. currently, lung flora of cf patients is monitored by regular culturing of sputum, however, children unable to expectorate are limited to annual bronchoalveolar lavages (bal), which is invasive and requires general anaesthesia. saliva is useful for clinical assays as collection is simple, non-invasive. we are developing a standardized enzymelinked immunosorbent assay (elisa) to detect respiratory infection of p. aeruginosa in cf children who cannot expectorate. methods children ( - years) with cf and recent p. aeruginosa lung infection history and non cf children ( - years) with no previous p. aeruginosa infection history provided saliva as positive, negative controls respectively. saliva was obtained by spitting, or absorbed using cellulose swabs and later extracted. these cell-free supernatant samples were used in an elisa anti-p. aeruginosa iga using commercial antigen. all results were standardized to account for flow using total iga expression. results median value was increased fold in the recent p. aeruginosa lung infection group (mann-whitney test, n = , p Յ . ). there was no significance between mucoid and non mucoid samples, and detection was independent of cfu/ml. discussion early findings support that p. aeruginosa respiratory infection can be detected through specific analysis of salivary iga expression. larger population sampling ( positive, negative) will aid selection of cut-off values for specificity and sensitivity testing in the future to objectively determine the utility of this assay as a means of monitoring for p. aeruginosa and for determining effectiveness of treatment. medical thoracoscopy is utilized widely throughout europe and northern america by thoracic physicians for the management of pleural disease, including the undiagnosed pleural effusion, malignant effusions and less commonly pneumothorax (ptx). australia has limited experience in this modality. we report the success of medical thoracoscopy in both primary and secondary ptx requiring intervention. methods data were collected from to in patients treated with medical thoracoscopy for the treatment of ptx. results patients, male, female. average age (range - ). first episode primary spontaneous (ps) ptx, third episodes of ps, first secondary spontaneous (ss), second ssptx, third ssptx. underlying pulmonary disease in secondary ptx included: chronic obstructive pulmonary disease, lymphangioleiomyomatosis, mesothelioma, metastatic angiosarcoma and was secondary to a motor vehicle accident. had a history of smoking, were former smokers and were current smokers, with a mean pack year history (range - ). ptx were large, moderate. patients had an intercostal catheter (icc) inserted prior to thoracoscopy, had failed pleural aspirate. there was evidence of bronchopleural fistula in patients prior to the procedure. there was a median of days from ptx to thoracoscopy. light sedation was used for the procedure in patients, required a general anaesthesia with a double lumen endotracheal tube due to anxiety. single port entry, dry talc poudrage and a gauge french icc was used for all procedures. icc was removed a mean of days following thoracoscopy and patients discharged on day . pain was the most common complication, requiring narcotic analgesia. one patient died on day , secondary to metastatic angiosarcoma. there has been no recurrence of ptx in any patient. conclusion medical thoracoscopy, performed by thoracic physicians is an effective procedure for the treatment of pneumothorax requiring intervention, including selected patients with evidence of bronchopleural fistula. funding nil. conflict of interest nil. nomination for young investigator award no. background lung cancer incidence and mortality are high in tasmania. australia (aihw ) / / tasmania (cancer registry ) / / aims and objectives (a) to determine patient demographics in southern tasmania, (b) to determine compliance to identified measures of best practice and (c) assess referral rates, clinical utility and potential delay to positron emission tomography (pet) in a regional setting. methods a prospective database collected information on local clinical practice. cases presented at a multidisciplinary lung cancer meeting over a month period (march -april were analysed. data were available for n = / ( %). results are shown as mean Ϯ sd. results primary lung cancer cases were identified. the mean age was Ϯ years. % of patients were male and % were current or ex-smokers. % were non-small cell lung cancers (nsclc). tissue diagnosis % time from diagnosis to surgery ( Ϯ days) % < days macroscopically complete surgical resection ( / ) % pet for stage iiib before radical chemoradiotherapy % % of patients presenting with early or locally advanced disease underwent further staging with pet (n = / ). management was changed in % of cases ( / ). the average time from pet referral to scan was Ϯ days. conclusion a disproportionate number of lung cancers occurred in women. although surgery was performed within recognized timeframes, of patients had incomplete resections. pet influenced management decisions and was performed in a timely fashion. hp chan , , v tran , , c lewis , , p thomas exhaled breath condensate (ebc) is a simple, safe and non-invasive method of sampling breath and has the potential to investigate lung cancer and the associated neoplastic process in the lungs. increased oxidative stress has been implicated in the pathogenesis of lung cancer, and is characterized by elevated hydrogen ions, and hydrogen peroxide (h o ), which is formed from the conversion of superoxide anions by superoxide dismutase. airway ph has already been shown to be decreased in ebc of patients with other respiratory conditions, but not in lung cancer. therefore the concentration of h o and hydrogen ions in the ebc of lung cancer subjects was compared with matched controls. methods six subjects with newly diagnosed lung cancer were recruited and matched with control subjects: non-smokers, ex-smokers and smokers. ebc was collected and h o was then measured by an assay method based on oxidation of , ', , '-tetramethybenzidine by horseradish peroxidase and h o while ph was measured using a ph meter. results there was a significant difference (p = . , anova) in h o concentration between the groups with the lung cancer group having elevated mean h o concentration of . mm ( . (sem) compared to the controls: non-smokers, . mm ( . (sem); ex-smokers, . mm ( . (sem); and smokers, . mm ( . (sem). ph did not differ significantly (p = . , kruskal-wallis test) between the groups. conclusion these preliminary data suggest that there is significant difference in h o concentration between the groups. the demonstration of an elevated h o level in those with lung cancer indicates an increase in oxidative stress which implies that this may be part of the pathogenesis or response to neoplasia. supported by none. conflict of interest none. pro-inflammatory th cytokines produced by t cells and monocytes play an important role in the immune response to malignant cells. however, tumours may escape immune surveillance by inhibiting th response and promoting chronic inflammation at the tumour site. methods to investigate the effect of soluble factors released by lung cancer cells on t cell and monocyte pro-and anti-inflammatory cytokines, culture supernatants from several lung cancer cell lines and a normal epithelial cell line ( hbe) were cultured with whole blood for hours, then for a further hrs with and without stimuli. intracellular cytokine / chemokine production was determined using multiparameter flow cytometry. results in stimulated cultures, there was a significant decrease in t cell th pro-inflammatory cytokines ifng, tnfa and il- and a decrease in monocyte il- a, il- , il- , tnfa, mcp- and mcp- but an increase in antiinflammatory cytokine il- compared with hbe and control media. in non-stimulated blood cultures there was an increase in all monocyte inflammatory cytokines / chemokines in the presence of lung cancer supernatants. conclusions lung cancers secrete soluble factors that inhibit the antitumour pro-inflammatory th response by t cells and monocytes and upregulate monocyte anti-inflammatory cytokine il- following "antigenic challenge". lung cancer cells may also escape immune surveillance by secreting soluble factors that cause newly recruited monocytes to release inflammatory cytokines promoting chronic inflammation at the tumour site. cytotoxic t-cells (ctl's) are important barriers against tumour cells. ctl's induce apoptosis of target cells by mechanisms that include the release of pore-forming perforin and granule associated enzymes, such as granzyme b and granulysin. proteinase inhibitor- (pi- ) is the only known granzyme b inhibitor and its expression has been observed in some cancers. we hypothesized that pi- would be differentially expressed in lung cancer cells and may inhibit granzyme b-induced apoptosis in these cells. methods we investigated pi- , granulysin and granzyme b expression in various lung cancer cell lines ( ( , ( , and normal epithelial cells obtained from bronchial brushing using flow cytometry. peripheral bloodderived t-cells were then incubated with lung cancer cell line supernatants and levels of pi- , granzyme b and t-cell reactive oxygen species (ros) were assessed. results pi- expression was detected in all lung cancer cell lines, ( ( . %), ( . %), ( %), sbc- ( %)), at much higher levels than in normal bronchial epithelial cells ( . %). granzyme b and granulysin levels were undetectable or low in cancer cells ( - . %). increased expression of pi- and reduced levels of granzyme b were observed in cd + t-cells in the presence of all cancer cell supernatants tested (p < . ). interestingly, t-cell ros levels were significantly increased in cd + t-cells after incubation with cancer cell supernatants (p < . ). conclusions high pi- expression in lung cancer cells combined with a reduction in t-cell granzyme b expression and enhanced intracellular t-cell ros levels may be a mechanism of immune evasion of lung cancer cells to granzyme b-induced cytotoxicity. immunotherapy for lung malignancies such as lung cancer and mesothelioma is most likely to be successful it it can be combined with conventional tumour debulking approaches such as chemotherapy and surgery. but they scientific basis of such combinations is yet to be determined. to study this we evaluated ( ) the capacity of different lung chemotherapy drugs to alter tumour antigen cross-presentation and immunogencity, ( ) duration of antigen presentation and responsiveness to immunotherapy after debulking surgery with/without lymphadenectomy, and ( ) the pattern of tlr agonism which best synergized with chemotherapy and surgery. we used the ab -ha murine model of lung malignancy in balb/c mice. results ( ) the antimetabolite drugs gemcitabine and pemetrexed were most immunogenic compared to the cytotoxic antibiotics doxorubicin and mitomycin c and the alkylating agent cisplatin. gemcitabine delived large amounts of tumour antigen into the cross-presentation pathway. ( ) tumour antigen cross-presentation persisted for only days following resection. the optimal window for immunotherapy following cancer surgery is week for effector ctl stimulation and - weeks for memory ctl stimulation. ( ) the viral-like tlr agonists tlr , and were the most effective adjuvant tlr molecules, with tlr agonists generating the strongest systemic anti-tumour responses. conclusion these results help explain previous lung immunotherapy failures and will inform new clinical trials. background mesothelioma is a highly aggressive tumour with an increasing world wide incidence. the serum biomarker mesothelin is elevated in some individuals prior to development of clinical symptoms of the disease and may be useful for screening. we therefore studied the sensitivity and specificity of urinary versus serum levels of mesothelin for mesothelioma patients and evaluated the influence if renal function on the biomarker level. materials and methods concurrent sera and urine samples collected from patients with and control populations. mesothelin concentrations were determined by double-determinant elisa using the mesomark tm assay (fdi, pa). their estimated glomerular filtration rate (egfr) was also calculated. results mesothelin levels correlated between serum and urine samples (pearson's correlation . ; p < . ). mesothelin levels were significantly higher in patients with mesothelioma compared to those with asbestosis and/or pleural plaques in serum ( Ϯ . versus . Ϯ . nm; p < . , respectively), in urine ( . Ϯ . versus . Ϯ . ; p < . ) and in urine following normalization using creatine levels ( . Ϯ . versus . Ϯ . ). age and egfr were significantly associated with mesothelin levels. conclusion the sensitivity and specificity of mesothelin in urine and in serum were comparable. urine mesothelin may prove to be a useful alternative to serum mesothelin for mass screening of asbestos-exposed individuals. patients undergoing ct coronary angiogram (cta) are often former or current smokers with a high incidence of asymptomatic lung disease. overseas reports show a rate of lung abnormalities ranging from . % to %. there are no studies from australia and local factors such as the higher incidence of atypical mycobacteria may influence the rate of benign findings. we are therefore performing a prospective observational study to identify the prevalence and characteristics of incidental lung findings in people undergoing routine cta. methods population: patients undergoing routine cta after informed consent. intervention: radiologist evaluation of lung windows on diagnostic standard workstations. comparator: uncontrolled observational study of consecutive patients. outcomes: primary: prevalence and characteristics of abnormal findings, final diagnosis (clinical judgment, biopsy or long term followup). secondary: number of downstream investigations and costs. results ctas have been studied to date. in / ( %), abnormalities were noted on lung windows. in / ( %), there were lung nodules, in / ( %) there were hilar lymph node abnormalities, in / ( %), there was hemidiaphragm elevation and in / ( %) there were pleural plaques (data collection ongoing with study closure expected in february ). conclusions preliminary data indicate a substantial number of incidental pulmonary findings from cta; full results will be presented. further analysis is required to determine the impact (benefits, costs and harms) that may result from the concurrent examination of lung windows at routine cta. aim increased levels of nitrogen oxides (nox) and inflammatory markers have been found in bronchoalveolar fluid of lung cancer (lc) patients, but have not been investigated in exhaled breath condensate (ebc).the aim of this study was to compare nox and total protein levels in ebc of lc patients with control subjects. methods ebc was collected during tidal breathing through a glass collection device cooled to °c. ebc nox concentrations were measured by a fluorescent modification of the greiss method. total protein in ebc was determined employing the bicinchoninic acid (bca) assay. ebc nox data were log transformed. all data were analysed using anova and expressed as mean Ϯ sem. results a total of control subjects and patients with primary lc were recruited. nox and protein concentrations are shown in table . there was no significant difference in ebc nox levels (p > . ), but in total protein there was a significant difference between lung cancer patients and all control groups (p = . ). conclusion significantly increased ebc total protein levels were found in patients with lung cancer. these data suggest that protein mediator secretion or vascular leak may be present in those with lung cancer. future studies will focus upon the identification of these proteins. methods in this two stage case-control study lung cancer cases and healthy smoker controls were recruited. genetic markers (snps) implicated in lung cancer were screened in our test cohort of smokers and ex-smokers. snps whose genotypes (co-dominant or recessive model) were associated with either the healthy smokers (protective) or lung cancer (susceptibility) phenotype were identified. after genotyping this snp panel in a second cohort of subjects snps were chosen and assigned a simple composite genetic score that was combined with scores for age, history of copd and family history of lung cancer, weighted according to our multivariate regression analysis (n = total subjects). the lung cancer risk score was linearly related to the likelihood of lung cancer with odds ratios (referenced against the lowest score quintile) ranging from to in the highest quintile. on receiver operator curve analyses, the auc was . and the frequency distribution showed bimodal separation between healthy smokers and lung cancer cases. utility of the score was not affected by effects of age, smoking history or lung function. we suggest that genetic data may be combined with other risk variables to define smokers or ex-smokers at risk of lung cancer for targeted interventions such as smoking cessation and early detection of lung cancer. supported by health research council, nz. conflict of interest yes. tp v aiyappan , a graham department of medicine, maroondah hospital, melbourne, australia, and the new disease-modifying anti-rheumatic drug (dmard) leflunomide is being used increasingly to treat inflammatory arthritis. its association with interstitial lung disease needs to be considered before combining it with methotrexate. case report a -year-old male who was known to have rheumatoid arthritis and was on methotrexate was admitted with progressive dyspnoea and malaise. he had been recently started on leflunomide. investigations revealed interstitial lung disease and acute renal failure. he improved on conservative treatment (stoppage of disease modifying drugs (dmard), iv fluids and steroids). review of literature an epidemiological study by suissa et al has suggested that there is increased risk of ild associated with leflunomide in patients with a history of ild or methotrexate use but they attributed this to channelling bias. there has also been a report of leflunomide associated with iga glomerulonephritis.by this presentation we aim to increase the awareness of this entity. we also suggest that any patient who is started on combination dmard (i.e. methotrexate and leflunomide) should have a baseline chest x-ray and be monitored for development of interstitial lung disease. conclusion we are reporting the first ever case of interstitial lung disease and glomerulonephritis (in the same patient), due to usage of leflunomide. this entity needs to be thought about in any patient on combination dmards. background bone morphogenic protein receptor ii (bmpr-ii) mutations are associated with pulmonary artery hypertension. failure of the growth inhibitory effects of bmp may contribute to vascular obliteration and remodelling leading to pulmonary artery hypertension (pah) [ ] . pah has been observed following venous thrombembolic disease (vte), including pulmonary embolism (pe) and deep venous thrombosis (dvt) [ ] . local markers of the pulmonary vascular endothelium rather than traditional markers of thromobophilia are thought to be involved [ ] . methods plasma was collected from age and gender matched participants within hours of diagnosis of vte and prior to commencement of warfarin therapy. plasma samples were hybridized to individual human cytokine antibody arrays, to detect protein levels of bmp , bmp and bmpr-ii. results bmp and bmp levels were higher in patients with dvt than pe. no difference in the bmp level was observed between patients with pe and controls. soluble bmpr-ii receptor was lower in patients with pe than in controls or patients with dvt. conclusion in patients with pulmonary artery stress during the time of a pe the bmpr-ii receptor is reduced, which may predispose patients to vascular remodelling and obliteration. the bmp and levels are reduced at the same time, suggesting a possible overriding regulatory mechanism. the physiological role of bmp's and bmp receptors in patients with vte warrants further investigation. historically, cyclophosphamide has had a variable role in interstitial lung disease (ild), the rationale for its use based on the benefit seen in vasculitis and scleroderma, its rapid effect and low toxicity profile. in patients with severe progressive ild a rapidly effective, well-tolerated agent is desirable. for this reason a treatment protocol for the use of intravenous (iv) cyclophosphamide was implemented at our hospital. aim to review the indications, duration, tolerability and effect of intravenous cyclophosphamide in ild patients following the introduction of a treatment protocol. methods records of patients [dlco was Ϯ % and fvc Ϯ %] completing a course of iv cyclophosphamide during - were reviewed (excluding patients with systemic sclerosis). data covering months prior to and following treatment were collected. comparative analysis of paired pulmonary function data months before and after treatment was performed. % had underlying autoimmune disease. results primary treatment indications included progressive disease(n = ); severe disease (n = ); suspected vasculopathy (n = ); bridging therapy to transplantation (n = ); and accelerated decline (n = ). patients received mg/m [mean dose Ϯ mg, median number of pulses ( - )]. patients with paired pulmonary function data had a difference in median change in dlco% predicted from - . % (- . to . %) before treatment to + . % (- . to . %) following treatment (p < . ). this remained significant with exclusion of vasculitis, or any autoimmune disease, and independent of prior immunosuppression. therapy was well tolerated ( withdrew from treatment, deaths within yr, none directly related to treatment). conclusion iv cyclophosphamide is well tolerated, and associated with functional stability or improvement in the majority of patients. it remains a viable treatment alternative for consideration. pulmonary hypertension is common in interstitial lung disease (ild) and associated with a poor prognosis. as the gold-standard test, right-heart catheterization (rhc) is invasive, and resource-limited, reliable non-invasive measures of ph are needed. methods all ild patients referred for rhc during - were included (n = ; male; age . Ϯ yrs). all patients had concurrent echocardiography (tte) and pulmonary function. the relationship of rhc mean pulmonary artery pressure (mpap) to tte variables, pulmonary function, exercise capacity, as measured by six minute walk testing ( mwt, n = ) and brain natriuretic peptide (bnp, n = ), was examined. case a year old male, non-smoker for years, retired professor of anatomy (had chronic exposure to embalming fluids, formaldehyde, phenol, antifungal and other solvents, for years) presented with chronic cough and phlegm production. these symptoms were worse at night (waking him several times) and early morning. his pulmonary tests were stopped due to persistent cough. a chest x-ray revealed features of longstanding interstitial lung disease. the hrct revealed widespread subpleural interlobular thickening, worse at bases, in keeping with idiopathic pulmonary fibrosis (ipf). there was minimal fibrosis and honeycombing, but no groundglass opacification, large bullae, pleural calcification or pleural plaques. however, there was associated bronchiectasis at the lung bases considered to be due to traction. the ba lavage showed % macrophages, % neutrophils, % lymphocytes, and %, eosinophils and no infection. the patient declined to have a lung biopsy. as per his past x-rays, the duration of his ipf is a little over one year. he maintains that his symptoms started only after starting irbesartan (irb). introduction transbronchial lung biopsy (tbb) has a variable and unpredictable diagnostic yield in sarcoidosis. we hypothesized that the extent and pattern of parenchymal disease on ct would predict the likelihood of a positive tbb. methods data relating to ethnicity, symptoms, pulmonary function and site and results of tbb and bronchoalveolar lavage (bal) from sarcoidosis patients were recorded. all had a ct scan within weeks prior to the tbb procedure. cxr stage was determined from radiology report. ct scans were scored quantitatively for patterns of parenchymal disease (nodular, reticular, consolidation, ground glass and mosaic attenuation) on a lobar basis. results % patients had a positive tbb (total % of cohort had histological confirmation). symptoms, ethnicity, treatment, lung function and cxr stage were not predictors of a positive biopsy. positive biopsy was associated with higher bal lymphocyte count (p < . ) and female gender (p < . ). a reticular pattern (p < . ) and higher total lung score (excluding da) (p < . ) on ct scan predicted a positive biopsy. in those patients with tbb from right lower lobe ( / ) the total rll score on ct was predictive of positive biopsy (p < . ). on multivariate analysis gender, bal lymphocytosis and total lung score were independent predictors of a positive tbb (area under roc . ). pulmonary arterial hypertension has two histological variants; 'arterial-only pulmonary arterial hypertension' (artpah) and 'pulmonary veno-occlusive disease' (pvod). bosentan, a dual endothelin receptor antagonist, has been found to improve haemodynamics, functional capacity and survival in artpah. however, the response to bosentan in clinically diagnosed artpah is often variable. it was hypothesized that a lack of response to bosentan therapy in clinically diagnosed artpah can be explained by misdiagnosed pvod. aims included to: ( ) perform morphometric and qualitative pulmonary vessel analysis on normal controls and cases clinically diagnosed with artpah who had failed bosentan therapy; ( ) ascertain if pvod is present within the case group; ( ) correlate clinical variables and vessel microanatomy to identify the pathologies driving pulmonary pressure elevation. this study reviewed cases of clinically diagnosed artpah (idiopathic n = , associated with scleroderma n = ), who had failed bosentan therapy and had available lung tissue. controls (n = ) were obtained from explanted lungs for other causes and a prior transthoracic echocardiogram excluded pulmonary hypertension. vessel morphometry and qualitative analysis was performed with a novel technique of smooth muscle actin immunohistochemistry counterstained with verhoeff's elastin. baseline clinical data were retrieved. we found % of cases had pathology confirmed pvod. only % of cases had artpah, the original clinical diagnosis. in pvod, significant pathology was present in all vessel types. all vessels had significant smooth muscle hypertrophy. the obstructive, collagenous, pauci-cellular intimal fibrosis of the venules (p < . ) and arterioles (p < . ) was considerably different to the concentric laminar proliferation of smooth muscle observed in the muscular arteries (p < . ) and arterioles (p = . ) in artpah. artpah also had muscular artery smooth muscle hypertrophy (p = . ). the median time to bosentan failure was shorter in pvod than artpah ( vs. days). in conclusion, pvod is an under-diagnosed cause of pulmonary hypertension, is commonly clinically misdiagnosed as artpah and may present with a poor bosentan therapy response. finally, pvod is a vaso-occlusive, not a veno-occlusive disease, and is an independent type of pulmonary hypertension, not a subtype of pulmonary arterial hypertension. cutaneous t cell lymphomas (ctcl) are a heterogenous group of lymphoproliferative disorders. they show various clinical manifestations and diverse morphological, histological and immunological characteristics of the malignant cells. they are caused by clonally derived, skin invasive t cells. peripheral t cell lymphomas (ptcl) are generally more aggressive and have one of the lowest overall and failure-free survival rates. because of the rarity of these disorders, diagnosis and treatment remain challenging. this case report describes a -year-old woman presenting with progressive dyspnoea and cough, together with a distressing generalized pruritic rash. she was initially treated as left ventricular failure with the rash ascribed to a drug reaction as suggested by initial skin biopsies. the diagnosis was made on a third skin biopsy and flow cytometry of lymphocytes obtained by broncho-alveolar lavage months after presentation. despite an initial response to chemotherapy she succumbed to the disease months after diagnosis. clinical pathways to guide the investigation of suspected pulmonary embolism (pe) have been increasingly adopted by emergency departments (ed) worldwide. compliance with these diagnostic algorithms is critical in ensuring good patient outcomes. this study evaluated the compliance to the clinical pathway used in our ed that combines risk assessment (wells scoring system) with d-dimer test, vq scan or ctpa. the main objectives of this study were to identify those factors which contributed to compliance and to assess patient outcomes. methods a prospective observational study of consecutive patients who underwent investigation for pe in our ed. patient demographics, pathway parameters and patient outcomes at -month follow-up were collected. case we report the case of a year old woman who presented to the emergency department with a three day history of dry cough and dyspnoea. the patient was in her third pregnancy at weeks gestation. she had no fever, chest pain or coryzal symptoms. the patient had presented with a right sided spontaneous pneumothorax seven months prior to the current presentation. her past medical history included placental abruption, complicating her previous two pregnancies. her second pregnancy was complicated by placental abruption at weeks and the foetus had not survived. her first pregnancy was complicated by placental abruption at weeks with successful delivery of the foetus. at presentation, significant findings included tachycardia, hypoxemia, tachypnoea and reduced breath sounds over the right side of the chest. chest x-ray demonstrated a large right pneumothorax. a right intercostal catheter was inserted resulting in right lung re-expansion. the catheter was removed three days later. the patient returned to hospital twenty four hours after catheter removal with a recurrent right sided pneumothorax. the patient agreed to surgical intervention involving video-assisted thoracotomy and talc pleurodesis. the patient had no further complications with the pregnancy. she delivered a healthy baby at weeks gestation. discussion spontaneous pneumothorax in pregnancy is rare and there is little evidence to provide guidelines for the management of recurrent pneumothorax in high risk pregnancy. our case illustrates a successful outcome for mother and foetus with surgical intervention at weeks gestation. folfox is currently the standard adjuvant treatment for locally advanced (stage iii) colon cancer and increases disease free survival. its toxicity is well tolerated with common adverse effects being paraesthesia, bone marrow suppression and gastrointestinal disturbance. pulmonary toxicity has rarely been reported. three clinical cases of acute dyspnoea following folfox therapy ( ) ( ) ( ) for stage iii colon cancer are reported. all had an anterior resection followed by - cycles of folfox. each developed rapidly progressive dyspnoea requiring hospital admission within one week of their last cycle. one patient required invasive ventilation in icu. high resolution computed tomography (hrct) showed bilateral widespread honeycomb pattern with associated ground glass opacification consistent with pulmonary fibrosis. they had reduced lung volumes and gas transfer. transbronchial biopsy and bronchoalveolar lavage in one patient showed an acute eosinophilic pneumonitis. other causes of interstitial lung disease were carefully excluded. all three patients received high dose corticosteroids with one receiving additional cyclophosphamide. the first patient showed complete recovery following an eight week course of corticosteroids, with resolution of the hrct changes and improvement in lung function. the second had symptomatic improvement of dyspnoea, but a persistent moderate reduction in gas transfer. the final patient had persisting radiographic changes and a reduced gas transfer. he remained dependant on ambulatory oxygen months after his initial presentation. these patients' interstitial lung disease appears due to folfox with oxaliplatin being the most likely causative agent. the use of oxaliplatin chemotherapy has increased markedly over the last years and although rare, physicians should be aware of its potential for lung toxicity. lung function testing at baseline, during and towards the end of oxaliplatin treatment should be undertaken and may allow early detection and intervention in cases of pulmonary toxicity. the forced oscillation technique (fot) with broadband signals has been employed relatively rarely in the studies on respiratory mechanics. recent work from our laboratory [ ] indicated that the cheek support and the neck angle have minor influence on the impedance spectra around the first antiresonance (far, ), which makes the use of the broadband fot especially attractive in young children. methods we studied healthy children (c; female: ) and children with bronchopulmonary dysplasia (bpd; female: ), using multiple-frequency fot between and hz superimposed on spontaneous breathing. results groups c and bpd did not differ in age ( lung function impairment is common in children with cardiac defects associated with increases in pulmonary blood flow/pressure. to investigate the development of bronchial hyperreactivity (bhr), an aorto-caval shunt was created in a model of precapillary pulmonary hypertension. surgical shunt repair was performed to assess the reversibility of bhr. methods rats were divided into groups: group c (n = ) with sham surgery, group s (n = ) where an aorto-caval shunt was created (follow-up wks), group r (n = ) with aorto-caval shunt but surgical correction of the shunt at wks (follow-up wks). in all animals, respiratory input impedance (zrs) was measured at baseline and following increasing doses of methacholine (mch , , , mcg/kg). airway resistance (raw), inertance, tissue damping (g) and elastance were estimated from the zrs spectra by model fitting. measurements were repeated in all animals at wks and at wks for groups r and c. results there was a significant increase in raw and g in group s and rat wks at baseline and following mch ( fig.) which was reversed after surgery. to characterize the factors contributing to lung function impairment following cardiopulmonary bypass (cpb), functional residual capacity (frc), lung clearance index (lci) and respiratory mechanics were measured in children with pulmonary hypoperfusion (tetralogy of fallot, tof n = ) and hyperperfusion (ventricular septal defect, vsd n = ) undergoing surgical repair of congenital heart disease. methods frc and lci were measured using a sf washout technique and respiratory mechanics using a low frequency oscillation technique in the perioperative period. results while chest opening led to a significant improvement of lung volumes and respiratory mechanics in all patients (p < . ), a reduction in pulmonary blood flow during cpb decreased lung volumes and airway resistance in parallel but significantly more in children with tof compared with those with vsd. re-establishing pulmonary blood flow during cpb improved respiratory function particularly in children with tof ( figure) . conclusions sternotomy had a great impact on lung function with parallel improvement in alveolar recruitment, ventilation inhomogeneity and airway resistance. in contrast, onset of cpb led to lung function impairment with a significant drop in frc especially in children with pre-existing hypoperfused lungs. this suggest that pulmonary blood flow enhances alveolar stability through a tethering effect on the alveolar walls. children with advanced lung disease being considered for lung transplantation are likely to spend disproportionately longer periods on transplant waiting lists before appropriately sized donor organs become available. these longer waiting times reflect the lower organ donation rates seen in children; rates that are significantly lower than those reported in the adult population. we describe two children with advanced lung disease who deteriorated whilst on the waiting list for lung transplantation, and in the absence of appropriately sized donor lungs, underwent lobar lung transplantation. methods we describe the clinical course of two children, aged and years old, with advanced lung disease secondary to post-mycoplasma obliterative bronchiolitis and cystic fibrosis-associated bronchiectasis, respectively. results both children received a "cutdown" bilateral lobar transplant from two oversized adult brain-dead organ donors. in both cases the transplant operation involved implantation of the right middle and upper lobes, and of the left upper lobe from the donor. conclusion given the low organ donation rates in children, and in the absence of appropriately sized donor lungs, novel strategies such as lobar transplantation must be considered, particularly when children continue to clinically deteriorate whilst on the lung transplant waiting list. data from the west australian adult outcomes of extreme preterm birth study suggest that adult survivors of bronchopulmonary dysplasia (bpd) may be left with functional and structural pulmonary abnormalities, most notably emphysema. animal data suggest that the antenatal administration of corticosteroids may adversely affect lung development. we therefore sought to determine if maternal variables, including administration of corticosteroid, could predict emphysema severity in adulthood. methods bpd subjects (birthweight < g and oxygen dependence at weeks post-menstrual age) born prior to were identified and recruited prospectively via the statewide neonatal follow up program as previously described. pulmonary function tests and thin selective inspiratory and expiratory computerised (ct) images were acquired and scored for emphysema severity (voxel index (%)). the obstetric history was obtained from retrospective review of case notes. results adults ( females, aged - ) were studied, declined ct. all subjects had abnormal ct findings. fifteen ( %) had areas of emphysema. emphysema score and fev were not influenced by the administration of antenatal corticosteroids, indication for delivery, maternal age or presence or absence of chorioamnionitis. conclusion maternal factors, including the administration of antenatal corticosteroids, do not predict the long term respiratory outcome of bpd. the factors determining the severity of emphysema in this group remain unknown. the prevalence of childhood asthma is high in the torres strait. children have generally more severe asthma and asthma knowledge is poor. however, there is no culturally appropriate asthma education program for these children. we are conducting a randomized controlled trial to examine the additional benefits of an education intervention by indigenous health care workers (hcw) on asthma outcomes. we describe the study's objectives, design and baseline measurements. methods children with wheeze were reviewed by two paediatric respiratory physicians using a standardized protocol; children with asthma were eligible. after obtaining informed consent children were randomly allocated to: ( ) three additional asthma education sessions with a hcw; or ( ) no additional education from a hcw. trained hcws carried out the education sessions using culturally appropriate tools. primary outcome was the number of unscheduled hospital/doctor visits due to asthma exacerbation. all children were re-assessed at months. results we enrolled children aged to years, % were torres strait islanders and % aboriginal and torres strait islanders. the clinical spectrum of asthma was: % infrequent episodic asthma, % frequent episodic asthma and % chronic asthma. eighteen percent of the children knew what a written asthma action plan was; . % had one. carers' assessment of knowledge of medications showed that % could not name any asthma medication used by their child, % could not explain dosage, and % could not explain how beta agonists worked. conclusions asthma knowledge and possession of asthma action plans in this cohort is poor at baseline. there is substantial room for improvement and additional asthma education by hcws potentially has significant benefits. impulse oscillometry system (ios) measures respiratory function during normal breathing by transmitting mixed frequency rectangular pressure impulses down the airways and measuring reflected pressure. computer analysis calculates respiratory impedance and its components, airways resistance and reactance, at a range of frequencies from . hz to hz. no previous australian normative data exists. the ios software generates predictive normal values for each of the parameters measured including total airway resistance (r ), the proximal airway resistance (r ) as well as peripheral capacitive reactance (x ). however, they are based on german data. methods cross-sectional study of community dwelling adults, with males and females per -year cohort. inclusion criteria: age range - years, apparently good respiratory health. exclusion criteria: smokers, asthmatics and others with acute or chronic respiratory disease. both ios and spirometry were conducted on all participants. results australian predictive normal equations have been generated and compared to the current published equations. the ios parameters have been correlated with the spirometric data. results have been analysed by gender, age, height and weight and compared with the predictive normal values for each parameter provided by the german manufacturer of the ios instrument. analysis includes calculation of mean range, and lower limit of normal. conclusions a preliminary set of australian predictive equations have now been produced for the ios. these have been compared with international equations. ios has potential application in a range of respiratory disease states and in population screening for occupational health (e.g. mining, & high dust load environments). supported by phc red. rationale although clinical practice guidelines for both asthma and copd recommend spirometry for diagnosis and monitoring, beneficial effects on the management of chronic respiratory diseases in general practice have not been established. we hypothesized that spirometry would improve health outcomes compared to usual care. methods we are conducting a single masked rct with arms: group a receive monthly spirometry and followup, group b receive spirometry before and after the trial and group c usual care. general practices were recruited though divisions of general practice in melbourne. invitations were mailed by of these practices to patients who had been prescribed inhaled medications during the previous months. participants returned respiratory and generic quality of life questionnaires and an asthma score card. groups a and b were tested on a micromedical turbine spirometer following ats/ers guidelines. results eligible patients ( adults, children aged - and youths aged - years) entered the trial. were randomized to group a, to group b and to group c. the mean (sd) age of adult participants was . ( . ), children . ( . ) and youths ( . ) years. there were males and females. the adults were highly symptomatic in the previous months: % reporting wheeze, % chest tightness on waking, % shortness of breath on exertion, % nocturnal cough, % morning cough and % sputum. symptoms of chronic bronchitis were reported by % of adults and a diagnosis of copd by %. asthma was reported by %, confirmed by a doctor in % and % had experienced an attack in the last months. only % had a written asthma action plan. % of adults had ever visited a hospital ed and % had been admitted. conclusion it is possible to recruit asthma and copd patients from general practice and to randomize them to spirometry or usual care. whether spirometry is associated with fewer symptoms, changes in medication, uptake of action plans or improvement in lung function or quality of life requires further followup. supported by nhmrc. s shah , jk roydhouse , b toelle , s sawyer , c jenkins for the pace australia management committee university of sydney, woolcock institute of medical research, sydney, nsw , and royal children's hospital, melbourne, vic it is widely held that recruitment of general practitioners for research can be challenging. in this paper, we discuss the recruitment experience from a current study evaluating the impact of an educational asthma intervention on patient outcomes. our aim is to describe the two different strategies utilized to date: ( ) in-house through an academic department of gp and ( ) outsourced to a private gp organization. methods initial interest was generated through faxes, presentations at gp divisional meetings and newsletter advertisements. gps who expressed interest were visited by project staff to discuss the study further. a major difference was recruiting one gp per practice in the first strategy versus multiple gps per practice in the second strategy. to assess the strategies, we examined participant characteristics, number of gps recruited and number retained. results participant characteristics: under both strategies, % of recruits had trained in asia and % were women. the first strategy recruited more gps who spoke at least two languages at home ( % vs %) and the second strategy recruited more recently graduated gps ( % vs %). recruitment: the first strategy recruited gps over months and the second recruited gps over months. retention: gps ( %) from the first strategy stayed in, compared to ( %) from the second. conclusions whilst absolute numbers of gps recruited were similar, retention was much higher under the second strategy. recruitment in primary care is difficult and requires a range of approaches which need to be re-evaluated and adapted as necessary during the course of the study. supported by the australian government department of health and ageing. bronchiectasis is a heterogeneous condition with a large number of causative factors and range of symptoms. the classification of this condition is often confusing and hard to remember. the aim of this study was to classify non-cf bronchiectasis into different clinical phenotypes. methods consecutive patients with non-cf bronchiectasis confirmed on high resolution ct scanning had a detailed clinical, spirometric and laboratory assessment performed by a respiratory physician (pk/mf/pw) and were then followed up for an average of Ϯ years (mean and sd) for a total of over reviews. results of the patients ( %) could be classified as belonging to phenotypic groups; ) bronchiectasis arising in childhood, ) bronchiectasis occurring in smokers and ) bronchiectasis occurring in the elderly. each group had different features which are listed in the there are few data on the long term outcomes of treatment for tuberculosis (tb) by directly observed therapy (dot) in low-incidence settings. the aim of this study was to assess the incidence of recurrent tb in nsw. methods data linkage was performed within the nsw department of health tb notifications database to identify cases that had more than one tb notification between and . recurrent tuberculosis was defined to include all patients with two or more culture positive episodes at least months apart, where patients had received at least six months treatment for the initial episode. in cases where data contained within the notification details was not sufficient to allow us to distinguish between true cases of recurrent disease, duplication notification for the same episode or persistent disease after incomplete treatment, additional information was obtained from the area tb coordinator. results there were tb notifications between and with being culture positive. cases of recurrent culture positive disease after completed treatment for the first episode were identified (recurrence rate: . %). conclusions in a population with a low tb incidence, treatment of active tuberculosis with dot results in a very low rate of disease recurrence over a long period of follow-up. support nhmrc ccre in respiratory and sleep medicine. introduction rhinoviruses (rvs) are the major cause of viral-induced exacerbation of asthma. to date, the molecular mechanisms of rv pathogenesis are not understood. recent findings suggest that rv pathology may involve host cell nucleocytoplasmic trafficking, inhibiting key cell functions such as transcription and translation. the study aims to investigate the mechanism of rv c protease nuclear trafficking. methods hela cells were infected with rv or transfected with plasmids and cellular localization of c analysed at various times thereafter using immunofluorescent confocal microscopy and western blotting with specific antibodies. results c protease was predominantly present in nuclei of rv infected cells up to hours after infection, becoming increasingly cytoplasmic thereafter. the nuclear membrane of infected cells became progressively indistinct with time. using a specific inhibitor we also found that c utilizes the crm- nuclear export pathway. c was predominantly in the form of cd in both cytoplasm and nucleus of infected cells; mature c protease was also detected from hours after infection. deletion analysis indicats that the nuclear localization domain and a nuclear export signal are most likely to be present within the n terminal amino acids. the nuclear export signal is inhibited in the full length protein, via an unknown mechanism. conclusion our data suggest that c and cd proteins localize to the nucleus in infected cells where they may play a key role in rv pathogenesis by disrupting cellular transcription and the nuclear transport machinery. chronic necrotizing pulmonary aspergillosis (cnpa) is a relatively uncommon, sub-acute, locally destructive process due to aspergillus invasion of the lung. the incidence and prognosis of cnpa are poorly described. case report we present a case of cnpa in a patient on intermittent low dose steroid therapy and recurrent refractory exacerbations of chronic obstructive pulmonary disease (copd).the patient presented with worsening shortness of breath and productive cough requiring recurrent inpatient admissions. human influenza virus is found to bind preferentially to saa , gal receptors found in the upper respiratory tract, while avian viruses bind to saa , gal receptors expressed in lower airways. this is thought to affect the ability of transmission to humans. our aim was to study the ability of avian and human influenza strains to infect bronchial epithelial cells and relate this to levels of the sialic acid receptor expression. methods calu- cells were used as a proximal airway cell and a were used as distal airway cell. human primary bronchial epithelial cells (pbecs) were obtained from healthy, asthmatic, and copd volunteers by endobronchial brushing. epithelial cells were stained with sambucus nigra lectin that binds saa , gal receptor, and maackia amurensis lectin ii that binds to saa , gal. the cells was analysed by flow cytometry. human influenza a/h n /wellington strain and low pathogenic avian influenza a/h n /sandpiper were chosen and were used at an moi of . to infect cells. the supernatants were harvested at hr post infection, of which was then analysed by plaque assay for virus replication. results the calu- showed greater expression of saa , gal linkage than saa , gal linkage, and a displayed slightly higher expression of both receptors compared to pbecs. despite this human and avian influenza virus replicated to similar titre at , pfu/ml in both cell lines, but showed low replication in pbecs. background treatment of community-acquired pneumonia remains based on 'best guess' empiric algorithms because of the poor utility of current pathogen tests. furthermore our ability to stratify patients into risk groups is crude at best, relying on scores such as the pneumonia severity index or the curb- have major limitations. we have been slowly improving real-time pcr assays for pneumococcus as a clinical tool in patients with pneumonia. methods building on previous research we assesed two targets in the autolysin (lyta) gene and the pneumolysin (ply) gene of s.pneumoniae using the lightcycler instrument and fluorescence resonance energy transfer (fret) probes. all common s. pneumoniae serotypes were detected while other bacteria and viruses were not. the lyta target had the best sensitivity with a detection range between ng to fg. both assays were then applied to whole blood samples from adult patients with community-acquired pneumonia, all of whom had blood cultures prior to antibiotic administration and urinary antigen testing for s.pneumoniae. the lyta pcr had the best performance characteristics with a sensitivity more than twice that of blood cultures in the clinical samples. most pcr+ve/culture -ve patients had positive urinary antigen tests. there was clinical evidence that urinary antigen +ve/ pcr -ve patients were false +ves. most significantly there was a strong correlation between quantitative bacterial count and clinical outcome. conclusions real-time quantitative pcr for pneumococcus has significant potential as both a diagnostic and therapeutic tool in patients with pneumonia. the pitjantjatjara lands are situated in the north-western corner of south australia, occupying an area of over square kilometres with a population of approximately . the population lives in small communities or homelands, and there is a high level of mobility between this region and other aboriginal communities in south australia and the northern territory. nganampa health council provides all health care services to the region. specialized support for tb control comes from both the south australia tb service based at royal adelaide hospital as well as a centre for disease control in alice springs. the prevalence of tuberculosis (tb) in this predominantly indigenous community is thought to be significantly higher than the national rate. there are considerable challenges in detecting and managing tuberculosis, relating to the community's geographical remoteness, migration of populations and access to health services. the aims of this study are to quantify the prevalence of tuberculosis in the pitjantjatjara lands, and describe the significant barriers to tb diagnosis and treatment. methods a retrospective study of all diagnoses of tuberculosis within the pitjantjatjara lands in the period - . outcomes include measures of tuberculosis diagnosis, the rates of completed tb treatment and rates of tuberculosis drug resistance. the study will draw conclusions about the reasons for high levels of tb prevalence in this community and identify barriers to effective tuberculosis treatment. conflict of interest no. patients admitted to hospital with a diagnosis of community-acquired pneumonia (cap) are usually treated with intravenous (iv) antibiotics irrespective of pneumonia severity. available guidelines vary in recommended timing and indications for switching to oral antibiotics. aim to examine the patterns of antibiotic choice and delivery method (iv, oral and time to switch) in patients admitted with cap. methods a retrospective chart review of admissions to the respiratory unit over a -month period with a diagnostic-related group (drg) coding of pneumonia. charts were reviewed. data collected included patient demographics, clinical features at presentation (temperature, pulse rate, respiratory rate, bp, oxygenation), initial investigations, initial antibiotic regime, time to change (iv to oral), subsequent antibiotic regime and duration, time to defervescence, length of stay and outcome. pneumonia severity was calculated using the revised british thoracic society system (curb- ), score Ն = severe. results patients were excluded due to incorrect coding. of the patients, age was Ϯ (mean Ϯ sd) yrs and ( %) were male. patients ( %) were febrile at presentation and the median curb- score was (range - ). patients ( %) received iv antibiotics. the curb- score was or (non-severe) in patients and of these patients received a combination of iv ceftriaxone and a macrolide. time to defervescence was . Ϯ . days. time from defervescence to switching to oral therapy was . Ϯ . days. in non-febrile patients, time to switch was . Ϯ . days. length of stay was . Ϯ . days. conclusions the time between defervescence and switch to an oral regime was relatively long, possibly contributing to an increased length of stay. many patients received ceftriaxone even with a curb- severity rating of or . implementing local guideline-based treatment protocols may reduce length of stay. ultrasonic flow sensors can determine flow, volume and molar mass (mm) of the gas flow simultaneously. during tidal breathing the expired molar mass curve can be used to compute co over expired volume and a capnography index (cpi) can be computed. the relationship between cpi and copd classification according to gold was investigated. methods prospective, controlled trial. consecutive patients who underwent routine lung function were enrolled to participate in a tidal breathing test using an ultrasonic flow sensor. each test consisted of three tidal breathing recordings of sec. flow, volume and molar mass were measured at hz and data were acquired using prototype wbreath data acquisition software. mean expirograms (mm over volume) were computed and the measurements were analyzed to determine the slope of exhaled phase ii (s ), the slope of phase iii (s ) and the relationship between s and s (cpi = s /s ). gold stages were determined from the lung function results and the ers predicted values. results volunteers participated in the study with a mean age of (sd ), were male, mean bmi (sd ), had never smoked. the mean pack/year smoking history was . there was a clear relationship between gold stage and cpi: gold stage 'normal' had a mean cpi of . (sd . , n = ), stage 'severe' had a mean cpi of . (sd = . , n = ). conclusion computation of cpi based on tidal breathing analysis using an ultrasonic flow and mm sensor correlates well with gold stages. it may therefore be possible to use a simple tidal breathing test to determine the severity of airways disease. background osa is common in tetraplegia and appears within weeks of injury. although cpap treatment is efficacious in able-bodied subjects, case series suggest that cpap is poorly tolerated in tetraplegia. no prospective study has examined cpap efficacy or adherence in tetraplegia. aim to determine the feasibility of cpap use to treat osa following acute tetraplegia. methods all acute admissions who consented and fulfilled the inclusion and exclusion criteria underwent full, portable polysomnography. those found to have an apnoea hypopnoea index of > events per hour (osa) were offered cpap, delivered via an auto-titrating device. results to date, patients have been admitted ( excluded, refused consent). no significant, adverse events have been observed. two patients did not have osa. of the nine with osa, four are mid-study, two had incomplete follow-up ( returned to uk and refused month assessment), two adhered with cpap and one did not due to severe, pre-existing nasal obstruction. preliminary analyses suggest that those who adhered to cpap had a marked reduction ( % compared with - %) in sleepiness and a greater reduction in the functional outcomes of sleepiness compared to either those without osa or who were unable to use cpap. patient accrual, recruitment and completion rates are consistent with our initial estimates. study recruitment will be completed by end-october . conclusion initial data suggest that auto-titrating cpap is a feasible treatment for osa in acute tetraplegia. these data will be used to finalize planning for a multi-national, multi-centre randomized controlled of therapy. this research was supported by the transport accident commission. visual recognition of cyanosis is an important clinical activity. cyanosis recognition is affected by lighting colour and there is anecdotal evidence that people with significant colour vision deficiencies (cvds) have particular difficulty. studies to date have centred on the colour change with oxygenation of isolated blood but it is not clear how this extrapolates to cyanotic patients in vivo. methods ten patients known to be chronically hypoxaemic and showing signs of cyanosis were recruited from the chronic respiratory program. ten normal subjects were recruited as controls. the spectral reflectances of their lips, nail beds and palm creases were measured using a topcon sr- telespectroradiometer. the patients were measured at rest and after exercise to lower their saturation by - %. the chromaticities were calculated and plotted. results both groups showed a spread of colours but they fell into two distinct ranges. the colour difference between the groups lies very close to the colour confusions made by congenital cvds. within the cyanosed group, the colour shift was not tightly related to decreasing oxygen saturation. this is most likely due to interpersonal factors such as pigmentation and vascular perfusion that affect colour and the difficulties in measuring the colour of heterogeneous anatomical features. conclusions these results quantify the anecdotal difficulties in detecting cyanosis and suggest that observers with cvd would have problems recognizing the condition. the photographs obtained from this study will be used to compare the ability of subjects with and without cvd to detect cyanosis. supported by the nsw ambulance service. baroreflex sensitivity is depressed in osa patients during sleep but effects during wakefulness are less clear. we have now examined relationships between awake brs and severity of sleep disordered breathing (sdb). methods immediately prior to overnight polysomnography, continuous ( min) beat-to-beat arterial blood pressure was measured via finger plethysmography (portapres) and heart rate via ecg in , supine, normotensive, untreated osa patients ( males; age: Ϯ years (mean Ϯ sd); bmi: Ϯ kg/m ). spontaneous baroreflex sensitivity (brs) was calculated using the sequence technique. sdb was characterized as apnoea hyponoea index (events/hour) and arousal index (ai). data were analysed via mathematical modelling and unpaired t test. results brs fell with increasing ahi. patients with ahi > events/hour (n = ) had a significantly lower brs ( . Ϯ . ms/mmhg) than those with ahi < events/hour ( . Ϯ . ms/mmhg, p < . ). brs was negatively related to both ahi and ai via fitted exponential functions (r = . and . , respectively). it is hypothesized that the analysis of morphology of the ecg waveform in combination with the heart rate patterns could lead to the possibility of detection of the start and duration of apnoea/hypopnoea events and consequently estimation of the apnoea-hypopnoea index (ahi). to the authors' knowledge the published ecg based algorithms for detecting sleep disordered breathing are only capable of minute by minute analysis rather than detection of individual respiratory events. methods changes to ecg parameters were investigated during respiratory events with no distinction made between apnoea and hypopnoea events. isolated respiratory events and controls of identical duration were obtained from polysomnographic studies, using a randomized procedure. features such as the r wave amplitude, t wave amplitude, qrs area and the r-r interval were extracted from the lead ecg. a number of physiological predictors based on these features were generated. a logistic regression model was used to investigate the association between the predictors and true events, using the statistical software, stata. results univariate and multivariate analyses were performed. three multivariate models were developed; heart parameters only, ecg waveform morphology parameters only and the combinations of the two. the area under the receiver operator characteristic curves (auc) for these models were compared. the best results were obtained with the combination of morphology and heart rate parameters (auc = . ( . (sd))) compared to the morphology (auc = . ( . (sd))) and heart rate (auc = . ( . (sd))) models. the multivariate analysis has shown encouraging results indicating that an algorithm using a combination of heart rate and ecg morphological parameters could potentially be constructed that would enable the determination of individual respiratory events and subsequently an ahi. supported by the arc. introduction sacin and scond are measures of ventilation heterogeneity in acinar and conducting airways, derived from analysis of mbnw. maintaining tidal volumes of l at - breaths/minute (bpm) is impossible for some. our aim was to examine the effect of different tidal volumes on sacin and scond in normals and asthmatics. methods normals ( - yrs) and asthmatics ( - yrs) underwent mbnw at tidal volumes of ml at - bpm, l at - bpm, and l at - bpm. scond and sacin, were determined from the normalized phase iii slopes of breaths between turnovers (cumulative ventilation/frc) . & . results the mean Ϯ sd %predicted fev was . Ϯ % in normals and Ϯ % in asthmatics. in normals, sacin at tv of . , and l were . Ϯ . l - , . Ϯ . l - and . Ϯ . l - , respectively (p = . , anova), while scond were . Ϯ . l - , . Ϯ . l - and . Ϯ . l - (p = . ), respectively. in asthmatics, sacin were . Ϯ . l - , . Ϯ . l - and . Ϯ . l - , respectively (p < . ), while scond were . Ϯ . l - , . Ϯ . l - and . Ϯ . l - , respectively (p < . ). conclusion increasing tidal volume while maintaining the same minute ventilation during mbnw led to large decreases in scond and sacin in both asthmatics and normals. this may be due to reduced inter-regional differences in specific ventilation with greater tv. the log-log relationship between sacin and tv allows an adjustment to be made for variations in tidal volume. funding crc for asthma and airways and nhmrc project grant # . dj smith , k bowden , t lloyd , j coucher , l garske respiratory medicine, and radiology, princess alexandra hospital, brisbane, australia introduction we have shown diaphragmatic flattening and decreased diaphragmatic excursion qualitatively assessed on ultrasound is strongly predictive of dyspnea severity and lower lung inflation in patients with pleural effusion. we sought to quantitatively measure diaphragm length and movement and determine how closely these are related to dyspnea severity and lung inflation. methods patients with unilateral pleural effusions had ct imaging of their diaphragm during a measured inspiratory capacity manoeuvre. maximal sagittal length was measured at tlc, and frc. patients had a baseline dyspnea index (bdi: - ) and respiratory function measured. results patients with unilateral effusion (all right side; malignant mesothelioma, inflammatory) had a mean (sd) bdi of . ( . ), and tlc of % ( . ) predicted. the right diaphragm on the side of the effusion tended to be shorter than the left at frc (p = . ), and had a trend to reduced shortening with inspiration (p = . ). conclusions the right diaphragm is known to be longer than the left in health. the strong trend to a shorter and less mobile right diaphragm associated with effusion suggests this is a potential mechanism for dyspnea. further recruitment will enable correlation between bdi, tlc and diaphragm length and mobility. ) ) that was slightly worse than an able bodied, control population ( . ( . )), but better than an able-bodied population with untreated osa ( . ( . )). the mapi predicted that % of the sample were likely to have osa. these data will be complimented by full sleep studies to be performed at the participants' homes in late , early . conclusion our interim data suggest that the rate of subjective sleep complaints are not substantially different in the population with tetraplegia compared with the able-bodied. this research was supported by the victorian neurotrauma initiative. it has long been assumed that the ventilation heterogeneity associated with lung disease could in itself affect the measurement of carbon monoxide transfer factor. the aim of this study was to investigate the potential estimation errors of carbon monoxide diffusing capacity (tlco) measurement that are specifically due to conductive ventilation heterogeneity. we induced conductive airway ventilation heterogeneity in never-smoker normal subjects by histamine provocation, and related the resulting changes in ventilation heterogeneity (derived from the multiple breath washout test) to corresponding changes in diffusing capacity, alveolar volume and inspired vital capacity (derived from the single breath tlco method). average conductive ventilation heterogeneity doubled (p < . ), while tlco decreased by % (p < . ), with no correlation between individual data (p > . ). when dividing diffusing capacity by alveolar volume, the resulting transfer coefficient was not significantly different pre versus post histamine (p = . ). these findings can be brought in agreement with recent modelling work, where specific ventilation heterogeneity resulting from different distributions of either inspired volume or end-expiratory lung volume have been shown to affect tlco estimation errors in opposite ways. the combination of these errors appears to largely cancel out in our experimental situation of induced ventilation heterogeneity comparable to that observed in lung disease. we conclude that conductive ventilation heterogeneity per se has a negligible effect on diffusing capacity measurement. an important determinant of airway function in humans is vagal-mediated cholinergic tone in airway smooth muscle (asm). this airway tone may be altered in disease states. the use of mouse models for the study of airway diseases, including asthma, pulmonary fibrosis and copd is well established. however, it is not known whether mice actually possess basal asm tone or, if it does exist, how this tone changes in disease models. this study was undertaken to determine whether mice have detectable asm tone in vivo. methods respiratory system impedance (zrs) was measured in female adult balb/c mice using a wave-tube modification of the forced oscillation technique. zrs was measured during slow (~ s) inflation-deflation manoeuvres between the transrespiratory pressures of and cmh o. baseline lung mechanics and thoracic lung volumes (tgv) were measured before and after each mouse was allocated to one of four treatment groups: 'saline' mice received an i.p injection of saline, 'atropine' mice received i.p. atropine sulphate, 'vagotomy' mice had their left and right cervical vagus nerves isolated by blunt dissection and cut, and 'sham' mice had the area of the vagus nerves exposed but the nerves were not cut. results there were no post-treatment changes in tgv, airway resistance, tissue damping, tissue elastance, inertance or tissue hysteresivity in any of the four groups. conclusions the lack of change in lung mechanics post-atropine or postvagotomy in balb/c mice suggests that, unlike humans and many other species, the airways of mice have no baseline asm tone. supported by nhmrc grant# . nomination none. conflict of interest none. both male gender and increased mandibular enclosure volume predict more severe sleep disordered breathing in obstructive sleep apnoea patients. we now examine gender/body size/mandibular enclosure volume relationships for normal subjects stepwise multiple linear regression analysis was used to model body size/enclosure volume interactions. results for the whole group, mv was . Ϯ . ml (mean Ϯ se) while rmv was . Ϯ . ml. head circumference (positive) and forehead height (negative) were both independent predictors for mv and rmv (both p < . ), while hip circumference was an additional positive predictive factor for rmv (p < . ). after adjusting for these parameters, male mv and rmv were larger than for females conclusion these findings suggest that mandibular enclosure volumes are relatively larger in males, even after adjusting for body size/cranial dimension. differing body size/mandibular enclosure volume interactions may contribute to gender influences on the severity of sleep disordered breathing. supported by nhmrc of australia nomination john read prize for sleep and physiological research tp audit of ctpa in a regional hospital y raje, s vincent, g simpson department of thoracic medicine, cairns base hospital, cairns, qld since the introduction of computerized tomographic pulmonary angiograms (ctpa) at our institution the number of requests for this investigation at our institution has grown at an alarming rate. the purpose of this study was to evaluate the clinical assessment of suspected pulmonary embolism (pe). methods ctpa were reviewed. results female, male. mean age yrs (range - ). ctpa requests came from department of medicine, from emergency department, from surgical teams and from oncology outpatients. patients presented with chest pain (pleuritic in cases), had dyspnea, presented with collapse. patients had haemoptysis. hypoxaemia was recorded in . none were clinically shocked and only one had a recorded tachycardia. d-dimer requested in patients and was elevated in . arterial blood gases performed in only patients ( %). patients had prior chest x-ray which was normal in ( %). patients had consolidation on chest x-ray, pleural effusions, atelectasis and fractured ribs. recorded risk factors included patients with previous dvt or pe, patients with malignancy and patients were immediately post-operative. only ctpas ( %) demonstrated evidence of pe. of these had recent dvt and were post-operative. had a history of bowel cancer. there was no formal record of pre-test clinical probability of pe (eg wells' score) for any of the cases. retrospective calculation of the cases of pe, had a wells' score of . and of with the remaining patient with wells' score of under . only patients (one with clinically probable pe) had received fractionated heparin prior to the ctpa. conclusion ( ) ctpas performed at our institution have a low yield ( %).( ) pre-investigation clinical assessment was poor and there was poor adherence to published guidelines, ( ) this results in many unnecessary ctpa examinations generating increased work and expense for the medical imaging department and exposes many patients to unnecessary and potentially harmful radiation exposure. the evaluation and management of hereditary hemorrhagic telangiectasia involves a multidisciplinary approach according to international guidelines. the aim of this audit was to compare the assessment process in one centre with that of the international recommendations. methods retrospective comparison was made by medical chart review of all patients with a diagnosis of hht between the years to . demographic along with clinical data with diagnostic investigations, complications, treatment and genetic evaluation, including family screening was collected. the proportion of patients evaluated and managed as per the international recommendations was determined. results the audit identified patients with the diagnosis of hht, with the mean age years. diagnostic criteria were met in % of the cohort. of the known clinical features, % had a family history, and % epistaxis. cutaneous telangiectasia was present in % and visceral involvement in %. pulmonary arterio-venous malformations (pavm) were seen in patients, cerebral avm in , gastrointestinal telangiectasia was documented in . one patient had a spinal (cervical) avm, and another had pulmonary hypertension in association with this condition. only patients underwent diagnostic or screening investigations in accordance with the international recommendations. furthermore, one patient was referred for a genetic evaluation. conclusions this clinical audit found that % of patients referred to this centre were evaluated in accordance with the international recommendations. genetic assessment was lacking. the study supports the need for a coordinated, multidisciplinary approach to the evaluation and management of hht in this centre. lm young , n good , d milne , w fergusson , i zeng , j kolbe , ml wilsher background while airflow limitation is the most common physiological impairment in sarcoidosis, there are limited data on airway hyperresponsiveness (ahr). understanding the role of ahr in sarcoidosis, if any, may help to identify individuals who might benefit from inhaled therapies. aims ( ) to determine the prevalence of ahr in sarcoidosis. ( ) to determine the correlation between responses to direct (using histamine) and indirect (using hypertonic saline) bronchial challenge. ( ) to determine the clinical, physiological and radiological predictors of ahr. methods subjects with a diagnosis of sarcoidosis based on typical clinical presentation and compatible hrct features and/or tissue biopsy and with a baseline fev > % predicted were recruited. subjects underwent standard hypertonic ( % fall in fev ) and histamine ( % fall in fev ) challenge (> day but < days apart), lung function testing and high resolution computed tomography (hrct) of the chest. results the subjects ( Ϯ years, % female, % european, % stage i, % stage ii, % stage iii, % stage iv) had well preserved lung function overall (fev = . l Ϯ . . % predicted). ahr was detected in / ( %) to hypertonic saline and / ( %) to histamine challenge. on univariate analysis, response to histamine challenge was predicted by conglomerate fibrosis (p = . ) and reticular pattern (p = . ) on hrct. the baseline % predicted fev was significantly associated with ahr on univariate (p = . ), and multivariate analysis (p = . ) when adjusted by hrct patterns. conclusions there is a high prevalence of ahr using histamine challenge in this study of sarcoidosis subjects. ahr most strongly associates with baseline % predicted fev but also conglomerate fibrosis and reticular pattern on hrct. these findings may reflect the consequence of airway remodelling following inflammation. further studies are warranted to confirm these findings. background upper airway shunt represents a significant source of measurement artefact in the use of the forced oscillation technique (fot), with increasing importance in young children. changes in respiratory system admittance, ars (or zrs - ), are theoretically independent of the upper airway shunt. this study examines the possible clinical benefit of ars in preschool children by assessing any increased ability to differentiate responses to bronchial challenges in the routine clinical setting. we hypothesized the use of ars would provide improved sensitivity to clinically relevant obstruction, bronchodilator responsiveness (bdr) and airway hyper-responsiveness (ahr) in young children with respiratory disease. method previous fot measurements were re-analysed and ars calculated to derive: ( ) ars reference equations in healthy young children (n = ); ( ) bdr in ars, respiratory system resistance (rrs) and reactance (xrs) in healthy children (n = ), children with cystic fibrosis (n = ), neonatal chronic lung disease (n = ), asthma (n = ) and wheeze (n = ); ( ) ahr to inhaled adenosine- ′-monosphate (amp) in children. fisher's exact tests were used to assess changes in diagnostic outcomes between ars and conventional fot outcomes (rrs and xrs). results ars was no more sensitive to bronchodilator induced changes than conventional fot outcomes. amp challenges resulted in equivalent responses measured by relative changes in rrs and ars while absolute changes in ars were the least sensitive variable. conclusion this study does not support a clinical advantage in using ars in measuring responses to either inhaled bronchodilator or amp. c hollier , , c menadue , , d flunt , , aj piper , department of respiratory and sleep medicine, royal prince alfred hospital, nsw , and woolcock institute of medical research, nsw serial measurement of arterial carbon dioxide (paco ), ph and bicarbonate (hco -) is essential in the management of patients with hypercapnic respiratory failure (hrf). this information is usually obtained from a sample of arterial blood (abg). the procedure can be painful and distressing for patients, and is sometimes technically difficult due to obesity or contractures. our aim was to determine the validity and feasibility of arterialized venous blood (av) sampling as an alternative to abgs in measuring paco , ph and hco levels in patients with chronic hrf. method eighteen patients completed the study. venous blood was arterialized by heating forearm skin to a temperature of - °c with an electric heating pad. an av sample was taken from a cannula positioned in a vein of the heated forearm simultaneously with an abg. in addition, the reliability of av sampling within the recommended temperature range ( - °c) was investigated in ten healthy volunteers placed on volume cycled ventilation in order to maintain constant ventilation. av samples were taken at . °c temperature intervals from . - °c results the table below summarizes results for validation of av sampling: based on the evidence that cardiovascular dynamics are altered due to obstructive sleep apnea, this study aims to identify the onset and termination of each apnea event using power spectral density (psd) and morphological features of single lead ecg signal over second period. methods ecgs from patients overnight sleep studies were examined for location of the pre-scored apnea events. onset (n = ), maximum (n = ) and termination (n = ) of each apnea event and normal events (n = ) were annotated on second windows. features extracted were psd, amplitudes of r and t wave of second ecgs. receiver operating characteristics (roc) analysis was used to gauge the event recognition ability of all features. weight loss causes an improvement in the severity of osa, however substantial weight loss is very difficult for obese patients. the very low caloric diet (vlcd) has been shown to be successful in causing significant weight loss in obese patients. this is a pilot study on the use of a formal screening protocol to identify osa patients who are potentially eligible for the supervised vlcd program offered by the endocrinology department at auckland city hospital. method consecutive patients who attended the sleep laboratory at ach between june to december were screened using the protocol. patients who are eligible to be considered for the vlcd program are identified as having a combination of obesity (bmi > ), osa (ahi > on sleep study) and being residents within the auckland district healthboard region. results / patients screened did not fulfil the inclusion criteria: lived outside the adhb region; had bmi < ; patients did not have osa (ahi < ). patients fulfilled the inclusion criteria. / patients ( %) were excluded due to medical or psychiatric contraindications to vlcd. patients ( %) who did not have contraindications to vlcd were contacted. patients were contacted successfully. patients were either unavailable to phone contacts on separate days or were disconnected. / patients consented to being referred ( %). / patients declined referral ( %). conclusion this pilot study is the first study using a formal comprehensive screening protocol in the recruitment of obese osa patients into a medically supervised vlcd program. only a small proportion ( %) of patients proceeded to being referred to the vlcd program. key: cord- - wqdlha authors: nan title: oral session date: - - journal: respirology doi: . /j. - . . .x sha: doc_id: cord_uid: wqdlha nan introduction rheumatic heart disease, predominantly mitral stenosis is a chronic disease that produces an increase in the left atrial pressure and consequently venous pulmonary hypertension. preoperative lung function which could be obtained from spirometry can evaluate respiratory reserve in cardiopulmonary patients who will undergo surgery. however, data on the use of spirometry in predicting the rate and extent of regression of preoperative pulmonary artery hypertension is limited. methods we determined the usefulness of preoperative lung function by spirometry in predicting regression of pulmonary hypertension after surgical correction of mitral stenosis among patients who underwent mitral valve surgery at philippine heart center from july to december . results among the twenty patients included in the study, one had normal spirometry and another one had mild obstructive abnormality. majority of the patients ( / ) had restrictive abnormality. nineteen patients had regression of pap. among them, patients were noted to have restrictive abnormality and one with normal spirometry. there was only one patient who did not have regression of pap and found to have a mild obstructive abnormality. correlation of the severity of restrictive lung defect with the change in pap classifi cation among nineteen patients showed lack of correlation with a spearman coeffi cient of . and p-value of . . (figure ) conclusion this study showed that majority of rhd patients particularly mitral stenosis will have a preoperative spirometric abnormality of restrictive pattern. among the study group, almost all patients ( / ) will have regression of pulmonary hypertension after surgery except for one patient with obstructive lung abnormality. though results were not signifi cant, we cannot conclude that preoperative lung function is not predictive of regression of pulmonary hypertension after surgical correction of mitral stenosis due to inadequacy of sample size. thus, further investigation is warranted. introduction drug-induced interstitial lung disease (ild), particularly pulmonary fi brosis, is a serious clinical concern and myofi broblasts have been suggested to play a major role, with it recently being revealed that some of these myofi broblasts are derived from lung epithelial cells through epithelial-mesenchymal transition (emt). in this study, we used cultured epithelial cells to examine the emt-inducing abilities of drugs known to induce ild clinically. methods induction of emt in cultured lung epithelial cells were monitored by up-regulation of the expression of myofi broblast marker proteins and downregulation of the expression of epithelial cell marker proteins. the severity of lung injury and fi brosis in mice was assessed by various methods, such as histopathologic evaluation, histochemical analysis of collagen and determination of hydroxyproline. results emt-like phenotypes were induced by a , an active metabolite of lefl unomide having an inhibitory effect on dihydroorotate dehydrogenase (dhodh). smad interacting protein (a transcription factor regulating emt) and the notch-signaling pathway were shown to be involved. when the cultures were supplemented with exogenous uridine, the a -induced emtlike phenotypes disappeared. likewise, an a analog without inhibitory activity on dhodh produced no induction, suggesting that this process is mediated through the inhibition of dhodh. in vivo, administration of lefl unomide stimulated bleomycin-induced emt-like phenomenon in pulmonary tissue, and exacerbated bleomycin-induced pulmonary fi brosis, both of which were suppressed by co-administration of uridine. conclusion these fi ndings suggest that lefl unomide-dependent exacerbation of bleomycin-induced pulmonary fi brosis is mediated by stimulation of emt of lung epithelial cells, providing the fi rst evidence that drug-induced pulmonary fi brosis involves emt of these cells. we consider that this lefl unomide-dependent exacerbation of bleomycin-induced pulmonary fi brosis provides a suitable animal model of drug-induced ild, which is important to establish not only a clinical protocol for its treatment but also an assay system that will facilitate screening in order to eliminate candidate drugs with the potential to produce this type of side effect. introduction to observe the infl uence of arsenic trioxide on the bleomycininduced pulmonary fi brosis in rats and its mechanisms. methods pulmonary fi brosis was induced in sprague-dawley (sd) rats by intratracheal instillation of bleomycin(blm). the rats of the treatment group, the steroid group and model group were intraperitoneally injected with arsenic trioxide(ato), dexamethasone or normal saline(ns)respectively, while the control rats received ns both intratracheally and intraperitoneally. the effects of interference were evaluated by median survival time, hydroxyproline level in lung, semi-quantitative grading of alveolitis and pulmonary fi brosis and quantititative analysis of collagen in lung (masson's trichrome stain). apoptosis index (ai) of lung was detected by using the terminal transferase dutpdigoxygenin nick end-labeling (tunel) method and the results of the immunohistochemical staining of some cytokines were quantitatively analyzed. results ato might ( ) prolong the median survival time of blm-induced pulmonary fi brosis rats at some extent; ( ) attenuate the alveolitis and pulmonary fi brosis, reduce hydroxyproline level and collagen deposition in lung tissue; ( ) increase the ai of lung tissue at a certain phase; and decrease the levels of transforming growth factor-β (tgf-β ) and tissue inhibitor of metalloproteinase- (timp- ), increase the content of interferon-γ(ifn-γ) signifi cantly. conclusion ato might attenuate blm-induced pulmonary fi brosis in rats via increasing the ai of lung tissue. introduction combined pulmonary fi brosis and emphysema (cpfe) is a syndrome involving both emphysema and diffuse parenchymal lung disease with fi brosis on chest computed tomography (ct). the clinical characteristics of cpfe have been described; however, the differences between the syndrome and interstitial pneumonia (ip) or chronic obstructive pulmonary disease (copd) are not fully understood. the purpose of this study was to clarify the differences in respiratory resistance and reactance using a forced oscillation technique. methods the subjects included patients with cpfe, with ip, and with copd. respiratory resistance and reactance were measured using most-graph- (chest mi co., ltd., tokyo, japan), and pulmonary function tests were also performed on the same examination day. results the fev and fev /fvc values were signifi cantly lower in copd patients compared to those with cpfe and ip. there was no signifi cant difference in vc between cpfe, ip, and copd patients. the carbon monoxide transfer coeffi cient values were signifi cantly lower in cpfe and copd patients compared to those with ip. resistance at hz (r : cmh /l/s) was significantly elevated in patients with copd (cpfe, . ; ip, . ; and copd, . , respectively, p < . for cpfe vs. copd), while r was elevated in patients with ip and copd compared to those with cpfe (cpfe, . ; ip, . ; and copd, . , respectively, p < . for cpfe vs. ip and for cpfe vs. copd). the resonant frequency (hz), a parameter of reactance, was signifi cantly higher in copd patients compared to cpfe and ip patients (cpfe, . ; ip, . ; and copd, . , respectively, p < . for cpfe vs. copd and for ip vs. copd). conclusion cpfe patients exhibited no airfl ow limitation or restrictive impairment, but showed severe gas exchange abnormality similar to that in copd patients. the absence of an elevation of respiratory resistance or reactance refl ects homogenous ventilatory mechanics in cpfe, thereby differentiating it from ip and copd. these results suggest that cpfe is a distinct syndrome differing from ip or copd. pneumonectomy is a surgical removal of a lung. it poses several adverse consequences as it substantially diminishes diffusion capacity by reducing total number of alveoli and vasculature available for gas exchange. the challenge is to maintain adequate gas exchange following resection of the lung tissue. literature revealed a good prognosis for pneumonectomized infant. there is enhancement of diffusion capacity in remnant lung through generation of new pulmonary gas exchange units. this was evidenced by normal lung volumes of the pneumonectomized infants after years. in this article, we present a day old female who was noted to be tachypneic, with chest indrawing and subcostal retractions. chest roentgenogram done revealed collapsed right lung, dextrocardia with hyperinfl ated and hyperluscent left lung. d echo showed no anatomic anomaly, except for dextroposed heart probably secondary to the collapsed right lung. impression then was congenital cystic adenomatoid malformation versus congenital lobar emphysema, left lung. extensive work-up was done. chest ct scan showed overly infl ated and hyperluscent lung segment arising from left lower lobe which is characteristic of a congenital lobar adenomatoid malformation. lung perfusion scan demonstrated diminished perfusion of the left lung with differential contribution to the total perfusion of the % left lung and % right lung. patient then underwent open thoracotomy with pneumonectomy of the left lung. biopsy revealed congenital cystic adenomatoid malformation type ii. three months after the surgery, she has gained weight, not receiving any medications and is symptom free. introduction despite the importance of infection and infl ammation in the pathogenesis and management of bronchiectasis, there are few published data on lower airway microbiology and cellularity in these children. methods children attending a single centre ( to ) with non-cystic fi brosis bronchiectasis who underwent bronchoalveolar lavage (bal) within weeks of diagnosis were identifi ed. the point prevalence of infection (> colony-forming units (cfu)/ml of respiratory bacterial pathogens), its effects upon airway cellularity and the impact of clinical and demographic variables on infection risk were evaluated. results of children with bronchiectasis, ( %) had bal evidence (> cfu/ml) of infection, which was frequently polymicrobial and caused mostly by haemophilus infl uenzae, streptococcus pneumoniae and moraxella catarrhalis. in contrast, pseudomonas aeruginosa was uncommon and mycobacterial and fungal species were undetected. upper airway commensal organisms were also isolated in large numbers (> cfu/ml) from ( %) bal cultures. the median (interquartile range; iqr) bal fl uid total cell counts (tcc × /l) and neutrophil percentages were signifi cantly higher in those with, than without, infection [tcc ( - ) vs ( - ); p = . and neutrophil percentage % ( - ) vs % ( - ); p = . respectively]. only age at diagnosis was associated with infection. conclusion bal microbiology of children with newly diagnosed bronchiectasis substantially differs from adults. children have marked airway neutrophilia, particularly when bacterial loads were high. younger children were more likely to have a lower airway infection at diagnosis. the role and interactions of respiratory bacterial fl ora in initiating and progressing airway damage in bronchiectasis requires further study. the radiological defi nition of airway dilatation and bronchiectasis in children has substantial limitations. bronchoarterial ratio is a commonly used criterion to defi ne airway dilatation despite the lack of normative pediatric data. the objective of our study was to determine the range of normal bronchial to accompanying arterial diameter ratio on high resolution ct scan of the chest in children and compare it with the available adult data. methods children undergoing mdct chest for non-pulmonary conditions at a single centre were prospectively identifi ed. high resolution reconstruction was performed on those included and both airway and vessel diameters were measured in the upper and lower lobes of both lungs. mean bronchoarterial (ba) ratio was calculated for each included child and its correlation with age assessed. results forty one children were included, the mean (sd) ba ratio was . ( . ) (range . to . ). this ratio was clinically similar though statistically lower than comparable adult data [combined mean (sd) . ( . ); p = . ]. no correlation was found with age in our cohort (r = − . , p = . ). there was no difference in the ratio based on laterality or lobe. conclusion in pediatric age-group, the airway is signifi cantly smaller than the adjoining vessel. using the radiological criteria of ba ratio greater than one to defi ne bronchial dilatation would under estimate the presence and extent of bronchiectasis leading to delayed and missed diagnosis. this highlights the need to redefi ne the criteria for bronchial dilatation in children. introduction sleep disordered breathing, especially obstructive sleep apnea syndrome, has been found to be associated with endothelial dysfunction in both adult and paediatric populations. however, the role of non-apnoeic snoring on endothelial function has not been investigated. methods children aged - years with habitual snoring were recruited from our sleep disorder clinic. non-snoring controls were recruited from participants of a community growth survey. all participants underwent nocturnal polysomnography (psg) and ultrasonographic fl ow mediated dilation (fmd) evaluation on the same day. fasting blood was taken for glucose level and lipid profi le determination. subjects with an obstructive apnoea hypopnoea index (oahi) < but reported by parents to have habitual snoring (at least nights per week) in the past months were defi ned as primary snorers (ps). those having an oahi < without habitual snoring in the past months were grouped as non-snorers. children with body mass index of greater than the th percentile of the local reference were defi ned as overweight. subjects were divided into groups of normal weight, overweight, non-snorers and ps for comparisons. results in total, children, of whom were boys, with a mean (sd) age of . ( . ) years were recruited. sixty-six of them were ps. subjects with ps had signifi cantly reduced fmd than non-snoring controls for both the normal weight group (p = . ) and the overweight group (p = . ) ( table ) . multivariate linear regression model showed that primary snoring (p < . ) were independently associated with fmd after controlling for possible confounders including overweight, gender, baseline vessel diameter and log-transformed oahi. conclusion primary snoring in children is independently associated with impaired endothelial function. introduction children with cyanotic congenital heart disease live with baseline oxygen saturations in the mid s, so hence they exist on the steep part of the oxyhemoglobin dissociation curve. these patients are at increased risk for the hemodynamic variations occurring during apneas/hypopneas. longterm outcomes for children with congenital heart disease could be adversely affected since the etiology of pulmonary hypertension is believed to be secondary to the hypoxia and hypercarbia seen in chronic airway obstruction paired with the sympathetic overstimulation caused by frequent sleep arousals. methods a prospective two part questionnaire for the screening of sdb for pediatric patients was performed. part one consists validated pediatric sleep questionnaire (psq). part two consisted of subjective assessment of the subject's cardiovascular and respiratory symptom. all odd ratios of greater than with p-values less than . were considered signifi cant covariates. results a total of children met the inclusion criteria and were included in the fi nal analysis. the prevalence of sleep disordered breathing (sdb) was high at . %. among the factors analyzed, an increased frequency of pulmonary diseases (greater than times/year) was statistically correlated with increased psq scores (p = . ). likewise, early palliative repair (p = . ) was statistically associated. a high total cardiac score is almost four times associated with increased psq ratings (p = . ). conclusion increased frequency of pulmonary diseases and early palliative repair was statistically correlated with increased pediatric sleep questioner scores. a high total cardiac score is almost four times associated with increased psq ratings. hence patients with congenital heart disease and sleep disordered breathing are more likely to have worse cardiac symptoms. patient with congenital heart disease shoukl be routinely examined for the presence of sleep disordered breathing because these sub group of pediatric patients are x have more high risk for developing sleep disordered breathing. introduction atelectasis, is a common pulmonary complication of patient who underwent open heart surgery. deep breathing exercise is one of the interventions implemented to prevent the occurrence of this complication postoperatively. among preschoolers however, making them perform this breathing exercise and maintaining compliance is a challenge since children in this age group have a short attention span and may get bored easily. with this problem at hand, the investigators conceptualized an innovative technique, blowing bubbles as a breathing exercise, in order to prevent atelectasis among post open heart surgery preschoolers. methods this study is an open-label randomized control trial that compared blowing bubbles with the traditional deep breathing exercise among preschoolers who underwent open heart surgery. it took months to complete the study and there were patients screened but only qualifi ed based on the inclusion/exclusion criteria. thirty were assigned randomly to the blowing bubbles group and to the deep breathing exercise. atelectasis as documented on chest x-rays was the outcome measured. results out of the participants in the deep breathing group, developed atelectasis while in the blowing bubbles group, out had atelectasis this generated a p-value of . which is statistically signifi cant, favoring the blowing bubbles group. furthermore, risk analysis showed an absolute risk reduction of . % and a relative risk of less than which means that atelectasis is less likely to occur in the blowing bubbles group in comparison to the traditional breathing exercise group. conclusion blowing bubbles signifi cantly reduces the occurrence of atelectasis among post-open heart surgery preschoolers as opposed to deep breathing exercise. the use of blowing bubbles as a deep breathing modality incorporated through play activity is recommended among preschoolers. introduction severe acute respiratory syndrome (sars) is a novel contagious respiratory infection caused by the sars coronavirus (sars cov). in adults, a mortality rate of % has been reported, and respiratory complications can occur in up to % of survivors. the disease pattern is different in children [ , ] but prevalence of longer term respiratory complications in children is unknown. the aim of this study was to investigate the aerobic capacity of children at years after the diagnosis of sars. methods twenty-seven patients (mean age of . years) who completed both pulmonary function and maximal aerobic capacity (peak vo ) tests at and months after the acute illness were invited for re-assessment. they underwent anthropometric assessment, full pulmonary function and exercise treadmill test. subjects with abnormal hrct at months underwent repeat scanning. results at this -month assessment, subjects refused to take part, and the main reasons of refusal were work commitments or time clashes with school activities. the remaining subjects ( % female) provided complete pulmonary function and exercise data. pulmonary function test was normal in all patients. peak vo , peak oxygen pulse, and ventilatory anaerobic threshold (vat) at this assessment were signifi cantly higher than that recorded at and months. ventilatory effi ciency (ventilatory equivalents for oxygen, ve/vo ) and perfusion to the lungs (end-tidal partial carbon dioxide pressure, petco ) signifi cantly improved since months and maintained at months. though peak vo further improved at months in patients with persistent or without radiological abnormalities, their values were % and % respectively of normal controls. conclusion this study is the most comprehensive report of post-sars exercise responses in children and adolescents. improvements in aerobic capacity over a period of months after the initial illness were demonstrated, but the values remained suboptimal when compared to normal reference. introduction domestic mites are an important source of indoor allergens responsible for the development of allergic diseases worldwide. to date, there is no local epidemiology data on the allergic sensitization to domestic mites among adult patients with asthma and allergic rhinitis. methods from november to june , we prospectively recruited adult patients with asthma and/or allergic rhinitis from an urban-based specialist medical centre in penang, malaysia, carefully profi ling their allergic sensitization to domestic mites by means of skin prick tests and clinico-demographic details. of the patients [mean age (ci) years ( - ); % male] recruited, skin allergic rates to dermatophagoides pteronyssinus, d. farinae, blomia tropicalis and tyrophagus putrescentiae were %, %, % and % respectively. there was no signifi cant difference in these rates among patients with asthma, allergic rhinitis or both. there were signifi cant associations between the number of people living in the same house with rates of d. pteronyssinus (p = . ) and d. farinae (p = . ), and the frequency of bed sheet changing with the rate of tyrophagus putrescentiae (p = . ). with younger age, there were also signifi cant higher allergic rates with d. pteronyssinus (p < . ), d. farinae (p < . ), b. tropicalis (p < . ) and tyrophagus putrescentiae (p = . ). conclusion our preliminary data shows a high prevalence of allergic sensitization to domestic mites in our local adult patients with asthma and/or allergic rhinitis. the fi ndings have implication on allergen control with the view of disease mitigation. introduction a study was carried out to compare the effi cacy and sensory perception of mometasone furoate and ciclesonide aqueous nasal spray in moderate-severe allergic rhinitis. methods a single blind study of months on patient of both sexes, > years, diagnosed as moderate-severe allergic rhinitis as per aria workshop( ) , with skin test positivity to at least two aeroallergens was carried out on patients. patients were divided into two, i.e. mometasone (group a) and ciclesonide groups (group b). group a received microgram/day of mometasone furoate and group b received microgram/day of ciclesonide, nasal spray once daily in the morning. the evaluation was made at , , , , weeks by total nasal symptoms score (tnss), visual analogue scale (vas) and sinonasal outcome test- (snot- ). sensory perception of both nasal steroids was carried out on initial visit before allocating groups, employing a sensory perception questionnaire with a sensory items ( points scale). patients were given one nasal spray, and immediate and after two minutes response was noted in questionnaire. after minutes of washout period, second drug was given and response was noted in similar way. results after months, both mometasone and ciclesonide signifi cantly decreased nasal symptoms as assessed by tnss (p-value = . ) and vas (p-value = . ) and improved quality of life signifi cantly as assessed by snot- (p-value = . ). however there was no statistically signifi cant difference among two drugs. the sensory perception, in favour of mometasone was observed immediately after drug administration, than ciclesonide by providing more comfort during administration, less irritation, odor prference (all p-value . to . ). however, after minutes of drug application, there was no signifi cant difference among both drugs in strength of taste, amount of medication rundown and irritation. the overall acceptance by patients was for mometasone over ciclesonide (p-value = . ). conclusion both mometasone and ciclesonide adequately controlled symptoms of allergic rhinitis in months. the sensory perception preference for many of the sensory attributes in mometasone group were in favour of mometasone. thus, mometasone has equal effi cacy but slightly better acceptability over ciclesonide in the treatment of allergic rhinitis. results of patients, . % were male and . % females. % patients had used alternative asthma therapies: homeopathy, ayrurveda and yoga with poor results and . % had used multiple therapies prior to visit our centre. patients reported being afraid of acute attack ( . %) and hospitalization ( . %). although inhalers were used by indian patients in . % but still oral drugs were used regularly by . % patients. compared to . % in only . % were inhaler naïve (t-value . ). only / ( . %) patients were using spacer with mdi's and % ( / ) being able to demonstrate correct use. common errors seen in mdi's use were: a) slow and steady inhalation ( . %) and b) breath holding after deep inhalation ( . %). formoterol and budesonide dpi was considered most effective by indian patients in controlling disease when asked to rate their devices and drugs. when counseled by experts % were sure to be regular on treatment but month latter % remained regular (t-value . ). fear of addiction ( . %) and cost of therapy ( . %) were cited causes for noncompliance. conclusion indian patients use alternative therapy for asthma treatment before coming to tertiary centre and still prefer oral therapy. despite extensive education being afraid of attacks become noncompliant due to fear of addiction and cost of therapy. the oesophagus and airways have a common origin. refl uxrelated respiratory symptoms may be triggered by aspiration of gastric refl uxate into airways or a vagally mediated oesophago-tracheo-bronchial. this association has not been reported previously in sri lanka. the aim of this study was to describe the association between gastro-oesophageal refl ux (gor) events and respiratory symptoms in a cohort of adult asthmatics in sri lanka. methods thirty stable, mild asthmatics (american thoracic society criteria) underwent dual-sensor ambulatory oesophageal ph monitoring. respiratory symptoms (cough, wheeze, diffi cult breathing, chest tightness) during monitoring were recorded and correlated with refl ux events. results both proximal and distal gor parameters were signifi cantly higher in asthmatics than controls (p < . ; mann-whitney u-test). however, there was no difference in any parameter between asthmatics with and without respiratory symptoms. abnormal proximal acid refl ux was documented in . % and distal refl ux in . % of asthmatics. of respiratory symptoms in all asthmatics, majority ( %) were cough episodes. in total, % of coughs, % of wheeze and all of chest tightness was refl ux-associated, where in most, refl ux events preceded respiratory symptoms. of asthmatics with respiratory symptoms, acid exposure was normal in ( %), abnormally high in proximal oesophagus in ( %) and abnormally high in the distal oesophagus in ( %) and abnormal at both levels in ( %). most refl ux events in asthmatics occurred in the upright position. conclusion asthmatics have more gor and associated respiratory symptoms than non-asthmatic volunteers, with refl ux episodes preceding respiratory symptoms in most cases. distal gor and upright acid exposure was more prominent than proximal gor. in , fi rst population-based studies to determine the magnitude of the asthma problem have been carried out in bangladesh, to defi ne the prevalence of asthma and to identify the risk factors of asthma in bangladesh. after years, same study carried out to fi nd out trends of asthma in bangladesh. methods a cross-sectional study was conducted from january to august on people and same study carried out from november to april on subjects. data collected from stratifi ed randomly selected primary sampling units of all districts. face-to-face interviews were performed with housewives or other guardians at the household level using a structured questionnaire. results in , the prevalence of asthma (wheeze in the last months) was . % ( % ci: . - . ) whereas in it is . % ( % ci: . - . ). in , prevalence of other asthma defi nitions were: ever wheeze (lifetime wheeze) . % ( % ci: . - . ); perceived asthma (perception of having asthma) . % ( % ci: . - . ); doctor diagnosed asthma (diagnosis of asthma by any category of doctor either qualifi ed or unqualifi ed) . % ( % ci: . - . ). in , ever wheeze (lifetime wheeze) . % ( % ci: . - . ); perceived asthma (perception of having asthma) . % ( % ci: . - . ); doctor diagnosed asthma (diagnosis of asthma by any category of doctor either qualifi ed or unqualifi ed) . % ( % ci : . - . ).the prevalence of asthma in children ( - years) was higher than in adults ( - years) ( . % versus . %; odds ratio [or] = . , % ci: . - . ). trends of asthma in bangladesh remains, almost static over last years although at present prevalence is more in adults than children. in adults ( - years) all categories were slightly higher than in children ( - years) ( . % versus . %; odds ratio [or] = . , % ci: . - . ). it is found to be significantly higher in house-holds with one to fi ve members than in larger households (or = . , % ci: . - . ). the poor two quintiles (or = . , % ci: . - . ) and illiterate group (or = . , % ci: . - . ) and primary level of education (or = . , % ci: . - . ) were more vulnerable to asthma attacks than the highincome group and more educated people, respectively. conclusion asthma has increased from million people to million over last years although prevalence is almost similar. introduction secretory gvpla is an inducible protein and an essential signaling molecule for airway infl ammation and airway hyperresponsiveness in immunosensitized and lps-induced ali in mice. however, identifi cation of secretory gvpla in human airway diseases has not been identifi ed previously. methods donors were classifi ed as non-asthmatic, asthmatic, copd or ipf from prior medical records. identifi cation of gvpla in airway microsections was quantifi ed by immunofl uorescence analysis. expression of gvpla in was analyzed using criteria for intensity scoring in a single-blinded method. in separate studies, airway smooth muscle cells (asmc) obtained from asthmatic and non-asthmatic subjects (regional organ bank of illinois) were cultured within h from death. adhesion was assessed by measuring the eosinophil peroxidase activity of adherent eosinophils to asmc. inhibition of adhesion was assessed using neutralizing mabs against surface adhesion molecules and mab against gvpla . results gvpla was abundantly expressed in airway smooth muscle, epithelium and endothelium of patients with a history of asthma compared to non-asthmatic. low expression of gvpla was observed in tissues from copd and ipf subjects. in cultured asthmatic asmc, surface icam- and vcam- also were upregulated. activation of asthmatic asmc with methacholine caused release of gvpla , which corresponded to augmented eosinophil adhesion; mcl- g , a mab against gvpla , prevented these responses. blockade of surface β -/β -integrin on eosinophils or its counter-ligands on asmc blocked also the adhesion. conclusion our data demonstrated that gvpla is highly expressed in asthmatic asm but not in patients having, no history of asthma, copd or ipf. gvpla secreted from activated asmc augments eosinophil adhesion; mcl- g specifi cally blocked the cell-cell ligation. these data are the fi rst demonstration that the upregulated eosinophil adhesion to the surface of asthmatic asmc is linked directly to the secretory gvpla . based on our fi ndings, it is likely that the asmc, which is the natural source of gvpla , regulates airway infl ammation and airway hyperreactivity, which are hallmarks of asthma. supported by nih grant hl- and uk gsk center of excellence in asthma. introduction currently, there is still a lack of operational research analyzing the infl uence of an adequate tb curriculum in medical school. this study, aims to determine the effi ciency of integration of tb program into the medical school curriculum, measured through the knowledge, attitudes, and practices of medical clerks on tb. methods a questionnaire-based survey on the knowledge, attitudes and practices on tuberculosis was conducted among medical clerks (fourth year medical students) in the ust hospital. in total, questionnaires were randomly distributed, of which ( % response rate) of the questionnaires were returned fully accomplished. this was done over a period of one week. the questionnaire used was developed by hong, et al ; huebner, et al ; and yu, et al . and modifi ed by the present authors. results a total of . % (n- / ) of the clerks believed that sputum exam and culture are still the standard diagnostic modalities; quadruple therapy for - months as the standard treatment regimen. in total, . % (n = / ) realized the magnitude of the problem of tb in the philippines; half of them rated the directly-observed therapy, short course (dots) program as good. in order to avoid infection, % wear masks, . % keep their distance, and only . % open windows. only . % would add two drugs to the current regimen of a patient with suspected drug resistance; while . % responded with adding just one drug. conclusion the integration of tb program in the curriculum of ust medical students is effective in enhancing knowledge and improving attitudes of the medical clerks. however, there is still a need to stress the importance of other practices aside from wearing masks in order to avoid infection, and to clarify issues on drug resistance. the study was undertaken to assess the feasibility of diagnosing pulmonary tuberculosis (ptb) by collecting two sputum samples on a single day ( -day protocol) and to compare the same with the national policy of collecting two samples on consecutive days ( -day protocol). methods five hundred and thirteen individuals with cough exceeding weeks were screened for pulmonary tuberculosis (ptb) by collecting three sputum samples, viz. day- spot sample, sample collected hour after the fi rst sample and next day morning sample. for the -day protocol, performance of the fi rst and third samples were considered, while the -day protocol was evaluated using the two day- samples. staining and microscopy were undertaken by two different technicians in a blinded manner. results out of patients, patients defaulted on second day. of the total number of patients recruited, ( . %) were smear-positive. the -day protocol was capable of detecting patients ( . %), whereas in the -day protocol patients ( . %) were smear-positive (p = . ). of the drop-out patients, ( . %) were smear-positive. comparing the variation in results between spot and morning samples, collection of morning sample exhibited no signifi cant benefi t over the collection of a second spot sample. conclusion because the -day protocol does not lead to a statistically signifi cant diagnostic difference compared to the -day protocol, the latter can be adopted as an alternative protocol, particularly in subjects who are more likely to default. introduction tuberculosis, an important preventable and treatable cause of death, is a major health problem worldwide. detecting patients with active pulmonary tuberculosis is an important component of tuberculosis control as early appropriate treatment renders these patients noninfectious and interrupts the chain of disease transmission. sputum microscopy remains the test of choice as initial work-up for symptomatic patients with tuberculosis. however, in patients with a compatible clinical picture, sputum smears do not always reveal acid-fast bacilli. patients symptomatic for tuberculosis but are found to be smear-negative are recommended to undergo further tests including fi beroptic bronchoscopy and sputum induction. the latter, however, is invasive and more costly. this study aims to compare the sensitivity and specifi city of sputum induction and bronchscopy in the diagnosis of sputum smear-negative tuberculosis by means of meta-analysis. methods computer search was done to obtain studies meeting inclusion criteria. the sensitivity, specifi city and other measures of accuracy were pooled using forest plots. diagnostic odds ratios were obtained. summary receiver operating characteristic curves were used to summarize overall test performance. funnel plots and egger regression analysis were used to examine for publication bias. results five prospective studies comparing diagnostic accuracy of fi beroptic bronchsocopy and sputum induction to diagnose sputum smear negative tb were obtained. the pooled summary indeces showed that for bronchial lavage, the sensitivity is . ( % ci, . to . ) while specifi city is . ( % ci, . to . ). whereas for sputum induction, the sensitivity is . ( % ci, . to . ) and specifi city is . ( % ci, . to . ). the summary dor for bronchial lavage was . ( % ci, . to . ) while the summary dor for sputum induction was meaning sputum induction test had a higher level of overall accuracy ( % ci, to ). conclusion sputum induction has comparable sensitivity and specifi city and higher level of overall accuracy compared to bronchial lavage in diagnosing for sputum smear negative tuberculosis. introduction much of tuberculosis control is based on the current understanding of factors that infl uence transmission of mycobacterium tuberculosis and that lead to active tuberculosis among persons who acquire the infection. one of these activities, contact investigation, is intended to identify persons who have acquired tuberculosis infection from a newly discovered active case, thereby enabling targeting of preventive treatment to a group at high risk of developing active tuberculosis, this being the main goal of activity. methods the charts of close contacts of mdrtb patients enrolled in the programmatic mdrtb management of lcp phdu from january to june was reviewed. results there were contacts of culture and dst-confi rmed mdrtb patients identifi ed from january to june . among these contacts, ( . %) were traced and underwent evaluation and screening tests. among the contacts > years old, ( . %) had a positive chest x-ray, ( . %) were afb +, ( . %) were positive for mtb culture and sensitivity. in contacts < years old, ( . %) had positive chest x-ray results, but none had positive results on afb smear, and mtb culture and sensitivity. tuberculosis was identifi ed in of contacts < years old and of contacts > years old. there were mdrtb cases identifi ed ( confi rmed by culture and dst, and treated empirically), all from contacts > years old. all identifi ed mdrtb cases were treated with category iv regimens under pmdt, while other tb (non-mdrtb) cases were managed under dots. conclusion contact tracing remains a helpful tool in public health programs at the lung center of the philippines. although the average contact per index is . , . % were successfully traced, which is comparable to other studies abroad. among the screening tools, the chest x-ray was the most commonly utilized and also the most productive; afb smear, tuberculin test, and mtb culture were performed in less than %. among identifi ed contacts, mdrtb was noted in . %. introduction active pulmonary tuberculosis (tb) requiring intensive care is rare but known to be of poor outcome. the present study aimed to describe the characteristics of patients with this condition and to identify the mortality rate and risk factors that predicts in-hospital mortality. methods from january to december , patients were admitted to tuberculosis intensive care unit (tbicu) of mackay memorial hospital, taipei, taiwan. among these, patients were enrolled and were followed up for days. incidence of in-hospital deaths was documented in the medical records and all possible parameters contributing to mortality were collected for analysis. results the patients' median age was years (range - years). the median length of intensive care unit stay was days (range - days) and the median duration of mechanical ventilation was days (range - days). overall in-hospital mortality was % ( / ). sepsis and shock were independently associated with in-hospital mortality. conclusion these data indicated a high mortality of patients with active tuberculosis requiring intensive care, especially in those with sepsis and shock. introduction we have shown that two commonly used prediction model s (va and mayo) estimate poorly the probability of malignancy of solitary pulmonary nodules (spn) in the philippines. this is due to a large proportion of spn arising from tuberculosis (tb). in the philippines, and possibly for other countries with a high tb-burden, our clinical prediction model has a better estimate to the probability of spn than both the va and mayo. methods we developed a prediction model to identify malignant lung nodules based on clinical data and radiographic characteristics among patients with spn identifi ed retrospectively (october to march ) in our institution. univariate and multiple logistic regression analysis were used to identify independent clinical variables. we applied the model to a new set of spn patients (april and august ) and described its accuracy by comparing the predicted probability of malignancy with the fi nal diagnosis. we constructed receiver operating characteristic (roc) curves and reported % confi dence interval. calibration was done by dividing the sample into fi ve equal groups based on predicted probability and plotting the median probability of each quintile against the observed frequency of malignancy for that group. results seventy-six spn patients were included in the development of the prediction model, where size, margin and smoking history were found significant in the multivariate analysis. prevalence of malignancy was %. the area under the receiver operating characteristic (roc) curve was . ; % confidence interval (ci) of . - . . the equation was obtained based on the identifi ed predictors. fifty-eight patients with spn were included in the validation sample. prevalence of malignancy was %. the roc curve was . ; % c.i. of . - . . median predicted probabilities in all quintiles were lower than the observed frequency of malignant nodules, probably refl ective of the validation sample's higher prevalence of malignancy. conclusion the local clinical model appeared to be suffi ciently accurate to inform clinical decisions about the choice and interpretation of subsequent diagnostic tests. the accuracy of the local clinical prediction model was similar to that reported in its development. introduction in a high-burden country for pulmonary tuberculosis like philippines, it's not uncommon for intracthoracic masses be treated empirically with anti-tuberculosis regimen. we aim to describe patients' profi les, determine outcomes of empiric anti-tuberculosis treatment for such lesions. methods we monitored patients with intrathoracic mass given empiric antituberculosis regimen until "end-of-treatment," decision to pursue diagnosis, or mortality. a -year prospective, observational, open-label, descriptive, cohort study, in a tertiary government hospital. percentage association analysis was done at end of the study. results in total, patients presenting with intrathoracic mass lesions on chest x-ray/chest ct scan were treated empirically with anti-tuberculosis medicines without histopathologic evidence suggestive of pulmonary tuberculosis for the mass. patients' choices, clinical and fi nancial status were factors considered by physicians in the decision for empiric treatment. there were males, females, with average age years. most common chief complaints were cough ( %), pain ( %), hemoptysis ( %), shortness of breath ( %). patients had pulmonary consult within months of initial radiography. histology of mass was confi rmed within months of pulmonary consult in patients. patients had the histopathology prior to starting empiric anti-tb treatment, which revealed non-specifi c fi ndings. a total of patients were treated empirically prior to attempts for histologic diagnosis. two of these patients never had diagnostics due to fi nancial constraints. while patients went on to pursue histopathology, which revealed underlying malignancy in eight patients. malignancy was seen more on males, older age (≥ years), signifi cant smoking history, larger mass size (∼ - cm). seven patients had clinical/radiographic improvement, two patients died, three were lost to follow-up. conclusion our study suggests no role for empiric anti-tb treatment for intrathoracic masses, even in a high-burden country like philippines. we should vigorously pursue and search for defi nite histological diagnosis, as it will translate to cost-effectiveness, avoidance in delayed diagnosis, early institution of appropriate therapeutic management. we recommend further studies with larger sample size, to characterize patients' profi les, do subset analysis, identify who may need anti-tuberculosis treatment. introduction the use of viruses as targeted cancer therapy has shown signifi cant promise for novel anticancer therapy. actually, a small number of enteroviruses, such as coxsackievirus a (cva) and echovirus, have been reported to possess oncolytic activities against various human malignancies. however, a single intratumoral administration of cva in vivo induces severe progressive muscle paralysis necessitating euthanasia of mice. in this context, we discovered that coxsackievirus b (cvb) displayed a high level of tropism and lytic activities for human lung cancer cell lines as a result of screening of representative enteroviruses. cvb specifi cally destroyed both human non-small and small cell lung carcinoma via surface virus receptors of coxsackievirus and adenovirus receptor (car) at a multiplicity of infection (moi) of . , whereas it did not destroy normal lung cells at even a higher moi of . the mts cell proliferation assay also supported those results. furthermore, our in vivo study showed that consecutive intratumor injections of cvb remarkably inhibited the growth of subcutaneously pre-established lung tumors, with signifi cantly more increased survival than untreated mice (p < . ). surprisingly, in metastatic tumor mice model, intratumoral cvb injection into primary tumors in the right fl ank also signifi cantly retarded the growth of pre-established contra-lateral tumors compared with untreated mice. according to the results of fragmented parp detection assay, the oncolytic effects of cvb against tumors could be partially attributed to their apoptosis as well as cellular degenerative destruction. furthermore, fl ow cytometric analyses showed that cvb could possess an immuno-stimulatory ability through robust infi ltrated dendritic cells maturation in treated tumors. moreover, none of mice died of cvb administration, suggesting the feasibility of clinical trials in the future, although analyses of serum biochemistry revealed moderate hepatic dysfunction due to cvb administration. conclusion our fi ndings suggest that intratumor cvb administration could be a novel therapeutic modality against not only primary human lung cancer but also metastasized lesions. introduction radio frequency ablation (rfa) is a technique that employs high-energy radio frequency waves to destroy non-small cell lung cancer. the radio frequency ablation probe, le-veen multiple array needle electrodes, is placed inside a tumor and opened like a tiny umbrella with curved prongs that spring into the surrounding tumor tissue. with this tool tumor cells are somewhat heated until they boil and become inert. methods patients with medically inoperable or unresectable single nodule nsclc underwent treatments, in different centers of bangladesh. multimodality treatment was mode of management. on the basis of intention to treat, patients were divided into fi ve groups for fi ve mode of treatment. group : percutaneous rfa (n = ); group : rfa followed by radiotherapy (n = ); group : chemotherapy with rfa (n = ); group : radiotherapy alone (n = ); and group : chemo radiation (n = ) during -year period ( - ). patients' characteristics, local recurrences and overall and disease-free survivals were compared. results in total, patients were selected for study since december . mean size of tumors were ± . (range . - . cm). follow-up range was from to months, median . months. survival rate of group : only percutaneous rfa was % at year, % at years and % at years; for group : rfa and ebrt % at months, . % at year, . % at years, and . % at years; group : patients treated rfa with chemo therapy % at year, % at years and % at years; group : with radiotherapy alone % at year, % at years, and % at years; for group : similar patients treated with chemoradiation % at year, % at years and % at years. irrespective of stages, patients with tumor size cm (n = ) had an average survival ± months. local recurrence occurred in . % having tumors size cm. developed pneumothorax and had lung infections, of them had fetal. a total of patients died of co morbid diseases while died of disease progression within years following rfa and ebrt or chemotherapy or rfa alone. conclusion the rfa followed by ebrt or rfa along with adjuvant or neo adjuvant chemotherapy for inoperable nsclc has a relatively low rate of complications that are easily managed and above all survival has improved compared with other combination therapy, i.e. chemoradiation. nb: rfa plus chemotherapy was only applied in stage ii and iii. introduction patients with chronic or debilitating illness such as lung cancer usually accompanied by some form of emotional responses such as denial, anxiety, and depression. clinician should be aware of these condition for better lung cancer management. methods hamilton rating scale for anxiety and depression questionnaire were administered to all patients diagnosed with lung cancer in dept pulmonology-respiratory medicine university of indonesia/persahabatan hospital consecutively. follow-up evaluation will be done to evaluate anxiety/depression after a -month therapy. results among lung cancer patients , ( %) has anxiety, patients ( %) has depression and all patients with depression also has anxiety. these conditions commonly found in male than female ( out of male patients ( %) vs. out of female patients ( %)). further evaluation are underway to evaluate the degree of these disorders and other factors correlate with these disorder. conclusion depression and anxiety were also found in lung cancer patients and need further evaluation and attention from clinician. to compare the preoperative classifi cation of lung carcinoma made on histological specimens by fiberoptic bronchoscopy(fob)with the postoperative classifi cation made on resected specimen and how often was used term of nsclc. methods we reviewed the records patients who had a diagnosis ofthe lung cancer made by fi beroptic bronchoscopic biopsy (at yedikule chest hospital, istanbul in ) and who underwent a lung resection.postoperative histological classifi cation were made according to the who classifi cation of the lung tumours. results fifty one of squamous carcinoma, of adenocarsinoma and of carcinoid tumours were correctly typed with the small biopsy obtained by fob. forty eight patients who had a diagnosis of lung cancer established by fi breoptic bronchoscopy were labelled as nsclc, %, % and % of them were classifi ed squamous carcinoma , adenocarcinoma and other tumour type respectively with examination of tissue obtained by surgical resection. conclusion accurate cell typing by specimens obtained at fi breoptic bronchoscopy may be extremely diffi cult.if clearcut morphological criteria can not be satisfi ed , the diagnosis of "lung cancer ,non-small cell" type should be made. introduction the nsclc patients who experienced good clinical responses even sometimes dramatic responses to egfr-tkis gefi tinib or erlotinib will inevitably develop acquired resistance. however, the clinical defi nition of acquired resistance is not clear. we investigated the clinical characteristics of acquired resistance to gefi tinib in nsclc retrospectively. methods we analyzed four hundred and forty nsclc patients who had taken gefi tinib more than months duration. all clinical data were obtained from centers of korean molecular lung cancer group (kmlcg). the timing, clinical manifestations, and the association of egfr genotype were analyzed in the aspect of acquired resistance development. the mean duration of gefi tinib prescription was . + . months. signifi cant predominance in female ( . %) and non-smoker ( . %) was noted. among the patients who examined egfr genotype, the mutation rate was . % ( / ), relatively lower than expectation. the relative ratio of local vs. systemic progression is . %: . % and symptomatic progression rate is . %. the survival time after the development of acquired resistance is . + . months. conclusion these retrospectively analyzed clinical data for the development of acquired resistance to gefi tinib will help set up the clinical defi nition of acquired resistance to egfr-tki. introduction numerous studies have documented overall effectiveness and safety of chemical pleurodesis using variety of agents. although reports regarding complications post-talc pleurodesis were minimal, concerns on the adverse effect profi les remains, especially on occurrences of serious and life threatening respiratory insuffi ciency and ards following talc pleurodesis. methods records of patients admitted at lcp who underwent talc pleurodesis from january to december were reviewed and all complications post pleurodesis were noted. results a total of charts of patients admitted at lcp who underwent pleurodesis from january to december were reviewed. the mean age was ± y/o with male predominance compared to female at ( . %) and ( . %) respectively. of the total procedures evaluated, ( . %) involved all post procedure complications, ( . %) patients developed minor complications while ( . %) had major complications. there was no statistically signifi cant association noted with age, sex, smoking history, co-morbid illness, underlying disease, and method of pleurodesis, while chest tube drainage time more than days was noted to be associated with greater incidence of major complications which was statistically signifi cant. most common minor complications were fever ( . %), followed by tachycardia ( . %), chest pain ( . %) and dyspnea ( . %). the top major complications were hypoxemia, hypotension and pneumonia. there were ( . %) patients who died post pleurodesis that is believed to be related to ards following talc slurry. conclusion talc pleurodesis is an effective agent for chemical pleurodesis but not without adverse effects. cardiovascular complications are potentially avoidable by proper patient selection and preparation prior to talc pleurodesis. respiratory failure and ards are rare but serious complications that should be promptly recognized and addressed rapidly and effectively. introduction nebulized antibiotic is an established safe and effective therapy for bronchiectasis. gentamicin are considered among the most useful classes of antibiotics for treating pseudomonas aeruginosa infections.the major drawback of aminoglycosides is the need for their relatively high dose intravenous administrations which carries the potential systemic toxicity.when gentamicin is given intravenously in maximum safe doses, only relatively low sputum concentration are achievable. these limitations can be circumvented by direct delivery of aerosolized antibiotic to the airways. methods this study was carried out in nidch dhaka. in total, patients were taken initially for the study. introduction immune-modulator nutrition may decrease mortality among patients who are mechanically ventilated due to severe community acquired pneumonia (cap). methods we compared an immuno-modulator nutrition and standard feeding formula to determine the effect on in-hospital mortality as well as days mortality among mechanically ventilated patients due to severe cap. the mean number of ventilator days, icu stay, as well as clinical parameter (clinical pneumonia infection score (cpis) and pao /fio ratio from arterial blood gas) was also compared. in total, eligible patients were randomized, double blind, to receive either immuno-modulator nutrition (supportan sp) or standard feeding formula (sf). follow-up was done on day , and on cpis and pao /fio ratio. results primary outcome was mortality. no signifi cant difference noted between the two groups (p = . ; % ci: − . to . ). the day mortality on patients revealed patients ( . %) died on sf group and patient ( . %) on sp group (p = . ; % ci: − . to . ). the mean ventilator days on the sf group and sp group was . days and . days respectively (p = . ; % ci: − . to . ), although not signifi cant, it suggests a trend favoring sp group. the mean icu stay in the sp group was noted to be signifi cantly shorter ( . days) than in the sf group ( . days) (p = . ; % ci: . to . ). the cpis and pao /fio ratio were done on day , and . on day , the mean pao /fio ratio was still signifi cantly higher on the sp group (p = . ; % ci: − . to − . ); while the mean cpis was still the same with baseline (p = . ; % ci: − . to . ). on day , no significant difference was noted (p = . ; % ci: − . to . and p = . ; % ci: − . to . , respectively), as well as those on day (p = . ; % ci: − . to . and p = . ; % ci: − . to . , respectively). conclusion we found no difference on mortality between sf and sp group. however, it suggests trend of earlier extubation and signifi cant shorter in icu stay, in patients who received immuno-modulator nutrition. introduction several equations to predict lung function of individuals of different population are available. however it is desirable that lung function laboratories use reference equations that most closely describe the population they test. the objective of the study was to develop a prediction equation for the malaysian population. methods spirometry was performed on a total of "healthy", lifetime non smoker volunteers ( males and females) all measurements met the ats acceptability and reproducibility criteria. prediction equations were derived for both men and women for fvc and fev . the equations were validated on a new group of subjects (n = , males and females) who met the same inclusion and exclusion criteria as the main cohort. introduction patients with severe asthma (experiencing previous hospital admissions and/or daily symptoms) have occasionally been seen with poor or weak complaints. several studies have analyzed the psychiatric status of the patients with severe asthma, but few studies have the japan respiratory society (jrs) has proposed new predicting scores, called the i-road system for hospital acquired pneumonia (hap) in . depending on the presence of the parameters listed below, patients with hap were stratifi ed into those with high, moderate or low-risk. the high-risk group was defi ned as patients with three or more of the following risk factors: 'malignant tumor or immunocompromised status', 'impaired consciousness', 'requiring fraction of inspired oxygen (fio ) > % to maintain spo > %', 'male aged years or older, or female aged years or older' and 'oliguria or dehydration'. the moderaterisk group was defi ned as patients with any of the secondary risk factors as follows: 'crp ≥ mg/dl' and 'extent of infi ltration on cxr covers at least / of one lung'. the low-risk group was defi ned as all other patients. the aim of this study was to confi rm whether i-road is useful in predicting severity of cap and hcap. methods all patients with an admission diagnosis of cap and hcap from january -july were reviewed. clinical and laboratory features at presentation in electrical medical records were used to calculate severity scores using the curb- ( ), a-drop ( ) and i-road ( ). results consecutive patients ( % cap) of mean age . years were included in the analysis. nineteen ( . %) patients with cap and seventeen ( . %) patients with hcap died. the roc analysis for predicting mortality at days showed that i-road score has similar predictive accuracy for short-term mortality to curb- and a-drop in patients with cap, but shortterm mortality of the patients with hcap are not similar to them. conclusion the jrs i-road could be used to assess severity of cap, and gives similar results to curb- and a-drop. os - introduction numerous asthma and copd patients repeatedly return to hospital ed for urgent therapeutic care despite referral to their primary care provider. this study was aimed to identify these respective populations with frequent ed visits and assess the current therapeutic management of acute exacerbation of asthma and copd at hospital kuala lumpur, malaysia. methods the demographic and medical data was prospectively collected and recorded in march using convenient sampling, and then descriptively analyzed using spss version . appropriate statistical analysis were applied with p < . was considered as signifi cant. the study recruited patients (male . %) with . % asthmatics and . % copd. malays signifi cantly presented to ed the most ( . %) followed by indians ( . %) and chinese ( . %). most patients were between - years old ( . %) with mean age of . . about . % were smokers ( . % ex-smokers) with an average duration of smoking . years and . pack-years. for occupational data, . % were belonging to non-professional group. about . % asthma and . % copd patients had visited ed last year with average visit of . and . times and mean number of hospitalization was . and . , per year, respectively. about . % patients without scheduled appointments and . % were not on any prescribed medications for asthma or copd. among patients with prescribed medications, . % were on saba and . % on inhaled corticosteroids. respiratory infections remained as main triggering factors of admission ( . %), followed by weather ( . %) and air pollution ( . %). average duration of treatment was about minutes with mean direct therapy cost of rm per patient excluding the standard admission fee. whil hr monitoring, the level of oxygen saturation and pefr were signifi cantly improved post treatment. oxygen-driven nebulised saba and iv hydrocortisone were the mainstay of treatment. however, the use of an anticholinergic as a step up approach in nebulised treatment was underused. most discharged patients were given oral saba ( . %) and prednisolone ( . %). pefr measurement was not practiced post treatment regularly. conclusion limited number of staff contributed towards omitted monitoring steps. involvement of ed pharmacists in respective therapeutic management is highly suggested. introduction fluid volume is an important factor when considering pleural drainage. however, there is limited literature regarding accurate quantifi cation of pleural effusion by ultrasonography. in a study by visperas et al, they quantifi ed the pleural effusion volume by measuring the length, width, and depth of the fl uid, while the patient was in a sitting upright position, and the actual volume drained. they postulated a linear regression equation to quantify estimate the pleural fl uid volume that will be drained. introduction insomnia disorder is the most common sleep disorder which affected more than people in bangladesh. people develop chronic insomnia disorder with symptoms of diffi culty falling asleep for more than minutes and last for more than month. patients with insomnia disorder in bangladesh took sleeping pills each year for insomnia disorder. however, there were still some side effects about sleeping pills such as allergy, amnesia, hallucination etc. because of the side-effects of modern medicine and because of the inability of modern medicine to cure insomnia disorder, international scientifi c interest has re-focused on the traditional uses of medicinal plants to fi nd effective cure for insomnia disorder as well as hundred of other disorders. a study of the traditional health practitioners in the habiganj district of bangladesh suggested that some of the herbal medicines prepared from medicinal plants might be quite effective for insomnia disorder. methods information was collected through a series of interviews with the traditional health practitioners, rural and urban people. field notes were recorded on the medicinal plants and their uses; following the methodology of bhat et al. ( ) and martin ( ) . the identifi ed medicinal plant specimens were stored at the bangladesh national herbarium; under the author's collector series. results the following medicinal plants or plant parts were found to be used as remedy for insomnia disorder: cyrtandra cupulata ridl., bacopa monnieri (l.) pennell, ocimum gratissimum l., lawsonia inermis l., cinnamomum camphora (l.) sieb., aconitum napellus l., datura metel l., mimosa pudica l., achyranthes aspera l., piper betle l., randia dumetorum (retz.) poir., ficus glomerata roxb., nigella sativa l., agaricus albolutescens zeller, ipomoea aquatica forssk., stephania japonica (thunb.) miers, withania somnifera (l.) duna, cannabis sativa l., calamus rotang l., uraria picta (jacq.) dc., sesamum indicum l., asparagus racemosus willd., abrus precatorius l., and brassica napus l. conclusion information on indigenous use of medicinal plants has led to discovery of many medicines in use today. it is important that modern scientifi c studies be conducted on these medicinal plants towards isolation and identifi cation of compounds through which insomnia disorder can be effectively treated. introduction existing data on the association between sleep duration and blood pressure in adolescents are inconsistent and confl icting. this study aims to determine the relationship between sleep duration and -hour ambulatory blood pressure in adolescents. methods subjects aged - . years were recruited from the community. they underwent nocturnal polysomnography (psg) and -hour ambulatory blood pressure monitoring (abpm) on the same day. daytime, nocturnal and -hour average systolic and diastolic blood pressure (sbp and dbp) were converted to z score with reference to height and gender according to normal reference. a -day sleep diary was completed prior to psg. daily sleep duration was defi ned as the average of nocturnal sleep duration plus the average of daytime nap duration over week. subjects with body mass index (bmi) greater than the th percentile of the local normal reference were classifi ed as overweight. those who were overweight and had an obstructive apnoea hypopnoea index (oahi) greater than or equal to were excluded from the analysis. results one hundred forty one subjects ( boys) with a mean (sd) age of . ( . ) years were recruited. they were divided into groups according to their daily sleep duration (< . vs. . - . vs. . - . vs. > . ). subjects with shorter sleep duration tended to have higher daytime sbp (p < . ), nocturnal sbp (p = . ) and -hour sbp (p < . ). similar results were found after converting the bp data into z score (p = . , . introduction some studies have shown decreased plasma and hair zn in human asthmatics which may indicate a state of zinc defi ciency. we have shown, in a well characterized murine model of allergic airway infl ammation, that there were marked losses of zinquin-stainable (labile) zn in the infl amed airway epithelium (ae); when these mice were placed on low zn diets, there was excessive cell death in the ae, and increased airway infl ammation. we have proposed that labile zn protects the ae from premature cell death and loss of this zn contributes to the ae fragility and infl ammation in asthma. a screen of whole lung gene expression of the two major families of zip infl ux transporters and znt effl ux transporters, indicated a marked loss of znt in the infl amed lungs. the hypotheses being tested here are ) ae zn is normally stored in vesicles within the apical cytoplasm, ) znt is responsible for transporting zn into these bodies and ) loss of znt expression in asthma may result in a failure of zn to be sequestered. methods human nasal epithelial brushings were obtained from healthy, consenting donors. lung tissue was obtained from balb/c mice sensitized and aerosol-challenged with ovalbumin or saline (controls). distributions of zinc were determined by zinquin fl uorescence or in vivo selenite autometallography (se-amg). distributions of znt were determined by immunofl uorescence. results zinquin fl uorescence of human and murine ae indicated abundant labile zn with a vesicle-like pattern of staining in the apical cytoplasm. se-amg confi rmed the presence of apical zn vesicles at an ultrastructural level. there was strong immunolabelling for znt in the same region. furthermore, there was an almost complete loss of znt protein in the bronchial epithelium of mice with allergic airway infl ammation. conclusion colocalization of znt with labile zn in ae may indicate a role for this zinc transporter in replenishing zn storage pools in this tissue. loss of znt protein during airway infl ammation would then result in failure to sequestrate zn, depleting critical storage pools of zn in the lung and airways, leading to increased ae damage and cell death. this work was supported by nhmrc project grant . introduction community-acquired pneumonia remains a major cause of mortality in developed countries. there is much discrepancy in the literature regarding factors infl uencing the outcome in the elderly population. methods data were derived from a multicentre prospective study initiated by the german competence network for community-acquired pneumonia. patients with community-acquired pneumonia (n = , ; , aged < years and , aged ≥ years) were evaluated, of whom . % were hospitalised and . % treated in the community. clinical history, residence status, course of disease and antimicrobial treatment were prospectively documented. microbiological investigations included cultures and pcr of respiratory samples and blood cultures. factors related to mortality were included in multivariate analyses. results the overall -day mortality was . %. elderly patients exhibited a signifi cantly higher mortality rate that was independently associated with the following: age; residence status; confusion, urea, respiratory frequency and blood pressure (curb) score; comorbid conditions; and failure of initial therapy. increasing age remained predictive of death in the elderly. nursing home residents showed a four-fold increased mortality rate and an increased rate of gram-negative bacillary infections compared with patients dwelling in the community. conclusion the curb score and cerebrovascular disease were confi rmed as independent predictors of death in this subgroup. age and residence status are independent risk factors for mortality after controlling for comorbid conditions and disease severity. failure of initial therapy was the only modifi able prognostic factor. introduction hospital-acquired pneumonia (hap) attributes to % of all nosocomial infections. mortality rate is as high as - %. guidelines for the management of adults with hap were recently updated. despite the emergence of evidence-based medicine, the use of these guidelines in daily clinical practice is still limited. currently, there is no literature published regarding the impact of adherence to the guidelines and clinical outcomes of hap. methods a total of patients (male: %; female: %) admitted and diagnosed with hap at our center were followed up to investigate the rate of adherence of physicians on the diagnosis and treatment of hap based on level i and ii ats/idsa recommendations and to determine its association with outcome (mortality, mechanical ventilation, icu stay, hospital stay). adherence to diagnostics and therapeutic management were computed per patient. management of patients was classifi ed as adherent if it meets more than % of the guidelines that should be enforced. results in this cohort, % of the physicians adhered to the currently recommended guidelines. age, gender, and co-morbid conditions such as hypertension, diabetes mellitus, copd, ckd and cerebrovascular disease were not statistically associated with the outcome of the study. a total of % of the subjects were eventually mechanically ventilated (p = . ). a total of % of patients who adhered to the recommendations consequently died during hospitalization (p = . ). similarly, univariate analysis of variance revealed that there is no signifi cant association of adherence to length of icu stay and hospital stay (p = . , . respectively). of the level i and ii current recommendations, request of blood culture showed signifi cant association with adherence (p = . ). however, logistic regression analysis showed that there is no association of adherence in doing blood culture to mortality. conclusion this analysis showed that compliance with the currently recommended ats/idsa recommendations is %. blood culture is the most signifi cantly associated recommendation. rate of endotracheal intubation, length of icu and hospital stay and mortality however was not signifi cantly associated with adherence. introduction reportedly high arsenic level in drinking water causes increased mortality and morbidity in adult copd patients. arsenic related health hazards include respiratory symptoms with decreased lung function added to skin lesion. currently million people of bangladesh are at potential risk of consuming arsenic contaminated drinking water and a major section of them showed many symptoms including alteration of lung function. methods the present study was conducted on chronic arsenicosis patients in selected areas of bangladesh to assess lung function status by measuring fvc, fev , fev / fvc% & pefr. in total, subjects of - years of age of both sexes were selected. apparently healthy subjects were selected from non arsenic residency as well as not exposed to arsenic in their tube-well water and were grouped as healthy control. of subjects from area exposed to arsenic contaminated tube-well water, were patients of chronic arsenicosis with skin lesions were considered as experimental group, whereas subjects without skin lesions were regarded as exposed control. results the mean measured values of the lung function parameters of nonarsenic exposed healthy control and exposed control were within normal ranges. but these values were signifi cantly lower in chronic arsenicosis patients with skin lesions. the parameters showed negative correlation with age, arsenic concentration in tube-well water but positive correlation with duration of the consumption. but these relationships were not statistically significant. all the patients of arsenocosis complained about respiratory symptoms in the morning. conclusion the present study reveals that arsenicosis patients are suffering from respiratory insuffi ciency and symptomatic respiratory illnesses. in addition, populations consuming higher arsenic concentration in drinking water are at the risk of lung function impairment and ultimately may lead to respiratory disorders, though it would be better to draw a defi nite conclusion from a further study involving large sample size. introduction despite of the detailed study of community-acquired pneumonia, the role of atypical microorganisms such as m. pneumoniae, c. pneumoniae and l. pneumophilla is not still defi ned. also there are some discussions about role of the associations of these bacteria with the other so-called typical microorganisms as s. pneumoniae and h. infl uenzae as well as the place of the viral pathogens in community-acquired pneumonia ethiology structure. the aim of our research was to defi ne the etiology of the community-acquried pneumoniae in young adults ( - years, fi rst group) and to compare the results with the data gained in aged patients (< years, second group). methods the young and aged patients with community-acquired pneumonia were screened with bacteriological, disk-diffusion with mic, pcr and other methods. antimicrobial agents resistance was checked to nccls standards and the clonality of the isolates was checked by pfge and mlst for the most frequent clones. results bacterial associations were defi ned in % versus % in the second group. m. pneumoniae was identifi ed in % vs %, c. pneumoniae . % vs %. the bacterial pathogens were represented with the species s. pneumoniae ( . %/ %), h. infl uenzae ( . %/ %), m. catarrhalis ( . %/ %). among the viral pathogens the most often was metapneumovirus in young adults ( %), and infl uenzae virus in aged patients ( %). the most prevalence bacteria were genotyped and there were revealed the relations between several isolates of m. pneumoniae and s. pneumoniae existing as association in several cases of different age groups what proved the epidemiological character of the spread of this association. so, the most frequent clone of s. pneumoniae was recognized as st , as well as st . pfge typing of atypical microorganisms also revealed the spread of the several clones. conclusion some changes in etiology structure of community-acquired pneumonia seems to be connected with the changes in immunology peculiarities of different age groups, as well as with the other epidemiology reasons. introduction despite of the detailed study, the role of acinetobacter baumanii pathogen as the a ubiquitous opportunistic nosocomial pathogen is still appreciated. the most of epidemiological aspects of this infection are still discussed though the problem of the microbiology charecteristics of this pathogen are of keen microbiology interest. it is often isolated in immunocompromised hosts in different forms of hospital-acquired infections, but more often it was recognized as the main pathogen agent of hospital-acquired pneumonia. the aim of our research was to establish clinical signifi cance of a. baumanii in development of hospital-acquired pneumonia, to defi ne its epidemiology and to characterize antimicrobial agents resistance pattern. methods we made -year surveillance of all hospital-acquired pneumonias (hap) in adult patients in the main clinics of vladivostok (hospital Ð , Ð ), defi ned etiology with standard microbiology methods. all isolates of a. baumanii were tested for antimicrobial agents resistabce according to nccls. the strains with the same antimicrobial agents resistance pattern were checked to clonality by pulsed-fi eld gel electrophoresis (pfge). results during - , we studied all cases of hap in adult patients (< years) admitted to icu and revealed that a. baumanii has taken the second place in etiology structure ( . %, cultures from patients). the fi rst place was in pseudomonas aeruginosa ( . %, strains) and the third one was in stenotrophomonas maplthophila ( . %, strains). mostly ( strains, . %), a. baumanii was isolated as monoinfection, but in other cases it was isolated in association with another strains of a. baumanii, or p. aeruginosae, s. palthophila, s. aureus, e. feacalis, e. cloaceae. there were defi ned lower resistance to ciprofl oxacin. the clonality research revealed about genotype clusters what could allow to suggest the genetic relatedness of the isolates. conclusion acinetobacter baumanii should be studied to defi ne the role in hospital-acquired infections, as well as it confi rms the fact that the importance of local surveillance programs in correctly guiding empiric therapy and local intervention programs in attempt to reduce antimicrobial resistance. introduction community acquired pneumonia (cap) is the most common cause of death associated with infectious disease. locally, it is the leading cause of morbidity and the fi fth cause of mortality according to the department of health. the initial management decision after diagnosis is to determine the site of care: outpatient, hospitalization in a medical ward, or admission to an icu. the decision to admit the patient is the most costly issue in the management of cap, because the cost of inpatient care for pneumonia is up to times greater than that of outpatient care. it is a well documented fact that signifi cant variation in admission rates among hospitals and among individual physicians occurs. physicians often overestimate severity and hospitalize a signifi cant number of patients at low risk for death. because of these issues, interest in objective site-of-care criteria has led to attempts by a number of groups to develop such criteria. the two foremost criteria are the british thoracic society criteria (curb- ) and the pneumonia severity index (psi). the idsa/ats committee preferred the curb- criteria because of ease of use and because they were designed to measure illness severity more than the likelihood of mortality. patients with a curb- score > are not only at increased risk of death but also are likely to have clinically important physiologic derangements requiring active intervention. these patients should usually be considered for hospitalization. therefore, the study was done to determine and compare mortality rates of the admitted cases of community acquired pneumonia assessed by either curb- criteria or the philippine clinical practice guidelines on cap, and to determine the applicability of curb- as a site-of-care tool in the admission of patients with community acquired pneumonia either at the wards or the intensive care unit. methods all patients seen at the emergency room and out-patient department with the diagnosis of community acquired pneumonia were included in the study. thorough history-taking and physical examination was taken by the er/opd fellow whom would determine if the patient has pneumonia. subsequently, laboratories (cxr, cbc, bun, abg) was requested. randomization was done for severity assessment: one group was assessed via the curb- criteria, while the other group was assessed using the philippine clinical practice guidelines for cap. severity assessment was done by the er fellow together with the investigator not more than one hour of the patient's arrival at the er/opd. patient was followed-up by the investigator within hours of admission (ward or icu) and until discharge or death. results a total of patients diagnosed with community acquired pneumonia (cap) were included in the study. the age range for the curb group is from to years of age with a mean age of . ± . years, while in the cpg group, to years of age with a mean age of . ± . years. no significant difference were noted (p = . ). no signifi cant difference were also noted in the gender of both groups (p = . ). there was a signifi cant difference noted in the presence of comorbidities (p = . ) between the two groups, . % and . %, curb group and cpg group, respectively. the presence of previous ptb treatment, cardiovascular disease and copd, ranks as the three most common comorbidity. dyspnea ( . %), cough ( %) and fever ( . %) were the three most common symptoms noted. there were no signifi cant difference noted in these symptoms (p = . , . , . , respectively). with regards to the physical fi ndings: crackles ( . %), tachypnea ( . %), wheezes ( . %) were the three most common signs noted. no signifi cant difference were noted in most of the signs, except for "tachypnea" and "hypotension" (p = . , . , respectively). there were no signifi cant difference in the radiographic fi ndings between both groups. no signifi cant difference were also noted in the complete blood count results be it leukocytosis (p = . ), anemia (p = . ) and leukopenia (p = . ). there is a signifi cant difference in the blood urea nitrogen (p = . ). no signifi cant difference was also noted in the arterial blood gas result: hypoxemia (p = . ) and hypercapnia (p = . ). for the curb- group, more than half of the population was assessed to have a score of (in-patient), ( . %). for the cpg group, more than half was assessed to be under the moderate risk, ( . %). all of the patients assessed in the lower severity class, either thru the curb- or the cpg, had been discharged improved. the overall mortality rate per group was: . % for the curb- group, out of the patients, and . % for the cpg group, out of the patients. mortalities were noted only on those with higher severity ratings. on further determination of mortality rate per level of severity, it revealed that those with a curb- score of ≥ has a mortality rate of . % ( out of the patients), while those on the cpg, . % ( out of the patients). conclusion in this study, we determined that all of the mortality came from the higher severity levels: curb- score ≥ ( . %), cpg-high risk ( . %), none from the lower severity ratings the curb- criteria is a useful site-of-care tool, though, the usage of curb- criteria does not offer additional benefi ts compared to the use of the cpg, in fact because of familiarity of physicians with the latter, they are more adept in using it. introduction acute exacerbation has been a major complication of interstitial lung disease (ild). the rapid recognition of a bacterial pneumonia and an acute exacerbation of underlying ild appears to be clinically important for proper treatment. procalcitonin (pct), a precursor peptide of the hormone calcitonin is commonly detected at elevated levels under bacterial infection conditions. this study was to assess whether or not serum procalcitonin levels were useful as a biomarker for the differential diagnosis of ild exacerbation from bacterial pneumonia. methods we had planned a prospective observational study. our study enrolled ild patients who had presented with recently progressive dyspnea, and newly infi ltrates of the chest in underlying ild. results nine of them evidenced bacterial pneumonia with high pct level. serum pct levels in ild exacerbation group were signifi cantly lower than in the pulmonary infection group (the mean value . ng/ml vs . ng/ml, % [ci]). sensitivity, specifi city, and negative predictive value of serum pct level were . %, %, . % respectively. conclusion the fi ndings of this study suggest that serum pct value is useful in the differential diagnosis of bacterial pneumonia from exacerbation in patients with interstitial lung disease. introduction it has been well confi rmed that malnutrition and muscle wasting are important extra-pulmonary manifestations of chronic obstructive pulmonary disease (copd), which are recognized as contributing to an increase in morbidity and decrease in quality of life. myostatin, a transforming growth factorbeta superfamily member, is mainly expressed in skeletal muscle and has been characterized as a negative regulator of skeletal muscle mass. studies have showed that myostatin is implicated in several diseases involved in muscle wasting and cachexia. recently, there is evidence of myostatin secretion and circulation in animals and human blood, and more recently, studies have shown that intramuscular myostatin expression accelerated in copd patients; while levels of circulating myostatin in copd remain unclear. we therefore analyzed serum myostatin levels to investigate the relationship between circulating myostain levels and nutritional depletion and muscle wasting in copd; and the relationship between circulating myostain levels and systemic cytokines such as tumor necrosis factor (tnf)-α and interleukin (il)- in copd. methods fifty-four male patients with stable copd and twenty-one agematched, healthy, male control subjects participated in the study. total-body skeletal muscle mass (smm) were calculated according to a validated formula by using body weight, height and age. nutritional status was evaluated by anthropometric measurements and serum protein levels; the former included body mass index (bmi), triceps skin-fold thickness (tsf) and mid-upper arm circumference (mac), and the latter included serum prealbumin, transferrin and albumin. serum levels of myostatin, tnf-α and il- were detected by elisa. results out of the patients with copd, ones ( . %) had malnutrition, with bmi less than kg/m . serum levels of myostatin were signifi cantly elevated in copd patients compared with controls ( . ± . ng/ml vs. . ± . ng/ml, p < . ), and the levels were even much higher in those with malnutrition ( . ± . ng/ml). however, smm was signifi cantly decreased in copd patients compared with controls ( . ± . kg vs. . ± . kg, p < . ). all the nutritional parameters except of prealbumin were signifi cantly decreased in copd patients compared with controls, with each p < . . there is an inverse correlation between myostatin levels and smm (r = − . , p = . ) and a positive correlation between myostatin and tnf-α levels (r = . , p = . ) in copd group, but no correlation between myostatin levels and serum proteins concentrations. conclusion this study demonstrates that circulating myostatin levels were elevated in patients with copd and that the elevated myostatin levels are closely related with malnutrition and muscle wasting in patients with copd. introduction chronic obstructive pulmonary disease (copd) is defi ned by airfl ow limitation that is not fully reversible and no medication exists that clearly improves the mortality. oxidative molecules, in particular superoxide anion, are believed to play an important role in copd-associated abnormal infl ammatory response due to increase in the level of pro-infl ammatory cytokines and chemokines and pulmonary emphysema due to proteases/antiproteases imbalance and apoptosis. superoxide dismutase (sod) catalyses the dismutation of superoxide anion to hydrogen peroxide, which is subsequently detoxifi ed to oxygen and water. lecithinized sod (pc-sod) has overcome a number of previous clinical limitations of sod, including low tissue affi nity and low stability in plasma. in this study, we examine the effect of pc-sod on elastase-or cigarette smoke-induced pulmonary emphysema, animal models for copd. methods severity of pulmonary emphysema in mice was assessed by various methods, such as the number of leucocytes (neutrophils, lymphocytes and alveolar macrophages) in bronchoalveolar lavage fl uid (balf) and enlargement of airspace (increase in mean linear intercept). lung mechanics were assessed by a computer-controlled ventilator. the pulmonary level of superoxide anion was estimated by electron spin resonance analysis and the level of -hydroxy- ′-deoxyguanosine. results not only intravenous administration but also inhalation of pc-sod suppressed elastase-induced pulmonary emphysema and dysfunction. inhalation of pc-sod showed therapeutic effect against elastase-induced pulmonary emphysema and dysfunction even when it administered after the development of emphysema. inhalation of pc-sod suppressed elastase-induced increase in the pulmonary level of superoxide anion and apoptosis. inhalation of pc-sod also suppressed elastase-dependent activation of proteases and induction of expression of pro-infl ammatory cytokines and chemokines. we also found that inhalation of pc-sod suppressed cigarette smoke-induced pulmonary emphysema and dysfunction. conclusion results suggest that pc-sod protects against pulmonary emphysema through decreasing the pulmonary level of superoxide anion and resulting inhibition of infl ammation, apoptosis and activation of proteases. we propose that inhalation of pc-sod is therapeutically benefi cial for copd. introduction tiotropium is a recently developed inhaled anticholinergic in the management of copd, exhibiting a prolonged duration of action and a kinetic selectivity to specifi c muscarinic receptors, leading to a more effective bronchodilator response at once-daily dosing. we determined the effi cacy of long-term tiotropium use on clinical endpoints such as mortality, exacerbations, and hospitalizations compared to inhaled long-acting beta- agonists among patients with copd. methods search methods rcts were identifi ed from electronic databases. bibliographies and relevant reviews were also searched. the date of the last search is august , . selection criteria rcts among patients with copd comparing tiotropium monotherapy with inhaled labas with at least months follow-up were selected for inclusion. data on all-cause mortality, mortality from pulmonary causes, mortality from cardiovascular causes, rates of hospitalizations and exacerbations were identifi ed. data collection and analysis three investigators evaluated and extracted relevant data. any disagreements were discussed and consensus decisions were made. the data were analyzed using revman . studies were pooled to yield odds ratios and were reported using % confi dence intervals. results from rcts, clinical trials with a total of , patients met inclusion criteria. tiotropium did not reduce the odds of all-cause mortality (or . % ci . to . ) compared to inhaled labas. subgroup analysis also shows that tiotropium did not reduce the odds of mortality from pulmonary causes (or . % ci . to . ) but shows a trend that might increase mortality from cardiovascular causes (or . % ci to . ). tiotropium reduced the odds of hospitalizations from all causes (or . % ci . to . ) and showed a trend towards benefi t in reducing the odds of exacerbations (or . % ci . to . ). conclusion tiotropium did not reduce all-cause mortality among patients with copd compared to inhaled labas, although it showed a possible trend towards harm in causing cardiovascular mortality. it also reduced hospitalizations, although it did not decrease the odds of exacerbations among patients with copd. background patients from asia may have different outcomes compared to those from other backgrounds. we therefore examined outcomes in the subgroup of asian patients in the uplift trial. . more patients will be recruited until august in vietnam and singapore as well as in the above nine countries. this abstract contains an interim analysis. the recruited patients were mostly male ( . %) and elderly (mean age, . years). according to gold criteria, severity of airfl ow limitation was mild in . % of patients; moderate in . %; severe in . %; very severe in . %. a total of . % of patients were exposed to cigarette smoking; . % to dusty jobs. a total of . % of patients had symptoms of "chronic bronchitis -phenotype" viz. chronic cough with phlegm; . % had wheezing in the last months. a total of . % of patients were on regular medications, e.g. inhaled steroid combined with long-acting beta-agonist, theophylline, shortacting beta-agonist, tiotropium, combined inhaler of salbutamol and ipratropium, and inhaled steroid alone, in decreasing order. in the past one year, . % patients required/ were prescribed antibiotics for acute exacerbations and . % required/were prescribed oral steroids. of this cohort, % patients had unscheduled/ emergency visits to the er or were hospitalized. conclusion this interim report showed that asian copd patients are heterogeneous. a high proportion was exposed to dusty environments at their job sites and many were cigarette smokers. further studies are ongoing to fi nd out other characteristics of copd phenotypes including the infl uence of dusty job environment in the development and progression of copd in asia. introduction it is widely recognized that copd is not only a lung-based disease, but also a systemic disorder with systemic infl ammation, which further aggravates the disease progression at acute exasperation (aecopd). it is important to fi nd a systemic biomarker which is lung-specifi c and can be used to indicate the severity of the disease in the stable state (scopd) and at exacerbation. c reactive protein (crp) and tumor necrosis factor (tnf)-a have been attracted attention as they can refl ect the systemic burden of infl ammation, while they are not lung-specifi c. surfactant protein d (spd) is produced and secreted by alveolar type ii epithelial cells and clara cells. recently study has reported that spd can be used to track disease progression and predict clinical outcomes in copd. the present study was aimed to determine the value of spd as a biomarker of systemic infl ammation in staging the severity of copd and diagnosis of the exacerbation. methods we recruited three groups of subjects: patients experiencing aecopd (n = ), patients with scopd (n = ) and controls with normal lung function (n = ). elisa was used to analyze serum spd, crp and tnf-a levels. the bode scoring system was employed to evaluate health status of patients with copd, which included the four variables: body mass index, degree of airfl ow obstruction, dyspnea and exercise capacity. conclusion the present study confi rms that circulating spd levels are higher in copd and closely related with health status of the patients and severity of the disease; moreover, circulating spd can be regarded as a valid biomarker of systemic infl ammation and a potential diagnostic biomarker for aecopd. methods we reviewed all the records of bronchoscopies in our hospital from february , to january , and identifi ed patients diagnosed subsequently with primary lung cancer whose sputum cytology was negative or not performed prior to bronchoscopy. a total of patients with pulmonary tuberculosis were also identifi ed whose prebronchoscopic sputum acid-fast stains were negative or not performed. we reviewed the result of pathological examination of bronchoscopic specimens and postbronchoscopic sputum for the lung cancer patients and the result of mycobacterial culture of these specimens for the tuberculosis patients. of the lung cancer patients, postbronchoscopic sputum cytology was performed in patients and gave a positive result in ( . %) patients. the postbronchoscopic sputum was the only diagnostic specimen in ( . %) patients. meanwhile, postbronchoscopic sputum culture was performed in of the tuberculosis patients and was positive for m. tuberculosis in ( %) patients. of these patients, the culture of specimens obtained by bronchoscopy was negative in patients, of whom also had a negative result of prebronchoscopic sputum culture. conclusion postbronchoscopic sputum cytology has a limited role for the diagnosis of primary lung cancer and should not be performed in terms of cost-effectiveness. but its culture seems to provide additional information for the diagnosis of pulmonary tuberculosis and further studies are needed to determine when to obtain postbronchoscopic sputum specimens. for other malignant tumours -in ( . %) patients. in ( . %) patients with benign pathology procedures were performed for tracheomalacia -in ( . %), for tracheobronchial fi stula -in ( . %), for endobronchial lipoma -in ( . %) and for other pathology -in ( . %) patients. there were ( . %) unilateral, ( . %) -tracheal, ( . %) -tracheobronchial and ( . %) -bilateral bronchial procedures. on ( . %) occasions procedure was elective, on ( . %) -urgent and ( . %) times it was performed as an emergency. eight patients required stent replacement. stenting was performed under general anaesthesia using combination of rigid and fi beroptic bronchoscopy and in majority with intraoperative x-ray control. uncovered and covered ultrafl ex stents (boston scientifi c) have been mainly used. results there was no intra-operative mortality. eleven ( . %) patients died in hospital prior to discharge and of them died within hours after procedure. in all these patients urgent or emergency stenting was performed. tumour debulking and/or cryotherapy were required on occasions after stenting. hospital stay ranged from to (mean - . , median - ) days. in benign group there was one hospital death in a patient with tb stricture. in patients with malignant tumours total survival ranged from to (mean - . , median - ) days, in elective subgroup -from to (mean - . , median - ) and in urgent subgroup -from to (mean - . , median - ) days. all patients had signifi cant improvement of distressing symptoms. conclusion tracheobronchial stenting is rapid and effective technique of palliation in patients with malignant or in selected cases of benign tracheobronchial stenosis. it provides better outcome if performed electively. stent occlusion may be controlled by endobronchial cryotherapy. introduction in the clinical evaluation of airway disease, fi beroptic bronchosopy (fob) is a crucial tool in the diagnosis. however it is invasive, time-consuming and requires sedation. endobronchial lesions may be seen in both fi beroptic bronchoscopy and mdct virtual bronchoscopy (vb). the extensive image data acquired with vb permits the simulation of the internal as well as external appearance of the tracheobronchial tree. the objective of the study is to compare mdct virtual bronchoscopy with fiberoptic bronchoscopy in the detection and characterization of tracheobronchial (airway) pathology, particularly to determine the overall agreement in the fi ndings in both modalities. methods patients who underwent ct scan of the chest and then underwent fi beroptic bronchoscopy were included in the study. each patient was assessed into levels: trachea, carina, right mainstem bronchus, left mainstem bronchus, tracheobronchial branches. these levels were examined using virtual bronchoscopy for presence/absence of obstructive, endoluminal and mucosal lesions and compared with the actual fi beroptic fi ndings. the sensitivity and specifi city, ppv and npv of vb were determined with fob as the gold standard. results a total of patients were included in the study. sixty-fi ve (n = ; levels) levels were observed, of which / ( %) accounted for the same evaluation using fob and that of the vb. the sensitivity of vb in diagnosing endoluminal lesion was noted to be %, with specifi city of %. virtual bronchoscopy overestimated obstructive lesions with two false positive results and detected two false negative patients with endoluminal mass. none of the mucosal abnormalities (mucosal erythema, edema, etc.) are detected using vb. conclusion virtual bronchoscopy may be comparable with fi beroptic bronchoscopy in the localization, morphologic description of tracheobronchial lesions. however, it has limited capability to reconstruct subtle mucosal irregularities. consequently, it is prone to artifactual reconstruction for mucosal changes that may render a false positive fi nding. overall, virtual bronchoscopy best complements the fi beroptic bronchoscopy in thorough evaluation of the tracheobronchial pathologies and cannot obviate the need for this invasive approach in the diagnosis of early mucosal changes within the airway. results of patients ( %) were male. all patients had multiple comorbidities which include severe copd = ( %), ( %) patients each had heart failure, respiratory failure and anaemia,hypoalbuminemia = ( %), active tuberculosis = ( %), pah = ( %), cad, crf, cld in patients and age > years was in ( %) patients. all patients underwent ct thorax and fob and after localizing bleed underwent bae within h of admission. in / ( %), bae could not be done on account of technical reasons. immediate control of bleeding was achieved in / patients ( %). in total, / patients ( . %) reported no rebleed till months. none developed early rebleed (< month) while / ( . %) develop late rebleed (> months). one managed conservatively and other underwent lobectomy. only complication of bae was transient dysphagia in / ( . %). conclusion bae is safe and effective in immediate and long term control of massive haemoptysis in elderly patients with multiple comorbidities and should be considered even in such high risk group. introduction histologic specimens obtained by endobronchial ultrasoundguided transbronchial needle aspiration (ebus-tbna) often provide valuable information for diagnosis or management decisions. besides the conventional -gauge needle, a -gauge needle is now available for this procedure. the purpose of the present study was to compare the histologic specimen retrieval yields of ebus-tbna using -gauge and -gauge needles for sampling hilar/mediastinal lesions. methods sixty patients with hilar/mediastinal lymphadenopathy or a tumor adjacent to the central airway were enrolled in this study and randomized to undergo ebus-tbna using a -or -gauge needle. each histologic specimen obtained by ebus-tbna on the initial two punctures of each patient (total punctures) was interpreted separately and categorized by an experienced pathologist as follows: i, diagnostic; ii, nondiagnostic but adequate (e.g. lymphoid tissue); iii, nondiagnostic and inadequate (e.g. clot); and iv, no specimens. results median targeted lesion size in shortest diameter on ct in the group using a -gauge needle and a -gauge needle was . mm and mm, respectively. prevalence of malignancy on primary disease in each group was % and %, respectively. the specimens obtained by -gauge needle were interpreted as i in , ii in , iii in and iv in . the specimens obtained by -gauge needle were judged to be i in , ii in , iii in and iv in . the sampling yield of adequate histologic specimens (i and ii) obtained by the -and -gauge needle was % and % (p = . ). no complications were associated with the procedures. conclusion histologic specimens can be obtained with a high sampling yield by either of the needles. our study could not show any difference in sampling yield between the two needles. introduction diagnostic tuberculosis using acid fast bacilli (afb) microscopy and conventional lowenstein jensen (lj) culture remain the cornerstone but the sensitivity of these traditional methods is quite low, especially in the samples containing small number of organism. there is a need for rapid, sensitive and accurate detection of these organisms in clinical specimens to hasten the administration of appropriate antimycobacterial therapy and prevent the spread of infection in the community. sputum smear-negative pulmonary tuberculosis (ssn-ptb) is a common problem faced by clinicians. performing fi ber optic bronchoscopy (fob) and subjecting the bronchoalveolar lavage (bal) material to diagnostic methods of smear and mycobacterial culture appears to be helpful in the diagnosis of ssn-ptb. radiological and pulmonary function outcome of children with sars longer term follow up of aerobic capacity in children affected by severe acute respiratory syndrome (sars) the usefulness of virtual bronchoscopic navigation has been established for the diagnosis of small peripheral lesions. exclusive software (bf-navi) from olympus medical systems is commercially available, but because no function to display extra-airway structures has been installed, this could not be indicated for testing where the purpose is mediastinal/hilar lymph node aspiration. using an improved version of the software from olympus medical systems to permit lymph node visualization, this study evaluated the aspiration support function. methods before testing, size and position of lymph nodes for aspiration were established on mpr images of ct data. on the virtual navigation image, these were displayed in a transparent ellipse from the airway. besides rotation and back and forth movements, changes in angle of the bronchoscope tip are simulated, and a function is also available to move the virtual image fi eld up, down, left, and right. using these, the navigation image was compared with the real image, and the lymph nodes were aspirated. in patients with enlarged mediastinal/hilar lymph nodes, transbronchial needle aspiration (tbna) without using an ultrasound probe, or ebus-tbna, was selected for aspiration. results lymph nodes were aspirated under navigation in all patients. the diagnosis was primary lung cancer in fi ve patients, metastatic tumor in one patient, and sarcoidosis in two patients. depth perception was diffi cult for the transparently displayed lymph nodes, particularly # and # , and judging anterior-posterior relationships was diffi cult when nodes were superimposed. conclusion some room for improvement thus remains in the display method. however, this offers future promise as diagnostic support technology. key: cord- -af nihyi authors: nan title: copd sig: poster session date: - - journal: respirology doi: . /j. - . . _ .x sha: doc_id: cord_uid: af nihyi nan increased airway smooth muscle (asm) in asthma may be due to hyperplasia or hypertrophy of asm cells. the contribution of extracellular matrix (ecm) within asm bundles has not previously been accounted for when estimating asm cell volume. aim to estimate the mean asm cell volume in asm bundles in asthma. methods post-mortem tissues from control subjects (c n = ); nonfatal (nfa n = ) and fatal (fa n = ) cases of asthma were studied. on mm transverse airway sections stained with haematoxylin, the volume density (nv) of asm cell nuclei was estimated using an optical disector (¥ ). the mean cell volume (vc = /nv) was calculated, correcting for the volume fraction of asm (fasm) within the asm bundle (corrected vc = /(nv ¥ fasm)). fasm was estimated on . mm thick sections of the same airway stained with masson's trichrome. basement membrane perimeter (pbm) was used to indicate airway size. results table shows mean Ϯ sd. (one-way anova) *p < . for c v fa, nfa v fa. conclusion these data suggest that although asm area is increased in asthma, mean asm cell volume is unchanged. therefore hyperplasia, not hypertrophy, of asm cells is present in both mild and severe asthma. these results were similar for both large and small airways. asthma is characterized by airway inflammation and remodelling which contribute to airway hyperresponsiveness and episodic airflow obstruction. mast cell (mc) densities are higher on the smooth muscle (asm) in asthma so their mediators may modulate other asm functions as well as cause contraction. aim to investigate the effect of mc mediators on chemokine and extracellular matrix (ecm) production by asm cells from donors with and without asthma. methods mc were isolated from the resected lung samples of patients, resuspended at cells/ml in dmem + % fbs and stimulated with ige/anti-ige. supernatants (sn) were collected after and h and the mc lysed. sub-confluent asm cells from donors with and without asthma were serum deprived for h before mc sn/lysates were added in dmem + %fbs for h. il- and eotaxin levels in all asm sn and mc sn/lysates were measured by elisa. fibronectin and collagen iv deposition was measured in situ by immunoassay following asm cell lysis. results in asthmatic and non-asthmatic asm cells all mc sn and lysates reduced eotaxin release by up to % and %, whereas the - h mc sn significantly increased il- release to Ϯ . % (p = . ) and Ϯ % (p = . ) of the fbs control respectively. however, only nonasthmatic asm cell il- release was increased by the mc - h sn ( Ϯ %; p = . ) and cell lysates ( Ϯ %; p = . ). the - h mc sn also increased fibronectin deposition to Ϯ % (p = . ) by asthmatic asm cells only. mc sn and lysates had no effect on collagen iv deposition. conclusions activated mast cell mediators differentially modulated chemokine and ecm secretion by asm cells from donors with and without asthma. thus mast cells may modulate their own recruitment to the smooth muscle and remodelling locally in the airways in asthma. supported by nhmrc. the technique of ige passive sensitization reproduces ige-related allergic responses in vitro and studies have validated this technique for investigations modelling allergic smooth muscle responses. there are no studies investigating effects of ige sensitization on rhinovirus (rv) infection. we hypothesized that rv infection is enhanced by ige sensitization, a consequence of diminished early innate immune responses. methods beas- b epithelial cells and primary culture airway fibroblasts were sensitized with ige h- d prior to infection with rv . samples of tissue culture supernatant and cell lysates were collected over a h period after infection for analysis. viral replication was measured by real-time rt-qpcr and viral titration and type i interferon mrna by rt-qpcr. ige receptor mrna expression was examined using rt-pcr. results initial studies to establish the model used human serum high in ige (> iu/ml), this yielded inconsistent results and it was found that purified ige ( iu/ml) provided more reliable responses. sensitization was established after h ige incubation and was comparable with up to d. rt-pcr detected mrna for the ige low affinity receptor only after sensitization. following rv infection, vrna was increased after h in ige sensitized cells (p < . ), but this effect varied noticeably between and within cell lines. cellular expression of ifn-b mrna increased with viral infection but in cells sensitized with ige lower levels of expression were noted (p < . ). conclusions ige passive sensitization enhanced rv replication in vitro but the model is constrained by significant variability between and within cell lines. the effect of sensitization on rv replication may occur through the low affinity ige receptor. activated mast cells (mc) are present in higher numbers on the airway smooth muscle (asm) in asthma compared with other inflammatory airway diseases. matrix metallo-proteinases (mmps) cleave chemokines and alter chemokine gradients by degrading the extracellular matrix and thus may modulate mc migration to the asm. aim to determine the levels of mmp- , mmp- and their inhibitors, timp- and timp- , secreted by asm cells from donors with and without asthma. method confluent asm cells were washed, serum-starved for h and then stimulated with th (il- , tnf and ifn) or th (il- , il- and il- ) cytokines or left unstimulated. after and h,the sn were collected. the relative amount of pro and active forms of mmp- and mmp- in sn were determined by gelatine zymography. timp- and timp- levels in the sn were measured by elisa. results pro-and active mmp- were not detected. however, pro-mmp- levels were high in sn of asm cells from donors with ( . Ϯ . % positive control/ cells) and without ( . Ϯ . % positive control/ cells) asthma. a trend to increased active mmp- production by asm cells from donors with ( . Ϯ . % positive control/ cells, n = ) compared to without ( . Ϯ . % positive control/ cells, n = ) asthma after h was not significant (p = . ). timp- and timp- levels respectively were high in the sn of cells from donors with ( . Ϯ . and . Ϯ . ng/ cells, n = ) and without ( . Ϯ . and . Ϯ . ng/ cells, n = ) asthma. th and th cytokine stimulation did not affect mmp or timp release. conclusions th and th cytokines did not regulate asm cell production of mmp- , timp- and timp- . altered asm mmp- activity is unlikely to play a role in mc chemotaxis to asm cells from donors with asthma in vitro or their presence on the asm in asthma. there has been a marked increase in the prevalence of asthma and other allergic diseases in the last few decades. one of the explanations for this is the change in our diet. one of the characteristics of the "western diet" is a high intake of both saturated and polyunsaturated fat. this prompted us to compare the effects of high fat and low fat meals on the numbers of circulating eosinophils and other leukocytes. methods we studied volunteers who had allergic rhinitis and/or asthma and a peripheral eosinophil count at baseline of Ն ¥ /l. this was a randomized, crossover trial with participants studied on two different days. on each occasion they arrived fasting and after bloods were drawn consumed a calorie meal. one of the meals was high in saturated fat and refined carbohydrate. the other meal was low in saturated fat and high in fruit and fibre. bloods were drawn postprandially every hour for five hours. results eosinophil counts were highest in the early morning and fell over the course of the day but the decrease was less with the high fat meal (p = . ). over the same period of time the increase in lymphocytes (p = . ) was greater with the high fat meal. the high fat meal was also associated with greater increases in triglycerides (p < . ) and cholesterol ( . ). conclusions in atopic individuals a high fat meal was associated with higher circulating numbers of eosinophils and lymphocytes than an isocaloric meal that was low in fat. further studies of the effect of dietary fat on eosinophilic inflammation are warranted. supported by the university of auckland research committeee. intravenous gamma globulin therapy (ivig), which is therapeutic in a variety of immune diseases, has been reported to be effective on patients with severe steroid-dependent asthma. although fcer are known to play important roles in asthma, there are few reports about the role of fcg?receptors in asthma. fcg receptor iib (fcgriib) is unique inhibitory receptor, which suppresses immune response. in this study, we evaluated the effect of ivig in allergic airway inflammation in ova-challenged mice and the mechanism of the inhibitory effects of ivig and fcgriib. method c bl/ mice (wt) and fcgriib deficient mice (ko) were sensitized with ovalbumin (ova) and alum and subsequently challenged with nebulized ova. before ova challenge rabbit igg was administered intravenously. the airway inflammation and effects of igg were assessed by histology, cell counts of bal fluid and airway hyperresponsiveness. result histology showed that igg treatment ameliorated the inflammation around the airway and the vessels and hypertrophy of goblet cells induced by ova challenge. the migratory activity of dcs is modulated in inflammatory diseases such as asthma. recently, we reported that immature dcs express kinin receptors and that bradykinin (bk) significantly enhances the migration of immature dc in vitro. as kinins mediate many of the pathophysiological effects associated with asthma, we hypothesized that lys-des[arg ]-bk, which is produced during inflammation and acts via the b receptor (b r), would inhibit migration of mature dcs. methods day cultured human monocyte-derived dcs were matured with lps, tnfa +il- b or cd l in the absence or presence of lys-des[arg ]-bk. maturation of dc was analysed by flow cytometry (facs). b r expression was assessed by reverse-transcriptase pcr and quantitative confocal microscopy. migration of mature dc was assessed in transwell chambers with lysdes [arg ]-bk and the chemokine ccl used as chemoattractants. results maturation of dcs was found to result in down-regulation of b r expression to varying degrees depending upon the maturation stimulus used. mature dcs all demonstrated an ability to migrate toward lys-des[arg ]-bk and ccl . however pre-treatment with lys-des[arg ]-bk decreased the migratory ability of all mature dcs to both chemoattractants. conclusions along with chemokines, lys-des[arg ]-bk is likely to play a crucial role in regulating the in vivo migration of mature dc during inflammation. the production of lys-des [arg ]-bk during inflammation potentially immobilizes mature dcs thereby facilitating locally-mediated immune responses within inflamed tissues. supported by the asthma foundation of western australia. introduction alternative or aberrant splicing is a major contributor to protein diversity, in which a single gene can generate structurally and functionally distinct protein isoforms. the role of alternative splicing in asthma pathogenesis has not been previously investigated. we hypothesized that specific alternatively spliced asthma candidate genes contribute to the development of asthma. we chose to use a new and innovative approach involving the use of the genechip (r) exon array system together with real-time quantitative pcr to study asthma candidate genes in human monocyte-derived dendritic cells. asthmatic and non-asthmatic subjects provided ml of blood from which peripheral blood mononuclear cells (pbmc) were isolated by ficoll-paque gradient centrifugation. monocytes were separated from other leukocytes by adherence method, and differentiated into dendritic cells following incubation with defined concentrations of gm-csf and il- . rna was isolated and reverse transcribed for real-time semi-quantitative pcr and densitometry. chi squared test was used to assess associations between alternative splicing and asthma. results data indicate splice variant expression in dendritic cells from asthmatic patients is influenced by asthma severity. conclusion exon expression array analysis has generated a number of asthma candidate genes with alternative splice variants. further studies to validate these data in a replicate data set and establish the functional significance of our findings in asthma are underway. alternative or aberrant splicing occurs in more than % of genes and is a major contributor to protein diversity, in which a single gene can generate structurally and functionally distinct protein isoforms . the role of alternative splicing in asthma pathogenesis has not been previously investigated. we hypothesized that specific alternatively spliced asthma candidate genes contribute to the development of asthma. we chose to study one asthma candidate gene in human stimulated and unstimulated: ( ) monocytes, ( ) monocytederived dendritic cells and ( ) lung smooth muscle cells. methods asthmatic and non-asthmatic subjects provided ml of blood from which peripheral blood mononuclear cells (pbmc) were isolated by ficoll-paque gradient centrifugation. monocytes were separated from other leukocytes by adherence method. up to % of the monocytes were then differentiated into dendritic cells following incubation with defined concentrations of gm-csf and il- . induction experiments used mg/ml lps and cells were stimulated for an optimal period of hrs. rna was isolated and reverse transcribed for real-time semi-quantitative pcr and densitometry. chi squared test was used to assess associations between alternative splicing and asthma. results data from stimulation experiments indicate splice variant production can be regulated by the inflammatory response and that this response is influenced by asthma status. conclusion preliminary experiments have confirmed the presence of an aberrant splice variant for an asthma candidate gene in the primary cells studied. further studies to confirm these data and establish the functional significance of our findings in asthma are underway. exposure to environmental factors, such as environmental tobacco smoke (ets), plays a significant role in modulating pre-existing genetic susceptibilities to diseases including asthma. the glutathione s-transferase enzymes (gsts) play an important role in the detoxification of ets. there are several gst isoforms and gstp codes for the gst pi isoform, which is the primary gst isoform expressed in human lung tissue. two single nucleotide polymorphisms (snps) at positions and have been reported in gstp and associated with asthma and atopy. the aim of this study was to examine the effect of these snps in combination with ets, on asthma phenotypes in a cohort of asthmatic children. children were recruited during an acute episode requiring presentation at an emergency department. genotyping using pcr-rflp was completed on children and ets exposure was determined by parental questionnaire. urinary cotinine was measured in the children and was in agreement with questionnaire responses. statistical analyses were performed using spss. there were no significant associations between the genotypes and asthma severity during acute exacerbations. significant associations were found between the snps and atopy in this population with an odds ratio of . for the aa genotype (p = . ) and or of . for the cc genotype (p = . ). however, when an interaction with ets was included, the odds ratios increased to . for aa (p = . ) and . for cc (p = . ). these results suggest that there is a significant gene/environment interaction impacting on atopy in this cohort. the rage gene encodes the receptor for advanced glycation end-products (rage), a member of the immunoglobulin superfamily. rage activation by ligands, including amphoterin and s /calgranulins, leads to prolonged nf-kb signalling and has been associated with chronic inflammation. despite high levels of rage expression in lung tissue, little research has been undertaken into the role of rage in the chronic inflammatory asthma phenotypes of severe and aspirin-sensitive asthma. objective determine genetic associations between functional polymorphisms in the rage promoter and severe and aspirin-sensitive asthma phenotypes. methods pcr and restriction fragment length polymorphism (rflp) were used to genotype three rage promoter polymorphisms, - t>c, - t>a and a bp deletion from - to - , in a large case-control asthma population phenotyped for asthma severity, atopy and aspirin sensitivity. results no associations were identified between any of the polymorphisms and the occurrence of asthma. however, the - a allele was linked with both severe asthma (p = . ) and aspirin-sensitive asthma (p < . ). likewise, genotypes containing the - a allele were strongly associated with both severe asthma (or . , % ci . - . ) and aspirin-sensitive asthma (or . , % ci . - . ). conclusions the - a allele of the rage gene, previously shown to lead to a -fold increase in promoter activity, is associated with the chronic inflammatory asthma phenotypes of severe and aspirin-sensitive asthma. these results suggest that increased rage expression, with a concomitant increase in nf-kb signalling, may in part contribute to the inflammatory response seen in these conditions. the global prevalence of allergic diseases is rising and australia has one of the highest prevalence rates in the world. the role of early childhood infections in the development of allergic disease remains controversial. objective to examine the association between early childhood infections and the development of allergic diseases in later childhood, in high risk children. methods data were analysed from the melbourne atopic cohort study (macs) of infants with or more first-degree family members with atopic disease. primary risk factors assessed were otitis media, bronchitis and gastroenteritis reported in the first two years of life. outcomes were current asthma, hay fever and eczema at years of age. logistic regression was used to estimate crude and adjusted odds ratios. results asthma was the most common allergic condition ( . %, % ci . - . %), followed by eczema ( . %, % ci . - . %) and hayfever ( . %, % ci . - . %). the most commonly reported infection was otitis media ( . %, % ci . - . %), then gastroenteritis ( . %, % ci . - . %) and then bronchitis ( . %, % ci . [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . %). all types of infection within the first years of life were associated with increased risk of asthma. an increased risk of asthma at years was seen with otitis media (or = . , % ci . - . ), bronchitis (or = . , % ci . - . ) and gastroenteritis (or = . , % ci . - . ). when the frequency of infection was examined, those who reported at least episodes of gastroenteritis had a - -fold increased risk and an almost % absolute increased risk (rd . , % ci . - . ). conclusion these findings appear to contradict the hygiene hypothesis. the findings for gastroenteritis are novel. further examination of these associations and possible underlying mechanisms is warranted. grant support asthma foundation of victoria, nestle. background knowledge about incident cases of asthma in australia is limited because they are not routinely reported. the ability to predict the number of new cases of asthma would be helpful in allocating resources for asthma education, management and care. data on first use of medications for asthma gives an indication of the incidence of asthma. the objective of this study was to estimate the incidence rate of asthma by investigating asthma medication use in individuals. methods pharmaceutical benefits scheme (pbs) records for all prescriptions filled for inhaled corticosteroids (alone or combined formulation), cromones and leukotriene receptor antagonists from july to june were included. using a -year look back window, any persons who had their first prescription for any of these drugs dispensed between july and june were assumed to be incident cases. overall and age-specific incidence rates were calculated per asthma-medication-free individuals. results there were , individuals who had their first asthma medication dispensed between july and june , which equates to an overall incidence rate for asthma of . per . the incidence was higher among children aged - years ( . ) and adults aged years and over ( . ) . conclusions our estimated incidence rates were consistent with those reported by others in the literature. while the pbs database was designed for administrative purposes, it can be used to estimate incidence rates for asthma. support acam is a collaborating unit of the australian institute of health and welfare and is funded by the department of health and ageing (doha). we acknowledge the pharmaceutical pricing and estimates section of doha for provision of pbs data. keywords asthma incidence, pharmaceutical benefits scheme. rosario ampon , guy marks , teresa to , leanne poulos , anne-marie waters australian centre for asthma monitoring (acam), sydney, australia, and hospital for sick children, toronto, canada background the ability to assess individual patterns of asthma medication use would have clinical relevance in targeting effective asthma education and management for this common condition. to describe longitudinal patterns of asthma medication use, we used a population-based prescription database to follow individuals from the first time they filled an asthma prescription. asthma is more commonly listed on death certificates as an associated cause of death, in people whose deaths are attributed to other causes, than as an underlying cause of death. understanding the importance of these associations would contribute towards an overall appreciation of the impact of asthma on mortality. the objective of this analysis was to estimate the prevalence of asthma as an associated cause of death when various other diseases were attributed as the underlying cause of death. background acam currently recommend indicators to measure population-level asthma health and outcomes. we examined correlations among several asthma indicators covering prevalence, morbidity and mortality to try and produce a condensed set of indicators which minimized redundancy. methods seven of the indicators were included in this study: prevalence of ever having doctor diagnosed asthma, prevalence of current asthma, asthma-related general practice (gp) encounters, proportion of people with asthma with an asthma action plan (aap), hospitalizations for asthma, hospital patient days for asthma, and deaths due to asthma. a correlation matrix was created for these indicators by age groups. pearson correlation coefficients Ն . or Յ- . were considered strong. results there were strong positive correlations between prevalence of ever asthma and current asthma (r = . ); gp visits and aap possession (r = . ), hospitalization (r = . ) and patient days (r = . ); and hospitalization and patient days (r = . ) and aap possession (r = . ). recent australian reports have shown that the prevalence of asthma and respiratory symptoms has decreased over the last - years. as part of a larger study investigating child health and air quality we have collected nationwide data from schoolchildren living in act, victoria, queensland, wa and sa. methods schools were selected based on proximity to air quality monitoring stations. classes from years to were randomly selected and all children were invited to participate. parents self completed a questionnaire that included questions about diagnosed asthma and respiratory symptoms. results a total of children provided questionnaires for analysis. the response rate varied between states and territories and ranged from % to %. the sample comprised . % girls and the mean age of children was . years. ever diagnosed asthma . current asthma ('does he/she still have asthma? ') . wheeze in the past months . respiratory symptoms limiting activities . missed school due to asthma or wheezing . conclusions despite the relatively low participation rate, the prevalence estimates for current asthma are similar to those reported in the national health survey - [ ] . there is no evidence of any recent increase in the prevalence of childhood asthma. methods tahs is a longitudinal population-based respiratory study of subjects which commenced in when they were years of age. since the initial study another follow-ups have been conducted, including the most recent follow-up when subjects were years of age. lung function of the total sample was measured at baseline and in sub-samples in subsequent followups. asthma was categorized as persistent, frequent or episodic when participants reported asthma symptoms in at least follow-ups, in follow-ups or in follow-up respectively. results by age years ever asthma prevalence was %. at age , % of those who had not reported asthma by age had asthma symptoms while % of those who reported asthma by age had no asthma symptoms. hence over all only % of the asthma symptoms at age were attributable to asthma developed by age . in contrast, % of the persistent and frequent asthmatics had developed their asthma by age . persistent and frequent asthmatics had more symptoms and poorer lung function at age , and as well as more reversibility at age (p < . ). childhood asthmatics who also had a productive cough by age were more likely to have persistent asthma than those without a cough (p < . ). conclusions although the majority of middle-age asthma is related to postchildhood onset asthma, most severe middle-age asthma has its origin in persistent childhood disease. having productive cough in childhood may identify high risk asthmatics who require especially rigorous management in early life. one third of women experience an improvement in asthma during pregnancy, and symptoms improve in most women in the late third trimester. we hypothesized that the exacerbation rate would be reduced and that symptoms during exacerbations would be less severe in the third trimester compared to the second trimester. methods pregnant women with asthma (n = ) were prospectively followed from recruitment ( . weeks ( sd) ) to delivery at clinic visits ( , , weeks and during exacerbation), and fortnightly phone calls. the asthma control questionnaire (acq) was administered at each contact and exacerbations classified as severe (requiring medical intervention) or mild (selfmanaged). lung function, medication use, fractional exhaled nitric oxide (feno) and full blood counts were assessed. paracetamol is commonly used in infants as an analgesic and antipyretic. it has been hypothesized that frequent paracetamol consumption may result in reduced lung capacity to cope with oxidative stress and increase risk of respiratory disease. to date, no study has examined exposure to paracetamol during infancy, when lungs are still developing, and risk of childhood asthma. method a birth cohort of infants with an atopic family history was recruited. frequency of paracetamol exposure was prospectively documented up to years of age. interviews were conducted at and years to ascertain asthma in the previous months. results paracetamol exposure in infancy was common ( % exposed by two years of age), with some infants receiving paracetamol on up to days. it has been hypothesized that mucosal immune response requires a particular micro-flora milieu in the infant's gastro-intestinal tract, and that early life antibiotic exposure may disrupt this process and increase risk of allergic disease. method a birth cohort of infants with an atopic family history was recruited. exposure to oral antibiotics was prospectively documented up to months of age. interviews were conducted at and years to ascertain asthma in the previous months. results by one year of age, approximately % of infants had received at least one course of oral antibiotics. the prevalence of current asthma in childhood was approximately % ( / ). frequent use of antibiotics (more than days exposure during first year of life) was associated with increased risk of childhood asthma (or = . , % ci = . - . ) when compared to infant who had not been exposed. excluding infants with a diagnosis of asthma within the first two years of life, reduced this association by about % (or = . , % ci = . - . ) and adjustment for gender, parental history of asthma and number of infections in the first year of life further reduced this association (or = . , % ci = . - . ). the increased risk of childhood asthma associated with antibiotic exposure in the first year of life is, at least in part, due to confounding with early life wheeze and infections. if real, the independent effect of antibiotic exposure on risk of childhood asthma is likely to be minimal in this high risk cohort. support dairy australia, crc for asthma and airways, vichealth, nestle. the epidemiological data on asthma suggest a gender difference that varies with age. hormonal effects have been suggested as a possible explanation for these differences. the aim of this study was to examine reproductive factors and risk of asthma among the females of the tasmanian longitudinal health study (tahs). methods the tahs is a longitudinal population-based cohort study of respiratory disease which commenced in when subjects were years of age. four follow-up studies have been conducted including the current most comprehensive follow-up with subjects at years of age. information has now been collected on reproductive factors such as number of pregnancies, age at pregnancies, age at menarche and contraceptive pill use as well as on asthma status. reproductive factors were examined as risk factors for asthma using multiple logistic regression to adjust for all likely confounders. results a total of , women completed the most recent postal survey. of these ( . %) had current asthma, and of these women with current asthma . % ( ) developed asthma after childhood. on average these women were in their mid-twenties when they developed asthma (mean Ϯ sd age = . Ϯ . yrs). we found with increasing age at first birth an approxi-mate~ % reduced risk of current asthma in women who developed their asthma post-childhood (trend p = . ). we did not observe any other associations between reproductive factors and risk of asthma. conclusions our results are consistent with the hypothesis that early pregnancy may promote asthma development by altering the immune response favouring a th pathway. a delay in the age of first pregnancy reduces this risk of asthma. grant support nhmrc, clifford craig foundation, victorian & tasmanian asthma foundations. introduction the association between exposure to pets in early life and subsequent development of sensitization and allergic disease remains controversial. the objective of this analysis was to examine the relationship between cat exposure before birth and development of cat sensitization over time within the melbourne atopic cohort study (macs). methods the macs is a prospective longitudinal cohort study that initially recruited women antenatal in melbourne from february to november . detailed information on cat exposure was collected at recruitment and frequently until two years of age. skin prick test (spt) were conducted at , , months and years. the data were analysed by logistic regression and using generalized estimating equations (gee) for the repeated measures design. results among subjects, ( . %) had a cat before birth. at months, . % (n = ) of subjects were sensitized to cat and by years of age . % (n = ) were sensitized. those who did not have cat before birth belong to a higher social class, and were more likely to have a father with allergic disease than those with a cat. those who developed sensitization to cat were more likely to have a paternal family history of allergic disease and more likely to be sensitized to other allergens. we did not observe any association between exposure to cat before birth and the development of sensitization to cat at months (or = . , % ci . - . ) , months (or = . , . - . ), months (or = . , . - . ) or years (or = . , . - . ) . these crosssectional results were confirmed by the gee analysis. conclusion our results fail to show an association between cat exposure before birth and development of sensitization to cat. furthermore exposure after birth in the first months of life was not associated with an increased or decrease risk of sensitization to cat. our results do not support either a benefit or risk associated with cat ownership and sensitization. introduction peri-natal events influence the development of asthma and atopic diseases in childhood but the current literature is contradictory on the effect of low birth weight, small for gestational age and prematurity on asthma risk. the aim of this study was to assess the relationship between these three exposures and asthma from childhood to adulthood. aim to assess the current prevalence of dda, wheeze (< months), atopy and ahr in children and adults in busselton. methods an age-and sex-stratified random sample of adults, selected from the electoral roll, was invited to complete a questionnaire and attend the local study centre for assessment of atopy (allergen skin tests) and ahr (methacholine). all children from participating primary and secondary schools were also invited to attend. the prevalences of dda, wheeze, atopy, ahr and "current asthma" (wheeze + ahr) were calculated. background asthma is often associated with comorbidity, however few studies have investigated comorbidities among people with this common condition. the objective of this analysis was to describe patterns of non-respiratory comorbidity among adults hospitalized with asthma in australia. methods data on hospitalizations for people aged years and over with a principal diagnosis of asthma (j , j ) were obtained from the australian institute of health and welfare's (aihw) national hospital morbidity database for the period - . patterns of comorbidity were examined by investigating additional diagnoses for non-respiratory disease according to icd- diseasespecific chapters. results among people aged years and over hospitalized in - with a principal diagnosis of asthma ( , hospitalizations; % female; % aged - years), % had at least one non-respiratory comorbidity. median length of stay was higher among those with at least one comorbidity ( days) than among those with no comorbidities ( days). among people aged - years, the most common comorbid condition was endocrine, nutritional and metabolic diseases ( %), while among those aged years and over it was diseases of the circulatory system ( %). conclusions a large proportion of asthma hospitalizations in australia are associated with non-respiratory comorbidity and a longer length of stay. further, the pattern of non-respiratory comorbidity associated with asthma hospitalizations varies by age. given our rapidly ageing population, the level of comorbidity associated with asthma has implications for coordinated health care and demand on health services. support acam is a collaborating unit of the aihw and is funded by the department of health and ageing. keywords comorbidity, hospitalization, asthma. background asthma exacerbations are often triggered by viral respiratory infections, yet the influence of respiratory infections on the morbidity of acute asthma beyond the immediate period is unknown. we examined the influence of nasopharyngeal (npa) respiratory viral, chlamydia and mycoplasma detection on asthma morbidity in children presenting to the emergency department for an acute exacerbation of asthma. methods a subset (n = ) of the children enrolled for a randomized controlled trial (rct) on the efficacy of vs days of oral prednisolone had an npa taken at presentation. npa were examined for chlamydia, mycoplasma and respiratory viruses (enteroviruses, coronaviruses, human metapneumovirus, adenovirus, parainfluenza, influenza, rsv, rhinoviruses) by pcr. enrolled children were aged - years with recurrent wheeze and required Ն ?g (mdi/spacer) or Ն . mg (nebulized) of salbutamol to reduce tachypnoea. parents filled validated diary cards for cough and asthma severity, and completed asthma qol data at enrolment and end of weeks and . results pcr for various viruses was positive in ( . %) children, with no significant difference in the groups the children were randomized into. rhinovirus pcr was positive in the npa of children, rsv in , hmpv in , adenovirus, parainfluenza, influenza a and b in one each. specimens were negative for the other micro-organisms listed above. children with a npa viral positive state were significantly (p = . ) younger than those with a negative state. however, there was no difference in the any of the asthma outcomes of children whose npa was positive or negative for the micro-organisms tested. conclusions in children with an acute asthma exacerbation presenting to emergency health facilities, a respiratory virus could be identified in > % but the presence of a respiratory virus did not influence the morbidity of the asthma exacerbation at presentation or at the end of week- and week- . the university of sydney, nsw , and royal north shore hospital, st leonards, nsw airway wall thickness measured using hrct is reported to be increased in asthmatic compared with control subjects. however, it is unknown whether wall thickness is a fixed structural characteristic of the airways or if it responds to transient changes in bronchomotor tone or airway size. aim to determine the effects of bronchomotor tone and lung volume on airway wall area measured by hrct. methods patients with doctor-diagnosed asthma had partial chest hrct scans, before and after bronchodilator (bd), at frc, tlc and a volume midway between (mid-volume). airway segments were identified between branch points and matched between consecutive lung volumes both before and after bd, and also at constant lung volume before and after bd. mean lumen areas and wall areas for each airway segment at each volume were measured using automated analysis software. paired t-tests were used to determine changes due to bd and lung inflation. results airways were matched before and after bd at frc. absolute airway wall area (wa) was related to airway lumen diameter (di wood smoke air pollution is of concern with respect to respiratory health due to its complex chemical composition and potential to carry air toxics into the lower respiratory system. launceston has a long history of poor winter air quality, primarily due to use of domestic wood heaters. participants in hobart had a similar prevalence of wood heater use, but hobart does not experience the same wood smoke pollution (due to differences in regional geography , asthma control and anxiety and depression were completed at baseline, immediately following ( wks), and mths after the intervention period. results clinically and statistically (p < . ) significant improvements in qol were observed in the exercise group at wks compared to the control group. this difference was not maintained at mths. mwd improved at wks and mths in the exercise group (p < . ), however the difference between groups was not significant. in the exercise group there was a trend towards improved asthma control and a reduction in anxiety and depression that was not observed in the control group. *p < . , change at wks vs baseline; home asthma monitoring is important for measuring day-to-day variation in lung function and symptoms. this approach requires the availability of complete diaries for a comprehensive assessment. we assessed the completeness of written diaries collected as part of a nation wide study of air quality and child health. methods children who had ever been diagnosed with asthma and had respiratory symptoms in the last year were identified from a cross-sectional study. these children were asked to record symptom scores and peak expiratory flows twice daily in diaries for a five week period. the diaries and peak flow devices were explained at a face-to-face meeting with parents and children. each week diaries were mailed back and parents received a phone call to encourage completion. completeness was defined as no missing responses to symptom questions or peak flow measurements in diaries from week two to week five. results data from the first children ( day records) were available for analysis. the sample included ( %) girls, mean age yrs. the overall frequencies for complete records were; morning symptoms %, morning peak flow %, evening symptoms % and evening peak flow %. there was a significant trend for more complete morning peak flow records over the four weeks (cochrane-armitage trend test p < . ). agreement between morning and evening symptom completeness and between morning and evening peak flow completeness was fairly poor (kappa < . ). conclusions the completeness of symptom and peak flow records collected in this study was very high. the comprehensive follow-up protocol implemented is likely to have had an important impact on the completeness of asthma diaries. daily peak expiratory flow (pef) monitoring has been used in epidemiological studies to assess changes in lung function over time. the value of written pef diaries has been questioned because of problems with completeness and validity. this study aimed to compare stored electronic pef data and a written diary record of those data in a panel study in children with weekly reminders to aid adherence. methods children who had ever been diagnosed with asthma and had respiratory symptoms in the last year were identified in a population study. they were given electronic pef devices with a digital readout (miniwright digital, mwd, clement clarke, uk) and written symptom and peak flow diaries and instructed in their use at a meeting with parents and children. each child was asked to complete three pef manoeuvres every morning and evening for five weeks and to record these in the written diary. background previous research suggests that comorbid anxiety is associated with lower asthma-related quality of life (aqol) in adults with asthma. however, research is scant on the role of psychological interventions in these patients. aim to evaluate the effectiveness of a four-session cognitive-behavioural therapy (cbt) intervention, in improving the aqol, in participants with anxiety and asthma. method participants identified with comorbid anxiety and asthma were randomly assigned to the cbt intervention group (n = ) and the asthma monitoring control group (n = ) and evaluated on aqol measures, at various intervals. results nine participants, in the cbt group, completed the study. seven participants showed a clinically significant improvement in asthma-related emotional functioning (ef) and six participants in total aqol scores, at the -week post-intervention assessment. additionally, six participants in the cbt group indicated clinically significant improvement in ef and five participants in total aqol scores, at the -month follow-up assessment. only three participants in the control group completed the study. none of these participants showed any improvement in aqol scores at the -week or -month assessment. conclusion this pilot study suggests that a higher number of participants in the cbt group showed clinically significant improvement in ef and total aqol scores with higher retention rates. further research needs to confirm these findings in a larger group, identifying the elements of a successful cbt intervention and characteristics of participants who respond to the cbt intervention. gastro-oesophageal reflux disease (gord) is a risk factor for uncontrolled asthma. we conducted an update of a systematic review to assess whether treatment of gastro-oesophageal reflux in subjects with asthma improved asthma outcomes. methods randomized controlled trials (rcts) of gord treatment in adults or children that reported asthma health outcomes and had symptomatic gord were included and assessed in accordance with the standard cochrane systematic review process. subjects received pharmacological therapies compared with conservative management. results from potentially relevant studies, rcts were included in the review. when compared to placebo, morning peak expiratory flow did not significantly improve (change from baseline wmd . , % ci: - . to . ) with proton pump inhibitor treatment (n = trials involving participants). asthma exacerbations were not significantly less in the intervention groups compared with the control groups (odds ratio . ; . - . ; n = ). conclusions while some trials reported evidence of asthma improvement with gord therapy, overall there appears to be no statistically significant evidence of a beneficial effect. it is clear that not all persons with gord and asthma will gain improved control over their asthma with gord therapy; this may be due to the heterogeneous pathophysiology of asthma. future large-scale trials would be required to demonstrate an effect on asthma exacerbations. kel and brd were supported by a cochrane airways group scholarship. background the ats/ers task force recommend the use of metered dose inhaler (mdi) and spacer for airflow limitation reversibility testing. salbutamol given via mdi & spacer has been shown to be equivalent to a nebulizer in the clinical setting. this has not been well studied in respiratory laboratory setting. aim to compare the methods of reversibility testing in a laboratory setting. methods we conducted a laboratory based crossover study in a secondary hospital. patients with asthma or copd were eligible. the patients firstly underwent spirometry and reversibility testing following a standard dose of nebulized salbutamol. they were asked to return for a second set of spirometry within the same week and at the same time of day when reversibility with an mdi and spacer was recorded. we used an incremental dose of salbutamol starting from puffs and up to puffs. spirometry parameters were recorded minutes after each intervention. the primary outcome was the percentage change in fev after each intervention. side effects were monitored for. results nine patients with asthma were recruited. the mean percentage change in fev was higher in the nebulizer group than after only puffs via mdi & spacer ( . Ϯ . vs . Ϯ [mean Ϯ sd], p = . ). however, there were no differences between the arms following higher doses of bronchodilator via mdi & spacer. the mean percentage change in fev after , and puffs were . Ϯ . , . Ϯ . , and . Ϯ . respectively (p = . , . and . respectively when compared to the nebulizer group). conclusion using an mdi and spacer for bronchodilator reversibility is equivalent to that of a nebulizer and should be the standard method of testing. the dose of bronchodilator needs to be at least puffs as recommended by the ats/ers; however puffs correlated best with a standard nebulizer route. further increments in bronchodilator dose provided little additional bronchodilatation. the study was limited by the small number of patients. asthma guidelines recommend a stepwise approach to treatment. the role of inhaled corticosteroid (ics) and long-acting beta-agonist (laba) combination therapy in asthma written action plans is not clear. objective to assess the efficacy of adjusting ics/laba combination therapy in a written action plan compared to fixed dosing in people with asthma requiring maintenance ics. methods cochrane systematic review of randomized controlled trials comparing ics/laba combination therapy in a single inhaler that is adjusted up or down according to a written action plan (wap) to comparison : budesonide/ formoterol given as a fixed maintenance dose (fd) (n = ) or comparison : fluticasone/salmeterol fd (n = ). results parallel randomized controlled trials describing interventions met the inclusion criteria. for the trials that compared wap to fd budesonide/ formoterol there were significant reductions for the wap group in exacerbations, (rr ( %ci): . ( . to . )), severe exacerbations (rr ( %ci): . ( . to . )) and study medications (wmd ( %ci): - . (- . to - . )) with no difference in asthma control or adverse events. the results for the two trials reporting wap budesonide/formoterol to fd fluticasone/ salmeterol were discordant and a homogenous pooled result could not be determined. of the australians who died from asthma in , over two thirds were over years of age. this trend resulted in the national asthma council of australia (nac) calling for better management of asthma in the elderly. we designed an educational intervention using evidence based educational strategies to improve the content and style of general practice consultations for older people with asthma. methods randomized controlled trial of a multi-faceted program consisting of a group educational session, a videotaped standardized simulated patient consultation, followed by an academic detailing session. forty-two gps were randomized into an active or a control group. gps provided the names of patients who would be happy to participate in the study and the program was evaluated by patient and gp outcomes. results gps recruited into our program reported improvements in a range of clinical areas. one hundred and ten patients were recruited, their outcomes are under analysis. conclusion gps were overwhelmingly positive about participation in this trial and our intervention successfully improved the capacity and confidence of gp's to deliver care to older people with asthma. our study also developed several tools that would enable dissemination of our findings. supported by an asthma targeted in studies where direct clinical assessment is not possible, urgent health care utilization (hcu) is often used as an indirect measure of asthma control. this study aimed to identify factors predicting urgent hcu and asthma control. methods patients in nsw with a doctor diagnosis of asthma were recruited from community pharmacies, a research volunteer database, and databases of asthma foundation nsw, to complete a questionnaire about asthma. poor asthma control was defined as asthma control questionnaire (acq) score Ն . . urgent hcu was defined as hospitalization, ed visit, or urgent doctor visit due to asthma. multiple logistic regression was used to identify predictors of poor control and urgent hcu. results questionnaires were completed by adults ( % female) with a doctor diagnosis of asthma (pharmacy , woolcock , asthma foundation ). % used inhaled corticosteroid (ics) Ϯ long-acting b -agonist in the last wks. median age was yrs (range - ), and % were current smokers. mean acq score was . ( % ci . - . ), with % of participants having poor asthma control (acq Ն . ). % had urgent hcu for asthma in the previous year. significant independent predictors for poor asthma control were younger age, current smoking, living in more disadvantaged areas, being retired, having only primary education, and holding a concession card. predictors for urgent hcu were younger age, being in full-time employment, having only primary education, and being of non-english speaking background. neither ics use nor possession of a written asthma action plan was associated with lower risk for either poor asthma control or hcu. conclusions poor asthma control is common in nsw even in patients using inhaled corticosteroids. although urgent hcu is often used as an indirect measure of poor asthma control, it is affected by different factors, perhaps because health care utilization represents a more complex balance between need and access. bronchial challenge tests with mannitol, to measure airway hyperresponsiveness, can take up to minutes and require inhalation of up to mg of mannitol. our aim was to determine if positive mannitol challenges can be detected after half the maximal dose ( mg) using the forced oscillation technique (fot) to measure response. methods non-asthmatic subjects and asthmatic subjects underwent standard mannitol challenge, up to mg mannitol. respiratory system conductance (grs) and reactance (xrs) was measured by fot at hz during sec tidal breathing immediately after each dose of mannitol. fev was measured after fot, within sec of mannitol administration. two point dose response slope (drs), was calculated for grs (drsgrs) and xrs (drsxrs) for standard tests, up to mg, and for short tests by excluding data from doses above mg. ability to detect a positive test, defined as pd fev < mg, was determined by the area under the roc curve (auc) and repeatability by intra-class correlation coefficient (icc). results asthmatic and non-asthmatic subjects had positive tests, with pd fev values from . to mg. auc ( %ci) did not differ between standard (std) and short tests for drsgrs (p = . ) or drsxrs ( combined use of inhaled steroids (ics) and long acting beta-agonists (laba) have an important role in asthma management. we used data from a population sample to examine medication use in adults and children. methods all adults ( - years) and children ( - years) from within four discrete zones in northern sydney were eligible for an interview survey, as part of a study investigating health effects associated with traffic-related air pollution. the prevalence of use of short-acting beta-agonists (saba), any ics (alone or combination) and combined formulations of ics/laba in the previous three months was estimated for the study population and those with diagnosed asthma. results there were children [mean (sd) age . ( . ) years and % female] and adults [mean (sd) age . ( . ) years and % female] interviewed in households, representing an overall response rate of %. the prevalence of ever diagnosed asthma was . % in children and . % in adults. medication data were missing for subjects. background asthma affects : adult australians and is a leading cause of rejection for recruitment into the australian defence force (adf). within this diagnosis there is a wide spectrum of disease activity and clinical outcomes. also asthma assessment and management has improved so that many asthmatics are now fully active without any significant disruption or risk to their lives. hypothesis: there is a subgroup of asthmatics who are at very low risk from significant adverse effects from asthma and who could be considered for recruitment to the adf. aims . to identify the subgroup of asthmatics who could be considered for recruitment to the adf. . to develop an assessment process to identify this subgroup (screening). . to develop a process to evaluate the outcomes of any change to the recruitment standard for asthma (evaluation). methods . a literature review of the natural history, assessment, management and response to treatment of mild episodic and mild persistent asthma. . a literature review of asthma in the military. . a clinical review of the outcomes of known asthmatics in the adf. . an expert group to review the above and to develop a screening process and an evaluation of the program. the literature review identified a subgroup of asthmatics, defined as mild episodic and mild persistent, who with appropriate management, have a low risk of significant adverse asthma outcomes. they can be identified by a combination of questionnaire, spirometry and bronchial provocation testing. a screening process has been developed which allows asthmatics to be recruited with a negative mannitol or hypertonic saline challenge on mg/day or less of budesonide (or equivalent) without laba. a methodology to evaluate the impact of these changes on the recruitment standard has also been developed. alexithymia is a personality trait associated with difficulty identifying and communicating emotional and physical feelings. it has been associated with poor control of asthma and near fatal asthma. the primary objectives of this study were to: ( ) identify alexithymia in a cohort of australian asthma patients; ( ) investigate the relationship between alexithymia and asthma control; ( ) investigate the relationship between alexithymia and asthma management. methods cross sectional study of moderate to severe asthma patients recruited from royal adelaide hospital outpatients. participants were either mailed the questionnaire pack or completed it after a clinic appointment. existing validated questionnaires were used. statistical analyses were performed using spss. results male ( %) and female ( %) patients with moderate to severe persistent asthma (mean age years, sd = ) participated. alexithymia scores ranged from . to . (x = . , sd = . ). % (n = ) of participants could be classified high alexithymia, % (n = ) borderline alexithymia and % (n = ) were low alexithymia. alexithymia mean scores were not statistically different across sociodemographic variables. a positive correlation/association was found between alexithymia score and asthma control score (r = . , p < . ), quality of life (r = - . , p < . ), and adherence (p = . ) but not satisfaction with communication (r = - . , p = . ) or number of hospitalizations (p = . ). conclusions this is the first australian study to identify alexithymia among asthma patients and investigate relationship to control as well as management and communication. associations between alexithymia and asthma control were confirmed. a larger sample size is needed to determine impact of alexithymia on self-management and provision of clinical care for asthma. port hedland is impacted by iron-containing dust particles (pm ) that may activate lung cells when inhaled. furthermore, the effects of port hedland pm may differ from the effects of urban pm impacting metropolitan areas. the aim of this study was to assess the effects of port hedland pm on production and release of the inflammatory cytokines, il- and il- , by human airway epithelial (a ) cells, and to compare these with the effects urban pm from metropolitan areas. methods human airway epithelial (a ) cells were exposed to pm collected at port hedland and at urban locations (sydney, perth). a cells were exposed to a range of pm concentrations ( - mg/ml) for h. lipopolysaccharide (lps) and phorbol myristate acetate (pma) were used as positive controls. supernatants from cell cultures were assayed for il- and il- using specific elisa kits. rna was extracted and reverse transcribed to cdna. il- and il- mrna expression was quantified by duplex real-time pcr using taqman primer/probes. results lps stimulated a . -fold increase in il- release and pma stimulated a -fold increase in il- release and a -fold increase in il- release. however, neither port hedland pm nor urban pm stimulated concentration dependent release of il- or il- by a cells. expression of il- or il- mrna was also not altered by port hedland or urban dust. cd + t-cells may cause airway epithelial cell apoptosis via the granzyme pathway. we have reported increased apoptosis of airway epithelial cells and increased bal t-cell expression of granzyme b in copd, and a positive correlation between the two. we hypothesized that the increased granzyme b would also be related to smoking history (pack years -pk/y), age and severity of airflow obstruction (fev %pred) in patients with copd. we further hypothesized that the t-cell granzyme b expression would be higher in the airway than the peripheral blood. methods we investigated t-cell intracellular granzyme b expression in blood from copd subjects ( current and ex-smokers) and never-smoker controls, and bronchoalveolar lavage (bal) and bronchial brushing (intraepithelial t-cells) from a cohort of these subjects using flow cytometry. correlations between granzyme b and pk/y, age or fev were performed using spearman's rank correlation. granzyme b in t-cells from blood, bal and bronchial brushings were compared. results there were significant correlations between fev and granzyme b expression in blood and bal (blood: r - . , p = . ; bal: r - . , p = . ). there was a significant correlation between pk/y and granzyme b expression in blood (r . , p = . ), but not in bal. there were no significant correlations between granzyme b and age. there were no significant differences in granzyme b expression in blood, bal or intra-epithelial compartments. conclusion granzyme b is expressed at similar levels in blood, bal and intra-epithelial compartments, supporting recent opinion that copd is a systemic disease. t-cell granzyme b is related to severity of airflow obstruction and smoking history in patients with copd and may be one mechanism of apoptosis leading to lung injury and airflow obstruction in copd. jc allen , t schlosser, ee ramsay , q ge , aj ammit as development of remodelled airways is correlated with deterioration of lung function, we require therapies that reduce and reverse structural changes in remodelled airways. in asthma, corticosteroids can halt some, but not all, aspects of airway remodelling. therefore, in order to aid future design of efficacious anti-remodelling agents we need a better understanding of the molecular mechanism/s underlying the development of airway remodelling and the effectiveness of corticosteroids. hyperplasia of airway smooth muscle (asm) is a feature of the remodelled airway in asthmatics. in this study we examined the effect of corticosteroids on a key regulator of g progressioncyclin d . asm cells from n = non-asthmatics and n = asthmatics were pretreated for h with vehicle or dexamethasone ( . mm). the temporal kinetics of cyclin d mrna and protein expression were measured up to h after stimulation with the mitogen platelet-derived growth factor-bb (pdgf-bb). pdgf-bb induced a significant increase in cyclin d mrna expression in asm from non-asthmatics ( . Ϯ . -fold) and asthmatics ( . Ϯ . -fold) after h stimulation. in non-asthmatics, the corticosteroid dexamethasone significantly (p < . ) reduced the amount of cyclin d mrna expressed (to . Ϯ . -fold). in contrast, cyclin d expression in asthmatics was relatively resistant to inhibition by dexamethasone; the amount of pdgf-bb-induced cyclin d expression in the absence or presence of dexamethasone was not significantly different ( sphingosine -phosphate (s p), a bioactive sphingolipid found elevated in the airways of asthmatics, modulates myriad airway smooth muscle (asm) functions that promote inflammation and remodelling in asthma. in this study, we uncover the molecular pathway/s underlying s p-induced secretion of il- , and investigate if, and how, corticosteroids inhibit il- secretion. using cultured asm cells from non-asthmatics, we found that s p induces il- secretion from asm cells via cre, but not ap- , c/ebp or nf-kb, transcriptional regulation of il- gene expression. cre-dependence was supported by s p-induced creb phosphorylation. although the corticosteroid dexamethasone reduced s p-induced il- secretion in a dose-dependant manner, this inhibition appeared to occur via a pathway independent of creb/cre, suggesting the existence of a parallel pathway. as we recently discovered that the antiinflammatory actions of corticosteroids in asm can be mediated via the induction of the endogenous mitogen-activated protein kinase (mapk) inhibitor, mapk phosphatase- (mkp- ), we investigated whether mapk represents the parallel pathway targeted by corticosteroids. we found that s p can induce activation of a variety of mapk, however, only p mapk phosphorylation was inhibited by dexamethasone; importantly, the increase in mkp- after corticosteroid treatment appeared to mirror the decrease in s p-induced p mapk phosphorylation. furthermore, exogenous expression of mkp- inhibited s pinduced il- secretion. taken together, these results suggest that parallel pathways exist to induce il- secretion (transcriptional via creb/cre and possibly post-transcriptional via p mapk) and serve to underscore the importance of mkp- upregulation as a mechanism of action of corticocosteroids in asm. angiogenesis is a hallmark feature of asthma. angiogenic promoters, such as vegf and tgfb are reported to be increased in airways of asthmatics. tumstatin, an endogenous angiogenic inhibitor, is the non-collagenous domain- (nc ) of the alpha chain of collagen iv. decreased levels of collagen iv have been reported in the airways of asthmatics. we investigated the presence of tumstatin in the airway of asthmatics and its potential role as an angiogenic inhibitor. we detected the six a chain nc domains of col iv and the s domain of the a chain using immunohistochemistry. the level of tumstatin in serum and bal-f was measured by dot blot. western blots were used to identify the association with the rest of the collagen iv molecule. a tube formation assay using primary pulmonary endothelial cells (ppec) was performed to evaluate the role of tumstatin in the airway. the effect of intranasal tumstatin on airway hyperresponsiveness and angiogenesis was studied in an ovalbumin mouse model. tumstatin was absent in the airways of asthmatics (n = ) while the remaining six collagen iv a chains were present. the s domain of the a chain was present in the asthmatic airway (n = ). tumstatin was detected in both serum and bal-f samples from asthmatic volunteers (n = ), however the level of expression was not significantly different from that in nonasthmatics (n = ). in asthmatic serum tumstatin was part of the whole collagen iv a chain. tumstatin was able to inhibit ppec tube formation in a dose related manner. tumstatin inhibited angiogenesis in the mice airways and was associated with an improvement in ahr. the fact that tumstatin is absent from asthmatic airways and inhibited airway hyperresponsiveness and angiogenesis may indicate potential for therapeutic intervention in airway remodelling. this work was supported by the crc for asthma and airways and nh&mrc. introduction epithelial egfr (epidermal growth factor receptor) expression correlates with disease severity and neutrophil infiltration in asthmatic airways. acute exacerbations of asthma and copd are also associated with steroid refractory neutrophilic inflammation, with rhinoviruses being the most common trigger. . mg/l and il- : . vs. . ng/l). since il- stimulates the acute phase response, we correlated its levels with the other markers. only crp was strongly correlated with il- (spearman r = . , p < . ), suggesting differential regulation of saa and ip . saa discriminated between non-pathogen (n = ) vs. pathogen-associated (n = ) events (saa: . vs. . mg/l p = . ), whereas no significant change was observed in the other markers (ip- : . vs. . ng/l, crp: vs. mg/l, il- : . vs. . ng/ l). however when aecopd marker levels were stratified on the basis of pathogen type (viral = , bacterial = , viral and bacterial = ), none of the markers were significantly altered. conclusions ip- is significantly elevated during an aecopd, however only saa differentiated non-pathogen from pathogen associated events. background severe persistent asthma is characterized by structural changes in the airways-airway remodelling. airway smooth muscle (asm) cells have the potential to play a key role in these processes through the release of growth factors, cytokines and extracellular matrix (ecm) proteins. we have previously studied the effects of budesonide and formoterol individually however, the effect of their combination on these characteristics of asm cells is not known. methods asm cells from asthmatic (n = ) and nonasthmatic (n = ) individuals were stimulated with transforming growth factor ß (tgfß) ( ng/ml) with or without budesonide ( - m) and formoterol ( - and - m) and fibronectin levels and interleukin- (il- ) release were measured by elisa. bronchial rings from nonasthmatic individuals (n = ) were incubated with tgfß with or without the drugs and ecm protein expression (fibronectin and collagen i) measured using immunohistochemistry. results in nonasthmatic cells, budesonide alone induced fibronectin deposition whether tgfß was present or not. formoterol decreased fibronectin induced by tgfß and, when combined with budesonide, reversed the increase in fibronectin. a similar pattern was observed in asthmatic cells, except that budesonide did not further increase the tgfß mediated fibronectin release. as before [ ] , il- was induced by formoterol but inhibited by budesonide. tgfßinduced il- was inhibited by both drugs and their combination in both cell types. in bronchial rings the presence of either drug did not affect tgfßinduced fibronectin or collagen i. severe combined immune deficiency (scid) spontaneous mutation specifically impairs differentiation of stem cells into mature lymphocytes. nod-cb prkd scid (known as nod-scid) lacked nk cells, hence is commonly used in cell transfer experiments for transferring tissue and haematological xenografts. the aim of this study was to establish lung inflamamtory model in nod-scid strain. methods balb/c and nod-scid balb/c mice (n = ) were exposed to cigarette smoke for days, and weeks ( cigarettes/day; days/week). bronchoalveolar lavage fluid (balf) and lung tissue were collected for inflammatory profiling and analysis for cytokines, chemokines and protease expression and/or activity. results nod-scid have significant accumulation of macrophages in lung after days, and weeks smoking as compared to no smoke control (p < . ) that was not different to balb/c (p > . ). nod-scid also have increased neutrophil number after and weeks smoking (p < . ). even though myeloid cell differentiation isn't affected by scid phenotype, nod-scid have one fold less neutrophil than balb/c mice (p < . ) that is also reflected in the reduced expression of matrix metalloproteinase- . consistent with the known lymphopenic phenotype, nod-scid have significant but less lymphocytes recruitment as compared to balb/c mice after weeks smoking (p < . ) despite the enhanced expression of inteferon inducible protein (lymphocytes specific chemokine) in lung. both mouse strains showed the same elevation of net gelatinase and serine protease activity in lung. nodscid mice also demonstrated comparable transcriptional induction of proinflammatory cytokines (tnfa, il- ), growth factors (gm-csf, g-csf) and chemokines (mcp- , mip- ), indicating susceptibility to smoke-induced injury. conclusions nod-scid mice are capable to mount smoke induced inflammatory response. this model may be useful to study localization and role of immunocytes, including adoptively transfer human cells in the pathogenesis of copd. supported by the nhmrc. rhinovirus (rv) is the cause of most common colds and up to % of asthma attacks. in our previous studies, plasminogen activator inhibitor (pai- ) was expressed at high levels and was induced in vivo and in vitro by rv infection. pai- may have antiviral properties suggested by antiviral activity in some models, high pai- expression levels and further upregulation by rv infection. methods to determine whether pai- has antiviral activities following rv infection, o-hela, pai- expression-deficient cells were first transfected with pai- or control genes. this was followed by infection with rv and effects on viral replication were assessed by rt-qpcr for vrna and by viral titration for virus release. ifn expression was assessed by rt-qpcr. results ifn-a and -b mrna expression were induced in response to rv infection and to pai- expression in cells. pai- expression followed by rv infection elicited a synergistic response and pai- over-expression reduced vrna by > fold and viral titre by > log (p < . ). however, this effect was not specific to pai- , as transfection of cells with control genes/plasmids reduced viral titre to a comparableextent. one of the pathological findings in idiopathic pulmonary fibrosis (ipf) is the presence on fibroblastic foci comprising cells which exhibit mesenchymal phenotypic features such as myofibroblast-like morphology, increased asma expression and collagen deposition. currently steroid treatment in ipf has shown limited efficacy. the cellular origins of these mesenchymal cells remain unclear, but evidence from other studies suggests that epithelial cells may undergo a transition to a mesenchymal cell phenotype (emt). transforming growth factor ß has been implicated in promoting this emt. in this study we have induced a morphological change in a cells using tgf-ß and assessed the influence of glucocorticoids, and the changes to the extracellular environment of the cells, on emt. methods a cells were grown on uncoated plastic cultures plates or those coated with monomeric or fibrillar collagen and treated with - pm tgf-ß . the influence of the glucocorticoid, dexamethasone (dex, - nm), or collagen type, on emt was assessed by microscopy, rt-pcr and western blotting for markers of myofibroblast phenotype. results tgf-ß induced an increase in mrna expression of asma ( . fold), collagen ( . fold) and fibronectin ( . fold). dex ( nm) partially inhibited the expression of collagen, but had no effect on asma levels. however, dex ( nm) reduced asma and ctgf protein levels. dex ( nm) also prevented the tgf-ß -induced morphological changes, regardless of ecm matrix. conclusion glucocorticoids appear to control some of the emt phenotype changes induced by tgf-ß . however, the inability to fully inhibit these changes may contribute to the resistance of ipf to glucocorticoids. the extracellular environment may also play a role in the development of fibroblastic foci and their pharmacological responses. defective alveolar macrophage (am) phagocytic function in the airway may perpetuate inflammation via secondary necrosis of uncleared apoptotic cells in copd. we have previously reported that low-dose azithromycin improved macrophage function in vitro, although the mechanisms for this effect were not identified. we explored the possible role of the collectin pathway in the azithromycin-mediated improvement in phagocytosis as well as possible defects in this pathway in copd subjects. methods ( ) mannose binding lectin (mbl), mannose receptor (mr), surfactant protein d (sp-d) were measured in copd subjects and controls. ( ) the in vitro effects of addition of rhmbl, and blocking mr with a specific antibody, on am phagocytic ability were assessed. in vitro effects of azithromycin on am expression of mr were also investigated. ( ) azithromycin ( mg orally ¥ weekly/ weeks) was administered to copd subjects. bronchoscopies were performed prior to and weeks following therapy. ex vivo assessments included am phagocytic ability, levels of mbl, sp-d and mr and apoptosis of bronchial epithelial cells. results am mr expression and levels of mbl and sp-d were significantly reduced in copd subjects vs controls. azithomycin ( ng/ml) increased mr expression by % in vitro. rhmbl induced a dose-dependent increase in am phagocytic ability (up to %). blocking mr significantly decreased am phagocytic ability by %. in copd patients following azithromycin therapy, we observed improved am phagcocytic ability, increased levels of mr and reduced levels of bronchial epithelial cell apoptosis. conclusions these findings strongly implicate the mr in both the defective phagocytic function of am in copd and as a target for the azithromycinmediated improvement in phagocytic ability. obstructive sleep apnea (osa) is associated with hypoxia and increased cardiovascular morbidity. t cells and monocytes play a significant role in atherogenesis via cytokine production. there have been reports of benefits of continuous positive airway pressure (cpap) therapy in osa. the purpose of this study was to characterize leucocyte inflammatory cytokine/chemokine production by t cells and monocytes in a group of osa patients and to investigate the therapeutic effects of cpap therapy. methods a comprehensive range of intracellular t-cell and monocyte proand anti-inflammatory cytokines/chemokines was investigated in peripheral blood from osa patients and aged-matched control subjects (with no evidence of sleep problems) using multiparameter flow cytometry. osa patients were again studied following days of cpap therapy. results in osa patients there was an increase in intracellular t-cell ifng and tnfa production but no change in il- , il- or tgfb compared with control. there was an increase in intracellular monocyte il- a, il- , tnfa, mcp- and mcp- in osa patients but no change in il- or il- . following cpap therapy, t-cell ifng and tnfa production returned to 'normal' levels. however, although intracellular monocyte cytokine/chemokine production was decreased following cpap, levels were significantly elevated compared with control. conclusions osa is associated with increased intracellular proinflammatory cytokine/chemokines, many of which are increased in atherosclerotic plaques. although one week of cpap therapy resulted in amelioration of t-cell pro-inflammatory cytokines, longer cpap use or alternative therapy may be required to reduce monocyte pro-inflammatory mediators associated with atherosclerosis in patients with osa. gp has been associated with the progression of fibrosis especially in patients with idiopathic pulmonary fibrosis (ipf). gp is the common subunit of the receptor complexes for the il- family of cytokines including il- and oncostatin m (osm), where gp -mediated signalling leads to activation of the erk or stat pathways. we have previously demonstrated exaggerated gp -stat signalling to be fundamental to the development of pulmonary fibrosis in a murine model of bleomycin-induced lung fibrosis. the aim of this study was to elucidate the role of the il- cytokine family in the development of pulmonary fibrosis by identifying which il- family cytokines regulate fibrosis in bleomycin treated mice, and determine the effects of these cytokines on cell function. bleomycin ( . u/mouse) or control saline was administered intranasally to wildtype mice (wt), genetically engineered mice containing point mutations to prevent gp erk signalling (gp f ) or gp stat signalling (gp dstat ), and duel il- and il- a-receptor knockout mice (il- -/-;il- ar -/-). the effect of bleomycin on collagen production was examined in lung tissue days post treatment by hplc. there was a significant increase in collagen levels in bleomycin treated wt lungs which was further increased in gp f lungs. the lungs of gp dstat and il- -/-;il- ar -/mice were protected from fibrosis suggesting that gp -stat signalling is important in inducing lung fibrosis which may be mediated through il- and/or il- . cell proliferation was examined in lung fibroblasts isolated from wt, gp dstat and gp f mice. il- , il- and osm were significantly mitogenic for gp dstat cells but not for wt or gp f cells, reflecting different responses to the different signalling pathways. changes in cytokine profiles are currently being examined in lung tissue and serum of control and bleomycin treated mice - days after treatment. in conclusion, il- and il- are likely to play a role in bleomycin-induced fibrosis via the gp -stat-mediated pathway, however this may not be due to regulation of proliferation induced by these cytokines. supported by the nhmrc. mimicking viral infection by application of various toll-like receptor ligands has shown clinical promise in the treatment of persistent viral infections and more recently with malignant tumours. commercially available toll-like receptor ligands (tlr l), such as those of the imidazoquinoline family have been applied clinically for the treatment of a number of conditions including basal cell carcinoma and hpv-induced genital warts. these compounds are known to retard tumour growth indirectly by promoting activation and migration of dcs, leading to a strong th cellular response, and directly via release of proinflammatory cytokines and promotion of tumour cell apoptosis. malignant mesothelioma (mm), an aggressive tumour with a mean survival of months, is highly resistant to chemotherapy, radiotherapy and surgery and is therefore an interesting candidate for immunotherapy in the form of tlr ligand treatment. whilst tlr is known to be selectively expressed in immune cells and its relative expression low amongst other cell and tissue types in mammals, its expression on tumour cells and the consequences of such expression on tumour growth are unknown. here we describe the presence of tlr (mrna and protein) directly in a range of different tumours, including several murine and human mm cell lines. reactive oxygen species (ros) produced during the innate immune response are important agents of anti-pathogen defense but may also cause oxidative lung damage. glutathione peroxidase- (gpx- ) is a detoxifying enzyme that may protect lungs from such damage. methods wild-type (wt) or mice deficient in glutathione peroxidase- (gpx- -/-) were placed in a perspex chamber and exposed to cigarette (cig) smoke generated from cigs per day for days. on the fifth day, mice were killed, the lungs lavaged with pbs and then harvested for proteomic and genomic analysis. results wt mice exposed to cig smoke for days had significantly more macrophages ( . Ϯ . (sem) ¥ ) and neutrophils ( . Ϯ . ¥ ) than sham-exposed mice ( . Ϯ . ¥ and , respectively) (n = , p < . ). however, gpx- mice exposed to cig smoke had significantly greater macrophages ( . Ϯ . ¥ ) and neutrophils ( . Ϯ . ¥ ) than smokeexposed wt mice (n = , p < . ). macrophage and neutrophil numbers in sham-exposed gpx- -/mice ( . Ϯ . ¥ and . Ϯ . ¥ ) were similar to those of sham-exposed wt mice ( . Ϯ . ¥ and ). in addition, we found that balf of gpx -/mice exposed to cig smoke had an increased proteolytic burden compared with smoke-exposed wt mice as assessed by zymography and net gelatinase activity assay. conclusions these data suggest that gpx- protects the lung from cigarette smoke-induced inflammation and that targeting gpx- may have therapeutic utility in inflammatory lung diseases where cigarette smoke plays a role. funded by nhmrc. the becs from subjects with chronic obstructive pulmonary disease (copd) are exposed to frequent infectious and inflammatory stimuli. infection with rv is known to trigger acute exacerbations and subjects with copd are particularly susceptible. we hypothesized that exposure of copd becs to these stimuli would alter their response to rv infection. methods bec were obtained by endobronchial brushing from subjects with gold stage copd (n = , all ex-smokers), subjects with mild persistent asthma (n = ) and healthy controls (hc, n = ). becs were cultured and then treated with tumour necrosis factor (tnf)a ng/ml or lps mg/ml for hrs and then infected with rv- , rv- b. response was measured by release of il- , il- and ip- mrna and by elisa. virus replication measured by cell titration assay. results infection with both rv strains led to increased release of il- and ip- in all groups. exposure of hc and asthma becs to both lps and tnf led to increased release of il- . in these becs there was no increase in release of il- exposed to lps and tnf and then infected with either rv. becs from subjects with copd released significantly less il- in response to all conditions and rv infection compared to hcs and asthma. no differences were seen in rv replication. the aim of this study was to determine opinions and attitudes to exercise from chronic obstructive pulmonary disease (copd) subjects after completion of a -month maintenance exercise program. methods following completion of a -month exercise study, which included a supervised program (intervention, n = ) and control group (control, n = ), copd subjects [mean age (sd): ( ); mean fev (% predicted) = % ( )] were asked to complete a questionnaire. the questionnaire included closedended questions using visual analogue scales ( mm). in copd the minute walk distance ( mwd) is known to increase with test repetition (familiarization) and in response to exercise training. it is unknown whether the magnitudes of these increases are related to the degree of disability of the individual patient. methods mwd was measured twice before and once after an week out-patient exercise program in patients ( males) aged Ϯ . yrs, fev Ϯ % predicted (meanϮsd) with stable copd. the changes in mwd following a familiarization test and following training were compared between patients grouped according to their degree of disability (defined as the pre-training mwd [best of tests] expressed as %predicted mwd). *p < . gp vs gp . conclusions before training, mwd increases following a familiarization test irrespective of the level of disability. the magnitude of this increase is similar in all groups when normalized for their pre-training mwd. following training, the increase in mwd is greatest in patients with the greatest disability (lowest pre-training mwd). in less disabled patients, the relatively smaller increase in mwd following training may reflect an inability to further increase stride length, thereby reducing the responsiveness of the mwt in this group. supported by nhmrc. endotoxin is a stimulant of the innate immune system and is a major component of cigarette smoke. smokers have evidence of increased airway neutrophils and inflammation. we hypothesized that endotoxin levels would be higher in the bronchial lavage (bl) of subjects who were former smokers and subjects with chronic obstructive pulmonary disease (copd). methods subjects were all ex-smokers for at least years (n = , copd, healthy controls) or never smokers (n = , asthma, healthy controls). bl was collected and analysed for cell count and differential, culture for microbiology. the supernatant was analysed for il- by elisa and endotoxin by quantitative kinetic lal assay. results median endotoxin levels were significantly higher in ex-smokers compared to never smokers . u/ml (p < . ). there were no differences between subjects with copd and hs. subjects with copd had higher median endotoxin levels ( u/ml), compared to asthma ( . u/ml) and hc ( . u/ml, p = . ). there was no correlation between endotoxin levels and bl total cell count, neutrophils (%) or fev % predicted. there was a strong correlation with previous packet years smoked and endotoxin levels (r = . , p < . ). conclusions bl endotoxin levels are higher in ex-smokers, including subjects with copd. despite this there is no relationship to increased neutrophilic inflammation. copd is associated with inflammation associated with ineffective repair of the injured epithelium and loss of structural integrity. we have shown that these changes may result from dysregulated 'efferocytosis' (increased apoptosis of bronchial epithelial cells and defective clearance of these cells by alveolar macrophages (am)). we have also reported that azithromycin, at subbactericidal dose, improved am phagocytic function ex vivo. methods we administered azithromycin at low dose ( mg/ twice weekly for weeks) to copd subjects ( male, age: Ϯ yr, current/ ex-smokers, fev : Ϯ % pred, fev /fvc: Ϯ %). the study was openlabel, uncontrolled and primarily focused on objective biological responses obtained from the bronchoscopy samples taken. phagocytic ability of am (from bal), apoptosis of bronchial epithelial cells (from bronchial brushing), markers of inflammation in blood, bal and breath condensate (crp, wcc and inflammatory cytokines), health status (st. george's respiratory questionnaire), ecg and lung function were assessed pre and post-administration of azithromycin. results azithromycin significantly improved phagocytic ability of am (by %) and reduced bronchial epithelial cell apoptosis (by %). antiinflammatory effects of azithromycin included significantly reduced blood wcc and crp. there were non-significant reductions in levels of pro-inflammatory cytokines il- , il- and tnf-a in blood, bal and breath condensate, and a trend for improved health status. conclusions our findings indicate a novel approach to supplement existing therapies in copd that may improve clearance of accumulated apoptotic material and reduce the risk of secondary necrosis and release of toxic cell contents that perpetuate inflammation. background the prevalence of gastro-oesophageal reflux disease (gord) across the disease spectrum in copd and bronchiectasis is not well described. the aim of this study was to determine the prevalence of symptomatic and silent gord in copd and bronchiectasis and its effect on lung function and quality of life (qol ] ) and healthy controls were recruited. the prevalence of gord in bronchiectasis was %; % in copd; % in controls. in copd and bronchiectasis, total nre and ri were increased in those with distal and proximal gord compared to those without gord (all p < . ). there was no difference in extent or severity of bronchiectasis in patients with or without gord (all p > . ). in copd, the relationship between proximal gord and fev was small to moderate (r = . ). sgrq symptom scores were higher in patients with bronchiectasis with increased ri (p = . ). increased proximal nre was associated with reduced physical (p = . ) and mental health (p = . ) in the sf- in copd. conclusions gord is a co-morbidity in patients with copd and bronchiectasis. the impact of gord on disease severity requires further evaluation. funding source nhmrc, the university of melbourne, monash university, physiotherapy research foundation. chronic obstructive pulmonary disease (copd) is prevalent among older people, however little is known about the influence of ageing on airway inflammation. the aim of this study was to compare airway inflammation in older people with obstructive airway disease to groups of older and younger healthy controls. methods participants (> years of age) with stable airway disease and incomplete reversibility (fev % predicted < % and fev /fvc < %; copd n = ) and healthy controls (n = , older > years and younger < years) were recruited from the respiratory ambulatory care clinic or by advertisement. participants underwent a clinical assessment, skin allergy test, hypertonic saline challenge, sputum induction and gas diffusion studies. results participants with copd had moderate airflow obstruction (mean (sd) fev % predicted ( )) and ( %) were current or ex-smokers with a median (iqr) pack year history of ( - ) pack years. ageing was associated with an increase in airway neutrophils (p = . ). compared to older controls, participants with copd had increased airway eosinophils and lymphopenia (p = . , p = . respectively), but no difference in airway neutrophils. conclusion airway neutrophilia is a feature of ageing and is not further increased in the presence of copd. copd is associated increased numbers of airway eosinophils with reduced lymphocytes which may impact on the ability of the immune system to combat infection. supported by nhmrc, the university of newcastle. chronic obstructive pulmonary disease (copd) is third leading cause of death and fourth leading cause of disease burden in australia. mechanisms involved in emphysema severity have not been fully understood. micrornas are noncoding rnas that regulate gene expression. we hypothesize that microrna expression differs between emphysema severity in copd patients. methods mirna profiling was performed using k agilent human oligo mirna microarrays on total rna extracted from non-tumour lung tissue from copd patients undergoing resection for lung cancer. the mirnas were quantile normalized and anova was used to find differentially expressed genes. results demographic characteristics of the copd patients (mean (sd)) were age ( ) years, fev ( ) % predicted and fev /fvc ratio (< %). anova identified mirnas that were differentially expressed when stratified into two classes according to kco % predicted > or < % (t-test, p < . ). discussion this mirna analysis has identified mirnas that may be important in emphysema severity in copd patients. further validation will be performed using qrt-pcr and mirna assays on the training set and an independent set, and target prediction and validation. t-helper type (th ) and type (th ) lymphocyte responses have been well recognized as being important pathways in inflammation. recently another form of inflammatory lymphocyte response has been described, the th pathway. th cells produce cytokines such as il- a to clear extra-cellular bacteria and fungi and have been implicated in autoimmune and chronic inflammatory diseases. the th response in copd is unknown. methods subjects were patients with copd (ex-smokers, fev < % predicted who had not had an exacerbation for at least month) and control subjects (ex-smokers and normal spirometry). serum samples were obtained for measurement of c reactive protein (crp) and il- a, the latter measured using enzyme-linked immunosorbent assay (elisa). production of il- a by t-cell subsets was also identified by intra-cellular cytokine staining and measured by flow cytometry. the mean fev of copd subjects was % predicted ( . sem, n = ) and mean fev of controls was % predicted ( . sem, n = ). the copd group had a higher mean level of crp . mg/l ( . sem) compared to the control group mean level of . mg/l ( . sem). the mean level of the il- in the copd group as measured by elisa was . pg/ml ( . sem, range - ) whilst no il- was measured in any of the control subjects. conclusions the findings of this pilot study suggest that il- may be elevated in association with crp in stable copd. airway obstruction is defined as a fev /fvc ratio below the lower limit of normal. airway obstruction may prolong the forced expiratory time (fet). method spirometry results from patients were categorized as obstructive, restrictive or normal. the mean, range and coefficient of variation were determined for fet in each diagnostic group. receiver operator characteristic (roc) curves were used to determine if fet could predict a low fev /fvc. the number of patients with airway obstruction in five fet groups: < ; ; - ; - ; and > seconds were determined. results the coefficient of variation was high for all groups. pair-wise comparisons showed a difference in mean fet between patients with normal lung function versus those with airway obstruction (p < . ). the best cut-point in the roc analysis of . seconds had a sensitivity of . , specificity . and area under the curve of . for predicting obstruction. the technique of skeletal muscle microbiopsy has previously been validated [ ] and shown to be minimally invasive and well tolerated in participants with stable copd. aim a study was undertaken to determine the feasibility and tolerability of obtaining microbiopsy muscle samples from the patient admitted for acute exacerbation of copd patient. methods written informed consent was obtained to collect the muscle, blood and sputum samples for research purposes. local anaesthetic was injected prior to the insertion of a gauge bard max core disposable biopsy instrument through the associated guide needle. multiple passes (up to ) were obtained. the patient was asked to evaluate the experience by rating it on the modified borg scale - . results to date patients and controls have participated in this study. the gold severity ranged from - and ats exacerbation severity - . the mean age years (range - years), bmi mean . kg m - (range . - . kg m - ) and fat free mass was determined using single frequency bioimpedance. the sample mass obtained ranged from . - . mg, with an increasing yield occurring with increased experience of the operator. the procedure has been well tolerated, the borg scale rating ranged from - / . all patients were ambulant post procedure; no haematoma or bruising was observed in any of the subjects. conclusion the microbiopsy technique allows the collection of muscle tissue with minimal discomfort to the participant. small tissue masses such as these are sufficient to obtain measures of local markers of wasting and may prove to be a useful adjunct to the collection of sputum and blood for the measure of biomarkers in copd research. introduction older people (op) with obstructive airways disease (oad) experience multiple problems that may impact on their quality of life (qol) and disease management. these problems may relate to pathophysiology, symptoms, self management skills, psychological issues, lifestyle or other problems identified as important by the patient. aim the aim of this study was to determine the frequency of clinical problems associated with oad and to determine if a problem based assessment (pba) could adequately identify these problems. methods a multidimensional assessment tool was developed and the content compared to clinical practice guidelines. participants over years with diagnosed oad underwent this assessment. results sixty-one consecutive patients, aged - years, with mean (sd) fev of . ( . ) % predicted were assessed. the assessment tool identified a mean (sd) of . ( . ) current and significant co morbidities with an additional ( . ) clinical problems per patient. qol was increasingly impaired with an increasing number of problems (p < . ). regression modelling identified that the number of identified clinical problems accounted for % of the qol impairment. the model demonstrated that every additional patient problem was associated with a clinically significant change in qol impairment ( . units) . conclusions op with oad experience multiple clinical problems and co morbidities that adversely impact their qol. a pba of op with oad identifies significant problems that may not be addressed in a diagnosis centred approach. there is a need to identify and effectively manage this array of problems in clinical practice. discussion in this diverse group of copd patients, there was a positive correlation between dlco and fev , but not kco and fev . the fev / kco plot identifies substantial numbers of patients with the potential ad and e phenotypes defined above. we intend to study inflammatory biomarkers in these groups. fat free mass index (ffmi) is a marker of morbidity and mortality in copd. measurement of ffm in the out-patient population is commonly undertaken using single frequency bioelectrical impedance analysis (bia). however the formulae to convert measured values to ffm are population dependent. schols et al (am j clin nutr, ) suggested that formula used for the general population may be inappropriate for patients with copd, and derived a specific formula from total body water (tbw) as measured by deuterium dilution. we compare this method of measuring ffm with others, along with tbw and ffm hydration. methods tbw was measured in outpatients with copd by bia and a difference method (weight-(protein+bone mineral+fat+non-bone mineral+ glycogen)) and ffm hydration was calculated. ffmi was measured by skin fold anthropometry (sfa), bia ( separate formulae), dual energy x-ray absorptiometry (dexa) and total body potassium by g-counter (tbk). comparison between methods for tbw and ffmi was made by bland-altman analysis and between methods of calculation of ffm hydration by paired t-test. the two methods of assessment of tbw showed little difference (bias - . , % limits of agreement - . to . ). however there was a significant difference in calculation of hydration of ffm (p = . ). sfa, bia (lukaski), bia (tanita) and tbk underestimated ffmi when compared to bia (schols), with bias of - . , - . , - . and - . respectively. dexa however had a bias of only . and % loa of - . to . . conclusions there are differences between methods of assessment of tbw and ffmi and comparing values between methods must be done with caution. this has implications for assessment of morbidity and mortality in copd. chronic obstructive pulmonary disease (copd) has been identified as a major health problem in australia. recent studies have suggested that respiratory viral infections are the major cause of a worsening of copd; however this has not been studied in australia. aim to characterize pef changes and identify viruses during copd exacerbations. methods a pilot prospective longitudinal cohort study was done. patients had confirmed copd with fev < % predicted and reversibility < % and/or ml. patients recorded daily peak expiratory flow (pef) measurements and daily chest and cold scores over a period of years. sputum samples and nasal aspirates were taken at -month review (control visit) and whenever they had symptoms of an exacerbation (worsening of copd symptoms -seemungal et. al. am j resp crit care med, ). nasal aspirates and sputum samples were obtained and analysed by rt-pcr for rhinovirus (rv). result five patients have finished years of study. a total of exacerbations were reported based on patient symptoms. only exacerbations were associated with significant reductions in pef and only one was linked to increases in nasal cold scores. all samples taken at control visits and nasal aspirates and sputum samples during exacerbations were negative for rv by rt-pcr. positive controls confirmed the accuracy of the assay. conclusion our data suggest that a symptom-based definition of copd exacerbation is not always accompanied by significant reductions in lung function parameters. these 'exacerbations' are also not associated with the commonest reported viral cause. our findings suggest that variability of copd may mimic. bronchiectasis is characterized by hypersecretion of mucus and impaired clearance that results in mucus accumulation, chronic cough, sputum production and recurrent infections. inhaled mannitol ( mg) improves clearance of mucus by increasing the airway hydration and by reducing the viscoelastic and surface properties of mucus. however, the effect of other doses of mannitol on the clearance of mucus in patients with bronchiectasis is unknown. methods fourteen patients, age: . Ϯ . yr, were studied on visits. clearance of mucus was measured using m tc-sulphur colloid and imaging with a gamma camera at baseline and with mannitol ( weight loss and skeletal muscle atrophy are major determinants of morbidity in chronic obstructive pulmonary disease (copd), which are independent of lung function impairment. thus, we examined if a high-fat diet (hfd) protected against the wasting associated with prolonged cigarette smoke exposure (se) in mice. methods male balb/c mice were exposed to the smoke of cigarettes/day, days/week for weeks. sham mice were handled identically without smoke exposure. mice consumed either standard laboratory chow ( . kcal/g, consisting of % fat) or a hfd ( . kcal/g, % consisting of fat). we examined the effect of se and hfd on hind limb skeletal muscles, lung (tissue & bronchoalveolar lavage (balf)) and systemic inflammation in the groups of mice (n = / group). results after weeks of hfd, sham and se mice were and % heavier (respectively, p < . ) than chow fed animals. conversely, se significantly decreased body weight of chow and hfd fed mice by and %, respectively, compared to sham animals (p < . ). the hfd did not protect against the decrease in soleus, tibialis anterior and gastrocnemius skeletal muscle weights induced by se (p < . ). se altered the mrna expression of a number of genes associated with the regulation of skeletal muscle mass including insulin-like growth factor-i (igf-i), atrogin- and interleukin (il)- . the mrna expression of pro-inflammatory cytokines and chemokines was significantly increased by se in the lung, as were the number of inflammatory cells in balf (p < . ). on the other hand, although obesity has been linked to systemic inflammation, the hfd exerted little direct effect on the skeletal muscle and lung parameters measured. se and hfd had no effect on two markers of systemic inflammation, il- and serum amyloid a, whereas se tended to reduce circulating igf-i, an anabolic hormone. conclusions the hfd was not protective against the weight loss and skeletal muscle wasting associated with cigarette smoke exposure. supported by the nhmrc and crc for chronic inflammatory diseases. background patients with copd and bronchiectasis undertake airway clearance therapy (act) and exercise as part of physiotherapy management but it is unknown whether these treatments provoke gastro-oesophageal reflux (gor). this study aimed to determine the impact of positive expiratory pressure (pep) therapy and exercise on gastro-oesophageal function. p. aeruginosa is a significant opportunistic lung pathogen in individuals with cystic fibrosis (cf) and is associated with increased lung disease and morbidity. early intervention is beneficial for the effective clearance of p. aeruginosa and better long-term health outcomes. currently, lung flora of cf patients is monitored by regular culturing of sputum, however, children unable to expectorate are limited to annual bronchoalveolar lavages (bal), which is invasive and requires general anaesthesia. saliva is useful for clinical assays as collection is simple, non-invasive. we are developing a standardized enzymelinked immunosorbent assay (elisa) to detect respiratory infection of p. aeruginosa in cf children who cannot expectorate. methods children ( - years) with cf and recent p. aeruginosa lung infection history and non cf children ( - years) with no previous p. aeruginosa infection history provided saliva as positive, negative controls respectively. saliva was obtained by spitting, or absorbed using cellulose swabs and later extracted. these cell-free supernatant samples were used in an elisa anti-p. aeruginosa iga using commercial antigen. all results were standardized to account for flow using total iga expression. results median value was increased fold in the recent p. aeruginosa lung infection group (mann-whitney test, n = , p Յ . ). there was no significance between mucoid and non mucoid samples, and detection was independent of cfu/ml. discussion early findings support that p. aeruginosa respiratory infection can be detected through specific analysis of salivary iga expression. larger population sampling ( positive, negative) will aid selection of cut-off values for specificity and sensitivity testing in the future to objectively determine the utility of this assay as a means of monitoring for p. aeruginosa and for determining effectiveness of treatment. medical thoracoscopy is utilized widely throughout europe and northern america by thoracic physicians for the management of pleural disease, including the undiagnosed pleural effusion, malignant effusions and less commonly pneumothorax (ptx). australia has limited experience in this modality. we report the success of medical thoracoscopy in both primary and secondary ptx requiring intervention. methods data were collected from to in patients treated with medical thoracoscopy for the treatment of ptx. results patients, male, female. average age (range - ). first episode primary spontaneous (ps) ptx, third episodes of ps, first secondary spontaneous (ss), second ssptx, third ssptx. underlying pulmonary disease in secondary ptx included: chronic obstructive pulmonary disease, lymphangioleiomyomatosis, mesothelioma, metastatic angiosarcoma and was secondary to a motor vehicle accident. had a history of smoking, were former smokers and were current smokers, with a mean pack year history (range - ). ptx were large, moderate. patients had an intercostal catheter (icc) inserted prior to thoracoscopy, had failed pleural aspirate. there was evidence of bronchopleural fistula in patients prior to the procedure. there was a median of days from ptx to thoracoscopy. light sedation was used for the procedure in patients, required a general anaesthesia with a double lumen endotracheal tube due to anxiety. single port entry, dry talc poudrage and a gauge french icc was used for all procedures. icc was removed a mean of days following thoracoscopy and patients discharged on day . pain was the most common complication, requiring narcotic analgesia. one patient died on day , secondary to metastatic angiosarcoma. there has been no recurrence of ptx in any patient. conclusion medical thoracoscopy, performed by thoracic physicians is an effective procedure for the treatment of pneumothorax requiring intervention, including selected patients with evidence of bronchopleural fistula. funding nil. conflict of interest nil. nomination for young investigator award no. background lung cancer incidence and mortality are high in tasmania. australia (aihw ) / / tasmania (cancer registry ) / / aims and objectives (a) to determine patient demographics in southern tasmania, (b) to determine compliance to identified measures of best practice and (c) assess referral rates, clinical utility and potential delay to positron emission tomography (pet) in a regional setting. methods a prospective database collected information on local clinical practice. cases presented at a multidisciplinary lung cancer meeting over a month period (march -april were analysed. data were available for n = / ( %). results are shown as mean Ϯ sd. results primary lung cancer cases were identified. the mean age was Ϯ years. % of patients were male and % were current or ex-smokers. % were non-small cell lung cancers (nsclc). tissue diagnosis % time from diagnosis to surgery ( Ϯ days) % < days macroscopically complete surgical resection ( / ) % pet for stage iiib before radical chemoradiotherapy % % of patients presenting with early or locally advanced disease underwent further staging with pet (n = / ). management was changed in % of cases ( / ). the average time from pet referral to scan was Ϯ days. conclusion a disproportionate number of lung cancers occurred in women. although surgery was performed within recognized timeframes, of patients had incomplete resections. pet influenced management decisions and was performed in a timely fashion. hp chan , , v tran , , c lewis , , p thomas exhaled breath condensate (ebc) is a simple, safe and non-invasive method of sampling breath and has the potential to investigate lung cancer and the associated neoplastic process in the lungs. increased oxidative stress has been implicated in the pathogenesis of lung cancer, and is characterized by elevated hydrogen ions, and hydrogen peroxide (h o ), which is formed from the conversion of superoxide anions by superoxide dismutase. airway ph has already been shown to be decreased in ebc of patients with other respiratory conditions, but not in lung cancer. therefore the concentration of h o and hydrogen ions in the ebc of lung cancer subjects was compared with matched controls. methods six subjects with newly diagnosed lung cancer were recruited and matched with control subjects: non-smokers, ex-smokers and smokers. ebc was collected and h o was then measured by an assay method based on oxidation of , ', , '-tetramethybenzidine by horseradish peroxidase and h o while ph was measured using a ph meter. results there was a significant difference (p = . , anova) in h o concentration between the groups with the lung cancer group having elevated mean h o concentration of . mm ( . (sem) compared to the controls: non-smokers, . mm ( . (sem); ex-smokers, . mm ( . (sem); and smokers, . mm ( . (sem). ph did not differ significantly (p = . , kruskal-wallis test) between the groups. conclusion these preliminary data suggest that there is significant difference in h o concentration between the groups. the demonstration of an elevated h o level in those with lung cancer indicates an increase in oxidative stress which implies that this may be part of the pathogenesis or response to neoplasia. supported by none. conflict of interest none. pro-inflammatory th cytokines produced by t cells and monocytes play an important role in the immune response to malignant cells. however, tumours may escape immune surveillance by inhibiting th response and promoting chronic inflammation at the tumour site. methods to investigate the effect of soluble factors released by lung cancer cells on t cell and monocyte pro-and anti-inflammatory cytokines, culture supernatants from several lung cancer cell lines and a normal epithelial cell line ( hbe) were cultured with whole blood for hours, then for a further hrs with and without stimuli. intracellular cytokine / chemokine production was determined using multiparameter flow cytometry. results in stimulated cultures, there was a significant decrease in t cell th pro-inflammatory cytokines ifng, tnfa and il- and a decrease in monocyte il- a, il- , il- , tnfa, mcp- and mcp- but an increase in antiinflammatory cytokine il- compared with hbe and control media. in non-stimulated blood cultures there was an increase in all monocyte inflammatory cytokines / chemokines in the presence of lung cancer supernatants. conclusions lung cancers secrete soluble factors that inhibit the antitumour pro-inflammatory th response by t cells and monocytes and upregulate monocyte anti-inflammatory cytokine il- following "antigenic challenge". lung cancer cells may also escape immune surveillance by secreting soluble factors that cause newly recruited monocytes to release inflammatory cytokines promoting chronic inflammation at the tumour site. cytotoxic t-cells (ctl's) are important barriers against tumour cells. ctl's induce apoptosis of target cells by mechanisms that include the release of pore-forming perforin and granule associated enzymes, such as granzyme b and granulysin. proteinase inhibitor- (pi- ) is the only known granzyme b inhibitor and its expression has been observed in some cancers. we hypothesized that pi- would be differentially expressed in lung cancer cells and may inhibit granzyme b-induced apoptosis in these cells. methods we investigated pi- , granulysin and granzyme b expression in various lung cancer cell lines ( ( , ( , and normal epithelial cells obtained from bronchial brushing using flow cytometry. peripheral bloodderived t-cells were then incubated with lung cancer cell line supernatants and levels of pi- , granzyme b and t-cell reactive oxygen species (ros) were assessed. results pi- expression was detected in all lung cancer cell lines, ( ( . %), ( . %), ( %), sbc- ( %)), at much higher levels than in normal bronchial epithelial cells ( . %). granzyme b and granulysin levels were undetectable or low in cancer cells ( - . %). increased expression of pi- and reduced levels of granzyme b were observed in cd + t-cells in the presence of all cancer cell supernatants tested (p < . ). interestingly, t-cell ros levels were significantly increased in cd + t-cells after incubation with cancer cell supernatants (p < . ). conclusions high pi- expression in lung cancer cells combined with a reduction in t-cell granzyme b expression and enhanced intracellular t-cell ros levels may be a mechanism of immune evasion of lung cancer cells to granzyme b-induced cytotoxicity. immunotherapy for lung malignancies such as lung cancer and mesothelioma is most likely to be successful it it can be combined with conventional tumour debulking approaches such as chemotherapy and surgery. but they scientific basis of such combinations is yet to be determined. to study this we evaluated ( ) the capacity of different lung chemotherapy drugs to alter tumour antigen cross-presentation and immunogencity, ( ) duration of antigen presentation and responsiveness to immunotherapy after debulking surgery with/without lymphadenectomy, and ( ) the pattern of tlr agonism which best synergized with chemotherapy and surgery. we used the ab -ha murine model of lung malignancy in balb/c mice. results ( ) the antimetabolite drugs gemcitabine and pemetrexed were most immunogenic compared to the cytotoxic antibiotics doxorubicin and mitomycin c and the alkylating agent cisplatin. gemcitabine delived large amounts of tumour antigen into the cross-presentation pathway. ( ) tumour antigen cross-presentation persisted for only days following resection. the optimal window for immunotherapy following cancer surgery is week for effector ctl stimulation and - weeks for memory ctl stimulation. ( ) the viral-like tlr agonists tlr , and were the most effective adjuvant tlr molecules, with tlr agonists generating the strongest systemic anti-tumour responses. conclusion these results help explain previous lung immunotherapy failures and will inform new clinical trials. background mesothelioma is a highly aggressive tumour with an increasing world wide incidence. the serum biomarker mesothelin is elevated in some individuals prior to development of clinical symptoms of the disease and may be useful for screening. we therefore studied the sensitivity and specificity of urinary versus serum levels of mesothelin for mesothelioma patients and evaluated the influence if renal function on the biomarker level. materials and methods concurrent sera and urine samples collected from patients with and control populations. mesothelin concentrations were determined by double-determinant elisa using the mesomark tm assay (fdi, pa). their estimated glomerular filtration rate (egfr) was also calculated. results mesothelin levels correlated between serum and urine samples (pearson's correlation . ; p < . ). mesothelin levels were significantly higher in patients with mesothelioma compared to those with asbestosis and/or pleural plaques in serum ( Ϯ . versus . Ϯ . nm; p < . , respectively), in urine ( . Ϯ . versus . Ϯ . ; p < . ) and in urine following normalization using creatine levels ( . Ϯ . versus . Ϯ . ). age and egfr were significantly associated with mesothelin levels. conclusion the sensitivity and specificity of mesothelin in urine and in serum were comparable. urine mesothelin may prove to be a useful alternative to serum mesothelin for mass screening of asbestos-exposed individuals. patients undergoing ct coronary angiogram (cta) are often former or current smokers with a high incidence of asymptomatic lung disease. overseas reports show a rate of lung abnormalities ranging from . % to %. there are no studies from australia and local factors such as the higher incidence of atypical mycobacteria may influence the rate of benign findings. we are therefore performing a prospective observational study to identify the prevalence and characteristics of incidental lung findings in people undergoing routine cta. methods population: patients undergoing routine cta after informed consent. intervention: radiologist evaluation of lung windows on diagnostic standard workstations. comparator: uncontrolled observational study of consecutive patients. outcomes: primary: prevalence and characteristics of abnormal findings, final diagnosis (clinical judgment, biopsy or long term followup). secondary: number of downstream investigations and costs. results ctas have been studied to date. in / ( %), abnormalities were noted on lung windows. in / ( %), there were lung nodules, in / ( %) there were hilar lymph node abnormalities, in / ( %), there was hemidiaphragm elevation and in / ( %) there were pleural plaques (data collection ongoing with study closure expected in february ). conclusions preliminary data indicate a substantial number of incidental pulmonary findings from cta; full results will be presented. further analysis is required to determine the impact (benefits, costs and harms) that may result from the concurrent examination of lung windows at routine cta. aim increased levels of nitrogen oxides (nox) and inflammatory markers have been found in bronchoalveolar fluid of lung cancer (lc) patients, but have not been investigated in exhaled breath condensate (ebc).the aim of this study was to compare nox and total protein levels in ebc of lc patients with control subjects. methods ebc was collected during tidal breathing through a glass collection device cooled to °c. ebc nox concentrations were measured by a fluorescent modification of the greiss method. total protein in ebc was determined employing the bicinchoninic acid (bca) assay. ebc nox data were log transformed. all data were analysed using anova and expressed as mean Ϯ sem. results a total of control subjects and patients with primary lc were recruited. nox and protein concentrations are shown in table . there was no significant difference in ebc nox levels (p > . ), but in total protein there was a significant difference between lung cancer patients and all control groups (p = . ). conclusion significantly increased ebc total protein levels were found in patients with lung cancer. these data suggest that protein mediator secretion or vascular leak may be present in those with lung cancer. future studies will focus upon the identification of these proteins. methods in this two stage case-control study lung cancer cases and healthy smoker controls were recruited. genetic markers (snps) implicated in lung cancer were screened in our test cohort of smokers and ex-smokers. snps whose genotypes (co-dominant or recessive model) were associated with either the healthy smokers (protective) or lung cancer (susceptibility) phenotype were identified. after genotyping this snp panel in a second cohort of subjects snps were chosen and assigned a simple composite genetic score that was combined with scores for age, history of copd and family history of lung cancer, weighted according to our multivariate regression analysis (n = total subjects). the lung cancer risk score was linearly related to the likelihood of lung cancer with odds ratios (referenced against the lowest score quintile) ranging from to in the highest quintile. on receiver operator curve analyses, the auc was . and the frequency distribution showed bimodal separation between healthy smokers and lung cancer cases. utility of the score was not affected by effects of age, smoking history or lung function. we suggest that genetic data may be combined with other risk variables to define smokers or ex-smokers at risk of lung cancer for targeted interventions such as smoking cessation and early detection of lung cancer. supported by health research council, nz. conflict of interest yes. tp v aiyappan , a graham department of medicine, maroondah hospital, melbourne, australia, and the new disease-modifying anti-rheumatic drug (dmard) leflunomide is being used increasingly to treat inflammatory arthritis. its association with interstitial lung disease needs to be considered before combining it with methotrexate. case report a -year-old male who was known to have rheumatoid arthritis and was on methotrexate was admitted with progressive dyspnoea and malaise. he had been recently started on leflunomide. investigations revealed interstitial lung disease and acute renal failure. he improved on conservative treatment (stoppage of disease modifying drugs (dmard), iv fluids and steroids). review of literature an epidemiological study by suissa et al has suggested that there is increased risk of ild associated with leflunomide in patients with a history of ild or methotrexate use but they attributed this to channelling bias. there has also been a report of leflunomide associated with iga glomerulonephritis.by this presentation we aim to increase the awareness of this entity. we also suggest that any patient who is started on combination dmard (i.e. methotrexate and leflunomide) should have a baseline chest x-ray and be monitored for development of interstitial lung disease. conclusion we are reporting the first ever case of interstitial lung disease and glomerulonephritis (in the same patient), due to usage of leflunomide. this entity needs to be thought about in any patient on combination dmards. background bone morphogenic protein receptor ii (bmpr-ii) mutations are associated with pulmonary artery hypertension. failure of the growth inhibitory effects of bmp may contribute to vascular obliteration and remodelling leading to pulmonary artery hypertension (pah) [ ] . pah has been observed following venous thrombembolic disease (vte), including pulmonary embolism (pe) and deep venous thrombosis (dvt) [ ] . local markers of the pulmonary vascular endothelium rather than traditional markers of thromobophilia are thought to be involved [ ] . methods plasma was collected from age and gender matched participants within hours of diagnosis of vte and prior to commencement of warfarin therapy. plasma samples were hybridized to individual human cytokine antibody arrays, to detect protein levels of bmp , bmp and bmpr-ii. results bmp and bmp levels were higher in patients with dvt than pe. no difference in the bmp level was observed between patients with pe and controls. soluble bmpr-ii receptor was lower in patients with pe than in controls or patients with dvt. conclusion in patients with pulmonary artery stress during the time of a pe the bmpr-ii receptor is reduced, which may predispose patients to vascular remodelling and obliteration. the bmp and levels are reduced at the same time, suggesting a possible overriding regulatory mechanism. the physiological role of bmp's and bmp receptors in patients with vte warrants further investigation. historically, cyclophosphamide has had a variable role in interstitial lung disease (ild), the rationale for its use based on the benefit seen in vasculitis and scleroderma, its rapid effect and low toxicity profile. in patients with severe progressive ild a rapidly effective, well-tolerated agent is desirable. for this reason a treatment protocol for the use of intravenous (iv) cyclophosphamide was implemented at our hospital. aim to review the indications, duration, tolerability and effect of intravenous cyclophosphamide in ild patients following the introduction of a treatment protocol. methods records of patients [dlco was Ϯ % and fvc Ϯ %] completing a course of iv cyclophosphamide during - were reviewed (excluding patients with systemic sclerosis). data covering months prior to and following treatment were collected. comparative analysis of paired pulmonary function data months before and after treatment was performed. % had underlying autoimmune disease. results primary treatment indications included progressive disease(n = ); severe disease (n = ); suspected vasculopathy (n = ); bridging therapy to transplantation (n = ); and accelerated decline (n = ). patients received mg/m [mean dose Ϯ mg, median number of pulses ( - )]. patients with paired pulmonary function data had a difference in median change in dlco% predicted from - . % (- . to . %) before treatment to + . % (- . to . %) following treatment (p < . ). this remained significant with exclusion of vasculitis, or any autoimmune disease, and independent of prior immunosuppression. therapy was well tolerated ( withdrew from treatment, deaths within yr, none directly related to treatment). conclusion iv cyclophosphamide is well tolerated, and associated with functional stability or improvement in the majority of patients. it remains a viable treatment alternative for consideration. pulmonary hypertension is common in interstitial lung disease (ild) and associated with a poor prognosis. as the gold-standard test, right-heart catheterization (rhc) is invasive, and resource-limited, reliable non-invasive measures of ph are needed. methods all ild patients referred for rhc during - were included (n = ; male; age . Ϯ yrs). all patients had concurrent echocardiography (tte) and pulmonary function. the relationship of rhc mean pulmonary artery pressure (mpap) to tte variables, pulmonary function, exercise capacity, as measured by six minute walk testing ( mwt, n = ) and brain natriuretic peptide (bnp, n = ), was examined. case a year old male, non-smoker for years, retired professor of anatomy (had chronic exposure to embalming fluids, formaldehyde, phenol, antifungal and other solvents, for years) presented with chronic cough and phlegm production. these symptoms were worse at night (waking him several times) and early morning. his pulmonary tests were stopped due to persistent cough. a chest x-ray revealed features of longstanding interstitial lung disease. the hrct revealed widespread subpleural interlobular thickening, worse at bases, in keeping with idiopathic pulmonary fibrosis (ipf). there was minimal fibrosis and honeycombing, but no groundglass opacification, large bullae, pleural calcification or pleural plaques. however, there was associated bronchiectasis at the lung bases considered to be due to traction. the ba lavage showed % macrophages, % neutrophils, % lymphocytes, and %, eosinophils and no infection. the patient declined to have a lung biopsy. as per his past x-rays, the duration of his ipf is a little over one year. he maintains that his symptoms started only after starting irbesartan (irb). introduction transbronchial lung biopsy (tbb) has a variable and unpredictable diagnostic yield in sarcoidosis. we hypothesized that the extent and pattern of parenchymal disease on ct would predict the likelihood of a positive tbb. methods data relating to ethnicity, symptoms, pulmonary function and site and results of tbb and bronchoalveolar lavage (bal) from sarcoidosis patients were recorded. all had a ct scan within weeks prior to the tbb procedure. cxr stage was determined from radiology report. ct scans were scored quantitatively for patterns of parenchymal disease (nodular, reticular, consolidation, ground glass and mosaic attenuation) on a lobar basis. results % patients had a positive tbb (total % of cohort had histological confirmation). symptoms, ethnicity, treatment, lung function and cxr stage were not predictors of a positive biopsy. positive biopsy was associated with higher bal lymphocyte count (p < . ) and female gender (p < . ). a reticular pattern (p < . ) and higher total lung score (excluding da) (p < . ) on ct scan predicted a positive biopsy. in those patients with tbb from right lower lobe ( / ) the total rll score on ct was predictive of positive biopsy (p < . ). on multivariate analysis gender, bal lymphocytosis and total lung score were independent predictors of a positive tbb (area under roc . ). pulmonary arterial hypertension has two histological variants; 'arterial-only pulmonary arterial hypertension' (artpah) and 'pulmonary veno-occlusive disease' (pvod). bosentan, a dual endothelin receptor antagonist, has been found to improve haemodynamics, functional capacity and survival in artpah. however, the response to bosentan in clinically diagnosed artpah is often variable. it was hypothesized that a lack of response to bosentan therapy in clinically diagnosed artpah can be explained by misdiagnosed pvod. aims included to: ( ) perform morphometric and qualitative pulmonary vessel analysis on normal controls and cases clinically diagnosed with artpah who had failed bosentan therapy; ( ) ascertain if pvod is present within the case group; ( ) correlate clinical variables and vessel microanatomy to identify the pathologies driving pulmonary pressure elevation. this study reviewed cases of clinically diagnosed artpah (idiopathic n = , associated with scleroderma n = ), who had failed bosentan therapy and had available lung tissue. controls (n = ) were obtained from explanted lungs for other causes and a prior transthoracic echocardiogram excluded pulmonary hypertension. vessel morphometry and qualitative analysis was performed with a novel technique of smooth muscle actin immunohistochemistry counterstained with verhoeff's elastin. baseline clinical data were retrieved. we found % of cases had pathology confirmed pvod. only % of cases had artpah, the original clinical diagnosis. in pvod, significant pathology was present in all vessel types. all vessels had significant smooth muscle hypertrophy. the obstructive, collagenous, pauci-cellular intimal fibrosis of the venules (p < . ) and arterioles (p < . ) was considerably different to the concentric laminar proliferation of smooth muscle observed in the muscular arteries (p < . ) and arterioles (p = . ) in artpah. artpah also had muscular artery smooth muscle hypertrophy (p = . ). the median time to bosentan failure was shorter in pvod than artpah ( vs. days). in conclusion, pvod is an under-diagnosed cause of pulmonary hypertension, is commonly clinically misdiagnosed as artpah and may present with a poor bosentan therapy response. finally, pvod is a vaso-occlusive, not a veno-occlusive disease, and is an independent type of pulmonary hypertension, not a subtype of pulmonary arterial hypertension. cutaneous t cell lymphomas (ctcl) are a heterogenous group of lymphoproliferative disorders. they show various clinical manifestations and diverse morphological, histological and immunological characteristics of the malignant cells. they are caused by clonally derived, skin invasive t cells. peripheral t cell lymphomas (ptcl) are generally more aggressive and have one of the lowest overall and failure-free survival rates. because of the rarity of these disorders, diagnosis and treatment remain challenging. this case report describes a -year-old woman presenting with progressive dyspnoea and cough, together with a distressing generalized pruritic rash. she was initially treated as left ventricular failure with the rash ascribed to a drug reaction as suggested by initial skin biopsies. the diagnosis was made on a third skin biopsy and flow cytometry of lymphocytes obtained by broncho-alveolar lavage months after presentation. despite an initial response to chemotherapy she succumbed to the disease months after diagnosis. clinical pathways to guide the investigation of suspected pulmonary embolism (pe) have been increasingly adopted by emergency departments (ed) worldwide. compliance with these diagnostic algorithms is critical in ensuring good patient outcomes. this study evaluated the compliance to the clinical pathway used in our ed that combines risk assessment (wells scoring system) with d-dimer test, vq scan or ctpa. the main objectives of this study were to identify those factors which contributed to compliance and to assess patient outcomes. methods a prospective observational study of consecutive patients who underwent investigation for pe in our ed. patient demographics, pathway parameters and patient outcomes at -month follow-up were collected. case we report the case of a year old woman who presented to the emergency department with a three day history of dry cough and dyspnoea. the patient was in her third pregnancy at weeks gestation. she had no fever, chest pain or coryzal symptoms. the patient had presented with a right sided spontaneous pneumothorax seven months prior to the current presentation. her past medical history included placental abruption, complicating her previous two pregnancies. her second pregnancy was complicated by placental abruption at weeks and the foetus had not survived. her first pregnancy was complicated by placental abruption at weeks with successful delivery of the foetus. at presentation, significant findings included tachycardia, hypoxemia, tachypnoea and reduced breath sounds over the right side of the chest. chest x-ray demonstrated a large right pneumothorax. a right intercostal catheter was inserted resulting in right lung re-expansion. the catheter was removed three days later. the patient returned to hospital twenty four hours after catheter removal with a recurrent right sided pneumothorax. the patient agreed to surgical intervention involving video-assisted thoracotomy and talc pleurodesis. the patient had no further complications with the pregnancy. she delivered a healthy baby at weeks gestation. discussion spontaneous pneumothorax in pregnancy is rare and there is little evidence to provide guidelines for the management of recurrent pneumothorax in high risk pregnancy. our case illustrates a successful outcome for mother and foetus with surgical intervention at weeks gestation. folfox is currently the standard adjuvant treatment for locally advanced (stage iii) colon cancer and increases disease free survival. its toxicity is well tolerated with common adverse effects being paraesthesia, bone marrow suppression and gastrointestinal disturbance. pulmonary toxicity has rarely been reported. three clinical cases of acute dyspnoea following folfox therapy ( ) ( ) ( ) for stage iii colon cancer are reported. all had an anterior resection followed by - cycles of folfox. each developed rapidly progressive dyspnoea requiring hospital admission within one week of their last cycle. one patient required invasive ventilation in icu. high resolution computed tomography (hrct) showed bilateral widespread honeycomb pattern with associated ground glass opacification consistent with pulmonary fibrosis. they had reduced lung volumes and gas transfer. transbronchial biopsy and bronchoalveolar lavage in one patient showed an acute eosinophilic pneumonitis. other causes of interstitial lung disease were carefully excluded. all three patients received high dose corticosteroids with one receiving additional cyclophosphamide. the first patient showed complete recovery following an eight week course of corticosteroids, with resolution of the hrct changes and improvement in lung function. the second had symptomatic improvement of dyspnoea, but a persistent moderate reduction in gas transfer. the final patient had persisting radiographic changes and a reduced gas transfer. he remained dependant on ambulatory oxygen months after his initial presentation. these patients' interstitial lung disease appears due to folfox with oxaliplatin being the most likely causative agent. the use of oxaliplatin chemotherapy has increased markedly over the last years and although rare, physicians should be aware of its potential for lung toxicity. lung function testing at baseline, during and towards the end of oxaliplatin treatment should be undertaken and may allow early detection and intervention in cases of pulmonary toxicity. the forced oscillation technique (fot) with broadband signals has been employed relatively rarely in the studies on respiratory mechanics. recent work from our laboratory [ ] indicated that the cheek support and the neck angle have minor influence on the impedance spectra around the first antiresonance (far, ), which makes the use of the broadband fot especially attractive in young children. methods we studied healthy children (c; female: ) and children with bronchopulmonary dysplasia (bpd; female: ), using multiple-frequency fot between and hz superimposed on spontaneous breathing. results groups c and bpd did not differ in age ( lung function impairment is common in children with cardiac defects associated with increases in pulmonary blood flow/pressure. to investigate the development of bronchial hyperreactivity (bhr), an aorto-caval shunt was created in a model of precapillary pulmonary hypertension. surgical shunt repair was performed to assess the reversibility of bhr. methods rats were divided into groups: group c (n = ) with sham surgery, group s (n = ) where an aorto-caval shunt was created (follow-up wks), group r (n = ) with aorto-caval shunt but surgical correction of the shunt at wks (follow-up wks). in all animals, respiratory input impedance (zrs) was measured at baseline and following increasing doses of methacholine (mch , , , mcg/kg). airway resistance (raw), inertance, tissue damping (g) and elastance were estimated from the zrs spectra by model fitting. measurements were repeated in all animals at wks and at wks for groups r and c. results there was a significant increase in raw and g in group s and rat wks at baseline and following mch ( fig.) which was reversed after surgery. to characterize the factors contributing to lung function impairment following cardiopulmonary bypass (cpb), functional residual capacity (frc), lung clearance index (lci) and respiratory mechanics were measured in children with pulmonary hypoperfusion (tetralogy of fallot, tof n = ) and hyperperfusion (ventricular septal defect, vsd n = ) undergoing surgical repair of congenital heart disease. methods frc and lci were measured using a sf washout technique and respiratory mechanics using a low frequency oscillation technique in the perioperative period. results while chest opening led to a significant improvement of lung volumes and respiratory mechanics in all patients (p < . ), a reduction in pulmonary blood flow during cpb decreased lung volumes and airway resistance in parallel but significantly more in children with tof compared with those with vsd. re-establishing pulmonary blood flow during cpb improved respiratory function particularly in children with tof ( figure) . conclusions sternotomy had a great impact on lung function with parallel improvement in alveolar recruitment, ventilation inhomogeneity and airway resistance. in contrast, onset of cpb led to lung function impairment with a significant drop in frc especially in children with pre-existing hypoperfused lungs. this suggest that pulmonary blood flow enhances alveolar stability through a tethering effect on the alveolar walls. children with advanced lung disease being considered for lung transplantation are likely to spend disproportionately longer periods on transplant waiting lists before appropriately sized donor organs become available. these longer waiting times reflect the lower organ donation rates seen in children; rates that are significantly lower than those reported in the adult population. we describe two children with advanced lung disease who deteriorated whilst on the waiting list for lung transplantation, and in the absence of appropriately sized donor lungs, underwent lobar lung transplantation. methods we describe the clinical course of two children, aged and years old, with advanced lung disease secondary to post-mycoplasma obliterative bronchiolitis and cystic fibrosis-associated bronchiectasis, respectively. results both children received a "cutdown" bilateral lobar transplant from two oversized adult brain-dead organ donors. in both cases the transplant operation involved implantation of the right middle and upper lobes, and of the left upper lobe from the donor. conclusion given the low organ donation rates in children, and in the absence of appropriately sized donor lungs, novel strategies such as lobar transplantation must be considered, particularly when children continue to clinically deteriorate whilst on the lung transplant waiting list. data from the west australian adult outcomes of extreme preterm birth study suggest that adult survivors of bronchopulmonary dysplasia (bpd) may be left with functional and structural pulmonary abnormalities, most notably emphysema. animal data suggest that the antenatal administration of corticosteroids may adversely affect lung development. we therefore sought to determine if maternal variables, including administration of corticosteroid, could predict emphysema severity in adulthood. methods bpd subjects (birthweight < g and oxygen dependence at weeks post-menstrual age) born prior to were identified and recruited prospectively via the statewide neonatal follow up program as previously described. pulmonary function tests and thin selective inspiratory and expiratory computerised (ct) images were acquired and scored for emphysema severity (voxel index (%)). the obstetric history was obtained from retrospective review of case notes. results adults ( females, aged - ) were studied, declined ct. all subjects had abnormal ct findings. fifteen ( %) had areas of emphysema. emphysema score and fev were not influenced by the administration of antenatal corticosteroids, indication for delivery, maternal age or presence or absence of chorioamnionitis. conclusion maternal factors, including the administration of antenatal corticosteroids, do not predict the long term respiratory outcome of bpd. the factors determining the severity of emphysema in this group remain unknown. the prevalence of childhood asthma is high in the torres strait. children have generally more severe asthma and asthma knowledge is poor. however, there is no culturally appropriate asthma education program for these children. we are conducting a randomized controlled trial to examine the additional benefits of an education intervention by indigenous health care workers (hcw) on asthma outcomes. we describe the study's objectives, design and baseline measurements. methods children with wheeze were reviewed by two paediatric respiratory physicians using a standardized protocol; children with asthma were eligible. after obtaining informed consent children were randomly allocated to: ( ) three additional asthma education sessions with a hcw; or ( ) no additional education from a hcw. trained hcws carried out the education sessions using culturally appropriate tools. primary outcome was the number of unscheduled hospital/doctor visits due to asthma exacerbation. all children were re-assessed at months. results we enrolled children aged to years, % were torres strait islanders and % aboriginal and torres strait islanders. the clinical spectrum of asthma was: % infrequent episodic asthma, % frequent episodic asthma and % chronic asthma. eighteen percent of the children knew what a written asthma action plan was; . % had one. carers' assessment of knowledge of medications showed that % could not name any asthma medication used by their child, % could not explain dosage, and % could not explain how beta agonists worked. conclusions asthma knowledge and possession of asthma action plans in this cohort is poor at baseline. there is substantial room for improvement and additional asthma education by hcws potentially has significant benefits. impulse oscillometry system (ios) measures respiratory function during normal breathing by transmitting mixed frequency rectangular pressure impulses down the airways and measuring reflected pressure. computer analysis calculates respiratory impedance and its components, airways resistance and reactance, at a range of frequencies from . hz to hz. no previous australian normative data exists. the ios software generates predictive normal values for each of the parameters measured including total airway resistance (r ), the proximal airway resistance (r ) as well as peripheral capacitive reactance (x ). however, they are based on german data. methods cross-sectional study of community dwelling adults, with males and females per -year cohort. inclusion criteria: age range - years, apparently good respiratory health. exclusion criteria: smokers, asthmatics and others with acute or chronic respiratory disease. both ios and spirometry were conducted on all participants. results australian predictive normal equations have been generated and compared to the current published equations. the ios parameters have been correlated with the spirometric data. results have been analysed by gender, age, height and weight and compared with the predictive normal values for each parameter provided by the german manufacturer of the ios instrument. analysis includes calculation of mean range, and lower limit of normal. conclusions a preliminary set of australian predictive equations have now been produced for the ios. these have been compared with international equations. ios has potential application in a range of respiratory disease states and in population screening for occupational health (e.g. mining, & high dust load environments). supported by phc red. rationale although clinical practice guidelines for both asthma and copd recommend spirometry for diagnosis and monitoring, beneficial effects on the management of chronic respiratory diseases in general practice have not been established. we hypothesized that spirometry would improve health outcomes compared to usual care. methods we are conducting a single masked rct with arms: group a receive monthly spirometry and followup, group b receive spirometry before and after the trial and group c usual care. general practices were recruited though divisions of general practice in melbourne. invitations were mailed by of these practices to patients who had been prescribed inhaled medications during the previous months. participants returned respiratory and generic quality of life questionnaires and an asthma score card. groups a and b were tested on a micromedical turbine spirometer following ats/ers guidelines. results eligible patients ( adults, children aged - and youths aged - years) entered the trial. were randomized to group a, to group b and to group c. the mean (sd) age of adult participants was . ( . ), children . ( . ) and youths ( . ) years. there were males and females. the adults were highly symptomatic in the previous months: % reporting wheeze, % chest tightness on waking, % shortness of breath on exertion, % nocturnal cough, % morning cough and % sputum. symptoms of chronic bronchitis were reported by % of adults and a diagnosis of copd by %. asthma was reported by %, confirmed by a doctor in % and % had experienced an attack in the last months. only % had a written asthma action plan. % of adults had ever visited a hospital ed and % had been admitted. conclusion it is possible to recruit asthma and copd patients from general practice and to randomize them to spirometry or usual care. whether spirometry is associated with fewer symptoms, changes in medication, uptake of action plans or improvement in lung function or quality of life requires further followup. supported by nhmrc. s shah , jk roydhouse , b toelle , s sawyer , c jenkins for the pace australia management committee university of sydney, woolcock institute of medical research, sydney, nsw , and royal children's hospital, melbourne, vic it is widely held that recruitment of general practitioners for research can be challenging. in this paper, we discuss the recruitment experience from a current study evaluating the impact of an educational asthma intervention on patient outcomes. our aim is to describe the two different strategies utilized to date: ( ) in-house through an academic department of gp and ( ) outsourced to a private gp organization. methods initial interest was generated through faxes, presentations at gp divisional meetings and newsletter advertisements. gps who expressed interest were visited by project staff to discuss the study further. a major difference was recruiting one gp per practice in the first strategy versus multiple gps per practice in the second strategy. to assess the strategies, we examined participant characteristics, number of gps recruited and number retained. results participant characteristics: under both strategies, % of recruits had trained in asia and % were women. the first strategy recruited more gps who spoke at least two languages at home ( % vs %) and the second strategy recruited more recently graduated gps ( % vs %). recruitment: the first strategy recruited gps over months and the second recruited gps over months. retention: gps ( %) from the first strategy stayed in, compared to ( %) from the second. conclusions whilst absolute numbers of gps recruited were similar, retention was much higher under the second strategy. recruitment in primary care is difficult and requires a range of approaches which need to be re-evaluated and adapted as necessary during the course of the study. supported by the australian government department of health and ageing. bronchiectasis is a heterogeneous condition with a large number of causative factors and range of symptoms. the classification of this condition is often confusing and hard to remember. the aim of this study was to classify non-cf bronchiectasis into different clinical phenotypes. methods consecutive patients with non-cf bronchiectasis confirmed on high resolution ct scanning had a detailed clinical, spirometric and laboratory assessment performed by a respiratory physician (pk/mf/pw) and were then followed up for an average of Ϯ years (mean and sd) for a total of over reviews. results of the patients ( %) could be classified as belonging to phenotypic groups; ) bronchiectasis arising in childhood, ) bronchiectasis occurring in smokers and ) bronchiectasis occurring in the elderly. each group had different features which are listed in the there are few data on the long term outcomes of treatment for tuberculosis (tb) by directly observed therapy (dot) in low-incidence settings. the aim of this study was to assess the incidence of recurrent tb in nsw. methods data linkage was performed within the nsw department of health tb notifications database to identify cases that had more than one tb notification between and . recurrent tuberculosis was defined to include all patients with two or more culture positive episodes at least months apart, where patients had received at least six months treatment for the initial episode. in cases where data contained within the notification details was not sufficient to allow us to distinguish between true cases of recurrent disease, duplication notification for the same episode or persistent disease after incomplete treatment, additional information was obtained from the area tb coordinator. results there were tb notifications between and with being culture positive. cases of recurrent culture positive disease after completed treatment for the first episode were identified (recurrence rate: . %). conclusions in a population with a low tb incidence, treatment of active tuberculosis with dot results in a very low rate of disease recurrence over a long period of follow-up. support nhmrc ccre in respiratory and sleep medicine. introduction rhinoviruses (rvs) are the major cause of viral-induced exacerbation of asthma. to date, the molecular mechanisms of rv pathogenesis are not understood. recent findings suggest that rv pathology may involve host cell nucleocytoplasmic trafficking, inhibiting key cell functions such as transcription and translation. the study aims to investigate the mechanism of rv c protease nuclear trafficking. methods hela cells were infected with rv or transfected with plasmids and cellular localization of c analysed at various times thereafter using immunofluorescent confocal microscopy and western blotting with specific antibodies. results c protease was predominantly present in nuclei of rv infected cells up to hours after infection, becoming increasingly cytoplasmic thereafter. the nuclear membrane of infected cells became progressively indistinct with time. using a specific inhibitor we also found that c utilizes the crm- nuclear export pathway. c was predominantly in the form of cd in both cytoplasm and nucleus of infected cells; mature c protease was also detected from hours after infection. deletion analysis indicats that the nuclear localization domain and a nuclear export signal are most likely to be present within the n terminal amino acids. the nuclear export signal is inhibited in the full length protein, via an unknown mechanism. conclusion our data suggest that c and cd proteins localize to the nucleus in infected cells where they may play a key role in rv pathogenesis by disrupting cellular transcription and the nuclear transport machinery. chronic necrotizing pulmonary aspergillosis (cnpa) is a relatively uncommon, sub-acute, locally destructive process due to aspergillus invasion of the lung. the incidence and prognosis of cnpa are poorly described. case report we present a case of cnpa in a patient on intermittent low dose steroid therapy and recurrent refractory exacerbations of chronic obstructive pulmonary disease (copd).the patient presented with worsening shortness of breath and productive cough requiring recurrent inpatient admissions. human influenza virus is found to bind preferentially to saa , gal receptors found in the upper respiratory tract, while avian viruses bind to saa , gal receptors expressed in lower airways. this is thought to affect the ability of transmission to humans. our aim was to study the ability of avian and human influenza strains to infect bronchial epithelial cells and relate this to levels of the sialic acid receptor expression. methods calu- cells were used as a proximal airway cell and a were used as distal airway cell. human primary bronchial epithelial cells (pbecs) were obtained from healthy, asthmatic, and copd volunteers by endobronchial brushing. epithelial cells were stained with sambucus nigra lectin that binds saa , gal receptor, and maackia amurensis lectin ii that binds to saa , gal. the cells was analysed by flow cytometry. human influenza a/h n /wellington strain and low pathogenic avian influenza a/h n /sandpiper were chosen and were used at an moi of . to infect cells. the supernatants were harvested at hr post infection, of which was then analysed by plaque assay for virus replication. results the calu- showed greater expression of saa , gal linkage than saa , gal linkage, and a displayed slightly higher expression of both receptors compared to pbecs. despite this human and avian influenza virus replicated to similar titre at , pfu/ml in both cell lines, but showed low replication in pbecs. background treatment of community-acquired pneumonia remains based on 'best guess' empiric algorithms because of the poor utility of current pathogen tests. furthermore our ability to stratify patients into risk groups is crude at best, relying on scores such as the pneumonia severity index or the curb- have major limitations. we have been slowly improving real-time pcr assays for pneumococcus as a clinical tool in patients with pneumonia. methods building on previous research we assesed two targets in the autolysin (lyta) gene and the pneumolysin (ply) gene of s.pneumoniae using the lightcycler instrument and fluorescence resonance energy transfer (fret) probes. all common s. pneumoniae serotypes were detected while other bacteria and viruses were not. the lyta target had the best sensitivity with a detection range between ng to fg. both assays were then applied to whole blood samples from adult patients with community-acquired pneumonia, all of whom had blood cultures prior to antibiotic administration and urinary antigen testing for s.pneumoniae. the lyta pcr had the best performance characteristics with a sensitivity more than twice that of blood cultures in the clinical samples. most pcr+ve/culture -ve patients had positive urinary antigen tests. there was clinical evidence that urinary antigen +ve/ pcr -ve patients were false +ves. most significantly there was a strong correlation between quantitative bacterial count and clinical outcome. conclusions real-time quantitative pcr for pneumococcus has significant potential as both a diagnostic and therapeutic tool in patients with pneumonia. the pitjantjatjara lands are situated in the north-western corner of south australia, occupying an area of over square kilometres with a population of approximately . the population lives in small communities or homelands, and there is a high level of mobility between this region and other aboriginal communities in south australia and the northern territory. nganampa health council provides all health care services to the region. specialized support for tb control comes from both the south australia tb service based at royal adelaide hospital as well as a centre for disease control in alice springs. the prevalence of tuberculosis (tb) in this predominantly indigenous community is thought to be significantly higher than the national rate. there are considerable challenges in detecting and managing tuberculosis, relating to the community's geographical remoteness, migration of populations and access to health services. the aims of this study are to quantify the prevalence of tuberculosis in the pitjantjatjara lands, and describe the significant barriers to tb diagnosis and treatment. methods a retrospective study of all diagnoses of tuberculosis within the pitjantjatjara lands in the period - . outcomes include measures of tuberculosis diagnosis, the rates of completed tb treatment and rates of tuberculosis drug resistance. the study will draw conclusions about the reasons for high levels of tb prevalence in this community and identify barriers to effective tuberculosis treatment. conflict of interest no. patients admitted to hospital with a diagnosis of community-acquired pneumonia (cap) are usually treated with intravenous (iv) antibiotics irrespective of pneumonia severity. available guidelines vary in recommended timing and indications for switching to oral antibiotics. aim to examine the patterns of antibiotic choice and delivery method (iv, oral and time to switch) in patients admitted with cap. methods a retrospective chart review of admissions to the respiratory unit over a -month period with a diagnostic-related group (drg) coding of pneumonia. charts were reviewed. data collected included patient demographics, clinical features at presentation (temperature, pulse rate, respiratory rate, bp, oxygenation), initial investigations, initial antibiotic regime, time to change (iv to oral), subsequent antibiotic regime and duration, time to defervescence, length of stay and outcome. pneumonia severity was calculated using the revised british thoracic society system (curb- ), score Ն = severe. results patients were excluded due to incorrect coding. of the patients, age was Ϯ (mean Ϯ sd) yrs and ( %) were male. patients ( %) were febrile at presentation and the median curb- score was (range - ). patients ( %) received iv antibiotics. the curb- score was or (non-severe) in patients and of these patients received a combination of iv ceftriaxone and a macrolide. time to defervescence was . Ϯ . days. time from defervescence to switching to oral therapy was . Ϯ . days. in non-febrile patients, time to switch was . Ϯ . days. length of stay was . Ϯ . days. conclusions the time between defervescence and switch to an oral regime was relatively long, possibly contributing to an increased length of stay. many patients received ceftriaxone even with a curb- severity rating of or . implementing local guideline-based treatment protocols may reduce length of stay. ultrasonic flow sensors can determine flow, volume and molar mass (mm) of the gas flow simultaneously. during tidal breathing the expired molar mass curve can be used to compute co over expired volume and a capnography index (cpi) can be computed. the relationship between cpi and copd classification according to gold was investigated. methods prospective, controlled trial. consecutive patients who underwent routine lung function were enrolled to participate in a tidal breathing test using an ultrasonic flow sensor. each test consisted of three tidal breathing recordings of sec. flow, volume and molar mass were measured at hz and data were acquired using prototype wbreath data acquisition software. mean expirograms (mm over volume) were computed and the measurements were analyzed to determine the slope of exhaled phase ii (s ), the slope of phase iii (s ) and the relationship between s and s (cpi = s /s ). gold stages were determined from the lung function results and the ers predicted values. results volunteers participated in the study with a mean age of (sd ), were male, mean bmi (sd ), had never smoked. the mean pack/year smoking history was . there was a clear relationship between gold stage and cpi: gold stage 'normal' had a mean cpi of . (sd . , n = ), stage 'severe' had a mean cpi of . (sd = . , n = ). conclusion computation of cpi based on tidal breathing analysis using an ultrasonic flow and mm sensor correlates well with gold stages. it may therefore be possible to use a simple tidal breathing test to determine the severity of airways disease. background osa is common in tetraplegia and appears within weeks of injury. although cpap treatment is efficacious in able-bodied subjects, case series suggest that cpap is poorly tolerated in tetraplegia. no prospective study has examined cpap efficacy or adherence in tetraplegia. aim to determine the feasibility of cpap use to treat osa following acute tetraplegia. methods all acute admissions who consented and fulfilled the inclusion and exclusion criteria underwent full, portable polysomnography. those found to have an apnoea hypopnoea index of > events per hour (osa) were offered cpap, delivered via an auto-titrating device. results to date, patients have been admitted ( excluded, refused consent). no significant, adverse events have been observed. two patients did not have osa. of the nine with osa, four are mid-study, two had incomplete follow-up ( returned to uk and refused month assessment), two adhered with cpap and one did not due to severe, pre-existing nasal obstruction. preliminary analyses suggest that those who adhered to cpap had a marked reduction ( % compared with - %) in sleepiness and a greater reduction in the functional outcomes of sleepiness compared to either those without osa or who were unable to use cpap. patient accrual, recruitment and completion rates are consistent with our initial estimates. study recruitment will be completed by end-october . conclusion initial data suggest that auto-titrating cpap is a feasible treatment for osa in acute tetraplegia. these data will be used to finalize planning for a multi-national, multi-centre randomized controlled of therapy. this research was supported by the transport accident commission. visual recognition of cyanosis is an important clinical activity. cyanosis recognition is affected by lighting colour and there is anecdotal evidence that people with significant colour vision deficiencies (cvds) have particular difficulty. studies to date have centred on the colour change with oxygenation of isolated blood but it is not clear how this extrapolates to cyanotic patients in vivo. methods ten patients known to be chronically hypoxaemic and showing signs of cyanosis were recruited from the chronic respiratory program. ten normal subjects were recruited as controls. the spectral reflectances of their lips, nail beds and palm creases were measured using a topcon sr- telespectroradiometer. the patients were measured at rest and after exercise to lower their saturation by - %. the chromaticities were calculated and plotted. results both groups showed a spread of colours but they fell into two distinct ranges. the colour difference between the groups lies very close to the colour confusions made by congenital cvds. within the cyanosed group, the colour shift was not tightly related to decreasing oxygen saturation. this is most likely due to interpersonal factors such as pigmentation and vascular perfusion that affect colour and the difficulties in measuring the colour of heterogeneous anatomical features. conclusions these results quantify the anecdotal difficulties in detecting cyanosis and suggest that observers with cvd would have problems recognizing the condition. the photographs obtained from this study will be used to compare the ability of subjects with and without cvd to detect cyanosis. supported by the nsw ambulance service. baroreflex sensitivity is depressed in osa patients during sleep but effects during wakefulness are less clear. we have now examined relationships between awake brs and severity of sleep disordered breathing (sdb). methods immediately prior to overnight polysomnography, continuous ( min) beat-to-beat arterial blood pressure was measured via finger plethysmography (portapres) and heart rate via ecg in , supine, normotensive, untreated osa patients ( males; age: Ϯ years (mean Ϯ sd); bmi: Ϯ kg/m ). spontaneous baroreflex sensitivity (brs) was calculated using the sequence technique. sdb was characterized as apnoea hyponoea index (events/hour) and arousal index (ai). data were analysed via mathematical modelling and unpaired t test. results brs fell with increasing ahi. patients with ahi > events/hour (n = ) had a significantly lower brs ( . Ϯ . ms/mmhg) than those with ahi < events/hour ( . Ϯ . ms/mmhg, p < . ). brs was negatively related to both ahi and ai via fitted exponential functions (r = . and . , respectively). it is hypothesized that the analysis of morphology of the ecg waveform in combination with the heart rate patterns could lead to the possibility of detection of the start and duration of apnoea/hypopnoea events and consequently estimation of the apnoea-hypopnoea index (ahi). to the authors' knowledge the published ecg based algorithms for detecting sleep disordered breathing are only capable of minute by minute analysis rather than detection of individual respiratory events. methods changes to ecg parameters were investigated during respiratory events with no distinction made between apnoea and hypopnoea events. isolated respiratory events and controls of identical duration were obtained from polysomnographic studies, using a randomized procedure. features such as the r wave amplitude, t wave amplitude, qrs area and the r-r interval were extracted from the lead ecg. a number of physiological predictors based on these features were generated. a logistic regression model was used to investigate the association between the predictors and true events, using the statistical software, stata. results univariate and multivariate analyses were performed. three multivariate models were developed; heart parameters only, ecg waveform morphology parameters only and the combinations of the two. the area under the receiver operator characteristic curves (auc) for these models were compared. the best results were obtained with the combination of morphology and heart rate parameters (auc = . ( . (sd))) compared to the morphology (auc = . ( . (sd))) and heart rate (auc = . ( . (sd))) models. the multivariate analysis has shown encouraging results indicating that an algorithm using a combination of heart rate and ecg morphological parameters could potentially be constructed that would enable the determination of individual respiratory events and subsequently an ahi. supported by the arc. introduction sacin and scond are measures of ventilation heterogeneity in acinar and conducting airways, derived from analysis of mbnw. maintaining tidal volumes of l at - breaths/minute (bpm) is impossible for some. our aim was to examine the effect of different tidal volumes on sacin and scond in normals and asthmatics. methods normals ( - yrs) and asthmatics ( - yrs) underwent mbnw at tidal volumes of ml at - bpm, l at - bpm, and l at - bpm. scond and sacin, were determined from the normalized phase iii slopes of breaths between turnovers (cumulative ventilation/frc) . & . results the mean Ϯ sd %predicted fev was . Ϯ % in normals and Ϯ % in asthmatics. in normals, sacin at tv of . , and l were . Ϯ . l - , . Ϯ . l - and . Ϯ . l - , respectively (p = . , anova), while scond were . Ϯ . l - , . Ϯ . l - and . Ϯ . l - (p = . ), respectively. in asthmatics, sacin were . Ϯ . l - , . Ϯ . l - and . Ϯ . l - , respectively (p < . ), while scond were . Ϯ . l - , . Ϯ . l - and . Ϯ . l - , respectively (p < . ). conclusion increasing tidal volume while maintaining the same minute ventilation during mbnw led to large decreases in scond and sacin in both asthmatics and normals. this may be due to reduced inter-regional differences in specific ventilation with greater tv. the log-log relationship between sacin and tv allows an adjustment to be made for variations in tidal volume. funding crc for asthma and airways and nhmrc project grant # . dj smith , k bowden , t lloyd , j coucher , l garske respiratory medicine, and radiology, princess alexandra hospital, brisbane, australia introduction we have shown diaphragmatic flattening and decreased diaphragmatic excursion qualitatively assessed on ultrasound is strongly predictive of dyspnea severity and lower lung inflation in patients with pleural effusion. we sought to quantitatively measure diaphragm length and movement and determine how closely these are related to dyspnea severity and lung inflation. methods patients with unilateral pleural effusions had ct imaging of their diaphragm during a measured inspiratory capacity manoeuvre. maximal sagittal length was measured at tlc, and frc. patients had a baseline dyspnea index (bdi: - ) and respiratory function measured. results patients with unilateral effusion (all right side; malignant mesothelioma, inflammatory) had a mean (sd) bdi of . ( . ), and tlc of % ( . ) predicted. the right diaphragm on the side of the effusion tended to be shorter than the left at frc (p = . ), and had a trend to reduced shortening with inspiration (p = . ). conclusions the right diaphragm is known to be longer than the left in health. the strong trend to a shorter and less mobile right diaphragm associated with effusion suggests this is a potential mechanism for dyspnea. further recruitment will enable correlation between bdi, tlc and diaphragm length and mobility. ) ) that was slightly worse than an able bodied, control population ( . ( . )), but better than an able-bodied population with untreated osa ( . ( . )). the mapi predicted that % of the sample were likely to have osa. these data will be complimented by full sleep studies to be performed at the participants' homes in late , early . conclusion our interim data suggest that the rate of subjective sleep complaints are not substantially different in the population with tetraplegia compared with the able-bodied. this research was supported by the victorian neurotrauma initiative. it has long been assumed that the ventilation heterogeneity associated with lung disease could in itself affect the measurement of carbon monoxide transfer factor. the aim of this study was to investigate the potential estimation errors of carbon monoxide diffusing capacity (tlco) measurement that are specifically due to conductive ventilation heterogeneity. we induced conductive airway ventilation heterogeneity in never-smoker normal subjects by histamine provocation, and related the resulting changes in ventilation heterogeneity (derived from the multiple breath washout test) to corresponding changes in diffusing capacity, alveolar volume and inspired vital capacity (derived from the single breath tlco method). average conductive ventilation heterogeneity doubled (p < . ), while tlco decreased by % (p < . ), with no correlation between individual data (p > . ). when dividing diffusing capacity by alveolar volume, the resulting transfer coefficient was not significantly different pre versus post histamine (p = . ). these findings can be brought in agreement with recent modelling work, where specific ventilation heterogeneity resulting from different distributions of either inspired volume or end-expiratory lung volume have been shown to affect tlco estimation errors in opposite ways. the combination of these errors appears to largely cancel out in our experimental situation of induced ventilation heterogeneity comparable to that observed in lung disease. we conclude that conductive ventilation heterogeneity per se has a negligible effect on diffusing capacity measurement. an important determinant of airway function in humans is vagal-mediated cholinergic tone in airway smooth muscle (asm). this airway tone may be altered in disease states. the use of mouse models for the study of airway diseases, including asthma, pulmonary fibrosis and copd is well established. however, it is not known whether mice actually possess basal asm tone or, if it does exist, how this tone changes in disease models. this study was undertaken to determine whether mice have detectable asm tone in vivo. methods respiratory system impedance (zrs) was measured in female adult balb/c mice using a wave-tube modification of the forced oscillation technique. zrs was measured during slow (~ s) inflation-deflation manoeuvres between the transrespiratory pressures of and cmh o. baseline lung mechanics and thoracic lung volumes (tgv) were measured before and after each mouse was allocated to one of four treatment groups: 'saline' mice received an i.p injection of saline, 'atropine' mice received i.p. atropine sulphate, 'vagotomy' mice had their left and right cervical vagus nerves isolated by blunt dissection and cut, and 'sham' mice had the area of the vagus nerves exposed but the nerves were not cut. results there were no post-treatment changes in tgv, airway resistance, tissue damping, tissue elastance, inertance or tissue hysteresivity in any of the four groups. conclusions the lack of change in lung mechanics post-atropine or postvagotomy in balb/c mice suggests that, unlike humans and many other species, the airways of mice have no baseline asm tone. supported by nhmrc grant# . nomination none. conflict of interest none. both male gender and increased mandibular enclosure volume predict more severe sleep disordered breathing in obstructive sleep apnoea patients. we now examine gender/body size/mandibular enclosure volume relationships for normal subjects stepwise multiple linear regression analysis was used to model body size/enclosure volume interactions. results for the whole group, mv was . Ϯ . ml (mean Ϯ se) while rmv was . Ϯ . ml. head circumference (positive) and forehead height (negative) were both independent predictors for mv and rmv (both p < . ), while hip circumference was an additional positive predictive factor for rmv (p < . ). after adjusting for these parameters, male mv and rmv were larger than for females conclusion these findings suggest that mandibular enclosure volumes are relatively larger in males, even after adjusting for body size/cranial dimension. differing body size/mandibular enclosure volume interactions may contribute to gender influences on the severity of sleep disordered breathing. supported by nhmrc of australia nomination john read prize for sleep and physiological research tp audit of ctpa in a regional hospital y raje, s vincent, g simpson department of thoracic medicine, cairns base hospital, cairns, qld since the introduction of computerized tomographic pulmonary angiograms (ctpa) at our institution the number of requests for this investigation at our institution has grown at an alarming rate. the purpose of this study was to evaluate the clinical assessment of suspected pulmonary embolism (pe). methods ctpa were reviewed. results female, male. mean age yrs (range - ). ctpa requests came from department of medicine, from emergency department, from surgical teams and from oncology outpatients. patients presented with chest pain (pleuritic in cases), had dyspnea, presented with collapse. patients had haemoptysis. hypoxaemia was recorded in . none were clinically shocked and only one had a recorded tachycardia. d-dimer requested in patients and was elevated in . arterial blood gases performed in only patients ( %). patients had prior chest x-ray which was normal in ( %). patients had consolidation on chest x-ray, pleural effusions, atelectasis and fractured ribs. recorded risk factors included patients with previous dvt or pe, patients with malignancy and patients were immediately post-operative. only ctpas ( %) demonstrated evidence of pe. of these had recent dvt and were post-operative. had a history of bowel cancer. there was no formal record of pre-test clinical probability of pe (eg wells' score) for any of the cases. retrospective calculation of the cases of pe, had a wells' score of . and of with the remaining patient with wells' score of under . only patients (one with clinically probable pe) had received fractionated heparin prior to the ctpa. conclusion ( ) ctpas performed at our institution have a low yield ( %).( ) pre-investigation clinical assessment was poor and there was poor adherence to published guidelines, ( ) this results in many unnecessary ctpa examinations generating increased work and expense for the medical imaging department and exposes many patients to unnecessary and potentially harmful radiation exposure. the evaluation and management of hereditary hemorrhagic telangiectasia involves a multidisciplinary approach according to international guidelines. the aim of this audit was to compare the assessment process in one centre with that of the international recommendations. methods retrospective comparison was made by medical chart review of all patients with a diagnosis of hht between the years to . demographic along with clinical data with diagnostic investigations, complications, treatment and genetic evaluation, including family screening was collected. the proportion of patients evaluated and managed as per the international recommendations was determined. results the audit identified patients with the diagnosis of hht, with the mean age years. diagnostic criteria were met in % of the cohort. of the known clinical features, % had a family history, and % epistaxis. cutaneous telangiectasia was present in % and visceral involvement in %. pulmonary arterio-venous malformations (pavm) were seen in patients, cerebral avm in , gastrointestinal telangiectasia was documented in . one patient had a spinal (cervical) avm, and another had pulmonary hypertension in association with this condition. only patients underwent diagnostic or screening investigations in accordance with the international recommendations. furthermore, one patient was referred for a genetic evaluation. conclusions this clinical audit found that % of patients referred to this centre were evaluated in accordance with the international recommendations. genetic assessment was lacking. the study supports the need for a coordinated, multidisciplinary approach to the evaluation and management of hht in this centre. lm young , n good , d milne , w fergusson , i zeng , j kolbe , ml wilsher background while airflow limitation is the most common physiological impairment in sarcoidosis, there are limited data on airway hyperresponsiveness (ahr). understanding the role of ahr in sarcoidosis, if any, may help to identify individuals who might benefit from inhaled therapies. aims ( ) to determine the prevalence of ahr in sarcoidosis. ( ) to determine the correlation between responses to direct (using histamine) and indirect (using hypertonic saline) bronchial challenge. ( ) to determine the clinical, physiological and radiological predictors of ahr. methods subjects with a diagnosis of sarcoidosis based on typical clinical presentation and compatible hrct features and/or tissue biopsy and with a baseline fev > % predicted were recruited. subjects underwent standard hypertonic ( % fall in fev ) and histamine ( % fall in fev ) challenge (> day but < days apart), lung function testing and high resolution computed tomography (hrct) of the chest. results the subjects ( Ϯ years, % female, % european, % stage i, % stage ii, % stage iii, % stage iv) had well preserved lung function overall (fev = . l Ϯ . . % predicted). ahr was detected in / ( %) to hypertonic saline and / ( %) to histamine challenge. on univariate analysis, response to histamine challenge was predicted by conglomerate fibrosis (p = . ) and reticular pattern (p = . ) on hrct. the baseline % predicted fev was significantly associated with ahr on univariate (p = . ), and multivariate analysis (p = . ) when adjusted by hrct patterns. conclusions there is a high prevalence of ahr using histamine challenge in this study of sarcoidosis subjects. ahr most strongly associates with baseline % predicted fev but also conglomerate fibrosis and reticular pattern on hrct. these findings may reflect the consequence of airway remodelling following inflammation. further studies are warranted to confirm these findings. background upper airway shunt represents a significant source of measurement artefact in the use of the forced oscillation technique (fot), with increasing importance in young children. changes in respiratory system admittance, ars (or zrs - ), are theoretically independent of the upper airway shunt. this study examines the possible clinical benefit of ars in preschool children by assessing any increased ability to differentiate responses to bronchial challenges in the routine clinical setting. we hypothesized the use of ars would provide improved sensitivity to clinically relevant obstruction, bronchodilator responsiveness (bdr) and airway hyper-responsiveness (ahr) in young children with respiratory disease. method previous fot measurements were re-analysed and ars calculated to derive: ( ) ars reference equations in healthy young children (n = ); ( ) bdr in ars, respiratory system resistance (rrs) and reactance (xrs) in healthy children (n = ), children with cystic fibrosis (n = ), neonatal chronic lung disease (n = ), asthma (n = ) and wheeze (n = ); ( ) ahr to inhaled adenosine- ′-monosphate (amp) in children. fisher's exact tests were used to assess changes in diagnostic outcomes between ars and conventional fot outcomes (rrs and xrs). results ars was no more sensitive to bronchodilator induced changes than conventional fot outcomes. amp challenges resulted in equivalent responses measured by relative changes in rrs and ars while absolute changes in ars were the least sensitive variable. conclusion this study does not support a clinical advantage in using ars in measuring responses to either inhaled bronchodilator or amp. c hollier , , c menadue , , d flunt , , aj piper , department of respiratory and sleep medicine, royal prince alfred hospital, nsw , and woolcock institute of medical research, nsw serial measurement of arterial carbon dioxide (paco ), ph and bicarbonate (hco -) is essential in the management of patients with hypercapnic respiratory failure (hrf). this information is usually obtained from a sample of arterial blood (abg). the procedure can be painful and distressing for patients, and is sometimes technically difficult due to obesity or contractures. our aim was to determine the validity and feasibility of arterialized venous blood (av) sampling as an alternative to abgs in measuring paco , ph and hco levels in patients with chronic hrf. method eighteen patients completed the study. venous blood was arterialized by heating forearm skin to a temperature of - °c with an electric heating pad. an av sample was taken from a cannula positioned in a vein of the heated forearm simultaneously with an abg. in addition, the reliability of av sampling within the recommended temperature range ( - °c) was investigated in ten healthy volunteers placed on volume cycled ventilation in order to maintain constant ventilation. av samples were taken at . °c temperature intervals from . - °c results the table below summarizes results for validation of av sampling: based on the evidence that cardiovascular dynamics are altered due to obstructive sleep apnea, this study aims to identify the onset and termination of each apnea event using power spectral density (psd) and morphological features of single lead ecg signal over second period. methods ecgs from patients overnight sleep studies were examined for location of the pre-scored apnea events. onset (n = ), maximum (n = ) and termination (n = ) of each apnea event and normal events (n = ) were annotated on second windows. features extracted were psd, amplitudes of r and t wave of second ecgs. receiver operating characteristics (roc) analysis was used to gauge the event recognition ability of all features. weight loss causes an improvement in the severity of osa, however substantial weight loss is very difficult for obese patients. the very low caloric diet (vlcd) has been shown to be successful in causing significant weight loss in obese patients. this is a pilot study on the use of a formal screening protocol to identify osa patients who are potentially eligible for the supervised vlcd program offered by the endocrinology department at auckland city hospital. method consecutive patients who attended the sleep laboratory at ach between june to december were screened using the protocol. patients who are eligible to be considered for the vlcd program are identified as having a combination of obesity (bmi > ), osa (ahi > on sleep study) and being residents within the auckland district healthboard region. results / patients screened did not fulfil the inclusion criteria: lived outside the adhb region; had bmi < ; patients did not have osa (ahi < ). patients fulfilled the inclusion criteria. / patients ( %) were excluded due to medical or psychiatric contraindications to vlcd. patients ( %) who did not have contraindications to vlcd were contacted. patients were contacted successfully. patients were either unavailable to phone contacts on separate days or were disconnected. / patients consented to being referred ( %). / patients declined referral ( %). conclusion this pilot study is the first study using a formal comprehensive screening protocol in the recruitment of obese osa patients into a medically supervised vlcd program. only a small proportion ( %) of patients proceeded to being referred to the vlcd program. key: cord- - y wdepc authors: traves, suzanne l; proud, david title: viral-associated exacerbations of asthma and copd date: - - journal: curr opin pharmacol doi: . /j.coph. . . sha: doc_id: cord_uid: y wdepc exacerbations of asthma and chronic obstructive pulmonary disease are major burdens on the healthcare system, and contribute significantly to the mortality and morbidity associated with these diseases. upper respiratory viral infections are associated with the majority of such disease exacerbations. the past few years have seen advances in the mechanisms by which viral infections induce pro-inflammatory chemokine production, and in our understanding of host antiviral and anti-inflammatory defence pathways that might regulate responses to infection. a more comprehensive understanding of the molecular basis of these processes could elucidate new therapeutic approaches to reduce the devastating impact that these exacerbations have on quality of life and healthcare costs. exacerbations of asthma and chronic obstructive pulmonary disease are major burdens on the healthcare system, and contribute significantly to the mortality and morbidity associated with these diseases. upper respiratory viral infections are associated with the majority of such disease exacerbations. the past few years have seen advances in the mechanisms by which viral infections induce pro-inflammatory chemokine production, and in our understanding of host antiviral and anti-inflammatory defence pathways that might regulate responses to infection. a more comprehensive understanding of the molecular basis of these processes could elucidate new therapeutic approaches to reduce the devastating impact that these exacerbations have on quality of life and healthcare costs. exacerbations of asthma and chronic obstructive pulmonary disease (copd) can be defined as 'a worsening of the patient's condition, beyond the day-to-day variability associated with the disease, that is sufficient enough to require a change in management, or to seek emergency medical intervention' [ , ] . exacerbations of both asthma and copd represent a major financial burden on the healthcare system as a result of costs associated with hospitalizations, increased medication usage, and days lost from work and school. in the case of asthma, exacerbations are responsible for % of the total healthcare costs, and for the deaths of americans each year [ ] . similarly in the case of copd, exacerbations account for % of healthcare costs, as well as being a substantial cause of hospitalizations [ ] . more importantly, recurrent exacerbations of copd result in a loss of lung function, thus hastening the progression of a currently fatal disease [ ] . in the current article, we discuss the evidence that common respiratory viruses are a major trigger factor for exacerbations of asthma and copd. we also review the current state of our knowledge on the mechanisms by which viruses might trigger such disease exacerbations, as well as the factors that could regulate susceptibility to viral exacerbations. finally, we consider the status of current therapies in the treatment of viral exacerbations of asthma and copd, and discuss potential novel approaches to treatment. the association between upper respiratory viral infections (uris) and exacerbations of asthma has been recognized for decades, but it was not until the development of rt-pcr methods for improved detection of viruses that the extent of this association became clear [ , ] . indeed, uris are the principal risk factor associated with asthma exacerbations [ , ] , and are associated with as many as - % of asthma exacerbations in children and adolescents [ , [ ] [ ] [ ] , and approximately - % of exacerbations in adults [ , ] . there is a clear temporal relationship between uris and asthma exacerbations in children. the peak of hospitalizations occurs in september, shortly after the return to school and at the peak time of year for human rhinovirus (hrv) infections [ , ] . consistent with this, hrv is associated with approximately % of viral-triggered exacerbations [ , , ] . other viral types associated with asthma exacerbations include influenza, coronaviruses, parainfluenza and respiratory syncytial virus. epidemiological evidence suggests that viruses may also interact with other causal factors linked to asthma exacerbations, such as allergens and pollution. studies of the interaction between experimental allergen exposure and experimental virus infection, however, have generated mixed results. in a murine model, influenza infection aids allergen sensitisation and enhances airway inflammation [ ] . in humans, however, chronic low-dose allergen provocations did not alter subsequent lower airway responses to hrv infection [ ] whereas, in the upper airways, acute allergen challenge delayed onset and shortened the duration of common colds. by , copd is predicted to become the third most common cause of death worldwide and the fifth leading cause of disability [ ] . exacerbations of copd occur more commonly in patients in the advanced gold ii or iii stages [ ] . (gold stands for the global initiative for chronic obstructive lung disease, and ranks disease in four stages: = at risk; stage i = mild copd; stage ii = moderate copd; stage iii = severe copd.) recent evidence has demonstrated that uris are a major trigger [ ] . in a recent study, % of severe exacerbations in patients with copd were associated with viral and/or bacterial infections, with viral infections accounting for % of these exacerbations [ ] . interestingly, viral-associated exacerbations of copd are more frequent, severe and have longer recovery times than those of non-viral origin [ ] . moreover, exacerbations associated with viral/bacterial co-infection also result in longer hospitalisation, and worse functional impairment for the patient [ ] . in patients with copd exacerbations requiring mechanical ventilation, a viral pathogen was detected in % of cases [ ] . in general, viral infections are responsible for approximately % of exacerbations of copd, with hrv being the dominant pathogen [ , ] . consistent with this, exacerbation frequency is associated with an increased frequency of acquiring the 'common cold' [ ] . moreover, experimental hrv infection in patients with gold stage ii copd resulted in symptoms and lung function changes representative of acute disease exacerbations [ ] . the specific mechanisms by which viruses invoke exacerbations of asthma and copd remain unclear. growing evidence, however, suggests direct infection of the lower respiratory tract, leading to a robust host inflammatory response, and an increase in bronchial hyperresponsiveness [ ] . because hrv is the major viral type associated with exacerbations, we focus on this virus as a prototype for the mechanisms by which viruses exert their effects. hrv infects both the upper and lower respiratory tracts, with the principal site of infection being the airway epithelial cell [ ] . although it has been reported that some strains of hrv can cause epithelial cell death in cultures grown at low density [ ] , the majority of studies found no overt cytotoxicity either in vitro or in vivo. epithelial cells are clearly the major site of hrv infection and sustain prolonged replication [ , ] . although hrv can bind to, and enter, a variety of other cell types in vitro, including fibroblasts, monocytes and macrophages [ , ] , the contribution of these individual cell types to pathogenesis in vivo is still unclear. hrv infection of cultured human airway epithelial cells results in production of several pro-inflammatory cytokines and chemokines, including interleukin (il)- , il- , il- , interferon (ifn)-inducible protein of kda (ip- ), regulated on activation normal t-cell expressed (rantes), granulocyte macrophage-colony stimulating factor and eotaxin [ ] [ ] [ ] . this profile of mediators could enhance airway inflammation via the recruitment and retention of a wide range of inflammatory cells ( figure ) that contribute to the pathogenesis of exacerbations [ ] . moreover, some of these chemokines have also been detected in airway secretions during viral infections [ ] . despite the potential for epithelial chemokines to recruit multiple cell types to the airways, experimental hrv infections and viral exacerbations of asthma and copd are dominantly associated with selective recruitment of neutrophils and lymphocytes [ ] . this implies that mechanisms must exist to limit the cell types recruited, but these mechanisms are not well understood. it has recently been reported that increased il- gene expression is observed during viral exacerbations of asthma, suggesting that immunoregulatory effects of il- include suppression of eosinophil influx [ ] . viral infections might also contribute to disease exacerbations by enhancing mucus production. hrv infection of epithelial cells has been shown to result in increased mrna expression for muc , muc , muc ac, muc b and muc . importantly, concentrations of muc ac and total mucin were also increased in supernatants and lysates from epithelial cells [ ] . although viral infection modulates epithelial cell function, the viral-induced signalling mechanisms involved are just beginning to be elucidated. induction of chemokines such as il- occurs early after hrv binding and does not require viral replication, but instead depends upon activation of both phosphatidylinositol -kinase and the p mitogen-activated protein kinase pathway [ ] . given that intercellular adhesion molecule- (icam- ), the receptor for the majority of hrv serotypes, has no inherent kinase activity or recognition motifs for receptorassociated kinases, it was unclear how viral binding initiated this signalling cascade. however, it has recently been shown that hrv binding to icam- leads to an association with the spleen tyrosine kinase syk. this association is mediated via the cytoskeletal linker protein ezrin, which binds both icam- and syk. formation of this complex leads to activation of syk, with subsequent downstream activation of the p mitogen-activated protein kinase pathway and increased expression of il- . thus, syk is an important signalling component in early virus responses [ ] . in contrast to the rapid generation of il- , other responses to viral infection, such as generation of rantes or ip- , do not occur until several hours after viral exposure and are absolutely dependent upon viral replication. this has led to intense investigation of the role of viral replication products, particularly double-stranded rna (dsrna), in cell responses. it is known that dsrna mimics several responses to viral infection and triggers host anti-viral responses. initially, dsrna was thought to be recognized exclusively by toll-like receptor (tlr) [ ] , but genetic deletion of tlr did not alter viral pathogenesis or host adaptive antiviral responses to several viruses [ ] . this apparent conundrum was resolved with the demonstration that two intracellular rna helicases -retinoic acid inducible gene (rig-i) [ , ] and melanomadifferentiation-associated gene (mda- ) [ ] -can also bind to dsrna. the helicase domain of these proteins binds dsrna, while a caspase activation and recruitment domain (card) permits binding of a downstream adaptor protein. this downstream mitochondrial-associated protein was identified independently by four groups and is known by the names cardif (card adapter inducing interferon-b), mavs (mitochondrial antiviral signalling), ips- (interferon-b promoter stimulator- ) and visa (virus-induced signalling adapter) [ ] . cardif binds to several proteins and induces both classical nuclear factor-kb (nf-kb) pathway activation and ikke/tankbinding kinase -mediated activation of interferon response factors [ ] . these pathways are also activated when dsrna binds to tlr (figure ) . controversy now exists regarding the relative roles of tlr , rig-i and mda- in viral recognition. it has been suggested that different viral types may preferentially utilize one of these three recognition proteins. to further complicate this picture, rig-i also recognizes single-stranded rna (ssrna) containing -phosphates. indeed, it has been reported that influenza a does not generate dsrna but, rather, activates rig-i via binding of genomic viral ssrna bearing -phosphates [ , ] . further studies are needed to clarify the preferential utilization of different intracellular recognition molecules by different viral types, and to determine if this also varies with cell type. mechanisms of virus-associated exacerbations of asthma and copd. viral infection of the epithelium results in the upregulation of icam- . pro-inflammatory mediators are also released that recruit inflammatory cells such as neutrophils and monocytes, which then differentiate into macrophages, lymphocytes and eosinophils. these inflammatory cells also release inflammatory mediators such as chemokines, cytokines, matrix metalloproteinases (mmps) and reactive oxygen species (ros), which perpetuate the inflammatory response culminating in an exacerbation. what determines susceptibility of a given individual to experience disease exacerbation upon viral infection is not clear but multiple factors are probably involved. those subjects whose underlying disease is well controlled are less likely to experience an acute viralmediated exacerbation. similarly, pre-existing specific immunity to a given pathogen will reduce the likelihood of that pathogen triggering an exacerbation. epithelial contributions to host innate antiviral immunity might also play a role. recent reports suggest that bronchial epithelial cells from asthmatic subjects show impaired production of both ifnb and type ifns [ , ] , and that this plays a role in the increased susceptibility of asthmatic subjects to lower airway disease. additional studies are needed to confirm these data and to put such defects in the context of why specific asthmatic subjects experience exacerbations. moreover, although type and type ifns contribute to host defence mainly via induction of numerous ifn-stimulated genes (isgs) that collectively limit virus replication and spread, there is a precedent for several viruses, including hrv, to induce isgs independently of ifn induction [ , ] . overview of the intracellular signalling pathway stimulated by rhinovirus. hrv binds to icam- on the surface of epithelial cells. the virus becomes internalised and, during replication, produces dsrna. dsrna can then bind tlr , which activates toll/il- -containing adaptor inducing interferon b (trif) and subsequently either interferon regulatory factor (irf) or nf-kb. dsrna can also bind either rig-i or mda- , resulting in the activation of irfor nf-kb-mediated pathways. it is thought that activation of irf and nf-kb stimulates the production of the anti-viral response. fadd, fas-associated death domain protein; ikk, inhibitor of nf-kb kinase family; ips- , interferon-b promoter stimulator ; mavs, mitochondrial antiviral signalling; rip- , kinase receptor interacting protein- ; tbk, tank-binding kinase; traf, tumor necrosis factor receptor-associated factor; visa, virus-induced signalling adaptor. nitric oxide (no) also appears to be an important component of the host antiviral response because it exerts direct antiviral activity against several viruses associated with exacerbations of asthma and copd, and also inhibits the viral-induced generation of several cytokines/chemokines from epithelial cells [ ] . viral infection of epithelial cells increases expression of inducible no synthase (inos) and, during in vivo hrv infections, epithelial inos induction correlates with levels of exhaled no. moreover, subjects with the highest levels of exhaled no cleared virus more rapidly and had fewer symptoms than those who exhaled lower levels [ ] . corticosteriods are crucial in the treatment of asthma [ ] and, when used alone or in combination with long-acting b-agonists or leukotriene receptor antagonists, they are known to improve asthma control and, thereby, reduce the number of exacerbations. acute asthma exacerbations tend to be treated with oxygen, inhaled short-acting b -adrenoceptor agonists, and intravenous or oral corticosteroids [ ] . although use of oral corticosteroids early in exacerbations can reduce subsequent relapse [ ] , there have been few studies looking specifically at exacerbations of known viral etiology. corticosteroids are ineffective in the treatment of hrvinduced colds and current evidence would suggest that they are of limited efficacy in viral-induced excerbations of asthma. asthmatics with prominent sputum neutrophilia, perhaps indicative of viral etiology, are poorly responsive to inhaled corticosteroids [ ] , and inhaled corticoisteroids did not significantly reduce lower airway inflammation induced by hrv infection of asthmatic subjects [ ] . moreover, administration of prednisolone to children hospitalized for viral-induced episodes of wheezy bronchiolitis did not reduce the duration of hospital stay [ ] . combination therapies of inhaled anticholinergic agents with short-acting b -adrenoceptor agonists have been reported to be more effective against exacerbations in school children [ ] ; furthermore, a leukotriene receptor antagonist decreased asthma exacerbations in -to -year-old patients with intermittent asthma [ ] . nedocromil sodium and inhaled corticosteroids might also be of limited benefit in asthma exacerbations in children [ ] . it must be noted, however, that most of these studies did not discriminate between exacerbations of viral and non-viral origin. although there is conflicting evidence over whether inhaled corticosteroids reduce exacerbations of copd, oral corticosteroids appear to hasten recovery from certain exacerbations [ ] . combined therapy with corticosteroids and long-acting b-adrenoceptor agonists has been shown to reduce the number of exacerbations in patients with copd, presumably by improving baseline control [ ] . again, however, there have been no studies specifi-cally examining the effects of corticosteroids, alone or in combination with long-acting b-adrenoceptor agonists, during copd exacerbations of known viral etiology. similarly, although antibiotic therapy is widely used in exacerbations of copd, their utility in virally triggered exacerbations is questionable. antiviral approaches appear to be a logical alternative to the treatment of viral exacerbations of asthma and copd, and influenza vaccine is clearly effective in preventing exacerbations triggered by this virus. vaccination approaches have not been successful for respiratory syncytial virus, however, and are not feasible for hrv, given the large number of viral serotypes. antiviral agents are available for influenza, and neuraminidase inhibitors have proven clinical efficacy in reducing the severity of symptoms during influenza infections. by contrast, antiviral approaches targeting hrv are still in development and have not yet been applied to viral exacerbations of asthma or copd. if the assumption that an over-exuberant host inflammatory response to viral infection plays a key role in disease exacerbation is valid, several potential therapeutic approaches can be suggested. the first would be to identify specific viral signaling pathways that would be targets for intervention. these could include, for example, specific early signaling pathways involving the spleen tyrosine kinase syk, or pathways triggered by viral interactions with the intracellular rna helicases. although targeting specific chemokines or chemokine receptors, such as cxcr or cxcr / , might also prove an attractive target, it remains to be determined which chemokine/chemokine-receptor systems are particularly important in disease pathogenesis. finally, enhancement of endogenous host antiviral pathways, or topical administration of drugs such as nitric oxide donors, could provide alternative approaches to reduce virally induced inflammation. there is an urgent need for additional therapeutic approaches to combat viral exacerbations of asthma and copd. although the past few years have seen a significant increase in our understanding of how viruses cause exacerbations, much remains to be learned. the complex signalling pathways triggered upon viral infection are not completely understood but, once delineated, could provide novel therapeutic targets. in addition, better understanding of host innate antiviral mechanisms could provide an alternative therapeutic approach if such pathways can be stimulated. pathophysiology of exacerbations of chronic obstructive pulmonary disease chronic obstructive pulmonary disease. : the aetiology of exacerbations of chronic obstructive pulmonary disease role of viral infections in asthma and chronic obstructive pulmonary disease how viral infections cause exacerbation of airway diseases allergens, viruses, and asthma exacerbations the role of rhinovirus in asthma exacerbations persistence of rhinovirus rna after asthma exacerbation in children study of modifiable risk factors for asthma exacerbations: virus infection and allergen exposure increase the risk of asthma hospital admissions in children viral infections in relation to age, atopy, and season of admission among children hospitalized for wheezing the september epidemic of asthma hospitalization: school children as disease vectors the relationship of rhinovirus-associated asthma hospitalizations with inhaled corticosteroids and smoking unravelling synergistic immune interactions between respiratory virus infections and allergic airway inflammation bronchial matrix and inflammation respond to inhaled steroids despite ongoing allergen exposure in asthma the global burden of disease molecular mechanisms of respiratory virus-induced asthma and copd exacerbations and pneumonia role of viruses in exacerbations of chronic obstructive pulmonary disease infections and airway inflammation in chronic obstructive pulmonary disease severe exacerbations virus infection in exacerbations of chronic obstructive pulmonary disease requiring ventilation epidemiological relationships between the common cold and exacerbation frequency in copd an experimental model of rhinovirus induced chronic obstructive pulmonary disease exacerbations: a pilot study quantitative and qualitative analysis of rhinovirus infection in bronchial tissues rhinovirus infection induces cytotoxicity and delays wound healing in bronchial epithelial cells proud d: human airway epithelial cells produce ip- (cxcl ) in vitro and in vivo upon rhinovirus infection rhinovirus induces airway epithelial gene expression through double-stranded rna and ifn-dependent pathways human rhinovirus induces robust ip- release by monocytic cells, which is independent of viral replication but linked to type i interferon receptor ligation and stat activation host defense function of the airway epithelium in health and disease: clinical background interleukin- gene expression in acute virus-induced asthma mechanisms of mucin production by rhinovirus infection in cultured human airway epithelial cells phosphatidylinositol -kinase is required for rhinovirus-induced airway epithelial cell interleukin- expression syk is downstream of intercellular adhesion molecule- and mediates human rhinovirus activation of p mapk in airway epithelial cells the authors demonstrate for the first time a molecular mechanism linking rhinovirus binding to icam- and downstream mediator production. they highlight the role of syk and ezrin as important signalling molecules following rhinovirus infection of epithelial cells recognition of double-stranded rna and activation of nf-kappab by toll-like receptor does toll-like receptor play a biological role in virus infections? the rna helicase rig-i has an essential function in double-stranded rna-induced innate antiviral responses differential roles of mda and rig-i helicases in the recognition of rna viruses using knockout mice for rig- and mda- , the authors show that these mice are more susceptible to viral infection, highlighting the role of these proteins in the anti-viral respsonse. they also demonstrate for the first time that rig-i and mda- bind different viruses, and that synthetic dsrna poly(i:c) mediates its effects via mda- card games between virus and host get a new player this short article brings together four independent studies which discovered the same card-containing protein (cardif/mavs/ips- /visa) that mediates the effects of rig-i and mda- . it outlines the major findings from the four groups, and highlights that possible signalling pathways of dsrna produced by the virus -triphosphate rna is the ligand for rig-i reis e sousa: rig-i-mediated antiviral responses to single-stranded rna bearing phosphates these two articles highlight for the first time that rig- can also bind ssrna, and that the -triphosphate is crucial for rig- activation. these articles are important, as it was previously thought that rig- could only bind dsrna asthmatic bronchial epithelial cells have a deficient innate immune response to infection with rhinovirus role of deficient type iii interferon-lambda production in asthma exacerbations they highlight deficiencies in the immune response to infection in asthma. they found that the production of ifnb and ifnl was severely impaired in epithelial cells and alveolar macrophages during asthma exacerbations, thus highlighting these compounds as potential therapies. . noyce rs nitric oxide and the common cold role of nasal nitric oxide in the resolution of experimental rhinovirus infection systemic corticosteroid therapy for acute asthma exacerbations comparison of asthma treatment given in addition to inhaled corticosteroids on airway inflammation and responsiveness rhinovirus-induced airway inflammation in asthma: effect of treatment with inhaled corticosteroids before and during experimental infection evaluation of the efficacy of prednisolone in early wheezing induced by rhinovirus or respiratory syncytial virus polos p: montelukast reduces asthma exacerbations in -to -year-old children with intermittent asthma limitations of maintenance therapy for viral respiratory infection-induced asthma dr traves acknowledges altana canada for postdoctoral fellowship support. dr proud is the recipient of a canada research chair in inflammatory airway diseases and thanks the canadian institutes of health research for support of our research. key: cord- -y z w x authors: nan title: copd sig: poster session date: - - journal: respirology doi: . /j. - . . _ .x sha: doc_id: cord_uid: y z w x nan patients with non-eosinophilic asthma (nea) or copd have increased numbers of neutrophils in the airways. we have shown a similar defect in the ability of alveolar macrophages (am) to phagocytose apoptotic cells, in sputum from patients with nea and copd. we have also shown that bal-derived am from patients with copd have reduced expression of key macrophage phagocytic recognition molecules. the aim of this pilot study was to investigate the expression of these macrophage markers in induced sputum from patients with eosinophilic asthma (ea, n = ), nea (n = ), copd (n = ) and controls (n = ). methods participants underwent clinical assessment, skin allergy test, hypertonic saline challenge and sputum induction. macrophage phagocytosis of apoptotic cells, expression of mannose receptor (mr), hspr (cd ) and pcam (cd ) was determined using fl ow cytometry. results phagocytosis was signifi cantly impaired in patients with nea and copd. expression of mr, cd and cd were decreased in patients with nea or copd, but not signifi cantly changed in ea conclusion impaired sputum-macrophage phagocytosis of apoptotic cells in nea is associated with reduced expression of key macrophage recognition molecules. this defect may contribute to the chronic infl ammation and persistent airway neutrophilia that characterizes this asthma subtype. the use of induced sputum as a surrogate for the more-invasive bronchoscopic sampling may provide a tool for investigating the mechanisms for the effect of therapies including azithromycin in lung disease. supported by nhmrc. neutrophilic asthma (na) has been associated with increased bacterial colonization of the airways and increased expression of innate immune factors in the lung. this suggests that infection may play an important role in the pathogenesis of na. na is an important health issue as sufferers are resistant to steroid treatment, which is the mainstay of asthma therapy and effective therapies are urgently required. using mouse models of chlamydia and haemophilus infl uenzae lung infection and ovalbumin (ova)-induced allergic airway disease (aad), we have shown how infection may be linked to na. both infections suppressed eosinophilic infl ammation and t-helper (th) type responses but increase neutrophilic infl ammation and innate and th and/or th responses in aad. in the current study, the effectiveness of steroid treatment for the suppression of infection-induced neutrophilic aad was assessed by treating infected ovasensitized mice intranasally with dexamethasone during ova challenge. whilst dexamethasone treatment suppressed th -mediated, eosinophilic aad in uninfected, ova-sensitized groups, chlamydia and haemophilus-induced neutrophilic aad were shown to be steroid-resistant. our fi ndings correlate with clinical observations which show associations between infection, neutrophilic infl ammation and steroid resistance in asthmatics. these models will be utilized to examine the effectiveness of a number of novel therapies for infection-induced neutrophilic aad and to develop improved treatment strategies for steroid-resistant asthma. supported by nhmrc, asthma foundation of nsw, hmri. kj baines , , jl simp s on , , rj scott , lg wood , , pg gibson , priority research centre's for asthma and respiratory disease, and information based medicine, the university of newcastle, nsw, australia, and respiratory & sleep medicine, hmri, john hunter hospital, nsw, australia rationale four infl ammatory phenotypes of asthma have been identifi ed including eosinophilic, neutrophilic, mixed granulocytic and paucigranulocytic asthma, based on the presence or absence of sputum granulocytes. the involvement of systemic infl ammation in the pathogenesis of infl ammatory phenotypes of asthma remains unknown. objective this study investigates differences in the whole genome gene expression profi le of peripheral blood in infl ammatory phenotypes of asthma. methods induced sputum and peripheral blood were collected from participants with asthma (n = ). infl ammatory cell counts were performed and infl ammatory phenotype assigned based on the eosinophil and neutrophil cutoffs of % and %, respectively. rna was extracted from whole blood, gene expression profi les were generated (illumina humanref- v ) and analysed using genespring gx . results participants with eosinophilic asthma had signifi cantly higher rates of atopy and levels of exhaled nitric oxide. there were genes classifi ed as differentially expressed between the asthma phenotypes including the α-defensins (defa) , b, and , neutrophil proteases cathepsin g (ctsg) and elastase (ela ), and the monocyte/macrophage serine esterase, carboxylesterase (ces ). expressions of defa , b, , , ctsg and ela were signifi cantly higher in neutrophilic asthma and expression of ces was significantly higher in mixed granulocytic asthma. microarray results of the α-defensins and neutrophil proteases were successfully validated using realtime pcr. conclusions there is systemic up-regulation of α-defensins and neutrophil proteases in neutrophilic asthma, and these molecules play an important role in neutrophil activation and migration. systemic activation of neutrophils is an important feature involved in the pathogenesis of neutrophilic asthma, which is signifi cantly different to other asthma phenotypes. supported by hmri and xstrata coal; the university of newcastle. confl ict of interest no. airway mucus hypersecretion is an important cause of morbidity and mortality in asthmatic patients. increases in goblet cell number and their secretions are likely to contribute to airfl ow obstruction in asthma. here, we take advantage of an established sheep model of asthma to investigate the association between allergen exposure and goblet cell activity. methods eight allergic sheep (high house dust mite (hdm)-specifi c serum ige) received weekly intra-lung challenges of hdm to the right caudal lobe, and weekly intra-lung challenges of hdm followed by weeks without allergen exposure to the left caudal lobe, with the right medial lobe serving as an untreated internal control. a separate group of sheep were also used as untreated controls. biopsy samples of segmental bronchi tissue were collected from the different lung lobes for histological analysis at and days post-hdm challenge. results the percentage of goblet cells, with respect to epithelial cells, signifi cantly increases following chronic challenge with hdm ( % hdm vs. % control p < . ). goblet cell numbers did not decline in lung lobes after a -week cessation of allergen challenges. goblet cell degranulation is significantly increased day following challenge with allergen, but returns to control levels by days post-allergen challenge ( % day vs. % control p < . ). furthermore, degranulation is increased in both the rested and internal control lobes day following allergen challenge of the right caudal lobe. conclusions in this sheep model of chronic asthma, repeated allergen challenges induces goblet cell hyperplasia which persists even after long-term withdrawal of allergen. additionally, exposure to allergen in one lobe induces goblet cell degranulation in both challenged and unchallenged lobes, suggesting neural mechanisms may be operating in this model. confl ict of interest no. the thickness of the airway smooth muscle (asm) layer is related to severity but not duration of asthma or age (james erj; : ) . it is unknown if the constituents of the asm layer change with age. aim to investigate the relation of mean asm cell volume (v c ), total number of cells per mm of airway (n l ) and fractions of asm (f asm ) and extracellular matrix (f ecm ) within the asm layer with age and age at onset of asthma. methods post-mortem tissues from control subjects (c n = ); non-fatal (nfa n = ) and fatal (fa n = ) cases of asthma were used. the volume density (n v ) of asm cell nuclei was estimated on μm transverse airway sections (haematoxylin) and mean cell volume (v c = /n v ) was calculated, correcting for the volume fraction of asm within the asm layer. f asm and f ecm were estimated on . -μm thick sections of the same airway (masson's trichrome). effects of age on asm cell parameters and tissue volume fractions were tested using general linear models, correcting for sex and study centre and by comparing age at onset of asthma (< vs. > years). results table shows assessment of airway smooth muscle (asm) cell size and number requires estimates of cell volume density (n v ), volume fraction of muscle (f asm ) within the asm layer and the volume of asm per length of airway. stereological techniques have now become the accepted standard for assessing asm cell parameters, but sources of variation remain unclear. aim to assess sources of variability in the estimation of asm cell parameters and volume fractions within the asm layer. methods large and small airways from subjects with and without asthma were examined. transverse airway sections were cut at . μm and μm (masson's trichrome technique), and μm (haematoxylin) and used to estimate asm cell number and volume, and the volume fraction of muscle (f asm ) within the layer of asm. stereological assessments of the possible sources of variation in these asm layer parameters were assessed. results increased section thickness overestimated f asm by < % ( . μm), % ( μm) and % ( μm). stable variation of < % in n v occurred if high-power fi elds (hpf) were used to estimate n v . variation in the depth of muscle in thick sections of the asm layer caused up to % overestimation of n v . although the absolute area of the asm layer varied by up to %, variation of f asm was < % around the airway circumference and along the airway length. f asm differed signifi cantly between large and small airways. conclusion these results suggest that partial thickness hpfs need to be excluded and that ≥ hpf should be used to estimate asm volume density, that a single . μm section of airway can be used to estimate f asm and that asm parameters should be compared separately in large and small airways. grants nhmrc # . nominations nil. confl ict of interest nil. no signifi cant correlation was seen with age for any asm cell parameters or tissue fractions. results were similar for medium and small airways. conclusion size and number of asm cells and the volume fractions of asm and ecm within the layer of asm are not related to age. support nhmrc australia (grants # ; # ). nomination nil. . ± . . ± . . ± . . ± . fa > . ± . . ± . . ± . . ± . background asthma is characterized by excessive airway narrowing to contractile stimuli, termed airway hyper-responsiveness (ahr). changes in airway smooth muscle (asm) protein expression or mass are possible contributing mechanisms underlying ahr and have been examined using cell culture techniques. however, how these cellular changes to asm relate to airway narrowing at the level of the whole airway is unclear. we describe a new method to track changes in airway narrowing (responsiveness) in culture. methods whole airway segments (generation - ) from sheep lungs were studied prior to (fresh) and after and hours in culture in dulbecco's modifi ed eagle medium with % bovine serum albumin, % l-glutamine and antibiotics. airway narrowing was measured from the % decrease in airway volume under a fi xed transmural pressure, using a servo-controlled syringe pump and organ bath apparatus. cumulative acetylcholine dose-response curves (ach, − m − × − m) were performed to determine maximal response (e max ) and sensitivity (pd , negative log of ec ). results fresh airway segments narrowed strongly and approached closure with an e max of . % ± . (±sem) and pd of . ± . . airway narrowing responses were preserved in culture, with no signifi cant difference in maximal response or sensitivity to ach after either (e max . % ± . , pd . ± . ) or hours in culture (e max . % ± . , pd . ± . ). conclusions the present study has validated a new method allowing changes occurring at the cellular level in culture to be related to changes in airway responsiveness at the whole airway level. future studies will assess the effects of chronic infl ammation in disease on airway responsiveness. background deep inspiration (di) produces a bronchodilator response in healthy humans, but this response is impaired in asthma. reduced airway compliance in disease could impair the response to di by limiting the stretch of smooth muscle. aim to show that isolated human bronchi dilate to di in an amplitudedependent manner and that the stretch caused by di depends on airway compliance. methods bronchi were obtained following lung resection from cancer patients who had normal spirometry (n = ). lumen narrowing was measured using a servo-control system which set transmural pressure and simulated breathing movements. bronchi were contracted to carbachol (cch × − m) during tidal breathing (from to cmh o, i.e. Δ cmh o transmural pressure, . hz) and infl ated to three different amplitudes of di (Δ , or cmh o) applied following contraction. results in cch-contracted airways, all three di amplitudes produced a transient bronchodilation. increasing the di amplitude caused a greater increase in luminal volume during the di and a greater bronchodilation following the di (p < . ). cch itself cause approximately a % fall in specifi c compliance (p < . ), which was reversed by di (p < . ). for each di amplitude, the change in lumen volume during the di was positively correlated to the specifi c compliance of the bronchi before di (r > . , p < . ). conclusions isolated human bronchi show a bronchodilation response to di that is proportional to the expansion of the airway caused by the di. the amount of stretch produced by a di depends on airway wall compliance suggesting that increased airway stiffness in disease could suppress the di response by limiting the stretch of bronchi during lung infl ation. confl ict of interest none. ja douglass , , , ea yu , , br thompson , , , gg king , , mj abramson , introduction increasing asthma prevalence and changes in environmental exposure suggest that there may be a relationship between asthma and dietary intake. however, to date, few studies have examined how dietary intakes of asthmatics differ from a healthy population. aim to measure and compare the dietary intakes of adults with stable asthma and healthy controls. methods in a cross-sectional study, dietary intakes calculated from a item food frequency questionnaire (ffq) of adults with stable asthma (n = , age years ± (sd)) were compared with intakes of healthy controls (n = , age years ± (sd)) matched for age and body mass index (bmi). spirometry, airway responsiveness to hypertonic saline, and induced sputum cell counts were also measured. results subjects with severe persistent asthma (n = ) had signifi cantly higher total fat intake than healthy controls ( ± (sem) versus ± (sem) g/day p = . ) and signifi cantly lower fi bre intakes ( ± (sem) versus ± (sem) g/day p = . ). lower fi bre intake in asthmatic subjects (n = ) was associated with lower %predicted fev (r = . , p = . ), %fvc (r = . , p = . ) and fev /fvc (r = . , p = . ). higher fat intake and lower fi bre intake were associated with higher absolute concentrations of sputum eosinophils (r = . , p = < . , n = ). conclusions subjects with severe persistent asthma have an eating pattern of lower diet quality with higher intakes of fat and lower intakes of fi bre than healthy controls, which is related to lower lung function and increased airway infl ammation. factors leading to altered dietary intake in severe asthma require further investigation. methods a randomized, placebo-controlled, single-blinded trial of tailored asthma education including device technique and utilizing pact to address patients' concerns versus brochure-only information for asthma patients over age . measurements of lung function, asthma control (acq), asthma related quality of life (aqol), medication use and adherence score (adh) were obtained at baseline, and months using standard, validated questionnaires. results sixty-fi ve participants ( f m, mean age ± . ) were randomized to the intervention group and ( f m, mean age ± . ) to the control. there were no statistically signifi cant differences between the groups' demographics or baseline measurements. a wilcoxon signed ranks test used to compare median pair ranking at baseline and months post-intervention revealed a signifi cant improvement in the active, but not the brochure-only information group at months in: acq mean ± sd = . ± . vs. . ± . (p = . ). aqol mean ± sd = . ± . vs. . ± . (p = . ). adh mean ± sd = . ± . vs. . ± . (p < . ). conclusion an educational intervention including device technique and addressing the concerns of older people with asthma signifi cantly improved acq, aqol and adh scores at months post-intervention. introduction greater exposure to ultraviolet radiation (uv) may increase the risk of allergic disease, but this association has not been investigated using estimates of time spent outdoors by individuals. the aim of this study was to investigate the relationship between self-reported doctor-diagnosed asthma and/or hayfever, and time spent outdoors. methods this analysis was based on cross-sectional baseline data from a subsample of the australian and up study, comprising men and women aged - years, living in new south wales. participants were randomly selected from the australian universal health insurance database. diagnoses of asthma and/or hayfever and the number of hours spent outdoors were derived by questionnaire. in general, the odds of a diagnosis of asthma and/or hayfever decreased with increasing time spent outdoors for both women and men. for example, in women, the adjusted odds ratios for asthma with hayfever were . ( % ci: . - . ), . ( . - . ), . ( . - . ) and . ( . - . ) for - , - , - and > hours spent outdoors on weekends, respectively, compared with < hour (p trend < . ). time spent outdoors was not associated with a diagnosis of asthma alone in men. conclusions there were statistically signifi cant inverse associations between time spent outdoors and diagnoses of asthma, hayfever or asthma with hayfever, in a large population of older australians. exposure to uv may protect against the development of allergic diseases, such as asthma and hayfever. no. background allergic rhinitis (ar) and eczema are highly prevalent and females are more commonly affected than males in adulthood. although there have been extensive studies on ar and eczema in females, little is known about the effect of reproductive factors and the development of late-onset ar/ eczema. we examined potential associations between reproductive factors and ar and eczema using the tasmanian longitudinal health study (tahs) data. methods the tahs is a population-based cohort study of respiratory disease. two thousand seven hundred sixty-four ( . %) females from the original tahs participants were surveyed in using postal questionnaire which collected information on reproductive factors such as ever pregnancy, age at fi rst child birth, use of oral contraceptive pills (ocp) and age of starting using the ocp. logistic regression was used to assess the predictors of ar and eczema and all analyses were mutually adjusted. of the participants, . % (n = ) had late-onset ar and . % (n = ) had late-onset eczema. maternal and paternal atopy were signifi cantly associated with ar (p < . ). the risk of developing eczema was decreased signifi cantly with increasing age at fi rst menstruation (or: . , % ci: . - . ) and the increased age at birth of fi rst child ( . , . - . ). a decreased risk in ar was observed with the increasing number of pregnancies ( . , . - . ). however, the associations between age of starting using ocp and ar/eczema were not signifi cant. conclusion later age at start of menses and later age at fi rst pregnancy were associated with a reduced risk of eczema which may be related to hormonal dysregulation. tp- airway responsiveness at and years is associated with asthma at years introduction asthma is the most common chronic childhood disease in australia. increased airway responsiveness (ar) is associated with asthma but not all individuals with increased ar have asthma. the perth infant asthma follow-up study recruited a birth cohort of individuals who have undergone longitudinal assessments of many factors associated with childhood ar. our previous work reported an association between increased ar in infancy and asthma at and years. aim to look at the relationship of increased ar and asthma in early adulthood at different time points from birth. methods individuals were recruited from among expectant parents attending an antenatal clinic at a local metropolitan clinic. at ages , and months and again at , and years, participants underwent an assessment that included a respiratory questionnaire and determination of ar (as evidenced by dose-response slope (drs) to histamine using the rapid technique). results children were initially recruited and studied in infancy. two hundred three, , , , and children subsequently had ar assessed at , and months, , and years, respectively. there was a signifi cant relationship between drs at and years and for both asthma at years (p = . and p < . , respectively) and 'wheeze in the past year' at years (p = . and p = . , respectively). there was no significant relationship between drs in infancy and asthma at . conclusion ar at and years is associated with asthma at years. in this study, there was no signifi cant relationship between ar in infancy and asthma at years. the pcaas has found that . % of children with acute asthma presenting to the princess margaret hospital for children emergency department (pmh ed) had hrv, of which % were hrv group c. furthermore, hrvc was associated with more severe attacks. however, the prevalence of hrvc in the community is unknown. aim to test the hypothesis that hrvc would be found more often in children requiring emergency treatment for an ari than sibling controls and determine the impact of days since symptoms began on the prevalence of hrv detection in children with an acute respiratory illness (ari) and sibling controls (sibs). methods ari (n = ) had nasal samples collected on presentation to the pmh ed and sibs with symptoms of a cold (n = ), within week of ari recruitment. viral rna was extracted and reverse transcribed. a two-step pcr of the hrv ' utr was used for detection, followed by dna sequencing for typing. results ari and sibs were % and % male, % and % asthmatic, with mean ages of . and . years, respectively. hrv +ve ari (n = , mean ± sd days of symptoms = . ± . ), hrv -ve ari (n = , . ± . ), hrv +ve sibs (n = , . ± . ) and hrv -ve sibs (n = , . ± . ). of the and hrv +ve ari and sibs, % and % had hrvc. conclusions hrvc is as common in children who have hrv but do/do not require hospital treatment. detection of hrv is more likely when the nasal sample is collected soon after the appearance of cold symptoms. support nhmrc program grant. nomination nil. introduction upper airway dysfunction may make asthma more diffi cult to control and should be suspected in asthmatics refractory to prescribed medical therapy. aim a novel imaging technique, dynamic -slice computerized tomography (ct), was used to examine laryngeal behaviour in healthy and asthmatic individuals. method vocal cord movement was imaged using -slice ct larynx. healthy volunteers were studied to develop and validate an analysis algorithm for quantifi cation of normal vocal cord function. further studies were then conducted in patients with diffi cult-to-treat asthma. in eight severe asthmatics with abnormal vocal cord movement, asthma outcomes were measured after speech therapy. results vocal cord movement was quantifi ed over the breathing cycle by ct using the ratio of vocal cord diameter to tracheal diameter. normal limits were calculated, validated and applied to evaluate diffi cult-to-treat asthma. vocal cord movement was abnormal with excessive narrowing in of ( %) asthmatics and severe in nine ( %) patients (abnormal > % of inspiration or expiration time). after speech therapy in a small subgroup, asthma symptoms and morbidity improved. conclusion non-invasive ct larynx quantifi cation of vocal cord movement was achieved. this new approach has identifi ed frequent upper airway dysfunction in asthma with potential implications for disease control and treatment. aim to investigate the characteristics and mechanisms of chronic cough (cc) following acute respiratory illness from laboratory-confi rmed h n infl uenza. methods subjects who had current symptoms and had been tested for h n infl uenza by pcr assay participated in this study. twenty-one of those continued onto clinical testing. investigations to assess cough included symptom questionnaires, hypertonic saline challenge and cough monitoring. results of the participants, % tested positive for h n and % tested negative for h n . h n -infected participants were younger and predominantly female. the prevalence of post-h n cc was . %, and for non-h n infection, . %. objectively measured cough frequency was times greater; there was a -fold increase in cough refl ex sensitivity, and greater quality-of-life impairment in the participants with chronic post-infectious cough than the non-cough participants. conclusions cc was found to be relatively common, mild in severity and tending to resolution with time. the characteristics of post-h n cc were similar to other post-infectious cough and were associated with cough refl ex hypersensitivity. aim upper airway dysfunction may accompany acute severe asthma, but this has not been investigated. a novel imaging technique, dynamic -slice computerized tomography (ct), was used to examine laryngeal behaviour in acute asthma exacerbation. methods patients were studied in the emergency department or as acute inpatients following admission for an acute exacerbation of asthma. vocal cord movement was imaged by -slice ct larynx and compared to normal vocal cord movement in a healthy cohort. results vocal cord movement was abnormal with excessive narrowing during either inspiration, expiration or both in of cases ( . %) with acute severe asthma. imaging again revealed that laryngeal dysfunction characterized the movement abnormality, rather than isolated vocal cord dysfunction. radiation exposure was low and generally < milli-sievert. conclusion non-invasive ct larynx quantifi cation of vocal cord movement was effectively achieved in acute severe asthma. we identifi ed frequent upper airway dysfunction in acute severe asthma suggesting that treatment of upper airway obstruction (e.g. using bipap) may be merited during asthma exacerbation. aim to determine whether eicosanoids could alter the deposition of extracellular matrix (ecm) proteins and cytokine release from human airway cells. methods airway smooth muscle cells (asm), fi broblasts and epithelial cells were stimulated with leukotrienes b , c , d , e and the prostaglandins e , d , f α and the pgi analogue mre- . after hours, culture medium was collected and il- and il- production and cell deposited ecm proteins tenascin c, fi bronectin and perlecan were assessed by elisa. to determine whether eicosanoids infl uenced cell proliferation, manual counting of cells in the experiments were carried out before and after stimulation. results neither leukotrienes or prostanoids altered cell proliferation after days of stimulation (n > ). leukotrienes had no effect on ecm protein deposition or cytokine release from asm or fi broblasts (n > ). leukotrienes did not alter either parameters in epithelial cells except leukotriene d , which increased tenascin c deposition (n = , p < . ). prostanoids induced il- and il- and other various changes in asm and fi broblasts (n > , p < . ) (see below). introduction the function of asthmatic airway epithelium is disrupted facilitating immune and infl ammatory responses resulting in epithelial damage. human rhinovirus (hrv) causes asthma exacerbations in children; however, paucity exists on how it affects barrier function. this study assessed how hrv infection affects epithelial barrier function and integrity in healthy and asthmatic epithelium. methods adult balb/c mice were intranasally infected with hrv- b and followed for days. tight junction (tj) expression was assessed using immunohistochemistry (ihc) and western blot analysis. primary airway epithelial cells from healthy and asthmatic children were assessed for tj gene and protein expression by qpcr and ihc, respectively. results occludin and zonal occludin- (zo- ) expression was lost and sustained in mice infected with hrv- b however was not observed in shaminjected mice. asthmatic airway epithelial cells were found to exhibit elevated basal gene expression levels of tjs (zo- , occludin and plakophilin- (pkp- )) but markedly lower corresponding protein levels. conclusion hrv- b compromises barrier function in vivo through sustained loss of tj proteins. the marked decreased expression of tj proteins in paediatric asthmatic epithelium may contribute towards increased susceptibility to viral infections. disparity between gene and protein tj expression could indicate either post-transcriptional regulation or compensatory effects by other tj proteins and requires further study. supported by asthma foundation wa; nhmrc. confl ict of interest none. conclusion leukotrienes alone did not affect the ecm proteins and cytokines assessed in this study. prostanoids decreased ecm protein deposition whilst increasing cytokine release without affecting cell proliferation. this study shows that prostanoids may have a more pronounced role on direct ecm remodelling than leukotrienes in airway cells. supported by merck. background toll-like receptor (tlr) is an innate immune receptor involved in the initial detection of pathogen-associated molecular patterns. the effect of ageing and chronic obstructive pulmonary disease (copd) on tlr responses and the impact of these innate immune responses in copd pathogenesis remain unclear. hypothesis expression and activity of tlr on peripheral blood mononuclear cells (pbmcs) is increased with healthy ageing and further increased in copd. methods pbmcs from healthy controls < years and > years; and participants with copd (n = per group) were cultured with or without pam c ys k (tlr agonist). cells and supernatants were collected at hours and protein (cytometric bead array or fl ow cytometry) and gene (real time pcr) expression was examined. results tlr activation led to increased release of interleukin (il)- , , β, and tumor necrosis factor (tnf)-α. tlr gene expression was increased with stimulation; however, cell surface receptor levels were unchanged. there was no difference in the level of tlr between the groups. in older people, tlr activation resulted in less il- β and tnf-α release, but similar release of il- and il- . similar results were seen in copd. at baseline in copd, there was up-regulation of tnf-α gene expression compared to the older healthy group; however, the tlr cytokine response did not differ between the groups. conclusion healthy ageing is characterized by an impaired systemic proinfl ammatory cytokine response to tlr -mediated innate immune activation. this effect persists in copd and is selective in the cytokine pathways involved. these altered infl ammatory mechanisms may affect responses to infection and injury impacting disease pathogenesis and warrant further evaluation. aim to investigate whether the inhibition of matrix metalloproteinase- (mmp- ) by a non-selective mmp inhibitor (doxycycline) and the specifi c mmp- inhibitor i (olic acid) can regulate cellular migration of tsc -null mouse embryonic fi broblasts (mefs), which act as a model for lymphangioleiomyomatosis (lam) cells, as compared to wild-type mefs. methods wild-type (tsc -positive) and tsc -null mefs were treated with diluent, doxycycline ( . pg/ml- μg/ml) or olic acid ( . - μm) for hours. mmp- levels were assessed by zymography and elisa. cell migration for hours was measured using a transwell migration assay. results under basal conditions, mmp- release and cellular migration was . -fold and . -fold higher, respectively, in tsc -null mefs compared to tsc -positive mefs (mmp- release, tsc -null (n = ) and tsc -positive (n = ), p < . ; cell migration, tsc -null (n = ) and tsc -positive (n = ), p < . ). mmp- release was reduced in tsc -null mefs after -hour treatment with doxycycline ( and μg/ml, n = , p < . ) and with olic acid ( - μm, n = , p < . ). treatment with doxycycline ( pg/ml- μg/ml, n = , p < . ) or olic acid ( - μm, n = , p < . ) also signifi cantly reduced cell migration of tsc -null mefs. copd is a leading cause of death worldwide. treatments are limited and restricted to symptomatic care. there is an urgent need for new treatment options targeting the infl ammation. tissue damage in copd is thought to result from an inability of the normal repair processes with accumulation of apoptotic material and impaired clearance of this material by macrophages in the airways. lung infl ammation and macrophage function involves the bioactive sphingolipid sphingosine -phosphate (s p). multiple studies have showed the involvement of these components in infl ammation. methods we investigated lung tissue samples from patients (copd or non copd controls) undergoing curative lobectomy for lung cancer. we analysed the mrna expression profi le, the sphingosine-kinase (sphk) protein activity and the localization and expression of individual proteins. results we show in this study for the fi rst time a comprehensive expression profi le of all synthesizing enzymes, receptors and degrading enzymes in the human lung. correlations between receptor subtypes, degrading enzymes and between s p receptor subtype were detected. multivariance anova showed that in copd, the relative mrna expression of s p receptor subtype was reduced. conclusion the correlations between receptors and enzymes involved in the sphingosine kinase signalling system in the lung suggest common regulatory mechanisms. s pr is expressed on dendritic and nk cells which are reduced under conditions of copd. therefore, our fi ndings of reduced s pr in copd may provide a novel target for pharmacotherapy. lung cancer is responsible for more cancer-related deaths than colon, breast and prostate cancers combined. in patients with copd and/or lung cancer, we have shown a reduction in lung and airway macrophage function, evident by a reduced ability to phagocytose apoptotic airway epithelial cells and neutrophils. the potential for lung cancer cells to directly inhibit this function (a potential immune evasion mechanism) has not been investigated. background kinins have been implicated in airway lung diseases such as asthma and lung cancer by regulating infl ammation, cell proliferation and migration. the effect of kinins is mediated through the binding of two receptors, kinin b and b receptors (b r and b r). a novel b r splice variant (sv) resulting in a shorter ' untranslated region (utr) was identifi ed in cultured airway epithelial and fi broblasts as well as in lung carcinoma tissue and leukocytes. this study aims to characterize the functional role of the novel b r sv in mrna stability, translation effi ciency and receptor expression in cultured airway epithelial cells. methods stability of b r sv was determined by measuring b r mrna levels over time in h cells after actinomycin d treatment. translational effi ciency of wt and sv 'utr was determined by measuring luciferase activity in transfected h cells. expression of wt and sv transcripts through q-rtpcr were compared in cells treated with a b r-specifi c agonist dakd. cell-surface receptor expression post-agonist stimulation was quantifi ed using facs. results mrna stability studies indicated that b r sv was ≈ % less stable than the wt transcript in h cells suggesting a stabilizing element 'utr. translation effi ciency of sv was no different to wt b r. dakd stimulation increased both wt and sv transcripts early in the time course, although the peak expression of wt and sv differed at hours and hours, respectively. dakd stimulated cells showed two phases of receptor expression, ( ) decrease of cell surface receptor up to . hours post-stimulation; ( ) increase in cell surface b r after . hours. conclusion this study has identifi ed a novel regulatory mechanism of b r expression through the production of a sv that alters the 'utr. the translation effi ciency of b r is not affected, but the sv was less stable than the wt in h cells and may play a role in allowing quicker changes in transcription. agonist-induced up-regulation of transcripts in a time-dependent manner may be important in maintaining a chronic response during infl ammation. circulating lymphocytes are increasingly used as a surrogate cell type to refl ect changes in adrβ density elsewhere in the body, particularly the respiratory system. however, adrβ density is non-uniform among lymphocyte subsets and it is unclear if, and the degree to which, adrβ density varies between individuals. aim to assess the extent of variability in adrβ density on human peripheral blood mononuclear cells (pbmc) including lymphocytes and monocytes. method pbmc were isolated from blood of healthy subjects by density gradient centrifugation with ficoll-paque. cell surface and total adrβ of intact and permeabilized lymphocytes (cd +) and monocytes (cd +) were measured using anti-adrβ via facs. geometric mean fl uorescence (gmf) was used as the indices for adrβ density per cell. result surface adrβ -gmf increased by . -and . -folds over negative controls for lymphocytes and monocytes, respectively. magnitude of foldchange was not signifi cantly different between these cells (p = . ), but the distribution of gmf intensity between samples suggests greater variability in adrβ density in lymphocytes versus monocytes (p = . ). proportion of cells-stained adrβ -positive was signifi cantly higher in monocytes versus lymphocytes ( . ± . % vs. . ± . %, p = . ). total adrβ -gmf increased by . ± . and . ± . -folds for lymphocytes and monocytes, respectively (p > . ). proportion of adrβ -positively stained cells were similar between samples (lymphocytes %, monocytes %, p = . ), but greater variability was observed for lymphocytes (range - %) versus monocytes ( - %). conclusions despite similarities in surface and total adrβ density, lymphocytes display greater inter-subject variability compared with monocytes. this will have implication in experimental designs and interpretation of changes in adrβ density in studies using human pbmc as an alternative to primary cells from the organ of interest. confl ict of interest no. pge plays a protective role in asthma by inhibiting airway infl ammation. it is predominantly produced by epithelial cells in response to pro-infl ammatory stimuli and acts as an autocrine and paracrine mediator. on the contrary, il- β is a highly potent cytokine that induces many pro-infl ammatory effects in the human airway including activation of the human lung epithelium which promotes production of pro-infl ammatory cytokines and chemokines. airway epithelial cells express all four known pge (e prostanoid (ep) receptors, but mechanisms underlying the regulation of expression of ep receptors in human lung epithelial cells have remained elusive. therefore, we investigated whether pge , an endogenous protective mechanism of the airways, can modulate il- β infl uence on ep receptor expression in human epithelial cells. methods ep receptor mrna and protein expression was quantifi ed in -hbe cells at basal levels and following stimulation with il- β or pge alone, or simultaneously, using real time rt pcr and facs analysis, respectively. results pge up-regulates all four ep receptors at mrna level, while il- β up-regulates ep , ep and ep and does not infl uence expression of ep . at protein level, preliminary results show transient increase of ep receptors in the presence of pge , while il- β down-regulates this receptor. ep and ep are up-regulated following stimulation with both stimuli. importantly, antiinfl ammatory ep receptor is up-regulated only in the presence of pge . conclusion we show for the fi rst time that pge may infl uence expression of its own receptors and oppose the effect of il- β in human lung epithelial cells. this may in turn alter pge production and autocrine activation with potential implication on the function of epithelial cells, which is important in modulation of immune response in asthma and lung infl ammatory diseases. nomination nil. confl ict of interest no. the burden of obstructive lung disease (bold) study is an international study designed to measure the prevalence, risk factors and burden of copd. data collection using the bold protocol has been undertaken at eight sites with inclusion of urban, rural, coastal and inland regions of australia. methods a random sample of adults aged ≥ years was identifi ed. information on respiratory symptoms and diagnosed copd were collected by questionnaire. post-bronchodilator fev and fvc were used to defi ne gold stage. the (un-weighted) prevalence rates are presented by age groups and sex. results s timmins , , , , g king , , , , c salome , , , r schoeffel , , , c walsh , , the extent of emphysema could increase ventilation heterogeneity independently of its effects on airway narrowing. the aim of this study was to examine the relationship between emphysema extent on computed tomography scans (ct), and airway narrowing and ventilation distribution in copd. methods subjects with copd underwent ct scanning, spirometry, dlco and nitrogen washout by single and multiple breath techniques. closing capacity (cc/tlc%), slope of phase iii (Δphase iii ) and indices of ventilation distribution conductive (scond) and diffusion-dependent airways (sacin) were derived from washouts. helical ct scans were performed at tlc. emphysema extent was measured as low attenuation areas < − hu using osirix program, expressed as % of ct total lung volume. results subjects were of mean (range) age years ( - ), bmi . ( . - . ), fev of ( - %) %predicted and dlco of ( - ) %predicted. emphysema extent was . % ( . - . ). geometric mean (ci) Δphase iii was . ( . - . ), sacin was increased at . l − ( . - . ) and cc/tlc% was % ( - ). emphysema extent correlated with fev / fvc (r = − . , p = . ), dlco (r = − . , p < . ), bmi (r = . , p = . ), Δphase iii (r = . , p = . ), and sacin (r = . p = . ). in multiple regression analysis, emphysema extent was predicted by fev /fvc and Δphase iii (model r = . , p = . ). conclusions the extent of emphysema increases the heterogeneity of ventilation independently of any effects on overall airway narrowing. supported by australian lung foundation webster memorial award, crcaa. conclusions self-reported wheeze in the last months is very common in adults over years. in the younger age group ( - years), many people with wheeze did not have airfl ow obstruction or reversible spirometry at the time of test. aim to determine whether there is any association between change in fev among copd patients and ambient ultrafi ne particle number concentrations in melbourne. methods participants with mild to moderate copd were asked to measure their fev using a portable electronic spirometer (piko) two times a day (morning and evening) for consecutive days. the same procedure was repeated on average months later. ambient ultrafi ne (diameter < . μm) particle number concentrations were measured for the same period using an ultrafi ne condensation particle counter and micro-orifi ce uniform deposit impactor. results aim to examine the implementation of, and barriers and enablers to, six high-evidence recommendations for copd management, in copd hospital inpatients. method observational, mixed methods study in consecutive copd patients admitted to a tertiary hospital. demographic, disease and admission characteristics are recorded. implementation (or not) of smoking cessation, pulmonary rehabilitation, long-term oxygen use if hypoxaemic, medication use, vaccinations and plans for future exacerbations are determined from medical records and patient interviews. interviews with medical offi cers examine their perspectives on recommendation implementation. of pilot data in copd patients (mean (sd) age ( ) years, length of stay ( ) days), were current smokers and had severe copd ( moderate). highest levels of implementation were fl u vaccination (completed by gps, n = ), medication (but not spacer) use, and oxygen use if hypoxaemic (investigated and implemented in all suitable, n = ). pulmonary rehabilitation was discussed with half of the patients, but only severe patients with long length of stay accepted further rehabilitation. exacerbation plans were in place for patient, and newly initiated in patients. doctor interviews (n = ) confi rmed pulmonary rehabilitation was considered mostly for severely unwell patients, and use of exacerbation plans was inconsistent. conclusion pilot data suggest pulmonary rehabilitation is offered and accepted by a small subset of copd patients. findings from this pilot will inform planned larger observational studies, and in turn, experimental studies to improve copd care. high-and extreme high-risk interventions were found by panel ( - . % extreme and . - . % high-risk interventions) and patients' respiratory physicians ( % extreme and % high-risk interventions). additionally, clinical pharmacist involvement was associated with many benefi ts such as: improvement in medication compliance, high level of patient satisfaction and identifi cation of patients with issues in medication knowledge. conclusion clinical pharmacist interventions were estimated to prevent extreme and high risks that might happen due to drug-related problems. clinical pharmacy consultation was associated with positive impact on other important measured outcomes. aerobic exercise training in the form of supervised -minute walks ( mw) reduces exertional dyspnoea in patients with copd. mw goal ( mwg) distances, aiming for a training effect, are generated from a baseline submaximal test ( -minute walk ( mwd), where wg = . × mwd/ × . aim to compare mwg with actual initial mw achieved and to examine the predictors of mwg achievers (ga). methods retrospective review of patients, % male, age ± years (mean ± sd), fev ± %predicted, who completed pulmonary rehabilitation (pr). patients were assessed at baseline and post-completion of pr. initial mwg was calculated from the best of two mwd at initial assessment and ga were defi ned as patients who achieved their mwg at their fi rst visit to pr. results for the group, there was a statistically signifi cant but not clinically signifi cant difference between mwg and actual mw achieved ( ± m vs. ± m, p < . , paired t-test). the patients ( %) who achieved their mwg exceeded the goal by ± m, whereas the patients who did not achieve their mwg fell short by ± m. there was no signifi cant difference between ga and non-ga in age or lung function, but ga had a higher initial mwd, with fewer rests, lower dyspnoea score and lower hr at start and fi nish (p < . , unpaired t-test). ga were also more likely to have a clinically signifi cant response to pr, measured by mwd, compared with non-ga (mean change m vs. m, p < . , chi-square). conclusion mw goals as currently calculated either signifi cantly underestimate or overestimate actual mw achieved. it may be that in non-ga, the mwd is functioning as a true maximal test and these are a group of patients who are truly ventilatory-limited, rather than deconditioned. the receptor for advanced glycation end products (rage) is a key candidate for promoting a self-perpetuating cycle of infl ammation and thereby is a major contributor to numerous chronic disease states. the potential of rage to function as a switch converting a transient infl ammatory response such as one generated by cigarette smoke to sustained cellular dysfunction allows it to act as a mediator for ongoing infl ammation in chronic obstructive pulmonary disease (copd). although the molecular mechanisms regulating rage expression have not been fully elucidated, altered rage activity arises from polymorphisms within the rage gene and its promoter. three polymorphisms in the rage promoter (− t/a, − t/c and a bp deletion from − to − ) increase transcriptional activity and rage expression. the rage g s allele results in an increased ligand-binding affi nity and activation of the infl ammatory mediators with subsequent up-regulation of infl ammatory response. the aim of this pilot cross-sectional study was to investigate the relationship between three known rage polymorphisms (− t/a, bp deletion, g s) and copd and disease severity. methods genomic dna was isolated from peripheral blood lymphocytes. pcr and taqman assays were used to genotype the three rage polymorphisms in copd patients, healthy non-smokers and healthy smokers. fev was measured in all subjects. disease severity was defi ned using gold guidelines. results there was no statistically signifi cant association between bp deletion and copd (p = . ), − t > a and copd (p = . ), g s and copd (p = . ). conclusion no association was found between the − t > a, bp deletion and g s polymorphisms and copd, disease severity or fev introduction the receptor for advanced glycation end products (rage) mediates neutrophil traffi cking and is implicated in the pathogenesis of chronic airways disease. we determined whether changes in airway and systemic levels of soluble rage (which acts as a receptor decoy to limit rage activation) and rage ligands are related to neutrophilic infl ammation in asthma and copd. methods bronchial lavage (bl) fl uid from subjects with moderate-severe persistent asthma or copd, and healthy controls were analysed for neutrophils, total srage (cleaved and secreted), secreted srage (esrage) and the rage ligands hmgb and serum amyloid a (saa). systemic levels srage and esrage were also determined in asthmatic and copd subjects. aims increased numbers of neutrophils are found in the lungs of copd patients, which contribute to airway infl ammation. while cigarette smoke exposure is the major risk factor for copd, it is unclear how cigarette smoke modifi es neutrophil function and activity. this study aimed to assess the effect of cigarette smoke extract (cse) on neutrophils in an in vitro model. methods neutrophils were isolated from peripheral blood donated by volunteers using percoll density gradient centrifugation. neutrophils were seeded in well plates ( cells/well), exposed to different concentrations of cse ( %, %) and monitored at , and hours. at each time point, viability of neutrophils was measured by trypan blue exclusion and supernatant was collected for measurement of cxcl release by elisa (r&d systems conclusions in neutrophils exposed to cse, viability is maintained and cxcl release increases with increasing dose of cse. we conclude that cigarette smoke stimulates an infl ammatory response by neutrophils, which would contribute to the infl ammatory burden in the airways in copd. introduction factor viii (f ) and collagen iv (c ) antibodies are used for quantifying vessels in tissue sections. we compared these two antibodies for vessels staining in bronchial biopsies (bb) in copd. methods bb from healthy non-smokers (h-n) and copd subjects were stained for both antibodies. number, area and mean vascular size (mvs) (surface area/vessel number) of vessels in the lamina propria (lp) to the depth of μm were measured and compared between the two antibodies and are reported as median (range). results number of vessels was not signifi cantly different between the two methods of staining. in copd and h-n, vascular area (μm /μm of lp × ) stained with f was less than that with c ( . ( . - ) vs. ( - . ), p < . and . ( . - . ) vs. . ( . - . ), p < . introduction previous studies have shown that c-reactive protein levels increase at the onset of some copd exacerbations; however, there is limited data on the normal fl uctuation in crp levels in stable patients. aim to investigate within patient variation in crp levels to determine the magnitude of normal day-to-day fl uctuations in stable patients and the correlation with patients' perception of symptom severity. methods early morning crp levels were measured on days , and from patients from the melbourne copd cohort (gold category ii-iv) who identifi ed themselves as stable. patients recorded daily symptom scores including: borg dyspnoea scale at rest, severity of wheeze, cough, dyspnoea, change in sputum colour or volume, night-time waking and the presence of viral symptoms. crp levels were measured by the clinical pathology service and using a point-of care device. variation in crp levels in stable copd and correlation between change in crp levels and symptoms were analysed. aim patient-completed diaries monitoring changes in key symptoms in copd are often used to recognize acute exacerbations (ae) both to prompt additional treatment and monitor treatment effi cacy. we assessed diary compliance and the predictive value of major symptoms of aes which required hospital attendance. methods inpatients recruited during an ae of copd completed daily paper or web-based diaries for months, recording changes from their stable state for: breathlessness, cough, sputum, subjective 'wellness', physical activity and use of reliever ( -point scale, mid-pt = no change). the predictive value of current and lagged symptom scores was compared for each and between symptoms. diagnostic accuracy was assessed by area under the curve (auc) and at specifi c cut-points. in participants ( m, f) with mean age ± and mean fev % predicted ± , there were such aes involving patients. duration of diary keeping was shorter with lower education attainment (p = . ), but compliance did not vary for other demographic or clinical factors. daily compliance while diaries were being kept was %. excluding the current day, the best predictor was the distributed lag score over days, sputum changes giving the strongest signal; relative risk . ( % ci . to . ) with most of the signal in the days prior to the ae. little was gained by combining symptoms. the predictive value was moderate auc = . . conclusions compliance with symptom diaries in severe copd is surprisingly good. however, with only a weak signal for an impending ae requiring hospital attendance up to hours before and for lagged symptom scores over days before, with low positive predictive values, the utility of keeping daily symptom diaries for raising alerts for impending severe aes in copd is questionable. results seven studies with inpatient participants were identifi ed; published as abstracts for which data were not available did not contribute to meta-analyses. no study specifi ed diagnostic criteria for copd and only one specifi ed ae criteria. short course treatment varied between - days and longer duration - days; studies used oral prednisolone (dose mg, studies, tapered dose) and studies used intravenous scs treatment. mean ages of participants ranged from to years. primary outcomes: likelihood of treatment failure did not differ by duration of treatment (odds ratio . ; % ci . to . ) ( studies, n = ). fev did not differ signifi cantly when measured up to days (mean difference (md) − . l; % ci − . to . ) or after days (md − . l; % ci − . to . ) ( studies, n = ). secondary outcomes: limited data ( study) precluded meta-analysis for readmission or mortality. the likelihood of an adverse event ( studies, n = ) was not signifi cantly lower for shorter scs (or . ; % ci . to . ). conclusions we found no signifi cant differences between short (≤ days) and longer (> days) corticosteroid therapy for ae of copd. this has implications for clinical practice and may reduce adverse effects for patients, shorten hospital admissions and reduce costs, but more studies are needed to confi rm these fi ndings. aim to explore factors which infl uence the self-management of exacerbations in patients with copd. methods a pilot cross-sectional study was undertaken to assess patients' compliance with their action plan and their action taken prior to an admission. patients were interviewed during an admission to hospital for exacerbation of copd. the effect of pulmonary rehabilitation on patients' knowledge of copd was also assessed. results % of patients were provided with a written action plan, and % with a verbal action plan. in response to an exacerbation, more than % of the patients stated that they used their action plan. however, where action plans were not adequately utilized, patients delayed seeking medical attention and failed to initiate oral prednisolone and antibiotics during an exacerbation despite being prescribed an emergency supply of these medications. pulmonary rehabilitation had a positive outcome towards enhancing the patients' knowledge of copd. clinical pharmacists have limited involvement in terms of copd and smoking cessation education. conclusion the need to offer a thorough self-management program along with providing a more comprehensive written action plan will encourage patients to start early treatment and follow their action plans. encouraging collaboration between the hcp and patients encourages self-management through discussing and agreeing on goals of treatment and developing a personalized written action plan. context dyspnoea is a common symptom in copd and increases during exacerbations. when respiratory failure supervenes, and assisted ventilation is required, non-invasive ventilation (niv) is the treatment of choice. objective to determine if niv relieves dyspnoea in inpatients with acute respiratory failure due to exacerbations of copd. data sources english language randomized controlled trials (rcts) published prior to august were identifi ed using medline, embase, cinahl, psychinfo and pubmed. additional studies were identifi ed by reviewing the reference list of included studies. search terms included niv, nippv, nppv, bilevel cpap, bipap, artifi cial ventilation, copd and randomized controlled trial. study selection rcts comparing usual medical care (umc) to umc plus niv and measuring dyspnoea at relevant time points were included. abstracts for potentially relevant articles were extracted by one author. these were assessed by a second author to ensure inclusion criteria were met. articles were reviewed to determine if dyspnoea was measured and appropriate statistical analysis reported. the search yielded individual articles. four articles met the review criteria. three articles fi nd that niv relieved dyspnoea to a statistically signifi cant level and two suggested that the relief of dyspnoea is clinically signifi cant. discussion in spite of the common use of niv to relieve dyspnoea, little work has analysed effi cacy in terms of this patient-reported outcome. while our results may suggest niv relieves dyspnoea, reporting or methodological fl aws in several articles limit the strength of the conclusions that may be drawn. these limitations make the conclusion that niv relieves dyspnoea contentious. conclusion despite over two decades of studies investigating niv, the therapeutic impact on breathlessness is poorly described. understanding the impact of niv on patient-reported outcomes is of critical importance in clinical care. confl ict of interest none. introduction in mice, the most direct lung dosing method delivers the agents directly into the trachea. for our cystic fi brosis gene-therapy studies, we deliver fl uids -an airway pretreatment followed by a lentiviral vector -directly into the mouse trachea to target conducting airways. despite using standardized delivery techniques, we see substantial variability in the amount and location of gene transfer. aim the aim of this experiment was to use synchrotron x-ray imaging to track the dynamics of fl uid doses delivered into the live mouse trachea. methods four nembutal anaesthetized c bl/ mice were imaged on the bl b beamline at the spring- synchrotron. mice were intubated and ventilated at br/min with image captured per breath. after minute of baseline, a -μl sample of iodine-based contrast fl uid (a surrogate for our airway pretreatment or gene-vector) was delivered over seconds. following minutes of data collection, an additional μl bolus was delivered over . seconds. image capture continued for a further minutes. frame differencing was used to reveal fl uid motion. results substantial dose losses may occur upon delivery into mouse trachea via immediate retrograde fl uid motion. the speed of bolus delivery into lung may also infl uence the relative targeting of conducting airways and deep lung. introduction use of effi cient nebulizers can enhance the quality of life of cf patients by reducing the treatment time and improving drug delivery effi ciency. the aim of this study was to determine which commonly recommended nebulizer was optimal for delivery of the most commonly used therapies to cf. methods seventeen children with cf ( - years) were recruited. delivery of three commonly used cf therapies ( % hypertonic saline ( ml, . g/ ml), tobramycin ( ml, mg/ml) and pulmozyme ( . ml, mg/ml)) by two vibrating membrane nebulizers, the eflow rapid and the aeroneb go, and a jet nebulizer lc sprint junior with pariboy sx ( . l/min) were tested. for each drug-nebulizer combination (in random order), each child was asked to inhale through an inspiratory fi lter, and drug delivery to the fi lter was measured. pulmozyme was quantifi ed using an enzymatic activity assay, tobramycin was measured using hplc and hypertonic saline was measured using conductivity. total nebulization time was recorded. the results showed that there was no difference in the amount of drug delivered to patients when the nebulizers were compared for all three therapies (p > . ). however, the nebulization time for the eflow rapid was signifi cantly shorter than that for the aeroneb go and lc sprint junior. similarly, the nebulization time for aeroneb go was shorter than that for the lc sprint junior (p > . ) for all therapies). conclusion overall, there were no signifi cant differences between nebulizers in delivered dose for three forms of cf therapy, due to inter-patient variability. despite this, both vibrating membrane nebulizers had shorter nebulization times than the lc sprint junior, with the eflow rapid delivering drug in the shortest time. confl ict of interest nil. introduction as the life expectancy of patients with cystic fi brosis (cf) increases, treatment-related morbidity is increasingly recognized. totally implantable venous access devices (tivads) offer reliable long-term central venous access but are associated with recognized complications including venous thrombosis. superior vena cava syndrome (svcs) however has been rarely reported in this setting. we report a single cf centre's experience of svcs associated with tivads. methods retrospective review of episodes of svcs in patients with cf and a tivad attending the adult cf centre, prince charles hospital, queensland. results between february and december , fi ve episodes of svcs occurred in patients with tivads from a clinic population of patients. all of the affected patients were female, with moderately severe lung disease (mean fev predicted . %). no patients had a recognized thrombophilia. four tivads were inserted at a centre different to our own, three were on oestrogen-based contraception, and two suffered with dehydration at presentation. svcs treatment consisted of anticoagulation ( ), line removal ( ), angioplasty ( ), thrombolysis ( ) noninvasive bioluminescence imaging has allowed for rapid in vivo quantifi cation of long-lasting gene transfer in experimental animals. we are testing the longevity of a single nasal delivery of our lentiviral (lv) gene transfer system in mouse airways. methods normal (c bl/ ) and cystic fi brosis (cf) mice received a nasal bolus of lysophosphatidylcholine (lpc) or a control (pbs) pretreatment hour prior to delivery of a lv vector containing the reporter-gene luciferase (lv-luc). another control group received lpc hour prior to an empty vector (lv-mt). bioluminescence was measured at week, , , , , , , , and months post-lv dosing to assess gene transfer. results normal mice: mice that received lpc/lv-luc treatment had significantly greater gene transfer compared to the two control groups at all time points (p < . , rm anova). no luminescence was detected in mice treated with lpc/lv-mt. unexpectedly, luciferase activity was also detected in the lung. there was no difference in lung luminescence between the lpc and pbs pretreated mice that received lv-luc. cf mice: a statistically signifi cant increase in nasal luminescence persisted for up to months following lpc/ lv-luc (p < . , rm anova). similar to normal mice, there was no statistical difference in lung luminescence between mice that received lpc and pbs lv-luc. conclusions lentiviral luciferase gene expression was signifi cantly improved in mouse nasal airways using lpc pretreatment in both strains. however, the longevity of transduction was reduced in cf mice, which may, in part, be due to reduced animal numbers at the later time points tested. supported by nh&mrc. background the nintendo-wii® facilitates exercise-based programs that may be considered novel, fun and potentially motivating. objective exercise outcomes using the wii have yet to be reported in the cystic fi brosis (cf) adult population. aim to investigate nintendo-wii® exercise training compared with standard exercise in adult cf patients whilst hospitalized for treatment of a pulmonary exacerbation. methods a within-subjects, randomized cross-over study. adult cf participants received two -minute exercise treatment sessions within a -hour period, at least day apart, during the last days of hospitalization. wii exercise consisted interval training with games such as boxing, dancing and track exercises. standard exercise consisted of interval training on treadmill or cycle ergometer at - % of heart rate maximum. results participants completed the study (mean (sd) age ( ) years, % females), with a mean fev % of ( )%. during exercise, no difference was found between groups in average heart rate (p = . ), oxygen desaturation (p = . ), borg rate of perceived exertion (p = . ) or modifi ed borg for dyspnoea (p = . ). on vas ( - ), participants reported the wii program to be more enjoyable (p < . ) and less fatiguing (p = . ). participants rated both exercise sessions as equally effective (p = . ). conclusions this study suggests that a nintendo-wii® exercise session provides an equivalent cardiovascular demand to a standard exercise session in an inpatient adult cf population. greater enjoyment levels and lower fatigue levels reported during nintendo-wii® training may have a positive infl uence on adherence to exercise. further study into the long-term effects of nintendo-wii® training needs to be undertaken. confl ict of interest nil. introduction ion transport is important to maintain the airway epithelial surface, as shown by the disease cystic fi brosis (cf) which is characterized by decreased clsecretion and increased na + absorption. we have previously shown that the cf airway can develop clresponses when the surface is nominally calcium free (middleton et al. ajrccm ; : - . aim to determine the effects of citrate on the nasal potential difference (npd) with and without amiloride pretreatment, and to compare these effects with other clinically relevant calcium chelators and dicarboxylic acids. methods npd was measured using standard techniques (erj ; : ) in cf and non-cf subjects. the nasal pd response to citrate, oxalate, malate, succinate and fumarate (all mm) was compared with the calcium chelators edta and egta. results citrate decreased the basal npd by ∼ mv, but in the presence of amiloride, citrate increased the pd by ∼ mv. with amiloride/low clpretreatment, citrate increased npd by - mv, which suggests that citrate increased clsecretion. in contrast, the other dicarboxylic acids and calcium chelators exhibited little response. conclusion the combination of these responses suggests that citrate exerts complex effects on airway ion transport, most likely dual effects of decreased na + absorption and increased clsecretion. aim to assess the validity of the international physical activity questionnaire (ipaq) in cf adults by comparing energy expenditure measured by the ipaq versus the accelerometer. methods with ethics approval, suitable successive adult patients with cf attending the alfred cf outpatient clinic were recruited. all participants wore an accelerometer (actigraph gt m) around the waist for days of awake time, at the end of which, they completed the ipaq. criterion validity of the ipaq was assessed by comparing the ipaq weekly energy expenditure (ee) in kilocalories (kcal) with weekly ee (kcal) from the accelerometer using spearman correlations and bland-altman procedures. results thirty participants ( % females) completed the assessment: mean (sd); age = ( ) years, fev %predicted = ( ) the median (range) ee: ipaq = ( , ) kcal, gt m = ( , ) kcal. spearman correlations of fev %predicted with ee were gt m ee r = . , p < . ; ipaq ee r = . , p > . . correlation of the ipaq ee with accelerometer ee was moderate (r = . , p = . ). there was a trend towards higher ee measured by the ipaq than measured by the accelerometer (wilcoxon signed ranks test: z = − . , p = . ). conclusion the ipaq underestimates physical activity for patients with lower energy expenditure activities and overestimates for those with higher energy expenditure activities in adults with cf. the ipaq would be a useful screening tool for exercise prescription and monitoring of physical activity longitudinally, but more quantifi able methods for assessment such as the accelerometer should be used in research. confl ict of interest none. infectious endometritis associated with pseudomonas aeruginosa (pa) is an important equine disease resulting in reduced fertility and decreased foal drop. previous typing studies of equine pa report clonal heterogeneity, suggestive of sporadic acquisition, and small clusters of indistinguishable strains. aim we performed molecular typing of a large sample of genital pa isolates from horses in s-e qld. methods thoroughbred genital tract pa isolates submitted to uq vet diagnostic lab during - (screening or infection suspected) were studied. eric-pcr fi ngerprint analysis was performed. isolates producing indistinguishable fi ngerprints were allocated to the same eric-pcr type. mlst was performed on a subset of isolates. results overall, genital (clitoral or uterine) swabs from mares and urethral fossa swabs from stallions located on stud farms were processed. pa was identifi ed in genital cultures from of the ( . %) mares but from none of the stallions. six clusters involving ≥ mares were detected. cluster-a was observed amongst isolates collected from ( %) mares from studs and each year. cluster-b isolates were present in mares from studs during - . clusters c-to-f each contained isolates from mares from or studs. conclusions overall, % of mares harbouring pa had clonally related strains. however, we found no evidence of horizontal transmission between stallions. these data raise the possibility of transmission via environmental or other sources. alternatively, specifi c strains may have trophism for the reproductive tract of horses. the fi nding of a dominant strain amongst thoroughbred mares in a geographic region has interesting parallels with recent evidence of the spread of highly prevalent clonal strains in cystic fi brosis clinics. aim to investigate the prevalence and impact of incontinence in adult men with cystic fi brosis (cf) as compared with age-and sex matched control subjects. methods men with cf were recruited through outpatient clinics and control subjects through advertisements to complete standardized questionnaires relating to respiratory symptoms, bladder and bowel function, mood and physical activity levels. demographic data were collected from medical records for the cf group. results seventy-four men with cf participated (mean (sd) age . ( . ) years). forty-nine men volunteered as controls ( . ( ) years), and were well matched in terms of physical activity levels. / ( %) in the cf group and / ( %) in the control group had reported episodes of urine leakage. in the men with cf, there was no difference in lung function between men with episodes of leak and those with no history of leak (fev % predicted ( )% vs. ( )%, p = . ). anxiety levels were higher in men from both groups with episodes of leak compared to those with no history of leak (hospital anxiety and depression anxiety score . ( . ) vs. . ( . ), p < . ). depression scores were also higher in men with episodes of leak compared to those with no history of leak ( . ( . ) vs. . ( . ), p < . ). conclusions urinary incontinence in men with cf is not associated with disease severity, as measured by lung function. anxiety and depression levels were higher in men with leakage of urine. confl ict of interest no. aim to investigate the bone mineral status of children and adolescents with cf and to explore the relationship between bone mineral density (bmd) and anthropometric and clinical parameters including height, body mass index (bmi), lung function tests and vitamin d levels ( -hydroxyvitamin d) in the cf centre at starship children's hospital, new zealand. methods bmd of the lumbar spine was assessed by dual x-ray absortiometry between january and december . the results of subjects with cf ( males) with a mean age of . years (range - . years) were collected. anthropometric data (height, bmi), forced expiratory volume in second as percent predicted (%fev ) and vitamin levels were assessed and related to bmd. results bmd in our subjects was low in . % and very low in . % when adjusted for age, sex and height (difference in bmd g/cm in the lumbar spine l -l ). there was a strong positive relationship between the lumbar areal bmd (abmd) and bmi z scores (p < . ), abmd and % fev z scores (p < . ), and abmd z scores and vitamin d levels (p < . ). conclusions bmd was normal in the younger and well-nourished subjects with normal or mild reduction of fev . low bmd appeared to evolve during adolescence with decreasing bmi and reduction in lung function. this will lead to ongoing bone disease in early adulthood. it is a further indication to maintain optimal nutritional status and maximize lung health. malnutrition in cf is associated with poorer pulmonary function and is an independent risk factor of survival. aim to compare the nutritional status of the adults attending an adult cf centre in with . method retrospective audit of patients ( excluded, incomplete data) including demographics, nutritional status, pancreatic enzyme replacement therapy (pert) usage, glucose tolerance and dietetic review. results the mean age of the clinic population increased from . to . years. mean (sd) bmi increased from ( . ± . kg/m ) to ( . ± . ) (p = . ). in , % of the clinic population was taking pert with a mean dose of ± iu lipase/kg/day. the proportion of patients with abnormal glucose tolerance has increased from % to % (p = . ). oral supplement use has increased from % to %, yet enteral feeding remained stable ( % − , % − ). this occurred during period of increased annual dietetic review of the patients attending the clinic from % in to % in (p = . ). discussion over a -year period, an improvement in mean bmi refl ects improvement in nutritional status. prevalence of abnormal glucose tolerance has increased; this is likely due to commencing a screening program ( ). use of oral supplements has increased and is higher than identifi ed in the recent daa survey of nutrition practices of cf dietitians ( %). annual review by the cf dietitian has increased despite a twofold increase in the cf population may be attributable to a stable and experienced workforce. current service provision of . a abbott , e cheung , l morgan aim to characterize the microbial colonization of a group of stable adults with non-cf bronchiectasis using an extended culture protocol. methods sputum was collected over an -month period from clinically stable patients. standard semi-quantitative bacterial culture was extended to days with the addition of fungal and mycobacterial culture as routine. results specimens of spontaneously expectorated sputum were collected from patients; mean age years ( - years); mean (sd) fev / fvc ratio % ( %); / never smokers; / on inhaled or oral corticosteroids. the bacteria identifi ed were p. aeruginosa ( % of specimens), h. infl uenzae ( %), h. parainfl uenzae ( %), acinetobacter baumanii ( %), enterobacteriaceae ( %). commensals only were identifi ed in % of specimens. fungi included candida species ( %), aspergillus fumigatus ( %) and penicillium species ( %). non-tuberculous mycobacteria (ntmb) were grown in % of specimens: m. gordonae ( %), m. intracellulare ( %) and m. lentifl avum ( %). the ntm identifi ed were all considered non-pathogenic. only the mycobacteria were identifi ed after day . conclusion microorganisms with potential pathogenicity are frequently identifi ed in adult patients with non-cystic fi brosis bronchiectasis who are not experiencing an acute exacerbation. all these organisms were identifi ed using a standard short culture protocol. the extended regimen, which was costly, did not identify any unusual or unexpected pathogens. it was rare for patients to be colonized with fungi. this study suggests there is limited value in requesting extended culture for bacterial pathogens, including looking for fungi or nmtb in this stable patient group as this adds little to the empiric antibiotic choice for infective exacerbations. confl ict of interest none. s stelzer-braid , , h alsubie , a neilsen , h johal , a steller , er tovey , k mckay , p van asperen , wd rawlinson , introduction respiratory infections are of fundamental importance in determining the morbidity and mortality associated with cystic fi brosis (cf) as such infections can lead to progressive and fatal obstructive lung disease. using polymerase chain reaction (pcr) to detect such infections has advantages over previous studies that used relatively insensitive traditional detection methods and could have underestimated viral prevalence. methods viral and bacterial multiplex pcrs were developed for detection of respiratory pathogens important for children with cf. nasal brush samples were collected from cf patients who were symptomatic or asymptomatic for acute respiratory illness (n = ). sputum and exhaled bioaerosols via a novel mask sampler were collected from a subset (n = ). results as expected, almost all ( %) sputum samples were positive for bacteria. detection of bacteria in the upper respiratory tract was lower ( . %). data from nasal samples indicated strong association of viral pathogen presence, particularly rhinovirus, with exacerbation of disease. results also showed good evidence for rhinovirus infection in the lower respiratory tract. the novel mask sampler is promising as a non-invasive sampling tool. conclusions our results demonstrate the importance of pathogens in exacerbations. early detection and understanding the development of bacterial and viral infections in cf patients is important in clinical decision-making as more and better antiviral and antibiotic agents become available. aim to determine the factors affecting microbiological yield from bronchoalveolar lavage (bal) in patients with suspected pulmonary infection and haematological malignancy or following stem cell transplantation at a tertiary bone marrow transplant centre. methods a retrospective -month audit of patients with pulmonary infi ltrates or febrile neutropenia with haematological malignancy or post-stem cell transplant who underwent bal for microbiological diagnosis. data were obtained on microbiological yield, radiographic appearances, current antimicrobial therapy, the presence and duration of neutropenia and complication rate. of the bal procedures performed, a clinically signifi cant microbiological result was obtained in % of cases ( / ). of these positive results, % ( / ) were exclusively viral pathogens, % ( / ) were fungal, % ( / ) were bacterial and polymicrobial infection was observed in % ( / ) of cases. a high proportion of patients had commenced anti-microbial treatment empirically, with % ( / ) receiving broad spectrum antibacterial treatment and % ( / ) receiving treatment doses of antifungal agents prior to bronchoscopy. in % ( / ), the results of the bal changed the patients therapy. the presence and duration of neutropenia or radiological appearances were not reliable discriminators of specifi c infective aetiologies. complication rates were low and included fevers in % ( / ), hypoxia % ( / ), small volume haemoptysis in % ( / ), atrial fi brillation in % ( / ) and pneumothorax in % ( / ). conclusion whilst bal remains a safe and important tool in establishing a microbiological diagnosis in immunosuppressed patients with pulmonary infi ltrates, a clinically signifi cant yield and changes to patient treatment occur in the minority of cases. clinicians should have a high degree of suspicion of viral infective aetiology when treating this population of patients. aim to examine the outcomes and complications of intercostal catheter (icc) treatment of pneumothoraces (primary (pp) and secondary (sp)) and effusions (malignant (me) and parapneumonic (pe)). methods retrospective review of all iccs in admitted patients in a respiratory unit over months. data collected included type of pneumothorax or effusion, icc type, insertion details, complications (major and minor) and outcome (success defi ned as resolution of pneumothorax or effusion with single tube insertion). results patients required icc treatment. forty-six iccs were used in patients with pneumothorax: pp ; sp ; iatrogenic ; hydropneumothorax . complication rate was % ( % major) and was signifi cantly less in pp ( %) compared with sp ( %), p < . , chi-square. success rate for pneumothorax icc drainage was % (signifi cantly higher for pp ( %) compared with sp ( %), p < . ). fifty-eight iccs were used in patients with pleural effusions: me , pe , other . complication rate was % ( % major) and was signifi cantly higher in me ( %) compared with pe ( %), p < . . success rate for effusion icc drainage was % (signifi cantly less in me ( %) compared with pe ( %), p < . ). small bore iccs (gauge < fr) were used for % of pneumothoraces and % of effusions. tube size did not signifi cantly infl uence complication or success rate for either pneumothoraces or effusions. conclusions compared with pp, icc treatment of sp was less successful and more likely to be associated with complications. similarly, compared with pe, intervention for me with icc was less successful and had a higher complication rate. we conclude that icc intervention is most successful for pp and pe, and speculate that sp and me should have early surgical intervention. introduction spontaneous pneumothorax is a common condition. current management guidelines recommend large pneumothoraces are managed by primary intercostal catheter insertion. we report a single centre's experience in the management of large spontaneous pneumothorax. methods retrospective audit of cases of spontaneous pneumothoraces managed at the prince charles hospital between january and december . patient demographics, co-morbidities, presenting symptoms, examination fi ndings, radiology, management and complications were reviewed. results forty-two patients ( male, female) experienced episodes of spontaneous pneumothorax. chest pain and dyspnoea were the most commonly reported symptoms ( ) %. there were forty-two ( %) episodes of large pneumothorax (≥ % of hemithorax). management of large pneumothoraces consisted of: observation, ( ) seldinger icc ( ) and large bore icc ( ). complications occurred in three patients with seldinger icc ( vasovagal, hydro-pneumothorax) compared to none with large bore icc. outcomes were similar for patients managed by observation compared to icc insertion. all recurrent cases ( %) were referred for consideration of surgical pleurodesis. conclusion patients with large pneumothorax managed by observation recovered similarly to those treated with icc, suggesting a higher threshold for icc insertion should be considered in the future. grant support nil. aim a pilot study of an instrument of pleural ultrasound training in thoracic physicians after a pleural ultrasound course. the instrument was tested for inter-observer agreement and also its ability to be used in a patient compared to a dedicated manikin. methods all chest physicians ( ) were novices in ultrasound and underwent a dedicated -day training course in pleural ultrasound at the australian institute of ultrasound. they were assessed months later by radiologists and one senior ultrasonographer using a specially designed pleural ultrasound training assessment tool (usgt-sat) on both a subject with pleural effusion and a dedicated ultrasound manikin. the mean scores, out of a maximum of , obtained by the each of the participants for the manikin were . , . , . and . , respectively, while the scores for the patient was . , . , . and . , respectively. the mean scores of the participants as a group for manikin were ± . and for the patient as . ± . . there was general agreement between the examiners with mean combined participant scores of . , . and . in the manikin, respectively, and mean score of . , . and . in the patient. conclusions this pilot study shows ranges of scores for design of future validation studies of the usgt-sat. test performance by the chest physicians after a short course in pleural ultrasound was generally good and results for the use of the manikin as an alternative to patients in pleural ultrasound training are encouraging. further studies with larger sample size are required. supported by nil. nomination nil. confl ict of interest no. since the fi rst commercial availability in , fl exible bronchoscopy has evolved from a simple 'look see' procedure to a more complex multifaceted one. today, fl exible bronchoscopy is a tool used for diagnostic procedures, surveillance, delivery of therapy and clinical trials. increasingly, it involves utilizing expensive purpose built equipment in complex diagnostic procedures. this evolution requires a specifi c knowledge base and skill set to safely perform the procedure and care for the equipment. this now mandates additional training by nursing and medical staff to develop and maintain the required skills. medical staff now rely on their nurses to assist in the full range of procedures. thus, the nurses must keep abreast of modern trends and techniques. the modern bronchoscopy suites team is an integrated one, with specifi c roles, defi ned to each member. the procedures performed will refl ect local needs and expertise. just as bronchoscopy has evolved into the speciality of interventional pulmonology, so must bronchoscopy suite nursing be accepted as a specialized area of nursing with a credentialed 'special interest group' to promote, educate and develop the subject as more therapeutic and diagnostic procedures evolve. this will allow nurses involved in bronchoscopy to be respected, recognized and accepted for their unique knowledge and abilities. confl ict of interest nil. background transthoracic pneumostomy (tp) is a novel treatment for patients with severe emphysema that aims to defl ate the lung and improve function. aim to assess the effect of unilateral tp on the volume of each lung and mechanical properties of the lungs. methods subjects were recruited for a multicentre trial of tp (see actrn ). in parallel with the main protocol, we measured ( ) in the six subjects recruited, compared to plethysmography, lung volume was overestimated by cxr (mean difference + . %, range − . to + . ) and underestimated but more closely correlated by ct (mean difference − . %, range − . to − . ). based on ct, the volume of the treated lung decreased in all patients after tp (mean − . %, range − . to − . ) whilst that of the untreated lung did not change (mean − . %, range − . to + . ). in patients with available data, tp reduced dynamic hyperinfl ation during exercise (mean − ml, − . % of ic, range + . % to − . %). lung mechanics were performed in patients. low lung elastic recoil prior to tp and an increase in elastic recoil after tp were associated with greater reductions in lung volume and greater improvements in exercise tolerance. conclusions supine chest ct provided reasonably accurate estimates of plethysmographic lung volume. unilateral tp defl ated the lung and there was no evidence of signifi cant compensatory hyperinfl ation of the contralateral lung. tp also reduced dynamic hyperinfl ation. measurement of lung elastic recoil may help select patients who are likely to benefi t from tp. support and confl ict of interest nil. methods we performed a retrospective chart review of all adult patients who had an icc over a -month period within a tertiary hospital respiratory service. we noted patient demographics, details surrounding chest drain insertion including image guidance and subsequent inpatient events. results over a -month period, there were small-bore icc insertions, of which were image-guided. mean patient age was years, males comprised / . forty drains were inserted for pneumothoraces, for malignant effusions, for parapneumonic effusions, for transudates and for undiagnosed exudative effusions. mean duration of drainage was . days. there were no life-threatening complications. three of the chest drains fell out and became blocked. six pneumothoraces were noted, all following insertion without direct image guidance; none required further intervention. local infection occurred in patient. insertion details were not documented in patients. conclusion insertion of small-bore iccs via the seldinger technique appears to be a safe method of draining pneumothoraces and pleural effusions. image guidance may reduce complication rate of this procedure. documentation of drain insertions could be improved. confl ict of interest nil. rationale pleural effusions are frequently encountered in clinical practice, and often require aspiration for diagnostic and/or therapeutic purposes. use of radiological guidance varies, despite current guidelines recommending routine use of ultrasound. furthermore, concerns exist regarding the downskilling of thoracic medicine trainees due to the increased use of interventional radiology. as a precursor to developing a procedural pleural ultrasound service, we performed a retrospective case review of our current practice. methods patients who had pleural fl uid sent to pathology between january and december were identifi ed on an existing database. patient records were reviewed and details regarding the drainage procedure and outcomes were recorded. information on patient location, method of procedure and performing clinician were also collected. results to date, pleural fl uid aspirations in patients have been identifi ed. overall, % of aspirations were carried out on the ward and % in the radiology department. two procedures occurred in the endoscopy suite on outpatients, and one in the emergency department. fifty percent of procedures were performed using an intravenous cannula for drainage and % utilized a pigtail catheter. all procedures occurring in the radiology department were performed under ultrasound guidance by a radiologist or radiology registrar. of the remaining procedures, % were performed by medical registrars and % were performed with ultrasound marking. six complications occurred following procedures: pneumothoraces, vasovagal and tube blockage. there were signifi cantly more pneumothoraces in patients who did not have an ultrasound marking ( of without marking, of with marking, p = . ). none of the complications required further intervention. conclusion these preliminary data suggest ultrasound marking signifi cantly reduces pneumothorax incidence, supporting the establishment of a pleural ultrasound service. this is likely to have the added benefi t of improved training for thoracic medicine trainees. aim to investigate differences between semi-recumbent and supine posture in terms of cough rate, degree of oxygen desaturation, oxygen supplementation, increase in pulse rate and sedative use during the initial phase of bronchoscopy. methods consecutive patients (n = ) undergoing diagnostic bronchoscopy at an endoscopy unit were recruited for this observational cohort study. the posture was determined by the bronchoscopist's usual practice. patient age, gender, % predicted fev and fvc, indication, pulse and oxygen saturation were recorded. the initial phase was defi ned as the time from bronchoscopy insertion to visualization plus lignocaine instillation of both distal main bronchi. cough rate, peak pulse, nadir oxygen saturation (spo ), range of oxygen supplementation and sedation use during the initial phase were recorded. a post-procedure questionnaire was administered to the patient and the attending nurse. results patients had bronchoscopy in the semi-recumbent posture and in the supine posture. three of bronchoscopists performed in both postures. there were no signifi cant differences in age, gender, smoking status and spirometry between the two groups. the semi-recumbent postures resulted in signifi cantly less cough rate (mean (sd) . ( . ) vs. . ( . ) coughs/min, p = . ) and less fentanyl use ( ( ) vs. ( ) mcg, p = . ) in the initial phase. there were no signifi cant differences in the nadir spo , fall in spo , oxygen supplementation or increase in pulse rate between the two groups. nurse perception of patient discomfort was lower in the semirecumbent position ( ( ) vs. ( ) mm on mm visual analogue scale, p = . ), and there was a trend towards less patient-perceived cough during the procedure in the semi-recumbent group ( ( ) introduction pulmonary infi ltrates in immunocompromised patients with haematological malignancy have a diverse aetiology and are a major source of morbidity. a specifi c diagnosis and targeted therapy may optimize outcomes and reduce the cost of treatment. the diagnostic value of fi breoptic bronchoscopy (fob) and the infl uence of timing of the procedure are unclear. aim to determine the yield of fob, its impact on antibiotic therapy and the infl uence of early vs late timing in this patient population. methods we conducted a retrospective review of immunosuppressed patients with underlying haematological malignancy and new pulmonary infi ltrates who underwent fob over a -month period. the outcomes of early (eb, ≤ days from initial respiratory consultation) and late (lb, ≥ days) fob were compared using fisher's exact test. results thirty-eight fobs, including bronchial or transbronchial biopsies, were performed in patients (males ). there were patients who received eb and who received lb. a specifi c diagnosis was obtained from procedures ( %), including infections ( in eb vs. in lb, p = . ) and non-infective diagnoses ( eb vs. lb, p = . ) based on histology. fob fi ndings from procedures ( %) ( eb vs. lb, p = . ) resulted in modifi cation of antibiotic therapy. there were no procedure-related severe complications. conclusions fob is a useful diagnostic procedure which infl uences diagnostic and therapeutic decisions in this patient group. although early procedures tended to be more likely to change antibiotic therapy than late procedures, the difference was not signifi cant. confl ict of interest none. capsule endoscopy is increasingly performed in gastroenterology to investigate possible small intestinal bleeding. the capsule endoscope is swallowed and then takes photographs every seconds for hours during its transit through the gastrointestinal tract. the images are downloaded by a radio link and the capsule is then passed normally and disposed of. in the present case, the capsule endoscope was inhaled and lodged in the bronchus intermedius. this was only recognized when the images from the capsule download were examined. removal of the capsule was effected with a fi breoptic bronchoscope using an ercp balloon and roth basket. this is believed the only capsule bronchoscopy so far reported. capsule endoscopes are large ( mm × mm diameter) and smooth. this case report shows the images from the capsule endoscope and describes the methods necessary to remove this unusual foreign body from the lung. support nil. background bronchoscopy with endobronchial biopsy (eb) is now an integral component of the research evaluation of airway diseases. there are no published safety data for eb in adult non-cf bronchiectasis. methods a subgroup of subjects enrolled in the bronchiectasis and low dose erythromycin study (bless) a randomized controlled trial of long-term prophylactic erythromycin (anzctrn ) underwent bronchoscopy with bronchoalveolar lavage (bal) and eb performed by a single operator. results ninety-nine bronchoscopies were performed (bal alone in ) in subjects. of procedures with eb, ( . %) were associated with very signifi cant bleeding (> ml either at time of eb or several days post-procedure) and a further ( . %) with immediate moderate bleeding ( - ml). one subject had a history of prior signifi cant haemoptysis. in the four subjects with very signifi cant bleeding, immediate bleeding of > ml occurred in subjects, ml in one subject and ml in one. immediate bleeding was controlled uneventfully. three of the subjects subsequently developed signifi cant haemoptysis (> ml) to days post-bronchoscopy without intervening haemoptysis, with one subject developing massive haemoptysis (> ml) on day post-bronchoscopy. further research ebs were ceased. in one of the subjects with 'delayed rebleeding', repeat bronchoscopy confi rmed the biopsied lobe as the bleeding site. haemoptysis settled in all subjects within hours with simple conservative measures. conclusions in contrast to the experience in asthma and copd, research eb in adults with non-cf bronchiectasis is associated with a signifi cant risk of bleeding, of potentially life-threatening magnitude in . % of cases. of particular concern was the observation of sudden onset delayed rebleeding developing up to days post-eb in spite of early local control. histopathological evaluation will clarify the potential contributions of airway wall vascularity and infl ammation to these events. malignant mesothelioma (mm) is an aggressive cancer which is often associated with exposure to asbestos and sv . this disease has a high latency period and a low survival rate. therefore, new strategies for therapeutic intervention must be developed. recent studies have shown that developmental pathways including the hedgehog (hh) pathway are associated with various types of cancers. the aberrant activation of key hedgehog pathway proteins has been shown to contribute to cancer progression. however, the role of this pathway in mm has yet to be explored. we hypothesize that aberrant activation of the hh pathway is a contributing factor for the development of mm. the mrna expression of hh pathway genes; sonic hedgehog (shh), patched - (ptch- ), smoothened (smo) and gli- were examined in mm cell lines and tumour tissues by rt-pcr and qrt-pcr. hh pathway proteins and mrna expression and distribution were then observed in the tumours by immunochistochemistry and in situ hybridization. we used real-time superarrays to examine the change in expression of a panel of key hh pathway genes by activating and inhibiting the pathway. we showed that the key hh pathway genes are expressed in both the cell lines and tissue samples. upon stimulation with the ligand shh, there was an increase in expression of indian hedgehog (ihh) and shh in most of the mouse and human cell lines that we looked at. interestingly, for the transcription factor gli- , there was a significant decrease in both mouse and human cell lines. inhibiting this pathway increased the expression of ptch in the mouse and human cell lines. the expression and up-regulation of key hh pathway components in mm at baseline and following stimulation suggests a role for the pathway in mm. methods incident cases were obtained from the australian and wa mesothelioma and cancer registries and death registries. exposure was calculated using measures of dustiness in the industry and the town for the period of employment or residence of each case. latency (time from fi rst exposure to diagnosis) by sex, age, smoking status, exposure variables and worker or resident status was estimated. multivariate linear regression modelling examined the determinants of latency. results the mean latency periods of . (sd = . ) years for lc and . (sd = . ) years for mm have increased linearly. increased duration of exposure was associated with reduced latency for mm after adjustment for age at fi rst exposure and age at diagnosis but not signifi cantly for lc. age at diagnosis was strongly associated with latency length for both lc and mm (p < . ). smoking, sex, cumulative exposure (log f/ml-year) and status at wittenoom were not related to latency. latency for lc with increasing age at fi rst exposure declined faster than for mm. conclusions age at diagnosis is associated with reduced shorter latency of mm and lc. duration of exposure is associated with shorter latency of mm. supported by nhmrc australia. confl ict of interest no. aim to assess overall survival of patients following resection for stage nsclc at a centre that has substantially greater resection rates than the nsw average. methods a retrospective audit of those patients who underwent lung resection for stage nsclc at nepean hospital between january and february . results patients ( m: f), mean age (range - ) underwent resection. there were pneumonectomies, bilobectomies and segmentectomies, one involving chest wall resection. the remaining procedures were lobectomies. there was one perioperative death from respiratory failure. actuarial overall survival at months was %, at months, % and at years %. survival was not infl uenced by histology or age. conclusion in our institution, we have an agreed aggressive approach to resection of stage nsclc and our resection rate is %. this pro-surgical policy is associated with good perioperative and long-term overall survival. confl ict of interest no. introduction malignant pleural effusions (mpes) are common, although their management varies widely. providing ambulatory care to minimize hospitalization is a key goal for patients with mpes. indwelling pleural catheters (ipcs) are a new treatment strategy that allows outpatient fl uid drainage. we hypothesized that mpe patients managed with ipcs require fewer hospital admissions. methods a prospective, multicentre, non-randomized study involving all three major respiratory centres in western australia. patients diagnosed to have mpes were prospectively followed, and admissions were recorded. in the absence of accepted guidelines for ipc use, the choice of treatments (thoracentesis, ipc, pleurodesis) was decided by clinicians in-charge. all complications were recorded. bacterial cultures of pleural fl uid were performed monthly for patients with ipcs. hm gallagher , ee duhig , ia yang , rv bowman , be clark , hm marshall , km fong aim to determine the concordance of histological subtyping of nsclc in diagnostic samples to the gold-standard lung resection specimens. methods we have so far evaluated consecutive subjects who underwent curative surgery for primary nsclc at the prince charles hospital between the years and . many of these had workup at other institutions. one hundred forty-seven had queensland health electronic record of positive preoperative diagnostic sampling. we correlated the fi nal nsclc who histological subtype with the subtypes diagnosed by samples prior to surgery including sputum, fi beroptic bronchoscopy (fob) and trans-thoracic needle aspiration (ttna). the resection subtype was set as the reference standard, and concordance was compared. results of the cases of resected nsclc, had malignancy on diagnostic sampling pre-resection, as shown in the results patients were included: median age years (range - ); % male; % living in major cities versus % in regional areas; % rightsided mpm; % epithelial subtype. median time from asbestos exposure to diagnosis was years (range - ). median time from fi rst symptoms or investigations to diagnosis was weeks (range - ). all patients had at least one chest x-ray and ct scan and % had pet scan. a variety of procedures led to the diagnosis: % thoracoscopy, % thoracotomy, % radiology-guided, % chest wall biopsy and % medical pleuroscopy, with % having had cytology alone. median number of diagnostic immunohistochemical stains used was (range - ), with calretinin ( %) the most commonly used mesothelial marker and carcinoembryonic antigen (cea; %) the most common carcinoma marker. median os for the cohort was . months ( % ci: . - . ), with no statistical difference in os between major city and regional patients ( vs. . months, respectively, p = . ). conclusions mpm appeared to affect mainly the elderly, and thoracoscopy was the most common diagnostic procedure. os did not differ between australian major city and regional patients and was comparable to the largest phase iii trial in mpm. aw musk , , p aboagye-scarfo , a reid , a miller, s ruwanpura, l mcleod, p bardin, n watkins, bj jenkins rationale lung cancer is the leading cause of cancer death worldwide. it is well established that cigarette smoking is linked to emphysema and lung cancer, and smokers with emphysema are at an increased risk of developing lung cancer. notably, recent epidemiological studies have indicated that emphysema can predispose to lung cancer irrespective of pack-year smoking history. although infl ammation has been proposed as a common mechanism linking these two diametrically opposed diseases, the conceptual inter-relationship between infl ammation, emphysema and lung cancer has been poorly investigated because existing experimentally induced and genetically modifi ed animal models for lung cancer occur in the absence of emphysema. method we have utilized a newly identifi ed mouse model (gp f/f ) of spontaneous lung infl ammation and emphysema in two well-established lung cancer models. the gp f/f mouse is characterized by deregulated cytokine signalling via gp , the critical co-receptor for the interleukin (il)- cytokine family, leading to hyper-activation of stat , a potent pro-infl ammatory and oncogenic latent transcription factor. in separate studies, we exposed gp f/f mice to a cigarette-derived carcinogen (nnk), and crossed them with the genetically susceptible kras(g d) strain of mice. results in both nnk-and kras(g d)-induced lung cancer models, the lungs of gp f/f mice were highly predisposed to hyperplasia and tumour formation. increased levels of cellular proliferation were observed in hyperplastic and tumour lesions, as well as surrounding areas, of these mice. these observations were verifi ed at the molecular level by gene expression profi ling of tumour-bearing lung tissue. conclusions these studies provide unique insights into the importance of interactions between the gp signalling axis and factors that predispose to lung tumourigenesis in emphysema. support nhmrc. aim to assess the preparedness of hospitals with respect to protecting health-care workers (hcws) during a pandemic. methods a self-administered questionnaire was performed between november and january , and a scoring system was developed to provide a quantifi able measure of preparedness. results a total of hospitals in nsw, australia, were approached -six regional hospitals (rhs) and six tertiary referral centres (trcs). the study was extended to assess three hospitals in england, allowing a limited comparison between the hospitals in australia that had faced the initial wave of the h n ('swine fl u') pandemic and the hospitals in the uk that had more time to prepare for the outbreak. response rates were % from the trcs, % from the rhs and % from the english hospitals. the overall preparedness scores were relatively high, with a median total score (adjusted) of . out of . the demographic that scored the highest total was tertiary referral centres in sydney. all english hospitals scored below the median. however, the range of scores across hospitals was quite narrow ( . - . adjusted). scores were generally high for the areas of preparedness, infection control, education and training. scores for vaccination were more variable. the category that consistently demonstrated the lowest scores was that of psychosocial welfare and assistance, despite this found in previous research to be an integral part of that which hcws have identifi ed as important. conclusions given their integral role in pandemic response, protecting hcws must be a priority as part of any pandemic preparedness plan. this goes beyond protection from infection, extending into aspects of physical and psychological wellbeing. identifying these issues and addressing them is the key to maximizing staff support and morale, and minimizing staff absenteeism at such a crucial time. aim to describe the relationship of respiratory and refl ux symptoms within the general population and relate this to the possible confounding factors of body mass index (bmi) and obstructive sleep apnoea (osa). methods data from a cross-sectional health survey, performed in bussleton, west australia in - , were used to examine the relative effects of bmi and osa on the relationship between respiratory and refl ux symptoms. questionnaire data included information on asthma, cough, wheeze, dyspnoea and gord symptoms. gord symptoms were categorized as never, monthly or less often and weekly or more often. bmi, risk of osa defi ned according to the berlin questionnaire, spirometry and airway hyperresponsiveness to methacholine were also recorded. logistic regression models obtained odds ratios for the associations between each gord symptoms, various respiratory symptoms, bmi and osa. results average age was years and recent wheeze was reported in % and cough and phlegm in %. twelve percent were current smokers. ahr was present in % and osa in %. gord symptoms occured in % and frequent symptoms (weekly or more often) were present in - %. there were strong positive associations between gord symptoms and cough/phlegm, breathlessness, chest tightness and wheeze in the last months. odds ratios increased with increasing frequency of refl ux p ≤ . . there was no effect of obesity or osa on the relationship between respiratory and gord. conclusion cough and phlegm, breathlessness, chest tightness and wheeze (ever or recent) are all strongly associated with symptoms of gord. this relationship is amplifi ed with increasing frequency of gord symptoms indicating a dose-response relationship between refl ux and respiratory symptoms. obesity and osa do not affect the association between gord and respiratory symptoms. introduction diesel exhaust particles (dep) make up the bulk of particulate matter in urban areas. high ambient levels of particulate matter are associated with increased hospitalization due to respiratory disease. we aimed to determine if exposure to dep exacerbates responses to acute viral infection. methods adult female balb/c mice were inoculated with μg dep or control . days after infection with . plaque forming units (pfu) of infl uenza a/mem (or control). six hours after dep inoculation, lung volume (tgv) and lung mechanics were measured by plethysmography and the forced oscillation technique, respectively. bronchoalveolar lavage fl uid was collected to assess cellular infl ammation and cytokine levels. results viral titre was signifi cantly higher in infl uenza-infected mice exposed to dep compared to those exposed to infl uenza alone (p = . ). both dep (p = . ) and infl uenza infection (p < . ) alone signifi cantly increased cellular infl ammation; however, there was no difference between mice exposed to both dep and infl uenza compared to those exposed to infl uenza alone (p = . ). a similar pattern was found in levels of cytokines in the bronchoalveolar lavage (tnf-α, mcp- , il- , ifn-γ). specifi c airway resistance, specifi c tissue damping, specifi c tissue elastance and hysteresivity were signifi cantly increased in infl uenza infected mice (p < . in all cases). none of these parameters were infl uenced by dep exposure alone (p > . in all cases) and there was no additive effect of dep on lung function (p > . in all cases) in infl uenza-infected mice. conclusions dep increases viral titre but is not suffi cient to physiologically exacerbate pre-existing respiratory disease caused by infl uenza infection in mice. supported by nhmrc. confl ict of interest no. introduction lack of treatments for post-transplant obliterative bronchiolitis (ob) is mainly due to the poor understanding of its pathogenesis and lack of small airway models. epithelial-mesenchymal transition (emt) may play a central role and could be crucial to developing treatment drugs. we hypothesize that emt induction may be prevented by pharmacologically available compounds. methods primary cultures of small and large airway epithelial cells (saec and laec) were established and emt induced by adding tgfβ ( ng/ml) (n = ). azithromycin ( - μm), mycophenolate ( . - mg/l) and rad ( . - ng/l) were then added and expression of epithelial (zo- , ck- ) and mesenchymal markers (eda-fn, vim) measured via western blot as well as mmp and activity via zymography. results signifi cantly lower increase in mesenchymal markers and lower decrease in epithelial markers, compared to controls was noted for azithromycin and mycophenolate indicating suppression of emt. mmp and activity increase was also signifi cantly suppressed. azithromycin suppressed emt to a greater extent compared to mycophenolate, but was equally effective in both small and large airway epithelia. rad appeared to have no effect. conclusions azithromycin and mycophenolate are both effective in preventing emt and thus have potential for the clinical treatment of ob. supported by abn foundation. confl ict of interest none. journal compilation © asian pacifi c society of respirology tp- g hodge , , s hodge , , c-l liew , , t-cell pro-infl ammatory cytokines are associated with acute lung transplant rejection. we have previously shown compartmentalization of production of these cytokines in bronchial intraepithelial t cells (iet) obtained by bronchial brushings from stable lung transplant patients. during acute rejection episodes, no signifi cant differences in iet cytokines were observed between stable and rejecting patients due to broad cytokine variability between patient groups. to overcome this limitation, we hypothesized that there would be increased graft pro-infl ammatory iet cytokines compared with native lung or trachea during acute rejection. methods cell cultures from stable patients, patients with evidence of acute rejection and bos and healthy controls were stimulated and intracellular cytokines determined using multiparameter fl ow cytometry. results there was a signifi cant increase in graft iet-cell ifnγ and tnfα in the lungs of patients with acute rejection compared with iet cells obtained from the native lung or trachea, but no changes were noted between other patient groups. there was a signifi cant correlation between increased graft iet-cell tnfα compared with trachea and lungs and acute rejection grade. conclusions differential expression of pro-infl ammatory cytokines by iet cells from graft, trachea or native lung distinguishes severity of acute rejection. improved monitoring response using this assay or therapeutic targeting of these pro-infl ammatory cytokines may reduce acute lung transplant rejection. supported by nhmrc. aim to determine the prevalence of reduced carbon monoxide transfer factor (dlco ≤ % predicted) in subjects undergoing pulmonary function testing (pfts) and to determine whether a cause has been identifi ed. methods a clinical audit of all subjects undergoing pfts at royal melbourne hospital from august to august who have a dlco ≤ % in the setting of normal spirometry. medical records and investigations including transthoracic echocardiogram (tte), high-resolution commuted tomography (hrct), ventilation/perfusion (v/q) scans were reviewed to determine whether a cause for the reduced dlco was established. where a cause was not clear, subjects were invited to participate in a telephone interview to evaluate symptoms and to undergo repeat pfts. subjects with a persistently reduced dlco were invited to undergo further investigation with tte, hrct and v/q scan. preliminary results pft results from subjects were reviewed. subjects with fev /fvc < , fev < % predicted and fvc < % predicted were excluded. three hundred seventy subjects ( %) had an isolated reduction in dlco. / ( %) of these subjects underwent tte with / ( %) demonstrating an elevated right ventricular systolic pressure (rvsp). in all cases where there was an elevated rvsp an identifi able cause was found. / ( %) of these subjects subsequently identifi ed as having pulmonary arterial hypertension (pah) and commenced appropriate therapy and / ( %) identifi ed as having pah where treatment was not commenced. there were / ( %) of subjects who appeared not to have undergone a tte. further evaluation of medical records of subjects who had not undergone tte and those with normal tte is continuing. review of subjects hrct, v/q scans and right heart catheterizations is currently proceeding. conclusions preliminary results suggest that a signifi cant proportion of subjects with isolated reduction of dlco on pfts do not undergo tte which is an important investigation in determining the cause for the reduced dlco. when a tte is performed and demonstrates an elevated rvsp, a cause for the elevated rvsp is identifi ed. sponsor actelion pharmaceuticals australia pty ltd. g hodge , , s hodge , , c-l liew , , , pn reynolds , , m holmes , , background t-cell pro-infl ammatory mediators are associated with acute lung transplant rejection. we have previously shown that bos was associated with lack of immunosuppression of t-cell pro-infl ammatory cytokines and increased t-cell granzyme b in peripheral blood. recently, we also showed that nkt-like cells are a major source of pro-infl ammatory cytokines and granzymes in the blood of stable lung transplant patients. we hypothesized that bos may be associated with lack of immunosuppression of these proinfl ammatory mediators in blood nk and nkt-like cells. method granzyme/perforin profi les from stable patients, patients with evidence of bos and healthy controls were determined and blood cultures stimulated and intracellular cytokines determined using multiparameter fl ow cytometry. results there was a signifi cant increase in the percentage of nk cells expressing granzymes and perforin in bos patients compared with stable patients and controls. there was an increase in the percentage of t, nk and nkt-like cells producing ifnγ and tnfα in bos compared with stable patients. there was a signifi cant correlation between increased nk ifnγ and tnfα and fev . conclusions bos is associated with increased peripheral blood nkt-like and nk cell granzymes, perforin and th pro-infl ammatory cytokines. therapeutic targeting of these pro-infl ammatory mediators and monitoring response using this assay may reduce bos. supported by nhmrc. confl ict of interest nil. rationale pulmonary embolism (pe) is the leading cause of maternal mortality in the developed world. consequently accurate diagnosis of pe is critical. this must be tempered by the potential radiation risk of investigations to the mother and foetus. we performed a retrospective case review to determine the incidence of pe in pregnant patients investigated for this condition. demographic information, the diagnostic algorithm utilized and the diagnostic yield of investigations were obtained. method pregnant women who underwent ventilation perfusion (vq) scanning or computed tomography pulmonary angiogram (ctpa) at our institution between january and january were identifi ed by an internal database audit. in addition to demographic data, information about the diagnostic pathway and fi nal diagnosis were collected. in cases where pe was not diagnosed, the medical records were reviewed for any subsequent events up until the date of delivery. results during the fi ve-year period, vq scans and ctpas were performed on pregnant women. the average gestation at investigation was weeks. only one patient had a previous history of venous thrombo-embolism. % underwent doppler ultrasound of the lower limbs prior to vq or ctpa. overall the incidence of pe was %, diagnosed by vq scan. otherwise the vq scans were normal in %, low probability in % and non-diagnostic in % cases. ctpa was non-diagnostic in % of cases. all other ctpa studies demonstrated no emboli. almost % of scans were done after hours ( % vq and % ctpa). no patients without pe were felt to have had the pe missed up to the time of delivery. conclusions the overall incidence of pe in patients being investigated was extremely low at %. during this study period slightly more vq studies were performed than ctpas, with each test having similar diagnostic rates. only % of patients had undergone venous doppler prior to undergoing radiationexposing investigations. nomination nil. introduction anti-ro- antibodies have been associated with idiopathic interstitial pneumonia (iip) in one small series (n = ). we hypothesize that ro- antibodies, just like myositis antibodies, can serve as a marker of undifferentiated connective tissue disease (ctd) with interstitial pneumonia as the primary phenotypic manifestation. the aim of this study was to examine the characteristics of patients with ro- and iip. methods retrospective study identifying patients with iip and ro- positivity, but negative for ctd and/or myositis antibodies, presenting between june and june . data relating to demographics, diagnosis, pulmonary function tests, length of follow-up and outcome were obtained. all hrct images were reviewed by an independent expert radiologist (dm). results / ro- positive subjects fulfi lled criteria ( male, median age ( - ), european, never smoked). / had ro- titers above and in the intermediate ( - ) range. three patients had raynauds phenomenon; there were no other ctd features. / patients had hrct diagnosis of nsip and / organizing pneumonia; / had extensive fi brosis. mean (sd) % predicted baseline fvc ( ), dlco ( ). median length of follow-up was months. all patients were treated and were considered overall stable at last follow-up, one had declined and one died of respiratory failure. conclusion this study confi rms an association between ro- positivity and interstitial pneumonia in the absence of defi ned connective tissue disease, suggesting an autoimmune basis for the interstitial lung disease in this group of patients. a larger cohort is required to determine the true signifi cance of this observation. background community acquired respiratory viral (carv) infections are believed to contribute to morbidity and mortality after lung transplantation, but previous studies have not conclusively established the evidence base in this area. patients and methods a prospective cohort study was performed at a single centre from august to march (n = lung transplant recipients). carv infection (human metapneumovirus (hmpv), respiratory syncytial virus (rsv), infl uenza a (flu a), infl uenza b (flu b), adenovirus and parainfl uenza virus (piv)) was confi rmed using polymerase chain reaction (pcr) of upper (nasopharangeal swab) and/or lower (bronchoalveolar lavage) respiratory tract secretions. carv infection and bos were included as segmented time-dependent covariates in a cox proportional hazards model with death as the outcome variable. results patients ( % of the total cohort) had a total of separate carv episodes: piv, hmpv, rsv, flu a, flu b, and adenovirus. infection with either rsv or hmpv was associated with an increased risk of death (p < . hr . , % confi dence interval, . - . ), and the effect persisted after multivariate analysis. bos was also a risk factor for acquiring hmpv or rsv infection (p = . or . , % confi dence interval, . - . ). conclusions infections with hmpv and rsv, but not other carvs, are associated with an increased likelihood of death. the presence of bos is a risk factor for symptomatic infection with hmpv and rsv. ns harun , k sanders , a stuart , cl steinfort department of respiratory medicine, barwon health, vic., australia, and department of clinical and biomedical sciences, barwon health, vic., australia aims nebulized colistin is used to treat recurrent exacerbations of bronchiectasis due to pseudomonas aeruginosa, a major pathogen regarded as diffi cult to eradicate. this case-control study aimed to establish if long-term colistin use could clear p. aeruginosa from the sputum of adults with non-cystic fi brosis bronchiectasis, and if so, whether colistin could be ceased in these patients. secondary outcomes included effects of colistin on quality of life (qol), symptom control, admission rates, lung function and tolerability. methods ( ) sputum was collected in bronchiectasis patients with p. aeruginosa. clearance rates in those on colistin were compared with a control group not on colistin. ( ) colistin patients cleared of p. aeruginosa ceased treatment. sputum was re-cultured at day and to detect recurrence. ( ) a questionnaire assessing qol, symptom control, and admission rates was performed on patients. outcomes were compared before and after colistin use. long-term colistin side-effects and lung function were also assessed. results ( ) % (n = / ) of colistin patients cleared p. aeruginosa from sputum compared with % (n = / ) in the controls (p = . ). ( ) % (n = / ) of patients ceasing colistin remained free of p. aeruginosa at day . ( ) there was no difference in frequency of breathlessness, sputum production or qol scores between the groups (p > . ). the colistin group had lower fvc ( . vs. . l, p = . ) and higher admission rates ( % vs. %, p = . ). on colistin, % of patients reported reduction in sputum frequency, breathlessness and improvement in qol. fifty percent reported decreased admission rates. there were no colistin side effects. conclusions clearance of p. aeruginosa in sputum is possible. clearance rates were similar in those with more severe bronchiectasis treated with colistin compared with stable patients not on colistin, and may suggest suppression of p. aeruginosa by colistin in this severe group. there are benefi ts of colistin on qol, symptom control and admission rates. continued sputum clearance after colistin cessation is achievable in some patients. nebulized colistin use is well tolerated. nomination janet elder travel award. confl ict of interest no. however, use of such agents is suboptimal in hospital patients. this study aims to determine whether a dedicated multidisciplinary education and reinforcement program improves the use of appropriate vte prophylaxis. methods prior to the education programme, we audited a bed general thoracic medical ward including patients with general medical conditions, lung cancer, chronic obstructive pulmonary disease, lung transplant and cystic fibrosis. our multidisciplinary research team developed and implemented an education program over months, using posters, leafl ets and oral presentations to increase awareness and promote adherence to vte prophylaxis guidelines for health care staff involved in direct patient management. following completion of the program, we reaudited the same bed ward. results prior to the education program, a total of patients (mean age ± ) were identifi ed as appropriate for vte prophylaxis. of these ( %) were on appropriate vte prophylaxis. the post education audit showed out of ( %) patients were on appropriate vte prophylaxis. (p = . ). conclusion an effective multi-faceted educational program can improve delivery of appropriate vte prophylaxis, leading to improved outcomes in hospitalized patients. supported by sanofi aventis. confl ict of interest nil. the anti-rheumatic anti-infl ammatory biological agents in clinical use are abatacept, anakinra, adalimumab, etanercept, infl iximab and rituximab. a variety of pulmonary side-effects have recently been reported for these agents and the purpose of this review is to compile the various reported pulmonary toxicities and their prevalence methods we performed a search of databases ovid medline® and embase of the english literature up to august using the mesh terms of abatacept, anakinra, rituximab, adalimumab, etanercept, infl iximab and respiratory tract disease with limits to include only human studies or case reports. in addition case reports of respiratory adverse effects reported to the australian drug reaction advisory committee (adrac) were obtained in order to identify the most common pulmonary reactions reported with each individual agent. results using the search criteria defi ned above and articles were identifi ed in the ovid medline and embase database respectively. the majority of adrac reports were associated with rituximab (n = ) and infliximab (n = ), followed by adalimumab (n = ) and etanercept (n = ). various pulmonary side-effects including interstitial lung disease associated with anti-infl ammatory agents were identifi ed. discussion from the articles reviewed, details about the duration between onset of treatment and incidence of pulmonary side effects, diagnosis, treatment options and outcome of patients were extracted and are presented here. conclusion this comprehensive systematic review hopes to improve the awareness about the serious and potentially life-threatening pulmonary sideeffects of this group of agents. confl ict of interest no. sj simpson , pd sly , p franklin , e lombardi , c calogero , m palumbo , gl hall , introduction the forced oscillation technique (fot) is effort independent and thus ideal for young children. the area under the reactance curve (ax) has been proposed to amplify clinically relevant signal by taking advantage of any shape change in the reactance (xrs) curve below the resonant frequency. this study aimed to develop reference values for resistance (rrs), xrs and ax in a large healthy population of children, and determine if ax conferred any additional clinical benefi t when examining disease in children born preterm. methods impedance spectra were obtained in healthy children ( male), aged less than years and with height less than cm using a commercial device (i m, chess medical, belgium). ax was calculated in of these children between hz and the resonant frequency. backwards stepwise linear regressions identifi ed the best predictors of ax, and xrs and rrs at hz (xrs , rrs ), and z scores were generated. z scores were calculated for children born preterm, of which received a neonatal diagnosis of bronchopulmonary dysplasia (bpd). chi squared tests examined the difference in proportion of children born preterm (with and without bpd) with abnormal z scores for each fot variable. results all fot variables were predicted by height (p < . ) and sex. mean (sd) z scores for preterm children with and without bpd for rrs ( . ( . ); . ( . )), xrs ( . ( . ); . ( . )) and ax ( . ( . ); . ( . )) were all signifi cantly different (p < . ) from the healthy population. the number of children born preterm with abnormal z scores was not significantly different when comparing ax, rrs and xrs . conclusions while ax is able to detect respiratory disease in preterm children with and without bpd, it is no more sensitive than xrs or rrs. supported by pmh foundation, nhmrc, asthma foundation wa, carivit, ngo 'solidarietà e servizio' viterbo. confl ict of interest no. introduction survivors of preterm birth born with bronchopulmonary dysplasia (bpd) in the pre-surfactant era of neonatal care (classical bpd) have a reduced pulmonary gas transfer capacity. there is, however, little data to describe gas transfer in preterm infants with bpd in the post-surfactant era (new bpd). objective assess gas transfer using carbon monoxide diffusing capacity (dl co ) and its components, pulmonary capillary blood volume (vc) and pulmonary membrane diffusion (d m ), in contemporary survivors of preterm birth. method gas transfer was assessed using single-breath dl co in children aged to years and born < weeks gestation with bpd (pb, n = ) and without bpd (pt, n = ), and in term born controls (tc, n = ). dl co z scores were calculated. d m and vc were determined in pb, pt and tc children. the mean (sd) dl co z score for the pb group was − . ( . ) differing signifi cantly from (p = . ) while the pt and tc groups ( . ( . ) and − . ( . ), respectively) did not (p > . ). d m was lower in the pb group than the pt and tc groups, with no difference between pt and tc groups. differences in d m were not signifi cant after adjusting for lung size. there were no differences in vc between groups. conclusion gas transfer is reduced in survivors of preterm birth with new bpd. the tendency for reduced d m and not vc in children with new bpd suggests that impaired gas transfer may be a result of alterations in the alveolar membrane rather than pulmonary vascular function. background bronchiectasis is common in indigenous populations such as alaska natives, australian aboriginal, and new zealand maori and pacifi ca. as part of an international collaborative interventional study, we sought the participation of maori and pacifi ca families -groups diffi cult to engage in research in the past. aim to engage, enrol and retain children from maori and pacifi ca families from auckland in a -year research study. methods a randomized controlled trial to determine whether azithromycin is superior to placebo in reducing exacerbations seeking to enrol children aged months to years with bronchiectasis. the enrolment procedure was modifi ed to a process deemed more appropriate to these cultures: ( ) request to defer the decision of enrolment until the process had been completed. ( ) a minimum of meetings; initial invitation, discussion in the home with the extended family, invitation to the extended family to participate in the day of enrolment. ( ) appointment of a 'whanau worker' (family worker) to sit with the family and empower them to get all the information they seek prior to enrolment. results of families approached, ( %) children (median age . years, range . - . years) enrolled with % samoan, % tongan, % maori and % mixed maori/pacifi ca heritage. after -year retention was ( %) with exiting the study after month with new non-pulmonary disease, and exiting after year, moving outside study area. conclusions these are high enrolment and retention fi gures reported in this population. we believe that following a prolonged procedure for enrolment, involving the extended family and appointing a worker to sit 'alongside' the family will improve their understanding of a research project and allow them to feel more comfortable about participating. aim bronchiolitis is the most common reason for hospital admission for infants globally ( ) . the use of macrolides for treating bronchiolitis in nonaffl uent settings remains controversial but potentially benefi cial. in our region readmission with lower respiratory illness in young children (particularly indigenous children) remains high. this rct aims to determine if a single dose of azithromycin reduces the morbidity of young children with bronchiolitis. methods double blinded rct. young children ≤ months admitted to royal darwin hospital (rdh) diagnosed with bronchiolitis are eligible. children are given a single dose ( mg/kg) of either azithromycin/placebo. primary outcome is length of stay for respiratory disease. secondary outcomes are duration of oxygen use and readmission for respiratory illness in -month period. respiratory viral infections often lead to exacerbations of chronic respiratory diseases such as asthma and copd though there is no similar data in noncystic fi brosis (cf) bronchiectasis. the objectives of our study were to ( ) determine the point prevalence and identify viruses associated with exacerbations and ( ) evaluate clinical and investigational differences between viral infection positive and negative exacerbations in children with non-cf bronchiectasis. methods a cohort of children (median age years; boys) with non-cf bronchiectasis was prospectively followed for child-months. polymerase chain reaction for respiratory viruses was performed on nasopharyngeal aspirates collected during paediatric pulmonologist defi ned exacerbations. data on clinical, parent cough-specifi c quality of life (pc-qol), systemic markers (crp, il , procalcitonin, amyloid-a, fi brinogen) and lung function parameters were also collected. results respiratory viruses were detected during ( %) exacerbations: picornavirus in episodes [human-rhinovirus (hrv) in , enterovirus in ]; human bocavirus in ; adenovirus, human meta-pneumovirus, infl uenza a, respiratory syncytial virus, parainfl uenza and in two each; coronavirus and parainfl uenza and in one each. viral co-detections occurred in ( %) exacerbations. among genotyped hrv's, more hrv-a's (n = ) were identifi ed than hrv-c's (n = ). children with proven viral infections were more likely to have fever (or . , % ci . - . ), wheeze and/or crackles (or . , % ci . - . ) and raised crp (or . , % ci . - . ) when compared with virus negative exacerbations. there were no other statistically signifi cant differences. conclusions respiratory viruses are commonly found during pulmonary exacerbations in children with non-cf bronchiectasis. hrv-a is the most frequently detected virus. time sequenced cohort studies during stable state, exacerbations and recovery periods are needed to determine the importance of viral infections and their possible interaction with bacteria. supported by anz trustees scholarship. confl ict of interest none. nominations none. to date children enrolled, % rsv+ve. median age . months. fifty percent have had at least one co-morbidity. readmission rate = %. conclusion co-morbidities are high in this population. antibiotics have the potential to help reduce the impact of additional respiratory burden. foundation. introduction foreign body inhalation is a relatively common presentation in young children, especially less than years of age. early recognition remains a critical factor in the treatment of foreign body inhalation in children. inhaled foreign bodies in children are most often organic material, with seeds and peanuts being the most common items. on review of the literature, there are very few case reports of inhaled metal screws. we report two unusual cases of inhaled metal screws that presented to our service. case presentation both cases presented to our emergency department with wheeze, respiratory distress and fever. foreign body inhalation was not considered as a cause for their symptoms until the object was identifi ed on chest x-ray. both foreign bodies were removed successfully but one child required invasive ventilation in our intensive care unit post removal. both children made a full recovery. interestingly, both metal screws came from fl at pack furniture purchased from a well known international home products store. conclusion foreign body inhalation must always be considered as a cause of respiratory distress in a child. with the increase in the number of fl at pack furniture in australian home's, we believe parents must be warned of the potential danger of loose metal screws to young children. supported by none. cough in children is a common symptom. data on causes of chronic cough in young children have previously been published by our units. however, differences in underlying diagnosis by age at presentation have not been assessed. we present the 'time to cessation' of cough in our multicentre rct using a standardized management algorithm in newly referred children with chronic cough (> weeks) from australian centres. methods parents completed validated cough diary and cough specifi c qol (pc-qol) at recruitment and at cessation of cough. the diagnosis made by the treating physician was based on tsanz position statement. results the median (range) age of the children recruited was . years ( . - . ); ( %) were boys. median (iqr) pc-qol post treatment of . ( . , . ) improved signifi cantly (p = . ) from . ( . , . ) at enrolment. the median (iqr) duration of cough at recruitment was weeks ( . , . ) and 'time to cessation' of cough after application of the management algorithm was weeks ( . , . ). there was no signifi cant difference (p = . ) in median (iqr) 'time to cessation' of cough among the three age cohorts: < years (n = , . %) was . weeks ( . , . ); - years (n = , . %) was weeks ( . , . ); and > years (n = , . %) was weeks ( . , . ). there was also no signifi cant difference in the fi nal primary diagnosis among the three age cohorts (p = . ). the most common diagnoses were protracted bacterial bronchitis (n = , %), asthma/reactive airways disease (n = , . %), tracheobronchomalacia (n = , . %) and bronchiectasis (n = , . %). children ( . %) had more than one diagnosis. conclusions the aetiology and 'time to cessation' of chronic cough in children managed in accordance to a standardized pathway were similar among the three age groups. it is likely that our previous fi ndings in very young children are also applicable to older children. supported by nhmrc grant number . confl ict of interest none. aim to determine the role of fl exible bronchoscopy with bronchial alveolar lavage (bal) in the management of patients with febrile neutropenia. methods a retrospective analysis was made of the number of patients admitted with febrile neutropenia at a single institution who underwent bronchoscopy plus bal from years to . computer database plus patient case notes were reviewed to establish clinical symptoms and signs, radiological fi ndings, antimicrobial treatment and mean duration to bronchoscopy following admission. results a total of episodes of febrile neutropenia were recorded years to . seven patients ( males and females) were referred for bronchoscopy plus bal. the mean age was . years (age range - years) and all had been diagnosed with acute lymphoblastic leukemia. all patients had at least cough as a clinical symptom along with radiological fi ndings. all patients had been on broad spectrum antibiotics at the time of bronchoscopy. the mean duration from admission to time of bronchoscopy was hours ( days) with a standard deviation of hours. of the seven patients one patient yielded a positive result on bal. this did not result in a change in management as the patient improved clinically before the result of the bal was confi rmed. conclusion in this retrospective case series the diagnostic yield of fl exible bronchoscopy plus bal in children with febrile neutropenia was low. prospective studies plus early timing towards bronchoscopy and bal should be conducted to further defi ne its role in the management of febrile neutropenic patients. confl ict of interest nil. methods prospective cohort study involving monthly follow-up with caregivers. two years post enrolment, children undergo clinical and lung function assessment (fot). presence of bronchiectasis is determined by physician review and radiological confi rmation (when indicated). the frequency of pbb episodes is recorded over the study period. of children recruited to the cohort study to date, % ( / ) were male. the median age at recruitment was months (iqr , ). % of children had recurrent pbb. of the children who have had -year clinical follow-up, were able to perform fot and % ( / ) showed abnormalities (reactance above normal range.) % ( / ) with pbb have had subsequent physician diagnosis of bronchiectasis or csld. conclusion the burden of cough in children with pbb years after diagnosis remains high. ongoing clinical follow-up of this cohort of children with pbb should provide further insight into the likelihood of progression from pbb to csld and bronchiectasis. support financial markets foundation for children (for project), allen & hanburys and qcmri (for dw), nhmrc (for ju and ac). introduction national streptococcus pneumoniae (sp) serotype surveillance reports only culture positive cases from sterile sites but the yield from culture is low. polymerase chain reaction (pcr) is more sensitive in detecting sp in culture negative samples. aim to determine whether enhanced molecular surveillance in childhood empyema provides additional sp serotype information compared to national surveillance methods. methods pleural fl uid from children with empyema underwent culture and pcr to identify sp-targeting autolysin (lyta) and multiplex pcr to identify sp serotypes. national surveillance data were obtained from the national notifiable diseases surveillance system (nndss) for the same time period and age groups. results empyema: children, male, median age . (range . - . ) were recruited from april for months. sp was cultured in / ( . %) in blood and / ( . %) in pleural fl uid. sp was identifi ed by pcr in / ( . %). serotypes: , n = ( . %); , n = ( . %); a, n = ( . %); f a, n = ( . %); v/ a, n = ( . %); f/ a, n = ( . %); non-typeable, n = ( . %). one subject had serotypes and in a serotype could not be established. nndss: sp culture positive cases were reported. serotypes: , n = ( . %); , n = ( . %); a, n = ( . %); f a, n = ( . %); v/ a, n = ( . %); f/ a, n = ( . %); non-typeable, n = ( . %). other serotypes were reported in sp positive cases. signifi cant differences between empyema and nsdss data were identifi ed for serotypes (p < . ) and (p < . ). conclusions the proportion of serotypes and were signifi cantly higher in empyema fl uid using pcr. this disease model provides additional serotype information to national surveillance data. this has important implications in monitoring replacement serotypes following the introduction of new vaccines. funded by glaxosmithkline, belgium. h giddings , l seccombe , p rogers , a corbett , e veitch recent theories on the pathophysiology of parkinson's disease (pd) emphasize early brainstem involvement. furthermore various respiratory function abnormalities have been reported without consistent pattern. we sought to study the effects of idiopathic pd on respiratory function and ventilatory response to hypercapnoea and hypoxia. methods patients with a diagnosis of pd but no known respiratory disease were recruited. subjects underwent lung function testing including respiratory muscle strength, ventilatory response to hypercapnoea (with central respiratory drive (p )) and a hypoxic simulation (fio % cough is the most common symptom presenting to doctors. paediatric cough is associated with signifi cant morbidity for both children and their parents. the symptom of cough is associated with airway hyper-reactivity and is a dominant symptom of airway infl ammation. inhaled corticosteroids (ics) can reduce airway infl ammation and hyper-reactivity. the objective of this review was to evaluate evidence for the effi cacy of ics in reducing the severity of cough in children with sub-acute cough (defi ned as cough duration of - weeks). methods search was conducted by the cochrane airways group using cochrane methodology. all randomized controlled trials (rcts) comparing ics with a control group for treatment of sub-acute cough in children were considered for inclusion. search results were analysed using pre-determined criteria for inclusion. results two studies were eligible for inclusion in the review, however there were limitations in that the participants of both these studies were infants, post acute bronchiolitis illness, and cough duration at start of study treatment was ill-defi ned. children were included in the meta-analysis. there was no signifi cant difference between groups in proportion of children 'not cured' (primary outcome measure), with a pooled or of . ( % ci . , . ) (using intention to treat analysis). conclusions there is currently no evidence to support the use of ics in sub-acute cough in children. however, this systematic review is limited by the small number of studies available for analysis and the quality and design of these studies. further well-designed rcts are required to support or refute the effi cacy of treatment with ics in children with sub-acute cough. once obstructive sleep apnoea (osa) is diagnosed, a cpap implementation sleep study is traditionally performed to determine the pressure required to control the upper airway. however, since modern cpap machines store sophisticated control data we reasoned it may equally be possible to commence cpap via a 'best guess' iterative approach without compromising osa control or compliance. aim to compare the outcomes at months of patients commencing cpap after best guess with those commencing cpap after a cpap implementation sleep study. methods we retrospectively reviewed the records of all patients referred by respiratory physicians to our cpap clinic between march and march , and the two methods of starting cpap were compared. data collected included age, sex, bmi, respiratory disturbance index (rdi), cpap pressure commenced, fi nal pressure at months, cpap usage data and cpap clinic contacts. results patients were identifi ed, aged ± years, %male, bmi . ± . , with severe osa, rdi ± . commenced cpap via best guess and after a cpap sleep study. the starting pressures in both groups were similar, . ± . versus . ± . cmh o. in those patients continuing to use cpap at months, there were no differences between the groups for fi nal pressure, numbers of patients changing pressure, control of osa with cpap, and hours cpap used per day. in the best guess group however, signifi cantly more patients were continuing to use cpap at months, % versus % (p = . ). conclusion this study demonstrates that it may no longer be necessary to perform cpap implementation sleep studies routinely and this will save hospital bed days. confl ict of interest nil. six required intubation and the rest were managed with non-invasive ventilation in icu. the average length of stay in icu was . days. polysomnographic data will be described. conclusions obesity hypoventilation as a cause of respiratory failure is likely to increase in frequency as the incidence of obesity increases. increased awareness by the lay public, as well as clinical suspicion and recognition of the condition by all clinicians at an earlier stage, is likely to prevent progression to the point of needing intensive care. it is hoped that this case series may provide a springboard for further study into why these patients presented at such a late stage of their disease process. supported by none. confl ict of interest none. although sa and sleepiness often co-exist, the commonest cause of sleepiness in a general community is depression, with sa being the th most common cause. in order to assist recognition of depression in a snoring population attending a sleep clinic, we introduced a simple two question 'beyond blue questionnaire(bbq)' into our routine assessment. aims to ( ) background indices of ventilation distribution in diffusion (s acin ) and convection (s cond ) dependent airways derived from multiple breath nitrogen washout (mbnw) may vary between interpreters because of differences in calculation of phase iii slopes (Δphase iii ). aims to compare s cond and s acin results of interpreters from a single mbnw in copd subjects. methods subjects with copd underwent mbnw. three washouts were analysed independently by experienced and novice interpreters using custom software for automated breath identifi cation. Δphase iii was fi tted automatically by least squares fi t between predetermined points, and then adjusted manually. s cond was the linear slope of Δphase iii plotted against lung turnover (cumulative expired volume/frc), between turnovers . - . s acin was the Δphase iii of the fi rst breath minus the s cond component. differences expressed as icc and cov, were examined by repeated measures anova. results mean ± sd age was ± years. fev was ± % predicted. s cond was greater while s acin was lower from the experienced introduction β-blockers may cause bronchoconstriction and mask the effect of β -adrenergic agonists. this has implications for the interpretation of routine diagnostic spirometry and bronchodilator response. this study examined this issue in a routine lung function laboratory, and whether it applied to both cardio-selective (c) and non-selective (nc) preparations. method all patients attending the lung function laboratory, royal adelaide hospital over a -month period were asked whether they were currently taking a β-blocker and to identify the drug. spirometry results were analysed to assess airfl ow obstruction and reversibility. results patients completed the survey and patients ( %) were taking β -blockers. the table shows the results of the patients who could be assessed for reversibility in spirometry. of the patients in this group patients ( %) were taking (c) and ( %) (nc) agents. fifty-three patients were unsure whether they were taking a β -blocker. no signifi cant differences were found in the percentage of patients with airfl ow obstruction or reversibility between the groups. aim to examine patterns of adult lung function in terms of airfl ow obstruction, hyperinfl ation and/or reduced diffusing capacity (d l co). this can then be related to the life-time history of risk factors such as smoking, asthma and infections. methods using the population-based tasmanian longitudinal health study (tahs) cohort followed since , an asthma-enriched sub-sample was selected consisting of % ever with asthma, of whom half reported current asthma. measurement of spirometry, d l co (uncorrected for haemoglobin) and lung volumes was performed, then lung function data were analysed using the mean predicted values. airfl ow obstruction was defi ned as post-bronchodilator fev /fvc (post-b.d. fer) < . , hyperinfl ation as total lung capacity (tlc) > % predicted, and reduced d l co as < % predicted. aim to examine the gender-specifi c differences in adult spirometry, d l co and lung volumes, with a view to relating them to life-time respiratory risk factors. methods using the population-based tasmanian longitudinal health study (tahs) followed since , an asthma-enriched sub-sample was selected consisting of % ever with asthma, of whom half reported current asthma. measurement of spirometry, d l co (corrected for haemoglobin) and lung volumes were performed. data were analysed using the statistical upper and lower limits of normal of reference equations by nhanes iii, roca et al and quanjer et al. of the caucasian adults ( females), % completed all tests. mean age . years (range - ). elevated rates of airfl ow obstruction and hyperinfl ation were seen. signifi cantly higher proportions of females than males had reduced d l co and d l co/v a (p < . ). only . % (n = ) of females had a low d l co with low fev /fvc ratio, and . % (n = ) had a reduced tlc overall. there were no signifi cant gender differences in v a , tlc, or ever and current active smoking. males and females averaged over kg more than the mediterranean adults described by roca et al., however weight is not relevant to d l co in males. conclusion a higher percentage of middle aged females have a reduced d l co and/or d l co /v a, compared to males, with an increased rate overall. grant support nhmrc, australian postgraduate association. d chapman , , , j kermode , , , n brown , , , n berend , , , g king , , , background during bronchoconstriction, a deep inspiration (di) dilates the airways, which then re-narrow once tidal breathing is resumed. re-narrowing occurs faster in asthmatic subjects and may be due reduced airway distensibility. aim to determine the association between baseline airway distensibility and the rate of re-narrowing after di. methods eleven asthmatic and fi ve non-asthmatic subjects had baseline airway distensibility measured by forced oscillation technique (fot). after methacholine challenge, respiratory system resistance (rrs) was measured during min of tidal breathing, followed by di to total lung capacity (tlc) and passive return to normal tidal breathing. dilatation was measured as the decrease in rrs between end tidal inspiration and tlc, and re-narrowing as end-expiratory rrs immediately after di, as per cent rrs at end-tidal expiration before the di. distensibility is presented as geometric mean ± %ci and re-narrowing as mean ± % ci. results airway distensibility was reduced in asthmatic compared to healthy subjects ( . s − .cmh o − ( . - . ) vs. . s − .cmh o − ( . - . ), p = . ). dilatation did not differ between groups (p = . ) but re-narrowing was increased in asthmatic compared to healthy subjects ( ± % vs. ± %, p = . ). airway distensibility did not correlate with airway re-narrowing (r s = - . , p = . ). conclusion the increased re-narrowing after di in asthmatic subjects is not due to reduced baseline airway distensibility and may be due to increased shortening velocity of airway smooth muscle or reduced elastic recoil. supported by the nhmrc and the crc for asthma and airways. nomination nil. confl ict of interest no. c ng , , , s jenkins , , , n cecins , , p eastwood , , aim to evaluate the measurement properties of two accelerometers: the activpal and the stepwatch activity monitor (sam) in people with copd. methods the activpal and sam were attached to the anterior right midthigh and the right ankle, respectively (as per device recommendations). each participant performed walking tasks; at a self-selected slow speed and at a self-selected normal speed. at each speed, one walk was performed with a -wheeled walker (ww) and the other without. results participants aged ( ) years (fev = ( ) % pred; males) completed the study. the slow and normal speeds were ( ) m·min − and ( ) m·min − , respectively. agreement between steps recorded by the sam with steps counted during observation did not differ with speed or ww use (p = . ). the mean difference was steps·min − and the limit of agreement (loa) was steps·min − . agreement between steps recorded by the activpal with steps counted was worse at slow speeds (mean difference steps·min − with loa of steps·min − ) compared with normal speeds (mean difference steps·min − with loa of steps·min - ) (p = . ), but was not affected by ww use. both accelerometers detected the small difference in walk speed irrespective of ww use (p < . ). conclusions neither the accuracy nor responsiveness of either accelerometer was affected by ww use. in contrast to the activpal, sam was accurate at both speeds and therefore can be used to detect steps in people who walk very slowly during daily life. breathing and sleep, heidelberg vic., eastern health, melbourne vic., northern health, epping vic., and monash university, clayton vic. aim to document the care and pathways patients with copd travel at three metropolitan health services. methods data were extracted from data sets for patients attending the emergency department of the three hospitals with a diagnosis of copd over year. the three hospitals included a city-based tertiary/quaternary hospital and two smaller community hospitals. analysis was completed on similarities and differences in admission and referral rates, average length of stay, and discharge destination, standardized by age, sex and mode of transport to the emergency department. results there were inpatient separations and emergency department presentations for patients with copd. discharge patterns related to the designated role of the hospital, with the community hospitals discharging to % of patients directly home and the more specialized city hospital discharging % to other hospitals and % home. there were signifi cant differences in the admission rates for category and patients among the hospitals. we found unexplained variation in the acute average lengths of stay of . , . and . days. conclusions the analysis confi rmed some expected patterns based on the type of hospital, but also identifi ed unexplained variation that suggests that factors other than patient characteristics may be contributing to the variation in care pathways. aims to: ( ) determine which tests of exercise capacity relate to average daily energy expenditure (dee) and; ( ) quantify the intensity at which activities of daily living (adl) are undertaken in people with chronic obstructive pulmonary disease (copd). methods a study was undertaken in subjects with stable copd (mean, sd) aged ( ) years with an fev of ( ) % predicted ( males). measures were collected of distance walked during the six-minute walk test ( mwd) and incremental shuttle walk test (iswd) and peak rate of oxygen uptake during a cycle ergometry test (vo peak ). the sensewear armband® was worn during the waking hours for . ( . ) days to measure dee. the intensity at which activities of daily living were undertaken was expressed as a percentage of vo peak . results dee was associated with mwd (r = . ; p = . ), iswd (r = . ; p = . ) but not vo peak (r = . ; p = . ). stronger associations were observed between dee and the body weight-walking product for mwd (r = . ; p < . ) and iswd (r = . ; p < . ). the average intensity of adl was equal to ( %) of vo peak (range to %). conclusions mwd and iswd, but not vo peak were related to dee. as adl were performed at a high percentage of vo peak it may be more realistic to increase dee by increasing the frequency or duration, rather than the intensity of physical activity. in patients with copd, two mwts are recommended prior to commencing a pulmonary rehabilitation program (prp) to allow for a learning effect. aim to determine the characteristics of patients with copd in whom -minute walk distance ( mwd) did not increase on a second test. methods patients ( males) with stable copd (aged , to years) naïve to the mwt performed two tests ( minutes apart) prior to commencing a prp. patients were categorized according to their change in mwd with test repetition. results mwd was the same or decreased on the second test in patients ( %) (table) . in the remaining patients ( %), mwd increased by m ( %) ( % ci to m, to %). logistic regression analysis identifi ed fev (l) as the only signifi cant variable (p < . ) that predicted the absence of a learning effect in mwd with test repetition. conclusions some patients with severe copd may not require a practice mwt to achieve their maximum performance at a prp baseline assessment. ( ) years, with stable ipf were evaluated in this study. demographic data and measures of pulmonary function (spirometry, diffusing capacity for carbon monoxide, (dl co )), dyspnoea (baseline dyspnoea index, bdi), peripheral muscle force (isometric quadriceps force (qf) and handgrip force (hf)), functional exercise capacity ( -minute walk distance, mwd), limitation in daily activities (activities of daily living (adl) score), and health status (sf- ) were assessed. relationships between mwd and mrc grade, pulmonary function, qf, bdi and adl score were examined. results the number of subjects in mrc grades , , and was ( %), ( %), ( %) and ( %), respectively. pulmonary function, bdi, qf, hf, mwd, adl score, and sf- decreased signifi cantly with increasing mrc grade (all p < . ). moderate to strong correlations were found between mwd and mrc grade (r = − . ), dl co (r = . ), qf (r = . ), bdi (r = . ) and adl score (r = . ) (all p < . ). conclusions these fi ndings suggest that the mrc dyspnoea scale can be used to discriminate and classify subjects with ipf according to the severity of impairment and disability. ( ) year (mean, sd) completed two assessment sessions on separate days. on one day, they exercised twice to symptom limitation (tlim) on a treadmill. on the other day, they exercised twice to tlim on a cycle ergometer. the order of exercise modality was randomized between days. on both days, the only difference between the exercise tests was that bipap, titrated to patient comfort, was used during the second test. measures were made of; ) tlim and, ( ) the difference in dyspnoea, using borg scores, at tlim during the fi rst test and the equivalent exercise time during the second test (i.e. iso-time). results bipap increased tlim on the treadmill ( ( ) seconds; p = . ) but not the bike ( ( ) seconds; p = . ). the reduction in dyspnoea at iso-time on the treadmill and bike was similar being, ( ) and ( ), respectively (p = . ). conclusions bipap may confer greater benefi t in exercise tolerance exercising on a treadmill compared with a cycle ergometer in patients awaiting lung or heart-lung transplant. infection with rhinovirus (rv) is known to trigger acute exacerbations in subjects with asthma and these subjects also have increased susceptibility to the effects of rv. the mechanisms remain poorly understood, but appear to involve a host innate immune defect in the airway epithelium. aim we sought to determine in bronchial epithelial cells (becs) if oxidative stress in the form of exposure to cigarette smoke extract (cse), hydrogen peroxide (h o ) and eosinophil peroxidise (epo) results in impaired mitochondrial function and if this directly impairs signalling of rv infection through mda and alters the release of type i and type iii interferons (ifns). methods pbecs were grown to confl uence. cells were then exposed to cse ( %, no fi lter) or h o ( . mm) or epo. cells were then infected with rv -b (moi = ). virus replication was measured by cell titration assay. following infection, il- , cxcl- , cxcl- was measured using cytometric bead array and fl ow cytometry. supernatants and whole cell lysates were collected for ifn-β, bax and mda detection by western blot. ifn-λ and cytochrome-c was measured using conventional elisa. cell viability was assessed by annexin v-pe staining and fl ow cytometry. results rv infection alone induced cxcl- , il- , cxcl- and ifn-λ. pbecs treated with each of the oxidative stressors had increased cytochromec release and increased apoptosis. this mitochondrial dysfunction led to degradation of mda expression and resulted in specifi c suppression of cxcl- and ifn-λ. conclusions exposure of becs to an oxidative stress results in mitochondrial dysfunction in airway epithelial cells. this leads to defective antiviral signalling in the airway epithelium after infection with rv. introduction pleural infection is associated with high morbidity. prompt drainage is key, but pus is often loculated and thick making drainage diffi cult. based on promising animal studies, we hypothesize that intrapleural therapy with t-pa and dnase, which lyse adhesions and reduce fl uid viscosity respectively, can signifi cantly improve pus evacuation in pleural infection. methods consecutive patients with pleural infection were treated with standard antibiotics and intercostal chest tube (ict) drainage. additionally, t-pa mg and dnase mg (each in ml of . % nacl) were instilled intrapleurally via an ict twice daily for up to six doses. the ict was clamped for minutes after each instillation. patients were followed clinically and with serial cxr. opacity from pleural effusion was quantifi ed on chest radiographs. results eleven patients ( male; mean age ) were treated. nine effusions were associated with community acquired pneumonia, of these, eight were visibly purulent, fi ve were culture positive and the mean fl uid ph was . (range . - . ). ten patients ( %) were successfully managed conservatively and one patient required surgery. median hospital stay from fi rst intrapleural treatment dose to discharge was days (range - ). the median amount of fl uid drained in the hours preceding t-pa/dnase treatment was ml (range - ), and improved signifi cantly to ml (range - ) following two doses of treatment. this was paralleled by a signifi cant reduction in radiographic opacity by a mean value of % of the hemithorax (range - %). four patients showed an initial rise in crp following t-pa/dnase, but all patients had resolution of sepsis and signifi cant reduction in crp. there were no major complications. pleuritic chest pain requiring opioid analgesia developed in three patients. methods clinical data were collected using a standardized form for aboriginal children aged days -< months hospitalized with alri and enrolled in a rct of vitamin a/zinc supplementation were matched with data collected during a population-based study of who-defi ned primary endpoint pneumonia (who-p). sensitivities, specifi cities, positive and negative predictive values (ppv, npv) for these signs were compared between who-p cases and lobar pneumonia assigned by a respiratory paediatrician. in episodes of hospitalized alri, who-p was diagnosed in ( . %); the respiratory paediatrician classifi ed ( . %) as lobar pneumonia. the sensitivities of clinical signs ranged from a high of % for tachypnoea to % for fever + tachypnoea + chest-indrawing; the ppv range was % to %, respectively. higher ppvs were observed against the paediatric respiratory physicians diagnosis compared to who-p. conclusions clinical signs on admission are not useful in predicting who-p in this population, presenting challenges for future pneumonia research in this population. who-p may underestimate alveolar consolidation in a clinical context and its use in clinical practice or in research designed to inform clinical management in this population should be avoided. the incidence of tb in the non-indigenous australian population is uncommon at . cases per population . in this paper, we report three cases of pulmonary tuberculosis in young australian born, non-indigenous adults in the hunter new england area where marijuana possibly was a signifi cant risk factor in transmission and severity of disease. all three cases had severe cavitating disease at time of presentation. contact tracing from the fi rst case, a regular heavy marijuana user, identifi ed mantoux positive contacts, one of whom developed active pulmonary tuberculosis. all contacts, mainly young adult males, denied sharing marijuana with the index case. contact tracing from the second case identifi ed mantoux positive contacts, of whom use marijuana regularly and shared bongs (water pipes) with the index case. there were positive mantoux contacts of the third case, one of whom shared bongs with the index case. health professionals need to remain aware of the possibility of tuberculosis in groups with historically low incidence rates. marijuana bong smoking is possibly associated with transmission and severity of tuberculosis . introduction in , these previously well women survived and made a good recovery from severe pneumonia and acute lung injury after retrieval on ecmo. streptococcus pyogenes is an unusual cause of pneumonia in adults. case a -year-old veterinarian with a history of mild asthma presented with days of fever and respiratory symptoms. the diagnosis was confi rmed by a fourfold rise in the anti-streptococcal antibody. this was complicated by respiratory failure, septic shock, acute renal failure, severe pulmonary hypertension and bilateral parapneumonic effusions. despite maximal interventions she deteriorated. femoral venous-venous ecmo was initiated on day at the calvary mater hospital in newcastle by a retrieval team from royal prince alfred hospital (rpa), sydney. she was transferred kms on ecmo in a large multipurpose ambulance. she developed lung abscesses and recurrent pneumothoraces and she required a pleurodesis. she required days of ventilation and days of ecmo. three months later she was asymptomatic, with mildly restrictive spirometry and minor cxr change. case a -year-old offi ce worker with s pyogenes bacteraemia made a similar presentation to our institution. she was ventilated for days, ecmo was initiated by the retrieval team and continued for days. three months later she was asymptomatic with a normal cxr and pulmonary function tests. introduction the urinary pneumococcal antigen (upa) test has been shown to have superior sensitivity to other investigations in determining the aetiology of community-acquired pneumonia (cap), but there is very limited data on its performance in local populations. the aims of this study are to establish the prevalence of positive upa testing in patients admitted to hospital with cap, and determine its utility. secondary aims are to identify associations with positive testing, as well as to determine if a positive test infl uences clinical outcomes. methods the study is a prospective, single-centre study that is still recruiting. adult patients are included upon admission to hospital if they have the diagnosis of cap, as defi ned by new infi ltrates on chest radiograph along with consistent clinical features. clinical data including curb- score of severity, current and prior antibiotics, co-morbidities, mortality and length of hospital stay are recorded. results preliminary results show a positive test prevalence of / ( . %, % ci . - . %) amongst patients admitted with cap. overall prevalence of pneumococcal pneumonia is / ( . %, ci . - . %). patients with a positive upa result have a higher mean curb- score of . compared with . in those with a negative result (p = . ). . % of patients with a positive result were admitted to the intensive care unit, compared with . % those with a negative result (p = . ). conclusions the overall prevalence of positive upa testing in patients admitted to hospital with cap is low. preliminary data suggests that patients with positive results are more likely to have greater severity pneumonia and to require intensive care support. comparative data on length of stay, mortality, previous antibiotic use and specifi c co-morbidities has not revealed any statistically signifi cant differences between positive and negative groups. confl ict of interests no. s herath , c lewis , m nisbet , respiratory department, auckland city hospital, auckland, new zealand, and infectious diseases department, auckland city hospital, auckland, new zealand rhodococcus equi (r. equi), previously known as corynebacterium equi is a gram positive bacillus that is found in soil and causes infection in grazing livestock. it is infrequently isolated from clinical specimens. it is usually associated with human disease in immunocompromised patients and is an uncommon cause of infection in immunocompetent patients. infection is usually acquired by the airborne route with pneumonia being the most common manifestation but it can also be acquired orally or by direct inoculation. we present a case of pneumonia caused by r. equi infection in a year old male builder who presented with cough, dyspnoea and night sweats. r. equi was cultured from a transbronchial aspirate from a subcarinal lymph node. despite extensive investigation, no contributing host immune defect was identifi ed. the patient recovered after three months of antibiotic treatment, initially with intravenous vancomycin and meropenem followed by oral clarithromycin and rifampicin. although infections due to r. equi have been increasingly reported in immunocompromised patients, since there have only been cases described in patients where no associated host immune defect was reported. in this cohort, the median age at presentation was years (range - ) and ( %) patients were male. ten ( %) of these cases had pulmonary infection. two ( %) patients died and the remainder were successfully treated with prolonged antibiotics. r. equi is an uncommon cause of infection in humans and rarely occurs in patients where a host immune defect cannot be identifi ed. introduction recognition of pulmonary involvement in extra pulmonary tuberculosis (ep-tb) may be an important public health issue, as it has been estimated that patients with smear negative pulmonary tb (ptb) are responsible for % of new infections. usually, all patients with ep-tb have a chest x-ray but sputum cultures are requested only if there is an abnormality. methods in this retrospective clinical audit, we aimed to evaluate the percentage of ep-tb patients with ptb despite a normal chest x ray (cxr), and to explore any clinical characteristics of this group. clinical notes, microbiology and cxr reports were reviewed from consecutive patients presenting with ep-tb between and . results of patients with ep-tb, % were male and the mean age was (range to ). most patients were of asian ethnicity (n = , %). the commonest presentation of ep-tb was lymphadenopathy (n = , %), followed by pleural (n = %) and bone (n = , . %) disease. ep-tb was diagnosed by biopsy/excision of the ep site in the majority (n = , . %), and by sputum testing alone in ( . %). sputum cultures were performed in n = , ( %) overall, with n = ( %) being positive. there was higher infl ammatory markers in the sputum culture positive group (esr . vs. . , p = . and crp . vs. . , p = . ). the majority had cxr abnormalities (n = , %). in the group with normal cxr (n = ), ( %) had sputum cultures performed. of these, were culture positive and of these also + smear positive ( on immunosuppression, with cough). conclusion a small number of patients with ep-tb and normal cxr had pulmonary tb, of whom were smear positive. thus, induced sputum testing should be considered in patients with ep-tb even if cxr is normal. this may aid diagnosis and determine infectivity. ntm are normal inhabitants of environmental reservoirs including water. disease due to ntm has been increasing in qld. aim to document the presence of ntm in potable water in brisbane, to compare the species isolated during summer and winter and to relate this to the geographic distribution of patients with ntm. methods water samples ( l) were collected from routine collection sites in winter and sites in summer . samples were processed in triplicate as previously described. h subcultures were taken from positive specimens, dna extracted, followed by s rrna sequencing. patient addresses were obtained from the qld tb control centre database. aim to gauge the full impact of pandemic h n infl uenza across demographic groups in the northern territory, particularly indigenous and remoteliving individuals. methods we performed two cross-sectional serological surveys on specimens from residents of the northern territory, with specimens obtained from january to may (pre-pandemic) and specimens from september (post-pandemic). specimens were selected from among serum tubes collected from ambulatory outpatients. antibody titres were measured by haemagglutination inhibition against the a/california/ / reference virus. all specimens had available data for gender, age, and address, with indigenous status determined in . % of cases. results protective antibody levels, defi ned as a titre of or greater, were present in . % of pre-pandemic specimens and . % of post-pandemic specimens. the pre-pandemic proportion immune was greater with increasing age, but did not differ by other demographic characteristics. the post-pandemic proportion immune was greater among aboriginal and torres strait islanders and in younger age groups, but did not differ by gender or socio-economic index for area. however, the proportion immune was geographically heterogeneous, particularly among remote-living and indigenous groups. the northern territory-wide attack rate adjusted to age, region and indigenous status was . %. conclusions pandemic infl uenza disproportionately affected children and indigenous australians in the northern territory in . the proportion of specimens demonstrating post-pandemic immunity was particularly variable among indigenous and remote-living individuals. the kormp found asymptomatic aboriginal children (ac) had more hrv than asymptomatic non-aboriginal children (non-ac) in a longitudinal communitybased cohort study where infants had nasopharyngeal aspirates (npa) collected regularly from birth to years of age. aim to compare the frequency of hrv groups in asymptomatic ac and non-ac in the kormp. methods npa positive for hrv (n = ) from the npa previously tested for respiratory viruses, had viral rna extracted and reverse transcribed. hrv was detected and typed using a two-step pcr of the hrv ' utr, followed by dna sequencing for typing. chi-square analyses were used. results hrv was detected and typed in npa (from children; ac and non-ac), could not be typed and were not positive for hrv. ac had more hrv in summer and autumn than non-ac and were more likely to be co-infected with at least / bacterial species identifi ed. hrva, b & c were found in . , . and . % of hrv detected. hrvb & c were increased in infants exposed than not exposed to tobacco smoke in utero (hrvb; . vs. . %, p = . and hrvc; . vs. . %, p = . ). of the npa, hrv-a was detected more often in npa from ac than non-ac ( . vs. . %, p = . ), particularly at - months of age (p = . ) and during summer (p < . ). hrvb was detected more often in npa from ac than non-ac in autumn (p < . ). hrvc was detected as often in ac as non-ac in each season except summer. aim to determine whether interferon-gamma release assay (igra) can be effectively used for diagnosis of latent tuberculosis infection in a remote location. methods subjects were enrolled from the darwin centre for disease control tuberculosis clinic and were eligible if a tuberculin skin test (tst) of mm or greater had been recorded for any indication. igras were performed using quantiferon®-tb gold whole blood in-tube assay according to manufacturer's instructions. specimens were incubated and centrifuged at the local laboratory before refrigeration for transport. interferon assay was performed at the reference laboratory, over km away. results igras were performed, with patients ( %) recording negative results, ( %) positive and only one result ( %) indeterminate. negative, and therefore discordant, test results were more common in bcg vaccinated individuals. this effect was not limited to those with tst results of - mm, but was seen primarily in those with results of mm and above. conclusions these results are broadly comparable to fi ndings for igra use in less remote settings. in particular, our low rate of indeterminate results suggests that igra testing is feasible at a remote site after local processing. this approach could be considered for use in the northern territory tuberculosis control program. inhaled medications form the mainstay of drug treatment for patients with airways disease. effectiveness of therapy is dependent on the appropriate selection and prescription of drug and device, correct supply and adherence to therapy with an effective technique. patients frequently admit to acute medical wards both with acute exacerbations and for other co-morbidities eg heart failure or pneumonia. inpatient episodes provide an opportunity to review inhaled therapy however anecdotally add to patient confusion and introduce complexity (rational or ad hoc changes to inhaled drug, device, strength, dose or frequency). aim identify prescribing accuracy and effectiveness of patients' inhaler technique. describe any discrepancies between inhaled therapy: ( ) used prior to admission, ( ) prescribed for inpatient use, ( ) available at the bedside and ( ) administered, prior to and after implementation of an inhaler prescribing and administration guide. methods a single day audit of all inpatients on general medical wards was conducted october (review of medication charts and inhalers in patients' bedside lockers, brief questioning and direct observation of patients' inhaler technique. results compared to post implement of the 'prescribing and administering inhalers' tool (audit in december ). results from ( %) patients had inhalers prescribed, (mean: . prescriptions per patient). % of prescriptions were accurate ( % patient had no errors). discrepancies between used prior to admission and inpatient prescriptions were found in ( %) patients while those between inpatient prescriptions and available at the bedside were found in %. self-administration ('s') was noted on medication charts of ( %) patients, of whom had an ineffective inhaler technique. / patients has a spacer at the bedside with a further r prescribed metered aerosol inhalers. post-intervention differences in prescribing, supply, administration and technique errors will be discussed. conclusions a combination of errors and prescription discrepancies reduce the effectiveness of inhaled therapy for inpatients. confl ict of interest no. males (n (%) % ci) females (n (%) % ci) adm and bed days bmi, body mass index hrqol, health related quality of life chronic respiratory disease questionnaire; adm, admissions, mean (sd) uberculosis notifi cations in australia a cluster of tuberculosis associated with use of a marijuana water pipe the prince charles hospital foundation cc dobler , , gb marks , woolcock institute of medical research, the university of sydney, nsw, and department of respiratory medicine, liverpool hospital, sydney, nsw aim to determine the incidence rate and nature of adverse events in patients taking treatment for latent tuberculosis infection (ltbi). methods records of all patients who received treatment for ltbi at the chest clinic of a large tertiary hospital between / and / were reviewed. an adverse event was defi ned as any change in health status or side effect that led to treatment interruption or cessation. liver function tests were not performed routinely during follow-up, except when the patient was considered to be at an increased risk of developing hepatitis. results of patients in whom treatment for ltbi was initiated ( %) received isoniazid for months, ( %) received a combination of isoniazid and rifampicin for months, and the remainder were treated with different regimens. their mean (sd) age was ( ) years and % were male. nineteen patients ( . %) experienced an adverse event. seven patients developed a rash, four had lethargy and/or mood disorders, three had subclinical hepatitis, four experienced severe nausea, vomiting and/or other gastrointestinal symptoms and three had features of peripheral neuropathy. in eight patients who experienced an adverse event medication was temporarily ceased and then re-started without change; in four the treatment regimen was changed; and in seven the treatment was ceased completely. the risk of adverse events was not signifi cantly related to age, sex, drug regimen (single drug versus combination therapy) or baseline transaminase levels. conclusions in this cohort almost in patients on treatment for ltbi experienced an adverse event. although the adverse events were generally mild to moderate, this risk has to be taken into account when deciding whether to advise treatment for ltbi. introduction human rhinovirus (hrv) is the commonest cause of asthma exacerbations in children. pernasal aspirate (pna) is the gold standard for microbiological sampling but is invasive and distressing for children. studies have showed that less invasive swabs may be just as effi cacious. aim to test the hypothesis that hrv detection is as effi cient using nasal fl ocked swabs or washes and more comfortable, compared with pna in children with respiratory illnesses. methods children were recruited on presentation to the emergency department with respiratory symptoms. pna was collected from one nostril of all children recruited and nasal fl ocked swab (n = ) or wash (n = ) collected from the other nostril alternately. subjects rated the comfort of each sampling method to (least to most). viral rna was extracted and reverse transcribed. a two-step pcr of the hrv ' utr was used for detection, followed by sequencing for typing. results to date, children ( % male, mean age of . years) had paired samples taken. of these children, % (n = ) presented with a diagnosis of viral induced wheeze and % (n = ) had a hrv positive sample. compared with pnas, nasal fl ocked swabs were % ( of pna positive) effective in detecting hrv, whilst nasal washes showed % ( of pna positive) effi cacy. of the successfully typed samples, had hrva and had hrvc. nasal washes had a better comfort rating (mean . , n = ) than fl ocked swabs (mean . , n = ) and pnas (mean . , n = ). conclusion our fi ndings suggest that whilst nasal fl ocked swabs are an effective sampling method for hrv detection, nasal washes were more effective, being as effective as pnas and were the most comfortable. support nhmrc, pmh foundation. nomination nil. aim to describe the inpatients treated by a dedicated niv service. methods a retrospective audit of inpatients treated by the alfred niv service between january and june . the defi nition of niv included patients treated with cpap and bilevel positive pressure ventilation. results patients (age: ± years (mean ± sd), gender: % male) were treated with niv on occasions (repeat admissions patients). commonest indications for niv were osa (n = , %), acute exacerbations (ae) of copd (n = , %), acute cardiogenic pulmonary oedema (acpo) (n = , %) and post-lung transplantation (n = , %). treatment was delivered primarily in the respiratory ward (n = , %), cardiac ward (n = , %), icu (n = , %) and general medical ward (n = , %). episodes of cpap (mean pressure ± cmh o), osa and acpo made up % of those treated. seventy-two episodes of bilevel pap (mean ipap ± cmh o and epap ± cmh o), aecopd and weaning post-mechanical ventilation made up % of those treated. outcome data was available in a subgroup of patients with acpo (n = ) andaecopd (n = ). in the acpo group, patients ( %) improved and niv was ceased. three patients ( %) deteriorated and were intubated and patients ( %) were palliated. in the aecopd group, patients ( %) improved andniv was ceased or they were discharged on therapy. patients either deteriorated on niv or could not tolerate therapy, of these ( %) continued ward management and ( %) were palliated. conclusion the alfred niv service model has managed a large number of referrals across a range of diseases in a variety of wards. this is likely to have reduced demand on icu, hdu and respiratory ward beds. compared to the published literature, theoutcomes for acpo are worse than expected but comparable for aecopd. this may be explained by local referral patterns for acpo. we believe that our service model provides a viable means of administering niv to an ever expanding referral base. transitional & community service, the university of south australia, adelaide, sa , the university of adelaide, adelaide, sa, , the mary potter hospice, north adelaide, sa, , thoracic medicine, the royal adelaide hospital, adelaide, sa, , the royal district nursing service, wayville, sa , and the palliative care council of sa eastwood, sa introduction: the adelaide health service is in the process of developing a new and innovative model of copd community based care. a number of initiatives have informed this development including a recent research project examining the experiences of participants with end stage copd and their carers. a growing body of evidence indicates the importance of a palliative approach, however this often takes the form of referral to a palliative care service rather than a broader application of palliative principles in both specialist and primary care. methods: fifteen participants were interviewed twice at monthly intervals to explore their needs and the services they accessed. a series of focus groups with key service providers in sa was also undertaken. data were analysed to identify how hospital, specialist palliative care units and primary care services currently interface to meet identifi ed patient and carer needs. results: the current service model is episodic and reactive with services activated through the acute care system. our research has shown that, as copd advances, current models of care do not address the importance of supporting quality of life (including a focus on adls) and carers in their ongoing role. also emphasised was the lack of co-ordination of care, collaboration between service providers and communication -the basics of chronic disease management. conclusions the outcomes of this study will inform the development of a proactive, multidisciplinary model of care which is no longer reliant on tertiary care, but places primary care at the centre of the model. greater collaboration between respiratory, palliative and primary care services will provide an integrated approach, focusing on the needs of the patient and carer. aim long term conditions are prevalent in south auckland and impact on the individual, the community and the health system. as nurses living within this community, and employed by counties manakau district health board, our aim was to explore funding opportunities available through the pacifi c health team. lotumoui was established to improve health outcomes/behaviours for pacifi c populations. the church we attend has wide cultural diversity and had no knowledge of the programme and the support provided to make healthy changes within our community. methods firstly a health committee was formed within the church, having 'sold' our vision to the parish council. we launched the group by undertaking free blood pressure checks, followed by a 'walk the talk' project for the days leading into easter. baseline observations were taken and pedometers issued. results the parishioners who attend regular exercise sessions are reporting improved quality of life, exercise tolerance and reducing waist lines. bp parameters are also reducing. conclusions a dedicated health committee within a parish community, supported by the district health board can impact on changes in lifestyle by simple interventions. the investment by the pacifi c team will reap benefi ts for the individual and the health sector. confl ict of interest no. key: cord- -p pxz a authors: nan title: cystic fibrosis sig: poster session date: - - journal: respirology doi: . /j. - . . _ .x sha: doc_id: cord_uid: p pxz a nan patients with non-eosinophilic asthma (nea) or copd have increased numbers of neutrophils in the airways. we have shown a similar defect in the ability of alveolar macrophages (am) to phagocytose apoptotic cells, in sputum from patients with nea and copd. we have also shown that bal-derived am from patients with copd have reduced expression of key macrophage phagocytic recognition molecules. the aim of this pilot study was to investigate the expression of these macrophage markers in induced sputum from patients with eosinophilic asthma (ea, n = ), nea (n = ), copd (n = ) and controls (n = ). methods participants underwent clinical assessment, skin allergy test, hypertonic saline challenge and sputum induction. macrophage phagocytosis of apoptotic cells, expression of mannose receptor (mr), hspr (cd ) and pcam (cd ) was determined using fl ow cytometry. results phagocytosis was signifi cantly impaired in patients with nea and copd. expression of mr, cd and cd were decreased in patients with nea or copd, but not signifi cantly changed in ea conclusion impaired sputum-macrophage phagocytosis of apoptotic cells in nea is associated with reduced expression of key macrophage recognition molecules. this defect may contribute to the chronic infl ammation and persistent airway neutrophilia that characterizes this asthma subtype. the use of induced sputum as a surrogate for the more-invasive bronchoscopic sampling may provide a tool for investigating the mechanisms for the effect of therapies including azithromycin in lung disease. supported by nhmrc. neutrophilic asthma (na) has been associated with increased bacterial colonization of the airways and increased expression of innate immune factors in the lung. this suggests that infection may play an important role in the pathogenesis of na. na is an important health issue as sufferers are resistant to steroid treatment, which is the mainstay of asthma therapy and effective therapies are urgently required. using mouse models of chlamydia and haemophilus infl uenzae lung infection and ovalbumin (ova)-induced allergic airway disease (aad), we have shown how infection may be linked to na. both infections suppressed eosinophilic infl ammation and t-helper (th) type responses but increase neutrophilic infl ammation and innate and th and/or th responses in aad. in the current study, the effectiveness of steroid treatment for the suppression of infection-induced neutrophilic aad was assessed by treating infected ovasensitized mice intranasally with dexamethasone during ova challenge. whilst dexamethasone treatment suppressed th -mediated, eosinophilic aad in uninfected, ova-sensitized groups, chlamydia and haemophilus-induced neutrophilic aad were shown to be steroid-resistant. our fi ndings correlate with clinical observations which show associations between infection, neutrophilic infl ammation and steroid resistance in asthmatics. these models will be utilized to examine the effectiveness of a number of novel therapies for infection-induced neutrophilic aad and to develop improved treatment strategies for steroid-resistant asthma. supported by nhmrc, asthma foundation of nsw, hmri. kj baines , , jl simp s on , , rj scott , lg wood , , pg gibson , priority research centre's for asthma and respiratory disease, and information based medicine, the university of newcastle, nsw, australia, and respiratory & sleep medicine, hmri, john hunter hospital, nsw, australia rationale four infl ammatory phenotypes of asthma have been identifi ed including eosinophilic, neutrophilic, mixed granulocytic and paucigranulocytic asthma, based on the presence or absence of sputum granulocytes. the involvement of systemic infl ammation in the pathogenesis of infl ammatory phenotypes of asthma remains unknown. objective this study investigates differences in the whole genome gene expression profi le of peripheral blood in infl ammatory phenotypes of asthma. methods induced sputum and peripheral blood were collected from participants with asthma (n = ). infl ammatory cell counts were performed and infl ammatory phenotype assigned based on the eosinophil and neutrophil cutoffs of % and %, respectively. rna was extracted from whole blood, gene expression profi les were generated (illumina humanref- v ) and analysed using genespring gx . results participants with eosinophilic asthma had signifi cantly higher rates of atopy and levels of exhaled nitric oxide. there were genes classifi ed as differentially expressed between the asthma phenotypes including the α-defensins (defa) , b, and , neutrophil proteases cathepsin g (ctsg) and elastase (ela ), and the monocyte/macrophage serine esterase, carboxylesterase (ces ). expressions of defa , b, , , ctsg and ela were signifi cantly higher in neutrophilic asthma and expression of ces was significantly higher in mixed granulocytic asthma. microarray results of the α-defensins and neutrophil proteases were successfully validated using realtime pcr. conclusions there is systemic up-regulation of α-defensins and neutrophil proteases in neutrophilic asthma, and these molecules play an important role in neutrophil activation and migration. systemic activation of neutrophils is an important feature involved in the pathogenesis of neutrophilic asthma, which is signifi cantly different to other asthma phenotypes. supported by hmri and xstrata coal; the university of newcastle. confl ict of interest no. airway mucus hypersecretion is an important cause of morbidity and mortality in asthmatic patients. increases in goblet cell number and their secretions are likely to contribute to airfl ow obstruction in asthma. here, we take advantage of an established sheep model of asthma to investigate the association between allergen exposure and goblet cell activity. methods eight allergic sheep (high house dust mite (hdm)-specifi c serum ige) received weekly intra-lung challenges of hdm to the right caudal lobe, and weekly intra-lung challenges of hdm followed by weeks without allergen exposure to the left caudal lobe, with the right medial lobe serving as an untreated internal control. a separate group of sheep were also used as untreated controls. biopsy samples of segmental bronchi tissue were collected from the different lung lobes for histological analysis at and days post-hdm challenge. results the percentage of goblet cells, with respect to epithelial cells, signifi cantly increases following chronic challenge with hdm ( % hdm vs. % control p < . ). goblet cell numbers did not decline in lung lobes after a -week cessation of allergen challenges. goblet cell degranulation is significantly increased day following challenge with allergen, but returns to control levels by days post-allergen challenge ( % day vs. % control p < . ). furthermore, degranulation is increased in both the rested and internal control lobes day following allergen challenge of the right caudal lobe. conclusions in this sheep model of chronic asthma, repeated allergen challenges induces goblet cell hyperplasia which persists even after long-term withdrawal of allergen. additionally, exposure to allergen in one lobe induces goblet cell degranulation in both challenged and unchallenged lobes, suggesting neural mechanisms may be operating in this model. confl ict of interest no. the thickness of the airway smooth muscle (asm) layer is related to severity but not duration of asthma or age (james erj; : ) . it is unknown if the constituents of the asm layer change with age. aim to investigate the relation of mean asm cell volume (v c ), total number of cells per mm of airway (n l ) and fractions of asm (f asm ) and extracellular matrix (f ecm ) within the asm layer with age and age at onset of asthma. methods post-mortem tissues from control subjects (c n = ); non-fatal (nfa n = ) and fatal (fa n = ) cases of asthma were used. the volume density (n v ) of asm cell nuclei was estimated on μm transverse airway sections (haematoxylin) and mean cell volume (v c = /n v ) was calculated, correcting for the volume fraction of asm within the asm layer. f asm and f ecm were estimated on . -μm thick sections of the same airway (masson's trichrome). effects of age on asm cell parameters and tissue volume fractions were tested using general linear models, correcting for sex and study centre and by comparing age at onset of asthma (< vs. > years). results table shows assessment of airway smooth muscle (asm) cell size and number requires estimates of cell volume density (n v ), volume fraction of muscle (f asm ) within the asm layer and the volume of asm per length of airway. stereological techniques have now become the accepted standard for assessing asm cell parameters, but sources of variation remain unclear. aim to assess sources of variability in the estimation of asm cell parameters and volume fractions within the asm layer. methods large and small airways from subjects with and without asthma were examined. transverse airway sections were cut at . μm and μm (masson's trichrome technique), and μm (haematoxylin) and used to estimate asm cell number and volume, and the volume fraction of muscle (f asm ) within the layer of asm. stereological assessments of the possible sources of variation in these asm layer parameters were assessed. results increased section thickness overestimated f asm by < % ( . μm), % ( μm) and % ( μm). stable variation of < % in n v occurred if high-power fi elds (hpf) were used to estimate n v . variation in the depth of muscle in thick sections of the asm layer caused up to % overestimation of n v . although the absolute area of the asm layer varied by up to %, variation of f asm was < % around the airway circumference and along the airway length. f asm differed signifi cantly between large and small airways. conclusion these results suggest that partial thickness hpfs need to be excluded and that ≥ hpf should be used to estimate asm volume density, that a single . μm section of airway can be used to estimate f asm and that asm parameters should be compared separately in large and small airways. grants nhmrc # . nominations nil. confl ict of interest nil. no signifi cant correlation was seen with age for any asm cell parameters or tissue fractions. results were similar for medium and small airways. conclusion size and number of asm cells and the volume fractions of asm and ecm within the layer of asm are not related to age. support nhmrc australia (grants # ; # ). nomination nil. . ± . . ± . . ± . . ± . fa > . ± . . ± . . ± . . ± . background asthma is characterized by excessive airway narrowing to contractile stimuli, termed airway hyper-responsiveness (ahr). changes in airway smooth muscle (asm) protein expression or mass are possible contributing mechanisms underlying ahr and have been examined using cell culture techniques. however, how these cellular changes to asm relate to airway narrowing at the level of the whole airway is unclear. we describe a new method to track changes in airway narrowing (responsiveness) in culture. methods whole airway segments (generation - ) from sheep lungs were studied prior to (fresh) and after and hours in culture in dulbecco's modifi ed eagle medium with % bovine serum albumin, % l-glutamine and antibiotics. airway narrowing was measured from the % decrease in airway volume under a fi xed transmural pressure, using a servo-controlled syringe pump and organ bath apparatus. cumulative acetylcholine dose-response curves (ach, − m − × − m) were performed to determine maximal response (e max ) and sensitivity (pd , negative log of ec ). results fresh airway segments narrowed strongly and approached closure with an e max of . % ± . (±sem) and pd of . ± . . airway narrowing responses were preserved in culture, with no signifi cant difference in maximal response or sensitivity to ach after either (e max . % ± . , pd . ± . ) or hours in culture (e max . % ± . , pd . ± . ). conclusions the present study has validated a new method allowing changes occurring at the cellular level in culture to be related to changes in airway responsiveness at the whole airway level. future studies will assess the effects of chronic infl ammation in disease on airway responsiveness. background deep inspiration (di) produces a bronchodilator response in healthy humans, but this response is impaired in asthma. reduced airway compliance in disease could impair the response to di by limiting the stretch of smooth muscle. aim to show that isolated human bronchi dilate to di in an amplitudedependent manner and that the stretch caused by di depends on airway compliance. methods bronchi were obtained following lung resection from cancer patients who had normal spirometry (n = ). lumen narrowing was measured using a servo-control system which set transmural pressure and simulated breathing movements. bronchi were contracted to carbachol (cch × − m) during tidal breathing (from to cmh o, i.e. Δ cmh o transmural pressure, . hz) and infl ated to three different amplitudes of di (Δ , or cmh o) applied following contraction. results in cch-contracted airways, all three di amplitudes produced a transient bronchodilation. increasing the di amplitude caused a greater increase in luminal volume during the di and a greater bronchodilation following the di (p < . ). cch itself cause approximately a % fall in specifi c compliance (p < . ), which was reversed by di (p < . ). for each di amplitude, the change in lumen volume during the di was positively correlated to the specifi c compliance of the bronchi before di (r > . , p < . ). conclusions isolated human bronchi show a bronchodilation response to di that is proportional to the expansion of the airway caused by the di. the amount of stretch produced by a di depends on airway wall compliance suggesting that increased airway stiffness in disease could suppress the di response by limiting the stretch of bronchi during lung infl ation. confl ict of interest none. ja douglass , , , ea yu , , br thompson , , , gg king , , mj abramson , introduction increasing asthma prevalence and changes in environmental exposure suggest that there may be a relationship between asthma and dietary intake. however, to date, few studies have examined how dietary intakes of asthmatics differ from a healthy population. aim to measure and compare the dietary intakes of adults with stable asthma and healthy controls. methods in a cross-sectional study, dietary intakes calculated from a item food frequency questionnaire (ffq) of adults with stable asthma (n = , age years ± (sd)) were compared with intakes of healthy controls (n = , age years ± (sd)) matched for age and body mass index (bmi). spirometry, airway responsiveness to hypertonic saline, and induced sputum cell counts were also measured. results subjects with severe persistent asthma (n = ) had signifi cantly higher total fat intake than healthy controls ( ± (sem) versus ± (sem) g/day p = . ) and signifi cantly lower fi bre intakes ( ± (sem) versus ± (sem) g/day p = . ). lower fi bre intake in asthmatic subjects (n = ) was associated with lower %predicted fev (r = . , p = . ), %fvc (r = . , p = . ) and fev /fvc (r = . , p = . ). higher fat intake and lower fi bre intake were associated with higher absolute concentrations of sputum eosinophils (r = . , p = < . , n = ). conclusions subjects with severe persistent asthma have an eating pattern of lower diet quality with higher intakes of fat and lower intakes of fi bre than healthy controls, which is related to lower lung function and increased airway infl ammation. factors leading to altered dietary intake in severe asthma require further investigation. methods a randomized, placebo-controlled, single-blinded trial of tailored asthma education including device technique and utilizing pact to address patients' concerns versus brochure-only information for asthma patients over age . measurements of lung function, asthma control (acq), asthma related quality of life (aqol), medication use and adherence score (adh) were obtained at baseline, and months using standard, validated questionnaires. results sixty-fi ve participants ( f m, mean age ± . ) were randomized to the intervention group and ( f m, mean age ± . ) to the control. there were no statistically signifi cant differences between the groups' demographics or baseline measurements. a wilcoxon signed ranks test used to compare median pair ranking at baseline and months post-intervention revealed a signifi cant improvement in the active, but not the brochure-only information group at months in: acq mean ± sd = . ± . vs. . ± . (p = . ). aqol mean ± sd = . ± . vs. . ± . (p = . ). adh mean ± sd = . ± . vs. . ± . (p < . ). conclusion an educational intervention including device technique and addressing the concerns of older people with asthma signifi cantly improved acq, aqol and adh scores at months post-intervention. introduction greater exposure to ultraviolet radiation (uv) may increase the risk of allergic disease, but this association has not been investigated using estimates of time spent outdoors by individuals. the aim of this study was to investigate the relationship between self-reported doctor-diagnosed asthma and/or hayfever, and time spent outdoors. methods this analysis was based on cross-sectional baseline data from a subsample of the australian and up study, comprising men and women aged - years, living in new south wales. participants were randomly selected from the australian universal health insurance database. diagnoses of asthma and/or hayfever and the number of hours spent outdoors were derived by questionnaire. in general, the odds of a diagnosis of asthma and/or hayfever decreased with increasing time spent outdoors for both women and men. for example, in women, the adjusted odds ratios for asthma with hayfever were . ( % ci: . - . ), . ( . - . ), . ( . - . ) and . ( . - . ) for - , - , - and > hours spent outdoors on weekends, respectively, compared with < hour (p trend < . ). time spent outdoors was not associated with a diagnosis of asthma alone in men. conclusions there were statistically signifi cant inverse associations between time spent outdoors and diagnoses of asthma, hayfever or asthma with hayfever, in a large population of older australians. exposure to uv may protect against the development of allergic diseases, such as asthma and hayfever. no. background allergic rhinitis (ar) and eczema are highly prevalent and females are more commonly affected than males in adulthood. although there have been extensive studies on ar and eczema in females, little is known about the effect of reproductive factors and the development of late-onset ar/ eczema. we examined potential associations between reproductive factors and ar and eczema using the tasmanian longitudinal health study (tahs) data. methods the tahs is a population-based cohort study of respiratory disease. two thousand seven hundred sixty-four ( . %) females from the original tahs participants were surveyed in using postal questionnaire which collected information on reproductive factors such as ever pregnancy, age at fi rst child birth, use of oral contraceptive pills (ocp) and age of starting using the ocp. logistic regression was used to assess the predictors of ar and eczema and all analyses were mutually adjusted. of the participants, . % (n = ) had late-onset ar and . % (n = ) had late-onset eczema. maternal and paternal atopy were signifi cantly associated with ar (p < . ). the risk of developing eczema was decreased signifi cantly with increasing age at fi rst menstruation (or: . , % ci: . - . ) and the increased age at birth of fi rst child ( . , . - . ). a decreased risk in ar was observed with the increasing number of pregnancies ( . , . - . ). however, the associations between age of starting using ocp and ar/eczema were not signifi cant. conclusion later age at start of menses and later age at fi rst pregnancy were associated with a reduced risk of eczema which may be related to hormonal dysregulation. tp- airway responsiveness at and years is associated with asthma at years introduction asthma is the most common chronic childhood disease in australia. increased airway responsiveness (ar) is associated with asthma but not all individuals with increased ar have asthma. the perth infant asthma follow-up study recruited a birth cohort of individuals who have undergone longitudinal assessments of many factors associated with childhood ar. our previous work reported an association between increased ar in infancy and asthma at and years. aim to look at the relationship of increased ar and asthma in early adulthood at different time points from birth. methods individuals were recruited from among expectant parents attending an antenatal clinic at a local metropolitan clinic. at ages , and months and again at , and years, participants underwent an assessment that included a respiratory questionnaire and determination of ar (as evidenced by dose-response slope (drs) to histamine using the rapid technique). results children were initially recruited and studied in infancy. two hundred three, , , , and children subsequently had ar assessed at , and months, , and years, respectively. there was a signifi cant relationship between drs at and years and for both asthma at years (p = . and p < . , respectively) and 'wheeze in the past year' at years (p = . and p = . , respectively). there was no significant relationship between drs in infancy and asthma at . conclusion ar at and years is associated with asthma at years. in this study, there was no signifi cant relationship between ar in infancy and asthma at years. the pcaas has found that . % of children with acute asthma presenting to the princess margaret hospital for children emergency department (pmh ed) had hrv, of which % were hrv group c. furthermore, hrvc was associated with more severe attacks. however, the prevalence of hrvc in the community is unknown. aim to test the hypothesis that hrvc would be found more often in children requiring emergency treatment for an ari than sibling controls and determine the impact of days since symptoms began on the prevalence of hrv detection in children with an acute respiratory illness (ari) and sibling controls (sibs). methods ari (n = ) had nasal samples collected on presentation to the pmh ed and sibs with symptoms of a cold (n = ), within week of ari recruitment. viral rna was extracted and reverse transcribed. a two-step pcr of the hrv ' utr was used for detection, followed by dna sequencing for typing. results ari and sibs were % and % male, % and % asthmatic, with mean ages of . and . years, respectively. hrv +ve ari (n = , mean ± sd days of symptoms = . ± . ), hrv -ve ari (n = , . ± . ), hrv +ve sibs (n = , . ± . ) and hrv -ve sibs (n = , . ± . ). of the and hrv +ve ari and sibs, % and % had hrvc. conclusions hrvc is as common in children who have hrv but do/do not require hospital treatment. detection of hrv is more likely when the nasal sample is collected soon after the appearance of cold symptoms. support nhmrc program grant. nomination nil. introduction upper airway dysfunction may make asthma more diffi cult to control and should be suspected in asthmatics refractory to prescribed medical therapy. aim a novel imaging technique, dynamic -slice computerized tomography (ct), was used to examine laryngeal behaviour in healthy and asthmatic individuals. method vocal cord movement was imaged using -slice ct larynx. healthy volunteers were studied to develop and validate an analysis algorithm for quantifi cation of normal vocal cord function. further studies were then conducted in patients with diffi cult-to-treat asthma. in eight severe asthmatics with abnormal vocal cord movement, asthma outcomes were measured after speech therapy. results vocal cord movement was quantifi ed over the breathing cycle by ct using the ratio of vocal cord diameter to tracheal diameter. normal limits were calculated, validated and applied to evaluate diffi cult-to-treat asthma. vocal cord movement was abnormal with excessive narrowing in of ( %) asthmatics and severe in nine ( %) patients (abnormal > % of inspiration or expiration time). after speech therapy in a small subgroup, asthma symptoms and morbidity improved. conclusion non-invasive ct larynx quantifi cation of vocal cord movement was achieved. this new approach has identifi ed frequent upper airway dysfunction in asthma with potential implications for disease control and treatment. aim to investigate the characteristics and mechanisms of chronic cough (cc) following acute respiratory illness from laboratory-confi rmed h n infl uenza. methods subjects who had current symptoms and had been tested for h n infl uenza by pcr assay participated in this study. twenty-one of those continued onto clinical testing. investigations to assess cough included symptom questionnaires, hypertonic saline challenge and cough monitoring. results of the participants, % tested positive for h n and % tested negative for h n . h n -infected participants were younger and predominantly female. the prevalence of post-h n cc was . %, and for non-h n infection, . %. objectively measured cough frequency was times greater; there was a -fold increase in cough refl ex sensitivity, and greater quality-of-life impairment in the participants with chronic post-infectious cough than the non-cough participants. conclusions cc was found to be relatively common, mild in severity and tending to resolution with time. the characteristics of post-h n cc were similar to other post-infectious cough and were associated with cough refl ex hypersensitivity. aim upper airway dysfunction may accompany acute severe asthma, but this has not been investigated. a novel imaging technique, dynamic -slice computerized tomography (ct), was used to examine laryngeal behaviour in acute asthma exacerbation. methods patients were studied in the emergency department or as acute inpatients following admission for an acute exacerbation of asthma. vocal cord movement was imaged by -slice ct larynx and compared to normal vocal cord movement in a healthy cohort. results vocal cord movement was abnormal with excessive narrowing during either inspiration, expiration or both in of cases ( . %) with acute severe asthma. imaging again revealed that laryngeal dysfunction characterized the movement abnormality, rather than isolated vocal cord dysfunction. radiation exposure was low and generally < milli-sievert. conclusion non-invasive ct larynx quantifi cation of vocal cord movement was effectively achieved in acute severe asthma. we identifi ed frequent upper airway dysfunction in acute severe asthma suggesting that treatment of upper airway obstruction (e.g. using bipap) may be merited during asthma exacerbation. aim to determine whether eicosanoids could alter the deposition of extracellular matrix (ecm) proteins and cytokine release from human airway cells. methods airway smooth muscle cells (asm), fi broblasts and epithelial cells were stimulated with leukotrienes b , c , d , e and the prostaglandins e , d , f α and the pgi analogue mre- . after hours, culture medium was collected and il- and il- production and cell deposited ecm proteins tenascin c, fi bronectin and perlecan were assessed by elisa. to determine whether eicosanoids infl uenced cell proliferation, manual counting of cells in the experiments were carried out before and after stimulation. results neither leukotrienes or prostanoids altered cell proliferation after days of stimulation (n > ). leukotrienes had no effect on ecm protein deposition or cytokine release from asm or fi broblasts (n > ). leukotrienes did not alter either parameters in epithelial cells except leukotriene d , which increased tenascin c deposition (n = , p < . ). prostanoids induced il- and il- and other various changes in asm and fi broblasts (n > , p < . ) (see below). introduction the function of asthmatic airway epithelium is disrupted facilitating immune and infl ammatory responses resulting in epithelial damage. human rhinovirus (hrv) causes asthma exacerbations in children; however, paucity exists on how it affects barrier function. this study assessed how hrv infection affects epithelial barrier function and integrity in healthy and asthmatic epithelium. methods adult balb/c mice were intranasally infected with hrv- b and followed for days. tight junction (tj) expression was assessed using immunohistochemistry (ihc) and western blot analysis. primary airway epithelial cells from healthy and asthmatic children were assessed for tj gene and protein expression by qpcr and ihc, respectively. results occludin and zonal occludin- (zo- ) expression was lost and sustained in mice infected with hrv- b however was not observed in shaminjected mice. asthmatic airway epithelial cells were found to exhibit elevated basal gene expression levels of tjs (zo- , occludin and plakophilin- (pkp- )) but markedly lower corresponding protein levels. conclusion hrv- b compromises barrier function in vivo through sustained loss of tj proteins. the marked decreased expression of tj proteins in paediatric asthmatic epithelium may contribute towards increased susceptibility to viral infections. disparity between gene and protein tj expression could indicate either post-transcriptional regulation or compensatory effects by other tj proteins and requires further study. supported by asthma foundation wa; nhmrc. confl ict of interest none. conclusion leukotrienes alone did not affect the ecm proteins and cytokines assessed in this study. prostanoids decreased ecm protein deposition whilst increasing cytokine release without affecting cell proliferation. this study shows that prostanoids may have a more pronounced role on direct ecm remodelling than leukotrienes in airway cells. supported by merck. background toll-like receptor (tlr) is an innate immune receptor involved in the initial detection of pathogen-associated molecular patterns. the effect of ageing and chronic obstructive pulmonary disease (copd) on tlr responses and the impact of these innate immune responses in copd pathogenesis remain unclear. hypothesis expression and activity of tlr on peripheral blood mononuclear cells (pbmcs) is increased with healthy ageing and further increased in copd. methods pbmcs from healthy controls < years and > years; and participants with copd (n = per group) were cultured with or without pam c ys k (tlr agonist). cells and supernatants were collected at hours and protein (cytometric bead array or fl ow cytometry) and gene (real time pcr) expression was examined. results tlr activation led to increased release of interleukin (il)- , , β, and tumor necrosis factor (tnf)-α. tlr gene expression was increased with stimulation; however, cell surface receptor levels were unchanged. there was no difference in the level of tlr between the groups. in older people, tlr activation resulted in less il- β and tnf-α release, but similar release of il- and il- . similar results were seen in copd. at baseline in copd, there was up-regulation of tnf-α gene expression compared to the older healthy group; however, the tlr cytokine response did not differ between the groups. conclusion healthy ageing is characterized by an impaired systemic proinfl ammatory cytokine response to tlr -mediated innate immune activation. this effect persists in copd and is selective in the cytokine pathways involved. these altered infl ammatory mechanisms may affect responses to infection and injury impacting disease pathogenesis and warrant further evaluation. aim to investigate whether the inhibition of matrix metalloproteinase- (mmp- ) by a non-selective mmp inhibitor (doxycycline) and the specifi c mmp- inhibitor i (olic acid) can regulate cellular migration of tsc -null mouse embryonic fi broblasts (mefs), which act as a model for lymphangioleiomyomatosis (lam) cells, as compared to wild-type mefs. methods wild-type (tsc -positive) and tsc -null mefs were treated with diluent, doxycycline ( . pg/ml- μg/ml) or olic acid ( . - μm) for hours. mmp- levels were assessed by zymography and elisa. cell migration for hours was measured using a transwell migration assay. results under basal conditions, mmp- release and cellular migration was . -fold and . -fold higher, respectively, in tsc -null mefs compared to tsc -positive mefs (mmp- release, tsc -null (n = ) and tsc -positive (n = ), p < . ; cell migration, tsc -null (n = ) and tsc -positive (n = ), p < . ). mmp- release was reduced in tsc -null mefs after -hour treatment with doxycycline ( and μg/ml, n = , p < . ) and with olic acid ( - μm, n = , p < . ). treatment with doxycycline ( pg/ml- μg/ml, n = , p < . ) or olic acid ( - μm, n = , p < . ) also signifi cantly reduced cell migration of tsc -null mefs. copd is a leading cause of death worldwide. treatments are limited and restricted to symptomatic care. there is an urgent need for new treatment options targeting the infl ammation. tissue damage in copd is thought to result from an inability of the normal repair processes with accumulation of apoptotic material and impaired clearance of this material by macrophages in the airways. lung infl ammation and macrophage function involves the bioactive sphingolipid sphingosine -phosphate (s p). multiple studies have showed the involvement of these components in infl ammation. methods we investigated lung tissue samples from patients (copd or non copd controls) undergoing curative lobectomy for lung cancer. we analysed the mrna expression profi le, the sphingosine-kinase (sphk) protein activity and the localization and expression of individual proteins. results we show in this study for the fi rst time a comprehensive expression profi le of all synthesizing enzymes, receptors and degrading enzymes in the human lung. correlations between receptor subtypes, degrading enzymes and between s p receptor subtype were detected. multivariance anova showed that in copd, the relative mrna expression of s p receptor subtype was reduced. conclusion the correlations between receptors and enzymes involved in the sphingosine kinase signalling system in the lung suggest common regulatory mechanisms. s pr is expressed on dendritic and nk cells which are reduced under conditions of copd. therefore, our fi ndings of reduced s pr in copd may provide a novel target for pharmacotherapy. lung cancer is responsible for more cancer-related deaths than colon, breast and prostate cancers combined. in patients with copd and/or lung cancer, we have shown a reduction in lung and airway macrophage function, evident by a reduced ability to phagocytose apoptotic airway epithelial cells and neutrophils. the potential for lung cancer cells to directly inhibit this function (a potential immune evasion mechanism) has not been investigated. background kinins have been implicated in airway lung diseases such as asthma and lung cancer by regulating infl ammation, cell proliferation and migration. the effect of kinins is mediated through the binding of two receptors, kinin b and b receptors (b r and b r). a novel b r splice variant (sv) resulting in a shorter ' untranslated region (utr) was identifi ed in cultured airway epithelial and fi broblasts as well as in lung carcinoma tissue and leukocytes. this study aims to characterize the functional role of the novel b r sv in mrna stability, translation effi ciency and receptor expression in cultured airway epithelial cells. methods stability of b r sv was determined by measuring b r mrna levels over time in h cells after actinomycin d treatment. translational effi ciency of wt and sv 'utr was determined by measuring luciferase activity in transfected h cells. expression of wt and sv transcripts through q-rtpcr were compared in cells treated with a b r-specifi c agonist dakd. cell-surface receptor expression post-agonist stimulation was quantifi ed using facs. results mrna stability studies indicated that b r sv was ≈ % less stable than the wt transcript in h cells suggesting a stabilizing element 'utr. translation effi ciency of sv was no different to wt b r. dakd stimulation increased both wt and sv transcripts early in the time course, although the peak expression of wt and sv differed at hours and hours, respectively. dakd stimulated cells showed two phases of receptor expression, ( ) decrease of cell surface receptor up to . hours post-stimulation; ( ) increase in cell surface b r after . hours. conclusion this study has identifi ed a novel regulatory mechanism of b r expression through the production of a sv that alters the 'utr. the translation effi ciency of b r is not affected, but the sv was less stable than the wt in h cells and may play a role in allowing quicker changes in transcription. agonist-induced up-regulation of transcripts in a time-dependent manner may be important in maintaining a chronic response during infl ammation. circulating lymphocytes are increasingly used as a surrogate cell type to refl ect changes in adrβ density elsewhere in the body, particularly the respiratory system. however, adrβ density is non-uniform among lymphocyte subsets and it is unclear if, and the degree to which, adrβ density varies between individuals. aim to assess the extent of variability in adrβ density on human peripheral blood mononuclear cells (pbmc) including lymphocytes and monocytes. method pbmc were isolated from blood of healthy subjects by density gradient centrifugation with ficoll-paque. cell surface and total adrβ of intact and permeabilized lymphocytes (cd +) and monocytes (cd +) were measured using anti-adrβ via facs. geometric mean fl uorescence (gmf) was used as the indices for adrβ density per cell. result surface adrβ -gmf increased by . -and . -folds over negative controls for lymphocytes and monocytes, respectively. magnitude of foldchange was not signifi cantly different between these cells (p = . ), but the distribution of gmf intensity between samples suggests greater variability in adrβ density in lymphocytes versus monocytes (p = . ). proportion of cells-stained adrβ -positive was signifi cantly higher in monocytes versus lymphocytes ( . ± . % vs. . ± . %, p = . ). total adrβ -gmf increased by . ± . and . ± . -folds for lymphocytes and monocytes, respectively (p > . ). proportion of adrβ -positively stained cells were similar between samples (lymphocytes %, monocytes %, p = . ), but greater variability was observed for lymphocytes (range - %) versus monocytes ( - %). conclusions despite similarities in surface and total adrβ density, lymphocytes display greater inter-subject variability compared with monocytes. this will have implication in experimental designs and interpretation of changes in adrβ density in studies using human pbmc as an alternative to primary cells from the organ of interest. confl ict of interest no. pge plays a protective role in asthma by inhibiting airway infl ammation. it is predominantly produced by epithelial cells in response to pro-infl ammatory stimuli and acts as an autocrine and paracrine mediator. on the contrary, il- β is a highly potent cytokine that induces many pro-infl ammatory effects in the human airway including activation of the human lung epithelium which promotes production of pro-infl ammatory cytokines and chemokines. airway epithelial cells express all four known pge (e prostanoid (ep) receptors, but mechanisms underlying the regulation of expression of ep receptors in human lung epithelial cells have remained elusive. therefore, we investigated whether pge , an endogenous protective mechanism of the airways, can modulate il- β infl uence on ep receptor expression in human epithelial cells. methods ep receptor mrna and protein expression was quantifi ed in -hbe cells at basal levels and following stimulation with il- β or pge alone, or simultaneously, using real time rt pcr and facs analysis, respectively. results pge up-regulates all four ep receptors at mrna level, while il- β up-regulates ep , ep and ep and does not infl uence expression of ep . at protein level, preliminary results show transient increase of ep receptors in the presence of pge , while il- β down-regulates this receptor. ep and ep are up-regulated following stimulation with both stimuli. importantly, antiinfl ammatory ep receptor is up-regulated only in the presence of pge . conclusion we show for the fi rst time that pge may infl uence expression of its own receptors and oppose the effect of il- β in human lung epithelial cells. this may in turn alter pge production and autocrine activation with potential implication on the function of epithelial cells, which is important in modulation of immune response in asthma and lung infl ammatory diseases. nomination nil. confl ict of interest no. the burden of obstructive lung disease (bold) study is an international study designed to measure the prevalence, risk factors and burden of copd. data collection using the bold protocol has been undertaken at eight sites with inclusion of urban, rural, coastal and inland regions of australia. methods a random sample of adults aged ≥ years was identifi ed. information on respiratory symptoms and diagnosed copd were collected by questionnaire. post-bronchodilator fev and fvc were used to defi ne gold stage. the (un-weighted) prevalence rates are presented by age groups and sex. results s timmins , , , , g king , , , , c salome , , , r schoeffel , , , c walsh , , the extent of emphysema could increase ventilation heterogeneity independently of its effects on airway narrowing. the aim of this study was to examine the relationship between emphysema extent on computed tomography scans (ct), and airway narrowing and ventilation distribution in copd. methods subjects with copd underwent ct scanning, spirometry, dlco and nitrogen washout by single and multiple breath techniques. closing capacity (cc/tlc%), slope of phase iii (Δphase iii ) and indices of ventilation distribution conductive (scond) and diffusion-dependent airways (sacin) were derived from washouts. helical ct scans were performed at tlc. emphysema extent was measured as low attenuation areas < − hu using osirix program, expressed as % of ct total lung volume. results subjects were of mean (range) age years ( - ), bmi . ( . - . ), fev of ( - %) %predicted and dlco of ( - ) %predicted. emphysema extent was . % ( . - . ). geometric mean (ci) Δphase iii was . ( . - . ), sacin was increased at . l − ( . - . ) and cc/tlc% was % ( - ). emphysema extent correlated with fev / fvc (r = − . , p = . ), dlco (r = − . , p < . ), bmi (r = . , p = . ), Δphase iii (r = . , p = . ), and sacin (r = . p = . ). in multiple regression analysis, emphysema extent was predicted by fev /fvc and Δphase iii (model r = . , p = . ). conclusions the extent of emphysema increases the heterogeneity of ventilation independently of any effects on overall airway narrowing. supported by australian lung foundation webster memorial award, crcaa. conclusions self-reported wheeze in the last months is very common in adults over years. in the younger age group ( - years), many people with wheeze did not have airfl ow obstruction or reversible spirometry at the time of test. aim to determine whether there is any association between change in fev among copd patients and ambient ultrafi ne particle number concentrations in melbourne. methods participants with mild to moderate copd were asked to measure their fev using a portable electronic spirometer (piko) two times a day (morning and evening) for consecutive days. the same procedure was repeated on average months later. ambient ultrafi ne (diameter < . μm) particle number concentrations were measured for the same period using an ultrafi ne condensation particle counter and micro-orifi ce uniform deposit impactor. results aim to examine the implementation of, and barriers and enablers to, six high-evidence recommendations for copd management, in copd hospital inpatients. method observational, mixed methods study in consecutive copd patients admitted to a tertiary hospital. demographic, disease and admission characteristics are recorded. implementation (or not) of smoking cessation, pulmonary rehabilitation, long-term oxygen use if hypoxaemic, medication use, vaccinations and plans for future exacerbations are determined from medical records and patient interviews. interviews with medical offi cers examine their perspectives on recommendation implementation. of pilot data in copd patients (mean (sd) age ( ) years, length of stay ( ) days), were current smokers and had severe copd ( moderate). highest levels of implementation were fl u vaccination (completed by gps, n = ), medication (but not spacer) use, and oxygen use if hypoxaemic (investigated and implemented in all suitable, n = ). pulmonary rehabilitation was discussed with half of the patients, but only severe patients with long length of stay accepted further rehabilitation. exacerbation plans were in place for patient, and newly initiated in patients. doctor interviews (n = ) confi rmed pulmonary rehabilitation was considered mostly for severely unwell patients, and use of exacerbation plans was inconsistent. conclusion pilot data suggest pulmonary rehabilitation is offered and accepted by a small subset of copd patients. findings from this pilot will inform planned larger observational studies, and in turn, experimental studies to improve copd care. high-and extreme high-risk interventions were found by panel ( - . % extreme and . - . % high-risk interventions) and patients' respiratory physicians ( % extreme and % high-risk interventions). additionally, clinical pharmacist involvement was associated with many benefi ts such as: improvement in medication compliance, high level of patient satisfaction and identifi cation of patients with issues in medication knowledge. conclusion clinical pharmacist interventions were estimated to prevent extreme and high risks that might happen due to drug-related problems. clinical pharmacy consultation was associated with positive impact on other important measured outcomes. aerobic exercise training in the form of supervised -minute walks ( mw) reduces exertional dyspnoea in patients with copd. mw goal ( mwg) distances, aiming for a training effect, are generated from a baseline submaximal test ( -minute walk ( mwd), where wg = . × mwd/ × . aim to compare mwg with actual initial mw achieved and to examine the predictors of mwg achievers (ga). methods retrospective review of patients, % male, age ± years (mean ± sd), fev ± %predicted, who completed pulmonary rehabilitation (pr). patients were assessed at baseline and post-completion of pr. initial mwg was calculated from the best of two mwd at initial assessment and ga were defi ned as patients who achieved their mwg at their fi rst visit to pr. results for the group, there was a statistically signifi cant but not clinically signifi cant difference between mwg and actual mw achieved ( ± m vs. ± m, p < . , paired t-test). the patients ( %) who achieved their mwg exceeded the goal by ± m, whereas the patients who did not achieve their mwg fell short by ± m. there was no signifi cant difference between ga and non-ga in age or lung function, but ga had a higher initial mwd, with fewer rests, lower dyspnoea score and lower hr at start and fi nish (p < . , unpaired t-test). ga were also more likely to have a clinically signifi cant response to pr, measured by mwd, compared with non-ga (mean change m vs. m, p < . , chi-square). conclusion mw goals as currently calculated either signifi cantly underestimate or overestimate actual mw achieved. it may be that in non-ga, the mwd is functioning as a true maximal test and these are a group of patients who are truly ventilatory-limited, rather than deconditioned. the receptor for advanced glycation end products (rage) is a key candidate for promoting a self-perpetuating cycle of infl ammation and thereby is a major contributor to numerous chronic disease states. the potential of rage to function as a switch converting a transient infl ammatory response such as one generated by cigarette smoke to sustained cellular dysfunction allows it to act as a mediator for ongoing infl ammation in chronic obstructive pulmonary disease (copd). although the molecular mechanisms regulating rage expression have not been fully elucidated, altered rage activity arises from polymorphisms within the rage gene and its promoter. three polymorphisms in the rage promoter (− t/a, − t/c and a bp deletion from − to − ) increase transcriptional activity and rage expression. the rage g s allele results in an increased ligand-binding affi nity and activation of the infl ammatory mediators with subsequent up-regulation of infl ammatory response. the aim of this pilot cross-sectional study was to investigate the relationship between three known rage polymorphisms (− t/a, bp deletion, g s) and copd and disease severity. methods genomic dna was isolated from peripheral blood lymphocytes. pcr and taqman assays were used to genotype the three rage polymorphisms in copd patients, healthy non-smokers and healthy smokers. fev was measured in all subjects. disease severity was defi ned using gold guidelines. results there was no statistically signifi cant association between bp deletion and copd (p = . ), − t > a and copd (p = . ), g s and copd (p = . ). conclusion no association was found between the − t > a, bp deletion and g s polymorphisms and copd, disease severity or fev introduction the receptor for advanced glycation end products (rage) mediates neutrophil traffi cking and is implicated in the pathogenesis of chronic airways disease. we determined whether changes in airway and systemic levels of soluble rage (which acts as a receptor decoy to limit rage activation) and rage ligands are related to neutrophilic infl ammation in asthma and copd. methods bronchial lavage (bl) fl uid from subjects with moderate-severe persistent asthma or copd, and healthy controls were analysed for neutrophils, total srage (cleaved and secreted), secreted srage (esrage) and the rage ligands hmgb and serum amyloid a (saa). systemic levels srage and esrage were also determined in asthmatic and copd subjects. aims increased numbers of neutrophils are found in the lungs of copd patients, which contribute to airway infl ammation. while cigarette smoke exposure is the major risk factor for copd, it is unclear how cigarette smoke modifi es neutrophil function and activity. this study aimed to assess the effect of cigarette smoke extract (cse) on neutrophils in an in vitro model. methods neutrophils were isolated from peripheral blood donated by volunteers using percoll density gradient centrifugation. neutrophils were seeded in well plates ( cells/well), exposed to different concentrations of cse ( %, %) and monitored at , and hours. at each time point, viability of neutrophils was measured by trypan blue exclusion and supernatant was collected for measurement of cxcl release by elisa (r&d systems conclusions in neutrophils exposed to cse, viability is maintained and cxcl release increases with increasing dose of cse. we conclude that cigarette smoke stimulates an infl ammatory response by neutrophils, which would contribute to the infl ammatory burden in the airways in copd. introduction factor viii (f ) and collagen iv (c ) antibodies are used for quantifying vessels in tissue sections. we compared these two antibodies for vessels staining in bronchial biopsies (bb) in copd. methods bb from healthy non-smokers (h-n) and copd subjects were stained for both antibodies. number, area and mean vascular size (mvs) (surface area/vessel number) of vessels in the lamina propria (lp) to the depth of μm were measured and compared between the two antibodies and are reported as median (range). results number of vessels was not signifi cantly different between the two methods of staining. in copd and h-n, vascular area (μm /μm of lp × ) stained with f was less than that with c ( . ( . - ) vs. ( - . ), p < . and . ( . - . ) vs. . ( . - . ), p < . introduction previous studies have shown that c-reactive protein levels increase at the onset of some copd exacerbations; however, there is limited data on the normal fl uctuation in crp levels in stable patients. aim to investigate within patient variation in crp levels to determine the magnitude of normal day-to-day fl uctuations in stable patients and the correlation with patients' perception of symptom severity. methods early morning crp levels were measured on days , and from patients from the melbourne copd cohort (gold category ii-iv) who identifi ed themselves as stable. patients recorded daily symptom scores including: borg dyspnoea scale at rest, severity of wheeze, cough, dyspnoea, change in sputum colour or volume, night-time waking and the presence of viral symptoms. crp levels were measured by the clinical pathology service and using a point-of care device. variation in crp levels in stable copd and correlation between change in crp levels and symptoms were analysed. aim patient-completed diaries monitoring changes in key symptoms in copd are often used to recognize acute exacerbations (ae) both to prompt additional treatment and monitor treatment effi cacy. we assessed diary compliance and the predictive value of major symptoms of aes which required hospital attendance. methods inpatients recruited during an ae of copd completed daily paper or web-based diaries for months, recording changes from their stable state for: breathlessness, cough, sputum, subjective 'wellness', physical activity and use of reliever ( -point scale, mid-pt = no change). the predictive value of current and lagged symptom scores was compared for each and between symptoms. diagnostic accuracy was assessed by area under the curve (auc) and at specifi c cut-points. in participants ( m, f) with mean age ± and mean fev % predicted ± , there were such aes involving patients. duration of diary keeping was shorter with lower education attainment (p = . ), but compliance did not vary for other demographic or clinical factors. daily compliance while diaries were being kept was %. excluding the current day, the best predictor was the distributed lag score over days, sputum changes giving the strongest signal; relative risk . ( % ci . to . ) with most of the signal in the days prior to the ae. little was gained by combining symptoms. the predictive value was moderate auc = . . conclusions compliance with symptom diaries in severe copd is surprisingly good. however, with only a weak signal for an impending ae requiring hospital attendance up to hours before and for lagged symptom scores over days before, with low positive predictive values, the utility of keeping daily symptom diaries for raising alerts for impending severe aes in copd is questionable. results seven studies with inpatient participants were identifi ed; published as abstracts for which data were not available did not contribute to meta-analyses. no study specifi ed diagnostic criteria for copd and only one specifi ed ae criteria. short course treatment varied between - days and longer duration - days; studies used oral prednisolone (dose mg, studies, tapered dose) and studies used intravenous scs treatment. mean ages of participants ranged from to years. primary outcomes: likelihood of treatment failure did not differ by duration of treatment (odds ratio . ; % ci . to . ) ( studies, n = ). fev did not differ signifi cantly when measured up to days (mean difference (md) − . l; % ci − . to . ) or after days (md − . l; % ci − . to . ) ( studies, n = ). secondary outcomes: limited data ( study) precluded meta-analysis for readmission or mortality. the likelihood of an adverse event ( studies, n = ) was not signifi cantly lower for shorter scs (or . ; % ci . to . ). conclusions we found no signifi cant differences between short (≤ days) and longer (> days) corticosteroid therapy for ae of copd. this has implications for clinical practice and may reduce adverse effects for patients, shorten hospital admissions and reduce costs, but more studies are needed to confi rm these fi ndings. aim to explore factors which infl uence the self-management of exacerbations in patients with copd. methods a pilot cross-sectional study was undertaken to assess patients' compliance with their action plan and their action taken prior to an admission. patients were interviewed during an admission to hospital for exacerbation of copd. the effect of pulmonary rehabilitation on patients' knowledge of copd was also assessed. results % of patients were provided with a written action plan, and % with a verbal action plan. in response to an exacerbation, more than % of the patients stated that they used their action plan. however, where action plans were not adequately utilized, patients delayed seeking medical attention and failed to initiate oral prednisolone and antibiotics during an exacerbation despite being prescribed an emergency supply of these medications. pulmonary rehabilitation had a positive outcome towards enhancing the patients' knowledge of copd. clinical pharmacists have limited involvement in terms of copd and smoking cessation education. conclusion the need to offer a thorough self-management program along with providing a more comprehensive written action plan will encourage patients to start early treatment and follow their action plans. encouraging collaboration between the hcp and patients encourages self-management through discussing and agreeing on goals of treatment and developing a personalized written action plan. context dyspnoea is a common symptom in copd and increases during exacerbations. when respiratory failure supervenes, and assisted ventilation is required, non-invasive ventilation (niv) is the treatment of choice. objective to determine if niv relieves dyspnoea in inpatients with acute respiratory failure due to exacerbations of copd. data sources english language randomized controlled trials (rcts) published prior to august were identifi ed using medline, embase, cinahl, psychinfo and pubmed. additional studies were identifi ed by reviewing the reference list of included studies. search terms included niv, nippv, nppv, bilevel cpap, bipap, artifi cial ventilation, copd and randomized controlled trial. study selection rcts comparing usual medical care (umc) to umc plus niv and measuring dyspnoea at relevant time points were included. abstracts for potentially relevant articles were extracted by one author. these were assessed by a second author to ensure inclusion criteria were met. articles were reviewed to determine if dyspnoea was measured and appropriate statistical analysis reported. the search yielded individual articles. four articles met the review criteria. three articles fi nd that niv relieved dyspnoea to a statistically signifi cant level and two suggested that the relief of dyspnoea is clinically signifi cant. discussion in spite of the common use of niv to relieve dyspnoea, little work has analysed effi cacy in terms of this patient-reported outcome. while our results may suggest niv relieves dyspnoea, reporting or methodological fl aws in several articles limit the strength of the conclusions that may be drawn. these limitations make the conclusion that niv relieves dyspnoea contentious. conclusion despite over two decades of studies investigating niv, the therapeutic impact on breathlessness is poorly described. understanding the impact of niv on patient-reported outcomes is of critical importance in clinical care. confl ict of interest none. introduction in mice, the most direct lung dosing method delivers the agents directly into the trachea. for our cystic fi brosis gene-therapy studies, we deliver fl uids -an airway pretreatment followed by a lentiviral vector -directly into the mouse trachea to target conducting airways. despite using standardized delivery techniques, we see substantial variability in the amount and location of gene transfer. aim the aim of this experiment was to use synchrotron x-ray imaging to track the dynamics of fl uid doses delivered into the live mouse trachea. methods four nembutal anaesthetized c bl/ mice were imaged on the bl b beamline at the spring- synchrotron. mice were intubated and ventilated at br/min with image captured per breath. after minute of baseline, a -μl sample of iodine-based contrast fl uid (a surrogate for our airway pretreatment or gene-vector) was delivered over seconds. following minutes of data collection, an additional μl bolus was delivered over . seconds. image capture continued for a further minutes. frame differencing was used to reveal fl uid motion. results substantial dose losses may occur upon delivery into mouse trachea via immediate retrograde fl uid motion. the speed of bolus delivery into lung may also infl uence the relative targeting of conducting airways and deep lung. introduction use of effi cient nebulizers can enhance the quality of life of cf patients by reducing the treatment time and improving drug delivery effi ciency. the aim of this study was to determine which commonly recommended nebulizer was optimal for delivery of the most commonly used therapies to cf. methods seventeen children with cf ( - years) were recruited. delivery of three commonly used cf therapies ( % hypertonic saline ( ml, . g/ ml), tobramycin ( ml, mg/ml) and pulmozyme ( . ml, mg/ml)) by two vibrating membrane nebulizers, the eflow rapid and the aeroneb go, and a jet nebulizer lc sprint junior with pariboy sx ( . l/min) were tested. for each drug-nebulizer combination (in random order), each child was asked to inhale through an inspiratory fi lter, and drug delivery to the fi lter was measured. pulmozyme was quantifi ed using an enzymatic activity assay, tobramycin was measured using hplc and hypertonic saline was measured using conductivity. total nebulization time was recorded. the results showed that there was no difference in the amount of drug delivered to patients when the nebulizers were compared for all three therapies (p > . ). however, the nebulization time for the eflow rapid was signifi cantly shorter than that for the aeroneb go and lc sprint junior. similarly, the nebulization time for aeroneb go was shorter than that for the lc sprint junior (p > . ) for all therapies). conclusion overall, there were no signifi cant differences between nebulizers in delivered dose for three forms of cf therapy, due to inter-patient variability. despite this, both vibrating membrane nebulizers had shorter nebulization times than the lc sprint junior, with the eflow rapid delivering drug in the shortest time. confl ict of interest nil. introduction as the life expectancy of patients with cystic fi brosis (cf) increases, treatment-related morbidity is increasingly recognized. totally implantable venous access devices (tivads) offer reliable long-term central venous access but are associated with recognized complications including venous thrombosis. superior vena cava syndrome (svcs) however has been rarely reported in this setting. we report a single cf centre's experience of svcs associated with tivads. methods retrospective review of episodes of svcs in patients with cf and a tivad attending the adult cf centre, prince charles hospital, queensland. results between february and december , fi ve episodes of svcs occurred in patients with tivads from a clinic population of patients. all of the affected patients were female, with moderately severe lung disease (mean fev predicted . %). no patients had a recognized thrombophilia. four tivads were inserted at a centre different to our own, three were on oestrogen-based contraception, and two suffered with dehydration at presentation. svcs treatment consisted of anticoagulation ( ), line removal ( ), angioplasty ( ), thrombolysis ( ) noninvasive bioluminescence imaging has allowed for rapid in vivo quantifi cation of long-lasting gene transfer in experimental animals. we are testing the longevity of a single nasal delivery of our lentiviral (lv) gene transfer system in mouse airways. methods normal (c bl/ ) and cystic fi brosis (cf) mice received a nasal bolus of lysophosphatidylcholine (lpc) or a control (pbs) pretreatment hour prior to delivery of a lv vector containing the reporter-gene luciferase (lv-luc). another control group received lpc hour prior to an empty vector (lv-mt). bioluminescence was measured at week, , , , , , , , and months post-lv dosing to assess gene transfer. results normal mice: mice that received lpc/lv-luc treatment had significantly greater gene transfer compared to the two control groups at all time points (p < . , rm anova). no luminescence was detected in mice treated with lpc/lv-mt. unexpectedly, luciferase activity was also detected in the lung. there was no difference in lung luminescence between the lpc and pbs pretreated mice that received lv-luc. cf mice: a statistically signifi cant increase in nasal luminescence persisted for up to months following lpc/ lv-luc (p < . , rm anova). similar to normal mice, there was no statistical difference in lung luminescence between mice that received lpc and pbs lv-luc. conclusions lentiviral luciferase gene expression was signifi cantly improved in mouse nasal airways using lpc pretreatment in both strains. however, the longevity of transduction was reduced in cf mice, which may, in part, be due to reduced animal numbers at the later time points tested. supported by nh&mrc. background the nintendo-wii® facilitates exercise-based programs that may be considered novel, fun and potentially motivating. objective exercise outcomes using the wii have yet to be reported in the cystic fi brosis (cf) adult population. aim to investigate nintendo-wii® exercise training compared with standard exercise in adult cf patients whilst hospitalized for treatment of a pulmonary exacerbation. methods a within-subjects, randomized cross-over study. adult cf participants received two -minute exercise treatment sessions within a -hour period, at least day apart, during the last days of hospitalization. wii exercise consisted interval training with games such as boxing, dancing and track exercises. standard exercise consisted of interval training on treadmill or cycle ergometer at - % of heart rate maximum. results participants completed the study (mean (sd) age ( ) years, % females), with a mean fev % of ( )%. during exercise, no difference was found between groups in average heart rate (p = . ), oxygen desaturation (p = . ), borg rate of perceived exertion (p = . ) or modifi ed borg for dyspnoea (p = . ). on vas ( - ), participants reported the wii program to be more enjoyable (p < . ) and less fatiguing (p = . ). participants rated both exercise sessions as equally effective (p = . ). conclusions this study suggests that a nintendo-wii® exercise session provides an equivalent cardiovascular demand to a standard exercise session in an inpatient adult cf population. greater enjoyment levels and lower fatigue levels reported during nintendo-wii® training may have a positive infl uence on adherence to exercise. further study into the long-term effects of nintendo-wii® training needs to be undertaken. confl ict of interest nil. introduction ion transport is important to maintain the airway epithelial surface, as shown by the disease cystic fi brosis (cf) which is characterized by decreased clsecretion and increased na + absorption. we have previously shown that the cf airway can develop clresponses when the surface is nominally calcium free (middleton et al. ajrccm ; : - . aim to determine the effects of citrate on the nasal potential difference (npd) with and without amiloride pretreatment, and to compare these effects with other clinically relevant calcium chelators and dicarboxylic acids. methods npd was measured using standard techniques (erj ; : ) in cf and non-cf subjects. the nasal pd response to citrate, oxalate, malate, succinate and fumarate (all mm) was compared with the calcium chelators edta and egta. results citrate decreased the basal npd by ∼ mv, but in the presence of amiloride, citrate increased the pd by ∼ mv. with amiloride/low clpretreatment, citrate increased npd by - mv, which suggests that citrate increased clsecretion. in contrast, the other dicarboxylic acids and calcium chelators exhibited little response. conclusion the combination of these responses suggests that citrate exerts complex effects on airway ion transport, most likely dual effects of decreased na + absorption and increased clsecretion. aim to assess the validity of the international physical activity questionnaire (ipaq) in cf adults by comparing energy expenditure measured by the ipaq versus the accelerometer. methods with ethics approval, suitable successive adult patients with cf attending the alfred cf outpatient clinic were recruited. all participants wore an accelerometer (actigraph gt m) around the waist for days of awake time, at the end of which, they completed the ipaq. criterion validity of the ipaq was assessed by comparing the ipaq weekly energy expenditure (ee) in kilocalories (kcal) with weekly ee (kcal) from the accelerometer using spearman correlations and bland-altman procedures. results thirty participants ( % females) completed the assessment: mean (sd); age = ( ) years, fev %predicted = ( ) the median (range) ee: ipaq = ( , ) kcal, gt m = ( , ) kcal. spearman correlations of fev %predicted with ee were gt m ee r = . , p < . ; ipaq ee r = . , p > . . correlation of the ipaq ee with accelerometer ee was moderate (r = . , p = . ). there was a trend towards higher ee measured by the ipaq than measured by the accelerometer (wilcoxon signed ranks test: z = − . , p = . ). conclusion the ipaq underestimates physical activity for patients with lower energy expenditure activities and overestimates for those with higher energy expenditure activities in adults with cf. the ipaq would be a useful screening tool for exercise prescription and monitoring of physical activity longitudinally, but more quantifi able methods for assessment such as the accelerometer should be used in research. confl ict of interest none. infectious endometritis associated with pseudomonas aeruginosa (pa) is an important equine disease resulting in reduced fertility and decreased foal drop. previous typing studies of equine pa report clonal heterogeneity, suggestive of sporadic acquisition, and small clusters of indistinguishable strains. aim we performed molecular typing of a large sample of genital pa isolates from horses in s-e qld. methods thoroughbred genital tract pa isolates submitted to uq vet diagnostic lab during - (screening or infection suspected) were studied. eric-pcr fi ngerprint analysis was performed. isolates producing indistinguishable fi ngerprints were allocated to the same eric-pcr type. mlst was performed on a subset of isolates. results overall, genital (clitoral or uterine) swabs from mares and urethral fossa swabs from stallions located on stud farms were processed. pa was identifi ed in genital cultures from of the ( . %) mares but from none of the stallions. six clusters involving ≥ mares were detected. cluster-a was observed amongst isolates collected from ( %) mares from studs and each year. cluster-b isolates were present in mares from studs during - . clusters c-to-f each contained isolates from mares from or studs. conclusions overall, % of mares harbouring pa had clonally related strains. however, we found no evidence of horizontal transmission between stallions. these data raise the possibility of transmission via environmental or other sources. alternatively, specifi c strains may have trophism for the reproductive tract of horses. the fi nding of a dominant strain amongst thoroughbred mares in a geographic region has interesting parallels with recent evidence of the spread of highly prevalent clonal strains in cystic fi brosis clinics. aim to investigate the prevalence and impact of incontinence in adult men with cystic fi brosis (cf) as compared with age-and sex matched control subjects. methods men with cf were recruited through outpatient clinics and control subjects through advertisements to complete standardized questionnaires relating to respiratory symptoms, bladder and bowel function, mood and physical activity levels. demographic data were collected from medical records for the cf group. results seventy-four men with cf participated (mean (sd) age . ( . ) years). forty-nine men volunteered as controls ( . ( ) years), and were well matched in terms of physical activity levels. / ( %) in the cf group and / ( %) in the control group had reported episodes of urine leakage. in the men with cf, there was no difference in lung function between men with episodes of leak and those with no history of leak (fev % predicted ( )% vs. ( )%, p = . ). anxiety levels were higher in men from both groups with episodes of leak compared to those with no history of leak (hospital anxiety and depression anxiety score . ( . ) vs. . ( . ), p < . ). depression scores were also higher in men with episodes of leak compared to those with no history of leak ( . ( . ) vs. . ( . ), p < . ). conclusions urinary incontinence in men with cf is not associated with disease severity, as measured by lung function. anxiety and depression levels were higher in men with leakage of urine. confl ict of interest no. aim to investigate the bone mineral status of children and adolescents with cf and to explore the relationship between bone mineral density (bmd) and anthropometric and clinical parameters including height, body mass index (bmi), lung function tests and vitamin d levels ( -hydroxyvitamin d) in the cf centre at starship children's hospital, new zealand. methods bmd of the lumbar spine was assessed by dual x-ray absortiometry between january and december . the results of subjects with cf ( males) with a mean age of . years (range - . years) were collected. anthropometric data (height, bmi), forced expiratory volume in second as percent predicted (%fev ) and vitamin levels were assessed and related to bmd. results bmd in our subjects was low in . % and very low in . % when adjusted for age, sex and height (difference in bmd g/cm in the lumbar spine l -l ). there was a strong positive relationship between the lumbar areal bmd (abmd) and bmi z scores (p < . ), abmd and % fev z scores (p < . ), and abmd z scores and vitamin d levels (p < . ). conclusions bmd was normal in the younger and well-nourished subjects with normal or mild reduction of fev . low bmd appeared to evolve during adolescence with decreasing bmi and reduction in lung function. this will lead to ongoing bone disease in early adulthood. it is a further indication to maintain optimal nutritional status and maximize lung health. malnutrition in cf is associated with poorer pulmonary function and is an independent risk factor of survival. aim to compare the nutritional status of the adults attending an adult cf centre in with . method retrospective audit of patients ( excluded, incomplete data) including demographics, nutritional status, pancreatic enzyme replacement therapy (pert) usage, glucose tolerance and dietetic review. results the mean age of the clinic population increased from . to . years. mean (sd) bmi increased from ( . ± . kg/m ) to ( . ± . ) (p = . ). in , % of the clinic population was taking pert with a mean dose of ± iu lipase/kg/day. the proportion of patients with abnormal glucose tolerance has increased from % to % (p = . ). oral supplement use has increased from % to %, yet enteral feeding remained stable ( % − , % − ). this occurred during period of increased annual dietetic review of the patients attending the clinic from % in to % in (p = . ). discussion over a -year period, an improvement in mean bmi refl ects improvement in nutritional status. prevalence of abnormal glucose tolerance has increased; this is likely due to commencing a screening program ( ). use of oral supplements has increased and is higher than identifi ed in the recent daa survey of nutrition practices of cf dietitians ( %). annual review by the cf dietitian has increased despite a twofold increase in the cf population may be attributable to a stable and experienced workforce. current service provision of . a abbott , e cheung , l morgan aim to characterize the microbial colonization of a group of stable adults with non-cf bronchiectasis using an extended culture protocol. methods sputum was collected over an -month period from clinically stable patients. standard semi-quantitative bacterial culture was extended to days with the addition of fungal and mycobacterial culture as routine. results specimens of spontaneously expectorated sputum were collected from patients; mean age years ( - years); mean (sd) fev / fvc ratio % ( %); / never smokers; / on inhaled or oral corticosteroids. the bacteria identifi ed were p. aeruginosa ( % of specimens), h. infl uenzae ( %), h. parainfl uenzae ( %), acinetobacter baumanii ( %), enterobacteriaceae ( %). commensals only were identifi ed in % of specimens. fungi included candida species ( %), aspergillus fumigatus ( %) and penicillium species ( %). non-tuberculous mycobacteria (ntmb) were grown in % of specimens: m. gordonae ( %), m. intracellulare ( %) and m. lentifl avum ( %). the ntm identifi ed were all considered non-pathogenic. only the mycobacteria were identifi ed after day . conclusion microorganisms with potential pathogenicity are frequently identifi ed in adult patients with non-cystic fi brosis bronchiectasis who are not experiencing an acute exacerbation. all these organisms were identifi ed using a standard short culture protocol. the extended regimen, which was costly, did not identify any unusual or unexpected pathogens. it was rare for patients to be colonized with fungi. this study suggests there is limited value in requesting extended culture for bacterial pathogens, including looking for fungi or nmtb in this stable patient group as this adds little to the empiric antibiotic choice for infective exacerbations. confl ict of interest none. s stelzer-braid , , h alsubie , a neilsen , h johal , a steller , er tovey , k mckay , p van asperen , wd rawlinson , introduction respiratory infections are of fundamental importance in determining the morbidity and mortality associated with cystic fi brosis (cf) as such infections can lead to progressive and fatal obstructive lung disease. using polymerase chain reaction (pcr) to detect such infections has advantages over previous studies that used relatively insensitive traditional detection methods and could have underestimated viral prevalence. methods viral and bacterial multiplex pcrs were developed for detection of respiratory pathogens important for children with cf. nasal brush samples were collected from cf patients who were symptomatic or asymptomatic for acute respiratory illness (n = ). sputum and exhaled bioaerosols via a novel mask sampler were collected from a subset (n = ). results as expected, almost all ( %) sputum samples were positive for bacteria. detection of bacteria in the upper respiratory tract was lower ( . %). data from nasal samples indicated strong association of viral pathogen presence, particularly rhinovirus, with exacerbation of disease. results also showed good evidence for rhinovirus infection in the lower respiratory tract. the novel mask sampler is promising as a non-invasive sampling tool. conclusions our results demonstrate the importance of pathogens in exacerbations. early detection and understanding the development of bacterial and viral infections in cf patients is important in clinical decision-making as more and better antiviral and antibiotic agents become available. aim to determine the factors affecting microbiological yield from bronchoalveolar lavage (bal) in patients with suspected pulmonary infection and haematological malignancy or following stem cell transplantation at a tertiary bone marrow transplant centre. methods a retrospective -month audit of patients with pulmonary infi ltrates or febrile neutropenia with haematological malignancy or post-stem cell transplant who underwent bal for microbiological diagnosis. data were obtained on microbiological yield, radiographic appearances, current antimicrobial therapy, the presence and duration of neutropenia and complication rate. of the bal procedures performed, a clinically signifi cant microbiological result was obtained in % of cases ( / ). of these positive results, % ( / ) were exclusively viral pathogens, % ( / ) were fungal, % ( / ) were bacterial and polymicrobial infection was observed in % ( / ) of cases. a high proportion of patients had commenced anti-microbial treatment empirically, with % ( / ) receiving broad spectrum antibacterial treatment and % ( / ) receiving treatment doses of antifungal agents prior to bronchoscopy. in % ( / ), the results of the bal changed the patients therapy. the presence and duration of neutropenia or radiological appearances were not reliable discriminators of specifi c infective aetiologies. complication rates were low and included fevers in % ( / ), hypoxia % ( / ), small volume haemoptysis in % ( / ), atrial fi brillation in % ( / ) and pneumothorax in % ( / ). conclusion whilst bal remains a safe and important tool in establishing a microbiological diagnosis in immunosuppressed patients with pulmonary infi ltrates, a clinically signifi cant yield and changes to patient treatment occur in the minority of cases. clinicians should have a high degree of suspicion of viral infective aetiology when treating this population of patients. aim to examine the outcomes and complications of intercostal catheter (icc) treatment of pneumothoraces (primary (pp) and secondary (sp)) and effusions (malignant (me) and parapneumonic (pe)). methods retrospective review of all iccs in admitted patients in a respiratory unit over months. data collected included type of pneumothorax or effusion, icc type, insertion details, complications (major and minor) and outcome (success defi ned as resolution of pneumothorax or effusion with single tube insertion). results patients required icc treatment. forty-six iccs were used in patients with pneumothorax: pp ; sp ; iatrogenic ; hydropneumothorax . complication rate was % ( % major) and was signifi cantly less in pp ( %) compared with sp ( %), p < . , chi-square. success rate for pneumothorax icc drainage was % (signifi cantly higher for pp ( %) compared with sp ( %), p < . ). fifty-eight iccs were used in patients with pleural effusions: me , pe , other . complication rate was % ( % major) and was signifi cantly higher in me ( %) compared with pe ( %), p < . . success rate for effusion icc drainage was % (signifi cantly less in me ( %) compared with pe ( %), p < . ). small bore iccs (gauge < fr) were used for % of pneumothoraces and % of effusions. tube size did not signifi cantly infl uence complication or success rate for either pneumothoraces or effusions. conclusions compared with pp, icc treatment of sp was less successful and more likely to be associated with complications. similarly, compared with pe, intervention for me with icc was less successful and had a higher complication rate. we conclude that icc intervention is most successful for pp and pe, and speculate that sp and me should have early surgical intervention. introduction spontaneous pneumothorax is a common condition. current management guidelines recommend large pneumothoraces are managed by primary intercostal catheter insertion. we report a single centre's experience in the management of large spontaneous pneumothorax. methods retrospective audit of cases of spontaneous pneumothoraces managed at the prince charles hospital between january and december . patient demographics, co-morbidities, presenting symptoms, examination fi ndings, radiology, management and complications were reviewed. results forty-two patients ( male, female) experienced episodes of spontaneous pneumothorax. chest pain and dyspnoea were the most commonly reported symptoms ( ) %. there were forty-two ( %) episodes of large pneumothorax (≥ % of hemithorax). management of large pneumothoraces consisted of: observation, ( ) seldinger icc ( ) and large bore icc ( ). complications occurred in three patients with seldinger icc ( vasovagal, hydro-pneumothorax) compared to none with large bore icc. outcomes were similar for patients managed by observation compared to icc insertion. all recurrent cases ( %) were referred for consideration of surgical pleurodesis. conclusion patients with large pneumothorax managed by observation recovered similarly to those treated with icc, suggesting a higher threshold for icc insertion should be considered in the future. grant support nil. aim a pilot study of an instrument of pleural ultrasound training in thoracic physicians after a pleural ultrasound course. the instrument was tested for inter-observer agreement and also its ability to be used in a patient compared to a dedicated manikin. methods all chest physicians ( ) were novices in ultrasound and underwent a dedicated -day training course in pleural ultrasound at the australian institute of ultrasound. they were assessed months later by radiologists and one senior ultrasonographer using a specially designed pleural ultrasound training assessment tool (usgt-sat) on both a subject with pleural effusion and a dedicated ultrasound manikin. the mean scores, out of a maximum of , obtained by the each of the participants for the manikin were . , . , . and . , respectively, while the scores for the patient was . , . , . and . , respectively. the mean scores of the participants as a group for manikin were ± . and for the patient as . ± . . there was general agreement between the examiners with mean combined participant scores of . , . and . in the manikin, respectively, and mean score of . , . and . in the patient. conclusions this pilot study shows ranges of scores for design of future validation studies of the usgt-sat. test performance by the chest physicians after a short course in pleural ultrasound was generally good and results for the use of the manikin as an alternative to patients in pleural ultrasound training are encouraging. further studies with larger sample size are required. supported by nil. nomination nil. confl ict of interest no. since the fi rst commercial availability in , fl exible bronchoscopy has evolved from a simple 'look see' procedure to a more complex multifaceted one. today, fl exible bronchoscopy is a tool used for diagnostic procedures, surveillance, delivery of therapy and clinical trials. increasingly, it involves utilizing expensive purpose built equipment in complex diagnostic procedures. this evolution requires a specifi c knowledge base and skill set to safely perform the procedure and care for the equipment. this now mandates additional training by nursing and medical staff to develop and maintain the required skills. medical staff now rely on their nurses to assist in the full range of procedures. thus, the nurses must keep abreast of modern trends and techniques. the modern bronchoscopy suites team is an integrated one, with specifi c roles, defi ned to each member. the procedures performed will refl ect local needs and expertise. just as bronchoscopy has evolved into the speciality of interventional pulmonology, so must bronchoscopy suite nursing be accepted as a specialized area of nursing with a credentialed 'special interest group' to promote, educate and develop the subject as more therapeutic and diagnostic procedures evolve. this will allow nurses involved in bronchoscopy to be respected, recognized and accepted for their unique knowledge and abilities. confl ict of interest nil. background transthoracic pneumostomy (tp) is a novel treatment for patients with severe emphysema that aims to defl ate the lung and improve function. aim to assess the effect of unilateral tp on the volume of each lung and mechanical properties of the lungs. methods subjects were recruited for a multicentre trial of tp (see actrn ). in parallel with the main protocol, we measured ( ) in the six subjects recruited, compared to plethysmography, lung volume was overestimated by cxr (mean difference + . %, range − . to + . ) and underestimated but more closely correlated by ct (mean difference − . %, range − . to − . ). based on ct, the volume of the treated lung decreased in all patients after tp (mean − . %, range − . to − . ) whilst that of the untreated lung did not change (mean − . %, range − . to + . ). in patients with available data, tp reduced dynamic hyperinfl ation during exercise (mean − ml, − . % of ic, range + . % to − . %). lung mechanics were performed in patients. low lung elastic recoil prior to tp and an increase in elastic recoil after tp were associated with greater reductions in lung volume and greater improvements in exercise tolerance. conclusions supine chest ct provided reasonably accurate estimates of plethysmographic lung volume. unilateral tp defl ated the lung and there was no evidence of signifi cant compensatory hyperinfl ation of the contralateral lung. tp also reduced dynamic hyperinfl ation. measurement of lung elastic recoil may help select patients who are likely to benefi t from tp. support and confl ict of interest nil. methods we performed a retrospective chart review of all adult patients who had an icc over a -month period within a tertiary hospital respiratory service. we noted patient demographics, details surrounding chest drain insertion including image guidance and subsequent inpatient events. results over a -month period, there were small-bore icc insertions, of which were image-guided. mean patient age was years, males comprised / . forty drains were inserted for pneumothoraces, for malignant effusions, for parapneumonic effusions, for transudates and for undiagnosed exudative effusions. mean duration of drainage was . days. there were no life-threatening complications. three of the chest drains fell out and became blocked. six pneumothoraces were noted, all following insertion without direct image guidance; none required further intervention. local infection occurred in patient. insertion details were not documented in patients. conclusion insertion of small-bore iccs via the seldinger technique appears to be a safe method of draining pneumothoraces and pleural effusions. image guidance may reduce complication rate of this procedure. documentation of drain insertions could be improved. confl ict of interest nil. rationale pleural effusions are frequently encountered in clinical practice, and often require aspiration for diagnostic and/or therapeutic purposes. use of radiological guidance varies, despite current guidelines recommending routine use of ultrasound. furthermore, concerns exist regarding the downskilling of thoracic medicine trainees due to the increased use of interventional radiology. as a precursor to developing a procedural pleural ultrasound service, we performed a retrospective case review of our current practice. methods patients who had pleural fl uid sent to pathology between january and december were identifi ed on an existing database. patient records were reviewed and details regarding the drainage procedure and outcomes were recorded. information on patient location, method of procedure and performing clinician were also collected. results to date, pleural fl uid aspirations in patients have been identifi ed. overall, % of aspirations were carried out on the ward and % in the radiology department. two procedures occurred in the endoscopy suite on outpatients, and one in the emergency department. fifty percent of procedures were performed using an intravenous cannula for drainage and % utilized a pigtail catheter. all procedures occurring in the radiology department were performed under ultrasound guidance by a radiologist or radiology registrar. of the remaining procedures, % were performed by medical registrars and % were performed with ultrasound marking. six complications occurred following procedures: pneumothoraces, vasovagal and tube blockage. there were signifi cantly more pneumothoraces in patients who did not have an ultrasound marking ( of without marking, of with marking, p = . ). none of the complications required further intervention. conclusion these preliminary data suggest ultrasound marking signifi cantly reduces pneumothorax incidence, supporting the establishment of a pleural ultrasound service. this is likely to have the added benefi t of improved training for thoracic medicine trainees. aim to investigate differences between semi-recumbent and supine posture in terms of cough rate, degree of oxygen desaturation, oxygen supplementation, increase in pulse rate and sedative use during the initial phase of bronchoscopy. methods consecutive patients (n = ) undergoing diagnostic bronchoscopy at an endoscopy unit were recruited for this observational cohort study. the posture was determined by the bronchoscopist's usual practice. patient age, gender, % predicted fev and fvc, indication, pulse and oxygen saturation were recorded. the initial phase was defi ned as the time from bronchoscopy insertion to visualization plus lignocaine instillation of both distal main bronchi. cough rate, peak pulse, nadir oxygen saturation (spo ), range of oxygen supplementation and sedation use during the initial phase were recorded. a post-procedure questionnaire was administered to the patient and the attending nurse. results patients had bronchoscopy in the semi-recumbent posture and in the supine posture. three of bronchoscopists performed in both postures. there were no signifi cant differences in age, gender, smoking status and spirometry between the two groups. the semi-recumbent postures resulted in signifi cantly less cough rate (mean (sd) . ( . ) vs. . ( . ) coughs/min, p = . ) and less fentanyl use ( ( ) vs. ( ) mcg, p = . ) in the initial phase. there were no signifi cant differences in the nadir spo , fall in spo , oxygen supplementation or increase in pulse rate between the two groups. nurse perception of patient discomfort was lower in the semirecumbent position ( ( ) vs. ( ) mm on mm visual analogue scale, p = . ), and there was a trend towards less patient-perceived cough during the procedure in the semi-recumbent group ( ( ) introduction pulmonary infi ltrates in immunocompromised patients with haematological malignancy have a diverse aetiology and are a major source of morbidity. a specifi c diagnosis and targeted therapy may optimize outcomes and reduce the cost of treatment. the diagnostic value of fi breoptic bronchoscopy (fob) and the infl uence of timing of the procedure are unclear. aim to determine the yield of fob, its impact on antibiotic therapy and the infl uence of early vs late timing in this patient population. methods we conducted a retrospective review of immunosuppressed patients with underlying haematological malignancy and new pulmonary infi ltrates who underwent fob over a -month period. the outcomes of early (eb, ≤ days from initial respiratory consultation) and late (lb, ≥ days) fob were compared using fisher's exact test. results thirty-eight fobs, including bronchial or transbronchial biopsies, were performed in patients (males ). there were patients who received eb and who received lb. a specifi c diagnosis was obtained from procedures ( %), including infections ( in eb vs. in lb, p = . ) and non-infective diagnoses ( eb vs. lb, p = . ) based on histology. fob fi ndings from procedures ( %) ( eb vs. lb, p = . ) resulted in modifi cation of antibiotic therapy. there were no procedure-related severe complications. conclusions fob is a useful diagnostic procedure which infl uences diagnostic and therapeutic decisions in this patient group. although early procedures tended to be more likely to change antibiotic therapy than late procedures, the difference was not signifi cant. confl ict of interest none. capsule endoscopy is increasingly performed in gastroenterology to investigate possible small intestinal bleeding. the capsule endoscope is swallowed and then takes photographs every seconds for hours during its transit through the gastrointestinal tract. the images are downloaded by a radio link and the capsule is then passed normally and disposed of. in the present case, the capsule endoscope was inhaled and lodged in the bronchus intermedius. this was only recognized when the images from the capsule download were examined. removal of the capsule was effected with a fi breoptic bronchoscope using an ercp balloon and roth basket. this is believed the only capsule bronchoscopy so far reported. capsule endoscopes are large ( mm × mm diameter) and smooth. this case report shows the images from the capsule endoscope and describes the methods necessary to remove this unusual foreign body from the lung. support nil. background bronchoscopy with endobronchial biopsy (eb) is now an integral component of the research evaluation of airway diseases. there are no published safety data for eb in adult non-cf bronchiectasis. methods a subgroup of subjects enrolled in the bronchiectasis and low dose erythromycin study (bless) a randomized controlled trial of long-term prophylactic erythromycin (anzctrn ) underwent bronchoscopy with bronchoalveolar lavage (bal) and eb performed by a single operator. results ninety-nine bronchoscopies were performed (bal alone in ) in subjects. of procedures with eb, ( . %) were associated with very signifi cant bleeding (> ml either at time of eb or several days post-procedure) and a further ( . %) with immediate moderate bleeding ( - ml). one subject had a history of prior signifi cant haemoptysis. in the four subjects with very signifi cant bleeding, immediate bleeding of > ml occurred in subjects, ml in one subject and ml in one. immediate bleeding was controlled uneventfully. three of the subjects subsequently developed signifi cant haemoptysis (> ml) to days post-bronchoscopy without intervening haemoptysis, with one subject developing massive haemoptysis (> ml) on day post-bronchoscopy. further research ebs were ceased. in one of the subjects with 'delayed rebleeding', repeat bronchoscopy confi rmed the biopsied lobe as the bleeding site. haemoptysis settled in all subjects within hours with simple conservative measures. conclusions in contrast to the experience in asthma and copd, research eb in adults with non-cf bronchiectasis is associated with a signifi cant risk of bleeding, of potentially life-threatening magnitude in . % of cases. of particular concern was the observation of sudden onset delayed rebleeding developing up to days post-eb in spite of early local control. histopathological evaluation will clarify the potential contributions of airway wall vascularity and infl ammation to these events. malignant mesothelioma (mm) is an aggressive cancer which is often associated with exposure to asbestos and sv . this disease has a high latency period and a low survival rate. therefore, new strategies for therapeutic intervention must be developed. recent studies have shown that developmental pathways including the hedgehog (hh) pathway are associated with various types of cancers. the aberrant activation of key hedgehog pathway proteins has been shown to contribute to cancer progression. however, the role of this pathway in mm has yet to be explored. we hypothesize that aberrant activation of the hh pathway is a contributing factor for the development of mm. the mrna expression of hh pathway genes; sonic hedgehog (shh), patched - (ptch- ), smoothened (smo) and gli- were examined in mm cell lines and tumour tissues by rt-pcr and qrt-pcr. hh pathway proteins and mrna expression and distribution were then observed in the tumours by immunochistochemistry and in situ hybridization. we used real-time superarrays to examine the change in expression of a panel of key hh pathway genes by activating and inhibiting the pathway. we showed that the key hh pathway genes are expressed in both the cell lines and tissue samples. upon stimulation with the ligand shh, there was an increase in expression of indian hedgehog (ihh) and shh in most of the mouse and human cell lines that we looked at. interestingly, for the transcription factor gli- , there was a significant decrease in both mouse and human cell lines. inhibiting this pathway increased the expression of ptch in the mouse and human cell lines. the expression and up-regulation of key hh pathway components in mm at baseline and following stimulation suggests a role for the pathway in mm. methods incident cases were obtained from the australian and wa mesothelioma and cancer registries and death registries. exposure was calculated using measures of dustiness in the industry and the town for the period of employment or residence of each case. latency (time from fi rst exposure to diagnosis) by sex, age, smoking status, exposure variables and worker or resident status was estimated. multivariate linear regression modelling examined the determinants of latency. results the mean latency periods of . (sd = . ) years for lc and . (sd = . ) years for mm have increased linearly. increased duration of exposure was associated with reduced latency for mm after adjustment for age at fi rst exposure and age at diagnosis but not signifi cantly for lc. age at diagnosis was strongly associated with latency length for both lc and mm (p < . ). smoking, sex, cumulative exposure (log f/ml-year) and status at wittenoom were not related to latency. latency for lc with increasing age at fi rst exposure declined faster than for mm. conclusions age at diagnosis is associated with reduced shorter latency of mm and lc. duration of exposure is associated with shorter latency of mm. supported by nhmrc australia. confl ict of interest no. aim to assess overall survival of patients following resection for stage nsclc at a centre that has substantially greater resection rates than the nsw average. methods a retrospective audit of those patients who underwent lung resection for stage nsclc at nepean hospital between january and february . results patients ( m: f), mean age (range - ) underwent resection. there were pneumonectomies, bilobectomies and segmentectomies, one involving chest wall resection. the remaining procedures were lobectomies. there was one perioperative death from respiratory failure. actuarial overall survival at months was %, at months, % and at years %. survival was not infl uenced by histology or age. conclusion in our institution, we have an agreed aggressive approach to resection of stage nsclc and our resection rate is %. this pro-surgical policy is associated with good perioperative and long-term overall survival. confl ict of interest no. introduction malignant pleural effusions (mpes) are common, although their management varies widely. providing ambulatory care to minimize hospitalization is a key goal for patients with mpes. indwelling pleural catheters (ipcs) are a new treatment strategy that allows outpatient fl uid drainage. we hypothesized that mpe patients managed with ipcs require fewer hospital admissions. methods a prospective, multicentre, non-randomized study involving all three major respiratory centres in western australia. patients diagnosed to have mpes were prospectively followed, and admissions were recorded. in the absence of accepted guidelines for ipc use, the choice of treatments (thoracentesis, ipc, pleurodesis) was decided by clinicians in-charge. all complications were recorded. bacterial cultures of pleural fl uid were performed monthly for patients with ipcs. hm gallagher , ee duhig , ia yang , rv bowman , be clark , hm marshall , km fong aim to determine the concordance of histological subtyping of nsclc in diagnostic samples to the gold-standard lung resection specimens. methods we have so far evaluated consecutive subjects who underwent curative surgery for primary nsclc at the prince charles hospital between the years and . many of these had workup at other institutions. one hundred forty-seven had queensland health electronic record of positive preoperative diagnostic sampling. we correlated the fi nal nsclc who histological subtype with the subtypes diagnosed by samples prior to surgery including sputum, fi beroptic bronchoscopy (fob) and trans-thoracic needle aspiration (ttna). the resection subtype was set as the reference standard, and concordance was compared. results of the cases of resected nsclc, had malignancy on diagnostic sampling pre-resection, as shown in the results patients were included: median age years (range - ); % male; % living in major cities versus % in regional areas; % rightsided mpm; % epithelial subtype. median time from asbestos exposure to diagnosis was years (range - ). median time from fi rst symptoms or investigations to diagnosis was weeks (range - ). all patients had at least one chest x-ray and ct scan and % had pet scan. a variety of procedures led to the diagnosis: % thoracoscopy, % thoracotomy, % radiology-guided, % chest wall biopsy and % medical pleuroscopy, with % having had cytology alone. median number of diagnostic immunohistochemical stains used was (range - ), with calretinin ( %) the most commonly used mesothelial marker and carcinoembryonic antigen (cea; %) the most common carcinoma marker. median os for the cohort was . months ( % ci: . - . ), with no statistical difference in os between major city and regional patients ( vs. . months, respectively, p = . ). conclusions mpm appeared to affect mainly the elderly, and thoracoscopy was the most common diagnostic procedure. os did not differ between australian major city and regional patients and was comparable to the largest phase iii trial in mpm. aw musk , , p aboagye-scarfo , a reid , a miller, s ruwanpura, l mcleod, p bardin, n watkins, bj jenkins rationale lung cancer is the leading cause of cancer death worldwide. it is well established that cigarette smoking is linked to emphysema and lung cancer, and smokers with emphysema are at an increased risk of developing lung cancer. notably, recent epidemiological studies have indicated that emphysema can predispose to lung cancer irrespective of pack-year smoking history. although infl ammation has been proposed as a common mechanism linking these two diametrically opposed diseases, the conceptual inter-relationship between infl ammation, emphysema and lung cancer has been poorly investigated because existing experimentally induced and genetically modifi ed animal models for lung cancer occur in the absence of emphysema. method we have utilized a newly identifi ed mouse model (gp f/f ) of spontaneous lung infl ammation and emphysema in two well-established lung cancer models. the gp f/f mouse is characterized by deregulated cytokine signalling via gp , the critical co-receptor for the interleukin (il)- cytokine family, leading to hyper-activation of stat , a potent pro-infl ammatory and oncogenic latent transcription factor. in separate studies, we exposed gp f/f mice to a cigarette-derived carcinogen (nnk), and crossed them with the genetically susceptible kras(g d) strain of mice. results in both nnk-and kras(g d)-induced lung cancer models, the lungs of gp f/f mice were highly predisposed to hyperplasia and tumour formation. increased levels of cellular proliferation were observed in hyperplastic and tumour lesions, as well as surrounding areas, of these mice. these observations were verifi ed at the molecular level by gene expression profi ling of tumour-bearing lung tissue. conclusions these studies provide unique insights into the importance of interactions between the gp signalling axis and factors that predispose to lung tumourigenesis in emphysema. support nhmrc. aim to assess the preparedness of hospitals with respect to protecting health-care workers (hcws) during a pandemic. methods a self-administered questionnaire was performed between november and january , and a scoring system was developed to provide a quantifi able measure of preparedness. results a total of hospitals in nsw, australia, were approached -six regional hospitals (rhs) and six tertiary referral centres (trcs). the study was extended to assess three hospitals in england, allowing a limited comparison between the hospitals in australia that had faced the initial wave of the h n ('swine fl u') pandemic and the hospitals in the uk that had more time to prepare for the outbreak. response rates were % from the trcs, % from the rhs and % from the english hospitals. the overall preparedness scores were relatively high, with a median total score (adjusted) of . out of . the demographic that scored the highest total was tertiary referral centres in sydney. all english hospitals scored below the median. however, the range of scores across hospitals was quite narrow ( . - . adjusted). scores were generally high for the areas of preparedness, infection control, education and training. scores for vaccination were more variable. the category that consistently demonstrated the lowest scores was that of psychosocial welfare and assistance, despite this found in previous research to be an integral part of that which hcws have identifi ed as important. conclusions given their integral role in pandemic response, protecting hcws must be a priority as part of any pandemic preparedness plan. this goes beyond protection from infection, extending into aspects of physical and psychological wellbeing. identifying these issues and addressing them is the key to maximizing staff support and morale, and minimizing staff absenteeism at such a crucial time. aim to describe the relationship of respiratory and refl ux symptoms within the general population and relate this to the possible confounding factors of body mass index (bmi) and obstructive sleep apnoea (osa). methods data from a cross-sectional health survey, performed in bussleton, west australia in - , were used to examine the relative effects of bmi and osa on the relationship between respiratory and refl ux symptoms. questionnaire data included information on asthma, cough, wheeze, dyspnoea and gord symptoms. gord symptoms were categorized as never, monthly or less often and weekly or more often. bmi, risk of osa defi ned according to the berlin questionnaire, spirometry and airway hyperresponsiveness to methacholine were also recorded. logistic regression models obtained odds ratios for the associations between each gord symptoms, various respiratory symptoms, bmi and osa. results average age was years and recent wheeze was reported in % and cough and phlegm in %. twelve percent were current smokers. ahr was present in % and osa in %. gord symptoms occured in % and frequent symptoms (weekly or more often) were present in - %. there were strong positive associations between gord symptoms and cough/phlegm, breathlessness, chest tightness and wheeze in the last months. odds ratios increased with increasing frequency of refl ux p ≤ . . there was no effect of obesity or osa on the relationship between respiratory and gord. conclusion cough and phlegm, breathlessness, chest tightness and wheeze (ever or recent) are all strongly associated with symptoms of gord. this relationship is amplifi ed with increasing frequency of gord symptoms indicating a dose-response relationship between refl ux and respiratory symptoms. obesity and osa do not affect the association between gord and respiratory symptoms. introduction diesel exhaust particles (dep) make up the bulk of particulate matter in urban areas. high ambient levels of particulate matter are associated with increased hospitalization due to respiratory disease. we aimed to determine if exposure to dep exacerbates responses to acute viral infection. methods adult female balb/c mice were inoculated with μg dep or control . days after infection with . plaque forming units (pfu) of infl uenza a/mem (or control). six hours after dep inoculation, lung volume (tgv) and lung mechanics were measured by plethysmography and the forced oscillation technique, respectively. bronchoalveolar lavage fl uid was collected to assess cellular infl ammation and cytokine levels. results viral titre was signifi cantly higher in infl uenza-infected mice exposed to dep compared to those exposed to infl uenza alone (p = . ). both dep (p = . ) and infl uenza infection (p < . ) alone signifi cantly increased cellular infl ammation; however, there was no difference between mice exposed to both dep and infl uenza compared to those exposed to infl uenza alone (p = . ). a similar pattern was found in levels of cytokines in the bronchoalveolar lavage (tnf-α, mcp- , il- , ifn-γ). specifi c airway resistance, specifi c tissue damping, specifi c tissue elastance and hysteresivity were signifi cantly increased in infl uenza infected mice (p < . in all cases). none of these parameters were infl uenced by dep exposure alone (p > . in all cases) and there was no additive effect of dep on lung function (p > . in all cases) in infl uenza-infected mice. conclusions dep increases viral titre but is not suffi cient to physiologically exacerbate pre-existing respiratory disease caused by infl uenza infection in mice. supported by nhmrc. confl ict of interest no. introduction lack of treatments for post-transplant obliterative bronchiolitis (ob) is mainly due to the poor understanding of its pathogenesis and lack of small airway models. epithelial-mesenchymal transition (emt) may play a central role and could be crucial to developing treatment drugs. we hypothesize that emt induction may be prevented by pharmacologically available compounds. methods primary cultures of small and large airway epithelial cells (saec and laec) were established and emt induced by adding tgfβ ( ng/ml) (n = ). azithromycin ( - μm), mycophenolate ( . - mg/l) and rad ( . - ng/l) were then added and expression of epithelial (zo- , ck- ) and mesenchymal markers (eda-fn, vim) measured via western blot as well as mmp and activity via zymography. results signifi cantly lower increase in mesenchymal markers and lower decrease in epithelial markers, compared to controls was noted for azithromycin and mycophenolate indicating suppression of emt. mmp and activity increase was also signifi cantly suppressed. azithromycin suppressed emt to a greater extent compared to mycophenolate, but was equally effective in both small and large airway epithelia. rad appeared to have no effect. conclusions azithromycin and mycophenolate are both effective in preventing emt and thus have potential for the clinical treatment of ob. supported by abn foundation. confl ict of interest none. journal compilation © asian pacifi c society of respirology tp- g hodge , , s hodge , , c-l liew , , t-cell pro-infl ammatory cytokines are associated with acute lung transplant rejection. we have previously shown compartmentalization of production of these cytokines in bronchial intraepithelial t cells (iet) obtained by bronchial brushings from stable lung transplant patients. during acute rejection episodes, no signifi cant differences in iet cytokines were observed between stable and rejecting patients due to broad cytokine variability between patient groups. to overcome this limitation, we hypothesized that there would be increased graft pro-infl ammatory iet cytokines compared with native lung or trachea during acute rejection. methods cell cultures from stable patients, patients with evidence of acute rejection and bos and healthy controls were stimulated and intracellular cytokines determined using multiparameter fl ow cytometry. results there was a signifi cant increase in graft iet-cell ifnγ and tnfα in the lungs of patients with acute rejection compared with iet cells obtained from the native lung or trachea, but no changes were noted between other patient groups. there was a signifi cant correlation between increased graft iet-cell tnfα compared with trachea and lungs and acute rejection grade. conclusions differential expression of pro-infl ammatory cytokines by iet cells from graft, trachea or native lung distinguishes severity of acute rejection. improved monitoring response using this assay or therapeutic targeting of these pro-infl ammatory cytokines may reduce acute lung transplant rejection. supported by nhmrc. aim to determine the prevalence of reduced carbon monoxide transfer factor (dlco ≤ % predicted) in subjects undergoing pulmonary function testing (pfts) and to determine whether a cause has been identifi ed. methods a clinical audit of all subjects undergoing pfts at royal melbourne hospital from august to august who have a dlco ≤ % in the setting of normal spirometry. medical records and investigations including transthoracic echocardiogram (tte), high-resolution commuted tomography (hrct), ventilation/perfusion (v/q) scans were reviewed to determine whether a cause for the reduced dlco was established. where a cause was not clear, subjects were invited to participate in a telephone interview to evaluate symptoms and to undergo repeat pfts. subjects with a persistently reduced dlco were invited to undergo further investigation with tte, hrct and v/q scan. preliminary results pft results from subjects were reviewed. subjects with fev /fvc < , fev < % predicted and fvc < % predicted were excluded. three hundred seventy subjects ( %) had an isolated reduction in dlco. / ( %) of these subjects underwent tte with / ( %) demonstrating an elevated right ventricular systolic pressure (rvsp). in all cases where there was an elevated rvsp an identifi able cause was found. / ( %) of these subjects subsequently identifi ed as having pulmonary arterial hypertension (pah) and commenced appropriate therapy and / ( %) identifi ed as having pah where treatment was not commenced. there were / ( %) of subjects who appeared not to have undergone a tte. further evaluation of medical records of subjects who had not undergone tte and those with normal tte is continuing. review of subjects hrct, v/q scans and right heart catheterizations is currently proceeding. conclusions preliminary results suggest that a signifi cant proportion of subjects with isolated reduction of dlco on pfts do not undergo tte which is an important investigation in determining the cause for the reduced dlco. when a tte is performed and demonstrates an elevated rvsp, a cause for the elevated rvsp is identifi ed. sponsor actelion pharmaceuticals australia pty ltd. g hodge , , s hodge , , c-l liew , , , pn reynolds , , m holmes , , background t-cell pro-infl ammatory mediators are associated with acute lung transplant rejection. we have previously shown that bos was associated with lack of immunosuppression of t-cell pro-infl ammatory cytokines and increased t-cell granzyme b in peripheral blood. recently, we also showed that nkt-like cells are a major source of pro-infl ammatory cytokines and granzymes in the blood of stable lung transplant patients. we hypothesized that bos may be associated with lack of immunosuppression of these proinfl ammatory mediators in blood nk and nkt-like cells. method granzyme/perforin profi les from stable patients, patients with evidence of bos and healthy controls were determined and blood cultures stimulated and intracellular cytokines determined using multiparameter fl ow cytometry. results there was a signifi cant increase in the percentage of nk cells expressing granzymes and perforin in bos patients compared with stable patients and controls. there was an increase in the percentage of t, nk and nkt-like cells producing ifnγ and tnfα in bos compared with stable patients. there was a signifi cant correlation between increased nk ifnγ and tnfα and fev . conclusions bos is associated with increased peripheral blood nkt-like and nk cell granzymes, perforin and th pro-infl ammatory cytokines. therapeutic targeting of these pro-infl ammatory mediators and monitoring response using this assay may reduce bos. supported by nhmrc. confl ict of interest nil. rationale pulmonary embolism (pe) is the leading cause of maternal mortality in the developed world. consequently accurate diagnosis of pe is critical. this must be tempered by the potential radiation risk of investigations to the mother and foetus. we performed a retrospective case review to determine the incidence of pe in pregnant patients investigated for this condition. demographic information, the diagnostic algorithm utilized and the diagnostic yield of investigations were obtained. method pregnant women who underwent ventilation perfusion (vq) scanning or computed tomography pulmonary angiogram (ctpa) at our institution between january and january were identifi ed by an internal database audit. in addition to demographic data, information about the diagnostic pathway and fi nal diagnosis were collected. in cases where pe was not diagnosed, the medical records were reviewed for any subsequent events up until the date of delivery. results during the fi ve-year period, vq scans and ctpas were performed on pregnant women. the average gestation at investigation was weeks. only one patient had a previous history of venous thrombo-embolism. % underwent doppler ultrasound of the lower limbs prior to vq or ctpa. overall the incidence of pe was %, diagnosed by vq scan. otherwise the vq scans were normal in %, low probability in % and non-diagnostic in % cases. ctpa was non-diagnostic in % of cases. all other ctpa studies demonstrated no emboli. almost % of scans were done after hours ( % vq and % ctpa). no patients without pe were felt to have had the pe missed up to the time of delivery. conclusions the overall incidence of pe in patients being investigated was extremely low at %. during this study period slightly more vq studies were performed than ctpas, with each test having similar diagnostic rates. only % of patients had undergone venous doppler prior to undergoing radiationexposing investigations. nomination nil. introduction anti-ro- antibodies have been associated with idiopathic interstitial pneumonia (iip) in one small series (n = ). we hypothesize that ro- antibodies, just like myositis antibodies, can serve as a marker of undifferentiated connective tissue disease (ctd) with interstitial pneumonia as the primary phenotypic manifestation. the aim of this study was to examine the characteristics of patients with ro- and iip. methods retrospective study identifying patients with iip and ro- positivity, but negative for ctd and/or myositis antibodies, presenting between june and june . data relating to demographics, diagnosis, pulmonary function tests, length of follow-up and outcome were obtained. all hrct images were reviewed by an independent expert radiologist (dm). results / ro- positive subjects fulfi lled criteria ( male, median age ( - ), european, never smoked). / had ro- titers above and in the intermediate ( - ) range. three patients had raynauds phenomenon; there were no other ctd features. / patients had hrct diagnosis of nsip and / organizing pneumonia; / had extensive fi brosis. mean (sd) % predicted baseline fvc ( ), dlco ( ). median length of follow-up was months. all patients were treated and were considered overall stable at last follow-up, one had declined and one died of respiratory failure. conclusion this study confi rms an association between ro- positivity and interstitial pneumonia in the absence of defi ned connective tissue disease, suggesting an autoimmune basis for the interstitial lung disease in this group of patients. a larger cohort is required to determine the true signifi cance of this observation. background community acquired respiratory viral (carv) infections are believed to contribute to morbidity and mortality after lung transplantation, but previous studies have not conclusively established the evidence base in this area. patients and methods a prospective cohort study was performed at a single centre from august to march (n = lung transplant recipients). carv infection (human metapneumovirus (hmpv), respiratory syncytial virus (rsv), infl uenza a (flu a), infl uenza b (flu b), adenovirus and parainfl uenza virus (piv)) was confi rmed using polymerase chain reaction (pcr) of upper (nasopharangeal swab) and/or lower (bronchoalveolar lavage) respiratory tract secretions. carv infection and bos were included as segmented time-dependent covariates in a cox proportional hazards model with death as the outcome variable. results patients ( % of the total cohort) had a total of separate carv episodes: piv, hmpv, rsv, flu a, flu b, and adenovirus. infection with either rsv or hmpv was associated with an increased risk of death (p < . hr . , % confi dence interval, . - . ), and the effect persisted after multivariate analysis. bos was also a risk factor for acquiring hmpv or rsv infection (p = . or . , % confi dence interval, . - . ). conclusions infections with hmpv and rsv, but not other carvs, are associated with an increased likelihood of death. the presence of bos is a risk factor for symptomatic infection with hmpv and rsv. ns harun , k sanders , a stuart , cl steinfort department of respiratory medicine, barwon health, vic., australia, and department of clinical and biomedical sciences, barwon health, vic., australia aims nebulized colistin is used to treat recurrent exacerbations of bronchiectasis due to pseudomonas aeruginosa, a major pathogen regarded as diffi cult to eradicate. this case-control study aimed to establish if long-term colistin use could clear p. aeruginosa from the sputum of adults with non-cystic fi brosis bronchiectasis, and if so, whether colistin could be ceased in these patients. secondary outcomes included effects of colistin on quality of life (qol), symptom control, admission rates, lung function and tolerability. methods ( ) sputum was collected in bronchiectasis patients with p. aeruginosa. clearance rates in those on colistin were compared with a control group not on colistin. ( ) colistin patients cleared of p. aeruginosa ceased treatment. sputum was re-cultured at day and to detect recurrence. ( ) a questionnaire assessing qol, symptom control, and admission rates was performed on patients. outcomes were compared before and after colistin use. long-term colistin side-effects and lung function were also assessed. results ( ) % (n = / ) of colistin patients cleared p. aeruginosa from sputum compared with % (n = / ) in the controls (p = . ). ( ) % (n = / ) of patients ceasing colistin remained free of p. aeruginosa at day . ( ) there was no difference in frequency of breathlessness, sputum production or qol scores between the groups (p > . ). the colistin group had lower fvc ( . vs. . l, p = . ) and higher admission rates ( % vs. %, p = . ). on colistin, % of patients reported reduction in sputum frequency, breathlessness and improvement in qol. fifty percent reported decreased admission rates. there were no colistin side effects. conclusions clearance of p. aeruginosa in sputum is possible. clearance rates were similar in those with more severe bronchiectasis treated with colistin compared with stable patients not on colistin, and may suggest suppression of p. aeruginosa by colistin in this severe group. there are benefi ts of colistin on qol, symptom control and admission rates. continued sputum clearance after colistin cessation is achievable in some patients. nebulized colistin use is well tolerated. nomination janet elder travel award. confl ict of interest no. however, use of such agents is suboptimal in hospital patients. this study aims to determine whether a dedicated multidisciplinary education and reinforcement program improves the use of appropriate vte prophylaxis. methods prior to the education programme, we audited a bed general thoracic medical ward including patients with general medical conditions, lung cancer, chronic obstructive pulmonary disease, lung transplant and cystic fibrosis. our multidisciplinary research team developed and implemented an education program over months, using posters, leafl ets and oral presentations to increase awareness and promote adherence to vte prophylaxis guidelines for health care staff involved in direct patient management. following completion of the program, we reaudited the same bed ward. results prior to the education program, a total of patients (mean age ± ) were identifi ed as appropriate for vte prophylaxis. of these ( %) were on appropriate vte prophylaxis. the post education audit showed out of ( %) patients were on appropriate vte prophylaxis. (p = . ). conclusion an effective multi-faceted educational program can improve delivery of appropriate vte prophylaxis, leading to improved outcomes in hospitalized patients. supported by sanofi aventis. confl ict of interest nil. the anti-rheumatic anti-infl ammatory biological agents in clinical use are abatacept, anakinra, adalimumab, etanercept, infl iximab and rituximab. a variety of pulmonary side-effects have recently been reported for these agents and the purpose of this review is to compile the various reported pulmonary toxicities and their prevalence methods we performed a search of databases ovid medline® and embase of the english literature up to august using the mesh terms of abatacept, anakinra, rituximab, adalimumab, etanercept, infl iximab and respiratory tract disease with limits to include only human studies or case reports. in addition case reports of respiratory adverse effects reported to the australian drug reaction advisory committee (adrac) were obtained in order to identify the most common pulmonary reactions reported with each individual agent. results using the search criteria defi ned above and articles were identifi ed in the ovid medline and embase database respectively. the majority of adrac reports were associated with rituximab (n = ) and infliximab (n = ), followed by adalimumab (n = ) and etanercept (n = ). various pulmonary side-effects including interstitial lung disease associated with anti-infl ammatory agents were identifi ed. discussion from the articles reviewed, details about the duration between onset of treatment and incidence of pulmonary side effects, diagnosis, treatment options and outcome of patients were extracted and are presented here. conclusion this comprehensive systematic review hopes to improve the awareness about the serious and potentially life-threatening pulmonary sideeffects of this group of agents. confl ict of interest no. sj simpson , pd sly , p franklin , e lombardi , c calogero , m palumbo , gl hall , introduction the forced oscillation technique (fot) is effort independent and thus ideal for young children. the area under the reactance curve (ax) has been proposed to amplify clinically relevant signal by taking advantage of any shape change in the reactance (xrs) curve below the resonant frequency. this study aimed to develop reference values for resistance (rrs), xrs and ax in a large healthy population of children, and determine if ax conferred any additional clinical benefi t when examining disease in children born preterm. methods impedance spectra were obtained in healthy children ( male), aged less than years and with height less than cm using a commercial device (i m, chess medical, belgium). ax was calculated in of these children between hz and the resonant frequency. backwards stepwise linear regressions identifi ed the best predictors of ax, and xrs and rrs at hz (xrs , rrs ), and z scores were generated. z scores were calculated for children born preterm, of which received a neonatal diagnosis of bronchopulmonary dysplasia (bpd). chi squared tests examined the difference in proportion of children born preterm (with and without bpd) with abnormal z scores for each fot variable. results all fot variables were predicted by height (p < . ) and sex. mean (sd) z scores for preterm children with and without bpd for rrs ( . ( . ); . ( . )), xrs ( . ( . ); . ( . )) and ax ( . ( . ); . ( . )) were all signifi cantly different (p < . ) from the healthy population. the number of children born preterm with abnormal z scores was not significantly different when comparing ax, rrs and xrs . conclusions while ax is able to detect respiratory disease in preterm children with and without bpd, it is no more sensitive than xrs or rrs. supported by pmh foundation, nhmrc, asthma foundation wa, carivit, ngo 'solidarietà e servizio' viterbo. confl ict of interest no. introduction survivors of preterm birth born with bronchopulmonary dysplasia (bpd) in the pre-surfactant era of neonatal care (classical bpd) have a reduced pulmonary gas transfer capacity. there is, however, little data to describe gas transfer in preterm infants with bpd in the post-surfactant era (new bpd). objective assess gas transfer using carbon monoxide diffusing capacity (dl co ) and its components, pulmonary capillary blood volume (vc) and pulmonary membrane diffusion (d m ), in contemporary survivors of preterm birth. method gas transfer was assessed using single-breath dl co in children aged to years and born < weeks gestation with bpd (pb, n = ) and without bpd (pt, n = ), and in term born controls (tc, n = ). dl co z scores were calculated. d m and vc were determined in pb, pt and tc children. the mean (sd) dl co z score for the pb group was − . ( . ) differing signifi cantly from (p = . ) while the pt and tc groups ( . ( . ) and − . ( . ), respectively) did not (p > . ). d m was lower in the pb group than the pt and tc groups, with no difference between pt and tc groups. differences in d m were not signifi cant after adjusting for lung size. there were no differences in vc between groups. conclusion gas transfer is reduced in survivors of preterm birth with new bpd. the tendency for reduced d m and not vc in children with new bpd suggests that impaired gas transfer may be a result of alterations in the alveolar membrane rather than pulmonary vascular function. background bronchiectasis is common in indigenous populations such as alaska natives, australian aboriginal, and new zealand maori and pacifi ca. as part of an international collaborative interventional study, we sought the participation of maori and pacifi ca families -groups diffi cult to engage in research in the past. aim to engage, enrol and retain children from maori and pacifi ca families from auckland in a -year research study. methods a randomized controlled trial to determine whether azithromycin is superior to placebo in reducing exacerbations seeking to enrol children aged months to years with bronchiectasis. the enrolment procedure was modifi ed to a process deemed more appropriate to these cultures: ( ) request to defer the decision of enrolment until the process had been completed. ( ) a minimum of meetings; initial invitation, discussion in the home with the extended family, invitation to the extended family to participate in the day of enrolment. ( ) appointment of a 'whanau worker' (family worker) to sit with the family and empower them to get all the information they seek prior to enrolment. results of families approached, ( %) children (median age . years, range . - . years) enrolled with % samoan, % tongan, % maori and % mixed maori/pacifi ca heritage. after -year retention was ( %) with exiting the study after month with new non-pulmonary disease, and exiting after year, moving outside study area. conclusions these are high enrolment and retention fi gures reported in this population. we believe that following a prolonged procedure for enrolment, involving the extended family and appointing a worker to sit 'alongside' the family will improve their understanding of a research project and allow them to feel more comfortable about participating. aim bronchiolitis is the most common reason for hospital admission for infants globally ( ) . the use of macrolides for treating bronchiolitis in nonaffl uent settings remains controversial but potentially benefi cial. in our region readmission with lower respiratory illness in young children (particularly indigenous children) remains high. this rct aims to determine if a single dose of azithromycin reduces the morbidity of young children with bronchiolitis. methods double blinded rct. young children ≤ months admitted to royal darwin hospital (rdh) diagnosed with bronchiolitis are eligible. children are given a single dose ( mg/kg) of either azithromycin/placebo. primary outcome is length of stay for respiratory disease. secondary outcomes are duration of oxygen use and readmission for respiratory illness in -month period. respiratory viral infections often lead to exacerbations of chronic respiratory diseases such as asthma and copd though there is no similar data in noncystic fi brosis (cf) bronchiectasis. the objectives of our study were to ( ) determine the point prevalence and identify viruses associated with exacerbations and ( ) evaluate clinical and investigational differences between viral infection positive and negative exacerbations in children with non-cf bronchiectasis. methods a cohort of children (median age years; boys) with non-cf bronchiectasis was prospectively followed for child-months. polymerase chain reaction for respiratory viruses was performed on nasopharyngeal aspirates collected during paediatric pulmonologist defi ned exacerbations. data on clinical, parent cough-specifi c quality of life (pc-qol), systemic markers (crp, il , procalcitonin, amyloid-a, fi brinogen) and lung function parameters were also collected. results respiratory viruses were detected during ( %) exacerbations: picornavirus in episodes [human-rhinovirus (hrv) in , enterovirus in ]; human bocavirus in ; adenovirus, human meta-pneumovirus, infl uenza a, respiratory syncytial virus, parainfl uenza and in two each; coronavirus and parainfl uenza and in one each. viral co-detections occurred in ( %) exacerbations. among genotyped hrv's, more hrv-a's (n = ) were identifi ed than hrv-c's (n = ). children with proven viral infections were more likely to have fever (or . , % ci . - . ), wheeze and/or crackles (or . , % ci . - . ) and raised crp (or . , % ci . - . ) when compared with virus negative exacerbations. there were no other statistically signifi cant differences. conclusions respiratory viruses are commonly found during pulmonary exacerbations in children with non-cf bronchiectasis. hrv-a is the most frequently detected virus. time sequenced cohort studies during stable state, exacerbations and recovery periods are needed to determine the importance of viral infections and their possible interaction with bacteria. supported by anz trustees scholarship. confl ict of interest none. nominations none. to date children enrolled, % rsv+ve. median age . months. fifty percent have had at least one co-morbidity. readmission rate = %. conclusion co-morbidities are high in this population. antibiotics have the potential to help reduce the impact of additional respiratory burden. foundation. introduction foreign body inhalation is a relatively common presentation in young children, especially less than years of age. early recognition remains a critical factor in the treatment of foreign body inhalation in children. inhaled foreign bodies in children are most often organic material, with seeds and peanuts being the most common items. on review of the literature, there are very few case reports of inhaled metal screws. we report two unusual cases of inhaled metal screws that presented to our service. case presentation both cases presented to our emergency department with wheeze, respiratory distress and fever. foreign body inhalation was not considered as a cause for their symptoms until the object was identifi ed on chest x-ray. both foreign bodies were removed successfully but one child required invasive ventilation in our intensive care unit post removal. both children made a full recovery. interestingly, both metal screws came from fl at pack furniture purchased from a well known international home products store. conclusion foreign body inhalation must always be considered as a cause of respiratory distress in a child. with the increase in the number of fl at pack furniture in australian home's, we believe parents must be warned of the potential danger of loose metal screws to young children. supported by none. cough in children is a common symptom. data on causes of chronic cough in young children have previously been published by our units. however, differences in underlying diagnosis by age at presentation have not been assessed. we present the 'time to cessation' of cough in our multicentre rct using a standardized management algorithm in newly referred children with chronic cough (> weeks) from australian centres. methods parents completed validated cough diary and cough specifi c qol (pc-qol) at recruitment and at cessation of cough. the diagnosis made by the treating physician was based on tsanz position statement. results the median (range) age of the children recruited was . years ( . - . ); ( %) were boys. median (iqr) pc-qol post treatment of . ( . , . ) improved signifi cantly (p = . ) from . ( . , . ) at enrolment. the median (iqr) duration of cough at recruitment was weeks ( . , . ) and 'time to cessation' of cough after application of the management algorithm was weeks ( . , . ). there was no signifi cant difference (p = . ) in median (iqr) 'time to cessation' of cough among the three age cohorts: < years (n = , . %) was . weeks ( . , . ); - years (n = , . %) was weeks ( . , . ); and > years (n = , . %) was weeks ( . , . ). there was also no signifi cant difference in the fi nal primary diagnosis among the three age cohorts (p = . ). the most common diagnoses were protracted bacterial bronchitis (n = , %), asthma/reactive airways disease (n = , . %), tracheobronchomalacia (n = , . %) and bronchiectasis (n = , . %). children ( . %) had more than one diagnosis. conclusions the aetiology and 'time to cessation' of chronic cough in children managed in accordance to a standardized pathway were similar among the three age groups. it is likely that our previous fi ndings in very young children are also applicable to older children. supported by nhmrc grant number . confl ict of interest none. aim to determine the role of fl exible bronchoscopy with bronchial alveolar lavage (bal) in the management of patients with febrile neutropenia. methods a retrospective analysis was made of the number of patients admitted with febrile neutropenia at a single institution who underwent bronchoscopy plus bal from years to . computer database plus patient case notes were reviewed to establish clinical symptoms and signs, radiological fi ndings, antimicrobial treatment and mean duration to bronchoscopy following admission. results a total of episodes of febrile neutropenia were recorded years to . seven patients ( males and females) were referred for bronchoscopy plus bal. the mean age was . years (age range - years) and all had been diagnosed with acute lymphoblastic leukemia. all patients had at least cough as a clinical symptom along with radiological fi ndings. all patients had been on broad spectrum antibiotics at the time of bronchoscopy. the mean duration from admission to time of bronchoscopy was hours ( days) with a standard deviation of hours. of the seven patients one patient yielded a positive result on bal. this did not result in a change in management as the patient improved clinically before the result of the bal was confi rmed. conclusion in this retrospective case series the diagnostic yield of fl exible bronchoscopy plus bal in children with febrile neutropenia was low. prospective studies plus early timing towards bronchoscopy and bal should be conducted to further defi ne its role in the management of febrile neutropenic patients. confl ict of interest nil. methods prospective cohort study involving monthly follow-up with caregivers. two years post enrolment, children undergo clinical and lung function assessment (fot). presence of bronchiectasis is determined by physician review and radiological confi rmation (when indicated). the frequency of pbb episodes is recorded over the study period. of children recruited to the cohort study to date, % ( / ) were male. the median age at recruitment was months (iqr , ). % of children had recurrent pbb. of the children who have had -year clinical follow-up, were able to perform fot and % ( / ) showed abnormalities (reactance above normal range.) % ( / ) with pbb have had subsequent physician diagnosis of bronchiectasis or csld. conclusion the burden of cough in children with pbb years after diagnosis remains high. ongoing clinical follow-up of this cohort of children with pbb should provide further insight into the likelihood of progression from pbb to csld and bronchiectasis. support financial markets foundation for children (for project), allen & hanburys and qcmri (for dw), nhmrc (for ju and ac). introduction national streptococcus pneumoniae (sp) serotype surveillance reports only culture positive cases from sterile sites but the yield from culture is low. polymerase chain reaction (pcr) is more sensitive in detecting sp in culture negative samples. aim to determine whether enhanced molecular surveillance in childhood empyema provides additional sp serotype information compared to national surveillance methods. methods pleural fl uid from children with empyema underwent culture and pcr to identify sp-targeting autolysin (lyta) and multiplex pcr to identify sp serotypes. national surveillance data were obtained from the national notifiable diseases surveillance system (nndss) for the same time period and age groups. results empyema: children, male, median age . (range . - . ) were recruited from april for months. sp was cultured in / ( . %) in blood and / ( . %) in pleural fl uid. sp was identifi ed by pcr in / ( . %). serotypes: , n = ( . %); , n = ( . %); a, n = ( . %); f a, n = ( . %); v/ a, n = ( . %); f/ a, n = ( . %); non-typeable, n = ( . %). one subject had serotypes and in a serotype could not be established. nndss: sp culture positive cases were reported. serotypes: , n = ( . %); , n = ( . %); a, n = ( . %); f a, n = ( . %); v/ a, n = ( . %); f/ a, n = ( . %); non-typeable, n = ( . %). other serotypes were reported in sp positive cases. signifi cant differences between empyema and nsdss data were identifi ed for serotypes (p < . ) and (p < . ). conclusions the proportion of serotypes and were signifi cantly higher in empyema fl uid using pcr. this disease model provides additional serotype information to national surveillance data. this has important implications in monitoring replacement serotypes following the introduction of new vaccines. funded by glaxosmithkline, belgium. h giddings , l seccombe , p rogers , a corbett , e veitch recent theories on the pathophysiology of parkinson's disease (pd) emphasize early brainstem involvement. furthermore various respiratory function abnormalities have been reported without consistent pattern. we sought to study the effects of idiopathic pd on respiratory function and ventilatory response to hypercapnoea and hypoxia. methods patients with a diagnosis of pd but no known respiratory disease were recruited. subjects underwent lung function testing including respiratory muscle strength, ventilatory response to hypercapnoea (with central respiratory drive (p )) and a hypoxic simulation (fio % cough is the most common symptom presenting to doctors. paediatric cough is associated with signifi cant morbidity for both children and their parents. the symptom of cough is associated with airway hyper-reactivity and is a dominant symptom of airway infl ammation. inhaled corticosteroids (ics) can reduce airway infl ammation and hyper-reactivity. the objective of this review was to evaluate evidence for the effi cacy of ics in reducing the severity of cough in children with sub-acute cough (defi ned as cough duration of - weeks). methods search was conducted by the cochrane airways group using cochrane methodology. all randomized controlled trials (rcts) comparing ics with a control group for treatment of sub-acute cough in children were considered for inclusion. search results were analysed using pre-determined criteria for inclusion. results two studies were eligible for inclusion in the review, however there were limitations in that the participants of both these studies were infants, post acute bronchiolitis illness, and cough duration at start of study treatment was ill-defi ned. children were included in the meta-analysis. there was no signifi cant difference between groups in proportion of children 'not cured' (primary outcome measure), with a pooled or of . ( % ci . , . ) (using intention to treat analysis). conclusions there is currently no evidence to support the use of ics in sub-acute cough in children. however, this systematic review is limited by the small number of studies available for analysis and the quality and design of these studies. further well-designed rcts are required to support or refute the effi cacy of treatment with ics in children with sub-acute cough. once obstructive sleep apnoea (osa) is diagnosed, a cpap implementation sleep study is traditionally performed to determine the pressure required to control the upper airway. however, since modern cpap machines store sophisticated control data we reasoned it may equally be possible to commence cpap via a 'best guess' iterative approach without compromising osa control or compliance. aim to compare the outcomes at months of patients commencing cpap after best guess with those commencing cpap after a cpap implementation sleep study. methods we retrospectively reviewed the records of all patients referred by respiratory physicians to our cpap clinic between march and march , and the two methods of starting cpap were compared. data collected included age, sex, bmi, respiratory disturbance index (rdi), cpap pressure commenced, fi nal pressure at months, cpap usage data and cpap clinic contacts. results patients were identifi ed, aged ± years, %male, bmi . ± . , with severe osa, rdi ± . commenced cpap via best guess and after a cpap sleep study. the starting pressures in both groups were similar, . ± . versus . ± . cmh o. in those patients continuing to use cpap at months, there were no differences between the groups for fi nal pressure, numbers of patients changing pressure, control of osa with cpap, and hours cpap used per day. in the best guess group however, signifi cantly more patients were continuing to use cpap at months, % versus % (p = . ). conclusion this study demonstrates that it may no longer be necessary to perform cpap implementation sleep studies routinely and this will save hospital bed days. confl ict of interest nil. six required intubation and the rest were managed with non-invasive ventilation in icu. the average length of stay in icu was . days. polysomnographic data will be described. conclusions obesity hypoventilation as a cause of respiratory failure is likely to increase in frequency as the incidence of obesity increases. increased awareness by the lay public, as well as clinical suspicion and recognition of the condition by all clinicians at an earlier stage, is likely to prevent progression to the point of needing intensive care. it is hoped that this case series may provide a springboard for further study into why these patients presented at such a late stage of their disease process. supported by none. confl ict of interest none. although sa and sleepiness often co-exist, the commonest cause of sleepiness in a general community is depression, with sa being the th most common cause. in order to assist recognition of depression in a snoring population attending a sleep clinic, we introduced a simple two question 'beyond blue questionnaire(bbq)' into our routine assessment. aims to ( ) background indices of ventilation distribution in diffusion (s acin ) and convection (s cond ) dependent airways derived from multiple breath nitrogen washout (mbnw) may vary between interpreters because of differences in calculation of phase iii slopes (Δphase iii ). aims to compare s cond and s acin results of interpreters from a single mbnw in copd subjects. methods subjects with copd underwent mbnw. three washouts were analysed independently by experienced and novice interpreters using custom software for automated breath identifi cation. Δphase iii was fi tted automatically by least squares fi t between predetermined points, and then adjusted manually. s cond was the linear slope of Δphase iii plotted against lung turnover (cumulative expired volume/frc), between turnovers . - . s acin was the Δphase iii of the fi rst breath minus the s cond component. differences expressed as icc and cov, were examined by repeated measures anova. results mean ± sd age was ± years. fev was ± % predicted. s cond was greater while s acin was lower from the experienced introduction β-blockers may cause bronchoconstriction and mask the effect of β -adrenergic agonists. this has implications for the interpretation of routine diagnostic spirometry and bronchodilator response. this study examined this issue in a routine lung function laboratory, and whether it applied to both cardio-selective (c) and non-selective (nc) preparations. method all patients attending the lung function laboratory, royal adelaide hospital over a -month period were asked whether they were currently taking a β-blocker and to identify the drug. spirometry results were analysed to assess airfl ow obstruction and reversibility. results patients completed the survey and patients ( %) were taking β -blockers. the table shows the results of the patients who could be assessed for reversibility in spirometry. of the patients in this group patients ( %) were taking (c) and ( %) (nc) agents. fifty-three patients were unsure whether they were taking a β -blocker. no signifi cant differences were found in the percentage of patients with airfl ow obstruction or reversibility between the groups. aim to examine patterns of adult lung function in terms of airfl ow obstruction, hyperinfl ation and/or reduced diffusing capacity (d l co). this can then be related to the life-time history of risk factors such as smoking, asthma and infections. methods using the population-based tasmanian longitudinal health study (tahs) cohort followed since , an asthma-enriched sub-sample was selected consisting of % ever with asthma, of whom half reported current asthma. measurement of spirometry, d l co (uncorrected for haemoglobin) and lung volumes was performed, then lung function data were analysed using the mean predicted values. airfl ow obstruction was defi ned as post-bronchodilator fev /fvc (post-b.d. fer) < . , hyperinfl ation as total lung capacity (tlc) > % predicted, and reduced d l co as < % predicted. aim to examine the gender-specifi c differences in adult spirometry, d l co and lung volumes, with a view to relating them to life-time respiratory risk factors. methods using the population-based tasmanian longitudinal health study (tahs) followed since , an asthma-enriched sub-sample was selected consisting of % ever with asthma, of whom half reported current asthma. measurement of spirometry, d l co (corrected for haemoglobin) and lung volumes were performed. data were analysed using the statistical upper and lower limits of normal of reference equations by nhanes iii, roca et al and quanjer et al. of the caucasian adults ( females), % completed all tests. mean age . years (range - ). elevated rates of airfl ow obstruction and hyperinfl ation were seen. signifi cantly higher proportions of females than males had reduced d l co and d l co/v a (p < . ). only . % (n = ) of females had a low d l co with low fev /fvc ratio, and . % (n = ) had a reduced tlc overall. there were no signifi cant gender differences in v a , tlc, or ever and current active smoking. males and females averaged over kg more than the mediterranean adults described by roca et al., however weight is not relevant to d l co in males. conclusion a higher percentage of middle aged females have a reduced d l co and/or d l co /v a, compared to males, with an increased rate overall. grant support nhmrc, australian postgraduate association. d chapman , , , j kermode , , , n brown , , , n berend , , , g king , , , background during bronchoconstriction, a deep inspiration (di) dilates the airways, which then re-narrow once tidal breathing is resumed. re-narrowing occurs faster in asthmatic subjects and may be due reduced airway distensibility. aim to determine the association between baseline airway distensibility and the rate of re-narrowing after di. methods eleven asthmatic and fi ve non-asthmatic subjects had baseline airway distensibility measured by forced oscillation technique (fot). after methacholine challenge, respiratory system resistance (rrs) was measured during min of tidal breathing, followed by di to total lung capacity (tlc) and passive return to normal tidal breathing. dilatation was measured as the decrease in rrs between end tidal inspiration and tlc, and re-narrowing as end-expiratory rrs immediately after di, as per cent rrs at end-tidal expiration before the di. distensibility is presented as geometric mean ± %ci and re-narrowing as mean ± % ci. results airway distensibility was reduced in asthmatic compared to healthy subjects ( . s − .cmh o − ( . - . ) vs. . s − .cmh o − ( . - . ), p = . ). dilatation did not differ between groups (p = . ) but re-narrowing was increased in asthmatic compared to healthy subjects ( ± % vs. ± %, p = . ). airway distensibility did not correlate with airway re-narrowing (r s = - . , p = . ). conclusion the increased re-narrowing after di in asthmatic subjects is not due to reduced baseline airway distensibility and may be due to increased shortening velocity of airway smooth muscle or reduced elastic recoil. supported by the nhmrc and the crc for asthma and airways. nomination nil. confl ict of interest no. c ng , , , s jenkins , , , n cecins , , p eastwood , , aim to evaluate the measurement properties of two accelerometers: the activpal and the stepwatch activity monitor (sam) in people with copd. methods the activpal and sam were attached to the anterior right midthigh and the right ankle, respectively (as per device recommendations). each participant performed walking tasks; at a self-selected slow speed and at a self-selected normal speed. at each speed, one walk was performed with a -wheeled walker (ww) and the other without. results participants aged ( ) years (fev = ( ) % pred; males) completed the study. the slow and normal speeds were ( ) m·min − and ( ) m·min − , respectively. agreement between steps recorded by the sam with steps counted during observation did not differ with speed or ww use (p = . ). the mean difference was steps·min − and the limit of agreement (loa) was steps·min − . agreement between steps recorded by the activpal with steps counted was worse at slow speeds (mean difference steps·min − with loa of steps·min − ) compared with normal speeds (mean difference steps·min − with loa of steps·min - ) (p = . ), but was not affected by ww use. both accelerometers detected the small difference in walk speed irrespective of ww use (p < . ). conclusions neither the accuracy nor responsiveness of either accelerometer was affected by ww use. in contrast to the activpal, sam was accurate at both speeds and therefore can be used to detect steps in people who walk very slowly during daily life. breathing and sleep, heidelberg vic., eastern health, melbourne vic., northern health, epping vic., and monash university, clayton vic. aim to document the care and pathways patients with copd travel at three metropolitan health services. methods data were extracted from data sets for patients attending the emergency department of the three hospitals with a diagnosis of copd over year. the three hospitals included a city-based tertiary/quaternary hospital and two smaller community hospitals. analysis was completed on similarities and differences in admission and referral rates, average length of stay, and discharge destination, standardized by age, sex and mode of transport to the emergency department. results there were inpatient separations and emergency department presentations for patients with copd. discharge patterns related to the designated role of the hospital, with the community hospitals discharging to % of patients directly home and the more specialized city hospital discharging % to other hospitals and % home. there were signifi cant differences in the admission rates for category and patients among the hospitals. we found unexplained variation in the acute average lengths of stay of . , . and . days. conclusions the analysis confi rmed some expected patterns based on the type of hospital, but also identifi ed unexplained variation that suggests that factors other than patient characteristics may be contributing to the variation in care pathways. aims to: ( ) determine which tests of exercise capacity relate to average daily energy expenditure (dee) and; ( ) quantify the intensity at which activities of daily living (adl) are undertaken in people with chronic obstructive pulmonary disease (copd). methods a study was undertaken in subjects with stable copd (mean, sd) aged ( ) years with an fev of ( ) % predicted ( males). measures were collected of distance walked during the six-minute walk test ( mwd) and incremental shuttle walk test (iswd) and peak rate of oxygen uptake during a cycle ergometry test (vo peak ). the sensewear armband® was worn during the waking hours for . ( . ) days to measure dee. the intensity at which activities of daily living were undertaken was expressed as a percentage of vo peak . results dee was associated with mwd (r = . ; p = . ), iswd (r = . ; p = . ) but not vo peak (r = . ; p = . ). stronger associations were observed between dee and the body weight-walking product for mwd (r = . ; p < . ) and iswd (r = . ; p < . ). the average intensity of adl was equal to ( %) of vo peak (range to %). conclusions mwd and iswd, but not vo peak were related to dee. as adl were performed at a high percentage of vo peak it may be more realistic to increase dee by increasing the frequency or duration, rather than the intensity of physical activity. in patients with copd, two mwts are recommended prior to commencing a pulmonary rehabilitation program (prp) to allow for a learning effect. aim to determine the characteristics of patients with copd in whom -minute walk distance ( mwd) did not increase on a second test. methods patients ( males) with stable copd (aged , to years) naïve to the mwt performed two tests ( minutes apart) prior to commencing a prp. patients were categorized according to their change in mwd with test repetition. results mwd was the same or decreased on the second test in patients ( %) (table) . in the remaining patients ( %), mwd increased by m ( %) ( % ci to m, to %). logistic regression analysis identifi ed fev (l) as the only signifi cant variable (p < . ) that predicted the absence of a learning effect in mwd with test repetition. conclusions some patients with severe copd may not require a practice mwt to achieve their maximum performance at a prp baseline assessment. ( ) years, with stable ipf were evaluated in this study. demographic data and measures of pulmonary function (spirometry, diffusing capacity for carbon monoxide, (dl co )), dyspnoea (baseline dyspnoea index, bdi), peripheral muscle force (isometric quadriceps force (qf) and handgrip force (hf)), functional exercise capacity ( -minute walk distance, mwd), limitation in daily activities (activities of daily living (adl) score), and health status (sf- ) were assessed. relationships between mwd and mrc grade, pulmonary function, qf, bdi and adl score were examined. results the number of subjects in mrc grades , , and was ( %), ( %), ( %) and ( %), respectively. pulmonary function, bdi, qf, hf, mwd, adl score, and sf- decreased signifi cantly with increasing mrc grade (all p < . ). moderate to strong correlations were found between mwd and mrc grade (r = − . ), dl co (r = . ), qf (r = . ), bdi (r = . ) and adl score (r = . ) (all p < . ). conclusions these fi ndings suggest that the mrc dyspnoea scale can be used to discriminate and classify subjects with ipf according to the severity of impairment and disability. ( ) year (mean, sd) completed two assessment sessions on separate days. on one day, they exercised twice to symptom limitation (tlim) on a treadmill. on the other day, they exercised twice to tlim on a cycle ergometer. the order of exercise modality was randomized between days. on both days, the only difference between the exercise tests was that bipap, titrated to patient comfort, was used during the second test. measures were made of; ) tlim and, ( ) the difference in dyspnoea, using borg scores, at tlim during the fi rst test and the equivalent exercise time during the second test (i.e. iso-time). results bipap increased tlim on the treadmill ( ( ) seconds; p = . ) but not the bike ( ( ) seconds; p = . ). the reduction in dyspnoea at iso-time on the treadmill and bike was similar being, ( ) and ( ), respectively (p = . ). conclusions bipap may confer greater benefi t in exercise tolerance exercising on a treadmill compared with a cycle ergometer in patients awaiting lung or heart-lung transplant. infection with rhinovirus (rv) is known to trigger acute exacerbations in subjects with asthma and these subjects also have increased susceptibility to the effects of rv. the mechanisms remain poorly understood, but appear to involve a host innate immune defect in the airway epithelium. aim we sought to determine in bronchial epithelial cells (becs) if oxidative stress in the form of exposure to cigarette smoke extract (cse), hydrogen peroxide (h o ) and eosinophil peroxidise (epo) results in impaired mitochondrial function and if this directly impairs signalling of rv infection through mda and alters the release of type i and type iii interferons (ifns). methods pbecs were grown to confl uence. cells were then exposed to cse ( %, no fi lter) or h o ( . mm) or epo. cells were then infected with rv -b (moi = ). virus replication was measured by cell titration assay. following infection, il- , cxcl- , cxcl- was measured using cytometric bead array and fl ow cytometry. supernatants and whole cell lysates were collected for ifn-β, bax and mda detection by western blot. ifn-λ and cytochrome-c was measured using conventional elisa. cell viability was assessed by annexin v-pe staining and fl ow cytometry. results rv infection alone induced cxcl- , il- , cxcl- and ifn-λ. pbecs treated with each of the oxidative stressors had increased cytochromec release and increased apoptosis. this mitochondrial dysfunction led to degradation of mda expression and resulted in specifi c suppression of cxcl- and ifn-λ. conclusions exposure of becs to an oxidative stress results in mitochondrial dysfunction in airway epithelial cells. this leads to defective antiviral signalling in the airway epithelium after infection with rv. introduction pleural infection is associated with high morbidity. prompt drainage is key, but pus is often loculated and thick making drainage diffi cult. based on promising animal studies, we hypothesize that intrapleural therapy with t-pa and dnase, which lyse adhesions and reduce fl uid viscosity respectively, can signifi cantly improve pus evacuation in pleural infection. methods consecutive patients with pleural infection were treated with standard antibiotics and intercostal chest tube (ict) drainage. additionally, t-pa mg and dnase mg (each in ml of . % nacl) were instilled intrapleurally via an ict twice daily for up to six doses. the ict was clamped for minutes after each instillation. patients were followed clinically and with serial cxr. opacity from pleural effusion was quantifi ed on chest radiographs. results eleven patients ( male; mean age ) were treated. nine effusions were associated with community acquired pneumonia, of these, eight were visibly purulent, fi ve were culture positive and the mean fl uid ph was . (range . - . ). ten patients ( %) were successfully managed conservatively and one patient required surgery. median hospital stay from fi rst intrapleural treatment dose to discharge was days (range - ). the median amount of fl uid drained in the hours preceding t-pa/dnase treatment was ml (range - ), and improved signifi cantly to ml (range - ) following two doses of treatment. this was paralleled by a signifi cant reduction in radiographic opacity by a mean value of % of the hemithorax (range - %). four patients showed an initial rise in crp following t-pa/dnase, but all patients had resolution of sepsis and signifi cant reduction in crp. there were no major complications. pleuritic chest pain requiring opioid analgesia developed in three patients. methods clinical data were collected using a standardized form for aboriginal children aged days -< months hospitalized with alri and enrolled in a rct of vitamin a/zinc supplementation were matched with data collected during a population-based study of who-defi ned primary endpoint pneumonia (who-p). sensitivities, specifi cities, positive and negative predictive values (ppv, npv) for these signs were compared between who-p cases and lobar pneumonia assigned by a respiratory paediatrician. in episodes of hospitalized alri, who-p was diagnosed in ( . %); the respiratory paediatrician classifi ed ( . %) as lobar pneumonia. the sensitivities of clinical signs ranged from a high of % for tachypnoea to % for fever + tachypnoea + chest-indrawing; the ppv range was % to %, respectively. higher ppvs were observed against the paediatric respiratory physicians diagnosis compared to who-p. conclusions clinical signs on admission are not useful in predicting who-p in this population, presenting challenges for future pneumonia research in this population. who-p may underestimate alveolar consolidation in a clinical context and its use in clinical practice or in research designed to inform clinical management in this population should be avoided. the incidence of tb in the non-indigenous australian population is uncommon at . cases per population . in this paper, we report three cases of pulmonary tuberculosis in young australian born, non-indigenous adults in the hunter new england area where marijuana possibly was a signifi cant risk factor in transmission and severity of disease. all three cases had severe cavitating disease at time of presentation. contact tracing from the fi rst case, a regular heavy marijuana user, identifi ed mantoux positive contacts, one of whom developed active pulmonary tuberculosis. all contacts, mainly young adult males, denied sharing marijuana with the index case. contact tracing from the second case identifi ed mantoux positive contacts, of whom use marijuana regularly and shared bongs (water pipes) with the index case. there were positive mantoux contacts of the third case, one of whom shared bongs with the index case. health professionals need to remain aware of the possibility of tuberculosis in groups with historically low incidence rates. marijuana bong smoking is possibly associated with transmission and severity of tuberculosis . introduction in , these previously well women survived and made a good recovery from severe pneumonia and acute lung injury after retrieval on ecmo. streptococcus pyogenes is an unusual cause of pneumonia in adults. case a -year-old veterinarian with a history of mild asthma presented with days of fever and respiratory symptoms. the diagnosis was confi rmed by a fourfold rise in the anti-streptococcal antibody. this was complicated by respiratory failure, septic shock, acute renal failure, severe pulmonary hypertension and bilateral parapneumonic effusions. despite maximal interventions she deteriorated. femoral venous-venous ecmo was initiated on day at the calvary mater hospital in newcastle by a retrieval team from royal prince alfred hospital (rpa), sydney. she was transferred kms on ecmo in a large multipurpose ambulance. she developed lung abscesses and recurrent pneumothoraces and she required a pleurodesis. she required days of ventilation and days of ecmo. three months later she was asymptomatic, with mildly restrictive spirometry and minor cxr change. case a -year-old offi ce worker with s pyogenes bacteraemia made a similar presentation to our institution. she was ventilated for days, ecmo was initiated by the retrieval team and continued for days. three months later she was asymptomatic with a normal cxr and pulmonary function tests. introduction the urinary pneumococcal antigen (upa) test has been shown to have superior sensitivity to other investigations in determining the aetiology of community-acquired pneumonia (cap), but there is very limited data on its performance in local populations. the aims of this study are to establish the prevalence of positive upa testing in patients admitted to hospital with cap, and determine its utility. secondary aims are to identify associations with positive testing, as well as to determine if a positive test infl uences clinical outcomes. methods the study is a prospective, single-centre study that is still recruiting. adult patients are included upon admission to hospital if they have the diagnosis of cap, as defi ned by new infi ltrates on chest radiograph along with consistent clinical features. clinical data including curb- score of severity, current and prior antibiotics, co-morbidities, mortality and length of hospital stay are recorded. results preliminary results show a positive test prevalence of / ( . %, % ci . - . %) amongst patients admitted with cap. overall prevalence of pneumococcal pneumonia is / ( . %, ci . - . %). patients with a positive upa result have a higher mean curb- score of . compared with . in those with a negative result (p = . ). . % of patients with a positive result were admitted to the intensive care unit, compared with . % those with a negative result (p = . ). conclusions the overall prevalence of positive upa testing in patients admitted to hospital with cap is low. preliminary data suggests that patients with positive results are more likely to have greater severity pneumonia and to require intensive care support. comparative data on length of stay, mortality, previous antibiotic use and specifi c co-morbidities has not revealed any statistically signifi cant differences between positive and negative groups. confl ict of interests no. s herath , c lewis , m nisbet , respiratory department, auckland city hospital, auckland, new zealand, and infectious diseases department, auckland city hospital, auckland, new zealand rhodococcus equi (r. equi), previously known as corynebacterium equi is a gram positive bacillus that is found in soil and causes infection in grazing livestock. it is infrequently isolated from clinical specimens. it is usually associated with human disease in immunocompromised patients and is an uncommon cause of infection in immunocompetent patients. infection is usually acquired by the airborne route with pneumonia being the most common manifestation but it can also be acquired orally or by direct inoculation. we present a case of pneumonia caused by r. equi infection in a year old male builder who presented with cough, dyspnoea and night sweats. r. equi was cultured from a transbronchial aspirate from a subcarinal lymph node. despite extensive investigation, no contributing host immune defect was identifi ed. the patient recovered after three months of antibiotic treatment, initially with intravenous vancomycin and meropenem followed by oral clarithromycin and rifampicin. although infections due to r. equi have been increasingly reported in immunocompromised patients, since there have only been cases described in patients where no associated host immune defect was reported. in this cohort, the median age at presentation was years (range - ) and ( %) patients were male. ten ( %) of these cases had pulmonary infection. two ( %) patients died and the remainder were successfully treated with prolonged antibiotics. r. equi is an uncommon cause of infection in humans and rarely occurs in patients where a host immune defect cannot be identifi ed. introduction recognition of pulmonary involvement in extra pulmonary tuberculosis (ep-tb) may be an important public health issue, as it has been estimated that patients with smear negative pulmonary tb (ptb) are responsible for % of new infections. usually, all patients with ep-tb have a chest x-ray but sputum cultures are requested only if there is an abnormality. methods in this retrospective clinical audit, we aimed to evaluate the percentage of ep-tb patients with ptb despite a normal chest x ray (cxr), and to explore any clinical characteristics of this group. clinical notes, microbiology and cxr reports were reviewed from consecutive patients presenting with ep-tb between and . results of patients with ep-tb, % were male and the mean age was (range to ). most patients were of asian ethnicity (n = , %). the commonest presentation of ep-tb was lymphadenopathy (n = , %), followed by pleural (n = %) and bone (n = , . %) disease. ep-tb was diagnosed by biopsy/excision of the ep site in the majority (n = , . %), and by sputum testing alone in ( . %). sputum cultures were performed in n = , ( %) overall, with n = ( %) being positive. there was higher infl ammatory markers in the sputum culture positive group (esr . vs. . , p = . and crp . vs. . , p = . ). the majority had cxr abnormalities (n = , %). in the group with normal cxr (n = ), ( %) had sputum cultures performed. of these, were culture positive and of these also + smear positive ( on immunosuppression, with cough). conclusion a small number of patients with ep-tb and normal cxr had pulmonary tb, of whom were smear positive. thus, induced sputum testing should be considered in patients with ep-tb even if cxr is normal. this may aid diagnosis and determine infectivity. ntm are normal inhabitants of environmental reservoirs including water. disease due to ntm has been increasing in qld. aim to document the presence of ntm in potable water in brisbane, to compare the species isolated during summer and winter and to relate this to the geographic distribution of patients with ntm. methods water samples ( l) were collected from routine collection sites in winter and sites in summer . samples were processed in triplicate as previously described. h subcultures were taken from positive specimens, dna extracted, followed by s rrna sequencing. patient addresses were obtained from the qld tb control centre database. aim to gauge the full impact of pandemic h n infl uenza across demographic groups in the northern territory, particularly indigenous and remoteliving individuals. methods we performed two cross-sectional serological surveys on specimens from residents of the northern territory, with specimens obtained from january to may (pre-pandemic) and specimens from september (post-pandemic). specimens were selected from among serum tubes collected from ambulatory outpatients. antibody titres were measured by haemagglutination inhibition against the a/california/ / reference virus. all specimens had available data for gender, age, and address, with indigenous status determined in . % of cases. results protective antibody levels, defi ned as a titre of or greater, were present in . % of pre-pandemic specimens and . % of post-pandemic specimens. the pre-pandemic proportion immune was greater with increasing age, but did not differ by other demographic characteristics. the post-pandemic proportion immune was greater among aboriginal and torres strait islanders and in younger age groups, but did not differ by gender or socio-economic index for area. however, the proportion immune was geographically heterogeneous, particularly among remote-living and indigenous groups. the northern territory-wide attack rate adjusted to age, region and indigenous status was . %. conclusions pandemic infl uenza disproportionately affected children and indigenous australians in the northern territory in . the proportion of specimens demonstrating post-pandemic immunity was particularly variable among indigenous and remote-living individuals. the kormp found asymptomatic aboriginal children (ac) had more hrv than asymptomatic non-aboriginal children (non-ac) in a longitudinal communitybased cohort study where infants had nasopharyngeal aspirates (npa) collected regularly from birth to years of age. aim to compare the frequency of hrv groups in asymptomatic ac and non-ac in the kormp. methods npa positive for hrv (n = ) from the npa previously tested for respiratory viruses, had viral rna extracted and reverse transcribed. hrv was detected and typed using a two-step pcr of the hrv ' utr, followed by dna sequencing for typing. chi-square analyses were used. results hrv was detected and typed in npa (from children; ac and non-ac), could not be typed and were not positive for hrv. ac had more hrv in summer and autumn than non-ac and were more likely to be co-infected with at least / bacterial species identifi ed. hrva, b & c were found in . , . and . % of hrv detected. hrvb & c were increased in infants exposed than not exposed to tobacco smoke in utero (hrvb; . vs. . %, p = . and hrvc; . vs. . %, p = . ). of the npa, hrv-a was detected more often in npa from ac than non-ac ( . vs. . %, p = . ), particularly at - months of age (p = . ) and during summer (p < . ). hrvb was detected more often in npa from ac than non-ac in autumn (p < . ). hrvc was detected as often in ac as non-ac in each season except summer. aim to determine whether interferon-gamma release assay (igra) can be effectively used for diagnosis of latent tuberculosis infection in a remote location. methods subjects were enrolled from the darwin centre for disease control tuberculosis clinic and were eligible if a tuberculin skin test (tst) of mm or greater had been recorded for any indication. igras were performed using quantiferon®-tb gold whole blood in-tube assay according to manufacturer's instructions. specimens were incubated and centrifuged at the local laboratory before refrigeration for transport. interferon assay was performed at the reference laboratory, over km away. results igras were performed, with patients ( %) recording negative results, ( %) positive and only one result ( %) indeterminate. negative, and therefore discordant, test results were more common in bcg vaccinated individuals. this effect was not limited to those with tst results of - mm, but was seen primarily in those with results of mm and above. conclusions these results are broadly comparable to fi ndings for igra use in less remote settings. in particular, our low rate of indeterminate results suggests that igra testing is feasible at a remote site after local processing. this approach could be considered for use in the northern territory tuberculosis control program. inhaled medications form the mainstay of drug treatment for patients with airways disease. effectiveness of therapy is dependent on the appropriate selection and prescription of drug and device, correct supply and adherence to therapy with an effective technique. patients frequently admit to acute medical wards both with acute exacerbations and for other co-morbidities eg heart failure or pneumonia. inpatient episodes provide an opportunity to review inhaled therapy however anecdotally add to patient confusion and introduce complexity (rational or ad hoc changes to inhaled drug, device, strength, dose or frequency). aim identify prescribing accuracy and effectiveness of patients' inhaler technique. describe any discrepancies between inhaled therapy: ( ) used prior to admission, ( ) prescribed for inpatient use, ( ) available at the bedside and ( ) administered, prior to and after implementation of an inhaler prescribing and administration guide. methods a single day audit of all inpatients on general medical wards was conducted october (review of medication charts and inhalers in patients' bedside lockers, brief questioning and direct observation of patients' inhaler technique. results compared to post implement of the 'prescribing and administering inhalers' tool (audit in december ). results from ( %) patients had inhalers prescribed, (mean: . prescriptions per patient). % of prescriptions were accurate ( % patient had no errors). discrepancies between used prior to admission and inpatient prescriptions were found in ( %) patients while those between inpatient prescriptions and available at the bedside were found in %. self-administration ('s') was noted on medication charts of ( %) patients, of whom had an ineffective inhaler technique. / patients has a spacer at the bedside with a further r prescribed metered aerosol inhalers. post-intervention differences in prescribing, supply, administration and technique errors will be discussed. conclusions a combination of errors and prescription discrepancies reduce the effectiveness of inhaled therapy for inpatients. confl ict of interest no. males (n (%) % ci) females (n (%) % ci) adm and bed days bmi, body mass index hrqol, health related quality of life chronic respiratory disease questionnaire; adm, admissions, mean (sd) uberculosis notifi cations in australia a cluster of tuberculosis associated with use of a marijuana water pipe the prince charles hospital foundation cc dobler , , gb marks , woolcock institute of medical research, the university of sydney, nsw, and department of respiratory medicine, liverpool hospital, sydney, nsw aim to determine the incidence rate and nature of adverse events in patients taking treatment for latent tuberculosis infection (ltbi). methods records of all patients who received treatment for ltbi at the chest clinic of a large tertiary hospital between / and / were reviewed. an adverse event was defi ned as any change in health status or side effect that led to treatment interruption or cessation. liver function tests were not performed routinely during follow-up, except when the patient was considered to be at an increased risk of developing hepatitis. results of patients in whom treatment for ltbi was initiated ( %) received isoniazid for months, ( %) received a combination of isoniazid and rifampicin for months, and the remainder were treated with different regimens. their mean (sd) age was ( ) years and % were male. nineteen patients ( . %) experienced an adverse event. seven patients developed a rash, four had lethargy and/or mood disorders, three had subclinical hepatitis, four experienced severe nausea, vomiting and/or other gastrointestinal symptoms and three had features of peripheral neuropathy. in eight patients who experienced an adverse event medication was temporarily ceased and then re-started without change; in four the treatment regimen was changed; and in seven the treatment was ceased completely. the risk of adverse events was not signifi cantly related to age, sex, drug regimen (single drug versus combination therapy) or baseline transaminase levels. conclusions in this cohort almost in patients on treatment for ltbi experienced an adverse event. although the adverse events were generally mild to moderate, this risk has to be taken into account when deciding whether to advise treatment for ltbi. introduction human rhinovirus (hrv) is the commonest cause of asthma exacerbations in children. pernasal aspirate (pna) is the gold standard for microbiological sampling but is invasive and distressing for children. studies have showed that less invasive swabs may be just as effi cacious. aim to test the hypothesis that hrv detection is as effi cient using nasal fl ocked swabs or washes and more comfortable, compared with pna in children with respiratory illnesses. methods children were recruited on presentation to the emergency department with respiratory symptoms. pna was collected from one nostril of all children recruited and nasal fl ocked swab (n = ) or wash (n = ) collected from the other nostril alternately. subjects rated the comfort of each sampling method to (least to most). viral rna was extracted and reverse transcribed. a two-step pcr of the hrv ' utr was used for detection, followed by sequencing for typing. results to date, children ( % male, mean age of . years) had paired samples taken. of these children, % (n = ) presented with a diagnosis of viral induced wheeze and % (n = ) had a hrv positive sample. compared with pnas, nasal fl ocked swabs were % ( of pna positive) effective in detecting hrv, whilst nasal washes showed % ( of pna positive) effi cacy. of the successfully typed samples, had hrva and had hrvc. nasal washes had a better comfort rating (mean . , n = ) than fl ocked swabs (mean . , n = ) and pnas (mean . , n = ). conclusion our fi ndings suggest that whilst nasal fl ocked swabs are an effective sampling method for hrv detection, nasal washes were more effective, being as effective as pnas and were the most comfortable. support nhmrc, pmh foundation. nomination nil. aim to describe the inpatients treated by a dedicated niv service. methods a retrospective audit of inpatients treated by the alfred niv service between january and june . the defi nition of niv included patients treated with cpap and bilevel positive pressure ventilation. results patients (age: ± years (mean ± sd), gender: % male) were treated with niv on occasions (repeat admissions patients). commonest indications for niv were osa (n = , %), acute exacerbations (ae) of copd (n = , %), acute cardiogenic pulmonary oedema (acpo) (n = , %) and post-lung transplantation (n = , %). treatment was delivered primarily in the respiratory ward (n = , %), cardiac ward (n = , %), icu (n = , %) and general medical ward (n = , %). episodes of cpap (mean pressure ± cmh o), osa and acpo made up % of those treated. seventy-two episodes of bilevel pap (mean ipap ± cmh o and epap ± cmh o), aecopd and weaning post-mechanical ventilation made up % of those treated. outcome data was available in a subgroup of patients with acpo (n = ) andaecopd (n = ). in the acpo group, patients ( %) improved and niv was ceased. three patients ( %) deteriorated and were intubated and patients ( %) were palliated. in the aecopd group, patients ( %) improved andniv was ceased or they were discharged on therapy. patients either deteriorated on niv or could not tolerate therapy, of these ( %) continued ward management and ( %) were palliated. conclusion the alfred niv service model has managed a large number of referrals across a range of diseases in a variety of wards. this is likely to have reduced demand on icu, hdu and respiratory ward beds. compared to the published literature, theoutcomes for acpo are worse than expected but comparable for aecopd. this may be explained by local referral patterns for acpo. we believe that our service model provides a viable means of administering niv to an ever expanding referral base. transitional & community service, the university of south australia, adelaide, sa , the university of adelaide, adelaide, sa, , the mary potter hospice, north adelaide, sa, , thoracic medicine, the royal adelaide hospital, adelaide, sa, , the royal district nursing service, wayville, sa , and the palliative care council of sa eastwood, sa introduction: the adelaide health service is in the process of developing a new and innovative model of copd community based care. a number of initiatives have informed this development including a recent research project examining the experiences of participants with end stage copd and their carers. a growing body of evidence indicates the importance of a palliative approach, however this often takes the form of referral to a palliative care service rather than a broader application of palliative principles in both specialist and primary care. methods: fifteen participants were interviewed twice at monthly intervals to explore their needs and the services they accessed. a series of focus groups with key service providers in sa was also undertaken. data were analysed to identify how hospital, specialist palliative care units and primary care services currently interface to meet identifi ed patient and carer needs. results: the current service model is episodic and reactive with services activated through the acute care system. our research has shown that, as copd advances, current models of care do not address the importance of supporting quality of life (including a focus on adls) and carers in their ongoing role. also emphasised was the lack of co-ordination of care, collaboration between service providers and communication -the basics of chronic disease management. conclusions the outcomes of this study will inform the development of a proactive, multidisciplinary model of care which is no longer reliant on tertiary care, but places primary care at the centre of the model. greater collaboration between respiratory, palliative and primary care services will provide an integrated approach, focusing on the needs of the patient and carer. aim long term conditions are prevalent in south auckland and impact on the individual, the community and the health system. as nurses living within this community, and employed by counties manakau district health board, our aim was to explore funding opportunities available through the pacifi c health team. lotumoui was established to improve health outcomes/behaviours for pacifi c populations. the church we attend has wide cultural diversity and had no knowledge of the programme and the support provided to make healthy changes within our community. methods firstly a health committee was formed within the church, having 'sold' our vision to the parish council. we launched the group by undertaking free blood pressure checks, followed by a 'walk the talk' project for the days leading into easter. baseline observations were taken and pedometers issued. results the parishioners who attend regular exercise sessions are reporting improved quality of life, exercise tolerance and reducing waist lines. bp parameters are also reducing. conclusions a dedicated health committee within a parish community, supported by the district health board can impact on changes in lifestyle by simple interventions. the investment by the pacifi c team will reap benefi ts for the individual and the health sector. confl ict of interest no. key: cord- - qnrcgnk authors: slebos, dirk-jan; ryter, stefan w; choi, augustine mk title: heme oxygenase- and carbon monoxide in pulmonary medicine date: - - journal: respir res doi: . / - - - sha: doc_id: cord_uid: qnrcgnk heme oxygenase- (ho- ), an inducible stress protein, confers cytoprotection against oxidative stress in vitro and in vivo. in addition to its physiological role in heme degradation, ho- may influence a number of cellular processes, including growth, inflammation, and apoptosis. by virtue of anti-inflammatory effects, ho- limits tissue damage in response to proinflammatory stimuli and prevents allograft rejection after transplantation. the transcriptional upregulation of ho- responds to many agents, such as hypoxia, bacterial lipopolysaccharide, and reactive oxygen/nitrogen species. ho- and its constitutively expressed isozyme, heme oxygenase- , catalyze the rate-limiting step in the conversion of heme to its metabolites, bilirubin ixα, ferrous iron, and carbon monoxide (co). the mechanisms by which ho- provides protection most likely involve its enzymatic reaction products. remarkably, administration of co at low concentrations can substitute for ho- with respect to anti-inflammatory and anti-apoptotic effects, suggesting a role for co as a key mediator of ho- function. chronic, low-level, exogenous exposure to co from cigarette smoking contributes to the importance of co in pulmonary medicine. the implications of the ho- /co system in pulmonary diseases will be discussed in this review, with an emphasis on inflammatory states. the heme oxygenase- /carbon monoxide (ho- /co) system has recently seen an explosion of research interest due to its newly discovered physiological effects. this metabolic pathway, first characterized by tenhunen et al. [ , ] , has only recently revealed its surprising cytoprotective properties [ , ] . research in ho- /co now embraces the entire field of medicine where reactive oxygen/nitrogen species, inflammation, growth control, and apoptosis represent important pathophysiological mechanisms [ ] [ ] [ ] [ ] . indeed, the number of publications in recent years concerning ho- has increased exponentially, while the list of diseases and physiological responses associated with changes in ho- continues to expand [ ] . until now, relatively few studies have addressed the role of ho- /co in pulmonary medicine. several investigators have focused on the diagnostic application of the ho- /co system, by measuring exhaled co (e-co) in various pathological pulmonary conditions, such as asthma or chronic obstructive pulmonary disease (copd) [ ] . in another experimental approach, investigators have examined the expression of ho- in lung tissue from healthy or diseased subjects [ , ] . this review will highlight the actions of ho- /co in the context of heme degradation have antioxidant properties [ , ] . the liberated heme iron undergoes detoxification either by extracellular efflux or by sequestration into ferritin, an intracellular iron-storage molecule with potential cytoprotective function [ ] [ ] [ ] [ ] . of the three known isoforms of ho (ho- , ho- , and ho- ), only ho- responds to xenobiotic induction [ ] [ ] [ ] [ ] . constitutively expressed in many tissues, ho- occurs at high levels in nervous and vascular tissues, and may respond to regulation by glucocorticoids [ , , ] . ho- and ho- differ in genetic origin, in primary structure, in molecular weight, and in their substrate and kinetic parameters [ , ] . ho- displays a high sequence homology with ho- but has little enzymatic activity [ ] . this review will focus on the inducible, ho- , form. in addition to the physiological substrate heme, ho- responds to induction by a wide variety of stimuli associated with oxidative stress. such inducing agents include hypoxia, hyperoxia, cytokines, nitric oxide (no), heavy metals, ultraviolet-a ( - nm) radiation, heat shock, shear stress, hydrogen peroxide, and thiol (-sh)-reactive substances [ ] . the multiplicity of toxic inducers suggest that ho- may function as a critical cytoprotective molecule [ , ] . many studies have suggested that ho- acts as an inducible defense against oxidative stress, in models of inflammation, ischemia-reperfusion, hypoxia, and hyperoxia-mediated injury (reviewed in [ ] ). the mechanisms by which ho- can mediate cytoprotection are still poorly understood. all three products of the ho reaction potentially participate in cellular defense, of which the gaseous molecule co has recently received the most attention [ , ] . the administration of co at low concentrations can compensate for the protective effects of ho- in the presence of competitive inhibitors of ho- activity [ ] [ ] [ ] . while ho- gene transfer confers protection against oxidative stress in a number of systems, clearly not all studies support a beneficial role for ho- expression. cell-culture studies have suggested that the protective effects of ho- overexpression fall within a critical range, such that the excess production of ho- or ho- may be counterprotective due to a transient excess of reactive iron generated during active heme metabolism [ , ] . thus, an important caveat of comparative studies on the therapeutic effects of co administration versus ho- gene delivery arises from the fact that the latter approach, in addition to producing co, may have profound effects on intracellular iron metabolism. ho- expression is primarily regulated at the transcriptional level. genetic analyses have revealed two enhancer sequences (e , e ) in the murine ho- gene located at - kb (e ) and - kbp (e ) of the transcriptional start site [ , ] . these enhancers mediate the induction of ho- by many agents, including heavy metals, phorbol esters, endotoxin, oxidants, and heme. e and e contain repeated stress-responsive elements, which consist of overlapping binding sites for transcription factors including activator protein- (ap- ), v-maf oncoprotein, and the cap'n'collar/basic-leucine zipper family of proteins (cnc-bzip), of which nrf (nf-e -related factor) may play a critical role in ho- transcription [ ] . the promoter region of ho- also contains potential binding sites for nuclear factor κb (nf-κb), though the functional significance of these are not clear [ ] . both nf-κb and ap- have been identified as regulatory elements responsive to oxidative cellular stress [ , ] . in response to hyperoxic stress, ap- factors mediated the induction of ho- in cooperation with signal-transducer and activator of transcription (stat) proteins [ ] . furthermore, a distinct hypoxia-response element (hre), which mediates the ho- response to hypoxia, represents a binding site for the hypoxia-inducible factor- (hif- ) [ ] . the toxic properties of co are well known in the field of pulmonary medicine. this invisible, odorless gas still claims many victims each year by accidental exposure. co evolves from the combustion of organic materials and is present in smoke and automobile exhaust. the toxic actions of co relate to its high affinity for hemoglobin ( -fold greater than that of o ). co replaces o rapidly from hemoglobin, causing tissue hypoxia [ ] [ ] [ ] . at high concentrations, other mechanisms of co-induced toxicity may include apoptosis, lipid peroxidation, and inhibition of drug metabolism and respiratory enzyme functions [ ] . only recently has it become known that, at very low concentrations, co participates in many physiological reactions. where a co exposure of , parts per million (ppm) ( % by volume co in air) is toxic, - ppm (one hundredth to one fortieth as much) will stimulate the physiological effects without apparent toxicity [ ] . the majority of endogenous co production originates from active heme metabolism (> %), though a portion may be produced in lipid peroxidation and drug metabolism reactions [ ] . cigarette smoking, still practiced by many lung patients, represents a major source of chronic lowlevel exposure to co. inhaled co initially targets alveolar macrophages and respiratory epithelial cells. the exact mechanisms by which co acts at the molecular level remain incompletely understood. co potentially exerts its physiological effects by influencing at least three known pathways (fig. ). by complexation with the heme moiety of the enzyme, co activates soluble guanylate cyclase (sgc), stimulating the production of cyclic ': 'guanosine monophosphate (cgmp) [ ] . the sgc/cgmp pathway mediates the effects of co on vascular relaxation, smooth muscle cell relaxation, bronchodilation, neurotransmission, and the inhibition of platelet aggregation, coagulation, and smooth muscle proliferation [ ] [ ] [ ] [ ] . furthermore, co may cause vascular relaxation by directly activating calcium-dependent potassium channels [ ] [ ] [ ] . co potentially influences other intracellular signal transduction pathways. the mitogen-activated protein kinase (mapk) pathways, which transduce oxidative stress and inflammatory signaling (i.e. response to lipopolysaccharide), may represent an important target possible mechanism(s) of carbon monoxide action figure possible mechanism(s) of carbon monoxide action. endogenous carbon monoxide (co) arises principally as a product of heme metabolism, from the action of heme oxygenase enzymes, although a portion may arise from environmental sources such as pharmacological administration or accidental exposure, or other endogenous processes such as drug and lipid metabolism. the vasoregulatory properties of co, including its effects on cellular proliferation, platelet aggregation, and vasodilation, have been largely ascribed to the stimulation of guanylate cyclase by direct heme binding, leading to the generation of cyclic gmp. the anti-inflammatory properties of co are associated with the downregulation of proinflammatory cytokine production, dependent on the selective modulation of mitogen-activated protein kinase (mapk), such as the kilodalton protein (p mapk). in addition to these two mechanisms, co may potentially interact with any hemoprotein target, though the functional consequences of these interactions with respect to cellular signaling remain poorly understood. anti-platelet aggregation anti-proliferation ? inhibition of pro-inflammatory cytokine production modulation of hemoprotein function of co action [ , , , ]. an anti-apoptotic effect of co and its relation to mapk has recently been described. the overexpression of ho- or the exogenous administration of co prevented tumor necrosis factor α (tnf-α)induced apoptosis in murine fibroblasts [ ] . in endothelial cells, the anti-apoptotic effect of co depended on the modulation of the p ( kilodalton protein) mapk pathway [ ] . the role of the remaining heme metabolites, (i.e. fe and biliverdin ixα) in the modulation of apoptosis is currently being investigated and is beyond the scope of this review. recent studies have reported a potent anti-inflammatory effect of co, involving the inhibition of proinflammatory cytokine production after endotoxin stimulation, dependent on the modulation of p mapk [ ] . the clinical relevance of p mapk lies in the possibility of modulating this pathway in various clinical conditions to downregulate the inflammatory response [ ] . oxidative stress arising from an imbalance between oxidants and antioxidants plays a central role in the pathogenesis of airway disease [ ] . in lung tissue, ho- expression may occur in respiratory epithelial cells, fibroblasts, endothelial cells, and to a large extent in alveolar macrophages [ , , ] . ho- induction in these tissues, in vitro and in vivo, responds to common causes of oxidative stress to the airways, including hyperoxia, hypoxia, endotoxemia, heavy metal exposure, bleomycin, diesel exhaust particles, and allergen exposure [ , , ] . induction of ho- or administration of co can protect cells from these stressful stimuli [ , ] . in one of the experiments that best illustrate the protective role of co in vivo, rats were exposed to hyperoxia (> % o ) in the absence or presence of co at low concentration ( ppm). the co-treated rats showed increased survival and a diminished inflammatory response to the hyperoxia [ ] . as demonstrated in a model of endotoxin-induced inflammation, the protection afforded by co most likely resulted from the downregulated synthesis of proinflammatory cytokines (i.e. tnf-α, il- β) and the upregulation of the anti-inflammatory cytokine interleukin- (il- ) [ ] . furthermore, increases in exhaled co (e-co) have been reported in a number of pathological pulmonary conditions, such as unstable asthma, copd, and infectious lung disease; these increases may reflect increased endogenous ho- activity [ ] . elevated carboxyhemoglobin (hb-co) levels have also been reported in these same diseases in nonsmoking subjects, where both the e-co and hb-co levels decrease to normal levels in response to therapy [ ] . e-co in humans originates primarily from both systemic heme metabolism, which produces co in various tissues, and localized (lung) heme metabolism, as a result of the combined action of inducible ho- and constitutive ho- enzymatic activity. endogenously produced or inspired co is eliminated exclusively by respiration [ ] . elevation of e-co may also reflect an increase in exogenous sources such as smoking or air pollution. in addition to changes in environmental factors, elevations of e-co in lung diseases may reflect an increase in blood hb-co levels in response to systemic inflammation, as well as an increase in pulmonary ho- expression in response to local inflammation [ , , ] . the diagnostic value of measuring e-co remains controversial due to many conflicting reports (i.e. some reports indicate differences in e-co measurements between disease activity and controls, and some reports do not). the possible explanations for these discrepancies include large differences in patient populations and in the methods used for measuring e-co, and undefined corrections for background levels of co. furthermore, remarkable differences arise between studies in the magnitude of the e-co levels in the control groups as well as in treated or untreated asthma patients. when active or passive smoking occurs, or in the presence of high background levels of co, the measurement of e-co is not particularly useful for monitoring airway inflammation. in patients who smoke, e-co can be used only to confirm the smoking habit [ , ] . comparable to the beginning era of measurements of exhaled no, a standardization in techniques and agreement on background correction should be reached for e-co measurements, to allow proper conclusions to be drawn in this area of investigation. asthma, a form of allergic lung disease, features an accumulation of inflammatory cells and mucus in the airways, associated with bronchoconstriction and a generalized airflow limitation. inflammation, a key component of asthma, involves multiple cells and mediators where an imbalance in oxidants/antioxidants contributes to cell damage. several pathways associated with oxidative stress may participate in asthma. for example, the redox-sensitive transcription factors nf-κb and ap- control the expression of proinflammatory mediators [ , [ ] [ ] [ ] . in light of the potential protective effects of ho- /co on inflammatory processes, the study of ho- in asthma has gained popularity. in a mouse model of asthma, ho- expression increased in lung tissue in response to ovalbumin aerosol challenge, indicating a role for ho- in asthma [ ] . in a similar model of aeroallergen-induced asthma in ovalbumin-sensitized mice, exposure to a co atmosphere resulted in a marked attenuation of eosinophil content in bronchoalveolar lavage fluid (balf) and downregulation of the proinflammatory cytokine il- [ ] . this experiment showed that exogenous co can inhibit asthmatic responses to allergens in mice. recent human studies have revealed higher ho- expression in the alveolar macrophages and higher e-co in untreated asthmatic patients than in healthy nonsmoking controls [ , ] . patients with exacerbations of asthma and patients who were withdrawn from inhaled steroids showed higher e-co levels than steroid-treated asthmatics or healthy controls [ ] . higher levels of e-co may also occur in children with persistent asthma than in healthy controls [ ] . e-co levels may correlate with functional parameters such as peak expiratory flow rate. a low rate in asthma exacerbations correlated with high e-co, whereas normalization of the rate with oral glucocorticoid treatment resulted in a reduction of e-co [ ] . furthermore, increased e-co was associated with greater expression of ho- in airway alveolar macrophages obtained by induced sputum in untreated asthmatic patients than in controls. these asthma patients also showed higher bilirubin levels in the induced sputum, indicating higher ho activity [ ] . furthermore, patients with asthma show an increased hb-co level at the time of exacerbation, with values decreasing to control levels after oral glucocorticoid treatment [ ] . in human asthmatics, e-co and airway eosinophil counts decreased in response to a one-month treatment with inhaled corticosteroids [ ] . in direct contrast to such studies promoting e-co as a useful noninvasive tool for monitoring airway inflammation, other studies reported no difference in e-co levels of asthma patients versus healthy controls, or between patients with stable and unstable asthma. in one such report, no further change in e-co occurred in asthma patients after a one-month treatment of inhaled corticosteroids, despite observed decreases in airway eosinophil content and bronchial responsiveness to metacholine [ ] . a recent study accentuates this finding in asthma excerbations, where no decrease in e-co of children with asthma could be detected after oral prednisolone treatment [ ] . in human allergic responses, results on elevation of e-co are also inconclusive. a clear elevation of e-co after allergen exposure occurred in patients with asthma during the late response, and during the early response immediately after the inhalation [ ] . however, another report showed that no elevation of e-co occurred in allergen-induced asthma within hours after allergen challenge [ ] . finally, increases in e-co were measured in allergic rhinitis, correlating with seasonal changes in exposure to allergen (pollen) [ ] . airway inflammation plays an important role in the development of copd, characterized by the presence of macrophages, neutrophils, and inflammatory mediators such as proteinases, oxidants, and cytokines. further-more, the inflammatory consequences of chronic microbiological infections may contribute to the progression of the disease. the current paradigm for the pathogenesis of copd involves imbalances in protease/antiprotease activities and antioxidant/pro-oxidant status. proteases with tissue-degrading capacity, (i.e. elastases and matrix metalloproteinases), when insufficiently inhibited by antiproteases, can induce tissue damage leading to emphysema. oxidants that supersede cellular antioxidant defenses can furthermore inactivate antiproteases, cause direct injury to lung tissue, and interfere with the repair of the extracellular matrix. smoking plays an important role in both hypotheses. cigarette smoke will act primarily on alveolar macrophages and epithelial cells, which react to this oxidative stress by producing proinflammatory cytokines and chemokines and releasing growth factors. nevertheless, smoking cannot be the only factor in the development of copd, since only - % of smokers develop the disease [ , ] . exposure to reactive oxygen species (from cigarette smoke or chronic infections) and an imbalance in oxidant/antioxidant status are the main risk factors for the development of copd. to defend against oxidative stress, cells and tissues contain endogenous antioxidant defense systems, which include millimolar concentrations of the tripeptide glutathione (gsh). a close relation exists between gsh concentration and ho- , whereby depletion of gsh augments the transcriptional regulation of ho- by oxidants, suggesting that the ho- /co system acts as a secondary defense against oxidative stress [ ] [ ] [ ] [ ] . accumulating clinical evidence suggests that ho- / co may also play an important part in copd. alveolar macrophages, which produce a strong ho- response to stimuli, may represent the main source of co production in the airways [ , ] . patients with copd have displayed higher e-co than healthy nonsmoking controls [ ] . furthermore, much higher levels of ho- have been observed in the airways of smokers than in nonsmokers [ ] . among subjects who formerly smoked, patients with copd have lower ho- expression in alveolar macrophages than healthy subjects [ ] . a microsatellite polymorphism that is linked with the development of copd may occur in the promoter region of ho- , resulting in a lower production of ho- in people who have the polymorphism. thus, a genetically dependent downregulation of ho- expression may arise in subpopulations, possibly linked to increased susceptibility to oxidative stress [ ] [ ] [ ] . future studies on both genetic predisposition and possible therapeutic modalities will reveal the involvement of the ho- /co system in copd. cystic fibrosis (cf) involves a deposition of hyperviscous mucus in the airways associated with pulmonary dysfunc-tion and pancreatic insufficiency, which may be accompanied by chronic microbiological infections. e-co readings were higher in untreated versus oral-steroidtreated cf patients [ ] . furthermore, e-co increased in patients during exacerbations of cf, correlating to deterioration of the forced expiratory volume in one second (fev ), with normalization of the e-co levels after treatment [ ] . e-co levels may correlate with exhaled ethane, a product of lipid peroxidation that serves as an indirect marker of oxidative stress. both e-co and exhaled ethane were higher in steroid-treated and untreated cf patients than in healthy controls [ ] . e-co was higher in children with cf than in control patients. in addition to the inflammatory and oxidative stress responses to continuous infectious pressure in these patients, e-co may possibly respond to hypoxia. e-co increased further in cf children following an exercise test, and correlated with the degree of oxyhemoglobin desaturation, a finding suggestive of an increased ho- expression in cf patients during hypoxic states induced by exercise [ ] . in patients with pneumonia, higher hb-co levels can be measured at the onset of illness, with values decreasing to control levels after antibiotic treatment [ ] . e-co levels were reported to be higher in lower-respiratory-tract infections and bronchiectasis, with normalization after antibiotic treatment [ , ] . furthermore, e-co levels in upper-respiratory-tract infections were higher than in healthy controls [ , ] . the relationship between higher measured e-co in these infectious states and higher hb-co levels cannot be concluded from these studies. the role of ho- in the development of interstitial lung disease remains undetermined. comparative immunohistochemical analysis has revealed that lung tissue of control subjects, patients with sarcoidosis, usual interstitial pneumonia, and desquamative interstitial pneumonia, all showed a high expression of ho- in the alveolar macrophages but a weak expression in the fibrotic areas [ ] . the antiproliferative properties of ho- suggest a possible beneficial role in limiting fibrosis; however, this hypothesis is complicated by a newly discovered relation between il- and ho- . il- produced by bronchial epithelial cells promotes the growth and proliferation of lung fibroblasts [ ] . ho- expression and co treatment have been shown to increase the production of il- in macrophages following proinflammatory stimuli [ ] . conversely, il- induces ho- production, which is apparently required for the anti-inflammatory action of il- [ ] . a recent report clearly shows the suppression of bleomycin-induced pulmonary fibrosis by adenovirus-mediated ho- gene transfer and overexpression in c bl/ mice, involving the inhibition of apoptotic cell death [ ] . overall, more research is needed to elucidate the mechanisms of ho- in interstitial lung disease and its possible therapeutic implications. ho- action may be of great importance in solid tumors, an environment that fosters hypoxia, oxidative stress, and neovascularization. ho- may have both pro-and antagonistic effects on tumor growth and survival. ho- and co cause growth arrest in cell-culture systems and thus may represent a potential therapeutic modality in modulating tumor growth [ ] . the overexpression of ho- or administration of co in mesothelioma and adenocarcinoma mouse models resulted in improved survival (> %) as well as reduction in tumor size (> %) [ ] . furthermore, ho- expression in oral squamous cell carcinomas can be useful in identifying patients at low risk of lymph node metastasis. high expression of ho- was detected in groups without lymph node metastasis in this report [ ] . in contrast to growth arrest, ho- may protect solid tumors from oxidative stress and hypoxia, possibly by promoting neovascularization. in one study, zinc protoporphyrin, a competitive inhibitor of ho- enzyme activity, suppressed tumor growth [ ] . co may represent a critical mediator of the body's adaptive response to hypoxia, a common feature in pulmonary vascular disease [ ] . since co can modulate vascular tone by inducing cgmp and large, calcium-dependent potassium channels, ho- and co probably play important roles in pulmonary vascular diseases [ ] . a nomediated ho- induction occurred in the hepatopulmonary syndrome during cirrhosis, associated with enhancement of vascular relaxation [ ] . in portopulmonary hypertension, elevated levels of cgmp and inducible nitric oxide synthase (inos) expression in the vascular endothelium, and ho- expression in macrophages and bronchial epithelium have been described [ ] . in transgenic mice models, ho- -/and ho- +/+ mice did not differ in their development of pulmonary hypertension following chronic hypoxia treatment, despite the development of right ventricular dilation and right myocardial infarction in ho- -/mice [ ] . the preinduction of ho- protein with chemical inducers, however, prevented the development of pulmonary hypertension in the rat lung as a consequence of chronic hypoxia treatment [ ] . transgenic mice overexpressing ho- in the lung were resistant to hypoxia-induced inflammation and hypertension [ ] . further research is needed to elucidate the potential role of ho- and co in primary human lung vascular diseases such as primary pulmonary hypertension. supplemental oxygen therapy is often used clinically in the treatment of respiratory failure. exposure to high oxygen tension (hyperoxia) may cause acute and chronic lung injury, by inducing an extensive inflammatory response in the lung that degrades the alveolar-capillary barrier, leading to impaired gas exchange and pulmonary edema [ , ] . hyperoxia-induced lung injury causes symptoms in rodents that resemble human acute respiratory distress syndrome [ ] . hyperoxia induced ho- expression in adult rats but apparently not in neonatal rats, in which the expression and activities of ho- and ho- are developmentally upregulated during the prenatal and early postnatal period [ ] . both ho- and ho- potentially influence pulmonary adaptation to high o levels. in one example, the adenoviral-mediated gene transfer of ho- into rat lungs protected against the development of lung apoptosis and inflammation during hyperoxia [ ] . in vitro studies showed that the overexpression of ho- in lung epithelial cells or rat fetal lung cells caused growth arrest and conferred resistance against hyperoxia-induced cell death [ , ] . an oxygen-tolerant variant of hamster fibroblasts that moderately overexpressed ho- in comparison with the parent line resisted oxygen toxicity in vitro. the treatment of this oxygen-tolerant strain with ho- antisense oligonucleotides reduced the resistance to hyperoxia. in contrast, additional, vector-mediated, ho- expression did not further increase oxygen tolerance in this model [ ] . in vivo studies with gene-deleted mouse strains have provided much information on the roles of ho- and ho- in oxygen tolerance. dennery et al. demonstrated that heme oxygenase- knockout mice (ho- -/-) were more sensitive to the lethal effects of hyperoxia than wild-type mice [ ] . in addition to the absence of ho- expression, however, the mice displayed a compensatory increase in ho- protein expression, and higher total lung ho activity. thus, in this model, the combination of ho- deletion and ho- overexpression resulted in a hyperoxiasensitive phenotype. recent studies of dennery et al. have shown that ho- -deleted (ho- -/-) mice were more resistant to the lethal effects of hyperoxia than the corresponding wild type [ ] . the hyperoxia resistance observed in the ho- -/strain could be reversed by the reintroduction of ho- by adenoviral-mediated gene transfer [ ] . in contrast, mouse embryo fibroblasts derived from ho- -/mice showed increased sensitivity to the toxic effects of hemin and h o and generated more intracellular reactive oxygen species in response to these agents [ ] . both ho- -/-and ho- -/strains were anemic, yet displayed abnormal accumulations of tissue iron. specifically, ho- -/accumulated nonheme iron in the kidney and liver and had decreased total iron content in the lung, while ho- -/mice accumulated total lung iron in the absence of a compensatory increase in ferritin levels [ , ] . the mechanism(s) by which ho- or ho- deletions result in accumulation of tissue iron remain unclear. these studies, taken together, have indicated that animals deficient in either ho- and ho- display altered sensitivity to oxidative stress conditions. aberrations in the distribution of intra-and extra-cellular iron, may underlie in part, the differential sensitivity observed [ , ] . otterbein et al. have shown that exogenous co, through anti-inflammatory action, may protect the lung in a rat model of hyperoxia-induced lung injury. the presence of co ( ppm) prolonged the survival of rats in a hyperoxic (> % o ) environment, and inhibited the appearance of markers of hyperoxia-induced lung injury (i.e. hemorrhage, fibrin deposition, edema, airway protein accumulation, and balf neutrophil influx) [ ] . furthermore, in a mouse model, co inhibited the expression of proinflammatory cytokines (tnf-α, il- β, and il- ) in mice induced by the hyperoxia treatment. using genedeleted mice, otterbein and colleagues also observed that the protection afforded by co in this model, similar to a lipopolysaccharide-induced model of lung injury, depended on the p mapk pathway (otterbein et al., unpublished observation, as reviewed in [ ] ). in direct contrast to these studies, the group of piantadosi and colleagues reported no significant difference in the hyperoxia tolerance of rats at co doses between and ppm [ ] . in their model, co did not alter the accumulation of fluid in the airway. furthermore, co, when applied in combination with hyperoxia, increased the activity of myeloperoxidase, a marker of airway neutrophil influx. this study also suggested that inhalation of co ( - ppm) did not alter the expression of ho- or other antioxidant enzymes such as manganese superoxide dismutase (mnsod) in vivo [ ] . furthermore, piantadosi and colleagues were able to induce oxygen tolerance in rats and ho- expression with hemoglobin treatment, but this tolerance also occurred in the presence of ho inhibitors, thereby not supporting a role for ho activity in oxygen tolerance [ ] . although no consensus has been reached as to the protective role of co inhalation and/or ho- induction in hyperoxic lung injury, human studies will be required to show if co will supersede no in providing a significant therapeutic benefit in the context of severe lung diseases [ ] . while antioxidant therapies have been examined, until now no human studies exist on the role of ho- and co in acute respiratory distress syndrome (ards) and bronchopulmonary dysplasia [ ] . lung transplantation is the ultimate and often last therapeutic option for several end-stage lung diseases. after lung transplantation, there remains an ongoing hazardous situation in which both acute and chronic graft failure, as well as complications of the toxic immunosuppressive regimen used (i.e. severe bacterial, fungal, and viral infections; renal failure; and epstein-barr-virus-related lymphomas), determine the outcome [ ] . the development of chronic graft failure, obliterative bronchiolitis (ob), determines the overall outcome after lung transplantation. ob, which may develop during the first months after transplantation, is the main cause of morbidity and death following the first half-year after transplantation, despite therapeutic intervention. once ob has developed, retransplantation remains the only therapeutic option available [ , ] . little is known about the pathophysiological background of ob. the possible determinants of developing ob include ongoing immunological allograft response, hladr mismatch, cytomegalovirus infection, acute rejection episodes, organ-ischemia time, and recipient age [ ] . ob patients displayed elevated neutrophil counts in the balf, and evidence of increased oxidant activity, such as increased methionine oxidation in balf protein and decreases in the ratio of gsh to oxidized glutathione (gssg) in epithelial lining fluid. [ , ] . so far, only very limited research data are available on the possible role for ho- in allograft rejection after lung transplantation. higher ho- expression has been detected in alveolar macrophages from lung tissue in lung transplant recipients with either acute or chronic graft failure than in stable recipients [ ] . the protective role of ho- against allograft rejection has been shown in other transplantation models, in which solid organ transplantation typically benefits from ho- modulation. a higher expression of protective genes such as ho- has been observed in episodes of acute renal allograft rejection [ ] . furthermore, the induction of ho- alleviates graft-versus-host disease [ ] . adenoviral-ho- gene therapy resulted in remarkable protection against rejection in rat liver transplants [ ] . the upregulation of ho- protected pancreatic islet cells from fas-mediated apoptosis in a dose-dependent fashion, supporting an anti-apoptotic function of ho- [ , ] . ho- may confer protection in the early phase after transplantation by inducing th -dependent cytokines such as il- and il- , while suppressing interferon-γ and il- production, as demonstrated in a rat liver allograft model [ ] . beneficial effects of ho- modulation have also been described in xenotransplantation models, in which ho- gene expression appears functionally associated with xenograft survival [ ] . in a mouse-to-rat heart trans-plant model, the effects of ho- upregulation could be mimicked by co administration, suggesting that hoderived co suppressed the graft rejection [ ] . the authors proposed that co suppressed graft rejection by inhibition of platelet aggregation, a process that facilitates vascular thrombosis and myocardial infarction. ho- may also contribute to ischemic preconditioning, a process of acquired cellular protection against ischemia/ reperfusion injury, as observed in guinea pig transplanted lungs [ ] . ho- overexpression provided potent protection against cold ischemia/reperfusion injury in a rat model through an anti-apoptotic pathway [ , ] . the induction of ho- in rats undergoing liver transplantation with cobalt-protoporphyrin or adenoviral-ho- gene therapy resulted in protection against ischemia/ reperfusion injury and improved survival after transplantation, possibly by suppression of th -cytokine production and decreased apoptosis after reperfusion [ , ] . until now, no reports have addressed e-co measurements in lung transplantation, where it is possible that differences in e-co will be found in patients with acute and chronic allograft rejection. the evolution of co in exhaled breath may serve as a general marker and diagnostic indicator of inflammatory disease states of the lung, though more research will be required to verify its reliability. increases in exhaled co presumably reflect changes in systemic and airway heme metabolic activity from the action of ho enzymes. evidence from numerous in vitro and animal studies indicates that ho- provides a protective function in many, if not all, diseases that involve inflammation and oxidative stress. thus, the exploitation of ho- for therapeutic gain could be achieved through the modulation of ho- enzyme activity or its up-and downstream regulatory factors, either by gene transfer, pharmacological inducers, or direct application of co by gas administration or chemical delivery [ ] [ ] [ ] [ ] . the co-releasing molecules (transition metal carbonyls) developed by motterlini et al. [ ] show promise in the pharmacological delivery of co for therapeutic applications in vascular and immune regulation. the co-releasing molecules have been shown to limit hypertension in vivo and promote vasorelaxation in isolated heart and aortic rings [ ] . ultimately, the challenge remains in applying the therapeutic potentials of ho- to the treatment of human diseases. in vivo models of transplantation have shown that ho- gene therapy protects against allograft rejection [ , ] . given the toxic therapy that every transplant patient receives, especially after lung transplantation, the field of transplantation medicine may bring the first frontier for human applications of ho- gene therapy or exogenous co administration. the potential use of inhalation co as a clinical therapeutic in inflammatory lung diseases has also appeared on the horizon. in one promising study, an inhalation dose of ppm co at the rate of times per day for a week produced no cardiovascular side effects [ ] . cigarette smoking and co inhalation at identical intervals produced comparable hb-co levels of approximately %. the question of whether or not co can be used as an inhalation therapy will soon be replaced by questions of "how much, how long, and how often?" the fear of administering co must be weighed against the severe toxicity of the immunosuppressive agents in current use, and the often negative outcome of solid organ transplantation. microsomal heme oxygenase, characterization of the enzyme the enzymatic conversion of heme to bilirubin by microsomal heme oxygenase heme oxygenase/ carbon monoxide signaling pathways: regulation and functional significance heme oxygenase: colors of defence against cellular stress heme oxygenase- . the "emerging molecule" has arrived heme oxygenase: a novel target for the modulation of the inflammatory response haemoxygenase- induction and exhaled markers of oxidative stress in lung diseases expression of heme oxygenase isoenzymes and in normal and 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antioxidant effect of free bilirubin on cumene-hydroperoxide treated human leukocytes haem oxygenase- prevents cell death by regulating cellular iron oxidative stress resulting from ultraviolet a irradiation of human skin fibroblasts leads to a heme oxygenase-dependent increase in ferritin heme oxygenase- mediates an adaptive response to oxidative stress in human skin fibroblasts the antioxidant defense protein ferritin is a novel and specific target for pentaerithrityl tetranitrate in endothelial cells evidence suggesting that the two forms of heme oxygenase are products of different genes heme oxygenase: clinical applications and functions characterization of two constitutive forms of rat liver microsomal heme oxygenase. only one molecular species of the enzyme is inducible isolation and characterization of a cdna from the rat brain that encodes hemoprotein heme oxygenase- heme oxygenase : endothelial and neuronal localization and role in endothelium-dependent relaxation regulation of heme oxygenase- by glucocorticoids in neonatal rat brain: characterization of a functional glucocorticoid response element changing views on carbon monoxide inhaled co: deadly gas or novel therapeutic carbon monoxide has anti-inflammatory effects involving the mitogen-activated protein kinase pathway carbon monoxide generated by heme oxygenase- suppresses the rejection of mouse-to-rat cardiac transplants carbon monoxide generated by heme oxygenase- suppresses endothelial cell apoptosis protective effects of transient ho- overexpression on susceptibility to oxygen toxicity in lung cells heme oxygenase activity causes transient hypersensitivity to oxidative ultraviolet a radiation that depends on release of iron from heme multiple elements within the ' distal enhancer of the mouse heme oxygenase- gene mediate induction by heavy metals identification of a second region upstream of the mouse heme oxygenase- gene that functions as a basal level and inducer-dependent transcription 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of inhaled corticosteroids exhaled carbon monoxide levels after a course of oral prednisone in children with asthma exacerbation changes in exhaled carbon monoxide and nitric oxide levels following allergen challenge in patients with asthma alterations in exhaled gas profile during allergen-induced asthmatic response increased carbon monoxide levels in the nasal airways of subjects with a history of seasonal allergic rhinitis and in patients with upper respiratory tract infection markers of active airway inflammation and remodelling in chronic obstructive pulmonary disease future research directions in copd endogenous glutathione levels modulate both constitutive and uva radiation/hydrogen peroxide inducible expression of the human heme oxygenase gene oxidative stress and regulation of glutathione in lung inflammation glutathione depletion induces heme oxygenase- (hsp ) mrna and protein in rat brain prior induction of ho- with glutathione depletor ameliorates the renal ischemia and reperfusion in the rat exhaled carbon monoxide and nitric oxide in copd haemoxygenase- expression in broncho-alveolar lavage fluid alveolar macrophages is diminished in patients with copd abstract microsatellite polymorphism in the heme oxygenase- gene promoter is associated with susceptibility to emphysema genes, oxidative stress, and the risk of copd the genetics of chronic obstructive pulmonary disease increased carbon monoxide in exhaled air of patients with cystic fibrosis increase in exhaled co during exacerbations of cystic fibrosis exhaled ethane is elevated in cystic fibrosis and correlates with carbon monoxide levels and airway obstruction exhaled carbon monoxide concentration increases after exercise in children with cystic fibrosis exhaled carbon monoxide in patients with lower respiratory tract infection increased levels of co in bronchiectasis: a new marker of oxidative stress expression and regulation of hemeoxygenase in healthy human lung and interstitial lung disorders bronchial epithelial cellderived cytokine il- and lung fibroblast proliferation heme oxygenase- mediates the antiinflammatory effect of interleukin- in mice adenovirus-mediated transfer and overexpression of heme oxygenase cdna in lung prevents bleomycin-induced pulmonary fibrosis via a fas-fas ligand-independent pathway heme oxygenase- expression in oral squamous cell carcinoma as involved in lymph node metastasis induction of haem oxygenase- nitric oxide and ischaemia in experimental solid tumours and implications for tumour growth hypoxia and carbon monoxide in the vasculature regulation of heme oxygenase- by nitric oxide during hepatopulmonary syndrome pulmonary expression of inos and ho- protein is upregulated in a rat model of prehepatic portal hypertension hypoxia induces severe right ventricular dilatation and infarction in heme oxygenase- null mice prevention of hypoxia-induced pulmonary hypertension by enhancement of endogenous heme oxygenase- in the rat targeted expression 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pathway heme oxygenase- induction in islet cells results in protection from apoptosis and improved in vivo function after transplantation heme oxygenase- protects pancreatic beta cells from apoptosis caused by various stimuli heme oxygenase- gene therapy: a novel immunomodulatory approach in liver allograft recipients? expression of heme oxygenase- can determine cardiac xenograft survival carbon monoxide generated by heme oxygenase- suppresses the rejection of mouse-to-rat cardiac transplants role of ischemic preconditioning on ischemia-reperfusion injury of the lung a novel strategy against ischemia and reperfusion injury: cytoprotection with heme oxygenase system heme oxygenase- overexpression protects rat hearts from cold ischemia/reperfusion injury via an anti-apoptotic pathway upregulation of heme oxygenase- protects genetically fat zucker rat livers from ischemia/reperfusion injury heme oxygenase- overexpression protects rat livers from ischemia/reperfusion injury with extended cold preservation gene regulation of ho- as a therapeutic target gene therapy strategy for long-term myocardial protection using adeno-associated virus-mediated delivery of heme oxygenase gene carbon monoxide-releasing molecules: characterization of biochemical and vascular activities sb a p mapk inhibitor, reduces neutrophilia, inflammatory cytokines, mmp- , and fibrosis in lung cardiovascular effects of carbon monoxide and cigarette smoking key: cord- -qohntipf authors: porter, p.; brisbane, j.; abeyratne, u.; bear, n.; wood, j.; peltonen, v.; della, p.; purdie, f.; smith, c.; claxton, s. title: rapid, point of care detection of chronic obstructive pulmonary disease using a cough-centred algorithm in acute care settings. date: - - journal: nan doi: . / . . . sha: doc_id: cord_uid: qohntipf rapid and accurate diagnosis of chronic obstructive pulmonary disease (copd) is problematic in acute-care settings, particularly in the presence of infective comorbidities. the aim of this study was to develop a rapid, smartphone-based algorithm for the detection of copd, in the presence or absence of acute respiratory infection, and then evaluate diagnostic accuracy on an independent validation set. subjects aged - years with or without symptoms of respiratory disease who had no chronic respiratory condition apart from copd, chronic bronchitis or emphysema, were recruited into the study. the algorithm analysed five cough sounds and four patient-reported clinical symptoms providing a diagnosis in less than one minute. clinical diagnoses were determined by a specialist physician using all available case notes, including spirometry where available. the algorithm demonstrated high percent agreement (pa) with reference clinical diagnosis for copd in the total cohort (n= , positive pa= . %, negative pa= . %, auc= . ); in subjects with pneumonia or infective exacerbations of copd (n= , ppa= . %, npa= . %, auc= . ) and in subjects without an infective comorbidity (n= , ppa= . %, npa= . %, auc= . .) in those who had their copd confirmed by spirometry (n= ), ppa = . % and npa = . %, auc= . . the algorithm demonstrates high agreement with clinical diagnosis and rapidly detects copd in subjects presenting with or without other infective lung illnesses. the algorithm can be installed on a smartphone to provide bedside diagnosis of copd in acute care settings, inform treatment regimens and identify those at increased risk of mortality due to seasonal or other respiratory ailments. chronic obstructive pulmonary disease (copd) is the fourth leading cause of mortality, affecting more than million individuals worldwide [ ] , and is characterised by airflow limitation and a progressive decline in lung function [ ] . the population prevalence of copd, via spirometry screening, is reported to be - % in those greater than years old [ ] . it is estimated that % of people with copd are undiagnosed [ ] and up to % of those with a diagnosis of copd were found to be misdiagnosed upon subsequent spirometry [ , ] . - % of patients who have been diagnosed by a physician with copd have not undergone spirometry testing [ ] . in a study of copd patients, % of those with spirometry tests did not show obstruction and % did not fulfil quality criteria [ ] . copd should be considered in patients who present with dyspnoea, chronic cough, sputum production or recurrent lower respiratory tract infections and who have been exposed to tobacco or air pollution. airflow limitation, demonstrated by a fev /fvc ratio of < . on post-bronchodilator spirometry is considered diagnostic of copd according to criteria stipulated by the global initiative for chronic obstructive lung disease (gold) [ ] . severity of airflow limitation in copd can be classified by the degree of reduction in fev as a percentage of the predicted value [ ] . however, spirometry is not routinely used in emergency departments or primary care settings due to inexperience, time constraints and availability of equipment [ ] . early and accurate diagnosis of copd is imperative to ensure initiation of correct treatment, particularly as evidence suggests the incipient stages represent a period of rapid decline in lung function where cessation of smoking and intervention may be of value [ ] . rapid identification and management of copd is important in acute care settings as there is a heightened risk of mortality from respiratory infections such as seasonal influenza [ ] . sars-cov- has a reported case fatality rate of . % for patients without comorbid conditions vs . % for those with chronic respiratory conditions [ ] . screening for copd in primary care settings using spirometry in asymptomatic patients has not been found to be efficient as high numbers need to be screened to detect any cases [ ] . screening questionnaires such as the copd diagnostic questionnaire (cdq) have performed poorly in an asymptomatic cohort in the primary care setting [ ] . we propose that the best use of an algorithm for screening is in a scenario where patients present to a healthcare facility with symptoms, where there is a higher pre-test probability of case detection. we have previously demonstrated high diagnostic agreement of a similar automated algorithm with clinical diagnoses for paediatric respiratory diseases including croup, asthma, bronchiolitis and pneumonia. the algorithm also accurately separated upper-from lower-respiratory tract conditions [ ] . the technology, which has regulatory approval, is similar to that used in speech recognition software and uses cough sounds and simple patient-reported clinical symptoms to derive the diagnostic probability output [ ] . cough sounds are recorded by a standard smartphone; the in-built diagnostic algorithm provides a rapid result without requiring clinical examination or additional diagnostic tests. in this paper, we describe the development and evaluate the accuracy of an algorithm for diagnosing copd from a cohort of mixed respiratory disorders including acute respiratory infections. the intended use population is those who present to health settings with suspected respiratory illness. between jan and march , a convenience study sample was obtained by prospectively recruiting participants from the emergency department, low-acuity ambulatory care and in-patient wards of a large, general hospital in western australia; and from the consulting rooms of a respiratory physician. this diagnostic accuracy study is part of a larger development program (breathe easy / anzctr: actrn ). subjects were approached if they presented to a participating site with signs or symptoms of respiratory disease or to specialist rooms for a lung function test. subjects with no discernible symptoms of respiratory disease were also recruited. subjects were excluded if they were on ventilatory support, had terminal disease, were medically unstable, had structural upper airway disease or had a medical contraindication to providing a voluntary cough (eg severe respiratory distress; eye, chest or abdominal surgery within months; history of pneumothorax). subjects with uncontrolled heart failure/cardiomyopathy, neuromuscular disease or lobectomy/pneumonectomy were also excluded. from this cohort, only subjects aged - years were used for the copd development program. written informed consent was obtained from all participants and the study was approved by a human research ethics committee (reference number: ). there were no adverse events reported. the study did not interfere with clinical care and all treatment decisions were at the discretion of the treating physician. the development of the mathematical techniques used to derive the algorithm have been described elsewhere [ ] [ ] [ ] [ ] . briefly, an independent training cohort (n= ) was used to obtain clinical data and cough samples (from which mathematical features were extracted). in developing the algorithm, selected features were weighted and combined to build various continuous classifier models used to determine the probability of a copd diagnosis (reference test). the probability output of the algorithm represents the specific, weighted combination of features used and thus the performance of individual features cannot be reported separately. the optimal model and corresponding probability decision threshold was selected using a receiver operating characteristic (roc) curve with due consideration given to achieving a balance of ppa and npa [ ] . different algorithms could be developed looking at different outputs such as very high specificity. once the optimal model was developed, an independent testing set was prospectively recruited. subjects provided five coughs that were recorded using a smartphone (iphone ) held approximately cm away from the subject at a -degree angle to the direction of the airflow. recordings were undertaken in standard clinical environments; however, care was taken to ensure that other people's coughs and voices were not recorded. the cough recording was obtained within minutes of the physical examination of the patient to ensure the clinical features had not changed. if the subject was unable to provide five coughs that were recognised by the coughdetection software or the cough recording became corrupted, the subject was excluded from further analysis. the following four clinical symptoms were selected in building the model: subject age; smoking pack-years and subject-reported presence of acute cough or fever during this illness. one smoking pack-year is defined as cigarettes or g tobacco, smoked each day over the course of year [ ] . where the clinical symptoms were unknown, the algorithm did not return a response. a full medical assessment was performed on all participants at time of enrolment, including history and clinical examination. diagnostic tests were ordered by the treating clinician independently of the study and results were available to researchers. a specialist physician assigned a clinical diagnosis to each subject based on a review of their medical file including: discharge diagnosis, all outpatient and inpatient notations and radiology/laboratory results. the clinical diagnosis definitions (table ) were employed in both the testing set (described here) and in the training set used for algorithm development: . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted september , . . https://doi.org/ . / . . . doi: medrxiv preprint spirometry was conducted according to standard methodology [ , ] . where the case definition was not met or the symptoms were significantly altered by treatment, the subject was scored as "unsure" and was excluded from further analysis. diagnostic accuracy tests were performed for four groups using an independent, test set of subjects. the same inclusion and exclusion criteria were used for both training and test sets ( table ) : . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted september , . of group , excluding those whose copd has not been confirmed by spirometry . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted september , . . https://doi.org/ . / . . . doi: medrxiv preprint when a clinical diagnosis had been assigned to all subjects, the database was locked and the software algorithm was run by an independent researcher to ensure blinding was maintained. each subject's cough sound recording and clinical diagnosis were only used once in the prospective test. power calculations were derived as follows. based on expected positive and negative percent agreement greater than % from the training program, to obtain a superiority end-point of % (lower bound % ci of maximum width ± . ) a minimum of cases were required. positive percent agreement (ppa) is defined as the percentage of subjects with a positive index test result for a specified condition who also have a positive reference standard for the same condition. negative percent agreement (npa) is the percentage of subjects who returned negative results for both tests. the primary study endpoint was defined as ppa and npa of the index test with the reference standard, with % confidence intervals calculated using the method of clopper-pearson. the probability of positive clinical diagnosis was calculated for each subject by the final classifier model and was used as the decision thresholds in the derived roc curve. from the prospective testing set, participants met inclusion criteria for, and were enrolled in the copd diagnostic study. of these were from the hospital emergency department or inpatient wards, and were respiratory outpatients or from the ambulatory acute care unit. two hundred and fifty-two participants provided a valid index and reference test (figure ). two were excluded as the clinical diagnosis was recorded as unsure. the mean age of participants was . ± . years, . % were female. those with copd were older than those without ( . vs . years, p< . ), although the sex proportion did not differ with diagnosis. . % of the entire cohort had at least one of the following respiratory symptoms: acute, chronic or productive cough; fever; rhinorrhoea; sob; wheeze; or hoarse voice. subject characteristics are shown in table including spirometry results where available. . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted september , . . https://doi.org/ . / . . . doi: medrxiv preprint cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted september , . for cases where spirometry (n= ) was used to confirm the presence or absence of copd, the mean age was . ± . years and . % were female with fev measurements as shown in table . the copd negative group includes six chronic, fixed asthmatic patients with fev below %. . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted september , . . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted september , . . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted september , . . https://doi.org/ . / . . . doi: medrxiv preprint although the algorithm was developed to discriminate based on gold criteria we repeated the analysis using lower limit of normal (lln) thresholds to diagnose copd. test performance in the "copd confirmed by spirometry group" (n= ) returned ppa of . % [ . %, . %] and npa of . % [ . %, . %]. . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted september , . . https://doi.org/ . / . . . doi: medrxiv preprint we have described a simple, rapid diagnostic test for copd which demonstrates high agreement with clinical diagnosis in the acute setting. diagnostic agreement of the software algorithm with clinical diagnosis of copd was ppa . % and npa . %. agreement was maintained when the patient had an acute respiratory infection (ppa . % and npa . %). importantly, the index test retains high diagnostic agreement in cases of spirometry-confirmed copd: ppa ( . %) and npa ( . %). accurate diagnosis of copd requires confirmation by spirometry, the gold standard tool for copd diagnosis [ ] . we used the gold criteria for copd diagnosis (fev /fvc< . ) when developing our algorithms although copd can also be defined using lower limit of normal (lln). when calculated using the lln thresholds, test performance was not significantly different from values obtained using gold criteria. it should be noted that as our model was developed to recognise copd diagnosed using the gold criteria, we would expect a poorer performance when the diagnostic criteria were changed. in many european countries, spirometry is available in acute and primary care settings [ ] although uptake of the test is limited, leading to underdiagnosis or misdiagnosis of patients [ ] . a number of barriers to using spirometry in primary and acute care settings have been reported including limitations in access, expertise and time; as well as expense [ ] . alternative testing methods have been developed. a meta-analysis of the copd diagnostic questionnaire (cdq) among ever smokers had a pooled sensitivity of . % ( % ci . % to . %) and specificity . % ( . % to . %) from four studies. analysis of handheld flow meters showed a sensitivity of . % ( % ci . % to . %) and specificity . % ( . % to . %) from three studies [ ] . in a scenario comparable to our study, when the cdq was performed on symptomatic patients in primary care, the auc was . , sensitivity was . %/ . % and specificity . %/ . % for low risk and high risk of having copd respectively [ ] . the performance of our software algorithm exceeds that of currently available copd screening questionnaires; outperforms the sensitivity of handheld flow meters with comparable specificity and demonstrates high agreement with the gold-standard (spirometry) in under one minute. this algorithm is intended to be used as a stand-alone device allowing for real-time diagnosis. as it is easy to operate and requires no physical patient contact, infection risk is minimised. we envisage this algorithm could be positioned as an initial screening test in acute care settings for patients who present with non-specific respiratory symptoms. a positive result could be used to guide immediate care in the acute setting. confirmatory testing by spirometry remains the gold standard test and could be performed during subsequent specialist follow up. population and primary care surveys have demonstrated that mild (fev ≥ % of percent predicted) and moderate (fev - % of percent predicted) airflow limitation is seldom diagnosed by clinicians [ , ] . in our study, % of those with clinically-diagnosed copd had only mild or moderate airflow limitation (table ) . this group represents those who would benefit most from this algorithm, both by virtue of new treatment possibilities and also because they are frequently underdiagnosed. in this study we were able to accurately identify the presence or absence of copd in patients with lrti including pneumonia. in these situations, spirometry can be difficult to perform adequately, and an initial diagnostic test will help detect copd in acutely unwell patients and identify those individuals most at risk of developing complications. individuals with copd are known to experience more frequent complications and mortality due to seasonal illnesses such as influenza [ ] . more recently, a meta-analysis examining risk of severe outcomes from sars-cov- infection (admission to icu, mechanical ventilation or death) showed a greater than five-fold increase in risk of severe disease in patients with coexistent copd [ ] . the authors recommend that all copd patients with a suspected infection should be carefully monitored in view of this increased risk. the diagnosis of copd in patients presenting with sars-cov- or similar respiratory infections, would allow more focused therapeutic pathways and usefully guide healthcare resources to this at-risk group. there are several limitations to this study. our study population was recruited in an urban setting with smoking-related copd. the generalisability of these results to copd of differing aetiologies and in other settings requires confirmation. the tests were performed by trained research personnel in controlled environments, although we would consider the device less onerous to use than spirometry. the cough recording can be affected by background noise and positioning of the device, although the program will alert the user if background noise is excessive. the population recruited reflects the intended age range of the population, however as expected, those with diagnosed copd were slightly older than those without and it will be important to replicate this study using an older control group. this copd diagnostic algorithm may be used in combination with a suite of other respiratory diagnostic algorithms developed in the breathe easy program, including tests for asthma, pneumonia and lower respiratory tract disease [ ] . the software would provide a diagnostic output for each condition simultaneously. in conclusion, the algorithm was able to accurately identify copd even in the presence of infection. the algorithm operates as a stand-alone tool and provides a rapid result. it may find application in the acute-care setting as a screening tool to alert clinicians to the presence of copd and allow more rapid, targeted and appropriate management. . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted september , . . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted september , . . https://doi.org/ . / . . . doi: medrxiv preprint global health epidemiology reference, global and regional estimates of copd prevalence: systematic review and meta-analysis global initiative for chronic obstructive pulmonary disease. global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease implementation of a targeted screening program to detect airflow obstruction suggestive of chronic obstructive pulmonary disease within a presurgical screening clinic prevalence, severity and underdiagnosis of copd in the primary care setting under-and over-diagnosis of copd: a global perspective. breathe (sheff) underdiagnosis and overdiagnosis of chronic obstructive pulmonary disease how often is diagnosis of copd confirmed with spirometry misdiagnosis of asthma and copd and underuse of spirometry in primary care unselected patients new developments in the assessment of copd: early diagnosis is key risk of severe influenza among adults with chronic medical conditions date last updated screening for chronic obstructive pulmonary disease using spirometry: summary of the evidence for the u.s. preventive services task force diagnostic accuracy of screening tests for copd: a systematic review and meta-analysis a prospective multicentre study testing the diagnostic accuracy of an automated cough sound centred analytic system for the identification of common respiratory disorders in children cough sound analysis can rapidly diagnose childhood pneumonia automatic croup diagnosis using cough sound recognition stratifying asthma severity in children using cough sound analytic technology quantification and chemical markers of tobacco-exposure standardisation of spirometry barriers to the use of spirometry in general practice external validation of a copd diagnostic questionnaire prevalence and underdiagnosis of copd by disease severity and the attributable fraction of smoking report from the obstructive lung disease in northern sweden studies the prevalence of undiagnosed chronic obstructive pulmonary disease in a primary care key: cord- -p jb gf authors: kong, qing; mo, shuming; wang, wenqian; tang, zihui; wei, ying; du, yijie; liu, baojun; kong, lingwen; lv, yubao; dong, jingcheng title: efficacy and safety of jia wei bushen yiqi formulas as an adjunct therapy to systemic glucocorticoids on acute exacerbation of copd: study protocol for a randomized, double-blinded, multi-center, placebo-controlled clinical trial date: - - journal: trials doi: . /s - - - sha: doc_id: cord_uid: p jb gf background: systemic glucocorticoids are effective for the management of chronic obstructive pulmonary disease (copd) exacerbation but have serious adverse effects. traditional chinese medicine (tcm) can bring additional benefits to these patients but has few adverse effects. the present study aims to evaluate the efficacy and safety of jia wei bushen yiqi (jwby) formulas in patients who suffer from copd exacerbations and to investigate whether the short-term ( -days) systemic glucocorticoid therapy is non-inferior to the long-term ( -day) regime. methods: in this multi-center, randomized, double-blinded trial, eligible inpatients with copd exacerbation are randomly assigned to four groups (a, b, c, and d). group a will receive placebo plus -day prednisone, group b will receive placebo plus -day prednisone, group c will receive jwby formulas plus -day prednisone, and group d will receive jwby formulas plus -day prednisone. the primary outcomes are the time interval to the patient’s next exacerbation during a -day following up and the copd assessment test (cat) during treatment. secondary outcomes include lung function, tcm syndrome assessment, laboratory tests, and safety. the changes of the hypothalamic pituitary adrenaline axis (hpa axis) and inflammatory cytokine will be measured as well. discussion: by demonstrating the advantages of utilizing tcm and an appropriate duration of systemic glucocorticoids, this effectiveness comparison trial will provide new references to physicians on how to improve the management of copd exacerbation. the results of hpa axis and inflammation cytokine measurements will shed light on the molecular mechanisms and entail further mechanism studies. trial registration: www.chictr.org.cn chictr . registered on may . chronic obstructive pulmonary disease (copd) will become the third leading cause of death worldwide in [ ] . . % of the population over years old suffer from copd in china [ ] , creating a large socioeconomic burden [ ] [ ] [ ] . copd exacerbation is defined as the acute worsening of respiratory symptoms that require additional therapy [ ] [ ] [ ] . acute exacerbations of copd impair pulmonary function and exponentially increase the risk of death [ ] . therefore, effective management of copd is critical to human health. according to international guidelines and evidencebased reviews, systemic glucocorticoids are recommended to treat copd exacerbation [ ] [ ] [ ] [ ] [ ] [ ] . the advantages include shortened recovery time and hospitalization duration, improved lung function and oxygenation, and reduced relapse risk and treatment failure, which have been demonstrated by numerous randomized clinical trials (rct) [ ] [ ] [ ] [ ] [ ] [ ] [ ] . however, the side effects like hypertension, hyperglycemia, gastrointestinal bleeding, psychiatric disease, and hypothalamic pituitary adrenal axis (hpa axis) suppression increase with the extension of treatment duration and the escalation of dose [ ] . controversy over the optional duration continues. on one hand, a dose of mg prednisone (a common oral systemic glucocorticoid) daily for days has been recommended by the global initiative for chronic obstructive lung disease (gold) science committee report based on the reduce randomized clinical trial since [ ] . the trial indicated the efficacy of -day systemic glucocorticoids is noninferior to -day systemic glucocorticoids regarding relapse within a -month follow-up, but significantly reduced glucocorticoid exposure. on the other hand, a dose of - mg prednisone daily for - days [ , , ] was suggested by another academy of china, korea, and europe in . yet, no clinical trials have determined the difference between the -day and -day regimes. in addition, treatment individualization brings benefits. for instance, an inhaled corticosteroid (ics) is more efficacious in patients with high blood eosinophils [ ] [ ] [ ] . however, present pharmacotherapy has failed to reverse the downtrend in pulmonary function completely [ ] . hopefully, traditional chinese medicines (tcm) can expand copd treatment in terms of syndromic difference, also called zheng [ ] . not only has tcm alleviated symptoms such as coughing, shortness of breath, and sputum for thousands of years, but also has demonstrated its efficacy and safety [ ] [ ] [ ] [ ] [ ] . however, there are rarely studies focused on copd patients during the acute exacerbation period, most of them focused on the relatively stable period. we conducted a randomized and placebo-controlled trial enrolling stable copd patients in , which illustrated that tcm formulas called bushen yiqi (by) formulas can improve the lung function, reduce the frequency of acute exacerbation of copd, and modulate the hpa axis [ ] . dr. shen replaced glucocorticoid therapy with tcm formula (by) totally in chronic inflammatory disease [ ] . moreover, several ingredients in by can decrease the inflammatory reactions in copd animal models [ ] . recently, we have observed that by formulae combined with another two chinese herbs-huang qin (scutellaria) and chi shao (paeoniae rubra radix)-demonstrate more effectiveness on the management of acute exacerbation of copd in clinical practice, such as relieving the symptoms including the cough, sputum, as well as shortness of breath. interestingly, the laboratory experiments showed that the main compound of these two chinese herbs benefits the animal of copd model. for instance, scutellaria baicalensis in huang qin significantly improved lung function, ameliorated the pathological damage, and attenuated inflammatory cytokines infiltration into the lungs [ ] . similarly, paeonol in chi shao showed antiinflammatory and antioxidant effects against cs-induced lung inflammation in both in vivo and in vitro experiments [ ] . therefore, we propose that jia wei bushen yiqi formulae (jwby)-bushen yiqi formulae combined with huang qin and chi shao-will benefit patients with acute exacerbation of copd. this study aims to demonstrate non-inferiority of a -day therapy compared with a -day regimen of systemic glucocorticoids based on the copd outcome during the -day follow-up period. it also seeks to determine the relative inferiority of jwby formula as an adjunct treatment to systemic glucocorticoids compared with systemic glucocorticoids alone for copd exacerbation. this is a multi-center, double-blinded, placebocontrolled, randomized clinical trial. this trial will be conducted in two stages: a -day treatment and then a -day follow-up. qualified patients will be randomized to groups: group a will receive placebo plus -day prednisone, group b will receive placebo plus -day prednisone, group c will receive jwby formulas plus day prednisone, and group d will receive jwby formulas plus -day prednisone. assessments will be performed on day and on day during treatment and telephone calls will be conducted on day and on day when patients are discharged (fig. ) . the day-treatment is chosen for two reasons. first, it is because of the two aims that were mentioned above. second, the -day treatment period is based on our investigation result that most copd exacerbation symptoms can be alleviated within days. in other words, days are the common hospitalization time in ten subcenters. therefore, the day-treatment is a good time for patients to complete the study during hospitalization, which will promote the compliance of patients and collect as much data as possible. the -day follow-up time is based on the results from the reduce randomized clinical trial research published on jama in . it is reported in this trial that the median number of days of follow-up was in both the conventional group ( th percentile, ; th percentile, days) and in the short-term treatment group ( th percentile, ; th percentile, days). this trial will be conducted at ten hospitals located in shanghai, yunnan, xinjiang, and jiangsu province in china. five hospitals are selected because they are attached to universities and another five hospitals are selected because they are experienced in rct. also, these hospitals are spread out throughout china ( table ). the principal investigator (pi) work at huashan hospital and is responsible for the steering committee meeting, which includes protocol training, supervision of safety, quality control, feedback of progress, and study reports. pis of other hospitals will organize their clinical physicians and nurses to carry out recruitment and follow-up. patients that are hospitalized with copd acute exacerbation and meet the inclusion and exclusion criteria ( table ) will be eligible to be study participants. acute exacerbation of copd with clinical grade is defined as follows: respiratory rate > times/min, application of assisted respiratory muscles, no mental state change, hypoxemia can be improved by the %- % oxygen concentration in the inner cover of the venturi, and hypercapnia or partial pressure of carbon dioxide (paco ) increases to - mmhg from the baseline value. patients who are diagnosed as having respiratory failure but without the risk of death are appropriate for ordinary hospitalization, as recommended by the chinese expert consensus on the diagnosis and treatment of acute exacerbation of chronic obstructive pulmonary disease (aecopd) ( update) [ ] . in other words, a moderate degree of copd exacerbation does not indicate the need for intensive care unit (icu) admission according to gold guideline [ ] . tcm syndrome differentiation-fei_shen_qi_xu_yu_ re zheng in chinese-specifies people who have lung and kidney qi deficiency mixed with blood stasis and (table ) . study centers are selected from level a hospital in china. the investigators will be selected from attending physician who majors in respiratory disease. prior to the trial, all sub-center physicians, nurses, and other staff will be trained to understand the protocol. attending physician who will take charge of the patients obtains consent from potential participants or authorized surrogates. firstly, attending physician will introduce the trial including the origin of tcm formula, the prednisone effect, what they should do, and what will benefit them if they volunteer to participate in this trial. then, physician will reply to the questions that confuse patients. finally, both the physician and patient will sign the informed consent form to indicate the patient's full understanding of the protocol. in the consent form, participants will be asked if they agree to use of their data should they choose to withdraw from the trial, and if they are volunteer to provide another ml blood for storage, which are used to explore their inflammation level, hpa axis function, and the relationship between effectiveness and gene type. participants will also be asked for permission for the research team to share relevant data with people from the hospitals who take part in the research. as we mentioned in background, prednisone of - mg once daily is recommend for copd exacerbation management since by golg guideline. the evidence is from a clinical trial that compare the efficacy of days of prednisone treatment with days. the participants come from sweden. as in other countries like china, the duration of prednisone treatment is recommended as - days. the differences of the outcomes between days of treatment and days are unknown in the chinese patients. since we choose the relatively mild patients with copd exacerbation, the minimum dose of prednisone mg once daily is decided in this trial. in addition, tcm formula has been used for copd therapy for thousands of years. we have observed the superiority of tcm as an adjunct therapy in copd administration. but there is no evidence to show the exact outcomes. the doses of five tcm herbs are decided by a group of experienced tcm physician who used the principle of tcm in treating copd for many years. the control group is placebo that contains % true herbs with the same appearance and smelling as the drugs. severe impairment of heart, liver and kidney function (heart function - degree, aspartate aminotransferase (alt) and/or alanine aminotransferase (ast) exceeds . times of the upper limit of normal, creatinine (cr) exceeds the upper limit of normal) . received systemic glucocorticoids within weeks or participation in other drug clinical trials within months prior to the trial . other conditions that the investigators consider to be improper all the participants will be provided with standard of care (soc) according to the gold guideline for copd exacerbation during hospitalization and after discharge (table ) . a -day adjunct medication includes systemic glucocorticoids and tcm herbs or their placebo. a basic dose of mg prednisone daily for days will be provided for all participants. the prednisone will be continued in the long-term glucocorticoids arm of the trial in the following days and replaced with the placebo in short-term glucocorticoids arm of the trial. the -day treatment period is based on the fact that most copd exacerbation can be relieved within days. meanwhile, participants will be treated with tcm herbs or placebo. participants will be randomized to four groups with different adjunct medication ( fig. ) . because of the complex and variety in copd exacerbation, variation among patients will be allowed. any variation like another antibiotic used for the indication will be recorded in the case report form (crf). tcm treatment is in accordance with the most common tcm syndromes of copd in a real-world study [ ] . the dosage of jwby formula is selected according to the pharmacopeia of chinese medicine, and the effective ingredient of its granules is determined according to the pharmacopeia of pharmacopeia. jwby formulas contain kinds of herbs: huang qi (astragalus) g, yin yang huo (epimedy) g, sheng di huang (radix rehmaniae) g, chi shao (red peony) g, and huang qin (scutellaria) g, concentrated as . g granules. to use, patients can infuse . g granules into ml of boiling water and ingest orally after breakfast and supper, twice daily. its placebo is identical in appearance, shape, size, and package with jwby formulas, but only contains % real herbs. the granules will be produced and packed by huarui sanjiu pharmaceutical industry in shenzhen, china. granule production will be certified to get the standard certification of the tcm national drug regulatory authority. modification or discontinuation of the intervention will be decided by the pis in each center, according to the requests from participants, or when a participant's disease is worsened to grade which indicates the need for icu admission, or when unexpected adverse effects happen. prednisone and jwby granules are free as study drugs. five-day drugs will be provided to participants at baseline by a sub-center investigator and another -day drug at day . participants will use patient diaries for recording medication and changes in symptoms. all unused packs of drugs and empty bags will be returned to investigational site on day and on day . compliance will be calculated by counting drugs or empty bags for a day course. compliance % of medication = [actual dose/ (specified daily dose × days)] × %. total medication consistency ranging from to % will be eligible for the protocol analysis set. patients enrolled in the trial will be all hospitalized and all the laboratory tests will be performed on standard schedule, which aids in the monitoring of adherence. once the patient is randomized, the investigators will take every reasonable effort to follow the patient for the entire course of the study. all examination and transportation costs in the -day will be covered and the results of symptoms and physical exams will be explained at every visit. messages will be sent through wechat or by phone prior to every visit to remind the patients of the follow-up visits. extra copd-related drugs, such as leukotriene receptor antagonists, antihistamines, immunosuppressants, and antioxidants, will be forbidden during the trial. tcm herbs that are tonifying kidney, benefiting qi, clearing away heat, and promoting blood circulation, whose tcm characteristics are like those within jwby formulas, will be avoided. drug combinations will be recorded in the case report form at each follow-up visit. "tonifying kidney" ("bushen" in chinese) is a tcm term of treatment, which aims at the tcm syndrome "deficiency of kidney" ("shen_xu" zheng in chinese). the chinese herbs used in "tonifying kidney" treatment can relieve "deficiency of kidney" syndrome including shortness of breath, deterioration with movement, fatigue, waist and knee area sore, and their weakness, tinnitus, dizziness, incontinence, or heavy urine volume. patients that are enrolled into the study will be covered by indemnity through the standard national health service indemnity arrangements. the pi will provide the compensation to those who suffer due to trial participation. primary outcomes measurements ) the time to the next exacerbation of copd during the -day follow-up is defined as one primary outcome. the definition of exacerbation is deterioration of the cardinal symptom of dyspnea, increased sputum purulence and volume, and purulent sputum. this may be combined with one of the other symptoms: increased cough and wheeze, sore throat, nasal congestion due to cold, fever (oral temperature > . °c), increased cough, and increased wheezing. the above changes should last for ≥ days at least. a minimum of week between two exacerbations is needed in order for them to be considered as separate events. the duration of exacerbation is measured from the onset of acute exacerbation to a significant reduction which is defined as the symptoms return to the level before the exacerbation per the records in patients' dairies. the diaries are distributed to participants during the treatment and after the treatment. participants record changes of their symptoms and their health status by choosing the right description in terms of feeling. the primary symptom is measured with modified british medical research council (mmrc) and copd assessment test (cat) scores. the days of exacerbation are calculated from the onset date of the primary symptom to the date when all symptoms disappear. the degree is classified as mild (treated with short acting bronchodilators only, sabds), moderate (treated with sabds plus antibiotics and/or oral corticosteroids), or severe (patient requires hospitalization or visits to the emergency room). severe exacerbations may be associated with acute respiratory failure. ) the mean difference of cat scores between day or day and baseline is another primary outcome. the cat involves an -dimension measurement of health-status impairment in copd. cat is universally acknowledged as a reliable and valid measurement in evaluating the changes of copd. ) tcm syndrome assessment will be evaluated from baseline to day and day . according to the guiding principles for clinical research of new drugs in traditional chinese medicine, the syndrome score is calculated as efficacy index n = (pre-treatment score − post-treatment score)/ pre-treatment score × %. in terms of mild, moderate, and severe symptoms, the primary symptoms are given , , and points while the secondary symptoms are given , , and points respectively. total score = scores of the primary symptoms + scores of the secondary symptoms. ) lung ventilation function will be assessed by forced expiratory volume in s (fev ), forced vital capacity (fvc), and peak expiratory flow (pef) from baseline to day and day with standardized equipment (erich jaeger uk ltd., market harborough, uk jaeger master-screen, germany) and per the standard procedure recommended by american thoracic society (ats) [ ] . ) blood gas analyses including partial pressure of oxygen (pao ), partial pressure of carbon dioxide (paco ), infectious indexes including blood eosinophil count in cells per micrometer (eos), creactive protein (crp), and proclamation will be tested by clinical laboratories in the sub-center from baseline to day and day . side effects will be collected at day , day , and day during follow-up. this specifically refers to ( ) the changes in hyperglycemia: fasting plasma glucose ≥ . mmol/l or random plasma glucose ≥ . mmol/l or rise ≥ % in daily doses of insulin or any increase in oral anti-diabetic drugs or initiation of one or more antidiabetic therapeutics, ( ) changes in hypertension: systolic blood pressure ≥ mmhg and/or diastolic blood pressure ≥ mmhg or the addition of one or more anti-hypertensive drugs to previous treatment regimens, and ( ) the number of psychiatric symptoms, asphalt, vomiting coffee samples, and new infection. laboratory tests which include routine blood test, routine urine test, electrocardiogram (ecg), kidney and liver function, and x-ray computed tomography (ct scan/x-ray) of the chest will be conducted at baseline, day , and day during the follow-up. if the results of ct scan/x-ray and ecg are normal at baseline, it will be skipped in the follow-up. the pathology of copd is relevant to the inflammation and the suppression of the hpa axis that follows the treatment with glucocorticoids. therefore, changes in the hpa axis including corticotropin-releasing hormone (crh), adrenocorticotropic hormone (acth), and cortisol and the inflammation cytokines including interleukin- , interleukin- , and interleukin- at baseline and on day and day will be measured. there are four groups with two variables in this trial-tcm treatment and systemic glucocorticoid treatment. therefore, according to primary endpoints collected from previous trial [ , ] , we choose the maximum sample size needed, as calculated by two way on http:// www.powerandsamplesize.com (table ). at the % significance level, a total of patients per group will be required for a -group, -sided calculation to achieve % power and the differences of . ± . and . ± . in cat mean score between the tcm treatment group and placebo group (table ) . meanwhile, a total of participants will be required for a group non-inferiority calculation to achieve the mean difference of the time to next exacerbation ( . , ) and a non-inferiority margin of , under the condition that the standard deviation of the groups is equal to (table ) . a loss of - % to follow-up is predicted based on experience-this increases the sample size to participants per group, resulting in in total. all investigators in the sub-center will advertise and distribute posters in their emergency department and nearby communities. in addition, we will set up a hierarchical medical system in shanghai-communities refer the potential patients to huashan hospital directly where the clinical trial is undertaken. participants will be randomized with equal probability ( : : : ) to receive one of the four treatments that were mentioned above. as the size of each group is predicted to be , the allocation sequence is generated with sample randomization and stratification by trial center. the sequences will be generated by software and in excel format. before the study begins, a series of random numbers will be generated by the computer, and the pharmacists involved in the study place the random numbers in plain, closed envelopes marked with patient numbers. envelopes will be made and stored at the pharmacy and opened by the pharmacist only when the subjects are randomized. the envelopes will be not accessible to individuals directly involved in the study. allocation sequence will be generated by a statistician who will not participate in enrolling participants. participants will be blindly randomized and allocated with an identified number. principal investigators including attending physician and nurses will involve in enrolling participants. pharmacist will distribute an independent emergency envelope for each participant, which contains the treatment assignment. the participants in the placebo group will be given the same number of pills and followed the same medication schedule as the treatment group. to ensure the implementation of the blinding method, the pill and herbs in both the treatment group and the placebo group will be made in the same shapes, smells and tastes. trial participants, care providers including attending physician and nurse, outcome assessors including pi and sub-pi, and data analysts will be blinded after the assignment of interventions. double-grade unblinding will be adopted. first grade unblinding: it will be conducted before the data analysis. after the double input of all the crf data into the computer and blinded review, the data will be locked. afterwards, the personnel who keep the blinded materials will unblind them for the first time, which is to divide the groups corresponding to the case numbers into blinded codes of two groups and to tell the statisticians so as to statistically analyze all the data. second grade unblinding is after the statistical analysis and the completion of clinical trial report. it will be conducted at the wrap up meeting for the clinical trial. the treatment group and control group will be unblinded. place of unblinding will be the unit where the clinical trial is in charged. executive personnel will be the chief researcher and statisticians of the unit that are in charge of the trial. if there is severe adverse event, which impedes the progress of the trial and the selection of the treatment measures, urgent unblinding can be carried out. during the process, all the researcher, sub-pi, and clinical supervisors should take part. the local administrative unit should be informed within h. the reason, time, and place of unblinding should be recorded in detail and all the records should be signed off. afterwards, the clinical supervisors should be informed timely. the case data should be kept intact. prior to the start of the trial, sub-center physicians will be trained. the results of laboratory tests from different hospitals are adjusted per the huashan hospital standards during analysis. demographic information (date of birth, gender, etc.) and medical condition (medical history, concomitant medication, etc.) will be recorded at baseline. all the questionnaires will be answered by patients without inducement. when adverse events that are related to study drugs happen, emergency envelope can be considered as needed to be opened by pis and physician. the investigators will report the reasons and outcome to the pi within h. prior investigation shows that the mean hospitalization duration time is about - days in these hospitals, which matches the trial requirement of days of treatment. after screening and completing baseline evaluations, participants will visit the physician at day and day during adjunctive treatments and day when patients are discharged (fig. ) . we will provide free tcm granules and partial examination reimbursement to participants. the participants and their family member will be informed that standardized treatment is beneficial to reduce copd exacerbation, which will reduce medical expenses the benefits. two telephone calls will be conducted on day and day . the writing and transfer of case report the case report will be written by the doctor who has participated in the trial. every case should have a complete case report. the case report, once completed, should be checked by the supervisor. afterwards, it will be transferred to the data administrator for data entry and management. all the information in crf table will be recorded in a specialized clinical experimental database that is designed by chinese academy of traditional chinese medicine. the format of the database should be close to that of the crf table so as to facilitate the data entry. the variables in the crf table will be encoded and the codes will be kept unchanged during the whole process of clinical research. the crf data will be entered by highly trained specialists from the research centers. the audit of data can be divided into two forms: manual audit and system audit. the former refers that the administrator checks the consistency and logic of the data so as to find the mistakes and to generate the question list. sas software sets the limit of all variables and rules out automatically the unqualified data by running the system program. the question list is sent to the clinical supervisor who transfers it to the researcher for reconfirmation. the related revision should be signed and dated by the researcher. the researcher will correct the data for the last time after the return of all question lists. all the corrections and updates should be recorded and filed. after the data is verified, the data administration meeting will be held so that the corrections and updates can be summarized. at last, the data administrator will announce the locking of database and keep the cipher code. the statistical analysis prospectus will not be changed after the database lock. the data will be transferred to the statistical department for analysis. all the data should be kept according to the requirements of gcp. after the experiment, all the original copy of case reports and records for the administrations of clinical drugs should be checked, signed, and stamped by the supervisors, head researchers, and representatives from gcp office of each clinical center, and finally, these records will be sent to the leading site where the database will be established and the data will processed. statisticians will analyze the data and materials from the participating centers, and the summary of the clinical trial will be completed in the leading site. case report form (crf) collects all the information throughout the trial for every participant. as soon as verification is completed, data will be securely stored and sent to huashan hospital from the sub-centers. a data management group will be established, and the information will be entered into the database provided by http://www.rilintech.comt through independent doubledata entry. the errors and inconsistencies of data will be checked during the entry process. the user identification code and password will be protected by the data management group. the pis will be given access to the cleaned data sets. sub-investigators will only have access to the data sets in their own hospital. original paper forms will be kept in huashan hospital for years. plans for collection, laboratory evaluation, and storage of biological specimens for genetic or molecular analysis in this trial/future use { } the process and collection of blood samples separation of - ml of plasma from ml of whole blood the anticoagulant and aprotinin (for concentration and amount, please refer to the note) will be added to the blood-collection tube, which is placed at °c for precooling, and then . ml of whole blood will be collected. the samples will be mixed in the tube slowly, and afterwards, the mixture will be centrifuged at a low temperature ( °c, r/min, - min). . ml of plasma will be collected and kept at a low temperature (− °c). if the collected blood cannot be centrifuged immediately, it can only be stored in °c freezer for up to h. note: the concentration and amount of anticoagulant and aprotinin. anticoagulant: . medta. na concentration ( ul/ ml) or % heparin ( ul/ml); aprotinin ( iu/ml). there are two kinds of aprotinin: liquid (the concentration will be noted on the label) and solid ( , iu/mg). the solid form of aprotinin can be dissolved in normal saline, so its concentration can be adjusted to iu/ μl. requirements for sample storage the samples should be kept immediately in − °freezer. throughout the transportation, the samples cannot be taken out. in huashan hospital, all of the samples are checked. the samples should be labeled with case codes and collection date. blood serum should be kept in dry ice for transportation. primary and secondary outcomes the tcm intervention arm-jwby (jia wei bushen yiqi formulas)-will be compared against the placebo. the short-term systemic glucocorticoid (ssg) arm will be compared against the long-term systemic glucocorticoid (lsg) arm. four groups will be compared with each other independently. statistical package for social sciences for windows, version . (spss, chicago, il, usa) will be used for analysis. the tests will be -sided, and a p value with alpha ≤ . level is considered significant. p values will be reported to four decimal places with p values less than . reported as p < . . the bonferroni method will be used to appropriately adjust the overall level of significance for multiple comparisons, assuming an exchangeable correlation structure. categorical variables will be summarized by absolute numbers and percentages of total. the difference of categorical variables will be assessed with the generalized estimating equations (gee). gee will also be used to assess the impact of potential clustering of participants in the same hospital. safety outcomes will be analyzed with summary statistics (frequency, count, percentage). the method of analysis of each variable are summarized in table . the score of copd assessment test (cat) will be collected at baseline, day , day , and in the days, days, days after discharge. the mixed effect normal model (menm) will be used to compare each outcome against the tcm intervention group and placebo. the estimate of treatment effect will be presented as unadjusted rate ratio followed by an adjusted ratio with adjustment for a set of pre-specified baseline variables. the list of pre-specified variables is as follows: centers (as a random effect), age (in years), gender (male or female), weight (in kilogram), smoking (pack per year), fev % predicted, the number of copd exacerbation in the previous year, and home-oxygen therapy. fixed effects will include the visit number, treatment, and all the prespecified variables. participant and visit interaction will be fitted as random effects. an autoregressive correction structure will be used throughout. the difference of interval time to next exacerbation during follow-up in the days, days, and days will be compared between ssg and lsg groups using the generalized linear model (glm) with a log-link function, a propriety over dispersion parameter, and length of time as an offset. the numbers will be described respectively in three gradesoutpatient, inpatient, and icu. durations of copd exacerbation will be compared between each two of the four groups with glm in the similar manner as before. specially, the shortness of breath measured by mmrc dyspnea scale ( - degree) in the diary will be undertaken in the logit link function independently. the changes in tcm syndrome score, infectious index, lung function, blood gas analysis, inflammatory cytokine levels, and hpa axis will be collected in baseline, at day , and at day . glm will be used to analyze the change between each two of the four groups as well. none. in this trial, interventions for participants include days of tcm granules and or days of prednisone. these two interventions will be carried out during hospitalization and they are routine treatments in china, so there are no anticipated problems that will be detrimental to the participant. therefore, there will be no interim analyses and there are not anticipated formal stopping rules for the trial. methods for additional analyses (e.g., subgroup analyses) { b} subgroup analysis the potential subgroups have been listed in table . the analysis of primary outcomes will be repeated in the subgroups. methods in analysis to handle protocol non-adherence and any statistical methods to handle missing data { c} analysis will be in accordance with the intent-to-treat principles. the safety set (ss) includes participants that are randomized and have received adjunct treatments and one post-treatment safety assessment at least. the full analysis set (fas) includes participants that are randomized and have received adjunct treatment, and their primary outcomes are available at least in one visit. the per protocol set (pps) includes participants in accordance with all the following conditions: valid baseline values, compliance with the program, no violation of the inclusion and exclusion criteria specified in the program, completion of all assessments, and good compliance (defined as participants taking at least % of expected doses of study drugs as determined by counting). missing data is predicted to appear on day and during the two telephone calls after discharge. the imputation of all the outcomes will be replaced by the mean of the group. plans to give access to the full protocol, participant level data, and statistical code { c} full protocol participant level dataset in chinese will be accessible in the register site. and statistical code will be provided by trial statistician. for sharing purpose, data will be available to outside investigators at the end of the trial. the finding of this trial will be published in peerreviewed journals and presented at conferences. the results of the study will be released to the participating physician and patients. composition of the coordinating center and trial steering committee { d} multi-center trial coordination committee will be established. the huashan hospital affiliated to fudan university will take charge of the committee, and the main researchers of the participating units will serve as the members. the committee will be responsible for the implementation of the whole experiment and resolve problems during the trial process. the head researcher should strengthen quality surveillance of the clinical trial in his own center. composition of the data monitoring committee, its roles and reporting structure { a} the data monitoring committee is unnecessary in this trial, because the drug duration in this trial is short- days. tcm granules and prednisone are routine treatment in china and will be carried out during hospitalization; only minimal risks are anticipated. adverse event report regardless of whether it is related to the study drug or not, any clinically significant abnormalities of medical events or laboratory tests will be defined as an adverse event (ae). for all adverse events, the time, duration, treatment measures and outcomes, the severity of the disease, and the association with the study drug will be evaluated and recorded. it is divided into mild, moderate, and severe according to the following list: conscious symptoms, ability to tolerate, impact on daily activities, duration, whether it is relieved during continued medication, and whether treatment is required. serious adverse events (sae) will be defined as death or life-threatening events. if a sae occurs, the doctor will immediately take emergency measures and report it to the pi and the ethics committee within h. according to the occurrence of adverse events and a reasonable time interval, and alleviation after withdrawal of the study drugs, the correlation between adverse events and study drugs will be evaluated as affirmative (sure), probably related (very likely), may be relevant (possible), may be unrelated (suspicious), and irrelevant (impossible). due to the unsatisfactory treatment effect, the patient will withdraw from the trial. the emergency letter of the case will be opened, and the patient's family will coordinate with the follow-up and report the result to the lead center. the relevant information will be recorded in the case report form. although the formula is optimized to instant granule instead of tcm herbs decoration in our study, some participants who never accepted tcm herbal previously may have gastrointestinal reactions such as nausea and vomiting. they will be suspended for days and evaluated on their abilities to continue to participate in. because the participants are in the acute exacerbation period, their disease may deteriorate to grade at any time with the worsening of clinical symptoms including increase of dyspnea, mental consciousness changes, blood gas analysis of acidosis, and hypoxemia that cannot be improved by oxygen absorption or other treatments. participants will be admitted to the intensive care unit (icu) if it happens. due to the worsening of the disease or the unsatisfactory effect, the emergency letter of the case will be opened. the physician-incharge will communicate with the patient's family if participant needs to withdraw from the study. the relevant information is reported to pi and recorded in the case report form. as for any deterioration syndromes that arise after discharged, participants will be advised to come to the hospital. the investigator will provide free medical services appropriately. the recommend dose of prednisone by chinese consensus is - mg daily for - days. the low dose of mg is chosen. extra management measures were suggested during the initial meeting. first, the participants will be informed that the withdrawal symptoms include fatigue, joint muscle soreness, low mood, poor appetite, and even nausea and vomiting. second, participants discharged from the hospital with adrenal insufficiency will receive instructions on how to take less than mg daily if they cannot tolerate the treatment. finally, participants will be advised to take the following preventive measures against possible adverse events. closely and modulate the number of hypoglycemic agents or insulin. ) investigators will pay attention to whether the patient has abdominal pain, vomiting of coffee-like substances, or tar-like black stool. if this occurs, the patient should promptly come to the emergency department and be treated with acid-suppressing stomach and other drugs. ) investigators will observe the patient's neuropsychiatric symptoms closely, such as euphoria, excitement, mania, and insomnia. if necessary, advise patients to seek medical help. the designated monitor will visit each investigational site once a month. the monitor will check that if the regulatory binder is complete and all that associated documents is stored well or not, including crf, informed consent forms, and adverse events reports. and the monitor will help the investigational site resolve the issues happened in the trial. plans for communicating important protocol amendments to relevant parties (e.g., trial participants, ethical committees) { } any modification to the protocol which may impact the conduct of the study and the potential benefit of the patients will be reported to ethic committee. the amendments will be approved by the ethics committee before it is announced to each investigational site. and an investigator training about new protocol will be held through wechat video meeting. participants will be informed of the new protocol. participant information will not be released outside of the study without the permission of individuals except for monitoring. blood samples, data collection, and administrative forms will be identified with the same code and stored separately in a locked place. all data will be uploaded to the resman original data sharing platform (ipd sharing platform) http://www.medresman. org of the china clinical trial registry, which is available to outside investigators when the trial ends. the result will be published in peer-reviewed journals and shared at conferences. the findings of the trial will be released to the participating physicians and patients. with the design of tcm as an adjunct to systemic glucocorticoids to treat copd exacerbation in this randomized trial, we will test the non-inferiority of two different treatment terms of systemic glucocorticoids in copd exacerbation. the finding will bring new proofs to the controversial applications of glucocorticoids. in addition, we will clarify a pragmatic method to identify the efficacy of classic description based on tcm syndrome differences despite limitations like bias of measurement and the subjectivity of the questionnaire assessment which may be exacerbated by the loss of some participant during follow-up. the difference between the four groups will indicate that tcm reduces the suppression of the hpa axis and strengthens the anti-inflammation effect of glucocorticoids. tcm may strongly support and enrich the management of copd exacerbation. however, there are some limitations in this protocol. firstly, we choose one of the specific tcm syndromes as the criteria. the result is hard to be extended to the whole patients with copd exacerbation. in addition, we use the chinese guideline to evaluate the degree of copd exacerbation, which relies on the subjective assessment of symptoms of the enrolled participants by the physician. hopefully, an objective method will be proposed to assess the copd exacerbation. our trial has enrolled volunteers in shanghai from august up to today. we have modified protocol according to the practice and standard protocol items [ , ] . in the meantime, we proposed amendment to ethics commitment and chinese clinical trial registry in july of . the protocol version is ky - , , , july, . the new protocol was reported to all subcenter pis in a group meeting. due to covid- , we expect to complete the recruitment process around october and report the results as soon as possible. supplementary information accompanies this paper at https://doi.org/ . /s - - - . additional file . burden of copd prevalence and risk factors of chronic obstructive pulmonary disease in china (the china pulmonary health cph study): a national cross-sectional study prevention and management of copd in china: successes and major challenges chronic obstructive pulmonary disease in china: a nationwide prevalence study mortality, morbidity, and risk factors in china and its provinces, - : a systematic analysis for the global burden of disease study international variation in the prevalence of copd (the bold study): a population-based prevalence study copd exacerbations: defining their cause and prevention symptom variability in patients with severe copd: a pan-european cross-sectional study acute copd exacerbations expert consensus on acute exacerbation of chronic obstructive pulmonary disease in the people's republic of china treatment with systemic steroids in severe chronic obstructive pulmonary disease exacerbations: use of short regimens in routine clinical practice and their impact on hospital stay copd clinical practice guideline of the korean academy of tuberculosis and respiratory disease: a summary diagnosis, prevention and treatment of stable copd and acute exacerbations of copd: the swiss recommendations use of glucocorticoids in patients with copd exacerbations in china: a retrospective observational study controlled trial of oral prednisone in outpatients with acute copd exacerbation oral corticosteroids in patients admitted to hospital with exacerbations of chronic obstructive pulmonary disease: a prospective randomised controlled trial effect of systemic glucocorticoids on exacerbations of chronic obstructive pulmonary disease oral or iv prednisolone in the treatment of copd exacerbations -a randomized, controlled, double-blind study efficacy of corticosteroid therapy in patients with an acute exacerbation of chronic obstructive pulmonary disease receiving ventilatory support systemic corticosteroids in acute exacerbation of copd: a metaanalysis of controlled studies with emphasis on icu patients prednisone in copd exacerbation requiring ventilatory support: an open-label randomised evaluation global strategy for the diagnosis, management, and prevention of chronic obstructive lung disease: the gold science committee report susceptibility to exacerbation in chronic obstructive pulmonary disease acute exacerbations of chronic obstructive pulmonary disease identification of biologic clusters and their biomarkers blood eosinophils to direct corticosteroid treatment of exacerbations of chronic obstructive pulmonary disease: a randomized placebo-controlled trial effects of smoking intervention and the use of an inhaled anticholinergic bronchodilator on the rate of decline of fev ( ) -the lung health study zheng: a systems biology approach to diagnosis and treatments oral chinese herbal medicine for improvement of quality of life in patients with stable chronic obstructive pulmonary disease: a systematic review efficacy and safety of indacaterol and mu g in chronic obstructive pulmonary disease patients from six asian areas including japan: a -week, placebo-controlled study bu-fei yi-shen granule combined with acupoint sticking therapy in patients with stable chronic obstructive pulmonary disease: a randomized, double-blind, double-dummy, active-controlled, -centre study effects of comprehensive therapy based on traditional chinese medicine patterns in stable chronic obstructive pulmonary disease: a four-centre, open-label, randomized, controlled study effects of yupingfeng granules on acute exacerbations of copd: a randomized, placebo-controlled study effects of two chinese herbal formulae for the treatment of moderate to severe stable chronic obstructive pulmonary disease: a multicentre, double-blind, randomized controlled trial important action of improving adrenocortical function for certain diseases recovery effect and mechanism of several traditional chinese medicine components on inflammatory response of chronic obstructive pulmonary disease caused by exposure to cigarette smoke scutellaria baicalensis attenuates airway remodeling via pi k/akt/nf-kappab pathway in cigarette smoke mediated-copd rats model paeonol attenuates cigarette smoke-induced lung inflammation by inhibiting ros-sensitive inflammatory signaling a real-world evidence study for distribution of traditional chinese medicine syndrome and its elements on respiratory disease short-term vs conventional glucocorticoid therapy in acute exacerbations of chronic obstructive pulmonary disease: the reduce randomized clinical trial spirit statement: defining standard protocol items for clinical trials spirit explanation and elaboration: guidance for protocols of clinical trials publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations we thank dr. yiyuan zeng and dr. waijiao cai from school of public health, boston university, for their linguistic assistance during the preparation of this manuscript. qing kong and shuming mo drafted the manuscript. wenqian wang, zihui tang, baojun liu, yijie du and lingwen kong participated in the design of the study. zihui tang participated in the statistic plan. ying wei, yubao lv and jingcheng dong conceived the study, participated in its design and coordination, and drafted the manuscript. all authors read and approved the final manuscript. all named authors adhere to the authorship guidelines of trials; no professional writers have been involved. the enrolled participants who sign the informed consent forms about clinical data and bio-sample collection are provided with free medication of jwby formulas and prednisone for days as needed. participants' information will not be released outside of the study without the permission of individuals except for monitoring. blood samples, data collection, and administrative forms will be identified with the same code and stored separately in a locked place. all data will be uploaded to the resman original data sharing platform (ipd sharing platform) http://www.medresman.org of the china clinical trial registry, which is available to outside investigators when the trial ends. the result will be published in peer-reviewed journals and shared at conferences. the findings of the trial will be released to the participating physicians and patients. central ethics committee approval has been obtained from ethics committee of huashan hospital affiliated to fudan university in shanghai, china (id: ky- ). the local ethics committee of other ten hospitals has approved the protocol, too. the trial was registered on www.chictr.org.cn (id: chictr ) on may , . the investigator will make safety and progress reports to the ethics committee monthly. protocol amendment will be approved by the ethics committee prior to the implementation of amended protocol at the sub-centers. all investigators are trained to carry out the new protocol. there is no conflict of interests among the subcenters. informed consent will be obtained from all study participants. these are available from the corresponding author upon request. there are no competing interests in this work.author details key: cord- -b w zrl authors: nan title: oeld/population health sig: poster session date: - - journal: respirology doi: . /j. - . . _ .x sha: doc_id: cord_uid: b w zrl nan patients with non-eosinophilic asthma (nea) or copd have increased numbers of neutrophils in the airways. we have shown a similar defect in the ability of alveolar macrophages (am) to phagocytose apoptotic cells, in sputum from patients with nea and copd. we have also shown that bal-derived am from patients with copd have reduced expression of key macrophage phagocytic recognition molecules. the aim of this pilot study was to investigate the expression of these macrophage markers in induced sputum from patients with eosinophilic asthma (ea, n = ), nea (n = ), copd (n = ) and controls (n = ). methods participants underwent clinical assessment, skin allergy test, hypertonic saline challenge and sputum induction. macrophage phagocytosis of apoptotic cells, expression of mannose receptor (mr), hspr (cd ) and pcam (cd ) was determined using fl ow cytometry. results phagocytosis was signifi cantly impaired in patients with nea and copd. expression of mr, cd and cd were decreased in patients with nea or copd, but not signifi cantly changed in ea conclusion impaired sputum-macrophage phagocytosis of apoptotic cells in nea is associated with reduced expression of key macrophage recognition molecules. this defect may contribute to the chronic infl ammation and persistent airway neutrophilia that characterizes this asthma subtype. the use of induced sputum as a surrogate for the more-invasive bronchoscopic sampling may provide a tool for investigating the mechanisms for the effect of therapies including azithromycin in lung disease. supported by nhmrc. neutrophilic asthma (na) has been associated with increased bacterial colonization of the airways and increased expression of innate immune factors in the lung. this suggests that infection may play an important role in the pathogenesis of na. na is an important health issue as sufferers are resistant to steroid treatment, which is the mainstay of asthma therapy and effective therapies are urgently required. using mouse models of chlamydia and haemophilus infl uenzae lung infection and ovalbumin (ova)-induced allergic airway disease (aad), we have shown how infection may be linked to na. both infections suppressed eosinophilic infl ammation and t-helper (th) type responses but increase neutrophilic infl ammation and innate and th and/or th responses in aad. in the current study, the effectiveness of steroid treatment for the suppression of infection-induced neutrophilic aad was assessed by treating infected ovasensitized mice intranasally with dexamethasone during ova challenge. whilst dexamethasone treatment suppressed th -mediated, eosinophilic aad in uninfected, ova-sensitized groups, chlamydia and haemophilus-induced neutrophilic aad were shown to be steroid-resistant. our fi ndings correlate with clinical observations which show associations between infection, neutrophilic infl ammation and steroid resistance in asthmatics. these models will be utilized to examine the effectiveness of a number of novel therapies for infection-induced neutrophilic aad and to develop improved treatment strategies for steroid-resistant asthma. supported by nhmrc, asthma foundation of nsw, hmri. kj baines , , jl simp s on , , rj scott , lg wood , , pg gibson , priority research centre's for asthma and respiratory disease, and information based medicine, the university of newcastle, nsw, australia, and respiratory & sleep medicine, hmri, john hunter hospital, nsw, australia rationale four infl ammatory phenotypes of asthma have been identifi ed including eosinophilic, neutrophilic, mixed granulocytic and paucigranulocytic asthma, based on the presence or absence of sputum granulocytes. the involvement of systemic infl ammation in the pathogenesis of infl ammatory phenotypes of asthma remains unknown. objective this study investigates differences in the whole genome gene expression profi le of peripheral blood in infl ammatory phenotypes of asthma. methods induced sputum and peripheral blood were collected from participants with asthma (n = ). infl ammatory cell counts were performed and infl ammatory phenotype assigned based on the eosinophil and neutrophil cutoffs of % and %, respectively. rna was extracted from whole blood, gene expression profi les were generated (illumina humanref- v ) and analysed using genespring gx . results participants with eosinophilic asthma had signifi cantly higher rates of atopy and levels of exhaled nitric oxide. there were genes classifi ed as differentially expressed between the asthma phenotypes including the α-defensins (defa) , b, and , neutrophil proteases cathepsin g (ctsg) and elastase (ela ), and the monocyte/macrophage serine esterase, carboxylesterase (ces ). expressions of defa , b, , , ctsg and ela were signifi cantly higher in neutrophilic asthma and expression of ces was significantly higher in mixed granulocytic asthma. microarray results of the α-defensins and neutrophil proteases were successfully validated using realtime pcr. conclusions there is systemic up-regulation of α-defensins and neutrophil proteases in neutrophilic asthma, and these molecules play an important role in neutrophil activation and migration. systemic activation of neutrophils is an important feature involved in the pathogenesis of neutrophilic asthma, which is signifi cantly different to other asthma phenotypes. supported by hmri and xstrata coal; the university of newcastle. confl ict of interest no. airway mucus hypersecretion is an important cause of morbidity and mortality in asthmatic patients. increases in goblet cell number and their secretions are likely to contribute to airfl ow obstruction in asthma. here, we take advantage of an established sheep model of asthma to investigate the association between allergen exposure and goblet cell activity. methods eight allergic sheep (high house dust mite (hdm)-specifi c serum ige) received weekly intra-lung challenges of hdm to the right caudal lobe, and weekly intra-lung challenges of hdm followed by weeks without allergen exposure to the left caudal lobe, with the right medial lobe serving as an untreated internal control. a separate group of sheep were also used as untreated controls. biopsy samples of segmental bronchi tissue were collected from the different lung lobes for histological analysis at and days post-hdm challenge. results the percentage of goblet cells, with respect to epithelial cells, signifi cantly increases following chronic challenge with hdm ( % hdm vs. % control p < . ). goblet cell numbers did not decline in lung lobes after a -week cessation of allergen challenges. goblet cell degranulation is significantly increased day following challenge with allergen, but returns to control levels by days post-allergen challenge ( % day vs. % control p < . ). furthermore, degranulation is increased in both the rested and internal control lobes day following allergen challenge of the right caudal lobe. conclusions in this sheep model of chronic asthma, repeated allergen challenges induces goblet cell hyperplasia which persists even after long-term withdrawal of allergen. additionally, exposure to allergen in one lobe induces goblet cell degranulation in both challenged and unchallenged lobes, suggesting neural mechanisms may be operating in this model. confl ict of interest no. the thickness of the airway smooth muscle (asm) layer is related to severity but not duration of asthma or age (james erj; : ) . it is unknown if the constituents of the asm layer change with age. aim to investigate the relation of mean asm cell volume (v c ), total number of cells per mm of airway (n l ) and fractions of asm (f asm ) and extracellular matrix (f ecm ) within the asm layer with age and age at onset of asthma. methods post-mortem tissues from control subjects (c n = ); non-fatal (nfa n = ) and fatal (fa n = ) cases of asthma were used. the volume density (n v ) of asm cell nuclei was estimated on μm transverse airway sections (haematoxylin) and mean cell volume (v c = /n v ) was calculated, correcting for the volume fraction of asm within the asm layer. f asm and f ecm were estimated on . -μm thick sections of the same airway (masson's trichrome). effects of age on asm cell parameters and tissue volume fractions were tested using general linear models, correcting for sex and study centre and by comparing age at onset of asthma (< vs. > years). results table shows assessment of airway smooth muscle (asm) cell size and number requires estimates of cell volume density (n v ), volume fraction of muscle (f asm ) within the asm layer and the volume of asm per length of airway. stereological techniques have now become the accepted standard for assessing asm cell parameters, but sources of variation remain unclear. aim to assess sources of variability in the estimation of asm cell parameters and volume fractions within the asm layer. methods large and small airways from subjects with and without asthma were examined. transverse airway sections were cut at . μm and μm (masson's trichrome technique), and μm (haematoxylin) and used to estimate asm cell number and volume, and the volume fraction of muscle (f asm ) within the layer of asm. stereological assessments of the possible sources of variation in these asm layer parameters were assessed. results increased section thickness overestimated f asm by < % ( . μm), % ( μm) and % ( μm). stable variation of < % in n v occurred if high-power fi elds (hpf) were used to estimate n v . variation in the depth of muscle in thick sections of the asm layer caused up to % overestimation of n v . although the absolute area of the asm layer varied by up to %, variation of f asm was < % around the airway circumference and along the airway length. f asm differed signifi cantly between large and small airways. conclusion these results suggest that partial thickness hpfs need to be excluded and that ≥ hpf should be used to estimate asm volume density, that a single . μm section of airway can be used to estimate f asm and that asm parameters should be compared separately in large and small airways. grants nhmrc # . nominations nil. confl ict of interest nil. no signifi cant correlation was seen with age for any asm cell parameters or tissue fractions. results were similar for medium and small airways. conclusion size and number of asm cells and the volume fractions of asm and ecm within the layer of asm are not related to age. support nhmrc australia (grants # ; # ). nomination nil. . ± . . ± . . ± . . ± . fa > . ± . . ± . . ± . . ± . background asthma is characterized by excessive airway narrowing to contractile stimuli, termed airway hyper-responsiveness (ahr). changes in airway smooth muscle (asm) protein expression or mass are possible contributing mechanisms underlying ahr and have been examined using cell culture techniques. however, how these cellular changes to asm relate to airway narrowing at the level of the whole airway is unclear. we describe a new method to track changes in airway narrowing (responsiveness) in culture. methods whole airway segments (generation - ) from sheep lungs were studied prior to (fresh) and after and hours in culture in dulbecco's modifi ed eagle medium with % bovine serum albumin, % l-glutamine and antibiotics. airway narrowing was measured from the % decrease in airway volume under a fi xed transmural pressure, using a servo-controlled syringe pump and organ bath apparatus. cumulative acetylcholine dose-response curves (ach, − m − × − m) were performed to determine maximal response (e max ) and sensitivity (pd , negative log of ec ). results fresh airway segments narrowed strongly and approached closure with an e max of . % ± . (±sem) and pd of . ± . . airway narrowing responses were preserved in culture, with no signifi cant difference in maximal response or sensitivity to ach after either (e max . % ± . , pd . ± . ) or hours in culture (e max . % ± . , pd . ± . ). conclusions the present study has validated a new method allowing changes occurring at the cellular level in culture to be related to changes in airway responsiveness at the whole airway level. future studies will assess the effects of chronic infl ammation in disease on airway responsiveness. background deep inspiration (di) produces a bronchodilator response in healthy humans, but this response is impaired in asthma. reduced airway compliance in disease could impair the response to di by limiting the stretch of smooth muscle. aim to show that isolated human bronchi dilate to di in an amplitudedependent manner and that the stretch caused by di depends on airway compliance. methods bronchi were obtained following lung resection from cancer patients who had normal spirometry (n = ). lumen narrowing was measured using a servo-control system which set transmural pressure and simulated breathing movements. bronchi were contracted to carbachol (cch × − m) during tidal breathing (from to cmh o, i.e. Δ cmh o transmural pressure, . hz) and infl ated to three different amplitudes of di (Δ , or cmh o) applied following contraction. results in cch-contracted airways, all three di amplitudes produced a transient bronchodilation. increasing the di amplitude caused a greater increase in luminal volume during the di and a greater bronchodilation following the di (p < . ). cch itself cause approximately a % fall in specifi c compliance (p < . ), which was reversed by di (p < . ). for each di amplitude, the change in lumen volume during the di was positively correlated to the specifi c compliance of the bronchi before di (r > . , p < . ). conclusions isolated human bronchi show a bronchodilation response to di that is proportional to the expansion of the airway caused by the di. the amount of stretch produced by a di depends on airway wall compliance suggesting that increased airway stiffness in disease could suppress the di response by limiting the stretch of bronchi during lung infl ation. confl ict of interest none. ja douglass , , , ea yu , , br thompson , , , gg king , , mj abramson , introduction increasing asthma prevalence and changes in environmental exposure suggest that there may be a relationship between asthma and dietary intake. however, to date, few studies have examined how dietary intakes of asthmatics differ from a healthy population. aim to measure and compare the dietary intakes of adults with stable asthma and healthy controls. methods in a cross-sectional study, dietary intakes calculated from a item food frequency questionnaire (ffq) of adults with stable asthma (n = , age years ± (sd)) were compared with intakes of healthy controls (n = , age years ± (sd)) matched for age and body mass index (bmi). spirometry, airway responsiveness to hypertonic saline, and induced sputum cell counts were also measured. results subjects with severe persistent asthma (n = ) had signifi cantly higher total fat intake than healthy controls ( ± (sem) versus ± (sem) g/day p = . ) and signifi cantly lower fi bre intakes ( ± (sem) versus ± (sem) g/day p = . ). lower fi bre intake in asthmatic subjects (n = ) was associated with lower %predicted fev (r = . , p = . ), %fvc (r = . , p = . ) and fev /fvc (r = . , p = . ). higher fat intake and lower fi bre intake were associated with higher absolute concentrations of sputum eosinophils (r = . , p = < . , n = ). conclusions subjects with severe persistent asthma have an eating pattern of lower diet quality with higher intakes of fat and lower intakes of fi bre than healthy controls, which is related to lower lung function and increased airway infl ammation. factors leading to altered dietary intake in severe asthma require further investigation. methods a randomized, placebo-controlled, single-blinded trial of tailored asthma education including device technique and utilizing pact to address patients' concerns versus brochure-only information for asthma patients over age . measurements of lung function, asthma control (acq), asthma related quality of life (aqol), medication use and adherence score (adh) were obtained at baseline, and months using standard, validated questionnaires. results sixty-fi ve participants ( f m, mean age ± . ) were randomized to the intervention group and ( f m, mean age ± . ) to the control. there were no statistically signifi cant differences between the groups' demographics or baseline measurements. a wilcoxon signed ranks test used to compare median pair ranking at baseline and months post-intervention revealed a signifi cant improvement in the active, but not the brochure-only information group at months in: acq mean ± sd = . ± . vs. . ± . (p = . ). aqol mean ± sd = . ± . vs. . ± . (p = . ). adh mean ± sd = . ± . vs. . ± . (p < . ). conclusion an educational intervention including device technique and addressing the concerns of older people with asthma signifi cantly improved acq, aqol and adh scores at months post-intervention. introduction greater exposure to ultraviolet radiation (uv) may increase the risk of allergic disease, but this association has not been investigated using estimates of time spent outdoors by individuals. the aim of this study was to investigate the relationship between self-reported doctor-diagnosed asthma and/or hayfever, and time spent outdoors. methods this analysis was based on cross-sectional baseline data from a subsample of the australian and up study, comprising men and women aged - years, living in new south wales. participants were randomly selected from the australian universal health insurance database. diagnoses of asthma and/or hayfever and the number of hours spent outdoors were derived by questionnaire. in general, the odds of a diagnosis of asthma and/or hayfever decreased with increasing time spent outdoors for both women and men. for example, in women, the adjusted odds ratios for asthma with hayfever were . ( % ci: . - . ), . ( . - . ), . ( . - . ) and . ( . - . ) for - , - , - and > hours spent outdoors on weekends, respectively, compared with < hour (p trend < . ). time spent outdoors was not associated with a diagnosis of asthma alone in men. conclusions there were statistically signifi cant inverse associations between time spent outdoors and diagnoses of asthma, hayfever or asthma with hayfever, in a large population of older australians. exposure to uv may protect against the development of allergic diseases, such as asthma and hayfever. no. background allergic rhinitis (ar) and eczema are highly prevalent and females are more commonly affected than males in adulthood. although there have been extensive studies on ar and eczema in females, little is known about the effect of reproductive factors and the development of late-onset ar/ eczema. we examined potential associations between reproductive factors and ar and eczema using the tasmanian longitudinal health study (tahs) data. methods the tahs is a population-based cohort study of respiratory disease. two thousand seven hundred sixty-four ( . %) females from the original tahs participants were surveyed in using postal questionnaire which collected information on reproductive factors such as ever pregnancy, age at fi rst child birth, use of oral contraceptive pills (ocp) and age of starting using the ocp. logistic regression was used to assess the predictors of ar and eczema and all analyses were mutually adjusted. of the participants, . % (n = ) had late-onset ar and . % (n = ) had late-onset eczema. maternal and paternal atopy were signifi cantly associated with ar (p < . ). the risk of developing eczema was decreased signifi cantly with increasing age at fi rst menstruation (or: . , % ci: . - . ) and the increased age at birth of fi rst child ( . , . - . ). a decreased risk in ar was observed with the increasing number of pregnancies ( . , . - . ). however, the associations between age of starting using ocp and ar/eczema were not signifi cant. conclusion later age at start of menses and later age at fi rst pregnancy were associated with a reduced risk of eczema which may be related to hormonal dysregulation. tp- airway responsiveness at and years is associated with asthma at years introduction asthma is the most common chronic childhood disease in australia. increased airway responsiveness (ar) is associated with asthma but not all individuals with increased ar have asthma. the perth infant asthma follow-up study recruited a birth cohort of individuals who have undergone longitudinal assessments of many factors associated with childhood ar. our previous work reported an association between increased ar in infancy and asthma at and years. aim to look at the relationship of increased ar and asthma in early adulthood at different time points from birth. methods individuals were recruited from among expectant parents attending an antenatal clinic at a local metropolitan clinic. at ages , and months and again at , and years, participants underwent an assessment that included a respiratory questionnaire and determination of ar (as evidenced by dose-response slope (drs) to histamine using the rapid technique). results children were initially recruited and studied in infancy. two hundred three, , , , and children subsequently had ar assessed at , and months, , and years, respectively. there was a signifi cant relationship between drs at and years and for both asthma at years (p = . and p < . , respectively) and 'wheeze in the past year' at years (p = . and p = . , respectively). there was no significant relationship between drs in infancy and asthma at . conclusion ar at and years is associated with asthma at years. in this study, there was no signifi cant relationship between ar in infancy and asthma at years. the pcaas has found that . % of children with acute asthma presenting to the princess margaret hospital for children emergency department (pmh ed) had hrv, of which % were hrv group c. furthermore, hrvc was associated with more severe attacks. however, the prevalence of hrvc in the community is unknown. aim to test the hypothesis that hrvc would be found more often in children requiring emergency treatment for an ari than sibling controls and determine the impact of days since symptoms began on the prevalence of hrv detection in children with an acute respiratory illness (ari) and sibling controls (sibs). methods ari (n = ) had nasal samples collected on presentation to the pmh ed and sibs with symptoms of a cold (n = ), within week of ari recruitment. viral rna was extracted and reverse transcribed. a two-step pcr of the hrv ' utr was used for detection, followed by dna sequencing for typing. results ari and sibs were % and % male, % and % asthmatic, with mean ages of . and . years, respectively. hrv +ve ari (n = , mean ± sd days of symptoms = . ± . ), hrv -ve ari (n = , . ± . ), hrv +ve sibs (n = , . ± . ) and hrv -ve sibs (n = , . ± . ). of the and hrv +ve ari and sibs, % and % had hrvc. conclusions hrvc is as common in children who have hrv but do/do not require hospital treatment. detection of hrv is more likely when the nasal sample is collected soon after the appearance of cold symptoms. support nhmrc program grant. nomination nil. introduction upper airway dysfunction may make asthma more diffi cult to control and should be suspected in asthmatics refractory to prescribed medical therapy. aim a novel imaging technique, dynamic -slice computerized tomography (ct), was used to examine laryngeal behaviour in healthy and asthmatic individuals. method vocal cord movement was imaged using -slice ct larynx. healthy volunteers were studied to develop and validate an analysis algorithm for quantifi cation of normal vocal cord function. further studies were then conducted in patients with diffi cult-to-treat asthma. in eight severe asthmatics with abnormal vocal cord movement, asthma outcomes were measured after speech therapy. results vocal cord movement was quantifi ed over the breathing cycle by ct using the ratio of vocal cord diameter to tracheal diameter. normal limits were calculated, validated and applied to evaluate diffi cult-to-treat asthma. vocal cord movement was abnormal with excessive narrowing in of ( %) asthmatics and severe in nine ( %) patients (abnormal > % of inspiration or expiration time). after speech therapy in a small subgroup, asthma symptoms and morbidity improved. conclusion non-invasive ct larynx quantifi cation of vocal cord movement was achieved. this new approach has identifi ed frequent upper airway dysfunction in asthma with potential implications for disease control and treatment. aim to investigate the characteristics and mechanisms of chronic cough (cc) following acute respiratory illness from laboratory-confi rmed h n infl uenza. methods subjects who had current symptoms and had been tested for h n infl uenza by pcr assay participated in this study. twenty-one of those continued onto clinical testing. investigations to assess cough included symptom questionnaires, hypertonic saline challenge and cough monitoring. results of the participants, % tested positive for h n and % tested negative for h n . h n -infected participants were younger and predominantly female. the prevalence of post-h n cc was . %, and for non-h n infection, . %. objectively measured cough frequency was times greater; there was a -fold increase in cough refl ex sensitivity, and greater quality-of-life impairment in the participants with chronic post-infectious cough than the non-cough participants. conclusions cc was found to be relatively common, mild in severity and tending to resolution with time. the characteristics of post-h n cc were similar to other post-infectious cough and were associated with cough refl ex hypersensitivity. aim upper airway dysfunction may accompany acute severe asthma, but this has not been investigated. a novel imaging technique, dynamic -slice computerized tomography (ct), was used to examine laryngeal behaviour in acute asthma exacerbation. methods patients were studied in the emergency department or as acute inpatients following admission for an acute exacerbation of asthma. vocal cord movement was imaged by -slice ct larynx and compared to normal vocal cord movement in a healthy cohort. results vocal cord movement was abnormal with excessive narrowing during either inspiration, expiration or both in of cases ( . %) with acute severe asthma. imaging again revealed that laryngeal dysfunction characterized the movement abnormality, rather than isolated vocal cord dysfunction. radiation exposure was low and generally < milli-sievert. conclusion non-invasive ct larynx quantifi cation of vocal cord movement was effectively achieved in acute severe asthma. we identifi ed frequent upper airway dysfunction in acute severe asthma suggesting that treatment of upper airway obstruction (e.g. using bipap) may be merited during asthma exacerbation. aim to determine whether eicosanoids could alter the deposition of extracellular matrix (ecm) proteins and cytokine release from human airway cells. methods airway smooth muscle cells (asm), fi broblasts and epithelial cells were stimulated with leukotrienes b , c , d , e and the prostaglandins e , d , f α and the pgi analogue mre- . after hours, culture medium was collected and il- and il- production and cell deposited ecm proteins tenascin c, fi bronectin and perlecan were assessed by elisa. to determine whether eicosanoids infl uenced cell proliferation, manual counting of cells in the experiments were carried out before and after stimulation. results neither leukotrienes or prostanoids altered cell proliferation after days of stimulation (n > ). leukotrienes had no effect on ecm protein deposition or cytokine release from asm or fi broblasts (n > ). leukotrienes did not alter either parameters in epithelial cells except leukotriene d , which increased tenascin c deposition (n = , p < . ). prostanoids induced il- and il- and other various changes in asm and fi broblasts (n > , p < . ) (see below). introduction the function of asthmatic airway epithelium is disrupted facilitating immune and infl ammatory responses resulting in epithelial damage. human rhinovirus (hrv) causes asthma exacerbations in children; however, paucity exists on how it affects barrier function. this study assessed how hrv infection affects epithelial barrier function and integrity in healthy and asthmatic epithelium. methods adult balb/c mice were intranasally infected with hrv- b and followed for days. tight junction (tj) expression was assessed using immunohistochemistry (ihc) and western blot analysis. primary airway epithelial cells from healthy and asthmatic children were assessed for tj gene and protein expression by qpcr and ihc, respectively. results occludin and zonal occludin- (zo- ) expression was lost and sustained in mice infected with hrv- b however was not observed in shaminjected mice. asthmatic airway epithelial cells were found to exhibit elevated basal gene expression levels of tjs (zo- , occludin and plakophilin- (pkp- )) but markedly lower corresponding protein levels. conclusion hrv- b compromises barrier function in vivo through sustained loss of tj proteins. the marked decreased expression of tj proteins in paediatric asthmatic epithelium may contribute towards increased susceptibility to viral infections. disparity between gene and protein tj expression could indicate either post-transcriptional regulation or compensatory effects by other tj proteins and requires further study. supported by asthma foundation wa; nhmrc. confl ict of interest none. conclusion leukotrienes alone did not affect the ecm proteins and cytokines assessed in this study. prostanoids decreased ecm protein deposition whilst increasing cytokine release without affecting cell proliferation. this study shows that prostanoids may have a more pronounced role on direct ecm remodelling than leukotrienes in airway cells. supported by merck. background toll-like receptor (tlr) is an innate immune receptor involved in the initial detection of pathogen-associated molecular patterns. the effect of ageing and chronic obstructive pulmonary disease (copd) on tlr responses and the impact of these innate immune responses in copd pathogenesis remain unclear. hypothesis expression and activity of tlr on peripheral blood mononuclear cells (pbmcs) is increased with healthy ageing and further increased in copd. methods pbmcs from healthy controls < years and > years; and participants with copd (n = per group) were cultured with or without pam c ys k (tlr agonist). cells and supernatants were collected at hours and protein (cytometric bead array or fl ow cytometry) and gene (real time pcr) expression was examined. results tlr activation led to increased release of interleukin (il)- , , β, and tumor necrosis factor (tnf)-α. tlr gene expression was increased with stimulation; however, cell surface receptor levels were unchanged. there was no difference in the level of tlr between the groups. in older people, tlr activation resulted in less il- β and tnf-α release, but similar release of il- and il- . similar results were seen in copd. at baseline in copd, there was up-regulation of tnf-α gene expression compared to the older healthy group; however, the tlr cytokine response did not differ between the groups. conclusion healthy ageing is characterized by an impaired systemic proinfl ammatory cytokine response to tlr -mediated innate immune activation. this effect persists in copd and is selective in the cytokine pathways involved. these altered infl ammatory mechanisms may affect responses to infection and injury impacting disease pathogenesis and warrant further evaluation. aim to investigate whether the inhibition of matrix metalloproteinase- (mmp- ) by a non-selective mmp inhibitor (doxycycline) and the specifi c mmp- inhibitor i (olic acid) can regulate cellular migration of tsc -null mouse embryonic fi broblasts (mefs), which act as a model for lymphangioleiomyomatosis (lam) cells, as compared to wild-type mefs. methods wild-type (tsc -positive) and tsc -null mefs were treated with diluent, doxycycline ( . pg/ml- μg/ml) or olic acid ( . - μm) for hours. mmp- levels were assessed by zymography and elisa. cell migration for hours was measured using a transwell migration assay. results under basal conditions, mmp- release and cellular migration was . -fold and . -fold higher, respectively, in tsc -null mefs compared to tsc -positive mefs (mmp- release, tsc -null (n = ) and tsc -positive (n = ), p < . ; cell migration, tsc -null (n = ) and tsc -positive (n = ), p < . ). mmp- release was reduced in tsc -null mefs after -hour treatment with doxycycline ( and μg/ml, n = , p < . ) and with olic acid ( - μm, n = , p < . ). treatment with doxycycline ( pg/ml- μg/ml, n = , p < . ) or olic acid ( - μm, n = , p < . ) also signifi cantly reduced cell migration of tsc -null mefs. copd is a leading cause of death worldwide. treatments are limited and restricted to symptomatic care. there is an urgent need for new treatment options targeting the infl ammation. tissue damage in copd is thought to result from an inability of the normal repair processes with accumulation of apoptotic material and impaired clearance of this material by macrophages in the airways. lung infl ammation and macrophage function involves the bioactive sphingolipid sphingosine -phosphate (s p). multiple studies have showed the involvement of these components in infl ammation. methods we investigated lung tissue samples from patients (copd or non copd controls) undergoing curative lobectomy for lung cancer. we analysed the mrna expression profi le, the sphingosine-kinase (sphk) protein activity and the localization and expression of individual proteins. results we show in this study for the fi rst time a comprehensive expression profi le of all synthesizing enzymes, receptors and degrading enzymes in the human lung. correlations between receptor subtypes, degrading enzymes and between s p receptor subtype were detected. multivariance anova showed that in copd, the relative mrna expression of s p receptor subtype was reduced. conclusion the correlations between receptors and enzymes involved in the sphingosine kinase signalling system in the lung suggest common regulatory mechanisms. s pr is expressed on dendritic and nk cells which are reduced under conditions of copd. therefore, our fi ndings of reduced s pr in copd may provide a novel target for pharmacotherapy. lung cancer is responsible for more cancer-related deaths than colon, breast and prostate cancers combined. in patients with copd and/or lung cancer, we have shown a reduction in lung and airway macrophage function, evident by a reduced ability to phagocytose apoptotic airway epithelial cells and neutrophils. the potential for lung cancer cells to directly inhibit this function (a potential immune evasion mechanism) has not been investigated. background kinins have been implicated in airway lung diseases such as asthma and lung cancer by regulating infl ammation, cell proliferation and migration. the effect of kinins is mediated through the binding of two receptors, kinin b and b receptors (b r and b r). a novel b r splice variant (sv) resulting in a shorter ' untranslated region (utr) was identifi ed in cultured airway epithelial and fi broblasts as well as in lung carcinoma tissue and leukocytes. this study aims to characterize the functional role of the novel b r sv in mrna stability, translation effi ciency and receptor expression in cultured airway epithelial cells. methods stability of b r sv was determined by measuring b r mrna levels over time in h cells after actinomycin d treatment. translational effi ciency of wt and sv 'utr was determined by measuring luciferase activity in transfected h cells. expression of wt and sv transcripts through q-rtpcr were compared in cells treated with a b r-specifi c agonist dakd. cell-surface receptor expression post-agonist stimulation was quantifi ed using facs. results mrna stability studies indicated that b r sv was ≈ % less stable than the wt transcript in h cells suggesting a stabilizing element 'utr. translation effi ciency of sv was no different to wt b r. dakd stimulation increased both wt and sv transcripts early in the time course, although the peak expression of wt and sv differed at hours and hours, respectively. dakd stimulated cells showed two phases of receptor expression, ( ) decrease of cell surface receptor up to . hours post-stimulation; ( ) increase in cell surface b r after . hours. conclusion this study has identifi ed a novel regulatory mechanism of b r expression through the production of a sv that alters the 'utr. the translation effi ciency of b r is not affected, but the sv was less stable than the wt in h cells and may play a role in allowing quicker changes in transcription. agonist-induced up-regulation of transcripts in a time-dependent manner may be important in maintaining a chronic response during infl ammation. circulating lymphocytes are increasingly used as a surrogate cell type to refl ect changes in adrβ density elsewhere in the body, particularly the respiratory system. however, adrβ density is non-uniform among lymphocyte subsets and it is unclear if, and the degree to which, adrβ density varies between individuals. aim to assess the extent of variability in adrβ density on human peripheral blood mononuclear cells (pbmc) including lymphocytes and monocytes. method pbmc were isolated from blood of healthy subjects by density gradient centrifugation with ficoll-paque. cell surface and total adrβ of intact and permeabilized lymphocytes (cd +) and monocytes (cd +) were measured using anti-adrβ via facs. geometric mean fl uorescence (gmf) was used as the indices for adrβ density per cell. result surface adrβ -gmf increased by . -and . -folds over negative controls for lymphocytes and monocytes, respectively. magnitude of foldchange was not signifi cantly different between these cells (p = . ), but the distribution of gmf intensity between samples suggests greater variability in adrβ density in lymphocytes versus monocytes (p = . ). proportion of cells-stained adrβ -positive was signifi cantly higher in monocytes versus lymphocytes ( . ± . % vs. . ± . %, p = . ). total adrβ -gmf increased by . ± . and . ± . -folds for lymphocytes and monocytes, respectively (p > . ). proportion of adrβ -positively stained cells were similar between samples (lymphocytes %, monocytes %, p = . ), but greater variability was observed for lymphocytes (range - %) versus monocytes ( - %). conclusions despite similarities in surface and total adrβ density, lymphocytes display greater inter-subject variability compared with monocytes. this will have implication in experimental designs and interpretation of changes in adrβ density in studies using human pbmc as an alternative to primary cells from the organ of interest. confl ict of interest no. pge plays a protective role in asthma by inhibiting airway infl ammation. it is predominantly produced by epithelial cells in response to pro-infl ammatory stimuli and acts as an autocrine and paracrine mediator. on the contrary, il- β is a highly potent cytokine that induces many pro-infl ammatory effects in the human airway including activation of the human lung epithelium which promotes production of pro-infl ammatory cytokines and chemokines. airway epithelial cells express all four known pge (e prostanoid (ep) receptors, but mechanisms underlying the regulation of expression of ep receptors in human lung epithelial cells have remained elusive. therefore, we investigated whether pge , an endogenous protective mechanism of the airways, can modulate il- β infl uence on ep receptor expression in human epithelial cells. methods ep receptor mrna and protein expression was quantifi ed in -hbe cells at basal levels and following stimulation with il- β or pge alone, or simultaneously, using real time rt pcr and facs analysis, respectively. results pge up-regulates all four ep receptors at mrna level, while il- β up-regulates ep , ep and ep and does not infl uence expression of ep . at protein level, preliminary results show transient increase of ep receptors in the presence of pge , while il- β down-regulates this receptor. ep and ep are up-regulated following stimulation with both stimuli. importantly, antiinfl ammatory ep receptor is up-regulated only in the presence of pge . conclusion we show for the fi rst time that pge may infl uence expression of its own receptors and oppose the effect of il- β in human lung epithelial cells. this may in turn alter pge production and autocrine activation with potential implication on the function of epithelial cells, which is important in modulation of immune response in asthma and lung infl ammatory diseases. nomination nil. confl ict of interest no. the burden of obstructive lung disease (bold) study is an international study designed to measure the prevalence, risk factors and burden of copd. data collection using the bold protocol has been undertaken at eight sites with inclusion of urban, rural, coastal and inland regions of australia. methods a random sample of adults aged ≥ years was identifi ed. information on respiratory symptoms and diagnosed copd were collected by questionnaire. post-bronchodilator fev and fvc were used to defi ne gold stage. the (un-weighted) prevalence rates are presented by age groups and sex. results s timmins , , , , g king , , , , c salome , , , r schoeffel , , , c walsh , , the extent of emphysema could increase ventilation heterogeneity independently of its effects on airway narrowing. the aim of this study was to examine the relationship between emphysema extent on computed tomography scans (ct), and airway narrowing and ventilation distribution in copd. methods subjects with copd underwent ct scanning, spirometry, dlco and nitrogen washout by single and multiple breath techniques. closing capacity (cc/tlc%), slope of phase iii (Δphase iii ) and indices of ventilation distribution conductive (scond) and diffusion-dependent airways (sacin) were derived from washouts. helical ct scans were performed at tlc. emphysema extent was measured as low attenuation areas < − hu using osirix program, expressed as % of ct total lung volume. results subjects were of mean (range) age years ( - ), bmi . ( . - . ), fev of ( - %) %predicted and dlco of ( - ) %predicted. emphysema extent was . % ( . - . ). geometric mean (ci) Δphase iii was . ( . - . ), sacin was increased at . l − ( . - . ) and cc/tlc% was % ( - ). emphysema extent correlated with fev / fvc (r = − . , p = . ), dlco (r = − . , p < . ), bmi (r = . , p = . ), Δphase iii (r = . , p = . ), and sacin (r = . p = . ). in multiple regression analysis, emphysema extent was predicted by fev /fvc and Δphase iii (model r = . , p = . ). conclusions the extent of emphysema increases the heterogeneity of ventilation independently of any effects on overall airway narrowing. supported by australian lung foundation webster memorial award, crcaa. conclusions self-reported wheeze in the last months is very common in adults over years. in the younger age group ( - years), many people with wheeze did not have airfl ow obstruction or reversible spirometry at the time of test. aim to determine whether there is any association between change in fev among copd patients and ambient ultrafi ne particle number concentrations in melbourne. methods participants with mild to moderate copd were asked to measure their fev using a portable electronic spirometer (piko) two times a day (morning and evening) for consecutive days. the same procedure was repeated on average months later. ambient ultrafi ne (diameter < . μm) particle number concentrations were measured for the same period using an ultrafi ne condensation particle counter and micro-orifi ce uniform deposit impactor. results aim to examine the implementation of, and barriers and enablers to, six high-evidence recommendations for copd management, in copd hospital inpatients. method observational, mixed methods study in consecutive copd patients admitted to a tertiary hospital. demographic, disease and admission characteristics are recorded. implementation (or not) of smoking cessation, pulmonary rehabilitation, long-term oxygen use if hypoxaemic, medication use, vaccinations and plans for future exacerbations are determined from medical records and patient interviews. interviews with medical offi cers examine their perspectives on recommendation implementation. of pilot data in copd patients (mean (sd) age ( ) years, length of stay ( ) days), were current smokers and had severe copd ( moderate). highest levels of implementation were fl u vaccination (completed by gps, n = ), medication (but not spacer) use, and oxygen use if hypoxaemic (investigated and implemented in all suitable, n = ). pulmonary rehabilitation was discussed with half of the patients, but only severe patients with long length of stay accepted further rehabilitation. exacerbation plans were in place for patient, and newly initiated in patients. doctor interviews (n = ) confi rmed pulmonary rehabilitation was considered mostly for severely unwell patients, and use of exacerbation plans was inconsistent. conclusion pilot data suggest pulmonary rehabilitation is offered and accepted by a small subset of copd patients. findings from this pilot will inform planned larger observational studies, and in turn, experimental studies to improve copd care. high-and extreme high-risk interventions were found by panel ( - . % extreme and . - . % high-risk interventions) and patients' respiratory physicians ( % extreme and % high-risk interventions). additionally, clinical pharmacist involvement was associated with many benefi ts such as: improvement in medication compliance, high level of patient satisfaction and identifi cation of patients with issues in medication knowledge. conclusion clinical pharmacist interventions were estimated to prevent extreme and high risks that might happen due to drug-related problems. clinical pharmacy consultation was associated with positive impact on other important measured outcomes. aerobic exercise training in the form of supervised -minute walks ( mw) reduces exertional dyspnoea in patients with copd. mw goal ( mwg) distances, aiming for a training effect, are generated from a baseline submaximal test ( -minute walk ( mwd), where wg = . × mwd/ × . aim to compare mwg with actual initial mw achieved and to examine the predictors of mwg achievers (ga). methods retrospective review of patients, % male, age ± years (mean ± sd), fev ± %predicted, who completed pulmonary rehabilitation (pr). patients were assessed at baseline and post-completion of pr. initial mwg was calculated from the best of two mwd at initial assessment and ga were defi ned as patients who achieved their mwg at their fi rst visit to pr. results for the group, there was a statistically signifi cant but not clinically signifi cant difference between mwg and actual mw achieved ( ± m vs. ± m, p < . , paired t-test). the patients ( %) who achieved their mwg exceeded the goal by ± m, whereas the patients who did not achieve their mwg fell short by ± m. there was no signifi cant difference between ga and non-ga in age or lung function, but ga had a higher initial mwd, with fewer rests, lower dyspnoea score and lower hr at start and fi nish (p < . , unpaired t-test). ga were also more likely to have a clinically signifi cant response to pr, measured by mwd, compared with non-ga (mean change m vs. m, p < . , chi-square). conclusion mw goals as currently calculated either signifi cantly underestimate or overestimate actual mw achieved. it may be that in non-ga, the mwd is functioning as a true maximal test and these are a group of patients who are truly ventilatory-limited, rather than deconditioned. the receptor for advanced glycation end products (rage) is a key candidate for promoting a self-perpetuating cycle of infl ammation and thereby is a major contributor to numerous chronic disease states. the potential of rage to function as a switch converting a transient infl ammatory response such as one generated by cigarette smoke to sustained cellular dysfunction allows it to act as a mediator for ongoing infl ammation in chronic obstructive pulmonary disease (copd). although the molecular mechanisms regulating rage expression have not been fully elucidated, altered rage activity arises from polymorphisms within the rage gene and its promoter. three polymorphisms in the rage promoter (− t/a, − t/c and a bp deletion from − to − ) increase transcriptional activity and rage expression. the rage g s allele results in an increased ligand-binding affi nity and activation of the infl ammatory mediators with subsequent up-regulation of infl ammatory response. the aim of this pilot cross-sectional study was to investigate the relationship between three known rage polymorphisms (− t/a, bp deletion, g s) and copd and disease severity. methods genomic dna was isolated from peripheral blood lymphocytes. pcr and taqman assays were used to genotype the three rage polymorphisms in copd patients, healthy non-smokers and healthy smokers. fev was measured in all subjects. disease severity was defi ned using gold guidelines. results there was no statistically signifi cant association between bp deletion and copd (p = . ), − t > a and copd (p = . ), g s and copd (p = . ). conclusion no association was found between the − t > a, bp deletion and g s polymorphisms and copd, disease severity or fev introduction the receptor for advanced glycation end products (rage) mediates neutrophil traffi cking and is implicated in the pathogenesis of chronic airways disease. we determined whether changes in airway and systemic levels of soluble rage (which acts as a receptor decoy to limit rage activation) and rage ligands are related to neutrophilic infl ammation in asthma and copd. methods bronchial lavage (bl) fl uid from subjects with moderate-severe persistent asthma or copd, and healthy controls were analysed for neutrophils, total srage (cleaved and secreted), secreted srage (esrage) and the rage ligands hmgb and serum amyloid a (saa). systemic levels srage and esrage were also determined in asthmatic and copd subjects. aims increased numbers of neutrophils are found in the lungs of copd patients, which contribute to airway infl ammation. while cigarette smoke exposure is the major risk factor for copd, it is unclear how cigarette smoke modifi es neutrophil function and activity. this study aimed to assess the effect of cigarette smoke extract (cse) on neutrophils in an in vitro model. methods neutrophils were isolated from peripheral blood donated by volunteers using percoll density gradient centrifugation. neutrophils were seeded in well plates ( cells/well), exposed to different concentrations of cse ( %, %) and monitored at , and hours. at each time point, viability of neutrophils was measured by trypan blue exclusion and supernatant was collected for measurement of cxcl release by elisa (r&d systems conclusions in neutrophils exposed to cse, viability is maintained and cxcl release increases with increasing dose of cse. we conclude that cigarette smoke stimulates an infl ammatory response by neutrophils, which would contribute to the infl ammatory burden in the airways in copd. introduction factor viii (f ) and collagen iv (c ) antibodies are used for quantifying vessels in tissue sections. we compared these two antibodies for vessels staining in bronchial biopsies (bb) in copd. methods bb from healthy non-smokers (h-n) and copd subjects were stained for both antibodies. number, area and mean vascular size (mvs) (surface area/vessel number) of vessels in the lamina propria (lp) to the depth of μm were measured and compared between the two antibodies and are reported as median (range). results number of vessels was not signifi cantly different between the two methods of staining. in copd and h-n, vascular area (μm /μm of lp × ) stained with f was less than that with c ( . ( . - ) vs. ( - . ), p < . and . ( . - . ) vs. . ( . - . ), p < . introduction previous studies have shown that c-reactive protein levels increase at the onset of some copd exacerbations; however, there is limited data on the normal fl uctuation in crp levels in stable patients. aim to investigate within patient variation in crp levels to determine the magnitude of normal day-to-day fl uctuations in stable patients and the correlation with patients' perception of symptom severity. methods early morning crp levels were measured on days , and from patients from the melbourne copd cohort (gold category ii-iv) who identifi ed themselves as stable. patients recorded daily symptom scores including: borg dyspnoea scale at rest, severity of wheeze, cough, dyspnoea, change in sputum colour or volume, night-time waking and the presence of viral symptoms. crp levels were measured by the clinical pathology service and using a point-of care device. variation in crp levels in stable copd and correlation between change in crp levels and symptoms were analysed. aim patient-completed diaries monitoring changes in key symptoms in copd are often used to recognize acute exacerbations (ae) both to prompt additional treatment and monitor treatment effi cacy. we assessed diary compliance and the predictive value of major symptoms of aes which required hospital attendance. methods inpatients recruited during an ae of copd completed daily paper or web-based diaries for months, recording changes from their stable state for: breathlessness, cough, sputum, subjective 'wellness', physical activity and use of reliever ( -point scale, mid-pt = no change). the predictive value of current and lagged symptom scores was compared for each and between symptoms. diagnostic accuracy was assessed by area under the curve (auc) and at specifi c cut-points. in participants ( m, f) with mean age ± and mean fev % predicted ± , there were such aes involving patients. duration of diary keeping was shorter with lower education attainment (p = . ), but compliance did not vary for other demographic or clinical factors. daily compliance while diaries were being kept was %. excluding the current day, the best predictor was the distributed lag score over days, sputum changes giving the strongest signal; relative risk . ( % ci . to . ) with most of the signal in the days prior to the ae. little was gained by combining symptoms. the predictive value was moderate auc = . . conclusions compliance with symptom diaries in severe copd is surprisingly good. however, with only a weak signal for an impending ae requiring hospital attendance up to hours before and for lagged symptom scores over days before, with low positive predictive values, the utility of keeping daily symptom diaries for raising alerts for impending severe aes in copd is questionable. results seven studies with inpatient participants were identifi ed; published as abstracts for which data were not available did not contribute to meta-analyses. no study specifi ed diagnostic criteria for copd and only one specifi ed ae criteria. short course treatment varied between - days and longer duration - days; studies used oral prednisolone (dose mg, studies, tapered dose) and studies used intravenous scs treatment. mean ages of participants ranged from to years. primary outcomes: likelihood of treatment failure did not differ by duration of treatment (odds ratio . ; % ci . to . ) ( studies, n = ). fev did not differ signifi cantly when measured up to days (mean difference (md) − . l; % ci − . to . ) or after days (md − . l; % ci − . to . ) ( studies, n = ). secondary outcomes: limited data ( study) precluded meta-analysis for readmission or mortality. the likelihood of an adverse event ( studies, n = ) was not signifi cantly lower for shorter scs (or . ; % ci . to . ). conclusions we found no signifi cant differences between short (≤ days) and longer (> days) corticosteroid therapy for ae of copd. this has implications for clinical practice and may reduce adverse effects for patients, shorten hospital admissions and reduce costs, but more studies are needed to confi rm these fi ndings. aim to explore factors which infl uence the self-management of exacerbations in patients with copd. methods a pilot cross-sectional study was undertaken to assess patients' compliance with their action plan and their action taken prior to an admission. patients were interviewed during an admission to hospital for exacerbation of copd. the effect of pulmonary rehabilitation on patients' knowledge of copd was also assessed. results % of patients were provided with a written action plan, and % with a verbal action plan. in response to an exacerbation, more than % of the patients stated that they used their action plan. however, where action plans were not adequately utilized, patients delayed seeking medical attention and failed to initiate oral prednisolone and antibiotics during an exacerbation despite being prescribed an emergency supply of these medications. pulmonary rehabilitation had a positive outcome towards enhancing the patients' knowledge of copd. clinical pharmacists have limited involvement in terms of copd and smoking cessation education. conclusion the need to offer a thorough self-management program along with providing a more comprehensive written action plan will encourage patients to start early treatment and follow their action plans. encouraging collaboration between the hcp and patients encourages self-management through discussing and agreeing on goals of treatment and developing a personalized written action plan. context dyspnoea is a common symptom in copd and increases during exacerbations. when respiratory failure supervenes, and assisted ventilation is required, non-invasive ventilation (niv) is the treatment of choice. objective to determine if niv relieves dyspnoea in inpatients with acute respiratory failure due to exacerbations of copd. data sources english language randomized controlled trials (rcts) published prior to august were identifi ed using medline, embase, cinahl, psychinfo and pubmed. additional studies were identifi ed by reviewing the reference list of included studies. search terms included niv, nippv, nppv, bilevel cpap, bipap, artifi cial ventilation, copd and randomized controlled trial. study selection rcts comparing usual medical care (umc) to umc plus niv and measuring dyspnoea at relevant time points were included. abstracts for potentially relevant articles were extracted by one author. these were assessed by a second author to ensure inclusion criteria were met. articles were reviewed to determine if dyspnoea was measured and appropriate statistical analysis reported. the search yielded individual articles. four articles met the review criteria. three articles fi nd that niv relieved dyspnoea to a statistically signifi cant level and two suggested that the relief of dyspnoea is clinically signifi cant. discussion in spite of the common use of niv to relieve dyspnoea, little work has analysed effi cacy in terms of this patient-reported outcome. while our results may suggest niv relieves dyspnoea, reporting or methodological fl aws in several articles limit the strength of the conclusions that may be drawn. these limitations make the conclusion that niv relieves dyspnoea contentious. conclusion despite over two decades of studies investigating niv, the therapeutic impact on breathlessness is poorly described. understanding the impact of niv on patient-reported outcomes is of critical importance in clinical care. confl ict of interest none. introduction in mice, the most direct lung dosing method delivers the agents directly into the trachea. for our cystic fi brosis gene-therapy studies, we deliver fl uids -an airway pretreatment followed by a lentiviral vector -directly into the mouse trachea to target conducting airways. despite using standardized delivery techniques, we see substantial variability in the amount and location of gene transfer. aim the aim of this experiment was to use synchrotron x-ray imaging to track the dynamics of fl uid doses delivered into the live mouse trachea. methods four nembutal anaesthetized c bl/ mice were imaged on the bl b beamline at the spring- synchrotron. mice were intubated and ventilated at br/min with image captured per breath. after minute of baseline, a -μl sample of iodine-based contrast fl uid (a surrogate for our airway pretreatment or gene-vector) was delivered over seconds. following minutes of data collection, an additional μl bolus was delivered over . seconds. image capture continued for a further minutes. frame differencing was used to reveal fl uid motion. results substantial dose losses may occur upon delivery into mouse trachea via immediate retrograde fl uid motion. the speed of bolus delivery into lung may also infl uence the relative targeting of conducting airways and deep lung. introduction use of effi cient nebulizers can enhance the quality of life of cf patients by reducing the treatment time and improving drug delivery effi ciency. the aim of this study was to determine which commonly recommended nebulizer was optimal for delivery of the most commonly used therapies to cf. methods seventeen children with cf ( - years) were recruited. delivery of three commonly used cf therapies ( % hypertonic saline ( ml, . g/ ml), tobramycin ( ml, mg/ml) and pulmozyme ( . ml, mg/ml)) by two vibrating membrane nebulizers, the eflow rapid and the aeroneb go, and a jet nebulizer lc sprint junior with pariboy sx ( . l/min) were tested. for each drug-nebulizer combination (in random order), each child was asked to inhale through an inspiratory fi lter, and drug delivery to the fi lter was measured. pulmozyme was quantifi ed using an enzymatic activity assay, tobramycin was measured using hplc and hypertonic saline was measured using conductivity. total nebulization time was recorded. the results showed that there was no difference in the amount of drug delivered to patients when the nebulizers were compared for all three therapies (p > . ). however, the nebulization time for the eflow rapid was signifi cantly shorter than that for the aeroneb go and lc sprint junior. similarly, the nebulization time for aeroneb go was shorter than that for the lc sprint junior (p > . ) for all therapies). conclusion overall, there were no signifi cant differences between nebulizers in delivered dose for three forms of cf therapy, due to inter-patient variability. despite this, both vibrating membrane nebulizers had shorter nebulization times than the lc sprint junior, with the eflow rapid delivering drug in the shortest time. confl ict of interest nil. introduction as the life expectancy of patients with cystic fi brosis (cf) increases, treatment-related morbidity is increasingly recognized. totally implantable venous access devices (tivads) offer reliable long-term central venous access but are associated with recognized complications including venous thrombosis. superior vena cava syndrome (svcs) however has been rarely reported in this setting. we report a single cf centre's experience of svcs associated with tivads. methods retrospective review of episodes of svcs in patients with cf and a tivad attending the adult cf centre, prince charles hospital, queensland. results between february and december , fi ve episodes of svcs occurred in patients with tivads from a clinic population of patients. all of the affected patients were female, with moderately severe lung disease (mean fev predicted . %). no patients had a recognized thrombophilia. four tivads were inserted at a centre different to our own, three were on oestrogen-based contraception, and two suffered with dehydration at presentation. svcs treatment consisted of anticoagulation ( ), line removal ( ), angioplasty ( ), thrombolysis ( ) noninvasive bioluminescence imaging has allowed for rapid in vivo quantifi cation of long-lasting gene transfer in experimental animals. we are testing the longevity of a single nasal delivery of our lentiviral (lv) gene transfer system in mouse airways. methods normal (c bl/ ) and cystic fi brosis (cf) mice received a nasal bolus of lysophosphatidylcholine (lpc) or a control (pbs) pretreatment hour prior to delivery of a lv vector containing the reporter-gene luciferase (lv-luc). another control group received lpc hour prior to an empty vector (lv-mt). bioluminescence was measured at week, , , , , , , , and months post-lv dosing to assess gene transfer. results normal mice: mice that received lpc/lv-luc treatment had significantly greater gene transfer compared to the two control groups at all time points (p < . , rm anova). no luminescence was detected in mice treated with lpc/lv-mt. unexpectedly, luciferase activity was also detected in the lung. there was no difference in lung luminescence between the lpc and pbs pretreated mice that received lv-luc. cf mice: a statistically signifi cant increase in nasal luminescence persisted for up to months following lpc/ lv-luc (p < . , rm anova). similar to normal mice, there was no statistical difference in lung luminescence between mice that received lpc and pbs lv-luc. conclusions lentiviral luciferase gene expression was signifi cantly improved in mouse nasal airways using lpc pretreatment in both strains. however, the longevity of transduction was reduced in cf mice, which may, in part, be due to reduced animal numbers at the later time points tested. supported by nh&mrc. background the nintendo-wii® facilitates exercise-based programs that may be considered novel, fun and potentially motivating. objective exercise outcomes using the wii have yet to be reported in the cystic fi brosis (cf) adult population. aim to investigate nintendo-wii® exercise training compared with standard exercise in adult cf patients whilst hospitalized for treatment of a pulmonary exacerbation. methods a within-subjects, randomized cross-over study. adult cf participants received two -minute exercise treatment sessions within a -hour period, at least day apart, during the last days of hospitalization. wii exercise consisted interval training with games such as boxing, dancing and track exercises. standard exercise consisted of interval training on treadmill or cycle ergometer at - % of heart rate maximum. results participants completed the study (mean (sd) age ( ) years, % females), with a mean fev % of ( )%. during exercise, no difference was found between groups in average heart rate (p = . ), oxygen desaturation (p = . ), borg rate of perceived exertion (p = . ) or modifi ed borg for dyspnoea (p = . ). on vas ( - ), participants reported the wii program to be more enjoyable (p < . ) and less fatiguing (p = . ). participants rated both exercise sessions as equally effective (p = . ). conclusions this study suggests that a nintendo-wii® exercise session provides an equivalent cardiovascular demand to a standard exercise session in an inpatient adult cf population. greater enjoyment levels and lower fatigue levels reported during nintendo-wii® training may have a positive infl uence on adherence to exercise. further study into the long-term effects of nintendo-wii® training needs to be undertaken. confl ict of interest nil. introduction ion transport is important to maintain the airway epithelial surface, as shown by the disease cystic fi brosis (cf) which is characterized by decreased clsecretion and increased na + absorption. we have previously shown that the cf airway can develop clresponses when the surface is nominally calcium free (middleton et al. ajrccm ; : - . aim to determine the effects of citrate on the nasal potential difference (npd) with and without amiloride pretreatment, and to compare these effects with other clinically relevant calcium chelators and dicarboxylic acids. methods npd was measured using standard techniques (erj ; : ) in cf and non-cf subjects. the nasal pd response to citrate, oxalate, malate, succinate and fumarate (all mm) was compared with the calcium chelators edta and egta. results citrate decreased the basal npd by ∼ mv, but in the presence of amiloride, citrate increased the pd by ∼ mv. with amiloride/low clpretreatment, citrate increased npd by - mv, which suggests that citrate increased clsecretion. in contrast, the other dicarboxylic acids and calcium chelators exhibited little response. conclusion the combination of these responses suggests that citrate exerts complex effects on airway ion transport, most likely dual effects of decreased na + absorption and increased clsecretion. aim to assess the validity of the international physical activity questionnaire (ipaq) in cf adults by comparing energy expenditure measured by the ipaq versus the accelerometer. methods with ethics approval, suitable successive adult patients with cf attending the alfred cf outpatient clinic were recruited. all participants wore an accelerometer (actigraph gt m) around the waist for days of awake time, at the end of which, they completed the ipaq. criterion validity of the ipaq was assessed by comparing the ipaq weekly energy expenditure (ee) in kilocalories (kcal) with weekly ee (kcal) from the accelerometer using spearman correlations and bland-altman procedures. results thirty participants ( % females) completed the assessment: mean (sd); age = ( ) years, fev %predicted = ( ) the median (range) ee: ipaq = ( , ) kcal, gt m = ( , ) kcal. spearman correlations of fev %predicted with ee were gt m ee r = . , p < . ; ipaq ee r = . , p > . . correlation of the ipaq ee with accelerometer ee was moderate (r = . , p = . ). there was a trend towards higher ee measured by the ipaq than measured by the accelerometer (wilcoxon signed ranks test: z = − . , p = . ). conclusion the ipaq underestimates physical activity for patients with lower energy expenditure activities and overestimates for those with higher energy expenditure activities in adults with cf. the ipaq would be a useful screening tool for exercise prescription and monitoring of physical activity longitudinally, but more quantifi able methods for assessment such as the accelerometer should be used in research. confl ict of interest none. infectious endometritis associated with pseudomonas aeruginosa (pa) is an important equine disease resulting in reduced fertility and decreased foal drop. previous typing studies of equine pa report clonal heterogeneity, suggestive of sporadic acquisition, and small clusters of indistinguishable strains. aim we performed molecular typing of a large sample of genital pa isolates from horses in s-e qld. methods thoroughbred genital tract pa isolates submitted to uq vet diagnostic lab during - (screening or infection suspected) were studied. eric-pcr fi ngerprint analysis was performed. isolates producing indistinguishable fi ngerprints were allocated to the same eric-pcr type. mlst was performed on a subset of isolates. results overall, genital (clitoral or uterine) swabs from mares and urethral fossa swabs from stallions located on stud farms were processed. pa was identifi ed in genital cultures from of the ( . %) mares but from none of the stallions. six clusters involving ≥ mares were detected. cluster-a was observed amongst isolates collected from ( %) mares from studs and each year. cluster-b isolates were present in mares from studs during - . clusters c-to-f each contained isolates from mares from or studs. conclusions overall, % of mares harbouring pa had clonally related strains. however, we found no evidence of horizontal transmission between stallions. these data raise the possibility of transmission via environmental or other sources. alternatively, specifi c strains may have trophism for the reproductive tract of horses. the fi nding of a dominant strain amongst thoroughbred mares in a geographic region has interesting parallels with recent evidence of the spread of highly prevalent clonal strains in cystic fi brosis clinics. aim to investigate the prevalence and impact of incontinence in adult men with cystic fi brosis (cf) as compared with age-and sex matched control subjects. methods men with cf were recruited through outpatient clinics and control subjects through advertisements to complete standardized questionnaires relating to respiratory symptoms, bladder and bowel function, mood and physical activity levels. demographic data were collected from medical records for the cf group. results seventy-four men with cf participated (mean (sd) age . ( . ) years). forty-nine men volunteered as controls ( . ( ) years), and were well matched in terms of physical activity levels. / ( %) in the cf group and / ( %) in the control group had reported episodes of urine leakage. in the men with cf, there was no difference in lung function between men with episodes of leak and those with no history of leak (fev % predicted ( )% vs. ( )%, p = . ). anxiety levels were higher in men from both groups with episodes of leak compared to those with no history of leak (hospital anxiety and depression anxiety score . ( . ) vs. . ( . ), p < . ). depression scores were also higher in men with episodes of leak compared to those with no history of leak ( . ( . ) vs. . ( . ), p < . ). conclusions urinary incontinence in men with cf is not associated with disease severity, as measured by lung function. anxiety and depression levels were higher in men with leakage of urine. confl ict of interest no. aim to investigate the bone mineral status of children and adolescents with cf and to explore the relationship between bone mineral density (bmd) and anthropometric and clinical parameters including height, body mass index (bmi), lung function tests and vitamin d levels ( -hydroxyvitamin d) in the cf centre at starship children's hospital, new zealand. methods bmd of the lumbar spine was assessed by dual x-ray absortiometry between january and december . the results of subjects with cf ( males) with a mean age of . years (range - . years) were collected. anthropometric data (height, bmi), forced expiratory volume in second as percent predicted (%fev ) and vitamin levels were assessed and related to bmd. results bmd in our subjects was low in . % and very low in . % when adjusted for age, sex and height (difference in bmd g/cm in the lumbar spine l -l ). there was a strong positive relationship between the lumbar areal bmd (abmd) and bmi z scores (p < . ), abmd and % fev z scores (p < . ), and abmd z scores and vitamin d levels (p < . ). conclusions bmd was normal in the younger and well-nourished subjects with normal or mild reduction of fev . low bmd appeared to evolve during adolescence with decreasing bmi and reduction in lung function. this will lead to ongoing bone disease in early adulthood. it is a further indication to maintain optimal nutritional status and maximize lung health. malnutrition in cf is associated with poorer pulmonary function and is an independent risk factor of survival. aim to compare the nutritional status of the adults attending an adult cf centre in with . method retrospective audit of patients ( excluded, incomplete data) including demographics, nutritional status, pancreatic enzyme replacement therapy (pert) usage, glucose tolerance and dietetic review. results the mean age of the clinic population increased from . to . years. mean (sd) bmi increased from ( . ± . kg/m ) to ( . ± . ) (p = . ). in , % of the clinic population was taking pert with a mean dose of ± iu lipase/kg/day. the proportion of patients with abnormal glucose tolerance has increased from % to % (p = . ). oral supplement use has increased from % to %, yet enteral feeding remained stable ( % − , % − ). this occurred during period of increased annual dietetic review of the patients attending the clinic from % in to % in (p = . ). discussion over a -year period, an improvement in mean bmi refl ects improvement in nutritional status. prevalence of abnormal glucose tolerance has increased; this is likely due to commencing a screening program ( ). use of oral supplements has increased and is higher than identifi ed in the recent daa survey of nutrition practices of cf dietitians ( %). annual review by the cf dietitian has increased despite a twofold increase in the cf population may be attributable to a stable and experienced workforce. current service provision of . a abbott , e cheung , l morgan aim to characterize the microbial colonization of a group of stable adults with non-cf bronchiectasis using an extended culture protocol. methods sputum was collected over an -month period from clinically stable patients. standard semi-quantitative bacterial culture was extended to days with the addition of fungal and mycobacterial culture as routine. results specimens of spontaneously expectorated sputum were collected from patients; mean age years ( - years); mean (sd) fev / fvc ratio % ( %); / never smokers; / on inhaled or oral corticosteroids. the bacteria identifi ed were p. aeruginosa ( % of specimens), h. infl uenzae ( %), h. parainfl uenzae ( %), acinetobacter baumanii ( %), enterobacteriaceae ( %). commensals only were identifi ed in % of specimens. fungi included candida species ( %), aspergillus fumigatus ( %) and penicillium species ( %). non-tuberculous mycobacteria (ntmb) were grown in % of specimens: m. gordonae ( %), m. intracellulare ( %) and m. lentifl avum ( %). the ntm identifi ed were all considered non-pathogenic. only the mycobacteria were identifi ed after day . conclusion microorganisms with potential pathogenicity are frequently identifi ed in adult patients with non-cystic fi brosis bronchiectasis who are not experiencing an acute exacerbation. all these organisms were identifi ed using a standard short culture protocol. the extended regimen, which was costly, did not identify any unusual or unexpected pathogens. it was rare for patients to be colonized with fungi. this study suggests there is limited value in requesting extended culture for bacterial pathogens, including looking for fungi or nmtb in this stable patient group as this adds little to the empiric antibiotic choice for infective exacerbations. confl ict of interest none. s stelzer-braid , , h alsubie , a neilsen , h johal , a steller , er tovey , k mckay , p van asperen , wd rawlinson , introduction respiratory infections are of fundamental importance in determining the morbidity and mortality associated with cystic fi brosis (cf) as such infections can lead to progressive and fatal obstructive lung disease. using polymerase chain reaction (pcr) to detect such infections has advantages over previous studies that used relatively insensitive traditional detection methods and could have underestimated viral prevalence. methods viral and bacterial multiplex pcrs were developed for detection of respiratory pathogens important for children with cf. nasal brush samples were collected from cf patients who were symptomatic or asymptomatic for acute respiratory illness (n = ). sputum and exhaled bioaerosols via a novel mask sampler were collected from a subset (n = ). results as expected, almost all ( %) sputum samples were positive for bacteria. detection of bacteria in the upper respiratory tract was lower ( . %). data from nasal samples indicated strong association of viral pathogen presence, particularly rhinovirus, with exacerbation of disease. results also showed good evidence for rhinovirus infection in the lower respiratory tract. the novel mask sampler is promising as a non-invasive sampling tool. conclusions our results demonstrate the importance of pathogens in exacerbations. early detection and understanding the development of bacterial and viral infections in cf patients is important in clinical decision-making as more and better antiviral and antibiotic agents become available. aim to determine the factors affecting microbiological yield from bronchoalveolar lavage (bal) in patients with suspected pulmonary infection and haematological malignancy or following stem cell transplantation at a tertiary bone marrow transplant centre. methods a retrospective -month audit of patients with pulmonary infi ltrates or febrile neutropenia with haematological malignancy or post-stem cell transplant who underwent bal for microbiological diagnosis. data were obtained on microbiological yield, radiographic appearances, current antimicrobial therapy, the presence and duration of neutropenia and complication rate. of the bal procedures performed, a clinically signifi cant microbiological result was obtained in % of cases ( / ). of these positive results, % ( / ) were exclusively viral pathogens, % ( / ) were fungal, % ( / ) were bacterial and polymicrobial infection was observed in % ( / ) of cases. a high proportion of patients had commenced anti-microbial treatment empirically, with % ( / ) receiving broad spectrum antibacterial treatment and % ( / ) receiving treatment doses of antifungal agents prior to bronchoscopy. in % ( / ), the results of the bal changed the patients therapy. the presence and duration of neutropenia or radiological appearances were not reliable discriminators of specifi c infective aetiologies. complication rates were low and included fevers in % ( / ), hypoxia % ( / ), small volume haemoptysis in % ( / ), atrial fi brillation in % ( / ) and pneumothorax in % ( / ). conclusion whilst bal remains a safe and important tool in establishing a microbiological diagnosis in immunosuppressed patients with pulmonary infi ltrates, a clinically signifi cant yield and changes to patient treatment occur in the minority of cases. clinicians should have a high degree of suspicion of viral infective aetiology when treating this population of patients. aim to examine the outcomes and complications of intercostal catheter (icc) treatment of pneumothoraces (primary (pp) and secondary (sp)) and effusions (malignant (me) and parapneumonic (pe)). methods retrospective review of all iccs in admitted patients in a respiratory unit over months. data collected included type of pneumothorax or effusion, icc type, insertion details, complications (major and minor) and outcome (success defi ned as resolution of pneumothorax or effusion with single tube insertion). results patients required icc treatment. forty-six iccs were used in patients with pneumothorax: pp ; sp ; iatrogenic ; hydropneumothorax . complication rate was % ( % major) and was signifi cantly less in pp ( %) compared with sp ( %), p < . , chi-square. success rate for pneumothorax icc drainage was % (signifi cantly higher for pp ( %) compared with sp ( %), p < . ). fifty-eight iccs were used in patients with pleural effusions: me , pe , other . complication rate was % ( % major) and was signifi cantly higher in me ( %) compared with pe ( %), p < . . success rate for effusion icc drainage was % (signifi cantly less in me ( %) compared with pe ( %), p < . ). small bore iccs (gauge < fr) were used for % of pneumothoraces and % of effusions. tube size did not signifi cantly infl uence complication or success rate for either pneumothoraces or effusions. conclusions compared with pp, icc treatment of sp was less successful and more likely to be associated with complications. similarly, compared with pe, intervention for me with icc was less successful and had a higher complication rate. we conclude that icc intervention is most successful for pp and pe, and speculate that sp and me should have early surgical intervention. introduction spontaneous pneumothorax is a common condition. current management guidelines recommend large pneumothoraces are managed by primary intercostal catheter insertion. we report a single centre's experience in the management of large spontaneous pneumothorax. methods retrospective audit of cases of spontaneous pneumothoraces managed at the prince charles hospital between january and december . patient demographics, co-morbidities, presenting symptoms, examination fi ndings, radiology, management and complications were reviewed. results forty-two patients ( male, female) experienced episodes of spontaneous pneumothorax. chest pain and dyspnoea were the most commonly reported symptoms ( ) %. there were forty-two ( %) episodes of large pneumothorax (≥ % of hemithorax). management of large pneumothoraces consisted of: observation, ( ) seldinger icc ( ) and large bore icc ( ). complications occurred in three patients with seldinger icc ( vasovagal, hydro-pneumothorax) compared to none with large bore icc. outcomes were similar for patients managed by observation compared to icc insertion. all recurrent cases ( %) were referred for consideration of surgical pleurodesis. conclusion patients with large pneumothorax managed by observation recovered similarly to those treated with icc, suggesting a higher threshold for icc insertion should be considered in the future. grant support nil. aim a pilot study of an instrument of pleural ultrasound training in thoracic physicians after a pleural ultrasound course. the instrument was tested for inter-observer agreement and also its ability to be used in a patient compared to a dedicated manikin. methods all chest physicians ( ) were novices in ultrasound and underwent a dedicated -day training course in pleural ultrasound at the australian institute of ultrasound. they were assessed months later by radiologists and one senior ultrasonographer using a specially designed pleural ultrasound training assessment tool (usgt-sat) on both a subject with pleural effusion and a dedicated ultrasound manikin. the mean scores, out of a maximum of , obtained by the each of the participants for the manikin were . , . , . and . , respectively, while the scores for the patient was . , . , . and . , respectively. the mean scores of the participants as a group for manikin were ± . and for the patient as . ± . . there was general agreement between the examiners with mean combined participant scores of . , . and . in the manikin, respectively, and mean score of . , . and . in the patient. conclusions this pilot study shows ranges of scores for design of future validation studies of the usgt-sat. test performance by the chest physicians after a short course in pleural ultrasound was generally good and results for the use of the manikin as an alternative to patients in pleural ultrasound training are encouraging. further studies with larger sample size are required. supported by nil. nomination nil. confl ict of interest no. since the fi rst commercial availability in , fl exible bronchoscopy has evolved from a simple 'look see' procedure to a more complex multifaceted one. today, fl exible bronchoscopy is a tool used for diagnostic procedures, surveillance, delivery of therapy and clinical trials. increasingly, it involves utilizing expensive purpose built equipment in complex diagnostic procedures. this evolution requires a specifi c knowledge base and skill set to safely perform the procedure and care for the equipment. this now mandates additional training by nursing and medical staff to develop and maintain the required skills. medical staff now rely on their nurses to assist in the full range of procedures. thus, the nurses must keep abreast of modern trends and techniques. the modern bronchoscopy suites team is an integrated one, with specifi c roles, defi ned to each member. the procedures performed will refl ect local needs and expertise. just as bronchoscopy has evolved into the speciality of interventional pulmonology, so must bronchoscopy suite nursing be accepted as a specialized area of nursing with a credentialed 'special interest group' to promote, educate and develop the subject as more therapeutic and diagnostic procedures evolve. this will allow nurses involved in bronchoscopy to be respected, recognized and accepted for their unique knowledge and abilities. confl ict of interest nil. background transthoracic pneumostomy (tp) is a novel treatment for patients with severe emphysema that aims to defl ate the lung and improve function. aim to assess the effect of unilateral tp on the volume of each lung and mechanical properties of the lungs. methods subjects were recruited for a multicentre trial of tp (see actrn ). in parallel with the main protocol, we measured ( ) in the six subjects recruited, compared to plethysmography, lung volume was overestimated by cxr (mean difference + . %, range − . to + . ) and underestimated but more closely correlated by ct (mean difference − . %, range − . to − . ). based on ct, the volume of the treated lung decreased in all patients after tp (mean − . %, range − . to − . ) whilst that of the untreated lung did not change (mean − . %, range − . to + . ). in patients with available data, tp reduced dynamic hyperinfl ation during exercise (mean − ml, − . % of ic, range + . % to − . %). lung mechanics were performed in patients. low lung elastic recoil prior to tp and an increase in elastic recoil after tp were associated with greater reductions in lung volume and greater improvements in exercise tolerance. conclusions supine chest ct provided reasonably accurate estimates of plethysmographic lung volume. unilateral tp defl ated the lung and there was no evidence of signifi cant compensatory hyperinfl ation of the contralateral lung. tp also reduced dynamic hyperinfl ation. measurement of lung elastic recoil may help select patients who are likely to benefi t from tp. support and confl ict of interest nil. methods we performed a retrospective chart review of all adult patients who had an icc over a -month period within a tertiary hospital respiratory service. we noted patient demographics, details surrounding chest drain insertion including image guidance and subsequent inpatient events. results over a -month period, there were small-bore icc insertions, of which were image-guided. mean patient age was years, males comprised / . forty drains were inserted for pneumothoraces, for malignant effusions, for parapneumonic effusions, for transudates and for undiagnosed exudative effusions. mean duration of drainage was . days. there were no life-threatening complications. three of the chest drains fell out and became blocked. six pneumothoraces were noted, all following insertion without direct image guidance; none required further intervention. local infection occurred in patient. insertion details were not documented in patients. conclusion insertion of small-bore iccs via the seldinger technique appears to be a safe method of draining pneumothoraces and pleural effusions. image guidance may reduce complication rate of this procedure. documentation of drain insertions could be improved. confl ict of interest nil. rationale pleural effusions are frequently encountered in clinical practice, and often require aspiration for diagnostic and/or therapeutic purposes. use of radiological guidance varies, despite current guidelines recommending routine use of ultrasound. furthermore, concerns exist regarding the downskilling of thoracic medicine trainees due to the increased use of interventional radiology. as a precursor to developing a procedural pleural ultrasound service, we performed a retrospective case review of our current practice. methods patients who had pleural fl uid sent to pathology between january and december were identifi ed on an existing database. patient records were reviewed and details regarding the drainage procedure and outcomes were recorded. information on patient location, method of procedure and performing clinician were also collected. results to date, pleural fl uid aspirations in patients have been identifi ed. overall, % of aspirations were carried out on the ward and % in the radiology department. two procedures occurred in the endoscopy suite on outpatients, and one in the emergency department. fifty percent of procedures were performed using an intravenous cannula for drainage and % utilized a pigtail catheter. all procedures occurring in the radiology department were performed under ultrasound guidance by a radiologist or radiology registrar. of the remaining procedures, % were performed by medical registrars and % were performed with ultrasound marking. six complications occurred following procedures: pneumothoraces, vasovagal and tube blockage. there were signifi cantly more pneumothoraces in patients who did not have an ultrasound marking ( of without marking, of with marking, p = . ). none of the complications required further intervention. conclusion these preliminary data suggest ultrasound marking signifi cantly reduces pneumothorax incidence, supporting the establishment of a pleural ultrasound service. this is likely to have the added benefi t of improved training for thoracic medicine trainees. aim to investigate differences between semi-recumbent and supine posture in terms of cough rate, degree of oxygen desaturation, oxygen supplementation, increase in pulse rate and sedative use during the initial phase of bronchoscopy. methods consecutive patients (n = ) undergoing diagnostic bronchoscopy at an endoscopy unit were recruited for this observational cohort study. the posture was determined by the bronchoscopist's usual practice. patient age, gender, % predicted fev and fvc, indication, pulse and oxygen saturation were recorded. the initial phase was defi ned as the time from bronchoscopy insertion to visualization plus lignocaine instillation of both distal main bronchi. cough rate, peak pulse, nadir oxygen saturation (spo ), range of oxygen supplementation and sedation use during the initial phase were recorded. a post-procedure questionnaire was administered to the patient and the attending nurse. results patients had bronchoscopy in the semi-recumbent posture and in the supine posture. three of bronchoscopists performed in both postures. there were no signifi cant differences in age, gender, smoking status and spirometry between the two groups. the semi-recumbent postures resulted in signifi cantly less cough rate (mean (sd) . ( . ) vs. . ( . ) coughs/min, p = . ) and less fentanyl use ( ( ) vs. ( ) mcg, p = . ) in the initial phase. there were no signifi cant differences in the nadir spo , fall in spo , oxygen supplementation or increase in pulse rate between the two groups. nurse perception of patient discomfort was lower in the semirecumbent position ( ( ) vs. ( ) mm on mm visual analogue scale, p = . ), and there was a trend towards less patient-perceived cough during the procedure in the semi-recumbent group ( ( ) introduction pulmonary infi ltrates in immunocompromised patients with haematological malignancy have a diverse aetiology and are a major source of morbidity. a specifi c diagnosis and targeted therapy may optimize outcomes and reduce the cost of treatment. the diagnostic value of fi breoptic bronchoscopy (fob) and the infl uence of timing of the procedure are unclear. aim to determine the yield of fob, its impact on antibiotic therapy and the infl uence of early vs late timing in this patient population. methods we conducted a retrospective review of immunosuppressed patients with underlying haematological malignancy and new pulmonary infi ltrates who underwent fob over a -month period. the outcomes of early (eb, ≤ days from initial respiratory consultation) and late (lb, ≥ days) fob were compared using fisher's exact test. results thirty-eight fobs, including bronchial or transbronchial biopsies, were performed in patients (males ). there were patients who received eb and who received lb. a specifi c diagnosis was obtained from procedures ( %), including infections ( in eb vs. in lb, p = . ) and non-infective diagnoses ( eb vs. lb, p = . ) based on histology. fob fi ndings from procedures ( %) ( eb vs. lb, p = . ) resulted in modifi cation of antibiotic therapy. there were no procedure-related severe complications. conclusions fob is a useful diagnostic procedure which infl uences diagnostic and therapeutic decisions in this patient group. although early procedures tended to be more likely to change antibiotic therapy than late procedures, the difference was not signifi cant. confl ict of interest none. capsule endoscopy is increasingly performed in gastroenterology to investigate possible small intestinal bleeding. the capsule endoscope is swallowed and then takes photographs every seconds for hours during its transit through the gastrointestinal tract. the images are downloaded by a radio link and the capsule is then passed normally and disposed of. in the present case, the capsule endoscope was inhaled and lodged in the bronchus intermedius. this was only recognized when the images from the capsule download were examined. removal of the capsule was effected with a fi breoptic bronchoscope using an ercp balloon and roth basket. this is believed the only capsule bronchoscopy so far reported. capsule endoscopes are large ( mm × mm diameter) and smooth. this case report shows the images from the capsule endoscope and describes the methods necessary to remove this unusual foreign body from the lung. support nil. background bronchoscopy with endobronchial biopsy (eb) is now an integral component of the research evaluation of airway diseases. there are no published safety data for eb in adult non-cf bronchiectasis. methods a subgroup of subjects enrolled in the bronchiectasis and low dose erythromycin study (bless) a randomized controlled trial of long-term prophylactic erythromycin (anzctrn ) underwent bronchoscopy with bronchoalveolar lavage (bal) and eb performed by a single operator. results ninety-nine bronchoscopies were performed (bal alone in ) in subjects. of procedures with eb, ( . %) were associated with very signifi cant bleeding (> ml either at time of eb or several days post-procedure) and a further ( . %) with immediate moderate bleeding ( - ml). one subject had a history of prior signifi cant haemoptysis. in the four subjects with very signifi cant bleeding, immediate bleeding of > ml occurred in subjects, ml in one subject and ml in one. immediate bleeding was controlled uneventfully. three of the subjects subsequently developed signifi cant haemoptysis (> ml) to days post-bronchoscopy without intervening haemoptysis, with one subject developing massive haemoptysis (> ml) on day post-bronchoscopy. further research ebs were ceased. in one of the subjects with 'delayed rebleeding', repeat bronchoscopy confi rmed the biopsied lobe as the bleeding site. haemoptysis settled in all subjects within hours with simple conservative measures. conclusions in contrast to the experience in asthma and copd, research eb in adults with non-cf bronchiectasis is associated with a signifi cant risk of bleeding, of potentially life-threatening magnitude in . % of cases. of particular concern was the observation of sudden onset delayed rebleeding developing up to days post-eb in spite of early local control. histopathological evaluation will clarify the potential contributions of airway wall vascularity and infl ammation to these events. malignant mesothelioma (mm) is an aggressive cancer which is often associated with exposure to asbestos and sv . this disease has a high latency period and a low survival rate. therefore, new strategies for therapeutic intervention must be developed. recent studies have shown that developmental pathways including the hedgehog (hh) pathway are associated with various types of cancers. the aberrant activation of key hedgehog pathway proteins has been shown to contribute to cancer progression. however, the role of this pathway in mm has yet to be explored. we hypothesize that aberrant activation of the hh pathway is a contributing factor for the development of mm. the mrna expression of hh pathway genes; sonic hedgehog (shh), patched - (ptch- ), smoothened (smo) and gli- were examined in mm cell lines and tumour tissues by rt-pcr and qrt-pcr. hh pathway proteins and mrna expression and distribution were then observed in the tumours by immunochistochemistry and in situ hybridization. we used real-time superarrays to examine the change in expression of a panel of key hh pathway genes by activating and inhibiting the pathway. we showed that the key hh pathway genes are expressed in both the cell lines and tissue samples. upon stimulation with the ligand shh, there was an increase in expression of indian hedgehog (ihh) and shh in most of the mouse and human cell lines that we looked at. interestingly, for the transcription factor gli- , there was a significant decrease in both mouse and human cell lines. inhibiting this pathway increased the expression of ptch in the mouse and human cell lines. the expression and up-regulation of key hh pathway components in mm at baseline and following stimulation suggests a role for the pathway in mm. methods incident cases were obtained from the australian and wa mesothelioma and cancer registries and death registries. exposure was calculated using measures of dustiness in the industry and the town for the period of employment or residence of each case. latency (time from fi rst exposure to diagnosis) by sex, age, smoking status, exposure variables and worker or resident status was estimated. multivariate linear regression modelling examined the determinants of latency. results the mean latency periods of . (sd = . ) years for lc and . (sd = . ) years for mm have increased linearly. increased duration of exposure was associated with reduced latency for mm after adjustment for age at fi rst exposure and age at diagnosis but not signifi cantly for lc. age at diagnosis was strongly associated with latency length for both lc and mm (p < . ). smoking, sex, cumulative exposure (log f/ml-year) and status at wittenoom were not related to latency. latency for lc with increasing age at fi rst exposure declined faster than for mm. conclusions age at diagnosis is associated with reduced shorter latency of mm and lc. duration of exposure is associated with shorter latency of mm. supported by nhmrc australia. confl ict of interest no. aim to assess overall survival of patients following resection for stage nsclc at a centre that has substantially greater resection rates than the nsw average. methods a retrospective audit of those patients who underwent lung resection for stage nsclc at nepean hospital between january and february . results patients ( m: f), mean age (range - ) underwent resection. there were pneumonectomies, bilobectomies and segmentectomies, one involving chest wall resection. the remaining procedures were lobectomies. there was one perioperative death from respiratory failure. actuarial overall survival at months was %, at months, % and at years %. survival was not infl uenced by histology or age. conclusion in our institution, we have an agreed aggressive approach to resection of stage nsclc and our resection rate is %. this pro-surgical policy is associated with good perioperative and long-term overall survival. confl ict of interest no. introduction malignant pleural effusions (mpes) are common, although their management varies widely. providing ambulatory care to minimize hospitalization is a key goal for patients with mpes. indwelling pleural catheters (ipcs) are a new treatment strategy that allows outpatient fl uid drainage. we hypothesized that mpe patients managed with ipcs require fewer hospital admissions. methods a prospective, multicentre, non-randomized study involving all three major respiratory centres in western australia. patients diagnosed to have mpes were prospectively followed, and admissions were recorded. in the absence of accepted guidelines for ipc use, the choice of treatments (thoracentesis, ipc, pleurodesis) was decided by clinicians in-charge. all complications were recorded. bacterial cultures of pleural fl uid were performed monthly for patients with ipcs. hm gallagher , ee duhig , ia yang , rv bowman , be clark , hm marshall , km fong aim to determine the concordance of histological subtyping of nsclc in diagnostic samples to the gold-standard lung resection specimens. methods we have so far evaluated consecutive subjects who underwent curative surgery for primary nsclc at the prince charles hospital between the years and . many of these had workup at other institutions. one hundred forty-seven had queensland health electronic record of positive preoperative diagnostic sampling. we correlated the fi nal nsclc who histological subtype with the subtypes diagnosed by samples prior to surgery including sputum, fi beroptic bronchoscopy (fob) and trans-thoracic needle aspiration (ttna). the resection subtype was set as the reference standard, and concordance was compared. results of the cases of resected nsclc, had malignancy on diagnostic sampling pre-resection, as shown in the results patients were included: median age years (range - ); % male; % living in major cities versus % in regional areas; % rightsided mpm; % epithelial subtype. median time from asbestos exposure to diagnosis was years (range - ). median time from fi rst symptoms or investigations to diagnosis was weeks (range - ). all patients had at least one chest x-ray and ct scan and % had pet scan. a variety of procedures led to the diagnosis: % thoracoscopy, % thoracotomy, % radiology-guided, % chest wall biopsy and % medical pleuroscopy, with % having had cytology alone. median number of diagnostic immunohistochemical stains used was (range - ), with calretinin ( %) the most commonly used mesothelial marker and carcinoembryonic antigen (cea; %) the most common carcinoma marker. median os for the cohort was . months ( % ci: . - . ), with no statistical difference in os between major city and regional patients ( vs. . months, respectively, p = . ). conclusions mpm appeared to affect mainly the elderly, and thoracoscopy was the most common diagnostic procedure. os did not differ between australian major city and regional patients and was comparable to the largest phase iii trial in mpm. aw musk , , p aboagye-scarfo , a reid , a miller, s ruwanpura, l mcleod, p bardin, n watkins, bj jenkins rationale lung cancer is the leading cause of cancer death worldwide. it is well established that cigarette smoking is linked to emphysema and lung cancer, and smokers with emphysema are at an increased risk of developing lung cancer. notably, recent epidemiological studies have indicated that emphysema can predispose to lung cancer irrespective of pack-year smoking history. although infl ammation has been proposed as a common mechanism linking these two diametrically opposed diseases, the conceptual inter-relationship between infl ammation, emphysema and lung cancer has been poorly investigated because existing experimentally induced and genetically modifi ed animal models for lung cancer occur in the absence of emphysema. method we have utilized a newly identifi ed mouse model (gp f/f ) of spontaneous lung infl ammation and emphysema in two well-established lung cancer models. the gp f/f mouse is characterized by deregulated cytokine signalling via gp , the critical co-receptor for the interleukin (il)- cytokine family, leading to hyper-activation of stat , a potent pro-infl ammatory and oncogenic latent transcription factor. in separate studies, we exposed gp f/f mice to a cigarette-derived carcinogen (nnk), and crossed them with the genetically susceptible kras(g d) strain of mice. results in both nnk-and kras(g d)-induced lung cancer models, the lungs of gp f/f mice were highly predisposed to hyperplasia and tumour formation. increased levels of cellular proliferation were observed in hyperplastic and tumour lesions, as well as surrounding areas, of these mice. these observations were verifi ed at the molecular level by gene expression profi ling of tumour-bearing lung tissue. conclusions these studies provide unique insights into the importance of interactions between the gp signalling axis and factors that predispose to lung tumourigenesis in emphysema. support nhmrc. aim to assess the preparedness of hospitals with respect to protecting health-care workers (hcws) during a pandemic. methods a self-administered questionnaire was performed between november and january , and a scoring system was developed to provide a quantifi able measure of preparedness. results a total of hospitals in nsw, australia, were approached -six regional hospitals (rhs) and six tertiary referral centres (trcs). the study was extended to assess three hospitals in england, allowing a limited comparison between the hospitals in australia that had faced the initial wave of the h n ('swine fl u') pandemic and the hospitals in the uk that had more time to prepare for the outbreak. response rates were % from the trcs, % from the rhs and % from the english hospitals. the overall preparedness scores were relatively high, with a median total score (adjusted) of . out of . the demographic that scored the highest total was tertiary referral centres in sydney. all english hospitals scored below the median. however, the range of scores across hospitals was quite narrow ( . - . adjusted). scores were generally high for the areas of preparedness, infection control, education and training. scores for vaccination were more variable. the category that consistently demonstrated the lowest scores was that of psychosocial welfare and assistance, despite this found in previous research to be an integral part of that which hcws have identifi ed as important. conclusions given their integral role in pandemic response, protecting hcws must be a priority as part of any pandemic preparedness plan. this goes beyond protection from infection, extending into aspects of physical and psychological wellbeing. identifying these issues and addressing them is the key to maximizing staff support and morale, and minimizing staff absenteeism at such a crucial time. aim to describe the relationship of respiratory and refl ux symptoms within the general population and relate this to the possible confounding factors of body mass index (bmi) and obstructive sleep apnoea (osa). methods data from a cross-sectional health survey, performed in bussleton, west australia in - , were used to examine the relative effects of bmi and osa on the relationship between respiratory and refl ux symptoms. questionnaire data included information on asthma, cough, wheeze, dyspnoea and gord symptoms. gord symptoms were categorized as never, monthly or less often and weekly or more often. bmi, risk of osa defi ned according to the berlin questionnaire, spirometry and airway hyperresponsiveness to methacholine were also recorded. logistic regression models obtained odds ratios for the associations between each gord symptoms, various respiratory symptoms, bmi and osa. results average age was years and recent wheeze was reported in % and cough and phlegm in %. twelve percent were current smokers. ahr was present in % and osa in %. gord symptoms occured in % and frequent symptoms (weekly or more often) were present in - %. there were strong positive associations between gord symptoms and cough/phlegm, breathlessness, chest tightness and wheeze in the last months. odds ratios increased with increasing frequency of refl ux p ≤ . . there was no effect of obesity or osa on the relationship between respiratory and gord. conclusion cough and phlegm, breathlessness, chest tightness and wheeze (ever or recent) are all strongly associated with symptoms of gord. this relationship is amplifi ed with increasing frequency of gord symptoms indicating a dose-response relationship between refl ux and respiratory symptoms. obesity and osa do not affect the association between gord and respiratory symptoms. introduction diesel exhaust particles (dep) make up the bulk of particulate matter in urban areas. high ambient levels of particulate matter are associated with increased hospitalization due to respiratory disease. we aimed to determine if exposure to dep exacerbates responses to acute viral infection. methods adult female balb/c mice were inoculated with μg dep or control . days after infection with . plaque forming units (pfu) of infl uenza a/mem (or control). six hours after dep inoculation, lung volume (tgv) and lung mechanics were measured by plethysmography and the forced oscillation technique, respectively. bronchoalveolar lavage fl uid was collected to assess cellular infl ammation and cytokine levels. results viral titre was signifi cantly higher in infl uenza-infected mice exposed to dep compared to those exposed to infl uenza alone (p = . ). both dep (p = . ) and infl uenza infection (p < . ) alone signifi cantly increased cellular infl ammation; however, there was no difference between mice exposed to both dep and infl uenza compared to those exposed to infl uenza alone (p = . ). a similar pattern was found in levels of cytokines in the bronchoalveolar lavage (tnf-α, mcp- , il- , ifn-γ). specifi c airway resistance, specifi c tissue damping, specifi c tissue elastance and hysteresivity were signifi cantly increased in infl uenza infected mice (p < . in all cases). none of these parameters were infl uenced by dep exposure alone (p > . in all cases) and there was no additive effect of dep on lung function (p > . in all cases) in infl uenza-infected mice. conclusions dep increases viral titre but is not suffi cient to physiologically exacerbate pre-existing respiratory disease caused by infl uenza infection in mice. supported by nhmrc. confl ict of interest no. introduction lack of treatments for post-transplant obliterative bronchiolitis (ob) is mainly due to the poor understanding of its pathogenesis and lack of small airway models. epithelial-mesenchymal transition (emt) may play a central role and could be crucial to developing treatment drugs. we hypothesize that emt induction may be prevented by pharmacologically available compounds. methods primary cultures of small and large airway epithelial cells (saec and laec) were established and emt induced by adding tgfβ ( ng/ml) (n = ). azithromycin ( - μm), mycophenolate ( . - mg/l) and rad ( . - ng/l) were then added and expression of epithelial (zo- , ck- ) and mesenchymal markers (eda-fn, vim) measured via western blot as well as mmp and activity via zymography. results signifi cantly lower increase in mesenchymal markers and lower decrease in epithelial markers, compared to controls was noted for azithromycin and mycophenolate indicating suppression of emt. mmp and activity increase was also signifi cantly suppressed. azithromycin suppressed emt to a greater extent compared to mycophenolate, but was equally effective in both small and large airway epithelia. rad appeared to have no effect. conclusions azithromycin and mycophenolate are both effective in preventing emt and thus have potential for the clinical treatment of ob. supported by abn foundation. confl ict of interest none. journal compilation © asian pacifi c society of respirology tp- g hodge , , s hodge , , c-l liew , , t-cell pro-infl ammatory cytokines are associated with acute lung transplant rejection. we have previously shown compartmentalization of production of these cytokines in bronchial intraepithelial t cells (iet) obtained by bronchial brushings from stable lung transplant patients. during acute rejection episodes, no signifi cant differences in iet cytokines were observed between stable and rejecting patients due to broad cytokine variability between patient groups. to overcome this limitation, we hypothesized that there would be increased graft pro-infl ammatory iet cytokines compared with native lung or trachea during acute rejection. methods cell cultures from stable patients, patients with evidence of acute rejection and bos and healthy controls were stimulated and intracellular cytokines determined using multiparameter fl ow cytometry. results there was a signifi cant increase in graft iet-cell ifnγ and tnfα in the lungs of patients with acute rejection compared with iet cells obtained from the native lung or trachea, but no changes were noted between other patient groups. there was a signifi cant correlation between increased graft iet-cell tnfα compared with trachea and lungs and acute rejection grade. conclusions differential expression of pro-infl ammatory cytokines by iet cells from graft, trachea or native lung distinguishes severity of acute rejection. improved monitoring response using this assay or therapeutic targeting of these pro-infl ammatory cytokines may reduce acute lung transplant rejection. supported by nhmrc. aim to determine the prevalence of reduced carbon monoxide transfer factor (dlco ≤ % predicted) in subjects undergoing pulmonary function testing (pfts) and to determine whether a cause has been identifi ed. methods a clinical audit of all subjects undergoing pfts at royal melbourne hospital from august to august who have a dlco ≤ % in the setting of normal spirometry. medical records and investigations including transthoracic echocardiogram (tte), high-resolution commuted tomography (hrct), ventilation/perfusion (v/q) scans were reviewed to determine whether a cause for the reduced dlco was established. where a cause was not clear, subjects were invited to participate in a telephone interview to evaluate symptoms and to undergo repeat pfts. subjects with a persistently reduced dlco were invited to undergo further investigation with tte, hrct and v/q scan. preliminary results pft results from subjects were reviewed. subjects with fev /fvc < , fev < % predicted and fvc < % predicted were excluded. three hundred seventy subjects ( %) had an isolated reduction in dlco. / ( %) of these subjects underwent tte with / ( %) demonstrating an elevated right ventricular systolic pressure (rvsp). in all cases where there was an elevated rvsp an identifi able cause was found. / ( %) of these subjects subsequently identifi ed as having pulmonary arterial hypertension (pah) and commenced appropriate therapy and / ( %) identifi ed as having pah where treatment was not commenced. there were / ( %) of subjects who appeared not to have undergone a tte. further evaluation of medical records of subjects who had not undergone tte and those with normal tte is continuing. review of subjects hrct, v/q scans and right heart catheterizations is currently proceeding. conclusions preliminary results suggest that a signifi cant proportion of subjects with isolated reduction of dlco on pfts do not undergo tte which is an important investigation in determining the cause for the reduced dlco. when a tte is performed and demonstrates an elevated rvsp, a cause for the elevated rvsp is identifi ed. sponsor actelion pharmaceuticals australia pty ltd. g hodge , , s hodge , , c-l liew , , , pn reynolds , , m holmes , , background t-cell pro-infl ammatory mediators are associated with acute lung transplant rejection. we have previously shown that bos was associated with lack of immunosuppression of t-cell pro-infl ammatory cytokines and increased t-cell granzyme b in peripheral blood. recently, we also showed that nkt-like cells are a major source of pro-infl ammatory cytokines and granzymes in the blood of stable lung transplant patients. we hypothesized that bos may be associated with lack of immunosuppression of these proinfl ammatory mediators in blood nk and nkt-like cells. method granzyme/perforin profi les from stable patients, patients with evidence of bos and healthy controls were determined and blood cultures stimulated and intracellular cytokines determined using multiparameter fl ow cytometry. results there was a signifi cant increase in the percentage of nk cells expressing granzymes and perforin in bos patients compared with stable patients and controls. there was an increase in the percentage of t, nk and nkt-like cells producing ifnγ and tnfα in bos compared with stable patients. there was a signifi cant correlation between increased nk ifnγ and tnfα and fev . conclusions bos is associated with increased peripheral blood nkt-like and nk cell granzymes, perforin and th pro-infl ammatory cytokines. therapeutic targeting of these pro-infl ammatory mediators and monitoring response using this assay may reduce bos. supported by nhmrc. confl ict of interest nil. rationale pulmonary embolism (pe) is the leading cause of maternal mortality in the developed world. consequently accurate diagnosis of pe is critical. this must be tempered by the potential radiation risk of investigations to the mother and foetus. we performed a retrospective case review to determine the incidence of pe in pregnant patients investigated for this condition. demographic information, the diagnostic algorithm utilized and the diagnostic yield of investigations were obtained. method pregnant women who underwent ventilation perfusion (vq) scanning or computed tomography pulmonary angiogram (ctpa) at our institution between january and january were identifi ed by an internal database audit. in addition to demographic data, information about the diagnostic pathway and fi nal diagnosis were collected. in cases where pe was not diagnosed, the medical records were reviewed for any subsequent events up until the date of delivery. results during the fi ve-year period, vq scans and ctpas were performed on pregnant women. the average gestation at investigation was weeks. only one patient had a previous history of venous thrombo-embolism. % underwent doppler ultrasound of the lower limbs prior to vq or ctpa. overall the incidence of pe was %, diagnosed by vq scan. otherwise the vq scans were normal in %, low probability in % and non-diagnostic in % cases. ctpa was non-diagnostic in % of cases. all other ctpa studies demonstrated no emboli. almost % of scans were done after hours ( % vq and % ctpa). no patients without pe were felt to have had the pe missed up to the time of delivery. conclusions the overall incidence of pe in patients being investigated was extremely low at %. during this study period slightly more vq studies were performed than ctpas, with each test having similar diagnostic rates. only % of patients had undergone venous doppler prior to undergoing radiationexposing investigations. nomination nil. introduction anti-ro- antibodies have been associated with idiopathic interstitial pneumonia (iip) in one small series (n = ). we hypothesize that ro- antibodies, just like myositis antibodies, can serve as a marker of undifferentiated connective tissue disease (ctd) with interstitial pneumonia as the primary phenotypic manifestation. the aim of this study was to examine the characteristics of patients with ro- and iip. methods retrospective study identifying patients with iip and ro- positivity, but negative for ctd and/or myositis antibodies, presenting between june and june . data relating to demographics, diagnosis, pulmonary function tests, length of follow-up and outcome were obtained. all hrct images were reviewed by an independent expert radiologist (dm). results / ro- positive subjects fulfi lled criteria ( male, median age ( - ), european, never smoked). / had ro- titers above and in the intermediate ( - ) range. three patients had raynauds phenomenon; there were no other ctd features. / patients had hrct diagnosis of nsip and / organizing pneumonia; / had extensive fi brosis. mean (sd) % predicted baseline fvc ( ), dlco ( ). median length of follow-up was months. all patients were treated and were considered overall stable at last follow-up, one had declined and one died of respiratory failure. conclusion this study confi rms an association between ro- positivity and interstitial pneumonia in the absence of defi ned connective tissue disease, suggesting an autoimmune basis for the interstitial lung disease in this group of patients. a larger cohort is required to determine the true signifi cance of this observation. background community acquired respiratory viral (carv) infections are believed to contribute to morbidity and mortality after lung transplantation, but previous studies have not conclusively established the evidence base in this area. patients and methods a prospective cohort study was performed at a single centre from august to march (n = lung transplant recipients). carv infection (human metapneumovirus (hmpv), respiratory syncytial virus (rsv), infl uenza a (flu a), infl uenza b (flu b), adenovirus and parainfl uenza virus (piv)) was confi rmed using polymerase chain reaction (pcr) of upper (nasopharangeal swab) and/or lower (bronchoalveolar lavage) respiratory tract secretions. carv infection and bos were included as segmented time-dependent covariates in a cox proportional hazards model with death as the outcome variable. results patients ( % of the total cohort) had a total of separate carv episodes: piv, hmpv, rsv, flu a, flu b, and adenovirus. infection with either rsv or hmpv was associated with an increased risk of death (p < . hr . , % confi dence interval, . - . ), and the effect persisted after multivariate analysis. bos was also a risk factor for acquiring hmpv or rsv infection (p = . or . , % confi dence interval, . - . ). conclusions infections with hmpv and rsv, but not other carvs, are associated with an increased likelihood of death. the presence of bos is a risk factor for symptomatic infection with hmpv and rsv. ns harun , k sanders , a stuart , cl steinfort department of respiratory medicine, barwon health, vic., australia, and department of clinical and biomedical sciences, barwon health, vic., australia aims nebulized colistin is used to treat recurrent exacerbations of bronchiectasis due to pseudomonas aeruginosa, a major pathogen regarded as diffi cult to eradicate. this case-control study aimed to establish if long-term colistin use could clear p. aeruginosa from the sputum of adults with non-cystic fi brosis bronchiectasis, and if so, whether colistin could be ceased in these patients. secondary outcomes included effects of colistin on quality of life (qol), symptom control, admission rates, lung function and tolerability. methods ( ) sputum was collected in bronchiectasis patients with p. aeruginosa. clearance rates in those on colistin were compared with a control group not on colistin. ( ) colistin patients cleared of p. aeruginosa ceased treatment. sputum was re-cultured at day and to detect recurrence. ( ) a questionnaire assessing qol, symptom control, and admission rates was performed on patients. outcomes were compared before and after colistin use. long-term colistin side-effects and lung function were also assessed. results ( ) % (n = / ) of colistin patients cleared p. aeruginosa from sputum compared with % (n = / ) in the controls (p = . ). ( ) % (n = / ) of patients ceasing colistin remained free of p. aeruginosa at day . ( ) there was no difference in frequency of breathlessness, sputum production or qol scores between the groups (p > . ). the colistin group had lower fvc ( . vs. . l, p = . ) and higher admission rates ( % vs. %, p = . ). on colistin, % of patients reported reduction in sputum frequency, breathlessness and improvement in qol. fifty percent reported decreased admission rates. there were no colistin side effects. conclusions clearance of p. aeruginosa in sputum is possible. clearance rates were similar in those with more severe bronchiectasis treated with colistin compared with stable patients not on colistin, and may suggest suppression of p. aeruginosa by colistin in this severe group. there are benefi ts of colistin on qol, symptom control and admission rates. continued sputum clearance after colistin cessation is achievable in some patients. nebulized colistin use is well tolerated. nomination janet elder travel award. confl ict of interest no. however, use of such agents is suboptimal in hospital patients. this study aims to determine whether a dedicated multidisciplinary education and reinforcement program improves the use of appropriate vte prophylaxis. methods prior to the education programme, we audited a bed general thoracic medical ward including patients with general medical conditions, lung cancer, chronic obstructive pulmonary disease, lung transplant and cystic fibrosis. our multidisciplinary research team developed and implemented an education program over months, using posters, leafl ets and oral presentations to increase awareness and promote adherence to vte prophylaxis guidelines for health care staff involved in direct patient management. following completion of the program, we reaudited the same bed ward. results prior to the education program, a total of patients (mean age ± ) were identifi ed as appropriate for vte prophylaxis. of these ( %) were on appropriate vte prophylaxis. the post education audit showed out of ( %) patients were on appropriate vte prophylaxis. (p = . ). conclusion an effective multi-faceted educational program can improve delivery of appropriate vte prophylaxis, leading to improved outcomes in hospitalized patients. supported by sanofi aventis. confl ict of interest nil. the anti-rheumatic anti-infl ammatory biological agents in clinical use are abatacept, anakinra, adalimumab, etanercept, infl iximab and rituximab. a variety of pulmonary side-effects have recently been reported for these agents and the purpose of this review is to compile the various reported pulmonary toxicities and their prevalence methods we performed a search of databases ovid medline® and embase of the english literature up to august using the mesh terms of abatacept, anakinra, rituximab, adalimumab, etanercept, infl iximab and respiratory tract disease with limits to include only human studies or case reports. in addition case reports of respiratory adverse effects reported to the australian drug reaction advisory committee (adrac) were obtained in order to identify the most common pulmonary reactions reported with each individual agent. results using the search criteria defi ned above and articles were identifi ed in the ovid medline and embase database respectively. the majority of adrac reports were associated with rituximab (n = ) and infliximab (n = ), followed by adalimumab (n = ) and etanercept (n = ). various pulmonary side-effects including interstitial lung disease associated with anti-infl ammatory agents were identifi ed. discussion from the articles reviewed, details about the duration between onset of treatment and incidence of pulmonary side effects, diagnosis, treatment options and outcome of patients were extracted and are presented here. conclusion this comprehensive systematic review hopes to improve the awareness about the serious and potentially life-threatening pulmonary sideeffects of this group of agents. confl ict of interest no. sj simpson , pd sly , p franklin , e lombardi , c calogero , m palumbo , gl hall , introduction the forced oscillation technique (fot) is effort independent and thus ideal for young children. the area under the reactance curve (ax) has been proposed to amplify clinically relevant signal by taking advantage of any shape change in the reactance (xrs) curve below the resonant frequency. this study aimed to develop reference values for resistance (rrs), xrs and ax in a large healthy population of children, and determine if ax conferred any additional clinical benefi t when examining disease in children born preterm. methods impedance spectra were obtained in healthy children ( male), aged less than years and with height less than cm using a commercial device (i m, chess medical, belgium). ax was calculated in of these children between hz and the resonant frequency. backwards stepwise linear regressions identifi ed the best predictors of ax, and xrs and rrs at hz (xrs , rrs ), and z scores were generated. z scores were calculated for children born preterm, of which received a neonatal diagnosis of bronchopulmonary dysplasia (bpd). chi squared tests examined the difference in proportion of children born preterm (with and without bpd) with abnormal z scores for each fot variable. results all fot variables were predicted by height (p < . ) and sex. mean (sd) z scores for preterm children with and without bpd for rrs ( . ( . ); . ( . )), xrs ( . ( . ); . ( . )) and ax ( . ( . ); . ( . )) were all signifi cantly different (p < . ) from the healthy population. the number of children born preterm with abnormal z scores was not significantly different when comparing ax, rrs and xrs . conclusions while ax is able to detect respiratory disease in preterm children with and without bpd, it is no more sensitive than xrs or rrs. supported by pmh foundation, nhmrc, asthma foundation wa, carivit, ngo 'solidarietà e servizio' viterbo. confl ict of interest no. introduction survivors of preterm birth born with bronchopulmonary dysplasia (bpd) in the pre-surfactant era of neonatal care (classical bpd) have a reduced pulmonary gas transfer capacity. there is, however, little data to describe gas transfer in preterm infants with bpd in the post-surfactant era (new bpd). objective assess gas transfer using carbon monoxide diffusing capacity (dl co ) and its components, pulmonary capillary blood volume (vc) and pulmonary membrane diffusion (d m ), in contemporary survivors of preterm birth. method gas transfer was assessed using single-breath dl co in children aged to years and born < weeks gestation with bpd (pb, n = ) and without bpd (pt, n = ), and in term born controls (tc, n = ). dl co z scores were calculated. d m and vc were determined in pb, pt and tc children. the mean (sd) dl co z score for the pb group was − . ( . ) differing signifi cantly from (p = . ) while the pt and tc groups ( . ( . ) and − . ( . ), respectively) did not (p > . ). d m was lower in the pb group than the pt and tc groups, with no difference between pt and tc groups. differences in d m were not signifi cant after adjusting for lung size. there were no differences in vc between groups. conclusion gas transfer is reduced in survivors of preterm birth with new bpd. the tendency for reduced d m and not vc in children with new bpd suggests that impaired gas transfer may be a result of alterations in the alveolar membrane rather than pulmonary vascular function. background bronchiectasis is common in indigenous populations such as alaska natives, australian aboriginal, and new zealand maori and pacifi ca. as part of an international collaborative interventional study, we sought the participation of maori and pacifi ca families -groups diffi cult to engage in research in the past. aim to engage, enrol and retain children from maori and pacifi ca families from auckland in a -year research study. methods a randomized controlled trial to determine whether azithromycin is superior to placebo in reducing exacerbations seeking to enrol children aged months to years with bronchiectasis. the enrolment procedure was modifi ed to a process deemed more appropriate to these cultures: ( ) request to defer the decision of enrolment until the process had been completed. ( ) a minimum of meetings; initial invitation, discussion in the home with the extended family, invitation to the extended family to participate in the day of enrolment. ( ) appointment of a 'whanau worker' (family worker) to sit with the family and empower them to get all the information they seek prior to enrolment. results of families approached, ( %) children (median age . years, range . - . years) enrolled with % samoan, % tongan, % maori and % mixed maori/pacifi ca heritage. after -year retention was ( %) with exiting the study after month with new non-pulmonary disease, and exiting after year, moving outside study area. conclusions these are high enrolment and retention fi gures reported in this population. we believe that following a prolonged procedure for enrolment, involving the extended family and appointing a worker to sit 'alongside' the family will improve their understanding of a research project and allow them to feel more comfortable about participating. aim bronchiolitis is the most common reason for hospital admission for infants globally ( ) . the use of macrolides for treating bronchiolitis in nonaffl uent settings remains controversial but potentially benefi cial. in our region readmission with lower respiratory illness in young children (particularly indigenous children) remains high. this rct aims to determine if a single dose of azithromycin reduces the morbidity of young children with bronchiolitis. methods double blinded rct. young children ≤ months admitted to royal darwin hospital (rdh) diagnosed with bronchiolitis are eligible. children are given a single dose ( mg/kg) of either azithromycin/placebo. primary outcome is length of stay for respiratory disease. secondary outcomes are duration of oxygen use and readmission for respiratory illness in -month period. respiratory viral infections often lead to exacerbations of chronic respiratory diseases such as asthma and copd though there is no similar data in noncystic fi brosis (cf) bronchiectasis. the objectives of our study were to ( ) determine the point prevalence and identify viruses associated with exacerbations and ( ) evaluate clinical and investigational differences between viral infection positive and negative exacerbations in children with non-cf bronchiectasis. methods a cohort of children (median age years; boys) with non-cf bronchiectasis was prospectively followed for child-months. polymerase chain reaction for respiratory viruses was performed on nasopharyngeal aspirates collected during paediatric pulmonologist defi ned exacerbations. data on clinical, parent cough-specifi c quality of life (pc-qol), systemic markers (crp, il , procalcitonin, amyloid-a, fi brinogen) and lung function parameters were also collected. results respiratory viruses were detected during ( %) exacerbations: picornavirus in episodes [human-rhinovirus (hrv) in , enterovirus in ]; human bocavirus in ; adenovirus, human meta-pneumovirus, infl uenza a, respiratory syncytial virus, parainfl uenza and in two each; coronavirus and parainfl uenza and in one each. viral co-detections occurred in ( %) exacerbations. among genotyped hrv's, more hrv-a's (n = ) were identifi ed than hrv-c's (n = ). children with proven viral infections were more likely to have fever (or . , % ci . - . ), wheeze and/or crackles (or . , % ci . - . ) and raised crp (or . , % ci . - . ) when compared with virus negative exacerbations. there were no other statistically signifi cant differences. conclusions respiratory viruses are commonly found during pulmonary exacerbations in children with non-cf bronchiectasis. hrv-a is the most frequently detected virus. time sequenced cohort studies during stable state, exacerbations and recovery periods are needed to determine the importance of viral infections and their possible interaction with bacteria. supported by anz trustees scholarship. confl ict of interest none. nominations none. to date children enrolled, % rsv+ve. median age . months. fifty percent have had at least one co-morbidity. readmission rate = %. conclusion co-morbidities are high in this population. antibiotics have the potential to help reduce the impact of additional respiratory burden. foundation. introduction foreign body inhalation is a relatively common presentation in young children, especially less than years of age. early recognition remains a critical factor in the treatment of foreign body inhalation in children. inhaled foreign bodies in children are most often organic material, with seeds and peanuts being the most common items. on review of the literature, there are very few case reports of inhaled metal screws. we report two unusual cases of inhaled metal screws that presented to our service. case presentation both cases presented to our emergency department with wheeze, respiratory distress and fever. foreign body inhalation was not considered as a cause for their symptoms until the object was identifi ed on chest x-ray. both foreign bodies were removed successfully but one child required invasive ventilation in our intensive care unit post removal. both children made a full recovery. interestingly, both metal screws came from fl at pack furniture purchased from a well known international home products store. conclusion foreign body inhalation must always be considered as a cause of respiratory distress in a child. with the increase in the number of fl at pack furniture in australian home's, we believe parents must be warned of the potential danger of loose metal screws to young children. supported by none. cough in children is a common symptom. data on causes of chronic cough in young children have previously been published by our units. however, differences in underlying diagnosis by age at presentation have not been assessed. we present the 'time to cessation' of cough in our multicentre rct using a standardized management algorithm in newly referred children with chronic cough (> weeks) from australian centres. methods parents completed validated cough diary and cough specifi c qol (pc-qol) at recruitment and at cessation of cough. the diagnosis made by the treating physician was based on tsanz position statement. results the median (range) age of the children recruited was . years ( . - . ); ( %) were boys. median (iqr) pc-qol post treatment of . ( . , . ) improved signifi cantly (p = . ) from . ( . , . ) at enrolment. the median (iqr) duration of cough at recruitment was weeks ( . , . ) and 'time to cessation' of cough after application of the management algorithm was weeks ( . , . ). there was no signifi cant difference (p = . ) in median (iqr) 'time to cessation' of cough among the three age cohorts: < years (n = , . %) was . weeks ( . , . ); - years (n = , . %) was weeks ( . , . ); and > years (n = , . %) was weeks ( . , . ). there was also no signifi cant difference in the fi nal primary diagnosis among the three age cohorts (p = . ). the most common diagnoses were protracted bacterial bronchitis (n = , %), asthma/reactive airways disease (n = , . %), tracheobronchomalacia (n = , . %) and bronchiectasis (n = , . %). children ( . %) had more than one diagnosis. conclusions the aetiology and 'time to cessation' of chronic cough in children managed in accordance to a standardized pathway were similar among the three age groups. it is likely that our previous fi ndings in very young children are also applicable to older children. supported by nhmrc grant number . confl ict of interest none. aim to determine the role of fl exible bronchoscopy with bronchial alveolar lavage (bal) in the management of patients with febrile neutropenia. methods a retrospective analysis was made of the number of patients admitted with febrile neutropenia at a single institution who underwent bronchoscopy plus bal from years to . computer database plus patient case notes were reviewed to establish clinical symptoms and signs, radiological fi ndings, antimicrobial treatment and mean duration to bronchoscopy following admission. results a total of episodes of febrile neutropenia were recorded years to . seven patients ( males and females) were referred for bronchoscopy plus bal. the mean age was . years (age range - years) and all had been diagnosed with acute lymphoblastic leukemia. all patients had at least cough as a clinical symptom along with radiological fi ndings. all patients had been on broad spectrum antibiotics at the time of bronchoscopy. the mean duration from admission to time of bronchoscopy was hours ( days) with a standard deviation of hours. of the seven patients one patient yielded a positive result on bal. this did not result in a change in management as the patient improved clinically before the result of the bal was confi rmed. conclusion in this retrospective case series the diagnostic yield of fl exible bronchoscopy plus bal in children with febrile neutropenia was low. prospective studies plus early timing towards bronchoscopy and bal should be conducted to further defi ne its role in the management of febrile neutropenic patients. confl ict of interest nil. methods prospective cohort study involving monthly follow-up with caregivers. two years post enrolment, children undergo clinical and lung function assessment (fot). presence of bronchiectasis is determined by physician review and radiological confi rmation (when indicated). the frequency of pbb episodes is recorded over the study period. of children recruited to the cohort study to date, % ( / ) were male. the median age at recruitment was months (iqr , ). % of children had recurrent pbb. of the children who have had -year clinical follow-up, were able to perform fot and % ( / ) showed abnormalities (reactance above normal range.) % ( / ) with pbb have had subsequent physician diagnosis of bronchiectasis or csld. conclusion the burden of cough in children with pbb years after diagnosis remains high. ongoing clinical follow-up of this cohort of children with pbb should provide further insight into the likelihood of progression from pbb to csld and bronchiectasis. support financial markets foundation for children (for project), allen & hanburys and qcmri (for dw), nhmrc (for ju and ac). introduction national streptococcus pneumoniae (sp) serotype surveillance reports only culture positive cases from sterile sites but the yield from culture is low. polymerase chain reaction (pcr) is more sensitive in detecting sp in culture negative samples. aim to determine whether enhanced molecular surveillance in childhood empyema provides additional sp serotype information compared to national surveillance methods. methods pleural fl uid from children with empyema underwent culture and pcr to identify sp-targeting autolysin (lyta) and multiplex pcr to identify sp serotypes. national surveillance data were obtained from the national notifiable diseases surveillance system (nndss) for the same time period and age groups. results empyema: children, male, median age . (range . - . ) were recruited from april for months. sp was cultured in / ( . %) in blood and / ( . %) in pleural fl uid. sp was identifi ed by pcr in / ( . %). serotypes: , n = ( . %); , n = ( . %); a, n = ( . %); f a, n = ( . %); v/ a, n = ( . %); f/ a, n = ( . %); non-typeable, n = ( . %). one subject had serotypes and in a serotype could not be established. nndss: sp culture positive cases were reported. serotypes: , n = ( . %); , n = ( . %); a, n = ( . %); f a, n = ( . %); v/ a, n = ( . %); f/ a, n = ( . %); non-typeable, n = ( . %). other serotypes were reported in sp positive cases. signifi cant differences between empyema and nsdss data were identifi ed for serotypes (p < . ) and (p < . ). conclusions the proportion of serotypes and were signifi cantly higher in empyema fl uid using pcr. this disease model provides additional serotype information to national surveillance data. this has important implications in monitoring replacement serotypes following the introduction of new vaccines. funded by glaxosmithkline, belgium. h giddings , l seccombe , p rogers , a corbett , e veitch recent theories on the pathophysiology of parkinson's disease (pd) emphasize early brainstem involvement. furthermore various respiratory function abnormalities have been reported without consistent pattern. we sought to study the effects of idiopathic pd on respiratory function and ventilatory response to hypercapnoea and hypoxia. methods patients with a diagnosis of pd but no known respiratory disease were recruited. subjects underwent lung function testing including respiratory muscle strength, ventilatory response to hypercapnoea (with central respiratory drive (p )) and a hypoxic simulation (fio % cough is the most common symptom presenting to doctors. paediatric cough is associated with signifi cant morbidity for both children and their parents. the symptom of cough is associated with airway hyper-reactivity and is a dominant symptom of airway infl ammation. inhaled corticosteroids (ics) can reduce airway infl ammation and hyper-reactivity. the objective of this review was to evaluate evidence for the effi cacy of ics in reducing the severity of cough in children with sub-acute cough (defi ned as cough duration of - weeks). methods search was conducted by the cochrane airways group using cochrane methodology. all randomized controlled trials (rcts) comparing ics with a control group for treatment of sub-acute cough in children were considered for inclusion. search results were analysed using pre-determined criteria for inclusion. results two studies were eligible for inclusion in the review, however there were limitations in that the participants of both these studies were infants, post acute bronchiolitis illness, and cough duration at start of study treatment was ill-defi ned. children were included in the meta-analysis. there was no signifi cant difference between groups in proportion of children 'not cured' (primary outcome measure), with a pooled or of . ( % ci . , . ) (using intention to treat analysis). conclusions there is currently no evidence to support the use of ics in sub-acute cough in children. however, this systematic review is limited by the small number of studies available for analysis and the quality and design of these studies. further well-designed rcts are required to support or refute the effi cacy of treatment with ics in children with sub-acute cough. once obstructive sleep apnoea (osa) is diagnosed, a cpap implementation sleep study is traditionally performed to determine the pressure required to control the upper airway. however, since modern cpap machines store sophisticated control data we reasoned it may equally be possible to commence cpap via a 'best guess' iterative approach without compromising osa control or compliance. aim to compare the outcomes at months of patients commencing cpap after best guess with those commencing cpap after a cpap implementation sleep study. methods we retrospectively reviewed the records of all patients referred by respiratory physicians to our cpap clinic between march and march , and the two methods of starting cpap were compared. data collected included age, sex, bmi, respiratory disturbance index (rdi), cpap pressure commenced, fi nal pressure at months, cpap usage data and cpap clinic contacts. results patients were identifi ed, aged ± years, %male, bmi . ± . , with severe osa, rdi ± . commenced cpap via best guess and after a cpap sleep study. the starting pressures in both groups were similar, . ± . versus . ± . cmh o. in those patients continuing to use cpap at months, there were no differences between the groups for fi nal pressure, numbers of patients changing pressure, control of osa with cpap, and hours cpap used per day. in the best guess group however, signifi cantly more patients were continuing to use cpap at months, % versus % (p = . ). conclusion this study demonstrates that it may no longer be necessary to perform cpap implementation sleep studies routinely and this will save hospital bed days. confl ict of interest nil. six required intubation and the rest were managed with non-invasive ventilation in icu. the average length of stay in icu was . days. polysomnographic data will be described. conclusions obesity hypoventilation as a cause of respiratory failure is likely to increase in frequency as the incidence of obesity increases. increased awareness by the lay public, as well as clinical suspicion and recognition of the condition by all clinicians at an earlier stage, is likely to prevent progression to the point of needing intensive care. it is hoped that this case series may provide a springboard for further study into why these patients presented at such a late stage of their disease process. supported by none. confl ict of interest none. although sa and sleepiness often co-exist, the commonest cause of sleepiness in a general community is depression, with sa being the th most common cause. in order to assist recognition of depression in a snoring population attending a sleep clinic, we introduced a simple two question 'beyond blue questionnaire(bbq)' into our routine assessment. aims to ( ) background indices of ventilation distribution in diffusion (s acin ) and convection (s cond ) dependent airways derived from multiple breath nitrogen washout (mbnw) may vary between interpreters because of differences in calculation of phase iii slopes (Δphase iii ). aims to compare s cond and s acin results of interpreters from a single mbnw in copd subjects. methods subjects with copd underwent mbnw. three washouts were analysed independently by experienced and novice interpreters using custom software for automated breath identifi cation. Δphase iii was fi tted automatically by least squares fi t between predetermined points, and then adjusted manually. s cond was the linear slope of Δphase iii plotted against lung turnover (cumulative expired volume/frc), between turnovers . - . s acin was the Δphase iii of the fi rst breath minus the s cond component. differences expressed as icc and cov, were examined by repeated measures anova. results mean ± sd age was ± years. fev was ± % predicted. s cond was greater while s acin was lower from the experienced introduction β-blockers may cause bronchoconstriction and mask the effect of β -adrenergic agonists. this has implications for the interpretation of routine diagnostic spirometry and bronchodilator response. this study examined this issue in a routine lung function laboratory, and whether it applied to both cardio-selective (c) and non-selective (nc) preparations. method all patients attending the lung function laboratory, royal adelaide hospital over a -month period were asked whether they were currently taking a β-blocker and to identify the drug. spirometry results were analysed to assess airfl ow obstruction and reversibility. results patients completed the survey and patients ( %) were taking β -blockers. the table shows the results of the patients who could be assessed for reversibility in spirometry. of the patients in this group patients ( %) were taking (c) and ( %) (nc) agents. fifty-three patients were unsure whether they were taking a β -blocker. no signifi cant differences were found in the percentage of patients with airfl ow obstruction or reversibility between the groups. aim to examine patterns of adult lung function in terms of airfl ow obstruction, hyperinfl ation and/or reduced diffusing capacity (d l co). this can then be related to the life-time history of risk factors such as smoking, asthma and infections. methods using the population-based tasmanian longitudinal health study (tahs) cohort followed since , an asthma-enriched sub-sample was selected consisting of % ever with asthma, of whom half reported current asthma. measurement of spirometry, d l co (uncorrected for haemoglobin) and lung volumes was performed, then lung function data were analysed using the mean predicted values. airfl ow obstruction was defi ned as post-bronchodilator fev /fvc (post-b.d. fer) < . , hyperinfl ation as total lung capacity (tlc) > % predicted, and reduced d l co as < % predicted. aim to examine the gender-specifi c differences in adult spirometry, d l co and lung volumes, with a view to relating them to life-time respiratory risk factors. methods using the population-based tasmanian longitudinal health study (tahs) followed since , an asthma-enriched sub-sample was selected consisting of % ever with asthma, of whom half reported current asthma. measurement of spirometry, d l co (corrected for haemoglobin) and lung volumes were performed. data were analysed using the statistical upper and lower limits of normal of reference equations by nhanes iii, roca et al and quanjer et al. of the caucasian adults ( females), % completed all tests. mean age . years (range - ). elevated rates of airfl ow obstruction and hyperinfl ation were seen. signifi cantly higher proportions of females than males had reduced d l co and d l co/v a (p < . ). only . % (n = ) of females had a low d l co with low fev /fvc ratio, and . % (n = ) had a reduced tlc overall. there were no signifi cant gender differences in v a , tlc, or ever and current active smoking. males and females averaged over kg more than the mediterranean adults described by roca et al., however weight is not relevant to d l co in males. conclusion a higher percentage of middle aged females have a reduced d l co and/or d l co /v a, compared to males, with an increased rate overall. grant support nhmrc, australian postgraduate association. d chapman , , , j kermode , , , n brown , , , n berend , , , g king , , , background during bronchoconstriction, a deep inspiration (di) dilates the airways, which then re-narrow once tidal breathing is resumed. re-narrowing occurs faster in asthmatic subjects and may be due reduced airway distensibility. aim to determine the association between baseline airway distensibility and the rate of re-narrowing after di. methods eleven asthmatic and fi ve non-asthmatic subjects had baseline airway distensibility measured by forced oscillation technique (fot). after methacholine challenge, respiratory system resistance (rrs) was measured during min of tidal breathing, followed by di to total lung capacity (tlc) and passive return to normal tidal breathing. dilatation was measured as the decrease in rrs between end tidal inspiration and tlc, and re-narrowing as end-expiratory rrs immediately after di, as per cent rrs at end-tidal expiration before the di. distensibility is presented as geometric mean ± %ci and re-narrowing as mean ± % ci. results airway distensibility was reduced in asthmatic compared to healthy subjects ( . s − .cmh o − ( . - . ) vs. . s − .cmh o − ( . - . ), p = . ). dilatation did not differ between groups (p = . ) but re-narrowing was increased in asthmatic compared to healthy subjects ( ± % vs. ± %, p = . ). airway distensibility did not correlate with airway re-narrowing (r s = - . , p = . ). conclusion the increased re-narrowing after di in asthmatic subjects is not due to reduced baseline airway distensibility and may be due to increased shortening velocity of airway smooth muscle or reduced elastic recoil. supported by the nhmrc and the crc for asthma and airways. nomination nil. confl ict of interest no. c ng , , , s jenkins , , , n cecins , , p eastwood , , aim to evaluate the measurement properties of two accelerometers: the activpal and the stepwatch activity monitor (sam) in people with copd. methods the activpal and sam were attached to the anterior right midthigh and the right ankle, respectively (as per device recommendations). each participant performed walking tasks; at a self-selected slow speed and at a self-selected normal speed. at each speed, one walk was performed with a -wheeled walker (ww) and the other without. results participants aged ( ) years (fev = ( ) % pred; males) completed the study. the slow and normal speeds were ( ) m·min − and ( ) m·min − , respectively. agreement between steps recorded by the sam with steps counted during observation did not differ with speed or ww use (p = . ). the mean difference was steps·min − and the limit of agreement (loa) was steps·min − . agreement between steps recorded by the activpal with steps counted was worse at slow speeds (mean difference steps·min − with loa of steps·min − ) compared with normal speeds (mean difference steps·min − with loa of steps·min - ) (p = . ), but was not affected by ww use. both accelerometers detected the small difference in walk speed irrespective of ww use (p < . ). conclusions neither the accuracy nor responsiveness of either accelerometer was affected by ww use. in contrast to the activpal, sam was accurate at both speeds and therefore can be used to detect steps in people who walk very slowly during daily life. breathing and sleep, heidelberg vic., eastern health, melbourne vic., northern health, epping vic., and monash university, clayton vic. aim to document the care and pathways patients with copd travel at three metropolitan health services. methods data were extracted from data sets for patients attending the emergency department of the three hospitals with a diagnosis of copd over year. the three hospitals included a city-based tertiary/quaternary hospital and two smaller community hospitals. analysis was completed on similarities and differences in admission and referral rates, average length of stay, and discharge destination, standardized by age, sex and mode of transport to the emergency department. results there were inpatient separations and emergency department presentations for patients with copd. discharge patterns related to the designated role of the hospital, with the community hospitals discharging to % of patients directly home and the more specialized city hospital discharging % to other hospitals and % home. there were signifi cant differences in the admission rates for category and patients among the hospitals. we found unexplained variation in the acute average lengths of stay of . , . and . days. conclusions the analysis confi rmed some expected patterns based on the type of hospital, but also identifi ed unexplained variation that suggests that factors other than patient characteristics may be contributing to the variation in care pathways. aims to: ( ) determine which tests of exercise capacity relate to average daily energy expenditure (dee) and; ( ) quantify the intensity at which activities of daily living (adl) are undertaken in people with chronic obstructive pulmonary disease (copd). methods a study was undertaken in subjects with stable copd (mean, sd) aged ( ) years with an fev of ( ) % predicted ( males). measures were collected of distance walked during the six-minute walk test ( mwd) and incremental shuttle walk test (iswd) and peak rate of oxygen uptake during a cycle ergometry test (vo peak ). the sensewear armband® was worn during the waking hours for . ( . ) days to measure dee. the intensity at which activities of daily living were undertaken was expressed as a percentage of vo peak . results dee was associated with mwd (r = . ; p = . ), iswd (r = . ; p = . ) but not vo peak (r = . ; p = . ). stronger associations were observed between dee and the body weight-walking product for mwd (r = . ; p < . ) and iswd (r = . ; p < . ). the average intensity of adl was equal to ( %) of vo peak (range to %). conclusions mwd and iswd, but not vo peak were related to dee. as adl were performed at a high percentage of vo peak it may be more realistic to increase dee by increasing the frequency or duration, rather than the intensity of physical activity. in patients with copd, two mwts are recommended prior to commencing a pulmonary rehabilitation program (prp) to allow for a learning effect. aim to determine the characteristics of patients with copd in whom -minute walk distance ( mwd) did not increase on a second test. methods patients ( males) with stable copd (aged , to years) naïve to the mwt performed two tests ( minutes apart) prior to commencing a prp. patients were categorized according to their change in mwd with test repetition. results mwd was the same or decreased on the second test in patients ( %) (table) . in the remaining patients ( %), mwd increased by m ( %) ( % ci to m, to %). logistic regression analysis identifi ed fev (l) as the only signifi cant variable (p < . ) that predicted the absence of a learning effect in mwd with test repetition. conclusions some patients with severe copd may not require a practice mwt to achieve their maximum performance at a prp baseline assessment. ( ) years, with stable ipf were evaluated in this study. demographic data and measures of pulmonary function (spirometry, diffusing capacity for carbon monoxide, (dl co )), dyspnoea (baseline dyspnoea index, bdi), peripheral muscle force (isometric quadriceps force (qf) and handgrip force (hf)), functional exercise capacity ( -minute walk distance, mwd), limitation in daily activities (activities of daily living (adl) score), and health status (sf- ) were assessed. relationships between mwd and mrc grade, pulmonary function, qf, bdi and adl score were examined. results the number of subjects in mrc grades , , and was ( %), ( %), ( %) and ( %), respectively. pulmonary function, bdi, qf, hf, mwd, adl score, and sf- decreased signifi cantly with increasing mrc grade (all p < . ). moderate to strong correlations were found between mwd and mrc grade (r = − . ), dl co (r = . ), qf (r = . ), bdi (r = . ) and adl score (r = . ) (all p < . ). conclusions these fi ndings suggest that the mrc dyspnoea scale can be used to discriminate and classify subjects with ipf according to the severity of impairment and disability. ( ) year (mean, sd) completed two assessment sessions on separate days. on one day, they exercised twice to symptom limitation (tlim) on a treadmill. on the other day, they exercised twice to tlim on a cycle ergometer. the order of exercise modality was randomized between days. on both days, the only difference between the exercise tests was that bipap, titrated to patient comfort, was used during the second test. measures were made of; ) tlim and, ( ) the difference in dyspnoea, using borg scores, at tlim during the fi rst test and the equivalent exercise time during the second test (i.e. iso-time). results bipap increased tlim on the treadmill ( ( ) seconds; p = . ) but not the bike ( ( ) seconds; p = . ). the reduction in dyspnoea at iso-time on the treadmill and bike was similar being, ( ) and ( ), respectively (p = . ). conclusions bipap may confer greater benefi t in exercise tolerance exercising on a treadmill compared with a cycle ergometer in patients awaiting lung or heart-lung transplant. infection with rhinovirus (rv) is known to trigger acute exacerbations in subjects with asthma and these subjects also have increased susceptibility to the effects of rv. the mechanisms remain poorly understood, but appear to involve a host innate immune defect in the airway epithelium. aim we sought to determine in bronchial epithelial cells (becs) if oxidative stress in the form of exposure to cigarette smoke extract (cse), hydrogen peroxide (h o ) and eosinophil peroxidise (epo) results in impaired mitochondrial function and if this directly impairs signalling of rv infection through mda and alters the release of type i and type iii interferons (ifns). methods pbecs were grown to confl uence. cells were then exposed to cse ( %, no fi lter) or h o ( . mm) or epo. cells were then infected with rv -b (moi = ). virus replication was measured by cell titration assay. following infection, il- , cxcl- , cxcl- was measured using cytometric bead array and fl ow cytometry. supernatants and whole cell lysates were collected for ifn-β, bax and mda detection by western blot. ifn-λ and cytochrome-c was measured using conventional elisa. cell viability was assessed by annexin v-pe staining and fl ow cytometry. results rv infection alone induced cxcl- , il- , cxcl- and ifn-λ. pbecs treated with each of the oxidative stressors had increased cytochromec release and increased apoptosis. this mitochondrial dysfunction led to degradation of mda expression and resulted in specifi c suppression of cxcl- and ifn-λ. conclusions exposure of becs to an oxidative stress results in mitochondrial dysfunction in airway epithelial cells. this leads to defective antiviral signalling in the airway epithelium after infection with rv. introduction pleural infection is associated with high morbidity. prompt drainage is key, but pus is often loculated and thick making drainage diffi cult. based on promising animal studies, we hypothesize that intrapleural therapy with t-pa and dnase, which lyse adhesions and reduce fl uid viscosity respectively, can signifi cantly improve pus evacuation in pleural infection. methods consecutive patients with pleural infection were treated with standard antibiotics and intercostal chest tube (ict) drainage. additionally, t-pa mg and dnase mg (each in ml of . % nacl) were instilled intrapleurally via an ict twice daily for up to six doses. the ict was clamped for minutes after each instillation. patients were followed clinically and with serial cxr. opacity from pleural effusion was quantifi ed on chest radiographs. results eleven patients ( male; mean age ) were treated. nine effusions were associated with community acquired pneumonia, of these, eight were visibly purulent, fi ve were culture positive and the mean fl uid ph was . (range . - . ). ten patients ( %) were successfully managed conservatively and one patient required surgery. median hospital stay from fi rst intrapleural treatment dose to discharge was days (range - ). the median amount of fl uid drained in the hours preceding t-pa/dnase treatment was ml (range - ), and improved signifi cantly to ml (range - ) following two doses of treatment. this was paralleled by a signifi cant reduction in radiographic opacity by a mean value of % of the hemithorax (range - %). four patients showed an initial rise in crp following t-pa/dnase, but all patients had resolution of sepsis and signifi cant reduction in crp. there were no major complications. pleuritic chest pain requiring opioid analgesia developed in three patients. methods clinical data were collected using a standardized form for aboriginal children aged days -< months hospitalized with alri and enrolled in a rct of vitamin a/zinc supplementation were matched with data collected during a population-based study of who-defi ned primary endpoint pneumonia (who-p). sensitivities, specifi cities, positive and negative predictive values (ppv, npv) for these signs were compared between who-p cases and lobar pneumonia assigned by a respiratory paediatrician. in episodes of hospitalized alri, who-p was diagnosed in ( . %); the respiratory paediatrician classifi ed ( . %) as lobar pneumonia. the sensitivities of clinical signs ranged from a high of % for tachypnoea to % for fever + tachypnoea + chest-indrawing; the ppv range was % to %, respectively. higher ppvs were observed against the paediatric respiratory physicians diagnosis compared to who-p. conclusions clinical signs on admission are not useful in predicting who-p in this population, presenting challenges for future pneumonia research in this population. who-p may underestimate alveolar consolidation in a clinical context and its use in clinical practice or in research designed to inform clinical management in this population should be avoided. the incidence of tb in the non-indigenous australian population is uncommon at . cases per population . in this paper, we report three cases of pulmonary tuberculosis in young australian born, non-indigenous adults in the hunter new england area where marijuana possibly was a signifi cant risk factor in transmission and severity of disease. all three cases had severe cavitating disease at time of presentation. contact tracing from the fi rst case, a regular heavy marijuana user, identifi ed mantoux positive contacts, one of whom developed active pulmonary tuberculosis. all contacts, mainly young adult males, denied sharing marijuana with the index case. contact tracing from the second case identifi ed mantoux positive contacts, of whom use marijuana regularly and shared bongs (water pipes) with the index case. there were positive mantoux contacts of the third case, one of whom shared bongs with the index case. health professionals need to remain aware of the possibility of tuberculosis in groups with historically low incidence rates. marijuana bong smoking is possibly associated with transmission and severity of tuberculosis . introduction in , these previously well women survived and made a good recovery from severe pneumonia and acute lung injury after retrieval on ecmo. streptococcus pyogenes is an unusual cause of pneumonia in adults. case a -year-old veterinarian with a history of mild asthma presented with days of fever and respiratory symptoms. the diagnosis was confi rmed by a fourfold rise in the anti-streptococcal antibody. this was complicated by respiratory failure, septic shock, acute renal failure, severe pulmonary hypertension and bilateral parapneumonic effusions. despite maximal interventions she deteriorated. femoral venous-venous ecmo was initiated on day at the calvary mater hospital in newcastle by a retrieval team from royal prince alfred hospital (rpa), sydney. she was transferred kms on ecmo in a large multipurpose ambulance. she developed lung abscesses and recurrent pneumothoraces and she required a pleurodesis. she required days of ventilation and days of ecmo. three months later she was asymptomatic, with mildly restrictive spirometry and minor cxr change. case a -year-old offi ce worker with s pyogenes bacteraemia made a similar presentation to our institution. she was ventilated for days, ecmo was initiated by the retrieval team and continued for days. three months later she was asymptomatic with a normal cxr and pulmonary function tests. introduction the urinary pneumococcal antigen (upa) test has been shown to have superior sensitivity to other investigations in determining the aetiology of community-acquired pneumonia (cap), but there is very limited data on its performance in local populations. the aims of this study are to establish the prevalence of positive upa testing in patients admitted to hospital with cap, and determine its utility. secondary aims are to identify associations with positive testing, as well as to determine if a positive test infl uences clinical outcomes. methods the study is a prospective, single-centre study that is still recruiting. adult patients are included upon admission to hospital if they have the diagnosis of cap, as defi ned by new infi ltrates on chest radiograph along with consistent clinical features. clinical data including curb- score of severity, current and prior antibiotics, co-morbidities, mortality and length of hospital stay are recorded. results preliminary results show a positive test prevalence of / ( . %, % ci . - . %) amongst patients admitted with cap. overall prevalence of pneumococcal pneumonia is / ( . %, ci . - . %). patients with a positive upa result have a higher mean curb- score of . compared with . in those with a negative result (p = . ). . % of patients with a positive result were admitted to the intensive care unit, compared with . % those with a negative result (p = . ). conclusions the overall prevalence of positive upa testing in patients admitted to hospital with cap is low. preliminary data suggests that patients with positive results are more likely to have greater severity pneumonia and to require intensive care support. comparative data on length of stay, mortality, previous antibiotic use and specifi c co-morbidities has not revealed any statistically signifi cant differences between positive and negative groups. confl ict of interests no. s herath , c lewis , m nisbet , respiratory department, auckland city hospital, auckland, new zealand, and infectious diseases department, auckland city hospital, auckland, new zealand rhodococcus equi (r. equi), previously known as corynebacterium equi is a gram positive bacillus that is found in soil and causes infection in grazing livestock. it is infrequently isolated from clinical specimens. it is usually associated with human disease in immunocompromised patients and is an uncommon cause of infection in immunocompetent patients. infection is usually acquired by the airborne route with pneumonia being the most common manifestation but it can also be acquired orally or by direct inoculation. we present a case of pneumonia caused by r. equi infection in a year old male builder who presented with cough, dyspnoea and night sweats. r. equi was cultured from a transbronchial aspirate from a subcarinal lymph node. despite extensive investigation, no contributing host immune defect was identifi ed. the patient recovered after three months of antibiotic treatment, initially with intravenous vancomycin and meropenem followed by oral clarithromycin and rifampicin. although infections due to r. equi have been increasingly reported in immunocompromised patients, since there have only been cases described in patients where no associated host immune defect was reported. in this cohort, the median age at presentation was years (range - ) and ( %) patients were male. ten ( %) of these cases had pulmonary infection. two ( %) patients died and the remainder were successfully treated with prolonged antibiotics. r. equi is an uncommon cause of infection in humans and rarely occurs in patients where a host immune defect cannot be identifi ed. introduction recognition of pulmonary involvement in extra pulmonary tuberculosis (ep-tb) may be an important public health issue, as it has been estimated that patients with smear negative pulmonary tb (ptb) are responsible for % of new infections. usually, all patients with ep-tb have a chest x-ray but sputum cultures are requested only if there is an abnormality. methods in this retrospective clinical audit, we aimed to evaluate the percentage of ep-tb patients with ptb despite a normal chest x ray (cxr), and to explore any clinical characteristics of this group. clinical notes, microbiology and cxr reports were reviewed from consecutive patients presenting with ep-tb between and . results of patients with ep-tb, % were male and the mean age was (range to ). most patients were of asian ethnicity (n = , %). the commonest presentation of ep-tb was lymphadenopathy (n = , %), followed by pleural (n = %) and bone (n = , . %) disease. ep-tb was diagnosed by biopsy/excision of the ep site in the majority (n = , . %), and by sputum testing alone in ( . %). sputum cultures were performed in n = , ( %) overall, with n = ( %) being positive. there was higher infl ammatory markers in the sputum culture positive group (esr . vs. . , p = . and crp . vs. . , p = . ). the majority had cxr abnormalities (n = , %). in the group with normal cxr (n = ), ( %) had sputum cultures performed. of these, were culture positive and of these also + smear positive ( on immunosuppression, with cough). conclusion a small number of patients with ep-tb and normal cxr had pulmonary tb, of whom were smear positive. thus, induced sputum testing should be considered in patients with ep-tb even if cxr is normal. this may aid diagnosis and determine infectivity. ntm are normal inhabitants of environmental reservoirs including water. disease due to ntm has been increasing in qld. aim to document the presence of ntm in potable water in brisbane, to compare the species isolated during summer and winter and to relate this to the geographic distribution of patients with ntm. methods water samples ( l) were collected from routine collection sites in winter and sites in summer . samples were processed in triplicate as previously described. h subcultures were taken from positive specimens, dna extracted, followed by s rrna sequencing. patient addresses were obtained from the qld tb control centre database. aim to gauge the full impact of pandemic h n infl uenza across demographic groups in the northern territory, particularly indigenous and remoteliving individuals. methods we performed two cross-sectional serological surveys on specimens from residents of the northern territory, with specimens obtained from january to may (pre-pandemic) and specimens from september (post-pandemic). specimens were selected from among serum tubes collected from ambulatory outpatients. antibody titres were measured by haemagglutination inhibition against the a/california/ / reference virus. all specimens had available data for gender, age, and address, with indigenous status determined in . % of cases. results protective antibody levels, defi ned as a titre of or greater, were present in . % of pre-pandemic specimens and . % of post-pandemic specimens. the pre-pandemic proportion immune was greater with increasing age, but did not differ by other demographic characteristics. the post-pandemic proportion immune was greater among aboriginal and torres strait islanders and in younger age groups, but did not differ by gender or socio-economic index for area. however, the proportion immune was geographically heterogeneous, particularly among remote-living and indigenous groups. the northern territory-wide attack rate adjusted to age, region and indigenous status was . %. conclusions pandemic infl uenza disproportionately affected children and indigenous australians in the northern territory in . the proportion of specimens demonstrating post-pandemic immunity was particularly variable among indigenous and remote-living individuals. the kormp found asymptomatic aboriginal children (ac) had more hrv than asymptomatic non-aboriginal children (non-ac) in a longitudinal communitybased cohort study where infants had nasopharyngeal aspirates (npa) collected regularly from birth to years of age. aim to compare the frequency of hrv groups in asymptomatic ac and non-ac in the kormp. methods npa positive for hrv (n = ) from the npa previously tested for respiratory viruses, had viral rna extracted and reverse transcribed. hrv was detected and typed using a two-step pcr of the hrv ' utr, followed by dna sequencing for typing. chi-square analyses were used. results hrv was detected and typed in npa (from children; ac and non-ac), could not be typed and were not positive for hrv. ac had more hrv in summer and autumn than non-ac and were more likely to be co-infected with at least / bacterial species identifi ed. hrva, b & c were found in . , . and . % of hrv detected. hrvb & c were increased in infants exposed than not exposed to tobacco smoke in utero (hrvb; . vs. . %, p = . and hrvc; . vs. . %, p = . ). of the npa, hrv-a was detected more often in npa from ac than non-ac ( . vs. . %, p = . ), particularly at - months of age (p = . ) and during summer (p < . ). hrvb was detected more often in npa from ac than non-ac in autumn (p < . ). hrvc was detected as often in ac as non-ac in each season except summer. aim to determine whether interferon-gamma release assay (igra) can be effectively used for diagnosis of latent tuberculosis infection in a remote location. methods subjects were enrolled from the darwin centre for disease control tuberculosis clinic and were eligible if a tuberculin skin test (tst) of mm or greater had been recorded for any indication. igras were performed using quantiferon®-tb gold whole blood in-tube assay according to manufacturer's instructions. specimens were incubated and centrifuged at the local laboratory before refrigeration for transport. interferon assay was performed at the reference laboratory, over km away. results igras were performed, with patients ( %) recording negative results, ( %) positive and only one result ( %) indeterminate. negative, and therefore discordant, test results were more common in bcg vaccinated individuals. this effect was not limited to those with tst results of - mm, but was seen primarily in those with results of mm and above. conclusions these results are broadly comparable to fi ndings for igra use in less remote settings. in particular, our low rate of indeterminate results suggests that igra testing is feasible at a remote site after local processing. this approach could be considered for use in the northern territory tuberculosis control program. inhaled medications form the mainstay of drug treatment for patients with airways disease. effectiveness of therapy is dependent on the appropriate selection and prescription of drug and device, correct supply and adherence to therapy with an effective technique. patients frequently admit to acute medical wards both with acute exacerbations and for other co-morbidities eg heart failure or pneumonia. inpatient episodes provide an opportunity to review inhaled therapy however anecdotally add to patient confusion and introduce complexity (rational or ad hoc changes to inhaled drug, device, strength, dose or frequency). aim identify prescribing accuracy and effectiveness of patients' inhaler technique. describe any discrepancies between inhaled therapy: ( ) used prior to admission, ( ) prescribed for inpatient use, ( ) available at the bedside and ( ) administered, prior to and after implementation of an inhaler prescribing and administration guide. methods a single day audit of all inpatients on general medical wards was conducted october (review of medication charts and inhalers in patients' bedside lockers, brief questioning and direct observation of patients' inhaler technique. results compared to post implement of the 'prescribing and administering inhalers' tool (audit in december ). results from ( %) patients had inhalers prescribed, (mean: . prescriptions per patient). % of prescriptions were accurate ( % patient had no errors). discrepancies between used prior to admission and inpatient prescriptions were found in ( %) patients while those between inpatient prescriptions and available at the bedside were found in %. self-administration ('s') was noted on medication charts of ( %) patients, of whom had an ineffective inhaler technique. / patients has a spacer at the bedside with a further r prescribed metered aerosol inhalers. post-intervention differences in prescribing, supply, administration and technique errors will be discussed. conclusions a combination of errors and prescription discrepancies reduce the effectiveness of inhaled therapy for inpatients. confl ict of interest no. males (n (%) % ci) females (n (%) % ci) adm and bed days bmi, body mass index hrqol, health related quality of life chronic respiratory disease questionnaire; adm, admissions, mean (sd) uberculosis notifi cations in australia a cluster of tuberculosis associated with use of a marijuana water pipe the prince charles hospital foundation cc dobler , , gb marks , woolcock institute of medical research, the university of sydney, nsw, and department of respiratory medicine, liverpool hospital, sydney, nsw aim to determine the incidence rate and nature of adverse events in patients taking treatment for latent tuberculosis infection (ltbi). methods records of all patients who received treatment for ltbi at the chest clinic of a large tertiary hospital between / and / were reviewed. an adverse event was defi ned as any change in health status or side effect that led to treatment interruption or cessation. liver function tests were not performed routinely during follow-up, except when the patient was considered to be at an increased risk of developing hepatitis. results of patients in whom treatment for ltbi was initiated ( %) received isoniazid for months, ( %) received a combination of isoniazid and rifampicin for months, and the remainder were treated with different regimens. their mean (sd) age was ( ) years and % were male. nineteen patients ( . %) experienced an adverse event. seven patients developed a rash, four had lethargy and/or mood disorders, three had subclinical hepatitis, four experienced severe nausea, vomiting and/or other gastrointestinal symptoms and three had features of peripheral neuropathy. in eight patients who experienced an adverse event medication was temporarily ceased and then re-started without change; in four the treatment regimen was changed; and in seven the treatment was ceased completely. the risk of adverse events was not signifi cantly related to age, sex, drug regimen (single drug versus combination therapy) or baseline transaminase levels. conclusions in this cohort almost in patients on treatment for ltbi experienced an adverse event. although the adverse events were generally mild to moderate, this risk has to be taken into account when deciding whether to advise treatment for ltbi. introduction human rhinovirus (hrv) is the commonest cause of asthma exacerbations in children. pernasal aspirate (pna) is the gold standard for microbiological sampling but is invasive and distressing for children. studies have showed that less invasive swabs may be just as effi cacious. aim to test the hypothesis that hrv detection is as effi cient using nasal fl ocked swabs or washes and more comfortable, compared with pna in children with respiratory illnesses. methods children were recruited on presentation to the emergency department with respiratory symptoms. pna was collected from one nostril of all children recruited and nasal fl ocked swab (n = ) or wash (n = ) collected from the other nostril alternately. subjects rated the comfort of each sampling method to (least to most). viral rna was extracted and reverse transcribed. a two-step pcr of the hrv ' utr was used for detection, followed by sequencing for typing. results to date, children ( % male, mean age of . years) had paired samples taken. of these children, % (n = ) presented with a diagnosis of viral induced wheeze and % (n = ) had a hrv positive sample. compared with pnas, nasal fl ocked swabs were % ( of pna positive) effective in detecting hrv, whilst nasal washes showed % ( of pna positive) effi cacy. of the successfully typed samples, had hrva and had hrvc. nasal washes had a better comfort rating (mean . , n = ) than fl ocked swabs (mean . , n = ) and pnas (mean . , n = ). conclusion our fi ndings suggest that whilst nasal fl ocked swabs are an effective sampling method for hrv detection, nasal washes were more effective, being as effective as pnas and were the most comfortable. support nhmrc, pmh foundation. nomination nil. aim to describe the inpatients treated by a dedicated niv service. methods a retrospective audit of inpatients treated by the alfred niv service between january and june . the defi nition of niv included patients treated with cpap and bilevel positive pressure ventilation. results patients (age: ± years (mean ± sd), gender: % male) were treated with niv on occasions (repeat admissions patients). commonest indications for niv were osa (n = , %), acute exacerbations (ae) of copd (n = , %), acute cardiogenic pulmonary oedema (acpo) (n = , %) and post-lung transplantation (n = , %). treatment was delivered primarily in the respiratory ward (n = , %), cardiac ward (n = , %), icu (n = , %) and general medical ward (n = , %). episodes of cpap (mean pressure ± cmh o), osa and acpo made up % of those treated. seventy-two episodes of bilevel pap (mean ipap ± cmh o and epap ± cmh o), aecopd and weaning post-mechanical ventilation made up % of those treated. outcome data was available in a subgroup of patients with acpo (n = ) andaecopd (n = ). in the acpo group, patients ( %) improved and niv was ceased. three patients ( %) deteriorated and were intubated and patients ( %) were palliated. in the aecopd group, patients ( %) improved andniv was ceased or they were discharged on therapy. patients either deteriorated on niv or could not tolerate therapy, of these ( %) continued ward management and ( %) were palliated. conclusion the alfred niv service model has managed a large number of referrals across a range of diseases in a variety of wards. this is likely to have reduced demand on icu, hdu and respiratory ward beds. compared to the published literature, theoutcomes for acpo are worse than expected but comparable for aecopd. this may be explained by local referral patterns for acpo. we believe that our service model provides a viable means of administering niv to an ever expanding referral base. transitional & community service, the university of south australia, adelaide, sa , the university of adelaide, adelaide, sa, , the mary potter hospice, north adelaide, sa, , thoracic medicine, the royal adelaide hospital, adelaide, sa, , the royal district nursing service, wayville, sa , and the palliative care council of sa eastwood, sa introduction: the adelaide health service is in the process of developing a new and innovative model of copd community based care. a number of initiatives have informed this development including a recent research project examining the experiences of participants with end stage copd and their carers. a growing body of evidence indicates the importance of a palliative approach, however this often takes the form of referral to a palliative care service rather than a broader application of palliative principles in both specialist and primary care. methods: fifteen participants were interviewed twice at monthly intervals to explore their needs and the services they accessed. a series of focus groups with key service providers in sa was also undertaken. data were analysed to identify how hospital, specialist palliative care units and primary care services currently interface to meet identifi ed patient and carer needs. results: the current service model is episodic and reactive with services activated through the acute care system. our research has shown that, as copd advances, current models of care do not address the importance of supporting quality of life (including a focus on adls) and carers in their ongoing role. also emphasised was the lack of co-ordination of care, collaboration between service providers and communication -the basics of chronic disease management. conclusions the outcomes of this study will inform the development of a proactive, multidisciplinary model of care which is no longer reliant on tertiary care, but places primary care at the centre of the model. greater collaboration between respiratory, palliative and primary care services will provide an integrated approach, focusing on the needs of the patient and carer. aim long term conditions are prevalent in south auckland and impact on the individual, the community and the health system. as nurses living within this community, and employed by counties manakau district health board, our aim was to explore funding opportunities available through the pacifi c health team. lotumoui was established to improve health outcomes/behaviours for pacifi c populations. the church we attend has wide cultural diversity and had no knowledge of the programme and the support provided to make healthy changes within our community. methods firstly a health committee was formed within the church, having 'sold' our vision to the parish council. we launched the group by undertaking free blood pressure checks, followed by a 'walk the talk' project for the days leading into easter. baseline observations were taken and pedometers issued. results the parishioners who attend regular exercise sessions are reporting improved quality of life, exercise tolerance and reducing waist lines. bp parameters are also reducing. conclusions a dedicated health committee within a parish community, supported by the district health board can impact on changes in lifestyle by simple interventions. the investment by the pacifi c team will reap benefi ts for the individual and the health sector. confl ict of interest no. key: cord- -i e uj s authors: heffner, john e; highland, kristin b title: chronic obstructive pulmonary disease in geriatric critical care date: - - journal: crit care clin doi: . /s - ( ) -x sha: doc_id: cord_uid: i e uj s copd is a progressive disorder that is punctuated in its later stages with acute exacerbations that present a risk for respiratory failure. copd has a disproportionate impact on older patients. in the icu, therapy is directed toward unloading fatigued respiratory muscles, treating airway infection, and prescribing bronchodilatory drugs. most patients survive hospitalization in the icu for an episode of respiratory failure. the severity of the underlying lung disease, however, underlies the poor outcomes of patients in terms of postdischarge survival and quality of life. worldwide impact, predicted to become the fifth leading burden to world health by [ ] . copd now causes million deaths worldwide each year [ ] . the elderly are especially subject to the health effects of copd. copd is the primary or contributing diagnosis for more than % of hospitalizations of patients years of age [ ] . medicare health care expenditures are . times higher for elderly patients with copd compared with age-matched persons without this condition ($ , versus $ , ) [ ] . the mean per-person direct medical expenditures among persons with copd years of age is $ , in dollars [ ] . results from two large epidemiologic studies-the third national health and nutrition examination survey and the estudio epidemiolólico de la epoc en españa survey-note the highest copd occurrence rates in the elderly [ , ] . between % to % of current smokers in older age groups were noted to have symptomatic copd in these large population-based surveys [ , ] . because of recent trends in smoking habits, the prevalence of copd is higher in women than in men. the prevalence and societal impact of copd are predicted to increase. feenstra et al [ ] projected with a dynamic life-table model that loss of life years due to copd in the netherlands will increase by % in compared with the baseline year of . health care costs due to copd are predicted to increase by % over the same -year period. elderly patients with moderate to severe copd experience acute exacerbations of their airway disease, each of which presents a risk for acute respiratory failure. although definitions of acute exacerbations vary, recent consensus statements define exacerbations by the presence of one or more of the cardinal symptoms of increased dyspnea, increased sputum volume, and increased sputum purulence [ ] . using this definition, the severity of acute exacerbations is graded by the winnepeg criteria (box ) [ ] . an international working group of pulmonary physicians has recommended a more comprehensive definition of acute exacerbations. this group contends that the requirement for symptoms of bronchitis (cough and purulent sputum) underidentifies patients with acute exacerbations. their proposed definition of an exacerbation is ''a sustained worsening of the patient's condition, from the stable state and beyond normal day-to-day variations, that is acute in onset and necessitates a change in regular medication in a patient with underlying copd'' [ ] . the severity of acute exacerbations using this definition are graded by the level of health care used (see box ) [ ] . regardless of the definition used, elderly patients with advanced copd experience on average two to three acute exacerbations each year, with each episode lasting days [ ] . the pathophysiology of acute exacerbations of copd is incompletely understood, but increased concentrations of proinflammatory mediators and inflammatory cells in expectorated sputum, broncho-alveolar lavage samples, and tissue biopsied from the lung during exacerbations demonstrate the presence of inflammation within and surrounding airways [ - ] . during an acute exacerbation, this inflammation assumes characteristics of an allergic response increased eosinophils and upregulation of rantes (regulated upon activation, normal t-cell expressed and secreted) in the epithelium and subepithelium [ ] . common triggers for acute exacerbations of copd include airway infections [ ] , particulate air pollution [ ] , and environmental temperature changes [ ] , although up to % of patients have no clinically apparent etiologic factor [ ] . patients with acute exacerbations commonly have associated conditions such as congestive heart failure, pulmonary emboli, and extrapulmonary infections. bronchial infections are important causes of acute exacerbations with bacterial, atypical bacterial, and viral pathogens being the most commonly identified microbes (box ) [ ] . although the lower airway of patients with copd harbors a mixed flora of bacteria, airway inflammation and bacterial load increases during an acute exacerbation [ , ] these observations suggest that new or more virulent bacterial strains introduced into the airway population of colonized bacteria promote an inflammatory response that triggers acute exacerbations of box . criteria for grading the severity of an acute exacerbation of chronic bronchitis american college of chest physicians-american college of physicians/american society of internal medicine guidelines [ ] mild exacerbation: presence of any one of the cardinal symptoms of increased dyspnea, increased sputum volume, or increased sputum purulence with the addition of an upper respiratory infection within the past days, fever with no other cause, increased wheezing or cough, or a % rise over baseline in respiratory rate or heart rate. moderate exacerbation: presence of any two of the three cardinal symptoms of an exacerbation. severe exacerbation: presence of all three of the cardinal symptoms of an exacerbation. international consensus group [ ] mild exacerbation: patient has an increased need for medicaiton, which can be managed in the patient's normal environment. moderate exacerbation: patient has an increased need for medication and feels the need to seek additional medical assistance. severe exacerbation: patient/caregiver recognizes obvious and/ or rapid deterioration in condition, requiring hospitalization. copd [ ] . ten to % of patients with acute exacerbations have infections with two or more pathogens. among atypical pathogens, chlamydia pneumoniae has been estimated to account for % to % of acute exacerbations but up to % of exacerbations that result in admission to the icu [ , ] . viral bronchitis is found in % to % of patients with acute exacerbations but only % of those who require icu admission [ - ] . one recent study indicates that exacerbations due to viral bronchitis are more severe compared with nonviral exacerbations, and are associated with a longer time to recovery [ ] . viral particles have also been shown to produce latent infections, which can augment the inflammatory response to a subsequent stimulant of airway reactivity [ ] . elderly patients with an acute exacerbation of airway disease experience increased resistance to expiratory airflow and increased work of breathing, which can cause respiratory muscle fatigue. as shown by the spirometric flow-volume loops in fig. , normal individuals breathe at rest with expiratory air flows that are well within the limits of their maximal flow rate capacity. healthy persons, therefore, do not reach their maximal flow rates even with vigorous exercise. in contrast, patients with moderate to severe copd have tidal volume flow rates [ ] . during an acute exacerbation, patients' attempts to increase minute ventilation by increasing tidal volume are limited by the low maximal flow rates. patients respond with an increased respiratory rate, which decreases the time available for expiratory emptying of alveoli through narrowed airways. patients experience progressive trapping of air within the lung (''dynamic hyperinflation''), which increases work of breathing [ ] . eventually, increasing fatigue prevents patients from meeting their ventilatory demands and causes hypercapnic respiratory failure [ ] . based on this pathophysiology of respiratory failure in copd, management centers on decreasing airway resistance and decreasing work of breathing by ''unloading'' ventilatory demands on respiratory muscles to treat or prevent respiratory muscle fatigue. most therapeutic recommendations for managing elderly patients in the icu with acute exacerbations of copd derive from expert consensus because of the paucity of large prospective randomized trials [ ] . initial management includes supplemental oxygen by nasal cannulae or through a face mask that controls oxygen flow. oxygen flows are titrated with goals of achieving oxygen saturation between % and % and a partial pressure of arterial oxygen between to mm hg. oxygen flow is monitored to prevent hypercapnia, which can result from the effects of supplemental oxygen on increasing dead-space ventilation and ventilation-perfusion mismatching. inhaled bronchodilators promote bronchodilation that can achieve a % to % increase in fev and fvc within to hours [ ] . fourteen randomized trials support the conclusion that short-acting b-agonists (albuterol, levalbuterol, pirbuterol, bitolterol, fenoterol, metaproterenol, terbutaline) and anticholinergictype inhaled bronchodilators (ipratropium bromide) have similar efficacy for managing acute exacerbations, and both are more effective than parenteral bronchodilators [ ] . the faster onset of action of b-agonists and the lower frequency of adverse effects with anticholinergic drugs determine drug selection for individual patients. no differences exist between the administration of inhaled bronchodilators by meter dose inhalers with a spacer or a jet nebulizer [ ] . initial therapy is usually started with a nebulizer, however, because critically ill patients with acute respiratory distress may experience difficulties using meter dose inhalers [ ] . patients are switched to metered dose inhaler (mdi) therapy as soon as they regain an ability to synchronize their breathing with the mdi device. although clinicians often combine inhaled short-acting b-agonists with ipratropium bromide for patients with acute exacerbations, existing data demonstrate only marginal benefits with combined therapy. the recent evidence-based consensus statement by the american college of chest physicians and the american college of physicians/american society of internal medicine recommends initial treatment with ipratropium bromide with the addition of a shortacting b-adrenergic agonist if patients do not respond to a maximal dose of the anticholinergic drug [ ] . other experts recommend the reverse approach beginning with a b-agonist drug [ ] . the ideal dosing schedule for short-acting b-agonists and ipratropium bromide has not been established. high doses of b-agonists may cause tachyarrythmias, tremor, idiosyncratic bronchoconstriction, and tachyphylaxis [ , ] . data do not support the use of parenteral aminophylline for critically ill elderly patients hospitalized in the icu with acute exacerbations of copd. in emergency department settings, short-term use of aminophylline demonstrates either no change in measurable outcomes [ ] or a decreased risk of subsequent hospitalization [ ] . the high rates of adverse effects in patients treated with aminophylline combined with its questionable benefit have markedly decreased the use of this drug in the icu. recent guidelines do not recommend the use of aminophylline for acute exacerbations of copd [ ] . the role of bacterial infections in causing exacerbations of airway disease support the use of antibiotics, although no studies have been performed in critically ill patients [ ] . cumulative findings from several studies, however, demonstrate benefit for patients with acute exacerbations who have severe exacerbations as marked by the presence of purulent sputum [ , , ] . because most studies of antibiotic efficacy for acute exacerbations were performed before the era of multidrug resistant bacteria, the appropriate selection of antibiotics for critically ill patients remains unclear. ''first-line'' antibiotics (doxycycline, trimethoprimsulfamethoxazole, amoxacillin) have been recommended for general ambulatory patients with acute exacerbations [ ] . many clinicians, however, use newer classes of more broad-spectrum antibiotics for hospitalized patients. demonstration of superiority of these newer drugs awaits randomized controlled trials. pending the results of these studies, it is reasonable to recommend newer macrolides (azithromycin or clarithromycin), newer cephalosporins (cefpodoxime, cefprozil), amoxicillin/clavulanate, or doxycycline for hospitalized patients. critically ill patients and patients with risk factors for poor outcomes (baseline fev < % predicted, comorbid conditions, three or more exacerbations during the last months) benefit from newer fluoroquinolones (levofloxacin, gatifloxacin, moxifloxacin) because of the risk of gram-negative organisms. if pseudomonas aeruginosa is suspected (baseline fev < % predicted, underlying bronchiectasis, multiple courses of antibiotics), ciprofloxacin is the preferred antibiotic [ ] . prospective, randomized controlled trials demonstrate that systemic corticosteroids improve outcome for patients with acute exacerbations, as demonstrated by more rapid improvement in measured airflow, gas exchange, and respiratory symptoms with decreased treatment failure rates and relapse rates [ ] . existing studies have used different treatment regimens so the optimal dose and duration of corticosteroids are unknown. the largest study to date of hospitalized patients, however, used methylprednisolone, mg iv every hours for days followed by a corticosteroid tapering schedule using oral prednisone [ ] . patients treated for weeks with corticosteroids did as well as patients treated for weeks. hyperglycemia is the major complication of corticosteroid therapy for hospitalized patients with acute exacerbations [ ] . no studies support the use of expectorants, mucolytic agents, or mucokinetic drugs in managing critically ill patients with copd [ ] . physical therapy with postural drainage and chest clappage may acutely worsen respiratory function without providing any measurable benefit. positive pressure ventilation unloads respiratory muscles and prevents or treats respiratory muscle fatigue. ventilatory support can be provided by a tight-fitting face mask in the form of noninvasive positive pressure ventilation (nippv) or by tracheal intubation with mechanical ventilation. nippv has been shown in randomized controlled trials to provide benefits to subsets of patients with acute respiratory failure by decreasing the need for intubation, shortening hospital stay, and increasing survival [ - ] . many of these benefits occur because of the lower risk for pneumonia with nippv compared with intubation and mechanical ventilation [ ] . the rationale for nippv derives from the respiratory muscle unloading that occurs during ventilatory support that allows patients to maintain adequate breathing until the underlying airway problems reverse [ ] . all hospitalized elderly patients who present with respiratory distress from acute exacerbations should be evaluated for nippv. patients admitted with even mild respiratory acidosis may benefit from nippv [ ] . unfortunately, only % of hospitalized patients are candidates for nippv [ ] . poor candidates for nippv include patients with cardiovascular instability, respiratory arrest, limited ability to clear increased airway secretions, poor airway control, agitation or severe encephalopathy (glascow coma scale < ), uncooperability, upper gastrointestinal bleeding, upper airway obstruction, high risk for aspiration, and facial features that interfere with proper fitting of a face mask [ ] . recent studies demonstrate that the use of nippv does not require more nursing or respiratory therapist time compared with intubation and mechanical ventilation [ ] . basic principles for initiating nippv are listed in (box ). the key to successful application of nippv for patients with copd is thoughtful individualization of care and cautious titration of the positive pressure support. patients with severe respiratory failure who are not candidates for nippv require intubation and mechanical ventilation. ventilatory support provides an increased minute ventilation to correct abnormalities in gas exchange, and unloads respiratory muscles to allow recovery from respiratory muscle fatigue. identify appropriate patient review the equipment with the patient and explain care fit an appropriate-sized mask adjust ventilator initially at a low pressure ( - cm h o inspiration; - cm h o expiration) with the patient holding the mask in place. ask the patient to report comfort level and adjust ventilator pressures accordingly adjust oxygen flow rates to meet target oxygen saturation levels adjust the mask to avoid leaks monitor patient frequently and coach breathing patterns gradually increase inspiratory pressures for maximal relief of dyspnea although the specific techniques of mechanical ventilation are beyond the scope of the present article, general principles center on the avoidance of dynamic hyperinflation. patients with acute respiratory failure have increased airflow limitation, which slows expiratory airflow and delays alveolar empyting. mechanical ventilation with large tidal volumes and rapid respiratory rates produce dynamic hyperinflation and raised alveolar pressures at end expiration, which is termed autopositive end expiratory pressure (auto-peep). auto-peep interferes with patients' abilities to spontaneously trigger the ventilator, creates discomfort that may require heavy sedation, and compromises cardiac function. strategies to avoid dynamic hyperinflation include use of lower tidal volumes, increased inspiratory flow rates, and moderate respiratory rates. use of applied-peep at a lower level than measured auto-peep may enhance ventilator triggering and promote patient comfort. more detailed reviews of ventilator strategies for patients with copd are reviewed elsewhere [ ] . most patients intubated for respiratory failure due to copd improve within the first hours of care and undergo successful weaning and early extubation. goals for these patients are to reverse bronchospasm, rest fatigued ventilatory muscles, prevent dynamic hyperinflation, and avoid oversedation, which is associated with increased risks for nosocomial pneumonia and delayed weaning. patients who require mechanical ventilation for longer than hours are at increased risk of death and long-term mechanical ventilation [ ] . although no prospective, randomized data support the role of early tracheotomy for ventilator-dependent patients with copd [ ] , we have found tracheotomy valuable in promoting patient comfort with decreased need for analgesics and sedatives, improved nutrition, articulated speech, and patient mobility [ ] . these factors combined with the improved access to the lower airways for pulmonary toilet and decreased airway resistance during weaning trials promote successful weaning. we evaluate patients for tracheotomy after days of intubation. if successful extubation appears unlikely during the next several days, we proceed to tracheotomy to promote patient comfort and an early weaning from ventilatory support [ ] . copd is a progressive disease characterized by a long preclinical phase and a gradual decline in lung function over years after patients become symptomatic. some patients experience an abrupt and permanent loss of lung function during acute exacerbations. it is not possible to predict the clinical course of individual patients with copd because of the variability of the disease and limitations of studies that examine clinical predictors. studies have observed, however, accelerated decline in lung function in heavy and current smokers and in patients with mucus hypersecretion, low functional status, airway hyperreactivity, polymorphism in the tnf-a gene promoter region, and elevated levels of fibrinogen [ - ] . the prognosis for patients hospitalized with an acute exacerbation associated with hypercapnia is poor in terms of survival and postdischarge health-related quality of life. prognosis is determined more by the severity of the underlying copd than by factors associated with the hospitalization. more than % of patients admitted with an acute exacerbation require rehospitalization within months [ , ] . the mortality of patients hospitalized for an acute exacerbation is % to % [ ] , but mortality climbs to % to % for patients who require icu admission [ , ] . the -day, -day, -year, and -year mortality for patients discharged after an acute exacerbation is %, %, %, and %, respectively [ , ] . six months after discharge, only % of patients are alive and able to report a good, very good, or excellent quality of life [ ] . disabling symptoms of dyspnea are the most important factors decreasing quality of life [ ] . in view of this poor long-term prognosis both in terms of survival and quality of life, risk stratification models to identify patients at high risk of inpatient death or a poor postdischarge outcome would assist patient selection for intubation. niewoehner et al observed that the fev at admission and over the first several days of hospitalization is highly associated with clinical outcome [ ] . for patients who require intubation and mechanical ventilation, comorbidities, and acute illness severity scores are predictive of survival [ ] . requirements for mechanical ventilation beyond hours and extubation followed by reintubation are associated with a high mortality [ ] . connors et al reported data from the study to understand prognoses and preferences for outcomes and risks of treatments that found an independent association of severity of illness scores, body mass index, older age, prior functional status, severity of hypoxia, congestive heart failure, serum albumin, and the presence of cor pulmonale with survival [ ] . almagro et al [ ] recently reported that quality of life, marital status, depressive symptoms, comorbidity, and prior hospital admission identified hospitalized patients with a poor postdischarge survival [ ] . unfortunately, none of these models successfully identifies individual patients who have greater than % likelihood of dying [ ] . moreover, most of these prediction models have not been validated in an independent cohort. consequently, no existing system for predicting inpatient mortality or postdischarge functional capacity is suitable for selecting patients for instituting, continuing, or withdrawing life-sustaining therapies [ , ] . palliative and end-of-life care in the icu most patients with advanced copd want to make their own decisions regarding life-supportive care either by communicating with their physicians directly or through an appointed surrogate or instrument of advance care planning [ ] . to make informed decisions, however, patients need to understand the nature of life-supportive interventions and the probability of different outcomes if life interventions are used for respiratory failure. unfortunately, most elderly patients with moderate to severe copd have not discussed with their primary care physicians the appropriateness of life-supportive care or the nature of intubation and mechanical ventilation [ ] . if advance care planning has not occurred in the outpatient setting, discussions regarding the appropriateness of life-sustaining care should take place during the hospitalization for an acute exacerbation. ideally, the primary physician who knows the patient most intimately should initiate these discussions, which has been termed ''captaincy'' [ ] . often, however, the primary care physician is not available to discuss end-of-life care during hospitalization in the icu, which requires the critical care physician to serve this role. in discussing end-of-life care, critical care physicians need to inform patients and families about the anticipated value of life-supportive care. they should adopt, however, a broader approach to advance care planning that incorporates the patient's perspective. physicians in the icu often over focus on discussions regarding the life-sustaining interventions that should be applied in various clinical circumstances. patients and families, however, have more overarching goals that pertain to preparing for death, achieving a sense of control, and securing personal relationships with friends and families. patients with terminal copd are oriented toward their psychologic, emotional, and spiritual needs. discussions may shift from patient -physician discussions on the use of lifesupportive interventions to patient -family -friend communications to fortify relationships and share decisions about life-supportive care through mutual support [ ] . patients with acute exacerbations who choose to forego life-supportive care or have it withdrawn need relief of pain and suffering and expert management of their end-of-life care [ ] . they also benefit from reassurance that their physicians and nurses will not back away from their care. disabling symptoms of cough, dyspnea, anxiety, and depression typically complicate the terminal course of patients dying with copd [ ] . most patients at the terminal stage of copd choose not to use ventilator support, or to use it only for a time-limited span, if they can be sure of competent relief of terrifying dyspnea. copd is a progressive disorder that is punctuated in its later stages with acute exacerbations that present a risk for respiratory failure. copd has a disproportionate impact on older patients. in the icu, therapy is directed toward unloading fatigued respiratory muscles, treating airway infection, and prescribing bronchodilatory drugs. most patients survive hospitalization in the icu for an episode of respiratory failure. the severity of the underlying lung disease, however, under-lies the poor outcomes of patients in terms of postdischarge survival and quality of life. report of final morbidity statistics the impact of copd on lung health worldwide: epidemiology and incidence copd: epidemiology, prevalence, morbidity and mortality, and disease heterogeneity mortality patterns: preliminary data: united states- direct medical costs of chronic obstructive pulmonary disease: chronic bronchitis and emphysema evidence-based health policy: lessons from the global burden of diseases study world health organization. world health report : full report; world health . geneva: world health organization capitation, managed care, and chronic obstructive pulmonary disease the costs of treating copd in the united states the prevalence of copd: using smoking rates to estimate disease frequency in the general population early detection of copd in a high-risk population using spirometric screening the impact of aging and smoking on the future burden of chronic obstructive pulmonary disease. a model analysis in the netherlands the evidence base for management of acute exacerbations of copd: clinical practice guideline, part antibiotic therapy in exacerbations of chronic obstructive pulmonary disease toward a consensus definition for copd exacerbations time course and recovery of exacerbations in patients with chronic obstructive pulmonary disease relation of sputum inflammatory markers to symptoms and lung function changes in copd exacerbations airway eosinophilia in chronic bronchitis during exacerbations airway eosinophilia and expression of interleukin- protein in asthma and in exacerbations of chronic bronchitis exacerbations of bronchitis: bronchial eosinophilia and gene expression for interleukin- , interleukin- , and eosinophil chemoattractants relationship of sputum color to nature and outpatient management of acute exacerbations of copd air pollution and daily admissions for chronic obstructive pulmonary disease in european cities: results from the aphea project effect of temperature on lung function and symptoms in chronic obstructive pulmonary disease randomized, doubleblind study of ciprofloxacin and cefuroxime axetil for treatment of acute bacterial exacerbations of chronic bronchitis. the bronchitis study group infectious etiology of acute exacerbations of chronic bronchitis human immune response to nontypeable haemophilus influenzae in chronic bronchitis chlamydia pneumoniae infection in acute exacerbations of copd bronchial microbial patterns in severe exacerbations of chronic obstructive pulmonary disease (copd) requiring mechanical ventilation role of infection in chronic bronchitis respiratory viruses, symptoms, and inflammatory markers in acute exacerbations and stable chronic obstructive pulmonary disease latent adenoviral infection in the pathogenesis of chronic airways obstruction dynamic hyperinflation and exercise intolerance in chronic obstructive pulmonary disease expiratory flow limitation effect of dynamic airway compression on breathing pattern and respiratory sensation in severe chronic obstructive pulmonary disease acute exacerbations of chronic obstructive pulmonary disease equivalence of continuous flow nebulizer and metered dose inhaler with reservoir bag for treatment of acute airflow obstruction global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. nhlbi/who global initiative for chronic obstructive lung disease (gold) workshop summary comparison of the anticholinergic bronchodilator ipratropium bromide with metaproterenol in chronic obstructive pulmonary disease. a -day multi-center study the risk of myocardial infarction associated with inhaled beta-adrenoceptor agonists aminophylline for acute exacerbations of chronic obstructive pulmonary disease. a controlled trial aminophylline therapy for acute bronchospastic disease in the emergency room antibiotics in chronic obstructive pulmonary disease exacerbations. a meta-analysis management of acute exacerbations of copd: a summary and appraisal of published evidence relationship between flora in sputum and functional impairment in patients with acute exacerbations of copd. study group of bacterial infection in copd effect of systemic glucocorticoids on exacerbations of chronic obstructive pulmonary disease. department of veterans affairs cooperative study group comparison of the acute effects on gas exchange of nasal ventilation and doxapram in exacerbations of chronic obstructive pulmonary disease noninvasive ventilation for acute exacerbations of chronic obstructive pulmonary disease randomized, prospective trial of noninvasive positive pressure ventilation in acute respiratory failure international consensus conferences in intensive care medicine. noninvasive positive pressure ventilation in acute respiratory failure noninvasive positive pressure ventilation in the setting of severe, acute exacerbations of chronic obstructive pulmonary disease: more effective and less expensive early use of non-invasive ventilation for acute exacerbations of chronic obstructive pulmonary disease on general respiratory wards: a multicentre randomised controlled trial one year period prevalence study of respiratory acidosis in acute exacerbations of copd: implications for the provision of non-invasive ventilation and oxygen administration mechanical ventilation in chronic obstructive lung disease predictors of outcome for patients with copd requiring invasive mechanical ventilation the role of tracheotomy in weaning tracheostomy management in the chronically ventilated patient timing of tracheotomy in mechanically ventilated patients effects of smoking intervention and the use of an inhaled anticholinergic bronchodilator on the rate of decline of fev . the lung health study methacholine reactivity predicts changes in lung function over time in smokers with early chronic obstructive pulmonary disease. the lung health study research group association of chronic mucus hypersecretion with fev decline and chronic obstructive pulmonary disease morbidity. copenhagen city heart study group chronic mucus hypersecretion in copd and death from pulmonary infection functional status and survival following pulmonary rehabilitation outcomes following acute exacerbation of severe chronic obstructive lung disease does increased access to primary care reduce hospital readmissions? veterans affairs cooperative study group on primary care and hospital readmission the necessary length of hospital stay for chronic pulmonary disease dying with lung cancer or chronic obstructive pulmonary disease: insights from support. study to understand prognoses and preferences for outcomes and risks of treatments living and dying with chronic obstructive pulmonary disease relation of fev( ) to clinical outcomes during exacerbations of chronic obstructive pulmonary disease. department of veterans affairs cooperative study group mortality after hospitalization for copd evaluation of prognostic criteria for determining hospice eligibility in patients with advanced lung, heart, or liver disease. support investigators. study to understand prognoses and preferences for outcomes and risks of treatments chronic obstructive pulmonary disease-ethical considerations of care attitudes regarding advance directives among patients in pulmonary rehabilitation advance end-of-life treatment planning. a research review ethical issues in the chronically critically ill patient advanced lung disease: palliation and terminal care key: cord- -rwjxk v authors: nan title: asthma & allergy sig: poster session date: - - journal: respirology doi: . /j. - . . _ .x sha: doc_id: cord_uid: rwjxk v nan patients with non-eosinophilic asthma (nea) or copd have increased numbers of neutrophils in the airways. we have shown a similar defect in the ability of alveolar macrophages (am) to phagocytose apoptotic cells, in sputum from patients with nea and copd. we have also shown that bal-derived am from patients with copd have reduced expression of key macrophage phagocytic recognition molecules. the aim of this pilot study was to investigate the expression of these macrophage markers in induced sputum from patients with eosinophilic asthma (ea, n = ), nea (n = ), copd (n = ) and controls (n = ). methods participants underwent clinical assessment, skin allergy test, hypertonic saline challenge and sputum induction. macrophage phagocytosis of apoptotic cells, expression of mannose receptor (mr), hspr (cd ) and pcam (cd ) was determined using fl ow cytometry. results phagocytosis was signifi cantly impaired in patients with nea and copd. expression of mr, cd and cd were decreased in patients with nea or copd, but not signifi cantly changed in ea conclusion impaired sputum-macrophage phagocytosis of apoptotic cells in nea is associated with reduced expression of key macrophage recognition molecules. this defect may contribute to the chronic infl ammation and persistent airway neutrophilia that characterizes this asthma subtype. the use of induced sputum as a surrogate for the more-invasive bronchoscopic sampling may provide a tool for investigating the mechanisms for the effect of therapies including azithromycin in lung disease. supported by nhmrc. neutrophilic asthma (na) has been associated with increased bacterial colonization of the airways and increased expression of innate immune factors in the lung. this suggests that infection may play an important role in the pathogenesis of na. na is an important health issue as sufferers are resistant to steroid treatment, which is the mainstay of asthma therapy and effective therapies are urgently required. using mouse models of chlamydia and haemophilus infl uenzae lung infection and ovalbumin (ova)-induced allergic airway disease (aad), we have shown how infection may be linked to na. both infections suppressed eosinophilic infl ammation and t-helper (th) type responses but increase neutrophilic infl ammation and innate and th and/or th responses in aad. in the current study, the effectiveness of steroid treatment for the suppression of infection-induced neutrophilic aad was assessed by treating infected ovasensitized mice intranasally with dexamethasone during ova challenge. whilst dexamethasone treatment suppressed th -mediated, eosinophilic aad in uninfected, ova-sensitized groups, chlamydia and haemophilus-induced neutrophilic aad were shown to be steroid-resistant. our fi ndings correlate with clinical observations which show associations between infection, neutrophilic infl ammation and steroid resistance in asthmatics. these models will be utilized to examine the effectiveness of a number of novel therapies for infection-induced neutrophilic aad and to develop improved treatment strategies for steroid-resistant asthma. supported by nhmrc, asthma foundation of nsw, hmri. kj baines , , jl simp s on , , rj scott , lg wood , , pg gibson , priority research centre's for asthma and respiratory disease, and information based medicine, the university of newcastle, nsw, australia, and respiratory & sleep medicine, hmri, john hunter hospital, nsw, australia rationale four infl ammatory phenotypes of asthma have been identifi ed including eosinophilic, neutrophilic, mixed granulocytic and paucigranulocytic asthma, based on the presence or absence of sputum granulocytes. the involvement of systemic infl ammation in the pathogenesis of infl ammatory phenotypes of asthma remains unknown. objective this study investigates differences in the whole genome gene expression profi le of peripheral blood in infl ammatory phenotypes of asthma. methods induced sputum and peripheral blood were collected from participants with asthma (n = ). infl ammatory cell counts were performed and infl ammatory phenotype assigned based on the eosinophil and neutrophil cutoffs of % and %, respectively. rna was extracted from whole blood, gene expression profi les were generated (illumina humanref- v ) and analysed using genespring gx . results participants with eosinophilic asthma had signifi cantly higher rates of atopy and levels of exhaled nitric oxide. there were genes classifi ed as differentially expressed between the asthma phenotypes including the α-defensins (defa) , b, and , neutrophil proteases cathepsin g (ctsg) and elastase (ela ), and the monocyte/macrophage serine esterase, carboxylesterase (ces ). expressions of defa , b, , , ctsg and ela were signifi cantly higher in neutrophilic asthma and expression of ces was significantly higher in mixed granulocytic asthma. microarray results of the α-defensins and neutrophil proteases were successfully validated using realtime pcr. conclusions there is systemic up-regulation of α-defensins and neutrophil proteases in neutrophilic asthma, and these molecules play an important role in neutrophil activation and migration. systemic activation of neutrophils is an important feature involved in the pathogenesis of neutrophilic asthma, which is signifi cantly different to other asthma phenotypes. supported by hmri and xstrata coal; the university of newcastle. confl ict of interest no. airway mucus hypersecretion is an important cause of morbidity and mortality in asthmatic patients. increases in goblet cell number and their secretions are likely to contribute to airfl ow obstruction in asthma. here, we take advantage of an established sheep model of asthma to investigate the association between allergen exposure and goblet cell activity. methods eight allergic sheep (high house dust mite (hdm)-specifi c serum ige) received weekly intra-lung challenges of hdm to the right caudal lobe, and weekly intra-lung challenges of hdm followed by weeks without allergen exposure to the left caudal lobe, with the right medial lobe serving as an untreated internal control. a separate group of sheep were also used as untreated controls. biopsy samples of segmental bronchi tissue were collected from the different lung lobes for histological analysis at and days post-hdm challenge. results the percentage of goblet cells, with respect to epithelial cells, signifi cantly increases following chronic challenge with hdm ( % hdm vs. % control p < . ). goblet cell numbers did not decline in lung lobes after a -week cessation of allergen challenges. goblet cell degranulation is significantly increased day following challenge with allergen, but returns to control levels by days post-allergen challenge ( % day vs. % control p < . ). furthermore, degranulation is increased in both the rested and internal control lobes day following allergen challenge of the right caudal lobe. conclusions in this sheep model of chronic asthma, repeated allergen challenges induces goblet cell hyperplasia which persists even after long-term withdrawal of allergen. additionally, exposure to allergen in one lobe induces goblet cell degranulation in both challenged and unchallenged lobes, suggesting neural mechanisms may be operating in this model. confl ict of interest no. the thickness of the airway smooth muscle (asm) layer is related to severity but not duration of asthma or age (james erj; : ) . it is unknown if the constituents of the asm layer change with age. aim to investigate the relation of mean asm cell volume (v c ), total number of cells per mm of airway (n l ) and fractions of asm (f asm ) and extracellular matrix (f ecm ) within the asm layer with age and age at onset of asthma. methods post-mortem tissues from control subjects (c n = ); non-fatal (nfa n = ) and fatal (fa n = ) cases of asthma were used. the volume density (n v ) of asm cell nuclei was estimated on μm transverse airway sections (haematoxylin) and mean cell volume (v c = /n v ) was calculated, correcting for the volume fraction of asm within the asm layer. f asm and f ecm were estimated on . -μm thick sections of the same airway (masson's trichrome). effects of age on asm cell parameters and tissue volume fractions were tested using general linear models, correcting for sex and study centre and by comparing age at onset of asthma (< vs. > years). results table shows assessment of airway smooth muscle (asm) cell size and number requires estimates of cell volume density (n v ), volume fraction of muscle (f asm ) within the asm layer and the volume of asm per length of airway. stereological techniques have now become the accepted standard for assessing asm cell parameters, but sources of variation remain unclear. aim to assess sources of variability in the estimation of asm cell parameters and volume fractions within the asm layer. methods large and small airways from subjects with and without asthma were examined. transverse airway sections were cut at . μm and μm (masson's trichrome technique), and μm (haematoxylin) and used to estimate asm cell number and volume, and the volume fraction of muscle (f asm ) within the layer of asm. stereological assessments of the possible sources of variation in these asm layer parameters were assessed. results increased section thickness overestimated f asm by < % ( . μm), % ( μm) and % ( μm). stable variation of < % in n v occurred if high-power fi elds (hpf) were used to estimate n v . variation in the depth of muscle in thick sections of the asm layer caused up to % overestimation of n v . although the absolute area of the asm layer varied by up to %, variation of f asm was < % around the airway circumference and along the airway length. f asm differed signifi cantly between large and small airways. conclusion these results suggest that partial thickness hpfs need to be excluded and that ≥ hpf should be used to estimate asm volume density, that a single . μm section of airway can be used to estimate f asm and that asm parameters should be compared separately in large and small airways. grants nhmrc # . nominations nil. confl ict of interest nil. no signifi cant correlation was seen with age for any asm cell parameters or tissue fractions. results were similar for medium and small airways. conclusion size and number of asm cells and the volume fractions of asm and ecm within the layer of asm are not related to age. support nhmrc australia (grants # ; # ). nomination nil. . ± . . ± . . ± . . ± . fa > . ± . . ± . . ± . . ± . background asthma is characterized by excessive airway narrowing to contractile stimuli, termed airway hyper-responsiveness (ahr). changes in airway smooth muscle (asm) protein expression or mass are possible contributing mechanisms underlying ahr and have been examined using cell culture techniques. however, how these cellular changes to asm relate to airway narrowing at the level of the whole airway is unclear. we describe a new method to track changes in airway narrowing (responsiveness) in culture. methods whole airway segments (generation - ) from sheep lungs were studied prior to (fresh) and after and hours in culture in dulbecco's modifi ed eagle medium with % bovine serum albumin, % l-glutamine and antibiotics. airway narrowing was measured from the % decrease in airway volume under a fi xed transmural pressure, using a servo-controlled syringe pump and organ bath apparatus. cumulative acetylcholine dose-response curves (ach, − m − × − m) were performed to determine maximal response (e max ) and sensitivity (pd , negative log of ec ). results fresh airway segments narrowed strongly and approached closure with an e max of . % ± . (±sem) and pd of . ± . . airway narrowing responses were preserved in culture, with no signifi cant difference in maximal response or sensitivity to ach after either (e max . % ± . , pd . ± . ) or hours in culture (e max . % ± . , pd . ± . ). conclusions the present study has validated a new method allowing changes occurring at the cellular level in culture to be related to changes in airway responsiveness at the whole airway level. future studies will assess the effects of chronic infl ammation in disease on airway responsiveness. background deep inspiration (di) produces a bronchodilator response in healthy humans, but this response is impaired in asthma. reduced airway compliance in disease could impair the response to di by limiting the stretch of smooth muscle. aim to show that isolated human bronchi dilate to di in an amplitudedependent manner and that the stretch caused by di depends on airway compliance. methods bronchi were obtained following lung resection from cancer patients who had normal spirometry (n = ). lumen narrowing was measured using a servo-control system which set transmural pressure and simulated breathing movements. bronchi were contracted to carbachol (cch × − m) during tidal breathing (from to cmh o, i.e. Δ cmh o transmural pressure, . hz) and infl ated to three different amplitudes of di (Δ , or cmh o) applied following contraction. results in cch-contracted airways, all three di amplitudes produced a transient bronchodilation. increasing the di amplitude caused a greater increase in luminal volume during the di and a greater bronchodilation following the di (p < . ). cch itself cause approximately a % fall in specifi c compliance (p < . ), which was reversed by di (p < . ). for each di amplitude, the change in lumen volume during the di was positively correlated to the specifi c compliance of the bronchi before di (r > . , p < . ). conclusions isolated human bronchi show a bronchodilation response to di that is proportional to the expansion of the airway caused by the di. the amount of stretch produced by a di depends on airway wall compliance suggesting that increased airway stiffness in disease could suppress the di response by limiting the stretch of bronchi during lung infl ation. confl ict of interest none. ja douglass , , , ea yu , , br thompson , , , gg king , , mj abramson , introduction increasing asthma prevalence and changes in environmental exposure suggest that there may be a relationship between asthma and dietary intake. however, to date, few studies have examined how dietary intakes of asthmatics differ from a healthy population. aim to measure and compare the dietary intakes of adults with stable asthma and healthy controls. methods in a cross-sectional study, dietary intakes calculated from a item food frequency questionnaire (ffq) of adults with stable asthma (n = , age years ± (sd)) were compared with intakes of healthy controls (n = , age years ± (sd)) matched for age and body mass index (bmi). spirometry, airway responsiveness to hypertonic saline, and induced sputum cell counts were also measured. results subjects with severe persistent asthma (n = ) had signifi cantly higher total fat intake than healthy controls ( ± (sem) versus ± (sem) g/day p = . ) and signifi cantly lower fi bre intakes ( ± (sem) versus ± (sem) g/day p = . ). lower fi bre intake in asthmatic subjects (n = ) was associated with lower %predicted fev (r = . , p = . ), %fvc (r = . , p = . ) and fev /fvc (r = . , p = . ). higher fat intake and lower fi bre intake were associated with higher absolute concentrations of sputum eosinophils (r = . , p = < . , n = ). conclusions subjects with severe persistent asthma have an eating pattern of lower diet quality with higher intakes of fat and lower intakes of fi bre than healthy controls, which is related to lower lung function and increased airway infl ammation. factors leading to altered dietary intake in severe asthma require further investigation. methods a randomized, placebo-controlled, single-blinded trial of tailored asthma education including device technique and utilizing pact to address patients' concerns versus brochure-only information for asthma patients over age . measurements of lung function, asthma control (acq), asthma related quality of life (aqol), medication use and adherence score (adh) were obtained at baseline, and months using standard, validated questionnaires. results sixty-fi ve participants ( f m, mean age ± . ) were randomized to the intervention group and ( f m, mean age ± . ) to the control. there were no statistically signifi cant differences between the groups' demographics or baseline measurements. a wilcoxon signed ranks test used to compare median pair ranking at baseline and months post-intervention revealed a signifi cant improvement in the active, but not the brochure-only information group at months in: acq mean ± sd = . ± . vs. . ± . (p = . ). aqol mean ± sd = . ± . vs. . ± . (p = . ). adh mean ± sd = . ± . vs. . ± . (p < . ). conclusion an educational intervention including device technique and addressing the concerns of older people with asthma signifi cantly improved acq, aqol and adh scores at months post-intervention. introduction greater exposure to ultraviolet radiation (uv) may increase the risk of allergic disease, but this association has not been investigated using estimates of time spent outdoors by individuals. the aim of this study was to investigate the relationship between self-reported doctor-diagnosed asthma and/or hayfever, and time spent outdoors. methods this analysis was based on cross-sectional baseline data from a subsample of the australian and up study, comprising men and women aged - years, living in new south wales. participants were randomly selected from the australian universal health insurance database. diagnoses of asthma and/or hayfever and the number of hours spent outdoors were derived by questionnaire. in general, the odds of a diagnosis of asthma and/or hayfever decreased with increasing time spent outdoors for both women and men. for example, in women, the adjusted odds ratios for asthma with hayfever were . ( % ci: . - . ), . ( . - . ), . ( . - . ) and . ( . - . ) for - , - , - and > hours spent outdoors on weekends, respectively, compared with < hour (p trend < . ). time spent outdoors was not associated with a diagnosis of asthma alone in men. conclusions there were statistically signifi cant inverse associations between time spent outdoors and diagnoses of asthma, hayfever or asthma with hayfever, in a large population of older australians. exposure to uv may protect against the development of allergic diseases, such as asthma and hayfever. no. background allergic rhinitis (ar) and eczema are highly prevalent and females are more commonly affected than males in adulthood. although there have been extensive studies on ar and eczema in females, little is known about the effect of reproductive factors and the development of late-onset ar/ eczema. we examined potential associations between reproductive factors and ar and eczema using the tasmanian longitudinal health study (tahs) data. methods the tahs is a population-based cohort study of respiratory disease. two thousand seven hundred sixty-four ( . %) females from the original tahs participants were surveyed in using postal questionnaire which collected information on reproductive factors such as ever pregnancy, age at fi rst child birth, use of oral contraceptive pills (ocp) and age of starting using the ocp. logistic regression was used to assess the predictors of ar and eczema and all analyses were mutually adjusted. of the participants, . % (n = ) had late-onset ar and . % (n = ) had late-onset eczema. maternal and paternal atopy were signifi cantly associated with ar (p < . ). the risk of developing eczema was decreased signifi cantly with increasing age at fi rst menstruation (or: . , % ci: . - . ) and the increased age at birth of fi rst child ( . , . - . ). a decreased risk in ar was observed with the increasing number of pregnancies ( . , . - . ). however, the associations between age of starting using ocp and ar/eczema were not signifi cant. conclusion later age at start of menses and later age at fi rst pregnancy were associated with a reduced risk of eczema which may be related to hormonal dysregulation. tp- airway responsiveness at and years is associated with asthma at years introduction asthma is the most common chronic childhood disease in australia. increased airway responsiveness (ar) is associated with asthma but not all individuals with increased ar have asthma. the perth infant asthma follow-up study recruited a birth cohort of individuals who have undergone longitudinal assessments of many factors associated with childhood ar. our previous work reported an association between increased ar in infancy and asthma at and years. aim to look at the relationship of increased ar and asthma in early adulthood at different time points from birth. methods individuals were recruited from among expectant parents attending an antenatal clinic at a local metropolitan clinic. at ages , and months and again at , and years, participants underwent an assessment that included a respiratory questionnaire and determination of ar (as evidenced by dose-response slope (drs) to histamine using the rapid technique). results children were initially recruited and studied in infancy. two hundred three, , , , and children subsequently had ar assessed at , and months, , and years, respectively. there was a signifi cant relationship between drs at and years and for both asthma at years (p = . and p < . , respectively) and 'wheeze in the past year' at years (p = . and p = . , respectively). there was no significant relationship between drs in infancy and asthma at . conclusion ar at and years is associated with asthma at years. in this study, there was no signifi cant relationship between ar in infancy and asthma at years. the pcaas has found that . % of children with acute asthma presenting to the princess margaret hospital for children emergency department (pmh ed) had hrv, of which % were hrv group c. furthermore, hrvc was associated with more severe attacks. however, the prevalence of hrvc in the community is unknown. aim to test the hypothesis that hrvc would be found more often in children requiring emergency treatment for an ari than sibling controls and determine the impact of days since symptoms began on the prevalence of hrv detection in children with an acute respiratory illness (ari) and sibling controls (sibs). methods ari (n = ) had nasal samples collected on presentation to the pmh ed and sibs with symptoms of a cold (n = ), within week of ari recruitment. viral rna was extracted and reverse transcribed. a two-step pcr of the hrv ' utr was used for detection, followed by dna sequencing for typing. results ari and sibs were % and % male, % and % asthmatic, with mean ages of . and . years, respectively. hrv +ve ari (n = , mean ± sd days of symptoms = . ± . ), hrv -ve ari (n = , . ± . ), hrv +ve sibs (n = , . ± . ) and hrv -ve sibs (n = , . ± . ). of the and hrv +ve ari and sibs, % and % had hrvc. conclusions hrvc is as common in children who have hrv but do/do not require hospital treatment. detection of hrv is more likely when the nasal sample is collected soon after the appearance of cold symptoms. support nhmrc program grant. nomination nil. introduction upper airway dysfunction may make asthma more diffi cult to control and should be suspected in asthmatics refractory to prescribed medical therapy. aim a novel imaging technique, dynamic -slice computerized tomography (ct), was used to examine laryngeal behaviour in healthy and asthmatic individuals. method vocal cord movement was imaged using -slice ct larynx. healthy volunteers were studied to develop and validate an analysis algorithm for quantifi cation of normal vocal cord function. further studies were then conducted in patients with diffi cult-to-treat asthma. in eight severe asthmatics with abnormal vocal cord movement, asthma outcomes were measured after speech therapy. results vocal cord movement was quantifi ed over the breathing cycle by ct using the ratio of vocal cord diameter to tracheal diameter. normal limits were calculated, validated and applied to evaluate diffi cult-to-treat asthma. vocal cord movement was abnormal with excessive narrowing in of ( %) asthmatics and severe in nine ( %) patients (abnormal > % of inspiration or expiration time). after speech therapy in a small subgroup, asthma symptoms and morbidity improved. conclusion non-invasive ct larynx quantifi cation of vocal cord movement was achieved. this new approach has identifi ed frequent upper airway dysfunction in asthma with potential implications for disease control and treatment. aim to investigate the characteristics and mechanisms of chronic cough (cc) following acute respiratory illness from laboratory-confi rmed h n infl uenza. methods subjects who had current symptoms and had been tested for h n infl uenza by pcr assay participated in this study. twenty-one of those continued onto clinical testing. investigations to assess cough included symptom questionnaires, hypertonic saline challenge and cough monitoring. results of the participants, % tested positive for h n and % tested negative for h n . h n -infected participants were younger and predominantly female. the prevalence of post-h n cc was . %, and for non-h n infection, . %. objectively measured cough frequency was times greater; there was a -fold increase in cough refl ex sensitivity, and greater quality-of-life impairment in the participants with chronic post-infectious cough than the non-cough participants. conclusions cc was found to be relatively common, mild in severity and tending to resolution with time. the characteristics of post-h n cc were similar to other post-infectious cough and were associated with cough refl ex hypersensitivity. aim upper airway dysfunction may accompany acute severe asthma, but this has not been investigated. a novel imaging technique, dynamic -slice computerized tomography (ct), was used to examine laryngeal behaviour in acute asthma exacerbation. methods patients were studied in the emergency department or as acute inpatients following admission for an acute exacerbation of asthma. vocal cord movement was imaged by -slice ct larynx and compared to normal vocal cord movement in a healthy cohort. results vocal cord movement was abnormal with excessive narrowing during either inspiration, expiration or both in of cases ( . %) with acute severe asthma. imaging again revealed that laryngeal dysfunction characterized the movement abnormality, rather than isolated vocal cord dysfunction. radiation exposure was low and generally < milli-sievert. conclusion non-invasive ct larynx quantifi cation of vocal cord movement was effectively achieved in acute severe asthma. we identifi ed frequent upper airway dysfunction in acute severe asthma suggesting that treatment of upper airway obstruction (e.g. using bipap) may be merited during asthma exacerbation. aim to determine whether eicosanoids could alter the deposition of extracellular matrix (ecm) proteins and cytokine release from human airway cells. methods airway smooth muscle cells (asm), fi broblasts and epithelial cells were stimulated with leukotrienes b , c , d , e and the prostaglandins e , d , f α and the pgi analogue mre- . after hours, culture medium was collected and il- and il- production and cell deposited ecm proteins tenascin c, fi bronectin and perlecan were assessed by elisa. to determine whether eicosanoids infl uenced cell proliferation, manual counting of cells in the experiments were carried out before and after stimulation. results neither leukotrienes or prostanoids altered cell proliferation after days of stimulation (n > ). leukotrienes had no effect on ecm protein deposition or cytokine release from asm or fi broblasts (n > ). leukotrienes did not alter either parameters in epithelial cells except leukotriene d , which increased tenascin c deposition (n = , p < . ). prostanoids induced il- and il- and other various changes in asm and fi broblasts (n > , p < . ) (see below). introduction the function of asthmatic airway epithelium is disrupted facilitating immune and infl ammatory responses resulting in epithelial damage. human rhinovirus (hrv) causes asthma exacerbations in children; however, paucity exists on how it affects barrier function. this study assessed how hrv infection affects epithelial barrier function and integrity in healthy and asthmatic epithelium. methods adult balb/c mice were intranasally infected with hrv- b and followed for days. tight junction (tj) expression was assessed using immunohistochemistry (ihc) and western blot analysis. primary airway epithelial cells from healthy and asthmatic children were assessed for tj gene and protein expression by qpcr and ihc, respectively. results occludin and zonal occludin- (zo- ) expression was lost and sustained in mice infected with hrv- b however was not observed in shaminjected mice. asthmatic airway epithelial cells were found to exhibit elevated basal gene expression levels of tjs (zo- , occludin and plakophilin- (pkp- )) but markedly lower corresponding protein levels. conclusion hrv- b compromises barrier function in vivo through sustained loss of tj proteins. the marked decreased expression of tj proteins in paediatric asthmatic epithelium may contribute towards increased susceptibility to viral infections. disparity between gene and protein tj expression could indicate either post-transcriptional regulation or compensatory effects by other tj proteins and requires further study. supported by asthma foundation wa; nhmrc. confl ict of interest none. conclusion leukotrienes alone did not affect the ecm proteins and cytokines assessed in this study. prostanoids decreased ecm protein deposition whilst increasing cytokine release without affecting cell proliferation. this study shows that prostanoids may have a more pronounced role on direct ecm remodelling than leukotrienes in airway cells. supported by merck. background toll-like receptor (tlr) is an innate immune receptor involved in the initial detection of pathogen-associated molecular patterns. the effect of ageing and chronic obstructive pulmonary disease (copd) on tlr responses and the impact of these innate immune responses in copd pathogenesis remain unclear. hypothesis expression and activity of tlr on peripheral blood mononuclear cells (pbmcs) is increased with healthy ageing and further increased in copd. methods pbmcs from healthy controls < years and > years; and participants with copd (n = per group) were cultured with or without pam c ys k (tlr agonist). cells and supernatants were collected at hours and protein (cytometric bead array or fl ow cytometry) and gene (real time pcr) expression was examined. results tlr activation led to increased release of interleukin (il)- , , β, and tumor necrosis factor (tnf)-α. tlr gene expression was increased with stimulation; however, cell surface receptor levels were unchanged. there was no difference in the level of tlr between the groups. in older people, tlr activation resulted in less il- β and tnf-α release, but similar release of il- and il- . similar results were seen in copd. at baseline in copd, there was up-regulation of tnf-α gene expression compared to the older healthy group; however, the tlr cytokine response did not differ between the groups. conclusion healthy ageing is characterized by an impaired systemic proinfl ammatory cytokine response to tlr -mediated innate immune activation. this effect persists in copd and is selective in the cytokine pathways involved. these altered infl ammatory mechanisms may affect responses to infection and injury impacting disease pathogenesis and warrant further evaluation. aim to investigate whether the inhibition of matrix metalloproteinase- (mmp- ) by a non-selective mmp inhibitor (doxycycline) and the specifi c mmp- inhibitor i (olic acid) can regulate cellular migration of tsc -null mouse embryonic fi broblasts (mefs), which act as a model for lymphangioleiomyomatosis (lam) cells, as compared to wild-type mefs. methods wild-type (tsc -positive) and tsc -null mefs were treated with diluent, doxycycline ( . pg/ml- μg/ml) or olic acid ( . - μm) for hours. mmp- levels were assessed by zymography and elisa. cell migration for hours was measured using a transwell migration assay. results under basal conditions, mmp- release and cellular migration was . -fold and . -fold higher, respectively, in tsc -null mefs compared to tsc -positive mefs (mmp- release, tsc -null (n = ) and tsc -positive (n = ), p < . ; cell migration, tsc -null (n = ) and tsc -positive (n = ), p < . ). mmp- release was reduced in tsc -null mefs after -hour treatment with doxycycline ( and μg/ml, n = , p < . ) and with olic acid ( - μm, n = , p < . ). treatment with doxycycline ( pg/ml- μg/ml, n = , p < . ) or olic acid ( - μm, n = , p < . ) also signifi cantly reduced cell migration of tsc -null mefs. copd is a leading cause of death worldwide. treatments are limited and restricted to symptomatic care. there is an urgent need for new treatment options targeting the infl ammation. tissue damage in copd is thought to result from an inability of the normal repair processes with accumulation of apoptotic material and impaired clearance of this material by macrophages in the airways. lung infl ammation and macrophage function involves the bioactive sphingolipid sphingosine -phosphate (s p). multiple studies have showed the involvement of these components in infl ammation. methods we investigated lung tissue samples from patients (copd or non copd controls) undergoing curative lobectomy for lung cancer. we analysed the mrna expression profi le, the sphingosine-kinase (sphk) protein activity and the localization and expression of individual proteins. results we show in this study for the fi rst time a comprehensive expression profi le of all synthesizing enzymes, receptors and degrading enzymes in the human lung. correlations between receptor subtypes, degrading enzymes and between s p receptor subtype were detected. multivariance anova showed that in copd, the relative mrna expression of s p receptor subtype was reduced. conclusion the correlations between receptors and enzymes involved in the sphingosine kinase signalling system in the lung suggest common regulatory mechanisms. s pr is expressed on dendritic and nk cells which are reduced under conditions of copd. therefore, our fi ndings of reduced s pr in copd may provide a novel target for pharmacotherapy. lung cancer is responsible for more cancer-related deaths than colon, breast and prostate cancers combined. in patients with copd and/or lung cancer, we have shown a reduction in lung and airway macrophage function, evident by a reduced ability to phagocytose apoptotic airway epithelial cells and neutrophils. the potential for lung cancer cells to directly inhibit this function (a potential immune evasion mechanism) has not been investigated. background kinins have been implicated in airway lung diseases such as asthma and lung cancer by regulating infl ammation, cell proliferation and migration. the effect of kinins is mediated through the binding of two receptors, kinin b and b receptors (b r and b r). a novel b r splice variant (sv) resulting in a shorter ' untranslated region (utr) was identifi ed in cultured airway epithelial and fi broblasts as well as in lung carcinoma tissue and leukocytes. this study aims to characterize the functional role of the novel b r sv in mrna stability, translation effi ciency and receptor expression in cultured airway epithelial cells. methods stability of b r sv was determined by measuring b r mrna levels over time in h cells after actinomycin d treatment. translational effi ciency of wt and sv 'utr was determined by measuring luciferase activity in transfected h cells. expression of wt and sv transcripts through q-rtpcr were compared in cells treated with a b r-specifi c agonist dakd. cell-surface receptor expression post-agonist stimulation was quantifi ed using facs. results mrna stability studies indicated that b r sv was ≈ % less stable than the wt transcript in h cells suggesting a stabilizing element 'utr. translation effi ciency of sv was no different to wt b r. dakd stimulation increased both wt and sv transcripts early in the time course, although the peak expression of wt and sv differed at hours and hours, respectively. dakd stimulated cells showed two phases of receptor expression, ( ) decrease of cell surface receptor up to . hours post-stimulation; ( ) increase in cell surface b r after . hours. conclusion this study has identifi ed a novel regulatory mechanism of b r expression through the production of a sv that alters the 'utr. the translation effi ciency of b r is not affected, but the sv was less stable than the wt in h cells and may play a role in allowing quicker changes in transcription. agonist-induced up-regulation of transcripts in a time-dependent manner may be important in maintaining a chronic response during infl ammation. circulating lymphocytes are increasingly used as a surrogate cell type to refl ect changes in adrβ density elsewhere in the body, particularly the respiratory system. however, adrβ density is non-uniform among lymphocyte subsets and it is unclear if, and the degree to which, adrβ density varies between individuals. aim to assess the extent of variability in adrβ density on human peripheral blood mononuclear cells (pbmc) including lymphocytes and monocytes. method pbmc were isolated from blood of healthy subjects by density gradient centrifugation with ficoll-paque. cell surface and total adrβ of intact and permeabilized lymphocytes (cd +) and monocytes (cd +) were measured using anti-adrβ via facs. geometric mean fl uorescence (gmf) was used as the indices for adrβ density per cell. result surface adrβ -gmf increased by . -and . -folds over negative controls for lymphocytes and monocytes, respectively. magnitude of foldchange was not signifi cantly different between these cells (p = . ), but the distribution of gmf intensity between samples suggests greater variability in adrβ density in lymphocytes versus monocytes (p = . ). proportion of cells-stained adrβ -positive was signifi cantly higher in monocytes versus lymphocytes ( . ± . % vs. . ± . %, p = . ). total adrβ -gmf increased by . ± . and . ± . -folds for lymphocytes and monocytes, respectively (p > . ). proportion of adrβ -positively stained cells were similar between samples (lymphocytes %, monocytes %, p = . ), but greater variability was observed for lymphocytes (range - %) versus monocytes ( - %). conclusions despite similarities in surface and total adrβ density, lymphocytes display greater inter-subject variability compared with monocytes. this will have implication in experimental designs and interpretation of changes in adrβ density in studies using human pbmc as an alternative to primary cells from the organ of interest. confl ict of interest no. pge plays a protective role in asthma by inhibiting airway infl ammation. it is predominantly produced by epithelial cells in response to pro-infl ammatory stimuli and acts as an autocrine and paracrine mediator. on the contrary, il- β is a highly potent cytokine that induces many pro-infl ammatory effects in the human airway including activation of the human lung epithelium which promotes production of pro-infl ammatory cytokines and chemokines. airway epithelial cells express all four known pge (e prostanoid (ep) receptors, but mechanisms underlying the regulation of expression of ep receptors in human lung epithelial cells have remained elusive. therefore, we investigated whether pge , an endogenous protective mechanism of the airways, can modulate il- β infl uence on ep receptor expression in human epithelial cells. methods ep receptor mrna and protein expression was quantifi ed in -hbe cells at basal levels and following stimulation with il- β or pge alone, or simultaneously, using real time rt pcr and facs analysis, respectively. results pge up-regulates all four ep receptors at mrna level, while il- β up-regulates ep , ep and ep and does not infl uence expression of ep . at protein level, preliminary results show transient increase of ep receptors in the presence of pge , while il- β down-regulates this receptor. ep and ep are up-regulated following stimulation with both stimuli. importantly, antiinfl ammatory ep receptor is up-regulated only in the presence of pge . conclusion we show for the fi rst time that pge may infl uence expression of its own receptors and oppose the effect of il- β in human lung epithelial cells. this may in turn alter pge production and autocrine activation with potential implication on the function of epithelial cells, which is important in modulation of immune response in asthma and lung infl ammatory diseases. nomination nil. confl ict of interest no. the burden of obstructive lung disease (bold) study is an international study designed to measure the prevalence, risk factors and burden of copd. data collection using the bold protocol has been undertaken at eight sites with inclusion of urban, rural, coastal and inland regions of australia. methods a random sample of adults aged ≥ years was identifi ed. information on respiratory symptoms and diagnosed copd were collected by questionnaire. post-bronchodilator fev and fvc were used to defi ne gold stage. the (un-weighted) prevalence rates are presented by age groups and sex. results s timmins , , , , g king , , , , c salome , , , r schoeffel , , , c walsh , , the extent of emphysema could increase ventilation heterogeneity independently of its effects on airway narrowing. the aim of this study was to examine the relationship between emphysema extent on computed tomography scans (ct), and airway narrowing and ventilation distribution in copd. methods subjects with copd underwent ct scanning, spirometry, dlco and nitrogen washout by single and multiple breath techniques. closing capacity (cc/tlc%), slope of phase iii (Δphase iii ) and indices of ventilation distribution conductive (scond) and diffusion-dependent airways (sacin) were derived from washouts. helical ct scans were performed at tlc. emphysema extent was measured as low attenuation areas < − hu using osirix program, expressed as % of ct total lung volume. results subjects were of mean (range) age years ( - ), bmi . ( . - . ), fev of ( - %) %predicted and dlco of ( - ) %predicted. emphysema extent was . % ( . - . ). geometric mean (ci) Δphase iii was . ( . - . ), sacin was increased at . l − ( . - . ) and cc/tlc% was % ( - ). emphysema extent correlated with fev / fvc (r = − . , p = . ), dlco (r = − . , p < . ), bmi (r = . , p = . ), Δphase iii (r = . , p = . ), and sacin (r = . p = . ). in multiple regression analysis, emphysema extent was predicted by fev /fvc and Δphase iii (model r = . , p = . ). conclusions the extent of emphysema increases the heterogeneity of ventilation independently of any effects on overall airway narrowing. supported by australian lung foundation webster memorial award, crcaa. conclusions self-reported wheeze in the last months is very common in adults over years. in the younger age group ( - years), many people with wheeze did not have airfl ow obstruction or reversible spirometry at the time of test. aim to determine whether there is any association between change in fev among copd patients and ambient ultrafi ne particle number concentrations in melbourne. methods participants with mild to moderate copd were asked to measure their fev using a portable electronic spirometer (piko) two times a day (morning and evening) for consecutive days. the same procedure was repeated on average months later. ambient ultrafi ne (diameter < . μm) particle number concentrations were measured for the same period using an ultrafi ne condensation particle counter and micro-orifi ce uniform deposit impactor. results aim to examine the implementation of, and barriers and enablers to, six high-evidence recommendations for copd management, in copd hospital inpatients. method observational, mixed methods study in consecutive copd patients admitted to a tertiary hospital. demographic, disease and admission characteristics are recorded. implementation (or not) of smoking cessation, pulmonary rehabilitation, long-term oxygen use if hypoxaemic, medication use, vaccinations and plans for future exacerbations are determined from medical records and patient interviews. interviews with medical offi cers examine their perspectives on recommendation implementation. of pilot data in copd patients (mean (sd) age ( ) years, length of stay ( ) days), were current smokers and had severe copd ( moderate). highest levels of implementation were fl u vaccination (completed by gps, n = ), medication (but not spacer) use, and oxygen use if hypoxaemic (investigated and implemented in all suitable, n = ). pulmonary rehabilitation was discussed with half of the patients, but only severe patients with long length of stay accepted further rehabilitation. exacerbation plans were in place for patient, and newly initiated in patients. doctor interviews (n = ) confi rmed pulmonary rehabilitation was considered mostly for severely unwell patients, and use of exacerbation plans was inconsistent. conclusion pilot data suggest pulmonary rehabilitation is offered and accepted by a small subset of copd patients. findings from this pilot will inform planned larger observational studies, and in turn, experimental studies to improve copd care. high-and extreme high-risk interventions were found by panel ( - . % extreme and . - . % high-risk interventions) and patients' respiratory physicians ( % extreme and % high-risk interventions). additionally, clinical pharmacist involvement was associated with many benefi ts such as: improvement in medication compliance, high level of patient satisfaction and identifi cation of patients with issues in medication knowledge. conclusion clinical pharmacist interventions were estimated to prevent extreme and high risks that might happen due to drug-related problems. clinical pharmacy consultation was associated with positive impact on other important measured outcomes. aerobic exercise training in the form of supervised -minute walks ( mw) reduces exertional dyspnoea in patients with copd. mw goal ( mwg) distances, aiming for a training effect, are generated from a baseline submaximal test ( -minute walk ( mwd), where wg = . × mwd/ × . aim to compare mwg with actual initial mw achieved and to examine the predictors of mwg achievers (ga). methods retrospective review of patients, % male, age ± years (mean ± sd), fev ± %predicted, who completed pulmonary rehabilitation (pr). patients were assessed at baseline and post-completion of pr. initial mwg was calculated from the best of two mwd at initial assessment and ga were defi ned as patients who achieved their mwg at their fi rst visit to pr. results for the group, there was a statistically signifi cant but not clinically signifi cant difference between mwg and actual mw achieved ( ± m vs. ± m, p < . , paired t-test). the patients ( %) who achieved their mwg exceeded the goal by ± m, whereas the patients who did not achieve their mwg fell short by ± m. there was no signifi cant difference between ga and non-ga in age or lung function, but ga had a higher initial mwd, with fewer rests, lower dyspnoea score and lower hr at start and fi nish (p < . , unpaired t-test). ga were also more likely to have a clinically signifi cant response to pr, measured by mwd, compared with non-ga (mean change m vs. m, p < . , chi-square). conclusion mw goals as currently calculated either signifi cantly underestimate or overestimate actual mw achieved. it may be that in non-ga, the mwd is functioning as a true maximal test and these are a group of patients who are truly ventilatory-limited, rather than deconditioned. the receptor for advanced glycation end products (rage) is a key candidate for promoting a self-perpetuating cycle of infl ammation and thereby is a major contributor to numerous chronic disease states. the potential of rage to function as a switch converting a transient infl ammatory response such as one generated by cigarette smoke to sustained cellular dysfunction allows it to act as a mediator for ongoing infl ammation in chronic obstructive pulmonary disease (copd). although the molecular mechanisms regulating rage expression have not been fully elucidated, altered rage activity arises from polymorphisms within the rage gene and its promoter. three polymorphisms in the rage promoter (− t/a, − t/c and a bp deletion from − to − ) increase transcriptional activity and rage expression. the rage g s allele results in an increased ligand-binding affi nity and activation of the infl ammatory mediators with subsequent up-regulation of infl ammatory response. the aim of this pilot cross-sectional study was to investigate the relationship between three known rage polymorphisms (− t/a, bp deletion, g s) and copd and disease severity. methods genomic dna was isolated from peripheral blood lymphocytes. pcr and taqman assays were used to genotype the three rage polymorphisms in copd patients, healthy non-smokers and healthy smokers. fev was measured in all subjects. disease severity was defi ned using gold guidelines. results there was no statistically signifi cant association between bp deletion and copd (p = . ), − t > a and copd (p = . ), g s and copd (p = . ). conclusion no association was found between the − t > a, bp deletion and g s polymorphisms and copd, disease severity or fev introduction the receptor for advanced glycation end products (rage) mediates neutrophil traffi cking and is implicated in the pathogenesis of chronic airways disease. we determined whether changes in airway and systemic levels of soluble rage (which acts as a receptor decoy to limit rage activation) and rage ligands are related to neutrophilic infl ammation in asthma and copd. methods bronchial lavage (bl) fl uid from subjects with moderate-severe persistent asthma or copd, and healthy controls were analysed for neutrophils, total srage (cleaved and secreted), secreted srage (esrage) and the rage ligands hmgb and serum amyloid a (saa). systemic levels srage and esrage were also determined in asthmatic and copd subjects. aims increased numbers of neutrophils are found in the lungs of copd patients, which contribute to airway infl ammation. while cigarette smoke exposure is the major risk factor for copd, it is unclear how cigarette smoke modifi es neutrophil function and activity. this study aimed to assess the effect of cigarette smoke extract (cse) on neutrophils in an in vitro model. methods neutrophils were isolated from peripheral blood donated by volunteers using percoll density gradient centrifugation. neutrophils were seeded in well plates ( cells/well), exposed to different concentrations of cse ( %, %) and monitored at , and hours. at each time point, viability of neutrophils was measured by trypan blue exclusion and supernatant was collected for measurement of cxcl release by elisa (r&d systems conclusions in neutrophils exposed to cse, viability is maintained and cxcl release increases with increasing dose of cse. we conclude that cigarette smoke stimulates an infl ammatory response by neutrophils, which would contribute to the infl ammatory burden in the airways in copd. introduction factor viii (f ) and collagen iv (c ) antibodies are used for quantifying vessels in tissue sections. we compared these two antibodies for vessels staining in bronchial biopsies (bb) in copd. methods bb from healthy non-smokers (h-n) and copd subjects were stained for both antibodies. number, area and mean vascular size (mvs) (surface area/vessel number) of vessels in the lamina propria (lp) to the depth of μm were measured and compared between the two antibodies and are reported as median (range). results number of vessels was not signifi cantly different between the two methods of staining. in copd and h-n, vascular area (μm /μm of lp × ) stained with f was less than that with c ( . ( . - ) vs. ( - . ), p < . and . ( . - . ) vs. . ( . - . ), p < . introduction previous studies have shown that c-reactive protein levels increase at the onset of some copd exacerbations; however, there is limited data on the normal fl uctuation in crp levels in stable patients. aim to investigate within patient variation in crp levels to determine the magnitude of normal day-to-day fl uctuations in stable patients and the correlation with patients' perception of symptom severity. methods early morning crp levels were measured on days , and from patients from the melbourne copd cohort (gold category ii-iv) who identifi ed themselves as stable. patients recorded daily symptom scores including: borg dyspnoea scale at rest, severity of wheeze, cough, dyspnoea, change in sputum colour or volume, night-time waking and the presence of viral symptoms. crp levels were measured by the clinical pathology service and using a point-of care device. variation in crp levels in stable copd and correlation between change in crp levels and symptoms were analysed. aim patient-completed diaries monitoring changes in key symptoms in copd are often used to recognize acute exacerbations (ae) both to prompt additional treatment and monitor treatment effi cacy. we assessed diary compliance and the predictive value of major symptoms of aes which required hospital attendance. methods inpatients recruited during an ae of copd completed daily paper or web-based diaries for months, recording changes from their stable state for: breathlessness, cough, sputum, subjective 'wellness', physical activity and use of reliever ( -point scale, mid-pt = no change). the predictive value of current and lagged symptom scores was compared for each and between symptoms. diagnostic accuracy was assessed by area under the curve (auc) and at specifi c cut-points. in participants ( m, f) with mean age ± and mean fev % predicted ± , there were such aes involving patients. duration of diary keeping was shorter with lower education attainment (p = . ), but compliance did not vary for other demographic or clinical factors. daily compliance while diaries were being kept was %. excluding the current day, the best predictor was the distributed lag score over days, sputum changes giving the strongest signal; relative risk . ( % ci . to . ) with most of the signal in the days prior to the ae. little was gained by combining symptoms. the predictive value was moderate auc = . . conclusions compliance with symptom diaries in severe copd is surprisingly good. however, with only a weak signal for an impending ae requiring hospital attendance up to hours before and for lagged symptom scores over days before, with low positive predictive values, the utility of keeping daily symptom diaries for raising alerts for impending severe aes in copd is questionable. results seven studies with inpatient participants were identifi ed; published as abstracts for which data were not available did not contribute to meta-analyses. no study specifi ed diagnostic criteria for copd and only one specifi ed ae criteria. short course treatment varied between - days and longer duration - days; studies used oral prednisolone (dose mg, studies, tapered dose) and studies used intravenous scs treatment. mean ages of participants ranged from to years. primary outcomes: likelihood of treatment failure did not differ by duration of treatment (odds ratio . ; % ci . to . ) ( studies, n = ). fev did not differ signifi cantly when measured up to days (mean difference (md) − . l; % ci − . to . ) or after days (md − . l; % ci − . to . ) ( studies, n = ). secondary outcomes: limited data ( study) precluded meta-analysis for readmission or mortality. the likelihood of an adverse event ( studies, n = ) was not signifi cantly lower for shorter scs (or . ; % ci . to . ). conclusions we found no signifi cant differences between short (≤ days) and longer (> days) corticosteroid therapy for ae of copd. this has implications for clinical practice and may reduce adverse effects for patients, shorten hospital admissions and reduce costs, but more studies are needed to confi rm these fi ndings. aim to explore factors which infl uence the self-management of exacerbations in patients with copd. methods a pilot cross-sectional study was undertaken to assess patients' compliance with their action plan and their action taken prior to an admission. patients were interviewed during an admission to hospital for exacerbation of copd. the effect of pulmonary rehabilitation on patients' knowledge of copd was also assessed. results % of patients were provided with a written action plan, and % with a verbal action plan. in response to an exacerbation, more than % of the patients stated that they used their action plan. however, where action plans were not adequately utilized, patients delayed seeking medical attention and failed to initiate oral prednisolone and antibiotics during an exacerbation despite being prescribed an emergency supply of these medications. pulmonary rehabilitation had a positive outcome towards enhancing the patients' knowledge of copd. clinical pharmacists have limited involvement in terms of copd and smoking cessation education. conclusion the need to offer a thorough self-management program along with providing a more comprehensive written action plan will encourage patients to start early treatment and follow their action plans. encouraging collaboration between the hcp and patients encourages self-management through discussing and agreeing on goals of treatment and developing a personalized written action plan. context dyspnoea is a common symptom in copd and increases during exacerbations. when respiratory failure supervenes, and assisted ventilation is required, non-invasive ventilation (niv) is the treatment of choice. objective to determine if niv relieves dyspnoea in inpatients with acute respiratory failure due to exacerbations of copd. data sources english language randomized controlled trials (rcts) published prior to august were identifi ed using medline, embase, cinahl, psychinfo and pubmed. additional studies were identifi ed by reviewing the reference list of included studies. search terms included niv, nippv, nppv, bilevel cpap, bipap, artifi cial ventilation, copd and randomized controlled trial. study selection rcts comparing usual medical care (umc) to umc plus niv and measuring dyspnoea at relevant time points were included. abstracts for potentially relevant articles were extracted by one author. these were assessed by a second author to ensure inclusion criteria were met. articles were reviewed to determine if dyspnoea was measured and appropriate statistical analysis reported. the search yielded individual articles. four articles met the review criteria. three articles fi nd that niv relieved dyspnoea to a statistically signifi cant level and two suggested that the relief of dyspnoea is clinically signifi cant. discussion in spite of the common use of niv to relieve dyspnoea, little work has analysed effi cacy in terms of this patient-reported outcome. while our results may suggest niv relieves dyspnoea, reporting or methodological fl aws in several articles limit the strength of the conclusions that may be drawn. these limitations make the conclusion that niv relieves dyspnoea contentious. conclusion despite over two decades of studies investigating niv, the therapeutic impact on breathlessness is poorly described. understanding the impact of niv on patient-reported outcomes is of critical importance in clinical care. confl ict of interest none. introduction in mice, the most direct lung dosing method delivers the agents directly into the trachea. for our cystic fi brosis gene-therapy studies, we deliver fl uids -an airway pretreatment followed by a lentiviral vector -directly into the mouse trachea to target conducting airways. despite using standardized delivery techniques, we see substantial variability in the amount and location of gene transfer. aim the aim of this experiment was to use synchrotron x-ray imaging to track the dynamics of fl uid doses delivered into the live mouse trachea. methods four nembutal anaesthetized c bl/ mice were imaged on the bl b beamline at the spring- synchrotron. mice were intubated and ventilated at br/min with image captured per breath. after minute of baseline, a -μl sample of iodine-based contrast fl uid (a surrogate for our airway pretreatment or gene-vector) was delivered over seconds. following minutes of data collection, an additional μl bolus was delivered over . seconds. image capture continued for a further minutes. frame differencing was used to reveal fl uid motion. results substantial dose losses may occur upon delivery into mouse trachea via immediate retrograde fl uid motion. the speed of bolus delivery into lung may also infl uence the relative targeting of conducting airways and deep lung. introduction use of effi cient nebulizers can enhance the quality of life of cf patients by reducing the treatment time and improving drug delivery effi ciency. the aim of this study was to determine which commonly recommended nebulizer was optimal for delivery of the most commonly used therapies to cf. methods seventeen children with cf ( - years) were recruited. delivery of three commonly used cf therapies ( % hypertonic saline ( ml, . g/ ml), tobramycin ( ml, mg/ml) and pulmozyme ( . ml, mg/ml)) by two vibrating membrane nebulizers, the eflow rapid and the aeroneb go, and a jet nebulizer lc sprint junior with pariboy sx ( . l/min) were tested. for each drug-nebulizer combination (in random order), each child was asked to inhale through an inspiratory fi lter, and drug delivery to the fi lter was measured. pulmozyme was quantifi ed using an enzymatic activity assay, tobramycin was measured using hplc and hypertonic saline was measured using conductivity. total nebulization time was recorded. the results showed that there was no difference in the amount of drug delivered to patients when the nebulizers were compared for all three therapies (p > . ). however, the nebulization time for the eflow rapid was signifi cantly shorter than that for the aeroneb go and lc sprint junior. similarly, the nebulization time for aeroneb go was shorter than that for the lc sprint junior (p > . ) for all therapies). conclusion overall, there were no signifi cant differences between nebulizers in delivered dose for three forms of cf therapy, due to inter-patient variability. despite this, both vibrating membrane nebulizers had shorter nebulization times than the lc sprint junior, with the eflow rapid delivering drug in the shortest time. confl ict of interest nil. introduction as the life expectancy of patients with cystic fi brosis (cf) increases, treatment-related morbidity is increasingly recognized. totally implantable venous access devices (tivads) offer reliable long-term central venous access but are associated with recognized complications including venous thrombosis. superior vena cava syndrome (svcs) however has been rarely reported in this setting. we report a single cf centre's experience of svcs associated with tivads. methods retrospective review of episodes of svcs in patients with cf and a tivad attending the adult cf centre, prince charles hospital, queensland. results between february and december , fi ve episodes of svcs occurred in patients with tivads from a clinic population of patients. all of the affected patients were female, with moderately severe lung disease (mean fev predicted . %). no patients had a recognized thrombophilia. four tivads were inserted at a centre different to our own, three were on oestrogen-based contraception, and two suffered with dehydration at presentation. svcs treatment consisted of anticoagulation ( ), line removal ( ), angioplasty ( ), thrombolysis ( ) noninvasive bioluminescence imaging has allowed for rapid in vivo quantifi cation of long-lasting gene transfer in experimental animals. we are testing the longevity of a single nasal delivery of our lentiviral (lv) gene transfer system in mouse airways. methods normal (c bl/ ) and cystic fi brosis (cf) mice received a nasal bolus of lysophosphatidylcholine (lpc) or a control (pbs) pretreatment hour prior to delivery of a lv vector containing the reporter-gene luciferase (lv-luc). another control group received lpc hour prior to an empty vector (lv-mt). bioluminescence was measured at week, , , , , , , , and months post-lv dosing to assess gene transfer. results normal mice: mice that received lpc/lv-luc treatment had significantly greater gene transfer compared to the two control groups at all time points (p < . , rm anova). no luminescence was detected in mice treated with lpc/lv-mt. unexpectedly, luciferase activity was also detected in the lung. there was no difference in lung luminescence between the lpc and pbs pretreated mice that received lv-luc. cf mice: a statistically signifi cant increase in nasal luminescence persisted for up to months following lpc/ lv-luc (p < . , rm anova). similar to normal mice, there was no statistical difference in lung luminescence between mice that received lpc and pbs lv-luc. conclusions lentiviral luciferase gene expression was signifi cantly improved in mouse nasal airways using lpc pretreatment in both strains. however, the longevity of transduction was reduced in cf mice, which may, in part, be due to reduced animal numbers at the later time points tested. supported by nh&mrc. background the nintendo-wii® facilitates exercise-based programs that may be considered novel, fun and potentially motivating. objective exercise outcomes using the wii have yet to be reported in the cystic fi brosis (cf) adult population. aim to investigate nintendo-wii® exercise training compared with standard exercise in adult cf patients whilst hospitalized for treatment of a pulmonary exacerbation. methods a within-subjects, randomized cross-over study. adult cf participants received two -minute exercise treatment sessions within a -hour period, at least day apart, during the last days of hospitalization. wii exercise consisted interval training with games such as boxing, dancing and track exercises. standard exercise consisted of interval training on treadmill or cycle ergometer at - % of heart rate maximum. results participants completed the study (mean (sd) age ( ) years, % females), with a mean fev % of ( )%. during exercise, no difference was found between groups in average heart rate (p = . ), oxygen desaturation (p = . ), borg rate of perceived exertion (p = . ) or modifi ed borg for dyspnoea (p = . ). on vas ( - ), participants reported the wii program to be more enjoyable (p < . ) and less fatiguing (p = . ). participants rated both exercise sessions as equally effective (p = . ). conclusions this study suggests that a nintendo-wii® exercise session provides an equivalent cardiovascular demand to a standard exercise session in an inpatient adult cf population. greater enjoyment levels and lower fatigue levels reported during nintendo-wii® training may have a positive infl uence on adherence to exercise. further study into the long-term effects of nintendo-wii® training needs to be undertaken. confl ict of interest nil. introduction ion transport is important to maintain the airway epithelial surface, as shown by the disease cystic fi brosis (cf) which is characterized by decreased clsecretion and increased na + absorption. we have previously shown that the cf airway can develop clresponses when the surface is nominally calcium free (middleton et al. ajrccm ; : - . aim to determine the effects of citrate on the nasal potential difference (npd) with and without amiloride pretreatment, and to compare these effects with other clinically relevant calcium chelators and dicarboxylic acids. methods npd was measured using standard techniques (erj ; : ) in cf and non-cf subjects. the nasal pd response to citrate, oxalate, malate, succinate and fumarate (all mm) was compared with the calcium chelators edta and egta. results citrate decreased the basal npd by ∼ mv, but in the presence of amiloride, citrate increased the pd by ∼ mv. with amiloride/low clpretreatment, citrate increased npd by - mv, which suggests that citrate increased clsecretion. in contrast, the other dicarboxylic acids and calcium chelators exhibited little response. conclusion the combination of these responses suggests that citrate exerts complex effects on airway ion transport, most likely dual effects of decreased na + absorption and increased clsecretion. aim to assess the validity of the international physical activity questionnaire (ipaq) in cf adults by comparing energy expenditure measured by the ipaq versus the accelerometer. methods with ethics approval, suitable successive adult patients with cf attending the alfred cf outpatient clinic were recruited. all participants wore an accelerometer (actigraph gt m) around the waist for days of awake time, at the end of which, they completed the ipaq. criterion validity of the ipaq was assessed by comparing the ipaq weekly energy expenditure (ee) in kilocalories (kcal) with weekly ee (kcal) from the accelerometer using spearman correlations and bland-altman procedures. results thirty participants ( % females) completed the assessment: mean (sd); age = ( ) years, fev %predicted = ( ) the median (range) ee: ipaq = ( , ) kcal, gt m = ( , ) kcal. spearman correlations of fev %predicted with ee were gt m ee r = . , p < . ; ipaq ee r = . , p > . . correlation of the ipaq ee with accelerometer ee was moderate (r = . , p = . ). there was a trend towards higher ee measured by the ipaq than measured by the accelerometer (wilcoxon signed ranks test: z = − . , p = . ). conclusion the ipaq underestimates physical activity for patients with lower energy expenditure activities and overestimates for those with higher energy expenditure activities in adults with cf. the ipaq would be a useful screening tool for exercise prescription and monitoring of physical activity longitudinally, but more quantifi able methods for assessment such as the accelerometer should be used in research. confl ict of interest none. infectious endometritis associated with pseudomonas aeruginosa (pa) is an important equine disease resulting in reduced fertility and decreased foal drop. previous typing studies of equine pa report clonal heterogeneity, suggestive of sporadic acquisition, and small clusters of indistinguishable strains. aim we performed molecular typing of a large sample of genital pa isolates from horses in s-e qld. methods thoroughbred genital tract pa isolates submitted to uq vet diagnostic lab during - (screening or infection suspected) were studied. eric-pcr fi ngerprint analysis was performed. isolates producing indistinguishable fi ngerprints were allocated to the same eric-pcr type. mlst was performed on a subset of isolates. results overall, genital (clitoral or uterine) swabs from mares and urethral fossa swabs from stallions located on stud farms were processed. pa was identifi ed in genital cultures from of the ( . %) mares but from none of the stallions. six clusters involving ≥ mares were detected. cluster-a was observed amongst isolates collected from ( %) mares from studs and each year. cluster-b isolates were present in mares from studs during - . clusters c-to-f each contained isolates from mares from or studs. conclusions overall, % of mares harbouring pa had clonally related strains. however, we found no evidence of horizontal transmission between stallions. these data raise the possibility of transmission via environmental or other sources. alternatively, specifi c strains may have trophism for the reproductive tract of horses. the fi nding of a dominant strain amongst thoroughbred mares in a geographic region has interesting parallels with recent evidence of the spread of highly prevalent clonal strains in cystic fi brosis clinics. aim to investigate the prevalence and impact of incontinence in adult men with cystic fi brosis (cf) as compared with age-and sex matched control subjects. methods men with cf were recruited through outpatient clinics and control subjects through advertisements to complete standardized questionnaires relating to respiratory symptoms, bladder and bowel function, mood and physical activity levels. demographic data were collected from medical records for the cf group. results seventy-four men with cf participated (mean (sd) age . ( . ) years). forty-nine men volunteered as controls ( . ( ) years), and were well matched in terms of physical activity levels. / ( %) in the cf group and / ( %) in the control group had reported episodes of urine leakage. in the men with cf, there was no difference in lung function between men with episodes of leak and those with no history of leak (fev % predicted ( )% vs. ( )%, p = . ). anxiety levels were higher in men from both groups with episodes of leak compared to those with no history of leak (hospital anxiety and depression anxiety score . ( . ) vs. . ( . ), p < . ). depression scores were also higher in men with episodes of leak compared to those with no history of leak ( . ( . ) vs. . ( . ), p < . ). conclusions urinary incontinence in men with cf is not associated with disease severity, as measured by lung function. anxiety and depression levels were higher in men with leakage of urine. confl ict of interest no. aim to investigate the bone mineral status of children and adolescents with cf and to explore the relationship between bone mineral density (bmd) and anthropometric and clinical parameters including height, body mass index (bmi), lung function tests and vitamin d levels ( -hydroxyvitamin d) in the cf centre at starship children's hospital, new zealand. methods bmd of the lumbar spine was assessed by dual x-ray absortiometry between january and december . the results of subjects with cf ( males) with a mean age of . years (range - . years) were collected. anthropometric data (height, bmi), forced expiratory volume in second as percent predicted (%fev ) and vitamin levels were assessed and related to bmd. results bmd in our subjects was low in . % and very low in . % when adjusted for age, sex and height (difference in bmd g/cm in the lumbar spine l -l ). there was a strong positive relationship between the lumbar areal bmd (abmd) and bmi z scores (p < . ), abmd and % fev z scores (p < . ), and abmd z scores and vitamin d levels (p < . ). conclusions bmd was normal in the younger and well-nourished subjects with normal or mild reduction of fev . low bmd appeared to evolve during adolescence with decreasing bmi and reduction in lung function. this will lead to ongoing bone disease in early adulthood. it is a further indication to maintain optimal nutritional status and maximize lung health. malnutrition in cf is associated with poorer pulmonary function and is an independent risk factor of survival. aim to compare the nutritional status of the adults attending an adult cf centre in with . method retrospective audit of patients ( excluded, incomplete data) including demographics, nutritional status, pancreatic enzyme replacement therapy (pert) usage, glucose tolerance and dietetic review. results the mean age of the clinic population increased from . to . years. mean (sd) bmi increased from ( . ± . kg/m ) to ( . ± . ) (p = . ). in , % of the clinic population was taking pert with a mean dose of ± iu lipase/kg/day. the proportion of patients with abnormal glucose tolerance has increased from % to % (p = . ). oral supplement use has increased from % to %, yet enteral feeding remained stable ( % − , % − ). this occurred during period of increased annual dietetic review of the patients attending the clinic from % in to % in (p = . ). discussion over a -year period, an improvement in mean bmi refl ects improvement in nutritional status. prevalence of abnormal glucose tolerance has increased; this is likely due to commencing a screening program ( ). use of oral supplements has increased and is higher than identifi ed in the recent daa survey of nutrition practices of cf dietitians ( %). annual review by the cf dietitian has increased despite a twofold increase in the cf population may be attributable to a stable and experienced workforce. current service provision of . a abbott , e cheung , l morgan aim to characterize the microbial colonization of a group of stable adults with non-cf bronchiectasis using an extended culture protocol. methods sputum was collected over an -month period from clinically stable patients. standard semi-quantitative bacterial culture was extended to days with the addition of fungal and mycobacterial culture as routine. results specimens of spontaneously expectorated sputum were collected from patients; mean age years ( - years); mean (sd) fev / fvc ratio % ( %); / never smokers; / on inhaled or oral corticosteroids. the bacteria identifi ed were p. aeruginosa ( % of specimens), h. infl uenzae ( %), h. parainfl uenzae ( %), acinetobacter baumanii ( %), enterobacteriaceae ( %). commensals only were identifi ed in % of specimens. fungi included candida species ( %), aspergillus fumigatus ( %) and penicillium species ( %). non-tuberculous mycobacteria (ntmb) were grown in % of specimens: m. gordonae ( %), m. intracellulare ( %) and m. lentifl avum ( %). the ntm identifi ed were all considered non-pathogenic. only the mycobacteria were identifi ed after day . conclusion microorganisms with potential pathogenicity are frequently identifi ed in adult patients with non-cystic fi brosis bronchiectasis who are not experiencing an acute exacerbation. all these organisms were identifi ed using a standard short culture protocol. the extended regimen, which was costly, did not identify any unusual or unexpected pathogens. it was rare for patients to be colonized with fungi. this study suggests there is limited value in requesting extended culture for bacterial pathogens, including looking for fungi or nmtb in this stable patient group as this adds little to the empiric antibiotic choice for infective exacerbations. confl ict of interest none. s stelzer-braid , , h alsubie , a neilsen , h johal , a steller , er tovey , k mckay , p van asperen , wd rawlinson , introduction respiratory infections are of fundamental importance in determining the morbidity and mortality associated with cystic fi brosis (cf) as such infections can lead to progressive and fatal obstructive lung disease. using polymerase chain reaction (pcr) to detect such infections has advantages over previous studies that used relatively insensitive traditional detection methods and could have underestimated viral prevalence. methods viral and bacterial multiplex pcrs were developed for detection of respiratory pathogens important for children with cf. nasal brush samples were collected from cf patients who were symptomatic or asymptomatic for acute respiratory illness (n = ). sputum and exhaled bioaerosols via a novel mask sampler were collected from a subset (n = ). results as expected, almost all ( %) sputum samples were positive for bacteria. detection of bacteria in the upper respiratory tract was lower ( . %). data from nasal samples indicated strong association of viral pathogen presence, particularly rhinovirus, with exacerbation of disease. results also showed good evidence for rhinovirus infection in the lower respiratory tract. the novel mask sampler is promising as a non-invasive sampling tool. conclusions our results demonstrate the importance of pathogens in exacerbations. early detection and understanding the development of bacterial and viral infections in cf patients is important in clinical decision-making as more and better antiviral and antibiotic agents become available. aim to determine the factors affecting microbiological yield from bronchoalveolar lavage (bal) in patients with suspected pulmonary infection and haematological malignancy or following stem cell transplantation at a tertiary bone marrow transplant centre. methods a retrospective -month audit of patients with pulmonary infi ltrates or febrile neutropenia with haematological malignancy or post-stem cell transplant who underwent bal for microbiological diagnosis. data were obtained on microbiological yield, radiographic appearances, current antimicrobial therapy, the presence and duration of neutropenia and complication rate. of the bal procedures performed, a clinically signifi cant microbiological result was obtained in % of cases ( / ). of these positive results, % ( / ) were exclusively viral pathogens, % ( / ) were fungal, % ( / ) were bacterial and polymicrobial infection was observed in % ( / ) of cases. a high proportion of patients had commenced anti-microbial treatment empirically, with % ( / ) receiving broad spectrum antibacterial treatment and % ( / ) receiving treatment doses of antifungal agents prior to bronchoscopy. in % ( / ), the results of the bal changed the patients therapy. the presence and duration of neutropenia or radiological appearances were not reliable discriminators of specifi c infective aetiologies. complication rates were low and included fevers in % ( / ), hypoxia % ( / ), small volume haemoptysis in % ( / ), atrial fi brillation in % ( / ) and pneumothorax in % ( / ). conclusion whilst bal remains a safe and important tool in establishing a microbiological diagnosis in immunosuppressed patients with pulmonary infi ltrates, a clinically signifi cant yield and changes to patient treatment occur in the minority of cases. clinicians should have a high degree of suspicion of viral infective aetiology when treating this population of patients. aim to examine the outcomes and complications of intercostal catheter (icc) treatment of pneumothoraces (primary (pp) and secondary (sp)) and effusions (malignant (me) and parapneumonic (pe)). methods retrospective review of all iccs in admitted patients in a respiratory unit over months. data collected included type of pneumothorax or effusion, icc type, insertion details, complications (major and minor) and outcome (success defi ned as resolution of pneumothorax or effusion with single tube insertion). results patients required icc treatment. forty-six iccs were used in patients with pneumothorax: pp ; sp ; iatrogenic ; hydropneumothorax . complication rate was % ( % major) and was signifi cantly less in pp ( %) compared with sp ( %), p < . , chi-square. success rate for pneumothorax icc drainage was % (signifi cantly higher for pp ( %) compared with sp ( %), p < . ). fifty-eight iccs were used in patients with pleural effusions: me , pe , other . complication rate was % ( % major) and was signifi cantly higher in me ( %) compared with pe ( %), p < . . success rate for effusion icc drainage was % (signifi cantly less in me ( %) compared with pe ( %), p < . ). small bore iccs (gauge < fr) were used for % of pneumothoraces and % of effusions. tube size did not signifi cantly infl uence complication or success rate for either pneumothoraces or effusions. conclusions compared with pp, icc treatment of sp was less successful and more likely to be associated with complications. similarly, compared with pe, intervention for me with icc was less successful and had a higher complication rate. we conclude that icc intervention is most successful for pp and pe, and speculate that sp and me should have early surgical intervention. introduction spontaneous pneumothorax is a common condition. current management guidelines recommend large pneumothoraces are managed by primary intercostal catheter insertion. we report a single centre's experience in the management of large spontaneous pneumothorax. methods retrospective audit of cases of spontaneous pneumothoraces managed at the prince charles hospital between january and december . patient demographics, co-morbidities, presenting symptoms, examination fi ndings, radiology, management and complications were reviewed. results forty-two patients ( male, female) experienced episodes of spontaneous pneumothorax. chest pain and dyspnoea were the most commonly reported symptoms ( ) %. there were forty-two ( %) episodes of large pneumothorax (≥ % of hemithorax). management of large pneumothoraces consisted of: observation, ( ) seldinger icc ( ) and large bore icc ( ). complications occurred in three patients with seldinger icc ( vasovagal, hydro-pneumothorax) compared to none with large bore icc. outcomes were similar for patients managed by observation compared to icc insertion. all recurrent cases ( %) were referred for consideration of surgical pleurodesis. conclusion patients with large pneumothorax managed by observation recovered similarly to those treated with icc, suggesting a higher threshold for icc insertion should be considered in the future. grant support nil. aim a pilot study of an instrument of pleural ultrasound training in thoracic physicians after a pleural ultrasound course. the instrument was tested for inter-observer agreement and also its ability to be used in a patient compared to a dedicated manikin. methods all chest physicians ( ) were novices in ultrasound and underwent a dedicated -day training course in pleural ultrasound at the australian institute of ultrasound. they were assessed months later by radiologists and one senior ultrasonographer using a specially designed pleural ultrasound training assessment tool (usgt-sat) on both a subject with pleural effusion and a dedicated ultrasound manikin. the mean scores, out of a maximum of , obtained by the each of the participants for the manikin were . , . , . and . , respectively, while the scores for the patient was . , . , . and . , respectively. the mean scores of the participants as a group for manikin were ± . and for the patient as . ± . . there was general agreement between the examiners with mean combined participant scores of . , . and . in the manikin, respectively, and mean score of . , . and . in the patient. conclusions this pilot study shows ranges of scores for design of future validation studies of the usgt-sat. test performance by the chest physicians after a short course in pleural ultrasound was generally good and results for the use of the manikin as an alternative to patients in pleural ultrasound training are encouraging. further studies with larger sample size are required. supported by nil. nomination nil. confl ict of interest no. since the fi rst commercial availability in , fl exible bronchoscopy has evolved from a simple 'look see' procedure to a more complex multifaceted one. today, fl exible bronchoscopy is a tool used for diagnostic procedures, surveillance, delivery of therapy and clinical trials. increasingly, it involves utilizing expensive purpose built equipment in complex diagnostic procedures. this evolution requires a specifi c knowledge base and skill set to safely perform the procedure and care for the equipment. this now mandates additional training by nursing and medical staff to develop and maintain the required skills. medical staff now rely on their nurses to assist in the full range of procedures. thus, the nurses must keep abreast of modern trends and techniques. the modern bronchoscopy suites team is an integrated one, with specifi c roles, defi ned to each member. the procedures performed will refl ect local needs and expertise. just as bronchoscopy has evolved into the speciality of interventional pulmonology, so must bronchoscopy suite nursing be accepted as a specialized area of nursing with a credentialed 'special interest group' to promote, educate and develop the subject as more therapeutic and diagnostic procedures evolve. this will allow nurses involved in bronchoscopy to be respected, recognized and accepted for their unique knowledge and abilities. confl ict of interest nil. background transthoracic pneumostomy (tp) is a novel treatment for patients with severe emphysema that aims to defl ate the lung and improve function. aim to assess the effect of unilateral tp on the volume of each lung and mechanical properties of the lungs. methods subjects were recruited for a multicentre trial of tp (see actrn ). in parallel with the main protocol, we measured ( ) in the six subjects recruited, compared to plethysmography, lung volume was overestimated by cxr (mean difference + . %, range − . to + . ) and underestimated but more closely correlated by ct (mean difference − . %, range − . to − . ). based on ct, the volume of the treated lung decreased in all patients after tp (mean − . %, range − . to − . ) whilst that of the untreated lung did not change (mean − . %, range − . to + . ). in patients with available data, tp reduced dynamic hyperinfl ation during exercise (mean − ml, − . % of ic, range + . % to − . %). lung mechanics were performed in patients. low lung elastic recoil prior to tp and an increase in elastic recoil after tp were associated with greater reductions in lung volume and greater improvements in exercise tolerance. conclusions supine chest ct provided reasonably accurate estimates of plethysmographic lung volume. unilateral tp defl ated the lung and there was no evidence of signifi cant compensatory hyperinfl ation of the contralateral lung. tp also reduced dynamic hyperinfl ation. measurement of lung elastic recoil may help select patients who are likely to benefi t from tp. support and confl ict of interest nil. methods we performed a retrospective chart review of all adult patients who had an icc over a -month period within a tertiary hospital respiratory service. we noted patient demographics, details surrounding chest drain insertion including image guidance and subsequent inpatient events. results over a -month period, there were small-bore icc insertions, of which were image-guided. mean patient age was years, males comprised / . forty drains were inserted for pneumothoraces, for malignant effusions, for parapneumonic effusions, for transudates and for undiagnosed exudative effusions. mean duration of drainage was . days. there were no life-threatening complications. three of the chest drains fell out and became blocked. six pneumothoraces were noted, all following insertion without direct image guidance; none required further intervention. local infection occurred in patient. insertion details were not documented in patients. conclusion insertion of small-bore iccs via the seldinger technique appears to be a safe method of draining pneumothoraces and pleural effusions. image guidance may reduce complication rate of this procedure. documentation of drain insertions could be improved. confl ict of interest nil. rationale pleural effusions are frequently encountered in clinical practice, and often require aspiration for diagnostic and/or therapeutic purposes. use of radiological guidance varies, despite current guidelines recommending routine use of ultrasound. furthermore, concerns exist regarding the downskilling of thoracic medicine trainees due to the increased use of interventional radiology. as a precursor to developing a procedural pleural ultrasound service, we performed a retrospective case review of our current practice. methods patients who had pleural fl uid sent to pathology between january and december were identifi ed on an existing database. patient records were reviewed and details regarding the drainage procedure and outcomes were recorded. information on patient location, method of procedure and performing clinician were also collected. results to date, pleural fl uid aspirations in patients have been identifi ed. overall, % of aspirations were carried out on the ward and % in the radiology department. two procedures occurred in the endoscopy suite on outpatients, and one in the emergency department. fifty percent of procedures were performed using an intravenous cannula for drainage and % utilized a pigtail catheter. all procedures occurring in the radiology department were performed under ultrasound guidance by a radiologist or radiology registrar. of the remaining procedures, % were performed by medical registrars and % were performed with ultrasound marking. six complications occurred following procedures: pneumothoraces, vasovagal and tube blockage. there were signifi cantly more pneumothoraces in patients who did not have an ultrasound marking ( of without marking, of with marking, p = . ). none of the complications required further intervention. conclusion these preliminary data suggest ultrasound marking signifi cantly reduces pneumothorax incidence, supporting the establishment of a pleural ultrasound service. this is likely to have the added benefi t of improved training for thoracic medicine trainees. aim to investigate differences between semi-recumbent and supine posture in terms of cough rate, degree of oxygen desaturation, oxygen supplementation, increase in pulse rate and sedative use during the initial phase of bronchoscopy. methods consecutive patients (n = ) undergoing diagnostic bronchoscopy at an endoscopy unit were recruited for this observational cohort study. the posture was determined by the bronchoscopist's usual practice. patient age, gender, % predicted fev and fvc, indication, pulse and oxygen saturation were recorded. the initial phase was defi ned as the time from bronchoscopy insertion to visualization plus lignocaine instillation of both distal main bronchi. cough rate, peak pulse, nadir oxygen saturation (spo ), range of oxygen supplementation and sedation use during the initial phase were recorded. a post-procedure questionnaire was administered to the patient and the attending nurse. results patients had bronchoscopy in the semi-recumbent posture and in the supine posture. three of bronchoscopists performed in both postures. there were no signifi cant differences in age, gender, smoking status and spirometry between the two groups. the semi-recumbent postures resulted in signifi cantly less cough rate (mean (sd) . ( . ) vs. . ( . ) coughs/min, p = . ) and less fentanyl use ( ( ) vs. ( ) mcg, p = . ) in the initial phase. there were no signifi cant differences in the nadir spo , fall in spo , oxygen supplementation or increase in pulse rate between the two groups. nurse perception of patient discomfort was lower in the semirecumbent position ( ( ) vs. ( ) mm on mm visual analogue scale, p = . ), and there was a trend towards less patient-perceived cough during the procedure in the semi-recumbent group ( ( ) introduction pulmonary infi ltrates in immunocompromised patients with haematological malignancy have a diverse aetiology and are a major source of morbidity. a specifi c diagnosis and targeted therapy may optimize outcomes and reduce the cost of treatment. the diagnostic value of fi breoptic bronchoscopy (fob) and the infl uence of timing of the procedure are unclear. aim to determine the yield of fob, its impact on antibiotic therapy and the infl uence of early vs late timing in this patient population. methods we conducted a retrospective review of immunosuppressed patients with underlying haematological malignancy and new pulmonary infi ltrates who underwent fob over a -month period. the outcomes of early (eb, ≤ days from initial respiratory consultation) and late (lb, ≥ days) fob were compared using fisher's exact test. results thirty-eight fobs, including bronchial or transbronchial biopsies, were performed in patients (males ). there were patients who received eb and who received lb. a specifi c diagnosis was obtained from procedures ( %), including infections ( in eb vs. in lb, p = . ) and non-infective diagnoses ( eb vs. lb, p = . ) based on histology. fob fi ndings from procedures ( %) ( eb vs. lb, p = . ) resulted in modifi cation of antibiotic therapy. there were no procedure-related severe complications. conclusions fob is a useful diagnostic procedure which infl uences diagnostic and therapeutic decisions in this patient group. although early procedures tended to be more likely to change antibiotic therapy than late procedures, the difference was not signifi cant. confl ict of interest none. capsule endoscopy is increasingly performed in gastroenterology to investigate possible small intestinal bleeding. the capsule endoscope is swallowed and then takes photographs every seconds for hours during its transit through the gastrointestinal tract. the images are downloaded by a radio link and the capsule is then passed normally and disposed of. in the present case, the capsule endoscope was inhaled and lodged in the bronchus intermedius. this was only recognized when the images from the capsule download were examined. removal of the capsule was effected with a fi breoptic bronchoscope using an ercp balloon and roth basket. this is believed the only capsule bronchoscopy so far reported. capsule endoscopes are large ( mm × mm diameter) and smooth. this case report shows the images from the capsule endoscope and describes the methods necessary to remove this unusual foreign body from the lung. support nil. background bronchoscopy with endobronchial biopsy (eb) is now an integral component of the research evaluation of airway diseases. there are no published safety data for eb in adult non-cf bronchiectasis. methods a subgroup of subjects enrolled in the bronchiectasis and low dose erythromycin study (bless) a randomized controlled trial of long-term prophylactic erythromycin (anzctrn ) underwent bronchoscopy with bronchoalveolar lavage (bal) and eb performed by a single operator. results ninety-nine bronchoscopies were performed (bal alone in ) in subjects. of procedures with eb, ( . %) were associated with very signifi cant bleeding (> ml either at time of eb or several days post-procedure) and a further ( . %) with immediate moderate bleeding ( - ml). one subject had a history of prior signifi cant haemoptysis. in the four subjects with very signifi cant bleeding, immediate bleeding of > ml occurred in subjects, ml in one subject and ml in one. immediate bleeding was controlled uneventfully. three of the subjects subsequently developed signifi cant haemoptysis (> ml) to days post-bronchoscopy without intervening haemoptysis, with one subject developing massive haemoptysis (> ml) on day post-bronchoscopy. further research ebs were ceased. in one of the subjects with 'delayed rebleeding', repeat bronchoscopy confi rmed the biopsied lobe as the bleeding site. haemoptysis settled in all subjects within hours with simple conservative measures. conclusions in contrast to the experience in asthma and copd, research eb in adults with non-cf bronchiectasis is associated with a signifi cant risk of bleeding, of potentially life-threatening magnitude in . % of cases. of particular concern was the observation of sudden onset delayed rebleeding developing up to days post-eb in spite of early local control. histopathological evaluation will clarify the potential contributions of airway wall vascularity and infl ammation to these events. malignant mesothelioma (mm) is an aggressive cancer which is often associated with exposure to asbestos and sv . this disease has a high latency period and a low survival rate. therefore, new strategies for therapeutic intervention must be developed. recent studies have shown that developmental pathways including the hedgehog (hh) pathway are associated with various types of cancers. the aberrant activation of key hedgehog pathway proteins has been shown to contribute to cancer progression. however, the role of this pathway in mm has yet to be explored. we hypothesize that aberrant activation of the hh pathway is a contributing factor for the development of mm. the mrna expression of hh pathway genes; sonic hedgehog (shh), patched - (ptch- ), smoothened (smo) and gli- were examined in mm cell lines and tumour tissues by rt-pcr and qrt-pcr. hh pathway proteins and mrna expression and distribution were then observed in the tumours by immunochistochemistry and in situ hybridization. we used real-time superarrays to examine the change in expression of a panel of key hh pathway genes by activating and inhibiting the pathway. we showed that the key hh pathway genes are expressed in both the cell lines and tissue samples. upon stimulation with the ligand shh, there was an increase in expression of indian hedgehog (ihh) and shh in most of the mouse and human cell lines that we looked at. interestingly, for the transcription factor gli- , there was a significant decrease in both mouse and human cell lines. inhibiting this pathway increased the expression of ptch in the mouse and human cell lines. the expression and up-regulation of key hh pathway components in mm at baseline and following stimulation suggests a role for the pathway in mm. methods incident cases were obtained from the australian and wa mesothelioma and cancer registries and death registries. exposure was calculated using measures of dustiness in the industry and the town for the period of employment or residence of each case. latency (time from fi rst exposure to diagnosis) by sex, age, smoking status, exposure variables and worker or resident status was estimated. multivariate linear regression modelling examined the determinants of latency. results the mean latency periods of . (sd = . ) years for lc and . (sd = . ) years for mm have increased linearly. increased duration of exposure was associated with reduced latency for mm after adjustment for age at fi rst exposure and age at diagnosis but not signifi cantly for lc. age at diagnosis was strongly associated with latency length for both lc and mm (p < . ). smoking, sex, cumulative exposure (log f/ml-year) and status at wittenoom were not related to latency. latency for lc with increasing age at fi rst exposure declined faster than for mm. conclusions age at diagnosis is associated with reduced shorter latency of mm and lc. duration of exposure is associated with shorter latency of mm. supported by nhmrc australia. confl ict of interest no. aim to assess overall survival of patients following resection for stage nsclc at a centre that has substantially greater resection rates than the nsw average. methods a retrospective audit of those patients who underwent lung resection for stage nsclc at nepean hospital between january and february . results patients ( m: f), mean age (range - ) underwent resection. there were pneumonectomies, bilobectomies and segmentectomies, one involving chest wall resection. the remaining procedures were lobectomies. there was one perioperative death from respiratory failure. actuarial overall survival at months was %, at months, % and at years %. survival was not infl uenced by histology or age. conclusion in our institution, we have an agreed aggressive approach to resection of stage nsclc and our resection rate is %. this pro-surgical policy is associated with good perioperative and long-term overall survival. confl ict of interest no. introduction malignant pleural effusions (mpes) are common, although their management varies widely. providing ambulatory care to minimize hospitalization is a key goal for patients with mpes. indwelling pleural catheters (ipcs) are a new treatment strategy that allows outpatient fl uid drainage. we hypothesized that mpe patients managed with ipcs require fewer hospital admissions. methods a prospective, multicentre, non-randomized study involving all three major respiratory centres in western australia. patients diagnosed to have mpes were prospectively followed, and admissions were recorded. in the absence of accepted guidelines for ipc use, the choice of treatments (thoracentesis, ipc, pleurodesis) was decided by clinicians in-charge. all complications were recorded. bacterial cultures of pleural fl uid were performed monthly for patients with ipcs. hm gallagher , ee duhig , ia yang , rv bowman , be clark , hm marshall , km fong aim to determine the concordance of histological subtyping of nsclc in diagnostic samples to the gold-standard lung resection specimens. methods we have so far evaluated consecutive subjects who underwent curative surgery for primary nsclc at the prince charles hospital between the years and . many of these had workup at other institutions. one hundred forty-seven had queensland health electronic record of positive preoperative diagnostic sampling. we correlated the fi nal nsclc who histological subtype with the subtypes diagnosed by samples prior to surgery including sputum, fi beroptic bronchoscopy (fob) and trans-thoracic needle aspiration (ttna). the resection subtype was set as the reference standard, and concordance was compared. results of the cases of resected nsclc, had malignancy on diagnostic sampling pre-resection, as shown in the results patients were included: median age years (range - ); % male; % living in major cities versus % in regional areas; % rightsided mpm; % epithelial subtype. median time from asbestos exposure to diagnosis was years (range - ). median time from fi rst symptoms or investigations to diagnosis was weeks (range - ). all patients had at least one chest x-ray and ct scan and % had pet scan. a variety of procedures led to the diagnosis: % thoracoscopy, % thoracotomy, % radiology-guided, % chest wall biopsy and % medical pleuroscopy, with % having had cytology alone. median number of diagnostic immunohistochemical stains used was (range - ), with calretinin ( %) the most commonly used mesothelial marker and carcinoembryonic antigen (cea; %) the most common carcinoma marker. median os for the cohort was . months ( % ci: . - . ), with no statistical difference in os between major city and regional patients ( vs. . months, respectively, p = . ). conclusions mpm appeared to affect mainly the elderly, and thoracoscopy was the most common diagnostic procedure. os did not differ between australian major city and regional patients and was comparable to the largest phase iii trial in mpm. aw musk , , p aboagye-scarfo , a reid , a miller, s ruwanpura, l mcleod, p bardin, n watkins, bj jenkins rationale lung cancer is the leading cause of cancer death worldwide. it is well established that cigarette smoking is linked to emphysema and lung cancer, and smokers with emphysema are at an increased risk of developing lung cancer. notably, recent epidemiological studies have indicated that emphysema can predispose to lung cancer irrespective of pack-year smoking history. although infl ammation has been proposed as a common mechanism linking these two diametrically opposed diseases, the conceptual inter-relationship between infl ammation, emphysema and lung cancer has been poorly investigated because existing experimentally induced and genetically modifi ed animal models for lung cancer occur in the absence of emphysema. method we have utilized a newly identifi ed mouse model (gp f/f ) of spontaneous lung infl ammation and emphysema in two well-established lung cancer models. the gp f/f mouse is characterized by deregulated cytokine signalling via gp , the critical co-receptor for the interleukin (il)- cytokine family, leading to hyper-activation of stat , a potent pro-infl ammatory and oncogenic latent transcription factor. in separate studies, we exposed gp f/f mice to a cigarette-derived carcinogen (nnk), and crossed them with the genetically susceptible kras(g d) strain of mice. results in both nnk-and kras(g d)-induced lung cancer models, the lungs of gp f/f mice were highly predisposed to hyperplasia and tumour formation. increased levels of cellular proliferation were observed in hyperplastic and tumour lesions, as well as surrounding areas, of these mice. these observations were verifi ed at the molecular level by gene expression profi ling of tumour-bearing lung tissue. conclusions these studies provide unique insights into the importance of interactions between the gp signalling axis and factors that predispose to lung tumourigenesis in emphysema. support nhmrc. aim to assess the preparedness of hospitals with respect to protecting health-care workers (hcws) during a pandemic. methods a self-administered questionnaire was performed between november and january , and a scoring system was developed to provide a quantifi able measure of preparedness. results a total of hospitals in nsw, australia, were approached -six regional hospitals (rhs) and six tertiary referral centres (trcs). the study was extended to assess three hospitals in england, allowing a limited comparison between the hospitals in australia that had faced the initial wave of the h n ('swine fl u') pandemic and the hospitals in the uk that had more time to prepare for the outbreak. response rates were % from the trcs, % from the rhs and % from the english hospitals. the overall preparedness scores were relatively high, with a median total score (adjusted) of . out of . the demographic that scored the highest total was tertiary referral centres in sydney. all english hospitals scored below the median. however, the range of scores across hospitals was quite narrow ( . - . adjusted). scores were generally high for the areas of preparedness, infection control, education and training. scores for vaccination were more variable. the category that consistently demonstrated the lowest scores was that of psychosocial welfare and assistance, despite this found in previous research to be an integral part of that which hcws have identifi ed as important. conclusions given their integral role in pandemic response, protecting hcws must be a priority as part of any pandemic preparedness plan. this goes beyond protection from infection, extending into aspects of physical and psychological wellbeing. identifying these issues and addressing them is the key to maximizing staff support and morale, and minimizing staff absenteeism at such a crucial time. aim to describe the relationship of respiratory and refl ux symptoms within the general population and relate this to the possible confounding factors of body mass index (bmi) and obstructive sleep apnoea (osa). methods data from a cross-sectional health survey, performed in bussleton, west australia in - , were used to examine the relative effects of bmi and osa on the relationship between respiratory and refl ux symptoms. questionnaire data included information on asthma, cough, wheeze, dyspnoea and gord symptoms. gord symptoms were categorized as never, monthly or less often and weekly or more often. bmi, risk of osa defi ned according to the berlin questionnaire, spirometry and airway hyperresponsiveness to methacholine were also recorded. logistic regression models obtained odds ratios for the associations between each gord symptoms, various respiratory symptoms, bmi and osa. results average age was years and recent wheeze was reported in % and cough and phlegm in %. twelve percent were current smokers. ahr was present in % and osa in %. gord symptoms occured in % and frequent symptoms (weekly or more often) were present in - %. there were strong positive associations between gord symptoms and cough/phlegm, breathlessness, chest tightness and wheeze in the last months. odds ratios increased with increasing frequency of refl ux p ≤ . . there was no effect of obesity or osa on the relationship between respiratory and gord. conclusion cough and phlegm, breathlessness, chest tightness and wheeze (ever or recent) are all strongly associated with symptoms of gord. this relationship is amplifi ed with increasing frequency of gord symptoms indicating a dose-response relationship between refl ux and respiratory symptoms. obesity and osa do not affect the association between gord and respiratory symptoms. introduction diesel exhaust particles (dep) make up the bulk of particulate matter in urban areas. high ambient levels of particulate matter are associated with increased hospitalization due to respiratory disease. we aimed to determine if exposure to dep exacerbates responses to acute viral infection. methods adult female balb/c mice were inoculated with μg dep or control . days after infection with . plaque forming units (pfu) of infl uenza a/mem (or control). six hours after dep inoculation, lung volume (tgv) and lung mechanics were measured by plethysmography and the forced oscillation technique, respectively. bronchoalveolar lavage fl uid was collected to assess cellular infl ammation and cytokine levels. results viral titre was signifi cantly higher in infl uenza-infected mice exposed to dep compared to those exposed to infl uenza alone (p = . ). both dep (p = . ) and infl uenza infection (p < . ) alone signifi cantly increased cellular infl ammation; however, there was no difference between mice exposed to both dep and infl uenza compared to those exposed to infl uenza alone (p = . ). a similar pattern was found in levels of cytokines in the bronchoalveolar lavage (tnf-α, mcp- , il- , ifn-γ). specifi c airway resistance, specifi c tissue damping, specifi c tissue elastance and hysteresivity were signifi cantly increased in infl uenza infected mice (p < . in all cases). none of these parameters were infl uenced by dep exposure alone (p > . in all cases) and there was no additive effect of dep on lung function (p > . in all cases) in infl uenza-infected mice. conclusions dep increases viral titre but is not suffi cient to physiologically exacerbate pre-existing respiratory disease caused by infl uenza infection in mice. supported by nhmrc. confl ict of interest no. introduction lack of treatments for post-transplant obliterative bronchiolitis (ob) is mainly due to the poor understanding of its pathogenesis and lack of small airway models. epithelial-mesenchymal transition (emt) may play a central role and could be crucial to developing treatment drugs. we hypothesize that emt induction may be prevented by pharmacologically available compounds. methods primary cultures of small and large airway epithelial cells (saec and laec) were established and emt induced by adding tgfβ ( ng/ml) (n = ). azithromycin ( - μm), mycophenolate ( . - mg/l) and rad ( . - ng/l) were then added and expression of epithelial (zo- , ck- ) and mesenchymal markers (eda-fn, vim) measured via western blot as well as mmp and activity via zymography. results signifi cantly lower increase in mesenchymal markers and lower decrease in epithelial markers, compared to controls was noted for azithromycin and mycophenolate indicating suppression of emt. mmp and activity increase was also signifi cantly suppressed. azithromycin suppressed emt to a greater extent compared to mycophenolate, but was equally effective in both small and large airway epithelia. rad appeared to have no effect. conclusions azithromycin and mycophenolate are both effective in preventing emt and thus have potential for the clinical treatment of ob. supported by abn foundation. confl ict of interest none. journal compilation © asian pacifi c society of respirology tp- g hodge , , s hodge , , c-l liew , , t-cell pro-infl ammatory cytokines are associated with acute lung transplant rejection. we have previously shown compartmentalization of production of these cytokines in bronchial intraepithelial t cells (iet) obtained by bronchial brushings from stable lung transplant patients. during acute rejection episodes, no signifi cant differences in iet cytokines were observed between stable and rejecting patients due to broad cytokine variability between patient groups. to overcome this limitation, we hypothesized that there would be increased graft pro-infl ammatory iet cytokines compared with native lung or trachea during acute rejection. methods cell cultures from stable patients, patients with evidence of acute rejection and bos and healthy controls were stimulated and intracellular cytokines determined using multiparameter fl ow cytometry. results there was a signifi cant increase in graft iet-cell ifnγ and tnfα in the lungs of patients with acute rejection compared with iet cells obtained from the native lung or trachea, but no changes were noted between other patient groups. there was a signifi cant correlation between increased graft iet-cell tnfα compared with trachea and lungs and acute rejection grade. conclusions differential expression of pro-infl ammatory cytokines by iet cells from graft, trachea or native lung distinguishes severity of acute rejection. improved monitoring response using this assay or therapeutic targeting of these pro-infl ammatory cytokines may reduce acute lung transplant rejection. supported by nhmrc. aim to determine the prevalence of reduced carbon monoxide transfer factor (dlco ≤ % predicted) in subjects undergoing pulmonary function testing (pfts) and to determine whether a cause has been identifi ed. methods a clinical audit of all subjects undergoing pfts at royal melbourne hospital from august to august who have a dlco ≤ % in the setting of normal spirometry. medical records and investigations including transthoracic echocardiogram (tte), high-resolution commuted tomography (hrct), ventilation/perfusion (v/q) scans were reviewed to determine whether a cause for the reduced dlco was established. where a cause was not clear, subjects were invited to participate in a telephone interview to evaluate symptoms and to undergo repeat pfts. subjects with a persistently reduced dlco were invited to undergo further investigation with tte, hrct and v/q scan. preliminary results pft results from subjects were reviewed. subjects with fev /fvc < , fev < % predicted and fvc < % predicted were excluded. three hundred seventy subjects ( %) had an isolated reduction in dlco. / ( %) of these subjects underwent tte with / ( %) demonstrating an elevated right ventricular systolic pressure (rvsp). in all cases where there was an elevated rvsp an identifi able cause was found. / ( %) of these subjects subsequently identifi ed as having pulmonary arterial hypertension (pah) and commenced appropriate therapy and / ( %) identifi ed as having pah where treatment was not commenced. there were / ( %) of subjects who appeared not to have undergone a tte. further evaluation of medical records of subjects who had not undergone tte and those with normal tte is continuing. review of subjects hrct, v/q scans and right heart catheterizations is currently proceeding. conclusions preliminary results suggest that a signifi cant proportion of subjects with isolated reduction of dlco on pfts do not undergo tte which is an important investigation in determining the cause for the reduced dlco. when a tte is performed and demonstrates an elevated rvsp, a cause for the elevated rvsp is identifi ed. sponsor actelion pharmaceuticals australia pty ltd. g hodge , , s hodge , , c-l liew , , , pn reynolds , , m holmes , , background t-cell pro-infl ammatory mediators are associated with acute lung transplant rejection. we have previously shown that bos was associated with lack of immunosuppression of t-cell pro-infl ammatory cytokines and increased t-cell granzyme b in peripheral blood. recently, we also showed that nkt-like cells are a major source of pro-infl ammatory cytokines and granzymes in the blood of stable lung transplant patients. we hypothesized that bos may be associated with lack of immunosuppression of these proinfl ammatory mediators in blood nk and nkt-like cells. method granzyme/perforin profi les from stable patients, patients with evidence of bos and healthy controls were determined and blood cultures stimulated and intracellular cytokines determined using multiparameter fl ow cytometry. results there was a signifi cant increase in the percentage of nk cells expressing granzymes and perforin in bos patients compared with stable patients and controls. there was an increase in the percentage of t, nk and nkt-like cells producing ifnγ and tnfα in bos compared with stable patients. there was a signifi cant correlation between increased nk ifnγ and tnfα and fev . conclusions bos is associated with increased peripheral blood nkt-like and nk cell granzymes, perforin and th pro-infl ammatory cytokines. therapeutic targeting of these pro-infl ammatory mediators and monitoring response using this assay may reduce bos. supported by nhmrc. confl ict of interest nil. rationale pulmonary embolism (pe) is the leading cause of maternal mortality in the developed world. consequently accurate diagnosis of pe is critical. this must be tempered by the potential radiation risk of investigations to the mother and foetus. we performed a retrospective case review to determine the incidence of pe in pregnant patients investigated for this condition. demographic information, the diagnostic algorithm utilized and the diagnostic yield of investigations were obtained. method pregnant women who underwent ventilation perfusion (vq) scanning or computed tomography pulmonary angiogram (ctpa) at our institution between january and january were identifi ed by an internal database audit. in addition to demographic data, information about the diagnostic pathway and fi nal diagnosis were collected. in cases where pe was not diagnosed, the medical records were reviewed for any subsequent events up until the date of delivery. results during the fi ve-year period, vq scans and ctpas were performed on pregnant women. the average gestation at investigation was weeks. only one patient had a previous history of venous thrombo-embolism. % underwent doppler ultrasound of the lower limbs prior to vq or ctpa. overall the incidence of pe was %, diagnosed by vq scan. otherwise the vq scans were normal in %, low probability in % and non-diagnostic in % cases. ctpa was non-diagnostic in % of cases. all other ctpa studies demonstrated no emboli. almost % of scans were done after hours ( % vq and % ctpa). no patients without pe were felt to have had the pe missed up to the time of delivery. conclusions the overall incidence of pe in patients being investigated was extremely low at %. during this study period slightly more vq studies were performed than ctpas, with each test having similar diagnostic rates. only % of patients had undergone venous doppler prior to undergoing radiationexposing investigations. nomination nil. introduction anti-ro- antibodies have been associated with idiopathic interstitial pneumonia (iip) in one small series (n = ). we hypothesize that ro- antibodies, just like myositis antibodies, can serve as a marker of undifferentiated connective tissue disease (ctd) with interstitial pneumonia as the primary phenotypic manifestation. the aim of this study was to examine the characteristics of patients with ro- and iip. methods retrospective study identifying patients with iip and ro- positivity, but negative for ctd and/or myositis antibodies, presenting between june and june . data relating to demographics, diagnosis, pulmonary function tests, length of follow-up and outcome were obtained. all hrct images were reviewed by an independent expert radiologist (dm). results / ro- positive subjects fulfi lled criteria ( male, median age ( - ), european, never smoked). / had ro- titers above and in the intermediate ( - ) range. three patients had raynauds phenomenon; there were no other ctd features. / patients had hrct diagnosis of nsip and / organizing pneumonia; / had extensive fi brosis. mean (sd) % predicted baseline fvc ( ), dlco ( ). median length of follow-up was months. all patients were treated and were considered overall stable at last follow-up, one had declined and one died of respiratory failure. conclusion this study confi rms an association between ro- positivity and interstitial pneumonia in the absence of defi ned connective tissue disease, suggesting an autoimmune basis for the interstitial lung disease in this group of patients. a larger cohort is required to determine the true signifi cance of this observation. background community acquired respiratory viral (carv) infections are believed to contribute to morbidity and mortality after lung transplantation, but previous studies have not conclusively established the evidence base in this area. patients and methods a prospective cohort study was performed at a single centre from august to march (n = lung transplant recipients). carv infection (human metapneumovirus (hmpv), respiratory syncytial virus (rsv), infl uenza a (flu a), infl uenza b (flu b), adenovirus and parainfl uenza virus (piv)) was confi rmed using polymerase chain reaction (pcr) of upper (nasopharangeal swab) and/or lower (bronchoalveolar lavage) respiratory tract secretions. carv infection and bos were included as segmented time-dependent covariates in a cox proportional hazards model with death as the outcome variable. results patients ( % of the total cohort) had a total of separate carv episodes: piv, hmpv, rsv, flu a, flu b, and adenovirus. infection with either rsv or hmpv was associated with an increased risk of death (p < . hr . , % confi dence interval, . - . ), and the effect persisted after multivariate analysis. bos was also a risk factor for acquiring hmpv or rsv infection (p = . or . , % confi dence interval, . - . ). conclusions infections with hmpv and rsv, but not other carvs, are associated with an increased likelihood of death. the presence of bos is a risk factor for symptomatic infection with hmpv and rsv. ns harun , k sanders , a stuart , cl steinfort department of respiratory medicine, barwon health, vic., australia, and department of clinical and biomedical sciences, barwon health, vic., australia aims nebulized colistin is used to treat recurrent exacerbations of bronchiectasis due to pseudomonas aeruginosa, a major pathogen regarded as diffi cult to eradicate. this case-control study aimed to establish if long-term colistin use could clear p. aeruginosa from the sputum of adults with non-cystic fi brosis bronchiectasis, and if so, whether colistin could be ceased in these patients. secondary outcomes included effects of colistin on quality of life (qol), symptom control, admission rates, lung function and tolerability. methods ( ) sputum was collected in bronchiectasis patients with p. aeruginosa. clearance rates in those on colistin were compared with a control group not on colistin. ( ) colistin patients cleared of p. aeruginosa ceased treatment. sputum was re-cultured at day and to detect recurrence. ( ) a questionnaire assessing qol, symptom control, and admission rates was performed on patients. outcomes were compared before and after colistin use. long-term colistin side-effects and lung function were also assessed. results ( ) % (n = / ) of colistin patients cleared p. aeruginosa from sputum compared with % (n = / ) in the controls (p = . ). ( ) % (n = / ) of patients ceasing colistin remained free of p. aeruginosa at day . ( ) there was no difference in frequency of breathlessness, sputum production or qol scores between the groups (p > . ). the colistin group had lower fvc ( . vs. . l, p = . ) and higher admission rates ( % vs. %, p = . ). on colistin, % of patients reported reduction in sputum frequency, breathlessness and improvement in qol. fifty percent reported decreased admission rates. there were no colistin side effects. conclusions clearance of p. aeruginosa in sputum is possible. clearance rates were similar in those with more severe bronchiectasis treated with colistin compared with stable patients not on colistin, and may suggest suppression of p. aeruginosa by colistin in this severe group. there are benefi ts of colistin on qol, symptom control and admission rates. continued sputum clearance after colistin cessation is achievable in some patients. nebulized colistin use is well tolerated. nomination janet elder travel award. confl ict of interest no. however, use of such agents is suboptimal in hospital patients. this study aims to determine whether a dedicated multidisciplinary education and reinforcement program improves the use of appropriate vte prophylaxis. methods prior to the education programme, we audited a bed general thoracic medical ward including patients with general medical conditions, lung cancer, chronic obstructive pulmonary disease, lung transplant and cystic fibrosis. our multidisciplinary research team developed and implemented an education program over months, using posters, leafl ets and oral presentations to increase awareness and promote adherence to vte prophylaxis guidelines for health care staff involved in direct patient management. following completion of the program, we reaudited the same bed ward. results prior to the education program, a total of patients (mean age ± ) were identifi ed as appropriate for vte prophylaxis. of these ( %) were on appropriate vte prophylaxis. the post education audit showed out of ( %) patients were on appropriate vte prophylaxis. (p = . ). conclusion an effective multi-faceted educational program can improve delivery of appropriate vte prophylaxis, leading to improved outcomes in hospitalized patients. supported by sanofi aventis. confl ict of interest nil. the anti-rheumatic anti-infl ammatory biological agents in clinical use are abatacept, anakinra, adalimumab, etanercept, infl iximab and rituximab. a variety of pulmonary side-effects have recently been reported for these agents and the purpose of this review is to compile the various reported pulmonary toxicities and their prevalence methods we performed a search of databases ovid medline® and embase of the english literature up to august using the mesh terms of abatacept, anakinra, rituximab, adalimumab, etanercept, infl iximab and respiratory tract disease with limits to include only human studies or case reports. in addition case reports of respiratory adverse effects reported to the australian drug reaction advisory committee (adrac) were obtained in order to identify the most common pulmonary reactions reported with each individual agent. results using the search criteria defi ned above and articles were identifi ed in the ovid medline and embase database respectively. the majority of adrac reports were associated with rituximab (n = ) and infliximab (n = ), followed by adalimumab (n = ) and etanercept (n = ). various pulmonary side-effects including interstitial lung disease associated with anti-infl ammatory agents were identifi ed. discussion from the articles reviewed, details about the duration between onset of treatment and incidence of pulmonary side effects, diagnosis, treatment options and outcome of patients were extracted and are presented here. conclusion this comprehensive systematic review hopes to improve the awareness about the serious and potentially life-threatening pulmonary sideeffects of this group of agents. confl ict of interest no. sj simpson , pd sly , p franklin , e lombardi , c calogero , m palumbo , gl hall , introduction the forced oscillation technique (fot) is effort independent and thus ideal for young children. the area under the reactance curve (ax) has been proposed to amplify clinically relevant signal by taking advantage of any shape change in the reactance (xrs) curve below the resonant frequency. this study aimed to develop reference values for resistance (rrs), xrs and ax in a large healthy population of children, and determine if ax conferred any additional clinical benefi t when examining disease in children born preterm. methods impedance spectra were obtained in healthy children ( male), aged less than years and with height less than cm using a commercial device (i m, chess medical, belgium). ax was calculated in of these children between hz and the resonant frequency. backwards stepwise linear regressions identifi ed the best predictors of ax, and xrs and rrs at hz (xrs , rrs ), and z scores were generated. z scores were calculated for children born preterm, of which received a neonatal diagnosis of bronchopulmonary dysplasia (bpd). chi squared tests examined the difference in proportion of children born preterm (with and without bpd) with abnormal z scores for each fot variable. results all fot variables were predicted by height (p < . ) and sex. mean (sd) z scores for preterm children with and without bpd for rrs ( . ( . ); . ( . )), xrs ( . ( . ); . ( . )) and ax ( . ( . ); . ( . )) were all signifi cantly different (p < . ) from the healthy population. the number of children born preterm with abnormal z scores was not significantly different when comparing ax, rrs and xrs . conclusions while ax is able to detect respiratory disease in preterm children with and without bpd, it is no more sensitive than xrs or rrs. supported by pmh foundation, nhmrc, asthma foundation wa, carivit, ngo 'solidarietà e servizio' viterbo. confl ict of interest no. introduction survivors of preterm birth born with bronchopulmonary dysplasia (bpd) in the pre-surfactant era of neonatal care (classical bpd) have a reduced pulmonary gas transfer capacity. there is, however, little data to describe gas transfer in preterm infants with bpd in the post-surfactant era (new bpd). objective assess gas transfer using carbon monoxide diffusing capacity (dl co ) and its components, pulmonary capillary blood volume (vc) and pulmonary membrane diffusion (d m ), in contemporary survivors of preterm birth. method gas transfer was assessed using single-breath dl co in children aged to years and born < weeks gestation with bpd (pb, n = ) and without bpd (pt, n = ), and in term born controls (tc, n = ). dl co z scores were calculated. d m and vc were determined in pb, pt and tc children. the mean (sd) dl co z score for the pb group was − . ( . ) differing signifi cantly from (p = . ) while the pt and tc groups ( . ( . ) and − . ( . ), respectively) did not (p > . ). d m was lower in the pb group than the pt and tc groups, with no difference between pt and tc groups. differences in d m were not signifi cant after adjusting for lung size. there were no differences in vc between groups. conclusion gas transfer is reduced in survivors of preterm birth with new bpd. the tendency for reduced d m and not vc in children with new bpd suggests that impaired gas transfer may be a result of alterations in the alveolar membrane rather than pulmonary vascular function. background bronchiectasis is common in indigenous populations such as alaska natives, australian aboriginal, and new zealand maori and pacifi ca. as part of an international collaborative interventional study, we sought the participation of maori and pacifi ca families -groups diffi cult to engage in research in the past. aim to engage, enrol and retain children from maori and pacifi ca families from auckland in a -year research study. methods a randomized controlled trial to determine whether azithromycin is superior to placebo in reducing exacerbations seeking to enrol children aged months to years with bronchiectasis. the enrolment procedure was modifi ed to a process deemed more appropriate to these cultures: ( ) request to defer the decision of enrolment until the process had been completed. ( ) a minimum of meetings; initial invitation, discussion in the home with the extended family, invitation to the extended family to participate in the day of enrolment. ( ) appointment of a 'whanau worker' (family worker) to sit with the family and empower them to get all the information they seek prior to enrolment. results of families approached, ( %) children (median age . years, range . - . years) enrolled with % samoan, % tongan, % maori and % mixed maori/pacifi ca heritage. after -year retention was ( %) with exiting the study after month with new non-pulmonary disease, and exiting after year, moving outside study area. conclusions these are high enrolment and retention fi gures reported in this population. we believe that following a prolonged procedure for enrolment, involving the extended family and appointing a worker to sit 'alongside' the family will improve their understanding of a research project and allow them to feel more comfortable about participating. aim bronchiolitis is the most common reason for hospital admission for infants globally ( ) . the use of macrolides for treating bronchiolitis in nonaffl uent settings remains controversial but potentially benefi cial. in our region readmission with lower respiratory illness in young children (particularly indigenous children) remains high. this rct aims to determine if a single dose of azithromycin reduces the morbidity of young children with bronchiolitis. methods double blinded rct. young children ≤ months admitted to royal darwin hospital (rdh) diagnosed with bronchiolitis are eligible. children are given a single dose ( mg/kg) of either azithromycin/placebo. primary outcome is length of stay for respiratory disease. secondary outcomes are duration of oxygen use and readmission for respiratory illness in -month period. respiratory viral infections often lead to exacerbations of chronic respiratory diseases such as asthma and copd though there is no similar data in noncystic fi brosis (cf) bronchiectasis. the objectives of our study were to ( ) determine the point prevalence and identify viruses associated with exacerbations and ( ) evaluate clinical and investigational differences between viral infection positive and negative exacerbations in children with non-cf bronchiectasis. methods a cohort of children (median age years; boys) with non-cf bronchiectasis was prospectively followed for child-months. polymerase chain reaction for respiratory viruses was performed on nasopharyngeal aspirates collected during paediatric pulmonologist defi ned exacerbations. data on clinical, parent cough-specifi c quality of life (pc-qol), systemic markers (crp, il , procalcitonin, amyloid-a, fi brinogen) and lung function parameters were also collected. results respiratory viruses were detected during ( %) exacerbations: picornavirus in episodes [human-rhinovirus (hrv) in , enterovirus in ]; human bocavirus in ; adenovirus, human meta-pneumovirus, infl uenza a, respiratory syncytial virus, parainfl uenza and in two each; coronavirus and parainfl uenza and in one each. viral co-detections occurred in ( %) exacerbations. among genotyped hrv's, more hrv-a's (n = ) were identifi ed than hrv-c's (n = ). children with proven viral infections were more likely to have fever (or . , % ci . - . ), wheeze and/or crackles (or . , % ci . - . ) and raised crp (or . , % ci . - . ) when compared with virus negative exacerbations. there were no other statistically signifi cant differences. conclusions respiratory viruses are commonly found during pulmonary exacerbations in children with non-cf bronchiectasis. hrv-a is the most frequently detected virus. time sequenced cohort studies during stable state, exacerbations and recovery periods are needed to determine the importance of viral infections and their possible interaction with bacteria. supported by anz trustees scholarship. confl ict of interest none. nominations none. to date children enrolled, % rsv+ve. median age . months. fifty percent have had at least one co-morbidity. readmission rate = %. conclusion co-morbidities are high in this population. antibiotics have the potential to help reduce the impact of additional respiratory burden. foundation. introduction foreign body inhalation is a relatively common presentation in young children, especially less than years of age. early recognition remains a critical factor in the treatment of foreign body inhalation in children. inhaled foreign bodies in children are most often organic material, with seeds and peanuts being the most common items. on review of the literature, there are very few case reports of inhaled metal screws. we report two unusual cases of inhaled metal screws that presented to our service. case presentation both cases presented to our emergency department with wheeze, respiratory distress and fever. foreign body inhalation was not considered as a cause for their symptoms until the object was identifi ed on chest x-ray. both foreign bodies were removed successfully but one child required invasive ventilation in our intensive care unit post removal. both children made a full recovery. interestingly, both metal screws came from fl at pack furniture purchased from a well known international home products store. conclusion foreign body inhalation must always be considered as a cause of respiratory distress in a child. with the increase in the number of fl at pack furniture in australian home's, we believe parents must be warned of the potential danger of loose metal screws to young children. supported by none. cough in children is a common symptom. data on causes of chronic cough in young children have previously been published by our units. however, differences in underlying diagnosis by age at presentation have not been assessed. we present the 'time to cessation' of cough in our multicentre rct using a standardized management algorithm in newly referred children with chronic cough (> weeks) from australian centres. methods parents completed validated cough diary and cough specifi c qol (pc-qol) at recruitment and at cessation of cough. the diagnosis made by the treating physician was based on tsanz position statement. results the median (range) age of the children recruited was . years ( . - . ); ( %) were boys. median (iqr) pc-qol post treatment of . ( . , . ) improved signifi cantly (p = . ) from . ( . , . ) at enrolment. the median (iqr) duration of cough at recruitment was weeks ( . , . ) and 'time to cessation' of cough after application of the management algorithm was weeks ( . , . ). there was no signifi cant difference (p = . ) in median (iqr) 'time to cessation' of cough among the three age cohorts: < years (n = , . %) was . weeks ( . , . ); - years (n = , . %) was weeks ( . , . ); and > years (n = , . %) was weeks ( . , . ). there was also no signifi cant difference in the fi nal primary diagnosis among the three age cohorts (p = . ). the most common diagnoses were protracted bacterial bronchitis (n = , %), asthma/reactive airways disease (n = , . %), tracheobronchomalacia (n = , . %) and bronchiectasis (n = , . %). children ( . %) had more than one diagnosis. conclusions the aetiology and 'time to cessation' of chronic cough in children managed in accordance to a standardized pathway were similar among the three age groups. it is likely that our previous fi ndings in very young children are also applicable to older children. supported by nhmrc grant number . confl ict of interest none. aim to determine the role of fl exible bronchoscopy with bronchial alveolar lavage (bal) in the management of patients with febrile neutropenia. methods a retrospective analysis was made of the number of patients admitted with febrile neutropenia at a single institution who underwent bronchoscopy plus bal from years to . computer database plus patient case notes were reviewed to establish clinical symptoms and signs, radiological fi ndings, antimicrobial treatment and mean duration to bronchoscopy following admission. results a total of episodes of febrile neutropenia were recorded years to . seven patients ( males and females) were referred for bronchoscopy plus bal. the mean age was . years (age range - years) and all had been diagnosed with acute lymphoblastic leukemia. all patients had at least cough as a clinical symptom along with radiological fi ndings. all patients had been on broad spectrum antibiotics at the time of bronchoscopy. the mean duration from admission to time of bronchoscopy was hours ( days) with a standard deviation of hours. of the seven patients one patient yielded a positive result on bal. this did not result in a change in management as the patient improved clinically before the result of the bal was confi rmed. conclusion in this retrospective case series the diagnostic yield of fl exible bronchoscopy plus bal in children with febrile neutropenia was low. prospective studies plus early timing towards bronchoscopy and bal should be conducted to further defi ne its role in the management of febrile neutropenic patients. confl ict of interest nil. methods prospective cohort study involving monthly follow-up with caregivers. two years post enrolment, children undergo clinical and lung function assessment (fot). presence of bronchiectasis is determined by physician review and radiological confi rmation (when indicated). the frequency of pbb episodes is recorded over the study period. of children recruited to the cohort study to date, % ( / ) were male. the median age at recruitment was months (iqr , ). % of children had recurrent pbb. of the children who have had -year clinical follow-up, were able to perform fot and % ( / ) showed abnormalities (reactance above normal range.) % ( / ) with pbb have had subsequent physician diagnosis of bronchiectasis or csld. conclusion the burden of cough in children with pbb years after diagnosis remains high. ongoing clinical follow-up of this cohort of children with pbb should provide further insight into the likelihood of progression from pbb to csld and bronchiectasis. support financial markets foundation for children (for project), allen & hanburys and qcmri (for dw), nhmrc (for ju and ac). introduction national streptococcus pneumoniae (sp) serotype surveillance reports only culture positive cases from sterile sites but the yield from culture is low. polymerase chain reaction (pcr) is more sensitive in detecting sp in culture negative samples. aim to determine whether enhanced molecular surveillance in childhood empyema provides additional sp serotype information compared to national surveillance methods. methods pleural fl uid from children with empyema underwent culture and pcr to identify sp-targeting autolysin (lyta) and multiplex pcr to identify sp serotypes. national surveillance data were obtained from the national notifiable diseases surveillance system (nndss) for the same time period and age groups. results empyema: children, male, median age . (range . - . ) were recruited from april for months. sp was cultured in / ( . %) in blood and / ( . %) in pleural fl uid. sp was identifi ed by pcr in / ( . %). serotypes: , n = ( . %); , n = ( . %); a, n = ( . %); f a, n = ( . %); v/ a, n = ( . %); f/ a, n = ( . %); non-typeable, n = ( . %). one subject had serotypes and in a serotype could not be established. nndss: sp culture positive cases were reported. serotypes: , n = ( . %); , n = ( . %); a, n = ( . %); f a, n = ( . %); v/ a, n = ( . %); f/ a, n = ( . %); non-typeable, n = ( . %). other serotypes were reported in sp positive cases. signifi cant differences between empyema and nsdss data were identifi ed for serotypes (p < . ) and (p < . ). conclusions the proportion of serotypes and were signifi cantly higher in empyema fl uid using pcr. this disease model provides additional serotype information to national surveillance data. this has important implications in monitoring replacement serotypes following the introduction of new vaccines. funded by glaxosmithkline, belgium. h giddings , l seccombe , p rogers , a corbett , e veitch recent theories on the pathophysiology of parkinson's disease (pd) emphasize early brainstem involvement. furthermore various respiratory function abnormalities have been reported without consistent pattern. we sought to study the effects of idiopathic pd on respiratory function and ventilatory response to hypercapnoea and hypoxia. methods patients with a diagnosis of pd but no known respiratory disease were recruited. subjects underwent lung function testing including respiratory muscle strength, ventilatory response to hypercapnoea (with central respiratory drive (p )) and a hypoxic simulation (fio % cough is the most common symptom presenting to doctors. paediatric cough is associated with signifi cant morbidity for both children and their parents. the symptom of cough is associated with airway hyper-reactivity and is a dominant symptom of airway infl ammation. inhaled corticosteroids (ics) can reduce airway infl ammation and hyper-reactivity. the objective of this review was to evaluate evidence for the effi cacy of ics in reducing the severity of cough in children with sub-acute cough (defi ned as cough duration of - weeks). methods search was conducted by the cochrane airways group using cochrane methodology. all randomized controlled trials (rcts) comparing ics with a control group for treatment of sub-acute cough in children were considered for inclusion. search results were analysed using pre-determined criteria for inclusion. results two studies were eligible for inclusion in the review, however there were limitations in that the participants of both these studies were infants, post acute bronchiolitis illness, and cough duration at start of study treatment was ill-defi ned. children were included in the meta-analysis. there was no signifi cant difference between groups in proportion of children 'not cured' (primary outcome measure), with a pooled or of . ( % ci . , . ) (using intention to treat analysis). conclusions there is currently no evidence to support the use of ics in sub-acute cough in children. however, this systematic review is limited by the small number of studies available for analysis and the quality and design of these studies. further well-designed rcts are required to support or refute the effi cacy of treatment with ics in children with sub-acute cough. once obstructive sleep apnoea (osa) is diagnosed, a cpap implementation sleep study is traditionally performed to determine the pressure required to control the upper airway. however, since modern cpap machines store sophisticated control data we reasoned it may equally be possible to commence cpap via a 'best guess' iterative approach without compromising osa control or compliance. aim to compare the outcomes at months of patients commencing cpap after best guess with those commencing cpap after a cpap implementation sleep study. methods we retrospectively reviewed the records of all patients referred by respiratory physicians to our cpap clinic between march and march , and the two methods of starting cpap were compared. data collected included age, sex, bmi, respiratory disturbance index (rdi), cpap pressure commenced, fi nal pressure at months, cpap usage data and cpap clinic contacts. results patients were identifi ed, aged ± years, %male, bmi . ± . , with severe osa, rdi ± . commenced cpap via best guess and after a cpap sleep study. the starting pressures in both groups were similar, . ± . versus . ± . cmh o. in those patients continuing to use cpap at months, there were no differences between the groups for fi nal pressure, numbers of patients changing pressure, control of osa with cpap, and hours cpap used per day. in the best guess group however, signifi cantly more patients were continuing to use cpap at months, % versus % (p = . ). conclusion this study demonstrates that it may no longer be necessary to perform cpap implementation sleep studies routinely and this will save hospital bed days. confl ict of interest nil. six required intubation and the rest were managed with non-invasive ventilation in icu. the average length of stay in icu was . days. polysomnographic data will be described. conclusions obesity hypoventilation as a cause of respiratory failure is likely to increase in frequency as the incidence of obesity increases. increased awareness by the lay public, as well as clinical suspicion and recognition of the condition by all clinicians at an earlier stage, is likely to prevent progression to the point of needing intensive care. it is hoped that this case series may provide a springboard for further study into why these patients presented at such a late stage of their disease process. supported by none. confl ict of interest none. although sa and sleepiness often co-exist, the commonest cause of sleepiness in a general community is depression, with sa being the th most common cause. in order to assist recognition of depression in a snoring population attending a sleep clinic, we introduced a simple two question 'beyond blue questionnaire(bbq)' into our routine assessment. aims to ( ) background indices of ventilation distribution in diffusion (s acin ) and convection (s cond ) dependent airways derived from multiple breath nitrogen washout (mbnw) may vary between interpreters because of differences in calculation of phase iii slopes (Δphase iii ). aims to compare s cond and s acin results of interpreters from a single mbnw in copd subjects. methods subjects with copd underwent mbnw. three washouts were analysed independently by experienced and novice interpreters using custom software for automated breath identifi cation. Δphase iii was fi tted automatically by least squares fi t between predetermined points, and then adjusted manually. s cond was the linear slope of Δphase iii plotted against lung turnover (cumulative expired volume/frc), between turnovers . - . s acin was the Δphase iii of the fi rst breath minus the s cond component. differences expressed as icc and cov, were examined by repeated measures anova. results mean ± sd age was ± years. fev was ± % predicted. s cond was greater while s acin was lower from the experienced introduction β-blockers may cause bronchoconstriction and mask the effect of β -adrenergic agonists. this has implications for the interpretation of routine diagnostic spirometry and bronchodilator response. this study examined this issue in a routine lung function laboratory, and whether it applied to both cardio-selective (c) and non-selective (nc) preparations. method all patients attending the lung function laboratory, royal adelaide hospital over a -month period were asked whether they were currently taking a β-blocker and to identify the drug. spirometry results were analysed to assess airfl ow obstruction and reversibility. results patients completed the survey and patients ( %) were taking β -blockers. the table shows the results of the patients who could be assessed for reversibility in spirometry. of the patients in this group patients ( %) were taking (c) and ( %) (nc) agents. fifty-three patients were unsure whether they were taking a β -blocker. no signifi cant differences were found in the percentage of patients with airfl ow obstruction or reversibility between the groups. aim to examine patterns of adult lung function in terms of airfl ow obstruction, hyperinfl ation and/or reduced diffusing capacity (d l co). this can then be related to the life-time history of risk factors such as smoking, asthma and infections. methods using the population-based tasmanian longitudinal health study (tahs) cohort followed since , an asthma-enriched sub-sample was selected consisting of % ever with asthma, of whom half reported current asthma. measurement of spirometry, d l co (uncorrected for haemoglobin) and lung volumes was performed, then lung function data were analysed using the mean predicted values. airfl ow obstruction was defi ned as post-bronchodilator fev /fvc (post-b.d. fer) < . , hyperinfl ation as total lung capacity (tlc) > % predicted, and reduced d l co as < % predicted. aim to examine the gender-specifi c differences in adult spirometry, d l co and lung volumes, with a view to relating them to life-time respiratory risk factors. methods using the population-based tasmanian longitudinal health study (tahs) followed since , an asthma-enriched sub-sample was selected consisting of % ever with asthma, of whom half reported current asthma. measurement of spirometry, d l co (corrected for haemoglobin) and lung volumes were performed. data were analysed using the statistical upper and lower limits of normal of reference equations by nhanes iii, roca et al and quanjer et al. of the caucasian adults ( females), % completed all tests. mean age . years (range - ). elevated rates of airfl ow obstruction and hyperinfl ation were seen. signifi cantly higher proportions of females than males had reduced d l co and d l co/v a (p < . ). only . % (n = ) of females had a low d l co with low fev /fvc ratio, and . % (n = ) had a reduced tlc overall. there were no signifi cant gender differences in v a , tlc, or ever and current active smoking. males and females averaged over kg more than the mediterranean adults described by roca et al., however weight is not relevant to d l co in males. conclusion a higher percentage of middle aged females have a reduced d l co and/or d l co /v a, compared to males, with an increased rate overall. grant support nhmrc, australian postgraduate association. d chapman , , , j kermode , , , n brown , , , n berend , , , g king , , , background during bronchoconstriction, a deep inspiration (di) dilates the airways, which then re-narrow once tidal breathing is resumed. re-narrowing occurs faster in asthmatic subjects and may be due reduced airway distensibility. aim to determine the association between baseline airway distensibility and the rate of re-narrowing after di. methods eleven asthmatic and fi ve non-asthmatic subjects had baseline airway distensibility measured by forced oscillation technique (fot). after methacholine challenge, respiratory system resistance (rrs) was measured during min of tidal breathing, followed by di to total lung capacity (tlc) and passive return to normal tidal breathing. dilatation was measured as the decrease in rrs between end tidal inspiration and tlc, and re-narrowing as end-expiratory rrs immediately after di, as per cent rrs at end-tidal expiration before the di. distensibility is presented as geometric mean ± %ci and re-narrowing as mean ± % ci. results airway distensibility was reduced in asthmatic compared to healthy subjects ( . s − .cmh o − ( . - . ) vs. . s − .cmh o − ( . - . ), p = . ). dilatation did not differ between groups (p = . ) but re-narrowing was increased in asthmatic compared to healthy subjects ( ± % vs. ± %, p = . ). airway distensibility did not correlate with airway re-narrowing (r s = - . , p = . ). conclusion the increased re-narrowing after di in asthmatic subjects is not due to reduced baseline airway distensibility and may be due to increased shortening velocity of airway smooth muscle or reduced elastic recoil. supported by the nhmrc and the crc for asthma and airways. nomination nil. confl ict of interest no. c ng , , , s jenkins , , , n cecins , , p eastwood , , aim to evaluate the measurement properties of two accelerometers: the activpal and the stepwatch activity monitor (sam) in people with copd. methods the activpal and sam were attached to the anterior right midthigh and the right ankle, respectively (as per device recommendations). each participant performed walking tasks; at a self-selected slow speed and at a self-selected normal speed. at each speed, one walk was performed with a -wheeled walker (ww) and the other without. results participants aged ( ) years (fev = ( ) % pred; males) completed the study. the slow and normal speeds were ( ) m·min − and ( ) m·min − , respectively. agreement between steps recorded by the sam with steps counted during observation did not differ with speed or ww use (p = . ). the mean difference was steps·min − and the limit of agreement (loa) was steps·min − . agreement between steps recorded by the activpal with steps counted was worse at slow speeds (mean difference steps·min − with loa of steps·min − ) compared with normal speeds (mean difference steps·min − with loa of steps·min - ) (p = . ), but was not affected by ww use. both accelerometers detected the small difference in walk speed irrespective of ww use (p < . ). conclusions neither the accuracy nor responsiveness of either accelerometer was affected by ww use. in contrast to the activpal, sam was accurate at both speeds and therefore can be used to detect steps in people who walk very slowly during daily life. breathing and sleep, heidelberg vic., eastern health, melbourne vic., northern health, epping vic., and monash university, clayton vic. aim to document the care and pathways patients with copd travel at three metropolitan health services. methods data were extracted from data sets for patients attending the emergency department of the three hospitals with a diagnosis of copd over year. the three hospitals included a city-based tertiary/quaternary hospital and two smaller community hospitals. analysis was completed on similarities and differences in admission and referral rates, average length of stay, and discharge destination, standardized by age, sex and mode of transport to the emergency department. results there were inpatient separations and emergency department presentations for patients with copd. discharge patterns related to the designated role of the hospital, with the community hospitals discharging to % of patients directly home and the more specialized city hospital discharging % to other hospitals and % home. there were signifi cant differences in the admission rates for category and patients among the hospitals. we found unexplained variation in the acute average lengths of stay of . , . and . days. conclusions the analysis confi rmed some expected patterns based on the type of hospital, but also identifi ed unexplained variation that suggests that factors other than patient characteristics may be contributing to the variation in care pathways. aims to: ( ) determine which tests of exercise capacity relate to average daily energy expenditure (dee) and; ( ) quantify the intensity at which activities of daily living (adl) are undertaken in people with chronic obstructive pulmonary disease (copd). methods a study was undertaken in subjects with stable copd (mean, sd) aged ( ) years with an fev of ( ) % predicted ( males). measures were collected of distance walked during the six-minute walk test ( mwd) and incremental shuttle walk test (iswd) and peak rate of oxygen uptake during a cycle ergometry test (vo peak ). the sensewear armband® was worn during the waking hours for . ( . ) days to measure dee. the intensity at which activities of daily living were undertaken was expressed as a percentage of vo peak . results dee was associated with mwd (r = . ; p = . ), iswd (r = . ; p = . ) but not vo peak (r = . ; p = . ). stronger associations were observed between dee and the body weight-walking product for mwd (r = . ; p < . ) and iswd (r = . ; p < . ). the average intensity of adl was equal to ( %) of vo peak (range to %). conclusions mwd and iswd, but not vo peak were related to dee. as adl were performed at a high percentage of vo peak it may be more realistic to increase dee by increasing the frequency or duration, rather than the intensity of physical activity. in patients with copd, two mwts are recommended prior to commencing a pulmonary rehabilitation program (prp) to allow for a learning effect. aim to determine the characteristics of patients with copd in whom -minute walk distance ( mwd) did not increase on a second test. methods patients ( males) with stable copd (aged , to years) naïve to the mwt performed two tests ( minutes apart) prior to commencing a prp. patients were categorized according to their change in mwd with test repetition. results mwd was the same or decreased on the second test in patients ( %) (table) . in the remaining patients ( %), mwd increased by m ( %) ( % ci to m, to %). logistic regression analysis identifi ed fev (l) as the only signifi cant variable (p < . ) that predicted the absence of a learning effect in mwd with test repetition. conclusions some patients with severe copd may not require a practice mwt to achieve their maximum performance at a prp baseline assessment. ( ) years, with stable ipf were evaluated in this study. demographic data and measures of pulmonary function (spirometry, diffusing capacity for carbon monoxide, (dl co )), dyspnoea (baseline dyspnoea index, bdi), peripheral muscle force (isometric quadriceps force (qf) and handgrip force (hf)), functional exercise capacity ( -minute walk distance, mwd), limitation in daily activities (activities of daily living (adl) score), and health status (sf- ) were assessed. relationships between mwd and mrc grade, pulmonary function, qf, bdi and adl score were examined. results the number of subjects in mrc grades , , and was ( %), ( %), ( %) and ( %), respectively. pulmonary function, bdi, qf, hf, mwd, adl score, and sf- decreased signifi cantly with increasing mrc grade (all p < . ). moderate to strong correlations were found between mwd and mrc grade (r = − . ), dl co (r = . ), qf (r = . ), bdi (r = . ) and adl score (r = . ) (all p < . ). conclusions these fi ndings suggest that the mrc dyspnoea scale can be used to discriminate and classify subjects with ipf according to the severity of impairment and disability. ( ) year (mean, sd) completed two assessment sessions on separate days. on one day, they exercised twice to symptom limitation (tlim) on a treadmill. on the other day, they exercised twice to tlim on a cycle ergometer. the order of exercise modality was randomized between days. on both days, the only difference between the exercise tests was that bipap, titrated to patient comfort, was used during the second test. measures were made of; ) tlim and, ( ) the difference in dyspnoea, using borg scores, at tlim during the fi rst test and the equivalent exercise time during the second test (i.e. iso-time). results bipap increased tlim on the treadmill ( ( ) seconds; p = . ) but not the bike ( ( ) seconds; p = . ). the reduction in dyspnoea at iso-time on the treadmill and bike was similar being, ( ) and ( ), respectively (p = . ). conclusions bipap may confer greater benefi t in exercise tolerance exercising on a treadmill compared with a cycle ergometer in patients awaiting lung or heart-lung transplant. infection with rhinovirus (rv) is known to trigger acute exacerbations in subjects with asthma and these subjects also have increased susceptibility to the effects of rv. the mechanisms remain poorly understood, but appear to involve a host innate immune defect in the airway epithelium. aim we sought to determine in bronchial epithelial cells (becs) if oxidative stress in the form of exposure to cigarette smoke extract (cse), hydrogen peroxide (h o ) and eosinophil peroxidise (epo) results in impaired mitochondrial function and if this directly impairs signalling of rv infection through mda and alters the release of type i and type iii interferons (ifns). methods pbecs were grown to confl uence. cells were then exposed to cse ( %, no fi lter) or h o ( . mm) or epo. cells were then infected with rv -b (moi = ). virus replication was measured by cell titration assay. following infection, il- , cxcl- , cxcl- was measured using cytometric bead array and fl ow cytometry. supernatants and whole cell lysates were collected for ifn-β, bax and mda detection by western blot. ifn-λ and cytochrome-c was measured using conventional elisa. cell viability was assessed by annexin v-pe staining and fl ow cytometry. results rv infection alone induced cxcl- , il- , cxcl- and ifn-λ. pbecs treated with each of the oxidative stressors had increased cytochromec release and increased apoptosis. this mitochondrial dysfunction led to degradation of mda expression and resulted in specifi c suppression of cxcl- and ifn-λ. conclusions exposure of becs to an oxidative stress results in mitochondrial dysfunction in airway epithelial cells. this leads to defective antiviral signalling in the airway epithelium after infection with rv. introduction pleural infection is associated with high morbidity. prompt drainage is key, but pus is often loculated and thick making drainage diffi cult. based on promising animal studies, we hypothesize that intrapleural therapy with t-pa and dnase, which lyse adhesions and reduce fl uid viscosity respectively, can signifi cantly improve pus evacuation in pleural infection. methods consecutive patients with pleural infection were treated with standard antibiotics and intercostal chest tube (ict) drainage. additionally, t-pa mg and dnase mg (each in ml of . % nacl) were instilled intrapleurally via an ict twice daily for up to six doses. the ict was clamped for minutes after each instillation. patients were followed clinically and with serial cxr. opacity from pleural effusion was quantifi ed on chest radiographs. results eleven patients ( male; mean age ) were treated. nine effusions were associated with community acquired pneumonia, of these, eight were visibly purulent, fi ve were culture positive and the mean fl uid ph was . (range . - . ). ten patients ( %) were successfully managed conservatively and one patient required surgery. median hospital stay from fi rst intrapleural treatment dose to discharge was days (range - ). the median amount of fl uid drained in the hours preceding t-pa/dnase treatment was ml (range - ), and improved signifi cantly to ml (range - ) following two doses of treatment. this was paralleled by a signifi cant reduction in radiographic opacity by a mean value of % of the hemithorax (range - %). four patients showed an initial rise in crp following t-pa/dnase, but all patients had resolution of sepsis and signifi cant reduction in crp. there were no major complications. pleuritic chest pain requiring opioid analgesia developed in three patients. methods clinical data were collected using a standardized form for aboriginal children aged days -< months hospitalized with alri and enrolled in a rct of vitamin a/zinc supplementation were matched with data collected during a population-based study of who-defi ned primary endpoint pneumonia (who-p). sensitivities, specifi cities, positive and negative predictive values (ppv, npv) for these signs were compared between who-p cases and lobar pneumonia assigned by a respiratory paediatrician. in episodes of hospitalized alri, who-p was diagnosed in ( . %); the respiratory paediatrician classifi ed ( . %) as lobar pneumonia. the sensitivities of clinical signs ranged from a high of % for tachypnoea to % for fever + tachypnoea + chest-indrawing; the ppv range was % to %, respectively. higher ppvs were observed against the paediatric respiratory physicians diagnosis compared to who-p. conclusions clinical signs on admission are not useful in predicting who-p in this population, presenting challenges for future pneumonia research in this population. who-p may underestimate alveolar consolidation in a clinical context and its use in clinical practice or in research designed to inform clinical management in this population should be avoided. the incidence of tb in the non-indigenous australian population is uncommon at . cases per population . in this paper, we report three cases of pulmonary tuberculosis in young australian born, non-indigenous adults in the hunter new england area where marijuana possibly was a signifi cant risk factor in transmission and severity of disease. all three cases had severe cavitating disease at time of presentation. contact tracing from the fi rst case, a regular heavy marijuana user, identifi ed mantoux positive contacts, one of whom developed active pulmonary tuberculosis. all contacts, mainly young adult males, denied sharing marijuana with the index case. contact tracing from the second case identifi ed mantoux positive contacts, of whom use marijuana regularly and shared bongs (water pipes) with the index case. there were positive mantoux contacts of the third case, one of whom shared bongs with the index case. health professionals need to remain aware of the possibility of tuberculosis in groups with historically low incidence rates. marijuana bong smoking is possibly associated with transmission and severity of tuberculosis . introduction in , these previously well women survived and made a good recovery from severe pneumonia and acute lung injury after retrieval on ecmo. streptococcus pyogenes is an unusual cause of pneumonia in adults. case a -year-old veterinarian with a history of mild asthma presented with days of fever and respiratory symptoms. the diagnosis was confi rmed by a fourfold rise in the anti-streptococcal antibody. this was complicated by respiratory failure, septic shock, acute renal failure, severe pulmonary hypertension and bilateral parapneumonic effusions. despite maximal interventions she deteriorated. femoral venous-venous ecmo was initiated on day at the calvary mater hospital in newcastle by a retrieval team from royal prince alfred hospital (rpa), sydney. she was transferred kms on ecmo in a large multipurpose ambulance. she developed lung abscesses and recurrent pneumothoraces and she required a pleurodesis. she required days of ventilation and days of ecmo. three months later she was asymptomatic, with mildly restrictive spirometry and minor cxr change. case a -year-old offi ce worker with s pyogenes bacteraemia made a similar presentation to our institution. she was ventilated for days, ecmo was initiated by the retrieval team and continued for days. three months later she was asymptomatic with a normal cxr and pulmonary function tests. introduction the urinary pneumococcal antigen (upa) test has been shown to have superior sensitivity to other investigations in determining the aetiology of community-acquired pneumonia (cap), but there is very limited data on its performance in local populations. the aims of this study are to establish the prevalence of positive upa testing in patients admitted to hospital with cap, and determine its utility. secondary aims are to identify associations with positive testing, as well as to determine if a positive test infl uences clinical outcomes. methods the study is a prospective, single-centre study that is still recruiting. adult patients are included upon admission to hospital if they have the diagnosis of cap, as defi ned by new infi ltrates on chest radiograph along with consistent clinical features. clinical data including curb- score of severity, current and prior antibiotics, co-morbidities, mortality and length of hospital stay are recorded. results preliminary results show a positive test prevalence of / ( . %, % ci . - . %) amongst patients admitted with cap. overall prevalence of pneumococcal pneumonia is / ( . %, ci . - . %). patients with a positive upa result have a higher mean curb- score of . compared with . in those with a negative result (p = . ). . % of patients with a positive result were admitted to the intensive care unit, compared with . % those with a negative result (p = . ). conclusions the overall prevalence of positive upa testing in patients admitted to hospital with cap is low. preliminary data suggests that patients with positive results are more likely to have greater severity pneumonia and to require intensive care support. comparative data on length of stay, mortality, previous antibiotic use and specifi c co-morbidities has not revealed any statistically signifi cant differences between positive and negative groups. confl ict of interests no. s herath , c lewis , m nisbet , respiratory department, auckland city hospital, auckland, new zealand, and infectious diseases department, auckland city hospital, auckland, new zealand rhodococcus equi (r. equi), previously known as corynebacterium equi is a gram positive bacillus that is found in soil and causes infection in grazing livestock. it is infrequently isolated from clinical specimens. it is usually associated with human disease in immunocompromised patients and is an uncommon cause of infection in immunocompetent patients. infection is usually acquired by the airborne route with pneumonia being the most common manifestation but it can also be acquired orally or by direct inoculation. we present a case of pneumonia caused by r. equi infection in a year old male builder who presented with cough, dyspnoea and night sweats. r. equi was cultured from a transbronchial aspirate from a subcarinal lymph node. despite extensive investigation, no contributing host immune defect was identifi ed. the patient recovered after three months of antibiotic treatment, initially with intravenous vancomycin and meropenem followed by oral clarithromycin and rifampicin. although infections due to r. equi have been increasingly reported in immunocompromised patients, since there have only been cases described in patients where no associated host immune defect was reported. in this cohort, the median age at presentation was years (range - ) and ( %) patients were male. ten ( %) of these cases had pulmonary infection. two ( %) patients died and the remainder were successfully treated with prolonged antibiotics. r. equi is an uncommon cause of infection in humans and rarely occurs in patients where a host immune defect cannot be identifi ed. introduction recognition of pulmonary involvement in extra pulmonary tuberculosis (ep-tb) may be an important public health issue, as it has been estimated that patients with smear negative pulmonary tb (ptb) are responsible for % of new infections. usually, all patients with ep-tb have a chest x-ray but sputum cultures are requested only if there is an abnormality. methods in this retrospective clinical audit, we aimed to evaluate the percentage of ep-tb patients with ptb despite a normal chest x ray (cxr), and to explore any clinical characteristics of this group. clinical notes, microbiology and cxr reports were reviewed from consecutive patients presenting with ep-tb between and . results of patients with ep-tb, % were male and the mean age was (range to ). most patients were of asian ethnicity (n = , %). the commonest presentation of ep-tb was lymphadenopathy (n = , %), followed by pleural (n = %) and bone (n = , . %) disease. ep-tb was diagnosed by biopsy/excision of the ep site in the majority (n = , . %), and by sputum testing alone in ( . %). sputum cultures were performed in n = , ( %) overall, with n = ( %) being positive. there was higher infl ammatory markers in the sputum culture positive group (esr . vs. . , p = . and crp . vs. . , p = . ). the majority had cxr abnormalities (n = , %). in the group with normal cxr (n = ), ( %) had sputum cultures performed. of these, were culture positive and of these also + smear positive ( on immunosuppression, with cough). conclusion a small number of patients with ep-tb and normal cxr had pulmonary tb, of whom were smear positive. thus, induced sputum testing should be considered in patients with ep-tb even if cxr is normal. this may aid diagnosis and determine infectivity. ntm are normal inhabitants of environmental reservoirs including water. disease due to ntm has been increasing in qld. aim to document the presence of ntm in potable water in brisbane, to compare the species isolated during summer and winter and to relate this to the geographic distribution of patients with ntm. methods water samples ( l) were collected from routine collection sites in winter and sites in summer . samples were processed in triplicate as previously described. h subcultures were taken from positive specimens, dna extracted, followed by s rrna sequencing. patient addresses were obtained from the qld tb control centre database. aim to gauge the full impact of pandemic h n infl uenza across demographic groups in the northern territory, particularly indigenous and remoteliving individuals. methods we performed two cross-sectional serological surveys on specimens from residents of the northern territory, with specimens obtained from january to may (pre-pandemic) and specimens from september (post-pandemic). specimens were selected from among serum tubes collected from ambulatory outpatients. antibody titres were measured by haemagglutination inhibition against the a/california/ / reference virus. all specimens had available data for gender, age, and address, with indigenous status determined in . % of cases. results protective antibody levels, defi ned as a titre of or greater, were present in . % of pre-pandemic specimens and . % of post-pandemic specimens. the pre-pandemic proportion immune was greater with increasing age, but did not differ by other demographic characteristics. the post-pandemic proportion immune was greater among aboriginal and torres strait islanders and in younger age groups, but did not differ by gender or socio-economic index for area. however, the proportion immune was geographically heterogeneous, particularly among remote-living and indigenous groups. the northern territory-wide attack rate adjusted to age, region and indigenous status was . %. conclusions pandemic infl uenza disproportionately affected children and indigenous australians in the northern territory in . the proportion of specimens demonstrating post-pandemic immunity was particularly variable among indigenous and remote-living individuals. the kormp found asymptomatic aboriginal children (ac) had more hrv than asymptomatic non-aboriginal children (non-ac) in a longitudinal communitybased cohort study where infants had nasopharyngeal aspirates (npa) collected regularly from birth to years of age. aim to compare the frequency of hrv groups in asymptomatic ac and non-ac in the kormp. methods npa positive for hrv (n = ) from the npa previously tested for respiratory viruses, had viral rna extracted and reverse transcribed. hrv was detected and typed using a two-step pcr of the hrv ' utr, followed by dna sequencing for typing. chi-square analyses were used. results hrv was detected and typed in npa (from children; ac and non-ac), could not be typed and were not positive for hrv. ac had more hrv in summer and autumn than non-ac and were more likely to be co-infected with at least / bacterial species identifi ed. hrva, b & c were found in . , . and . % of hrv detected. hrvb & c were increased in infants exposed than not exposed to tobacco smoke in utero (hrvb; . vs. . %, p = . and hrvc; . vs. . %, p = . ). of the npa, hrv-a was detected more often in npa from ac than non-ac ( . vs. . %, p = . ), particularly at - months of age (p = . ) and during summer (p < . ). hrvb was detected more often in npa from ac than non-ac in autumn (p < . ). hrvc was detected as often in ac as non-ac in each season except summer. aim to determine whether interferon-gamma release assay (igra) can be effectively used for diagnosis of latent tuberculosis infection in a remote location. methods subjects were enrolled from the darwin centre for disease control tuberculosis clinic and were eligible if a tuberculin skin test (tst) of mm or greater had been recorded for any indication. igras were performed using quantiferon®-tb gold whole blood in-tube assay according to manufacturer's instructions. specimens were incubated and centrifuged at the local laboratory before refrigeration for transport. interferon assay was performed at the reference laboratory, over km away. results igras were performed, with patients ( %) recording negative results, ( %) positive and only one result ( %) indeterminate. negative, and therefore discordant, test results were more common in bcg vaccinated individuals. this effect was not limited to those with tst results of - mm, but was seen primarily in those with results of mm and above. conclusions these results are broadly comparable to fi ndings for igra use in less remote settings. in particular, our low rate of indeterminate results suggests that igra testing is feasible at a remote site after local processing. this approach could be considered for use in the northern territory tuberculosis control program. inhaled medications form the mainstay of drug treatment for patients with airways disease. effectiveness of therapy is dependent on the appropriate selection and prescription of drug and device, correct supply and adherence to therapy with an effective technique. patients frequently admit to acute medical wards both with acute exacerbations and for other co-morbidities eg heart failure or pneumonia. inpatient episodes provide an opportunity to review inhaled therapy however anecdotally add to patient confusion and introduce complexity (rational or ad hoc changes to inhaled drug, device, strength, dose or frequency). aim identify prescribing accuracy and effectiveness of patients' inhaler technique. describe any discrepancies between inhaled therapy: ( ) used prior to admission, ( ) prescribed for inpatient use, ( ) available at the bedside and ( ) administered, prior to and after implementation of an inhaler prescribing and administration guide. methods a single day audit of all inpatients on general medical wards was conducted october (review of medication charts and inhalers in patients' bedside lockers, brief questioning and direct observation of patients' inhaler technique. results compared to post implement of the 'prescribing and administering inhalers' tool (audit in december ). results from ( %) patients had inhalers prescribed, (mean: . prescriptions per patient). % of prescriptions were accurate ( % patient had no errors). discrepancies between used prior to admission and inpatient prescriptions were found in ( %) patients while those between inpatient prescriptions and available at the bedside were found in %. self-administration ('s') was noted on medication charts of ( %) patients, of whom had an ineffective inhaler technique. / patients has a spacer at the bedside with a further r prescribed metered aerosol inhalers. post-intervention differences in prescribing, supply, administration and technique errors will be discussed. conclusions a combination of errors and prescription discrepancies reduce the effectiveness of inhaled therapy for inpatients. confl ict of interest no. males (n (%) % ci) females (n (%) % ci) adm and bed days bmi, body mass index hrqol, health related quality of life chronic respiratory disease questionnaire; adm, admissions, mean (sd) uberculosis notifi cations in australia a cluster of tuberculosis associated with use of a marijuana water pipe the prince charles hospital foundation cc dobler , , gb marks , woolcock institute of medical research, the university of sydney, nsw, and department of respiratory medicine, liverpool hospital, sydney, nsw aim to determine the incidence rate and nature of adverse events in patients taking treatment for latent tuberculosis infection (ltbi). methods records of all patients who received treatment for ltbi at the chest clinic of a large tertiary hospital between / and / were reviewed. an adverse event was defi ned as any change in health status or side effect that led to treatment interruption or cessation. liver function tests were not performed routinely during follow-up, except when the patient was considered to be at an increased risk of developing hepatitis. results of patients in whom treatment for ltbi was initiated ( %) received isoniazid for months, ( %) received a combination of isoniazid and rifampicin for months, and the remainder were treated with different regimens. their mean (sd) age was ( ) years and % were male. nineteen patients ( . %) experienced an adverse event. seven patients developed a rash, four had lethargy and/or mood disorders, three had subclinical hepatitis, four experienced severe nausea, vomiting and/or other gastrointestinal symptoms and three had features of peripheral neuropathy. in eight patients who experienced an adverse event medication was temporarily ceased and then re-started without change; in four the treatment regimen was changed; and in seven the treatment was ceased completely. the risk of adverse events was not signifi cantly related to age, sex, drug regimen (single drug versus combination therapy) or baseline transaminase levels. conclusions in this cohort almost in patients on treatment for ltbi experienced an adverse event. although the adverse events were generally mild to moderate, this risk has to be taken into account when deciding whether to advise treatment for ltbi. introduction human rhinovirus (hrv) is the commonest cause of asthma exacerbations in children. pernasal aspirate (pna) is the gold standard for microbiological sampling but is invasive and distressing for children. studies have showed that less invasive swabs may be just as effi cacious. aim to test the hypothesis that hrv detection is as effi cient using nasal fl ocked swabs or washes and more comfortable, compared with pna in children with respiratory illnesses. methods children were recruited on presentation to the emergency department with respiratory symptoms. pna was collected from one nostril of all children recruited and nasal fl ocked swab (n = ) or wash (n = ) collected from the other nostril alternately. subjects rated the comfort of each sampling method to (least to most). viral rna was extracted and reverse transcribed. a two-step pcr of the hrv ' utr was used for detection, followed by sequencing for typing. results to date, children ( % male, mean age of . years) had paired samples taken. of these children, % (n = ) presented with a diagnosis of viral induced wheeze and % (n = ) had a hrv positive sample. compared with pnas, nasal fl ocked swabs were % ( of pna positive) effective in detecting hrv, whilst nasal washes showed % ( of pna positive) effi cacy. of the successfully typed samples, had hrva and had hrvc. nasal washes had a better comfort rating (mean . , n = ) than fl ocked swabs (mean . , n = ) and pnas (mean . , n = ). conclusion our fi ndings suggest that whilst nasal fl ocked swabs are an effective sampling method for hrv detection, nasal washes were more effective, being as effective as pnas and were the most comfortable. support nhmrc, pmh foundation. nomination nil. aim to describe the inpatients treated by a dedicated niv service. methods a retrospective audit of inpatients treated by the alfred niv service between january and june . the defi nition of niv included patients treated with cpap and bilevel positive pressure ventilation. results patients (age: ± years (mean ± sd), gender: % male) were treated with niv on occasions (repeat admissions patients). commonest indications for niv were osa (n = , %), acute exacerbations (ae) of copd (n = , %), acute cardiogenic pulmonary oedema (acpo) (n = , %) and post-lung transplantation (n = , %). treatment was delivered primarily in the respiratory ward (n = , %), cardiac ward (n = , %), icu (n = , %) and general medical ward (n = , %). episodes of cpap (mean pressure ± cmh o), osa and acpo made up % of those treated. seventy-two episodes of bilevel pap (mean ipap ± cmh o and epap ± cmh o), aecopd and weaning post-mechanical ventilation made up % of those treated. outcome data was available in a subgroup of patients with acpo (n = ) andaecopd (n = ). in the acpo group, patients ( %) improved and niv was ceased. three patients ( %) deteriorated and were intubated and patients ( %) were palliated. in the aecopd group, patients ( %) improved andniv was ceased or they were discharged on therapy. patients either deteriorated on niv or could not tolerate therapy, of these ( %) continued ward management and ( %) were palliated. conclusion the alfred niv service model has managed a large number of referrals across a range of diseases in a variety of wards. this is likely to have reduced demand on icu, hdu and respiratory ward beds. compared to the published literature, theoutcomes for acpo are worse than expected but comparable for aecopd. this may be explained by local referral patterns for acpo. we believe that our service model provides a viable means of administering niv to an ever expanding referral base. transitional & community service, the university of south australia, adelaide, sa , the university of adelaide, adelaide, sa, , the mary potter hospice, north adelaide, sa, , thoracic medicine, the royal adelaide hospital, adelaide, sa, , the royal district nursing service, wayville, sa , and the palliative care council of sa eastwood, sa introduction: the adelaide health service is in the process of developing a new and innovative model of copd community based care. a number of initiatives have informed this development including a recent research project examining the experiences of participants with end stage copd and their carers. a growing body of evidence indicates the importance of a palliative approach, however this often takes the form of referral to a palliative care service rather than a broader application of palliative principles in both specialist and primary care. methods: fifteen participants were interviewed twice at monthly intervals to explore their needs and the services they accessed. a series of focus groups with key service providers in sa was also undertaken. data were analysed to identify how hospital, specialist palliative care units and primary care services currently interface to meet identifi ed patient and carer needs. results: the current service model is episodic and reactive with services activated through the acute care system. our research has shown that, as copd advances, current models of care do not address the importance of supporting quality of life (including a focus on adls) and carers in their ongoing role. also emphasised was the lack of co-ordination of care, collaboration between service providers and communication -the basics of chronic disease management. conclusions the outcomes of this study will inform the development of a proactive, multidisciplinary model of care which is no longer reliant on tertiary care, but places primary care at the centre of the model. greater collaboration between respiratory, palliative and primary care services will provide an integrated approach, focusing on the needs of the patient and carer. aim long term conditions are prevalent in south auckland and impact on the individual, the community and the health system. as nurses living within this community, and employed by counties manakau district health board, our aim was to explore funding opportunities available through the pacifi c health team. lotumoui was established to improve health outcomes/behaviours for pacifi c populations. the church we attend has wide cultural diversity and had no knowledge of the programme and the support provided to make healthy changes within our community. methods firstly a health committee was formed within the church, having 'sold' our vision to the parish council. we launched the group by undertaking free blood pressure checks, followed by a 'walk the talk' project for the days leading into easter. baseline observations were taken and pedometers issued. results the parishioners who attend regular exercise sessions are reporting improved quality of life, exercise tolerance and reducing waist lines. bp parameters are also reducing. conclusions a dedicated health committee within a parish community, supported by the district health board can impact on changes in lifestyle by simple interventions. the investment by the pacifi c team will reap benefi ts for the individual and the health sector. confl ict of interest no. key: cord- - fn ei f authors: hanania, nicola a.; king, monroe j.; braman, sidney s.; saltoun, carol; wise, robert a.; enright, paul; falsey, ann r.; mathur, sameer k.; ramsdell, joe w.; rogers, linda; stempel, david a.; lima, john j.; fish, james e.; wilson, sandra r.; boyd, cynthia; patel, kushang v.; irvin, charles g.; yawn, barbara p.; halm, ethan a.; wasserman, stephen i.; sands, mark f.; ershler, william b.; ledford, dennis k. title: asthma in the elderly: current understanding and future research needs—a report of a national institute on aging (nia) workshop date: - - journal: j allergy clin immunol doi: . /j.jaci. . . sha: doc_id: cord_uid: fn ei f asthma in the elderly is underdiagnosed and undertreated, and there is a paucity of knowledge on the subject. the national institute on aging convened this workshop to identify what is known and what gaps in knowledge remain and suggest research directions needed to improve the understanding and care of asthma in the elderly. asthma presenting at an advanced age often has similar clinical and physiologic consequences as seen with younger patients, but comorbid illnesses and the psychosocial effects of aging might affect the diagnosis, clinical presentation, and care of asthma in this population. at least phenotypes exist among elderly patients with asthma; those with longstanding asthma have more severe airflow limitation and less complete reversibility than those with late-onset asthma. many challenges exist in the recognition and treatment of asthma in the elderly. furthermore, the pathophysiologic mechanisms of asthma in the elderly are likely to be different from those seen in young asthmatic patients, and these differences might influence the clinical course and outcomes of asthma in this population. states is currently about % but is projected to grow from about million in to more than million by , accounting for % of the population. the age group with the largest growth will be those older than years, which is estimated to be more than million by . , in , the us prevalence of asthma for those years or older was %, with , , reporting an asthma attack in the previous months. older asthmatic patients are more likely to be underdiagnosed, undertreated, , and hospitalized than younger asthmatic patients. they also have the highest death rate ( . per million persons) of any other age group. older women are hospitalized more than twice as often as older men. asthma in older adults is superimposed on a background of aging-related changes in respiratory and immune physiology and often on multiple diseases and conditions common in older age. recognizing the paucity of research, the many challenges that exist in the recognition and treatment of asthma in older adults, and the opportunity to bridge geriatrics and the clinical specialties that focus on asthma, the national institute on aging (nia) sponsored a workshop on asthma in the elderly in herndon, virginia, on september and , . the workshop was planned by a committee of physician-scientists from us academic institutions or from the division of geriatrics and clinical gerontology in the nia. the planning committee selected speakers and participants for their expertise in asthma, pulmonology, allergy/immunology, primary care, emergency medicine, geriatrics, and/or gerontologic science (see the list of participants in appendix ). the immediate goals of this workshop were to summarize the current understanding of the mechanisms of asthma in older persons and to identify knowledge gaps and research opportunities leading to improved medical care and health outcomes for older persons with asthma. these research opportunities are discussed in the body of this report and summarized in table i . [ ] [ ] [ ] in addition, the nia, in collaboration with the national heart, lung, and blood institute and the national institute of allergy and infectious diseases, recently issued a set of program announcements inviting research proposals on asthma in older adults (http:// grants.nih.gov/grants/guide/pa-files/pa- - .html, http://grants. nih.gov/grants/guide/pa-files/pa- - .html, and http://grants. nih.gov/grants/guide/pa-files/pa- - .html). it is a central principle of gerontology that aging itself is not a disease. yet there are physiological changes within organs, tissues, and cells that result in diminished functional reserve and thereby increased susceptibility to stressors, disease, or both. a second principle is that these aging changes are highly variable and account for the great constitutional heterogeneity among older persons from very ''fit'' to very ''frail.'' in fact, the concept of frailty, both its causes and consequences, has become a focus of concentrated gerontologic investigation. at the root of age-associated physiological changes are a number of genetic, epigenetic, and environmental factors. molecular damage accumulates over time, and the capacity for dna repair decreases. cellular senescence, which is believed to be the consequence of accumulated dna and protein damage and reduced proliferative capacity, is becoming increasingly understood at the molecular level. however, just how this correlates with the phenotypic changes of advanced age remains incompletely understood. there has been much written about cellular senescence and the events that lead to cell death. [ ] [ ] [ ] after a finite number of divisions, normal somatic cells invariably enter a state of irreversibly arrested growth, a process termed replicative senescence. in fact, it has been proposed that escape from the regulators of senescence is the antecedent of malignant transformation. however, the role of replicative senescence as an explanation of organismal aging remains the subject of vigorous debate. the controversy relates, in part, to the fact that certain organisms (eg, drosophila species and caenorhabditis elegans) undergo an aging process, yet all of their adult cells are postreplicative. what is clear is that the loss of the proliferative capacity of human cells in culture is intrinsic to the cells and not dependent on environmental factors or even culture conditions. unless transformation occurs, cells age with each successive division. the number of divisions turns out to be more important than the actual amount of time passed. thus cells held in a quiescent state for months, when allowed back into a proliferative environment, will continue approximately the same number of divisions as those that were allowed to proliferate without a quiescent period. the question remains whether this in vitro phenomenon is relevant to animal aging. one suggestive observation is that fibroblasts cultured from samples of old skin undergo fewer cycles of replication than those from young skin. furthermore, when various species are compared, replicative potential is directly and significantly related to lifespan. an unusual b-galactosidase with activity peaks at ph has proved to be a useful biomarker of in vitro senescence because it is expressed by senescent but not presenescent or quiescent fibroblasts. this particular b-galactosidase isoform was found to have the predicted pattern of expression in skin from young and old donors, with measurably increased levels in dermal fibroblasts and epidermal keratinocytes with advancing age. the nature of the expression of this in vivo biomarker of aging in other tissues will be important to discern. for clinical investigators, frailty has proved hard to define primarily because of the seemingly insurmountable heterogeneity inherent in geriatric populations on the basis of these variable rates of organ system decrease and the presence or absence of or more diseases. yet, regardless of the pathway taken to frailty, the clinical picture has common features, including a reduction in lean body mass (sarcopenia), loss of bone mass (osteopenia), cognitive impairment, functional decline, and anemia. on the basis of data derived from large cohorts of elderly patients, fried et al have offered an operational definition of frailty incorporating an assessment of specific characteristics to ascribe a frailty index. on this -point scale, a score of or more has been shown to be independently predictive of a range of adverse clinical outcomes, including acute illness, falls, hospitalization, nursing home placement, and early mortality. [ ] [ ] [ ] furthermore, simple performance measures, such as the assessment of walking speed, are predictive of important outcomes, including survival. with the phenotype better defined, attention has shifted to pathophysiology. although frailty can occur in the absence of a diagnosable illness, the fact that some become frail and others do not suggests an inherent or acquired variability in homeostatic pathways. recent evidence from observational studies has raised suspicion that dysregulated inflammatory processes are involved in, if not central to, the variable patterns of aging. increased serum levels of certain proinflammatory cytokines, most notably il- , are increasingly present with advancing age and to a greater extent with frailty. , furthermore, the appearance of this and other inflammatory markers has been associated with a number of adverse clinical outcomes, including decreased strength and mobility, falls, dementia, and mortality. life expectancy, lifespan, and maximum survival from the perspective of those who study aging, there is an important distinction made between median (life expectancy) and maximum lifespan. over the past several decades, with the advent of modern sanitation, refrigeration, and other public health measures, including vaccination and antibiotics, there has been a dramatic increase in median survival. early deaths have been diminished, and more patients are reaching old age. in the united states today, life expectancy now approaches years. median survival is what concerns public health officials and health care providers, but for those studying the biology of aging, it is maximum survival that is the focus of greatest attention. it is worthwhile to note that it has been estimated that if atherosclerosis and cancer were eliminated from the population as a cause of death, about years would be added to the average lifespan, yet there would be no change in maximum lifespan. although several theories have been proposed, none suffice to account for the complexities of aging. lifespan is finite and varies generally from species to species and much less so within species. mice live, on average, ½ years, monkeys years, and human subjects about years. among species, larger animals generally live longer than smaller animals, but within species, smaller animals are likely to live longer. it is clear that aging is not entirely explained by dna sequence. for example, mice and bats have only . % difference in their primary dna sequence, but bats live for years, times longer than mice. a commonly held notion is that regulation of gene expression accounts for a longevity difference between species. the aging lung large, longitudinal, and more complete studies to determine the effects of aging on the function of the respiratory system improved knowledge about lung structure-function relationships in older age using techniques of imaging and measures of lung function not requiring effort (eg, high-resolution computed tomographic scanning and forced oscillation) improved assessment of lung processes underlying airflow limitation attributable to aging versus copd or asthma, especially in asthmatic patients who smoke studies to examine the effects of aging in ethnic groups and the role of gender epidemiology, effect, diagnosis, and management determine the true prevalence and cost of asthma in the older population develop a uniform definition of asthma to be applied to health care records that will distinguish asthma from copd and mixed asthma/copd evaluate evidence-based treatment algorithms for older asthmatic patients, such as those developed by the national heart, lung, and blood institute and global initiative for asthma guidelines assess the effect of asthma treatment, including direct medical costs of care, indirect costs of care, and value of treatment in improving quality of life , assess the effect of comorbid conditions, especially copd and congestive heart failure, on asthma characterize phenotypes of elderly asthma with regard to responses to therapy and long-term outcomes based on age of onset, duration of disease, and environmental triggers develop algorithms for electronic medical record systems that are asthma-specific evaluate effects of current asthma medications in older patients compared with younger patients identify pharmacogenetic determinants of response to asthma medications in older adults identify simpler and safer drug delivery systems and schedules for older adults develop simple methods to differentiate copd from asthma exacerbations in older adults understand how environmental or aging-related factors affect epigenetic changes in asthma in older adults identify differences between older and younger asthmatic patients or between lsa and loa with regard to inflammation, remodeling, intracellular mechanisms, responses to environmental pollutants, and allergy sensitization and their effects on the metabolism and action of asthma drugs identify naturally occurring age-related changes in airway cellular patterns develop animal models of age-related airway inflammation understand the significance of allergy sensitization associated with asthma in older adults (eg, through larger prospective studies) identify the utility of allergy tests, either skin tests or serum specific ige measurement, in reflecting allergy sensitization in older adults identify the role of the microbiome in patients with loa understand the role of non-ige mechanisms in older adults' inflammatory responses to inhalant allergens or pollutants (eg, t h lymphocytes producing il- or protease receptor responses to molds and dust mites) determine the roles of adaptive versus innate immune mechanisms on asthma development, progression, and response to treatment in older adults determine whether there are environmental pollutants peculiar to institutional settings identify viruses and other microbiological agents responsible for, and the mechanisms by which they cause, asthma exacerbations in older adults, which might lead to the development of vaccine-or antiviral drug-based interventions determine effects of asthma medications, viral or bacterial load, or allergy status on susceptibility to exacerbations in older patients define rates of infection and specific pathogens in older asthmatic patients distinguish roles of innate immunity in eosinophilic versus neutrophilic asthma it is now clearly established that certain specific genes can alter lifespan, at least in lower animals, but whether these same genes regulate ''aging'' is still in question. for example, transgenic drosophila species expressing increased copies of the free radical scavenging enzymes superoxide dismutase and catalase live on average a third longer than the appropriate controls. in even lower species (eg, yeast and nematodes) the identification of specific genes that influence lifespan , has led to the optimistic impression that analogous genes in higher organisms will lead greater insights into the aging process. yet the identification and functional analysis of analogous genes in human subjects remains elusive. the oldest human being alive today is approximately years old. what is intriguing is that the record has remained stable and unchanged by the public health initiatives mentioned above. in fact, there has been some recent data presented that the maximum survival is actually decreasing in the united states. , what is interesting is that, unlike the public health initiatives in human subjects in which median but not maximum survival has been enhanced, experimental interventions in lower species have resulted in prolongation of maximum survival. as mentioned above, transgenic drosophila species producing extra copies of superoxide dismutase and catalase survived about % longer than controls, and similarly, the maximum survival in c bl/ mice fed a calorically restricted diet enhanced by % or more. , the true mechanisms of aging might well be uncovered with a better understanding of how these interventions affect longer survival. future research in aging should attempt to improve our understanding of the basic biology of aging and interventions that retard the aging process. there is a need for the development and application of a standardized definition of frailty for future clinical investigation. investigations directed at the role of comorbidities in accelerating the aging process are important. furthermore, future research should focus on the development of cellular and animal models of typical, delayed, and accelerated aging and of large collaborative networks in which populations and resources can be shared to study aging and frailty. leveraging on well-characterized existing cohorts, when possible, is recommended. the lungs, like other organs, age and exhibit continued loss of function as a person grows old. lung function is traditionally assessed by means of a number of standardized methods. the most common measurement used is spirometry with the determination of fev and forced vital capacity (fvc). fev and fvc both show continuous decreases of between and ml with each year of life after about age years. the cause of this decrease is usually attributed to the loss of the driving forces for airflow as a result of reduced respiratory muscle performance, loss of static elastic recoil, or both. , the decrease in fev in asthmatic patients is largely a function of the decrease in fvc because of the increase in residual volume. stiffening of the chest wall and reduced respiratory muscle performance result in a decrease in total lung capacity and an increase in residual volume because of ever-increasing closing volume. accordingly, these aging processes lead to airflow limitation that might be hard to distinguish from an active disease process. not all older persons are able to perform spirometry, especially those with decreased cognition, coordination, and frailty. in addition, spirometry is effort dependent, and the very old can tire quickly. techniques of imaging and measures of lung function not requiring effort (ie, forced oscillation) should be used in future studies to extend our knowledge about lung structure-function relationships at the very end of life. bronchodilator responses are known to be less marked in the elderly, perhaps as a consequence of the aging effects attributed to the emphysema-like state of the senile lung ; however, this would not explain the slow temporal response to bronchodilators. other studies do not find such age-related bronchodilator differences. furthermore, although methacholine responsiveness has been reported to increase with aging, the exact mechanism for this is not apparent. increased incidence and prevalence of many lung diseases occur with age. alterations in immune function increase the risk of many of these diseases. studies of systemic immunity suggest that sustained antigenic stress over a lifetime leads to a decrease in naive t-cell numbers, an accumulation of memory t cells, and a decrease in t-cell repertoire and b-cell functions but a lesser decrease in innate immunity. , little is known about what happens to the immune/inflammatory pathways in older asthmatic patients. the immune system changes seen with aging will be discussed in more detail in the section on pathophysiology. in the united states the national health interview survey asks questions regarding lifetime history of asthma, current asthma prevalence, and asthma attacks in the last months. for all age groups, asthma prevalence has been steadily increasing since . for the years and older age group, asthma is consistently more prevalent in female than male subjects. the national center for health statistics tracks data on physician encounters for asthma. the national ambulatory medical care survey reported that those years or older have the second-highest rate of outpatient office visits after those aged to years. those years and older did not have significantly different emergency department visits than the other adult groups. the years and older age group accounts for a greater proportion of hospitalizations ( %) than the size of its population ( %) would indicate. not surprisingly, the elderly population is a high user of medical resources for the treatment of asthma. hospitalizations and emergency department visits are more common for these patients than for other adult cohorts. some of the increased costs are related to comorbid disease. for example, the presence of comorbid chronic obstructive pulmonary disease (copd) increases the risk of an asthma-related hospitalization in medicare patients . -fold, respiratory medical costs almost -fold, and total medical costs -fold. elderly female subjects appear at greater risk than elderly male subjects. [ ] [ ] [ ] [ ] asthma mortality increased steadily from until it peaked in . the highest mortality rates for asthma occur in the years and older group. in fact, the increase in asthma mortality between and was primarily driven by the years and older group. in addition, the decrease in asthma mortality between and was most evident in this age group. elderly women with asthma tend to have higher mortality rates than elderly men with asthma. one reason for the increasing prevalence of asthma in the elderly might be the improved longevity of the population. also, increased office visits for asthma in the elderly might be responsible for fewer attacks. increasing hospital admissions might account for decreased mortality. by continuing to gather surveillance data on asthma, reasons for these trends could become clearer. in addition, surveillance data help to focus intervention efforts in areas of greatest need. in the cardiovascular health study, a large community-based cohort of subjects older than years, questions were asked that were relevant to asthma and provided more insight into the prevalence and effect of asthma in this population. , , definite asthma was defined as a positive response to the questions indicating that the patient had current asthma and that a physician confirmed the diagnosis. probable asthma was defined as a history of wheezing in the past year associated with chest tightness or breathlessness. excluding smokers and those with a diagnosis of congestive heart failure, % of subjects had definite asthma, and % had probable asthma. among those who smoked, % had definite asthma, and % had probable asthma. among nonsmokers, subjects were identified who had definite or probable asthma; % were women, and % were older than years. the age of asthma onset was spread approximately evenly among decades. twenty-seven percent had late onset of disease after age years, and % had onset of disease before age years. as expected, respiratory symptoms in the older asthmatic subjects were more prevalent, with a -to -fold increase in cough, phlegm, wheezing, and dyspnea. dyspnea on exertion was . -fold more likely to be present in asthmatic patients than in those without the diagnosis. lung function was reduced in those with a diagnosis of asthma. mean fev was % of predicted value in those with definite asthma and % of predicted value in those with probable asthma compared with % in those who did not have asthma. forty-one percent of those with a diagnosis of asthma had airflow obstruction below the fifth percentile for the age group, and peak flow lability was increased. elderly asthmatic patients reported the most common trigger was a viral infection in % compared with animal allergies in %. two thirds reported seasonal worsening. asthma had a significant effect on quality of life, with % of patients with definite or probable asthma reporting a fair or poor health status compared with % of elderly patients without asthma. sixty percent of patients with definite asthma reported seasonal allergic rhinitis compared with only % in the nonasthma group. despite the high prevalence and morbidity of asthma in this population, inadequate treatment was common. only % of those with definite asthma had a rescue albuterol inhaler, and only % had inhaled corticosteroid use. , , , the pathophysiology of asthma in the older adult is poorly understood and understudied. many questions about this issue remain: is asthma the same disease in older adults as it is in children and younger adults? is late-onset asthma (loa; asthma that starts in middle age or older) different from longstanding asthma (lsa; asthma of early onset that has persisted into older adulthood)? if loa and lsa are the same disease, then the diagnosis and treatment should be similar. however, if loa and lsa are different phenotypes or at least have a different cause and pathophysiology, then the diagnosis and treatment might differ (table ii) . the traditional view of disease susceptibility has been expanded to include epigenetics to account for the influence of environmental factors and aging on the genomic blueprint. epigenetics is defined as heritable changes in gene expression that occur without alterations in dna sequence. it is the process by which genotype interacts with environment to produce a phenotype and explains differences between cells, tissues, and organs despite identical genetic information. genes function in a milieu determined by the developmental and environmental history of the cell, which constitutes the epigenotype. , epigenetic changes or marks can play a major role in human disease. , the most common examples of epigenetic marks are dna methylation of cpg islands by dna methyltransferases and chromatin modification of histone proteins, particularly acetylation by histone acetyltransferases and histone deacetylases. , the function of epigenetic changes is to regulate gene expression. epigenetic changes are known to contribute to cancer and autoimmune disease and are thought to contribute to common diseases, including cardiovascular disease, diabetes, and the loss of response to stress caused by aging. asthma is a markedly heterogeneous disease, and recent evidence suggests that environmentally induced epigenetic changes contribute to asthma phenotypes and that airway inflammation in patients with asthma and copd might involve epigenetic regulation. , , methylation patterns and chromatin structure change with age and are thought to contribute to the increase in the incidence of common diseases that begin in middle age. , the incidence of asthma in the elderly resembles the incidence of common diseases. moreover, characteristics and asthma drug response in the elderly asthmatic patient differ from those seen in childhood asthma. compared with younger cohorts, elderly asthmatic patients have a higher prevalence, higher rates of bronchial hyperreactivity, more severe asthma, and a lower prevalence of atopy. the symptoms of elderly asthmatic patients are more difficult to control with drug therapy, and these patients have steroid resistance and might respond better to leukotriene receptor antagonists compared with inhaled corticosteroids. [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] the contribution of epigenetics to differences observed between elderly asthmatic patients and younger cohorts is unknown. unlike genetic variants that contribute to disease, epigenetic changes can be reversed and therefore represent potential drug targets. older asthmatic patients are less responsive to albuterol treatments given in the emergency department and are more frequently admitted for hospitalization. thus it appears that the responsiveness to treatment is diminished and the severity of asthma exacerbations is greater. the exact reason for these disparities is not known. immune cell function decreases with aging, a property often termed immunosenescence. one often-confusing aspect of immunosenescence is the observation that aging might be associated with opposing immunologic effects. for example, t-cell secretion of il- , il- , or ifn-g has been shown to be both decreased with aging and also increased with aging. it is likely that both phenomena are correct but are dependent on the context of the immune function. thus the effect of aging on t-cell function in the context of allergen stimulation might be different than the effects of aging on t-cell function in the context of viral infection. given that asthma is an inflammatory disorder of the airway, it is of interest to determine whether asthmatic airway inflammation of the elderly might differ from that of younger asthmatic patients and thus represent a distinct phenotype of asthma. these changes might have implications for susceptibility to exacerbations because of viruses or other pathogens, as well as response to treatment. the aging process has been shown to exhibit changes in airway inflammation. an examination of the cellular composition of bronchoalveolar lavage fluid from -to -year-old subjects without a history of allergies, pulmonary disease, or gastroesophageal reflux showed increased airway neutrophilia, as well as increased numbers of cd t cells. , the t cells also appeared to be more activated in the elderly, with increased expression of hla-dr and cd . the increase in airway neutrophils with aging has also been observed in asthmatic patients. because there is a phenotype of severe asthma characterized by a predominantly neutrophilic airway inflammation, the question arises as to whether the increased presence of neutrophils contributes to greater asthma severity in the elderly. some of the prominent inflammatory cells recruited into the airway in asthmatic patients are eosinophils, neutrophils, and t cells, which are capable of secreting numerous inflammatory mediators, including leukotrienes and cytokines. it is not known whether immunosenescence affects the production of these mediators in elderly asthmatic patients, either at baseline or during an exacerbation of symptoms. furthermore, it is not known whether age-related changes in their production would have any implication for the clinical presentation or management of asthma in the elderly. peripheral blood eosinophils were isolated from younger ( - years old) and older ( - years old) subjects for in vitro functional assays. the eosinophil effector functions of degranulation and superoxide production were diminished in the older compared with the younger asthmatic patients. in another study examining the expression of neutrophil mediators in younger and older asthmatic patients, there was decreased baseline expression of leukotriene b in the sputum of older asthmatic patients despite greater numbers of neutrophils. whether these findings have implications during an asthma exacerbation has yet to be determined. nevertheless, the results demonstrate agerelated changes in the function of an inflammatory cell considered pathognomonic for allergic asthma and raise the question of whether additional effects of immunosenescence are relevant to airway inflammation in asthmatic patients. there have been several studies of animal models to address age-related changes in the airway inflammation induced by allergen challenge of sensitized aged animals (see experimental approaches section below). these studies yielded conflicting results, and there is concern that the animal models do not accurately represent the chronic features of human asthma with seasonal allergen exposure and intermittent exacerbations. the aged animals were both sensitized and challenged at old age, which is in contrast to the typical elderly human asthmatic patient who might be exposed to allergens for several decades. typically, nasal and ocular symptoms on exposure to allergens diminish with age. allergen-triggered asthma symptoms also diminish with age. the epidemiology and natural history of asthma (tenor) study examined the natural history of asthma in older (> years old) compared with younger patients and found that older asthmatic patients had lower total ige levels, fewer positive skin prick test responses, and less concomitant allergic rhinitis or atopic dermatitis. several studies have demonstrated age-related decreases in total ige and allergen-specific ige levels, [ ] [ ] [ ] [ ] [ ] [ ] suggesting that this might be the explanation for the decrease in allergy symptoms. there is also evidence for an age-related decrease in skin prick test responses to allergens. however, the relationship between total ige levels and allergic disease persists in the elderly, such that subjects with greater ige levels remain more likely to have allergic rhinitis or asthma. , given the changes in allergic inflammation with aging, one might conclude that asthma in the elderly should be milder. however, there are several other common triggers for exacerbations of asthma, including irritants (eg, cold air) and respiratory tract infections. estimates suggest that up to % of asthma exacerbations in adults are caused by viral upper respiratory tract infections. the role of environmental exposures and allergy in older asthmatic patients is largely unknown. in the general population, evidence regarding the effect of indoor pollution on asthma is summarized in ''clearing the air: asthma and indoor air exposure'' by the institute of medicine for the environmental protection agency published in . evidence was reported for asthma development related to house dust mites and for asthma development associated with environmental tobacco smoke in preschool children. the report also showed evidence for causation of asthma exacerbations for house dust mite, environmental tobacco smoke (in preschool children), cat, and cockroach; an association with exacerbations was found for dogs, fungi, formaldehyde, and rhinovirus. in addition, evidence associating exacerbation of asthma-related symptoms with self-reported damp air was reported in a review of damp indoor spaces and health. , there are only a few studies that have evaluated the role of atopy in elderly patients with asthma. one large national study of allergy skin tests that included older adults and several small studies of allergy skin tests in older adults with asthma , - j allergy clin immunol volume , number were reviewed. allergy skin test results were positive in % to % of all older adults. the prevalence of positive skin test results or specific ige levels to at least allergen in older adults with asthma ranged from % to %. those whose asthma had an unknown age of onset ranged from % to %, those with onset before age years ranged from % to %, and those with onset greater than age years ranged from % to % (table iii) . , , although there were no studies of allergen room exposure or bronchial challenge in older adults, neither prick-puncture skin test results nor specific ige levels predicted the nasal challenge response to dust mites. safety concerns for allergen challenges in older adults are unresolved. technical limitations of allergens, environmental measurements, and age-specific norms and cutoff levels for laboratory and physiologic tests are needed. a few epidemiologic studies suggest an association between outdoor environmental exposures and emergency department or hospital admissions in older adults. , in summary, studies of the general population suggest a causation or association between indoor air pollutants and allergy exposure and asthma. there are several small studies suggesting higher levels of positive allergy test results in older adults with asthma than in the general population of older adults. when age of onset is considered, asthma with an early onset (< years of age) has a much higher association with positive allergy test results than late-onset asthma. viral respiratory tract infections are common precipitants of asthma exacerbations during childhood. in approximately % of children with acute asthma exacerbations, a respiratory tract virus can be detected, with rhinovirus being the most frequent pathogen identified. although it is likely that viruses also lead to exacerbations of asthma in older adults, comprehensive studies regarding the rates and specific pathogens are lacking. several issues have made defining the role of viruses in adult asthmatic patients problematic and include difficulty distinguishing copd from asthma, lack of sensitive diagnostic tests, and issues with asymptomatic infection. a number of investigators have explored the incidence of viral infection in adult asthmatic patients. , , older studies using viral culture and serology for diagnosis demonstrated infection rates of % to %. in contrast, more recent studies, which include rt-pcr, have shown significantly higher infection rates of % to %. , similar to results found in children, rhinoviruses are the most frequently detected pathogen. few older persons were included in these studies, in which the mean ages of subjects were to years. the incidence of acute respiratory tract infections decreases steadily with advancing age, and rates of viral infection in older adults are influenced by place of residence. among community-dwelling older adults, rates of acute respiratory tract infections are roughly % to % per year, whereas rates in senior day care centers and long-term care facilities are substantially higher at % to %. in addition, the epidemiology of respiratory tract infections can be quite complex in these semiclosed populations, with multiple pathogens circulating simultaneously. influenza a, respiratory syncytial virus (rsv), and human metapneumovirus (hmpv) are the most commonly identified viruses among older persons hospitalized with acute cardiopulmonary conditions. , most patients who require hospitalization during a viral respiratory tract infection have underlying heart and lung conditions. although studies to date have largely focused on the role of viruses in copd exacerbations, it is reasonable to extrapolate infection rates and specific pathogens from these studies to older adults with asthma. johnston, in ontario, canada, found a seasonal peak in emergency department visits for all acute respiratory tract infections, as well as exacerbations of both copd and asthma, for persons younger and older than years. all the common respiratory tract viruses have been associated with copd exacerbations, and depending on the methodology and season of study, the specific rates of influenza, rsv, parainfluenza viruses, coronaviruses, hmpv, and rhinoviruses vary. , wheezing appears to be a common symptom in older adults infected with any of the respiratory tract viruses, particularly rsv and hmpv, and % of adults hospitalized with rsv will have a discharge diagnosis of asthma. , because most adult infections represent reinfection, the viral load in respiratory secretions tends to be low, making detection with conventional techniques difficult. viral culture and rapid antigen testing, which can be used successfully in children, have poor sensitivity in older adults. the use of molecular diagnostics has vastly improved the ability to detect a number of viruses, such as rsv, parainfluenza, and rhinoviruses, and allows the detection of hitherto uncultivable agents, such as hmpv and coronaviruses. viral infections appear to aggravate reactive airway disease through a number of different mechanisms. it has been postulated that viral infection disrupts the negative feedback loop of acetylcholine on the m receptor, leading to increased levels of acetylcholine and increased constriction of bronchiolar smooth muscle. infection of the respiratory epithelium also induces chemokines, cytokines, and immune and growth factors, which result in a proinflammatory state. , immunosenescence might affect the ability of older adults to clear viruses efficiently, and thus greater and more prolonged inflammation can result. in summary, respiratory viral tract infections are common among older adults and are likely precipitants of acute asthma exacerbations. furthermore, viral respiratory tract infections might likely precipitate the onset of loa, although this needs to be further examined. comprehensive studies regarding the rates and specific pathogens are lacking in older adults. distinguishing copd from asthma, lack of sensitive diagnostic tests, and issues with asymptomatic infections make it difficult to define the role of infections in older adults. classic symptoms of asthma in the elderly are mostly similar to those seen in younger asthmatic patients. , data on the clinical features of asthma in the elderly have been derived from both longitudinal community surveys and case studies. , , , , [ ] [ ] [ ] most patients complain of episodic wheezing, shortness of breath, and chest tightness. these symptoms are often worse at night and with exertion and, like those in younger asthmatic patients, are often precipitated by an upper respiratory tract infection. in fact, the majority of elderly patients who have asthma after age years have their first asthmatic symptom preceded immediately by or concomitant with an upper respiratory tract infection. asthma can often be triggered by environmental exposures, such as aeroallergens, irritants (cigarette smoke, household aerosols, and paints), strong odors (perfumes), and inhalation of metabisulfites (found in beer, wine, and food preservatives). asthmatic symptoms can also be triggered by medications, such as aspirin, nonsteroidal anti-inflammatory agents, angiotensin-converting enzyme inhibitors, or b-blockers, which are commonly used by this patient population. this emphasizes the need for the physician to perform a comprehensive review of medications taken by the older asthmatic patient. studies have consistently shown that elderly patients and their physicians frequently overlook symptoms caused by asthma. , , several factors contribute to the underdiagnosis and misdiagnosis of asthma. one reason, as shown in large community studies, is that most patients first have asthma in childhood or adolescence, and many physicians have had the misconception that asthma is a childhood disease. another important reason is that the symptoms of asthma are more commonly associated with other diseases seen in this age group. the symptoms of asthma in the elderly are therefore nonspecific and might be caused by conditions that mimic asthma. the differential diagnosis of asthma in the elderly is greater than seen in younger asthmatic patients and includes congestive heart failure, emphysema and chronic bronchitis (copd), chronic aspiration, gastroesophageal reflux disease (gerd), and tracheobronchial tumors. comorbid illnesses and the psychosocial effects of aging might also profoundly affect the diagnosis, clinical presentation, and care of asthma in the elderly. one particular diagnosis that is often difficult to detect and frequently overlooked by the patient and physician until the condition is advanced is upper airway obstruction, including the extrathoracic and intrathoracic central airways. common causes of upper airway obstruction include malignancy, infection, inflammatory disorders, trauma, and extrinsic compression related to enlargement of adjacent structures (eg, an enlarged thyroid gland). it appears that malignancy and benign strictures related to airway instrumentation (eg, endotracheal intubation and tracheostomy) are becoming increasingly more prevalent in the older age group. distinguishing chronic asthma from copd can be very challenging, and in some patients asthma cannot be distinguished from copd with widely available diagnostic tests. the management of these patients might have similarities to that of asthma. the distinction between loa and copd can be difficult to define precisely. the lung health study showed that methacholine-induced airways reactivity is present in many patients with mild-to-moderate copd (ie, % of men and % of women). approximately % of patients with tobacco-related copd demonstrate bronchodilator reversibility at least once on repeated testing sessions. the distinction between copd and asthma can be confounded by either the coexistence of the common disease entities, the progression of common pathobiologic mechanisms induced by different environmental agents, or different disease mechanisms leading to an overlapping clinical syndrome. it has been known for more than a century that early-morning wheezing is a prominent symptom of congestive heart failure. it has been called cardiac asthma because it can mimic the clinical picture of typical asthma. the usual symptoms of gastroesophageal reflux in the elderly, such as vomiting and heartburn, might be absent. in a study of elderly patients with esophageal reflux proved by means of intraesophageal ph monitoring, chronic cough, hoarseness, and wheezing were present in % of patients. in addition to causing asthma-like symptoms, there is also evidence that gerd might be a cause of worsening asthma. shortness of breath is a common symptom in the elderly and is most commonly caused by heart or lung diseases. it is usually experienced during exertion. shortness of breath at rest is not typical of heart disease or lung diseases, such as copd or interstitial lung disease, except in advanced stages. when present, it should prompt an investigation for asthma because sudden bronchospasm can cause respiratory distress at rest or exercise. paroxysmal nocturnal dyspnea, which is typical of congestive heart failure, is found in a smaller number of elderly patients with asthma. many elderly patients limit their activity to avoid experiencing dyspnea, and others assume that their dyspnea results from their aging process and thus avoid seeking medical attention early in their disease process. however, aging per se does not cause dyspnea, and a cause needs to be always pursued in assessing an elderly patient who complains of breathlessness. there are several other reasons why the diagnosis of asthma in the elderly might be delayed or not made at all. elderly patients have been shown to have a reduced perception of bronchoconstriction, and this might delay medical intervention. many elderly patients are fearful of having an illness and dying and are reluctant to admit they are having symptoms. underreporting of symptoms in the elderly might have many causes, including depression, cognitive impairment, social isolation, denial, and confusing symptoms with those of other comorbid illnesses. cough is a very prominent symptom and might occasionally be the only presenting symptom. wheezing, on the other hand, might not be as prominent, and its presence is not very specific and does not correlate with severity of obstruction. physical examination in elderly patients with asthma is usually nonspecific and might misguide the diagnosis: a negative examination result does not rule out asthma, and wheezing can be found in a number of conditions, such as copd, recurrent aspiration, and ''cardiac asthma'' (congestive heart failure). two distinct clinical presentations have been described for asthma in the elderly. these are based on the onset and duration of the disease state. , , patients with loa start having asthma symptoms for the first time when they are years of age or older (some studies have suggested middle age or older). some studies of elderly asthmatic patients have shown that, as a group, as many as % will have their first attack after the age of years. patients belonging to this group tend to have fewer atopic manifestations, higher baseline fev , and a more pronounced bronchodilator response than those with lsa. patients with lsa start having asthma symptoms early in life. patients belonging to this group tend to have a higher incidence of atopic diseases, more severe and irreversible or partially reversible airway obstruction, and more hyperinflation. the duration of the disease in this group is an important determinant of severity and of the development of irreversible airflow obstruction. longitudinal studies of asthmatic populations, whether new onset or long standing, have shown that remission from asthma is uncommon in older groups, occurring in less than % of patients. this contrasts with asthma in children and adolescents, in whom remission of asthma symptoms is common, especially in the second decade of life, and might be seen in as many as % to % of patients. objective measures to confirm the diagnosis of asthma are uncommonly performed in primary care settings. inhalers are prescribed for patients who are evaluated for asthma-like symptoms, and during a follow-up visit, the patient is asked whether the controller inhaler reduced the frequency of asthma symptoms or whether the albuterol inhaler quickly relieved the symptoms. such an empiric approach might work most of the time for young patients with mild asthma but is more likely to result in an incorrect diagnosis, poorly efficacious treatment, or unnecessary medication side effects in older patients. the onset of wheezing, shortness of breath, and cough in an elderly patient is likely to cause concern. although the adage ''all that wheezes is not asthma'' is true at any age, it is especially true in the elderly. diagnosis based on objective measures is essential. moreover, lung function testing, even in the presence of minimal symptoms, is especially important in this age group because there is thought to be an age-related reduction in the perception of exertional dyspnea in the elderly. an older patient with chronic, untreated, severe airway obstruction caused by asthma might reduce activity to avoid dyspnea and stoically deny impairment of activity. this might reflect either neurocognitive function or changes in lifestyle that favor sedentary activities. there exist some barriers to lung function testing in the elderly. spirometry might be difficult to perform in some situations because of physical or cognitive impairments. however, % to % of elderly persons are able to perform goodquality spirometry when tested by skilled technologists. [ ] [ ] [ ] [ ] [ ] the global initiative for obstructive lung disease guidelines for diagnosing the airway obstruction of copd by using a fixed fev /fvc ratio of less than . caused a high misclassification rate in older persons. however, almost all computerized spirometers automatically calculate the appropriate lower limit of the normal range for fev /fvc ratio and for fev by using race-specific national health and nutrition examination survey iii reference equations. in addition, it is hard to define the lower limits of predicted normal values in this age group. although complete reversibility of airflow obstruction is frequently seen with young asthmatic patients, most elderly asthmatic patients show incomplete reversibility despite continuous intense therapy, and many show fixed airflow obstruction as if they have copd. however, objective measures of lung function, such as spirometric and peak flow measurements, are generally underused in elderly patients, and this also contributes to the delay or absence of diagnosis. , lung function testing is especially important in this age group because of the age-related reduction in the perception of dyspnea seen in the elderly. spirometry is easily performed to determine that fev and fev /fvc ratio are demonstrated with the timed vital capacity maneuver. the flow-volume loop, which also measures inspiratory flow, is especially useful when the cause of respiratory tract symptoms is not known and an upper airway obstruction is in the differential diagnosis. although it might be difficult to perform spirometry in the elderly in some situations because of physical and poor cognitive impairment, studies have demonstrated that between % and % of elderly patients are able to perform the test properly. [ ] [ ] [ ] [ ] [ ] on the other hand, it might be more difficult to define the lower limits of predicted normal values in this age group. traditionally, an fev /fvc ratio of less than % increases the probability of asthma in an elderly patient with asthma symptoms, but this ratio normally decreases with age because of a decrease in elastic recoil, and a ratio lower that % might be a normal finding. a brisk response to a short-acting bronchodilator might demonstrate the second cardinal feature of asthma: reversible airflow obstruction (ie, ''a responder''). when airflow obstruction is found in an elderly patient, attempts should be made to demonstrate reversibility after the inhalation of a short-acting b-adrenergic agent, such as albuterol. evidence of reversibility (postbronchodilator fev or fvc increases of > % and ml) increases the probability of a diagnosis of asthma. elderly asthmatic patients, however, might have an impaired b-agonist bronchodilator response because the number of b-adrenergic receptors on smooth airway muscles is decreased with aging. although the bronchodilator response to inhaled b-agonists decreases with age, this is not the case with anticholinergic agents. airway obstruction might be absent at the time of testing, and further testing might be needed to facilitate the diagnosis. bronchoprovocation testing with a methacholine challenge can be useful, and it is a safe and effective method to uncover asthma in older adults. , a negative test result will rule out asthma; a positive test result must be interpreted and include an assessment of pretest probability. in addition, some studies have shown that bronchial responsiveness is heightened in older adults, and therefore aging might be an independent factor that influences airway responsiveness. there is a relationship between the degree of bronchial hyperresponsiveness and prechallenge pulmonary function; a low fev predicts heightened responsiveness. other factors that might contribute to heightened airway responsiveness in the older population are atopy and current or previous smoking history. peak expiratory flow variability might be helpful in the diagnosis and follow-up of younger patients with asthma, but poor coordination and muscle weakness in some elderly patients might lead to an inaccurate reading. , a prospective study did not demonstrate any advantage of peak flow monitoring over symptom monitoring as an asthma management strategy for older adults with moderate-to-severe asthma when used in a comprehensive asthma management program. other tests, such as measuring the carbon monoxide diffusing capacity of the lung, have been advocated to distinguish between asthma and copd because the diffusing capacity of the lung is reduced by parenchymal destruction found with emphysema. however, studies have shown that differences in lung function tests, although statistically significant, cannot be used clinically to separate the groups of subjects because of a large overlap. there is growing evidence that the airway function of young and middle-aged asthmatic patients decreases at a greater rate than that of healthy subjects. [ ] [ ] [ ] the rate of decrease increases with increasing age and in those who smoke cigarettes. , in patients with loa, there is evidence that lung function is reduced even before a diagnosis is made and decreases rapidly shortly after diagnosis. , thereafter, it remains fairly stable. although the effect on older asthmatic patients with lsa is variable, in a random survey of elderly asthmatic patients older than years, only in patients had normal pulmonary function (fev > % of predicted value), whereas a similar number showed moderate-to-severe airflow obstruction (fev < % of predicted value) after an inhaled short-acting bronchodilator. because structural changes of emphysema are minimal in elderly asthmatic patients, except if they are previous smokers, airway remodeling is thought to be the main cause of fixed airflow obstruction. nitric oxide (no) is a gas generated by the action of no synthase from the substrates molecular oxygen and arginine. it was originally identified as a biologically important signaling molecule with the properties of an activity previously described as endothelial-derived relaxing factor. this molecule is important in regulating vascular integrity and blood flow and is thought to be a regulator of vascular smooth muscle relaxation. more recently, it has been found that no can be generated by a variety of inflammatory cells, including polymorphonuclear leukocytes, mononuclear cells, and, importantly, eosinophils. this finding led to the identification of no as a molecule present in exhaled breath. studies of no exhalation have found that it is increased in infection and inflammation of the airway. although high levels of no are found in nasally expired air, studies in pulmonary inflammation have avoided this by redirecting airflow through the oral airway. it has been found that exhaled no reflects airways inflammation and particularly eosinophilic inflammation. exhaled no levels are increased during the allergy season in atopic subjects. inhaled glucocorticoids promptly suppress exhaled no and do so in conjunction with suppression of eosinophilic inflammatory infiltrates. studies have demonstrated that monitoring exhaled no might permit better regulation of asthmatic symptoms, exacerbations, and total steroid use than treatments based on guidelines or symptoms. furthermore, increases in exhaled no levels might predict asthma exacerbations. it is of interest that no levels in expired air decrease after bronchoconstrictive stimulation of asthmatic airways. little is known of the effects of age on no levels in the expired air. it appears that no production and vascular responses to no might be diminished in the elderly, but that effect might be overcome by exercise to increase fitness. an unanswered question in airways biology is whether no is causative of airways dysfunction, a marker for this dysfunction, or an ineffective homeostatic response to airways constriction. [ ] [ ] [ ] [ ] [ ] challenges in defining asthma in the elderly there is agreement that asthma is both a common and underrecognized health problem for the elderly that leads to impairments of lung function and quality of health and life. the first question that needs to be addressed is why we need to make such a diagnosis rather than just treat the symptoms. there are reasons that physicians must strive to assign a diagnosis to a patient with a symptom complex. the patient is given relief by letting him or her know what is wrong by giving the illness a name, which implies a cause, establishes a prognosis, and initiates a treatment plan. moreover, advancement of the understanding of epidemiology, natural history, pathobiology, and treatment require a definable disease entity. whether the threshold for diagnostic criteria is set at a high level of sensitivity, a high level of specificity, or a high level of accuracy depends entirely on the costs and benefits of an incorrect diagnosis versus a missed diagnosis. for example, enumeration of a disease might require a high level of accuracy, whereas diagnosis of an uncommon and difficult-to-treat disease (eg, metastatic cancer) ought to be highly specific. the diagnosis of a common and easily treatable disease (eg, vitamin deficiency) ought to be highly sensitive, even if there is a risk of overdiagnosis. asthma tends to be one of those disorders that is relatively easy (although not inexpensive) to treat and has morbid consequences if left untreated, suggesting that the diagnostic criteria ought to be highly sensitive. although medical students are taught the rigorous discipline of data collection, differential diagnosis, and test confirmation, most physicians do not practice this way. in practice, physicians typically rely on a constellation of signs and symptoms along with demographic characteristics and recent experiences to establish diagnoses through the process of pattern recognition. there are no shortages of official definitions of asthma, and modifications seem to be added every year. most of these definitions involve the definition of a clinical syndrome (episodic cough, wheezing, and dyspnea), an underlying pathophysiology (airway hyperresponsiveness, variable, and reversible airflow obstruction), an underlying biological process (chronic eosinophilic or neutrophilic inflammation of the airways), and an associated morbid anatomy (basement membrane thickening, smooth muscle hypertrophy, and mucus cell metaplasia). given this, why is it so challenging to diagnose asthma in the elderly? first, the syndrome of asthma is often confused with other common diseases in the elderly, such as copd, congestive heart failure, paroxysmal arrhythmias, pulmonary emboli, recurrent aspiration, and gerd. second, asthma can often coexist with these other conditions, and it can be impossible to determine which of the conditions is responsible for the patient's ill health. this diagnostic confusion can be amplified by the different manifestations of asthma in the elderly. elderly asthmatic patients can be insensitive to exertional dyspnea because of a sedentary lifestyle. they tend to be less atopic and have an incomplete response to bronchodilators. the elderly without asthma tend to show some signs suggestive of asthma: slower emptying of the lung during forced expiration, decreased lung elastic recoil, and a higher prevalence of nonspecific airways reactivity. the hope that formal testing of airways reactivity would prove useful in diagnosing asthma has led to disappointment. in young adults a history of asthma, wheeze, or treatment for asthma plus a positive methacholine challenge test result is highly specific for asthma ( %) but misses about half of the asthmatic population. in epidemiologic studies that have examined various criteria for diagnosing asthma, it turns out that the solution is relatively j allergy clin immunol volume , number simple. patients who answer yes to the question ''have you ever had asthma?'' have nearly % specificity and % to % sensitivity when compared with those receiving an independent expert's diagnosis. , the problem of diagnosing asthma in the elderly is more complicated because of the overlap with copd. asthma is typically considered a disease of onset in youth driven by atopy and eosinophilic inflammation causing reversible airflow limitation. copd, in contrast, is considered to be a disease of onset in middle age driven by cigarette smoking and neutrophilic inflammation and leading to irreversible airflow limitation. as evidence presented in this workshop has shown, asthma in the elderly displays many of the features of copd. the disease can have its symptomatic onset late in life, often is only partially reversible, and is associated with neutrophilic inflammation. moreover, the current cohort of elderly patients has a high prevalence of past smoking, reflecting the health habits in the united states in the s and s. the failure to deal with the population of elderly patients who have overlapping signs of asthma and copd is not just a matter of classification of disease. it has significant health consequences in that such patients are systematically eliminated from clinical trials and are not covered by treatment guidelines. little is known about how best to treat the elderly patient with asthma who smokes or the elderly patient with copd who has reversible airflow limitation. this confusion is manifest by diagnostic coding in older medicaid patients. of those who were hospitalized with an initial diagnosis of copd, % had an asthma diagnosis within years. of those who had an initial hospital diagnosis of asthma, % had a diagnosis of copd within years. price et al attempted to develop a discriminant function using clinical and demographic information that would separate patients with copd from those with asthma by using strict physiologic criteria. although several discriminating characteristics were found, the best diagnostic criteria were only % sensitive and only % specific. we need to ask whether it really is important to make the distinction between asthma and copd in the elderly in terms of prognosis or treatment. one study by hansen et al suggests that regardless of whether a person is given a diagnosis of asthma or copd, the prognosis is mostly determined by the impairment in fev . there are a number of ways to measure the effect of asthma in both young and elderly patients. assessments of symptoms, functional limitations, quality-of-life measures, and risk of adverse events are several that have been suggested by current asthma guidelines. in addition, measuring a patient's satisfaction with his or her asthma symptom control and overall asthma care has been advocated. the use of objective measures of asthma control and satisfaction can be especially important in the elderly because the perception of symptoms might be impaired with advancing age. in addition, many elderly patients unconsciously accommodate to their symptoms or assume that the symptoms are a function of the aging process itself. because the number of unscheduled ambulatory visits, emergency department visits, and hospitalizations are high in elderly asthmatic patients, , and quality-of-life scores are low in elderly patients with persistent asthma when compared with those with mild asthma or no asthma at all, careful assessment of asthma control is essential in this age group. despite severe symptoms and physiologic impairment, most elderly patients with asthma can lead active productive lives if their asthma is appropriately managed. in fact, when elderly patients with severe or difficult-to-treat asthma have been identified by a physician's assessment, they appear to do better than younger patients. in the tenor study, despite lower lung function, older asthmatic patients (mean age, years) had lower rates of unscheduled office visits, emergency department visits, and corticosteroid bursts. patients reported in the tenor study received more aggressive care than younger adults, including higher use of inhaled and oral corticosteroids, and this undoubtedly had an effect on outcomes. the tools to measure asthma outcomes include questionnaires and other self-report tools, such as diaries and standardized medical history forms. standardized questionnaires that assess asthma impairment include the asthma control test, , the asthma control questionnaire, , the asthma therapy assessment questionnaire, , and others. [ ] [ ] [ ] [ ] there are many tools available to clinicians to assess the quality of life of asthmatic patients. [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] unfortunately, these psychometric instruments that claim to measure the same outcomes might produce disparate results, and none have been targeted for the elderly. in general, results that measure several domains are more accurate when a composite score is derived rather than when subscores of specific domains are compared. medical, administrative, and pharmacy records have also been used, especially to study larger asthmatic populations; these have proved useful for the assessment of a patient's change over time and to measure group differences. clinical trials of asthma therapy and educational, selfmanagement, and health services interventions have used psychometric instruments to assess elderly patients with asthma. in most of these studies, however, the majority of subjects are younger. there are no studies that have specifically determined the reliability and validity of these instruments in elderly persons. this is true of patient-satisfaction measures that have been used to assess asthma care. [ ] [ ] [ ] this is much needed because using lung function testing to measure outcomes has potential limitations in this age group. there are difficulties in defining normal predicted values at a very advanced age, and many patients with physical or cognitive impairment cannot reliably perform these tests. it is hopeful that newer biomarkers of lung inflammation have a particular role to play in the assessment of asthma control in the elderly. tools assessing physical function: self-reported and objective a major goal of geriatric and gerontologic research is to reduce the decrease in cognitive and physical function and prevent disability among older adults. accordingly, many functional status measures have been developed and used to understand the disabling process, as well as to evaluate interventions to prevent functional decline. it is useful to identify instruments that measure functional limitations and disability to investigate the functional consequences of asthma in older adults and to understand the pathway from asthma to disability. functional limitations are restrictions in performing basic physical and mental actions at the whole-person level (eg, walking or climbing stairs), whereas disability refers to limitations or difficulty in performing socially defined roles or tasks of everyday living in a given environmental context (eg, grocery shopping or bathing). , both self-reported and objective measures can be used to measure these different stages of disablement. self-reported measures can provide an indication of how well a patient is functioning in daily life and provide an assessment of care needs. these measures incorporate self-perception of function and can assess adaptations made to compensate for decrements in function. for disability assessment, self-reported difficulty or inability to perform basic activities of daily living (adl) is commonly used. for example, a composite score of adl items has been used as an outcome to evaluate the efficacy of a program to prevent functional decline in frail older adults. other composite scores assessing difficulty in ambulation, stair climbing, transferring, upper extremity function, and basic and instrumental adls have been developed. these comprehensive instruments of function and disability are amenable to computer adaptive testing. several objective measures of physical performance are used in studies of older adults and in disease-specific patient populations. tests of physical performance eliminate subjective attitudinal differences in the patient's reporting of physical function limitations. they have the advantage of providing an objective measure for comparisons across populations. these tests are sensitive to change over time and can detect decrements in function that might not be observed with self-reported instruments. many studies in older adults have used physical performance tests as predictors of adverse health events, as well as outcomes. for example, the short physical performance battery, which consists of timed balance, walking, and chair-rise tasks, is a powerful predictor of disability, nursing home admission, and mortality. , the short physical performance battery was also used as a screening instrument to identify functionally limited older adults and as an outcome in a randomized controlled trial of exercise. increasingly, objective measures of physical function are used to summarize the effect of total disease burden, including subclinical conditions and impairments, and to identify physiologic reserve that might help some older adults cope with disease burden. clinically meaningful differences have been established for commonly used performance measures. the goals of asthma therapy in elderly patients are not different from those for younger asthmatic patients. they are to treat acute symptoms, prevent chronic symptoms, decrease emergency department visits and hospitalizations, preserve normal activity level, and optimize pulmonary function with a minimal adverse effect from medications. , , optimal management should also focus on improving health status (quality of life) in these patients, which is often complicated by depressive symptoms and side effects from the drugs commonly used for asthma. unlike many younger adults who might require no medication or just asneeded b-agonist therapy for occasional symptoms, most older asthmatic patients need continuous treatment programs to control their disease. at a time when memory loss is common and financial resources are often limited, many older patients require complicated and frequent dosing with multiple expensive drugs. unfortunately, this has led to a significant rate of noncompliance among the elderly population in general. sex, socioeconomic factors, educational level, marital status, and severity of disease do not seem to be good predictors of compliance in elderly asthmatic patients. in summary, there are many challenges in the treatment of asthma in the elderly, which include a greater propensity to experience adverse events from medication use, as well as potential drug interactions with medications used for the treatment of comorbidities, , and thus it is particularly important to treat any disease in the elderly, including asthma, with a minimum of therapy while attaining maximum efficacy. a thorough understanding is required regarding which medications will be most effective in the treatment of asthma in the elderly to achieve this balance. because many current therapeutic options and those in development for asthma focus on specific inflammatory cells and mediators, any age-related changes in the airway inflammatory milieu will likely affect their therapeutic efficacy. therefore a rigorous characterization of age-related changes in airway inflammation will facilitate the management of asthma in the elderly. the therapeutic approach to asthma in elderly patients does not differ from what is recommended for young patients. statements on the standard of care for treating asthma have been published by the national institutes of health and are widely used as guidelines. , treatment protocols use step-care pharmacologic therapy based on the intensity of asthma symptoms and the clinical response to these interventions. as symptoms and lung function worsen, step-up or add-on therapy is given. as symptoms improve, therapy can be stepped down. in this age group special attention should also be given to the potential adverse effects of commonly used medications. corticosteroids are capable of reducing airway inflammation, thereby improving lung function, decreasing bronchial hyperreactivity, reducing symptoms, and improving overall quality of life. oral corticosteroids should be avoided if possible because they place the patient at risk for bone fracture and increased likelihood of cataracts, muscle weakness, back pain, bruising, and oral candidiasis. many studies have shown that inhaled corticosteroids are safe and effective treatment for persistent asthma, but none have specifically targeted the elderly population. long-term use of inhaled corticosteroids has been associated with a good safety profile, but higher doses of inhaled steroids (eg, > mg/d) are capable of causing hypothalamicpituitary-adrenal axis suppression. local adverse effects, such as hoarseness, dysphonia, cough, and oral candidiasis, do occur but can usually be avoided by the use of a spacer or holding chamber with the metered-dose inhaler and by rinsing the mouth after each use. despite the pivotal role of inhaled corticosteroids in asthma, many elderly patients are undertreated with this group of medications. , leukotriene-modifying agents (ltms) are also asthma controllers. these agents have been shown to be effective in preventing allergen-induced asthma, exercise-induced asthma, and aspirin-induced bronchospasm. studies on their use in the elderly are limited. when compared with ltms, low-dose inhaled corticosteroids have favored the latter. the ltms might also reduce asthma exacerbation rates and the need for steroid bursts. the ltms are generally very safe. , b-adrenergic agents are important medications in the acute and chronic management of asthma. elderly patients with asthma j allergy clin immunol volume , number might be less responsive to certain bronchodilators compared with younger patients. , inhaled short-acting b -adrenergic agonists are the treatment of choice for the acute exacerbation of asthma symptoms. despite the minimal systemic absorption seen with these agents, slight tachycardia might be observed. this is presumably because of vasodilatation, which results from the stimulation of b -receptors in vascular smooth muscle. tremor can also occur and is especially troublesome in the geriatric patient. tremor is thought to be caused by stimulation of b -receptors in skeletal muscle. in general, they have been proven to be safe and effective in all age groups. however, b-agonists can cause ( ) a dose-dependent decrease in serum potassium levels and ( ) a dose-dependent increase in the qt interval on electrocardiography. because sudden death from ventricular arrhythmia can be caused by both of these mechanisms, as well as being a complication of ischemic heart disease, the use of b-agonists in the elderly should be closely monitored. short-acting b -agonists should be used for rescue of symptoms, whereas long-acting agents should be used as maintenance medications only as an add-on to inhaled corticosteroids and never as stand-alone therapy. anticholinergics, such as inhaled ipratropium, a short-acting bronchodilator, and tiotropium, a bronchodilator with -hour action, have an excellent safety profile in the elderly. they should be considered when additional bronchodilator therapy is necessary; however, their role in long-term maintenance of asthma in the elderly has not been established. theophylline is an effective bronchodilator and has some antiinflammatory properties. however, its use has been greatly reduced over the past decade because of safety concerns, especially in the elderly. the narrow therapeutic range of theophylline, the frequency of concomitant illnesses that alter theophylline kinetics, and many drug interactions that affect the clearance of theophylline make it essential to closely monitor blood theophylline levels in older asthmatic patients. theophylline toxicity can cause seizures and cardiac arrhythmias, such as atrial fibrillation, supraventricular tachycardia, ventricular ectopy, and ventricular tachycardia. the most common cause for theophylline toxicity is a self-administered increase in medication. controlling triggers. measures should be taken to avoid triggers that can cause worsening of symptoms. as with asthma at any age, education concerning avoidance of aggravating factors that can lead to severe bronchospasm is very useful. although aeroallergens are less important in provoking symptoms in the elderly than in young patients, a program implementing environmental control measures, such as avoiding or minimizing aeroallergen exposure, should be instituted in patients with documented sensitivity to specific allergens. however, such programs might not be successful in all cases, especially because lifestyle changes in the elderly population might be difficult. the most important provocative factors include viral respiratory tract infections and irritants, such as cigarette smoke, paints, varnish, and household aerosols. pharmacologic agents that are often prescribed for concomitant illnesses (ischemic heart disease and hypertension), such as b-adrenoreceptor antagonists (b-blockers), can also provoke bronchospasm. this includes both noncardioselective agents (propranolol, pindolol, and timolol) and, to a lesser extent, cardioselective agents (metoprolol and acebutolol). topical b-blockers are also widely used in the elderly to reduce intraocular pressure in wide-angle glaucoma. with such treatment, sufficient systemic absorption might cause fatal status asthmaticus. the severity of b-blocker-induced bronchoconstriction correlates with the severity of underlying airflow obstruction and the degree of bronchial reactivity and might be reduced by the use of a cardioselective topical b-blocking agent, such as betaxolol. aspirin and nonsteroidal anti-inflammatory agents might precipitate acute bronchospasm in certain asthmatic patients, and angiotensin-converting enzyme inhibitors might cause dry cough in some, worsening the symptoms of asthma. gerd should also be considered a cause of worsening asthma symptoms. asthma education. the complexity of the prescription regimen (number and frequency of medications), coupled with the memory loss and cognitive dysfunction that might be present in this group of patients, contribute partially to poor compliance with therapy. , patient education is an effective tool and should be an integral part in the management of asthma. active participation by a patient and family members in monitoring lung function, avoidance of provocative agents, and decisions regarding medications provide asthma management skills that give that patient the confidence to control his or her own disease. mastering the technique of an inhaled medication delivery device is a challenging problem in elderly patients, and the great majority of elderly patients are unable to properly use the metered-dose inhaler, even after proper instruction. [ ] [ ] [ ] [ ] use of dry powder devices, although simpler, requires the generation of an adequate inspiratory flow that might be suboptimal in frail patients and those with severe airway obstruction. in such situations the use of spacer devices or nebulizers might be beneficial. patients should recognize the rationale behind using the different medications, the correct way to use them, and their side effects, and polypharmacy should also be avoided. asthma in the elderly can be effectively managed, and despite severe symptoms and physiologic impairment, most patients can lead active and productive lives. a demographic study of low-income elderly persons in chicago found that ( %) without a previous diagnosis of asthma or emphysema had symptoms compatible with those of obstructive lung disease. of patients with a previous diagnosis, only % were compliant with medications, and this was largely due to the cost of medications. in addition, health care use was high in this population. telephone intervention offers a simple option in the management of elderly patients with asthma. it has been shown that asthma care by means of telephone triage of adult asthmatic patients can lead to a higher percentage of asthmatic patients being reviewed at less cost per patient and without loss of asthma control when compared with usual routine care in the outpatient clinic. however, it has not been determined whether such an intervention could improve asthma care specifically in persons aged years or older. the following study was designed to evaluate this question. fifty-two elderly asthmatic patients who used their rescue inhalers more than twice a week and had at least emergency department or urgent care visit in the previous year were randomized to an intervention or control group. all patients received telephone calls over a -month period. the intervention group received an asthma-specific questionnaire, and the control group received a general health questionnaire. medication use and health care use were evaluated at the beginning and end of a -month period. the study was completed by control and intervention subjects. baseline data were similar in both groups. after months, % (n ) of the intervention group was taking an inhaled corticosteroid compared with % (n ) of the control group. the intervention group had fewer emergency department visits when compared with the control group. sixtyfour percent (n ) of the intervention group had an asthma action plan compared with % (n ) of the control group. this study provides evidence that using a simple telephone questionnaire can successfully improve asthma care in the elderly. by empowering the elderly with the appropriate knowledge regarding their asthma, an appropriate discussion about their asthma care can be initiated with their primary care physicians. pulmonary rehabilitation. although pulmonary rehabilitation is recommended as the standard of care for patients with copd, there are only a few studies that evaluate the benefit of rehabilitation for asthmatic patients, and none of these consider elderly asthmatic patients. one study looked at the effects of a -week outpatient rehabilitation program for asthmatic patients after years. [ ] [ ] [ ] they found that of subjects continued to exercise regularly all years; there was a decreased number of emergency department visits and a decrease in asthma symptoms. further studies are needed to assess empowerment strategies for elderly patients with asthma, as well as the potential benefits of pulmonary rehabilitation on morbidity and mortality. asthma pathogenesis is complex and incompletely understood. research into the pathophysiologic mechanisms is made more difficult by multiple factors, including the heterogeneity of the disease itself, variable presentations in different stages of life, and the lack of highly relevant animal models. [ ] [ ] [ ] [ ] [ ] in the last decade, increasing interest in asthma in the elderly has triggered more intensive investigation in both human and animal systems by using ever more sophisticated immunologic methodologies. early investigation with rats revealed a lack of total and allergenspecific ige in response to ovalbumin. this was born out by several later in vivo studies. [ ] [ ] [ ] igg subset analysis (igg vs igg ) provided further support for this phenomenon. igg , correlating in the mouse to a t h response (vs igg [t h ]) was shown to follow a similar pattern. , recent studies [ ] [ ] [ ] of cytokine profiles in aged rodents compared with young control animals enhanced the paradigm that age resulted in less robust t h cytokines, particularly il- , il- , and il- , in favor of t h gene and protein expression. , this pattern was not fully supported in a recent chronic murine asthma model wherein il- was greater in aged sensitized mice, making the picture more complex. ifn-g, a key t h cytokine, has been consistently overexpressed in aged versus young rodents. [ ] [ ] [ ] [ ] eosinophilia, which is considered a key component of (allergic) asthma, was more pronounced in younger versus older animals (bronchoalveolar lavage fluid, lung tissue, or both) after most, [ ] [ ] [ ] although not all, sensitization paradigms. molecular genetics and t-cell subset analysis has allowed further insight into possible mechanisms underlying the waning t h response observed in most models. [ ] [ ] [ ] specifically, elderly mice appear to have more memory t cells, less activated cd t h cells, and less activated monocytes. , resident goblet cells also appear to express upregulation of mucin and mucin gene expression. a key to the impaired t h response was recently found in the gata pathway. elderly mice do not phosphorylate components of the extracellular signal-regulated protein kinase/mitogen-activated protein kinase pathway, resulting in lack of downstream signaling with gata , with subsequent impairment of promoter regions for key t h cytokines, including il- . this could be an overarching explanation for many findings in the elderly asthmatic patient, including less ige (il- and il- are needed for opening switch regions for ige production); il- and il- are highly associated with airway hyperreactivity, and il- is associated with eosinophil activation, survival, and, to a lesser extent, trafficking. finally, airway hyperreactivity has been universally found to be greater in young versus aged animals. [ ] [ ] [ ] [ ] the mechanisms might be complex, including both an altered key cytokine milieu and alterations in muscle function at the muscarinic receptor level. [ ] [ ] [ ] clinical and translational research research into the pathogenesis of asthma in recent years has led to the discovery of a number of novel, potentially important targets for the development of new treatment options. much of this research has focused on t h lymphocyte-driven processes underlying allergic asthma and its characteristic eosinophilic airway inflammation. abundant information supporting this research has been derived from bronchial biopsy and bronchoalveolar lavage studies largely carried out in a young adult population. it is recognized, however, that the role of allergy and allergic triggers in asthma diminishes with age. , in addition, loa is often less reversible, more severe, and frequently occurs in response to a viral respiratory tract infection. a distinct asthma phenotype characterized by normal airway eosinophil numbers has been described. moreover, normal airway eosinophilia might also be associated with abnormal sputum neutrophilia. , recent studies have shown that neutrophilic asthma might be associated with activation of innate immune pathways in contrast to the adaptive immune response associated with t h -mediated allergic asthma. thus alternative immune pathways involving natural killer t or t h lymphocyte subtypes have been hypothesized as being potentially important in the pathogenesis of asthma, particularly in adult-onset asthma. , just as the discovery of t h -related pathways has led to important leads in drug discovery for allergic asthma, further clinical research into these alternative pathways should be carried out with the goal of identifying new and exciting targets for future drug discovery. this research should focus not only on the discovery of new molecular targets but also on the identification of noninvasive biomarkers that will help predict the success of any new therapy in an individual patient. asthma is an important disease in the older adult, affecting % of the population older than years, which is 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guinea-pig bronchial preparation effects of age on muscarinic agonist-induced contraction and ip accumulation in airway smooth muscle total serum ige is associated with asthma independently of specific ige levels. the spanish group of the european study of asthma analysis of induced sputum in adults with asthma: identification of subgroup with isolated sputum neutrophilia and poor response to inhaled corticosteroids evidence that severe asthma can be divided pathologically into two inflammatory subtypes with distinct physiologic and clinical characteristics heterogeneity of airway inflammation in persistent asthma: evidence of neutrophilic inflammation and increased sputum interleukin- innate immune activation in neutrophilic asthma and bronchiectasis persistent activation of an innate immune response translates respiratory viral infection into chronic lung disease il- is increased in asthmatic airways and induces human bronchial fibroblasts to produce cytokines fla co-chair: nicola a. hanania, md, ms section of pulmonary and critical care medicine asthma clinical research center baylor college of medicine houston, tex members sidney s. braman, md warren alpert medical school, brown university division of pulmonary, critical care, and sleep medicine rhode island hospital providence, ri carol saltoun we thank the nia for recognizing the need for this workshop, especially susan nayfield, md, who convened the workshop and provided tremendous support in moving this research field forward; evan hadley, md, the director of the division of geriatrics and clinical gerontology; and basil eldadah, md, who continued the work of dr nayfield and contributed valuable advice and encouragement to the authors in completing these proceedings. key: cord- - wysernx authors: michas, marta; deuchar, lesly; leigh, richard; bhutani, mohit; rowe, brian h.; stickland, michael k.; ospina, maria b. title: factors influencing the implementation and uptake of a discharge care bundle for patients with acute exacerbation of chronic obstructive pulmonary disease: a qualitative focus group study date: - - journal: implement sci commun doi: . /s - - - sha: doc_id: cord_uid: wysernx background: chronic obstructive pulmonary disease (copd) is one of the most common causes of mortality and morbidity in high-income countries. in addition to the high costs of initial hospitalization, copd patients frequently return to the emergency department (ed) and are readmitted to hospital within days of discharge. a copd acute care discharge care bundle focused on optimizing care for patients with an acute exacerbation of copd has been shown to reduce ed revisits and hospital readmissions. the aim of this study was to explore and understand factors influencing implementation and uptake of copd discharge care bundle items in acute care facilities from the perspective of health care providers and patients. methods: qualitative methodology was adopted. nine focus groups were conducted using a semi-structured guide: seven with acute and primary/community health care providers and two with patients/family members. focus groups were audiotaped, transcribed verbatim, and coded and analyzed using a thematic approach. results: forty-six health care providers and patients/family members participated in the focus groups. health care providers and patients identified four factors that can challenge the implementation of copd discharge care bundles: process of care complexities, human capacity in care settings, communication and engagement, and attitudes and perceptions towards change. both health care providers and patients recognized process of care complexity as the most important determinant of the copd discharge bundle uptake. processes of care complexity include patient activities in seeking and receiving care, as well as practitioner activities in making a diagnosis and recommending or implementing treatment. important issues linked to human capacity in care settings included time constraints, high patient volume, and limited staffing. communication during transitions in care across settings and patient engagement were also broadly discussed. other important issues were linked to patients’, providers’, and system attitudes towards change and level of involvement in copd discharge bundle implementation. conclusions: complexities in the process of care were perceived as the most important determinant of copd discharge bundle implementation. early engagement of health providers and patients in the uptake of copd discharge bundle items as well as clear communication between acute and post-acute settings can contribute positively to bundle uptake and implementation success. chronic obstructive pulmonary disease (copd) is one of the most common causes of mortality and morbidity in canada and worldwide [ ] [ ] [ ] . an important part of the health care burden of treating individuals living with copd involves the management of acute exacerbations (aecopd) [ ] which become more frequent with disease progression. copd is one of the most common reasons for hospitalization in canada [ ] . in addition, individuals living with copd are the most common group to return to the emergency department (ed), and the largest group of patients readmitted to hospital within days of discharge [ ] . care bundles, defined as "a small set of evidencebased interventions for a defined patient population and segment/care setting that, when implemented together, will result in significantly better outcomes than when implemented individually" [ ] , have been shown to improve patient outcomes when implemented in hospital settings for diverse patient populations, particularly in critical care of mechanically-ventilated patients [ , ] . discharge care bundles in copd focus on optimizing care for patients with an aecopd as they transition from acute care settings back to the community. in a systematic review examining the effectiveness of copd discharge care bundles [ ] , evidence the research results permit providers to tailor strategies to mitigate these challenges. suggested that these discharge bundles may reduce ed revisits and hospital readmissions. although the idea of discharge care bundles seems straightforward, their successful implementation in clinical settings can be challenging [ ] and often requires a tailored strategy that maximizes patient and clinician engagement. further, sustaining adoption within the clinical setting is a unique challenge, with limited proven strategies to ensure long-term uptake. while the emergence of evidence in dissemination and implementation science provides tools and strategies for the design of practice improvements [ ] , challenges in bringing these same improvements to frontline clinicians and patients and subsequently sustaining the adoption of these improvements in clinical settings are addressed less often. as copd discharge bundles have been developed to facilitate transitions of care, their evaluations within trials have shown that actual uptake can be very low [ ] , necessitating a better understanding of implementation barriers and strategies [ , ] . the existing literature on implementation of discharge bundles for patients with copd exacerbations is very limited, and knowledge gaps remain regarding the challenges associated with implementing discharge care bundles. even more limited is the perspective of the patients and practitioners on the barriers and facilitators impacting uptake of the intervention. this manuscript uses the voice of patients and providers to contribute evidence to a common challenge in a field where a paucity of evidence is available. the aim of this study was to explore the perspectives of patients and health care providers about factors influencing successful implementation of copd discharge care bundles in acute care hospitals. this study will inform and support the development of implementation strategies designed to improve transitions of care from acute care settings into the community. this qualitative study using a focus group methodology is part of a broader project aimed at developing, implementing, and evaluating a discharge care bundle for individuals with aecopd admitted to acute inpatient and ed settings in alberta (canada). briefly, the broader project was planned to develop a copd discharge bundle (as part of an end-to-end pathway) to be implemented in both ed and acute inpatient settings across the province, and evaluate its effectiveness in reducing ed and hospital readmissions and improve patient-centered and economic outcomes. details of care bundle development are described elsewhere [ , ] and resulted in a copd discharge care bundle that includes seven interventions: ( ) ensure patient has demonstrated adequate inhaler technique, ( ) send discharge summary to family physician office and arrange follow-up, ( ) optimize and reconcile respiratory medications, ( ) provide a written discharge management plan and assess patient and care giver comprehension of discharge instructions, ( ) refer to pulmonary rehabilitation, ( ) screen for frailty and comorbid condition(s), and ( ) assess smoking cessation readiness, provide counseling, and refer to smoking cessation program, where appropriate. consensus was used to finalize the content of the evidence-based copd discharge bundle, and prior to its evaluation via a stepped-wedge trial (clinicaltrials.gov identifier: nct ), this qualitative research was conducted as part of the knowledge translation strategy to inform provincial implementation [ ] . focus groups were conducted in acute and community/primary care settings from large urban (edmonton, calgary), moderate-sized regional (red deer), and rural (slave lake) centers in alberta (canada) between october and february to seek input from both patients with copd and health care providers. ethics approval was obtained from the university of alberta research ethics board (pro ); written informed consent to participate in the study was obtained from participants. nine focus groups were conducted; segmentation was defined a priori, with seven focus groups being conducted with health care providers and two with patients. the recruitment aimed for between four and eight participants for each session; this size is suggested to be ideal for non-commercial focus groups [ ] . the study used purposive sampling to recruit participants. health care participants for the focus groups were initially invited through communication with unit managers and clinical leads in acute care sites, administrative managers in primary care settings, and direct email invitation sent to frontline staff. health care participants that were contacted directly were encouraged to invite their eligible colleagues. eligible health care participants included clinical staff caring for patients with copd and administrative staff from inpatient and ed units (acute care) or locations (primary care) that admit and/or care for patients with copd. the focus groups were conducted during regular working hours, and remuneration for participation was not provided; therefore, it was essential to establish a good rapport with clinical and administrative leaders in each setting so they would approve the -h commitment for this research activity, where the study team provided lunch or snacks. patient participants were recruited from two regular and well-established patient support groups, one in a large urban center (edmonton) and one in a regional center (red deer). in order to reduce the burden of travel for patients, the support group leaders were asked for permission to have the research team participate in one of their regular weekly meetings and conduct the focus group there. participants from large urban locations were individuals living with copd who had recently graduated from the pulmonary rehabilitation (pr) program at the local lung center, and patients from the regional center were long-term members of a support group that included patients with various lung diseases. for practical reasons, patients were not enrolled in rural health care facilities due to the lack of availability of research staff and well-established patient support groups in these settings. the focus groups were moderated by experienced (msc and phd-level) female research facilitators and members of the research team (mm, ld). none of the focus group facilitators were directly involved with the care of patients with copd nor knew any of the study participants prior to the focus groups. the focus group sessions lasted for h. sessions were audio recorded and transcribed verbatim by a note taker or research coordinator. additional field notes from each team member documented reflections during the focus group sessions. field notes were used to supplement the focus group findings during the thematic analysis. each focus group opened with a short overview presentation about the context of the study and background on how the various components of the project interdigitated. the facilitator highlighted that their information was being used to potentially help patients and health care providers improve care processes for the management of acute copd exacerbations. health care providers were offered a copy of the presentation slides, while patients were offered a plain language informal conversation to provide an overview of the project. in addition, all participants were provided with a written plan-language summary included in the consent forms. the focus groups were conducted with the aid of a semi-structured focus group guide (additional file ) developed according to the theoretical domains framework (tdf) [ ] . briefly, the tdf is a comprehensive framework of theoretical domains including individual (rational, cognitive, emotional) and external, organizational variables (working environment, resources) that influence behavioral change and innovation uptake. the tdf has been widely used to inform implementation of interventions in respiratory research and clinical practice [ ] [ ] [ ] . focus group verbatim transcripts were coded using the nvivo qualitative analysis software [ ] and prepared for thematic analysis. thematic analysis is a foundational method of qualitative analysis for identifying, organizing, describing, and reporting themes found within qualitative data [ , ] . this analytical approach is a useful method for examining the perspectives of different research participants (i.e., health providers and patients) [ , ] . three researchers (mm, ld, mbo) analyzed transcripts independently to identify and classify emerging themes. two of these researchers read the transcripts and coded them line by line using an iterative approach. codes with similar meaning were grouped together to form categories, which later were compared and merged into larger themes. we used the criteria suggested by krueger and others [ , ] as a framework for interpreting coded data: words, context, internal consistency, frequency and extensiveness of comments, specificity, and intensity of comments. theoretical saturation was reached when no additional data was found to develop additional themes in the data analysis [ ] . researchers met to discuss the thematic categories that emerged from the data, with discrepancies being independently resolved by a third researcher (mbo). field notes were used to triangulate the results and supplement the focus group findings. descriptive statistics were used to report extensiveness (coding coverage, defined as percentage of time spent on discussions about the identified themes). we used the consolidated criteria for reporting qualitative research (coreq) [ ] in the reporting (see additional file ). seven focus groups with health care providers (n = ) and two focus groups with patients (n = ) were conducted; the group sizes varied from to participants. abridged characteristics of the participating health care providers and patients are provided in tables and , respectively. we aimed to interview a broad spectrum of health care providers from various locations, clinical settings, and professions (table ) . acute care providers were located in tertiary care facilities in two large urban settings, while primary health care providers were located in one regional and one rural primary care setting where the number of patients would be less; however, the potential for stronger relationships between providers and between providers and patients exists. other settings included specialist clinics, walk-in clinics, and managerial/ administrative areas. the most represented clinical providers included respirologists and registered respiratory therapists, although all nursing roles combined (educators, administrators, and other non-bedside nursing roles) represented the highest proportion of participants. the analysis for all acute care participants (inpatient and ed) was combined into one group, and the analysis for primary/community care participants was combined into another group. in all further discussion, the following three units of analysis were used: acute care health providers, primary care/community health care providers, and patients. of the participants in the patient/family member focus groups (table ) , the majority lived with someone who could help them with their health care needs and were able to drive themselves to their medical appointments. while the majority of the patients participating in the focus groups had a diagnosis of copd, several were unsure of their lung health diagnosis. of the patients who were able to reflect on acute care admissions for aecopd, all reported shortcomings in their perception of the management of one or more of their hospital stays and openly shared where they saw or had heard of better ways to manage aecopd. all participants in the focus group conducted in a large urban location had a confirmed copd diagnosis as it was a qualifying condition for the participation in the pulmonary rehabilitation program; however, not all patients knew that the term applied to them. for the second focus group involving a lung support group operating in a smaller urban area, patients had various lung conditions; therefore, an additional question was added to the questionnaire (see "type of lung condition" field in table ). as this research relates to exploring barriers and facilitators to uptake of and adherence to clinical support guidelines and tools, the information this latter population shared was considered relevant to the study. the analysis identified four emerging themes influencing copd discharge care bundle implementation as discussed by participants: ( ) process of care, ( ) human capacity in care setting, ( ) communication and engagement, and ( ) attitudes and perceptions towards change. these highlevel themes were further divided into sub-categories (table ) on discussions about the identified themes) among health care provider and patient focus groups, respectively. the process of care theme was defined as "what is actually done in giving and receiving care." it includes patient activities related to seeking care and carrying out care instructions, as well as practitioner activities related to making a diagnosis and recommending or implementing treatment [ ] . processes of care were further subcategorized into those influencing patients (e.g., cost of medications), process of care influencing providers (e.g., uncertainty of roles when executing discharge care bundle), and process of care influencing the care system (e.g., access to pharmacists in the acute care setting). process of care was the theme most frequently discussed by all participant groups. patients spent the majority of the time discussing process of care influencing patients. some of these processes of care mentioned by patients included operational activities that, albeit not attributable to specific clinical interventions, they influence patients' uptake of copd discharge bundle implementations (e.g., waiting times, ability and support to book follow-up appointments, and connect with other level of care). some patients discussed the level of education they received from health care providers in both acute care and community settings as an important aspect of processes of care for patients, while others commented on the potential positive influence of a patient management plan or nr not reported *multiple responses were allowed **question only asked to patients in focus group # ; all patients in focus group # were pulmonary rehabilitation program graduates and had copd diagnosed at the admission ***question asked only to the participants of focus group # for processes of care influencing health care providers, acute care providers often discussed which members of the provider team should be responsible for executing discharge care bundle items (which varied across sites represented); the proper allocation of the tasks to qualified providers was seen as a challenge in the implementation process: acute care provider: [we don't know] (...) if it was nurse initiated actions, physician initiated actions, care coordinator or pharmacy, you know, the people involved in our area. primary and community health care providers' comments were process-focused, and their discussion of their own role in the implementation of care bundle items indicated a lack of continuity and provider/program linkage in the system as it serves patients currently: primary health care providers also noticed challenges in caring for patients with multiple comorbidities-a common problem with copd patients and a common problem in primary care, when the need of the patient is surrounding the coordination of up to five subspecialty clinics/providers. primary health care provider: (...) [patient] is in er and you have all the comorbidities, the way we are working at the moment we are going diagnosis specific. so the same nurse discharging the patient has a checklist for heart failure, for copd, for asthma and for how to manage the bone and joint. access to a registered respiratory therapist, pulmonary rehabilitation program (particularly in rural communities), lack of attachment to family doctors, and transitions in care were some of the subjects widely discussed under process of care influencing care system. primary health care provider: (…) in , % of our [rural] communities do not have the correct level of rt to sustain the services provided at that facility. so, even if we double or triple what we had, i can still not guarantee that they will be at the pulmonary rehab level primary health care provider: so, they might not have a family doctor (… ),, they might not have an easy access to them, [and] what kind of communication is coming from the hospital to the family doctor and their team to alert them that they can bring this patient in soon enough. human capacity in care settings was defined as the ability of the people directly engaged in the implementation (e.g., nurses, registered respiratory therapists) to ensure that the individual care bundle items are executed. human capacity was further divided into three sub-categories: time constraints related to the implementation (e.g., not enough time available to spend with each patient), volume and staffing issues (e.g., nursing shortages), and education and training of health care providers (e.g., sufficient or insufficient knowledge of the proper use of a discharge care bundle). human capacity in care setting was discussed more often among the community and primary health care providers than the acute care providers (which could be related to setting), while aspects related to the qualifications of health care providers gained the most interest among patient focus group participants. primary health care provider: (...) in emergency departments and hospitals, it is the nurses the ones who are doing a big education piece. they are not going to provide as good teaching as they could if they don't understand the disease process and a treatment for it. issues related to volume and staffing were rarely mentioned in both health care provider groups, except when it came to respiratory therapists, at which time the lack of access to a registered respiratory therapist was often mentioned among both acute care and primary health care provider participants. time required (to implement/uptake new practices) was minimally discussed among acute care providers and community and primary health care providers. these provider groups, however, recognized that implementation of the discharge care bundle would require additional time. patients did not identify and discuss issues related to human capacity in care settings. the communication and engagement theme was described as the level of engagement and communication to facilitate transitions in care within each setting (e.g., buyin from frontline staff-provider engagement), across specializations (e.g., acute primary care communicationssystem's engagement), and individual patient's interest in self-management (patient engagement). patient engagement was the most discussed sub-theme among both community and primary health care providers and patients (fig. , panel ) ; however, this subject was seldom discussed by acute care providers. community and primary health care providers primarily talked about the need to increase patient compliance, potentially through engagement in the care bundle implementation across programs and services: primary health care provider: most people (...) as soon as their cough starts to improve they are not going to stop (therapies). they realize this is how it works, this is why it does that, i have to continue for it to keep working. (a comment regarding the probability that once people see an effect from their therapies, they are more likely to continue using the therapy). patients often commented about the importance of engagement in self-management and importance of communication and establishing a relationship with both primary and specialist health care providers after hospital or ed discharge: patient: our doctor said if we are going south this year he would give us a care package and it would have a couple of antibiotics and five days of prednisone so if [we] did get sick we could get home, with the prednisone. provider engagement and system engagement received a small amount of attention from any of the participants, with the most significant coverage ( %) of provider engagement among acute care providers, and relating to the degree of attachment that patients had as well as the degree to which the patients were engaged in the bundle elements (education as an example). this theme was characterized by a set of psychological responses to planned change, comprised of both positive and negative participant responses to potential discharge care bundle implementation, such as patients' willingness or refusal to try new things, staff's positive or negative attitude towards checklist, or support or lack thereof from site management. among both groups of health care providers, provider's attitude was the most commonly discussed subtheme (fig. , panel ) within the attitudes and perception of change high-level theme. patients also discussed patient's attitude; however, system's attitude was discussed less frequently in all focus groups. acute care providers recognized that buy-in from their colleagues would be an important factor influencing discharge care bundle uptake and implementation. some providers were involved in unsuccessful implementations in the past and discussed skepticism regarding the current effort, or expressed negative attitude towards checklists/ bundles in general, based on past negative experiences. acute care provider: no offense though, i'm chasing physicians down left, right and center, so them filling out that paper? they're not going to fill that out. in general, primary health care providers recognized the importance of being involved in the copd pathway implementation effort but also pointed out there are competing projects that often restrict their time to participate wholly on one project for one system or disease, when their patients are often living with comorbid and complex health issues. primary health care provider: (...) this is only the second or third pathway coming down the pipeline, there is another hundred coming. patients expressed their willingness to follow recommendations, instructions, or referrals provided to them at or before discharge from the ed or hospital, based on their previous experiences being discharged from an acute care setting for copd care. this study provides insights about factors influencing implementation and use of a copd discharge care bundle in acute care facilities from the perspective of health care providers and patients. health care providers and patients in all focus groups identified complexities in process of care as the most important factor potentially affecting implementation and subsequent uptake of the copd discharge care bundle. acute care providers reflected mostly on system processes, while community and primary health care provider discussions reflected more on the impact on providers. patients concentrated mostly on how the process of care influenced themselves, such as lack of educational information, lack of access to pulmonary rehabilitation programs, or how difficulties in accessing family doctors may negatively impact the implementation and uptake of the discharge care bundle. patients commented on how the process of care led to positive beliefs about the benefits of instructions related to disease management given to them before discharge. the complexity of process of care is perceived as very context-driven and refers to tasks roles, continuity through referrals, and education. depending on the number of provider tasks, programs, and services available, the level of complexity in the processes of care is amplified. community and primary care providers and patients recognized patient engagement as having an impact on implementation and uptake of the discharge bundle; health care providers commented on engaging with patients to ensure better compliance while patients discussed the importance of self-management and engaging with health care providers after discharge. this common focus on patient engagement is a clear signal to implementation planners that shared decision-making between patients and providers across the care continuum has the potential to positively impact implementation and uptake of care bundles in acute care settings. interestingly, acute care providers did not see patient engagement having an impact on bundle implementation; with bundle initiation occurring in the acute care setting, the opportunity to improve the patient experience across the continuum of care is limited. attitudes and perception of change were discussed in all study groups. attitudes towards changes in practice were most often discussed sub-themes among health care providers and patients, respectively. from the provider perspective, ensuring proper buy-in from the frontline staff was recognized as a facilitator to implementation, although achieving this engagement in light of competing responsibilities may result in a negative attitude towards the intervention and was consequently perceived as a barrier. employees who are overwhelmed by parallel initiatives may show symptoms of change fatigue and would passively accept the imposed changes but not engage in the process [ , ] putting the implementation at risk of failure. it is worth noting that no symptoms of change resistance (actively criticizing and denying the need for a change [ , ] ) were registered during the focus groups. primary and community health care providers had challenges in recognizing where they fit in the whole process; they seemed to be discouraged by the sense of disconnection, which was also echoed in the discussion about buyin and attitude to change. in general, system attitude, defined as a set of psychological/administrative responses to planned change (e.g., administrative obstacles or support from executive management), were not seen as important factors for implementation, suggesting the forces influencing uptake were perceived to be related mostly to the frontline staff directly involved in the discharge care bundle execution. these results align with research conducted by khodyakov et al. [ ] on factors related to adoption of a surgical site infection prevention bundle, in which physician buy-in was perceived as a very important determinant of bundle implementation. in their case, however, staff resistance was also manifested, contrary to observations made during this study. time allocated to the implementation of the bundle was not seen as an important factor to successful implementation by all study groups. issues related to work volume and staffing, however, were noted by both acute and community and primary health care providers as a barrier to uptake. an example includes the lack of access to respiratory therapist which could negatively impact completion of several bundle elements (e.g., inhaler technique teaching and smoking cessation counseling). while community and primary health care providers saw education and training as a more vital contributor to uptake, they did not describe lack of time as a barrier. contrary to our findings, lennox et al. [ ] found lack of time ("staff too busy") as the most prominent barrier to bundle implementation in their study on implementation of a copd care bundle in hospitals in london (uk). however, similar to our study results, they recognized staff shortages, staff engagement, and added workload among the top four barriers to bundle implementation, barriers that the most robust implementation plan would be challenged with. our study showed that health care providers appreciate the importance and benefits of the copd discharge care bundle. the results suggest a benefit of early engagement of health providers in the implementation process, as some of the care bundle items require communication between acute and post-acute settings. engaging primary, community, and acute care providers directly involved in the copd discharge care bundle execution is an important aspect of uptake and sustainability of the change. while ideal, given the spread of providers in a community, at times accomplishing this goal may be difficult. moreover, patient engagement is necessary as some of the proposed items are associated with patient compliance. although, in this study, patients did not directly focus on barriers and facilitators for the discharge bundle implementation in the acute care settings, their comments on how the intervention affects them can be valuable when planning bundle implementation. the patients reflected on their own ability to impact outcomes, more than the role of the providers in either acute or primary care community. some evidence suggests that patient engagement and understanding of the implementation process may change staff behavior and attitude towards implementation and uptake through informed patients requesting staff to perform specific actions [ , ] . there are some noteworthy limitations to this study. first, there is the question of the generalizability. as participation in the focus group was voluntary, it is possible that acute and primary health care providers who volunteered were those who are most likely early adopters and more willing to engage in the early conversations and facilitate implementation. the health providers were experienced and older, and these results may not apply to younger or less-experienced health providers. health care focus group participants may not properly represent opinions of late adopters or those hesitant to change. for the patient participants, all patients were relatively healthy and were not housebound, and while most had experience with a copd hospitalization, most were infrequent users of the acute care system for copdrelated care. as patient participants were recruited from well-established patient support groups and some were graduates from pr programs, it is likely that their level of knowledge, engagement, and compliance differs from other patients discharged with copd that have not accessed these programs. further, the patients sampled had access to specialists (pulmonologists/respirologists), were attached to primary health care providers, and were participating in pulmonary rehabilitation programs or support groups in large urban and regional health centers. this group does not likely represent all individuals living with more advanced copd, those living in rural areas, or who are not well connected to primary or specialist providers. second, the study was conducted prior to finalization and implementation of a provincial standardized copd discharge care bundle. third, neither providers nor patients had experience with copd care bundles in practice, so experience in employing the tool could not be used to further inform the research. future research involving those with experience with the bundle is required for iterative revisions. finally, inpatient and ed health care providers were combined in one unit of analysis ("acute care providers"). the authors appreciate there are differences between inpatient and ed providers, their time constraints, and the granular level of their knowledge about copd. there are also differences between urban and rural settings; however, as the focus of the work was for participants to inform barriers and facilitators from their perspective, the authors felt they could aggregate inpatient and emergency feedback. by identifying clinically relevant factors influencing implementation and use of the copd discharge care bundle perceived by patients and health care providers, this study built an understanding of the challenges potentially associated with implementation and uptake of the said bundle in acute care settings. participants recognized complexity of process of care ("what is actually done in giving and receiving care"), including the patient's activities in seeking care and carrying it out ("as well as the practitioner's activities in making a diagnosis and recommending or implementing treatment" [ ] ), as the most important determinant of the copd discharge bundle adoption. other important issues were linked to human capacity in care settings (time constraints, volume and staffing, education and training of health providers); issues with engagement of patients, providers, and the health care system; and patients', providers', and system attitude and perception of change. the knowledge gained in this study will allow planning of strategies tailored to address and mitigate specific challenges and to stimulate successful bundle implementation and uptake. copd in alberta: examining the characteristics and health care use of high users. ottawa: canadian institute for health information estimating the prevalence of copd in canada: reported diagnosis versus measured airflow obstruction global health estimates : deaths by cause, age, sex, by country and by region global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease (gold) inpatient hospitalizations, surgeries and newborn indicators all-cause readmission to acute care and return to the emergency department. ottawa: canadian institute for health information using care bundles to improve health care quality. ihi innovation series white paper. cambridge: institute for healthcare improvement evidence-based clinical improvement for mechanically ventilated patients using a bundle approach to improve ventilator care processes and reduce ventilatorassociated pneumonia a systematic review of the effectiveness of discharge care bundles for patients with copd from best evidence to best practice: effective implementation of change in patients' care a systematic review of the use of the consolidated framework for implementation research evaluation of 'care bundles' for patients with chronic obstructive pulmonary disease (copd): a multisite study in the uk care bundles after discharging patients with chronic obstructive pulmonary disease exacerbation from the emergency department development of a patient-centred, evidence-based and consensus-based discharge care bundle for patients with acute exacerbation of chronic obstructive pulmonary disease copd discharge bundle delivered alone or enhanced through a care coordinator (prihs) focus groups: a practical guide for applied research. . sage: los angeles validation of the theoretical domains framework for use in behaviour change and implementation research barriers and enablers of copd telerehabilitation -a frontline staff perspective understanding the clinical management of obstructive sleep apnoea in tetraplegia: a qualitative study using the theoretical domains framework barriers and outcomes of an evidence-based approach to diagnosis and management of chronic obstructive pulmonary disease (copd) in australia: a qualitative study nvivo qualitative data analysis software; qsr international pty ltd. version using thematic analysis in psychology applied thematic analysis using templates in the thematic analysis of text focus groups for the social science researcher analyzing and reporting focus group results. thousand oaks; sage saturation in qualitative research: exploring its conceptualization and operationalization consolidated criteria for reporting qualitative research (coreq): a -item checklist for interviews and focus groups analyzing focus group data the quality of care. how can it be assessed? nurses amidst change: the concept of change fatigue offers an alternative perspective on organizational change change fatigue: development and initial validation of a new measure organizational cynicism: bases and consequences project joints: what factors affect bundle adoption in a voluntary quality improvement campaign? identifying the challenges and facilitators of implementing a copd care bundle patients' and health care professionals' attitudes towards the pink patient safety video an untapped resource: patient and public involvement in implementation comment on "knowledge mobilization in healthcare organizations: a view from the resource-based view of the firm supplementary information accompanies this paper at https://doi.org/ . /s - - - .additional file . semi-structured focus group guide on identification of care gaps, barriers and facilitators for the implementation copd care bundle in hospital and ed settings in alberta.additional file . consolidated criteria for reporting qualitative studies (coreq): -item checklist. the data supporting the findings of this study are available upon request from the corresponding author (mbo). the data are not publicly available due to containing information that could compromise research participant privacy.ethics approval and consent to participate ethics approval has been obtained from the university of alberta research ethics board (pro ); informed consent to participate in the study was obtained from individual participants. not applicable. the authors declare that they have no competing interests. publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. key: cord- -hpzs fvf authors: mcheick, hamid; sayegh, john; ajami, hicham title: context-aware healthcare adaptation model for copd diseases date: - - journal: the impact of digital technologies on public health in developed and developing countries doi: . / - - - - _ sha: doc_id: cord_uid: hpzs fvf nowadays, ubiquitous computing and mobile applications are controlling all our life’s aspects, from social media and entertainment to the very basic needs like commerce, learning, government, and health. these systems have the ability to self-adapt to meet changes in their execution environment and the user’s context. in the healthcare domain, information systems have proven their efficiency, not only by organizing and managing patients’ data and information but also by helping doctors and medical experts in diagnosing disease and taking precluding procedure to avoid serious conditions. in chronic diseases, telemonitoring systems provide a way to monitor the patient’s state and biomarkers within their usual life’s routine. in this article, we are combining the healthcare telemonitoring systems with the context awareness and self-adaptation paradigm to provide a self-adaptive framework architecture for copd patients. chronic obstructive pulmonary diseases (copd) have attracted research interest as a major public health problem, because according to the world health organization (who) [ ] , copd is currently considered the fourth, and will soon become the third, most frequent cause of death worldwide. it is also a disabling disease and therefore associated with high costs for treating and managing patients. as the disease progresses, patients become more susceptible to respiratory exacerbations which cause frequent hospital admissions and, thus, have a huge impact on patients' quality of life and healthcare costs [ , ] . monitoring patient's health conditions from home and transmitting these data to a healthcare center could be a great solution that facilitates the management of the growing number of patients with copd and reduce the burden on health services. this approach is called home tele-monitoring, which can be used for a timely assessment of acute exacerbation or as a mechanism to generate alarms to the patients and/or healthcare professionals when clinical changes that may constitute a risk to the patient occur [ ] . there are many systematic reviews and studies on the topic of telemonitoring in respiratory patients, specifically in patients with copd [ ] [ ] [ ] [ ] . all these studies are focusing on proving the effectiveness of applying home telemonitoring on copd patients, by studying the services that could be provided and their impacts on the patient's quality-of-life. however, none of these studies has provided a comprehensive proposal for a telemonitoring system that helps to control the burden of copd. we aim to design a telemonitoring healthcare application that helps copd patients with self-management and improve their quality of life, therefore reducing pressures on healthcare resources. we must develop a system that uses this data to provide an effective intervention that prevents exacerbation through the early recognition of symptoms and prompt treatment which may reduce the risk of hospitalization and control the burden of copd. based on this healthcare requirement, we realized the need of combining context awareness and self-adaptation with health telemonitoring, which will give our system the ability to be aware of the patient's data and context, then to adapt the required changes and act accordingly. the remainder of this paper is structured as follows. section introduces the concept of context-awareness and reviews the most common forms of self-adaptation frameworks. section highlights the characteristics of self-adaptive systems. section presents our self-adaptation healthcare system for copd. section then validates the proposed approach. finally, sect. presents our conclusions. context awareness and self-adaptation systems the notion of context has appeared implicitly for the first time in the ubiquitous computing area in by weiser "all the information that should be taken into consideration for an adjustment" [ ] . lieberman et al. [ ] proposed another interpretation of the context that exists within the field of computing: "context can be considered to be everything that affects the computation". this definition focuses on the application instead of the user, but nowadays with the widespread of mobile applications that focus on the user's lifestyle, health, and activities the factors that affect the user and these that affect the computation process become almost the same. in software systems, context awareness notion is mostly coupled with selfadaptation capability otherwise, there is no point in collecting contextual data. selfadaptation is a set of simultaneous and successive processes as an organized reaction to changes in the resources or environment of the system [ ] . self-adaptive systems dynamically modify their behaviors to respond effectively to changes in their operational environment [ ] . in the next section, an overview of many self-adaptation frameworks is provided. rainbow framework provides general mechanisms for developing reusable selfadaptive systems at a variety of different levels [ ] . model-driven approach is an automated self-adaptive model that supports adding and removing technical resources at run-time [ ] . meta-self is a service-oriented framework that provides a solid platform for the development of sas [ ] . this framework allows designers to identify system properties, architectural patterns, and different adaptation mechanisms. fusion is a reusable feature architecture that incorporates a learning-based adaptive cycle. the adaptation cycle consists of three main steps-detect, plan, and effect [ ] . moses is a service-oriented framework that focuses on quality of service (qos) requirements at runtime. moses provides a reusable implementation strategy of the adaptation logic following the mape cycle (monitoring, analysis, planning, and execution) [ ] . the contract-based adaptive software application framework (casa) [ ] is specialized in handling resources instability. the framework assumes that a system should not make any assumptions about the resources that will be available and should be prepared for any resource availability scenario cases. service-oriented architectures (ssoa) is a software framework that specifies any kind of adaptation by decomposing of functionalities [ ] . each of these functionalities shall be specialized to fit a particular purpose. caredroid is an adaptation framework for android context-aware applications [ ] . this framework caredroid monitors the contexts at run-time, and active methods only when it intercepts calls to sensitive methods. system requirements and self-adaptation characteristics and taxonomy the first step to designing a self-adaptive system is to well identify the system requirements; we will depend on w h-pattern [ ] , which presents six questions that would help us in eliciting adaptation requirements (table ) . [ ] , the change needs to be done in the application layer on both sides: user interface and physician interface when when do we need to make these changes? whenever an urgent update happens in the user contextual data like vital signs, environmental risk factors, and planned activities or periodical changes like the evaluation of treatment and decision support suggestions what what do we need to change? we need to update some system attributes that present the system state and these attributes in its turn could trigger new functions or activate new components why why these changes are required? in healthcare monitoring applications especially these related to chronic diseases, taking precluding actions is crucial in treatment plans. also being able to notify the patient and the medical experts about any threatening situation or abnormal signs make these kinds of applications more efficient who is any human intervention is required in the adaptation process? from the patient side, all his biomedical data and surrounding environments data will be collected from sensors. however, because physical activities do affect the copd patient's state, he needs to detect his planned physical activity (running, swimming) how how to determine what changes and actions are needed to be done in the adaptation process? ajami and mcheick [ ] provided a rule-based reasoning engine, depending on these generated rules all the required actions and changes can be deduced christian et al. [ ] presented a taxonomy of the different properties of self-adaptive software. we will analyze this work and do a projection on our system requirements and use the results to build our system. handte et al. [ ] provided two perspectives of temporal aspects: (i) reactive is when we have to adapt whenever a change in the context does happen. (ii) proactive is when the monitored data is used to forecast system behavior or environmental state [ ] . in our case, the adaptation will be reactive depending on the changes that happen in the user contextual data. reason: the adaptation could be triggered for three reasons: (i) change of the context, (ii) change in the technical resources, and (iii) change in the users. in our case, the adaptation is triggered due to contextual changes, which provide a potential solution for the multiscale nature of copd. level: in our system, the change needs to be done on the application layer, where we need to update the acceptable range for the different datasets or we need to activate new components or call new functions. technique: mckinley [ ] provided two techniques for adaptive software: parameter adaptation and compositional adaptation. parameter adaptation achieves a modified system behavior by adjusting system parameters. whereas compositional adaptation enables the exchange of algorithms or system components dynamically at runtime. we will use the first approach because it is suitable for a rule-based system. adaptation control: two approaches for implementing the adaptation logic can be found in the literature. the internal approach, which twists the adaptation logic with the system resources. the external approach splits the system into adaptation logic and managed resources, the ibm autonomic computing initiative provided mape model [ ] , which is an external, feedback control approach. another aspect of the adaptation logic is the degree of decentralization. we will follow a decentralized approach by implementing independent units that control different aspects of adaptation. self-adaptation healthcare system for copd ajami and mcheick [ ] have proposed an ontology-based approach to keep track of the physical status of patients, suggest recommendations and deliver interventions promptly, by developing a decision support system based on an ontological formal description that uses swrl rules. the main goal of this paper is to provide an adaptation architecture design for the application layer, which will address the connection between three different entities: -the end-user application: which is supposed to provide a certain service for both patient and physician. -the data sources (sensors and patient's records): that provides a continuous stream of contextual data and historical data about the patient. -the rules base: which presents the knowledge base in our system (fig. ) the adaptation engine consists of a central adaptation unit and multiple sub adaptation units. each subunit is responsible for monitoring and managing changes for a specific category tuple (data, rules, services). the system variables will be saved in a shared memory called the global state, which is a composition of sub-states. each sub-state is considered as a container for saving category-specific data and it will be updated and managed by the adaptation subunit that is responsible for monitoring the same category. we will divide all our sets of data, rules, and services into three categories ( table ) : now each subunit will be responsible for a specific category of the tuple. therefore, we will have three subunits: -the biometrics unit -the environmental unit -the activities unit (fig. ). -the biometrics unit will be responsible for monitoring all the patient's biomarkers upcoming from the biometrics sensors, and it will read all the stored data in the other two sub-states (the environmental state & the activities state), then depending on the vital related rules in the rules engine, it will update the biometrics state with the safe ranges for all the vital biomarkers and the current measurements for them. the same workflow will be applied in both the environmental unit and the activities unit. -the central adaptation unit: it is considered the main core of our system; it will be responsible for monitoring the global state, which will get rid of the burden of dealing with the continuous streaming of the patient's biometrics and the environmental data. by collecting all the contextual data in the global state, each category in its sub-state, we will have access to all the current biometrics and external factors value with the safe range for each one of them as well the current physical activity and the planned list of activities. depending on the previous data, the central unit will be able to detect any potential risk or abnormal situations by comparing the current value of each factor in the substates with its normal range, which had been adapted by every sub adaptation unit. when an abnormal situation is detected, the central unit will detect what action should be taken to prevent an exacerbation in the patient's health state. in order to test and validate our proposed system, we implemented a simulation app using some data obtained from medical records to simulate the streamed data and a set of copd rules extracted in [ ] to create some testing scenarios. the main focus of the validation process was on the efficiency of the system to provide continuous monitoring of the patient status, and the ability to apply and adapt the required changes to prevent any dangerous exacerbation. the testing scenarios we had performed, proofed the ability of our system to handle the complexity of monitoring the enormous amount of contextual data, and keep track of the latest updates in the global state. also, following an aspect-oriented approach facilitates the implementation of the adaptation logic, by separating the categories of data that each adaptation unit needs to be responsible for observing. after testing some rules that lead to call a sequential set of actions and multiple updates in the state units, the system was able to adapt the safe ranges for the different environmental and biometrical factors and detect suitable action in an abnormal situation. nevertheless, our system still needs to be tested when it is connected to the whole rules engine when all copd rules are inserted into the engine, which will be done in future work. in this paper, we have presented an architecture for a context-aware self-adaptive system that is used to develop a copd healthcare telemonitoring system. the system is backed out by a medical rules engine in the copd domain that is used as the knowledge base to determine the safe ranges for patient's biomarkers and external factors, then detect the precluding actions needed to be taken to prevent severe exacerbations in patient's health state. our main contribution in this work is providing a context-aware self-adaptive system architecture that is dealing with the huge variety and complexity of contextual data and different sets of services by implementing a decentralized adaptation unit, which makes the monitoring and adaptation task easier and less complex by applying the separation of concerns principle. the top causes of death integrated care prevents hospitalisations for exacerbations in copd patients global strategy for the diagnosis management and prevention of copd, global initiative for chronic obstructive lung disease (gold the use of remote monitoring technologies in managing chronic obstructive pulmonary disease insufficient evidence of benefit: a systematic review of home telemonitoring for copd home telehealth for chronic obstructive pulmonary disease: a systematic review and meta-analysis home telemonitoring forrespiratory conditions: a systematic review systematicreview of telemedicine services for patients affected by chronic obstructive pulmonary disease (copd) telehealthcare for chronic obstructive pulmonary disease: cochrane review and meta-analysis out of context: computer systems that adapt to, and learn from, context. ibm syst a survey on engineering approaches for self-adaptive systems an architecture-based approach to self-adaptive software rainbow: cost-effective software architecture-based self-adaptation comparison of approaches for developing self-adaptive systems metaself -an architecture and a development method for dependable self-* systems casa a contract-based adaptive software architecture framework towards a generic context-aware framework for self-adaptation of service-oriented architectures caredroid: adaptation framework for android context-aware applications getting to requirements: the w h challenge ontology-based model to support ubiquitous healthcare systems for copd patients a survey on engineering approaches for self-adaptive systems pc: system support for adaptive peer-to-peer pervasive computing composing adaptive software ibm: an architectural blueprint for autonomic computing a pervasive healthcare system for copd patients ), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the creative commons license and indicate if changes were made. the images or other third party material in this chapter are included in the chapter's creative commons license, unless indicated otherwise in a credit line to the material. if material is not included in the chapter's creative commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use key: cord- - ojvhwb authors: maddaloni, ernesto; d’onofrio, luca; alessandri, francesco; mignogna, carmen; leto, gaetano; pascarella, giuseppe; mezzaroma, ivano; lichtner, miriam; pozzilli, paolo; agrò, felice eugenio; rocco, monica; pugliese, francesco; lenzi, andrea; holman, rury r.; mastroianni, claudio maria; buzzetti, raffaella title: cardiometabolic multimorbidity is associated with a worse covid- prognosis than individual cardiometabolic risk factors: a multicentre retrospective study (covidiab ii) date: - - journal: cardiovasc diabetol doi: . /s - - - sha: doc_id: cord_uid: ojvhwb background: cardiometabolic disorders may worsen covid- outcomes. we investigated features and covid- outcomes for patients with or without diabetes, and with or without cardiometabolic multimorbidity. methods: we collected and compared data retrospectively from patients hospitalized for covid- with and without diabetes, and with and without cardiometabolic multimorbidity (defined as ≥ two of three risk factors of diabetes, hypertension or dyslipidaemia). multivariate logistic regression was used to assess the risk of the primary composite outcome (any of mechanical ventilation, admission to an intensive care unit [icu] or death) in patients with diabetes and in those with cardiometabolic multimorbidity, adjusting for confounders. results: of patients enrolled, those with diabetes (n = ), compared with those without diabetes (n = ), had characteristics associated with the primary composite outcome that included older age, higher prevalence of hypertension and chronic obstructive pulmonary disease (copd), higher levels of inflammatory markers and a lower pao /fio ratio. the risk of the primary composite outcome in the patients who completed the study as of may (th), , was higher in those with diabetes (adjusted odds ratio ((adj)or) . , %ci . – . , p = . ), hypertension ((adj)or . , %ci: . – . , p = . ) and copd ((adj)or . , %ci . – . , p = . ). patients with cardiometabolic multimorbidity were at higher risk compared to patients with no cardiometabolic conditions ((adj)or . %ci . – . , p = . ). the risk for patients with a single cardiometabolic risk factor did not differ with that for patients with no cardiometabolic risk factors ((adj)or . , . – . , (adj)p = . ). conclusions: patients with diabetes hospitalized for covid- present with high-risk features. they are at increased risk of adverse outcomes, likely because diabetes clusters with other cardiometabolic conditions. being frequent comorbidities in patients with covid- who require intensive care or die [ , ] . type diabetes, in particular, might hypothetically impact on all of the different aspects of sars-cov- infection, from the contagion to the clinical presentation and to disease severity [ ] . further, in-hospital hyperglycaemia has been associated with worse covid- outcomes [ ] , being a negative prognostic factor at hospital admission in both patients with and without diabetes [ ] . in addition, regardless of diabetes diagnosis, hyperglycaemia reduced the efficacy of treatment with tocilizumab in patients affected by covid- [ ] . on the other hand, a recent report from wuhan failed to show an independent association of type diabetes with covid- mortality after adjustment for other cardiovascular conditions [ ] . notably, most cardiometabolic disorders share a common pathogenic soil, often cluster together, and might reflect the same intermediate pathways that favour covid- progression [ ] [ ] [ ] . therefore, assessing the possible association of type diabetes with covid- outcomes based on individual cardiometabolic disorders may be subject to a collider bias, leading to distorted results [ , ] . this makes it difficult to disentangle independent associations covid- may have with single components of cardiometabolic multimorbidity, defined here as a group of main metabolic disorders that increase the risk of cardiovascular events, such as diabetes, hypertension and dyslipidaemia. nevertheless, most studies investigating diabetes as a risk factor for covid- progression searched for independent associations, leading to conflicting conclusions [ , [ ] [ ] [ ] . we, instead, hypothesized that people with diabetes may differ from those without diabetes in their clinical presentation, course and prognosis of covid- due to the propensity of diabetes to cluster with other cardiometabolic risk factors, such as hypertension and/or dyslipidaemia, which contribute to the increased pro-inflammatory and hypercoagulable states of people with diabetes. furthermore, most studies published to date on this topic come from asian countries, with few data available from western countries where differences in ethnic groups and healthcare systems may lead to different associations [ , ] . overall, there is an urgent need for additional data to clarify the relationships between diabetes, cardiometabolic multimorbidity and covid- [ ] which could provide significant insights of global health interest to help tackle this deadly pandemic in a large group of atrisk individuals. we aimed to describe in detail, using opportunistic data collected retrospectively, the clinical and biochemical features of patients with and without diabetes hospitalized for covid- in four academic hospitals in the lazio region, italy, to evaluate their outcomes, and to evaluate the impact of cardiometabolic multimorbidity. the covid- & diabetes (covidiab) study is a multicenter observational study which collected data retrospectively from medical charts of patients hospitalized for covid- from march st to may th , in four academic hospitals located in the lazio region of italy: umberto i "policlinico" general hospital and sant' andrea hospital, sapienza university of rome; santa maria goretti hospital, polo pontino of sapienza university in latina; campus bio-medico university hospital in rome [ ] . patients eligible for inclusion were aged ≥ years old with a diagnosis of covid- confirmed by at least one real-time polymerase chain reaction assay, in accordance with the protocol established by the world health organisation [ ] . after exclusion of patients with unknown diabetes status, baseline data for patients and clinical outcomes for patients up to may th , were available for inclusion in this analysis. the covidiab primary aim was to evaluate whether patients with diabetes, compared with those without diabetes, were at increased risk of adverse covid- outcomes, independent of age and sex. the composite primary outcome was defined as any of mechanical ventilation, admission to an intensive care unit (icu), or death. pre-specified secondary endpoints included a composite outcome of icu admission or death and allcause mortality (acm). in this study, we did not seek to test whether diabetes as a risk factor for covid- progression is independent of hypertension and dyslipidaemia, which may be considered as coexisting components of a single cardiometabolic disorder (or syndrome). instead, our secondary aim (if diabetes was confirmed to be associated with an increased risk of the primary composite outcome) was to evaluate whether cardiometabolic multimorbidity (defined as ≥ of three risk factors of diabetes, hypertension and dyslipidaemia) may be considered as a risk factor that differs from a single cardiometabolic condition. accordingly, patients were stratified into three mutually exclusive cardiometabolic groups: no conditions, one condition and two or three conditions. data collected included: demographic information (age and sex); presence of diabetes (defined as at least one random blood glucose value > mg/dl, or fasting blood glucose > mg/dl, or hba c > . %, or self-reported history of diabetes with ongoing anti-diabetes therapy), type of diabetes (type , type , other); smoking habits (never, ex, current); prior history of hypertension, dyslipidemia, chronic obstructive pulmonary disease (copd), heart failure, cardiovascular events (myocardial infarction, percutaneous coronary intervention, coronary artery-bass graft or stroke), malignancy (any neoplasia diagnosed within the last five years or active neoplasia); presenting symptoms of sars-cov- infection (fever, cough, cold, conjunctivitis, chest pain, dyspnea, nausea, vomiting, diarrhea). biochemical data measured at admission, where available, were: plasma glucose, serum creatinine, erythrocyte sedimentation rate (esr), c-reactive protein (crp), full blood count, lactate dehydrogenase, fibrinogen, d-dimer and blood gas analysis. body mass index (bmi) was calculated for the patients with height and weight data available. usual care medications at admission were ascertained from those reported by the inpatient-accepting physician. diabetes usual care medications were also retrieved from the web-based reimbursement system of lazio region (web-care lazio), as categorized by this system: euglycaemic agents (eugla: metformin, dipeptidyl peptidase inhibitors [dpp i], glucagon-like peptide receptor agonists [glp- ra], sodium-glucose co-transporter inhibitors [sglt i] and/or pioglitazone); oral hypoglycaemic agents (oha: sulfonylureas or glinides); basal insulin (alone or in combination with eugla or oha); multiple daily insulin injections (mdi: ≥ insulin injections per day). the webcare lazio system was also used to confirm a self-reported history of diabetes. continuous variables are presented as medians [ th- th percentile]. categorical variables are presented as number and percentages, calculated on the data available. we made no assumptions regarding missing data. kruskal-wallis, chi-squared and fisher exact tests were used for comparisons between groups, as appropriate. we estimated that at least patients completing the study would be required to provide % power to detect a . -fold higher incidence of the primary composite outcome in patients with diabetes hospitalized for covid- , compared with those without diabetes, using a one-sided alpha-level of . and allowing for adjustment of sex and age. logistic regression models adjusted for age and sex were used to investigate associations of the primary and secondary outcomes with diabetes, and with other risk factors explored in the study, namely hypertension, dyslipidemia, copd, heart failure, previous cardiovascular events, malignancy and smoking status (never vs. ever). the secondary aim of the study (association of cardiometabolic multimorbidity with the primary composite outcome) was also explored using a logistic regression model adjusted for age, sex and risk factors (other than hypertension, diabetes and dyslipidemia) that were univariately associated (p < . ) with the outcome after correction for age and sex. the wald test was used to test equality of the regression coefficients between cardiometabolic groups. stata/ic . software was used for data analysis and prism . software for graphical presentations. covidiab complies with the principle of the helsinki declaration and was approved by the ethical committee of umberto i "policlinico" general hospital. because of the study's retrospective design, informed consent was waived for patients who had been discharged, could not be contacted, or died. the privacy and anonymity of the data collected was guaranteed in accordance with current regulations. presenting characteristics for all patients are listed in table . patients with diabetes, compared with those without diabetes, were older (age ≥ years: . % vs. . %, p < . ) but with a similar sex distribution. they also presented with higher rates of hypertension ( . % vs. . %, p = . ), dyslipidemia ( . % vs. . %, p < . ), prior cardiovascular events ( . % vs. . %, p = . ), heart failure ( . % vs. . %, p = . ) and copd ( . % vs. . %, p = . ). no differences in smoking habits or malignancy rate were found. bmi did not differ between patients with and without diabetes. at no differences were observed in the frequencies of sars-cov- infection presenting symptoms between patients with and without diabetes (additional file : table s ). continuous variables are presented as median [ th, th percentile]; categorical variables are presented as number (percentage) # p-value for difference in never, ex and current mokers eugla, euglycemic agents (metformin, dipeptidyl peptidase inhibitors, glucagon-like peptide receptor agonists, sodium-glucose co-transporter inhibitors and/ or pioglitazone); oha, oral hypoglycaemic agents (sulfonylureas or glinides); mdi, multiple daily insulin injections; raas, renin-angiotensin-aldosterone system; acei, angiotensin converting enzyme inhibitors; arb, angiotensin receptor blocker; cv, cardiovascular; copd, chronic obstructive pulmonary disease; esr, erythrocytes the primary composite outcome occurred in ( . %) of the patients who completed the study (discharged alive or experiencing at least one component of the primary composite outcome). differences in clinical features between those experiencing the primary composite outcome and those discharged alive (n = ), mostly mirrored the differences seen between patients with and without diabetes ( table ) . those with, compared with those without the primary composite outcome, were more often > years old (p < . ) and more likely to have hypertension (p < . ), dyslipidemia (p = . ), heart failure ( . ) or copd (p = . ). there was no difference in prior history of cv events between groups but those with the primary composite outcome were less often current smokers than never smokers ( . % vs. . %, p = . ). bmi in the patients with bmi data and complete follow-up, was higher in those with the primary composite outcome compared with those discharged alive not requiring neither icu admission or mechanical ventilation ( differences in biochemical features between patients with, compared with those without the primary composite outcome, also paralleled the differences seen between patients with and without diabetes (table ) . those experiencing the primary composite outcome had higher plasma glucose (p < . ), serum creatinine (p = . ), crp (p < . ), white blood cell count (p < . ), neutrophil count (p < . ) and venous lactate (p = . ), and a lower pao /fio ratio (p < . ). they also had higher lactate dehydrogenase (p < . ) and d-dimer (p = . ) concentrations, but had a lower lymphocyte count (p = . ). frequencies of sars-cov- infection presenting symptoms were similar among patients with, compared with those without the primary composite outcome, apart from dyspnea which was more frequent among those experiencing the primary composite outcome ( . % vs. . %, p < . ) (additional file : table s ). age and sex adjusted regression models confirmed that covid- patients with the primary composite outcome were more likely to have diabetes (adjusted odds ratio [ adj or] . , % confidence interval [ci] . - . , p = . ), hypertension ( adj or . , %ci . - . , p = . ) or copd ( adj or . , %ci . - . , p = . ), while the associations with dyslipidemia and heart failure were lost (fig. a) . therapies for diabetes at admission did not differ between patients with diabetes in whom the primary composite outcome did or did not occur (table ) . similarly, there was no difference in the use of angiotensinconverting enzyme (ace) inhibitors or angiotensin receptor blockers (arb) between patients who did or did not experience the primary outcome ( . % vs . %, p = . and . % vs . %, p = . , respectively). of the patients completing the study, ( . %) did not have diabetes, hypertension or dyslipidaemia, ( . %) had just one of these risk factors ( with diabetes, with hypertension, with dyslipidaemia), and ( . %) had ≥ two of these risk factors meeting our study definition of cardiometabolic multimorbidity. the proportion of patients > years old (p < . ), with a prior cardiovascular event (p < . ), heart failure (p = . ) or copd (p = . ), and higher concentrations of plasma glucose (p < . ), creatinine (p = . ), crp (p = . ) and venous lactate (p < . ) increased with increasing numbers of cardiometabolic conditions, and with a decreasing pao /fio ratio (p = . ) ( table ) . the proportion of patients experiencing the composite primary outcome increased with increasing numbers of cardiometabolic risk factors (fig. ) , independently of age, sex and copd ( adj p = . ). the risk of the primary composite outcome in patients with cardiometabolic multimorbidity, compared with those with no cardiometabolic risk factors, was higher ( adj or [ % ci] . [ . - . ], adj p = . ). they also were at higher risk when compared with patients with a single cardiometabolic risk factor ( adj or . , . - . , adj p = . ). the risk for patients with a single cardiometabolic risk factor, however, did not differ with that for those with no cardiometabolic risk factors ( adj or . , . - . , adj p = . ). analyses examining the secondary outcomes of icu admission or death, and acm alone, were performed for patients who were admitted to icu, died or were discharged alive without icu admission (n = ), and for the those who died or were discharged alive at study end (n = ). icu admission or death occurred in ( . %) sedimentation rate; crp, c-reactive protein; pao , arterial po ; fio , fraction of inspired oxygen body mass index data were available for * , ** , *** and **** patients smoking data were available for ^ , ^^ , ^^^ and ^^^^ patients anti-diabetes therapy data were available for of the patients with diabetes who completed the study fig. proportion of patients experiencing the primary composite outcome (a), and the secondary outcomes of icu admission or death (b), or death (c) among patients with or without different comorbidities. age and sex adjusted odds ratios (or) with % confidence intervals (ci) for those with, compared with those without, each comorbidity are reported. error bars represent % confidence intervals in the former, and ( . %) of the latter died. after adjustment for age and sex, diabetes was not associated with either of these secondary outcomes, whereas a prior history of copd or heart failure was (fig. b, c and additional file : table s ). our study shows that the characteristics associated with worse covid- outcomes are found more frequently in patients with diabetes than in those without diabetes. these include older age, higher prevalence of chronic comorbidities such as hypertension or copd, higher levels of inflammatory markers, and a lower pao /fio ratio. accordingly, the risk of progression towards mechanical ventilation, icu admission or death was significantly higher among patients with diabetes than in those without, independent of age and sex. as we expected, only a minority of patients with diabetes ( . %) had neither hypertension nor dyslipidemia, supporting our choice not to consider these risk factors as independent variables. this observation suggests that findings from studies reporting diabetes is not associated with covid- severity after adjustment for other cardiovascular conditions should be interpreted with caution [ ] . in line with our hypothesis, patients with cardiometabolic multimorbidity had a higher risk of the primary outcome compared with patients with no or a single cardiometabolic risk factor (diabetes, hypertension or dyslipidaemia). compared with patients with no cardiometabolic risk factors, the primary composite outcome was also higher among patients with a single risk factor, but was not significant after adjustment for age, sex and presence of copd. of note, while drugs targeting the incretin system or the renin-angiotensin-aldosterone system have been hypothesized to be associated with covid- outcomes [ , ] , their use did not differ between patients with or without the primary outcome. overall our results confirm previous findings from other countries that covid- patients with diabetes are more likely to require intensive care or to die, compared with covid- patients without diabetes [ , , , ] , and in addition suggest this association is driven by the presence of cardiometabolic multimorbidity rather than by diabetes alone. in this regard, categorizing patients as having cardiometabolic multimorbidity, rather than a simply summing risk factors [ ] , seems to almost completely explain the interaction between cardiometabolic disorders and covid- . coexisting cardiometabolic risk factors may indeed either be the expression of a common pathogenic soil or cooperate with each other to predispose covid- patients to progress towards more severe clinical scenarios. in patients presenting with diabetes but not hypertension or dyslipidemia, pathogenic pathways involved may not be sufficiently affected to impact on the clinical course of covid- . the observation that cardiometabolic multimorbidity worsens covid- is of clinical relevance, highlighting the importance of tackling cardiovascular risk as a whole to improve covid- outcomes. of note, an estimation of the overall effects of the covid- outbreak according to underlying conditions has also suggested that cardiovascular comorbidities, together with copd, may be responsible for the majority of excess deaths associated with covid- pandemic from both direct and indirect effects [ ] . different mechanisms may be hypothesized to explain the association of cardiometabolic health with covid- outcomes. it has been suggested that covid- not only affects the respiratory system but also the vasculature [ ] [ ] [ ] [ ] . direct sars-cov- infection of endothelial cells causing endothelitis in several organs has been demonstrated in patients dying from covid- [ ] , suggesting covid- is an infectious disease affecting endothelial function. it is worth hypothesizing therefore, that cardiometabolic multimorbidity may predispose to worse covid- outcomes by weakening endothelial cells [ ] , which then become more susceptible to viral infection. additionally, the hypercoagulable and pro-inflammatory states often observed in cardiometabolic patients [ ] may also contribute towards the formation of the multiple blood clots and the cytokine storm that can occur in the most severe covid- cases [ , ] . this endothelial hypothesis accords with recent data suggesting that a high amount of visceral adiposity, a common feature of cardiometabolic patients associated with chronic lowgrade inflammation, associates with worse covid- outcomes [ ] . while measures of visceral adiposity were not available in our study, bmi was found to be higher in patients with the primary outcome, consistent with previous reports in other populations [ , ] . the trend we noted towards higher bmi with increasing number of cardiometabolic risk factor in the relatively low number of patients with bmi data available our population was not statistically significant. limitations to our study include retrospective collection of data from electronic and paper records, relatively few patients with bmi data available, and incomplete followup of some patients without an endpoint who were still hospitalized at the time of this analysis. also, we were not able to retrieve glycemic control data during hospitalization, which has been associated with worse covid- outcomes [ , ] . the small number of deaths does not allow us to make any conclusions about the non-significant association of diabetes with acm, which was however associated with prior history of hypertension, copd or heart failure. finally, we were not able to estimate insulin resistance, or surrogates such as triglyceride-glucose index [ ] , in our population, which is often considered the common soil for cardiometabolic conditions. similarly, the absence of waist circumference data not allow us to identify patients with the metabolic syndrome to assess its possible impact, although the utility of this categorisation in type diabetes has been increasingly questioned [ ] . unfortunately, due to the observational study design and the demanding work condition determined by the pandemic, we were unable to collect additional blood samples or to perform additional radiological investigations to test bio-markers not routinely measured in all patients, such as cardiac troponin, interleukins, or to assess visceral adiposity, all of which may be involved in the relationship between cardiometabolic multimorbidity and covid- progression [ , , ] . novel studies should be performed to evaluate whether the increased risk conferred by cardiovascular multimorbidity is associated to augmented cytokine storm and to central obesity. strengths of our study include a detailed characterization of the clinical and biochemical features of patients hospitalized for covid- , with and without diabetes, with good generalizability of the results thanks to the multicentre study design. furthermore, to the best of our knowledge, this is the first study assessing covid- outcomes in the context of cardiometabolic multimorbidity. our study shows that patients with diabetes hospitalized for covid- present with high-risk clinical and biochemical features and are at increased risk of mechanical ventilation, icu admission or death, likely because diabetes frequently clusters with cardiometabolic multimorbidity. supplementary information accompanies this paper at https ://doi. org/ . /s - - - . additional file : table s . sars-cov- infection symptoms at hospitalization in patients with, compared with those without, diabetes and in patients experiencing the primary composite compared with those without. table s . odds ratio (or) with [ % confidence intervals, ci] for secondary outcomes, unadjusted and adjusted for age and sex. abbreviations: cv, cardiovascular; copd, chronic obstructive pulmonary disease. characteristics of hospitalized adults with covid- in an integrated health care system in california clinical characteristics of covid- in new york city clinical characteristics of coronavirus disease in china presenting characteristics, comorbidities, and outcomes among patients hospitalized with covid- in the baseline characteristics and outcomes of patients infected with sars-cov- admitted to icus of the lombardy region italy impact of diabetes mellitus on clinical outcomes in patients affected by covid- are patients with hypertension and diabetes mellitus at increased risk for covid- infection? covid- and diabetes mellitus: unveiling the interaction of two pandemics outcomes in patients with hyperglycemia affected by covid- : can we do more on glycemic control? diabetes care hyperglycaemia on admission to hospital and covid- negative impact of hyperglycaemia on tocilizumab therapy in covid- patients clinical characteristics and risk factors for mortality of covid- patients with diabetes in wuhan high-risk multimorbidity patterns on the road to cardiovascular mortality multimorbidity of cardiometabolic diseases: prevalence and risk for mortality from one million chinese adults in a longitudinal cohort study multimorbidity: another key issue for cardiovascular medicine educational note: paradoxical collider effect in the analysis of non-communicable disease epidemiological data: a reproducible illustration and web application collider bias undermines our understanding of covid- disease risk and severity. medrxiv covid- in people with diabetes: urgently needed lessons from early reports diabetes is a risk factor for the progression and prognosis of covid- association of blood glucose control and outcomes in patients with covid- and pre-existing type diabetes frailty and geography: should these two factors be added to the abcde contemporary guide to diabetes therapy? cardiovascular multimorbidity: the effect of ethnicity on prevalence and risk factor management clinical features of patients with type diabetes with and without covid- : a case control study (covidiab i) world health organization. laboratory testing for coronavirus disease (covid- ) in suspected human cases could anti-hypertensive drug therapy affect the clinical prognosis of hypertensive patients with covid- infection? data from centers of southern italy dpp inhibition: preventing sars-cov- infection and/ or progression of covid- ? diabetes comorbidity and its impact on patients with covid- in china: a nationwide analysis estimating excess -year mortality associated with the covid- pandemic according to underlying conditions and age: a population-based cohort study covid- diagnosis and management: a comprehensive review pulmonary vascular endothelialitis, thrombosis, and angiogenesis in covid- potential effects of coronaviruses on the cardiovascular system hypertension, thrombosis, kidney failure, and diabetes: is covid- an endothelial disease? a comprehensive evaluation of clinical and basic evidence endothelial cell infection and endotheliitis in covid- vascular complications of diabetes: mechanisms of injury and protective factors prevention of atherothrombotic events in patients with diabetes mellitus: from antithrombotic therapies to new-generation glucose-lowering drugs hypercoagulability of covid- patients in intensive care unit. a report of thromboelastography findings and other parameters of hemostasis facing covid- in the icu: vascular dysfunction, thrombosis, and dysregulated inflammation the role of visceral adiposity in the severity of covid- : highlights from a unicenter cross-sectional pilot study in germany letter to the editor: obesity as a risk factor for greater severity of covid- in patients with metabolic associated fatty liver disease triglyceride-glucose index is associated with symptomatic coronary artery disease in patients in secondary care impact of the metabolic syndrome on macrovascular and microvascular outcomes in type diabetes mellitus cardiac troponin for the diagnosis and risk-stratification of myocardial injury in covid- : jacc review topic of the week em designed the study, analysed and interpreted data and wrote the first draft of the manuscript. ldo contributed to the design of the study, data acquisition, interpretation and manuscript writing. cm acquired data and helped in data interpretation; fa, gl, im, ml, fea, fp, and gp acquired data. pp, mc, al revised the manuscript for important intellectual content. rrh contributed to data interpretation and revised the manuscript for important intellectual content. cmm contributed to the design of the study and acquisition of the data. rb was responsible for the conception of the study, contributed to study design and data interpretation and revised the manuscript critically for important intellectual content. all authors read and approved the final manuscript. the study was in part supported through the efsd mentorship programme supported by astrazeneca. the datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. covidiab complies with the principle of the helsinki declaration and was approved by the ethical committee of umberto i "policlinico" general hospital. because of the study's retrospective design, informed consent was waived in cases of discharge, of impossibility of contact with patients and in case of death. the privacy and anonymity of the data collected was guaranteed in accordance with current regulations. not applicable. springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. key: cord- -ckuma j authors: mcdowell, g.; sumowski, m.; toellner, h.; karok, s.; o'dwyer, c.; hornsby, j.; lowe, d.; carlin, c. title: two-way remote monitoring allows effective and realistic provision of home-niv to copd patients with persistent hypercapnia. date: - - journal: nan doi: . / . . . sha: doc_id: cord_uid: ckuma j background outcomes for chronic obstructive pulmonary disease (copd) patients with persistent hypercapnic respiratory failure are improved by long-term home non-invasive ventilation (niv). provision of home-niv presents clinical and service challenges. the aim of this study was to assess outcomes of home-niv in hypercapnic copd patients managed remotely. methods retrospective analysis of a dataset of copd patients with persistent hypercapnic respiratory failure who commenced home-niv managed by two-way remote monitoring (lumis, airview, resmed) between february and january . the primary outcome of this study was time to readmission or death at months in patients receiving home-niv versus a retrospectively identified control cohort of patients with hypercapnic copd who had not been referred for home-niv. results the median time to readmission or death was significantly prolonged in patients who commenced home-niv (median days, % ci . - . ) versus the control cohort ( days, % ci . - . ; p< . ). average time to hospital readmission was days ( % ci, . - . ) and days ( % ci, . - . ; p< . ), respectively. median decrease in bicarbonate level of . mmol/l (p< . ) and daytime pco . kpa (p< . ) demonstrate efficacy of home-niv. a median reduction of occupied bed days per annum versus previous year prior to niv was observed per patient who continued home-niv throughout the study period (n= ). conclusion these findings confirm the benefits of home-niv in clinical practice and support the use of two-way remote monitoring as a feasible solution to managing the delivery of home-niv for copd patients with persistent hypercapnia. copd is the second most common cause of emergency hospital admission in the uk, accounting for over million bed days at a cost to the nhs of over £ million a year ( ) . around a third of those admitted to hospital following an exacerbation of copd are readmitted within days, which is also strongly associated with post-discharge mortality ( ) . avoiding copd exacerbations and hospitalisations is noted to be a key priority by copd patients ( , ) , and targeting a reduction in these is necessary to address the substantial health and economic burden imposed by copd. the risk of hospital readmissions and further life-threatening events is particularly high among patients with a severe exacerbation of copd that leads to hypercapnic respiratory failure ( ) . the first-line treatment for these patients in the acute setting is non-invasive ventilation (niv) ( ) , which has been shown to prevent intubation and invasive mechanical ventilation and reduce hospital mortality ( , ) . however, it was previously reported that more than % of patients treated with niv for acute hypercapnic respiratory failure were readmitted and nearly % died within the first year after discharge ( ) . a growing area of interest to improve outcomes for patients with severe copd focuses on the application of long-term niv in the home setting. in a recent landmark study, murphy et al. ( ) showed that the addition of home-niv to long-term home oxygen therapy in patients that remained severely hypercapnic to weeks after an exacerbation delayed and reduced hospital readmissions at months. a benefit on month overall survival was noted in an earlier randomised controlled trial involving stable hypercapnic patients treated with home-niv ( ) . the driver of clinical improvements across both studies can be attributed to higher inspiratory pressures targeting a reduction in co in patients who were persistently hypercapnic. a task force of the european respiratory society has since adopted home niv as recommended treatment for copd patients presenting with persistent hypercapnic respiratory failure ( ) . overall, the existing body of research suggests that there are some open questions with regards to patient selection and timing of home-niv ( , ) . for example, only % of patients screened in hot-hmv study were recruited to the trial, raising questions about the external validity of niv randomised controlled trial (rct) results. many of the patients excluded from niv rcts meet current guidance critieria for home niv provision. establishing whether beneficial outcomes from home niv copd rcts can be matched with routine clinical adoption is required. the feasibility of delivering home-niv to patients outside of controlled clinical trial settings also remains to be established, particularly in the context of covid- pandemic. provision for elective inpatient niv initiation and titration beyond clinical trials is limited, patients generally wish to avoid hospitalisations and severity of their illness limits capacity for outpatient attendances. regular follow-up helps to monitor the effectiveness of ventilation, encourages treatment adherence and optimises patient comfort and ventilator settings, but realistic delivery of intensive follow-up is problematic ( ) . the covid- pandemic has presented additional challenges to home niv provision. overall healthcare service pressures, social distancing requirements including need to protect vulnerable patients from nosocomial covid- , and infection control requirements for clinicians, with niv classified as an aerosol generating procedure will all continue to impact on breathing support service capacity. it has been demonstrated that copd patients at high risk for exacerbations can be taught to self-manage when offered ongoing support ( , ) . early evidence that compares remotely monitored copd patients with usual face-to-face care is encouraging in terms of patient quality of life and number of hospital admissions ( ) . with the recent advent of two-way tele-monitoring, healthcare providers can view live niv data from patients, adjust ventilator settings remotely and facilitate personalised care. a combination of patient education, self-management and remote monitoring may therefore be a realistic support pathway for home-niv. using this to channel shift service provision, replacing some aspects of inpatient niv setup and/or . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint the copyright holder for this this version posted november , . ; https://doi.org/ . / . . . doi: medrxiv preprint face-face outpatient niv follow-up on an individualised basis is attractive, particularly to mitigate risks and bolster service provision in face of covid- related challenges. nhs greater glasgow and clyde (gg&c) implemented a remote-monitored home-niv model for its copd population in . the present study retrospectively analysed all patients who were commenced on therapy over the first months of this service, with aim of determining whether outcomes similar to rcts were achieved in a real-world cohort of hypercapnic copd patients with typical comorbidities (which would have excluded many from niv rcts) who are managed with remote-monitored home niv. the primary outcome was median time to readmission or death over months in patients receiving home-niv versus a control cohort. this study is part of programme of work analysing outcomes in a dataset of copd patients provided by nhs gg&c safe haven. local privacy advisory committee approval was obtained for release of deidentified data for this study. two cohorts were sampled from the database as outlined in figure . the home-niv cohort consisted of consecutive patients with copd who commenced home-niv between february th and january th at the queen elizabeth university hospital. copd diagnosis was confirmed as per gold guidelines, and was the primary diagnosis responsible for hypercapnic respiratory failure in all patients in this cohort. hypercapnic respiratory failure was defined as pco > kpa at least weeks after index acute exacerbation and/or presence of persisting hypercapnia across current and previous copd episodes, with deferred niv assessment for attempted follow up post episode judged inappropriate. patients in this cohort continued home-niv throughout the -month study period ('niv users'). patients discontinued home-niv due to poor acceptance despite individualised interventions to optimise therapy during the study period ('niv non-users'). the control cohort comprised patients treated with acute niv at the queen elizabeth university hospital between march and november following a life-threatening exacerbation of copd that resulted in hypercapnic respiratory failure. this was in the period prior to adoption of routine screening of all acute niv patients for home niv at our institution. retrospective review noted that patients in this group were suitable for home-niv but they were not referred to the home-niv service during the follow up period of this study. none of these patients 'crossed over' to commence home niv during the study's observed follow up period. all patients were noted to be receiving guideline-based copd care, including home oxygen therapy unless contraindicated. since early our practice has been to offer trialling home niv to copd patients with persistent hypercapnia (pcco > kpa) at stable status, or during an acute episode if there has been recurrent hypercapnic respiratory failure where deferring commencing home niv to outpatient review is judged impractical or unsafe by patient-clinician consensus. often this decision to offer home niv within an acute episode is informed by high serum bicarbonate levels (implying chronic hypercapnia) and/or presence of suspected or confirmed osa overlapping with severe copd. patients in the home-niv cohort were commenced on remote monitored home-niv in ivaps auto-epap mode (lumis st-a, airview, resmed) if persisting hypercapnia was present at day case review to . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint the copyright holder for this this version posted november , . ; https://doi.org/ . / . . . doi: medrxiv preprint weeks following hospital discharge (n= / ) or during the index hospital admission if persisting hypercapnia had been demonstrated across previous copd episodes as per above noted criteria (n= / ) patients initiated on home-niv consented to their data being accessed and shared on the airview platform by the necessary healthcare professionals. airview data review was used to inform routine clinical care and identify niv therapy issues (usage, leak) as well as ventilation data patterns supporting optimized niv provision. patient telephone, community or clinic follow up was individualized based on and informed by the remote monitoring data. airview platform was used to make niv device therapy changes, when indicated. the supplementary material provides an overview of the copd niv therapy protocol implemented at nhs gg&c, with typical follow-up schedule as well as representative remote monitoring data. remotemonitoring pathway is used to support daycase niv initiation (rather than elective hospital admission), early hospital discharge (if niv initiated during inpatient episode our institution) or inpatient niv initiation at another hospital (rather than hospital-hospital transfer). remote-monitoring data is reviewed at day - , day - and weekly thereafter, combined where required with telephone or video consultation, until treatment is optimized. remote-adjustments to ivaps-autoepap niv settings, adjustment to niv interface and face-face at home or daycase review arrangement are made where remote-monitoring and consultation data indicates requirement. stability is judged based on patient comfort and symptoms, acceptable niv usage durations, minimized unintentional leak and appropriate pressure support and other ventilator parameters. clinic follow up within - weeks including repeat capillary blood gases is scheduled for stable patients who can attend. patients who are having persisting difficulties establishing home niv despite remote-monitoring inputs are offered elective admission. baseline descriptive data were recorded including gender, age, bmi, predicted fev % as well as comorbidities that could potentially contribute to hypercapnia. the primary outcome was time to readmission or death, censored at date of admission, date of death or th january . secondary outcome measures included time to hospital admissions and overall survival in the home-niv and control cohort. subgroup analyses of the home-niv cohort explored differences between niv users and niv non-users in the primary and secondary outcome measures. changes in healthcare usage (number of hospital admissions, occupied bed days (obds) and respiratory nurse home visits) were evaluated in niv users and niv non-users before and after home-niv. changes in capillary blood gases were analysed in the home-niv cohort in the form of capillary blood gas pco and bicarbonate (where available). baseline characteristics of the study population are presented as mean (standard deviation), median (interquartile range) or count (percentage), as appropriate. primary and secondary study outcome measures were compared between the home-niv and control cohort using kaplan-meier survival analysis and the mantel-cox log rank test. additional subgroup analyses compared primary and secondary outcome measures between the niv user group and the niv non-user group alongside the control cohort using kaplan-meier and mantel-cox tests. changes in healthcare usage (number of hospital admissions, obds, and respiratory nurse home visits) and capillary blood gas pco and bicarbonate between niv users, niv non-users and the control cohort were analysed using wilcoxon signed-rank test. statistical analyses were conducted using ibm spss statistics v. (ibm, new york, usa) and graphpad prism v . (graphpad software, san diego, usa). . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint the copyright holder for this this version posted november , . ; https://doi.org/ . / . . . doi: medrxiv preprint due to the nature of a retrospective analysis, the research was undertaken without patient involvement. patients were not invited to comment on the study design and were not consulted to develop patient relevant outcomes, interpret the results or to contribute to the writing or editing of this document for readability or accuracy. . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint the copyright holder for this this version posted november , . ; https://doi.org/ . / . . . doi: medrxiv preprint baseline characteristics are shown in table . gender, bmi and age are similar across all study cohorts except for a higher rate of males, lower bmi and a lower rate of notable comorbidities (suspected or confirmed overlapping osa, long term opiate therapy) in the niv non-user subgroup. the fev % predicted value was around % across all study groups, in line with a "severe" classification of copd ( ) particularly as in many patients the spirometry was an historical rather than contemporary result. the median time to readmission or death was significantly prolonged in patients with persisting hypercapnic respiratory failure treated with home-niv compared to a control cohort of hypercapnic copd patients (p< . , see figure a ). subgroup analyses showed significant differences between the niv user subgroup versus both the niv non-user group and the control cohort (both p< . ). improvement in time to readmission or death was not achieved in patients who discontinued home-niv (figure b ). table summarises time to readmission or death for each group. time to hospital readmission followed the same pattern as time to readmission or death. median time to hospital readmission was days for the home-niv cohort ( % ci, - ) and days ( % ci, - ; p< . ) for the control cohort. subgroup analyses showed that time to hospital readmission was significantly improved in niv-users when compared to niv non-users and the control group (both p< . ). there was no significant difference comparing the control group and niv non-users (p= . ). -month overall survival was . % in the home-niv cohort and . % in the control cohort. patients that continued to use home-niv during the study period had a -month overall survival rate of . %. due to the low number of recorded mortality events, group differences were not statistically significant in the primary (p= . ) or subgroup analyses (p= . ). service usage in nhs gg&c by the home-niv cohort in the months prior to commencing home-niv (pre-niv) and the months following initiation of home-niv (post-niv) are outlined in table . a significant reduction in total number of admissions and obds is noted following initiation of home-niv across all patients in the home-niv cohort, but is particularly pronounced in niv users (p< . , figure ). the data equate to a median reduction of obds per annum per patient who continued remote-monitored home-niv. requirements for respiratory nurse home visits did not change significantly with the initiation of home-niv. capillary blood gas measurements were available in patients before and after home-niv. significant improvements in median pco ( . kpa, p< . ) and bicarbonate ( . mmol/l, p< . ) measured at followup after initiation of home-niv relative to measurements at baseline indicate control of hypercapnic respiratory failure (figure ). . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint the copyright holder for this this version posted november , . table baseline characteristics table changes in healthcare usage before and after home-niv . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this this version posted november , . ; https://doi.org/ . / . . . doi: medrxiv preprint this study confirms the benefits of home-niv in copd patients with persisting hypercapnic respiratory failure in clinical practice. patients in the home-niv cohort had significantly fewer hospital readmissions compared to the control cohort, with the greatest improvements seen in those who continued with home-niv throughout the -month observed follow-up period. moreover, these data support the use of two-way remote monitoring as a feasible solution to managing the delivery of home-niv, maintaining care-quality while also substantially reducing demand on healthcare resources. the current results are consistent with the hot-hmv trial by murphy et al. ( ) reporting delayed and reduced hospital readmissions in copd patients randomised to receive home-niv compared to patients treated with home oxygen therapy alone. while there are some important differences to consider between the hot-hmv trial and this study -less severe documented airflow obstruction and higher bmi in this study's patient cohort -reporting similar outcomes to the hot-hmv trial is encouraging. our data indicates that home-niv is effective in a typical population of patients presenting in routine clinical practice with phenotypes which would have potentially excluded them from rct inclusion. the secondary analyses also broadly support the interpretation of hot-hmv and other landmark copd home-niv trials ( , ) indicating that patient selection for home-niv should be based on persisting hypercapnic respiratory failure, and that optimising niv to target improvement in hypercapnia is appropriate. the comparable outcomes of this study and hot-hmv importantly provide reassurance about safety and quality of a copd home-niv service model utilising assistive two-way remote-monitoring technology. in the hot-hmv trial, home-niv was noted to reduce exacerbation-related costs (by £ , per case) and patient-reported costs (by £ , ) relative to the control arm. niv device cost and cost per physician visit had the greatest impact on cost per qaly ( ) . in line with this, the present study notes a considerable reduction in healthcare usage among home-niv users. in addition to significant decreases in hospital admissions, a median reduction of occupied bed days per annum was observed per patient who continued home-niv. it seems likely that a copd home-niv management strategy based on remotemonitoring and individualised follow-up will reduces physician visit and patient travel costs and impact positively on patient quality of life. remote-monitoring based service model should reduce home niv costs and potentially further improve the quality of life benefit. future assessments are required to expand on the cost-effectiveness of home-niv and a proactive copd service model based on remote-monitoring. among various patient groups using niv at home, remote monitoring has been found to be non-inferior and at times more effective than usual face-to-face support, preferred by patients and associated with reduced healthcare utilisation ( , ( ) ( ) ( ) . the additional channel of two-way patient engagement -that is, early intervention with an niv therapy change to optimise settings based on remote-monitoring data -may prove particularly valuable to ensure continued treatment adherence ( ) . monitoring patients is a prerequisite for successful continuation of niv at home. maintaining the required level of contact face-to-face is particularly challenging for severe copd patients, who are often not fit to travel or who may require immediate intervention. remote-monitoring data can be utilised to support and enhance routine clinical care allowing positive endorsement to be relayed when monitoring data is reassuring, prioritising and focusing patientclinician interactions when issues are noted. we show for the first time that initiation and follow-up based exclusively on niv two-way remote monitoring can be an effective and realistic solution to providing access to home-niv to severe copd patients at the necessary scale. benchmarking of outcomes, with similar findings to published rct data provides reassurance about safety and maintained care-quality with a remote-monitoring based approach to home niv for hypercapnic copd. our findings broadly complement those from recent study reported from the netherlands, which demonstrated cost-effective provision of home initiation of niv for stable hypercapnic copd patients utilising remote-monitoring of ventilator and transcutaneous co data ( ) . as key additions, our data suggest that remote-monitoring can be used to . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint the copyright holder for this this version posted november , . ; https://doi.org/ . / . . . doi: medrxiv preprint safely support patients with persisting hypercapnia who are commenced on home niv at an acute episode as well as at stable status, and that overnight transcutaneous co monitoring can be omitted from routine follow-up of copd patients on home-niv. undertaking routine transcutaneous monitoring in this patient cohort would not be realistic in routine clinical practice at scale. continued supervision of this approach with reporting of outcomes to ensure safety and quality of home-niv therapy, alongside continued evaluation of other endpoints for respiratory failure monitoring is required. our approach to home-niv setup for hypercapnic copd patients differs from published protocols. we have accrued considerable experience with volume assured pressure support niv modes at our centre. our experience is that these allows niv optimisation to be undertaken more efficiently with enhanced patient comfort and improved treatment quality as well as additional benefits including anticipation that treatment will be responsive to predictable fluctuations in a patient's condition. we commence niv treatment for copd patients in ivaps autoepap mode, targeting symptom benefit, remote-monitored ventilation patterns and follow-up capillary blood gas results (see supplementary data file), rather than in-hospital titration of niv in st mode, targeting high pressure support with transcutaneous co monitoring. satisfactory clinical outcomes and follow-up blood gas data (median reduction pco . kpa) in this study provide reassurance about the quality and safety of this niv setup protocol. clinical user experience with this approach is positive, and it achieves reduction in occupied bed days with no additional staffing support required to deliver the service. whether matched clinical outcomes and similar efficiency would be achieved with remote-monitored niv utilising st mode (potentially with at home titration) requires additional study. our subgroup analyses consistently showed that outcomes in patients who discontinue home-niv align closely with outcomes from the control cohort. this suggests that patients with severe hypercapnic copd are not negatively affected by the process of initiating home-niv. further exploration is indicated in this sub-population of patients who do not tolerate long-term niv at home. it could be that greater attention to patient activation, treatment provision, ventilation optimisation or level of contact is required. the patients who discontinued home niv had significant remote-management based scrutiny and input, and were offered 'standard' in-hospital and/or outpatient face-face attendance to try and maintain niv use. other centres have noted progressive improvements in home niv adherence rates with multi-disciplinary 'niv failure' clinics . adoption of remote-monitoring can improve the workflow and prioritisation of niv mdt activity. whether additional mdt input than that provided in our described model would improve long term niv adherence is uncertain. the possibility that there are different responder groups regardless of optimisation efforts should also be considered. in our cohort, there was a higher proportion of female patients and higher mean bmi in niv users. we can speculate that these differences might reflect home support or early symptom benefit differences from home niv: obese patients may be more likely to have osa overlapping with hypercapnic copd. characterisation of these and other factors with remotemonitoring data comparing sustained users and non-users in future studies may allow further evaluation to a service model with evidence-based proactive prioritisation: intensive focused mdt input to those patients who require it, and minimised input to those where it is unnecessary or will be non-contributory. lastly, the presence of a control cohort, which consisted of patients who may have benefited but were not referred for home-niv from within an active tertiary niv centre, highlights the need for clinician education and other efforts to ensure equitable patient access to this evidence-based intervention. this study had several strengths, including the use of clinically meaningful outcomes and the real-world nature of the patient cohorts. however, we acknowledge several limitations. treatment allocation was not randomised and the impact of unrecognised confounding factors cannot be ruled out. we also did not have complete data on demographics, comorbidities or provision of and adherence to other copd treatments to ensure cohorts were otherwise matched. the statistical analyses of some of the subgroup analyses should be considered exploratory due to the limited sample size and the potential issue of multiple testing. finally, this study was not powered to find a difference in survival. while a survival benefit of home-niv has been . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint the copyright holder for this this version posted november , . ; https://doi.org/ . / . . . doi: medrxiv preprint previously demonstrated in a similar patient population ( ) , clear evidence of improved survival is still lacking and should be investigated in larger prospective trials. copd patients with persistent hypercapnic respiratory failure have poor outcomes with limited treatment options available. to our knowledge, this is the first study to confirm the benefits of remote-managed home-niv in this group of copd patients as they typically present in clinical practice. home-niv prolonged the time to readmission or death within months in patients with persistent hypercapnia following an acute exacerbation of copd. in addition to being the outcomes that copd patients rate as most important ( ) , exacerbation and hospitalisation avoidance address the substantial economic burden imposed by copd. we report significant reductions in healthcare usage among home-niv users and demonstrate that twoway remote monitoring can be an effective and realistic solution to providing access to home-niv for hypercapnic copd patients. the covid- pandemic has presented considerable challenges to home-niv service provision. our data provides reassurance that a service model based on outpatient or truncated inpatient niv initiation and remote-monitoring based follow up allows face-face contact to be safely minimised, reducing covid- transmission risks whilst maintaining niv care-quality. we gratefully acknowledge the comprehensive contribution of the respiratory physiologist and nurse specialist teams in nhs gg&c to the positive outcomes reported in this paper: they have adapted service models to realise benefits from assistive technologies, and continue to be enthusiastically committed to improving patient outcomes and providing realistic medicine. study participant flow diagram. kaplan-meier plot of time to readmission or death from study initiation to the end of study follow-up. (a) primary analysis shows significant differences between the home-niv and the control cohort. (b) subgroup analyses showed that the improvement in -month readmission avoidance is noted only in patients who continue home-niv throughout the study period. . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint the copyright holder for this this version posted november , . ; https://doi.org/ . / . . . doi: medrxiv preprint changes in healthcare usage before and after home-niv for niv users (circle) and niv non-users (triangle). changes in blood gas measurements at baseline and follow up after home-niv initiation. . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint the copyright holder for this this version posted november , . ; https://doi.org/ . / . . . doi: medrxiv preprint arnal jm, texereau j, garnero a. practical insight to monitor home niv in copd patients. copd. ; ( ): - . . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint the copyright holder for this this version posted november , . ; https://doi.org/ . / . . . doi: medrxiv preprint study participant flow diagram . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint the copyright holder for this this version posted november , . ; https://doi.org/ . / . . . doi: medrxiv preprint kaplan-meier plot of time to readmission or death from study initiation to the end of study follow-up. (a) primary analysis shows significant differences between the home-niv and the control cohort. (b) subgroup analyses showed that the improvement in -month readmission avoidance is noted only in patients who continue home-niv throughout the study period. . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint the copyright holder for this this version posted november , . ; https://doi.org/ . / . . . doi: medrxiv preprint changes in healthcare usage before and after home-niv for niv users (circle) and niv non-users (triangle). data on respiratory nurse home visits was not available in electronic health records for the patients whose residence is outside our health board. . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint the copyright holder for this this version posted november , . ; https://doi.org/ . / . . . doi: medrxiv preprint changes in blood gas measurements at baseline and follow up after home-niv initiation in niv users. data availability limited to subset of patients who attended for face-face follow up and had some or all components of post niv blood gas results inputted into electronic health record (including patients who had pco but not bicarbonate result available). patients had pco < kpa at time of niv initiation but had other standard indications to commence home niv. . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint the copyright holder for this this version posted november , . ; https://doi.org/ . / . . . doi: medrxiv preprint nhs. copd commissioning toolkit: a resource for commissioners /chronic-obstructive-pulmonary-disease-copd-commissioning-toolkit.pdf: nhs medical directorate risk of death and readmission of hospital-admitted copd exacerbations: european copd audit global strategy for the diagnosis, management, and prevention of chronic obstructive lung disease global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: gold executive summary readmission rates and life threatening events in copd survivors treated with non-invasive ventilation for acute hypercapnic respiratory failure effects of non-invasive ventilation in patients with acute respiratory failure excluding post-extubation respiratory failure, cardiogenic pulmonary edema and exacerbation of copd: a systematic review and meta-analysis non-invasive ventilation for the management of acute hypercapnic respiratory failure due to exacerbation of chronic obstructive pulmonary disease effect of home noninvasive ventilation with oxygen therapy vs oxygen therapy alone on hospital readmission or death after an acute copd exacerbation: a randomized clinical trial non-invasive positive pressure ventilation for the treatment of severe stable chronic obstructive pulmonary disease: a prospective, multicentre, randomised, controlled clinical trial. the lancet respiratory medicine european respiratory society guidelines on long-term home non-invasive ventilation for management of copd noninvasive ventilation in stable hypercapnic copd: what is the evidence? home noninvasive ventilatory support for patients with chronic obstructive pulmonary disease: patient selection and perspectives glasgow supported self-management trial (gsust) for patients with moderate to severe copd: randomised controlled trial innovative approach to copd improves disease impact, quality of life and reduces hospital admissions in glasgow telehealthcare for chronic obstructive pulmonary disease nocturnal non-invasive ventilation in copd patients with prolonged hypercapnia after ventilatory support for acute respiratory failure: a randomised, controlled, parallel-group study cost-effectiveness of home oxygen therapy-home mechanical ventilation (hot-hmv) for the treatment of chronic obstructive pulmonary disease (copd) with chronic hypercapnic respiratory failure following an acute exacerbation of copd in the united kingdom (uk). a determinants of outcomes and high-value care compliance with home noninvasive mechanical ventilation in patients with chronic respiratory failure: telemonitoring versus usual care surveillance -a randomized pilot study remote monitoring of home non-invasive ventilation: a feasibility study home telemonitoring of noninvasive ventilation decreases healthcare utilisation in a prospective controlled trial of patients with amyotrophic lateral sclerosis effect of a patient engagement tool on positive airway pressure adherence: analysis of a german healthcare provider database home initiation of chronic non-invasive ventilation in copd patients with chronic hypercapnic respiratory failure: a randomised controlled trial a systematic review of how patients value copd outcomes long term adherence to home mechanical ventilation: a -year retrospective, single-centre cohort study key: cord- -mupxzffk authors: diehl, j.-l.; piquilloud, l.; vimpere, d.; aissaoui, n.; guerot, e.; augy, j. l.; pierrot, m.; hourton, d.; arnoux, a.; richard, c.; mancebo, j.; mercat, a. title: physiological effects of adding ecco( )r to invasive mechanical ventilation for copd exacerbations date: - - journal: ann intensive care doi: . /s - - -y sha: doc_id: cord_uid: mupxzffk background: extracorporeal co( ) removal (ecco( )r) could be a valuable additional modality for invasive mechanical ventilation (imv) in copd patients suffering from severe acute exacerbation (ae). we aimed to evaluate in such patients the effects of a low-to-middle extracorporeal blood flow device on both gas exchanges and dynamic hyperinflation, as well as on work of breathing (wob) during the imv weaning process. study design and methods: open prospective interventional study in deeply sedated imv ae-copd patients studied before and after ecco( )r initiation. gas exchange and dynamic hyperinflation were compared after stabilization without and with ecco( )r (hemolung, alung, pittsburgh, usa) combined with a specific adjustment algorithm of the respiratory rate (rr) designed to improve arterial ph. when possible, wob with and without ecco( )r was measured at the end of the weaning process. due to study size, results are expressed as median (iqr) and a non-parametric approach was adopted. results: an improvement in paco( ), from ( ; ) to ( ; ) mmhg, p = . , and in ph, from . ( . ; . ) to . ( . ; . ), p = . , was observed after ecco( )r initiation and adjustment of respiratory rate, while intrinsic peep and functional residual capacity remained unchanged, from . ( . ; . ) to . ( . ; . ) cmh( )o and from ( ; ) to ( ; ) ml, p = . and p = . , respectively. wob measurements were possible in patients, indicating near-significant higher values after stopping ecco( )r: . ( . ; . ) versus . ( . ; . ) joules/min., p = . and . ( . ; . ) versus . ( . ; . ) joules/l, p = . . three patients died in-icu. other patients were successfully hospital-discharged. conclusions: using a formalized protocol of rr adjustment, ecco( )r permitted to effectively improve ph and diminish paco( ) at the early phase of imv in ae-copd patients, but not to diminish dynamic hyperinflation in the whole group. a trend toward a decrease in wob was also observed during the weaning process. trial registration clinicaltrials.gov: identifier: nct . chronic obstructive pulmonary disease (copd) is currently the fourth leading cause of death in the u.s. and is expected to become the third leading cause of death [ ] . value of non-invasive ventilation (niv) for severe ae-copd was formally demonstrated by randomized open access *correspondence: jean-luc.diehl@aphp.fr assistance publique -hôpitaux de paris, hôpital européen georges pompidou, service de médecine intensive -réanimation, rue leblanc, paris, france full list of author information is available at the end of the article clinical trials [ , ] . while the hospital mortality of patients successfully treated with niv has decreased over years, and is currently less than %, mortality in patients requiring imv after niv failure is close to % [ ] . among the techniques which could help to improve the prognosis of such patients, extracorporeal co removal (ecco r) seems to be a very promising approach [ , ] . however, most of the studies focused on ecco r in niv ae-copd patients, with the aim to prevent intubation [ ] [ ] [ ] or to provide an additional respiratory support after extubation [ ] . only a small number of imv copd patients were studied under ecco r, with the aim to facilitate extubation [ ] [ ] [ ] [ ] . ecco r was initiated early after intubation in studies [ , ] , while the delay between intubation and ecco r initiation was higher than days in another study [ ] . we preliminarily reported an ecco r-induced reduction in work of breathing and co production in such a setting [ ] , confirming and extending previous observations [ ] . in the present study, we hypothesized that the addition of ecco r at the early phase of imv could both improve gas exchanges and could also permit to diminish respiratory rate (rr), therefore, minimizing dynamic hyperinflation in ae-copd patients. beyond efficacy assessments, we also planned to describe the complications or adverse events associated with the technique, since bleeding and clotting complications were frequently reported in ae-copd patients [ ] . this interventional open prospective study was planned to recruit deeply sedated imv ae-copd patients in tertiary-level icus in france. an institutional ethic board (comité de protection des personnes ile-de-france vi, paris, france) approved the protocol (protocole ephebe p -id crb: -a - ). informed consent was obtained from patients' legal representatives. the study was prospectively registered in clinicaltrials.gov: identifier: nct . consecutive copd patients older than yrs. hospitalized for hypercapnic respiratory failure requiring imv were prospectively screened for inclusion in the study. inclusion criteria were: • ae of a known or suspected copd • intubation (whatever the reason for intubation which had to be specified) • mv since less than h. • persistent respiratory acidosis and hyperinflation, while the patients were deeply sedated and paralysed • written inform consent obtained from patient's legal surrogate criteria for persistent respiratory acidosis and hyperinflation were the combination of: ph < . , paco > mm hg and intrinsic peep (peepi) (endexpiratory occlusion) > cmh o, while on assist-controlled volume ventilation with the following settings: v t : ml/kg of predicted body weight (pbw), rr: /min., applied peep: cmh o, i/e ratio: / . non-inclusion criteria were as follows: body mass index (bmi) > kg/m , pao /fio < mm hg, history of haemorrhagic stroke, history of heparin-induced thrombocytopenia and any current severe bleeding. the protocol of the study was explained to the legal representatives and informed consent was obtained from patients legal representatives. when possible, the same explanations were further provided to the patient himself after full recovery, for obtaining a definitive post hoc written consent. the hemolung ® ecco r system (alung technologies, pittsburgh, pa) was used. it consists of an exchange cartridge (membrane surface . m ) which, in connection with a controller and tubing, ensures ecco r of about ml/min. at extracorporeal blood flow rates comprised between and ml/min. the vascular access is achieved by means of a double lumen . f central venous catheter. the maximum duration of use of the circuit, as specified by the manufacturer, is days. anticoagulation was achieved by the mean of continuous unfractionated heparin infusion aiming to obtain daily therapeutic antixa activities between . and . ui/ml. no systematic daily measurement of plasma free hemoglobin was performed during the study. the carescape r ventilator (general electric healthcare) was used allowing continuous measurement of the native lung's vco and serial measurements of the functional residual capacity (frc) (applied peep set at zero) or end-expiratory lung volume (eelv) (any positive applied peep) using the nitrogen washout/washin technique [ , ] . a nutrivent catheter (sidam, mirandola, italy) was inserted for esophageal pressure measurements, allowing the calculation of inspiratory work of breathing (wob) during the weaning process as previously described [ ] . figure illustrates the flowchart of the study. after inclusion in the study, we first calculate the target paco (paco target ) corresponding to a ph value of . , based on the henderson-hasselbach equation governing the relationship between paco , ph and bicarbonates plasma values. in cases of mixed respiratory and metabolic acidosis, any paco target below the normal paco value was replaced by the mmhg value. the second step of the study was to measure the physiological dead space (v d ) using the bohr-enghoff equation: v d /v t = (paco -p e co )/paco . the third step of the study was to start ecco r. after cannulation and initiation of the treatment, an increase in the sweep gas flow (using pure o ) generally up to l/min. induced a decrease in native lung's vco . we checked for stabilization of the latter, with a delay of h. the fourth part of the study was then to adjust rr for reaching paco target . for that purpose, we used the proportionality equation between alveolar ventilation, native lung's vco and paco : expressed as: assuming that v d was unchanged during the study. the fifth part of the study was to perform final measurements after waiting again for stability of the native lung's vco , with a further delay of h. if required, we adjusted the extracorporeal blood flow and/or sweep gas flow with the aim to keep unchanged the native lung's vco after the initial decrease. the primary outcome measure was peepi, measured during a prolonged expiratory pause at inclusion in the study and after initiation of ecco r combined with rr adjustment. we choose peepi as the primary outcome measure because we assumed that improvement in arterial ph and paco would be obvious and that the medical device would be powerful enough for achieving both improvements in respiratory acidosis and in dynamic hyperinflation. secondary end-points measured within the same time frame were: plateau pressure, peak pressure (ppeak), frc, paco , pao , arterial ph, hemoglobin saturation (sathbo ), extracorporeal vco , standard hemodynamic parameters. we also calculated v t /t e as a major determinant of dynamic hyperinflation. based on recorded files, wob at the end of the weaning process was measured just before extubation with and without ecco r under low pressure support ventilation as previously described [ ] . as a supplemental analysis, we also pooled the wob results of the present study with previously published results of pilot patients obtained using the same experimental design [ ] . ecco r-related adverse events were recorded during the whole icu-stay. this included severe hemolysis defined as a serum free hemoglobin level higher than mg/l and/or association to jaundice, hemoglobinuria or impaired renal function. time on ecco r, time on imv, length of stay in icu and in hospital and mortality at days were recorded. considering results obtained in preliminary pilot patients, we hypothesized a mean value of peepi at inclusion of cmh o along with an average reduction of cmh o of peepi after initiation of ecco r combined with rr adjustment (sd pooled = . -slightly below the average reduction). based on these assumptions, with evaluable patients, a paired t-test would reach a statistical power of % to conclude to the statistical significance of the difference before/after ecco r at the (two-sided) alpha level = . (nquery mot module). demographics and clinical characteristics of included patients at inclusion were described as follows: quantitative and qualitative variables were tabulated with medians, interquartile range (iqr) and range (min; max), and counts and proportions, respectively. we secondly described primary and secondary endpoints, at each time point, with the same statistical indicators. results are expressed in the results sections as median (iqr). due to study size, a non-parametric approach was adopted. for principal analysis on primary endpoint, we implemented wilcoxon signed-rank test to compare peepi at inclusion and peepi after initiation of ecco r combined with rr adjustment. regarding secondary endpoints, we performed the same test as for primary endpoint. for endpoints assessed several times, graphs representing variable distributions at each timepoint helped interpreting statistical parameters and tests. in this exploratory twelve patients were recruited during an -month period in centers. table shows characteristics at inclusion. causes of ae were viral pulmonary infections in patients, bacterial pulmonary infection in patients, pneumothoraxes in patients (all with successful pleural drainage at the time of measurement), and exacerbation in a post-surgical context for the last patient. after initiation of ecco r, the rr adjustment algorithm (aiming to improve arterial ph value) resulted in rr decrease in patients, in rr increase in patients, while rr was maintained unchanged in the remaining patients (fig. ) . as a consequence, median minute ventilation was not modified, from ( ; ) to ( ; ) ml/min., p = . . peepi after initiation of ecco r and rr adjustment was not significatively different from basal values: . ( . ; . ) to . ( . ; . ) cmh o, p = . . other respiratory parameters (mechanical ventilator settings, other parameters of hyperinflation, abg values and native lungs vco values) before ecco r initiation and after ecco r initiation combined with rr adjustment are mentioned in table , in additional file : fig. s (gas exchanges parameters) and additional file : fig. s (ventilatory parameters). in the patients with pure respiratory acidosis before ecco r initiation, we found that the rr adjustment in addition to ecco r led to increase in arterial ph from . ( . ; . ) to . ( . ; . ). median extracorporeal blood flow was ( ; ) ml/min., with a median sweep gas flow of ( ; ) l/ min. median extracorporeal vco was ( - ) ml/ min. no variations in hemodynamic parameters were observed without or with ecco r. median ecco r duration was . ( . ; . ) days. median sweep gas flow was l/min. from day to day . additional file : fig. s illustrates the course of total peep and eelv under ecco r until day . of note, an external positive peep (generally between and cmh o) was set after stopping deep sedation beyond the first days of imv, to favor the synchronization between the patient and the mechanical ventilator and to counteract flow limitation. additional file : fig. s illustrates the course of abg parameters and additional file : fig. s illustrates the course of hematological parameters under ecco r until day . mainly, a mild thrombocytopenia was observed in the whole group. inspiratory wob measurements with and without ecco r were possible in only patients during the weaning process, due to premature cessation of ecco r before readiness of patients to perform a low pressure support ventilation trial in patients (mainly in relation with hemorrhagic and thrombotic complications) and due to accidental removal of the nutrivent probe in one patient. wob measurements were performed in conscious patients while breathing at a low pressure support level with ecco r and after switching the sweep gas flow from current value to l/min. for a h period. results are indicated in table . results adding the previously published results of pilot patients using a similar design are presented as additional file : table s . three patients died in-icu and were successfully discharged from icu and hospital. the causes of death were one hemorrhagic stroke during ecco r we report a physiological and clinical evaluation of a low-to-middle extracorporeal blood flow veno-venous ecco r system in very severe ae-copd patients studied shortly after intubation. severity of the patients was assessed by the combination of respiratory acidosis and elevated intrinsic peep under pre-specified respiratory settings aimed to avoid excessive dynamic hyperinflation in deeply sedated imv patients. moreover, all patients were intubated after niv failure. dynamic hyperinflation was also assessed by frc and eelv measurements using the nitrogen washin-washout method, providing original results in this specific copd population. indeed, such patients were not included or were excluded from previous studies [ ] . as expected, we observed very high baseline frc values as compared to published reference values measured in the supine position [ ] . initiation of ecco r was associated with a median extracorporeal co removal amount of ml/min., corresponding to % of the pre-ecco r whole body co production. accordingly, there was a decrease in native lungs' co elimination, which, in conjunction with rr adjustment, permitted to improve arterial ph and to obtain a median absolute decrease in paco of mmhg. this could be beneficial at the early stage of imv in ae copd patients, mainly by minimizing the deleterious effects of acute hypercapnia on ventilator demands, therefore, allowing to shorten deep sedation periods and to rapidly initiate the imv weaning process. we didn't observe any ecco r-induced deleterious effect on oxygenation, as sometimes mentioned in copd patients [ , , ] . however, severely hypoxemic patients were excluded from our study. moreover, we used a low-to-middle blood flow ecco r device, therefore, minimizing the ecco r-induced imbalance between native lung's vo and vco [ ] . we also found a higher sathbo under ecco r, which could at least in part be explained by a left shift of the o dissociation curve due to a decrease in arterial paco and to a parallel increase in arterial ph. although probably too complex for a general clinical use, the algorithm for rr adjustment performed well for arterial ph improvement. such a result was favored by the hemodynamic stability of the patients during ecco r initiation associated with stability in whole body co production. by choice, we didn't retain an algorithm based on v t reduction. this was based on the fact that the absolute value of physiological dead space for co depends of the absolute value of v t , therefore, allowing easier calculations when keeping a fixed absolute v t value [ ] . however, despite the use of quasi-maximal extracorporeal blood and sweep gas flows, the algorithm led to a decrease in rr in only patients. this explains that no improvement in peepi, as the primary outcome measure, was observed in the whole group. the clinical correlate is that the ecco r system was not able in our group of very severe imv copd patients to both improve respiratory acidosis and improve dynamic hyperinflation. however, it's obvious that alternative adjustments algorithms would have been associated with different results. as an example, it could have been possible to first reduce rr and v t after ecco r initiation while keeping paco at the same level. such a strategy very probably would have been associated with a significant decrease in peepi. moreover, in the clinical setting, clinicians will have the possibility to tailor personalized strategies: by simply choosing different paco target and by calculating individual rr adjustment, clinicians have the possibility to arbitrate between respiratory acidosis and dynamic hyperinflation respective improvements. it's also likely that ecco r systems allowing higher extracorporeal co removal amounts could have been associated with higher improvements in hyperinflation parameters and in respiratory acidosis. altogether, this illustrates the need for clinicians to develop clinical strategies of ecco r initiation in deeply sedated imv copd patients. such strategies should be based on the severity of patients, mainly assessed by parameters of dynamic hyperinflation and respiratory acidosis. based on animal and clinical studies, clinicians should also take into account the performances of the different ecco r devices and their effects on native lungs respiratory co elimination [ , ] . providing such strategies could have important implications for the care of patients and for the design of future rcts aiming to prove important clinical benefits of ecco r in very severe ae-copd patients. in addition, we have to mention that our algorithm is not per se suitable for awake patients. this point is important, since ecco r can be proposed in ae-copd patients at high risk of niv failure, or in cases of difficult imv weaning. finally, such low-to-intermediate extracorporeal blood flow devices could be viewed as more suitable for paralyzed moderate ards patients with minimal co production rather than for very severe ae-copd patients. in line with peepi results, frc and v t /t e were not significantly improved in the whole group. one could question the validity of frc measurements in patients treated by ecco r, since ecco r can modify the native lung's respiratory quotient [ ] . however, the nitrogen fraction calculation is based on direct measurements of both o and co fractions when f i o is lower than %, as indicated by the manufacturer [ ] . since our study included only non-severely hypoxemic patients, with fio < %, we are confident in the validity of our results. also, the course of frc results was coherent with peepi results. we previously reported an ecco r-induced benefit in terms of breathing pattern and of work of breathing in imv ae-copd at the end of the weaning process [ ] . using the same design, we observed similar trends in patients. considering a possible lack of statistical power due to the number of patients, we pooled the results of the studies and observed significantly less wob (expressed either in joules per min, per liter of ventilation or per breath) under ecco r. however, since we cannot exclude selection bias, these results are presented with great caution and should not be extrapolated to clinical practice. such results obtained in non-sedated patients only suggest that ecco r could favor a more rapid liberation of imv, as compared to standard care of imv ae-copd patients [ , , ] . moreover, the fact that efficiency of ecco r was observed several days after initiation, could open the way for further studies of different clinical strategies for ecco r weaning. the median duration of ecco r was near to the maximal duration of the circuit as indicated by the manufacturer. such result is important to consider for the choice of ecco r devices and circuits in copd patients. we observed one fatal intracerebral bleeding. such fatality, along with other hemorrhagic complications and thrombosis, illustrate the need to improve the knowledge of the interaction between ecco r circuits, anticoagulation regimen and coagulation system of the patients. indeed, hemorrhagic complications can be favored by an usual mild thrombocytopenia as observed in our study and by other factors such as the occurrence of an acquired willebrand disease, as previously preliminary reported with the hemolung system [ ] and such as a severe endothelial dysfunction, as recently reported by our group [ ] . moreover, fewer side effects could also be expected with higher extracorporeal blood flow devices, as recently shown in ards patients [ ] . nevertheless, the in-hospital mortality rate was found to be lower than the mortality rate observed in imv ae-copd patients by burki et al. with the same device, which could suggest a benefit to initiate ecco r early in the course of imv in copd patients [ ] . one of the main limitations of the study was a too optimistic hypothesis at the time of conception of the study, leading to an overestimation of the ability of hemolung device for co removal in such severe ae-copd patient [ , ] . another limitation was the choice to use standardized mechanical ventilator settings, as part of our usual respiratory bundle in such severe ae-copd patients. it is, therefore, conceivable that more personalized settings could have been more appropriate for certain patients. one other limitation was the assumption of an unchanged v d /v t during all points of the study. indeed, there was a possibility of individual decrease (or increase) in v d /v t in patients with decrease (or increase) in rr. such variations in v d /v t after limited modifications in ventilatory settings have been reported previously in ae-copd patients [ ] . however, there were no differences in the whole group between peepi, plateau pressure, ppeak and eelv values at baseline and after initiation of ecco r combined with rr adjustments. the lack of standard of care control group was also a limit of the study for evaluating dynamic hyperinflation independently of ventilation on a more prolonged time. accordingly, the different initial time points were separated by a delay of h. therefore, we cannot exclude that a more delayed ecco r-induced improvement in regional ventilation could have occurred and allowed decreasing rr, i/e ratio or v t, all important determinants of dynamic hyperinflation. we didn't observed severe hemolysis in contrast to other reports [ , ] . however, the observation is limited by the lack of systematic daily plasma free hemoglobin measurement, which is now a standard practice in our centers. the low inclusion rate of the study and the fact that wob measurements were not possible for the majority of included patients are also clear limitations. using a formalized protocol of rr adjustment, ecco r permitted to effectively improve ph and diminish paco at the early phase of imv in ae-copd patients, but not to diminish dynamic hyperinflation in the whole group. such results could support the clinical implementation of fine-tuned algorithms derived from our protocol taken into account the main goals of ecco r at the early phase of imv, i.e., controlling both hyperinflation and respiratory acidosis. chronic obstructive pulmonary disease randomized, prospective trial of noninvasive positive pressure ventilation in acute respiratory failure noninvasive ventilation for acute exacerbations of chronic obstructive pulmonary disease outcomes of noninvasive ventilation for acute exacerbations of chronic obstructive pulmonary disease in the united states extracorporeal carbon dioxide removal for lowering the risk of mechanical ventilation: research questions and clinical potential for the future extracorporeal carbon dioxide removal for acute hypercapnic respiratory failure extracorporeal carbon dioxide removal in patients with chronic obstructive pulmonary disease: a systematic review extracorporeal co removal in hypercapnic patients at risk of noninvasive ventilation failure: a matched cohort study with historical control the feasibility and safety of extracorporeal carbon dioxide removal to avoid intubation in patients with copd unresponsive to noninvasive ventilation for acute hypercapnic respiratory failure (eclair study): multicentre case-control study control of respiratory drive by extracorporeal co removal in acute exacerbation of copd breathing on non-invasive nava a novel extracorporeal co removal system: results of a pilot study of hypercapnic respiratory failure in patients with pilot study of extracorporeal carbon dioxide removal to facilitate extubation and ambulation in exacerbations of chronic obstructive pulmonary disease venovenous extracorporeal co removal for early extubation in copd exacerbations requiring invasive mechanical ventilation effects of extracorporeal carbon dioxide removal on work of breathing in patients with chronic obstructive pulmonary disease effects of extracorporeal co removal on inspiratory effort and respiratory pattern in patients who fail weaning from mechanical ventilation estimation of functional residual capacity at the bedside using standard monitoring equipment: a modified nitrogen washout/washin technique requiring a small change of the inspired oxygen fraction peep-induced changes in lung volume in acute respiratory distress syndrome two methods to estimate alveolar recruitment lung stress and strain calculations in mechanically ventilated patients in the intensive care unit normal values of functional residual capacity in the sitting and supine positions understanding hypoxemia on ecco r: back to the alveolar gas equation effect of tidal volume on gas exchange and oxygen transport in the adult respiratory distress syndrome veno-venous extracorporeal co removal for the treatment of severe respiratory acidosis: pathophysiological and technical considerations utilisation de l'épuration extra-corporelle de dioxyde de carbone dans l'exacerbation de la maladie pulmonaire obstructive chronique: une revue narrative is extracorporeal co removal really "safe" and "less" invasive? observation of blood injury and coagulation impairment during ecco r severity of endothelial dysfunction is associated with the occurrence of hemorrhagic complications in copd patients treated by extracorporeal co removal (ecco r). intensive care med efficacy and safety of lower versus higher co extraction devices to allow ultraprotective ventilation: secondary analysis of the supernova study effects of inspiratory flow waveforms on lung mechanics, gas exchange, and respiratory metabolism in copd patients during mechanical ventilation a -year multicenter, observational, prospective, cohort study on extracorporeal co removal in a large metropolis area publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations not applicable. supplementary information accompanies this paper at https ://doi. org/ . /s - - -y.additional file : table s . work of breathing (wob) measurements in patients with and without ecco r. figure s . gas exchanges parameters before ecco r initiation and after ecco r initiation and adjustment aiming to improve arterial ph value. figure s . ventilatory parameters before ecco r initiation and after ecco r initiation and adjustment aiming to improve arterial ph value. figure s . daily course of total peep and eelv under ecco r until day . figure s . daily course of abg parameters under ecco r until day . figure s . course of hematological parameters under ecco r until day . the sponsor "direction de la recherche clinique, assistance publique -hôpitaux de paris" was in charge of the general organization of the research. the study was founded by alung (pittsburgh, usa). alung (pittsburgh, usa) and general electric healthcare also provided (non-financial) technical support for the study, mainly by providing ecco r and mechanical ventilator devices and consumables. the datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. an institutional ethic board (comité de protection des personnes ile-de-france vi, paris, france) approved the protocol (protocole ephebe p -id crb: -a - ). informed consent was obtained from patients' legal representatives. not applicable. dr. diehl reports grants and non-financial support from alung, non-financial support from general electric healthcare, during the conduct of the study; personal fees and non-financial support from xenios novalung (fresenius medical care) outside the submitted work.dr. aissaoui reports non-financial support from astrazeneca, non-financial support from medtronic, non-financial support from abiomed, outside the submitted work.dr. mercat reports personal fees from faron pharmaceuticals, personal fees from air liquide medical systems, grants and personal fees from fisher and paykel, personal fees from medtronic, personal fees from drager, non-financial support from general electric, outside the submitted work. key: cord- -hioh s authors: alfredo, potena; gaetano, caramori; paolo, casolari; marco, contoli; johnston, sebastian l; alberto, papi title: pathophysiology of viral-induced exacerbations of copd date: - - journal: int j chron obstruct pulmon dis doi: nan sha: doc_id: cord_uid: hioh s inflammation of the lower airways is a central feature of chronic obstructive pulmonary disease (copd). inflammatory responses are associated with an increased expression of a cascade of proteins including cytokines, chemokines, growth factors, enzymes, adhesion molecules and receptors. in most cases the increased expression of these proteins is the result of enhanced gene transcription: many of these genes are not expressed in normal cells under resting conditions but they are induced in the inflammatory process in a cell-specific manner. transcription factors regulate the expression of many pro-inflammatory genes and play a key role in the pathogenesis of airway inflammation. many studies have suggested a role for viral infections as a causative agent of copd exacerbations. in this review we will focus our attention on the relationship between common respiratory viral infections and the molecular and inflammatory mechanisms that lead to copd exacerbation. many epidemiological and clinical studies have suggested a role for respiratory viral infections in the natural history of chronic obstructive pulmonary disease (copd), particularly during their exacerbations highlighting the need for development of effective vaccines and/or treatment for these viruses. the precise cellular and molecular mechanisms underlying these events are still largely unknown (caramori et al ; mallia et al ) . lower airways infl ammation is a central feature of many lung diseases, including copd. although the specifi c characteristics of the infl ammatory responses and the site of infl ammation differ between one disease to another, they always involve recruitment and activation of infl ammatory cells and changes in structural cells of the lung. infl ammatory responses are associated with an increased expression of a cascade of proteins that includes cytokines, chemokines, growth factors, enzymes, adhesion molecules and receptors. in most cases the increased expression of these proteins is the result of enhanced gene transcription: many of the genes are not expressed in normal cells under resting conditions but they are induced in the infl ammatory process in a cell-specifi c manner. transcription factors regulate the expression of many genes, including infl ammatory genes and play a key role in the pathogenesis of respiratory infl ammatory diseases, including copd (caramori et al ) . in this review we will provide an overview of the relationship between respiratory virus infection and the molecular mechanisms involved in the activation of airway infl ammation in copd exacerbations. copd is a disease state characterized by airfl ow obstruction that is not fully reversible. the airfl ow obstruction is usually both progressive and associated with an abnormal infl ammatory response of the lung to noxious particles or gases. the main cause of copd is cigarette smoking (gold ) . chronic obstructive pulmonary disease (copd) is the fourth leading cause of mortality worldwide (gold ) . costs of copd are mainly related to exacerbations requiring hospitalization (sullivan et al ) . in addition to their enormous acute morbidity, mortality and cost, exacerbations are also associated with major reductions in long term quality of life and lung function (seemungal et al ; donaldson et al ) . despite the clinical and economic importance of severe copd exacerbations, their etiology and mechanisms are poorly understood. both bacterial (sethi and murphy ; white et al ) and viral infections (seemungal et al (seemungal et al , aaron et al ; rohde et al ; wedzicha ; beckham et al ; papi et al ) have been detected at increased frequencies during copd exacerbations. the most frequently respiratory viruses involved in the etiology of copd exacerbations are represented by rhinoviruses, infl uenza viruses, coronaviruses, and respiratory syncytial virus (rsv). more rarely parainfl uenza viruses and human metapneumoviruses (hmpv) have also been identifi ed (rohde et al ; hamelin et al ; falsey et al ; papi et al ) . a recent study has recently addressed the relative importance of viral versus bacterial infections in the etiology of severe (hospitalized) copd exacerbations (papi et al ) . viral and/or bacterial infection was detected in % of copd exacerbations ( . % bacterial, . % viral, % viral/bacterial co-infection). infectious exacerbations had longer hospitalizations and greater impairment of several measures of lung function than non-infectious exacerbations. importantly, exacerbations with co-infection had more marked lung function impairment and longer hospitalizations. similarly, when copd exacerbations not requiring hospitalization were evaluated, a greater lung function fall was documented in those patients where both bacterial infection and cold symptoms were present simultaneously (wilkinson et al ) . this data suggests that bacterial and viral infections could synergistically cooperate to increase severity of the exacerbations. whether viral infections can lead to bacteriological exacerbation (of previously colonizing bacteria) is still an open question that deserves properly designed longitudinal studies. determining the etiology of exacerbations will inform appropriate antibiotic and antiviral therapy. antibiotic therapy is already widely used, but not always appropriately, in the treatment of copd exacerbations (gold ) . indeed, a recent meta-analysis supports antibiotics only for those patients with copd exacerbations with increased cough and sputum purulence who are moderately or severely ill. analysis restricted to community-based studies did not fi nd any differences between antibiotic and placebo (ram et al ) . in asthma, recent study showed a signifi cation reduction of symptoms at exacerbations in those patients receiving telithromycin as compared to placebo. given that no relationship between bacteriologic status and the response to study treatment was found, the mechanisms of such a benefi t remain unclear (johnston et al ) . therefore, (i) there is an urgent need to develop simple clinical or biological markers to identify those patients at highest risk of bacterial infection and who will benefi t most from antibiotic therapy, (ii) further studies are needed to evaluate whether novel class of antibiotics can be more effective in the treatment of copd exacerbations. antiviral therapy, and in particular anti-rhinovirus therapy, is a "still theoretically" relevant therapeutic option since two thirds of exacerbations are associated with viral infections (seemungal ) . indeed, so far no study has investigated whether currently available antiviral treatment can reduce viral induced copd exacerbations. the use of anti-infl uenza neuraminidase inhibitors in copd exacerbations during infl uenza epidemic appears appropriate in non vaccinated patients and may reduce the number of hospitalizations (lalezari et al ; cooper et al ; kaiser et al ) , though further controlled clinical trials are needed to confi rm therapeutic benefi t. viral infections are the most frequent cause of copd exacerbation. whether copd patients are more susceptible to virus infection as compared to normal subjects is still debated. a recent study documented that patients with frequent copd exacerbation have more frequent episodes of naturally occurring colds as compared to patients with infrequent exacerbations (hurst et al ) . these results suggest that copd subjects with frequent exacerbations may represent a subgroup particularly susceptible to viral infections. thus, while there is solid evidence of impaired innate (wark et al ; contoli et al ) and possibly acquired (gern et al ; papadopoulos et al ) immune responses to viral infection in asthmatic patients, it is not yet clear whether copd patients have increased susceptibility to viral infections. intriguingly patients experiencing frequent colds had a signifi cantly higher exposure to cigarette smoke (hurst ) . recently, using a mouse model of cigarette smoke exposure, it has been demonstrated that cigarette smoke increases susceptibility to viral infections possibly via alteration/inhibition of immune response (robbins et al ) . another possible mechanism leading to increased susceptibility is related to up regulation of icam- , the receptor for the major group of human rhinoviruses. latent expression of adenoviral e a protein in alveolar epithelial cells of patients with emphysema increases icam- expression and this could be a potential mechanism for greater susceptibility to rhinovirus infection in copd (retamales et al ) . patients with copd are chronically colonized with airway bacteria, and the bacterial load is related to airway infl ammation and disease progression (patel et al ) . it has been postulated that bacterial colonization could contribute to increased susceptibility to viral infection in copd patients for example by increasing icam- expression in bronchial epithelial cells either directly or through induced infl ammation (sajjan et al ) . further studies are required to investigate the interaction between chronic bacterial colonization and respiratory viral infection and in particular whether chronic bacterial colonization can increase susceptibility to viral infection or vice versa. as the contribution of viruses to copd exacerbations has only recently been appreciated little research has been carried out into the mechanisms of virus-induced infl ammation. performing airway sampling at exacerbation in copd patients is even more diffi cult than in asthmatics due to their older age and high prevalence of co-morbidities. one way to overcome these obstacles is the development of a human experimental model that would allow studies to take place under controlled conditions. the fi rst step towards development of such a model has been recently realized with the reporting of the fi rst study evaluating the effects of an experimental viral infection in copd patients (mallia et al ) . copd exacerbations are associated with an increased numbers of inflammatory cells in the lower airways and increased/decreased release of pro-inflammatory/ anti-infl ammatory mediators (wedzicha and donaldson ) . through these mechanisms respiratory viral infections may enhance the pathological processes associated with cigarette smoking and contribute to the lung pathology and loss of lung function associated with copd. the type and the degree of activation of the different infl ammatory cells recruited to the lung during copd exacerbations has not been well studied (zhu et al ; qiu et al ) . despite growing clinical evidence for a role of respiratory viral infections in the pathogenesis of copd exacerbations, the precise mechanisms of respiratory virus-induced airway infl ammation and of host defenses against respiratory viruses are poorly understood (johnston ) . most of the data available relate to rhinovirus (rv) and respiratory syncytial virus (rsv), ie, the respiratory viruses that appear to be more frequently involved in copd exacerbations. human rhinoviruses (rv) are the largest genus in the picornaviridae family. they are single-stranded rna viruses. rhinovirus is the main cause of the common cold and several studies supported the role of this pathogen in both asthma and copd exacerbations. recent data documents that rhinovirus can reach and replicate in the lower airways. there is striking genetic diversity of the rv strains circulating in a given community during a short time (oliveira et al ) . rhinovirus serotypes are divided into two groups on the basis of receptor specifi city. the "major" receptor group (including rv and rv ) utilizes intercellular adhesion molecule- [(icam- ); cd ] as a receptor for infecting the target cells (greve et al ; terajima et al ) . using icam- , rv can infect airway epithelial cells, but there is little evidence of productive replication in other cells such as monocytes, macrophages and eosinophils granulocytes. the "minor" receptor group, do not bind icam- and instead bind the ldl receptor and related proteins (hofer et al ) . rhinovirus is transmitted by aerosol through infectious droplet nuclei emanating from infected subjects (myatt et al ; samet ). respiratory syncytial virus (rsv) is a member of the family paramyxoviridae, subfamily pneumovirus; it is an enveloped rna virus with a negative-sense, nonsegmented, singlestranded rna genome. rsv is a major respiratory pathogen, it is most common in infants where it causes a range of illnesses from asymptomatic infection through upper respiratory tract infection, bronchiolitis, and pneumonia (falsey and walsh ; hall ; falsey et al ) . in addition, during the past two decades, a growing number of studies have clearly established rsv as a severe pathogen in certain adult populations. the elderly, those with underlying cardiopulmonary disease (chronic heart failure, chronic obstructive pulmonary disease, bronchial asthma) and the immunocompromised patients appear to be at greatest risk of developing severe, even life-threatening lung disease following rsv infection (hall ; walsh and falsey ; falsey ; sethi and murphy ) . the primary site of rsv replication are the airway epithelial cells, whereas other cell types (monocytes/macrophages, airway smooth muscle cells eosinophils, neutrophils, mast cells, dendritic cells and endothelial cells) are targets of abortive replication or viral attachment only (arnold and konig ; de graaff et al ; guerrero-plata et al ) . in human bronchial epithelial cells rsv colocalize with icam- , and this binding can be inhibited by an antibody to the fusion f protein. these data suggests that rsv interaction with icam- involves the f protein and facilitates rsv entry and infection of human bronchial epithelial cells (behera et al ) . interestingly in vitro rsv infection of human lung endothelial cells increase their expression of icam- (arnold and konig ) . since rsv replication is largely restricted to airway epithelial cells, an hypothesis is that infl ammatory cell recruitment by the infected cells will start the later immunopathology (becker et al ; becker and soukup ) . the effects of rsv on airway infl ammation may be therefore partly mediated by sequential production of pro-infl ammatory cytokines/chemokines in the infected airway epithelium. the activation of several nuclear factors has recently been studied in copd (caramori ) . several studies have shown that both the promoter genomic regions and the related transcription factors that regulate infl ammatory mediator production are deeply affected by respiratory virus infection. most of the data published until now on this issue are mainly related to rhinovirus and respiratory syncytial virus infections. more research is required to clarify the molecular events that determine the changes in gene transcription determined by virus infection in target cells. to date the specifi c molecular mechanisms involved in the production of pro-infl ammatory mediators by bronchial/lung cells after rhinovirus infection are still not fully characterized. however, some studies have examined at the molecular level the transcription factors involved in rv-induced production of proinfl ammatory mediators from structural cells of the lungs. rhinovirus infection of primary bronchial epithelial cells induces a rapid increase of intracellular oxidants (superoxide anion) production that is maximal at the time of nuclear factor κb (nf-κb) activation. intriguingly, it has been shown, in the same model, that reducing agents inhibit rv-induced icam- up-regulation, icam- promoter activation and nf-κb activation . this data suggests that modulation of rv induced intracellular oxidant burst can be a novel pharmacological approach to treat/prevent rv induced copd exacerbations. several transcription factors appear to be activated after rhinovirus infection on a variety of respiratory cells (caramori ) . these proteins include nf-κb, ap- and gata families. activation of intracellular signaling pathways is induced by rhinovirus in epithelial cells, which may be dependent on surface receptor binding (icam- ), or by intracellular products during viral replication such as doublestranded rna (dsrna). it has been shown that dsrna can activate components of several signaling pathways including protein kinase r, nuclear factor-κb (nf-κb) and p mitogenactivated protein kinase (mapk) (alexopoulou et al ) . however, to date, no studies have investigated the role of these molecules in rhinovirus infection. rhinovirus-induced activation of nf-κb leads to an increased expression of proinfl ammatory cytokines (il- , il- , granulocyte colony-stimulating factor (g-csf) and gm-csf), cxc chemokines (il- ) and icam- (papi and johnston b) , whereas expression of vcam- seems to be mediated by the activation of both nf-κb and gata proteins (papi and johnston a) . it has been recently suggested that early activation of p mapk pathway by rhinovirus infection, which induces the activation of many transcription factors, could be a key event in the regulation of rhinovirusinduced cytokine transcription, and may provide a new target for inhibition of rhinovirusinduced asthma exacerbations. rsv-induced cytokine production in airway epithelial cells seems to play an important role in the pathogenesis of rsv respiratory tract infections. recent studies on rsv-epithelial cell interactions have demonstrated that rsv can act at the molecular level by altering pathophysiology of viral-induced exacerbations of copd cytokine gene transcription (jamaluddin et al ; mastronarde et al ) or mrna stability (koga et al ) . as for rv it has been shown that early activation of mitogen-activated protein kinases (mapks) by rsv infection is a key event in the regulation of rsv-induced pro-inflammatory transcription factors activation and cytokine/chemokines transcription in bronchial epithelial cells, however both p map kinase, mitogen-activated protein kinase kinase kinase / nf-κb-inducing kinase (map k /nik) and extracellular signal-regulated kinases (erks) pathways seem to be important (chen et al ; kong et al ; chouldhary et al ; rixon et al ) . several transcription factors appear to be activated after rsv infection on a variety of respiratory cells. these proteins include mainly the nf-κb and ap- families. nf-κb is activated by the m - protein of rsv (fiedler et al ; mastronarde ; casola et al ; chouldhary ; reimers et al ; spann et al ) . the mechanisms by which virus-enhanced infl ammation may pave the way to copd exacerbations are so far unknown. the recent availability of a human model of rv-induced copd exacerbations (mallia et al ) will foster the research and the progress in this important area. in copd this is so far the only model where a specifi c etiology has been experimentally proven to induce exacerbation. in this pilot study mild to moderate copd patients were safely experimentally infected with rhinovirus providing for the fi st time that, in in vivo experimental condition, rhinovirus infection in copd patients is per se suffi cient to trigger exacerbations. lower respiratory tract symptom scores were signifi cantly increased compared to baseline on days to , with peak lower respiratory tract symptoms on days and . when the individual symptoms were analyzed separately, all fi ve lower respiratory symptom domains (wheeze, cough, sputum production and dyspnea) increased from baseline however the increases were only statistically signifi cant for wheeze, cough and sputum production, but not for dyspnea. in terms of recovery, all symptom domains other than sputum production had recovered to baseline by day , however full recovery of sputum production took almost weeks (mallia et al ) . this important data suggests that the link between virus-induced copd exacerbation and increased dyspnea and sputum production is probably very complex and needs dedicated studies for a better comprehension. intriguingly, it has been recently shown that viral induced severe copd exacerbations with or without concomitant bacterial infection are characteristically associated with sputum eosinophilia whereas sputum neutrophilia is present during exacerbations in all subgroups independently from etiology (papi et al ) . this fi nding is in line with previous studies showing that in vivo experimental rhinovirus infection in normal subjects leads to lower airway eosinophilia (fraenkel et al ) . thus, enhanced airway eosinophilic infl ammation of the airway may be a hallmark of viral infection. further studies are required to confi rm and extend this pivotal observation and to evaluate whether modulation of rhinovirus-induced activation of pro-infl ammatory mediators (ie, nf-κb) might be of any relevance in the treatment/prevention of virus-induced copd exacerbations. many studies conducted in the last decade have produced convincing data on the molecular mechanisms involved in the pathogenesis of natural and experimental respiratory virus infections in humans, particularly rhinovirus (rv) and respiratory syncytial virus (rsv). most of the studies have been performed on human respiratory epithelial cells, which can be directly infected by rv and rsv. their infection by rv and rsv determines the production of several pro-infl ammatory molecules (such as cytokines, chemokines and adhesion molecules). conversely, very few studies have been conducted in vivo on the molecular mechanisms underlying the pro-infl ammatory derangement induced by respiratory viruses in the airways during copd exacerbations. collectively these studies suggest a critical role for several transcription factor families, including the nf-κb, ap- and gata families, in the production of pro-infl ammatory mediators after rv and rsv infection. the relative importance of each cell, mediator, signalling pathway and transcription factor will hopefully be clarifi ed in the next few years. the recent development of the fi rst human model of virus induced copd exacerbation, that has been demonstrated to be feasible and so far, safe, will facilitate identifi cation of novel pharmacological targets that will provide opportunities to develop new treatments for exacerbations of copd. granulocyte infl ammatory markers and airway infection during acute exacerbation of chronic obstructive pulmonary disease recognition of doublestranded rna and activation of nf-kappab by toll-like receptor respiratory syncytial virus infection of human lung endothelial cells enhances selectively intercellular adhesion molecule- expression respiratory syncytial virus infection of human primary nasal and bronchial epithelial cell cultures and bronchoalveolar macrophages airway epithelial cell-induced activation of monocytes and eosinophils in respiratory syncytial viral infection respiratory viral infections in patients with chronic, obstructive pulmonary disease blocking intercellular adhesion molecule- on human epithelial cells decreases respiratory syncytial virus infection transcription factors in asthma and copd molecular mechanisms of respiratory 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transcription polymerase chain reaction in adults with and without respiratory illness respiratory syncytial virus infection in elderly and high-risk adults respiratory syncytial virus infection in adults inhibition of viral replication reverses respiratory syncytial virus-induced nf-kappab activation and interleukin- gene expression in a cells lower airways infl ammation during rhinovirus colds in normal and in asthmatic subjects relationship of upper and lower airway cytokines to outcome of experimental rhinovirus infection global initiative for chronic obstructive lung disease, national institute of health, national heart lung, and blood institute. global strategy for the diagnosis, management and prevention of chronic obstructive pulmonary disease the major human rhinovirus receptor is icam- differential response of dendritic cells to human metapneumovirus and respiratory syncytial virus nosocomial respiratory syncytial virus infections: the "cold war" has not ended respiratory 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nf-kappab-mediated transcription reducing agents inhibit rhinovirus-induced up-regulation of the rhinovirus receptor intercellular adhesion molecule- (icam- ) in respiratory epithelial cells pathophysiology of viral-induced exacerbations of copd relationship between bacterial colonisation and the frequency, character, and severity of copd exacerbations biopsy neutrophilia, neutrophil chemokine and receptor gene expression in severe exacerbations of chronic obstructive pulmonary disease antibiotics for exacerbations of chronic obstructive pulmonary disease respiratory syncytial virus m - protein induces the activation of nuclear factor kappa b amplifi cation of infl ammation in emphysema and its association with latent adenoviral infection the respiratory syncytial virus small hydrophobic protein is phosphorylated via a mitogen-activated protein kinase p -dependent tyrosine kinase activity during virus infection cigarette smoke decreases pulmonary dendritic cells and impacts antiviral immune responsiveness respiratory viruses in exacerbations of chronic obstructive pulmonary disease requiring hospitalisation: a case-control study h. infl uenzae potentiates airway epithelial cell responses to rhinovirus by increasing icam- and tlr expression how do we catch colds? respiratory viruses, symptoms, and infl ammatory markers in acute exacerbations and stable chronic obstructive pulmonary disease time course and recovery of exacerbations in patients with chronic obstructive pulmonary disease effect of exacerbation on quality of life in patients with chronic obstructive pulmonary disease bacterial infection in chronic obstructive pulmonary disease in : a state-of-the-art review rsv infection -not for kids only effects of nonstructural proteins ns and ns of human respiratory syncytial virus on interferon regulatory factor , nf-kappab, and proinfl ammatory cytokines the economic burden of copd rhinovirus infection of primary cultures of human tracheal epithelium: role of icam- and il- beta age related differences in humoral immune response to respiratory syncytial virus infection in adults asthmatic bronchial epithelial cells have a defi cient innate immune response to infection with rhinovirus role of viruses in exacerbations of chronic obstructive pulmonary disease exacerbations of chronic obstructive pulmonary disease chronic obstructive pulmonary disease. : the aetiology of exacerbations of chronic obstructive pulmonary disease effect of interactions between lower airway bacterial and rhinoviral infection in exacerbations of copd exacerbations of bronchitis: bronchial eosinophilia and gene expression for interleukin- , interleukin- and eosinophil chemoattractants key: cord- -tkh k u authors: zhao, qianwen; meng, meng; kumar, rahul; wu, yinlian; huang, jiaofeng; lian, ningfang; deng, yunlei; lin, su title: the impact of copd and smoking history on the severity of covid‐ : a systemic review and meta‐analysis date: - - journal: j med virol doi: . /jmv. sha: doc_id: cord_uid: tkh k u comorbidities are associated with the severity of coronavirus disease (covid‐ ). this meta‐analysis aimed to explore the risk of severe covid‐ in patients with pre‐existing chronic obstructive pulmonary disease (copd) and ongoing smoking history. a comprehensive systematic literature search was carried out to find studies published from december to march from five databases. the languages of literature included english and chinese. the point prevalence of severe covid‐ in patients with pre‐existing copd and those with ongoing smoking was evaluated with this meta‐analysis. overall case series, published either in chinese or english language with a total of cases, were included in this study. the pooled or of copd and the development of severe covid‐ was . (fixed‐effects model; % ci: . ‐ . ), while the or of ongoing smoking was . (fixed‐effects model; % ci: . ‐ . ). there was no publication bias as examined by the funnel plot and egger's test (p = not significant). the heterogeneity of included studies was moderate for both copd and ongoing smoking history on the severity of covid‐ . copd and ongoing smoking history attribute to the worse progression and outcome of covid‐ . endpoints appropriate to the aim of the study, unbiased assessment of the study endpoint, follow-up period appropriate to the aim of the study, loss to follow up less than %, and prospective calculation of the study size. the items were scored " " if it was not reported, " " if it was reported but inadequate, " " if reported and adequate. data extraction and the evaluation of literature quality were conducted independently by two investigators (mm and qz). microsoft excel database was created to record the available information including baseline details and the rate of development of severe covid- in patients with different respiratory conditions. any disagreement was resolved by another investigator (sl). microsoft excel was used to analyze the clinical symptoms and laboratory results. meta-analysis was carried out using r-software (version . . , available on https://www.r-project.org). heterogeneity among studies was tested using the cochran χ test and i . when i was less than %, a fixed-effects model was used, and when i was more than %, a random-effects model was used. sensitivity analysis was conducted to determine the source of heterogeneity by excluding one study at a time. after excluding significant clinical heterogeneity, the random-effects model was used for meta-analysis. funnel plot and egger test were used to detect any publication bias. a p value of less than . was considered statistically significant. on the basis of predefined search strategy, a total of studies were found in the five online databases as described above. after removing the duplicate records, articles were obtained. besides, another articles were excluded as they were not relevant to current meta-analysis. full texts of the remaining articles were then assessed for eligibility, of which were removed for various reasons. eventually articles ( in chinese and in english) , [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] were included in the analysis ( figure ). the patient characteristics and demographic data of the included studies are shown in table . all the reported and thus included studies were case series, sample size calculation was not relevant. the follow-up period was either not or inadequately reported in most studies. the overall quality of available literature was moderate with minors scores ranging from to . the quality of the included articles is evaluated and shown in table s . figure d ). as the reported endpoints varied between including literatures, a subgroup analysis was performed to find out the impact of different endpoints on the effect of copd or smoking on covid- . as shown in figure a , pre-existing copd is significantly associated with me- however, in the subgroup analysis, this effect was no longer significant in either subgroup. the weight of a single study on the from sars to covid- : a previously unknown sars-related coronavirus (sars-cov- ) of pandemic potential infecting humans-call for a one health approach. one health coronavirus disease : what we know who coronavirus disease situation reports the neuroinvasive potential of sars-cov may play a role in the respiratory failure of covid- patients imaging and clinical features of patients with novel coronavirus sar-cov- : a systematic review and meta-analysis clinical characteristics of coronavirus disease in china active smoking is not associated with severity of coronavirus disease (covid- ) clinical features of patients infected with novel coronavirus in wuhan clinical and biochemical indexes from -ncov infected patients linked to viral loads and lung injury clinical characteristics of hospitalized patients with novel coronavirus-infected pneumonia in wuhan clinical course and outcomes of critically ill patients with sars-cov- pneumonia in wuhan, china: a single-centered, retrospective, observational study clinical course and risk factors for mortality of adult inpatients with covid- in wuhan, china: a retrospective cohort study clinical characteristics of patients infected with sars-cov- in wuhan, china. allergy clinical features of cases with coronavirus disease diagnostic utility of clinical laboratory data determinations for patients with the severe covid- retrospective study on the epidemiological characteristics of patients with novel coronavirus pneumonia on the effects of severity analysis of factors associated with disease outcomes in hospitalized patients with novel coronavirus disease cellular and structural bases of chronic obstructive pulmonary disease the role of acute and chronic respiratory colonization and infections in the pathogenesis of copd key: cord- -kc mi z authors: hausen, thomas; gesenhues, anne title: atemwege und lunge date: - - journal: praxisleitfaden allgemeinmedizin doi: . /b - - - - . - sha: doc_id: cord_uid: kc mi z nan durch schleimstraße; ▶ . . ); untere atemwege/lunge: reizung bronchialsystem nach akuter bronchitis (trocken, "kitzelnd"; ▶ . . ) , grippetracheitis, asthma (▶ . . ) , copd (▶ . . ) , fremdkörperaspiration (▶ . . , ▶ . . ) • pulmonal: pneumonie (fieber, gelb-grüner auswurf; ▶ . . ) , "raucherhusten", pleuritis (thorakale schmerzen beim husten u. bei tiefer inspiration; ▶ . . ) , bronchiektasen ("maulvoll" übel riechender auswurf, v. a. morgens), tumoren (oft trocken, > wo., gewichtsabnahme), sarkoidose (▶ . . ) , exogen-allergische alveolitis (▶ . . ), lungenembolie (▶ . . ) , tbc (trocken, über wo. subfebrile temp.; ▶ . . ) , pneumothorax (atemnot, schmerzen; ▶ . . ) • kardial definition sekret der atemwegsschleimhaut u. der nnh. • sputumbeschaffenheit: -weißlich: virusinfekt, copd -gelblich: allergisches asthma (cave: antiinflammatorische asthmather., keine ind. für antibiotika!) -gelb/grün: bakt. bronchitis, bronchiektasen, mukoviszidose, pneumonie, bronchiektasen; meist größere mengen) -blutig: akute/chron. bronchitis, zersetztes blut nach lungenembolie; bei wiederholtem auftreten: ausschluss lungen-ca, tbc -bräunlich: starke raucher, kohlearbeiter -fötid riechend: lungenabszess, einschmelzendes ca (anaerobier!) -wie bronchusausguss geformt: copd, asthma, bronchopulmonale aspergillose • sputumquantität: große mengen bei bronchiektasen (maulvoll) u. mukoviszidose • sputumdiagn. (▶ . . ) mit blutbeimengungen: abklärung erforderlich außer bei sicher akutem infekt. definition abhusten von hellrotem, schaumigem blut aus rachen, tracheobronchialbaum o. alveolarraum. hämoptoe: massive hämoptyse. abzugrenzen von hämatemesis (▶ . . ); erbrechen von dunkelrotem, klumpigem blut, evtl. kaffeesatzartig durch blutungsquelle in magen u. Ös. • entzündlich: bronchitis (▶ . . ) , copd (▶ . . ) , pneumonie, bronchiektasen (▶ . . ) , lungenabszess, tbc (▶ . . ) • hämodynamisch: lungeninfarkt, lungenödem (▶ . . ) , mitralstenose (▶ . . (covid- -erkrankung ▶ . . ), stand april Ätiologie ▶ . therapie symptomatisch, ggf. icu; bisher keine ther. und keine impfung bekannt. • bes. bei (allergischem) asthma (v. a., wenn bisher nicht bekannt) wird asthmatische symptomatik in frühjahrs-(bäume, gräser) u. herbstmonaten (hausstaubmilbe) sehr häufig als "infekt" missdeutet u. fälschlicherweise antibiotisch behandelt. sek. bakt. besiedlung, beginn einer copd (▶ . . ). cave: komplizierter verlauf, v. a. bei lungenemphysem, herzinsuff. ("stauungsbronchitis"), bekannten bronchiektasen u. restriktiven lungenerkr. im internet: s -leitlinie (update ): ▶ . . ambulant erworbene pneumonie (community-acquired pneumonia, cap): weltweit eine der häufigsten infektionserkr. in d . /j., davon . stationär. je nach verlauf deutliche reduktion der -jÜr! schneller therapiebeginn u. auswahl des richtigen antibiotikums (erregerwahrscheinlichkeit, aktuelle resistenzsituation) entscheiden über prognose. notwendiger wechsel im verlauf verschlechtert diese! letalität: amb.: , %, notwendigkeit zur stat. behandlung: , % ( , % < j., , % > j. labor bb (leukozytose mit linksverschiebung u. evtl. toxischen granulationen), bsg ↑, crp bei bakt. pneumonien ↑↑, pct ↑ (dd viral/bakt.). dd lungen-ca (▶ . . ), pneumonie (▶ . . , z. b. klebsiellen, staphylok.) , lungeninfarkt (selten im oberlappen), asthma (▶ . . ), copd (▶ . . ), sarkoidose (▶ . . ), malignes lymphom (▶ . . ) . bei kontaktpersonen: möglichst bald tuberkulintest (nach frühestens d); wenn dieser pos., rö-thorax. meldung an gesundheitsamt. • für tägl. arbeit ist empfehlenswert, an jedem arbeitsplatz sammlung von demo-geräten zu deponieren u. mit wenigen geräten zu beginnen (erfahrung sammeln). eher nein häufig nein broncholysetest positiv negativ hyperreaktivität +++ Ø-leicht hoch niedrig • kk, alte, behinderte pat. u. anderweitig in der bedienung des da einge- prognose akut: % gutartiger verlauf ohne ther. innerhalb von j.; chron.: bis % remission mit/ohne ther.; % chron. persistierend o. progredient; % letal. synonym hamman-rich-sy. notfalltasche!): pat. mit weit offenem mund möglichst tief atmen lassen; da mit raba schütteln u. vor den mund halten; im geeigneten moment deswegen Überdosierung kaum zu befürchten • o -gabe, wenn möglich! • glukokortikoid oral oder i. v. (meist - mg prednisolon ausreichend) atemwege oft mit schleim ausgegossen) ein anhaltend niedriger pef-wert zeigt persistierenden notfall an, obwohl pat. u. arzt von einem guten therapieeffekt überzeugt sind! • cave maßnahmen bei allergien beste allergiebehandlung ist auslöservermeidung. maßnahmen bei pollenallergie: • pollen meiden (urlaub in allergenfreier/-armer umgebung, z. b. inseln, hochgebirge) fenster nicht über nacht geöffnet lassen • pollenfilter im auto (regelmäßig gemäß herstellerangaben reinigen membranumhüllung von matratze, kopfkissen, oberbett: lässt feuchtigkeit, aber nicht milbenkot durch). wichtig: encasing auch für partner im selben schlafzimmer. kosten, ggf. auch für partner (heil-u. hilfsmittel) sind gkv-leistung • urlaub oberhalb - m ü. nn (je nach feuchtigkeit): milben dort nicht überlebensfähig • spez. immuntherapie (hyposensibilisierung) immuntherapie mit allergenen allergietest u. eindeutiger zusammenhang mit klin. symptomatik • allergenkarenz nicht möglich • sympt. ≥ j.; dauer mind • verfügbarkeit standardisierter/qualitativ hochwertiger allergenextrakte • wirksamkeitsnachweis • nutzen-risiko-abwägung biene/wespe, pollen, milbe; ther. erfolg nur bedingt: tierhaare, nahrungsmittel, medikamente (z. b. nsar) dosis selbst aufziehen, inj. ist arztsache. pat. muss nach inj. mind. min cave: jede infektexazerbation führt zu irreversiblem lufu-verlust! . rehabilitation: copd ist domäne der reha! regelmäßige sportliche aktivität reduziert sauerstoffbedarf u. damit die luftnot; folge: leistungsfähigkeit ↑, exazerbationsrate ↓, lebensqualität ↑, möglicherweise lebenserwartung ↑ medikamentöse ther.: richtet sich nach risikograd (ermittelt sympt ziele der medikamentösen ther.: symptomlinderung, obstruktion ↓, atemwegswiderstand ↓, lungenüberblähung ↓, atemarbeit ↓, entlastung der atemmuskulatur (pulmonale u. kard. leistungsfähigkeit ↑, lebensqualität ↑) • duale bronchodilatation kommt vor ics! ics werden bei copd zu oft unkritisch eingesetzt (fraglicher nutzen, kosten)! bei fehlender ind. (häufige exazerbation) kein nutzen, pneumonie-u. osteoporoserisiko ↑, ntm-infektionen ↑ (▶ . . )! komb. aus laba + lama reduzieren exazerbationsrate sogar besser! auswirkungen nicht sicher vorhersehbar (studienlage nicht eindeutig evident): meist o. risiko, evtl. zunahme von exazerb. und symptomen oder nicht; evtl. minimale abnahme der fev langzeitanwendung keine ind., nur nw • theophyllin: bronchodilatatorische effekte nachgewiesen; immer zunächst nur zeitlich begrenzt (ca. mon.). fortsetzung nur bei pos. effekt daxas®): ind. bei schwerer u. sehr schwerer atemflusslimitierung, symptomen einer bronchitis und exazerbationen als add-on (begründeter therapieversuch) standardther. der herzinsuff.; können bei gleichzeitig bestehender copd eingesetzt werden: mortalität ↓! selektive betablocker bevorzugen zusätzliche therapieoptionen • hilfe bei starker verschleimung (▶ . . ) lippenbremse: ausatmen gegen widerstand leicht geschlossener lippen (erhöhter widerstand schient bronchien, verhindert kollaps) -atmen mit aufgelegten armen lebensverlängerung bei hyperkapnie (voraussetzung: anwendung mind. h/d). bei stärkerer bel. der atemmuskulatur ggf. als intermittierende beatmung, bevorzugt als nichtinvasive (niv-)maskenbeatmung. cave: pat. erklären: es geht nicht um linderung von dyspnoe, sondern (laienhaft) um "herzentlastung erlernen von abhusten etc empfehlung: energiereiche ernährung (protein-, fettreich) emphysemchirurgie: voraussetzung: zwerchfellhochstand, emphysemblasen vorwiegend luft aus verschlossenen segmenten zu entfernen, damit platz für ventilation zu schaffen), endoskopisches lungenvolumenreduktionsverfahren (thermische vaporablation, hydrogel-schaum-ther.) -lungen-tx: eher ultima ratio. kritische phase nach - wo., % mortalität innerhalb des . j., durchschnittliche Überlebensrate - j. -anorganische stäube: z. b. silikose (▶ . . ), asbestose, aluminiumlunge sle (▶ . . ), sharp-sy., progressive systemische sklerose (▶ medikamenten-nw (▶ . ), ionisierende strahlen, chron. linksherzinsuff. (▶ . ) idiopathische, fibrosierende alveolitis aber sicher häufiger als angenommen. wg. leichter diagnosemöglichkeit (echokardiografie, rechtsherzkatheter) häufiger daran denken (bes. bei copd/emphysem) u. pah ausschließen! definition mittlerer pulmonaler druck (pap) > mmhg (ruhe), > mmhg (belastung) klassifikation nach Ätiologie (mod hypertonie: a) idiopathische form (v. a. jüngere ♀) b) hereditär c) assoziiert mit medikamenten (z. b. appetitzügler), drogen, toxinen d) assoziiert mit bindegewebserkr hypoxämie: copd (▶ . . ), interstitielle lungenerkr, schlafbezogene erkr hypertonie: chron. rezidiv. thrombembolien, obstruktion distaler pulmonalarterien müdigkeit, synkopen, tachykardien, körperl. belastbarkeit ↓, belastungsdyspnoe (rechtsherzinsuff.-zeichen können fehlen) bei cor pulmonale meist keine orthopnoe im gegensatz zur linksherzinsuff., sondern zunehmende dyspnoe bei körperl. belastung synkopen unter belastung u. bei hustenattacken diagnostik anamnese: pulmonale, kardiale o. andere vorerkr kardiale unters.: hebende herzaktionen parasternal o. im epigastrium, tachykardie, betonter pulmonaliston fortgeschrittenem stadium p pulmonale, rechtsdrehung elektrischen herzachse • sono abdomen: leberstauung, mangelhafter inspir. kollaps v. cava inf. • labor: hkt ↑, polyglobulie • Üw → fa pulmologie zu weiterer diagn.: -rö-thorax: rechtsbetontes herz mit vergrößerung re vorhof u. re ventrikel, prominenter hilus, dilatation der zentralen lungenarterien, kalibersprünge, helle u. gefäßarme lungenperipherie -lungenventilations-/perfusionsszinti: ausschluss gefäßverschluss -echo (wegweisend): rechtsherzhypertrophie, trikuspidalinsuff., bestimmung von pap s (systol. pulmonal-art. druck) -rechtsherzkatheter: druckerhöhung im re ventrikel u. in der a. pulmonalis bei normalem verschlussdruck (wedge-druck) ist beweisend erworbene vitien mit zyanose (▶ . . ) ambrisentan (volibris®), macitentan (opsumit®), phosphodiesterase- -inhibitor sildenafil (revatio®) der rechtsherzinsuff: diuretika • körperl. training: leistung ↑, lebensqualität ↑, evtl. Überleben ↑ cor pulmonale: pat. sterben nie am "cor cave: pat. müssen aufgeklärt werden, dass o -insufflation (kein spürbarer effekt) nicht zur behandlung von luftnot, sondern zur drucksenkung wichtig ist u definition akute/chron. verlegung der pulmonalen strombahn; evtl. mit ausgeprägten veränderungen bzgl. hämodynamik u. gasaustausch; fast immer thromben, seltener fruchtwasser % mortalität bei erstereignis, bei % der Überlebenden wird diagnose nicht gestellt, von denen wieder % an rezidiv/en sterben. ursprung: % tiefe beinvenen, selten obere extremität, re herz verbände (gips, schienung), kardiale insuff., grav resistenz gegen aktiviertes protein c, lupus-antikoagulans, fibrinogenerhöhung, freisetzung thromboplastisch aktiver substanzen (entzündung, malignome), thrombozytose andere prädisponierende faktoren: zunehmendes lebensalter, weibliches bes. in verbindung mit nikotinabusus, adipositas bild gemäß verlegungsausmaß art. lungenstrombahn: stumm, akut, oft rezid. symptome; respir. beeinträchtigung bis zum fulminanten tod pleuraerguss, pleuranahe verschattung, zwerchfellhochstand, prominente zentrale pulmonalgefäße, gefäßkalibersprünge. nur in % pos. westmark-zeichen mit peripherer gefäßrarefizierung u. hypoperfusion auf kontralateraler seite • echo: dilatation re ventrikel u. vorhof, seltener auch pulmonalisstamm. nachweismöglichkeit embolischen materials im hauptstamm unter guten schallbedingungen. dd akute/chron. rechtsherzbelastung mit hypertrophierten wänden möglich. doppler-technik ermöglicht bei trikuspidalinsuff myalgie • bei schmerzen im oberen abdomen thrombolyse le können zum cor pulmonale führen. bei mittleren bis großen embolien mortalität ca. % ohne antikoagulation, - % mit antikoagulation → antikoagulation bei begründetem verdacht einleiten bereits durch kleine embolien dekompensation möglich → großzügige ind. antikoagulation vorkommen % der bevölkerung im erwerbsfähigen alter, obstruktive sas (osas) bei % der ♂, % der ♀ > j., bes. bei adipositas. apnoefrequenz steigt mit zunehmendem alter, korreliert mit koronarverkalkung! sistieren bzw. -proz. luftflussabnahme mund u. nase > sek. dauer im schlaf durch path. erhöhte kollapsneigung der extrathorakalen atemwege anzahl apnoeepisoden/h schlafzeit. path. ist index ≥ /h. einschlaf-apnoephasen (auch bei gesunden auftretend) werden nicht berücksichtigt -bis < -proz. luftflussreduktion mit abnahme der art. sauerstoffsättigung um mind aktivität der atemmuskulatur (atembewegungen) bleibt erhalten. begünstigende faktoren im bereich oro-/nasopharynx: z. b. tonsillenhyperplasie, nasenpolypen, nasenseptumdeviation, makroglossie, retrognathie; auch alkohol -upper airway resistance syndrome (uars): verengung der oberen atemwege im tiefschlaf ohne apnoen obstruktion der oberen atemwege (< %): -zentrale schlafapnoe u. prim. alveoläre hypoventilation: intermittierende atemmuskulatur-innervationsstörung durch verminderte chemorezeptoren-stimulierbarkeit → thorakale u. abdom. atembewegungen bleiben vollständig aus -sonderform zentraler sas: cheyne-stokes-atmung mit fehlsteuerung des atemzentrums. zwischen den zentralen apnoen periodisches an-u. abschwellen der atemtiefe u. atemfrequenz mit arousals (weckreaktionen), vorkommen v. a. bei fortgeschrittener herzinsuff. -sek. alveoläre hypoventilation bei chron. lungenerkr., neuromuskulären, skelettalen erkr. u. adipositas • sonderform: overlap-sy pathogenese und folgen der obstruktiven schlafapnoe • unterbrechung alveoläre ventilation (hypoxämie u. hyperkapnie) • hohe intrathorakale druckschwankungen • zentralnervöse aufweckreaktionen (arousals) führen zur Öffnung der oberen atemwege unter lautem schnarchen u. reaktiver hyperventilation mit tachykardie gehäufte arousals bewirken schlafunterbrechungen (schlaffragmentation) u. schlafdefizit → tagesschläfrigkeit mit leistungsminderung, -fach erhöhtes unfallrisiko ( % aller tödlichen autounfälle!) tachykardie durch stressbedingte katecholaminausschüttung • nächtliche, vorwiegend bradykarde herzrhythmusstörungen • reaktive polyglobulie • verschlechterung vorbestehender herzinsuff persönlichkeitsveränderungen, depression. tagsüber schlafanfälle (cave: gefahr sekundenschlaf beim autofahren), nachtschweiß; verstärkung durch alkohol unters.: unspez. befunde, evtl. adipositas, hypertonus, herzinsuff.-zeichen, herzrhythmusstörungen, bradykardie; evtl. tonsillenhyperplasie • labor: bb (reaktive polyglobulie?), tsh basal (ausschluss hypothyreose) fa-Üw zum rö-thorax (ausschluss pulmonaler erkr.), ekg (rechtsherzbelastungszeichen?), langzeit-rr-messung (fehlende nachtabsenkung), langzeit-ekg -amb. screening wegweisend, kein ersatz für schlaflabor -Üw → fa pneumologie, evtl. polygrafie/polysomnografie -Üw → fa hno (große gaumensegel, tonsillenhyperplasie, stark gekrümmte nasenscheidewand als zusätzlich prädisponierende faktoren?) nach jeder behandlung erfolg objektivieren! • ther. von rf: adipositas, nasenseptumdeviation, tonsillenhyperplasie gewichtsabnahme > % reduziert apnoe-hypopnoe-index um % keine schweren mahlzeiten vor dem schlafen, regelmäßiger schlafrhythmus, alkoholverzicht am abend, nikotin u. apnoeverstärkende medikamente (sedativa, schlafmittel, betablocker) meiden Über % der betroffenen pat. mit ncpap gut einstellbar (druck - mbar). bei < % sind höhere drücke nötig; meist als bipap (bilevel positive airway pressure) mit inspir > % aller schlafapnoe-pat. betroffen; typisch: rr-anstieg während apnoephase mit max. bis mmhg über basalwert. später persistiert hypertonie auch tagsüber • herzrhythmusstörungen: v. a. nächtliche bradykardien u. ves • herzinsuff polyglobulie prognose • apnoe-index < /h: keine erhöhte mortalität • apnoe-index > /h: -j.-mortalitätsrate unbehandelt bis % (unfälle, herzinfarkt, schlaganfall); ncpap-ther insgesamt selten. erst bei fehlender größenzunahme innerh. j. darf man mit höherer exstirpation nur in ausnahmefällen bei funktionellen störungen o. zur klärung der dignität vom bronchialepithel, selten vom alveolarepithel ausgehend. % aller krebstodesfälle (in d risikofaktoren hauptrisiko: rauchen (risiko steigt mit intensität/d u. inhalationstiefe der inhalation). bei pfeifen-u. zigarrenrauchern höher als bei passivrauchern; weitere rf: radioaktive aerosole, asbest, kanzerogene metalle (arsen, chrom, nickel), kristallines siliziumdioxid narbenkarzinom"), genetische disposition, hiv, ältere zytostatika, bestrahlungen; luftverschmutzung in unseren breiten kein rf mehr sclc: small cell lung cancer, %); nicht kleinzelliges lungenkarzinom (nsclc: non small cell lung cancer, %): plattenepithel-, großzelliges ca schnelles aggressives wachstum mit frühzeitiger metastasierung ( % bei diagnosestellung schon vorhanden), mÜz ohne ther oft langsames wachstum • sonderform pancoast-tumor: in lungenspitze liegender tumor, der in thoraxwand einwächst u. durch schädigung des plexus brachialis typ. schulter-arm-schmerzen u. horner-sy. verursacht. meist plattenepithel-ca. metastasierung in regionale lk, lungengewebe, leber, knochen, nebennieren u. gehirn, unabhängig vom histolog hämoptoe ( - %, danach fragen!), rezid. pulmonale inf., seitendifferenter auskultationsbefund! dyspnoe, gewichtsverlust (v. a. fortgeschrittene stadien, - %), thoraxschmerz ( - %) plexusläsion, blutiges pleuraexsudat bedeuten fast immer inoperabilität. paraneoplastische sy. v. a. beim kleinzelligen ca, z. b. ektope adh-o. acth-produktion (▶ bei copd-pat.) immer auch an ca denken! • bei jedem verdacht großzügige ind alarmzeichen sind husten > wo., blutiges sputum cave: nur pos thorax in ebenen, evtl. mit tomografie: jede verschattung kann ca verbergen! dd: copd, pneumonie (cave: retentionspneumonie bei ca eine exazerbation einer copd wird gelegentlich als tumorprogression missdeutet! therapie nicht kleinzelliges lungen n - , m ): kurative resektion, wenn möglich iib (t - , n , m ): radikale resektion mit lk-dissektion, evtl. adjuvante chemother • stadium iiia (t - , n - , m ): prim. chir. vorgehen sinnvoll. evtl. alternativ bei inoperabilität komb. strahlen-/chemother., präop. chemo-/strahlenther. ohne vorteil • stadium iiib (t bis jedes t, n , m ): nur dann resektion, wenn t -tumor ausnahmsweise kurativ resektabel. alternativ: palliative radio-o • stadium iv (jedes t, jedes n, m ): geringe lebensverlängerung ( - mon.) durch chemother. op nur unter palliativen gesichtspunkten (tumorblutung, tumorzerfall mit inf multimodales therapiekonzept sinnvoll ): prim. resektion mit adjuvanter chemother bei allen pat. mit remission nach induktionsther. schädelbestrahlung . . andere pulmonale tumoren pleuramesotheliom definition von mesothelzellen der pleura ausgehender maligner tumor; in etwa % der fälle pos. asbestanamnese (berg-, schiffsbau-, isolationsindustrie, bremsbelagherstellung, filteranlagen, bk ▶ . . ); insgesamt selten pleuraerguss, dyspnoe, husten therapie bisher keine kurative o. lebensverlängernde ther. bekannt selten möglich, da meist bei diagnose bereits fortgeschritten • chemother.: relativ neu, aber wenig erfolgreich: pemetrexet rein palliativ • pleurodese: rein palliativ bei rezid. pleuraergüssen • schmerzther.: komb. peripher u. zentral wirksamer analgetika prognose bei ungünstiger prognose - mon. (im mittel geht von neuroendokrinen kulschitzky-zellen des bronchialepithels aus. häufigkeit: % aller bronchialtumoren. ♀ u. ♂ im jüngeren lebensalter karzinoid-sy. (selten!): flush, asthma, hohe exkretion von -hydroxyindolessigsäure im -h-urin tumorentfernung mit kompletter lk-dissektion, da mit regionalen lk-metastasen zu rechnen ist • polychemother.: bei hochmalignem atyp. karzinoid o. bei ausgedehnter metastasierung prognose nach radikaler entfernung gut ( -jÜr %), bei metastasierendem bronchuskarzinoid -jÜr %. sehr variabler verlauf / ): www.degam.de/files/ inhalte/leitlinien-inhalte/dokumente/degam-s -leitlinien/ leitlinien-entwuerfe/ - _husten/langfassung_leitlinie_husten_ .pdf • pneumonie: amwf-s -leitlinie: behandlung von erwachsenen patienten mit ambulant erworbener pneumonie u. prävention (update pneumonie_behandlung_praevention_ - - .pdf • inhalation: www.atemwegsliga.de/richtig-inhalieren.html selbsteinschätzung patienten (cat): www.atemwegsliga.de, www.catestonline.org; mmrc: www.goldcopd.org, s k-leitlinie zur diagnostik und therapie von patienten mit chronisch obstruktiver bronchitis und lungenemphysem (copd therapie und nachsorge des lungenkarzinoms therapie schlafbezogener atmungsstörungen: degam s -leitlinie nr. müdigkeit • notfall-, bedarfsther./leichte beschwerden: saba (fenoterol, salbutamol, terbutalin), sama (ipratropium), saba + sama (ipratropium + fenoterol) nicht zur key: cord- -qprj vlc authors: boixeda, r.; campins, l.; juanola, j.; force, l. title: is chronic obstructive pulmonary disease a protective factor in sars-cov- infection? the importance of bronchodilator treatment() date: - - journal: rev clin esp (barc) doi: . /j.rceng. . . sha: doc_id: cord_uid: qprj vlc nan correspondence ¿es la enfermedad pulmonar obstructiva crónica un factor protector en la infección por sars-cov- ? la importancia del tratamiento broncodilatador globally, viruses play an important role in exacerbations of chronic obstructive pulmonary disease (copd). in a systematic review of infections in patients with copd that required hospital admission, it was observed that the rhinovirus, respiratory syncytial virus (rsv), and influenza virus were the most prevalent agents, followed by parainfluenza and coronavirus. coronavirus is the most frequent upper respiratory tract infection and is predominant during the winter months. in a study conducted in spain, % of patients admitted during the flu season presented with copd as a comorbidity. other authors have reported a somewhat lower prevalence of copd in patients with the flu ( . %) and an even lower prevalence of copd in patients with rsv infection ( . %). there are also studies which have evaluated the presence of copd as a comorbidity in other coronavirus infections such as sars, with a rate of %, and mers, with a rate of %. in regard to the current sars-cov- pandemic, it was initially considered that people with chronic lung diseases could be more prone to presenting with symptoms of the infection or to developing a more severe infection. however, published case series show a low prevalence of patients with copd: . % in the united states of america, % in italy, and just . % in china. this low prevalence could give rise to different interpretations. first, the strict lockdown imposed by public health authorities could explain that these patients, who are supposedly more vulnerable to sars-cov- infection, had closely followed social distancing protocols, thus decreasing the risk of contact. second, there could be a protective effect that is not well established in the physiopathology of chronic respiratory disease, with a different immune response that could prevent infection in these patients or condition milder symptoms. one piece of data in favor of this protection against infection can be concluded from the study by mehta et al., which analyzes factors associated with a positive result on a sars-cov- diagnostic test in a sample of , people. of the total number of tests, , ( . %) were positive whereas in patients with copd, only ( . %) were positive (p < . ). therefore, it seems that copd as a comorbidity is associated with a lower probability of having covid- . third, it has been hypothesized that baseline inhaled treatments, such as inhaled corticosteroids and bronchodilators, could have a protective effect against sars-cov- infection. in vitro studies on inhaled corticosteroids (budesonide), either alone or in combination with other bronchodilators (glycopyrronium bromide and formoterol), have demonstrated a suppression of hcov- e coronavirus replication. likewise, another study on inhaled corticosteroids that included just patients, conducted in japan and without a control group, observed a lower requirement for ventilatory support. on this matter, a systematic review was recently published on the possible protective effect of inhaled corticosteroids; it was unable to establish either a beneficial or detrimental effect of this treatment. similarly, in an italian study on a cohort of patients with covid- , patients with sars-cov- infection were compared to the general population. no influence on progress related to either short-or long-term inhaled corticosteroids or beta-adrenergic agonists was noted. tiotropium bromide is one of the main treatments for copd and is usually used in approximately % of patients treated in primary care. recent studies have demonstrated how tiotropium reduces neutrophils and macrophages as well as il- and gamma interferon levels in the airways of rats exposed to tobacco smoke and infected with the a/pr/ / (h n ) influenza virus. the effect was greater than what was observed with fluticasone and roflumilast. this potential anti-inflammatory effect with cytokine inhibition in animal models could explain a greater protective effect of tiotropium versus other inhaled therapies in sars-cov- infection. we have analyzed the prevalence of copd in patients treated for covid- in our center, specifically evaluating their baseline treatment with inhalers as a potential protective factor against sars-cov- infection. a retrospective, observational study was carried out in the mataró hospital which identified patients hospitalized with a clinical and/or microbiological diagnosis of sars-cov- from march to april , . a diagnosis of copd was established when the physician had recorded it on the medical record or when a compatible spirometry was available. treatments with inhaled corticosteroids and anticholinergics were also recorded. during the study period, patients were identified. of them, ( %) had a clinical diagnosis and ( %) had a microbiological diagnosis of sars-cov- infection. of the patients identified, . % were men. the mean age was . ± . years and the overall mortality rate was . %. of all patients, had a diagnosis of copd ( . %), of which ( %) had spirometric confirmation. within the group of patients with copd, the mean age was . ± . years and they had a greater mortality rate of %. we compared the baseline treatment of patients with copd in our covid- cohort with other published series of patients with hospital admission due to copd exacerbation related to other respiratory pathogens or those in stable clinical condition. we did not note any differences in the use of inhaled corticosteroids between both groups. however, the use of tiotropium was significantly lower in patients with copd who had been hospitalized for covid- in relation to other cohorts of patients with stable copd and without sars-cov- infection and controlled in primary care ( % vs. . % and . %, p < . ) (table table ) . the analysis of our cohort of patients with sars-cov- confirms a low prevalence of patients with copd ( . %). these patients were older (p = . ), had greater mortality (p = . ), and there was a low percentage of patients treated with tiotropium (p = . ). given the discordance in the available information, large studies are needed that evaluate the presence of copd and baseline treatments as possible protective factors against sars-cov- infection, with special attention paid to treatment with tiotropium, which appeared to have a protective effect in our study. likewise, it seems necessary to evaluate different prognostic factors that allow for confirming whether presence of copd is associated with a worse disease prognosis or if there are other confounding factors that explain this higher mortality, such as age or the establishment of therapeutic limitations related to the comorbidity itself or the healthcare resources available in the context of a pandemic. appendix. members of the cocohmat (cohorte covid del hospital de mataró) group table treatment with inhaled corticosteroids and anticholinergics in patients with copd in series of patients hospitalized due to sars-cov- , severe exacerbation of copd, and patients in the stable phase (primary care) severe sars-cov- infection the relevance of respiratory viral infections in the exacerbations of chronic obstructive pulmonary disease-a systematic review influenza vaccine effectiveness in reducing severe outcomes over six influenza season, a case-case analysis, spain, / to / respiratory syncytial virus hospitalization in middle-aged and older adults clinical features and outcomes of severe acute respiratory syndrome and predictive factors respiratory distress syndrome risk factors for primary middle east respiratory syndrome coronavirus illness in humans, saudi arabia association of use of angiotensinconverting enzyme inhibidors and angiotensin ii receptor blockers with testing positive for coronavirus disease (covid- ) renin-angiotensinaldosterone system blockers and the risk of covid- clinical characteristics of patients infected with sars-cov- in wuhan inhibitory effects of glycopirronium, formoterol, and budesonide on coronavirus rna replication and cytokine production by primary cultures of human nasal and tracheal epithelial cells therapeutic potential of ciclesonide inhalation for covid- pneumonia inhaled corticosteroids and covid- : a systemic review and clinical perspective neumonías adquirides en la comunidad en pacientes con enfermedad obstructiva crónica tratados con corticoides inhalados u otros broncodilatadores. estudio pneumocort tiotropium attenuates virus-induced pulmonary inflammation in cigarrete smoke-exposed mice treatment strategies after acute exacerbations of chronic obstructive pulmonary disease: impact on mortality clinical significance in copd patients followed in a real practice key: cord- - nlpo a authors: mansfield, k. e.; mathur, r.; tazare, j.; henderson, a. d.; mulick, a.; carreira, h.; matthews, a. a.; bidulka, p.; gayle, a.; forbes, h.; cook, s.; wong, a.; strongman, h.; wing, k.; warren-gash, c.; cadogan, s. l.; smeeth, l.; hayes, j.; quint, j.; mckee, m.; langan, s. title: covid- collateral: indirect acute effects of the pandemic on physical and mental health in the uk date: - - journal: nan doi: . / . . . sha: doc_id: cord_uid: nlpo a background: concerns have been raised that the response to the uk covid- pandemic may have worsened physical and mental health, and reduced use of health services. however, the scale of the problem is unquantified, impeding development of effective mitigations. we asked what has happened to general practice contacts for acute physical and mental health outcomes during the pandemic? methods: using electronic health records from the clinical research practice datalink (cprd) aurum ( - ), we calculated weekly primary care contacts for selected acute physical and mental health conditions (including: anxiety, depression, acute alcohol-related events, asthma and chronic obstructive pulmonary disease [copd] exacerbations, cardiovascular and diabetic emergencies). we used interrupted time series (its) analysis to formally quantify changes in conditions after the introduction of population-wide restrictions ('lockdown') compared to the period prior to their introduction in march . findings: the overall population included , , individuals on st january . primary care contacts for all conditions dropped dramatically after introduction of population-wide restrictions. by july , except for unstable angina and acute alcohol-related events, contacts for all conditions had not recovered to pre-lockdown levels. the largest reductions were for contacts for: diabetic emergencies (or: . , % ci: . - . ), depression (or: . , % ci: . - . ), and self-harm (or: . , % ci: . - . ). interpretation: there were substantial reductions in primary care contacts for acute physical and mental conditions with restrictions, with limited recovery by july . it is likely that much of the deficit in care represents unmet need, with implications for subsequent morbidity and premature mortality. the conditions we studied are sufficiently severe that any unmet need will have substantial ramifications for the people experiencing the conditions and healthcare provision. maintaining access must be a key priority in future public health planning (including further restrictions). funding: wellcome trust senior fellowship (sml), health data research uk. evidence before this study a small study in gp practices in a largely deprived, urban area of the uk (salford) reported that primary care consultations for four broad diagnostic groups (circulatory disease, common mental health problems, type diabetes mellitus and malignant cancer) declined by - % between march and may , compared to what was expected based on data from january to march . we searched medline for other relevant evidence of the indirect effect of the covid- pandemic on physical and mental health from inception to september th , for articles published in english, with titles including the search terms ("covid*" or "coronavirus" or "sars-cov- "), and title or abstracts including the search terms ("indirect impact" or "missed diagnos*" or "missing diagnos*" or "delayed diagnos*" or (("present*" or "consult*" or "engag*" or "access*") and ("reduction" or "decrease" or "decline")). we found no further studies investigating the change in primary care contacts for specific physical-and mental-health conditions indirectly resulting from the covid- pandemic or its control measures. there has been a reduction in hospital admissions and presentations to accident and emergency departments in the uk, particularly for myocardial infarctions and cerebrovascular accidents. however, there is no published evidence specifically investigating the changes in primary care contacts for severe acute physical and mental health conditions. added value of this study to our knowledge this is the first study to explore changes in healthcare contacts for acute physical and mental health conditions in a large population representative of the uk. we used electronic primary care health records of nearly million individuals across the uk to investigate the indirect impact of covid- on primary care contacts for mental health, acute alcohol-related events, asthma/chronic obstructive pulmonary disease (copd) exacerbations, and cardiovascular and diabetic emergencies up to july . for all conditions studied, we found primary care contacts dropped dramatically following the introduction of population-wide restriction measures in march . by july , with the exception of unstable angina and acute alcoholrelated events, primary care contacts for all conditions studied had not recovered to pre-lockdown levels. in the general population, estimates of the absolute reduction in the number of primary care contacts up to july , compared to what we would expect from previous years varied from fewer than contacts per million for some cardiovascular outcomes, to , per million for depression and , for anxiety. in people with copd, we estimated there were , per million fewer contacts for copd exacerbations up to july than what we would expect from previous years. implicatins of all the available evidence while our results may represent some genuine reduction in disease frequency (e.g. the restriction measures may have improved diabetic glycaemic control due to more regular daily routines at home), it is more likely the reduced primary care conatcts we saw represent a substantial burden of unmet need (particularly for mental health conditions) that may be reflected in subsequent increased mortality and morbidity. health service providers should take steps to prepare for increased demand in the coming months and years due to the short and longterm ramifications of reduced access to care for severe acute physical and mental health conditions. maintaining access to primary care is key to future public health planning in relation to the pandemic. by october , novel coronavirus disease (covid- ) has been diagnosed in more than million individuals, with over one million deaths reported worldwide. much research and public health attention has, understandably, focused on preventing infections and reducing mortality. however, there are concerning reports of decreased health service use. [ ] [ ] [ ] [ ] inevitably, there will be impacts on non-covid- -related healthcare provision; healthcare resources have been reallocated to the covid- response and care delivery has been modified due to mitigation measures including social distancing. [ ] [ ] [ ] [ ] [ ] [ ] additionally, individuals may have delayed seeking care (due to fear of infection, or to avoid burdening health services). psychological health will have been affected by pandemic-related fears, employment and financial concerns, and control measures (including social distancing, closures of social spaces and isolation), , and lockdown measures are likely to have reduced access to mental health care (face-to-face visits and talking therapies). understanding the indirect effects of the pandemic and its control measures is essential for public health planning, particularly when/if the covid- pandemic is under control (or if further restrictions are needed), and for informing control measures for future pandemics. reports indicate that accident and emergency department attendance and hospital admissions for non-covid-related acute concerns in the uk have declined since march . [ ] [ ] [ ] however, it is not yet clear what has happened in primary care across the uk where clinical work has changed rapidly to include more remote consultations, - although a regional report indicates reduced primary care consultations. we asked how primary care contacts (including face-to-face or remote consultations, and recording of diagnoses from hospital discharge summaries) have changed for selected indirect acute physical and mental health effects of the covid- pandemic, to inform decisions on policy responses and resource allocation. although a wide range of diagnoses could be indirectly affected by the covid- pandemic, we focused on specific acute conditions that could plausibly be affected including: mental health conditions, acute alcoholrelated events, cardiovascular and diabetic emergencies, and asthma and chronic obstructive pulmonary disease (copd) exacerbations. we specifically selected diabetic and cardiovascular emergencies (including myocardial infarction, unstable angina), and asthma/copd exacerbations, as affected individuals are likely to be considered vulnerable (and asked to 'shield', i.e. advice for the vulnerable to avoid unnecessary contacts, to avoid infection), creating a barrier to accessing healthcare resources. we used routinely collected primary care data from electronic health records from general practices contributing to clinical research practice datalink (cprd) aurum database (august build) in the three years prior to the covid- pandemic and four months after introducing population-wide restrictions (i.e. 'lockdown') on rd march ( st january - th july ). code lists for defining all outcomes and stratifying variables, and analytic code are available (https://github.com/johntaz/covid-collateral). cprd aurum includes de-identified routinely collected primary care health record data from participating general practices covering % of the uk population, and is broadly representative of the english population with respect to age, sex, ethnicity, and geographic region. our overall study population included individuals with at least one year of registration with practices contributing to cprd aurum (january -july ). included populations (i.e. denominators) varied depending on the condition being investigated (table , figure s ). for example, for diabetic emergencies the study population (denominator) only included individuals (aged ≥ years) with an existing diabetes mellitus diagnosis, while for depression, the study included all individuals from the overall study population aged years and older. we followed all individuals from the latest of: study start ( st january ), one year from gp registration or, for diabetes and respiratory conditions, from meeting our definitions for having diabetes or respiratory disease, as appropriate (table ). follow-up ended for all study populations at the earliest of: end of registration with gp, death, practice stopped contributing to cprd, or end of the study period. our exposure was the introduction of population-wide covid- restrictions (i.e. 'lockdown' on rd march ). as outcomes, we considered the number of weekly primary care contacts for the following conditions (separately): mental health (i.e. depression, anxiety, fatal and non-fatal self-harm, severe mental illness, and eating and obsessive-compulsive disorders), acute alcohol-related events, diabetic emergencies (e.g. ketoacidosis), asthma and copd exacerbations, and acute cardiovascular (cvd) events (i.e. unstable angina, myocardial infarction, transient ischaemic attack, cerebrovascular accident, cardiac failure and venous thromboembolisms). we used the term 'contact' broadly to represent remote and face-to-face consultations, diagnoses from hospital discharge letters, and secondary care referrals. we identified conditions using primary care records for diagnoses, symptoms and/or prescribing (table ). all outcomes, except asthma/copd exacerbations, were captured based on presence/absence of specific morbidity codes. asthma/copd exacerbations were based on validated algorithms requiring a combination of specific morbidity codes and prescriptions for corticosteroids or, for copd additionally antibiotics. , for some conditions we defined an exclusion period during which we regarded further coding for the same outcome as representing the same acute event (e.g. for diabetic emergencies we regarded multiple records within seven days of each other as representing the same event). we used different condition-specific time periods to define outcome events to account for differences in natural history of study outcomes (table ) . we stratified on the following pre-specified variables: age (in -year bands), sex, geographic region, and ethnicity. we described all denominator study populations in the first week of january each year ( - ). we plotted the percentage of our study populations with contacts for particular conditions in given weeks in and historical averages for that week ( - ). we repeated analyses stratified by age, sex, region, and ethnicity. to quantify changes in consultation behaviour following introducing restrictions we used an interrupted time series (its) analysis separating our time series into two periods: ) pre-lockdown: st january to march st for all outcomes except self-harm (which excluded data from and , text s ); and ) withrestrictions: from th march to the study end ( th july ). although restrictions were announced on rd march, activity levels (measured by mobile phone applications and public transport journeys) had declined before the announcement. - to account for anticipatory behaviour, we conservatively defined the start of restrictions as the first week of march, and removed all data in march up to, and including, the week restrictions were announced from the its analysis. for our its analysis, we used binomial generalised linear models with number of weekly contacts weighted by dynamic population sizes (updated weekly). we included a linear effect of time to capture long-term behaviour trends, a binary pre-lockdown/with-restrictions variable to measure the direct 'step' change in behaviour, and an interaction between the two to allow for a recovery 'slope' change in behaviour. we accounted for seasonal effects by including calendar month as a categorical variable, and autocorrelation by including first order lagged residuals. standard errors were scaled to account for overdispersion. to estimate the reduction in contacts as restrictions were introduced (the `step' change) we reported odds ratios (ors) for the relative difference in contacts at the start of the with-restrictions period compared to the end of the pre-lockdown period. to estimate the recovery of contacts over time (the `slope') we used the coefficients from the its model to estimate the weekly log odds of contact during the with-restrictions period (further details: text s ). to estimate absolute effects of restrictions on the number of contacts, we repeated our analysis using poisson regression to generate linear predictions of the estimated log contact count and the estimated log count if the 'restrictions' term was set to zero (i.e. there had been no restrictions). to quantify absolute changes in behaviour over time we compared the point estimate of the estimated number of contacts with and without restrictions at two time points: month ( th april) and months after introduction of restrictions ( th june). we used stata version and r version . . for our analyses. our definitions for pre-lockdown and with-restrictions periods may have influenced our estimates, so we repeated the its analysis with the same pre-lockdown period but with variable data-exclusion periods ( and weeks, versus weeks in the main analysis) and repeated analyses with the pre-lockdown period ending on th march, the week before restriction introduction, excluding data for , , and weeks as sensitivity analyses. additionally, given the small number of diabetic emergency contacts we varied our definition using less specific codes in a post-hoc sensitivity analysis (text s ). is the author/funder, who has granted medrxiv a license to display the preprint in (which was not certified by peer review) preprint the copyright holder for this this version posted october , . ; https://doi.org/ . / . . . doi: medrxiv preprint covid- collateral: indirect acute effects of the covid- pandemic on physical and mental health in the uk mansfield, mathur, tazare, henderson, mulick, et al. the overall denominator population included , , individuals on st january and numbers remained relatively stable throughout the study ( table ). characteristics of condition-specific study populations are in the appendix (tables s -s ). figure shows the percentage of a given study populations with primary care contacts for each condition in (red line) and a -year historical average for the corresponding week (black line). across the majority of conditions, we observed rapid and sustained decreases in gp contacts between march and july compared to pre-lockdown periods. despite gradual increases in the percentage of contacts following restrictions, levels remained below the three-year average for all conditions except acute alcohol-related events, which were higher than the historical average in , and unstable angina. during march we observed pronounced increases in contacts related to asthma exacerbations. patterns were broadly consistent when stratified by age ( figure ), sex, region, and ethnicity ( figures s -s ). there was evidence that contacts for all studied conditions, except acute alcohol-related events, were lower after restrictions were announced compared to pre-restriction levels ( figure a ). the largest relative reductions in contact behaviour following restriction introduction were observed for diabetic emergencies (or: . , % ci: . - . ), depression (or: . , % ci: . - . ), and self-harm (or: . , % ci: . - . ) ( figure b , table s ). from march th , we saw evidence of increasing contacts for most conditions over time. acute alcohol-related events and unstable angina contacts appeared to recover faster ( - % increase in odds of contact per week) ( figure c , table s ) than, for example, mental health contacts, where odds of contact increased by - % per week, despite a - % drop following restrictions ( figure b , table s ). sensitivity analyses varying the choice of restriction period provided broadly consistent results over a wide range of scenarios with a notable exception of acute alcohol-related events (tables s -s , figures s -s ). table illustrates the potential impact of reduced contacts on relevant populations. while for some rare conditions, the absolute change in contacts was relatively small, other more common conditions had a larger absolute change in contacts, for example, in a population of million people with copd, from the end of march to the end of june, we estimated that there were cumulatively , fewer copd exacerbation contacts per million people with copd than expected. during the weeks commencing th april and th june we estimated there were , and , fewer contacts (per million) than expected respectively, indicating a slow return to pre-lockdown contact levels, but not complete recovery. for example, we estimated there were cumulatively fewer contacts for: ) asthma exacerbations ( , for every one million people with asthma; and ) depression and anxiety contacts ( , and , respectively) for every one million people in the general population (aged ³ years). . cc-by-nc-nd . international license it is made available under a perpetuity. is the author/funder, who has granted medrxiv a license to display the preprint in (which was not certified by peer review) preprint the copyright holder for this this version posted october , . ; https://doi.org/ . / . . . doi: medrxiv preprint covid- collateral: indirect acute effects of the covid- pandemic on physical and mental health in the uk mansfield, mathur, tazare, henderson, mulick, et al. primary care contacts for key physical and mental health conditions dropped dramatically after the introduction of population-wide restriction measures in march . by july , with the exception of unstable angina and acute alcohol-related contacts, primary care contacts for all conditions studied remained below pre-lockdown levels. we estimate that by july , per million people in the general population, there were very small (< ) drops in contacts for myocardial infarction, unstable angina and venous thromboembolism, but drops of around , and , anxiety and depression contacts. per million people with copd, we estimate , fewer exacerbation contacts. our study is the first to explore the effect of lockdown measures on primary care contacts for specific acute physical and mental health conditions across the uk. a study ( primary care practices) in a largely deprived urban area, badly affected by the pandemic in north west england (salford) suggested primary care consultations across four broad categories (common mental health problems, cardiovascular and cerebrovascular disease, type diabetes, and cancer) had reduced by up to % by the end of may . in contrast to the salford study, our sample was nationally representative and focused on contacts for specific disease categories we would expect to present to healthcare providers. our large sample size allowed us to investigate detailed diagnoses (for example, different types of cvd and mental health conditions). in september gps conducted more face-to-face appointments than any week since march, and more consultations overall than prior to the pandemic ( % were telephone appointments). , a study of gp practices already offering remote consultations before the pandemic indicated a dip in overall consultations at lockdown, but unlike our results for specific acute conditions, their post-lockdown overall consultation decrease was less extreme than during christmas . in england there was a % decrease in gp consultations from the beginning to the end of march , with an increase in calls to nhs , the nonurgent telephone helpline. however, over % ( , , / , , ) of these calls went unanswered. the reduced diabetic emergency contacts we observed are consistent with the % reduction in new type diabetes contacts (new prescriptions for metformin) in salford. while the salford study highlighted missed new diagnoses, our study identifies missed contacts for acute deteriorations. given that % of diabetes management is in primary care, the large relative reduction in the proportion of people with diabetes with diabetic emergency contacts is concerning. recent evidence indicates a two-way interaction between diabetes and covid- , with a potentially causal association between covid- infection and dysglycaemia, such that each condition exacerbates the other. , further, there is evidence that other emergency situations impair control of diabetes. [ ] [ ] [ ] consequently, we would expect an increase, rather than decrease, in diabetic emergency contacts. one potential explanation for our findings is that individuals experiencing diabetic emergencies may be presenting directly to secondary care with delayed recording in the primary care health record. . cc-by-nc-nd . international license it is made available under a perpetuity. is the author/funder, who has granted medrxiv a license to display the preprint in (which was not certified by peer review) preprint the copyright holder for this this version posted october , . ; the reduction in cvd contacts is consistent with reports from other uk studies. , taken alongside findings of similar reductions in emergency department presentations and hospital admissions for cardiovascular outcomes in the uk, our findings highlight an area of major concern, , particularly as evidence from france indicates increased out-of-hospital cardiac arrest. severe covid- affects the cardiovascular system; hence, increased primary and secondary care presentations for cvd are expected. indeed, it is possible that the more rapid recovery in unstable angina contacts (compared to other study conditions) may reflect covid- -related cvd (however, numbers were small). reports from germany, consistent with our findings, indicate reduced community and hospital presentations with acute copd exacerbations. copd is associated with more severe covid- infection; individuals with copd in the uk were recommended to avoid contact with others until september . , decreased emergency department visits for childhood asthma have been reported in the usa, consistent with our observations. there is no compelling evidence that individuals with asthma are at greater risk of severe covid- outcomes, although there was uncertainty at pandemic onset. [ ] [ ] [ ] viruses commonly trigger asthma exacerbations, so we might have expected to see more asthma contacts. anecdotally, gps reported increased prescription of asthma therapies around the lockdown period, which may explain initial increased asthma contacts. similar increases in copd exacerbation contacts were not seen around introduction of restrictions, despite our definition including prescriptions for oral corticosteroids. one explanation might be that, as copd is a progressive respiratory condition, individuals with copd may have repeat prescriptions, reducing need (compared to those with asthma) to stockpile drugs in a crisis. surveys have reported increased anxiety, depression and self-harm during the pandemic, , , - and exacerbations of existing ocd, severe mental illness (smi) and eating disorders have also been reported. [ ] [ ] [ ] however, we saw a sustained reduction in primary care contacts for anxiety, depression and other mental health conditions consistent with other reports; this is concerning as the majority of common mental disorders are managed in primary care. similarly, reduced healthcare contacts for people with smis are concerning, as people with smis are likely to be at greater risk of poor outcomes from covid- due to high prevalence of risk factors for adverse outcomes (e.g. cvd, deprivation - ). findings from surveys on alcohol consumption in lockdown are mixed, with some reporting increased alcohol consumption in up to a third of those surveyed, while others produced differing findings. we saw primary care contacts for acute alcohol-related events increase before and after restrictions, which is troubling given the reduction in contacts for other conditions studied (however, numbers were small). we performed a rapid assessment of changes in primary care contacts following the introduction of ukpopulation-wide restrictions up to july in a large sample respresentative of the uk population. historical data allowed us to compare observed patterns in to trends in the previous -years. we estimated relative and absolute changes in contact patterns, with a focus on easy to interpret measures. our study describes and quantifies the reduction in primary care contacts across a wide range of health conditions likely to be affected by covid- to generate hypotheses. further research is needed to understand the specific drivers behind these changes. it is important that we understand what happened to . cc-by-nc-nd . international license it is made available under a perpetuity. is the author/funder, who has granted medrxiv a license to display the preprint in (which was not certified by peer review) preprint the copyright holder for this this version posted october , . ; individuals who did not consult their gp. specifically, were they treated in secondary care or did they selfmanage, and how much of our findings can be explained by genuine changes in disease frequency? without hospital and mortality data, we are unable to investigate whether, for example, any reduction in gp contacts resulted in corresponding increases in hospital attendances or deaths. we focused on studying any record of study conditions, hence, our results reflect all primary care contacts, including diagnoses recorded by general practice staff from hospital discharge letters. to avoid problems arising from the timing of behaviour change associated with restrictions, our its analysis excluded a predefined intervention period when individuals' behaviour was changing dynamically. we took a conservative approach and defined our intervention period between st march and th march assuming that some people would have modified behaviour before the introduction of restrictions. sensitivity analyses varying the start date showed consistent findings. detailed exploration of whether consultation behaviour varied in those considered clinically vulnerable and advised to 'shield is beyond the scope of this paper, and any changes in health-seeking behaviour would not have reduced the need for care. given evidence suggesting reduced emergency department attendances and hospital admissions for our study conditions, while one explanation could be genuine changes in disease frequency (unlikely, given consistent results across disease categories), it is more likely our findings reflect missed opportunities for care. there are plausible mechanisms that might explain real reductions in frequency for some of our outcomes. for example: ) better glycaemic control in diabetes due to more regular routines when staying home; ) less respiratory disease due to lower exposure to air pollution during lockdown, and reduced community-aquired respiratory infections due to 'shielding' guidelines; and ) reduced alcohol consumption due to pub closure and reduced social contact. conversely, there are plausible mechanisms that could explain genuine increased frequency of these conditions (e.g. distress related to the pandemic affecting mental health and alcohol consumption, reduced exercise affecting cardiovascular health, changes in diet influencing glycaemic control); and for some of our outcomes, e.g., mental health conditions, there is some evidence indicating increased frequency. , , , , - increases in non-covid-related excess mortality also make it more likely our observed reduction in primary care contacts was due to behavioural changes rather than reduced disease frequency. , - further, emerging evidence of the systemic complications of covid- infection (particularly cvd and diabetes) , , indicates we might have expected more need for care for these conditions as a direct result of the pandemic. our results are likely to represent a large burden of unmet need, particularly in relation to copd and mental health conditions; healthcare providers should prepare for increases in morbidity and mortality. further research should address whether reduced clinical contact has resulted in excess mortality, and whether we need to increase service provision for individuals with increased healthcare needs resulting from delaying seeking access to care. while numbers of unstable angina events were small, we note more rapid (compared to other study outcomes) return to pre-pandemic consultation rates; this observation needs investigation as it may be a direct consequence of the pandemic. finally, our findings highlight a need to ensure equitable access to primary care in future pandemic planning. countries such as singapore, which had experienced sars, implemented control measures in primary care rapidly. the current pandemic has generated a wealth is the author/funder, who has granted medrxiv a license to display the preprint in (which was not certified by peer review) preprint the copyright holder for this this version posted october , . ; of experience with alternative ways to access care remotely. these lessons must be systematised and implemented. we saw substantial reductions in primary care contacts for acute physical and mental health conditions. our findings are likely to represent a considerable burden of unmet need, which may lead to substantial increases in subsequent mortality and morbidity. is the author/funder, who has granted medrxiv a license to display the preprint in (which was not certified by peer review) preprint the copyright holder for this this version posted october , . ; https://doi.org/ . / . . . doi: medrxiv preprint all study authors were involved in the development of the study. kem, rm, jt, ah and am contributed equally and are considered joint first authors. all authors contributed to the development of the code lists that defined the variables used in the study. jt, ah, rm, pb, hc, and aw were responsible for data management. jt, ah, rm and am were responsible for statistical analyses. kem, rm, jt, ah, and am wrote the first paper draft. all authors contributed to and approved the final manuscript. we would like to thank john burn-murdoch, as our main plot design was based on his work on excess mortality in the financial times (https://www.ft.com/content/a ce - eb - -b c-cbdf b ). this study is based in part on data from the clinical practice research datalink obtained under licence from the uk medicines and healthcare products regulatory agency. the data is provided by patients and collected by the nhs as part of their care and support. the interpretation and conclusions contained in this study are those of the authors alone. the study was approved by the independent scientific advisory committee (protocol number: _ r ). the study was approved by the london school of hygiene and tropical medicine research ethics committee (reference: /rr/ ) and by the cprd independent scientific advisory committee (isac protocol number: _ r ). no additional unpublished data are available as this study used existing data from the uk cprd electronic health record database that is only accessible to researchers with protocols approved by the cprd's independent scientific advisory committee. all data management and analysis computer code is available via github (https://github.com/johntaz/covid-collateral). all code is shared without investigator support. our study protocol and analysis plan are available as additional online-only supplementary material. all aggregated data will be freely available to explore by stratifiers through an r shiny app, available at https://a-henderson .shinyapps.io/covid_collateral_shiny/. all authors have completed the icmje uniform disclosure form (www.icmje.org/coi_disclosure.pdf). mm is a member of independent sage. is the author/funder, who has granted medrxiv a license to display the preprint in (which was not certified by peer review) preprint is the author/funder, who has granted medrxiv a license to display the preprint in (which was not certified by peer review) preprint is the author/funder, who has granted medrxiv a license to display the preprint in (which was not certified by peer review) preprint is the author/funder, who has granted medrxiv a license to display the preprint in (which was not certified by peer review) preprint is the author/funder, who has granted medrxiv a license to display the preprint in (which was not certified by peer review) preprint diabetic emergencies all individuals (aged ≥ years) with prevalent diagnoses of diabetes mellitus at the start of each week of follow-up. individuals contributed to the study population from the latest of the start of follow-up in the overall population and the date of their first record indicating a diagnosis of diabetes. any record of diabetes-related hyperglycaemia, hypoglycaemia, ketoacidosis, or diabetic coma. multiple records occurring within seven days of each other were considered as representing the same event. mental health anxiety all individuals (aged ≥ years) from the overall study population. any record of symptoms or diagnoses of: social phobia, agoraphobia, panic, generalized anxiety disorder, and mixed anxiety and depression. multiple records occurring within seven days of each other were considered as representing the same event. depression all children (aged - years) and adults (aged ≥ ) from the overall study population. any record of major depressive disorder, dysthymia, mixed anxiety and depression, and adjustment disorders with depressed mood. we also included codes for depressive symptoms. multiple records occurring within seven days of each other were considered as representing the same event. self-harm all children (aged - years) and adults (aged ≥ years) from the overall study population. self-harm defined as records that indicated explicit or undertermined intention to self-harm, non-suicidal or suicidal self-harm (including overdoses with drugs commonly implicated in suicide, e.g. paracetamol). multiple records occurring within seven days of each other were considered as representing the same event. serious mental illness all children (aged - years) and adults (aged ≥ years) from the overall study population. severe mental illness included diagnoses of schizophrenia and other psychotic disorders, and bipolar disorders. multiple records occurring within seven days of each other were considered as representing the same event. eating disorders all children (aged - years) and adults (aged ≥ years) from the overall study population. eating disorders included anorexia nervosa, bulimia nervosa, and other specified feeding and eating disorders. multiple records occurring within seven days of each other were considered as representing the same event. obsessive compulsive disorder all children (aged - years) and adults (aged ≥ years) from the overall study population. obsessive compulsive disorder was defined by codes for body dysmorphic disorders, hypochondriasis, hoarding disorder, and body focused repetitive behaviour disorders. multiple records occurring within seven days of each other were considered as representing the same event. denominator population (condition-specific denominator populations) condition definition respiratory asthma exacerbations all individuals (aged ≥ years) with a current asthma diagnosis (i.e. asthma code in the last two or three years if aged < years or + years, respectively). individuals joined the study population from the start of follow-up in the overall population if there was a current asthma diagnosis (i.e. within last - years) at this time or from the date of their first record indicating an asthma diagnosis within overall follow-up. participants remained in the study until there was no current asthma diagnosis or the end of overall follow-up. they were able to reenter the study if there was a later diagnostic code for asthma before the end of overall follow-up. following an existing definition, individuals years and over with asthma were considered as likely to have copd (and therefore not included in the asthma study population [denominator]) if they had a subsequent copd diagnosis recorded within the two years following the current asthma record. asthma exacerbations were defined as records for morbidity codes for asthma exacerbations and status asthmaticus, and a primary care prescription for an oral corticoseroid. multiple records occurring within days of each other were considered as representing the same event. copd exacerbations adults (aged ≥ years) with an established diagnosis of copd and evidence of a smoking history. individuals joined the study population from the latest of the start of follow-up in the overall population and the date of their first record indicating diagnosis of copd. exacerbations of copd were defined using morbidity codes in individuals with existing copd for copd exacerbations, lower respiratory tract infections, breathlessness or sputum production, and a new prescription for an oral corticosteroid or antibiotic. multiple records occurring within days of each other were considered as representing the same event. all adults (aged > years) any record for myocardial infarction allowing for a -year window between successive records. multiple records occurring within one year of each other were considered as representing the same event. unstable angina all adults (aged ≥ years) any record for unstable angina, allowing for a -month window between successive records. multiple records occurring within six months of each other were considered as representing the same event. transient ischaemic attacks all adults (aged ≥ years) any record for transient ischaemic, allowing for a -month window between successive records. multiple records occurring within six months of each other were considered as representing the same events cerebrovascular accident all adults (aged ≥ years) any record for cerebrovascular accidents, allowing for a -year window between successive records. multiple records occurring within one year of each other were considered as representing the same event. covid- collateral: indirect acute effects of the covid- pandemic on physical and mental health in the uk mansfield, mathur, tazare, henderson, mulick, et al. condition denominator population (condition-specific denominator populations) condition definition cardiac failure all adults (aged ≥ years) given the complexity with capturing acute events for a chronic condition, we only counted an individual's first ever diagnosis with cardiac failure. venous thromboembolism (pulmonary embolism and deep venous thrombosis) all adults (aged ≥ years) any record for venous thromboembolism, allowing for a -year window between successive records. multiple records occurring within one year of each other were considered as representing the same event. alcohol acute alcohol-related event all adults (aged ≥ years) any record for acute physical or psychological alcohol-related event, including acute alcoholic pancreatitis, multiple records occurring within days of each other were considered as representing the same event. estimated number of primary care contacts for acute physical and mental health conditions in a hypothetical non-covid year compared to the number of contacts estimated from our model for at two weekly time points: th april and th june . estimates for the number of contacts are in a hypothetical population of one million people but the reference populations are condition specific. for example, the estimated number of contacts for diabetic emergencies is among a population of million people aged years and older with a diabetes mellitus diagnosis, whereas the estimated number of people with depression contacts among one million individuals from the general population aged and over. week commencing , * estimates of the difference between scenarios and cumulative difference have been rounded to significant digits to avoid overly precise estimates. we did not intend to estimate the exact number of "missed" consultations but obtained an estimate of the absolute indirect effect of covid- on different conditions. if the expected difference was < or < then estimates have been censored for the same reason. is the author/funder, who has granted medrxiv a license to display the preprint in (which was not certified by peer review) preprint the copyright holder for this this version posted october , . ; https://doi.org/ . / . . . doi: medrxiv preprint percentage of the study populations with gp contacts for study conditions over , by age group. boxplots, historical average percentage of study population with gp contacts for the condition of interest. coloured lines, weekly percentage of eligible population with primary care contacts for the condition of interest in . red dotted line, introduction of restrictions in uk on march rd . note that cell counts with fewer than five contacts in one week in have been suppressed. j a n f e b m a r a p r m a y j u n j u l j a n f e b m a r a p r m a y j u n j u l j a n f e b m a r a p r m a y j u n j u l j a n f e b m a r a p r m a y j u n j u l j a n f e b m a r a p r m a y j u n j u l j a n f e b m a r a p r m a y j u n j u l j a n f e b m a r a p r m a y j u n j u l j a n f e b m a r a p r m a y j u n j u l j a n f e b m a r a p r m a y j u n j u l j a n f e b m a r a p r m a y j u n j u l j a n f e b m a r a p r m a y j u n j u l j a n f e b m a r a p r m a y j u n j u l j a n f e b m a r a p r m a y j u n j u l j a n f e b m a r a p r m a y j u n j u l j a n f e b m a r a p r m a y j u n j u l j a n is the author/funder, who has granted medrxiv a license to display the preprint in (which was not certified by peer review) preprint the copyright holder for this this version posted october , . ; https://doi.org/ . / . . . doi: medrxiv preprint an interrupted time series analysis of the change in gp contacts before and after introduction of uk-wide restrictions. a; grey line, the percentage of the study population with primary care contacts for each health condition. blue region, predicted percentage of contacts from the full its model. black vertical lines, data excluded data from the analysis from st march to th march (adjustment-to-restrictions period). b; % ci for the estimated relative reduction in the percentage of contacts for each health condition immediately after the adjustment-to-restrictions period ( th march ) compared to the pre-restriction period (or closer to shows a greater reduction in the estimated percentage of people with gp contacts). c; estimated effect of time (in weekly increments) post-restriction introduction on the percentage of contacts for each condition. (or greater that indicates increasing percentage of population with contacts over time). results for only are shown here ( figure s for full model fit to data from ) ( is the author/funder, who has granted medrxiv a license to display the preprint in (which was not certified by peer review) preprint is the author/funder, who has granted medrxiv a license to display the preprint in (which was not certified by peer review) preprint the copyright holder for this this version posted october , . diabetic emergencies acute alcohol−related event anxiety depression j a n f e b m a r a p r m a y j u n j u l j a n f e b m a r a p r m a y j u n j u l j a n f e b m a r a p r m a y j u n j u l j a n f e b m a r a p r m a y j u n j u l is the author/funder, who has granted medrxiv a license to display the preprint in (which was not certified by peer review) preprint the copyright holder for this this version posted october , . ; https://doi.org/ . / . . . doi: medrxiv preprint johns hopkins 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hortense title: carcinoembryonic antigen (cea)-related cell adhesion molecules are co-expressed in the human lung and their expression can be modulated in bronchial epithelial cells by non-typable haemophilus influenzae, moraxella catarrhalis, tlr , and type i and ii interferons date: - - journal: respir res doi: . / - - - sha: doc_id: cord_uid: fmsipqu background: the carcinoembryonic antigen (cea)-related cell adhesion molecules ceacam (bgp, cd a), ceacam (cea, cd e) and ceacam (nca, cd c) are expressed in human lung. they play a role in innate and adaptive immunity and are targets for various bacterial and viral adhesins. two pathogens that colonize the normally sterile lower respiratory tract in patients with chronic obstructive pulmonary disease (copd) are non-typable haemophilus influenzae (nthi) and moraxella catarrhalis. both pathogens bind to ceacams and elicit a variety of cellular reactions, including bacterial internalization, cell adhesion and apoptosis. methods: to analyze the (co-) expression of ceacam , ceacam and ceacam in different lung tissues with respect to copd, smoking status and granulocyte infiltration, immunohistochemically stained paraffin sections of donors were studied. to address short-term effects of cigarette smoke and acute inflammation, transcriptional regulation of ceacam , ceacam and different ceacam isoforms by cigarette smoke extract, interferons, toll-like receptor agonists, and bacteria was tested in normal human bronchial epithelial (nhbe) cells by quantitative pcr. corresponding ceacam protein levels were determined by flow cytometry. results: immunohistochemical analysis of lung sections showed the most frequent and intense staining for ceacam , ceacam and ceacam in bronchial and alveolar epithelium, but revealed no significant differences in connection with copd, smoking status and granulocyte infiltration. in nhbe cells, mrna expression of ceacam isoforms ceacam - l, ceacam - s, ceacam - l and ceacam - s were up-regulated by interferons alpha, beta and gamma, as well as the tlr agonist polyinosinic:polycytidylic acid (poly i:c). interferon-gamma also increased ceacam expression. these results were confirmed on protein level by facs analysis. importantly, also nthi and m. catarrhalis increased ceacam mrna levels. this effect was independent of the ability to bind to ceacam . the expression of ceacam was not affected by any treatment or bacterial infection. conclusions: while we did not find a direct correlation between ceacam expression and copd, the copd-associated bacteria nthi and m. catarrhalis were able to increase the expression of their own receptor on host cells. further, the data suggest a role for ceacam and ceacam in the phenomenon of increased host susceptibility to bacterial infection upon viral challenge in the human respiratory tract. able to mediate homophilic and heterophilic interactions and can trigger actin cytoskeleton re-organization [ , ] . ceacam -s can thus not only mediate adhesion as well as internalization of pathogens [ ] , but can also control the signaling activities of the long ceacam isoforms [ ] . chronic obstructive pulmonary disease (copd) is a major cause of morbidity and mortality and is expected to be the third leading cause of death, and the fifth leading cause of disability by [ ] . the global initiative for chronic obstructive lung disease defines copd as characterized by persistent airflow limitation that is usually progressive and associated with an enhanced chronic inflammatory response in the airways and the lung to noxious particles or gases. exacerbations are associated with increased airway and systemic inflammation, and evidence suggests that % may be caused by microorganisms [ ] . two pathogens that are associated with acute exacerbations and the progression of copd are the ceacam-interacting pathogens m. catarrhalis and h. influenzae, which often colonize the mucosa of the lower human respiratory tract in patients with copd [ ] [ ] [ ] . m. catarrhalis and h. influenzae express structurally unrelated outer membrane proteins, ubiquitous surface protein a (uspa ), and p homologous adhesin (p ), respectively, that share the ability to bind to the extracellular immunoglobulin v (igv)like domain of human ceacam [ , ] . the interaction of ceacam with m. catarrhalis results in reduced tlr -initiated inflammatory responses of primary pulmonary epithelial cells [ ] . ceacam and ceacam can mediate bacterial adhesion as well [ , , , ] . all three ceacams in human airway epithelia can therefore be of importance for the colonization of the lower airways and have a role in acute exacerbations. since the lower respiratory airways are normally sterile and protected by mucociliary clearance, ceacams expressed here are most likely to encounter bacteria in medical conditions leading to dysfunction of the mucociliary clearance, such as copd [ ] . to date, a comprehensive analysis of (co-) expression patterns of ceacam isoforms, ceacam and ceacam in the different lung tissues is lacking. in the present study, we found ceacam , ceacam , and ceacam expression on all pulmonary epithelia of the majority of the tested individuals. expression patterns were not dependent on copd, smoking status and granulocyte infiltration. in nhbe cells, ceacam expression was enhanced upon exposure to interferons, the tlr agonist polyinosinic:polycytidylic acid (poly i:c), m. catarrhalis, and nthi. however, there were no differences in the induction of the different ceacam isoforms tested (ceacam - l, ceacam - l, ceacam - s and ceacam - s). ceacam expression was increased by interferon-gamma and ceacam was unaffected by all treatments tested. all materials used were from sigma or merck unless stated otherwise. mouse monoclonal antibodies: b - and c - x (both mono-specific anti-human ceacam , b. b. singer/reliatech), c c and h - (both monospecific anti-human ceacam , b. b. singer), h and h - b (both mono-specific anti-human ceacam , genovac and b.b. singer), / c (mono-specific antihuman ceacam , b.b. singer), and igg isotype control antibody (antibodies-online). polyclonal antibodies: hrpcoupled rabbit anti-mouse igg (dako), hrp-coupled goat anti mouse igg (dianova), rabbit polyclonal anti-cea igg (dako), hrp-coupled goat anti-mouse igg (dianova), alexa fluor -conjugated goat anti-mouse igg (life technologies), pe-conjugated goat anti-mouse igg (h+l, antibodies-online). tissue was obtained from surgical specimens, patients underwent surgery for lung resection to treat lung cancer. a positive vote of the ethics committee of the university of heidelberg and informed consents were obtained. the resected tissue was fixed in formalin and embedded in paraffin using standard procedures [ ] . immunohistochemical staining for ceacam , ceacam , ceacam and ceacam using μg/ml of the monoclonal antibodies b - , c c , h - b and / c, respectively, was performed on paraffin wax sections obtained from different human lung sections. sections were deparaffinized (histoclear × min, ethanol % min, ethanol % min, ethanol % min, ethanol % min) and rehydrated (h o × min). rabbit serumblocking ( % in pbs) was performed before the sections were incubated with primary antibody over night at °c, and with hrp-coupled secondary rabbit antibody for h at rt. then the nickel-glucose oxidase development technique was performed to enhance the dab chromogen of the peroxidase immunohistochemistry. the specimens were counterstained with calcium red for - minutes to visualize the tissue structure. the result was a distinct purple/black staining product. as negative control served an igg istotype matched control antibody. non-cancer tissues from the sections were used for analysis. balf samples were obtained from individuals in whom a bronchoscopy was performed for different diagnostic or therapeutic purposes. all individuals underwent bronchoscopy following standard diagnostic procedures at the department of infectious diseases and pulmonary medicine at the charité -universitätsmedizin berlin with informed consents from the patients. the study was approved by the ethical committee of the charité and all samples were available as residual material without any personal information or clinical data. balf was centrifuged at , rpm and supernatants were then collected and stored in aliquots at − °c until processing for elisa. ceacam -, ceacam -, and ceacam -specific sandwich-elisa frozen balf samples were thawed and centrifuged at × g and °c for min. then ceacam , ceacam , and ceacam were assessed in the supernatants. well micro titer plates (maxisorb tm plates, nunc) were coated for h at room temperature with μg/ml rabbit anti-cea-antibody (dako) diluted in pbs. after washing the plate twice with . % tween (carl roth gmbh) in pbs all unbound sites were blocked for h at room temperature with pbs containing % bovine serum albumin (carl roth gmbh). to quantify the different ceacams in the samples appropriate standard curves were prepared by making serial dilutions of recombinant human ceacam -fc, recombinant human ceacam -fc and purified cea (from . ng/ml to ng/ml). the standard and the undiluted samples were incubated over night at °c and washed three times. then μg/ml c - x (anti-ceacam ), c c (ceacam ), or h - b (ceacam ) were added. plates were washed three times with pbs and supplemented with hrpcoupled goat anti mouse antibody (dianova) for h followed by three washing steps. then μl tmb-x-tra substrate (biotrend chemikalien gmbh) were added and incubated for up to min. the reaction was stopped by μl of n h so (carl roth) and optical densities were read at nm in a microplate reader (tecan). all antibodies, samples and standard curves were diluted in pbs containing . % bsa. the linear ranges for ceacams , , and were . ng/ml - ng/ml. preparation of aqueous phase cigarette smoke extract (cse) cse was prepared as described [ ] . briefly, smoke from one cigarette ( mg tar, . mg nicotine; camel filters, japan tobaco international) with the mouthpiece filter removed was bubbled through ml complete medium using a peristaltic pump (p- , ge healthcare) and filtered through a . μm filter. suction was regulated, so that sidestream smoke developed during the entire combustion, lasting min for each cigarette. the filtered cse was regarded as %. cse was used within min of preparation at a final concentration of %. lau et al. showed that nhbe cells were induced to secrete il- and remained viable after tratment with % cse for h [ ] . primary normal human bronchial epithelial (nhbe) cells (lonza) were propagated as suggested by the supplier in collagen i-coated flasks or plates (bd biosciences) in bronchial epithelial cell basal medium (bebm, lonza) supplemented with bovine pitituary extract (bpe), hydrocortisone, human epidermal growth factor (hegf) epinephrine, transferrin, insulin, retinoic acid and triiodothyronine (from the begm bullet kit, lonza). prior to stimulation, cells in passage - were grown to confluence. nhbe cells were treated for the indicated durations with ng/ml ifnα (interferon alpha a, immunotools), ng/ml ifnβ (interferon beta a, immunotools), ng/ml ifnγ (recombinant human interferon gamma, promokine), ng/ml tnfα (recombinant human tumor necrosis factor alpha, r&d systems), ng/ml malp- (enzo life sciences gmbh), ng/ml poly i:c (high molecular weight, invivogene), ng/ml flagellin (invivogene biotech), or % cse (see above). the concentrations chosen for the treatments described above are standard concentrations used for lung epithelial cells [ ] [ ] [ ] [ ] [ ] [ ] [ ] . infections werde done using the following strains: m. catarrhalis: (wild type, american type culture collection); bbh (wild type) and bbh . (adhesin uspa deletion mutant unable to bind ceacam ), both kindly provided by kristian riesbeck, malmö lund university, skåne university hospital, malmö, sweden; nontypable haemophilus influenzae (nthi): (wild type), kindly provided by edward swords, university of iowa, usa; (wild type) and f-(adhesin p deletion mutant unable to bind to ceacam ), both kindly provided by lauren o. bakaletz, the research institute at nationwide children's hospital and the ohio state university college of medicine, usa. for infection, bacteria were freshly grown over night at °c, % co on columbia agar or chocolate agar, respectively (both bd biosciences). bacteria were incubated to exponential growth (mid-log phase) in liquid brain heart infusion (bhi) broth at rpm, °c (bhi, bd biosciences; for nthi supplemented with μg/ml hemin, sigma aldrich, and μg/ml nad, mp biomedicals). bacteria were harvested by centrifugation and re-suspended in pbs. colony forming units (cfu) were determined by measurement of optical densities (m. catarrhalis: od nm = . correlates with × cfu/ml; nthi: od nm = . correlates with cfu/ml). cells were infected for h at a multiplicity of infection (moi) of (moraxella catarrhalis) or (nthi). optimal mois were determined in pilot experiments by analysis of maximal induction of interleukin secretion in the absence of cytotoxic effects (data not shown). immunoprecipitations from cell culture supernatants nhbe cell culture supernatants from confluent cells were harvested after h. ceacam , ceacam and ceacam were precipitated from ml supernatant using μl protein g-sepharose fast flow (ge healthcare) and μg of monoclonal antibodies b - , h - , and h , respectively. an igg isotype control was included. immunoprecipitations were analyzed by western blot using anti cea polyclonal antibody that cross-reacts with all three ceacams and hrp-coupled goat anti-rabbit igg. analysis was done using the fusion fx system (peqlab) and supersignal west pico chemiluminescent substrate (thermo scientific). to analyze the gene expression of ceacam , ceacam , and ceacam , total rna was extracted from × nhbe cells using the qiagen rneasy mini kit. residual genomic dna was removed by on-column incubation with dnasei (qiagen). a nanodrop d- spectrophotometer (thermo-fisher scientific) was then used to assess the amount and quality of the isolated rna samples. first-strand complementary dna (cdna) was synthesized from μg of rna using the high capacity cdna reverse transcription kit (applied biosystems). to detect the expression of the ceacam genes by pcr, specific primers for each target were designed using the on-line primer-blast tool of the national center for biotechnology information (ncbi, http://www.ncbi.nlm.nih.gov/ tools/primer-blast/). possible secondary structures at the primer binding sites were taken into account by characterizing the nucleotide sequence of the regions of interest using the mfold algorithm [ ] . primer design across different exon boundaries allowed for specific primer pairs targeting isoforms of ceacam . primers were also designed for ceacam , ceacam , two housekeeping genes, and ifnβ- a. pcrs of the cdnas were carried out on a s tm thermal cycler (biorad) in a μl reaction volume containing . μm primers, u taq dna polymerase ( -prime) and μm dntps. thermal conditions included an initial °c denaturation step for min, and then cycles of s at °c, s at °c and s at °c. the resulting pcr products were separated on an ethidium bromide containing agarose gel and visualized under a uv-transiluminator to confirm the expected amplicon size. to verify the identity of amplified pcr fragments of the ceacam genes and the different splicing variants of ceacam , pcr-products were purified and sequenced (eurofins mwg operon, ebersberg, germany). sequences were aligned with the corresponding ncbi-reference transcripts using clustalx [ ] . to quantify the relative expression of each gene, we used a cas- pipetting robot (qiagen) to set up the qpcrreactions and a corbett rotor-gene (qiagen) as real-time qpcr apparatus. each sample was analyzed in duplicate in a total reaction volume of μl containing μl of × sensimix sybr master mix (bioline) and . μm of each primer. the cycling conditions included an initial step of °c for min followed by cycles of °c for s, °c for s and °c for s. for each experiment, an rt-negative sample was included as a control. melting curve analysis and size verification by electrophoresis was used to confirm the specificity of the qpcr reactions. the relative expression of the target genes was analyzed using the pfaffl method [ ] . the expression levels were normalized to the geometric mean of housekeeping genes: hypoxanthine phosphoribosyltransferase (hprt ) and peptidylpropyl isomerase b (ppib). the stability of the housekeeping genes was assessed using the bestkeeper algorithm [ ] . relative differences in mrna expression between different experimental conditions were analyzed by pair-wise fixed randomization tests using the rest software [ ] . nhbe cells were grown on cover slips, fixed in pbs/ % paraformaldehyde and blocked with pbs/ % bovine serum albumin. confocal images of indirect immunofluorescence of ceacam , ceacam and ceacam (b - , h - , and h , respectively, and alexa fluor -conjugated goat anti-mouse igg), actin (tric-conjugated phalloidin) and nuclei (hoechst ) were taken using a zeiss confocal microscope equipped with the plan-apo x/ . oil objective. pictures were processed using the zen software (zeiss) and adobe photoshop. nhbe cells were cultured and treated as described above, detached using trypsin/edta (invitrogen/life science) and kept in pbs/ % fbs on ice. cells were stained using antibodies b - (ceacam ) and h - (ceacam ) at μg/ml, and : pe-conjugated goat anti-mouse igg. analysis was done using the facsaria ii (bd biosciences) and flowjo (tree star inc.) software. expression and co-expression patterns of ceacam , ceacam and ceacam in the human lung were analyzed. paraffin sections of lung tissues from donors who underwent surgery for lung resection to treat lung cancer (table ) were stained with an igg control antibody and antibodies specific for ceacam , and , as well as with an antibody specific for ceacam , which is solely expressed in human granulocytes. noncancer tissues from these sections were used for analysis. figure shows representative ceacam stainings of lung sections for the respective antibodies. table gives an overview of the number of positive tissues in the specimens. ceacam was expressed in out of lungs, ceacam in out of and ceacam in all lungs examined ( figure and table ). as expected, granulocyte-specific ceacam ( figure d , table ) showed strong staining if infiltrated granulocytes appeared (data not shown) and did not give any staining above igg background in granulocyte-free lung tissues (table ) . ceacam expression was most intense in bronchial epithelium, where it was found in specimens out of ( figure a , table ). blood vessel endothelium also showed distinct ceacam staining ( / ) . a weaker expression was found in alveolar epithelium and pleura ( / and / respectively). in some cases the adventitia submucosa was ceacam positive ( / ). ceacam displayed frequent and intense staining in bronchial and alveolar epithelium ( figure b , table ). the former tissue was always positive when found in the respective specimen ( / ), the latter in out of samples. also, pleura and blood vessel endothelium were often ceacam positive ( / and / , respectively). a weaker and less frequent ceacam expression was found in the adventitia submucosa ( / ) . ceacam showed an abundant and strong staining in the alveolar epithelium of all lungs examined ( figure c , table ). the bronchial epithelium of most specimens also displayed a strong ceacam expression ( / ) . in some cases, the pleura exhibited a weak ceacam staining ( / ). adventitia submucosa and blood vessel endothelium did not show any ceacam expression. the co-expression patterns of ceacam , ceacam and ceacam in the different lung tissues of the chronic obstructive pulmonary disease (copd) hypertension granulocyte infiltration specimens were also analyzed ( table ). in alveolar epithelium, ceacam was present in all specimens; therefore, only ceacam and ceacam expressions varied. ceacam was mostly co-expressed with both, ceacam and ceacam . in bronchial epithelium, ceacam was expressed in all specimens; only ceacam and ceacam expression varied. both proteins were co-expressed with ceacam alone and with each other. the adventitia submucosa was always negative for ceacam . ceacam and ceacam paraffin sections of human lung tissue from surgical specimens of lung cancer patients (n= ) were stained for ceacam , ceacam , ceacam , ceacam and an unspecific control igg. figure shows representative pictures of non-cancer tissues for these stainings. ceacam expression in non-cancer tissues was analyzed for alveolar epithelium, bronchial epithelium, adventitia submucosa, pleura and blood vessel endothelium. since not all tissue types were found for all specimens, the number of positive specimen and the number of total specimen including the respective tissue are given. *assessment of total staining includes alveolar epithelium, bronchial epithelium, adventitia submucosa, pleura and blood vessel endothelium and excludes present blood cells due to intrinsic peroxidase activity. § four lung sections showed enhanced background staining for the control igg or the anti-ceacam antibody. were expressed alone or co-expressed. when the pleura was positive for ceacam , at least one of the two other ceacams were co-expressed. most of the ceacam -negative specimens showed pleura staining for ceacam , and some for ceacam and ceacam . blood vessel endothelium was negative for ceacam and showed staining for ceacam and ceacam either alone or together (table ) . coexpression patterns showed no correlation to copd, smoking status and granulocyte infiltration in total staining analysis or in the individual lung tissues (alveolar epithelium, bronchial epithelium, adventitia submucosa, pleura and blood vessel endothelium; data not shown). ceacam expression in human lung does not correlate with copd, smoking status or granulocyte infiltration it was then examined whether the presence or expression level of ceacam , ceacam and ceacam were linked to copd or smoking status. table shows the relative staining intensity of the three ceacams. total staining of the paraffin sections, including alveolar epithelium, bronchial epithelium, adventitia submucosa, pleura and blood vessel endothelium, was assessed in the range of (no staining) to (strong staining). however, no correlation was found for either the presence (data not shown) or the expression levels (table ) of the tested ceacams according to two-tailed student's t-test. next, the interdependency of ceacam , ceacam and ceacam expression with granulocyte infiltration was analyzed, but again no correlation was detected (table ) . also, the correlation of ceacam expression with copd, smoking status and granulocyte infiltration in the individual lung tissues (alveolar epithelium, bronchial epithelium, adventitia submucosa, pleura and blood vessel endothelium) was examined, but no significant differences were found (data not shown). next, the presence of soluble ceacam , ceacam and ceacam in bronchoalveolar lavage fluid (balf) was evaluated. therefore balf samples were examined by elisa (figure a ). ceacam was found with an average concentration of ng/ml (± ng/ml sd) in out of balf samples ( . %). ceacam was present in . % of balf samples with an average concentration of ng/ml (± . ng/ml sd) and ceacam in all paraffin sections of human lung tissue from surgical specimens of lung cancer patients (n= ) were stained for ceacam , ceacam , and ceacam . figure shows representative pictures for these stainings. non-cancer tissues were analyzed for the co-expression of ceacam , ceacam and ceacam . numbers of specimens with the respective pattern denominated in column are given. *assessment of total staining includes alveolar epithelium, bronchial epithelium, adventitia submucosa, pleura and blood vessel endothelium, and excludes present blood cells due to intrinsic peroxidase activity. §one or more stainings for ceacam , ceacam or ceacam are missing for this tissue in a specimen preventing an evaluation. paraffin sections of human lung tissue from surgical specimens of lung cancer patients (n= ) were stained for ceacam , ceacam , ceacam , ceacam and an unspecific control igg. figure shows representative pictures for these stainings. relative total stainings (including alveolar epithelium, bronchial epithelium, adventitia submucosa, pleura and blood vessel endothelium) were assessed in the range of (no staining) to (strong staining). numbers given are mean intensity and standart deviation. no significant differences were found in comparison to the respective control groups according to two-tailed student's t-test. balf samples with at an average concentration of ng/ ml (± ng/ml sd). in order to approach soluble ceacam expression in human lung with an alternative method, normal human bronchial epithelial (nhbe) cells from healthy donors were used for transcription analysis. rt-pcr and subsequent sequencing of the obtained pcrproducts confirmed the expression of three soluble ceacam isoforms, ceacam - c , ceacam - and ceacam - c ( figure b ). however, mrnas of all three isoforms were not expressed at sufficient levels to allow for reliable quantification analysis by qpcr. to test for expressed and shedded soluble ceacams in nhbe cells, ceacam -, -, and -immunoprecipitations from cell culture supernatants were analyzed. western blot analysis revealed soluble ceacam and low amounts of soluble ceacam , but no soluble ceacam ( figure c ) in nhbe cell culture supernatants. in order to investigate the regulation of ceacams by cigarette smoke or in the presence of acute inflammation in human lung, nhbe cells were stimulated as described below and the expression of ceacams was analyzed using rt-pcr and qpcr. untreated confluent nhbe cells expressed ceacam and ceacam , as well as the ceacam isoforms ceacam - l, ceacam - s, ceacam - l and ceacam - s. this was shown through rt-pcr analysis with pairs of primers specific for each ceacam and isoforms ( table ). identity of the obtained pcr-products for each ceacam and isoforms was confirmed by sequencing. the intensity of the resulting bands after electrophoretic separation suggests that both ceacam isoforms bearing the long cytoplasmic domain were expressed to a much lesser extent than the two short ceacam isoforms. to address short-term effects of smoking on epithelial ceacam expression, nhbe cells were exposed to cse. to assess the tie of ceacam expression in human lung cells to innate immune responses, nhbe cells were treated with ifnα, ifnβ, ifnγ, tnfα, and the tlr agonists malp- (tlr / ), poly i:c (tlr ) and flagellin (tlr ). then, rna from these cells was isolated and qpcr analysis was used to check for differences in ceacam - l, ceacam - l, ceacam - s, ceacam - s, ceacam and ceacam mrna levels. to ensure an accurate normalization of their expression levels, we tested two candidate housekeeping genes for their stability across the unstimulated and stimulated samples. ppib (sd (±ct)= . ; cv(%ct)= . ) as well as hprt (sd(±ct)= . ; cv(%ct)= . ) showed a highly stable expression, allowing for normalization with the geometric means of both genes. the four transmembrane ceacam -isoforms ceacam - l, ceacam - l, ceacam - s and ceacam - s were basically co-regulated by all reagents that elicited a difference in transcription levels (table , figure b ). ifnα significantly upregulated the expression of ceacam - l ( . -fold, p < . ), ceacam - s ( . -fold, p < . ) and ceacam - s ( . -fold, p < . ), whereas the . -fold upregulation of ceacam - l failed to reach significance (p = . ). ifnβ and ifnγ significantly increased the expression of all four splicing variants of ceacam (p < . in all cases). in the case of ifnβ we could observe a slightly higher up-regulation of the two short isoforms ceacam - s ( . -fold) and ceacam - s ( . -fold) than the long isoforms ceacam - l ( . -fold) and ceacam - l ( . -fold). on the other side, ifnγ seemed to favor the two long isoforms ceacam - l ( . -fold) and ceacam - l ( . -fold) when compared to the short variants ceacam - s ( . -fold) and ceacam - s ( . -fold). however, no significant alteration in the ratios between long and short ceacam isoforms was observed. poly i:c treatment also upregulated all four isoforms of ceacam in a significant manner (p < . in all cases) with expression ratios ranging between . and . -fold ( figure b ). cse, tnfα, malp- and flagellin had no effect on any of the four ceacam transcripts despite of a significant increase of the il- mrna levels, which served as positive control of their efficacy (data not shown). in order to examine whether the positive responses of the ceacam isoforms to poly i:c were caused by the up-regulation of interferons, poly i:c treated nhbe cells were analyzed for ifnα, ifnβ and ifnγ mrna expression. ifnα and ifnγ mrnas were not expressed at sufficient levels to allow qpcr analysis (data not shown). however, qpcr showed that poly i:c strongly induced an immediate ifnβ expression ( -fold increase after h) that dissolved after h ( figure e ). qpcr showed that ifnγ treatment also significantly increased ceacam mrna levels in nhbe cells by . -fold ( figure c) . no difference in ceacam mrna levels were induced by cse, ifnα, ifnβ, tnfα, or any of the tlr agonists. ceacam expression levels in nhbe cells were not altered under any of the tested conditions ( figure d ). indirect immunofluorescence showed that ceacam , ceacam and ceacam were expressed on the cell surface of untreated confluent nhbe cells ( figure a) . while ceacam showed a low expression on most cells, ceacam and ceacam , respectively, were only expressed by a subpopulation. it was then tested whether the up-regulation of ceacam transcripts upon treatment with ifnα, ifnβ, ifnγ, and poly i:c were also reflected by higher cell surface protein levels. facs analysis confirmed an increased expression of ceacam on the cell surface of nhbe cells under all four conditions ( figure b ). the ceacam -specific antibody used for flow cytometry did not allow discrimination between the different isoforms. also, an increased ceacam cell surface expression upon ifnγ treatment could be confirmed by facs analysis ( figure c ). flow cytometry also verified that there was only a small subpopulation of nhbe cells that were ceacam positive in untreated control cells. upon ifnγ treatment, both, the number of ceacam positive cells and the expression level of ceacam on the cell surface, were increased ( figure c ). however, it remained only a defined portion of nhbe cells that expressed ceacam . structure of forward and reverse primers ( ′- ′) of all target genes and isoforms and the expected size of their respective amplified pcr-products. next, the effects of acute nthi and moraxella catarrhalis infection on ceacam , ceacam and ceacam mrna expression levels in nhbe cells were investigated ( figure ). qpcr analysis revealed no differences in ceacam and ceacam expression upon bacterial infection. the m. catarrhalis wild type strains and bbh as well as the nthi wild type strains and enhanced the mrna expression of all four transmembrane ceacam -isoforms to a similar degree in a co-regulatory manner ( figure a,b,d,e) . the mean induction of ceacam transcription by m. catarrhalis strains was twice as high as by nthi strains ( . - . fold vs. . - . fold). since all four pathogens can bind to ceacam , we next tested whether this interaction was essential to the up-regulation of ceacam . to that end we used the m. catarrhalis uspa deletion mutant bbh . and the nthi p deletion mutant f-, which both lack the respective ceacam -binding adhesin ( figure c,f) . again, the infection with these strains induced an elevated ceacam expression ( . - . fold and . - . fold, respectively) comparable to their parental strains, indicating a ceacam -independent, more general mechanism for this effect. we then tested whether the ceacam upregulation might be due to an increase in interferons. both here we present the first comprehensive study based on immunohistochemistry demonstrating that ceacam , ceacam , and ceacam are frequently co-expressed in several tissues of the human lung, including epithelia of the airways and alveoli. ceacam expression was not connected to copd, smoking status and granulocyte infiltration ( figure , tables and ). despite the analysis of non-cancer tissues from the specimen, the fact that the lung sections used for immunohistochemical analysis were from patients that underwent lung resection to treat lung cancer might conceal a regulatory effect of copd or smoking status on ceacam expression, since ceacam , ceacam , and ceacam have all been shown to be up-regulated in lung cancer [ ] [ ] [ ] [ ] [ ] . also, the inflammatory processes associated with cancers of the lung might have had an effect on the expression levels of the ceacams. for example, as discussed below, ifnγ can up-regulate ceacams , , and . importantly, we show that the copd-associated pathogens m. catarrhalis and nthi can also upregulate ceacam expression independent of their ability to bind to ceacam . the up-regulation by m. catarrhalis might be at least in part due to the induction of ifnβ production ( figure g ) and is in accordance with the observation of ceacam up-regulation by pathogenic neisseria in endothelial and epithelial cells [ , ] . ceacam and ceacam expression levels were not affected by m. catarrhalis and nthi. however, both receptors were already expressed at high levels and in all specimens (figure , tables and ). regarding colonization, the increase in ceacam on epithelial cells upon bacterial challenge is likely to increase bacterial adherence and infection. this interaction would be facilitated by an impaired mucocilliary clearance, which is associated with later phases of copd. thus, ceacam receptors might be at least in part responsible for the colonization of the lower airways by m. catarrhalis and nthi in copd patients. this setting would also explain the association of bacterial colonization with progressive/ advanced disease despite the fact that we did not find a regulation of ceacam expression by the chronic pathologic conditions copd, smoking status and granulocyte infiltration (figure , tables and ) . further studies including identification of pathogens in the lower airways will be necessary to shed light on this aspect of ceacam-pathogen interactions. it will be also important to take into account that an up-regulation of ceacams might be transient either due to temporary qualities of chronic/persistent disease or due to pathogen characteristics at distinct time points during the infection process. it will also be interesting to test human lung tissues for the presence of the other ceacams expressed on epithelial cells (ceacam , , and [ , ] ) and to analyze their ability to interact with pathogens. the up-regulation of membrane-bound ceacam receptors might be necessary to counteract the presence of soluble receptor forms that might act as decoys to prevent bacterial/viral infections or immune evasion. even though bacteria possess redundant targeting mechanisms, and bacterial adhesins often work in a sequential manner, hill et al. showed that perturbing ceacam -, ceacam -and ceacam -based adhesion by using a ceacam-binding peptide prevents host cell binding by m. catarrhalis, h. influenzae, n. meningitidis and n. gonorrhoeae in a cell culture model [ ] . the amounts of soluble ceacams, with high concentrations of soluble ceacam in all and lower concentrations of soluble ceacam in . % of the bronchoalveolar lavage fluid samples is mirrored in the expression levels of their membrane-bound counterparts in lung tissues (figures , , , and [ ] [ ] [ ] ). the fact that soluble ceacam is all but absent in balf ( % negative balf samples) increases the importance of this receptor for colonization by pathogens despite its comparatively low expression levels in human lung. in nhbe cells, ceacam mrna and protein levels were also increased by ifnα, ifnβ, ifnγ and the tlr agonist poly i:c ( figure b ). all membrane-bound ceacam isoforms examined here were basically coregulated under all conditions that affected their expression level (figures and ) . however, some differences were found for the differential up-regulation of the ceacam isoforms. type i interferons (ifnα and ifnβ) favored the two short isoforms while the type ii interferon ifnγ favored the long isoforms, and poly i:c favored the long and the short isoforms bearing extracellular domains. especially the former differences, even though not significant, are interesting with regard to the fact that in order to interfere with tlr signaling or with t-cell activation, binding of the shp- phosphatase to the immunoreceptor tyrosine-based inhibitory motif (itim) within the cytoplasmic domain of the long ceacam isoform was necessary [ , , ] . the two tyrosine residues that are part of the itim can bind to protein tyrosine kinases (e.g. c-src) as well as protein tyrosine phosphatases (e.g. shp- ) -leading to the stimulation or the inhibition of cell-signaling pathways, respectively. long and short ceacam isoforms can appear as monomers, dimers and oligomeric microclusters in the membrane [ , ] . trans-homophilic binding between different ceacam molecules increases cis-dimerization in the plane of the membrane via an allostery-based mechanism. binding of ceacam -l to shp- or c-src is dependent on the balance between the oligomeric states as well as the ratio of long and short isoforms [ , ] . interestingly, no cytoplasmic domain is necessary for the ceacam -mediated internalization of h. influenzae, m. catarrhalis and n. gonorrhea [ ] . but bacterial engagement of ceacam might, in addition to procuring adherence, also influence the cis-dimerization and subsequent inhibitory or activatory signaling of ceacam , either supporting pathogen colonization or host response. for example, the interaction of ceacam with m. catarrhalis and n. meningitidis proteins resulted in reduced tolllike receptor (tlr) -initiated inflammatory responses (the major mediator of m. catarrhalis-induced immune responses) of nhbe cells [ , , ] . part of the host response to microbial infection is the production of cytokines [ ] . type i interferons ifnα and ifnβ can be produced by most cell types and are the major effector cytokines of the host immune response against viral infections. however, the production of type i interferons is also induced in response to bacterial infections [ ] . the type ii interferon ifnγ plays an important role during the immune response to bacterial pathogens, but is also induced upon infection with viruses. it is produced predominantly by natural killer (nk) cells and natural killer t cells as part of the innate immune response and by th cd + and cd + cytotoxic t lymphocyte effector t cells once antigen-specific immunity develops [ ] . in the present study ceacam is up-regulated in nhbe cells by ifnγ, but not by type i interferons, and ceacam is increased by type i and type ii interferons (ifnβ and ifnγ, figure b and d). while for ceacam , ceacam and ceacam an upregulation by ifnγ and viral infections has been described in epithelial cells [ , [ ] [ ] [ ] [ ] [ ] , to our knowledge this is the first report that also type i interferons enhance ceacam expression. a temporal association between bacterial and viral infections is often observed in the human upper respiratory tract [ , ] . infection by opportunistic colonizers, including haemophilus influenzae and moraxella catarrhalis, increases considerably following influenza and/ or respiratory syncytial virus (rsv) infections [ , ] . copd is often associated with viral infections, mostly by rhinovirus, and it was recently shown that these infections indeed precipitate secondary bacterial infections, particularly in copd patients [ ] . importantly, the present study shows that in addition to the primarily viral induced type i interferons, tlr agonist poly i:c also increased ceacam expression ( figure b ). tlr plays a key role in anti-viral immune responses and recognizes synthetic dsrna like poly i:c and virus derived dsrna contained in cells infected by positive-stranded rna viruses and dna viruses [ , ] . it was shown recently that poly i:c enhances the susceptibility to secondary pulmonary infections by gram-positive bacteria in a mouse model [ ] . the positive-stranded rna virus rhinovirus enhances ceacam expression in human nasal epithelial cells and two negative-stranded rna viruses, respiratory syncytial virus (rsv) and human parainfluenza virus (hpiv- ), enhance ceacam expression in a and nhbe cells [ , ] . since the latter viruses have to be recognized via tlr or tlr , this is the first indication that the pathogen receptor ceacam might also be up-regulated by positive-stranded rna viruses via tlr . ceacam expression was not altered by any agent used in this investigation ( figure d ). this was probably due to its initially high expression level in the nhbe cells. fahlgren et al. showed that the ls t cell line that expressed high levels of ceacam and ceacam before ifnγ treatment did not show any enhanced expression after ifnγ exposure while ifnγ up-regulated both mrnas in two cell lines, ht- and t , that initially expressed low levels of ceacam and ceacam [ ] . however, the very high and constant ceacam expression in nhbe cells as well as in the lung specimens is in accordance with its proposed role as a surfactant [ , ] . the up-regulation via viruses and the effects of the inflammatory cytokine ifnγ imply a more general role for ceacam and ceacam in the inflammatory response to infection, and also in the spatial and temporal association between bacterial and viral infections. one of the underlying mechanisms for the colonization of copd patients by m. catarrhalis and nthi may consist of the up-regulation of specific host receptors, i.e. ceacam , by viral infections, as described for several cea family receptors [ , , , ] . for pathogenic neisseria it was demonstrated that increased ceacam expression levels correlated with an increase in bacterial invasion [ , ] . once established, m. catarrhalis and nthi themselves are also able to increase the expression of their receptor ceacam . whether the starting point is a viral or bacterial pathogen, the result is a continual cycle of infection-induced increase in cytokine levels and, subsequently, receptor expression which then promotes bacterial invasion. since viruses also recruit ceacams, elevated ceacam expression might aid viral infection as well [ , ] . ceacam is a well-established receptor for bacteria, including the human pathogens m. catarrhalis and h. influenza that both colonize about one third of all copd patients and cause acute exacerbations. while we did not find a direct correlation between ceacam expression and copd, these copd-linked bacteria were able to increase the expression of their own receptor on host cells. we also propose a role for the constitutively expressed ceacam as well as ceacam and ceacam in the phenomenon of increased host susceptibility to bacterial infection upon viral challenge in the human respiratory tract, as it occours for example in copd patients, since either enhanced ceacam expression induced by viruses or the copd-associated changes in the function of the mucociliary clearance that will allow an easy access to ceacams on respiratory epithelia are likely to increase 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cell survival through interaction with carcinoembryonic antigen-related cell adhesion molecule (ceacam ) protein coronavirus species specificity: murine coronavirus binds to a mouse-specific epitope on its carcinoembryonic antigen-related receptor glycoprotein submit your next manuscript to biomed central and take full advantage of: • convenient online submission • thorough peer review • no space constraints or color figure charges • immediate publication on acceptance • inclusion in pubmed, cas, scopus and google scholar • research which is freely available for redistribution we thank simone tänzer and birgit maranca-huewel for their excellent technical assistance. this work was supported by the german federal ministry of education and research (bmbf z jn to h.s and eo to ek/center for sepsis control and care), and by the german research foundation (dfg) (sl / - to hs). the authors declare that they have no competing interests.authors' contributions hs conceived, designed and coordinated the study. ek analyzed immunohistochemical pictures and performed statistical analysis. tek, ek and is designed, performed and analyzed qpcr experiments. mmm and ek performed and analyzed immunoprecipitations, western blots, and confocal microscopic studies. bbs did immunohistochemical experiments and performed and analyzed elisas. ah performed and analyzed facs experiments. ek, tek and kah accomplished nhbe stimulations. hd, cg and rb collected lung specimen and performed paraffin embedding and sectioning. ek and hs drafted the manuscript. all co-authors read and approved the final manuscript. key: cord- -vmbhok u authors: sichelstiel, anke; yadava, koshika; trompette, aurélien; salami, olawale; iwakura, yoichiro; nicod, laurent p.; marsland, benjamin j. title: targeting il- β and il- a driven inflammation during influenza-induced exacerbations of chronic lung inflammation date: - - journal: plos one doi: . /journal.pone. sha: doc_id: cord_uid: vmbhok u for patients with chronic lung diseases, such as chronic obstructive pulmonary disease (copd), exacerbations are life-threatening events causing acute respiratory distress that can even lead to hospitalization and death. although a great deal of effort has been put into research of exacerbations and potential treatment options, the exact underlying mechanisms are yet to be deciphered and no therapy that effectively targets the excessive inflammation is available. in this study, we report that interleukin- β (il- β) and interleukin- a (il- a) are key mediators of neutrophilic inflammation in influenza-induced exacerbations of chronic lung inflammation. using a mouse model of disease, our data shows a role for il- β in mediating lung dysfunction, and in driving neutrophilic inflammation during the whole phase of viral infection. we further report a role for il- a as a mediator of il- β induced neutrophilia at early time points during influenza-induced exacerbations. blocking of il- a or il- resulted in a significant abrogation of neutrophil recruitment to the airways in the initial phase of infection or at the peak of viral replication, respectively. therefore, il- a and il- β are potential targets for therapeutic treatment of viral exacerbations of chronic lung inflammation chronic obstructive pulmonary disease (copd) is currently ranked the th leading cause of death worldwide by the world health organization (who), and its incidence is increasing. the main risk factor of copd is exposure to tobacco smoke which triggers a cascade of inflammatory pathways leading to disease induction in susceptible people. major hallmarks of the disease pathology are the development of emphysema and chronic bronchitis that lead to a progressive and irreversible airflow limitation resulting in a continuous decline of lung function [ ] . copd severity has been associated with acute periods of disease worsening [ , ] , so-called exacerbations, a key factor in copd morbidity and mortality [ , ] . by causing acute respiratory distress, they impact on the quality of patient's health [ ] and are responsible for most hospital stays related to the disease [ ] . exacerbations are primarily caused by respiratory viral or bacterial infections. amongst those, viral-induced exacerbations account for approximately half of the cases [ , ] and are associated with more severe acute episodes and prolonged recovery time [ ] [ ] [ ] . the most common viral pathogen in exacerbated patients is rhinovirus, followed by influenza virus, rsv and coronavirus [ , , , ] . due to targeted vaccination of high risk groups, influenza infections occur less frequently in copd patients of westernized countries [ ] . however, they continue to be the predominant cause of viral exacerbations in hong kong [ ] and singapore [ ] . copd exacerbations have been linked to excessive inflammatory responses, including enhanced recruitment of inflammatory cells [ ] and upregulation of a variety of proinflammatory mediators [ , ] . nevertheless, the underlying mechanisms and the most effective therapeutic strategies are still poorly understood and first-line therapy still predominantly relies on corticosteroids and bronchodilators [ ] , which are limited in their efficacy [ , ] . thus, the study of cellular and molecular mechanisms leading to exacerbations is key for the identification of urgently required therapeutic targets. one of the proinflammatory cytokines that has been associated with copd is il- b, a major player in initiation and persistence of inflammation. in animal models mimicking features of copd, il- has been shown to be key to the induction of emphysema and inflammation [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . furthermore, its expression is significantly enhanced in copd patients during acute episodes of exacerbations [ , , , ] . unraveling the role of il- b in viral exacerbations might therefore not only result in an overall better understanding of mechanisms of exacerbations, but also indicate whether it qualifies as a valid therapeutic target. a promising candidate for therapeutic inhibition of il- b signaling is one of its inhibitors, the interleukin- receptor antagonist (il- ra) anakinra (kineret, amgen), which has been used effectively in treatment of rheumatoid arthritis. in order to investigate the role of il- b during copd exacerbations we utilized a model of lps and elastase induced chronic lung inflammation, followed by infection with influenza in wild type or il- b deficient mice. we found that il- b was a key driver of pulmonary inflammation, primarily concerning recruitment of neutrophils and lung dysfunction. il- b driven neutrophilia was mediated by il- a in the initial phase of viral infection, but became independent of il- a during the peak phase of viral replication. treatment with the il- ra, anakinra, proved efficient in reducing neutrophilic inflammation at the peak of viral replication while blocking of il- a abrogated neutrophilia in the early phase of viral infection. taken together our data indicate that blockade of il- b and il- a could be valid therapeutic approaches for treatment of virus-induced copd exacerbations. all animal experiments were performed according to institutional guidelines and swiss federal and cantonal laws on animal protection. animal experiments were approved by the following ethical committee: service de la consommation et des affaires vétérinaires, affaires vétérinaires, canton de vaud, switzerland (permit numbers and ). c bl/ or balb/c mice were between - weeks of age and were purchased from charles river laboratories. il- b deficient mice on c bl/ background were received from prof. iwakura [ ] , tokyo university of science, japan, and bred in house. mice were exposed intranasally to a mixture of mg lps from e. coli o :b (sigma-aldrich) and . u porcine pancreatic elastase (epc) in a total volume of ml, and treated once per week for four consecutive weeks ( figure a ). control mice were treated with pbs. two weeks after the last lps/elastase challenge, mice were infected with pfu influenza a virus, strain pr (a/puerto rico / , h n , viropur). the virus was administered intranasally in a total volume of ml pbs; control mice received only pbs. for all intranasal administrations c bl/ mice were anesthetized by intraperitoneal injection of . mg/kg ketamin (ketasol- , graeub) and . mg/kg xylazin (xylasol, graeub) and balb/c mice with mg/kg ketamin and . mg/kg xylazin. lungs were inflated with ml % formalin, embedded into paraffin and stained with hematoxylin and eosin. stained slides were analyzed by light microscopy. pulmonary emphysema was quantified using image j software by measuring the mean linear intercept for airspace enlargement and destruction index for alveolar wall destruction. fields of view at x magnification per section of lung were used for quantification as described previously [ , ] . airway cells were recovered by bronchoalveolar lavage and either analyzed by flow cytometry as described below or spun onto slides for differential cell counts. slides were stained with diff-quik (dade) and counts were performed according to standard criteria. total lung resistance was measured using the whole body restrained plethysmograph system flexivent from scireq. mice were anesthetized by intramuscular injection of mg/kg ketamine (ketasol- , graeub) and intraperitoneal injection of mg/kg pentobarbital (esconarkon, streuli pharma). subsequently, mice were tracheotomized and mechanically ventilated at a rate of breaths/min and a tidal volume of ml/kg bodyweight. single cell suspensions from the whole lung including airways and trachea were obtained by digestion with mg/ml collagenase iv (invitrogen) and u/ml dnasei (roche). neutrophils and monocytes in lung and bronchoalveolar lavage fluid were distinguished by staining with cd c apc-cy , cd b percp-cy . , ly- g biotin, ly- c pacific blue, streptavidin pe-cy . neutrophils were defined as cd c cd b + ly- c + ly- g + and inflammatory monocytes as cd c cd b + ly- c + ly- g low intermediate as precised in detail in figure s a . to analyze il- a production, cells from lung digests were stimulated with m pma, mg/ml ionomycin and m monensin for h at uc (indicated chemicals were purchased from sigma-aldrich). subsequently, cell subsets were distinguished by surface staining for cd percp-cy . , cd b fitc, cd tcr biotin, cd pacific blue, streptavidin pe-cy ( figure s b ) and il- a production was characterized by intracellularly staining with il- a alexa after fixation with bd lysis buffer (bd biosciences). all antibodies were purchased from biolegend. stained cells were acquired on a bd facs canto or bd facs lsrii and analyzed by using flowjo software (tree star). for neutralization of il- a, mice were treated with mg of anti-il- a (clone f ) or the corresponding isotype control antibody (clone mpoc- ) from bioxcell. the clone f uniquely reacts with the il- a and no other il- isoform [ ] . antibodies were administered intraperitoneally one day before viral infection and two days post infection. to block il- b signaling mice received mg of the interleukin- receptor antagonist (il- ra) anakinra (kineret, amgen) twice daily while control mice received only pbs. anakinra was kindly provided by prof. alexander so (centre hospitalier universitaire vaudois, lausanne, switzerland) and mme ghislaine aubel (centre hospitalier universitaire vaudois, lausanne, switzerland). total rna was isolated from lung and trachea with tri reagent (molecular research). all rna samples were checked for purity using a nanodrop spectrophotometer (thermo scientific) and met standard quality criteria. rna was subsequently transcribed into cdna by the iscript cdna synthesis kit (bio-rad) and quantitative real-time pcr was performed according to the manufacturer's instructions utilizing the ssoadvanced sybr green supermix from bio-rad. expression was determined by comparative delta-threshold cycle method using gapdh as a comparator. the following primers were used: to determine cytokine levels whole lung and trachea were collected and stored in protease inhibitor solution (roche) at uc until use. tissue homogenate was prepared using a tissuelyser (qiagen). il- b protein was determined using the mouse il- b elisa kit ready-set-go! from ebioscience by following the manufacturer's instructions. il- and tnfa were measured in a sandwich elisa using . mg/ml anti-mouse il- or tnfa (biolegend) for coating. bound protein was detected by mg/ml biotin labeled anti-il- or anti-tnfa antibody (biolegend) and subsequent incubation with alkaline phosphatase conjugated streptavidin (biolegend). plates were developed using the substrate p-nitrophenyl phosphate (sigma-aldrich) and od was measured using an elisa reader (biotek). statistical significant differences were assessed using the student's t test (two tailed, unpaired). p-values below . were considered significant and were depicted with p# . (*), p# . (**), p# . (***). standard error of the mean was applied. copd is a heterogeneous disease in humans but core features of its pathology can be reproduced in mice by repetitive exposure to lipopolysaccharide (lps) and elastase [ ] . lps is a bacterial endotoxin present in tobacco smoke [ , ] , the predominant risk factor of copd. it has been shown to cause inflammation, and particularly when co-administered with elastase, chronic emphysema-like changes develop in mouse lungs [ ] . as such, we exposed mice once a week for consecutive weeks to a mixture of mg lps and . u porcine pancreatic elastase via the intranasal route, as depicted in figure a . by this we induced strong emphysema ( figure b ,c) and sustained pulmonary inflammation ( figure b ,d) in balb/c and c bl/ mice. the development of emphysema was scored by increases in the mean linear intercept and the destructive index ( figure c ) from lung histology. in addition, we observed a strong airway inflammation, mainly driven by neutrophils and lymphocytes ( figure d ). both, emphysema and inflammation, remained above baseline levels for at least months (data not shown). thus, the response induced by repeated challenges with lps/elastase resembled the pathology of copd. as the disease severity was more pronounced in the balb/c strain ( figure b-d) , all experiments performed in wild type mice were conducted in balb/c mice. to study viral-induced exacerbations, mice were infected with influenza virus weeks after the last lps/elastase challenge, when the acute inflammation caused by lps/elastase exposure had subsided ( figure a ). the peak of viral replication was reached days after the infection ( figure b) and was followed by a rapid decline in viral titers ( figure b ) until complete viral clearance at day post infection (data not shown). the efficiency of the influenza infection was strikingly reduced in mice pretreated with lps/elastase compared to naïve mice, as revealed by significantly lower viral titers at the peak of viral infection, day and day post infection ( figure s ) which was also reflected by reduced amounts of viable virus in the lung on day (data not shown). this is likely to be due to the development of a polyclonal antibody response observed upon lps/elastase treatment ( [ , ] and data not shown). thus, the response to the influenza infection was not comparable between lps/elastase pretreated and naive mice, and was therefore not included in the remainder of the study. invasive measurements of pulmonary resistance in lps/elastase pretreated mice revealed a viral-induced acute exacerbation of airway dysfunction ( figure c ). pulmonary resistance can be influenced by a variety of factors, of which the severity of inflammation is likely to play one of the key roles during exacerbations. in line with this we detected a strong inflammatory response upon infection with influenza virus associated with an augmented absolute number of cells infiltrating into the airways and the lung ( figure d ). the cells were primarily neutrophils ( figure e , figure s a ) and inflammatory monocytes ( figure f , figure s a ). the peak of neutrophilic inflammation was reached at day post infection and neutrophil numbers declined afterwards ( figure e , figure s a ), directly correlating with the kinetics of viral replication ( figure b ). in line with this we observed increased expression of the proinflammatory cytokines il- and tnfa peaking at day or post infection, respectively, and subsiding at day after the infection ( figure g ). emphysematous damage upon lps/elastase treatment also resulted in an increase in the lung compliance. however the acute inflammatory changes induced by influenza infection had no impact on the increase in lung compliance (data not shown). acute pulmonary dysfunction, neutrophilic inflammation and enhanced levels of proinflammatory cytokines such as il- and tnfa have all been observed during exacerbations of copd patients, indicating that the viral-induced inflammation in our mouse model is in line with that seen in humans. il- has previously been shown to be a driving factor in the development of emphysema and inflammation in animal models of copd [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . as we observed an increase of il- b protein in the lungs of lps/elastase treated mice upon influenza infection ( figure a ), we hypothesized that it also promotes innate immune responses and influences pulmonary function during exacerbations. consequently, we exposed il- b deficient and c bl/ wild type mice to lps/elastase and infected them with influenza virus as described above. the c bl/ strain showed similar kinetics of neutrophil and inflammatory monocyte recruitment upon viral exacerbation as observed for the balb/c mice ( figure d , figure s b , s b). of note, viral replication was not altered in il- b deficient mice ( figure b ), demonstrating that any effects seen in the absence of il- b were not due to differences in the infection rate. c bl/ wild type mice exhibited a smaller change in pulmonary resistance in response to viral infection ( figure c ) in comparison to balb/c mice ( figure c) , with a slight increase at day post infection ( figure c ). nevertheless, pulmonary resistance in mice lacking il- b was significantly reduced already after lps/elastase exposure alone ( figure c ), thus supporting the described role for il- b in the development of chronic lung disease [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . furthermore, pulmonary resistance in il- b-deficient mice was also completely unaffected by the viral challenge ( figure c ). we did not detect any impact of il- b on inflammatory monocytes ( figure s b ); however, we found a decreased frequency and number of neutrophils in non-infected il- b deficient mice upon exposure to lps/elastase ( figure d , figure s c) . similarly, the recruitment of neutrophils to the airways and lung following viral infection was also significantly abrogated in the absence of il- b ( figure d , figure s c ). we observed significantly lower frequencies and absolute numbers of neutrophils including during the peak of neutrophil infiltration and viral replication at day post infection ( figure d , figure s c ). nevertheless, the control of the virus was unaffected as displayed by unaltered viral titers ( figure b ). considering its strong impact particularly upon neutrophils, we sought to address the mechanisms through which il- b mediated this neutrophilic inflammation. expression of the main neutrophil chemoattractants cxcl , cxcl , and cxcl were induced upon influenza infection, but were unaffected by il- b ( figure s ). in addition we did not detect any influence of il- b or the viral infection on the expression of g-csf ( figure s ). given there is substantial redundancy in neutrophil chemoattractants we thus next looked upstream at the proinflammatory cytokines il- a, il- , and tnfa, which can all stimulate neutrophilic inflamma-tion by inducing chemotactic, growth or survival factors [ , , ] . as expression of il- and tnfa were induced in our mouse model upon influenza infection ( figure g ), we hypothesized that il- b drove the observed inflammation by altering their production. the peak expression of il- and tnfa upon influenza infection was reached faster in c bl/ wild type mice at day post infection ( figure g ) as compared to day in balb/c mice ( figure e) , and thus coincided with the earlier response in pulmonary resistance observed in the c bl/ strain ( figure c ). il- protein levels followed similar kinetics in both mouse strains ( figure s a,b) , while tnfa protein production was below the sensitivity limit of our assay. however, lack of il- b did not impair the expression and production of il- ( figure e , figure s b ) and in fact increased the expression of tnfa ( figure e ). we therefore focused on il- a, a proinflammatory cytokine that has been shown to be elevated in copd patients [ , ] and whose induction partially depends on il- b [ ] [ ] [ ] . we found significantly reduced expression levels of il- a in lung homogenate in the absence of il- b, in both non-infected as well as influenza-infected lps/elastase exposed mice ( figure f ). il- a production was significantly reduced in the predominant cellular sources of il- a, such as the cd + t cells and the cd t cells in il- b deficient mice ( figure g ). further sources of il- a such as cd + cd cd cdtcr cells that might comprise nkt cells, and cd cells also showed reduced levels of il- a in the absence of il- b ( figure s a ). however, even in the wild type animals these cells represented a very minor population of cells relative to the il- a-producing t cells ( figure s a ). taken together our data showed that in addition to contributing to lung dysfunction, il- b played a key role in driving neutrophilic inflammation during influenza-induced exacerbations, an effect that was tightly linked to il- a expression. to assess whether il- a was indeed a mediator of il- b driven neutrophilia we neutralized il- a during influenza infection of lps/elastase treated mice. neutralization assays were performed in balb/c mice, which exhibited a similar induction of il- a as c bl/ mice ( figure s b ). mice received either an il- a neutralizing antibody or an isotype control antibody one day before and two days after the viral infection ( figure a ). il- a neutralization did not impact on the control of viral replication, as viral burden was comparable to the isotype control treated animals ( figure b ). we found that influenza-induced neutrophil recruitment to the airways and lung was indeed entirely attenuated h after the infection in absence of il- a ( figure c , figure s d ). however, neutrophils infiltrated into the lung and airways during the later stages of infection (day and respectively) to finally reach the same frequencies as in mice treated with the isotype control ( figure c, figure s d ); thus indicating that il- a was only required for the initial but not for the later recruitment of neutrophils. hence, il- b driven neutrophilia during influenza infection of lps/elastase exposed mice was mediated by il- a in the early phase of infection, but became independent of il- a. our data showed that a constitutive lack of il- b substantially impaired neutrophil infiltration into the airways and lung during influenza-induced exacerbations of chronic lung inflammation. thus, we sought to assess whether it is sufficient to block il- b signaling only during the course of infection, an important determinant regarding a potential therapeutic intervention. accordingly, recombinant il- ra (anakinra) or pbs was administered twice daily, starting two days prior to the viral infection ( figure a ). mice receiving anakinra displayed an impaired early control of viral infection leading to a higher viral burden at day post infection, although viral titers rapidly declined afterwards to levels similar to non-treated mice at day post infection ( figure b) , and virus was completely cleared at day post infection (data not shown). treatment with anakinra was efficient in reducing neutrophil frequencies and numbers in the airways at day post infection, the peak of neutrophilic infiltration and viral replication ( figure c , figure s e ). we did not observe an effect of anakinra on the recruitment of inflammatory monocytes ( figure s c ). similarly, we did not detect significant changes in lung function upon the treatment with anakinra (data not shown). in conclusion our data demonstrated that il- b influenced neutrophilic inflammation during influenza-induced exacerbation of chronic lung inflammation in mice throughout the entire phase of viral replication. neutrophil recruitment was mediated by il- a in the first h following viral challenge and could efficiently be blocked in the early phase of infection by antibodies neutralizing il- a. during the peak of inflammation and viral replication, il- b driven neutrophilia was independent of il- a, but could be significantly reduced by treatment with the il- ra anakinra ( figure ). in addition to a constant disease burden, copd patients suffer from episodes of acute symptom worsening causing a rapid decline in respiratory function that can necessitate hospitalization and even lead to death [ ] . indeed, a meta-analysis study estimated a case-fatality rate of . % following hospitalization due to an exacerbation [ ] . as there is a clear need to understand the mechanisms driving exacerbations and responsiveness to therapy, we examined viral-induced exacerbations in mice. in our model (figure a ), mice developed a strong inflammatory response characterized by a neutrophilic infiltrate into the airways and lung ( figure e ), enhanced expression of proinflammatory cytokines such as tnfa and il- ( figure g ), and impairment in lung function ( figure c ). decline in lung function and neutrophil accumulation are characteristic of exacerbations in humans [ ] [ ] [ ] , and elevated levels of tnfa and il- have similarly been measured in the sputum of patients undergoing an exacerbation [ , ] . thus, our mouse model reflects key pathological characteristics of copd exacerbations in humans. given the significant differences in susceptibility between the pbs treated and lps/elastase treated mice ( figure s and data not shown) which might be due to the development of a polyclonal b-cell response upon lps/elastase administration, we believe that conclusions can only be drawn from the comparison between stable disease versus episodes of exacerbation. notably, this is also supported by findings in cigarette smoke (cs) models of pulmonary inflammation where cs exposed mice showed a considerably altered response to influenza infection [ ] as well as the accelerated clearance of haemophilus influenza [ ] in comparison to control mice. in this study we specifically focused on the role of the proinflammatory cytokine il- b. il- signaling has been shown to be essential for the recruitment of neutrophils in other mouse models mimicking the pathology of stable copd, such as exposure to cigarette smoke [ , , , ] or to elastase alone [ ] . building upon these studies we found that during influenzainduced exacerbations, pulmonary accumulation of neutrophils was also driven by il- b ( figure d , figure s c ). our data is in line with results from a study of botelho et al. [ ] who investigated il- in a mouse model of acute cigarette smoke exposure. they found that interleukin- receptor (il- r) deficiency led to a reduction of neutrophils following infection with influenza and that this effect was independent of il- a. one could therefore speculate that il- b may play a critical role in neutrophil recruitment in their model as well. il- a, a cytokine that plays a central role in amplifying inflammatory cascades by inducing a variety of chemokines and cytokines, has also been reported to contribute to the development of emphysema [ , ] and to the immunopathology following influenza infections [ ] . in line with this, we found that il- a mediated early inflammation in our model of influenza-induced exacerbations of chronic lung disease ( figure c ). our data showed that il- b driven neutrophil recruitment during the first h of infection was mediated by ll- a, while it became independent of il- a at later time points during the exacerbation. we found that in the absence of il- b the expression of il- a was completely abrogated upon lps/elastase exposure as well as during exacerbations ( figure f ), thus demonstrating that il- b is required for the induction of il- a. il- a expression was induced by lps/elastase exposure alone, and levels were maintained throughout the viral-induced exacerbation ( figure f,g) ; however, while il- b levels increased during the later phase of infection ( figure a) , il- a expression surprisingly remained unaltered and even decreased at the peak of viral replication ( figure f ). nevertheless, we could block the recruitment of neutrophils at early time points following the influenza infection by neutralizing il- a ( figure c ). during the peak of viral replication, and thus a more severe state of inflammation, il- a neutralization could not prevent neutrophil influx. this might be due to an induction of cytokines during the progression of the infection, which could overcome the effect of il- a. therefore, treatment with anti-il- a seems to be favorable in the early phases of exacerbations while blocking il- b might be more advantageous during the ongoing infection. whether these findings translate into a clinical setting remains to be investigated. keeping in mind that neutrophil recruitment is elevated in the vast majority of cases of copd exacerbations regardless of their etiology [ ] , and furthermore that the increase of neutrophils in the sputum correlates with exacerbation severity [ ] , attenuating neutrophilia could be beneficial in patients undergoing a viralinduced exacerbation. current treatment relies mainly on corticosteroids and bronchodilators that have been shown to reduce the frequency of exacerbations [ ] [ ] [ ] , but have no positive effect on an ongoing episode of exacerbation. indeed, no reduction in the inflammatory response including neutrophil influx in mice and cytokine expression in humans could be achieved by treatment with steroids during copd exacerbations [ , ] . in contrast, corticosteroids have been shown to actually support neutrophil survival [ , ] . moreover, treatment with corticosteroids, efficient in reducing il- b levels in stable copd, did not affect the amount of il- b protein in exhaled breath condensate during exacerbations [ ] . as blocking of either il- a ( figure c ) or il- b ( figure d , figure s c ) efficiently reduced neutrophilic inflammation during viral exacerbation, these two molecules could be considered potential targets for therapeutic intervention. given the redundancies in these two inflammatory pathways, a combination therapy of anti-il- a and anti-il- b may prove more beneficial in improving lung function. within the context of targeting il- a or il- b in the clinic, one has to keep in mind that altering proinflammatory immune responses harbors the risk of interfering with the control of acute infection and of susceptibility to opportunistic infections. to shorten the duration of intervention and thereby reducing the risk of prolonged or secondary infections, we treated mice directly before and during the viral infection with anti-il- a ( figure a ) or il- ra ( figure a ). this was sufficient to abrogate neutrophil recruitment at the indicated time points. furthermore, neutralizing il- a did not promote elevated viral replication ( figure b ). treatment with il- ra, and thereby blocking both il- a and il- b, led to increased viral titers in the initial phase of infection ( figure b ), whereas the absence of il- b alone did not affect viral replication ( figure b ). it is therefore likely that in our model the initial control of the virus might be mediated rather by il- a than by il- b. this is in line with data from botelho et al. [ ] , who found similarly elevated viral titers upon neutralization of il -a as in the complete absence of il- r. our data thus suggest that targeting specifically il- b, and not its receptor, would be favorable in a therapeutic application. however, as treatment with anakinra did not interfere with final viral clearance it still could be considered as a therapeutic approach with the additional advantage of already being used in the clinic for other indications. taken together our data demonstrated that blocking of il- a or il- b signaling during influenza-induced exacerbations diminished neutrophilic infiltration at distinct phases of infection. whether those mechanisms apply also to other respiratory viral infections remains to be elucidated, however is plausible given the common early inflammatory pathways induced by respiratory viral infections. overall, blockade of il- a and il- b could be valuable therapeutic options for future treatment of viral induced exacerbations of chronic 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tomás; ortiz de lejarazu, raúl title: viral etiology of chronic obstructive pulmonary disease exacerbations during the a/h n pdm pandemic and postpandemic period date: - - journal: adv virol doi: . / / sha: doc_id: cord_uid: hodykbcb viral infections are one of the main causes of acute exacerbations of chronic obstructive pulmonary disease (ae-copd). emergence of a/h n pdm influenza virus in the pandemic changed the viral etiology of exacerbations that were reported before the pandemic. the aim of this study was to describe the etiology of respiratory viruses in spanish patients affected by ae-copd from the pandemic until the - influenza epidemic. during the study period ( – ), respiratory viruses were identified in . % of samples, and the proportion of viral detections in ae-copd was higher in patients aged – years than ≥ years. influenza a viruses were the pathogens most often detected during the pandemic and the following two influenza epidemics in contradistinction to human rhino/enteroviruses that were the main viruses causing ae-copd before the pandemic. the probability of influenza virus detection was . -fold higher in patients who are – years old than those ≥ . most respiratory samples were obtained during the pandemic, but the influenza detection rate was higher during the - epidemic. there is a need for more accurate ae-copd diagnosis, emphasizing the role of respiratory viruses. furthermore, diagnosis requires increased attention to patient age and the characteristics of each influenza epidemic. chronic obstructive pulmonary disease (copd) is a slowly progressive and largely irreversible clinical condition characterized by airflow limitation [ ] . in spain, copd affects over % of the population between and years of age [ , ] . acute exacerbations of copd (ae-copd) play a crucial role in the course of the disease, having a negative impact on morbidity, mortality, healthcare costs, and healthrelated quality of life [ , ] . patients with moderate and severe copd are prone to exacerbations, and the frequency of these episodes increases with the severity of disease [ ] . one of the key points in copd management programs is prevention and treatment of exacerbations [ ] . results of follow-up studies show that patients who suffer a high number of exacerbations during a given period of time will continue to suffer frequent exacerbations in the future [ ] . therefore, the frequency of exacerbations will depend on the patient's underlying severity of lung disease and number of prior exacerbations [ ] . the etiology of ae-copd is diverse. most ae-copd cases are attributed to bacterial or viral respiratory infections [ ] and to both types of microorganisms together [ ] . however to a minor extent, exacerbations are also associated with pollution, tobacco consumption, temperature changes, allergens, and other comorbidities such as heart failure and pulmonary thromboembolism [ , ] . respiratory viral infections have been associated with more frequent and severe ae-copd and also with longer recovery times than advances in virology episodes caused by other factors including bacteria [ , ] . studies conducted before emergence of the pandemic h n pdm strain showed that half of all ae-copd cases were associated with viral infections and that picornaviruses (especially human rhinovirus and enterovirus (hrev)) were the dominant viral pathogens diagnosed in these patients [ , ] . hrevs are the main viruses responsible for the common cold, with high prevalence throughout the whole year and without an established epidemic circulation period. currently they are the most important trigger of copd exacerbations [ ] . related with that, exacerbations treated with antibiotics could lead to the emergence of resistances in cases with other etiologies, which constitutes a problem particularly in southern mediterranean european countries where antibiotics are widely used for these kinds of patients [ ] . improvement of clinical diagnosis and correct identification of respiratory viruses may help reduce the use of these antibiotics. it is important to find clinical and analytical parameters to guide identification of the etiology of new ae-copd cases, especially considering the laborious techniques currently used for diagnosis [ ] . in the world experienced the first pandemic of influenza a virus in years, and this pathogen is now known as the h n pdm pandemic virus [ ] . during - , this virus spread worldwide, causing high infection rates but low mortality compared with previous pandemics (spanish flu, asian flu, and hong kong flu) [ ] . the pandemic resulted in a high rate of screening for respiratory viruses in patients with respiratory clinical manifestations, including those with copd. during this pandemic and following influenza epidemics, valladolid national influenza centre (valladolid nic, spain) and the microbiology & immunology service of clinic university hospital of valladolid worked closely on several topics related to influenza a/h n pdm [ , ] . consequently, we received a large number of respiratory samples from the hospital network of castile and león ( . million habitants) and currently we serve as a reference center for viral diagnostics for influenza-suspect cases and for other respiratory pathologies, including ae-copd. the aim of this study is to describe the etiological characteristics of respiratory viruses linked to copd exacerbations after a singular pandemic period caused by a new influenza virus. we have placed special emphasis on the differences of viral etiology of ae-copd between the pandemic and the following postpandemic period. this inclusion criterion was established by the chief pulmonologist of our hospital network following the anthonisen criteria [ ] in which one of the following symptoms were present: cough, dyspnea, or sputum increasing in volume or purulence. before the sample was included in the study, the clinical chart of each of the potentially included patients was checked for the presence of at least one of the cited symptoms. demographic data such as age and sex were also obtained from the order slips. clinical samples from ae-copd patients without anthonisen symptoms or who lacked clinical or demographic information were excluded from this study. because copd is a disease that affects only adults [ ] , only patients ≥ years old were included in this work. the infection rates and prevalence of the different respiratory viruses diagnosed in this work were obtained from local epidemiological surveillance data. this free information is provided weekly by the public health authorities through the influenza sentinel surveillance network (issn) of castile and león. we defined six study periods ( of the patients included in the study, ( . %) were between the ages of and years and ( . %) were ≥ years. the average age of all patients was . ± . years old and were males ( . %). from september until september , respiratory viruses were diagnoses in ae-copd samples ( . %), and no pathogen was detected in samples ( . %). the most frequently detected respiratory virus during this period was influenza a/h n pdm , present in cases ( . %), followed by hrev ( = ; . %), rsv ( = ; . %), and h n influenza virus ( = ; . %). twelve samples ( . %) were positive for other respiratory pathogens included in the molecular diagnostic assays. influenza b virus was detected in only one ae-copd patient ( . %), and cases ( . %) of coinfection were also detected. viral diagnostic findings in ae-copd patients decreased with age. viruses were found in samples ( . %) from patients in the - -year age group and in patients ( . %) in the ≥ -year age group (figure ). there was no age difference between ae-copd patients with viral infection ( . ± . years) and those that tested negative by molecular diagnostics ( . ± . years, = . ). influenza a/h n pdm was the most often detected virus in the - -year age group ( = ; . %). on the other hand, most of the viruses had prevalences similar to one another in the ≥ -year age group: a/h n pdm , . %; hrev, . %; other respiratory pathogens, . %. thus the absence of positive diagnostics was more common in this age group. the highest number of ae-copd episodes ( = ; . %) was recorded for the pandemic, followed by fluep ( = ; . %) and fluep ( = ; . %) ( table ). only ae-copd episodes occurred during any of the interepidemic periods, and none of them were diagnosed with respiratory viral infection. the average age of ae-copd patients during the pandemic, . ± . years (table ) , was not significantly different from the patient ages in the first or second epidemic. the proportion of viral findings in ae-copd patients increased from the pandemic ( = ; . %) until the end of the study period ( figure ). the maximum proportion occurred during fluep ( = ; . %) despite the low number of patients recruited in this period. in contrast, for the general spanish population, the maximum incidence of influenza occurred during the pandemic, . cases/ , inhabitants, rather than in the following two influenza epidemics, . cases/ , habitants during flue and . cases/ , habitants during fluep (figure ). influenza viruses were the most detected respiratory pathogens in ae-copd patients during the pandemic and following epidemics. specifically, influenza a/h n pdm was detected in cases ( . %) during the pandemic and in cases ( . %) during fluep , while h n influenza virus was detected in cases ( . %) during fluep . indeed, these two influenza strains represent together . % of viruses diagnosed in ae-copd episodes in this study. meanwhile, hrev and rsv were the second and third most diagnosed viruses during the pandemic ( = ; . % and = ; . %, resp.). however, diagnosis of these two viruses constantly increased in the two following influenza epidemics. also other respiratory pathogens increased in prevalence in ae-copd cases from the pandemic ( = ; . %) until fluep ( = ; . %). coinfections were more commonly detected during fluep . we used the or to analyze the probability of detection of viral categories (orp, hrev, any influenza virus, and rsv) as well as viral coinfections in ae-copd patients among different demographic and epidemiological characteristics such as gender, age groups, and the different periods analyzed. there was no gender difference in the rate of detection of respiratory viral or coinfections. the or for detecting influenza in the - -year age group was . fold (ci % = . - . ) greater than for the ≥ -year old group ( = . ). the probability for detecting rsv in the pandemic was significantly lower than detecting it in the first epidemic (or = . ; ci % = . - . ; = . ). additionally, the probability for detecting influenza virus in the first epidemic was significantly lower than in the second epidemic (or = . , ci % = . - . ; = . ). finally, the probability for detecting coinfection during the pandemic was significantly lower than in the second epidemic (or = . ; ic % = . - . ; = . ). accurate detection of the causes of ae-copd is important to develop and improve specific therapies and health care for patients that suffer this disease. in this way, clinicians and microbiology laboratories can be better prepared for the constant emergence of new respiratory pathogens such as avian influenza viruses and mers-coronavirus. our study has revealed differences between the pandemic and the following two influenza epidemics and other differences in the etiology dynamic of ae-copd described in the scientific literature before . even though most of the ae-copd respiratory samples were acquired during the pandemic, the viral etiology increased from . % in the pandemic to . % in the fluep . respiratory viruses affecting ae-copd episodes have been communicated in epidemics prior to , ranging from to % in previous publications [ , ] . also in several studies, viruses were associated with higher frequencies of ae-copd than bacterial infection or air pollution [ ] . furthermore, viral infections serve as causes of secondary bacterial infections that are associated with a rapid decline and severe respiratory symptoms [ , , ] . our findings are consistent with the global relevance of viruses in ae-copd as previously described [ , , ] . this suggests that, in addition to the independence of the viral epidemiologic characteristics, there exists a balance between bacterial and viral infections which promotes these exacerbations. the distribution of ae-copd patients within the - and the ≥ -year age groups was similar ( . and . %, resp.). within these age groups, there was a decrease of respiratory viruses in the ae-copd episodes with increasing age. thus viral infections were the etiology in . % of advances in virology ae-copd episodes in the - -year age group, while accounting for only . % of ae-copd cases in ≥ -yearold population. these data reveal a clear decrease in the role of respiratory viruses in ae-copd episodes as the susceptible population ages. thus, it is likely that bacterial infections or environmental conditions are the most frequent causes of exacerbations in elderly people. despite the fact that age seems to be a factor for detection of respiratory viruses in ae-copd episodes, we did not find any differences in the average age between people with respiratory infection and those with negative viral diagnostics. on the other hand, the average age of patients was also similar among the pandemic and influenza epidemics studied. the virus most frequently detected in ae-copd patients during the study period was influenza a/h n pdm , followed by hrev and rsv. analyzing each period, influenza a/h n pdm was the most frequent pathogen detected in the pandemic and during fluep . rsv was also diagnosed in the same proportion as influenza a/h n pdm during fluep . on the other hand, influenza a/h n was the most frequently diagnosed pathogen in ae-copd patients during fluep . before emergence of the new influenza strain a/h n pdm in , several works cited hrev as the main etiological agent causing ae-copd [ , ] . the prevalence of hrev ranged from to % of the total exacerbations, while other viruses like rsv and influenza a and b had prevalences ranging from to % and to %, respectively [ , ] . emergence of this new influenza virus seems to have changed the etiological viral pattern of ae-copd episodes. it resulted in higher rates of ae-copd of a influenza viruses compared to other different viral families such as the picornaviruses at least during the period studied. despite that, hrev remained as the second most frequent cause of ae-copd episodes in the patients included in this work. we analyzed the probability of detection of the different respiratory viruses and coinfections within the demographic and epidemiological characteristics of the study population. although copd is a chronic disease that has been historically more associated with males, it has been continuously increasing in women in the recent years [ ] . in our study, men represented more than % of population with ae-copd; however, we did not find differences in the detection of any virus or coinfections between men and women. we also studied the probability of detecting different viruses and coinfections between the two age groups. there were . -fold more influenza virus detections in adults aged - than in the elderly patients aged ≥ . on the other hand, all of the other viruses were detected at the same proportion in both age groups. most of the influenza viruses were subtyped as a/h n pdm influenza strain and were diagnosed during pandemic. this viral strain has strongly affected younger individuals since its emergence in . the apparent tropism of this influenza strain for younger people could be due to a low level or even absence of immunological memory and cross-immunity compared to that present in older individuals, phenomenon well demonstrated as a protective factor in this age group [ ] . we also studied the probability of detecting the different respiratory viruses and coinfections among the periods studied in this work. we found differences in detection of rsv in the pandemic and fluep , differences in coinfections in the pandemic and fluep , and differences in influenza detection between the two epidemics. these data support the dynamic etiology of the respiratory viruses on ae-copd episodes described in this study. our study shows that the emergence of a new pandemic influenza virus completely changed the etiology of viral infections in ae-copd patients. these changes were probably caused by the absence of immunity in a large part of the population. this change can be seen in the following years as fluctuations of the viruses causing these exacerbations. for this reason, it is necessary to continue studying this data series to know if the etiology of respiratory viruses can be absolutely changed in ae-copd by the emergence of a new virus or, alternatively, if this new behavior occurs only for a few years after a pandemic event. influenza viruses have been associated with mortality and morbidity in chronic lung disease [ ] . recent studies have focused on the importance of influenza vaccination with emphasis on risk groups such as copd patients and especially working adults ( - years old) with copd who are not usually covered by vaccination [ , ] . also, the early use of antiviral drugs against influenza viruses in hospitalized patient results in better management of ae-copd episodes [ ] , especially regarding the high proportion of patients that suffer an infection by influenza viruses causing ae-copd described in this work. for this reason, it is important to design empiric and rapid laboratory diagnostic strategies to start treatment as soon as possible for these kinds of patients. in connection with that, our data offers highly valuable information based on demographic and epidemiological characteristics that can help clinicians with the diagnosis of ae-copd patients. thus the criteria can be adapted to the specific clinical characteristics of each patient and time of the year. following these data, diagnostic suspicion may be supported on two different aspects: viral infections of ae-copd patients are more likely in younger patients than in older ones and that detection of viral respiratory infection causing ae-copd directly depends on influenza epidemic characteristics, at least in the years following a pandemic influenza emergence. also, these data support the need for multiplex microbiological diagnostic techniques that allow detecting the most frequent viral targets involved in ae-copd. the low number of samples after the pandemic limited the performance of more complex statistical analysis. specifically, the low number of recruited patients during the interepidemic periods impaired the ability to compare epidemics with periods without sustained influenza circulation. the lack of ae-copd clinical information in some microbiological order slips handled in the laboratory also generated a loss of ae-copd cases, which could not then be included in the study. however, recognition of this problem has generated a better dynamic on clinical requests completed by clinicians in their medical services. the high percentage of negative samples diagnosed showed the need for improved diagnostics to identify the role of bacterial infections in the ae-copd in our sanitary area. it is important to continue this study during following influenza epidemics to check for changes in the etiology dynamic after a/h n pdm has become completely epidemic. emergence of the new influenza pandemic virus a/ h n pdm caused influenza a viruses to be the main pathogens that affected copd patients during the period studied. however a/h n pdm did not change the global role of respiratory viruses as the primary cause of copd exacerbations during the pandemic and following two influenza epidemics. the presence of respiratory viruses in ae-copd episodes that require hospitalization is related with several demographic and epidemiological factors, such as the age of the patient and characteristics of the influenza epidemic activity. these factors need to be used by clinicians to complete clinical and laboratory diagnostic guides that are focused on the role of the respiratory viruses in exacerbations. vaccination and antiviral drug use is strongly recommended in these kinds of patients. pathogenesis of chronic obstructive pulmonary disease prevalence of copd in spain: impact of undiagnosed copd on quality of life and daily life activities recent trends in copd prevalence in spain: a repeated cross-sectional survey exacerbations of chronic obstructive pulmonary disease role of viral infections in asthma and chronic obstructive pulmonary disease the natural history of chronic airflow obstruction global initiative for chronic obstructive lung disease (gold) guidelines for chronic obstructive pulmonary disease relationship between airway inflammation and the frequency related copd factors associated with increased risk of exacerbation and hospital admission in a cohort of ambulatory copd patients: a multiple logistic regression analysis. the eolo study group bacterial infection in chronic obstructive pulmonary disease in : a state-of-the-art review effect of interactions between lower airway bacterial and rhinoviral infection in exacerbations of copd outcomes following acute exacerbation of severe chronic obstructive lung disease prevalence of viral infection detected by pcr and rt-pcr in patients with acute exacerbation of copd: a systematic review the influence of virus infections on the course of copd a community-based, time-matched, case-control study of respiratory viruses and exacerbations of copd respiratory viral infection in exacerbations of copd viral infections in patients with chronic obstructive pulmonary disease prevalence and outcome of severe chronic obstructive pulmonary disease exacerbations caused by multidrug-resistant bacteria microbiological study of patients hospitalized for acute exacerbation of chronic obstructive pulmonary disease (ae-copd) and the usefulness of analytical and clinical parameters in its identification (virae study) h n influenza global mortality estimates for the influenza pandemic from the glamor project: a modeling study interleukin- is a potential biomarker for severe pandemic h n influenza a infection viral infection is associated with an increased proinflammatory response in chronic obstructive pulmonary disease antiobiotic therapy in exacerbations of chronic obstructive pulmonary disease the first influenza pandemic of the st century differentiation of influenza b virus lineages yamagata and victoria by real-time pcr respiratory viruses, symptoms, and inflammatory markers in acute exacerbations and stable chronic obstructive pulmonary disease role of viruses in exacerbations of chronic obstructive pulmonary disease acute exacerbations of chronic obstructive pulmonary disease: identification of biologic clusters and their biomarkers rhinovirus infection induces degradation of antimicrobial peptides and secondary bacterial infection in chronic obstructive pulmonary disease seasonal influenza in adults and children-diagnosis, treatment, chemoprophylaxis, and institutional outbreak management: clinical practice guidelines of the infectious diseases society of america respiratory viral infections in adults with and without chronic obstructive pulmonary disease recent trends in physician diagnosed copd in women and men in the uk influenza virus h n pdm infections in the young and old: evidence of greater antibody diversity and affinity for the hemagglutinin globular head domain (ha domain) in the elderly than in young adults and children influenza vaccine for patients with chronic obstructive pulmonary disease effectiveness of influenza vaccine in the communitydwelling elderly impact of oseltamivir treatment on influenza-related lower respiratory tract complications and hospitalizations this work has been possible by the support of consejería de sanidad de la junta de castilla y león, valladolid, spain and instituto de estudios de ciencias de la salud de castilla y león (iecscyl), soria, spain. the authors declare that there is no conflict of interests regarding the publication of this paper. key: cord- - goz agp authors: hak, e.; hoes, a. w.; grobbee, d. e.; lammers, j. w. j.; van essen, g. a.; van loon, a. m.; verheij, t. j. m. title: conventional influenza vaccination is not associated with complications in working-age patients with asthma or chronic obstructive pulmonary disease date: - - journal: am j epidemiol doi: . /aje/kwg sha: doc_id: cord_uid: goz agp by using a nested case-control design, the authors studied the effectiveness of the influenza vaccine in reducing severe and fatal complications in , and , primary care, working-age patients aged – years who had asthma or chronic obstructive pulmonary disease during the – and – influenza epidemics in the netherlands. patients developing fatal or nonfatal exacerbations of lung disease, pneumonia, congestive heart failure, or myocardial infarction during either epidemic were considered cases. for each case, four age- and sex-matched controls were randomly sampled, and patient records were reviewed. conditional logistic regression and propensity scores were used to assess vaccine effectiveness after adjustment for confounding factors. in seasons one and two, respectively, % ( / ) and % ( / ) of the cases and % ( / ) and % ( / ) of the controls had been vaccinated. after adjustments, vaccination was not associated with reductions in complications (season one: odds ratio = . , % confidence interval (ci): . , . ; season two: odds ratio = . , % ci: . , . ; pooled odds ratio = . , % ci: . , . ). because influenza vaccination appeared not to be associated with a clinically relevant reduction in severe morbidity, other measures need to be explored. the risk of influenza-related morbidity and mortality during influenza epidemics is high ( ) ( ) ( ) ( ) , and nonexperimental studies have shown that vaccination against influenza prevents respiratory and cardiac complications during epidemics in elderly patients with chronic obstructive pulmonary disease (copd) ( , ) . however, relatively little information is available regarding working-age patients with copd. some studies have shown that these patients may account for many hospital admissions for respiratory illness during epidemics, but risk estimates are largely unknown ( ) ( ) ( ) . on the other hand, the sparse data available on acute respiratory illness in asthmatics suggest a relatively minor role for influenza ( , ) . although the vaccine does not lead to potentially adverse effects in asthmatics ( ) , the few available small-scale studies on the clinical benefits of influenza vaccination among working-age patients with copd have failed to demonstrate any effectiveness from annual vaccination ( , , ) . we determined the occurrence of respiratory and cardiac morbidity during influenza periods and the clinical effectiveness of vaccination in reducing these complications in patients aged - years who had asthma or copd by using a prospective, nested case-control design. our observations covered the - influenza outbreak (principally type b) and the - epidemic (mainly type a (h n )) ( , ) . since it is well known that influenza causes only part of the complications and that our outcome might therefore be nonspecific, as was the case in many previous reports ( ) ( ) ( ) ( ) , we also obtained nose and throat swabs from a sample of cases and controls to assess the relative contribution of influenza to complications. am j epidemiol ; : - study subjects were chosen from among primary care patients aged - years who had asthma or copd and had been targeted according to immunization guidelines for annual influenza vaccination ( , ) . seventy-eight general practitioners in computerized primary care centers across the netherlands participated in the study during the - influenza epidemic, and general practitioners in centers participated during the - epidemic. these general practitioners routinely integrate all patient information in text format or encoded in their computerized records by using the general practitioners information system elias (torex-hiscom, houten, the netherlands) ( ) . patients eligible for inclusion in our study were selected as of october and october by means of a dedicated software module. details on the module's stepwise selection procedures have been described elsewhere ( ) . briefly, patients were identified by age and the presence of copd, as indicated by international classification of primary care diagnostic codes (r , r , r ), anatomical therapeutic classification medical drug codes (class r ), and a tag in their computerized records indicating copd. next, the general practitioners were asked to verify whether the diagnosis of asthma or copd in the preselected patients had been made in accordance with the dutch college of general practitioners guidelines ( ) . in october and october , , and , eligible patients of a total of , and , study patients, respectively, preselected by using the search algorithm in the general practitioner information systems, were enrolled. since all data were supplied anonymously to the julius center for health sciences and primary care (utrecht, the netherlands), individual patient consent was not obtained. the medical ethical board of the university medical center utrecht approved the conduct of the study. subjects qualified as cases if they had a primary diagnosis of an episode of fatal or nonfatal severe exacerbation of underlying lung disease, pneumonia, congestive heart failure, or myocardial infarction during either epidemic (refer to the appendix). case criteria were verified by using a computerized questionnaire, which was integrated in the medical records of study patients and could be activated by their general practitioners during consultation. annual influenza surveillance was carried out by the national influenza center in collaboration with the sentinel practice network ( , ) . the epidemic periods were defined as the weeks in which the incidence of influenza-like illness reported by the sentinel practices was more than four per , inhabitants per week (between week of and week of (season one) and between week of and week of (season two)). during the first and largest wave of the - biphasic influenza outbreak, the influenza b-harbin-type virus predominated, followed by a smaller wave of a(h n )sydney. clinical influenza activity during the - season was predominantly associated with influenza type a(h n )sydney. in seasons one and two, six of and five of cases, respectively, were deemed ineligible for the study because it was unclear whether they had asthma or copd; therefore, these patients and their controls were excluded from further consideration. in addition, and patients with severe exacerbation of asthma or copd, five and patients with pneumonia, zero and one patient with congestive heart failure, and two and one patient who died, respectively, were considered eligible cases. no myocardial infarctions were recorded. in seasons one and two, eight and cases, respectively, were hospitalized. each time that a case was identified, we randomly selected four controls from the remainder of that season's cohort, matched by age (in the same -year age category) and sex. of the , controls selected from the database, were excluded because either no data were available for them or the baseline diagnosis was unclear or they had died or had been lost to follow-up before the relevant epidemics occurred. in the netherlands, almost all persons receive the influenza vaccine through a primary care vaccination program ( ) . in both seasons, the composition of the trivalent subunit influenza vaccine complied with world health organization recommendations and matched well with circulating influenza a and b strains, as quantified by high hemagglutinin inhibition titer in ferret sera ( , ) . a person was assumed to have been vaccinated if his or her general practitioner retrospectively confirmed receipt of influenza vaccination by reviewing the medical records. confirmed exposure/nonexposure to influenza vaccination within the months before either epidemic was in high agreement with the absence/presence of the international classification of primary care r . code for vaccination (kappa = . ). baseline demographic information, including age, sex, and health insurance coverage (private or national health service), was collected by using the software module ( ) . these data are required by health insurance companies and are therefore valid and reliable. further detailed information was obtained on potential risk factors by review of medical records by the participating general practitioners, who were unaware of the role of these covariate assessments in relation to the primary aim of the study. we extracted information on the presence of concomitant high-risk disease and previous hospital admissions in the months preceding the epidemic. in addition, influenza infection and influenza vaccination status in the previous season and chronic use of medications were registered, and the numbers of consultations in the preceding year were counted as an indicator of disease severity and use of medical services. some of the cases and controls in the second, - season ( of , ) participated in an additional questionnaire study (unpublished data). kappa values, as a measure of agreement between patient and general practitioner information, were satisfactory for some important variables: . for the presence or absence of chronic comorbid disease, . for the presence or absence of respiratory medication use, and . for the presence or absence of previous influenza vaccination. six primary care centers that included trained general practitioners from the utrecht academic network ( ) were asked to take nose and throat swabs from their cases and from a sample of controls for virologic assessment. specimens were put into ml of transport medium. swabs were vortexed for seconds and were centrifuged at , × g for minutes. one ml of the supernatant was used directly for rapid virus culturing and antigen testing by immunofluorescence with monoclonal antibodies against influenza virus. the other material was stored at - °c. nested, reverse transcriptase polymerase chain reaction was carried out blindly to test for the presence of influenza a or b virus; respiratory syncytial virus; picornaviruses (rhinovirus and enterovirus); parainfluenza viruses , , and ; and coronavirus ( ) . before starting the study, we estimated that a seasonal study population of cases and controls would give us a statistical power of more than percent to detect an odds ratio of . (i.e., reduction of percent allowing for nonspecificity, as observed in other studies) ( ) ( ) ( ) . we assumed a vaccination rate of percent, a case-control ratio of : , and a two-tailed α level of . . we approached data analysis in two ways. first, we applied multivariate conditional logistic regression analysis for matched case-control studies to assess vaccine effectiveness independent of confounding factors. in the modeling procedure, factors that appeared to be strongly associated with both exposure to vaccination and case status were first added to the naive model that included vaccination status only. additionally, those risk factors that substantially altered the odds ratio of vaccine effectiveness further (> percent) were entered in the model ( ) . although it has been shown that vaccine uptake is determined by patient rather than practice or physician factors ( ), we extended the analysis by matching by practice, which did not materially change the results. since circulating viruses and vaccination components differed in the two seasons and only a minority of subjects were admitted to the study during both seasons, we pooled the observations and performed similar analyses on case and control person-periods ( ) . moreover, we decided in advance to use statistical interaction terms to determine potential modification of vaccine effectiveness by age ( - , - years), sex, disease (asthma or copd), and care by a pulmonologist. adjusted odds ratios, as approximations of relative risks, and their percent confidence intervals were calculated. second, we applied the propensity score method, a recently introduced, powerful method of further removing "confounding by indication" ( , ) . this technique enables assessment of the association of an intervention, that is, vaccination, with outcomes in patients who have an equal probability of receiving the vaccine. potential predictors were included in a logistic regression analysis, with vaccination as the dependent variable. the analysis was used to estimate the probability of vaccination (propensity score) for each individual patient in the full data set ( cases, controls). the fit of the model that included age and sex, health insurance, underlying disease, use of prednisolone and inhaled corticosteroids, specialist care, and cardiac and other comorbidity was appropriate (hosmer-lemeshow goodness-of-fit test: p = . ), and the model's discriminative ability was moderate to good, with a value of . ( percent confidence interval (ci): . , . ) for the area under the receiver operating curve. in a patientmatching procedure, we searched for a vaccinated person who had a propensity score closest (within a range of . - . ) to that for each unvaccinated patient. thus, in this quasi-experiment, two comparison groups that had an equal probability of vaccination were formed, and, in an analogy to the analysis of trials, cumulative incidences of complications were compared. the overall cumulative incidence of complicationsmainly respiratory-was per , in the first season and per , in the second season (table ) . influenza morbidity was highest in the older age group ( - years), in females, and in those subjects who had copd. vaccinated subjects were older and had a higher prevalence of copd and of cardiac and other comorbidity, and they were more often insured through the national health service than were unvaccinated subjects (table ). in addition, vaccinated subjects had higher general practitioner consultation and hospitalization rates in the months preceding baseline and had more often been vaccinated against influenza in the previous season. eighty-seven percent of cases and percent of controls had been vaccinated in season one compared with percent of cases and percent of controls in season two (table ) . after we adjusted for the matching variables age and sex and for potential confounders, we found that the vaccine apparently was not associated with any reduction in the incidence of complications (season one: odds ratio = . , percent ci: . , . ; season two: odds ratio = . , percent ci: . , . ; pooled odds ratio = . , percent ci: . , . ). in addition, vaccine effectiveness was not significantly modified by age, sex, or underlying pulmonary disease or by care received from a pulmonologist. in the propensity score analysis, outcome rates for the vaccinated and unvaccinated subjects who had been matched on their equal probability of being vaccinated were equal (relative risk = . , percent ci: . , . ; refer to table ). assessment for the presence of influenza viruses in a sample of cases and controls (refer to the materials and methods section) showed that, in seasons one and two, / cases ( percent) and / cases ( percent), respectively, were positive for either influenza a or b, whereas only one control had an influenza infection (table ) . other respiratory viruses were found relatively infrequently in the cases. this study showed that, although influenza-associated respiratory morbidity is common among working-age patients who have asthma or copd, no evidence exists that the annual, conventional, inactivated trivalent subunit influenza vaccine reduces the incidence rate of these complications. since many immunization guidelines recommend influenza vaccination for patients with asthma or copd, vaccine effectiveness cannot be assessed in a placebo- controlled trial. the case-control approach enables assessment of the effects of vaccination on severe endpoints for which incidence is relatively low. an advantage of the nested case-control study includes reduction of bias due to inappropriate selection of controls. exposure rates in controls were similar in both seasons and were comparable with those in the baseline cohort. although the controls were somewhat older than the total cohort, the distribution of some important characteristics in vaccinated and unvaccinated controls was comparable with that in the baseline cohort. furthermore, potential recall bias was minimized by using computerized medical records. several potential limitations of our study need to be considered. a major issue in nonexperimental evaluation of vaccines is often that vaccinated and unvaccinated patients are not prognostically comparable. as expected, and as shown in the present and previous studies, vaccinees have more risk factors than nonvaccinees ( - , , ) . this fact may have obscured a positive effect of vaccination. however, we minimized this so-called confounding by indication in both the design and data-analysis phases of the study ( ) . first, we admitted into the study cohorts only those patients who had current asthma or copd. recent studies have shown that only in a few patients registered as having asthma or copd were the diagnoses not confirmed by spirometry ( , ) . second, since age and sex are major confounders, we matched cases and controls for these factors. in addition, matched analysis by general practice did not change our results. third, we had information on many potential confounders, and we adjusted for them by using conditional logistic regression. once we had controlled for the matching factors and just three additional risk factors (previous vaccination, specialist care, and prednisolone use in the previous year), further adjustment for eight additional risk factors did not alter the estimates of vaccine effectiveness. finally, we applied the propensity score method as an effective technique to control for confounding by indication ( , ) . although the statistical power of the latter approach was more limited, risk factors were apparently distributed similarly in the selected vaccinated and unvaccinated subjects, and no difference was found in the incidence of outcomes. obviously, only a large, randomized controlled trial will guarantee absence of confounding, but it is very unlikely that the observed lack of vaccine effectiveness in our nonexperimental study could be explained by residual confounding in our data. most studies of the effectiveness of vaccination in the elderly have been restricted to even more severe endpoints such as death or hospitalization for influenza or pneumonia, assuming that, during influenza outbreaks, the influenza is frequently a causal component of these outcomes ( , ) . however, from a societal point of view, the influenza-related needs for health care of patients of working-age are mainly limited to relatively less severe complications treated in primary care settings or at outpatient clinics (refer to the appendix). for example, rothbarth et al. ( ) estimated that, in the netherlands, excess deaths occur in this group of half a million persons during influenza epidemics. in other words, if the vaccine could prevent percent of the deaths ( ), more than , patients would need to be vaccinated to prevent one death. a major strength of our study is that virologic analyses of a sample of our cases and controls showed that influenza infection was frequently associated with these complications, and we found much higher prevalences than those reported in earlier influenza studies in this age group ( , ) . furthermore, in season one, which was predominated by influenza b types, most of the positive cases had influenza a infection. this finding accords with ours and findings from others that the incidence of cases was much lower in this season compared with the influenza a season. we were not able to verify retrospectively whether case ascertainment was complete. however, occurrence rates of pneumonia, acute cardiac disease, and death in the - influenza a season were comparable with data from a previous study in a smaller group of similar patients followed up during the - influenza a epidemic ( ) . although a positive relation between respiratory virus infections and exacerbations of asthma has been well established, the etiologic role of influenza viruses has long been underestimated. the underestimated role of influenza might mainly be due to the laboratory techniques used to detect these viruses; in recent years, polymerase chain reaction has become available for rapid diagnosis of influenza infection, considerably increasing diagnostic accuracy compared with conventional virologic analysis ( , ) . this study is one of the largest so far reported, and it covered two types of influenza outbreaks. although we had limited power to detect a clinically important reduction of at least percent in the first season, in the second season, and in pooled data from the two seasons combined, including case person-periods and control person-periods provided enough power to estimate an even smaller reduction of percent. since more than , working-age patients with asthma or copd are currently indicated for influenza vaccination at a cost of million euros (approximately $ million) annually, we are convinced that, from a cost-effectiveness point of view, lower than percent reductions in severe outcomes as a result of vaccination do not justify such a costly, large-scale campaign. other less severe endpoints such as productivity loss or minor exacerbations might be reduced by vaccination, although it is unlikely in light of our results. however, from a public health perspective, such possible benefits might also not justify this preventive program. our finding of a lack of benefit from influenza vaccination in respiratory patients of working-age corroborates some earlier observations. for example, paul et al. ( ) observed no reduction in acute respiratory illness in a small subset of vaccinated high-risk patients less than years of age during the - influenza epidemic. stenius-aarniala et al. ( ) also found no protective effect of the vaccine in reducing asthma exacerbations in a randomized controlled trial among asthmatics, although influenza activity during the follow-up period was low. wiselka et al. ( ) conducted a general practitioner-based study among more than adult asthmatics and found that influenza vaccination was not associated with any substantial reduction in either asthma exacerbations or severity of symptoms. these observations seem counterintuitive in the face of the beneficial effects of conventional influenza vaccination in high-risk children and the elderly, and they do not support international recommendations to immunize working-age patients with asthma or copd against influenza ( ) . although the occurrence of endpoints was twice as high in copd patients compared with asthmatics in our study, the vaccine did not reduce the incidence of endpoints in either group. it is still unclear why the vaccine is clinically not effective in both patient groups less than age years. one possible explanation could be that virus-induced allergy and hyperreactivity as precipitating factors may be a much more significant pathologic mechanism in adults than in young children and the elderly ( , , ) . if this explanation is true, preventive measures other than vaccination against influenza, such as self-management programs aimed at reducing the number and severity of exacerbations of asthma or copd, may have a larger impact on the influenza-related health burden in this particular group of high-risk patients than does annual influenza vaccination. the netherlands asthma foundation financially supported this study (no. . ). survey of underlying conditions of persons hospitalized with acute respiratory disease during influenza epidemics in houston impact of respiratory virus infections on persons with chronic underlying conditions reduction in mortality associated with influenza vaccine during - epidemic influenza vaccine effectiveness in preventing hospitalization among the elderly during influenza type a and type b seasons relation between influenza vaccination and outpatient visits, hospitalization, and mortality in elderly persons with chronic lung disease is immunising all patients with chronic lung disease in the community against influenza cost-effective? evidence from a general practice based clinical prospective cohort study in utrecht, the netherlands influenza-associated morbidity and mortality in young and middle-aged women excess pneumonia-and influenza-associated hospitalization during influenza epidemics in the united states, - acute respiratory disease hospitalizations as a measure of impact of epidemic influenza respiratory viruses and exacerbations of asthma in adults viral respiratory infection and exacerbations of asthma in adult patients the safety of inactivated influenza vaccine in adults and children with asthma vaccines for preventing influenza in people with asthma sense and nonsense of influenza vaccination in asthma and chronic obstructive pulmonary disease influenza season / ; composition of vaccine for influenza season implementing dutch college of general practitioners (nhg) guidelines for influenza vaccination: an intervention study prevention and control of influenza: recommendations of the influenza vaccination and asthma or copd centers for disease control and prevention the introduction of computer-based patient records in the netherlands improving influenza vaccination coverage among high-risk patients: a role for computer-supported prevention strategy? nhg standaard copd en astma bij volwassenen: diagnostiek simultaneous detection of influenza viruses a and b using real-time quantitative pcr confounding by indication in non-experimental evaluation of vaccine effectiveness: the example of prevention of influenza complications introducing a pneumococcal vaccine to an existing influenza immunization program: vaccination rates and predictors of non-compliance benefits of influenza vaccination for low-, intermediate-and high-risk senior citizens estimating causal effects from large data sets using propensity scores the effectiveness of right heart catherization in the initial care of critically ill patients use of the case-control approach in vaccine evaluation: efficacy and adverse effects spirometrie in een gezondheidscentrum. (in dutch) underdiagnosis of asthma: is the doctor or the patient to blame? the dimca project the impact of influenza epidemics on hospitalizations the efficacy and cost-effectiveness of vaccination against influenza among elderly persons living in the community rapid virological surveillance of community influenza infection in general practice acute respiratory illness among immunized and nonimmunized patients with high-risk factors during a split season of influenza a and b lack of clinical exacerbations in adults with chronic asthma after immunization with killed influenza virus influenza and asthma respiratory infection with influenza a virus interferes with the induction of tolerance to aeroallergens the incidence of respiratory tract infection in adults requiring hospitalization for asthma the participation of the general practitioners in data collection is gratefully acknowledged. the authors are indebted to f. leffers for technical assistance. they also thank dr. m. nijhuis and l. van elden for the virologic analyses. working-age patients with asthma or chronic obstructive pulmonary disease, the netherlands, - and - * copd, chronic obstructive pulmonary disease; fev , forced expiratory volume in second; pef, peak expiratory flow; ecg, electrocardiogram. cardiac illness death key: cord- -i mge authors: mallia, patrick; johnston, sebastian l. title: how viral infections cause exacerbation of airway diseases date: - - journal: chest doi: . /chest. . . sha: doc_id: cord_uid: i mge exacerbations of asthma and copd are major causes of morbidity, mortality, and health-care costs. over the last decade, studies using new molecular diagnostic techniques have established that respiratory viruses are a major cause of exacerbations of both asthma and copd. the most prevalent viruses detected during exacerbations are the rhinoviruses. despite the burden of disease associated with exacerbations, little is known about the mechanisms of virus-induced exacerbations of airway diseases. exacerbations are associated with increased airway inflammation in patients with both asthma and copd, but many questions remain unanswered regarding the key inflammatory cells and mediators involved. identifying the key inflammatory mediators involved in exacerbations holds the promise of developing diagnostic and prognostic markers of exacerbation. in addition, such studies can identify new therapeutic targets for the development of novel drugs for the prevention and treatment of exacerbations. m uch of the morbidity, mortality, and excess health-care utilization associated with asthma and copd are related to episodes of acute deterioration in health that are termed exacerbations. the precise definition of an exacerbation remains controversial, but most clinicians recognize an exacerbation as an increase in respiratory symptoms that usually causes a patient to seek medical help. asthma exacerbations are associated with shortness of breath, cough, wheezing, and chest tightness, and are accompanied by decreases in expiratory airflow mani-fested by reductions in peak expiratory flow. copd exacerbations are typically associated with shortness of breath, cough, increased sputum volume, and sputum purulence, and nonspecific symptoms such as fatigue and malaise. changes in measures of airflow are generally smaller and more variable than in patients with asthma. acute exacerbations can result in excess medication use, emergency department visits, hospitalization, and even death. they are the main drivers of asthma-related costs, accounting for almost % of total costs. copd patients experience a median of . exacerbations per year, and their frequency increases with increased severity of the disease. exacerbations result in a faster decline in lung function in patients with copd and so have a direct effect on progression of the disease. and stress, but the major cause of exacerbations is respiratory virus infection. an association between colds and asthma exacerbations has long been recognized, but early studies yielded low virus detection rates of approximately %. these studies used virus detection methods that have low sensitivity for rhinoviruses and coronaviruses, which between them account for the majority of colds. the optimum method for virus detection is with polymerase chain reaction (pcr)-based methods, and studies using pcr have shown that respiratory viruses are responsible for a much higher proportion of asthma exacerbations than was previously suspected. in a study, of children in the united kingdom, viruses were detected in to % of exacerbations; the most common viruses detected were rhinoviruses ( % of total exacerbations or % in which a virus was detected). respiratory viruses have also been detected in a high proportion of more severe exacerbations requiring hospitalization. a total of % of children seen in the emergency department in a south african study tested positive for a respiratory virus, as did % of children Ͼ years of age who were admitted to the hospital with wheezing illness in the united states. viruses have also been implicated in the pathogenesis of asthma exacerbations in adults. the first study using pcr to detect respiratory viruses in adults reported a respiratory virus in % of exacerbations ( % rhinoviruses). subsequent studies in patients with more severe exacerbations leading to presentation to the emergency department detected a virus in % and % of cases in two studies from australia, and in % of cases in a study in the united states. the prominent role of rhinovirus in asthma exacerbations has been further highlighted by a canadian study characterizing an annual september epidemic of asthma hospitalizations occurring first in school-aged children followed by preschool children and adults. respiratory viruses can act synergistically with other factors that cause asthma exacerbations. admission to the hospital with an acute asthma exacerbation is strongly associated with the combination of sensitization and exposure to an allergen, and concurrent viral infection. the presence of high ambient levels of nitrogen dioxide prior to a viral infection is associated with more lower respiratory tract symptoms and greater falls in peak expiratory flow during the exacerbation. factors associated with copd exacerbations include changes in air temperature and concentrations of air pollutants, but most exacerbations are associated with symptoms of respiratory infection. histor-ically, bacteria have been considered the main infective cause, but their exact role remains contentious as bacteria are only found in approximately half of copd exacerbations and are also found in patients who are clinically stable. older studies detected viruses in only to % of exacerbations ; however, as is the case in asthma patients, more recent studies using pcr have revealed that viruses have a more prominent role in the etiology of exacerbations. in a report from the east london copd cohort, a respiratory virus was identified in % of patients with exacerbations who were treated as outpatients, with rhinoviruses accounting for % of the viruses present. two studies , in copd patients with more severe exacerbations requiring hospital admission detected a respiratory virus in % and % of patients. in copd patients with very severe exacerbations requiring intubation and mechanical ventilation, viral infection was identified in %. most studies have focused exclusively on bacterial or viral infection, but a recent study that carried out sampling for both in sputum samples found evidence of coinfection in % of patients with exacerbations. together, these studies suggest that as many as to % of acute exacerbations of copd are associated with respiratory virus infection. despite the epidemiologic evidence linking respiratory virus infection to exacerbations of copd and asthma, the cellular and molecular mechanisms by which viruses cause exacerbations remain undetermined. the underlying pathology of asthma and copd differ markedly, and therefore a key question is whether the mechanisms of virus-induced exacerbations in the two diseases are similar or differ. the answer to this question is of more than academic interest as current treatments for exacerbations are inadequate, and new treatments are urgently needed. much of our knowledge regarding the mechanisms of virus-induced asthma exacerbations is derived from studies using experimental rhinovirus infection in asthmatic volunteers as a model of exacerbation. in view of the data available from the rhinovirus model and its role as the most commonly identified virus in patients with both asthma and copd, this review will focus mainly on the mechanisms of rhinovirus-induced exacerbations. a key issue regarding virus-induced exacerbations of airway diseases is whether upper respiratory tract viruses such as rhinoviruses can also infect the lower airway. the prevailing view for many years was that they could not, based on evidence that the optimal temperature for the growth of rhinoviruses was °c. however papadopoulos et al demonstrated that rhinovirus can replicate in the lower airway epithelium by using in situ hybridization to exclude sample contamination from the upper airways. therefore, viral infection of the lower airway is likely to occur and to contribute to virus-induced exacerbations of asthma and copd. the extent of epithelial cell destruction observed in the airway varies according to virus type. influenza typically causes extensive epithelial necrosis, whereas rhinovirus causes only patchy damage. the respiratory epithelium has important regulatory roles and contributes to the immune response following virus infection through the production of inflammatory mediators, cytokines, and chemokines. the disease syndrome following respiratory virus infection is a consequence both of the direct harmful effects of the virus itself and of immunopathology resulting from the host immune response. this has led to the concept that rhinovirus infection is at least in part an immune-mediated disease with proinflammatory cytokines, chemokines, and inflammatory cell products producing pathology, perhaps more than a direct cytotoxic effect of the virus. viral infection in asthmatic patients induces more lower respiratory tract symptoms and falls in lung function than that in nonasthmatic patients, but the molecular basis of the greater sensitivity of asthmatic patients to viral infection remains obscure. in vitro infection of airway epithelial cells with rhinovirus induces the secretion of a host of inflammatory mediators. this also occurs in vivo in both experimental and naturally acquired viral infections. the neutrophil chemokine interleukin (il)- and the proinflammatory cytokine il- have been detected in nasal samples during virus infections in asthmatic patients. , in the lower respiratory tract, increases in il- , il- , and the chemokine regulated on activation, normal t-cell expressed and secreted (rantes) have been documented in the sputum of asthmatic patients after experimental rhinovirus infection, , and il- has been detected in the sputum of children with naturally occurring exacerbations. while it is well-recognized that viral infection induces proinflammatory mediators, it is unclear whether the inflammatory response to viral infection differs quantitatively or qualitatively in asthmatic patients. one experimental rhinovirus infection study reported increased levels of il- and il- ␤ in nasal lavage samples in asthmatic patients but not in control subjects; however, another study reported no differences in il- , il- , il- , and granulocyte-monocyte-colony stimulating factor levels in either nasal lavage or sputum samples. a recent study in patients with naturally occurring virusassociated asthma exacerbations found increased levels of il- messenger rna in the sputum of asthmatic patients compared to virus-infected healthy subjects, but no differences in the level of rantes or il- between the two groups. these conflicting results highlight the need for further studies evaluating the inflammatory profile (preferably in the lower airway) in well-characterized patients during exacerbations. studies with control subjects of nonasthmatic patients will help to ascertain whether the inflammatory response in asthmatic patients differs from that of healthy subjects. the production of chemokines by epithelial cells in response to a viral infection leads to an influx of leukocytes into the airway. these cells are an essential part of the innate and adaptive immune responses but can also result in airway pathology. the release of inflammatory cell products such as neutrophil elastase from neutrophils, major basic protein and eosinophil cationic protein from eosinophils, and reactive oxygen species can cause tissue damage. in stable patients with asthma, the eosinophil and cd ϩ t cells have been identified as key cellular components of the asthma phenotype, but the cellular response during exacerbations is more heterogeneous. severe asthma exacerbations in children are associated with increased inflammatory cell numbers and the presence of both neutrophil and eosinophil markers in sputum samples. increased levels of sputum neutrophils have been reported in virusassociated exacerbations in adults, whereas exacerbations in which no virus is detected have a higher proportion of eosinophils. experimental rhinovirus infection studies have reported increased numbers of neutrophils in bal fluid samples but not in sputum samples. few studies have compared the inflammatory cellular response to viral infection in asthmatic patients and healthy subjects. increased numbers of lymphocytes and eosinophils in bronchial biopsy specimens are present after experimental rhinovirus infection in both asthmatic patients and healthy subjects ; however, at weeks postinfection the eosinophilia persists in the asthmatic patients only. a study greater total sputum inflammatory cell count and neutrophil count with a similar differential count in the asthmatic patients. therefore, it would seem that virus-induced exacerbations are at least partially driven by neutrophilic inflammation, and this may account for why therapy with inhaled corticosteroids is effective at suppressing (eosinophilic) airway inflammation in stable patients with asthma but are less successful at preventing exacerbations. new treatments may need to target neutrophils and neutrophil chemokines if virus-induced exacerbations are to be prevented or ameliorated. the adaptive immune response in asthma patients is associated with a t-helper (th) type cytokine profile (ie, il- , il- , and il- ), whereas adequate antiviral immune responses require the th cytokines interferon (ifn)-␥ and il- . th and th immune responses demonstrate mutual inhibition; therefore, within an airway with a preexisting th microenvironment there may be inhibition of th immune responses. there is some clinical evidence that imbalances in th /th immune responses influence the outcome of viral infections. peripheral blood mononuclear cells from asthmatic subjects exposed to rhinovirus have produced significantly lower levels of ifn-␥ and il- with a lower ifn-␥/il- ratio than in nonasthmatic patients. gern et al showed an inverse relationship between the ifn-␥/il- ratio in sputum samples and both the peak cold symptoms and time to virus clearance from sputum samples in asthmatic patients infected with rhinovirus, suggesting that a stronger th immune response is associated with less severe colds and faster viral clearance. there is also evidence that weak th responses are associated with more severe disease in infections with another respiratory virusrespiratory syncytial virus. it has been suggested that this may be another mechanism through which virus infection can exacerbate a preexisting th mediated lung disease. most immunologic research into asthma has focused on the role of the adaptive immune response in disease pathogenesis, but evidence is emerging suggesting that innate immunity may be impaired in asthmatic patients. wark et al have shown that bronchial epithelial cells obtained from asthmatic patients support markedly increased rhinovirus replication compared to cells from nonasthmatic patients. this is accompanied by reduced apoptosis of epithelial cells in the asthmatic patients and impaired production of the antiviral cytokine ifn-␤. impaired ifn-␤ production and cell apoptosis result in greater virus replication, eventually leading to cytotoxic cell death with the release of inflammatory mediators and large numbers of intact viral particles. the administration of ifn-␤ restores the virus protection observed in epithelial cells from normal airways. if confirmed in vivo, it will be interesting to see whether these novel observations translate into new therapies aimed at augmenting or replacing deficient ifn-␤ production in asthma patients. the key differences in the innate and acquired antiviral responses between asthmatic patients and nonasthmatic patients are summarized in figure . other components of the innate immune response may influence the host response to viral infection such as toll-like receptors (tlrs) and defensins. the tlrs induce antiviral responses such as type i ifns, as well as inflammatory cytokine release and the recruitment of cells required for host defense in response to microbial products, while defensins are antimicrobial peptides with multiple effects on both the innate and acquired immune response. one tlr (tlr ) is activated by double-stranded rna that is formed during viral replication. rhinovirus induces the expression of both tlr and the defensin human ␤-defensin- in respiratory epithelial cells. in addition, tlr is up-regulated by allergic airway inflammation. [ ] [ ] [ ] further studies are required to explore the possible interactions between viral infection and allergic inflammation in tlr expression and how this may influence the host response to respiratory virus infections. copd is associated with both a pulmonary and systemic inflammatory response. studies of airway inflammation in stable patients with copd have shown that the disease is characterized by pulmonary infiltration of macrophages, neutrophils, and cd ϩ t lymphocytes, together with increased expression of cytokines, chemokines, and adhesion molecules. much less work has been carried out studying airway inflammation during exacerbations, and the results have often been conflicting. comparing the results of different studies has often been hampered by the differing inclusion criteria (eg, chronic bronchitis vs copd), different definitions of copd, and different methods of airway sampling. unlike the th cytokines and eosinophil chemokines that are characteristic of asthma, copd is associated with proinflammatory cytokines and neutrophil chemokines such as tumor necrosis factor (tnf)-␣, il- , growth-related oncogene-␣, and leukotriene b (ltb ). airway inflammation is amplified during exacerbations, and the levels of inflam-matory mediators are increased compared to the stable state. increased levels of tnf-␣, , il- , , epithelial-derived neutrophil attractant (ena)- , ltb , rantes, and endothelin- have been reported during exacerbations. il- is believed to be a key neutrophil chemokine in copd, but while some studies , , have reported increased il- levels during exacerbations, others have not. , a study using bronchial biopsy specimens in patients with a severe exacerbation of copd reported positive correlations between neutrophils and cells positive for both il- and ena- , but the dominant cxc chemoattractant was ena- . exacerbations are associated with the activation of the transcription factor nuclear factor (nf)-b in macrophages in induced sputum samples. the activation of nf-b by rhinovirus has been demonstrated in vitro and may be one mechanism whereby respiratory viruses up-regulate proinflammatory mediators in the airways, although it is not known whether rhinoviruses infect macrophages. through their chemotactic effect on neutrophils (ie, il- , ena- , and ltb ), lymphocytes and monocytes (ie, rantes) and the up-regulation of adhesion molecules (ie, tnf-␣), these mediators may be central components of the increased inflammation that is characteristic of exacerbations (fig ) . available data regarding the role of exacerbation etiology on airway inflammation has not determined whether different etiologies are associated with specific profiles of inflammatory mediators. a number of studies , , have reported that bacterial exacerbations are associated with higher levels of sputum il- , tnf-␣, and ltb than those in which no bacterial pathogen is isolated. virus-associated exacerbations were associated with higher levels of sputum il- in one study, whereas in another study rhinovirus was not associated with significant changes in the levels of sputum inflammatory markers. others have reported that increases in the levels of airway inflammatory markers occur independently of a demonstrable viral or bacterial infection. the release of cytokines by airway epithelial cells after viral infection leads to an influx of inflammatory cells. these inflammatory cells release products such as neutrophil elastase and reactive oxygen species that can cause tissue damage, stimulate mucus production, and further stimulate cytokine production. however, not all studies of the cellular inflammatory response in copd exacerbations have had consis- in the normal airway epithelial cells, viral infection induces the production of ifn-␤, which in turn induces apoptosis in virus-infected cells and limits virus replication. this is followed by an adaptive immune response characterized by th cells that produce ifn-␥ and il- , leading to a strong antiviral response, rapid clearance of the virus, and minimal inflammation. in asthmatic patients, both innate and adaptive antiviral immunity may be impaired, resulting in cell necrosis and the release of inflammatory mediators and virus. the increased viral load and levels of inflammatory mediators released from necrotic cells result in uncontrolled airway inflammation and exacerbation. and increased neutrophil, eosinophil, and lymphocyte counts. , in a study of copd patients intubated with severe exacerbations, increased numbers of neutrophils were seen in bronchial biopsy specimens compared to stable patients with copd, but other cell types were not reported. only one study has attempted to correlate the patterns of airway inflammation with exacerbation etiology. in this study, the levels of sputum neutrophils were elevated during exacerbation regardless of etiology, but the levels of eosinophils were increased only in patients with viral infections. the variability in the results highlights the need for further studies in carefully selected populations coupled with the determination of exacerbation etiology. therefore, although it is well established that copd exacerbations are associated with increased airway inflammation, there is marked variability in the nature of the inflammatory response, and the relationship between airway inflammation and etiology has not been established. the identification of valid biomarkers of exacerbation will allow for a more objective diagnosis of exacerbations and the determination of severity. in addition, a marker that distinguishes between viral and bacterial infection has the potential for reducing the overuse of antibiotics and the targeted use of antiviral agents when these become available. despite the advances made in treatments for both asthma and copd, acute exacerbations remain a major cause of morbidity and mortality. recent years have seen the epidemiologic evidence linking viruses with exacerbations getting ever stronger, and the stage is now set for progress in identifying important mechanisms of virus-induced asthma exacerbations. viral infection is associated with airways inflammation, but studies of the cellular and molecular response to infection have not shown clear-cut qualitative or quantitative differences between asthmatic patients and nonasthmatic subjects. there are no studies comparing virus-induced inflammation in copd patients with healthy control subjects. the recent evidence of impaired innate immunity in chemokines attract inflammatory cells that release toxic products, stimulating mucus production and leading to tissue damage with possible long-term loss of lung function. some mediators such as endothelin- have a direct effect in causing bronchoconstriction and vasoconstriction, resulting in airflow obstruction and impaired gas exchange. mmp ϭ matrix metalloproteinase; ros ϭ reactive oxygen species. v/q ϭ ventilation/perfusion. asthmatic patients suggests that this may be a key mechanism in the pathogenesis of virus-induced asthma exacerbations. further work is needed to identify whether similar mechanisms are involved in copd exacerbations. identifying the key inflammatory mediators involved in exacerbations, as well as the host defense mechanisms providing protection, holds the promise of developing new therapeutic agents and so reducing the burden of disease associated with asthma and copd exacerbations. detection of rhinovirus in induced sputum at exacerbation of chronic obstructive pulmonary disease longitudinal changes in the nature, severity and frequency of copd exacerbations relationship between exacerbation frequency and lung function decline in chronic obstructive pulmonary disease viral respiratory tract infection and exacerbations of asthma in adult patients community study of role of viral infections in exacerbations of asthma in - year old children persistence of rhinovirus rna after asthma exacerbation in 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infection induces expression of its own receptor intercellular adhesion molecule (icam- ) via increased nf-b-mediated transcription systemic and upper and lower airway inflammation at exacerbation of chronic obstructive pulmonary disease mmp- , timp- and inflammatory cells in sputum from copd patients during exacerbation key: cord- -f tjmi authors: alcendor, donald j. title: racial disparities-associated covid- mortality among minority populations in the us date: - - journal: j clin med doi: . /jcm sha: doc_id: cord_uid: f tjmi severe acute respiratory syndrome coronavirus (sars-cov- ), a betacoronavirus that causes the novel coronavirus disease (covid- ), is highly transmissible and pathogenic for humans and may cause life-threatening disease and mortality, especially in individuals with underlying comorbidities. first identified in an outbreak in wuhan, china, covid- is affecting more than countries and territories around the world, with more than , , confirmed cases and more than , deaths. since december , sars-cov- transmission has become a global threat, which includes confirmed cases in all states within the united states (us). as of july , the johns hopkins whiting school of engineering center for systems science and engineering reports more than , , cases and , deaths. to date, health disparities are associated with covid- mortality among underserved populations. here, the author explores potential underlying reasons for reported disproportionate, increased risks of mortality among african americans and hispanics/latinos with covid- compared with non-hispanic whites. the author examines the underlying clinical implications that may predispose minority populations and the adverse clinical outcomes that may contribute to increased risk of mortality. government and community-based strategies to safeguard minority populations at risk for increased morbidity and mortality are essential. underserved populations living in poverty with limited access to social services across the us are more likely to have underlying medical conditions and are among the most vulnerable. societal and cultural barriers for ethnic minorities to achieve health equity are systemic issues that may be addressed only through shifts in governmental policies, producing long-overdue, substantive changes to end health care inequities. coronavirus disease is caused by the severe acute respiratory syndrome coronavirus (sars-cov- ) [ ] [ ] [ ] [ ] . to date, seven human coronaviruses (hcovs) have been identified, including two α-covs (hcov- e and hcov-nl ) and five betacoronaviruses (β-covs) (hcov-oc , hcov-hku , severe acute respiratory syndrome cov [sars-cov], middle east respiratory syndrome cov [mers-cov] , and most recently β-cov sars-cov- ) [ ] [ ] [ ] [ ] [ ] . the world health organization (who) has classified covid- as a β-cov of group b [ ] . covs cause respiratory, enteric, hepatic, and neurological diseases in various animal species, including camels, cattle, cats, and bats [ , ] . the β-cov lineages hcov-oc and hcov-hku typically are associated with self-limiting upper respiratory infections in immunocompetent hosts and occasionally lower respiratory tract infections in immunocompromised hosts and the elderly [ , ] . examination of the viral evolution reveals that bats and rodents are gene sources for most α-covs and β-covs, whereas avian species are the proposed gene sources of most δ-covs and γ-covs [ ] . covs often the health inequities in the us that impact minority communities were well in place prior to the covid- pandemic. these inequities have become more evident in some cities and states. in chicago, aas make up % of the population; yet, they represent % of covid- cases and approximately % of covid- deaths, most of which are concentrated in small numbers of the most vulnerable communities [ ] . in the states of louisiana and michigan, aas are impacted disproportionately by covid- deaths [ ] : blacks represent . % and %, respectively, and account for . % and % of covid- deaths, respectively [ ] . in new york city, which had the largest number of covid- cases and the highest number of deaths due to covid- in the us, minority communities disproportionately are impacted, as aas and h/ls account for % and % of the population, respectively, and account for % and % of deaths, respectively [ ] . an examination of predominantly aa counties shows a covid- infection rate of . per , and a death rate of . per , , which is three times higher than the predominant nhw counties. moreover, the death rate for the aa counties were found to be six times higher than the rate observed in predominant white counties. taken together, a disproportionate burden of covid- morbidity and mortality, which will require further investigation, exists among minority communities in the us. it is evident that social determinants of health play a critical role in population-level health disparities beyond the comorbidities associated with covid- in minority communities. in the early stages of the pandemic in the us, dismissing covid- as not infecting aas may have created a lack of awareness and best practices, including proper hand hygiene, use of masks in public places, and social distancing and physical isolation, likely contributing to sars-cov- transmission in these communities [ ] . even were that not the case, among vulnerable populations with low socioeconomic status, these transmission-mitigating practices are difficult to maintain over time. racial and ethnic disparities in the prevalence of type diabetes (t d) among adult minority populations have been documented [ , ] . more recently, the global epidemic of childhood obesity has contributed greatly to the higher prevalence of t d among adolescents who have more progressive clinical presentations of chronic kidney disease (ckd), cvd, diabetes-related eye disease, and poor glycemic control over time [ ] . higher rates of t d are seen among minority youth when compared with nhw youth [ ] . approximately % of youth with t d are from minority backgrounds [ ] . in addition, health disparities for t d are present in adults and youth among racial and ethnic minorities, and this likely will impact their response to covid- . covid- patients with diabetes are at increased risk of having adverse clinical complications, including death [ , ] . maintaining glycemic control in covid- patients is essential, as hyperglycemia could affect pulmonary function, the immune response to infection, and the development of the pro-inflammatory cytokine storm associated with more severe clinical disease ( figure ). the use of corticosteroid therapy to combat inflammation in covid- patients also may increase glucose levels in % of patients with diabetes as well as patients without diabetes [ ] ( figure ). . hypothetical model of uncontrolled glycemia in diabetic patients and increased risk for complications due to covid- . patients who clinically present with normal or high blood pressure may be subject to undue complications related to severe acute respiratory syndrome coronavirus (sars-cov- ) infection. this is an illustration of the pancreas, responsible for insulin production and regulation and the immediate surrounding tissue and organs. once infected with sars-cov- some patients will experience increased inflammation in the form of a cytokine storm. corticosteroids often are hypothetical model of uncontrolled glycemia in diabetic patients and increased risk for complications due to covid- . patients who clinically present with normal or high blood pressure may be subject to undue complications related to severe acute respiratory syndrome coronavirus (sars-cov- ) infection. this is an illustration of the pancreas, responsible for insulin production and regulation and the immediate surrounding tissue and organs. once infected with sars-cov- some patients will experience increased inflammation in the form of a cytokine storm. corticosteroids often are prescribed to suppress inflammation but also are known to induce high glucose levels in the blood of both hypoglycemic and hyperglycemic patients. high blood glucose levels have been implicated in pulmonary injury and may affect the immune response, resulting in poor or delayed viral clearance. the degree of lung injury will include angiotensin-converting enzyme (ace )-mediated infection by sars-cov- that leads to hypoxia, vascular leakage, and potentially fatal pneumonia. tcr (t-cell receptor), cd (cluster designation ), mhc (major histocompatibility). adapted from fraussen j et al. [ ] . the who concludes that hypertension is the most important risk factor for death and disability worldwide, affecting more than billion people and causing an estimated . million deaths annually [ ] . aa adults have the highest prevalence of hypertension in the us, affecting . % of men and . % of women, in contrast to significantly lower rates in nhw, non-hispanic asian (nha), and h/l men and women [ ] . hypertension is the most significant factor that directly contributes to disparities in cvd and renal disease among aas compared with nhws [ ] . in a study by zhou et al., the most common comorbidities associated with adverse clinical outcomes in covid- patients were hypertension ( %), diabetes ( %), and coronary heart disease ( %) [ ] . in a separate study by wu, the most common comorbidities associated with covid- patients who developed acute respiratory distress syndrome were hypertension ( %), diabetes ( %), and cvd ( %) [ ] . in these two major studies, hypertension was found to be the most significant comorbidity associated with the most severe complications from covid- . hypertension is not known to be causative in covid- pathobiology, and elderly patients are more likely to be hypertensive and are known to be at greater risk of severe disease. it also remains unclear whether medications used to treat hypertension, such angiotensin-converting enzyme inhibitors (aceis), have a role in acquisition or progressive development of covid- in patients. in humans, the liver produces angiotensinogen, which is converted to angiotensin i by renin from the kidneys, and angiotensin i is converted to angiotensin ii by the action of ace ( figure ). normally, angiotensin ii is converted to angiotensin- - by the monocarboxypetidase ace ( figure ). however, upon infection with sars-cov- , the ace protein serves as an entry receptor for the virus and is internalized with sars-cov- during membrane fusion and uptake by infected cells (figure ). this leads to a significant reduction in ace surface expression and a concomitant increase in angiotensin ii, further leading to vasoconstriction that impacts blood pressure and causes inflammation, fibrosis, and oxidative stress in infected tissues within multiple organs ( figure ) . thus, the downregulation of ace leads to the upregulation of aldosterone, which increases the activity of ace , which again leads to higher levels of angiotensin ii and an overall suppression of angiotensin- - , designed to mitigate the effects of angiotensin ii via vasodilation, anti-inflammatory effects, and anti-oxidation ( figure ). taken together, this may result in multi-organ dysfunction (mod) or failure. however, it is known that sars-cov- binds to the ace receptor, mainly in the lung, to enter cells [ , ] . therefore, it remains controversial whether treatment of hypertension with aceis is beneficial or counter-productive in covid- patients. studies have shown the aceis have a protective anti-inflammatory effect in the lung, and soluble aceis could bind free virus and serve as therapeutics to reduce virus load [ ] [ ] [ ] . if corticosteroid therapy is recommended for covid- patients, glucose levels should be monitored carefully to avoid pulmonary and immune dysfunction [ , ] (figure ). controversy surrounds the discontinuation of angiotensin receptor blockers (arbs) and aceis for diabetes and hypertension treatment in covid- patients [ ] . however, in a recent study involving renin-angiotensin-aldosterone system inhibitors, it is recommended that these drugs be continued in patients evaluated for covid- to avoid excess cardiovascular risk [ ] . optimal care of diabetes patients with covid- should involve careful monitoring of corticosteroid therapy when warranted, monitoring of regular blood glucose, and avoiding inappropriate discontinuation of arbs and aceis that may increase morbidity in covid- patients. ace also is expressed in heart, kidneys, vascular endothelium, and intestinal epithelium, supporting the notion that virus interaction with several organ systems could lead to mod, which may be observed in covid- patients [ , ] . treatment of hypertension with aceis is beneficial or counter-productive in covid- patients. studies have shown the aceis have a protective anti-inflammatory effect in the lung, and soluble aceis could bind free virus and serve as therapeutics to reduce virus load [ ] [ ] [ ] . if corticosteroid therapy is recommended for covid- patients, glucose levels should be monitored carefully to avoid pulmonary and immune dysfunction [ , ] (figure ). controversy surrounds the discontinuation of angiotensin receptor blockers (arbs) and aceis for diabetes and hypertension treatment in covid- patients [ ] . however, in a recent study involving renin-angiotensinaldosterone system inhibitors, it is recommended that these drugs be continued in patients evaluated for covid- to avoid excess cardiovascular risk [ ] . optimal care of diabetes patients with covid- should involve careful monitoring of corticosteroid therapy when warranted, monitoring of regular blood glucose, and avoiding inappropriate discontinuation of arbs and aceis that may increase morbidity in covid- patients. ace also is expressed in heart, kidneys, vascular endothelium, and intestinal epithelium, supporting the notion that virus interaction with several organ systems could lead to mod, which may be observed in covid- patients [ , ] . hypothetical model of uncontrolled blood pressure in patients with hypertension and increased risk for complications due to covid- . the liver produces angiotensinogen, a peptide hormone that causes vasoconstriction that increases blood pressure. angiotensinogen is converted to angiotensin i by renin from the kidneys then is converted to angiotensin ii by the action of ace (ace-i). normally angiotensin ii (ang. ii) is converted to angiotensin- - by the monocarboxypetidase acei homology ace . however, upon infection with sars-cov- the ace protein serves as the entry receptor for the virus and is internalized in the endosome with sars-cov- during membrane fusion and uptake by hypothetical model of uncontrolled blood pressure in patients with hypertension and increased risk for complications due to covid- . the liver produces angiotensinogen, a peptide hormone that causes vasoconstriction that increases blood pressure. angiotensinogen is converted to angiotensin i by renin from the kidneys then is converted to angiotensin ii by the action of ace (ace-i). normally angiotensin ii (ang. ii) is converted to angiotensin- - by the monocarboxypetidase acei homology ace . however, upon infection with sars-cov- the ace protein serves as the entry receptor for the virus and is internalized in the endosome with sars-cov- during membrane fusion and uptake by infected cells. this leads to significant reduction in ace surface expression and concomitant increase in angiotensin ii, further leading to vasoconstriction that impacts blood pressure, inflammation, fibrosis, and oxidative stress in infected cells and tissues in multiple organs. even more, the downregulation of ace leads to the upregulation of aldosterone, a steroid hormone produced by the zona glomerulosa of the adrenal cortex, which increases the activity of ace . this action leads to higher levels of angiotensin ii and an overall suppression of angiotensin- - , which is designed to mitigate the effects of angiotensin ii via vasodilation, anti-inflammatory effects, and anti-oxidation. these levels of angiotensin ii may result in mod or failure. raasa (renin-angiotensin-aldosterone system antagonist). ace i (angiotensin-converting enzyme ). african americans are two to three times more likely than nhws to die of preventable cvd and stroke even when accounting for the general decline in cvd mortality [ ] . from - , a study found that the prevalence of hypertension among aa adults ( . %) was higher than among nhw ( . %), nhw ( . %), and hispanic ( . %) adults [ ] . medication non-adherence is one of the greatest challenges to reducing health disparities associated with cvd morbidity and mortality [ ] . poor management of hypertension is linked to increased risk of cvd, stroke, and ckd; hypertension management among aas has been shown to be lower when compared with nhws [ ] . cvd is a common comorbidity in patients with covid- and is associated with patients who have the most severe disease [ ] . a recent meta-analysis of eight studies from china that included , covid- -infected patients showed the most prevalent comorbidities were hypertension ( ± %, % confidence interval (ci) - %) and diabetes ( ± %, % ci - %), followed by cvds ( ± %, % ci - %) [ ] . covid- interacts with the cardiovascular system, inducing myocardial injury. patients with advanced age and elevated troponin i levels have abnormal echocardiograms and are at the greatest risk for developing more severe covid- disease (figure ). these patients have been shown to have increased blood levels of interleukin- (il- ), ferritin, lactic acid dehydrogenase (ldh), and fibrin degradation product (d-dimer), which are associated with the cytokine storm that likely would contribute to cardiac injury ( figure ). for patients with cardiac insufficiency who have underlying heart disease, sars-cov- infection may lead to adverse clinical disease and death. aging, ace levels, waning of the immune response, and host factors that become pronounced in patients with cvd have been considered as possible explanations for the severe disease course observed in covid- patients. in a study in wuhan, china, which included covid- patients, researchers observed laboratory evidence of cardiac injury indicated by elevated troponin i levels, as well as abnormal echocardiograms in . % of patients ( ) overall, and % ( ) who required intensive care unit (icu) attention [ ] . zheng et al., reported that % of covid- patients who died without known cvd risk clinically presented with elevated levels of troponin i or cardiac arrest during their hospitalization [ ] . the connection between covid- and cvd remains unclear; however, it has been suggested that direct infection of the heart occurs via ace expression on myocardial tissue, with supporting evidence in a murine model demonstrating ace -dependent myocardial infection of sars-cov- [ ] (figure ). in addition, sars-cov- rna was detected in heart tissue from % of patients who died during the sars-cov- outbreak in toronto [ ] . a cytokine storm and calcium-dependent apoptosis of cardiomyocytes are among other mechanism that could link cvd and covid- [ ] (figure ). ace -related signaling pathways also may have a role in heart injury. heart transplant patients are expected to be especially vulnerable to sars-cov- infection due to immunosuppression; however, in a small study performed with heart transplant recipients in wuhan, china, no evidence of a higher risk of infection with sars-cov- was found when precautionary measures were taken [ ] . recommended guidelines reported as guidance for cardiothoracic transplant and mechanical circulatory support centers regarding sars cov- infection and covid- have been established and must be followed when performing heart transplantation [ ] . it is recommended that patients continue heart transplantation without changes in immunosuppression, provided the recipient has not tested positive for sars-cov- and has not had exposure to or symptoms of covid- in the prior two to four weeks [ ] it is also recommended to avoid donors with known or suspected covid- , and if donors had covid- , they should be covid- -free (as indicated by polymerase chain reaction) for at least days, owing to the incubation period of~ days and onset of symptoms in~ . days [ ] . hypothetical model of patients with cvd and increased risk for complications due to covid- . cvd patients with advanced age and elevated troponin i levels, and who have abnormal echocardiograms, are at high risk for developing more severe covid- disease. these patients have been shown to have increased blood levels of il- , ferritin, ldh, and d-dimer, which are associated with the cytokine storm that likely would contribute to cardiac injury. high levels of ace are known to be expressed on cardiomyocytes that could result in direct infection of heart tissue by sars-cov- , which is thought to induce hypoxia leading to increase calcium levels resulting in apoptosis and death of cardiomyocytes; this likely would contribute to myocardial injury. heart transplant patients are expected to be especially vulnerable to sars-cov- infection due to immunosuppression; however, in a small study performed with heart transplant recipients in wuhan, china, no evidence of a higher risk of infection with sars-cov- was found when precautionary measures were taken [ ] . recommended guidelines reported as guidance for cardiothoracic transplant and mechanical circulatory support centers regarding sars cov- infection and covid- have been established and must be followed when performing heart transplantation [ ] . it is recommended that patients continue heart transplantation without changes in immunosuppression, provided the recipient has not tested positive for sars-cov- and has not had exposure to or symptoms of covid- in the prior two to four weeks [ ] it is also recommended to avoid donors with known or suspected covid- , and if donors had covid- , they should be covid- -free (as indicated by polymerase chain reaction) for at least days, owing to the incubation period of ~ days and onset of symptoms in ~ . days [ ] . the american thoracic society/european respiratory society committee, and similarly healthy people , published a policy statement defining disparities in respiratory health as closely linked to racial ancestry, social, economic, and/or environmental differences [ ] . health disparities in respiratory diseases are times higher in minority populations with the lowest socioeconomic status when compared with populations with the highest socioeconomic status [ ] . globally, a disproportionate burden of chronic obstructive pulmonary disease (copd) is present among minority communities due to low socioeconomic status, differences in health behaviors, occupational and social environmental exposures, prenatal and childhood exposures, respiratory tract infections, hypothetical model of patients with cvd and increased risk for complications due to covid- . cvd patients with advanced age and elevated troponin i levels, and who have abnormal echocardiograms, are at high risk for developing more severe covid- disease. these patients have been shown to have increased blood levels of il- , ferritin, ldh, and d-dimer, which are associated with the cytokine storm that likely would contribute to cardiac injury. high levels of ace are known to be expressed on cardiomyocytes that could result in direct infection of heart tissue by sars-cov- , which is thought to induce hypoxia leading to increase calcium levels resulting in apoptosis and death of cardiomyocytes; this likely would contribute to myocardial injury. the american thoracic society/european respiratory society committee, and similarly healthy people , published a policy statement defining disparities in respiratory health as closely linked to racial ancestry, social, economic, and/or environmental differences [ ] . health disparities in respiratory diseases are times higher in minority populations with the lowest socioeconomic status when compared with populations with the highest socioeconomic status [ ] . globally, a disproportionate burden of chronic obstructive pulmonary disease (copd) is present among minority communities due to low socioeconomic status, differences in health behaviors, occupational and social environmental exposures, prenatal and childhood exposures, respiratory tract infections, and tobacco use. these factors are associated with the risk of developing copd and are associated with poor clinical outcomes related to copd clinical presentations [ ] . according to the who, > % of copd deaths occur in low-income and middle-income countries [ ] . social determinants of health, including economic stability, education, access to health care, and environment, play a critical role in establishing health equity that will reduce disparity-related respiratory diseases, such as copd, during a lifespan [ , ] . copd is a condition that predisposes covid- patients to worse clinical outcomes [ ] . smokers and individuals with copd have increased airway expression of the ace receptor for sar-cov- [ ] . covid- patients with copd who are current smokers and have other types of lung disease, including asthma, have poor clinical outcomes (figure ). sars-cov- infection via ace entry into the alveolar epithelial cells of copd patients who smoke may lead to increased surface-expression ace on lung epithelium, which may increase the rate of infection in the lung and contribute to higher viral loads ( figure ). alveolar cells pneumocytes type ii are highly permissive for sars-cov- infection resulting in alveolar dysfunction, inflammation, vascular leakage, development of pulmonary emboli, and acute respiratory distress from poor gas exchange (figure ) . progressive viral infection and the pro-inflammatory conditions lead to pulmonary vascular leakage, alveolar edema, monocyte infiltration, and pneumonia ( figure ). patients often require mechanical ventilation resulting in delayed recovery, respiratory failure, septic shock, or mod or failure (figure ). smokers and individuals with copd have increased airway expression of the ace receptor for sar-cov- [ ] . covid- patients with copd who are current smokers and have other types of lung disease, including asthma, have poor clinical outcomes (figure ) . sars-cov- infection via ace entry into the alveolar epithelial cells of copd patients who smoke may lead to increased surface-expression ace on lung epithelium, which may increase the rate of infection in the lung and contribute to higher viral loads (figure ). alveolar cells pneumocytes type ii are highly permissive for sars-cov- infection resulting in alveolar dysfunction, inflammation, vascular leakage, development of pulmonary emboli, and acute respiratory distress from poor gas exchange (figure ) . progressive viral infection and the pro-inflammatory conditions lead to pulmonary vascular leakage, alveolar edema, monocyte infiltration, and pneumonia ( figure ). patients often require mechanical ventilation resulting in delayed recovery, respiratory failure, septic shock, or mod or failure (figure ) . hypothetical model of patients with pulmonary disease and increased risk for complications due to covid- . sars-cov- infection via ace entry into alveolar epithelial cells in patients with copd who smoke may lead to increased surface-expression ace on lung epithelium that may increase the rate of infection in the lung and contribute to higher viral loads. shown is the alveolar organization and resident cells that include pneumocytes type i, pneumocytes type ii and alveolar macrophages. elastic fibers are also shown and sars-cov- particles are shown as blue ovals. alveolar cells pneumocytes type ii are highly permissive for sars-cov- infection resulting in alveolar dysfunction, inflammation, vascular leakage, development of pulmonary emboli, and acute respiratory distress from poor gas exchange. progressive viral infection and potential cytokine storm leads to pulmonary vascular leakage, alveolar edema, and monocyte infiltration at sites of infection, resulting in reduced lung function. patients often require mechanical ventilation increasing the risk of delayed recovery, respiratory failure, septic shock, and mod or failure. ards (acute respiratory distress syndrome). infection via ace entry into alveolar epithelial cells in patients with copd who smoke may lead to increased surface-expression ace on lung epithelium that may increase the rate of infection in the lung and contribute to higher viral loads. shown is the alveolar organization and resident cells that include pneumocytes type i, pneumocytes type ii and alveolar macrophages. elastic fibers are also shown and sars-cov- particles are shown as blue ovals. alveolar cells pneumocytes type ii are highly permissive for sars-cov- infection resulting in alveolar dysfunction, inflammation, vascular leakage, development of pulmonary emboli, and acute respiratory distress from poor gas exchange. progressive viral infection and potential cytokine storm leads to pulmonary vascular leakage, alveolar edema, and monocyte infiltration at sites of infection, resulting in reduced lung function. patients often require mechanical ventilation increasing the risk of delayed recovery, respiratory failure, septic shock, and mod or failure. ards (acute respiratory distress syndrome). differential expression of ace may help to explain the discrepancy in viral pathology associated with covid- . the production of ace among minority populations who smoke or have copd may partially explain the differences in covid- rates of morbidity and mortality among aas compared with nhws. leung et al. examined gene expression levels of ace in the airways of individuals with and without copd and found that active cigarette smoking and copd upregulate ace expression in lower airways and could contribute to the difference in disease burden observed among covid- patients [ ] . these findings were supported in a rat model that showed smoke exposure resulted in increased expression and activity of ace in the airways [ ] . individuals with uncontrolled asthma also appear to be at increased risk of a more severe course of covid- infection [ ] . lung function tests and the use of nebulizers as part of copd and asthma management should be performed with caution due to the risk of virus aerosolization and potential transmission during these procedures [ ] . disparities in t d among minority adults have been pervasive in diabetes complications, glycemic control, and diabetes care [ ] . glycemic control in all patients with diabetes is critical for avoiding complications such as ckd, cvd, and diabetes-related eye disease. it is projected that racial and ethnic disparities in t d prevalence will persist until [ ] . one of the most significant challenges in mitigating the effects of diabetes on the health and wellness of minority populations in the us is improving basic social determinants of health, including low socioeconomic status, poor access to educational opportunities, conditions of poverty, excess life stressors, poor health knowledge, and limited access to quality and affordable health care. strategies to mitigate diabetes among minority populations at greater risk for severe covid- disease would involve improving glycemic control among aas and h/ls, which is a major problem [ ] . management of hypertension has been problematic among minority populations with diabetes. it has been reported that % of adults with diabetes have high blood pressure, and blood pressure control among diabetics is essential to reduce the risk of developing retinopathy and neuropathy associated with diabetes [ ] . aas are more likely to have significantly higher, uncontrolled blood pressure than nhws [ ] . obesity and a sedentary lifestyle should be avoided among diabetics [ ] . the increased burden of diabetes among racial and ethnic minorities. diabetes is higher among black or african american, h/ls, and american indian individuals as compared to nhw [ ] . aas experiencing household or neighborhood-level poverty are at a higher risk of developing diabetes [ ] . the rates of diabetes in the southern u.s. is higher than the national average [ ] . this will require overall improvements in social determinants of health that tend to predispose these populations to the worst diabetes outcomes often superimposed on the pathogenesis of covid- disease burden. among racial and ethnic minorities, hypertension prevalence in the us is highest among aas, who have been shown to have less control of the disease when compared with nhws [ ] [ ] [ ] [ ] . pharmacotherapy in the form of thiazide-type diuretics, calcium channel blockers, aceis or angiotensin ii receptor blockers (arbs), and lifestyle changes are essential for hypertension control [ ] . medication adherence plays a critical role in the long-term management of hypertension, especially in minority communities, and is directly related to racial and ethnic disparities in cvd, stroke, and chronic kidney disease (ckd). ferdinand et al. report that strategies such as direct patient engagement, consumer-directed health care, utilization of patient portals, smart apps and text messages, digital pillboxes, pharmacist-led engagement, and cognitive-based behavior, could be important for improving medical adherence and reducing disparities in hypertension and its related complications [ ] . the centers for disease control and prevention (cdc) reports that % of individuals who died of covid- disease were older than years of age. age-related increase in systolic blood pressure suggests that % of adults in the us will develop hypertension in their lifetime. this age-related increase in blood pressure likely contributes to increased age-related mortality among the elderly with covid- . it has been proposed that cvd is more prevalent in older patients, as these patients are more likely to have impaired immune systems that loses the ability to responds effectively to infections and the reduced levels of ace observed among the elderly may predispose older patients to more severe complications of covid- due to loss of the protective effects of ace to regulate and control inflammation. therefore, patients with cvd should be subjected first to preventive measures, such as monitoring for elevated cardiac biomarkers, and if necessary, should be isolated from other patient populations that would place them at higher risk. in addition, a report from the national health commission of china revealed that almost % of covid- patients without known cvd risk had elevated troponin levels or cardiac arrest during hospitalization [ ] . this would suggest that sars-cov- -mediated infection may lead directly to myocardial dysfunction. potential benefit or harm from aceis and arbs, commonly prescribed for cardiovascular disorders, is still under investigation due to lack of available evidence. individuals with copd and confirmed covid- are at greater risk of severe complications and death than individuals without copd. optimal testing and diagnostics, as well as management of individuals with copd in underserved communities, should be made available for early intervention and treatment. these individuals should be screened for other comorbidities that are associated with the development of copd, such as asthma, lung infections, and other related respiratory diseases. affordability and access to treatments and palliative care should be made available to low-income copd patients. furthermore, copd patients should be allowed access to optimal life-extending treatments for their disease, including medical specialists, more effective drug treatments, smoking cessation counseling, supplemental oxygen, and non-invasive ventilation that often are unaffordable for these vulnerable populations [ ] . having copd and being a current smoker may greatly increase the risk of complications mortality from covid- . interventions in copd patients who smoke should include smoking cessation, as it has been demonstrated to improve pulmonary function in younger smokers compared with older smokers who have sustained cumulative lung damage over time [ ] . essential workers, who often are from minority communities and face occupational hazards, are at greater risk for developing occupation-related copd. understanding clinical risk factors and their mechanisms can benefit disparity populations by identifying at risk individuals early and developing early intervention strategies that are designed to manage these risk factors in the context of clinical trials where access to care and drug compliance can be controlled. the benefits of understanding these mechanisms could also provide information that contributes to innovative therapies that identify selective targets within these pathways among disparity populations based on unique genetic profiles. finally, an understanding of these mechanisms could lead to changes among health providers to be more aggressive in their care for these patients as clinical trial data become available, leading changes in health policy for underserved populations. changes in public policy are essential to combat the long-standing problems associated with health inequities in our health care system. these inequalities are more pronounced during a health care crisis, such as the current covid- pandemic. addressing these inequities would require a government-appointed race/inequity task force that is designed to implement pre-determined standards of care in minority communities at an early stage in a medical crisis. in addition, special provisions should be made for essential workers, many of whom are underserved, to be adequately equipped and compensated for vital services performed to maintain public health standards. adequate funding should be established to support these initiatives from both the public and private sectors to avoid disruptions in the readiness of our workforce, supply chains, and health care system to prevent unforeseen economic crisis. new policies must be flexible enough to accommodate changes in our scientific understanding of these emerging pathogens and the development of efficacious interventions to protect the public, including our most vulnerable populations. these policies would require a bipartisan commitment from government officials, ending a "wait and see if it goes away" strategy by replacing previous tactics with a standard plan of action, which would save lives and reduce the overall burden on our economy. policy changes would include the elimination of inequitable treatment within our health care system. doctor-patient relationships that include individuals from underserved communities in the us can be difficult due to systemic racism and implicit racial bias that has contributed to historic distrust in minority communities for health care providers. physicians could engage minority patients in ways that will help to assure them that they will receive the best possible care. for those minority populations who are essential workers that are at higher risk for covid- because of pre-existing health conditions, physicians should aggressively make them aware of the risks as well as precautionary measures they must take to avoid infection. aggressive strategies to help minority patients at higher risk understand the seriousness of covid- disease could include direct mailings, providing patients with samples of masks and sanitizers, covid- office placards, covid- infomercials in waiting areas, wellness checks, and covid- information for family members and caretakers. the social determinants of health (sdoh) for these individuals are directly linked to the development of risk factors that predispose them to more severe covid- disease. healthcare providers and patient navigators that have relationships with community based organizations (cbos) that work to improve sdoh among underserved communities could be an important option to support the long term health and wellness of disparity populations. front line health care providers in the covid- pandemic are being pushed to the limits of human endurance and are often overwhelmed which can trigger disparate responses to minority communities. policies need to be in place that confer oversight for when this occurs. physicians should be surveyed in ways to recognize implicit racial bias when caring for minority patients and be encouraged to take measures to constructively modify their behavior. in addition, there is a great need for more nurses and other medical practitioners to support physicians during this pandemic. some of these challenges can be met with volunteers that have past medical training as well as military medical staff. essential workers, many of whom are from minority communities are often forced to experience increased risk of virus transmission because of economic hardships and the lack of personal protective equipment (ppe). the lack of ppe is directly linked to the likelihood of virus transmission to essential workers and, therefore, should be recognized as a necessity that should be prioritized by the federal government as an emergency declaration that would be fully funded throughout this pandemic and policies put in place in this declaration for timely ramping-up of ppe supplies and development of government-owned ppe stockpiles for a future medical crisis. a commission of physicians, and nurses should be established to advocate the need for ppe on behalf of essential workers at risk for covid- and given the opportunity the make their case to policy makers. healthcare access is a core component of the sdoh for underserved communities and poor access to affordable healthcare is a major driver of health disparities in the us. these disparity populations are heavily impacted by this pandemic. the affordable care act (aca) represents a lifeline for the working poor and their families without health insurance. the aca should be maintained and arguably updated or revised to meet the changing needs of participants. the aca is a critical component of our existing healthcare infrastructure that directly addresses health inequities in the us and is not perfect in content and yet should be preserved. the existing political climate for legislation to directly address longstanding us racial/ethnic inequities in healthcare as well as other sdoh such as education, housing, and a living wage will require a continuance of the grass roots call for change and the acceptance by policy makers that these changes need to become law in america. longstanding health disparities such as diabetes, hypertension, cvd, and pulmonary disease among minority populations in the us may serve to predispose these communities to sars-cov- infection and increased risk for clinically severe covid- . the underlying social determinants of health and standards of care in minority communities must be improved to end these disparities. improvements will require changes in governmental policy and a long-term commitment to minority communities that includes early interventions and prevention strategies to reduce or eliminate major healthy disparities on the way to achieving health equity. the novel chinese coronavirus ( -ncov) infections: challenges for fighting the storm severe acute respiratory syndrome coronavirus (sars-cov- ) and coronavirus 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higher risk for severe illness; us department of health and human services residual lifetime risk for developing hypertension in middle-aged women and men treatment options for covid- : the reality and challenges review potential antiviral drugs for sars-cov- treatment: preclinical findings and ongoing clinical research higginson, i. palliative care and management of troublesome symptoms for people with chronic obstructive pulmonary disease this article is an open access article distributed under the terms and conditions of the creative commons attribution (cc by) license key: cord- - rrvm authors: dimopoulos, g; tsiodras, s; lerikou, m; chranioti, aik; perros, e; anagnostopoulou, u; karakitsos, p; armaganidis, a title: viral profile of copd exacerbations according to patients§ date: - - journal: open respir med j doi: . / sha: doc_id: cord_uid: rrvm background : to compare the differences between elderly and non-elderly patients with acute exacerbations of chronic obstructive pulmonary disease (aecopd) due to viral infections. methods : patients with chronic obstructive pulmonary disease (copd) exacerbation were recruited and classified as elderly (> years) and non-elderly (≤ years). sputum and oropharyngeal samples were assessed, pcr for respiratory viruses and cultures for common pathogens were performed. results : patients (median age: . ± . years) were recruited and categorized into group a: non-elderly patients [n= ( . %), median age ± . ] and group b: elderly patients [n= ( . %), median age . ± . ] years. in ( . %) patients a viral infection was identified and in ( . %) a bacterial pathogen was isolated from cultures. in ( . %) patients a double infection (bacterial+viral) was identified. in group b, the presence of cardiac failure ( . % vs . %, p< . ), renal failure ( . % vs %, p= . ), bacterial co-infection ( . % vs . %, p= . ), influenza vaccination rates ( . % vs , p< . ), and longer hospital stay ( . ± . vs . ± . days, p= . ) were higher than group a. the overall rate of viral infections did not differ according to age. a trend to higher rates of infection with parainfluenza [ ( %) patients in group b vs ( . %) patients in group a, p= . ] was observed in older patients. conclusion : no differences on the rate and type of viral infections were noted for elderly vs non elderly patients. however, they tended to have more bacterial co-infections that led to aecopd and longer hospitalization stays compared to non-elderly patients. the ageing process leads to a significant decline of physiologic and morphologic functions of the human body making the elderly patients more susceptible to infections [ ] . the relationship between older age and infections cannot be easily evaluated since limited data exist concerning specific conditions (e.g. severe community acquired pneumonia, nosocomial bacteremia) or subpopulations (postoperative patients) within the elderly [ ] . up to date most of the efforts are small single center cohorts that have tried to study elderly patients together with specific characteristics and risk factors associated with certain infection [ ] [ ] [ ] . *address correspondence to this author at the th pulmonary department, sotiria athens chest hospital, , rodopis str, glyfada, , athens, greece; tel/fax: + . . ; e-mail: mlerikou@yahoo.gr § part of this article has been previously published in pulmonary pharmacology & therapeutics; volume , issue , february , chronic obstructive pulmonary disease (copd) is complicated by frequent exacerbations, called acute exacerbations of chronic obstructive pulmonary disease (aecopd) which are associated with high morbidity, increased used of health resources and aggravation of the health status of the patients [ ] . the main risk factor for aecopd development is considered an infection of the respiratory system caused by a virus (up to %) or by bacteria (responsible approximately for % of those events) [ , ] . the significance of viral infections has been recognized during the last decade by the development and clinical application of newer molecular techniques able to detect viral species that are not easily detected by serology or viral cultures such as human metapneumovirus [ ] . recently, we evaluated the epidemiology of viral infections in a cohort of patients with aecopd where we showed that viral infections were strongly associated with aecopd development independent of the stage of copd and an infection with both a viral and a bacterial pathogen was common in these patients [ ] . in this cohort, we had a high percentage of elderly patients with aecopd due to viral infections. for this reason, we conducted the present study aiming to investigate possible differences among elderly and non-elderly patients with aecopd of viral origin. we have previously conducted a year prospective study focused on the infectious etiology of aecopd [ ] . briefly, in this cohort study, all patients (aged - years) who have visited the emergency department of a tertiary care hospital and were admitted into an inpatient facility because of a copd exacerbation (according to gold criteria), without hospitalization during the last three months or use of antibiotics during the last days and without a diagnosis of bronchial asthma were included [ ] . the patients reported no history of infection during the last month and were not receiving systemic corticosteroid therapy. the study period lasted from january to june . the study has taken approval by the ethical committee of the hospital and all the patients recruited in the study signed written informed consent. in the absence of a clear definition for "elderly" patient in the medical literature, the age cut off chosen for this study was based on the world health organization (who) definition for elderly. according to this statement most developed world countries have accepted the chronological age of years as a definition of "elderly" or older person. while this definition is considered somewhat arbitrary, however it is usually associated with the age at which a person can begin to receive pension benefits. currently, there is no united nations standard numerical criterion, but the un agreed to a cutoff of + years in order to refer to the older population [ ] [ ] [ ] [ ] . the following parameters were recorded on admission: age, sex, stage of copd (according to gold criteria), smoking habits and alcohol addiction, use of oxygen, influenza vaccination, comorbidities (confirmed by medical records), current medication as well as signs and symptoms of respiratory tract infection. all patients underwent routine blood examination, including c-reactive protein, chest radiograph and sputum culture for common bacteria. the patients were assigned to copd stages based on the gold criteria and according to the most recent available spirometric values (the last three months). patients with mild copd (stage i) had an fev /fvc < % and fev ≥ % of predicted values. patients with moderate copd (stage ii) had an fev /fvc < % and fev between % and % of predicted values. patients with severe copd (stage iii) had an fev /fvc < % and fev between % and % of predicted values and patients with very severe copd (stage iv) had an fev /fvc < % and fev < % of predicted values or fev < % of values predicted plus chronic respiratory failure. they all underwent spirometry after their discharge from hospital. all patients were followed-up throughout their recovery from exacerbation and until their discharge from the hospital. following first evaluation and before the initiation of any treatment, sputum and oropharyngeal samples (gargle) were collected and submitted for viral detection by clinical microarrays technique i.e. clart ® pneumovir kit (genomica, spain). this method is able to detect and characterize the most frequent types of human viruses responsible for respiratory infections, by identifying very small quantities of viral genomic material. it uses a sequence which corresponds to a highly preserved region within the viral genome and binding probes specific to each respiratory virus type. viruses analyzed include, human respiratory syncytial virus (hrsv) type a and b, human metapneumovirus (hmpv) type a and b influenza virus (all types a, b, c), rhinovirus, parainfluenza virus (hpiv) , , and (subtypes a and b), enterovirus (echovirus), adenovirus, coronavirus and bocavirus. the samples were collected in thin prep cytolyt ® solution and centrifuged at g. the molecular procedure was performed according to the manufacturer's instructions. in brief, viral dna/rna was extracted by using µl of clinical sample mixed with lysis buffer and then allowed to stand in room temperature for minutes. isopropanol was added and centrifugation was performed at rpm for min followed by removal of the supernatant. then the precipitate was resuspended with µl % ethanol followed by centrifugation at rpm for min. the supernatant was removed again and the sample was left to dry for min (until there were no ethanol residues left). at the end the pellet was resuspended in µl of dilution solution. the viral dna/rna extracts were stored at - °c until amplification. virus amplification was performed via two rt (reverse transcriptase) multiplex pcr reactions of a specific - bp fragment of the viral genome. the pcr employed the following thermal cycler settings: cycle of min at °c and min at °c, followed by cycles of sec at °c, , min at °c and min at °c and final cycle of min at °c. visualization of the amplified product was performed on a platform based on low-density micro-arrays, which is called array tube (at). this detection system is based on the precipitation of an insoluble product at those sites of the at where the hybridization of the products amplified by specific molecular probes is produced. the amplified products are labeled with biotin during the pcr. after the amplification, they hybridize with their respective specific probes that are immobilized in specific and known sites of the at, after which they are incubated with a streptavidin-peroxidase conjugate. the conjugate binds via streptavidin with the biotin present in the amplified products (which are also bound to their specific probes), while in the presence of o-dianisidine, the peroxidase activity of the conjugate induces the appearance of an insoluble product which precipitates at the hybridization sites of the at" [ ] . qualitative variables are expressed as counts and percentages and quantitative variables are expressed as means and standard deviations. the student's t test for independent samples was used to perform comparisons between means whereas the man-whitney test was used in case variables did not meet the criteria of normality. the chisquare or fisher's exact test were used for comparisons of proportions. a p value of less than . was considered significant. data were analyzed using statistical software (spss, version . ; spss; chicago, il). in total, patients were recruited in the study, did not signed the inform consent, did not meet the inclusion criteria while in patients the samples were not suitable for analysis (we obtained an invalid result from the clart pneumovir ® -the most common cause is that amplification process may have been interfered by an unknown substance which might inhibit the dna polymerase enzyme (Τable ) , without however a statistically difference between elderly and non-elderly patients ( table ) . in this study we found: a) a high frequency of aecopd due to viral infections in elderly and non-elderly patients without differences between the two groups, b) more frequent infections due to human parainfluenza virus (hpiv) and influenza in elderly patients compared to non-elderly longer and c) lengthier hospital stays for the elderly patients. in a recently published study where we evaluated the epidemiology of viral infections in patients with aecopd a high rate of viral infections ( . %) was detected which was in accordance with other previously published reports [ , , ] . in this study when comparing the frequency of viral infections among elderly and non-elderly patients no differences were detected. a possible explanation for this could be the fact that copd is a chronic systemic inflammatory syndrome affecting the immune response independently of the age and making these patients more prone to such infections [ , ] . the elderly is a large and even growing population, proportional to the age of the the open respiratory medicine journal, , volume fig. ( ) . elderly vs non-elderly patients with viral infections. general hospitalized population. this group of patients is characterized by a decline of the immunological response to infection, principally due to functional insufficiency of monocytes and macrophages that results to inadequate phagocytosis, by the lack of antigen presenting cells, such as dendritic cells (so are naive t-cells due to thymus gland involution), by the loss of memory capacity of mature tcells exhibiting a poor and/or altered cytokine production and by the decrease of the number of circulating b-cells resulting in a weaker response to antigenic challenges through immunoglobulin production [ , ] . elderly usually have higher rates of vaccination against influenza from their primary care physicians than non-elderly (although both are at risk) [ , ] . however, no difference was detected either in influenza virus or other viruses' detection rates. this could be explained by the fact that immune responses to vaccination decline substantially with age thus the elderly have impaired humoral and cell mediated immune responses to influenza vaccines compared with younger adults [ , , [ ] [ ] [ ] . it also points to the need for better prevention measures against respiratory viruses for this population. a strong association between comorbidities (number and type) and older age is well known [ ] . copd patients usually have increased number of comorbitities (cardiovascular diseases, respiratory tract diseases, metabolic diseases, haematological diseases / coagulopathies, musculoskeletal diseases, gastro-intestinal diseases, renal diseases, psychiatric diseases, neoplasias) known as "copd comorbidome" which are considered as copd-related (e.g. respiratory failure, pulmonary heart disease cachexia) or copd-non related (eg obesity, diabetes mellitus, arterial hypertension) [ ] [ ] [ ] . in our patients cardiac/ renal failure and diabetes mellitus were the most frequent detected comorbitities. this increased number could be explained by the orientation of our center as is a specialized site on cardio-respiratory diseases in greece. the infections due a bacterial pathogen were more common in elderly subjects and the hospital stay was lengthier. these patients need more time to recover because of the complexity of copd ( either a systemic oxidative stress syndrome or an inflammatory process or a combination of those), the weaker immune response as result of the inflammatory process and the frequent colonization by bacteria that lead to bacterial infections or co-infections (viral+bacterial) [ , [ ] [ ] [ ] [ ] [ ] [ ] . this is a main statement in a recently published study where a longer hospital stay in aecopd patients with co-existed candidiasis, anemia, psychological disorder, atrial fibrillation and congestive heart disease, asthma, respiratory failure and cachexia was detected [ ] . we didn't find any difference in the mortality in elderly aecopd patients with a viral infection compared to the non-elderly although mortality is higher in copd patients with lung cancer, pulmonary heart disease, heart failure, atrial fibrillation, obstructive sleep apnea, obesity, osteoporosis and asthma [ ] . the isolated type of viruses in two groups didn't present any difference ( table ) except hpiv detection. human parainfluenza viruses (hpivs) are considered to be one of the most common causes of lower respiratory tract infections in children [ ] [ ] [ ] but it is difficult to understand their biologic significance in this cohort. one possible explanation could have been the occurrence of a clonal hpiv outbreak during the study period. when analyzing the seasonal pattern of viral infections no statistically differences were noted although is well known, that copd patients present more commonly exacerbations during the cold seasons (winterautumn) and viral infections have a higher prevalence during this period associated with a longer recovery period, longer in house stay and increased likelihood of hospital admission [ , ] . also, despite the important role of viral infections, in this study it was difficult to examine their true pathogenic role since for some of these viruses there is an increasing evidence that they could colonize the respiratory tract; such colonizers may act as modulators of the local immune response in a subsequent bacterial upper tract infection in an already susceptible patient but the exact interaction of bacterial with viral colonizers is an issue for further debate [ , ] . this study has some limitations. first, no quantitative pcr techniques were performed in order to test the modifications of the viral load of a specific virus which could be indicatives of the (re)activation of the virus in a previously colonized patient before the exacerbation. second, patients with aecopd frequently receive home care for moderate-mild episodes and for this reason we could have missed a fraction of similar episodes occurring in the community. third, because of the low yield of sputum cultures regarding the confirmation of bacterial infections we could have missed some bacterial pathogens inhabiting or infecting the respiratory tract. forth, there is no evident a convinced explanation for the high detection of rsv. in conclusion, in a significant percentage of elderly people with aecopd a viral pathogen was detected in their upper respiratory tract. human parainfluenza viruses and mixed viral infections were more common in elderly subjects but the exact role of the different viral species is a matter for further research. ageing and infection epidemiology and outcome of nosocomial bloodstream infection in elderly critically ill patients: a comparison between middle-aged, old, and very old patients factors that predict outcome in intensive care treatment in very old patients: a review age still matters: prognosticating short-and long-term mortality for critically ill patients with pneumonia nosocomial 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in elderly patients with community-acquired pneumonia patterns of hospitalization in elderly patients with asthma and chronic obstructive pulmonary disease new strains of bacteria and exacerbations of chronic obstructive pulmonary disease relationship between bacterial colonization and the frequency, character, and severity of copd exacerbations population-based incidence of severe acute respiratory virus infections among children aged < years in rural bangladesh infections due to parainfluenza virus type in children parainfluenza viruses influence of season on exacerbation characteristics in patients with copd respiratory syncytial virus, airway inflammation, and fev decline in patients with chronic obstructive pulmonary disease latent adenovirus infection in copd declared none. the authors confirm that this article content has no conflict of interest. key: cord- - xc n authors: lipworth, brian; chan, rory; lipworth, samuel; ruiwen kuo, chris title: weathering the cytokine storm in susceptible patients with severe sars-cov- infection date: - - journal: j allergy clin immunol pract doi: . /j.jaip. . . sha: doc_id: cord_uid: xc n nan high-risk patients requiring hospitalization for severe acute respiratory syndrome coronavirus (sars-cov- ) infection are those over years old, males, obese, smokers, and those with common comorbidities including hypertension, cardiovascular disease, diabetes, and chronic lung disease. immunocompromised and cancer patients are also at greater risk. in one meta-analysis, the relative risk for experiencing severe versus nonsevere covid- disease was %, %, and % higher in patients with hypertension, respiratory disease, and cardiovascular disease, respectively. use of angiotensin-converting enzyme (ace) inhibitors and angiotensin receptor blockers (arbs) for hypertension, heart failure, and diabetes may upregulate expression of ace , the latter being involved in the binding and uptake of sars-cov- to the lung epithelium. ace may also be unregulated by smoking in small airway epithelia. it remains unclear whether the increased risk of covid- infection is attributable to hypertension or agerelated comorbidity per se. current hypertension or heart failure guidelines do not advocate stopping or switching ace inhibitors or arbs. upstream therapeutic strategies revolve around the use of antivirals ( figure ). one study showed no benefit in using lopinavir plus ritonavir over standard of care for sick hospitalized adult patients with severe covid- pneumonia even though the study was likely underpowered. this in turn perhaps infers that using upstream antiviral therapy alone may not be successful later on in the disease process once the downstream cytokine avalanche has been triggered, resulting in subsequent lung damage. having said that compassionate use of iv remdesivir in patients with severe covid- infection resulted in % having improved oxygenation status and % mortality among those receiving invasive ventilation, albeit with no control arm for comparison. there has also been interest in using azithromycin for covid- . it has been included in the action (nct ) and hyazout (nct ) trials on the basis of its immunomodulatory and putative antiviral activity, although its effects on sars-cov- remains speculative. caution is advised in trials evaluating azithromycin in conjunction with hydroxychloroquine (nct ), due to potential additive effects on qt interval prolongation and propensity for arrhythmias. blocking viral host cell entry with the antimalarial drugs hydroxychloroquine or chloroquine is another potential upstream modality ( figure ). hydroxychloroquine is safer and more potent in terms of in vitro sars-cov- suppression. , hydroxychloroquine acts via ace and increases endosomal ph to attenuate sars-cov- endocytic host cell entry into the lung epithelium. hydroxychloroquine has shown some promising preliminary clinical results in terms of attenuating in vivo sars-cov- viral load and has been included in the who solidarity trial as well as the nihr recovery and principle trials. hydroxychloroquine may also exhibit downstream immunosuppressive effects by reducing il- production from t cells and monocytes, which may explain in part its use in autoimmune conditions. to date one non peer reviewed randomised controlled trial from france with hydroxychloroquine added to usual care in patients with severe covid- pneumonia reported no significant impact on the primary end point of intensive care or death within days, while . % of patients had to stop hydroxychlorquine due to qt prolongation. bromhexine is an over-the-counter cough remedy that blocks receptor-mediated viral cell entry via the transmembrane protease, serine enzyme (tmprss ). theoretically, there could be potential synergy in terms of more effectively blocking viral host cell entry using combined hydroxychloroquine and bromhexine (nct ), but at present this only remains speculative. it remains to be seen whether such agents are more likely to be effective early on in covid- disease given that they prevent upstream viral entry. little consideration appears to have been given to susceptible patients with obstructive airways disease with regard to covid- infection. in particular, elderly patients with chronic obstructive pulmonary disease (copd) have impaired respiratory reserve and a plethora of comorbidities, which potentially confers both pathophysiological and pharmacological susceptibility. such individuals are at high risk of adverse outcomes as a result of severe sars-cov- infection. patients with copd taking inhaled corticosteroid (ics) combination therapy have an increased pneumonia risk, especially with lipophilic drugs such as fluticasone furoate, due to its prolonged lung retention and associated local immunosuppression in the presence of altered lung microbiome and impaired mucociliary clearance. moreover, suppression of interferon by fluticasone propionate is associated with an increased bacterial load after rhinovirus infection. corticosteroids may also attenuate production of the antibacterial protective peptide cathelicidin in the lung epithelium. thus, secondary bacterial infection might contribute to the cumulative inflammatory burden in addition to viral pneumonia. caution should be exercised in extrapolating from copd to asthma, even though up to % of patients with copd have a corticosteroid responsive eosinophilic component. hence, in patients with copd with blood eosinophils cells/ml, the benefit of fluticasone furoate in reducing severe exacerbations outweighs its risk in inducing severe pneumonia. nevertheless, one canadian cohort study of patients with asthma demonstrated that current ics use was associated with a % relative increased risk of pneumonia, amounting to an excess of . cases per patient-years. interestingly, ciclesonide and mometasone, but not budesonide, beclomethasone, or fluticasone, exhibit in vitro suppression of sars-cov- replication to a similar degree as lopinavir, albeit in preliminary non peer reviewed data. for ciclesonide, its target on viral replication appears to be nonstructural protein (nsp ). budesonide and formoterol independently suppress systemic suppression of il- in relation to acute lung injury in the mouse model. pointedly, asthmatics taking ics are % less likely to have a severe outcome after hospitalization for influenza a/h /n infection, perhaps inferring a generic protective ics class effect. in the meantime, the key message for patients with asthma is to adhere to their ics controller therapy as this is likely to offer the best protection against any viral insult including sars-cov- . at this juncture, no evidence can support switching patients with controlled asthma to inhaled ciclesonide or mometasone. a study evaluating ciclesonide in south figure . the cytokine cascade resulting from acute severe sars-cov- infection, with downstream il- activation considered to be a hallmark feature in terms of progression of covid- pneumonia to hyperinflammation and ards. also shown are the putative mechanisms of action for bromhexine and hydroxychloroquine in attenuating upstream sars-cov- tissue binding, the effect of antivirals on replication, azithromycin as an antiviral and immunomudulator, nonspecific cytokine suppression by corticosteroids, together with the selective downstream effect of il- blockade with tocilizumab or sarilumab and effects of anti-tnf and interferon beta- -a. ace , angiotensin converting enzyme ; acei, angiotensin converting enzyme inhibitor; arb, angiotensin ii receptor blocker; ards, acute respiratory distress syndrome; crp, c reactive protein; sars-cov- , severe acute respiratory syndrome coronavirus ; tnf, tumour necrosis factor; tmprss , transmembrane protease, serine . korea will look at the rate of sars-cov- eradication in patients with mild covid- infection (nct ). another study comparing high dose ciclesonide with usual care from japan will report on progression of severe covid pneumonia. corticosteroids may be considered as a rather blunt tool for dealing with the cytokine cascade in covid- infection as they exhibit a broad-spectrum suppressive effect. systemic corticosteroids are part of the routine management of acute viral exacerbations of asthma and copd and are effective at treating the eosinophilic component of type inflammation. corticosteroids may also suppress host immune responses and increase viral replication that is reversed by adjuvant interferon. a study with inhaled interferon-beta- a (sng ) will evaluate whether upregulating lung antiviral defenses is effective in covid- illness, whereas other trials will evaluate subcutaneous interferon-beta- a with lopinavir/ritonavir (nct ). one might postulate that nebulized interferon-beta- a may not achieve adequate alveolar drug concentrations in severe covid- infection because by the same token nebulized antibiotics are not effective in bacterial pneumonia. sars-cov- infection may induce a profound downstream cytokine cascade involving il- b, il- , il- , and tnf-a ( figure ) . this release of cytokines is followed by rapid development of lung tissue damage resulting in acute respiratory distress syndrome, sepsis, and organ failure, which may require assisted ventilatory support and extracorporeal membrane oxygenation. one non peer reviewed study in severe covid- infection found that the risk of respiratory failure in patients with maximal circulating il- levels > pg/ml was -fold higher with a median time to mechanical ventilation of . days. a more selective approach is therefore required to address the downstream cytokine storm. recent attention has centered around the possibility of therapeutic intervention with anti-il- drugs such as tocilizumab and sarilumab that are indicated for rheumatoid disease. there is emerging evidence that they may also be useful when repurposed for severe sars-cov- infection in terms of dampening the downstream cytokine response and the associated hyperinflammatory syndrome, the latter primarily characterized by secondary hemophagocytic lymphohistiocytosis. a compassionate use uncontrolled non peer reviewed study from china in patients infected with sars-cov- using the anti-il- agent tocilizumab showed a rapid reduction in fever, c reactive protein (crp), and oxygen requirement along with improved radiological appearances and normalization of lymphocyte counts within days of administration of a single mg dose. moreover, % of patients were discharged within a mean hospitalization period of . days after tocilizumab. all patients already had routine treatment for week including lopinavir and methylprednisolone before receiving tocilizumab. a significant limitation may therefore be survival bias in that sicker patients would be expected to have rapidly deteriorated within the first week of hospitalized illness. evidently, these data need urgent replication ideally in randomized controlled trials. a study is now under way recruiting hospitalized patients with sars-cov- (nct ) using the anti-il- agent sarilumab, whereas other studies are evaluating tocilizumab alone: covacta (nct ) and tocovid (nct ), or in combination with favipiravir (nct ) as well in the nihr recovery trial as part of the second randomization arm. we would advocate that patients with severe covid- infection should be screened for biomarkers of hyperinflammation including rising crp, ferritin, d-dimer, plasma viscosity, and cytopenia including falling platelet count, as these may highlight at-risk patients where il- suppression could be beneficial. there are cogent reasons to suggest that a combined treatment modality might be required to obviate upstream sars-cov- lung tissue binding with hydroxychloroquine or bromhexine, or instead with antivirals, together with downstream il- blockade by sarilumab or tocilizumab (figure ). with this in mind we believe studies are urgently warranted to investigate such combination therapy in older susceptible individuals with comorbidities who are at high risk for developing severe covid- pneumonia. ultimately, the indications for such combined therapies will be determined by factors such as stage of disease, safety, cost, and route of administration. severe sars-cov- infection with poor outcomes occurs in older susceptible patients who may be male, obese, smokers, and with multiple comorbidities. patients with eosinophilic asthma and copd should continue to use ics-containing therapy to maintain optimal control and protect against viral insults including sars-cov- infection. strategies including antiviral therapy such as lopinavirritonavir or blocking viral host cell entry with hydroxychloroquine may not be successful unless used earlier in the course of covid- infection. more severe covid- infection may produce a cytokine storm associated with hyperinflammatory syndrome and hemophagocytic lymphohistiocytosis, with il- levels being highly predictive of respiratory failure. screening for biomarkers of hyperinflammation such as cytopenia, crp, d-dimer, plasma viscosity, and ferritin may identify at-risk patients where cytokine suppression may be beneficial. clinical trials are urgently warranted to evaluate a combined therapeutic strategy to target upstream and downstream pathways in severe covid- disease. prevalence of comorbidities in the novel wuhan coronavirus (covid- ) infection: a systematic review and meta-analysis are patients with hypertension and diabetes mellitus at increased risk for covid- infection? ace- expression in the small airway epithelia of smokers and copd patients: implications for covid- a trial of lopinavir-ritonavir in adults hospitalized with severe covid- compassionate use of remdesivir for patients with severe covid- hydroxychloroquine and azithromycin as a treatment of covid- : results of an open-label non-randomized clinical trial in vitro antiviral activity and projection of optimized dosing design of hydroxychloroquine for the treatment of severe acute respiratory syndrome coronavirus (sars-cov- ) hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting sars-cov- infection in vitro selective regulation of cytokine secretion by hydroxychloroquine: inhibition of interleukin alpha (il- -alpha) and il- in human monocytes and t cells tmprss : a potential target for treatment of influenza virus and coronavirus infections oncedaily single-inhaler triple versus dual therapy in patients with copd current appraisal of single inhaler triple therapy in copd corticosteroid suppression of antiviral immunity increases bacterial loads and mucus production in copd exacerbations inhaled corticosteroid suppression of cathelicidin drives dysbiosis and bacterial infection in chronic obstructive pulmonary disease precision medicine urgency: the case of inhaled corticosteroids in copd pneumonia risk in asthma patients using inhaled corticosteroids: a quasi-cohort study the inhaled corticosteroid ciclesonide blocks coronavirus rna replication by targeting viral nsp acute lung injury induces cardiovascular dysfunction: effects of il- and budesonide/formoterol differences between asthmatics and nonasthmatics hospitalised with influenza a infection blood eosinophil guided prednisolone therapy for exacerbations of copd: a further analysis glucocorticosteroids enhance replication of respiratory viruses: effect of adjuvant interferon covid- : consider cytokine storm syndromes and immunosuppression level of il- predicts respiratory failure in hospitalized symptomatic covid- patients effective treatment of severe covid- patients with tocilizumab b. lipworth had the idea and is responsible for the overall content as guarantor. b. lipworth, r. chan, s. lipworth, and c. r. kuo all performed the literature search and contributed to the writing of the article. the corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted. key: cord- -ubtd vdq authors: tesfaigzi, yohannes; meek, paula; lareau, suzanne title: exacerbations of chronic obstructive pulmonary disease and chronic mucus hypersecretion date: - - journal: clin appl immunol rev doi: . /j.cair. . . sha: doc_id: cord_uid: ubtd vdq chronic obstructive pulmonary disease (copd) exacerbations are an important cause of the considerable morbidity and mortality found in copd. copd exacerbations increase with increasing severity of copd, and some patients are prone to frequent exacerbations leading to hospital admission and readmission. these frequent exacerbations may have considerable impact on quality of life and activities of daily living. factors that increase the risk for copd exacerbations are associated with increased airway inflammation caused by common pollutants and bacterial and/or viral infections. these inflammatory responses cause mucus hypersecretion and, thereby, airway obstruction and associated exacerbations. while chronic mucus hypersecretion is a significant risk factor for frequent and severe exacerbations, patients with chronic mucus hypersecretion have a lower rate of relapse after initial treatment for acute exacerbation. the benefit of antibiotics for treatment of copd exacerbations is small but significant. while the mechanisms of actions are not clear, mucolytic agents reduce the number of days of disability in subjects with exacerbations. reducing mucous cell numbers in small airways could be a useful way to reduce chronic mucus hypersecretion. our studies suggest that programmed cell death is crucial in the resolution of metaplastic mucous cells, and understanding these mechanisms may provide novel therapies to reduce the risk of copd exacerbations. chronic obstructive pulmonary disease (copd) is a chronic condition whereby airflow is limited. this limitation can be caused by a combination of underlying conditions, most notably chronic bronchitis and emphysema. chronic mucus hypersecretion (cmh) is a hallmark of chronic bronchitis. cmh is a common cause of morbidity and mortality, with an annual prevalence of diagnosed chronic bronchitis of . million in the united states [ ] . in emphysema, alveolar destruction is associated with a loss of elastic recoil of the lung. cigarette smoking is the major etiologic factor. the predominance of each condition varies among individuals. copd causes significant morbidity, mortality, and economic consequences to individuals. copd is the fourth leading cause of death and, of the five major diagnoses, only copd is projected to have an increase in annual deaths by [ ] . once copd has developed, there is no known cure for it. despite the fact that copd is often underdiagnosed, over million people in the united states are estimated to have copd, resulting in over hospitalizations and million office visits annually. copd costs $ billion annually [ ] , with % of medical expenditures occurring for hospitalization due to acute exacerbations [ ] . hospitalization is required when there is poor response to management such as unrelenting dyspnea and inability to perform activities of daily living. of all copd patients hospitalized, over % are admitted for acute exacerbations [ ] , and % of these are readmitted [ ] , often due to incomplete recovery [ ] . about % of patients will have a recurrence within months, and about % of these are readmitted within a year. the percentage of predicted forced expiratory volume in second (fev ) is used to measure the severity of copd and is associated with increasing occurrence of exacerbations as well as mortality. for example, mannino et al. [ ] found that patients with an fev of ! % have . exacerbations annually. miravitlles et al. reported that those with less severe disease (fev o %) have an average of . exacerbations annually [ ] . frequent exacerbations in the past is the best predictor of exacerbations in the future. spencer and jones demonstrated that recovery from exacerbations can take up to weeks, with a pattern of rapid improvement over weeks followed by prolonged recovery lasting up to months [ ] . in one of the most systematic studies of symptoms in exacerbations by seemungal et al., subjects were prospectively evaluated for . years [ ] . of this number, had o exacerbation and had r , with % of exacerbations identified by symptom diary cards. of a total exacerbations, only ( . %) were actually reported to the investigators [ ] . mortality increases with exacerbations, with death rates during hospital admission reported to be as low as % but increasing to % within a year. in those with high-risk factors, the -month mortality is %. for those requiring mechanical ventilation, mortality is %, with half of those o years dying within year [ ] . there is no universal definition of exacerbations [ ] , likely because no single cause has been identified and often two patients can present on different occasions with different pathologic findings as well as a different constellation of symptoms. a frequently accepted description of an exacerbation is a sudden, sustained worsening of copd, ''beyond the normal day-to-day variations'' in breathing [ ] or an event in the natural course of the disease characterized by a change in the patient's baseline dyspnea, cough, and/or sputum that dictates a change in management [ ] . the majority of exacerbations have in common a combination of the following symptoms: dyspnea, wheezing, increased cough, and an increase in amount or purulence of sputum [ ] . according to a commonly used definition, therefore, exacerbations are changes for consecutive days in three ''major'' signs and symptoms (dyspnea, volume of sputum, and sputum purulence). severity is determined by the presence of major or minor symptoms. ''minor'' symptoms are increased cough or wheezing, upper respiratory infection (uri) (sore throat, nasal discharge) in the past days, fever, and increased respiratory rate or heart rate % above baseline [ ] . severe exacerbation has been defined as an increase in all three major symptoms, moderate exacerbation as an increase in two major symptoms, and mild exacerbation as one major and one minor symptom. the importance of patient reports of symptoms in diagnosing exacerbations is underscored by the fact that objective measures (peak flow readings and spirometry) are not successful at detecting exacerbations early [ ] . early detection is key to early intervention and prevention of hospitalization. a greater understanding of the pathology of exacerbations most certainly should lead to better means of treating as well as preventing exacerbations. unfortunately, the cause of exacerbations is unclear and may vary within and between patients. copd patients are at great risk for repeat exacerbations following the initial event. however, half of the patients do not seek care when symptoms occur. copd patients tend to wait until experiencing extreme exacerbations either occasionally or frequently before reporting to the doctor. increased levels of interleukin (il)- and il- are found in the sputum of patients with frequent exacerbations at baseline when stable compared with those with infrequent exacerbations [ ] . because sputum cell counts for inflammatory cells were not increased at baseline in patients with more frequent exacerbations, the increased cytokine production may be originating from the bronchial epithelium in copd. during an exacerbation, inflammatory markers include levels of plasma fibrinogen and serum cytokines; il- rises [ ] and is higher in viral than in nonviral exacerbations [ ] . plasma fibrinogen levels vary in response to virally induced exacerbations. in a study of subjects, seemungal et al. reported that mean plasma fibrinogen levels were . g/l during viral exacerbations, versus . g/l during nonviral exacerbations [ ] . exacerbations can be caused by bacterial or viral infections and may lead to pneumonia. other conditions associated with exacerbations are environmental pollution and cold weather. seemungal et al. reported that in nearly % ( of events, n z ) of copd exacerbations, respiratory virus infections are found, rhinoviruses being the most common of the viruses [ ] . polymerase chain reaction (pcr) identified organisms in nasal aspirates of subjects with copd exacerbations. rhinovirus was the predominant organism followed by respiratory syncytial virus (rsv), coronavirus, influenza b, parainfluenza, and chlamydia pneumonia. viruses associated with change in sputum characteristics, such as increased volume or purulence, were not related to the viruses detected in nasal secretions. however, during copd exacerbations, patients with viral infection had a higher symptom score at onset of exacerbation compared with nonviral exacerbations, and the time required for % of exacerbations to resolve symptomatically was significantly longer for viral versus nonviral exacerbations ( vs. days) [ ] . a minimum of one respiratory virus was detected at exacerbation in % of patients, with these patients having a higher frequency of exacerbations (p ! . ). however, rsv does not appear to be related to the severity of exacerbations. viruses have been identified by pcr in serum or nasal aspirate samples. nasal cultures and serology, however, were negative in subjects who reported at least one exacerbation [ ] . therefore, analysis of nasal cultures does not appear to be a good method for detecting exacerbations. airways of copd patients often are colonized by bacteria, making the presence of bacteria insufficient to explain worsening of airway function. however, an increase in bacterial number, change in bacterial location in the airway, or acquisition of new, more virulent, or more pro-inflammatory bacterial species or strains could cause exacerbations [ ] . patients with frequent exacerbations have also an increased incidence of colonizations with bacteria (hemophilus influenza, moraxella catarrhalis, and streptococcus pneumonia) when stable. at exacerbation, there is an increased chance of detecting bacteria, especially if the exacerbation is associated with the presence of purulent sputum [ ] . in work by stockley et al., % of subjects with purulent sputum and % of those with mucoid sputum during an exacerbation tested positive for bacteria [ ] . patients who had h. influenza colonization when they were stable state experienced more symptoms and purulence during exacerbations [ ] . sputum purulence during an exacerbation is likely to be associated with a high bacterial load, while patients with symptoms of a cold or uri are likely to have exacerbations associated with a virus. chronic bronchitis is defined by the presence of chronic or recurrent increases in bronchial secretions that cannot be attributed to other pulmonary or cardiac causes and is sufficient to cause daily expectoration for a minimum of months a year, for at least successive years [ ] . population-based studies have reported an association of cmh with accelerated decline in fev [ ] . chronic bronchitis likely results from the interaction of both intrinsic and extrinsic factors [ ] . to prevent further airway disease, it is crucial not only to limit exogenous causes of airway damage but also to identify and treat endogenous ones. intrinsic factors may be based on genetic polymorphisms that make smokers susceptible to developing chronic bronchitis. our studies in animal models of chronic bronchitis suggest that dysregulated expression of bcl- may lead to prolonged presence of goblet cell metaplasia (gcm) [ ] . subjects with chronic bronchitis without airway obstruction show the same pathology in the airways as those with copd. the reasons for the natural cause of exacerbations in subjects with copd are not clear; however, there is evidence that environmental pollution, such as the levels of so and no in the environmental air, as well as allergens and infections can increase the incidence of symptoms in some patients with chronic bronchitis or emphysema [ ] . some of these conditions are not known to induce a specific type of inflammation but are likely to stimulate innate (acute) response immunity. it is, therefore, possible that as a result of this innate immune response to environmental pollutants, allergens, and infections, sudden secretion of mucus can be triggered from the increased numbers of mucus-producing cells to cause airway obstruction and the associated exacerbations. hospitalizations for exacerbations occur in over half of copd patients, with patients averaging one to four events annually [ ] . given the lack of knowledge about the pathology of exacerbations, prevention or interventions to reduce hospitalizations are poorly understood. frequent exacerbations have been demonstrated to have a negative impact on the quality of life of patients with copd [ ] . furthermore, they are the most frequent cause of hospital admission and death among patients with chronic lung disease. since copd exacerbations are an important event in the natural history of the disease, it is crucial to identify patients most at risk of suffering from them. the identification of risk factors for exacerbations may permit implementation of measures aimed at avoiding these complications. patient recognition of exacerbation symptoms and early treatment improves the recovery process and reduces the risk of hospitalization because early therapy improves outcomes of exacerbations in copd and reduces the cost of treatment [ ] . cmh is a significant predictor of hospitalization due to copd [ ] , and subjects with copd and cmh are more likely to die from pulmonary infections than subjects without cmh [ ] . cmh, which is the hallmark of chronic bronchitis, is particularly associated with mortality from an infectious cause [ ] . these observations may be explained by the affinity that bacteria have for mucus and impairment of mucociliary clearance in chronic bronchitis, providing bacteria that are inhaled or aspirated into the bronchial tree an opportunity to colonize the mucosa. the impairment in respiratory function may be very important in governing the outcome of a copd exacerbation caused by a bacterial infection [ ] . when chronic bronchitis is exacerbated by these factors, bronchitis, in turn, may predispose to a secondary bacterial infection [ ] . bacterial products certainly have the potential to be an independent stimulus of inflammation, for example, lipopolysaccharide (lps), a potent inducer of a variety of inflammatory mediators, including immunoregulatory cytokines from resident and inflammatory cells in the lung. we and others have shown that lps initially induces mucous secretion followed by extensive mucous cell metaplasia in airway epithelia [ , ] . the speed of recovery from symptoms of exacerbations is important in patients with chronic bronchial disease because patients with milder symptoms may return to work or to usual activities earlier, and patients with more severe symptoms may avoid respiratory failure if recovery of symptoms is achieved in a short period of time. knowing the time course of symptoms and the risk factors for late recovery may help physicians to schedule follow-up visits and interpret the outcomes of therapy. because failure to recover is associated with major economic implications, studies aimed at identifying risk factors for treatment failure in real-life conditions are required. a study by miravitlles et al. in [ ] followed the rate of recovery from copd exacerbation of patients. the primary outcome of this study was time to the resolution of symptoms. fast recovery was defined as the resolution of symptoms under days, the median duration of symptoms for the whole group, because % of the patients recovered before or at days. treatment failure was defined as failure to return to baseline before days or persistence or aggravation of symptoms and the requirement of new treatments or medications during the first days. patients with two or more exacerbations or hospitalization for exacerbation during the previous year were likely to have a slow recovery. interestingly, patients with chronic bronchitis had a reduced risk of treatment failure compared with patients with emphysema, suggesting that increased expectoration of sputum appears to help speedy recovery. these findings suggest that subjects unable to expectorate mucus may have breathing difficulties that limit activitydthe hallmark of acute exacerbationsdbecause of mucus obstructing the airways. in a cross-sectional observational study on copd patients, severity of fev impairment and the presence of cmh were found to be factors independently associated with increased risk of suffering two or more acute exacerbations of copd per year [ ] . while fev impairment was associated with increased risk of hospital admission, cmh was not significantly associated with the risk of admission, but the presence of significant comorbidity, such as diabetes mellitus, cardiac insufficiency, or ischemic heart disease. miravitlles et al. [ ] speculate that age and cmh are facilitating factors for exacerbations, but the severity and prognosis of exacerbation are best predicted by the presence or absence of significant comorbid conditions. several studies have established that comorbid conditions are risk factors for being referred to the hospital after being treated for an acute exacerbation [ ] . another prospective study evaluated the influence of cmh on the risk of frequent exacerbations [ ] . exacerbation frequency was related to bronchitic symptoms, although burrows and earle mention that no significant association of daily sputum production was observed with frequent exacerbations even though patients with bronchitic symptoms are usually defined as presenting persistent cough with sputum production [ ] . it is possible that patients reporting bronchitic symptoms were defined as having more severe symptoms than those only reporting sputum production. in this respect, one would consider cmh to be the daily emission of ml of expectorated matter or more. burrows and earle did not show any information regarding the quantitation of expectoration. the study by miravitlles et al. [ ] suggests that cmh renders the patient more prone to suffering recurring exacerbations but does not determine the severity of the exacerbations, as it appeared not to be a factor associated with hospital admissions. therefore, clinical assessment of copd patients in general practice should include these important and easily measurable variables. in summary, fev impairment explains part of the risk of hospital admissions caused by frequent exacerbations. cmh and increasing age are significantly associated with risk of frequent exacerbations, and severity of exacerbations provoking hospital admissions is associated with the presence of significant comorbidity. relapse after initial treatment for acute exacerbation may lead to prolonged disability, a new course of antibiotics, an emergency room visit, or even hospital admission; therefore, it is crucial to identify patients most at risk for relapse. identifying risk factors for ambulatory treatment failure may permit the implementation of more aggressive broad-spectrum treatment and closer follow-up. therefore, risk factors associated with relapse should be incorporated into the management guidelines to aid general practitioners in identifying at-risk patients. a study by miravitlles et al. [ ] estimated the probability of relapse after ambulatory treatment of an exacerbation of chronic bronchitis based on data collected in clinical records obtained after a visit to the general practitioner. in this study, diagnosis of acute exacerbation was based on the presence of any combination of the following symptoms: increased dyspnea and increased production and purulence of sputum. relapse was defined as an unscheduled visit to the general practitioner before month because of a persistence of or an increase in symptoms, which led to a change in drug prescription, an emergency visit, or a hospital admission. treatment administered for acute exacerbations included antibiotics in % of cases and oral corticosteroids in % of cases. only % of cases had mucolytic agents as treatment. approximately % of individuals with exacerbations of chronic bronchitis suffered a relapse of exacerbation following treatment. this study shows that after ambulatory treatment of acute exacerbations of chronic bronchitis, a patient with ischemic heart disease who visited the general practitioner three times in the last year for respiratory problems has a relapse probability of . %, which is statistically significantly higher than the mean % probability of the general cohort. similarly, ball et al. [ ] found that the only factors significant in predicting failure to recover from an acute infective exacerbation of chronic bronchitis were historical. neither clinical features of the presentation nor antibiotic treatment affected recovery. the best combination predicting return with a chest problem was history of cardiopulmonary disease and more than four acute exacerbations within the past months. considering the high prevalence of chronic bronchitis in the general population and the high number of medical consultations generated by this population, it is crucial to identify patients at risk for failure of treatment of exacerbations or at risk for repeated consultations for respiratory problems. patients exhibiting such factors should receive an energetic treatment with a broad-spectrum antibiotic and a short course of oral corticosteroids, and should be closely followed up in an attempt to avoid relapse, which in a significant number of cases may lead to hospital admission or even cause death [ ] . in general, antibiotics are commonly prescribed during exacerbations, but evidence that they appreciatively alter the outcome is not accepted [ ] . anthonisen et al. [ ] showed significant benefits for antibiotics compared with placebo in patients judged to have moderate to severe exacerbations on the basis of increased dyspnea, sputum production, and purulent sputum. stockley et al. [ ] further specified which of the patients who are likely to benefit from antibiotic treatment. the presence of green purulent sputum was specific for high bacterial load, and this subset of patients whose episodes were identified at presentation was likely to benefit from antibiotic treatment. the same study showed that patients who produced white mucoid sputum during acute exacerbations recovered without antibiotic treatment. a recent meta-analysis of trials that included placebo-controlled studies involving small numbers of patients showed that, overall, there was a small but significant benefit from antibiotic treatment in acute exacerbations of copd [ ] . most bacterial species that infect the bronchial tree also form part of the commensal of the nasal pharynx (e.g., h. influenza) or are opportunistic pathogens (e.g., p. aeruginosa). mucosal infections are usually superficial and the majority of bacteria reside in the lumen, associated with secretions, whereas a proportion adhere in the epithelial surface, particularly in areas of epithelial damage, and some will infiltrate the mucosa [ ] . repeated injury from high-dose inhalation of atmospheric pollutants such as tobacco smoke or ozone leads to a chronic inflammatory cell infiltrate in the mucosa by lymphocytes, monocytes, and macrophages. neutrophils and, to a lesser extent, eosinophils are attracted into the airway lumen, and their products may further impair the host defenses. neutrophils release proteases such as neutrophil elastase and reactive oxygen species that damage epithelial cells and stimulate mucus production. epithelial cells are also active participants in the inflammatory reactions because they release pro-inflammatory mediators, including cytokines, chemokines, and nitric oxide. this inflammatory response causes mucus hypersecretion, a change in the morphology of the airway involving a loss of ciliated cells, and an increase in the number of goblet cells in mucosal gland hypertrophy. the bronchitic airway is therefore vulnerable to infection, but there is also a well-primed immune system present that is ready to mount an inflammatory response to any further insult. bacteria avoid clearance by producing factors that impair mucociliary clearance by paralyzing ciliary beat and stimulating mucus production; producing enzymes that break down local immunoglobulin; displaying antigenic heterogeneity to avoid immune surveillance; growing in biofilms; adhering to epithelium; surviving within epithelial cells; and forming microcolonies surrounded by polysaccharide gel [ ] . a report by poole and black [ ] summarized the therapeutic potential of mucolytic agents in preventing exacerbations of chronic bronchitis and copd. in studies, patients were defined as having chronic bronchitis that was most often defined as the presence of cough productive of sputum on most days for a minimum of days per year for at least consecutive years. in the remaining two studies, patients had copd defined as a disease characterized by airflow limitation that is not fully reversible. it is likely that most of the patients with chronic bronchitis also had copd, as most of these patients were smokers, and when lung function was measured, there was evidence of airway obstruction. in of studies, the mucolytic agent used were n-acetylcysteine (nac), and mucolytic agents used were ambroxol, carbocysteine, sorbrerol, letosteine, cithiolone, iodinated glycerol, n-isobutyrylcysteine, and myrtol. ten of the studies were conducted in italy, three each in scandinavia and germany, four in the united kingdom, two in several european countries, and one in the united states. all studies had similar scoring standards. this review found the annualized exacerbation rate of . per year in the control group being reduced by % with treatment of patients with mucolytic agents. a similar study showed a reduction by %. another study [ ] found that % of patients who received mucolytic agents were twice as likely not to have an exacerbation during the study period than if they had received placebo. treatment with mucolytic agents resulted in . fewer days of disability per patient per month. this finding was based on six studies and was supported by the results of four other studies where mean days of disability but not standard deviation values were reported. in two systematic reviews of the effects of nac in patients with chronic bronchitis, it was shown that patients treated with nac were more likely to remain exacerbation free. these patients were more likely to report an improvement in symptoms with nac than with placebo. these mucolytic agents work in a variety of ways. potential mechanisms of actions include thinning of produced sputum, resulting in promotion of expectoration, and antioxidant and antibiotic activity. it has also been postulated that mucolytic agents may work via an antioxidant mechanism, which is generally accepted to play a role in the pathogenesis of copd. in acute exacerbations of copd, this oxidant/antioxidant imbalance is very profound and further studies will be needed to determine whether mucolytic agents acutely reduce the morbidity of these events. a third possibility is that mucolytic agents may work through antibacterial or immunostimulatory mechanisms because pretreatment with nac resulted in significantly fewer patients having positive cultures from intrabronchial samples [ ] . in addition, nac has been shown to reduce the adhesion of s. pneumonia to oropharyngeal epithelial cells [ ] . mucolytic therapy appears safe and well tolerated, with no suggestion from the studies of any increase in the incidence of adverse effects relative to placebo. nac is the mucolytic agent that has been most extensively studied; however, other mucolytic agents, overall, had similar effects on exacerbation rates. patients who have frequent or prolonged exacerbations or those who had repeatedly been admitted to a hospital would appear to have the most to gain. the broncus study [ ] compared the effect of nac and placebo in copd patients on the number of exacerbations per year and found that nac failed to be effective at preventing exacerbations in these patients but appeared to reduce the risk of exacerbation in patients not taking inhaled steroids. the difference in findings between this study and previous studies may be because of the fact that previous studies assessed chronic bronchitis rather than copd. furthermore, the authors of the broncus study acknowledge that greater doses of nac, that is, increasing the dose from mg daily, could have resulted in an improved effect. another study showed that mg daily improved lung function in idiopathic pulmonary fibrosis and was well tolerated. the main difficulties in interpreting the results or studies of treating chronic bronchitis exacerbations include the heterogeneity of the condition. the cause of an exacerbation can include acute viral bronchitis, environmental pollutants, and allergic responses as well as bacterial infections. furthermore, heterogeneity within the definition of the severity of an exacerbation exists. severity classifications based on the symptomatology of chronic bronchitis exacerbations have, thus far, been largely empirical and have not been validated by clinical trials [ ] . a classification of severity based on clinical parameters that can be easily evaluated would allow the detection of differences in efficacy of new therapies compared to placebo and improve conventional management of exacerbations. the site of most mucus hypersecretion is the large airway. histological studies show enlargement of tracheobronchial submucosal glands and hyperplasia [ ] . the presence of an increased number of goblet cells distinguishes patients with cmh and airway obstruction from patients with cmh but without obstruction [ ] . hyperplasia of mucous goblet cells and mucus plugging were noted in patients with chronic bronchitis but without emphysema [ ] . therefore, understanding the causes for the increased numbers of mucous cells is crucial to reduce the severity of copd exacerbations. detailed morphometric analysis of the amount of sustainable stored secretory product in the tracheobronchial airways of the rhesus monkey reveals at least twice as much mucus in the surface epithelium as in the submucosal glands [ ] . in the lower airways of the rhesus monkey, as in the majority of other animal species, glands are absent and surface epithelial mucous cells are the sole source of mucus. because surface epithelial mucous cells represent a great potential for secretion of mucosubstances [ ] , it is important to investigate how their numbers are regulated in airway epithelia. the normal tracheobronchial epithelium contains ciliated, basal, and secretory cells, which are maintained at fixed ratios by homeostatic mechanisms. the proportion of these cell types is perturbed following various inflammatory responses or mechanical injury to the epithelium due to proliferation [ ] . various studies have shown that nonciliated columnar cells are the main cell type that is recruited to the cell cycle in larger numbers [ ] . gcm following acute injury or inflammatory responses results from differentiation of pre-existing epithelial cells into mucous cells and differentiation of proliferating cells into mucous cells [ ] . following cessation of allergen exposure, airway epithelia return to the original proportion of cell types [ ] . various mechanisms may be responsible for the reduction of gcm, including the fact that inflammatory mediators responsible for mucin synthesis are no longer present. however, full recovery of the epithelium necessitates the reduction of epithelial cell numbers to the original state [ ] . our studies suggest that abrogation of these mechanisms may be, at least in part, responsible for the persistent change in airway epithelia as is observed in airways of subjects with cmh. the small airways of subjects with copd are detached from the alveolar connection, which results in a loss of support and closure of small airways during expiration [ ] . in addition, the airways are narrowed as a result of inflammation and scarring and, more importantly, due to the blocking of the lumen with mucous secretions [ ] . exacerbations can occur because a number of mucus-secreting cells in small airways are present that secrete their contents as a result of increased inflammation caused by exposures to new bacterial [ ] or viral infections [ ] , environmental pollutants such as ozone or other particles, or allergens. it is widely believed that these factors cause copd exacerbations, and they are believed to do so largely by increasing inflammation. increased inflammation may be primarily causing increased secretion of mucus from metaplastic goblet cells, which will immediately obstruct small airways and reduce or completely block airflow. increased numbers of mucous cells are present because the epithelium is not capable of regulating the numbers. while the presence of mucous cells is not detrimental under symptom-free conditions, increased inflammation can cause exacerbations, that is, reduced pulmonary function and increased cough or sputum secretion, due to the sudden secretion of large amounts of mucus into the lumen. the blockage of the airway is enhanced by the sticky nature of mucus that traps inflammatory cells [ ] that release dna and further increase mucus viscosity. we have developed an animal model in which epithelial cell number and gcm are increased in airway epithelia, and we have studied the role of bcl- in sustaining gcm. instillation of bacterial lps in rats causes the number of epithelial cells to increase by approximately %, and in addition to these proliferating cells, existing serous cells differentiate into mucous cells. following a recovery of days, the number of epithelial cells is reduced to that found in noninstilled control rats. in an attempt to understand the mechanisms that reduce numbers of metaplastic mucous cells after inflammatory responses subside, we analyzed the expression of regulators of programmed cell death [ ] . the bcl- family of cytoplasmic proteins can register diverse forms of intracellular damage, gauge whether other cells have provided a positive or negative death stimulus, and determine the progression or inhibition of the suicide program [ ] . bcl- , an inhibitor of apoptosis, belongs to a member of a family of proteins with anti-and pro-apoptotic properties that when overexpressed prevent or induce apoptosis, respectively. pro-and antiapoptotic family members can heterodimerize, and their relative concentration determines whether a cell lives or dies [ ] . these proteins function by regulating the release of cytochrome c from mitochondria, initiating a cascade of events leading to activation of caspases and dnases that are responsible for the appearance of apoptotic morphology including dna fragmentation, chromatin condensation, membrane blebbing, cell shrinkage, and disassembly of the cell [ ] . bcl- enhances cell survival by inhibiting apoptosis induced under a wide variety of circumstances. bcl- extends cell survival by preventing cell death in different cell types and in response to different stimuli; this suggests that bcl- acts at a central control point in the pathway to apoptotic cell death [ ] . bcl- expression is regulated by cytokines and other death-survival signals transcriptionally or posttranscriptionally by phosphorylation [ ] . we determined that the bcl- -positive mucous cells are derived not only from proliferating cells but also from pre-existing cells [ ] . these results showed that bcl- is not involved in cell cycle progression in these cells (fig. ) . the following observations suggest that bcl- expression sustains gcm: ( ) we have demonstrated in brown norway and fischer /n rats that following a single intratracheal instillation of lps, bcl- , an inhibitor of apoptosis, must be downregulated before mucous cell numbers can be reduced [ ] and ( ) bcl- mrna is downregulated with antisense oligodeoxynucleotides and gcm is subsequently reduced in organ cultures and in in vivo rats [ ] . in naïve rats, endogenous mucous cells are found in epithelia lining the proximal mid septa. in these cells, approximately % are bcl- positive, and this percentage does not change significantly following exposure to ozone. however, exposure to ozone induces gcm in transitional epithelia lining the lateral wall, and the nasal and maxillary turbinates, and the percentage of bcl- positivity in these metaplastic mucous cells exceeds % [ ] . these results show that bcl- is low in endogenous mucous cells but is expressed in a high percentage of metaplastic mucous cells in nasal epithelia. this observation suggests that bcl- could be a useful target for eliminating metaplastic mucous cells without affecting endogenous mucous cells. another group of researchers used microarray approaches to identify bcl- as one of the genes expressed following a smoke-induced injury to a human bronchial epithelial cell line, hbe . they confirmed their observation by northern blot assays [ ] . collectively, these studies show that bcl- expression in mucous cells is found in animals and humans. fig. . injury of the airway epithelium by lps causes airway epithelial hyperplasia and mucous cell metaplasia. proliferating (denoted by the black nuclei) and pre-existing cells can produce and store mucus (denoted by the vesicles in the columnar cells). bcl- -expressing cells are shown as mucous cells with black staining around the vesicles. following - days, the epithelial cell numbers are reduced to essentially the numbers observed before injury to the epithelium. gcm may persist in subjects with chronic bronchitis because of repeated injury of the epithelium due to repeated exposure to allergen, cigarette smoke, or environmental and/or occupational pollutants, chronic infections, or interactions of these various factors. it is also possible that there is a deficiency in the ability of the epithelium to reverse these changes during the wound-healing process. while the inflammatory response may subside, the genetic makeup of the epithelium leads to the inability of the epithelium to heal itself, causing gcm to persist. the following observations support this hypothesis: ( ) bcl- transgenic mice do not show resolution of lps-induced gcm at days after lps exposure, while their wild-type littermates do [ ] and ( ) horses with recurrent airway obstruction, also called copd, have increased airway secretions of mucus that obstructs airflow [ ] and have a significantly higher percentage of bcl- -positive mucous cells compared with control horses (personal observation). while increased gcm in copd between symptom-free periods is not detrimental, sudden mucus secretion from increased numbers of mucus-producing cells triggered by infections, environmental pollutants, or allergens may block the nonelastic airways of emphysema patients and cause exacerbations. this process can lead to dyspnea and increased sputum production, the hallmarks of acute exacerbation. identification of molecular mechanisms related to the development and persistence of copd and cmh may help develop novel strategies to reduce the debilitating symptoms associated with copd exacerbation. while the precise cause of copd exacerbations is not known, evidence suggests that an infectious process is taking place. this evidence is seen at the cellular level with biomarkers, infectious agents from cytology, and clinically observed changes in sputum. cmh is a risk factor for copd exacerbation, and treatment with mucolytic agents has been shown to reduce the days of disability in subjects with copd exacerbations. therefore, the effect of reducing the number of metaplastic goblet cells in small airways may be useful to reduce the risk for exacerbations and the rate of relapse after treatment for copd exacerbations. summary health statistics for u.s. adults: national health interview survey chronic obstructive pulmonary disease: definition and epidemiology obstructive lung disease deaths in the united states from through . an analysis using multiple-cause mortality data the costs of treating copd in the united states relation of fev( ) to clinical outcomes during exacerbations of chronic obstructive pulmonary disease. department of veterans affairs cooperative study group time course and recovery of exacerbations in patients with chronic obstructive pulmonary disease treatment of chronic obstructive pulmonary disease and its exacerbations in general practice. eolo group. estudio observacional de la limitacion obstructiva al flujo aereo time course of recovery of health status following an infective exacerbation of chronic bronchitis detection of rhinovirus in induced sputum at exacerbation of chronic obstructive pulmonary disease hospital and 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nature and outpatient management of acute exacerbations of copd relationship between bacterial colonisation and the frequency, character, and severity of copd exacerbations definition and classification of chronic bronchitis for clinical and epidemiologic purposes association of chronic mucus hypersecretion with fev decline and chronic obstructive pulmonary disease morbidity. copenhagen city heart study group the chronic bronchitis complex in children dna synthesis and bcl- expression during the development of mucous cell metaplasia in airway epithelium of rats exposed to lps air pollution and daily admissions for chronic obstructive pulmonary disease in european cities: results from the aphea project effect of exacerbation on quality of life in patients with chronic obstructive pulmonary disease early therapy improves outcomes of exacerbations of chronic obstructive pulmonary disease the value of mucus hypersecretion as a predictor of mortality and hospitalization. an -year register based follow-up study of a random population sample of men chronic mucus hypersecretion in copd and death from pulmonary infection new strains of bacteria and exacerbations of chronic obstructive pulmonary disease concurrent increases in the storage and release of mucin-like molecules by rat airway epithelial cells in response to bacterial endotoxin variables associated with recovery from acute exacerbations of chronic bronchitis and chronic obstructive pulmonary disease factors associated with increased risk of exacerbation and hospital admission in a cohort of ambulatory copd patients: a multiple logistic regression analysis. the eolo study group acute infective exacerbations of chronic bronchitis course and prognosis of chronic obstructive lung disease. a prospective study of patients factors associated with relapse after ambulatory treatment of acute exacerbations of chronic bronchitis. dafne study group canadian guidelines for the management of acute exacerbations of chronic bronchitis clinical studies in chronic bronchitis: a need for better definition and classification of severity antibiotics in chronic obstructive pulmonary disease exacerbations. a meta-analysis evidence of bacterial infection in acute exacerbations of chronic bronchitis preventing exacerbations of chronic bronchitis and copd: therapeutic potential of mucolytic agents randomised, double blind, placebo controlled study of fluticasone propionate in patients with moderate to severe chronic obstructive pulmonary disease: the isolde trial the intrabronchial microbial flora in chronic bronchitis patients: a target for n-acetylcysteine therapy? inhibitory effect of n-acetylcysteine on adherence of streptococcus pneumoniae and haemophilus influenzae to human oropharyngeal epithelial cells in vitro effects of n-acetylcysteine on outcomes in chronic obstructive pulmonary disease (bronchitis randomized on nac cost-utility study, broncus): a randomised placebo-controlled trial reassessment of inflammation of airways in chronic bronchitis morphometric analysis of intraluminal mucus in airways in chronic obstructive pulmonary disease bronchial asthma, mechanisms and therapies. boston tracheobronchial epithelium in the adult rhesus monkey: a quantitative histochemical and ultrastructural study airway goblet cells: responsive and adaptable front-line defenders plasticity in the airway epithelium the kinetics of cell proliferation in the tracheobronchial epithelia of rats with and without chronic respiratory disease induction, duration, and resolution of airway goblet cell hyperplasia in a murine model of atopic asthma: effect of concurrent infection with respiratory syncytial virus and response to dexamethasone bcl- sustains increased mucous and epithelial cell numbers in metaplastic airway epithelium small airways in copd the nature of small-airway obstruction in chronic obstructive pulmonary disease viral infections in obstructive airway diseases expression of bcl- during mucous cell metaplasia and remodeling in f /n rats the bcl- protein family: arbiters of cell survival bcl- family proteins proteases to die for roles of apoptosis in airway epithelia bcl- in lps-and allergen-induced hyperplastic mucous cells in airway epithelia of brown norway rats development of high-density dna microarray membrane for profiling smoke-and hydrogen peroxide-induced genes in a human bronchial epithelial cell line persistent mucin glycoprotein alterations in equine recurrent airway obstruction this research was supported by grants from the national heart, lung, and blood institute (hl ) and the national institutes of environmental health sciences (es ). key: cord- -nqj ctk authors: ogger, patricia p.; byrne, adam j. title: macrophage metabolic reprogramming during chronic lung disease date: - - journal: mucosal immunol doi: . /s - - - sha: doc_id: cord_uid: nqj ctk airway macrophages (ams) play key roles in the maintenance of lung immune tolerance. tissue tailored, highly specialised and strategically positioned, ams are critical sentinels of lung homoeostasis. in the last decade, there has been a revolution in our understanding of how metabolism underlies key macrophage functions. while these initial observations were made during steady state or using in vitro polarised macrophages, recent studies have indicated that during many chronic lung diseases (clds), ams adapt their metabolic profile to fit their local niche. by generating reactive oxygen species (ros) for pathogen defence, utilising aerobic glycolysis to rapidly generate cytokines, and employing mitochondrial respiration to fuel inflammatory responses, ams utilise metabolic reprogramming for host defence, although these changes may also support chronic pathology. this review focuses on how metabolic alterations underlie am phenotype and function during clds. particular emphasis is given to how our new understanding of am metabolic plasticity may be exploited to develop am-focused therapies. the respiratory mucosa is a unique site, as our airways are continually exposed to particulates, viruses, bacteria, and fungi, which challenge the pulmonary immune system . to maintain pulmonary homoeostasis and ensure efficient gas exchange, a complex regulatory system is in place, of which airway macrophages (ams) are a core component. ams are the most numerous immune cell type present in healthy lungs, are strategically positioned at the interface of airways and environment , and critical sentinels of barrier immunity. ams form the first line of defence against inhaled particles, pathogens and antigens . although inherently suppressive, ams exhibit significant functional and phenotypical specialisation, allowing efficient responses to environmental signals and rapid alterations in phenotype. increasing evidence suggests that metabolic alterations provide an additional layer of functional plasticity to am populations. activation of macrophages in vitro with a range of inflammatory stimuli, induce profound metabolic adaptations, such as the switch from oxidative phosphorylation (oxphos) to glycolysis in oxygen-sufficient conditions, similar to the "warburg effect" seen in some cancers . it is now clear that how macrophages utilise energy dictates immune responses, and that manipulating cellular metabolism can alter the inflammatory response . however in vivo, the unique oxygen rich environment of the airways coupled with specific local nutrient availabilities, shapes am phenotype and function. indeed, many recent studies have indicated that in chronic lung diseases (clds), such as asthma, chronic obstructive pulmonary disease (copd), cystic fibrosis (cf), idiopathic pulmonary fibrosis (ipf), and during infection such as with mycobacterium tuberculosis (mtb), there are significant alterations in am metabolic processes and that targeting these pathways could represent an exciting therapeutic approach , . this review focuses on how metabolic adaptations underlie am phenotype and function during clds. particular emphasis is given to how our new understanding of am metabolic plasticity may be exploited to develop am-focused therapies. airway macrophages: guardians of the lung environment to maintain gas exchange, it is critical that ams sustain a naturally hyporesponsive state whilst also reserving the ability to rapidly mount effective inflammatory responses. this balance is achieved through complex am-airway epithelial cell (aec) interactions via cell surface-expressed receptors and secreted products. ams express transforming growth factor beta receptor (tgf-βr), interleukin (il)- receptor (il- r), cd receptor (cd r) and signal regulatory protein-α, key components mediating am: aec crosstalk and in turn, regulating am activation . for example, am-aec contact decreases am phagocytosis and cytokine production in a tgf-β-dependent manner . conversely, loss of the integrin αvβ such as through loss of contact of ams with aec upon toll-like receptor (tlr) activation leads to initiation of the am pro-inflammatory phenotype and inflammatory response . ams are characterised by a distinct cellular phenotype. human ams highly express the lectin-binding transmembrane glycoprotein cd , the adhesion molecule cd , the integrin cd c and mannose receptor cd (fig. ). in mice, expression of the cd + cd + cd c hi cd b lo cell surface phenotype is conserved at steady state [ ] [ ] [ ] , while murine ams also express the mer tyrosine kinase (mertk), sialic acid dependent adhesion molecule siglecf, hormone receptor f / , glycoprotein cd and the cd receptor (fig. ) . recent work in mice has indicated that many tissue resident macrophages, including those in the airways, are foetally derived and self-maintain locally with minimal contribution from circulating monocytes, during steady state conditions [ ] [ ] [ ] [ ] [ ] . during murine prenatal development, foetal liver or yolk sac macrophages are the major contributing pool to am populations and am colonization of the lung occurs in sequential waves in the first week of life . furthermore, post birth and during maturation, circulating monocytes do not significantly contribute to lung macrophage populations at homoeostasis . during pulmonary inflammatory responses however, monocytes are recruited to the lung , and subsequently develop into am-like cells , . thus, post-injury murine airways contain at least two ontologically distinct am populations, tissue resident ams (tr-am) which are prenatally derived and monocytederived ams (mo-ams). several groups have studied samples from lung transplant patients to investigate the origins of ams in the human lung [ ] [ ] [ ] [ ] [ ] . utilizing bronchoalveolar lavage (bal) from sexmismatched lung transplant patients our group recently demonstrated that the majority of ams in human lung post-transplant are derived from peripheral classical monocytes . thus, the unique airway niche combined with distinct ontological origins, age and environmental exposures results in remarkable am plasticity and adaptability [ ] [ ] [ ] . while the recruitment of monocytes to the lungs to replenish the tr-am pool is relatively well understood in mice, the origins of ams in the human lung during healthy aging or clds requires further investigation; in particular clear markers which distinguish mo-ams and tr-am are not well established. airway macrophage metabolic phenotype at homoeostasis beyond delineation of macrophage populations based on anatomical location or ontological origin, macrophage populations are also classified according to their activation status. analogous to the th /th paradigm, in vitro cultured human monocyte derived macrophages (mdms) or murine bone marrow derived macrophages (bmdms) are categorised as m or m macrophages, respectively. seminal studies have demonstrated that pro-wound healing m (il- stimulated) macrophages in vitro rely on fatty acid oxidation (fao), an intact tricarboxylic acid cycle (tca) cycle, high rates of oxphos and increased expression of arginase (arg ), which catalyses the production of ornithine from arginine as precursor for collagen to facilitate wound healing , [ ] [ ] [ ] . conversely, pro-inflammatory m -macrophages rely on glycolysis and breaks in the tca cycle lead to accumulation of metabolites, many of which have signalling functions such as citrate, succinate, fumarate and α-ketoglutarate , , . however, although useful in defining the range of potential macrophage responses, in vitro derived cells do not recapitulate the core aspects of am phenotypes which are shaped by the local niche . as ams are highly adapted to the unique environment of the airway lumen, it is perhaps unsurprising that the metabolic state of ams is also distinct. glucose concentrations in the alveolar lumen are less than % of blood glucose concentrations and ams exhibit extremely low levels of glycolysis ; in stark contrast to bmdms, ams do not undergo glycolytic reprogramming in response to lps . consequently, ams readily engage oxphos and highly express the peroxisome proliferator-activated receptor gamma (pparγ) , which regulates lipid accumulation and promotes fao to sustain oxphos. ams also play a major role in the catabolism of pulmonary surfactant, a monolayer composed mainly of phosphocholinebased lipids, phospholipids and cholesterol which lines the alveoli, lowers surface tension and prevents alveolar collapse during expiration . mice lacking gm-csf and thus the am compartment, develop pulmonary alveolar proteinosis (pap), an inflammatory lung syndrome caused by the defective clearance of surfactant [ ] [ ] [ ] . in humans, mutations in genes encoding for gm-csf receptors, result in hereditary pap as a result of progressive alveolar surfactant accumulation [ ] [ ] [ ] [ ] . am phenotype and behaviour are influenced by surfactant exposure, which has major implications for am-mediated immune responses in pulmonary tissue. there are four principle surfactant proteins (sp-a-d) and sp-a and sp-d have been shown to directly influence am functions such as cell migration, phagocytosis and activation phenotypes . both sp-a and sp-d bind carbohydrates, lipids, and nucleic acids and initiate phagocytosis of inhaled pathogens and apoptotic cells . furthermore, sp-a blocks the binding of tlr ligands to tlr , tlr and tlr co-receptors and furthermore inhibits complement activation , . whilst the alveoli are covered with a monolayer of surfactant, a thin layer of mucus produced by goblet cells and ciliated epithelium protects the airways. mucus serves as a barrier and facilitates clearance of microbes and pollutants. a major component of mucus are mucin glycoproteins, which may be categorized as polymerizing, nonpolymerizing and cell-surface associated. of the cell-surface associated mucins, muc is expressed in ams and contributes to the resolution of inflammation by decreasing phagocytic potential and pro-inflammatory cytokine production . the polymerizing mucins include muc ac and muc b; in particular, muc b deficiency has been linked to particle accumulation in the lung, mucus obstruction and impaired macrophage phagocytosis . pro-inflammatory macrophages induce muc b expression to aid mucociliary clearance . furthermore, a single nucleotide polymorphism in the muc b promotor has been strongly associated with the risk of developing ipf, highlighting the importance of mucins for the pulmonary environment . in addition to low glucose and a lipid rich environment, the airways also have a unique distribution of amino acids and central carbon metabolites. surowiec et al. showed that whilst several glucogenic and ketogenic amino acids were present in the bronchial wash, only alanine is present in bal (fig. ). in addition, the central airways contained key glycolytic and oxphos metabolites such as fructose, glucose- -phosphate, fumarate and malate as well as oxidised gluthathione (gssg, indicating oxidative stress, fig. ) ; interestingly, these could not be detected murine ams express the lectin-binding transmembrane glycoprotein cd , the mer tyrosine kinase (mertk), the integrin alpha x chain protein cd c, the type i membrane glycoprotein cd receptor, the mannose receptor cd , the egf-like module-containing mucin-like hormone receptor-like (f / ), the sialic acid binding lectin siglec-f and the fc receptor cd . human ams express cd , the adhesion molecule cd , cd c, cd as well as mhc class ii receptor hla-dr. in the periphery, suggesting either minimal secretion, high utilisation or as a result of anatomical location (i.e. close proximity to nutrient rich pulmonary capillaries) . recently the lung microbiome has gained attention as a factor which modifies the pulmonary environment and directs immune responses by producing short chain fatty acids (scfa). whilst the airways and alveoli are colonised mainly by proteobacteria, bacteroidetes and firmicutes , , the nasal mucosa additionally hosts actinobacteria , (fig. ) . proteobacteria, bacteroidetes and firmicutes produce large amounts of scfa, including acetate, propionate and butyrate, which influence barrier function by regulating epithelial tight junctions and anti-inflammatory immune responses . recent advances in understanding the pulmonary microbiome during homoeostasis and clds are described in detail elsewhere , , . thus, at homoeostasis ams are exposed to a unique environment, with minimal glucose availability and a distinct distribution of nutrients and scfa, which depend on anatomical location (fig. ) . however, despite the profound influence that local substrate availabilities may exert on macrophage development, activation and function, this is an understudied area. new knowledge, which further defines especially human am substrate dependencies at homoeostasis is required in order to fully understand how local metabolic perturbations during clds may contribute to pathology. this is particularly relevant as already slight changes in nutrient availability during inflammation, such as succinate or citrate, can alter macrophage phenotypes through stabilization of hif α, post-translational modification of proteins and production of no and ros , thereby contributing to a pathological development. am metabolism during clds chronic lung diseases affect a significant proportion of the world's population, killing more than , people in the uk alone, each year . persistent inflammation, impaired repair processes and pulmonary remodelling are cardinal features of clds [ ] [ ] [ ] . there are multiple overlaps in environmental exposures driving clds, such as smoking, pollution and environmental exposures; viral infection can also exacerbate symptoms in each disease , , . interestingly, am metabolic adaptation may play a central role in dictating pathology during clds and present novel therapeutic opportunities (fig. ) . asthma. asthma is a heterogeneous disease of the airways characterized by airway remodelling, mucus production, airway hyperresponsiveness (ahr), and inflammation . although most patients have good control with standard medication, a proportion experience life-threatening, severe disease . ams are central to mediating type- inflammation against allergens and parasitic worms . in vitro, macrophages respond to type- cytokines such as il- that drive an 'alternative' m activation phenotype, linked to wound repair and type- pathology , . manipulation of am phenotype via genetic deletion of the transcription factor interferon regulatory factor (irf ), a master regulator of macrophage activation , promoted pulmonary remodelling, ahr and mucus secretion in mice, in an il- dependent manner . indeed, a recent study has shown that both cd + am (activated by il- and il- ) and pro-inflammatory irf + am are increased in asthmatic patients , highlighting the plasticity of macrophages and heterogeneity of human asthma. roles of ams during antigen induced airway inflammation include phagocytosis of apoptotic cells and eosinophils as well as triggering anti-inflammatory pathways to regulate airway hyper responsiveness, mucus secretion and matrix deposition . in severe asthma however, this protective function is impaired, resulting in the loss of phagocytic ability and anti-inflammatory programme , which can contribute to airway remodelling . thus, ams are uniquely involved in responses to allergen and type- inflammation, and aberrant amphenotypes can directly influence respiratory pathology. numerous lines of evidence suggest that metabolic stress leading to the production of reactive oxygen species (ros) plays a role in asthma. increased ros have been detected in ams of asthmatic patients , and contributes to lung injury and proinflammatory tumour necrosis factor-alpha (tnf-α) and il- β secretion by macrophages . furthermore, heme-oxygenase- (ho- ), which mediates ros production in response to chemical and physical agents, is increased in ams in asthmatics . in addition to these pro-inflammatory characteristics, ams show key features of a more anti-inflammatory phenotype in studies using ovalbumin to model allergic asthma. using this model, al-khami et al. show that expression of carnitine palmitoyltransferase (cpt) is increased in ams, shuttling fatty acids into the mitochondria, as well as increased gene expression of fao related genes . another functional pathway that is altered in asthmatic ams and links to the underlying metabolic phenotype is the eicosanoid pathway, which is induced by th cytokines il- and il- . eicosanoids, including prostaglandins and leukotrienes, are produced from the poly-unsaturated fatty acid arachidonic acid, which is released during asthma . increased production of the eicosanoid -hete and leukotrienes b (ltb ) and e (lte ) has been detected in ams from asthmatic patients stimulated ex vivo . this contributed to bronchial constriction and pro-inflammatory phenotype and failure to generate the anti-inflammatory eicosanoid -hete and prostaglandin e (pge ), which is associated with reduced am phagocytosis . lte has been shown to cause ahr in subjects with aspirin-induced asthma and can be produced in ams by γ-glutamyl transpeptidase , . il- furthermore induces arg , which may further contribute to the asthmatic phenotype via metabolism of collagen precursors ornithine and proline to collagen and airway remodelling , . several of these observed alterations have been targeted therapeutically, attempting to rewire am phenotype. these include the eicosanoid pathway, ros, glycolysis and fao. administration of the anti-inflammatory eicosanoid -hete inhibited leukotriene synthesis and reduced ahr in asthmatics . ex vivo, the corticosteroid dexamethasone decreased levels of thromboxane b and ltb in macrophages and asthmatic ams , while prednisone decreased ltb production in ams . treatment with the antioxidant ad improved ahr and airway inflammation by decreasing ros in the ova-sensitised mouse model of allergic airway disease (aad) , . together, these studies indicate that there is significant disruption of am metabolism during asthma and aad, notably via dysfunction in eicosanoid, glycolysis and fatty acid pathways. in fig. altered metabolic pathways in ams drive key features of chronic lung disease. several metabolic pathways are rewired during chronic lung disease. while this response exists to clear invading pathogens and launch an inflammatory response, long-term activation of these pathways has negative implications. the glycolysis pathway supports inflammatory responses of am, while iron and metabolites produced in the tca cycle can function as bacterial substrates and contribute to pathogen survival. while fatty acid synthesis and oxidation is useful as a way of storing energy and alternative energy source during times of macrophage activation, fatty acid synthesis can also contribute to mucus production. leukotrienes contribute to the am pro-inflammatory phenotype but also cause bronchial constriction and contribute to airway remodelling in asthmatics by causing smooth muscle thickening. the amino acid arginine is a proliferator for collagen via ornithine and proline and can thereby contribute to extracellular matrix deposition. order to evaluate candidate therapies, it is crucial that studies utilise relevant preclinical models and ex vivo patient samples to understand disease. models which more closely recapitulate the complex immune response to allergens, are more likely to reveal viable targets for intervention; in particular the ovalbumin model of aad, which requires an adjuvant and a sensitization phase , is a poor murine model of asthma. furthermore, our new understanding of asthma heterogeneity has allowed the development of biologics which target "type- high" asthma ; delineation of how metabolic changes underlie distinct asthma phenotypes could lead to new treatments for other phenotypes, such as neutrophilic and paucigranulocytic asthma. copd. copd is the th leading cause of death in high income countries , affecting over million people worldwide . copd is a heterogeneous disease, characterised by destruction of the parenchyma and emphysema, narrowing of the airways, remodelling and chronic inflammation driven by chronic exposure to cigarette smoke and particular matter . am numbers are increased in copd bal and contribute to copd pathology through numerous pathways. during copd, ams are found in areas of lung destruction and produce pro-inflammatory cytokines , chemokines and matrix metalloproteases (mmps) with elastolytic properties , . at the same time, tissue inhibitor of metalloproteases (timp)- is decreased in ams in copd and furthermore, decreased phagocytic capacity and impaired bacterial killing have been described in copd-ams [ ] [ ] [ ] . ams of copd patients experience a high level of oxidant burden induced through cigarette smoke and subsequent increased ros production is a key feature . compared to controls, copd-ams secrete increased levels of mitochondrial ros (mtros) , superoxide and hydrogen peroxide , whilst glutamyl cysteine ligase for gsh synthesis is downregulated . cigarette smoking also alters iron homoeostasis and ams in copd show increased sequestering of iron , which can furthermore contribute to ros production. bewley et al. showed recently that increased generation of mtros in copd ams results in impaired bacterial clearance . this study also reported a decrease in the mitochondrial membrane potential , which has recently been linked to am exposure to particulate matter . this may explain the impaired phagocytic capacity of ams in copd as decreased mitochondrial membrane potential results in energy failure in the cell, proton leakage and increased mtros . another study by o'beirne et al. further investigated the metabolic profile of ams from healthy smokers, non-smokers and copd patients. while all groups had similar baseline glycolysis rates, there was a decrease in coupling efficiency, maximal respiration and spare respiratory capacity in copd-ams, while proton leak was significantly increased . in addition, expression of genes related to glutathione metabolism, mitochondrial transport, pyruvate metabolism, tca cycle and electron transport chain were altered in smokers and copd patients, compared to nonsmoking healthy controls . other metabolic alterations in copd ams include increased expression of inducible nitric oxide synthase (inos) contributing to increased levels of nitric oxide (no) and increased levels of the adenosine receptor a br , suggesting increased adenosine metabolism, which might be linked to the increased levels of hif α in copd ams . while excessive ros production through oxidant burden and iron accumulation has been identified as an important regulator of am phenotype in copd, it has only recently been linked to mitochondrial dysfunction and metabolic reprogramming. it would be interesting to follow up on these transcriptomic and metabolic alterations to understand their underlying disease driving role and to identify ways to rewire am metabolism. as corticosteroids have been found to be particularly ineffective in copd, more specific pathways involved in am function and metabolism have been investigated recently, such as the ros pathway and iron accumulation. a study by harvey et al. showed that treatment with sulforaphane in copd ams ex vivo improved bacterial clearance by activating the antioxidant and antiinflammatory nrf pathway , while cloonan et al. found that treatment with an iron chelator or a low iron diet protected mice from cigarette smoke induced copd . furthermore, procysteine, a precursor of gsh, increased am efferocytosis in a mouse model of copd . overall, copd is marked by distinct iron sequestration, ros, no production and energetic dysfunction in ams; further delineation of how mitochondrial phenotype links to inflammatory processes and pathology in copd will allow the identification of molecular targets for modulating mitochondria during the disease. cystic fibrosis. cystic fibrosis (cf) is caused by mutation of the cf transmembrane conductance regulator (cftr), a chloride channel, which regulates fluid homoeostasis in mucosal surfaces. in the lung, cftr mutation and subsequent loss of function results in a reduced aqueous film covering the epithelium and mucus thickening, leading to impaired mucociliary clearance and frequent bacterial infection . cf is furthermore characterised by hyper-inflammation of the lungs, airway obstruction, structural damage and progressive reduction of lung function . during recurring airway inflammation, large numbers of neutrophils, macrophages and t lymphocytes infiltrate the lungs and secrete pro-inflammatory cytokines, while anti-inflammatory il- is reduced , . although am numbers are increased in cf patients , , pathogen clearance is attenuated, leading to colonisation of the airways and chronic inflammation , . meyer et al. report a more pro-inflammatory phenotype of ams in a murine model of cf, even in the absence of infection and mdms differentiated from cf patients show an increased inflammatory profile , while others have shown that monocytes from cf patients had an impairment in activation upon il- stimulation . cf-am phenotype can be heterogenous, depending on infection status and local environment. while ams from p. aeruginosa infected cf patients showed increased expression of mannose receptor cd and augmented arginase activity , in cf sputum ams a decrease in expression of cd and scavenger receptor marco was detected . furthermore, ams are involved in the structural damage in cf airways by secreting serine-and metalloproteases, which subsequently degrade connective tissue components . the lower volume of airway surface liquid in cf airways activates ams to increase their release of mmp , resulting in the cleavage of elastin and degradation of the airway and parenchyma . in cf airways, gsh is depleted , , while levels of iron, transferrin, haem and haemoglobin are increased , resulting in high oxidative stress and ros production. ros in turn can induce tgf-β , which has recently been shown to be increased in cf-bal and ams and inhibits cftr biogenesis and cellular trafficking to the surface of epithelial cells , while also contributing to airway remodelling by recruitment and differentiation of myofibroblasts . however, during infection with bacteria from the burkholderia family, both mdms and ams from cf patients showed reduced superoxide production as well as decreased phosphorylation of nadph oxidase (nox) components p phox and p phox , suggesting an inherent deficit in cf-ams generating oxidative bursts for pathogen defence . p. aeruginosa is one of the most common pathogens to cause recurrent pulmonary infection in cf patients and exploits the host to maintain infection by inducing production of the tca cycle metabolite itaconate in ams. itaconate exerts antimicrobial properties via inhibition of bacterial isocitrate lyase in the glyoxylate shunt and to evade this mechanism p. aeruginosa has developed a way to use itaconate as an energy source . similarly succinate, which is secreted in high levels during cf and especially during bacterial infection , can be utilised by p. aeruginosa and s. aureus as a substrate to generate oxidative stress. changes in lipid metabolism are a hallmark of cf and increased fao, lipid turnover in cell membranes and eicosanoid production in ams have been reported. furthermore, sterol regulatoryelement binding protein (srebp), a regulator of lipid homoeostasis, has been linked to cftr loss of function . this results in altered plasma and tissue fatty acid profiles, and while levels of the omega- fatty acid docosahexaenoic acid (dha) were unchanged in ams upon loss of cftr , ex vivo treatment with dha decreased tnf-α levels . furthermore, in cf ams the antiinflammatory lipoxin a (lxa ), which is synthesised from the fatty acid arachidonic acid, is reduced and the lxa /ltb ratio in cf bal is decreased , while the fatty acid metabolite resolvin d (rvd ) has been suggested as a biomarker . increased energy demand by ams in cf, either by manipulation through bacterial pathogens or to fight sustained infection, results in increased utilization of all available metabolic pathways. recently, lara-reyna et al. reported increased glycolysis, mitochondrial function, and production of tnf-α in cf macrophages is due to an alteration in the serine/threonine-protein kinase/ endoribonuclease ire α pathway and this supports exacerbated inflammation . while this study used pbmcs and monocytederived m macrophages from cf patients, it would be important to detect such a mechanism in ams and to target this pathway specifically. several of the above described pathways have been identified as potential drug targets in cf, however yet there are no treatments targeting ams. delivery of gsh to the lower respiratory tract improves the antioxidant barrier of cf epithelium , while treatment with cysteamine and restoration of microrna (mir ) and mir expression improves disease by restoring autophagy , . several studies administered omega- fatty acids (dha/epa) to cf patients [ ] [ ] [ ] [ ] , although only one trial reported improved fev after months treatment with dha . treatment with dha in a murine model of cf decreased liver inflammation but did not improve lung morphology . in conclusion, am metabolic phenotype during cf is marked by increased energy expenditure to support exacerbated inflammation and is readily exploited by bacterial pathogens, leaving ams deficient of oxidative burst capability during infection. it will be important to clarify the role of fatty acids in cf and furthermore, to target metabolic changes in ams such as increased glycolysis, oxphos and fao specifically to rewire am phenotype and prevent exploitation through bacterial pathogens. idiopathic pulmonary fibrosis (ipf). ipf is a chronic interstitial lung disease characterised by excessive extracellular matrix deposition in the lung parenchyma and has a particularly poor prognosis . repetitive alveolar injury in genetically susceptible individuals causes activation of mesenchymal cells, recruitment of fibroblasts and differentiation into myofibroblasts to replace damaged alveolar epithelial cells and provide a matrix for wound healing and tissue repair . during ipf, the wound healing process is dysregulated, leading to fibrotic plaque formation and excessive build-up of extracellular matrix, resulting in impaired gas exchange. ams have been identified as key contributors to the dysregulated wound healing process, by secreting large amounts of ros and tgf-β . furthermore, ams can shape the extracellular matrix by secreting factors contributing to the matrix (proline, collagen) and breaking down the matrix (plasmin, mmps) [ ] [ ] [ ] . several changes to the central carbon metabolism pathways have been identified recently in ams of ipf patients, including dysmorphic mitochondria . in murine models of pulmonary fibrosis, increased glucose consumption, glycolysis and enhanced expression of key glycolytic mediators was detected , while in ipf ams, expression of the pulmonary glucose transporter glut was increased , which enabled augmented glucose uptake . the increased glucose uptake via glut can furthermore sustain nadph production in the pentose phosphate pathway and tca cycle and is therefore a key substrate for ros production via nox . activation of macrophages results in the accumulation of endogenous metabolites capable of adopting immunomodulatory roles such as succinate and itaconate [ ] [ ] [ ] . recently, our laboratory identified itaconate as an endogenous anti-fibrotic in the human and murine lung. in patients with ipf, there were reduced levels of airway itaconate, and decreased expression of acod (which controls the synthesis of itaconate) in ams compared to healthy controls. acod deficiency in mice leads to more severe disease pathology and exogenous itaconate limits fibroblast activity . these data indicate that am metabolites may play a key role in the pathogenesis of lung fibrosis and may be exploited for the development of anti-fibrotic therapies. ros production is a key feature of ams in ipf and can occur during oxphos, by the membrane bound nox or by reaction of hydrogen peroxide with intracellular iron . nox, and subsequent superoxide production, is activated by binding gtp-bound rac , which is secreted from ams in ipf and can also activate the mtor signalling hub . superoxide produced by nox can further react with no to form peroxynitrite (oono -), another type of ros. at the expense of nadph, no is produced in the mitochondria by inos, which is upregulated in proinflammatory macrophages and in ipf-ams leading to increased levels of the cytotoxic oonoin ipf ams . in the bleomycin mouse model of pulmonary fibrosis, increased levels of superoxide, no and oonowere measured in ams . mtros is furthermore linked to expression of ppar-γ coactivator -alpha (pgc- α), which induces metabolic reprogramming to fao and is regulated by the mitochondrial calcium uniporter (mcu), which is increased in ipf ams . mcu has furthermore been shown to regulate expression of the fatty acid transporter cpt- , which is increased in ams from ipf patients and bleomycin exposed mice . while human ipf-ams have increased levels of mcu, mitochondrial calcium and expression of pgc- a, bleomycin exposed mice utilise increased fao , which is reduced in mice expressing dominant-negative mcu . furthermore, these mice were protected from bleomycin induced pulmonary fibrosis. these findings highlight calcium transport and fao as pathways to target in ipf ams; however, a better understanding of the linking mechanism will be necessary. ipf ams have also been shown to be iron laden , which further induces oxidative stress and ros production . using rna-sequencing, lee et al. show furthermore, that macrophage activation is increased in iron laden ams in ipf, suggesting that iron accumulation plays a role in macrophage activation . the proportion of ams expressing transferrin receptor (cd ), importing transferrin bound iron into the cell, are decreased in ipf ams, leading to an extracellular accumulation of transferrin. furthermore, numbers of cd -negative macrophages are an independent predictor of survival in ipf . iron metabolism is therefore likely a key pathway in ipf-ams and targeting it would be a viable option to decrease ros, oxidative stress and macrophage activation. recently, therapies targeting metabolic processes in ipf are of considerable interest. while antioxidant therapy in ipf was promising in vivo, the double-blind placebo controlled panther trial, administering either n-acetylcysteine or placebo to ipf patients for weeks did not show a change in lung function parameters . another arm of this study investigated the combined potential of corticosteroid prednisone, immunosuppressant azathioprine and n-acetylcysteine but was stopped prematurely due to increased mortality and adverse effects without evidence of benefit . another randomized, double-blind clinical trial assessed the safety and tolerability of n-acetylcysteine in patients already receiving pirfenidone anti-fibrotic therapy. while this trial showed that n-acetylcysteine in combination with pirfenidone was safe, no change in fvc, -minute walk test or occurrence of adverse effects was detected . another promising therapeutic avenue was the use of metformin, a potent metabolic remodelling drug often prescribed for type ii diabetes. while on a global level metformin lowers the amount of blood sugar in diabetic patients, on a cellular level metformin activates ampactivated protein kinase (ampk) leading to inhibition of tgf-β induced nox activity . sato et al., have shown that metformin inhibited tgf-β induced nox activity via ampk leading to inhibition of myo-fibroblast differentiation in vitro and reduced bleomycin induced collagen deposition in vivo . consistent with this, rangarajan et al. showed that metformin treatment reversed bleomycin induced pulmonary fibrosis via ampk activation, while in ipf patients ampk phosphorylation was decreased . a posthoc analysis study of the effect of metformin in ipf patients however showed no change in clinically outcomes , once again showing the difficulty of translating in vitro and in vivo findings into the clinic. another study investigating the nox-nrf imbalance as a therapeutic target showed that in vivo knockdown of nox and nox / inhibition restored the capacity of fibrosis resolution in aged mice . furthermore, treatment with nitrated fatty acids, reversed pulmonary fibrosis in a mouse model by promoting collagen uptake by ams and dedifferentiating myofibroblasts . while these treatment approaches targeted metabolic changes during pulmonary fibrosis, none was specific to ams. targeting macrophage specific metabolic reprogramming, which sustains ros and tgf-β production and contributes to dysregulated wound healing in ipf would therefore be a promising approach. during respiratory tract infections, activation of pattern recognition receptors expressed by am can elicit a variety of proinflammatory host responses . for example, severe coronavirus disease- (covid- ) associated pneumonia patients may exhibit features of systemic hyper-inflammation also known as macrophage activation syndrome or "cytokine storm" which is associated with sustained elevation of macrophage/monocytederived pro-inflammatory cytokines (e.g., il- , il- , tnf-α, il- β) leading to acute respiratory distress syndrome (ards) [ ] [ ] [ ] . using single cell approaches a recent study demonstrated that highly inflammatory, monocyte recruited ams, rather than quiescent pulmonary resident ams, predominate in the bal in covid- patients with severe pathology, implicating these cells in covid- -associated ards . rather than direct infection of ams, am:aec cross-talk has been identified as a major mechanism for control of many respiratory viral infections and aec have been shown to be a key source of pro-inflammatory cytokines, modulating am phenotype , . for example, rhinovirus (rv), the causative agent of the common cold, primarily infects the upper airways, however prior infection with rv attenuates subsequent am antibacterial responses . although ams are susceptible to influenza a viral infection (iav), replication within ams has been shown to be minimal with the exception of several highly virulent strains [ ] [ ] [ ] . here, we will focus on mycobacterium tuberculosis (mtb) infection, as ams are the primary infected cell type and metabolic changes in response to mtb infection are well studied. tuberculosis. tuberculosis (tb) is a contagious, chronic disease and one-third of the world's population is infected with mtb, the causative agent of tb, resulting in~ million deaths per year ( world health organization report) . during infection, mtb colonises ams intracellularly and disables innate intracellular defence mechanisms such as the phagolysosome and inflammasome and accesses macrophage intracellular nutrients . am host defence mechanisms against mtb include production of ros and reactive nitrogen species (rns) for bacterial killing and fusing mycobacteria-containing phagosomes with lysosomes as well as autophagy and apoptosis . however, virulent or multi-drug resistant strains can evade these host responses e.g. by preventing phagolysosome fusion and surviving ros/rns . during mtb infection, ams shift their metabolic programme from oxphos to aerobic glycolysis, which is regulated by hif α and interferon-gamma (ifn-γ). this metabolic shift and subsequent enhanced glycolytic flux in infected ams is crucial to control infection. mice lacking hif α in the myeloid lineage are more susceptible to infection and show decreased cytokine and antimicrobial effector production . to support this metabolic reprogramming, key glycolysis genes are upregulated in the early stages of granuloma formation in mice, supporting the shift towards aerobic glycolysis . mtb furthermore induce ferroptosis, associated with reduced levels of gsh, superoxide and increased free iron. the ferroptosis inhibitor ferrostatin- (fer- ) as well as iron chelation decreased necrotic cell death of mtb-infected macrophages in vitro, while in vivo treatment with fer- reduced bacterial load . mtb can cope in low iron environments however macrophage metabolic reprogramming during chronic lung disease pp ogger and aj byrne by downregulating their non-essential protein content via specific srna . several changes in fatty acid metabolism of mtb infected ams were identified recently. compared to interstitial macrophages during mtb infection, which are reliant on glycolysis, ams utilise fa, which is induced by ppar-α and have a lower burden of mtb infection . to escape host defence, mtb has developed a mechanism inhibiting pathways related to autophagy, lysosomal function and fao in support of replication by inducing microrna- (mir- ) in the host cell. silencing of mir- however induced am lipid catabolism and autophagy and rescued host defence . furthermore, amino acid metabolism is altered during mtb infection. in mice and macaque lungs, indoleamine , -dioxygenase (ido), which is involved in tryptophan catabolism, was increased during mtb infection, while inhibition of ido in a macaque model of tb decreased bacterial burden and pathology, as tryptophan metabolites suppress host immunity . while mtb relies on host lipids as energy source, existing therapies such as targeting ppar transcription factors or cholesterol synthesis have been successful mainly in animal models [ ] [ ] [ ] [ ] , whereas retrospective human studies, which investigated the effect of statins in diabetic tb patients did not show any results . as mtb can also utilise iron as a substrate, another approach is to prevent iron accumulation. treatment of mtb infected human mdms and primary am with iron chelator desferrioxamine (dfx) ex vivo induced the expression of glycolytic enzymes and enhanced glycolysis, as well as il- βα, thereby supporting host defence and offers a novel therapeutic approach, which will need to be investigated in clinical trials. together, these findings highlight the distinct phenotype of ams during mtb infection, which counteracts intracellular infection through aerobic glycolysis, but is also heavily exploited by mtb bacteria feeding on host lipids and iron. targeting metabolism during chronic lung disease many potential targets have been identified recently that could rewire macrophage metabolic and phenotypic changes driving chronic lung disease. since all cells depend on oxidative phosphorylation or cytoplasmic glycolysis to synthesize atp, there is the potential for unwanted side effects by targeting specific metabolic processes. however, it is becoming increasingly apparent that it is possible to safely target metabolic pathways in patients. for example, dimethyl fumarate, a known regulator of macrophage phenotype, is a first-line-treatment for relapsingremitting multiple sclerosis . indeed, metabolic processes are highly plastic with significant redundancy, modulation of these processes may have the added benefit of selectively targeting cells with high metabolic demands . targeted delivery to ams may add another layer of selectivity, improving efficacy, sustained drug release and evading capture by mucus . systems for inhaled am targeted drug delivery include the use of micro-and nanocarriers, including liposomes, which are phagocytosed by ams. rifampicin-loaded microspheres as a therapeutic approach for mtb have been described , and have been further refined to allow a one-step assembly for rifampicin containing microspheres . recently, aerosolised delivery of sirna, which posttranslationally downregulates gene expression, has been developed to target ams specifically , whilst mannose coated microspheres have been developed which exploit the phagocytotic activity of ams . many of these delivery vehicles have been developed to transport antibiotics targeting intracellular am bacterial infections, which are helpful for treating tb, however other drugs could be incorporated into aerosolised micro-or nano delivery systems. specifically, treatment with iron chelators, antioxidants and nitrated fatty acids has shown to rewire am phenotype and improve diverse chronic lung disease; these may be ideal candidates to develop novel, aerosolised vehicle-assisted drug delivery to ams during chronic lung disease. in the last decade enormous strides have been made regarding our understanding of how adaptations in metabolic pathways underlie macrophage phenotype and function. ams are remarkably plastic cells, orchestrating not only pathogen defence and efferocytosis, but also pulmonary tolerance and resolution. it has become increasingly clear that ams tailor their metabolic profile to fit their local niche generating ros for pathogen defence, utilising aerobic glycolysis to rapidly generate cytokines, employing the tca cycle to fuel inflammatory responses and generating metabolites with secondary signalling functions such as citrate, itaconate, succinate and fumarate. work elucidating the complexities of am metabolic alterations in the context of clds has highlighted many potential therapeutic targets (summarized in table ). indeed, a lack of understanding of shared cellular mechanisms, which underlie clds has been a major obstacle in respiratory biology; identification of common am-metabolic pathways/metabolites which directly influence core features of clds would be a significant advance on the route to devising new am-directed strategies to treat pulmonary diseases which affect millions worldwide. lung homeostasis: influence of age, microbes, and the immune system pulmonary macrophages: key players in the innate defence of the airways monocytes and macrophages: developmental pathways and tissue homeostasis metabolic reprograming in macrophage polarization macrophage immunometabolism: where are we (going)? metabolic disorders in chronic lung diseases alveolar macrophage immunometabolism and lung function impairment in smoking and chronic obstructive pulmonary disease alveolar macrophages: plasticity in a tissue-specific context alveolar macrophage in the driver's seat integrin αvβ : structure, function and role in health and disease pulmonary macrophages: a new therapeutic pathway in fibrosing lung disease? flow cytometric analysis of macrophages and dendritic cell subsets in the mouse lung identification of myeloid cell subsets in murine lungs using flow cytometry lung environment determines unique phenotype of alveolar macrophages a critical function for cd in lung immune homeostasis and the severity of influenza infection a lineage of myeloid cells independent of myb and hematopoietic stem cells alveolar macrophages develop from fetal monocytes that differentiate into long-lived cells in the first week of life via gm-csf tissue-resident macrophages self-maintain locally throughout adult life with minimal contribution from circulating monocytes yolk sac macrophages, fetal liver, and adult monocytes can colonize an empty niche and develop into functional tissue-resident macrophages the lung environment controls alveolar macrophage metabolism and responsiveness in type inflammation tissue-resident macrophage ontogeny and homeostasis developmental origin of lung macrophage diversity the fate and lifespan of human monocyte subsets in steady state and systemic inflammation monocyte recruitment during infection and inflammation transcriptome analysis highlights the conserved difference between embryonic and postnatal-derived alveolar macrophages cellular chimerism of the lung after transplantation: an interphase cytogenetic study long-term persistence of human donor alveolar macrophages in lung transplant recipients long-term persistence of donor alveolar macrophages in human lung transplant recipients that influences donor specific immune responses the human alveolar macrophage direct evidence for a bone marrow origin of the alveolar macrophage in man dynamics of human monocytes and airway macrophages during healthy aging and after transplant human monocyte subsets are transcriptionally and functionally altered in aging in response to pattern recognition receptor agonists aging is associated with chronic innate immune activation and dysregulation of monocyte phenotype and function agedependent alterations of monocyte subsets and monocyte-related chemokine pathways in healthy adults succinate is an inflammatory signal that induces il- β through hif- α succinate dehydrogenase supports metabolic repurposing of mitochondria to drive inflammatory macrophages cell-intrinsic lysosomal lipolysis is essential for alternative activation of macrophages network integration of parallel metabolic and transcriptional data reveals metabolic modules that regulate macrophage polarization metabolic reprogramming in macrophages and dendritic cells in innate immunity tissue-resident alveolar macrophages do not rely on glycolysis for lps-induced inflammation induction of the nuclear receptor ppar-γ by the cytokine gm-csf is critical for the differentiation of fetal monocytes into alveolar macrophages pulmonary surfactant protein a modulates the cellular response to smooth and rough lipopolysaccharides by interaction with cd gm-csf regulates pulmonary surfactant homeostasis and alveolar macrophage-mediated innate host defense gm-csf regulates alveolar macrophage differentiation and innate immunity in the lung through targeted pparγ deficiency in alveolar macrophages disrupts surfactant catabolism familial pulmonary alveolar proteinosis caused by mutations in csf ra adult-onset hereditary pulmonary alveolar proteinosis caused by a single-base deletion in csf rb hereditary pulmonary alveolar proteinosis caused by recessive csf rb mutations pulmonary alveolar proteinosis caused by deletion of the gm-csfrα gene in the x chromosome pseudoautosomal region protective role of the lung collectins surfactant protein a and surfactant protein d in airway inflammation surfactant protein a regulates complement activation surfactant protein a directly interacts with tlr and md- and regulates inflammatory cellular response: importance of supratrimeric oligomerization membrane-tethered muc mucin counter-regulates the phagocytic activity of macrophages muc b is required for airway defence macrophages are related to goblet cell hyperplasia and induce muc b but not muc ac in human bronchus epithelial cells a common muc b promoter polymorphism and pulmonary fibrosis multi-platform metabolomics assays for human lung lavage fluids in an air pollution exposure study the respiratory tract microbiome and lung inflammation: a two-way street respiratory microbiome and epithelial interactions shape immunity in the lungs the microbiome of the upper respiratory tract in health and disease the nasal cavity microbiota of healthy adults butyrate enhances the intestinal barrier by facilitating tight junction assembly via activation of ampactivated protein kinase in caco- cell monolayers understanding the holobiont: how microbial metabolites affect human health and shape the immune system the microbiota of the respiratory tract: gatekeeper to respiratory health immunometabolism: cellular metabolism turns immune regulator the european respiratory society. the burden of lung disease asthma-copd overlap syndrome: pathogenesis, clinical features, and therapeutic targets. - integrated genomics reveals convergent transcriptomic networks underlying chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis the pathogenesis of copd and ipf: distinct horns of the same devil? 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tgfβ human cystic fibrosis macrophages have defective calciumdependent protein kinase c activation of the nadph oxidase, an effect augmented by burkholderia cenocepacia irg expression in myeloid cells prevents immunopathology during m. tuberculosis infection pseudomonas aeruginosa utilizes host-derived itaconate to redirect its metabolism to promote biofilm formation pulmonary pathogens adapt to immune signaling metabolites in the airway lipid metabolism in cystic fibrosis alterations in immune response and ppar/lxr regulation in cystic fibrosis macrophages reduced -lipoxygenase and lipoxin a /leukotriene b ratio in children with cystic fibrosis pro-resolving lipid mediator resolvin d serves as a marker of lung disease in cystic fibrosis metabolic reprograming of cystic fibrosis macrophages via the ire α arm of the unfolded protein response results in exacerbated inflammation glutathione aerosol suppresses lung epithelial surface inflammatory cell-derived oxidants in cystic fibrosis 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mycobacterium tuberculosis infection on primary human macrophages by combined exploratory and targeted metabolomics competing interests: the authors declare no competing interests.publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. key: cord- - s tjrd authors: mcauley, hamish; hadley, kate; elneima, omer; brightling, christopher e; evans, rachael a; steiner, michael c; greening, neil j title: copd in the time of covid- : an analysis of acute exacerbations and reported behavioural changes in patients with copd date: - - journal: erj open res doi: . / . - sha: doc_id: cord_uid: s tjrd introduction: the impact of the sars-cov- pandemic, and lockdown measures, on acute exacerbations of copd (aecopd) is unknown. we aimed to evaluate the change in aecopd treatment frequency during the first weeks of lockdown in the uk compared with and assess changes in self-reported behaviour and well-being. methods: in this observational study in leicestershire, uk, patients with copd under a secondary care clinic were recruited. exacerbation frequency in the first weeks of covid lockdown was compared with the same period in using electronic health records. a telephone survey was used to assess changes in anxiety, inhaler adherence, physical activity, and behaviour during the pre-lockdown and lockdown periods compared to normal. results: participants were recruited (mean [sd] age . [ . ] years, [ %] male, fev . [ ] % predicted). [ %] reported at least one aecopd in the previous year. significantly more community treated exacerbations were observed in compared with ( versus , p= . ). the increase was a result of multiple courses of treatment, with a similar proportion of patients receiving at least one course ( . % versus . %). during “lockdown” participants reported significantly increased anxiety, adherence to their preventative inhalers, and good adherence to shielding advice (all p< . ). a significant reduction in self-reported physical activity and visitors was reported (both p< . ). discussion: treatment for aecopd events increased during the first weeks of the sars-cov- pandemic in the uk compared to . this was associated with increased symptoms of anxiety and significant behavioural change. acute exacerbations of chronic obstructive pulmonary disease (aecopd) are a frequent problem for people with copd, adversely affecting morbidity and mortality and are an important cause of unscheduled healthcare contacts including admission to hospital global initiative for copd (gold) report grades the severity of these events according to treatment requirement, defining moderate events as those needing community provision of oral antibiotics and corticosteroids and severe events as those requiring hospitalisation . healthcare provision for people with copd has been impacted by the severe acute respiratory syndrome coronavirus (sars-cov- ) pandemic through the requirement for more distant/remote contact with the healthcare team to reduce the risk of virus transmission . patients with copd who present with sars-cov- infection have a poorer prognosis , , highlighting the need for primary prevention and risk reduction . additionally, because of the appreciation of a greater risk of morbidity from sars-cov- infection more stringent social isolation has been recommended for people with copd during the period of societal lockdown that has been implemented in most countries affected by the pandemic. in the uk this has been termed "shielding" and includes advice against leaving home for any reason other than for essential work or shopping with very limited exceptions. during this time healthcare professionals providing care for people with copd have reported lower than expected presentation rates for aecopd in both community and acute hospital settings . however, it is unclear whether this is due to a genuine reduction in aecopd rates (potentially due to lower respiratory viral transmission and/or atmospheric pollution) or due to higher thresholds for patient reporting to healthcare services because of fearfulness about contracting sars-cov- in healthcare environments, particular hospitals. in addition there is limited understanding of the impact of enhanced shielding on the psychological wellbeing and physical activity in people with pre-existing respiratory disease such as copd . having a chronic condition such as copd does not appear to increase the likelihood of sars-cov- infection , it does convey increased risk of hospitalisation and death . firstly, in this observational study we recorded the change in moderate and severe aecopd treatment frequency (assessed objectively through prescription records or requirement for hospitalisation) during the first six weeks of societal lockdown in the uk compared with the equivalent period months previously. secondly, we assessed self-reported behaviour change during the pre-lockdown and lockdown period by telephone interview in order to explore potential reasons for any observed changes in aecopd treatment frequency we compared rates of treatment for exacerbations of copd managed in the community and hospital setting in a single centre between the first six-week period of the sars-cov- "lockdown" in england ( th march to th april ) with the same six-week period the previous year ( th march to th april ). participants were prospectively recruited between nd june, and th july, and provided informed consent. all recruitment and interview calls were made either by experienced respiratory research nurses or clinicians. ethics approval was granted by the electronic community prescription records were used to record community exacerbation events and electronic hospital records similarly for hospital exacerbations. the terms community and hospital exacerbation, rather than moderate or severe , are used in in this study due to the known change in hospital admission criteria during the peak of the sars-cov- pandemic in england when hospital bed capacity was considered of critical importance. community managed exacerbations were defined as those resulting in a prescription for oral corticosteroids and/or antibiotics but without hospital admission. only prescriptions for antibiotics that would typically be used to treat aecopd events in our region were included. hospitalised exacerbations were defined as admissions to hospital with a recorded discharge diagnosis of acute exacerbation of copd. as an additional analysis a scripted telephone survey was conducted to explore potential reasons for differences in exacerbation risk. participants were asked to compare behavioural and emotional changes with their baseline "normal" state as a reference. participants were asked to compare two discrete periods; ( ) pre-lockdown, defined as the two weeks prior to "lockdown" ( st march to th march ) when participants were likely to be more aware of the threat of sars-cov- but restrictions had not yet been placed and ( ) the "lockdown" itself ( th march to th april ). self-reported behaviour included; medication adherence to their regular prescribed inhaled therapy, anxiety, selfreported change in activity levels, and social behaviour (self-isolation, shielding, visitors to the home, arrangements for shopping). answers were captured with either a binary response (yes/no) or on a five-point likert scale (see online supplement for full details of questionnaire used). participants were eligible if they had a confirmed diagnosis of copd, under a specialist copd clinic (complex copd clinic, leicester, uk ), and able to provide informed verbal consent via english language telephone consultation. the specialist clinic accepts any patient with copd with ongoing symptoms (e.g. admission to hospital for aecopd, mmrc > , continued smoking, low body mass index, potentially lung volume reduction candidate, or established respiratory failure). all patients had confirmed airflow obstruction by gold criteria . patients were contacted sequentially from the research database held in our centre of patients alive at the start of the study who have previously consented to be contacted for research until this list was exhausted with a total of attempts to contact participants who did not initially. the telephone call was made by either a nurse or doctor and participants gave informed consent verbally with this documented by the investigator due to the remote nature of the consultation. electronic gp and hospital healthcare records were used to capture new prescriptions for oral antibiotics or corticosteroids during the periods of interest, hospital admissions, as well as baseline characteristics, including latest spirometry. all spirometry had been performed at their previous clinic visit to glenfield hospital, leicester to ers/ats standard . baseline data were described as mean (standard deviation), or n (%) as appropriate. paired data were compared using a paired t-test or signed-rank test for parametric data and nonparametric data respectively. categorical data were compared using chi squared. statistical analysis was performed using stata (statacorp, usa). from previous data from our copd clinic we anticipated . exacerbations per patient in the observation period with a sd of . . to detect a % difference in exacerbations within patients between and then participants would be required (alpha= . , power %). patients were recruited with baseline characteristics outlined in table . ( %) reported at least one exacerbation in the previous year, and the majority ( %) reported at least two. ( %) patients were prescribed triple inhaled therapy and ( %) were classed as gold stage or airflow obstruction. in the two weeks prior to lockdown ( %) participants reported using their maintenance inhalers with the same frequency as they would during their stable state. participants ( %) reporting increased use and ( . %) using less frequently than normal. during the lockdown period ( %) participants reported increased use, ( %) participants reported the same frequency of use and ( . %) reported using their regular inhaler less frequently than baseline (p< . ) (figure a). anxiety ( %) participants reported having more anxiety about their copd than normal during the pre-lockdown period compared to baseline, of which / ( %) reported anxiety as a "little more" than baseline and / ( %) as "much more". during the lockdown period ( %) reported increased anxiety compared to normal (p< . ), of which / ( %) were "a little more" anxious and / ( %) "much more" anxious (figure b). participants were also asked if they would avoid coming to hospital as an emergency during the pre-lockdown and lockdown periods due to fear of covid- . ( %) reported they would have avoided doing so during the pre-lockdown and ( %) reported they would avoid emergency hospital attendance during the lockdown period (p< . ). ( %) reported physical activity was unchanged compared to normal during the prelockdown period with ( %) reporting reduced activity and ( %) reporting increased activity levels. this contrasted sharply to the lockdown period where only ( %) reported maintaining the same level of activity as normal while ( . %) reported slightly less and ( %) reported doing a lot less physical activity than normal implying a significant decrease in activity levels (p< . ). only ( %) reported increased physical activity levels ( figure c) . when asked about participation in a home exercise program, ( %) patients and ( %) patients reported participating in a home exercise program during the prelockdown and lockdown periods respectively. [figure ] participants were asked about shopping behaviour during the pre-lockdown and lockdown periods with a significant change being noted; during the pre-lockdown ( . %) reported going shopping themselves, while ( . %) reported that this was performed by someone who lives in the house with them and ( . %) reported it being completed by someone who does not live with them or being delivered to them. in contrast to this, during the lockdown only ( . %) reported that they still did their own shopping, with ( . %) having this task completed by someone living in their home and ( %) reporting that it was done by someone who does not live in their home or delivered (pre-lockdown to lockdown, p< . ). in the pre-lockdown period ( . %) participants reported continuing normal behaviour with only ( %) shielding. once lockdown started only ( . %) reported continuing normal behaviour while ( . %) reported that they were shielding (p< . ). during the pre-lockdown period ( . %) reported that they had visitors to their home compared to ( . %) during the lockdown (p< . ). in this observational study a % increase in community managed exacerbation events during the covid- lockdown in was seen compared to the same six-week period in , as measured by primary care prescription records. the number of patients suffering an exacerbation was unchanged. self-reported anxiety and inhaler adherence increased whereas pa was lower initially during the pre-lockdown period, but most pronounced during lockdown. severe exacerbations, as measured by hospital admissions, were seen within the cohort and represented % of all exacerbations. we observed a % decrease in hospital managed aecopd events during the covid- lockdown compared the same dates in , though our study was insufficiently powered. a recent larger study, comparing hospital events, rather than individual patients, confirm our observations with a similar reduction in aecopd admission rates . this may represent an effect of the increased use of rescue medications in the community resulting in reduced need for hospital admissions, though other factors are also likely to have played a role. this is the first report of the impact of the sars-cov- pandemic (and consequent societal lockdown) on objectively measured aecopd rates. our findings contrasts to reports of reduced aecopd events during the lockdown with physicians and copd nursing teams . interestingly we did not observe an increase in the proportion of patients requiring rescue medication, but an increase in the number of multiple courses. possible explanations for these findings may result from either biological or behavioural differences. patients who would normally have been admitted to hospital with an exacerbation may have been managed in the community during the pandemic because of a combination of fearfulness on the part of the patient about transmission risk in hospital and a desire on the part of healthcare teams to reserve hospital bed capacity to manage patients suffering with covid- pneumonia. this behavioural explanation appears plausible, particularly as there was increased access to healthcare services via telephone consultations and reduced physical access to clinicians . national guidance, updated in , recommended an "action plan" which includes oral corticosteroids and antibiotics to be self-administered in the event of an aecopd . increased concerns on the part of clinicians about the risks of hospitalisation in a patient population perceived to be at greater risk from sars-cov- might have lowered thresholds for prescribing action plans. patient concern that access to primary or secondary healthcare teams and pharmacies might be restricted might also have resulted in stockpiling behaviour during the pandemic with patients potentially requesting multiple "rescue packs" to store in case they were unable to obtain these later. during remote telephone consultations clinicians may have felt unable to assess the severity of patients' symptoms resulting in a reduced threshold for prescribing acute rescue therapies. these behavioural aspects may provide cautions beyond the current pandemic in how future digital health services and clinics are arranged and incentivised. it is possible that the biological triggers for exacerbation events reduced for some patients because of reduced respiratory virus transmission and air pollution during lockdown. our study did not explore the underlying mechanisms of each exacerbation, which may be altered during the sars-cov- pandemic. it is possible that events could be driven by noninflammatory causes, termed "pauci-inflammatory" , which are less responsive to oral antibiotics or corticosteroids . we observed that the majority of participants reported increasing anxiety about their copd, particularly during the lockdown period. this would support a view that the observed increase in exacerbations may be underpinned by behavioural change and concerns around copd and emergency healthcare. it also highlights the need for potential psychological support in a vulnerable population, where anxiety and depression are common . in addition, it is clear from our data that adherence to shielding advice was widespread, likely reflecting a shared concern among patients about risks from covid- . likewise, we observed an increase in self-reported inhaler compliance suggesting greater health concern and vigilance. we also observed a greater dependence on others for day to day activities such as shopping and an overall reduction in physical activity among this cohort of patients with copd that contrasts to that reported amongst the general population during the lockdown . previous studies have demonstrated the association of reduced physical activity levels and aecopd readmission risk and while this study did not directly assess this effect it raises the additional possibility that exacerbation events increased because of increased breathlessness and reduced resilience due to deconditioning and sarcopenia , . the longer term consequences of such altered activity behaviours remains to be seen but is of significant concern given the difficulty in providing timely and effective pulmonary rehabilitation in the context of the pandemic . at the time of writing, we are approaching winter in the northern hemisphere and no sars-cov- vaccine has yet been demonstrated to be safe and effective , exacerbations of copd are likely to increase with this season and result in increased hospitalisation. this study is a timely reminder that increased understanding of community prescribing practice and patient behaviour are important and may reveal effective tools in reducing morbidity and mortality in this group. firstly, patients with copd are going to require ongoing support and treatment, even if they are less likely to present to specialist or hospital services. previous evidence has shown that pandemic influenza poses a significant risk to patients with copd with the consequence that viral pandemics such as sars-cov- are likely to pose a similar risk. developing robust and accessible systems to acutely review patients with copd remotely to guide them in their use of rescue and preventer medication may reduce symptom burden, hospital admissions and unnecessary courses of potentially harmful oral corticosteroids and antibiotics. it is less likely that the increased number of moderate exacerbations recorded from our prescription data represent an increase in airway inflammation but rather a composite of increased anxiety and caution with the aim of preventing hospital admissions and the consequence that other, non-pharmacological, interventions may have been effective in managing these events . the conclusions drawn from this study are limited by both the relatively small sample size and the severity of the copd seen in the cohort recruited. though patients has provided adequate power for statistically significant differences in community treated exacerbation and behavioural changes it has not been sufficiently large to detect changes in hospitalised events which would be better evaluated using larger datasets. in addition to this the cohort had established copd, under a specialist secondary care clinic, so results may not be applicable to those with milder disease, and less frequent exacerbations. adding further selection bias, patients recruited needed to be alive during the period of recruitment in may and june , meaning that there may be survivor bias compared to those that died in and during the peak of the pandemic. our use of a survey to assess associated factors and explore possible causes for patterns seen was notably limited by recollection bias with questionnaire calls taking place up to seven weeks after the end of the period of interest and by our use of non-validated questionnaires. in summary, this study revealed an increase in treatment for community treated aecopd events among patients with severe copd during the sar-cov- lockdown. this finding was unexpected but may be explained by factors such as anxiety, which was increased in our patient cohort. significant behaviour changes including reduced physical activity, adherence to shielding advice and increased inhaler compliance. - . . gold. global strategy for the diagnosis, management and prevention of chronic obstructive pulmonary disease covid- rapid guideline: community-based care of patients with chronic obstructive pulmonary disease (copd) nice guideline factors associated with covid- -related death using opensafely covid- and copd severity and mortality associated with copd and smoking in patients with covid- : a rapid systematic review and meta-analysis we continue to see very few #copd exacerbations, and not just because people aren't coming to hospital. i'd often wondered what 'intrinsic' exacerbation frequency might look like with cleaner air and much reduced transmission of (regular) viruses. the art of the possible disproportionate decline in admissions for exacerbated copd during the covid- pandemic acute exacerbations of chronic obstructive pulmonary disease: in search of diagnostic biomarkers and treatable traits caring for patients with copd and covid- : a viewpoint to spark discussion mental health and the covid- pandemic comorbidity and its impact on patients with covid- in china: a nationwide analysis comprehensive respiratory assessment in advanced copd: a 'campus to clinic' translational framework standardisation of spirometry digital technologies in the public-health response to covid- chronic obstructive pulmonary disease: diagnosis and management: summary of updated nice guidance beyond panic buying: consumption displacement and covid- acute exacerbations of chronic obstructive pulmonary disease: identification of biologic clusters and their biomarkers examining the relationship between anxiety and depression and exacerbations of copd which result in hospital admission: a systematic review comprehensive pulmonary rehabilitation for anxiety and depression in adults with chronic obstructive pulmonary disease: systematic review and meta-analysis is the covid- lockdown nudging people to be more active: a big data analysis risk factors of readmission to hospital for a copd exacerbation: a prospective study bedside assessment of quadriceps muscle using ultrasound following admission for acute exacerbations of chronic respiratory disease. american journal of respiratory and critical care medicine gait speed and readmission following hospitalisation for acute exacerbations of copd: a prospective study pulmonary rehabilitation at a time of social distancing: prime time for tele-rehabilitation? the role of viral infections in exacerbations of chronic obstructive pulmonary disease and asthma have you had any periods of worsening of your breathing symptoms since the st of march this year? if no -go to section b. if yes -go to question have you had to use additional medication for these episodes? if yes, what was this medication? a. salbutamol (blue) inhaler? b. steroids? if so how many five day courses and on what dates? c. antibiotics? if so how many courses and on what dates? have you attended hospital for any of these episodes? in no -go to section b. if yes -go to question if it weren't for covid do you think you have gone to hospital? were you diagnosed with an exacerbation of copd? . were you diagnosed with covid- ? if current or ex-smoker: estimate pack years . how many times did your copd symptoms worsen in the past months sufficiently that you needed extra treatment (steroids or antibiotics) at home or at hospital? (never / once / two or more times) all questions need two answers, one relating to the pre-lockdown and one to the lockdown periods. . during the pre-lockdown and lockdown periods did you? a. normal behaviour b. shielding (not leaving your home or interacting face to face avoiding close contact ( meters/ feet) with anyone who does not live in your home) during the pre-lockdown and lockdown periods who was living in your household? a. lived alone b. lived with a partner/spouse c. lived with working age children d. lived with (pre)school age children e. lived in an institutionalised setting during the pre-lockdown and lockdown periods did you have any visitors to your home? y/n if yes were they: a. adults b. (pre)school age children during the pre-lockdown and lockdown periods how did you obtain essential items and groceries? a. self b. another person who lives in your home c. deliveries/ someone who does not live in your home during the pre-lockdown and lockdown periods did you start any new medications? y/n if yes during the pre-lockdown and lockdown periods did you use your regular (non-salbutamol) inhalers more or less regularly? (less) during the pre-lockdown and lockdown periods did during the pre-lockdown and lockdown periods were you more or less active than normal? (less) - - - - (more) during the pre-lockdown and lockdown periods did you feel more or less anxious about your copd? (less) during the pre-lockdown and lockdown periods did you avoid coming to hospital as an emergency due to fear of covid we wish to acknowledge the work of the following members of the nihr leicester brc key: cord- - ylp edo authors: maremanda, krishna p.; sundar, isaac k.; li, dongmei; rahman, irfan title: age-dependent assessment of genes involved in cellular senescence, telomere and mitochondrial pathways in human lung tissue of smokers, copd and ipf: associations with sars-cov- covid- ace -tmprss -furin-dpp axis date: - - journal: res sq doi: . /rs. .rs- /v sha: doc_id: cord_uid: ylp edo aging is one of the key contributing factors for chronic obstructive pulmonary diseases (copd) and other chronic inflammatory lung diseases. cigarette smoke is a major etiological risk factor that has been shown to alter cellular processes involving mitochondrial function, cellular senescence and telomeric length. here we determined how aging contribute to the alteration in the gene expression of above mentioned cellular processes that play an important role in the progression of copd and ipf. we hypothesized that aging may differentially alter the expression of mitochondrial, cellular senescence and telomere genes in smokers and patients with copd and ipf compared to non-smokers. total rna from human lung tissues from non-smokers, smokers, and patients with copd and ipf were processed and analyzed based on their ages (younger: < yrs and older: > yrs). nanostring ncounter panel was used to analyze the gene expression profiles using a custom designed codeset containing genes including housekeeping controls (mitochondrial biogenesis and function, cellular senescence, telomere replication and maintenance). mrna counts were normalized, log transformed for differential expression analysis using linear models in the limma package (r/bioconductor). data from non-smokers, smokers and patients with copd and ipf were analyzed based on the age groups (pairwise comparisons between younger vs. older groups). several genes were differentially expressed in younger and older smokers, and patients with copd and ipf compared to non-smokers which were part of the mitochondrial biogenesis/function (hspd , fen , cox , cox , ucp & ), cellular senescence (pcna, pten, klotho, cdkn c, tnks , nfatc & , gadd a) and telomere replication/maintenance (parp , sirt , nbn, tert, rad , slx , hat ) target genes. interestingly, nox and tnks were increased in the young ipf as compared to the young copd patients. genes in the mitochondrial dynamics and other quality control mechanisms like fis and rhot were decreased in young ipf compared to their age matched copd subjects. ercc (excision repair cross-complementation group ) and gadd b were higher in young copd as compared to ipf. aging plays an important role in various infectious diseases. elderly patients with chronic lung disease and smokers were found to have high incidence and mortality rates in the current pandemic of sars-cov- infection. immunoblot analysis in the lung homogenates of smokers, copd and ipf subjects revealed increased protein abundance of important proteases and spike proteins like tmprss , furin and dpp in association with a slight increase in sars-cov- receptor ace levels. this may further strengthen the observation that smokers, copd and ipf subjects are more prone to covid- infection. overall, these findings suggest that altered transcription of target genes that regulate mitochondrial function, cellular senescence, and telomere attrition add to the pathobiology of lung aging in copd and ipf and other smoking-related chronic lung disease in associated with alterations in sars-cov- ace -tmprss -furin-dpp axis for covid- infection. aging is an important factor in uencing the overall lung health and function , . lung function declines with progress in age after lung maturation. evidences suggest that a signi cant contribution of various environmental factors in uence the ageing lung . according to the behavioral risk factor surveillance system (brfss) data from , . % (age-adjusted) us adults were reported to have chronic obstructive pulmonary disease (copd) . further, there has been an increasing reports of young copd population visiting for different hospital services . ageing in uences many chronic lung diseases like copd, idiopathic pulmonary brosis (ipf) and asthma. also chronic lung diseases like asthma and ipf share some of the common yet distinct features compared to copd . environmental stress factors like smoking remains a common in uencing factor for the disease progression in all these three cases. cigarette smoke (cs) is one of the strongest contributing risk factors in the pathogenesis of copd along with the decline in lung function . cellular senescence is a process of irreversible cell cycle arrest, having both bene cial and harmful effects depending on the cell state . cs plays a role in advancing the lung aging by altering the process of cellular senescence . several factors including oxidative stress in uence the process of cellular senescence. telomeres and mitochondria play a major role in in uencing the process of cellular senescence and are often associated with maintaining the lung health , , . earlier reports from our laboratory and others have shown that smoking and copd is associated with the mitochondrial damage and dysfunction, altering the process of cellular metabolism and function , . similarly, telomere dysfunction was also associated with smoking and copd , . mitochondrial and telomere dysfunction also play a causative role in the progression of ipf - . several molecular mechanisms were identi ed and reported in relation to cs causing copd and associated complications . cigarette smoke alters several key functions in the cells, among them the crucial genes related to mitochondrial function, cellular senescence and telomeric length were selected in the current study to observe for any differential changes among young and old age groups categorized as non-smokers, smokers and copd groups. our previous studies showed independent contributions of these canonical signaling pathways and how they contribute towards the development of premature lung aging in chronic lung diseases, such as copd/emphysema - . accumulating evidence suggest the close relationship of all these three pathways in in uencing lung ageing and disease , , . senescent cells are found in many age-related/chronic diseases . studies from our laboratory showed that mice from different age group when exposed to chronic air and cs in uence the process of lung in ammation and senescence. chronic cs exposure in lung epithelial cells and mice increases several markers of cellular senescence , . recently, it was reported that serum from copd patients can induce senescence in lung epithelial cells , giving strength to the importance of this area that needs to be explored further. several dna damaging agents occur in smoke, which may activate of dna damage response by in uencing telomere function over the time and tend to accumulate senescent cells. however, recent meta-analysis suggests that even though smokers are associated with shorter telomere length, the study implicates that smoking does not accelerate the telomere attrition in leucocytes . smoking and copd conditions altered the expressions of many key genes involved in the above three crucial pathways of cellular maintenance. the current study was undertaken to determine the changes in genes related to mitochondrial biogenesis and function, telomere function and cellular senescence with respect to their age in human lungs. this study is important in unraveling some of the potential biomarkers to differentiate and follow the course of ageing in copd. keeping in view the importance of these genes in both copd and ipf, we have also made comparisons between the similar age grouped copd and ipf subjects, using the same set of gene panels. aging is one of the key components, which decides the subject's susceptibility to various diseases and infections . in ammaging/immunosenescence de nes the condition to combat various recent pandemic of severe acute respiratory syndrome (ards) coronavirus (sars-cov- ) was thought to affect more elderly people especially men - . men with age-related comorbidities has higher mortality rate during coronavirus disease (covid- ) . comorbidities like cardiovascular disease, diabetes and chronic respiratory diseases present a high mortality rate . the studies involving the role of lung aging and senescence play an important role in understanding the role of multiple players involved in combating against sars-cov- infection and can lead to potential druggable targets to combat it. considering the important role played by some of the crucial receptors and targets in covid- , we determined the protein expression of sars-cov- receptor angiotensin converting enzyme (ace ) and aiding proteases like transmembrane protease serine protease- (tmprss- ) and spike protein furin in the lung homogenates of non-smokers, smokers, copd and ipf subjects. we have also determined for the levels of dipeptidyl peptidase (dpp ), which acts as a receptor for the similar class of coronavirus which is middle east respiratory syndrome coronavirus, (mers-cov) . scienti c rigor and reproducibility rigorous and unbiased approach were used to ensure full and detailed reporting of both methods and analyzed data. ethical approval: institutional biosafety an review board approvals ethics statement the current study was approved for the procurement of the human lung tissues as de-identi ed tissues by the materials transfer agreement and procurement (institutional review board), and laboratory protocols by the institutional biosafety committee of the university of rochester medical center, rochester, ny. patients' data or patients are not directly involved in this study as the lung tissues were procured from several agencies (see below). all patients/subjects were of age and above. all methods were carried out in accordance with relevant guidelines and regulations of the university of rochester, rochester, ny. the human peripheral lung tissues from non-smokers, smokers and copd were procured/obtained from the ndri (national disease research interchange; the samples were collected from patients with various cause of deaths reported such as cardiac arrest or trauma/accidents, for most of the samples lower peripheral lung lobes were used or as supplied), ltrc (lung tissue research consortium of the nhlbi) and department of medicine and pathology, and of the university of helsinki hospital, finland as described in our previous reports . the clinical characteristics of the subjects used in the current study are given in table . the subjects were broadly classi ed into two age groups: young age (≤ years) group, old age (> years) group, as per previous studies . although there were some co-morbid conditions reported for the specimens from copd patients (which were on various medications), the tissues were assigned to different groups based on the age, smoking status and lung disease status (normal vs smoker's normal vs copd) reported during the procurements of the specimens. even though the de nitions across various reports vary, the samples in the non-smokers group were either reported to have no smoking history or doesn't t under current smokers with a long past tobacco use specially in old non-smokers , but have normal lungs, smokers have current smoking history with lung function, and copd have diseased lungs classi ed as copd. additional comparisons were made between copd ( additional samples from above groups were added in addition to the samples mentioned in table ) and ipf lung samples ( in young ipf, in old ipf) based on their age to check for the changes in the same custom gene panel (tables and ). total rna was extracted from the human lung tissues stored at - °c or in the rna later, using direct-zol rna miniprep plus kit (zymo research, r ) according to the manufacturer's instructions. rna concentration was measured using a nanodrop (thermo sher scienti c, usa). various genes involved in mitochondrial biogenesis and function, telomere replication and maintenance and cellular senescence pathways were included in the custom code sets (supplementary table s ). the code set contained a total of genes including reference genes (abcf , hprt, polr b, rplp , ldha, gusb) for gene normalization (supplementary table s ). the samples were processed through the nanostring ncounter system (nanostring technologies seattle, wa, usa). a total of ng rna was submitted after adjusting the samples to a minimum of µg/µl as per the requirements. validation of gene targets using quantitative real-time pcr selected mrna, which were found to be signi cantly and differentially altered which were further validated for their expression using qpcr in samples (three samples per group) used in the study as described earlier . the primers were obtained from bio-rad, except for fen (f-cacctgatgggcatgttctac, r-ctcgcctgacttgagctgt) and s (f-gtaacccgttgaaccccatt, r-ccatccaatcggtagtagcg), used as internal control were obtained from integrated dna technologies. results were represented as pairwise comparisons to compliment the observations made by nanostring analysis. student t-test was used to determine the level of signi cance between two groups, while anova was used for multiple group comparisons. western blot analysis in human lung homogenates total protein isolated from the lung homogenates of non-smokers, smokers, copd and ipf were reduced and separated using the pre-made polyacrylamide gels (bio-rad) . the transferred membranes were probed for some of the important protein involved in the covid- , like tmprss (ab ), furin (ab ), dpp (ab ) and ace (ab ). all the antibodies used in the current study was procured from the abcam. the relative expression and equal loading as assessed using the ponceau s staining or b-actin after stripping of the blots. data processing and statistical analysis nanostring mrna counts were rst normalized using the nanostringnorm function in the statistical analysis software r on log transformed data. geometric mean of reference genes was used to remove the technique variation and background expression. differential analysis was conducted using linear models in the limma package (r/bioconductor) after adjusting for the gender difference. comparison among different experimental groups were performed using linear contrasts within the linear model framework; moderated t statistics was used to determine the differences in the gene expression levels between groups with empirical bayes approach. the benjamini-hochberg procedure was used to adjust the p values to control the false discovery rates at %. the analyzed data was represented in the graphs as y-axis showing the negative log p-value and x-axis representing log fold change across each pairwise comparisons as described previously . the signi cantly altered gene data were shown as dot plot representation in supplementary figures s - . four samples from each age group were used for comparisons among non-smokers, smokers and copd groups (as given in supplementary table s ) . comparisons with ipf includes all the samples as mentioned in the table . overall the study consisted of lung tissue samples from different sources as mentioned above. the collected tissues were classi ed into six different groups based on age, the smoking and disease status. further, comparative gene analysis was also done based on the smoking and disease status irrespective of the age. there were no genes in common that were changed in any of the comparisons involving all the three groups i.e. non-smokers, smokers and copd. however, the individual group wise comparisons were reported here. differentially expressed genes in young non-smokers versus young smokers versus young copd groups first, we analyzed differentially expressed transcript levels among young non-smokers vs. young smokers, young smokers vs. young copd and young non-smokers vs. young copd (figure ). we found genes were differentially expressed in young non-smokers vs. young smokers' pairwise comparison. out of genes, the transcript levels of genes (nfatc , nfatc , gadd a, and cdkn a) were decreased and gene (parp ) was increased in the young smokers as compared to young non-smokers group (figures and a) . next, we compared genes differentially expressed in young smokers vs. young copd pairwise comparison. out of genes, transcript levels of gene (sirt ) was decreased and the remaining genes (rad , cdkn c, cox and klotho) were signi cantly increased in young smokers as compared to young copd group (figures a and b ). finally, we found genes differentially expressed among young non-smokers vs. young copd pairwise comparison. out of genes, the transcript levels of genes cdkn c and klotho that belong to cellular senescence panel were decreased in the young copd as compared to young non-smokers group. while the transcript levels of remaining genes parp , sirt , tert and slx were increased in young copd as compared to young non-smokers group (figures a and c) . overall, genes parp , sirt , klotho and cdkn c were among the common target genes that were differentially expressed in young copd as compared to young non-smokers and young smokers groups. differentially expressed genes in old non-smokers versus old smokers versus old copd groups here we analyzed differentially expressed transcript levels among old non-smokers vs. old smokers, old smokers vs. old copd and old non-smokers vs. old copd groups. out of genes, we found genes igf , cox and rif were decreased and remaining genes nfatc , nfatc , rad and pcna were increased in old smokers as compared to old non-smokers group ( figures b and a ). the transcript levels of igf , parp , pten, nbn, hspd and rif were decreased and gar was increased in old smokers as compared to old copd group ( figures b and b ). only genes were affected among old non-smokers and old copd group; rpa and pcna were increased in old copd as compared to old nonsmokers group (figures b and c ). overall, a total of genes as mentioned above (igf , rif and pcna) were among the common targets that was found differentially expressed in old smokers as compared to old non-smokers and old copd groups. we then analyzed differentially expressed genes among young non-smokers vs. old non-smokers, young smokers vs. old smokers and young copd vs. old copd pairwise comparisons. transcript levels across different age groups were performed to better understand, whether age factor in uences the measured outcomes in the current study. accordingly, we found that genes were signi cantly elevated in young non-smokers as compared to old non-smokers group. the following are the genes that were increased among young non-smokers (pcna, nfatc , acd, gsk β, hat , ucp , cdkn a, cdkn c and sirt ) as compared to old non-smokers group (figures c and a) . although, young smokers show increased transcript levels of parp , ucp and e f genes but decreased levels of nfatc , nfatc , myc and gadd a as compared to old smokers group as seen in figures c and b . additionally, genes tnsk and pten were decreased in young copd as compared to old copd group. the transcript levels of gar , tert, h ax and fen tend to increase in younger copd as compared to old copd group (figures c and c ). interestingly, we noted that transcript levels of nfatc was decreased in lungs of old non-smokers, but increased in lungs of old smokers. we performed grouped analysis of differentially expressed transcripts (comparisons without considering the age factor (young or old) among non-smokers, smokers and patients with copd groups. data from young and old that belong to same experimental groups were combined (young nonsmokers with old non-smokers group, young smokers with old smokers group and young copd and old copd group; n= /group, as given in figures and a) . results indicated that smokers show decreased foxo and increased rad levels as compared to non-smokers group ( figure a ). while decreased parp and increased rad levels were observed in smokers as compared to copd group ( figure b ). in patients with copd klotho gene was decreased and parp and slx genes were increased as compared to non-smokers group ( figure c) . furthermore, these comparisons revealed that smokers have signi cantly higher levels of rad expression compared to both non-smokers and copd groups. whereas, copd patients showed signi cantly higher levels of parp as compared to both non-smokers and smokers groups. pairwise analysis of young non-smokers vs young ipf showed signi cantly altered genes, which were given in table . comparisons between old non-smokers and old ipf showed signi cantly altered genes, as listed in table along with their observed level of signi cance. the gene comparisons among these groups were given in figure b . altered gene expression levels in young and old copd versus ipf groups as detailed above both copd and ipf are chronic age related diseases that severely alter lung function and share certain common features for the disease occurrence and progression. here, we compared the altered gene levels related to the same pathways among copd and ipf subjects as detailed above. there was no change in any of the genes analyzed in comparisons between young ipf (n= ) and old ipf (n= ). while, genes were found to be altered in the comparisons between young (copd vs ipf), as indicated in table . a total of genes were altered in comparisons between old copd vs old ipf) as shown in table . gene expression analysis of differentially expressed targets some of the differentially expressed mrna targets predicted using nanostring were selected for qpcr study. as given in the figure the expression trends of these selected genes matches with the trend observed using the nanostring mrna analysis with varied levels of fold changes. combined gene analysis for parp was also given, and matches with the trend are given in figure . the results clearly indicate that the genes validated using qpcr are in agreement and signi cant across all the pairwise comparisons made. western blots analysis (figures and ) revealed a signi cant increase in the protein levels of tmprss protease (which plays a crucial role in the processing of the sars-cov- proteins) in copd subjects as compared to smokers and non-smokers. similarly, the levels of another important protease furin a spike protein, was also increased in smokers and copd subjects, with a signi cant expression in copd subjects. ace , which is considered crucial for the sars-cov binding as a receptor, was found to increase in smokers as compared to the rest of the groups. the samples were also further probed for the expression of dpp , another crucial protein which plays an important role in mers-cov binding. the dpp expression was found to be signi cantly higher in smokers as compared to copd and nonsmokers. these results indicate that the levels of proteases, which aid in the processing and binding of the viral spike proteins were highly expressed in copd and smokers. the expression results showed varied protein intensities in smokers and copd for tmprss and dpp in the lungs, which may suggest a varied effect of virus entry/susceptibility based on speci c cells in smokers and copd/ipf subjects.a discussion aging is a major contributor for the decline in lung function and as most of the copd are old aged, so there is a need to de ne the role of aging in uence in copd. on the other hand, smoking is one of the major contributing factors for the development of copd. copd, is commonly observed in the older subjects compared to younger ones. nonetheless there are growing evidences of young subjects with copd, which needs a thorough and careful phenotypic characterization for potential markers to understand the cause and progression of disease. the current study examined the changes in the gene expression in the normal lungs of non-smokers and smokers and patients with copd/ipf. the study included age as an in uencing factor apart from the lung disease status. the extracted rna was processed and analyzed using the sophisticated nanostring ncounter analysis platform. the nanostring has several advantages in simultaneous estimation of the several gene levels in a single sample with low amounts of sample input , . we have successfully used this platform to report the changes in gene levels using different gene set panels in our earlier studies , . in the current study, the custom designed panel included genes from three different pathways addressing the mitochondrial biogenesis and function, telomere function and cellular senescence, which play a major role in the lung in ammation and copd development. most of the chronic diseases like copd are associated with the mitochondrial dysfunctions. several reports claim the causal role of mitochondrial dysfunctions in the initiation and progression of smoking associated copd - . we have previously reported the presence of mitochondrial dysfunctions in csinduced lung damage models and in human lungs . further, we along with others have reported that telomere dysfunction is also seen in the copd patients and smoking plays as crucial role in in uencing the telomere genes , , . assessment of all these three pathway related genes in the same subjects throws light on the involvement and coordination of complex processes in smoking-related chronic lung disease such as copd. pairwise comparisons revealed that a total of genes were altered among the young and old subjects. among them some of the genes were earlier reported to be altered in smoker and copd patients. cdkn a (p ) which is a cell dependent kinase (cdk), plays a vital role in the cellular senescence and proliferation was reported to be increased in smokers and copd subjects . further, p disruption attenuated csinduced lung in ammation in mice . in the current study, there was a reduced expression in the p levels in the young smokers compared to ns in accordance with the previous reports, where cdkn c (p ), along with p was decreased in aging lungs of mice . among the other important targets klotho, sirt , parp and pcna were altered in the current study. copd patients has reduced klotho expression as compared to non-smokers, in accordance with previous reports . in similar lines parp was also elevated in the copd subjects compared to smokers and non-smokers, as reported earlier , . we have reported that tert levels were altered in mice (young and old) exposed to chronic cs . accordingly, the current results demonstrates that tert levels were signi cantly increased in copd patients, but this gene may be in uenced in a different way in humans, as younger copd patients has higher tert levels compared to older ones. nuclear factor of activated t cells c (nfatc ) levels were signi cantly higher in aged smokers as compared to younger ones. earlier reports claim that nfatc levels were increased by nicotine/smokers . it was also reported that nfatc enhances tumor-initiating phenotypes in lung adenocarcinoma . these observations were opposite in non-smokers, as they age the levels of nfatc were decreased. this suggests that nfatc may be used as a potential marker related to cs-induced lung damage. among the other important genes that were altered and are crucial in the maintenance of these three pathways are acd, which is related to tpp gene and coordinates with its function was elevated in copd , . fen could be a novel biomarker for copd which was increased in young copd as compared to old. prior studies showed mutation in fen linking lung cancer progression in an agedependent manner in mice exposed to benzo[α]pyrene which is present in tobacco smoke , . pairwise comparisons between non-smokers and ipf subjects revealed changes in some of the important genes like parp , pcna, fen , cdkn b, nfatc and gadd b, as discussed in above comparisons. however, the directionality of the changes varied between groups, which may be attributed to the small sample size in the study and the heterogeneity in the samples used. in view of the growing interests, comparisons were also made between the expression pro les of the young ipf and old ipf with their age matched copd subjects. interestingly some of the well characterized genes in ipf like nox , tnks was increased in the young ipf as compared to the young copd patients , . mitophagy is a well-known phenomenon occurring in both copd and ipf and regulates the mitochondrial related damage response towards the disease , . genes participating in the mitochondrial dynamics and other quality control mechanisms like fis and rhot were found to be decreased in young ipf compared to their age matched copd subjects. ercc (excision repair cross-complementation group ) was also found to be high in young copd as compared to ipf. earlier reports claim that ercc gene is strongly associated with copd subjects . some of the common gene targets like gadd b needs further attention and characterization especially in the chronic lung diseases like copd and ipf. recent biomarker identi cation study indicated gadd b in their list of genes that can be targeted in chronic diseases like asthma, ipf and copd . several studies indicate that the patients with underlying chronic disease conditions like diabetes, hypertension and copd are more prone to covid infections and have higher chances of the hospitalization rates and mortality , , . several crucial mechanisms and targets were reported to increases these susceptibility in these patients . in the current study, we have determined the expression of four such important protein targets reported to play an important role in sars-cov- covid- . as anticipated, copd and ipf patients in our study have higher levels of tmprss proteins in the lungs, suggesting the ideal condition for the processing of the viral protein and attachment to its receptor ace . ace receptor abundance expression was slightly increased, but was tend to be on higher side in smokers, copd and ipf subjects . furin, another crucial protease in the covid- infection was also found to be higher in smokers, copd and ipf as compared to the non-smokers. we have also assessed the levels of dpp in the same samples and found that dpp was signi cantly higher in the smokers as compared to non-smokers and copd. dpp was found to play an important role in the entry of mers-cov and acts as its receptor (belonging to the similar class of beta coronaviruses) in humans, was also suggested to play an important role in covid- infections . in agreement with recent reports , suggesting that smokers and copd have higher dpp , our ndings suggest increase in dpp in smokers, but to our surprise we didn't nd any increase in copd subjects. this may suggest a different mechanism in smokers and copd, which required further studies. nevertheless, the varied abundance of different sars-cov- covid- proteins suggest cell-speci c effects for viral entry in smokers and copd/ipf subjects. in conclusion, our study provides the novel directions in conducting the studies involving the crucial and interdependent mitochondrial, telomere and cellular senescence pathways in the same subjects in association with sars-cov- covid- proteins. whilst the study provides several differential gene expression patterns in non-smokers, smokers and copd/ipf, there is a limitation regarding the small sample size and smoking history. nonetheless the study is valuable in terms of approach and identifying a good number targets, which needs thorough characterizations in future studies. . n/a * old non-smoker samples obtained from ndri has a past smoking history. figure boxplot analysis of normalized mrna transcript analyzed by nanostring. boxplot shows distribution of normalized gene expression levels from young and old non-smokers, smokers and copd subjects. and red (decreased) colors. the green dotted horizontal line indicates the signi cance threshold of pvalues from comparisons at p < . . the benjamini-hochberg procedure was further used to adjust the p-values to control the false discovery rate at %. quantitative pcr validation of the selected genes, which were found to signi cantly and differentially altered across various pairwise comparisons. the values were deduced based -ΔΔct method. the genes represented were found to be signi cant in their pairwise comparisons (p < ). student t-test was used to compare the level of signi cance in pairwise comparisons, while anova was used for multiple comparisons. page / western blot analysis of the crucial targets involved in covid in non-smokers, smokers and copd subjects. five samples per groups were used to probe for the tmprss , furin, ace and dpp . data were shown as mean ± sem (n = /group). level of signi cance were indicated as * p < . and ** p < . across the groups. western blot analysis of the crucial targets involved in covid in non-smokers and ipf subjects. five samples per groups were used to probe for the tmprss , furin and ace . data were shown as mean ± sem (n = /group). level of signi cance were indicated as * p < . and ** p < . across the groups. this is a list of supplementary les associated with this preprint. click to download. supplementaryfigures ir.pdf the effects of aging on lung structure and function in uence of aging on lung function--clinical signi cance of changes from age aging and lung disease. clinical impact and cellular and molecular pathways chronic obstructive pulmonary disease and smoking status -united states optimizing outcomes in copd american thoracic society international conference abstracts a -a identi cation of biomarkers in common chronic lung diseases by co-expression networks and drug-target interactions analysis oxidative stress and redox regulation of lung in ammation in copd telomeres and cell senescence: implications for lung ageing and disease cigarette smoke induces cellular senescence mitochondrial dysfunction leads to telomere attrition and genomic instability mitochondrial redox system, dynamics, and dysfunction in lung in ammaging and copd impaired mitophagy leads to cigarette smoke stress-induced cellular senescence: implications for chronic obstructive pulmonary disease telomere shortening in smokers with and without copd telomere length, copd and emphysema as risk factors for lung cancer idiopathic pulmonary fibrosis: aging, mitochondrial dysfunction, and cellular bioenergetics mice with pulmonary fibrosis driven by telomere dysfunction clinical implications of telomere dysfunction in lung brosis comorbidities and chronic obstructive pulmonary disease: prevalence lung cellular senescence is independent of aging in a mouse model of copd/emphysema shelterin telomere protection protein reduction causes telomere attrition and cellular senescence via sirtuin deacetylase in chronic obstructive pulmonary disease sirt protects against emphysema via foxo -mediated reduction of premature senescence in mice role of histone deacetylase in epigenetics and cellular senescence: implications in lung in ammaging and copd copd as a disease of immunosenescence aging-and smoking-associated alteration in the relative content of mitochondrial dna in human lung mitoq counteracts telomere shortening and elongates lifespan of broblasts under mild oxidative stress aging, cell senescence, and chronic disease: emerging therapeutic strategies insu cient autophagy promotes bronchial epithelial cell senescence in chronic obstructive pulmonary disease serum from patients with chronic obstructive pulmonary disease induces senescence-related phenotype in bronchial epithelial cells smoking does not accelerate leucocyte telomere attrition: a meta-analysis of longitudinal cohorts the effect of aging on susceptibility to infection in amm-aging: why older men are the most susceptible to sars-cov- complicated outcomes covid- and immunity in aging populations -a new research agenda covid- and chronological aging: senolytics and other anti-aging drugs for the treatment or prevention of corona virus infection? the impact of copd and smoking history on the severity of covid- : a systemic review and meta-analysis prevalence of underlying diseases in hospitalized patients with covid- : a systematic review and meta-analysis sars-cov- cell entry depends on ace and tmprss and is blocked by a clinically proven protease inhibitor dpp , the middle east respiratory syndrome coronavirus receptor, is upregulated in lungs of smokers and chronic obstructive pulmonary disease patients dna methylation pro ling in peripheral lung tissues of smokers and patients with copd disease progression in young patients with copd: rethinking the fletcher and peto model protective role of mesenchymal stem cells and mesenchymal stem cell-derived exosomes in cigarette smoke-induced mitochondrial dysfunction in mice genetic ablation of histone deacetylase leads to lung cellular senescence and lymphoid follicle formation in copd/emphysema application of nanostring technologies in companion diagnostic nanostring ncounter technology: high-throughput rna validation mitochondrial dysfunction as a pathogenic mediator of chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis the role of mitochondria and oxidative/antioxidative imbalance in pathobiology of chronic obstructive pulmonary disease association of urine mitochondrial dna with clinical measures of copd in the spiromics cohort the role of p waf /cip in large airway epithelium in smokers with and without copd disruption of p attenuates lung in ammation induced by cigarette smoke, lps, and fmlp in mice age-dependent changes of p (kip ) and p (cip /waf ) expression in skeletal muscle and lung of mice klotho expression is reduced in copd airway epithelial cells: effects on in ammation and oxidant injury parp- inhibition ameliorates elastase induced lung in ammation and emphysema in mice cigarette smoke-induced autophagy is regulated by sirt -parp- -dependent mechanism: implication in pathogenesis of copd nicotine activates nuclear factor of activated t cells c (nfatc ) and prevents cell cycle entry in t cells nfatc enhances tumor-initiating phenotypes through the nfatc /sox /aldh axis in lung adenocarcinoma tpp /acd maintains genomic stability through a complex role in telomere high risk of benzo[alpha]pyrene-induced lung cancer in e d fen mutant mice reversal of persistent brosis in aging by targeting nox -nrf redox imbalance scaffold hopping approach on the route to selective tankyrase inhibitors genetic variants associated with the risk of chronic obstructive pulmonary disease with and without lung cancer ace- expression in the small airway epithelia of smokers and copd patients: implications for covid- the authors declare no competing interests. we declare that we have provided all the data in the manuscript.correspondence and requests for materials should be addressed to i.r. page / key: cord- -ft lkpzq authors: proud, david title: upper airway viral infections date: - - journal: pulm pharmacol ther doi: . /j.pupt. . . sha: doc_id: cord_uid: ft lkpzq upper airway viral infections (uri) are a major cause of absence from school and work. although morbidity is low in most of the subjects, the complications of uri, including otitis media, sinusitis and exacerbations of asthma and chronic obstructive pulmonary disease (copd) have an enormous health impact. despite the major health care consequences associated with these complications, our understanding of how uri trigger upper airway symptoms and cause exacerbations of lower airway diseases remains limited. this article reviews our current understanding of the pathogenesis of uri, and of viral exacerbations of asthma and copd, and considers host defense parameters that may regulate susceptibility to disease exacerbations. we will also consider current and potential therapeutic approaches for the treatment of uri and their lower airway complications. their complications uri, manifesting as the clinical syndrome we refer to as the common cold, is the most frequent acute respiratory illness experienced by humans. adults will experience to colds each year, while children experience to . as a result of this, according to the centers for disease control and prevention, million school days are lost annually in the united states due to colds. although common colds can be caused by a variety of different virus types, including coronaviruses, parainfluenza virus and respiratory syncytial virus (rsv), the predominant viral pathogens, particularly in the autumn season, are human rhinoviruses (hrv) [ ] [ ] [ ] . although simple colds in healthy individuals are associated with little morbidity, it has long been known that rhinovirus infections can precipitate or exacerbate other diseases, including otitis media [ ] , and sinusitis [ , ] . more recently, growing evidence also has implicated uri as the predominant risk factor associated with exacerbations of both asthma and chronic obstructive pulmonary disease (copd). in the case of asthma, there is a clear temporal relationship between increase in hospitalizations for asthma exacerbations and outbreaks of uri [ , ] , with a major spike in early september, which is the peak time for hrv infections. moreover, prospective studies using rt-pcr to assist in viral detection have demonstrated that common respiratory viruses are associated with up to % of asthma exacerbations in adults and over % of exacerbations in children [ , ] . although several viral types were found during these exacerbations, the dominant pathogen detected was hrv. hrv also was the most common viral pathogen associated with asthma attacks in young children over years of age presenting in the emergency room [ , ] . there also has been a growing appreciation regarding the important role of uri in triggering exacerbations of copd [ ] . recent studies indicate that about half of all copd exacerbations are associated with viral infections, and that hrv is, again, the dominant viral pathogen [ , ] . interestingly, respiratory viral infections are associated with copd exacerbations that are more frequent, severe and have longer recovery times [ ] . the ability of uri to serve as precipitants for exacerbations of asthma and copd has enormous consequences in terms of both health care costs and patient's quality of life. the total health care costs for asthma in the united states for the year was estimated at $ . billion [ ] , and acute exacerbations account for half of the total health care costs for the disease [ , ] . similarly, acute exacerbations of copd are a major cause of hospitalizations and death, and account for % of health care costs for the disease [ ] . moreover, exacerbation frequency is a major determinant of health status and quality of life for copd patients [ ] . despite the high incidence and serious complications of uri, the mechanisms by which viruses induce upper airway symptoms, or cause exacerbations of lower airway diseases, remain poorly understood. although it is possible that different viral types may induce these outcomes via variable mechanisms, it seems more likely that common aspects of viral pathogenesis dominate. given that hrv is the major viral pathogen associated with colds and exacerbations of asthma and copd, we will focus on the current status of our knowledge of the response to hrv infection as representative of viral pathogenesis, indicating differences with other viral types when appropriate. it is clear that uri are associated with increased airway inflammation. in particular, hrv infections lead to increased numbers of neutrophils and lymphocytes in the upper airways [ ] [ ] [ ] . hrv infections also induce neutrophilic recruitment to the lower airways in subjects with asthma [ , ] . consistent with this virally induced pattern, many acute asthma exacerbations seen in the clinical setting are characterized by increased levels of neutrophils and lymphocytes in the airways [ ] [ ] [ ] . asthmatics who display this neutrophilic profile show a poor response to inhaled corticosteroids [ ] . similarly, while stable copd is associated with a characteristic infiltration of the bronchial mucosa with cd + t lymphocytes and macrophages, severe exacerbations of copd are associated with increased neutrophilic and lymphocytic influx [ , ] . it seems reasonable, therefore, to infer that viruses may trigger exacerbations of asthma and copd by enhancing already existing inflammation in the lower airways. the mechanisms by which viral infections are able to enhance upper, and lower, airway inflammation are not fully defined, but growing evidence supports the concept that viral modulation of epithelial function may initiate the inflammatory response. the airway epithelial cell is the primary target for inhaled pathogens and expresses receptors for several viral types. indeed, the epithelial cell is the only cell type in which hrv has been detected, thus far, by in situ hybridization [ , ] , during in vivo infections. moreover, there is now strong evidence that, upon experimental nasal inoculation with hrv, virus spreads to infect epithelial cells in the lower airways [ , ] , suggesting that epithelial infection may also directly initiate lower airway inflammatory responses. in contrast to viruses such as influenza and rsv, hrv infections do not cause overt epithelial toxicity [ , ] . thus, while the cytotoxic effects of influenza and rsv may contribute to the severity of symptoms, it seems reasonable to assume that alterations of epithelial biology represent a common pathway of symptom development by multiple virus types. in support of this concept, infection of epithelial cells by hrv has been shown to generate a wide variety of proinflammatory chemokines and cytokines, including il- (cxcl ), ena- (cxcl ), ip- (cxcl ), rantes (ccl ), il- , il- and il- [ , [ ] [ ] [ ] [ ] [ ] [ ] . given that several of these products also are detected in airway secretions during hrv infections in vivo [ , , [ ] [ ] [ ] , it is likely that they contribute to recruitment and activation of inflammatory cells during infections. the ability to induce proinflammatory cytokine production from epithelial cells is also shared by other viruses. for example, influenza infection induces epithelial production of il- , il- and rantes [ ] , while rsv infections induce expression of a wide range of chemokine genes [ ] . although there is a clear potential for these chemokines and cytokines to induce inflammation, the profile of products described clearly has the capacity to recruit a plethora of inflammatory cell types to the airways. despite this, a relatively selective cellular profile is seen during infections in vivo. it is unclear what other parameters regulate this limited pattern of inflammatory cell recruitment. it also must be acknowledged that our understanding of the mechanisms by which virally induced chemokine production occurs remains limited. in the case of hrv infections, some chemokines are induced quickly after viral exposure and do not seem to require viral replication [ , ] , while other genes are not induced until several hours post-infection and are absolutely dependent upon replicating virus [ , ] . although both article in press phosphatidylinositol -kinase and mitogen activated protein kinase pathways have been implicated in viral induction of chemokines [ ] [ ] [ ] , the early signaling events induced by virus remain poorly elucidated. similarly, while the viral replication intermediate, double-stranded rna, and the rhinovirus c protease both have been implicated as mediators of late, replication dependent events [ , , ] , the pathways by which such products induce responses are not well defined. moreover, while it is clear that viral induction of some cytokines and chemokines occurs via transcriptional pathways involving nf-kb and/ or interferon regulatory factor [ , ] , our understanding of the control of transcriptional and post-transcriptional regulation of epithelial cytokine and chemokine production in response to viral infection also is limited and requires further study. delineating those aspects of signaling that may be unique for viral induction of chemokines may provide a rational basis for targeted interventions, while studies with selective chemokine or chemokine receptor antagonists will be required to provide a definitive answer on which are the key epithelial mediators involved in disease pathogenesis. once viral infection of the epithelium initiates a proinflammatory process, subsequent production of other mediators that are not of epithelial origin may further contribute to the inflammatory status of the airways. these mediators may be derived from plasma or from other cell types within the airway mucosa. of the mediators assessed thus far, some are relatively virus-specific, while others are observed with colds induced by multiple viral types. for example, while rsv infections have been reported to be associated with the generation of virus-specific ige and increased release of histamine into nasal secretions [ ] , levels of histamine are not increased in airway secretions during hrv infections [ ] . moreover, while older antihistamines that display anticholinergic and sedative properties do reduce rhinorrhea during colds, second generation antihistamines lacking these side effects are ineffective [ ] . by contrast, other mediators, such as kinins and leukotrienes have been associated with infections due to more than one type of common respiratory virus [ , [ ] [ ] [ ] . defining the role of each of these mediators in disease pathogenesis will, again, require studies with effective and selective antagonists. several factors are likely to play a role in determining the severity of the clinical outcome to upper airway viral responses, including the susceptibility of patients with asthma or copd to experience lower airway exacerbations. such factors include pre-existing immunity to a particular viral strain and, in the case of lower airways, the degree of disease control at the time of infection. another important factor is likely to be the variability of the individual host immune and antiviral response to infection. although both innate and specific immunity contribute to the host response to infection, it appears as though the innate response is dominant early after infection and is more likely to help regulate the symptomatic response. for example, while hrv infections elicit antigen-specific humoral and cellular immune responses, these are usually not detectable until after disease symptoms have resolved [ ] . as may be expected based on its central role in viral infection, the epithelial cell is a significant contributor to the innate response to infection. as noted above, infected cells release several cytokines and chemokines that can recruit, and activate, cells of the immune system to the airways. in addition, epithelial production of nitric oxide (no) appears to play an important role in host antiviral responses [ ] . infection of cultured epithelial cells with any of several common respiratory viruses leads to marked upregulation of inducible nitric oxide synthase (inos) and increased generation of no. a similar response occurs during experimental hrv infections in vivo, in that levels of epithelial inos induction correlate with levels of exhaled no. interestingly, in this study, subjects with the highest levels of exhaled no cleared virus more rapidly and had lower symptoms [ ] . a rationale for this is provided by several studies showing that no exerts direct antiviral activity against several common respiratory viruses, in part by nitroslyating key thiol residues in viral proteases. moreover, it has been shown that no also inhibits virally induced generation of several cytokines and chemokines from epithelial cells [ ] . it also should be noted that infection of epithelial cells with hrv induces the production of human b-defensin- (hbd- ) and hbd- [ ] . these peptides are chemotactic for immature dendritic cells expressing ccr , as well as other cell types contributing to the immune response, and likely play an important role in linking innate and specific immunity to hrv [ ] . hbd- also can reduce the extent of influenza infections by blocking the fusion of the virus with cell membranes [ ] . as viral replication progresses, and intact virus is released into airway secretions, it can interact with other cell types that may further contribute to the immune response. presumably, for example, dendritic cells initiate antigen presentation to t cells in the airways or lymph nodes to initiate the specific immune response. in addition, monocytes and macrophages may release additional cytokines, including interferons that can stimulate a variety of interferon (ifn)-stimulated genes (isgs) that collectively limit virus replication and spread. traditional approaches to mitigate the effects of uri have focused on symptomatic relief, although such approaches have generally had modest success. the topical anticholinergic, ipratropium bromide reduces rhinorrhea, an effect mimicked to some degree, as noted above, by older ''first generation'' antihistamines that are known to also have anticholinergic properties. similarly oral adrenergic drugs have modest benefit in terms of reducing nasal blockage, while topical agents have a greater efficacy but suffer from issues of rebound [ ] . a somewhat greater reduction in total symptoms was observed in experimental hrv infections when a combination of ifn-a b, together with the first generation antihistamine, chlorpheniramine, and ibuprofen was administered beginning h after viral challenge [ ] . although this represents an important proof of concept regarding the effectiveness of combining an antiviral compound with conventional compounds for symptomatic relief, the practical utility of this combination is limited by cost factors. there is also a growing literature on the use of ''natural' remedies for the treatment of colds. although the rationale for the use of zinc in the treatment of colds is not well established, multiple studies have evaluated the effectiveness of various zinc salts in this regard. overall, the results of these studies have been inconclusive. a recent, wellcontrolled trial, however, found that zinc salts had an extremely modest effect in reducing symptoms of experimental hrv infections and was ineffective in natural colds [ ] . similarly, echinacea and ginseng have been widely reported as herbal remedies for colds. most of the trials to evaluate such agents have been small and have generated conflicting data. recent randomized trials with relatively large number of subjects reported modest efficacy of a ginseng extract in reducing the frequency of natural colds [ ] , but found no significant effect of an extract of echinacea in experimental hrv infections [ ] . a major issue in regard to trials of herbal remedies, of course, is that there is no standardization of extracts used across studies. indeed, given that the identity of any proposed ''active'' ingredient is unknown, it is impossible to know what to standardize. all of the above trials have been limited to analyzing effects on nasal symptoms, and have never evaluated effects on viral exacerbations of asthma or copd. given the data reported, however, it seems unlikely that they will provide any major benefit. indeed, an interesting question is whether drugs that are currently used for the treatment of asthma and copd have any beneficial effects during viral exacerbations. there is no doubt that the use of corticosteroids, long acting b-agonists, or leukotriene receptor antagonists, alone or in combination, to maintain optimal asthma control has proven efficacious in reducing number of asthma exacerbations, and the use of oral corticosteroids early in exacerbations helps prevent relapses. effects on basal inflammation, however, may not necessarily translate to effects on viral-specific inflammation, and there have been no defined studies of the effects of these medications during asthma or copd exacerbations of known viral origin. corticosteroids have little efficacy in hrv-induced colds [ ] , and it is of interest that asthmatics who display prominent sputum neutrophilia, perhaps indicative of viral etiology, are poorly responsive to inhaled corticosteroids [ ] . because of these limitations, alternative therapeutic approaches to virally induced airway disease continue to be sought. an obvious strategy is to use antiviral approaches. influenza vaccine is clearly effective in reducing upper airway symptoms, and in preventing lower disease exacerbations, induced by this virus during the winter months. unfortunately, vaccination approaches are not feasible for hrv, given the large number of viral serotypes, and have, thus far, proven unsuccessful in the case of rsv infections. neutralizing antibody prophylaxis has proven effective in preventing rsv-induced bronchiolitis but cost factors limit a broader utility and, again, major feasibility issues would arise with using this approach for hrv. selective antiviral approaches have shown more promise. in the case of influenza, neuraminidase inhibitors have been available for several years and have proven clinical efficacy in reducing development and severity of symptoms. at least two approaches also have been used to develop potential antiviral agents against hrv. the novel capsid-binding inhibitor, pleconaril, prevents viral uncoating. in natural colds, oral pleconaril ( mg) administered three times daily led to a significant, but modest reduction in symptoms and also shortened the reported duration of colds [ ] . concerns regarding effects on cytochrome p a , however, precluded further development as an oral treatment. the alternative antiviral approach used for hrv infections has targeted inhibition of the viral c protease, which is necessary for cleavage of the viral polyprotein and, thus, replication. topical administration of one c inhibitor, ruprintrivir, significantly inhibited symptoms in experimental hrv infections even when administered beginning h after infection, although multiple daily dosing was required [ ] . neither of these drugs has been evaluated for their ability to limit hrvinduced exacerbations of lower airway diseases. upper respiratory tract viral infections and their complications lead to a significant burden on health care systems throughout the world. current treatments are less than ideal, and a greater insight into the molecular basis by which common viruses induce both upper and lower airway symptoms is needed if alternative therapeutic approaches are to be developed rationally. the delineation of which specific cytokines and chemokines are key contributors to disease pathogenesis, and elucidation of signaling pathways selective for viral modulation of epithelial cell function may identify novel targets for therapy. alternatively, endogenous enhancement of key host antiviral and host defense molecules, or the topical administration of such molecules may provide alternative approaches to reduce the sequelae of viral infection. upper respiratory viral infections (uri) and their complications rhinovirus infections in an industrial population. i. the occurrence of illness the tecumseh study of respiratory illness. ii. pattern of occurrence of infection with respiratory pathogens, - frequency and natural history of rhinovirus infections in adults during autumn rhinovirus in otitis media with effusion physiologic abnormalities of the paranasal sinuses during experimental rhinovirus colds computed 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preventing upper respiratorytract infections: a randomized controlled trial an evaluation of echinacea angustifolia in experimental rhinovirus infections a randomized controlled trial of glucocorticoid prophylaxis against experimental rhinovirus infection efficacy and safety of oral pleconaril for treatment of colds due to picornaviruses in adults: results of double-blind, randomized, placebo-controlled trials phase ii, randomized, double-blind, placebo-controlled studies of ruprintrivir nasal spray -percent suspension for prevention and treatment of experimentally induced rhinovirus colds in healthy volunteers key: cord- -vetdsk authors: woodfork, karen title: bronchitis date: - - journal: xpharm: the comprehensive pharmacology reference doi: . /b - - . - sha: doc_id: cord_uid: vetdsk bronchitis is characterized by bronchial inflammation that results in … bronchitis is characterized by bronchial inflammation that results in cough and sputum production. this inflammation can be acute in nature, usually resulting from a viral infection, or it may be a long-standing manifestation of chronic obstructive pulmonary disease. acute infectious bronchitis differs from chronic bronchitis with respect to etiology, pathophysiology, and treatment. acute bronchitis is among the most frequent reasons for visits to the physician's office. it can be defined as an infectious, generally viral, respiratory illness that last for - weeks that occurs in an otherwise healthy adult with cough as the predominate feature gonzales and sande ( ) . in addition to cough and usually sputum production, acute bronchitis frequently involves upper respiratory symptoms and constitutional complaints, such as fatigue and body aches. an illness comprised of these symptoms may be classified as acute bronchitis once the diagnosis of pneumonia is excluded. as a form of chronic obstructive pulmonary disease (copd), chronic bronchitis is characterized by irreversible or incompletely reversible airway obstruction that produces a decrease in maximal expiratory airflow chitkara and sarinas ( ) . the definition of chronic bronchitis is symptomatic. that is, it is a condition that results in a mucusproducing cough that is present for at least months of the year for consecutive years and does not have some other underlying etiology such as tuberculosiswisniewski ( ) . depending on its severity, chronic bronchitis may produce minimal to significant functional impairment. acute bronchitis is a form of lower respiratory tract infection gonzales and sande ( ) . although an etiology is formally identified in only a small percentage of clinical cases, the identity of the disease-producing organism may be used to classify acute bronchitis. chronic bronchitis is the most common form of chronic obstructive pulmonary disease (copd), a group of conditions involving airway obstruction, decreased maximal expiratory airflow, and breathing-related symptoms. emphysema, or destruction of the alveoli, is the other major manifestation of copd chitkara and sarinas ( ) . nonremittant asthma, involving bronchoconstriction that is irreversible or only partially reversible, may also be classified as cop d. it is not unusual for individuals to experience combined forms of copd involving sputum production, alveolar destruction, and bronchospasm. copd can be classified on the basis of severity pauwels et al ( ) . stage (at risk) is characterized by normal spirometric readings and the presence of chronic cough and/or sputum production. stages i, ii, or iii copd is present if the forced expiratory volume in second divided by the forced vital capacity (fev /fvc) is less than %. chronic both acute and chronic bronchitis give rise to a persistent, sputum-producing cough. bronchial hyperresponsiveness, wheezing, and difficulty breathing (dyspnea) may occur, and difficulty breathing upon exercise (exertional dyspnea) is fairly common. in most cases of acute bronchitis, the symptoms of cough and sputum production last for to weeks gonzales and sande ( ) . infections such as otitis media, sinusitis, and, more rarely, pneumonia may result from either the primary viral infection or a secondary bacterial infection. acute bronchitis resulting from influenza may additionally produce more rare complications of muscular inflammation (myositis) and muscle cell lysis leading to potentially fatal renal damage (rhabdomyolyisis). additional consequences of acute bronchitis are seen in children. reye syndrome may occur in children with influenza, particularly if they are treated with aspirin. viral lower respiratory infection in early life has been associated with the later development of asthma gern ( ) . in contrast to acute bronchitis, which resolves following the termination of the causative infection, chronic bronchitis generally worsens with time, even with optimal treatment chitkara and sarinas ( ) . cessation of exposure to a triggering stimulus, such as tobacco smoke, is the only currently available therapeutic management that can slow the progression of chronic bronchitis. usually, by the time treatment is sought, there is irreversible damage to the lungs. progression of chronic bronchitis leads to shortness of breath, initially manifesting only during exercise but also occurring at rest as the disease worsens. increasing pulmonary dysfunction can result in pulmonary hypertension, right ventricular enlargement, and right-sided heart failure (cor pulmonale). signs of cor pulmonale include peripheral edema, enlargement of the liver and other internal organs, and increased breathing difficulty. weight loss may occur, and muscle wasting can contribute to the development of exercise intolerance. an individual affected with chronic bronchitis is susceptible to repeated episodes in which the symptoms of cough, sputum production, and dyspnea worsen mccrory et al ( ) . these episodes, termed acute exacerbations of chronic bronchitis, may result from viral or, more rarely, bacterial infection. environmental exposure to tobacco smoke, air pollutants, or allergens may also produce acute exacerbations of chronic bronchitis. the cause of approximately one-third of acute exacerbations is unknown. immunocompromised individuals, persons with comorbid conditions, such as diabetes, cardiovascular disease, pulmonary disease, and alcoholics gonzales and sande ( ) . these individuals are also at higher risk of developing complications of acute bronchitis, such as pneumonia. chronic bronchitis is the most common form of chronic obstructive lung disease (copd), with emphysema (alveolar destruction) being the next most frequently observed manifestation. nonremittant asthma may also be classified as cop d. it is common for individuals with copd to exhibit characteristics of chronic bronchitis, emphysema, and/ or bronchospastic disease. individuals with copd are more susceptible to lower respiratory infections such as acute bronchitis and pneumonia ward and casaburi ( ) , chitkara and sarinas ( ) . in more advanced disease, they may develop pulmonary hypertension, resulting in right ventricular enlargement and, as the disease progresses, right-sided heart failure (cor pulmonale). acute bronchitis is usually caused by viruses associated with lower respiratory tract infections, including influenza a and b, parainfluenza, respiratory syncytial virus, and human metapneumovirus and upper respiratory tract infections, such as rhinovirus, corona virus, and adenovirus bandi et al ( ) . the most common cause of acute bronchitis is influenza, with a much smaller percentage of acute bronchitis cases resulting from bacterial infection. chlamydia pneumoniae has been responsible for several recent outbreaks, particularly in young adults. bordetella pertussis may cause atypical symptoms resulting in prolonged cases of acute bronchitis in previously immunized adults. mycoplasma pneumoniae is an additional established etiologic agent of acute bronchitis. there is very little evidence that acute bronchitis may be caused by bacterial species that are characteristic of pneumonia infections (e.g., streptococcus pneumoniae). chronic bronchitis most frequently develops in tobacco smokers, approximately - % of whom eventually show symptoms of this disorder viegi ( ) . passive exposure to smoke can also contribute to the development of chronic bronchitis. other causative factors include exposure to indoor or outdoor air pollution, occupational dusts (e.g., grain, coal), or chemical irritants (e.g., sulfur dioxide). chronic bronchitis may also develop in people with a history of recurrent lung infections or airway hyperresponsiveness hogg ( ) . acute exacerbations of chronic bronchitis are commonly associated with influenza, parainfluenza, coronavirus, or rhinovirus infections mccrory et al ( ) . elevated levels of particulate air pollution and ozone are also associated with acute exacerbations. the role of bacterial infection in acute exacerbation of chronic bronchitis remains controversial. pathogenic bacterial such as haemophilus influenzae, streptococcus pneumoniae, and moraxella catarrhalis are present in the sputum of approximately half of all those experiencing acute exacerbations but are also frequently present during periods of stable disease hirschmann ( ) . clinical trials have shown that antibiotic therapy is helpful in % or less of those with acute exacerbations. however, in the subset of exacerbations in which purulent sputum is a predominant feature, the extent of bacterial eradication correlates with the degree of resolution of the exacerbation and its associated inflammation white et al ( ) . thus, an increase in bacterial load, acquisition of a new bacterial pathogen, or a change in the antigenic makeup of the resident bacterial population, may be responsible for certain acute exacerbations of chronic bronchitis. the role of bacterial infection in the progression of chronic bronchitis is unclear wilson ( ) . acute bronchitis is a widespread condition that usually occurs in outbreaks and epidemics, especially during the winter months. its incidence is approximately - cases per , persons per year file ( ) . an elevated risk for the development of acute bronchitis is seen among the very young and the elderly, smokers, immunocompromised individuals, persons with comorbid conditions, such as cardiovascular or pulmonary disease, and alcoholics. such individuals are also at increased risk for developing complications such as pneumonia. chronic bronchitis and emphysema are related manifestations of chronic obstructive pulmonary disease (copd) and often coexist in an individual. according to the national health interview survey, . million americans have been diagnosed with chronic bronchitis, million with emphysema, and . million with both barnes et al ( ) . in the us, copd is the primary cause of death for over , people a year. a large number of cases may be undiagnosed, as a recent survey involving the direct measurement of pulmonary function suggests that nearly million individuals in the us suffer from copd mannino et al ( ) . chronic bronchitis is most commonly seen in individuals over the age of . it is more common in women than men across all age groups and may be more severe in women barnes et al ( ) . in the - and + age groups, it is more common in whites than blacks, whereas the reverse is true in the - age group. the most significant risk factor for the development of chronic bronchitis is cigarette smoking, with morbidity and mortality increasing in proportion to the extent and duration of smoking viegi ( ) . occupational exposures to dusts (e.g., coal, grain, and cadmium and other heavy metals) and industrial chemicals (e.g., isocyanates, certain adhesives, and welding fumes) also pose significant risk for the development of chronic bronchitis. environmental tobacco smoke and air pollution are also associated with an increased risk of developing copd. a history of childhood respiratory infections correlates with an increased risk of copd hogg ( ) . latent infection with adenovirus may enhance the inflammatory response to environmental causes of chronic bronchitis, as may infection with the ulcerogenic bacterium helicobacter pyloriroussos et al ( ) . colonization of the lower airways with haemophilus influenzae, a pulmonary pathogen, may be associated with chronic bronchitis and its acute exacerbations wilson ( ), bandi et al ( . host factors are also involved in the development of cop d. low socio-economic status, high alcohol consumption, and a tendency toward atopic allergic reactions and hypersensitivity are associated with copd viegi ( ) . low dietary intake of fresh fruit and vegetables, antioxidants such as vitamin c and beta-carotene, fish, and omega- fatty acids has also been associated with impaired lung function romieu and trenga ( ) . an inherited deficiency in alpha- antitrypsin (alpha- proteinase inhibitor) results in earlyonset emphysema viegi ( ) . genetic factors may also be involved in the development of chronic bronchitis in general. the signs and symptoms of acute bronchitis result from the pathogen itself and from the immune response to the infection. the acute phase of this illness lasts from - days and involves constitutional symptoms such as fever, fatigue, and muscle aches gonzales and sande ( ) , balter ( ) . it is during this phase that viral colonization of the tracheobronchial epithelium occurs. in response to this infection airway epithelial cells and resident monocytes and macrophages release cytokines that recruit and activate immune cells. infection with influenza a virus provides an example of this process. influenza a infection stimulates the release of chemotactic chemokines including rantes, monocyte chemotactic protein- (mcp- ), and macrophage inflammatory protein- alpha (mip- alpha), pro-inflammatory cytokines such as tumor necrosis factor-alpha (tnf-alpha), interleukin- beta, (il- beta), il- , and il- , and antiviral cytokines such as interferon-alpha (ifn-alpha) and ifn-betajulkunen et al ( ) . neutrophils are among the first cells recruited to the tracheobronchial epithelium, and their increased number correlates with the development of airway hyperresponsiveness. t lymphocytes are recruited and activated by rantes and other cytokines released by monocytes. eosinophils are recruited and activated and may persist for weeks after the initial infection. the protracted phase of acute bronchitis involves coughing, wheezing, and sputum production and lasts from - weeks. it frequently involves a significant decline in pulmonary function that can be measured as a decrease in the forced expiratory volume inn second (fev ). the bronchial hyperresponsiveness, which was initiated during the acute phase, persists for several weeks and correlates with the extended presence and activation of inflammatory cells. the pathological hallmark of chronic bronchitis is airflow limitation secondary to inflammation and increased mucus production in the large (> mm) airways. the disease process begins when damage to the airways initiates inflammation and remodeling of the airway epithelium, leading to mucus hypersecretion, obstruction of the airways, and increased susceptibility to bacterial colonization macnee ( ), turato et al ( ) , cosio- piqueras and cosio ( ) . the presence of pathogenic bacteria in the lung is a common cause of acute exacerbations of chronic bronchitis and may also be related to disease progression. an ongoing cycle ensues in which inflammation and infection produce further epithelial damage, which perpetuates additional inflammation and airway remodeling. chronic bronchitis is initiated when repeated exposure to tobacco smoke, environmental lung irritants (e.g., coal or grain dust, air pollutants), and/or respiratory infections produce damage in the large airways. recruitment of inflammatory cells results from upregulation of adhesion molecules such as icam- and e-selectin on the subepithelial blood vessels. neutrophils are the predominant cell type recruited into the lumen of the airways. macrophages and cd + t lymphocytes are the predominant cells that infiltrate the subepithelial space. eosinophils are prevalent in the subepithelium during acute exacerbations of chronic bronchitis, while large numbers of neutrophils are seen here only in severe disease. while enlargement of the mucous glands was formerly believed to a defining feature of chronic bronchitis, it is now believed that inflammation of these glands is more characteristic. inflammatory cells in the airway lumen and epithelium release mediators that control the inflammation and airway remodeling that is characteristic of chronic bronchitis reid and sallenave ( ) . neutrophils release reactive oxygen species such as superoxide and peroxynitrite that produce tissue damage and further inflammation. elevated levels of pro-inflammatory molecules, such as il- , ltb , and tnf-alpha, and diminished levels of the anti-inflammatory cytokine il- are seen in the sputum of individuals with chronic bronchitis. elevated levels of the mucus-stimulating cytokines il- and il- are seen in patients with chronic bronchitis. neutrophils in the airways release neutrophil elastase, a serine protease that increases the production of mucus and stimulates the proliferation of mucus-producing goblet cells. squamous metaplasia occurs, resulting in the replacement of many ciliated columnar epithelial cells with squamous epithelial cells. overall, these processes of excessive bronchial mucus secretion and impaired clearance result in airway obstruction, irritation, and an increased likelihood of infection. many similarities exist between the processes occurring in the large and small (< mm) airways of those with chronic bronchitis. subepithelial infiltration of cd + t lymphocytes and goblet cell proliferation contribute to inflammation and mucus secretion, respectively. in addition, fibrosis of the airway walls decreases the elastic recoil of the lung, while hypertrophy of the bronchiolar smooth muscle produces airflow restriction. attachments of the alveoli to the bronchioles may be lost as well. in the pulmonary arteries, chronic bronchitis causes proliferation of smooth muscle cells and deposition of elastic and collagen fibers turato et al ( ) . this appears to be the result of endothelial dysfunction that results from hypoxemia or other, unknown factors. pulmonary hypertension occurs as a consequence of pulmonary artery narrowing, and the right ventricle may become enlarged as a result of prolonged pumping against elevated arterial pressure. right ventricular failure (cor pulmonale) is a common complication of chronic bronchitis. the initial, acute phase of acute bronchitis begins with - days of constitutional symptoms such as fever, malaise, and muscle aches gonzales and sande ( ) . these symptoms are variable in extent and duration, and depend upon the nature of the infectious agent. for example, rhinovirus infection produces minimal or no constitutional symptoms whereas influenza and parainfluenza produce the most severe and prolonged symptoms. the protracted phase of acute bronchitis lasts for - weeks and involves coughing, increased sputum production, and wheezing. acute bronchitis is distinguished from upper respiratory infections by the presence of cough, sputum, and wheezing with the former. the signs and symptoms of acute bronchitis differ from those of pneumonia in that pneumonia causes abnormal lung sounds that indicate the presence of fluid (e.g., rales) and elevations in vital signs (heart rate > beats/minute, respiratory rate > breaths/minute, and temperature > c). while pneumonia can be confirmed with radiography, this is unwarranted in low-risk individuals who have elevated vital signs without abnormal lung sounds, particularly during a known viral outbreak. x-ray testing in the absence of abnormal lung sounds may be necessary in the elderly and in those with co-morbidities that place them at high risk of pneumonia and other complications. chronic bronchitis is a manifestation of chronic obstructive pulmonary disease (copd) involving cough and sputum production, with or without wheezing, that lasts for at least months for consecutive years chitkara and sarinas ( ) . it most frequently appears in smokers over the age of and is associated with acute exacerbations in which coughing, wheezing, and sputum production are increased. persons with chronic bronchitis are at increased risk of developing pneumonia and other respiratory infections. significant difficulty breathing during exercise, and, as the disease progresses, also at rest usually manifest during the mid-sixties to early seventies. spirometric measurement of the forced expiratory volume in second (fev ) and the forced vital capacity (fvc) may be used to assess pulmonary function and to stage the severity of copd pauwels et al ( ) , lenfant and khaltaev ( ) . a complete blood count can be used to rule out infection and may reveal an elevation in red blood cells resulting from chronic hypoxemia (polycythemia). a sputum culture may be used to check for acute infection. a chest x-ray can be performed to exclude other causes of cough such as pneumonia and lung cancer. in severe cases of chronic bronchitis, radiography may reveal right ventricular hypertrophy as well as enlargement and rapid tapering of the pulmonary arteries. if emphysema is present as well, each region of severe disease will be visible as a radiolucent area surrounded by a hairline shadow. acute exacerbations of chronic bronchitis are associated with worsened dyspnea and increased sputum production and purulence. acute exacerbations can be classified as severe (type ) if all three symptoms are present and moderate (type ) if two of the three are present mccrory et al ( ) . a mild exacerbation is diagnosed if one of the above symptoms occurs along with at least one indicator of recent respiratory infection (e.g., fever, cough, and wheezing). because of its predominantly viral nature, acute bronchitis is best treated symptomatically, unless an influenza etiology is established and antiviral treatment is initiated early enough to ensure effectiveness. antibiotics are useful in cases where bacterial infection is confirmed. the medications available for the treatment of chronic bronchitis/chronic obstructive pulmonary disease (copd) do not decrease the progressive decline in respiratory function that is characteristic of this condition. rather, they only lessen its symptoms and their complications. the only intervention that slows the progression of copd is decreased exposure(s) to substances that worsen this condition such as tobacco smoke, occupational dusts and chemicals, and air pollutants. smoking cessation is the most significant intervention that has the potential to slow the progression of chronic obstructive pulmonary disease chitkara and sarinas ( ) . pharmacological therapy for tobacco dependence is added to counseling to increase the likelihood of success. nicotine replacement therapy is most commonly given as a transdermal patch, with nicotine gum, nasal spray, inhaler, or lozenge used to counteract breakthrough cravings. smoking cessation is more likely to succeed when nicotine replacement therapy is used in combination with the antidepressant bupropion. with this combination, nicotine is gradually withdrawn while bupropion is maintained for months or longer. those with acute bronchitis frequently exhibit wheezing and other signs of reversible bronchoconstriction. although chronic obstructive pulmonary disease is characterized by bronchoconstriction that is incompletely reversible following administration of a bronchodilator, long-term therapy with bronchodilators decreases the symptoms of airflow limitation in individuals with chronic bronchitis. thus, bronchodilator therapy is central to the management of chronic bronchitis and its acute exacerbations chitkara and sarinas ( ) . inhalation is the preferred route of administration because it maximizes the delivery of the agent to the lungs and minimizes systemic side effects. short-acting beta- adrenoceptor agonists such as albuterol produce rapid bronchodilation by action on the beta- adrenoceptors on the airway smooth muscle. anticholinergics are the preferred drugs for the treatment of acute bronchitis smuncy et al ( ) . in the treatment of chronic bronchitis, beta- adrenoceptor agonists may be used on a scheduled basis or as-needed to treat acute bronchospasm. beta- adrenoceptor agonists are also used in the treatment of acute exacerbations of chronic bronchitis mccrory et al ( ) . the efficacy of long-acting beta- adrenoceptor agonists such as salmeterol is under study. the bronchodilatory effect of anticholinergics is additive with that of beta- adrenoceptor agonists. combination products that deliver a metered dose of a beta- adrenoceptor agonist and ipratropium can simplify drug administration. those with acute bronchitis frequently exhibit wheezing and other signs of reversible bronchoconstriction. although chronic obstructive pulmonary disease is characterized by bronchoconstriction that is incompletely reversible following administration of a bronchodilator, long-term therapy with bronchodilators decreases the symptoms of airflow limitation in individuals with chronic bronchitis. thus, bronchodilator therapy is central to the management of chronic bronchitis and its acute exacerbations chitkara and sarinas ( ) . inhalation is the preferred route of administration because it maximizes delivery of the agent to the lungs and minimizes systemic side effects. anticholinergic bronchodilators such as ipratropium block the muscarinic receptormediated bronchoconstriction, mucus secretion, and bronchial vasodilation that result from vagal stimulation of the airways. the duration of action of ipratropium is longer than that of the short-acting beta- adrenoceptor agonist bronchodilators. it can decrease the volume of sputum produced without altering its viscosity. an ipratropium inhaler may be used in acute bronchitis where bronchospasm is problematic smuncy et al ( ) . in chronic bronchitis, ipratropium is a mainstay of therapy chitkara and sarinas ( ) . some individuals who are nonresponsive to beta- adrenoceptor agonists derive symptomatic relief with ipratropium. the bronchodilatory effect of ipratropium is additive with that of beta- adrenoceptor agonists. combination products that deliver a metered dose of a beta- adrenoceptor agonist and ipratropium can simplify drug administration. although chronic obstructive pulmonary disease is characterized by bronchoconstriction that is incompletely reversible following administration of a bronchodilator, long-term therapy with bronchodilators decreases the symptoms of airflow limitation in individuals with chronic bronchitis. thus, bronchodilator therapy is central to the management of chronic bronchitis and its acute exacerbations chitkara and sarinas ( ) . theophylline exerts a wide variety of physiological actions including central nervous system stimulation, cardiac stimulation, and smooth muscle relaxation. its major action on the lung results from the inhibition of the cyclic nucleotide phosphodiesterases that break down cyclic amp and cgmp, second messengers that mediate bronchodilation. theophylline also inhibits the release of inflammatory mediators by immune cells. its narrow therapeutic index, potentially life-threatening side effects, and numerous drug interactions have made theophylline a second-line therapy for chronic bronchitis. while its efficacy as compared to other bronchodilators is questionable, a subset of patients appears to benefit from theophylline. lower therapeutic doses used in combination with a beta- adrenoceptor agonist may be beneficial in some cases. oxygen oxygen therapy is indicated when the symptoms of chronic obstructive pulmonary disease (copd) become severe enough to limit activities of daily living chitkara and sarinas ( ) . it may also be used as-needed during exercise in those who don't qualify for continuous oxygen use. oxygen therapy reduces mortality and improves quality of life in persons with severe cop d. it is also useful in the management of acute exacerbations of chronic bronchitis mccrory et al ( ). antibiotics although antibiotics are frequently prescribed for acute bronchitis, most cases are viral in origin, rendering them useless. antibiotic therapy does not decrease the duration of illness, limitation of activities, or loss of work time in most cases of acute bronchitis fahey et al ( ), smuncy et al ( , bent et al ( ) . thus, the frequency of antibiotic use can safely be reduced without affecting patient outcomes gonzales et al ( ) . in the rare cases in which acute bronchitis is caused by mycoplasma pneumoniae or chlamydia pneumoniae, fluoroquinolones, tetracycline, and macrolides are effective gonzales and sande ( ) . acute bronchitis caused by bordetella pertussis may be treated with erythromycin, but it is only effective early in the course of illness. the role of bacterial infection in acute exacerbation of chronic bronchitis remains controversial. in those exacerbations in which purulent sputum is a predominant feature, the extent of bacterial eradication correlates with the degree of resolution of inflammation associated with the exacerbation white et al ( ) . the united states national heart, lung, and blood institute and the world health organization recommended that antibiotics be given for acute exacerbations in which there is evidence of infection, e.g. increased sputum production, change in sputum color, and/or fever pauwels et al ( ) . commonly used antibiotics include amoxicillin-clavulanate, azithromycin, and several cephalosporins and fluoroquinolones. although glucocorticoids are frequently employed in the therapy of chronic bronchitis, their use is controversial chitkara and sarinas ( ) . glucocorticoids block immune cell activation, cytokine release, and mucus secretion in vitro, yet only - % of individuals with chronic obstructive pulmonary disease actually respond to them. it is impossible to predict who will respond to glucocorticoids. indeed, those who benefit from oral glucocorticoids during acute exacerbations may not realize any value from chronic inhaled glucocorticoid use. systemic glucocorticoids (e.g., prednisolone) are used for the treatment of acute exacerbations of chronic bronchitis and can alleviate symptoms, decrease hospitalization time, and reduce relapse rate among steroid-responsive individuals mccrory et al ( ) . chronic treatment with inhaled glucocorticoids such as fluticasone produces a modest reduction in the incidence of acute exacerbations, with no impact on the rate of functional decline. the united states national heart, lung, and blood institute and the world health organization recommend long-term maintenance therapy with inhaled glucocorticoids in symptomatic patients who exhibit a documented spirometric response to glucocorticoids or who have an fev- of < % of predicted and suffer from repeated exacerbations requiring antibiotic or glucocorticoid therapy pauwels et al ( ) . systemic glucocorticoids should be used in the management of acute exacerbation, but chronic treatment should be avoided due to the potential for severe adverse effects. because influenza vaccines significantly decrease morbidity and mortality in persons with chronic bronchitis, annual influenza vaccination is recommended pauwels et al ( ) . the pneumococcal vaccine has been used in patients with chronic bronchitis, but there are insufficient data to support its general use for this purpose. non-steroidal antiinflammatory drugs non-steroidal antiinflammatory agents such as ibuprofen and antipyretic pain relievers, such as acetaminophen, may be used to lessen the symptoms of the acute phase of acute bronchitis (e.g., fever, muscle aches) gonzales and sande ( ) . in cases of acute bronchitis caused by influenza a, amantadine or rimantadine may be effective if given within hours of the onset of symptoms gonzales and sande ( ) . these drugs block the proton channel required for the dissolution of the viral ribonucleoprotein complex early in the process of replication. zanamivir and oseltamivir are effective against influenza a and b and, like amantadine and rimantadine, must be taken within the first hours of illness. these drugs inhibit neuraminidase, a viral surface glycoprotein involved in the release of progeny virus and in the spread of infection from cell to cell. a large number of experimental therapies are under development for the treatment of chronic obstructive pulmonary disease. with the exception of novel antiinfective agents and the anticholinergic bronchodilator tiotropium, there are few experimental therapies under development for the treatment of acute infectious bronchitis. mucolytic agents because mucus hypersecretion and impaired mucociliary clearance are characteristic of chronic bronchitis, attempts are being made to speed the transport of mucus up the bronchiotracheal tree wegner ( ) . oral expectorants such as guaifenesin are of little benefit in chronic obstructive pulmonary disease. n-acetylcysteine is an orally administered glutathione precursor that reduces the sulfhydryl bonds of mucus proteins. it has been shown to thin the sputum without producing significant improvement in pulmonary function. preliminary studies suggest that n-acetylcysteine may reduce the frequency of acute exacerbations, an action that may be related to its efficacy as an antioxidant. heliox heliox is a mixture of helium and oxygen that changes pulmonary airflow from turbulent to laminar. it has been shown to decrease the work of breathing in severe, stable, chronic obstructive pulmonary disease and may potentially be useful in the treatment of acute exacerbations of chronic bronchitis chitkara and sarinas ( ) , rodrigo et al ( ) . phosphodiesterase- (pde- ) is a cyclic amp-specific phosphodiesterase that predominates in pro-inflammatory and immune cells. cilomilast is a new, orally active, selective inhibitor of pde- . initial studies of cilomilast revealed significant functional improvement of chronic obstructive pulmonary disease (copd) with minimal side effects giembycz ( ) . there is a significant decrease in the number of cd + and cd + inflammatory cells characteristic of copd without alteration of sputum values or fev- gamble et al ( ) . tiotropium is an inhaled anticholinergic that is available in europe and is pending fda approval in the united states barnes ( ) . it exhibits very slow dissociation from m- muscarinic receptors and m- muscarinic receptors, allowing it to provide once-daily dosing and a greater degree of stability in lung function than ipratropium. tiotropium may be useful in acute or chronic bronchitis. leukotriene b- (ltb- ) is a mediator of neutrophilic inflammation that is elevated in the sputum of persons with chronic bronchitis. several antagonists of ltb- receptors are in clinical development and may be useful in the treatment of chronic bronchitis kilfeather ( ) . a number of agents that act through cytokine pathways that mediate the symptoms of chronic obstructive lung disease (copd) are under investigation barnes ( ) , reid and sallenave ( ) . interleukin- (il- ), an anti-inflammatory cytokine, decreases in those with cop d. clinical trials of il- in various inflammatory disorders are underway. il- may hold promise in chronic bronchitis as well. interleukin- (il- ) is a neutrophil-attracting cytokine that is elevated in the sputum of persons with cop d. inhibitors of il- and antagonists of its receptor, cxcr , are being developed and may be useful in the treatment of chronic bronchitis. tumor necrosis factor-alpha (tnf-alpha) is a pro-inflammatory cytokine that activates various immune cells and stimulates the production of inflammatory cytokines and other mediators. its levels are elevated in the sputum of individuals with cop d. monoclonal antibodies directed against tnf-alpha, such as infliximab and recombinant soluble tnfalpha receptor (etanercept) are effective in rheumatoid arthritis and other inflammatory disorders and may be useful in the management of chronic bronchitis. inhibitors of oxidative stress n-acetylcysteine is a cysteine donor, enhancing the production of the antioxidant glutathione and decreasing oxidative stress. it has been shown to reduce the frequency of acute exacerbations of chronic bronchitis wegner ( ) . additional antioxidants, such as stable glutathione compounds and superoxide dismutase analogs, are in clinical development. inducible nitric oxide synthetase (inos) is responsible for the production of peroxynitrite, a potent oxidative species released during inflammation. inhibitors of inos are under development and may be useful in the treatment of chronic bronchitis. inhibitors of proteases (e.g., elastase) that are released by neutrophils during the inflammatory processes of chronic obstructive pulmonary disease are under development barnes ( ) . these compounds may slow the progression of emphysema that accompanies certain cases of chronic bronchitis. the p mitogen-activated protein (map) kinase is involved in the expression of inflammatory cytokines and proteases involved in chronic bronchitis. inhibitors of map kinase have been developed and may be useful in treating chronic bronchitis barnes ( ) . inhibitors of phosphoinositide- kinase-gamma (pi- kgamma), an enzyme involved in neutrophil activation, may also be of value. inhibitors of the nf-kappab signaling pathway are in development and may be tested for the treatment of chronic bronchitis. models of acute infectious bronchitis involve animals infected with a causative viral agent. for example, mice, ferrets, and chickens infected with influenza viruses are commonly used in the search for new anti-influenza drugs sidwell and smee ( ) . a number of animal models are commonly employed in the study of chronic bronchitis nikula and green ( ) . hamsters, dogs, or rats exposed to sulfur dioxide (so ) for - weeks develop clinical and histological signs of chronic bronchitis. mice, rats, guinea pigs, dogs, sheep, and monkeys have been used to study the role of cigarette smoke in the development of chronic bronchitis and emphysema. rats, mice, hamsters, and guinea pigs exposed to organic dusts (e.g., cotton dust) and bacterial endotoxin have been used to model occupational exposures, which result in chronic bronchitis and other forms of lung inflammation. exposure to other substances such as nickel and nitric acid has also been examined. lazarus, s.j., experts strive to better define the pathophysiology of cop d. this article examines new directions in the study of copd pathology: http://www.medscape.com/ viewarticle/ croxton, t.l., weinmann, g.g., senior, r.m., wise, r.a., crapo, j. d. and buist, a.s., clinical research in chronic obstructive pulmonary disease: needs and opportunities: http://www.nhlbi.nih.gov/meetings/workshops/copd_clinical.htm united states department of health and human services, cdc, nch s. national health interview survey. this web site contains data on the prevalence of copd symptoms in the united states and their impact on activity and daily life. it also has epidemiological information on a number of other medical conditions: http://www.cdc. gov/nchs/nhis.htm bandi, v.a., apicella, m.a., mason, e., murphy, t.f., siddiqi, a., atmar, r.l., greenberg, s.g., . nontypeable haemophilus influenzae in the lower respiratory tract of patients with chronic bronchitis. am. j. respir. crit. care med., , - . chronic obstructive pulmonary disease : new treatments for copd population:national health interview survey antibiotics in acute bronchitis: a meta-analysis recent advances in diagnosis and management of chronic bronchitis and emphysema disease of the airways in chronic obstructive pulmonary disease quantitative systematic review of randomised controlled trials comparing antibiotic with placebo for acute cough in adults the epidemiology of respiratory tract infections antiinflammatory effects of the phosphodiesterase- inhibitor cilomilast (ariflo) in chronic obstructive pulmonary disease viral and bacterial infections in the development and progression of asthma cilomilast: a second generation phosphodiesterase inhibitor for asthma and chronic obstructive pulmonary disease principles of appropriate antibiotic use for treatment of uncomplicated acute bronchitis: background uncomplicated acute bronchitis do bacteria cause exacerbations of copd childhood viral infection and the pathogenesis of asthma and chronic obstructive lung disease molecular pathogenesis of influenza a virus infection and virus-induced regulation of cytokine gene expression -lipoxygenase for the treatment of copd chronic obstructive pulmonary disease surveillance-united states management of acute exacerbations of copd: a summary and appraisal of published evidence animal models of chronic bronchitis and their relevance to studies of particle-induced disease gold scientific committee global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease cytokines in the pathogenesis of chronic obstructive pulmonary disease heliox for treatment of exacerbations of chronic obstructive pulmonary disease diet and obstructive lung diseases helicobacter pylori infection and respiratory diseases: a review in vitro and in vivo assay systems for study of influenza virus inhibitors beta -agonists for acute bronchitis (cochrane review) treatment for acute bronchitis? a metaanalysis pathogenesis and pathology of copd epidemiology of chronic obstructive pulmonary disease (copd) st century perspective on chronic obstructive pulmonary disease novel mechanistic targets for the treatment of sub-acute and chronic bronchitis resolution of bronchial inflammation is related to bacterial eradication following treatment of exacerbations of chronic bronchitis the role of infection in copd global initiative for chronic obstructive lung disease: pocket guide to copd diagnosis, management, and prevention bronchitis and acute febrile tracheobronchitis, including exacerbations of chronic bronchitis chronic bronchitis and emphysema costs of chronic bronchitis and copd: a -year follow-up study few smokers develop cop d. why clinical management of chronic obstructive pulmonary disease pulmonary pathophysiology: the essentials acute bronchitis is a very common respiratory illness. an elevated risk for the development of acute bronchitis is seen among the very young and the elderly, smokers, key: cord- -icowa wn authors: jouneau, stéphane; brinchault, graziella; desrues, benoît title: prise en charge des exacerbations : de la ville à l’hôpital date: - - journal: journal européen des urgences et de réanimation doi: . /j.jeurea. . . sha: doc_id: cord_uid: icowa wn points essentiels la société de pneumologie de langue française définie l’exacerbation aiguë de bronchopneumopathie chronique obstructive comme une majoration des symptômes respiratoires au-delà des variations quotidiennes (en pratique, d’une durée ≥ h ou justifiant une modification thérapeutique). la cause de ces exacerbations est principalement infectieuse : virale (rhinovirus, virus influenzae et parainfluenzae, coronavirus, adénovirus et virus respiratoire syncytial) ou bactérienne (principalement, haemophilus influenzae, streptococcus pneumoniae et moraxella catarrhalis). elles peuvent également résulter de l’exposition à certains polluants : no , so , ozone et pollution particulaire (pm et pm , ). elle reste indéterminée dans près de % des cas. les diagnostics différentiels incluent les pneumopathies infectieuses, les pneumothorax, les poussées d’insuffisance cardiaque et les embolies pulmonaires. la présence de signes de gravité conditionne l’hospitalisation : signes d’insuffisance respiratoire aiguë, de choc ou de défaillance neurologique, mais aussi en cas de patient fragile, d’absence de soutien familial à domicile ou de réponse au traitement initial. le traitement consiste en une majoration des bronchodilatateurs, une kinésithérapie respiratoire, une antibiothérapie en cas d’expectoration franchement purulente. la prescription de corticoïdes systémiques ne doit pas être systématique. la dose recommandée est de , mg/kg sur une courte période ( – jours). lors d’une hospitalisation, une oxygénothérapie et une thromboprophylaxie peuvent être instaurées. la ventilation non invasive est principalement indiquée en cas de persistance d’une hypercapnie malgré un traitement médical optimal. que le patient soit pris en charge en ambulatoire ou en hospitalisation, une réévaluation clinique à – h est indispensable. key points the société de pneumologie de langue française defines acute exacerbation of chronic obstructive pulmonary disease (ae copd) as an increase in daily respiratory symptoms, basically duration ≥ h or need for treatment adjustment. etiology of ea copd are mainly infectious, viral (rhinovirus, influenzae or parainfluenzae virus, coronavirus, adenovirus and respiratory syncytial virus) or bacterial (haemophilus influenzae, streptococcus pneumoniae, or moraxella catarrhalis). pollutant exposure can also lead to ae copd, such as no , so , ozone or particulates (pm and pm . ). in % the etiology remains unknown. differential diagnoses of ae copd include infectious pneumonia, pneumothorax, acute heart failure and pulmonary embolism. presences of signs of severity impose hospitalization: signs of respiratory distress, shock, acute confusion but also fragile patients, insufficient home support or absence of response to initial treatment. ae copd treatments consist on increase in bronchodilators, chest physiotherapy, and antibiotics if sputum is frankly purulent. systemic corticosteroids should not be systematic. recommended dose is . mg/kg on short course ( – days). during hospitalization, oxygen supplementation and thromboprophylaxis could be prescribed. the main interest in non-invasive ventilation is persistent hypercapnia despite optimal medical management. during ambulatory management or hospitalization, clinical assessment at – h is mandatory. l'exacerbation aiguë de bronchopneumopathie chronique obstructive (ea bpco) représente un événement important dans l'histoire naturelle de la bpco, notamment en cas d'hospitalisation. les ea bpco interviennent dans la gravité et l'évolution de la maladie ; et leur prévention est un des objectifs principal des traitements de fond. en l'absence de consensus international [ ] , la splf a défini l'ea bpco comme une majoration des symptômes respiratoires au-delà des variations quotidiennes (en pratique, d'une durée ≥ h ou justifiant une modification thérapeutique) [ ] . les critères couramment utilisés sont l'augmentation de la dyspnée, de la toux, du volume de l'expectoration ou la modification de l'expectoration (aspect purulent). le diagnostic est donc clinique, basé sur les données d'interrogatoire. l'ea bpco peut être un mode de découverte de la bpco. on nomme décompensations de bpco, les ea susceptibles d'engager le pronostic vital [ ] . on parle d'exacerbations fréquentes, à partir de épisodes d'ea au cours des derniers mois [ ] . la bpco est aujourd'hui la e maladie respiratoire après l'asthme et la e cause de mortalité en france. elle concerne à % de la population adulte. seulement à % des cas sont diagnostiqués et à % pris en charge. elle sera la e cause de mortalité dans le monde en [ ] . les patients exacerbateurs fréquents ont également une augmentation de la prévalence des comorbidités extrapulmonaires incluant les maladies cardiovasculaires, le reflux gastro-oesophagien, la dépression, l'ostéoporose et l'altération des fonctions cognitives [ ] . ces patients ont ainsi une qualité de vie altérée, un déclin accéléré de leur vems, une augmentation de leurs hospitalisations (et de leur mortalité), contribuant à augmenter la susceptibilité à une nouvelle exacerbation perpétuant le phénotype d'exacerbateur fréquent [ ] . l'ea bpco est un élément pronostique important. en effet, % des patients décèdent dans les ans qui suivent une hospitalisation pour ea bpco [ ] . parmi les facteurs de risque de décès (analyse multivariée) étaient retrouvés : l'âge ≥ ans, un indice de masse corporelle (imc) ≤ kg/m , un antécédent de cancer bronchique ou d'hospitalisation pour ea bpco, les comorbidités cardiovasculaires, la mise en jeu des muscles respiratoires accessoires ou un oedème des membres inférieurs à l'admission, et l'oxygénothérapie au long cours instaurée à la sortie de l'hospitalisation. le diagnostic positif d'une ea bpco est basé sur les critères de définition : majoration de la dyspnée et/ou de la toux et/ou de l'expectoration (volume, purulence) sur plus de jours ou avec modification thérapeutique [ ] . d'autres symptômes peuvent être présents tels que sibilants, sensation d'oppression thoracique, oedème des membres inférieurs ou asthénie. une douleur thoracique ou de la fièvre ne sont pas classiques [ ] . certains facteurs sont connus pour entraîner des ea bpco (figure ). les infections des voies aériennes basses représentent la cause la plus fréquente. les infections virales des voies aériennes supérieures sont souvent incriminées comme facteur déclenchant des ea bpco, surtout durant la période hivernale [ ] . les virus les plus fréquemment rencontrés sont les rhinovirus (virus du « rhume », le plus fréquent), les virus influenzae (virus de la grippe) et parainfluenzae, les coronavirus, les adénovirus et le virus respiratoire syncytial [ , ] . ils augmentent l'inflammation des voies aériennes inférieures (interleukines [il]- , il- ) et participent au stress oxydatif [ ] . bien que des bactéries puissent coloniser les voies aériennes inférieures des patients à l'état stable (≈ %) [ ] , elles sont également responsables d'ea bpco, en particulier en cas d'acquisition de nouvelles souches bactériennes [ ] . les principales bactéries responsables d'ea bpco sont haemophilus influenzae, streptococcus pneumoniae et moraxella catarrhalis [ , , ] . chez les patients les plus sévères il faut savoir rechercher certaines bactéries particulières telles que pseudomonas aeruginosa ou staphylococcus aureus [ ] . des bactéries intracellulaires telles que chlamydia pneumoniae pourraient également jouer un rôle dans les ea bpco. on retrouve une co-infection virus-bactérie dans un quart des ea bpco [ ] . les pics de pollution urbaine sont également des facteurs d'exacerbation. les polluants les plus communs sont représentés par le no , le so , l'ozone et les particules de diamètres inférieurs à m (pm ) et inférieur à , m (pm , ) [ ] . les mécanismes physiopathologiques exacts reliant la pollution aux ea bpco ne sont pas élucidés, mais impliqueraient une plus grande susceptibilité aux infections virales [ ] . enfin, dans environ % des cas, l'origine des ea bpco n'est pas identifiée [ ] . les ea bpco sont à différencier d'autres complications ou affections aiguës survenant assez fréquemment dans la bpco. ce sont principalement les pneumothorax, les poussées d'insuffisance cardiaque et les embolies pulmonaires. la fréquence de ces dernières est variable au cours des ea bpco, mais paraît élevée ( %) chez les malades hospitalisés pour exacerbation [ ] . il n'existe pas de signes clinique, biologique ou radiologique spécifiques de maladie veineuse thromboembolique, mais elle doit être suspectée devant une ea bpco avec douleur thoracique ou syncope, ou devant une diminution de la capnie chez un patient habituellement hypercapnique [ ] . la maladie veineuse thromboembolique prolonge une hospitalisation pour ea bpco de , jours en moyenne et augmente la mortalité à an de %. l'absence de diagnostic et d'instauration d'une anticoagulation curative augmente la mortalité de % durant l'hospitalisation [ ] . les pneumopathies infectieuses sont également à différencier d'une ea bpco. leur diagnostic est suspecté en cas de fièvre élevée (> , • c) ou de signes focalisés à l'auscultation (souffle tubaire, foyer de crépitants) et confirmé par la présence d'opacité systématisée sur la radiographie thoracique. les ea bpco sont associées à une augmentation de l'inflammation systémique (crp, fibrinogène, leucocytes, il- , il- , tumor necrosis factor [tnf]␣) et de l'inflammation des voies aériennes inférieures (il- , il- , tnf␣) (figure ) [ , ] . chez les exacerbateurs fréquents et les patients avec colonisation bactérienne, on retrouve un niveau d'inflammation bronchique basale plus élevé que chez les non-exacerbateurs fréquents [ ] . les ea bpco d'origine virale semblent associées à une inflammation systémique et bronchique plus élevée avec un temps de retour à l'état de base plus long [ ] . la fréquence des ea bpco semble augmenter avec la sévérité de la bpco jugée sur le stade gold [ ] . d'autre part, les ea bpco semblent également accélérer le déclin de la fonction respiratoire, diminuer la qualité de vie, réduire la force musculaire périphérique et augmenter la mortalité [ ] . enfin, plusieurs comorbidités semblent associées au phénotype « exacerbateur fréquent » : nombreuses comorbidités cardiovasculaires incluant athérosclérose, cardiopathie ischémique, hypertension artérielle, insuffisance cardiaque, accident vasculaire cérébral ; le reflux gastro-oesophagien ; l'anxiété et la dépression et l'ostéoporose [ ] . le meilleur traitement des ea bpco est la prévention. elle relève du sevrage tabagique, des vaccinations antigrippale et antipneumococcique, des traitements de fond inhalés ou le traitement curatif est principalement basé sur les bronchodilatateurs, la kinésithérapie de drainage bronchique et éventuellement l'antibiothérapie, la corticothérapie systémique et l'oxygénothérapie [ , , ] . que ce soit en ambulatoire ou en hospitalisation, la théophylline, les mucomodificateurs (type n-acétyl-cystéine, carbocystéine) ou les analeptiques respiratoires n'ont pas d'indication [ ] . les antitussifs ou les neurosédatifs sont contre-indiqués [ ] . en pratique, devant un patient ayant une ea bpco, il faut évaluer rapidement le degré de gravité (encadré ), en comparant l'importance des nouveaux symptômes par rapport aux signes habituels de la maladie [ , ] . si les données de la gazométrie artérielle à l'état de base sont disponibles, la comparaison est également essentielle. s'il n'existe pas de critère de gravité, la prise en charge peut être assurée au domicile du patient par le médecin généraliste. les comorbidités, l'âge et l'entourage au domicile sont également à prendre en compte lors de la décision d'hospitaliser ou non un patient. le diagnostic d'ea bpco est clinique. aucun examen complémentaire n'est indiqué en première intention, notamment pas d'examen cytobactériologique des crachats (ecbc) ni de radiographie thoracique, sauf en cas de fièvre élevée pour ne pas méconnaître une pneumopathie aiguë communautaire [ , ] . une étude de cohorte a montré que le traitement précoce des ea bpco réduisait le risque d'hospitalisation [ ] . il faut donc bien insister sur l'éducation du patient à la reconnaissance des signes d'ea bpco pour que leur prise en charge ambulatoire soit la plus précoce possible. le traitement bronchodilatateur doit être intensifié, soit en augmentant les doses habituelles soit éventuellement en associant plusieurs classes de bronchodilatateurs. lors des ea bpco, l'utilisation d'une chambre inhalation avec un spray semble aussi efficace que les nébulisations de bronchodilatateurs [ ] . la kinésithérapie respiratoire de drainage bronchique est indiquée en cas d'encombrement (difficulté à évacuer les sécrétions) [ ] . lorsque l'augmentation de la dyspnée s'accompagne d'une expectoration purulente, il est recommandé de prescrire une antibiothérapie [ , ] . l'antibiotique prescrit doit être actif sur les principaux germes : h. influenzae, s. pneumoniae et m. catarrhalis [ ] . la prise de corticoïdes par voie orale à la dose de , mg/kg/j de prednisolone ou équivalent pendant jours raccourcirait la durée des exacerbations selon une seule étude sur un très faible effectif [ ] . une étude randomisée en double aveugle a également montré que les patients traités, en plus des antibiotiques et bronchodilatateurs, par mg/j de prednisone pendant les jours qui suivent leur sortie des urgences avaient significativement moins de dyspnée et un meilleur vems que ceux sous placebo [ ] . au final, la corticothérapie systémique au cours d'une ea bpco ( , mg/kg/j pendant jours), n'est donc pas recommandée pour toutes les exacerbations, mais doit être réservée aux échecs de la prise en charge initiale [ , ] . dans tous les cas, la prise en charge thérapeutique est réévaluée à - heures (figure ) [ ] . le traitement des exacerbations graves doit être réalisé en milieu hospitalier. les critères d'hospitalisation sont essentiellement cliniques et portent sur la gravité des symptômes et les antécédents du patient (encadré ). des examens complémentaires sont faits à l'admission [ ] : radiographie thoracique, principalement pour écarter les diagnostics différentiels ; gazométrie artérielle ; électrocardiogramme (ecg) ; biologie basale simple incluant nfs, ionogramme sanguin, urée, créatininémie ; ecbc si l'expectoration est purulente ; hémocultures si le patient est fébrile. les dosages de crp et de nt-probnp ne font partie d'aucune recommandation nationale ou internationale dans la prise en charge des ea bpco. dès l'admission à l'hôpital, il faut déterminer si le patient doit être hospitalisé en réanimation, décision basée sur les signes cliniques et sur la gazométrie artérielle réalisée idéalement au débit d'oxygène habituel du patient. les critères d'hospitalisation en réanimation sont la présence d'une dyspnée de repos avec une tachypnée importante, de troubles de la conscience ainsi que d'une acidose respiratoire sévère ne répondant pas au traitement instauré en urgence. chez ce type de patients, si une ventilation mécanique n'est pas instituée rapidement, le risque de décès est très élevé. une oxygénothérapie est débutée si nécessaire afin de maintenir la saturation artérielle en o (sao ) ≥ %. elle est administrée à l'aide de lunettes nasales ou d'un masque venturi [ , ] . le débit d'oxygène doit être rapidement adapté en fonction de la spo . lorsqu'elle se situe entre et %, le débit d'o est maintenu minutes afin de réaliser une gazométrie artérielle de contrôle. celle-ci permet de vérifier qu'il n'apparaît pas une augmentation importante de la paco avec une acidose respiratoire sévère et de confirmer la correction partielle de l'hypoxémie (pao > mmhg ou , kpa). les ␤ -agonistes de courte durée d'action en nébulisation sont indiqués en première intention lors des ea bpco [ ] . en l'absence de réponse, on peut y associer du bromure d'ipratropium en nébulisation. le gaz propulseur, qui doit être spécifié sur la prescription, doit être l'air et non pas l'oxygène pour ne pas majorer l'hypercapnie [ ] . plusieurs études ont montré l'intérêt de la corticothérapie systémique en cas d'ea bpco nécessitant une hospitalisation ou un passage aux urgences : réduction de la durée d'hospitalisation ( h en moyenne), amélioration plus rapide de la fonction respiratoire et, pour les malades consultant aux urgences puis traités en ambulatoire, réduction du taux de rechutes à jours [ , , , ] . ces premières études présentaient certaines limites : les patients ayant déjà reçu une corticothérapie systémique avant l'arrivée aux urgences étaient exclus, il n'était retrouvé aucun bénéfice à moyen terme sur le taux global de succès thérapeutiques et, enfin, les effets indésirables n'étaient pas négligeables (déséquilibre glycémique, en particulier). néanmoins, ces travaux ont montré qu'une durée de corticothérapie supérieure à semaines n'a pas d'intérêt et souligné qu'une dose de , mg/kg/j de prednisolone est suffisante [ , ] . ceci a été confirmé dans un large essai (n = patients), randomisé en double aveugle, qui montrait qu'un traitement court (prednisone mg/jour pendant jours) n'était pas inférieur à un traitement long ( jours) [ ] . lors d'une ea bpco, une fièvre n'est pas prédictive d'une infection bactérienne, ce d'autant que l'absence de fièvre est classique dans les surinfections bronchiques de bpco [ , ] . les critères d'instauration d'une antibiothérapie dépendent du terrain du patient, principalement de la sévérité de sa bpco (stade gold), et du caractère purulent de l'expectoration [ , , , ] . pour les bpco stade , l'insuffisance respiratoire est sévère et même si l'origine infectieuse de l'exacerbation est peu probable, la prescription d'antibiotiques est large [ ] . l'antibiotique prescrit doit être actif sur les principaux germes : h. influenzae, s. pneumoniae et m. catarrhalis [ ] . les bêta-lactamines sont probablement les antibiotiques à privilégier en première ligne (amoxicilline ou amoxicilline + acide clavulanique, g × /jour pendant jours), suivis de la pristinamycine ( g × /jour pendant jours). les avantages de ces deux antibiotiques sont nombreux : recul important sur leur utilisation, relativement bien tolérés, avec un profil de tolérance connu et ils n'ont pas d'impact majeur sur l'écologie bactérienne [ ] . il faut limiter la prescription des fluoroquinolones actives sur le pneumocoque (fqap), du fait de l'acquisition rapide de résistance bactérienne même si ces molécules sont très actives [ , ] . en effet, plus le spectre d'une fluoroquinolone est large, plus l'impact sur l'écologie bactérienne du patient est important [ ] . en cas d'échec d'une antibiothérapie de première ligne, la réalisation d'un ecbc est recommandée, notamment pour rechercher des bactéries particulières telles que p. aeruginosa ou s. aureus [ , ] . le p. aeruginosa a été retrouvé dans les ecbc de % des patients hospitalisés pour une ea bpco dans deux cohortes prospectives [ , ] . dans l'étude espagnole, les facteurs de risque d'acquérir cette bactérie étaient un indice de bode plus élevé, une hospitalisation dans les mois précédents, une corticothérapie orale ou un précédent ecbc positif pour p. aeruginosa. À l'avenir, les décisions de mettre en place une antibiothérapie pourront s'aider des dosages de procalcitonine, dont l'utilisation permet de réduire le nombre d'antibiothérapies et leurs durées sans mettre en péril le devenir des malades [ , ] . la prescription d'une thromboprophylaxie doit être large lors d'une décompensation de bpco [ , , ] . la kinésithérapie respiratoire de désencombrement est indiquée [ ] . la réhabilitation pulmonaire peut être débutée au décours d'une ea bpco, en particulier si elle a conduit à une hospitalisation [ , ] . la ventilation non invasive (vni), par masque facial ou nasal, est efficace dans à % des cas où la ventilation mécanique est nécessaire. c'est le traitement de choix en cas de persistance d'une hypercapnie importante malgré un traitement médical optimal d'une ea bpco [ ] . l'utilisation de la vni diminue la durée d'hospitalisation, la mortalité et les risques de complications iatrogènes (infections nosocomiales, en particulier) [ , ] . la formation du personnel soignant est indispensable et l'initiation d'une vni chez un patient souffrant d'une ea bpco est consommatrice de temps médical mais aussi infirmier [ , ] . la vni est plus efficace si utilisée tôt dans la prise en charge d'une ea bpco. un ph très bas, des troubles de conscience marqués, d'importantes comorbidités et un score de gravité élevé à la prise en charge sont autant de facteurs d'échec de la vni [ ] . elle est recommandée dans les décompensations de bpco avec acidose respiratoire et ph < , , quelles que soient la cause de la décompensation et l'âge du patient [ ] . même si le risque d'échec augmente lorsque le ph diminue, la vni reste utile lorsque le ph est < , . le mode ventilatoire de première intention est la vs-ai-pep [ ] . il est à noter que le coma hypercapnique chez un patient souffrant d'une bpco n'est pas une contre-indication absolue à la vni. celle-ci peut être tentée sur une courte période en espérant diminuer la capnie et ainsi réveiller le patient et éviter une intubation trachéale. l'utilisation de la vni en post-extubation serait particulièrement bénéfique chez les patients atteints de bpco car permettrait de réduire la durée de ventilation mécanique invasive, la durée d'hospitalisation, le recours à la trachéotomie, et serait associée à une moindre fréquence de complications et une meilleure survie chez ces patients [ ] . les indications de la ventilation mécanique (intubation trachéale) sont résumées dans l'encadré [ ] . en cas d'exacerbation sévère, il est également nécessaire de corriger d'éventuels troubles métaboliques, de commencer une dans plusieurs pays, des études randomisées ont évalué la possibilité d'un retour à domicile précoce (dès la sortie des urgences ou après une très courte hospitalisation) de malades ayant des critères d'hospitalisation mais sans critère de gravité immédiate justifiant la réanimation et/ou la ventilation non invasive. le retour à domicile était rendu possible par la mise en place d'un dispositif multidisciplinaire similaire à celui de l'hospitalisation à domicile (had) : suivi infirmier rapproché, kinésithérapie respiratoire, oxygénothérapie et nébulisations de bronchodilatateurs [ ] . le médecin traitant était averti du retour au domicile de son patient, mais un autre médecin assurait la prise en charge de cette had. de telles stratégies ne sont effectivement pas délétères pour le devenir des malades et s'avèrent coûtefficaces [ , ] . pour le moment, il n'y a pas suffisamment de données pour sélectionner avec précision les patients les plus aptes à bénéficier de cette prise en charge à domicile [ ] . par ailleurs, on peut assister au développement des services en santé, avec comme exemple, le programme d'accompagnement du retour à domicile des patients hospitalisés (prado). il s'agit d'un programme de la caisse nationale d'assurance maladie existant pour d'autres pathologies chroniques, qui est en cours de déploiement pour la bpco. ses objectifs sont d'anticiper les besoins du patient liés à son retour à domicile et de fluidifier le parcours hôpital-ville du patient. enfin, la télémédecine et le télémonitoring ont été évalués dans la gestion à domicile des patients atteints de bpco stade ii ou iii avec au moins une exacerbation dans l'année précédente. il s'agissait de surveiller à domicile différents paramètres parmi lesquels la fréquence cardiaque, la saturation en oxygène, la température, l'activité physique, les symptômes respiratoires et l'observance des traitements. ces éléments étaient télétransmis et analysés par des médecins qui pouvaient intervenir pour traiter au plus tôt des ea bpco et ainsi éviter des passages aux urgences ou des hospitalisations. certains travaux ont montré un bénéfice du télémonitoring [ ] [ ] [ ] , alors qu'une autre étude n'a pas montré pas de différence entre le bras télémédecine et le bras contrôle [ ] . cette prise en charge semble intéressante chez les patients les plus sévères. d'autres travaux prospectifs, randomisés, avec de large effectifs sont nécessaires pour définir au mieux la place de la télémédecine chez les patients atteints de bpco. une réévaluation est toujours nécessaire au décours d'une ea bpco. le traitement de fond devra être tout particulièrement rediscuté et adapté aux recommandations en vigueur [ ] . si l'exacerbation révèle la bpco, un bilan spirométrique et radiologique devra être réalisé à mois après celle-ci [ ] . la récidive à court terme d'une ea bpco doit faire rechercher un foyer infectieux sous-jacent tel qu'un foyer dentaire (consultation spécialisée et orthopantomogramme) ou sinusien (scanner des sinus ± nasofibroscopie orl) [ ] . il faut savoir également écarter les diagnostics de cancer, cancer bronchique mais également orl ou oesophagien, ainsi qu'une insuffisance cardiaque gauche, systolique ou diastolique, une maladie thromboembolique veineuse ou un syndrome d'apnées obstructives du sommeil [ ] . les auteurs déclarent ne pas avoir de 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to fluoroquinolones in canada. canadian bacterial surveillance network pseudomonas aeruginosa in patients hospitalised for copd exacerbation: a prospective study sputum bacteriology in hospitalized patients with acute exacerbation of chronic obstructive pulmonary disease in taiwan with an emphasis on klebsiella pneumoniae and pseudomonas aeruginosa effect of procalcitonin-guided treatment on antibiotic use and outcome in lower respiratory tract infections: cluster-randomised, single-blinded intervention trial antibiotic treatment of exacerbations of copd: a randomized, controlled trial comparing procalcitonin-guidance with standard therapy troosters t. rehabilitation and acute exacerbations which patients with acute exacerbation of chronic obstructive pulmonary disease benefit from noninvasive positive-pressure ventilation? a systematic review of the literature mechanical ventilation: invasive versus noninvasive société de pneumologie de langue française (splf) et la société de réanimation de langue française (srlf) hospital at home for patients with acute exacerbations of chronic obstructive pulmonary disease: systematic review of evidence hospital at home for acute exacerbations of chronic obstructive pulmonary disease a home telemonitoring program reduced exacerbation and healthcare utilization rates in copd patients with frequent exacerbations efficacy of multiparametric telemonitoring on respiratory outcomes in elderly people with copd: a randomized controlled trial a home telehealth program for patients with severe copd: the promete study effectiveness of telemonitoring integrated into existing clinical services on hospital admission for exacerbation of chronic obstructive pulmonary disease: researcher blind, multicentre, randomised controlled trial position of the french language society of pulmonology regarding the version of the gold document key: cord- -a bqliei authors: ezzeldin, nada; shalaby, alaa; saad-hussein, amal; ezzeldin, howayda; el lebedy, dalia; farouk, hebatallah; kandil, dina m. title: association of tnf-α – g/a, sp-b c/t, il- – c/t gene polymorphisms and latent adenoviral infection with chronic obstructive pulmonary disease in an egyptian population date: - - journal: arch med sci doi: . /aoms. . sha: doc_id: cord_uid: a bqliei introduction: chronic obstructive pulmonary disease (copd) is a leading cause of disability and death. the most common cause of copd is smoking. there is evidence suggesting that genetic factors influence copd susceptibility and variants in several candidate genes have been significantly associated with copd. in this study, we aimed to investigate the possible association of the tnf-α – , spb+ , il- – gene polymorphisms and latent adenovirus c infection with copd in an egyptian population. material and methods: our study included subjects ( smokers with copd, resistant smokers and non-smokers) who were subjected to spirometric measurements, identification of adenovirus c and genotyping of tnf-α – g/a, sp-b+ c/t and il- – c/t polymorphisms by real-time pcr. results: the adenovirus c gene was identified in all subjects. the distribution of tnf-α genotypes showed no significant differences between different groups. however, homozygous a genotype was associated with a significant decrease in fev( ), fev( )/fvc and fef / % of predicted in copd (p < . ). as regards sp-b genotypes, resistant smokers had a significantly higher homozygous t genotype frequency compared to copd and non smokers (p = . ). interleukin genotypes showed no significant difference between different groups. there was a significant decrease in fef / % of predicted in t allele carriers in copd patients (p = . ). conclusions: the copd is a disease caused by the interaction of combined genes and environmental influences, in the presence of smoking and latent adenovirus c infection, tnf-α – a, spb + t and il- – t polymorphisms predispose to the development of copd. chronic obstructive pulmonary disease (copd) is a complex mix of signs and symptoms in patients with chronic bronchitis and emphysema that largely results from cigarette smoking [ ] . several lines of evidence strongly suggest that genetic factors influence copd susceptibility as well; severe α -antitrypsin deficiency is one of the proven genetic determinants of copd [ ] . variants in several candidate genes have been significantly associated with copd, suggesting an interaction between genetic and environmental influences [ ] . transforming growth factor-β (tgf-β ) is a reasonable pathophysiological candidate gene which has been associated with copd [ ] . in a case control study, the distribution of tgf-β genotypes in an egyptian population was demonstrated; the absence of the pro-pro alleles in all cases of the study denoted a high predisposition to copd in egyptian smokers. moreover, the pro allele of the tgf-β gene was expressed more commonly in resistant smokers than in smokers who developed copd, demonstrating a protective role against copd and an important effect in preserving further decline in forced expiratory volume in the s (fev ) [ ] . tumour necrosis factor α (tnf-α), a proinflammatory cytokine, has many effects relevant to the pathogenesis of copd, including neutrophil release from the bone marrow and neutrophil activation [ ] . enhanced levels of tnf-α have been detected in sputum [ ] and in circulation [ ] of copd patients, indicating that this cytokine is involved in both the local and systemic inflammation present in copd. analysis of possible tnf-α gene polymorphisms in copd could be related to a higher susceptibility to develop this disabling pathological condition. an association between the tnf-α - g/a polymorphism and copd was reported in taiwanese [ ] and japanese populations [ ] . surfactant protein b (sp-b) polymorphisms have been associated with copd susceptibility in the presence of a gene-environment interaction [ ] . interleukin (il- ) is strongly implicated in the development of asthma and copd, overexpression of il- in the adult murine lung caused emphysema, elevated mucus production, and inflammation reminiscent of human copd [ ] . an increased frequency of the - t allele in copd patients compared to healthy controls and smokers with normal lung functions was previously reported, implicating a functional role of il- promoter polymorphism in enhanced risk of copd development [ ] . adenovirus infection is a common cause of bronchiolitis in children and young adults [ ] that could predispose to copd in adulthood [ ] . in particular, group c adenovirus is endemic, and exposure to infection during childhood could lead to latent infection that persists in the lung [ ] , tonsils [ ] , and peripheral blood lymphocytes [ ] . the copd is characterized by cough, sputum production, peripheral airways obstruction, and emphysematous destruction of the lung surface area. all these components have been related to an inflammatory process located in the conducting airways and lung parenchyma [ ] . in this study we aimed to investigate the possible association of tnf-α - g/a, sp-b+ c/t, il- - c/t gene polymorphisms and latent adenovirus infection with copd in an egyptian population. this was a cohort study; all subjects were selected randomly from the chest outpatient clinic and pulmonary function unit in the national research centre and chest department of cairo university over months. our study included male subjects. their age ranged between and years. they were divided into non-copd groups, group (non-smokers) which included non-smoker healthy controls with normal spirometry and group (resistant smokers) which included smokers who did not develop copd proved clinically and by normal spirometry, and a copd group (group ) which included smokers with copd. patients were assigned to the study according to one or more of the following criteria: age above years, smoking history above pack years, clinical and radiological examination fulfilled the diagnostic criteria of copd [ ] . exclusion criteria included diseases other than copd and working in industrial areas. all patients gave written informed consent; the study was approved by the ethical committee of the national research centre. all subjects of the study were subjected to medical history taking, clinical examination, plain chest x-ray postero-anterior view, and pre-and post-bronchodilator spirometric measurements of fev , fev /fvc (forced vital capacity) and forced expiratory flow (fef) / % of predicted. normal pulmonary function test (pft) was considered as fev % of predicted > %, fev /fvc % of predicted > %. bronchodilators were stopped h before pft. thirteen of our copd patients were admitted to the icu for acute (on top of chronic) respiratory failure, so spirometric measurements were not performed on them. identification of adenovirus c gene and genotyping of tnf-α, sp-b, and il- gene single nucleotide polymorphisms (snps) were done by real-time polymerase chain reaction (real-time pcr). blood samples were collected using edta containing blood tubes and treated with sucrose lysis buffer and the nuclear cell pellets were stored at - °c until dna extraction. genomic dna was extracted from whole blood using the qiaamp dna extraction kit (qiagen hilden, germany, cat no. ) according to the manufacturer's instructions. the sequence of the adenovirus c (adv ) gene (bank accession no: nc_ ) was amplified by real-time pcr. primers used were: forward primer 'gccattacctttgactcttctgt ', reverse primer ' cctgttggtagtccttgtatt-tagtatc ' and the probe sequence was as follows: agaaacttccagcccatgagccg. real-time pcr was conducted using sybr green nucleic acid dye in light cycler. the reactions were carried out in a capillary tube with μl reaction volume containing μl of h o, μl of forward primer, μl of reverse primer, μl of sybr green master mix and μl of extracted dna. the following thermocycling profile was used for each reaction: °c for min to activate uracil n-glycosylase in the master mix, °c for min to activate enzyme followed by cycles of °c for s and °c for min. dissociation analysis was run at the end of each sybr green real-time pcr reaction to verify a single pcr amplicon. the studied snps were il- - c/t (rs in the ncbi, snp database), surfactant protein b + c/t (rs ), and tnf-α - g/a (rs ). the surrounding sequences of these snps were: ggtttctggaggacttctaggaaaa[c/t] gagggaagagca (vic/famggaaaaggcgaca) for il- - c/t, ctttgtccagaggcgactcctaacc[c/t] ttagcaggctctg (vic/famccctaacttaca) for sp-b+ c/t, and gaggcaataggttttgaggggcatg [g/a] ggacggggttc (vic/famagcctccagggtcc) for tnf-α- g/a, respectively. to amplify the regions containing polymorphisms, pcr was conducted for a -cycle amplification ( min at °c, s at °c and min at °c) using . μl of genomic dna diluted in dh o, . μl of taqman universal pcr master mix containing . mm dntp, . mm mgcl and unit of taq polymerase (boehringer mannheim), and . μl of genotyping assay mix × in each well. after amplification, genotyping of polymorphisms was carried out using taqman snp genotyping assay performed on an applied biosystems real-time pcr and abi prism sequence detection system which is optimized to work with taqman universal pcr master mix, and designed for the allelic discrimination of specific snps, enabling scoring of both alleles in a single well. software automatically determined genotypes and gen-erated an intuitive graphic representation of results in a cluster plot report. statistical package for social sciences (spss) version . was used for statistical analysis. the quantitative results were expressed as means ± standard deviation (sd). for comparing quantitative results between two groups, independent t-test was used, and for more than two groups anova and post hoc least significant test (lsd) were used. qualitative results were expressed as number (no.) and percent (%). pearson chi-square test (χ ) was used for statistical analysis of the qualitative data. differences were considered to be significant when the p-value was ≤ . . the study included male subjects. the age and the smoking history in the resistant smokers group and copd patients group were matched without significant differences ( table i) . the mean values of the post-bronchodilator fev , fev /fvc and fef / % of predicted in copd patients group were . %, . % and . %, respectively. they were significantly lower than in non-smokers ( . %, . % and . %, respectively) and resistant smokers ( . %, . % and . %, respectively) with value of p < . (table ii) . the mean values of the post-bronchodilator fev , fev /fvc and fef / % of predicted negatively correlated with age in copd patients (p < . , p < . and p < . , respectively). additionally, the mean values of the post-bronchodilator fev , fev /fvc% of predicted negatively correlated with their smoking history (p < . and p < . , respectively) ( table iii) . as regards the adenovirus c gene, it was identified in all subjects of the study (figure ). the genotype distribution of the tnf-α - g/a polymorphism was heterozygous in cases and homozygous a in cases. the frequency of the homozygous a genotype was . % of copd, . % of non-smokers and % of resistant smokers, with no statistical significant difference between the groups. homozygous g genotype was not detected in any of our subjects (table iv, figure ). the genotype distribution of the sp-b + c/t polymorphism showed that the resistant smokers had a significantly higher frequency of homozygous t than either copd patients or non-smokers (p = . ). however, homozygous c genotype frequency was higher in copd patients than in either resistant smokers or non-smokers, p = . (table iv, figure ) . meanwhile, the genotype distribution of the il- - c/t polymorphism showed no signifi-cant difference between the studied groups although there was a high frequency of the homozygous t genotype in copd patients ( %) compared to the resistant smokers ( . %) and nonsmokers ( . %) (table iv, figure ). figure shows the frequencies of different genotypes in different studied groups. the post-bronchodilator fev /fvc% of predicted was significantly decreased in tnf-α homozygous a genotype ( . ) compared to heterozygous g/a genotype ( . %) in resistant smokers (p < . ) ( table v) . in copd patients, there was a statistically significant decrease in the mean values of the postbronchodilator fev (table vi) . meanwhile, the mean values of the post-bronchodilator fef / % of predicted was significantly decreased in il- homozygous t and c/t genotypes ( . % and . %, respectively) compared to homozygous c genotype ( . %), p = . (table vii) . this study selected randomized samples of subjects of the same sex and race. the mean age of the subjects and their smoking index were statistically matched. all subjects were of caucasian origin; it was found that the frequency of an allele can vary in different racial groups [ ] . the mean values of the post-bronchodilator fev , fev /fvc and fef / % of predicted showed significant negative correlations with age and were significantly reduced in copd patients compared to non-copd groups (p < . ). our subjects had a heavy smoking history of more than pack years. mean values of the postbronchodilator fev , fev /fvc% of predicted had significant negative correlations with their smoking history. adenovirus c infects more than % of the human population early in life [ ] . moreover, near- ly % of adults have serum antibody to multiple serotypes -a finding indicating that infection is common in childhood [ ] . in a study that included children presenting with recurrent upper and/or lower respiratory tract infection done in the national research centre of egypt, it was demonstrated that passive cigarette smoking remains an enormous health problem and is a principal cause of recurrence of respiratory infections in children, mainly adenovirus c infection. high prevalence and persistence of adenovirus c infection, exceeding % of cases, were demonstrated in children by positive serum igg and documented by latent gene expression [ ] . in our study, identification of adenovirus c in copd and non-copd subjects demonstrated the persistence of latent infection during childhood and confirmed our previous study in children. although cigarette smoking is the major risk factor for the development of copd, only % to % of all smokers develop airway obstruction [ ] . therefore, adenovirus that remains from a previous infection of the lungs in a smoker may enhance the inflammatory process in their lungs [ ] . the correlation between adenovirus c, copd and deterioration of pulmonary function was not demonstrated in this study, because all included subjects were positive for adenovirus c and genotyping was not done. latent adenoviral infection contributes to chronic airway inflammation through e a-dependent nf-κb (nuclear factor-κβ) activation. it was found that e a regulation of the lipopolysaccharide (lps) response may play a role in acute exacerbations as a consequence of bacterial infections in copd. adenovirus e a s (adenovirus early gene product) moreover, it could contribute to airway remodeling in copd by the viral e a gene, inducing transforming growth factor-β (tgf-β ) and connective tissue growth factor (ctgf) expression and shifting cells to a more mesenchymal phenotype [ ] . the tnf-α mediated inflammation is thought to play a key role in both the respiratory and systemic features of copd. single nucleotide polymorphism (snp) in the promoter region of the tnf-α gene (g→a at position - ) directly affects gene regulation, and is associated with high tnf-α production [ ] . in the present study, the genotype distribution of tnf-α - polymorphism in caucasian populations was heterozygous g/a in cases ( . %) and homozygous a in cases ( . %). homozygous alleles g/g were not detected in the studied groups. the tnf-α - a allele frequency ranged from % [ ] to % [ ] in the white population, and from % [ ] to % [ ] in the asian population. the possible cause of this discrepancy may be an ethnic difference affecting prevalence. the study demonstrated no statistically significant difference between the groups in the distribution of homozygous a genotype. the heterozygous g/a was present in a higher percentage in the resistant smoker group compared to the other groups, with no statistically significant difference between them. these results were in accordance with several studies that fail to find an association between copd and tnf-α - g/a polymorphism in caucasians [ ] [ ] [ ] [ ] [ ] [ ] , which might be explained by variation in genotype frequencies between races, or by linkage disequilibrium with hla alleles, seen previously in the caucasian population [ ] . in contrast to these studies on white subjects, two studies on asian subjects showed an association of tnf-α - g/a polymorphism and copd [ , ] . alternatively, the allele could be in linkage disequilibrium with another gene that increases susceptibility to copd in smokers only in the asian population [ ] . on the other hand, the homogenous a genotype in copd patients in the current study was accompanied by a statistically significant reduction in the mean values of the post-bronchodilator fev , fev /fvc and fef / % of predicted compared to heterozygous g/a genotypes in copd (p < . ). our findings agreed with those of keatings et al. [ ] , who demonstrated that homozygosity for the a allele predisposes to a worse prognosis for copd. the surfactant proteins are hydrophobic proteins that contribute to regulation of surface tension in the alveoli. components of surfactant also have a role in host defense and control of inflammation. alterations of surfactant might therefore be a factor in copd [ ] . the genotype distribution of the sp-b + c/t gene polymorphism showed that the non-smokers had a higher frequency of the heterozygous c/t genotype compared to either resistant smokers or copd patients. meanwhile, resistant smokers had a significantly higher frequency of t/t genotype, and c/c genotype was higher in copd patients (p = . ). the allelic variation of sp-b + between smokers (c/c and t/t) and non-smokers (c/t) indicates that these alleles appeared to be "smoking-dependent". moreover, the homozygous alleles (c/c and t/t) were associated with significant impairment of pulmonary function in the copd group compared to that in the heterozygous alleles (c/t). in contrast to our findings, guo et al. [ ] in a mexican population with copd reported that the frequency of the homozygous alleles c/c represented % of cases and the heterozygous alleles c/t represented % of cases. when both marker alleles were present, the odds ratio (or) for copd was considerably increased (or = . , p < . ) compared to when both markers were absent. no significant differences were observed when one marker was present and the other was absent (or for t = . , p = . ; or for c = . , p = . ). in a study done in a chinese han population, it was concluded that the sp-b t allele was probably associated with increased susceptibility to copd [ ] . in spite of the difference in the distribution of allelic markers between populations, probably due to ethnic variation, all studies agreed that sp-b+ c/t is a smoking-dependent gene which plays a role in copd and that the t allele is associated with deterioration of pulmonary functions. but in the present study, sp-b homozygous alleles (either c/c or t/t) were found to be associated with worse prognosis of copd. studies in transgenic mice have shown that the targeted expression of il- in the adult lung causes emphysema, mucus metaplasia, and inflammation that mirror, in many ways, the lesions seen in human copd. the il- may play an important role in the pathogenesis of copd, particularly in patients with asthma-like features [ ] . the distribution of the genotype of il- - c/t polymorphism showed no significant difference between the studied groups although there was a higher frequency of homozygous t genotype in the copd patient group compared to other groups. also, the homozygous t and heterozygous c/t genotypes were associated with a significant reduction in the mean values of the post-bronchodilator fef / % of predicted compared to that in the case of homozygous c genotype in the copd group (p = . ). these results indicate that the t allele is associated with copd and deterioration of pulmonary functions. our results are in accordance with those of van der pouw kraan et al., who demonstrated that il- promoter region polymorphism - c→t, associated with increased il- production, is more common in copd patients [ ] . in conclusion, from our results we concluded that copd is a disease caused by the interaction of combined genes and environmental influences. in the presence of smoking and latent adenovirus c infection, tnf-α - g/a, sp-b+ c/t and il- - c/t gene polymorphisms predispose to the development of copd and decline of lung functions. progress in chronic obstructive pulmonary disease genetics siblings of patients with severe obstruction pulmonary disease have a significant risk of airflow obstruction transforming growth factor-beta genotype and susceptibility to chronic obstructive pulmonary disease estimation of tgf-beta genotypes in egyptian smokers: association with fev in copd patients association of tumor necrosis factor alpha gene promoter polymorphism with the presence of chronic obstructive pulmonary disease differences in interleukin- and tumor necrosis factor-alpha in induced sputum from patients with chronic obstructive pulmonary disease or asthma the relationship between chronic hypoxemia and activation of the tumor necrosis factor-alpha system in patients with chronic obstructive pulmonary disease tumor necrosis factor-alpha gene polymorphism in chronic bronchitis attempted replication of reported chronic obstructive pulmonary disease candidate gene associations inducible targeting of il- to the adult lung causes matrix metalloproteinase-and cathepsin-dependent emphysema chronic obstructive pulmonary disease is associated with the - il- promoter polymorphism adenovirus infections in young children the relationship between respiratory illness in childhood and chronic air-flow obstruction in adulthood latent adenoviral infection in the pathogenesis of chronic airways obstruction detection of adenovirus nucleic acid sequences in human tonsils in the absence of infectious virus group c adenovirus dna sequences in human lymphoid cells small airway dimensions in smokers with obstruction to airflow copd criteria of diagnosis prevalence and quantization of species c adenovirus dna in human mucosal lymphocytes common viral respiratory infections and severe acute respiratory syndrome (sars) detection of a latent adenovirus c gene in children with recurrent respiratory tract infection. passive smoking and infection natural history of chronic airflow obstruction emphysematous lung destruction by cigarette smoke: the effects of latent adenoviral infection on the lung inflammatory response latent adenoviral infection induces production of growth factors relevant to airway remodeling in copd the genetics of chronic obstructive pulmonary disease tumor necrosis factor gene complex in copd and disseminated bronchiectasis tumor necrosis factora gene promoter polymorphism in chronic obstructive pulmonary disease a polymorphism in the tumor necrosis factor-alpha gene promoter region may predispose to a poor prognosis in copd the international hapmap consortium. a haplotype map of the human genome susceptibility genes for rapid decline of lung function in the lung health study siblings of patients with severe obstruction pulmonary disease have a significant risk of airflow obstruction an allelic polymorphism within the human tumor necrosis factor alpha promoter region is strongly associated with hla a , b , and dr alleles tumor necrosis factor-alpha + g/a gene polymorphism is associated with chronic obstructive pulmonary disease surfactant protein gene a, b, and d marker alleles in chronic obstructive pulmonary disease of a mexican population surfactant protein b polymorphism is associated with susceptibility to chronic obstructive pulmonary disease in chinese han population key: cord- -s t kp x authors: liang, ying; chang, chun; chen, yahong; dong, fawu; zhang, linlin; sun, yongchang title: symptoms, management and healthcare utilization of copd patients during the covid- epidemic in beijing date: - - journal: int j chron obstruct pulmon dis doi: . /copd.s sha: doc_id: cord_uid: s t kp x background: social distancing and restriction measures during the covid- epidemic may have impacts on medication availability and healthcare utilization for copd patients, and thereby affect standard disease management. we aimed to investigate the change of respiratory symptoms, pharmacological treatment and healthcare utilization of copd patients during the epidemic in beijing, china. methods: we conducted a single-center, cross-sectional survey performed at peking university third hospital and recruited patients with copd who were interviewed by phone call. clinical data, including respiratory symptoms, pharmacological treatment, management and healthcare access before and during the covid- epidemic from january to april , , were collected. results: a total of patients were enrolled for analysis. before the epidemic, . % ( / ) had long-term maintenance medication and ics/laba ( . %) and lama ( . %) were most commonly used. during the epidemic, . % ( / ) maintained their pharmacological treatment and . % ( / ) had to reduce or stop taking medications, with a slight decrease of patients taking ics/laba ( . %) and lama ( . %). most of the patients [ . % ( / )] had a low symptom burden, with a cat score < during the epidemic. of patients, ( . %) patients reported worsening of respiratory symptoms but only . % ( / ) sought medical care in hospitals, while the remaining expressed concerns about cross-infection in the hospital ( . %, / ) or had mild symptoms which were managed by themselves ( . %, / ). conclusion: during the covid- epidemic in beijing, most of our copd patients maintained their long-term pharmacological treatment and had mild-to-moderate symptoms. approximately, . % of the patients experienced worsening of respiratory symptoms, but most of them did not seek medical care in the hospital due to concerns about cross-infection. coronavirus disease (covid- ) is a highly contagious infectious disease caused by severe acute respiratory syndrome coronavirus (sars-cov- ). to fight the pandemic, reallocation of healthcare resources may have negative impacts on the care of patients without covid- . in addition, measures to mitigate the transmission of covid- , such as social distancing and restrictions may also affect the standard care of patients with chronic diseases such as chronic obstructive pulmonary disease (copd). copd is a common chronic airway inflammatory disease characterized by persistent respiratory symptoms and airflow limitation. a large systematic review and metaanalysis estimated that there were million copd cases in , with a global prevalence of . % in the population aging from to years. in , the china pulmonary health (cph) study reported that the prevalence of copd was . % in the population aged years or older, and estimated that there were nearly million cases in china. during the covid- pandemic, studies have shown that copd is a common comorbidity of covid- , contributing to the progression and worse outcome of this infectious disease and increases the risk of -day mortality for more than folds. furthermore, patients with copd are mostly elderly and vulnerable to infection and transmission of sars-cov- , and therefore need particular attention during the pandemic. as contingency measures, experts and societies have proposed guidance on the management of copd during the pandemic. , however, these guidelines are largely based on existing guidelines and expert consensus because of the lack of relevant research data during the covid- pandemic. therefore, we conducted a cross-sectional study of symptoms, management and healthcare utilization of copd patients during the covid- epidemic in beijing, aiming to provide data for implementing relevant treatment strategy of copd during the pandemic. this was a single-center, retrospective, cross-sectional survey by telephone call performed in peking university third hospital. patients were selected randomly from the copd database in our hospital by the following inclusion criteria: ) years of age or older; ( ) a history of at least months of diagnosed copd according to global initiative for chronic obstructive lung disease (gold) report. patients who refused telephone interview or had cognitive dysfunction such as vascular dementia, alzheimer's disease were excluded. we used a design based on a table of random numbers to select a representative sample. sociodemographic information and clinical data, including respiratory symptoms, pharmacological treatment, management and healthcare access before and during the covid- epidemic from january to april , , were collected. the changes of respiratory symptoms, pharmacological treatment and healthcare utilization of copd patients during the epidemic were the major composite endpoints in this study. we conducted the study via telephone interview from april to may , . prior to the investigation, the physicians participating in this study and dialing to the patients were required to attend a centralized training session. any identifier to an individual patient, such as identification number and full name, was not collected. all data were inputted into a programmed database by two people independently for statistical analysis. the interviewing physician would explain the aim of this survey, the amount of time required, and the confidentiality and permissions for the collection of data in plain language. upon getting oral approval from the patients or their close relatives, the interviewer carried on asking the questions from a questionnaire designed by the experts in the department of respiratory and critical care medicine, which covered the following items: sex, age, ethnicity, height, weight, permanent residence, employment status, education level, medical insurances, and smoking status. history of copd, the numbers of copd exacerbations and hospitalizations due to copd exacerbation in the previous year. medications for copd treatment included inhaled shortacting β-agonist (saba), inhaled short-acting muscarinic antagonist (sama), inhaled corticosteroids plus longacting β-agonist (ics/laba), long-acting muscarinic antagonist (lama), and oral theophylline. management and healthcare utilization included personal action plan, attending to copd education program, seeking online consultation, and medical visits to hospitals. medications and healthcare utilization of copd during the covid- epidemic (from january to april , ) maintenance therapy for copd and the compliance, the causes of changes in maintenance medication, medicine prescription refill in outpatient visits, times of visit to any hospital during the epidemic and the causes of medical submit your manuscript | www.dovepress.com international journal of chronic obstructive pulmonary disease : visits (getting prescription for copd, review and assessment of disease, or worsening of respiratory symptoms), and online consultation. the modified medical research council (mmrc) dyspnea scale and copd assessment test (cat) were performed to assess the symptoms of copd. changes of respiratory symptoms were reviewed, including the patient's overall perception, respiratory symptom worsening and the patients' management of changes of symptoms. the data were analyzed anonymously. continuous variables were expressed as median [ th, th percentiles] or mean ± standard deviation. categorical variables were expressed as numbers (%). unpaired t-test was performed to assess the differences between continuous variables. chi-square test or fisher exact test was performed for categorical variables. statistical analyses were performed using spss software, version . (ibm, armonk, ny, usa). results were considered statistically significant at p< . . we contacted patients from april to may . sixtyfive patients refused to accept the interview, and finally, patients ( . %, / ) who completed the questionnaire were enrolled for analysis. none of them were infected by sars-cov- . the median age of the patients was ( - ) years and . % of the patients were male. approximately % of the patients were current smokers or former smokers. over % were urban residents and most of them had retired. seventeen patients ( . %) had no medical insurance. the detailed demographic and socioeconomic data are shown in table . the median history of copd was . years and the longest history was up to over years. in our study, patients ( . %) experienced exacerbation in the previous year before the epidemic and ( . %) were frequent exacerbators. eighteen patients ( . %) were ever hospitalized due to copd exacerbation in the previous year. the medical history data are shown in table . before the covid- epidemic, patients ( . %) had long-term maintenance medication for copd. ics/ laba and lama were the most commonly used pharmacological therapy. twenty-two patients ( . %) had long-term personalized action plan provided by their doctors. besides, patients ( . %) ever attended patient education sessions and only ( . %) ever sought online medical consultation for copd (table ) . during the covid- epidemic from january to april , , . % ( / ) of the patients did not go to any medical facilities, while . % ( / ) visited respiratory clinics for regular follow-up, medicine prescription or symptom aggravation. twenty patients ( . %) reported that they worried about the insufficient amount of maintenance medication and ( . %) had to reduce (table ) . four patients ( . %) sought online consultation for copd during the epidemic. comparison of maintenance medications and online consultation before and during the epidemic is shown in figure . during the epidemic, respiratory symptoms were assessed by mmrc dyspnea scale and cat score. most of the patients ( . %, / ) had a low symptom burden, with a cat score < during the epidemic. eighty-five patients ( . %) had a mmrc score < (table ). during the covid- epidemic, patients ( . %) reported worsening of respiratory symptoms. increased sputum volume, dyspnea and cough were the most common symptoms. in these patients, only ( . %, / ) went to hospital to seek further medical care, to the respiratory clinic, to the emergency department and hospitalized due to severe exacerbation. a large proportion ( . %, / ) of the patients who experienced respiratory symptom aggravation were concerned about cross-infection of covid- in the hospital and the remaining ( . %, / ) thought that their symptoms were not serious and took more medications by themselves (table ). in the patients who had to reduce medication dosing or stop taking medicine during the epidemic, . % ( / ) experienced respiratory symptom worsening. compared with patients without respiratory symptom worsening, more patients with respiratory worsening had cat ≥ ( . %, / vs . %, / , p< . ) and were frequent exacerbators in the past year ( . %, / vs . %, / , p = . ). age, sex, body mass index, smoking status and medication treatment were not statistically different between patients with and without respiratory worsening (table ). in this cross-sectional survey by phone call, we found that, during the covid- epidemic in beijing, most of our copd patients maintained their pharmacological treatment and had a low symptom burden as assessed by during the months of covid- epidemic, most of our copd patients were stable and had mild-to-moderate respiratory symptoms. more than % of these patients dovepress continued their maintenance therapy, mostly with ics/ laba and/or lama, which is consistent with current guidelines. compared with copenhagen general population study, the use rates of ics/laba and lama in our study were relevantly high, contributing to the maintenance of disease stability. in our survey, although nearly % of the patients had respiratory symptom worsening, only three patients had severe exacerbation requiring visiting to emergency department or hospitalization. the majority of our patients did not need to seek medical care in hospitals and some of them could have their symptoms relieved by taking more medications. the lower rate of severe exacerbation in our study population might be due to social distancing, public hygiene measures and wearing of masks when going out in public, thereby reducing infection-induced copd exacerbations. it needs to be noted that, for patients experiencing worsening of respiratory symptoms, a large proportion expressed worries about the risk of exposure to covid- and therefore did not go to the hospital, but had medications step-up by themselves and experienced symptom alleviation, indicating that optimal selfmanagement outside hospital can be useful for those patients with mild exacerbation. a recent report from american thoracic society patient education emphasized that an action plan for copd patients is important and helps patients to manage the lung condition and monitor the symptoms. this report also suggested that patients should maintain their medicines as directed and not delay getting refills. we found that patients experiencing a worsening of respiratory symptoms had greater cat score and more copd exacerbations in the past year, suggesting that patients with these high-risk factors should keep maintenance therapy and be monitored carefully. in our survey, very few patients utilized online medical services for disease assessment and follow-up, although it was not difficult to acquire these services. advanced age and education level of the copd patients may hinder the use of telehealth, which is encouraged in epidemic emergencies when outpatient service should be prioritized for those who have exacerbations. , in fact, a meta-analysis showed that telemedicine improved the quality of life and reduced the rates of hospitalization in copd patients. tobacco exposure is an important risk factor for the development of copd. nearly one half of the patients in our study were former-smokers. this was different from other previous large-scale cross-sectional studies, in which the prevalence of former-smokers in copd population was less than %. , however, our patients were elderly with a median age of more than years. older patients with copd were more likely to quit smoking than younger patients. a large-scale epidemiological investigation in china showed that the successful smoking cessation rate in copd patients was higher in those living in urban area and increased with age. in patients aged≥ years, the smoking cessation rate was up to . %. the high proportion of patients who had quit smoking may explain partly the low symptom burden of our study population. our study had several limitations. as a single-centered, cross-sectional telephone survey, the sample size was relatively small and recall bias could not be avoided. the majority of the patients were in advanced age with a median of ≥ , and therefore data from individuals ranging from to years old were scarce. finally, the study period was in spring, while it is well known that the rate and severity of copd exacerbations vary with seasons. during the covid- epidemic from january to april in beijing, most of our patients with copd maintained their long-term pharmacological treatment and had mild-tomoderate respiratory symptoms. approximately . % of the copd patients experienced worsening of respiratory symptoms, but most of them did not seek medical care in the hospital due to concerns about cross-infection or successful self-management. newer healthcare modalities such as telemedicine or online consultation may be needed for copd patients during emergency periods. the data that supports the findings of this study will not be shared openly with other third parties due to contractual statements related to intellectual property, confidentiality, and proprietary rights. the study protocol was approved by the independent ethics committee of the peking university third hospital (irb -m ). informed consent was informed by telephone and oral consents were obtained from the patients. global strategy for the diagnosis. management and prevention of chronic obstructive pulmonary disease, global initiative for chronic obstructive lung disease (gold) global and regional estimates of copd prevalence: systematic review and meta-analysis prevalence and risk factors of chronic obstructive pulmonary disease in china (the china pulmonary health [cph] study): a national cross-sectional study the impact of copd and smoking history on the severity of covid- : a systemic review and meta-analysis coronavirus disease in elderly patients: characteristics and prognostic factors based on -week follow-up chronic obstructive pulmonary disease of chinese association of chest physician covid- guidance usefulness of the medical research council (mrc) dyspnoea scale as a measure of disability in patients with chronic obstructive pulmonary disease development and first validation of the copd assessment test low use and adherence to maintenance medication in chronic obstructive pulmonary disease in the general population managing your chronic lung disease during the covid- pandemic coronavirus disease (covid- )/people who need extra precautions/people who are at higher risk/people with moderate to severe asthma covid- : pandemic contingency planning for the allergy and immunology clinic submit your manuscript | www effectiveness of telemedicine intervention for chronic obstructive pulmonary disease in china: a systematic review and meta-analysis gbd chronic respiratory disease collaborators. prevalence and attributable health burden of chronic respiratory diseases, - : a systematic analysis for the global burden of disease study chronic obstructive pulmonary disease in china: a nationwide prevalence study determinants of smoking cessation in patients with copd treated in the outpatient setting smoking cessation in chronic obstructive pulmonary disease patients aged years or older in china seasonal and regional variations in chronic obstructive pulmonary disease exacerbation rates in adults without cardiovascular risk factors all authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work. this study was supported by the national natural science foundation of china. [no. ]. the authors have no conflict of interest in this work. the international journal of copd is an international, peer-reviewed journal of therapeutics and pharmacology focusing on concise rapid reporting of clinical studies and reviews in copd. special focus is given to the pathophysiological processes underlying the disease, intervention programs, patient focused education, and self management protocols. this journal is indexed on pubmed central, medline and cas. the manuscript management system is completely online and includes a very quick and fair peer-review system, which is all easy to use. visit http://www.dovepress.com/testimonials.php to read real quotes from published authors. submit your manuscript here: https://www.dovepress.com/international-journal-of-chronic-obstructive-pulmonary-disease-journal submit your manuscript | www.dovepress.com international journal of chronic obstructive pulmonary disease : key: cord- - jzw p authors: leung, janice m.; niikura, masahiro; yang, cheng wei tony; sin, don d. title: covid- and copd date: - - journal: eur respir j doi: . / . - sha: doc_id: cord_uid: jzw p copd patients have increased risk of severe pneumonia and poor outcomes when they develop covid- . this may be related to poor underlying lung reserves or increased expression of ace- receptor in small airways. https://bit.ly/ dsb l nonetheless, there is increasing evidence that copd may be a risk factor for more severe covid- disease [ ] . an analysis of comorbidities in covid- patients across china found that copd carried an odds ratio of . ( % ci . - . ; p= . ) for icu admission, mechanical ventilation or death, even after adjustment for age and smoking [ ] ; . % of severe cases had a history of copd (compared with only . % in non-severe cases) and % of those who died were copd patients (compared with only . % in those who survived). in a multicentre chinese study, copd patients made up . % of the critically ill patients, but only . % of moderately ill patients ( p< . ) [ ] . other studies have found similar, if statistically weaker, differences in copd rates between icu admissions and non-icu admissions ( . % versus . %; p= . ) [ ] , severe and non-severe cases ( . % versus . %; p= . ) [ ] , and between non-survivors and survivors ( % versus %; p= . ) [ ] . why copd patients appear to suffer worse outcomes upon contracting covid- (even if their risk of contracting to begin with may not be high) is worth some speculation. first, recent evidence that copd patients and smokers may display the machinery required for sars-cov- cellular entry differently has come to light. similar to sars-cov (which was responsible for the - sars pandemic) [ ] , sars-cov- bears an envelope spike protein that is primed by the cellular serine protease tmprss to facilitate fusion of the virus with the cell's angiotensin-converting enzyme (ace- ) receptor and subsequent cell entry (figure ) [ ] [ ] [ ] [ ] . our group has recently demonstrated that in three separate cohorts with available gene expression profiles from bronchial epithelial cells, ace- expression was significantly elevated in copd patients compared to control subjects [ ] . current smoking was also associated with higher ace- expression compared with former and never smokers, an observation which has subsequently been validated by other groups in separate cohorts of lung tissue and airway epithelial samples [ ] [ ] [ ] and supported by additional evidence linking ace- expression with nicotine exposure [ , ] . it is important to note, though, that ace- expression alone has not been shown yet to confer increased susceptibility or increased severity of disease. moreover, the relatively low expression of ace- in the bronchial epithelium in comparison to the nasal epithelium [ ] has unclear implications for disease susceptibility in patients with predominantly small airways pathology. the management of copd patients during the covid- pandemic two challenges of clinical care in copd have emerged during this pandemic: ) whether the usual algorithms of pharmaceutical management in copd still apply and ) how to weather the dramatic curtailments in non-pharmaceutical interventions this pandemic has wrought. although our understanding of covid- has substantially increased in a short period of time, these problems have largely been the domain of expert opinion rather than being guided by rigorous scientific evidence. questions remain about the effects of common respiratory medications used by our copd patients such as inhaled (ics) and systemic corticosteroids, short-and long-acting β -agonists, and short-and long-acting muscarinic antagonists in either mitigating or exacerbating covid- infections. the epidemiological data emerging from china and other early epicentres have not yet provided the necessary granularity required to determine whether these medications are harmful or beneficial in covid- patients with copd. peters et al. [ ], however, have recently shown that ace- expression in airway epithelial cells obtained from asthmatic patients was decreased in those taking ics compared to those who were not on ics, raising the possibility that ics exposure could decrease viral entry. whether the same relationship holds true in the copd airway, in which the predisposition to pneumonia following ics use is well-documented, has not yet been established. for now, in the absence of data demonstrating definitive [ ] to show ace expression, with the respiratory system highlighted in red. c) the renin-angiotensin system (ras) and the proposed sars-cov- action. the generation of angiotensin ii from angiotensin i by angiotensin-converting enzyme (ace) induces vasoconstriction of blood vessels and pro-inflammatory effects through the binding of angiotensin ii receptor type (at r), while the receptor type (at r) may negatively regulate this pathway. ace inhibitors (acei) and angiotensin ii receptor blockers (arbs) are very successful anti-hypertensives by promoting vasodilation of blood vessels. ace- inhibits the activity of angiotensin ii by converting angiotensin i to angiotensin - and angiotensin ii to angiotensin - , which binds to the mas proto-oncogene (mas) receptor with anti-inflammatory effects. upon sars-cov- binding to ace- , there is a shift in the ace/ace- balance towards a predominance of ace, resulting in increased pro-inflammatory effects and tissue damage. https://doi.org/ . / . - harm or benefit, ics and other long-acting inhalers should not be routinely withdrawn nor should their use be escalated as a preventative measure for copd patients during this pandemic [ ] . of greater concern is the use of systemic corticosteroids, the backbone of copd exacerbation treatment. on balance, the historical evidence for systemic corticosteroids in viral pandemics has not been entirely favourable. lessons from the sars and middle east respiratory syndrome (mers) pandemics suggest potential harm, in fact. in sars, while the majority of studies were inconclusive, four studies showed harm, including delayed viral clearance and increased rates of psychosis [ ] . in mers, corticosteroid use was associated with increased mortality [ ] and delayed viral clearance [ ] . so far, the most promising preliminary data on corticosteroids and covid- are from a randomised controlled trial of dexamethasone (recovery) performed in the uk, which demonstrated a one-third reduction in mortality [ ] . published data, however, are derived from small retrospective studies and appear mixed, with two studies showing no benefit [ , ] and two studies showing improvements in rates of death and escalation of care [ , ] . because of the results of the recovery trial, however, it is likely that dexamethasone will become standard of care treatment for covid- patients including those with copd. the impact of the pandemic has been keenly felt by copd patients in myriad aspects of their lives. face-to-face clinic visits with their physicians have been curtailed, as have pulmonary rehabilitation sessions and copd home visit programmes. patients who may have normally presented to the hospital during an exacerbation might choose to stay home for fear of exposure, resulting in delayed care, as has occurred in other conditions like myocardial infarction [ , ] . the long-term effects of this pause in routine care have yet to be measured. for now, healthcare systems have had to adapt to these conditions by augmenting telehealth and virtual visits. fortunately, multiple randomised controlled trials assessing telehealth for copd patients have demonstrated its feasibility and at least non-inferiority to usual care when it comes to exacerbations, hospitalisations and quality of life [ ] [ ] [ ] [ ] [ ] . moreover, online pulmonary rehabilitation programmes appear to be as effective as in-person sessions [ ] [ ] [ ] . in the event that social distancing measures remain in place for many more months, we advocate for the establishment of these virtual programmes to ensure our patient population can continue to receive optimal care. specifically, we will have to address the following questions on covid- as they pertain to copd: • does the burden of disease, clinical manifestations, and outcomes of covid- in copd patients differ from the general population and if so, how? • given the multiple phenotypes associated with the term "copd" (i.e. frequent exacerbators, emphysema-predominant, eosinophilic-predominant, asthma overlap), does covid- infection in each of these phenotypes present and behave differently? • are routine medications used in copd such as inhaled and systemic corticosteroids, β -agonists, muscarinic antagonists and chronic azithromycin protective or harmful in the setting of covid- infection? • what will the impact of post-covid- infection disability be in copd patients and what resources will be required to adequately support the transition of copd patients from the hospital to home after covid- ? • how can we manipulate the unique airway pathology of copd patients and the ace- system to identify novel therapeutics? • what is the role of inhaled substances (e.g. tobacco, cannabis and e-cigarettes) and air pollution in increasing the susceptibility of copd patients to covid- ? • what can we learn from the experience of virtual care to copd patients during this pandemic that can be applied in future scenarios to reach isolated patient populations and resource limited settings? these research questions can best be answered by developing standards for transparent data reporting across the globe and harnessing the power of international networks that can quickly collate the data of covid- copd patients. similarly, the efforts of translational research scientists at the laboratory bench who are working to characterise the pathophysiology of covid- infections in the airway are critical to developing new therapies for a world in which there are currently 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patients with covid- pneumonia at hvidovre hospital icu and ventilator mortality among critically ill adults with coronavirus disease clinical features and outcomes of hospitalized patients with covid- in clinical and laboratory findings from patients with covid- pneumonia in babol north of iran: a retrospective cohort study clinical characterization of covid- patients in israel: preliminary report from a large tertiary center use of renin-angiotensin-aldosterone system inhibitors and risk of covid- requiring admission to hospital: a case-population study the spectrum of cardiac manifestations in coronavirus disease (covid- ) -a systematic echocardiographic study hospitalization and mortality among black patients and white patients with covid- characteristics and outcomes of coronavirus disease patients under nonsurge conditions characteristics and clinical outcomes of adult patients hospitalized with covid- -georgia covid- testing, hospital admission, and intensive care among united states veterans aged - years baseline characteristics and outcomes of patients with covid- admitted to intensive care units in vancouver, canada: a case series single-cell rna-seq data analysis on the receptor ace expression reveals the potential risk of different human organs vulnerable to -ncov infection key: cord- -ti cc m authors: wang, cuixue; zhou, jiedong; wang, jinquan; li, shujing; fukunaga, atsushi; yodoi, junji; tian, hai title: progress in the mechanism and targeted drug therapy for copd date: - - journal: signal transduct target ther doi: . /s - - -x sha: doc_id: cord_uid: ti cc m chronic obstructive pulmonary disease (copd) is emphysema and/or chronic bronchitis characterised by long-term breathing problems and poor airflow. the prevalence of copd has increased over the last decade and the drugs most commonly used to treat it, such as glucocorticoids and bronchodilators, have significant therapeutic effects; however, they also cause side effects, including infection and immunosuppression. here we reviewed the pathogenesis and progression of copd and elaborated on the effects and mechanisms of newly developed molecular targeted copd therapeutic drugs. among these new drugs, we focussed on thioredoxin (trx). trx effectively prevents the progression of copd by regulating redox status and protease/anti-protease balance, blocking the nf-κb and mapk signalling pathways, suppressing the activation and migration of inflammatory cells and the production of cytokines, inhibiting the synthesis and the activation of adhesion factors and growth factors, and controlling the camp-pka and pi k/akt signalling pathways. the mechanism by which trx affects copd is different from glucocorticoid-based mechanisms which regulate the inflammatory reaction in association with suppressing immune responses. in addition, trx also improves the insensitivity of copd to steroids by inhibiting the production and internalisation of macrophage migration inhibitory factor (mif). taken together, these findings suggest that trx may be the ideal drug for treating copd. chronic obstructive pulmonary disease (copd) is a slow-developing, incurable lung disease characterised by a sustaining airflow limitation that further develops into common diseases such as pulmonary heart disease and respiratory failure. copd is caused by a complex interaction between genes and the environment. cigarette smoking is the leading environmental risk factor for copd. fewer than % heavy smoker develop copd, it indicates that genetics may play a role in regulating the risk of copd in smokers. besides genetics, other risk factors are also involved in the development of copd, such as age and gender, , lung growth and development, , exposure to particles, - socioeconomic status, , asthma and airway hyper-reactivity, , chronic bronchitis , and infections. gender may effect whether a person smoke or experiences certain occupational or environmental exposures; socioeconomic status may be related to lung growth and development, and then influence on susceptibility to developing the disease; and long live will allow greater lifetime exposure to risk factors. asthma may be a risk factor for the development of copd. airway hyper-responsiveness is the second risk factor for copd, but airway hyper-responsiveness, as an independent predictor of copd can exist without asthma, suggesting inflammatory profiles of copd different from asthmatic subjects. the pathogenesis of copd remains unclear and has been generally suggested to be related to inflammation, oxidative stress, protease/anti-protease imbalance and decreased immunity. smoking, biofuel smoke-induced oxidative stress and excessive protease production are major factors in copd pathogenesis that cause alveolar cell death, destruction of the extracellular matrix in the alveolar region and loss of alveolar structure. , the primary manifestations in the respiratory tract include airway wall remodelling and mucus retention, and further development leads to a serious decline in the lung function. currently, the main approach is to deal with symptoms of the airflow limitation caused by the above-mentioned symptoms to improve the resulting dyspnoea through medication, oxygen treatment and rehabilitation therapy. however, there is currently no way to prevent the disease progression. drug treatment includes bronchodilators and glucocorticoids, with the main types of bronchodilators including the β receptor agonists and anticholinergic drugs; however, both have many adverse effects. for example, the main side effects of the β receptor agonists are rapid heartbeat, muscle tremors and metabolic disorders. the side-effects of anticholinergic drugs include dry mouth, blurred vision, urinary retention, postural hypotension, cognitive problems and cardiac rhythm disturbance. long-term use of glucocorticoids induces and exacerbates infections, cause hyperglycaemia, osteoporosis and even mental disorders. [ ] [ ] [ ] therefore, a series of new molecular targeted therapeutic drugs to block copd progression is under development. this article introduces the pathogenesis of copd and pharmacology of related anti-copd drugs. specifically, there is a focus on the effective role and mechanism of the small molecule secretory protein thioredoxin (trx) that is widely expressed in lung tissues such as the type ii alveolar cells, macrophages and bronchial epithelium. the occurrence and development of copd is a complex pathological process involving a variety of inflammatory cells, inflammatory mediators and related cell signalling pathways. copd also regulates the goblet cell proliferation, mucoprotein (muc) synthesis and mucus secretion. in recent years, molecular biology has revealed new insights regarding the pathogenesis of copd (fig. ). copd and oxidant/antioxidant imbalance oxidative stress is an important factor in copd pathogenesis. an increased oxidative burden occurs in the lungs of patients with copd, and oxidative stress may be involved in various the pathogenic processes, such as direct injury to lung cells, mucus hypersecretion, inactivation of antiproteases and enhancing lung inflammation through activation of redox-sensitive transcription factors. copd patients suffer from oxidative stress caused by the inhalation of cigarette smoke (cs) or harmful substances which causes an accumulation of pulmonary inflammatory cells (neutrophils, macrophages), leading to large numbers of reactive oxygen species (ros). excessive ros production leads to an oxidative inactivation of anti-proteases, alveolar epithelium damage, increased neutrophil retention and increased expression of various inflammatory mediators in the pulmonary microcirculation, aggravating the development of copd. [ ] [ ] [ ] in addition, ros-activated inflammatory cells, now acting as activated inflammatory cells, also generate ros to further aggravate oxidative stress in tissues. oxidant-generating systems, such as xanthine/xanthine oxidase, can cause airway epithelial mucus secretion. oxidative stress, generated by tobacco smoke and augmented by ros generated from both inflammatory cells and mitochondrial activity by cells resident in the respiratory tract, regulate mucous cell metaplasia and mucin gene expression such as muc ac and muc b. oxidants are also involved in the signalling pathways for epidermal growth factor, which has an important role in mucus production. a relative deficiency of anti-proteases, such as α -antitrypsin, because of their inactivation by oxidants from cigarette smoke or released from inflammatory leucocytes, causes a protease/ anti-protease imbalance in the lungs. cigarette smokeinduced oxidative stress plays role in enhancing inflammation by regulating redox-sensitive transcription factors, such as nuclear factor kappa-b (nf-κb) and activating protein (ap- ), the extra-cellular signal-regulated kinase (erk), c-jun n-terminal kinase (jnk), and p mitogen-activated protein kinase (p mapk) pathways. ros also decrease the activity of histone fig. the pathogenesis of copd is complex and diversified. oxidative stress may participate in various the pathogenic processes, such as direct injury to lung cells, mucus hypersecretion, inactivation of antiproteases and enhancing lung inflammation through activation of redoxsensitive transcription factors. under the stimulation of cigarette smoke, pathogen infection and other factors, oxidative stress is induced and the pulmonary inflammatory cells (neutrophils, cd t lymphocytes, macrophages) accumulate, resulting in a large number of reactive ros. the inflammatory cells are activated by the nf-κb, p mapk and pi k signalling. inflammatory cells (mainly neutrophils) migrate from the circulation to the inflammatory site under sequential regulation involving cytokines and adhesion molecules such as selectin. proteases are involved in tissue remodelling, inflammation and ecm degradation, thereby participating in the pathological process of copd. inflammatory cytokines and chemokines, such as ltb , il- and tnf-α, and other mediators are secreted into the lungs to aggravate the lung tissue damage and promote inflammatory responses. pde decreases camp levels in inflammatory cells and promotes inflammatory cell activity and the release of inflammatory factors. chronic inflammation stimulates the increase of egfr and tgf-β . activated egfr is involved in the proliferation of the airway epithelial goblet cells and mucus production. tgf-β chemoattracts neutrophils, macrophages and mast cells, and activates pi k/akt and/or p mapk signalling to induce pulmonary fibrosis and emt. endothelin- (et- ) produced by endothelial cells, stimulates the contraction and proliferation of vascular smooth muscle cells and the liver to produce more crp, and it also induces the synthesis of vegf. b-type natriuretic peptide (bnp) antagonises renin angiotensin aldosterone system, dilates blood vessels and reduces peripheral vascular resistance, and c-type natriuretic peptide (cnp) dilates blood vessels and inhibits the proliferation of vascular smooth muscle cells deacetylase (hdac) which recoil dna of the histone core to stop transcription, , and probably increase the activity of histone acetyltransferase, which uncoils dna from the histone core to allow transcription. this leads to the further recruitment of inflammatory cells, specifically the neutrophils and macrophages in the alveolar spaces. in addition, oxidative stress extends beyond the lung, contribute to several of the systemic manifestations. peripheral blood neutrophils of copd release more ros than in normal subjects and this is enhanced still further in exacerbation. products of lipid peroxidation are also increased in plasma in smokers with copd, particularly during exacerbations, resulting in dna damage and airway epithelial cell senescence and apoptosis. in addition, the reactive aldehydes such as acrolein and -hydroxy- -nonenal ( -hne) formed from lipid peroxidation cause damage to the epithelial cells, acrolein is unstable and toxic, whereas -hne in high concentrations is capable of inducing caspase (a major promoter of cell apoptosis). , nuclear factor e -related factor (nrf ) is a transcription factor that regulates many antioxidant genes and plays an important role in the body's antioxidant stress. normally, nrf is fixed in the cytoplasm by kelch-like ech-associated protein (keap- ). under oxidative stress, nrf and keap- dissociate, and nrf is transported to the nucleus, activating the transcription of antioxidant genes. , however, the level of nrf in copd patients is reduced, resulting in a reduction of endogenous antioxidants and weakening the body's protection against oxidative stress. sirtuins (sirt ) and sirt are also related to the redox state. sirt is a redox-sensitive protein with a wide range of biological functions, such as inhibition of autophagy, cell aging, emphysema and fibrosis, and inflammation. , , yao et al. demonstrated that sirt can resist the inflammatory response of cigarette smoke to lung cells caused by oxidative stress. inhibition of inflammation may be through deacetylation of nf-κb. , sirt is also associated with redox status and inhibits cell aging and fibrosis. , copd and protease/anti-protease imbalance the pathogenesis of copd is closely related to the imbalance of protease/anti-protease, which leads to the destruction of the elastin framework. proteases are involved in tissue remodelling, inflammation and degradation of the extracellular matrix (ecm) components and the pathology of copd. , in addition, the products of ecm decomposition, such as collagen and elastin, are themselves chemokines of inflammatory cells and cause persistent respiratory system inflammation in copd patients, even leading to systemic autoimmune diseases. elastase is an enzyme that hydrolyses peptides and other proteins, and there are three main types in lung disease: serine proteases, caspases and matrix metalloproteinases (mmps). among them, mmps are a highly conserved family of endopeptidases, consisting of known members, that depend on zinc and calcium ions. macrophages and their macrophagederived mmps may be the dominant factor in the formation of smoking-related emphysema and copd. among the mmps, mmp- and mmp- are most involved in emphysema. mmp- plays an influential role in severity of copd. mmps also play a role in vascular remodelling by modulating the migration and proliferation of smooth muscle cells and endothelial cells and mediating the release of the smooth muscle cell mitogens and growth factors, increasing the risk of copd pulmonary hypertension. [ ] [ ] [ ] [ ] the endogenous inhibitors of mmps are tissue inhibitors of metalloproteinases (timps). timps are a family of low-molecular-weight proteins with four known members. timp- inhibits active mmps, including mmp- , mmp- and mmp- . it has been reported that changes in mmp- poorly correlated with disease intensity and progression in copd. timp- binds to pro-mmp- to prevent the activation of pro-mmp- . however, neutrophil elastase acts by dissociating the binding of timp- to pro-mmp- , which allows mmp- to activate pro-mmp- to become mmp- . in serine proteases, neutrophil elastase (ne), cathepsin g and proteinase- destroy lung tissue by degrading ecm components, and induces epithelial cells and endothelial cells to release a variety of inflammatory factors to activate and chemoattract neutrophils to produce lung inflammation. , alpha-antitrypsin is a protease inhibitor synthesised by liver cells, which control over the proteolytic activity of ne, proteinase- , cathepsin g and neutrophils serine protease- . evidence from experimental models of emphysema and from individuals with genetic deficiency of alpha- antitrypsin provides strong evidence that an imbalance between the enzymes and inhibitors is important in tissue damage and the pathogenesis of copd. protease-anti-proteases imbalance during airway inflammation and airflow restriction may be an important factor affecting airway remodelling and airflow restriction. copd and inflammatory cells, cytokines and chemokines copd pathology is characterised by airway remodelling and inflammatory cell infiltration by the neutrophils, cd t lymphocytes and activated macrophages. neutrophils have been implicated in copd pathogenesis and the extent of neutrophilic infiltration in lung tissues correlates with copd severity. , inflammatory factors play a major role in the onset and development of copd. under the stimulation of cigarette smoke or other harmful substances, the respiratory tract epithelium secretes inflammatory cytokines and chemokines, such as leukotriene b (ltb ), interleukin- (il- ), il- (cxcl ) and tumour necrosis factor-α (tnf-α), and other mediators in the lungs. these inflammatory mediators aggravate the lung tissue damage and promote inflammatory responses. ltb is a lipid mediator derived from arachidonic acid by the sequential action of -lipoxygenase ( -lox), -lipoxygenase-activating protein (flap) and lta hydrolase (lta h) to stimulate leucocyte functions such as cytokines, chemokinesis, lysosomal enzyme release, superoxide anion production, adhesion to endothelial cells, generation of ros and so on. il- activates neutrophils, causing neutrophil infiltration at the inflammatory sites, inducing neutrophils to release elastase and various oxygen free radicals, destroying alveolar surfactants, increasing pulmonary vascular permeability and inducing pulmonary oedema. activated by il- , which is higher in bronchoalveolar lavage fluid (balf) and sputum of copd patients. il- has a similar effect and induces neutrophil migration to the airway and affects degranulation produced by various cell types. tnf-α stimulates the pulmonary microvascular endothelial cells to promote the accumulation, adhesion and migration of the polymorphonuclear leucocytes by inducing the expression of il- and upregulating endothelial adhesion molecules, causes release of lysosomal enzymes, elastase and large quantities of ros; and damages the endothelial cells and alveolar epithelium. tnf-α together with il- β has been identified as a key cytokine that is able to initiate inflammatory cascades during exacerbations of copd. monocyte chemotactic protein (mcp- , ccl- ), macrophage inflammatory protein- α (mip- α, ccl- ) are cc-chemokines, which act as chemoattractants for inflammatory cells like macrophages, lymphocytes. neutrophil-derived ccl- and ccl- are involved in macrophage recruitment into inflamed tissue. in patients with copd, several cc-chemokines like ccl- , ccl- are upregulated to attract specific inflammatory cells, like macrophages, neutrophils and cd (+) t-lymphocytes into the airway, suggesting the contribution of their respective receptor in the pathogenesis of the disease. copd and adhesion factors the inflammatory process of copd is characterised by a continued migration of inflammatory cells (mainly neutrophils) from the blood vessel to the lungs. neutrophil migration is a carefully regulated series of events involving cytokines and adhesion molecules including the selectins (l-, p-and e-selectin), intercellular adhesion molecule- (icam- ) and vascular cell adhesion molecule- (vcam- ). the migration has been described as a multistep process including slow rolling, adhesion strengthening, intraluminal crawling and finally paracellular or transcellular migration through the endothelium. the initial rolling is mediated by l-selectin (cd l) expressed on neutrophils, and eselectin and p-selectin expressed on the endothelium. the main ligand for these selectins is the p-selectin glycoprotein ligand (psgl)- (cd ) expressed on neutrophils and certain endothelial cells. furthermore, e-selectin binds e-selectin ligand (esl- ) and cd on the neutrophil surface, cause the slow rolling of the neutrophil. next, firm adhesion is mediated through, for example, the macrophage antigen- (mac- /cd b) expressed on neutrophils and its ligand icam- expressed on the endothelium. after the neutrophil has been fully arrested, the adhesion of the neutrophil to the endothelial surface is strengthened. stable binding of ligand to vla- (a b -integrin) is rapidly increasing neutrophil infiltration of the inflamed tissue, implicating that internal signals are required for increased adhesion. the third step, intravascular crawling, involves cd b and other β -integrins. prior to the final step, transendothelial migration, vcam- and icam- form the so-called docking structures on the endothelial cells. for the final transendothelial migration, the interaction between two platelet/ endothelial cell adhesion molecules (pecam)- , expressed at the endothelial cell boundary and on neutrophils, is essential for the ultimate transendothelial migration. , selectin l, e and p have been found in copd. psgl- levels were higher in all stable copd patients than those in in healthy controls. increased eselectin and serum icam- have also been reported in copd patients. , during migration, the neutrophils release substantial amounts of proteinases and ros. this process is known as obligate proteolysis and is an important cause for bystander tissue damage in copd. the epidermal growth factor (egf) is a single-chain polypeptide growth factor that promotes the division of epithelial cells and other cells by binding to a specific epidermal growth factor receptor (egfr) on target cells to stimulate and maintain a series of cell growth, proliferation and transformation processes. chronic inflammation increases levels of egfr and its ligands. the expression and activation of egfr are positively correlated with the airway epithelial goblet cell proliferation and mucus production. in the airways, activated neutrophils and their secretions play an important role in an egfr-dependent mucus production. activated neutrophils secrete tnf-α, which upregulates the egfr expression in airway epithelial cells and directly stimulates muc synthesis. the expression of egfr was higher in copd patients than in smokers with normal lung function, which indicated that copd was related to the overexpression of egfr. egfr and its ligand egf binding are the main causes of squamous cell metaplasia, and the growth of epithelial cells is most significant in smokers and copd. these indicate that egfr levels in the small airways of copd patients were associated with decrease in airway functionality. the transforming growth factor-β (tgf-β) family regulates cell proliferation, differentiation and the extracellular matrix synthesis. tgf-β is a chemoattractant for the neutrophils, macrophages and mast cells. tgf-β expression is significantly increased in the airway epithelial cells of copd patients, and an active tgf-β signalling is involved in copd pathogenesis. in copd patients, tgf-β promotes a fibrotic airway remodelling, which can further contribute to a diminished lung function. loss of the alveolar parenchymal tissue may be caused in part by an up-regulation of mmp expression in response to tgf-β signalling, leading to an ecm degradation. , in copd, epithelial to mesenchymal transition (emt) which is associated with airway remodelling and obliteration is activated by canonical pathways such as tgf-β, which induce expression of nuclear transcription factors psmad / and reduced inhibitory smad / expression. , tgf-β also induces and promotes the increased expression of egf, egfr and its related signalling pathways, and their synergism induces emt-related phenotypic changes. , copd and camp cyclic adenosine monophosphate (camp) is a ubiquitous secondary messenger that regulates a variety of essential processes in diverse cell types via camp-dependent effectors such as protein kinase a (pka) and/or the exchange proteins directly activated by camp (epac). epac and pka inhibit the human airway smooth muscle induced by a cigarette smoke extract (cse) by blocking the activation of the nf-κb and erk, respectively, and by releasing neutrophil chemokine il- , which together exert anti-inflammatory effects. camp also mediates the airway smooth muscle relaxation. , camp plays a key role in the functions of many airway cells including controlling ciliary beat frequency (critical for mucus clearance) in airway epithelial cells. in copd, increases in camp levels, activation of pka and enhanced protein phosphorylation have the potential to reduce inflammation and immunomodulation, relax airway smooth muscle, inhibit chemotaxis and abnormal release of inflammatory and cytotoxic mediators, and reduce proliferation and migration of inflammatory cells. phosphodiesterases (pdes) are the only way to degrade cyclic nucleotides in the body, thereby ending the biochemical effects conducted by these second messengers (camp or cgmp). in the balf from copd patients, camp levels are decreased while pde levels are increased. these indicate that camp is regulated via pdes, and two direct downstream effectors of camp (pka and epac). copd and peptide factor copd also includes a gradual increase in pulmonary arterial pressure, and - % (depending on the definition, severity and measurement of copd) have developed pulmonary hypertension. endothelin- (et- ) is an effective vasoconstrictor produced by endothelial cells, which can stimulate the contraction and proliferation of vascular smooth muscle cells. the synthesis and secretion of endothelin in patients with copd increase, and during the exacerbation of copd, the level of endothelin further rises and participates in the formation of pulmonary hypertension. , et- can also stimulate the liver to produce more c-reactive protein (crp) by up-regulating il- . crp further stimulates the release of a variety of biologically active substances, such as endothelin- , il- , etc. amplify the inflammatory effect. , in addition, et- can also participate in the pathological process of copd by inducing the synthesis of vascular permeability factor (vegf). the family of natriuretic peptides includes a-type natriuretic peptide, b-type natriuretic peptide (bnp) and c-type natriuretic peptide (cnp). bnp and cnp play a major role in the occurrence and development of copd. bnp antagonises the renin-angiotensin-aldosterone system, dilates blood vessels and reduces peripheral vascular resistance. cnp also has a strong vasodilator effect and inhibits the proliferation of vascular smooth muscle cells. cnp can block the synthesis of vegf induced by hypoxia and endothelin at the transcriptional level, thereby inhibiting vegf-mediated hyperplasia of endothelial cells. it may play an important role in the development of pulmonary hypertension. copd and the nf-κb pathway the transcription factor nf-κb is studied in systemic inflammation and has been noticed in copd patients. in an inactivated state, nf-κb is located in the cytosol and is complexed with the inhibitory protein inhibitor kappa b (iκb). there are a number of different iκb proteins such as iκbα, iκbβ, iκbγ, iκbɛ and bcl- . iκbβ is only phosphorylated by certain stimuli including lps (lipopolysaccharide) and il- β, whereas iκbα phosphorylation is triggered by most nf-κb activators. when a variety of extracellular stimuli act on receptors of the respiratory epithelium, iκb kinase (ikk) is activated. ikk, in turn, phosphorylates iκbα, resulting in ubiquitination and dissociation of iκbα from nf-κb. nf-κb (p and p ) is then translocated into the nucleus where it binds to specific sequences of dna to cause an inflammatory response. , nf-κb activates proinflammatory genes encoding cytokines and chemokines, such as il- β, il- and tnf-α. the cytokines produced by nf-κb pathway play essential roles in inflammatory cell migration and strengthen oxidative stress during copd development, further aggravating the condition. , both passive smoking and an intratracheal infusion of lps induce copd in rats via the nf-κb signalling pathway. in respiratory tract biopsies from copd patients, activated nf-κb levels were significantly higher than that of normal people, while the level of iκb in the lung tissue from smokers or copd patients was significantly lower than that of non-smoking healthy individuals. overexpression of ikk-β in mouse airway epithelial cells results in an increase in inflammatory mediators and neutrophilic inflammation that is reminiscent of the copd airway following bacterial challenge. in addition, inhibition of ikk-β in vivo and in vitro reduced tnf-α induced muc ac production. this indicates that the nf-κb pathway plays an important role in the occurrence and development of copd. copd and the p mapk p mapks are members of the mapk family activated by a variety of environmental stresses and inflammatory cytokines. it seems to be the most effective mapk, in stabilising, at post-transcriptional level, the mrnas for cytokines and chemokines relevant to copd pathogenesis. p mapks are divided into four subtypes: p α, p β, p δ and p γ. different subtypes are expressed in different tissues, and p α is most abundant in inflammatory cells. cs, lps, inflammatory factors and oxidative stress activate the p mapk pathway. in the airways and sputum of patients with copd, p mapk was significantly increased, and its activation was related to the severity of copd. in addition, the common pathogenic bacteria of copd, nontypeable haemophilus influenzae, contains cytoplasmic proteins that up-regulate human muc ac mucin transcription via a positive p mapk pathway and a negative phosphoinositide -kinase-akt pathway. the activation of p mapk associated with the degree of lung function impairment and alveolar wall inflammation. bacterial or viral infection is a common trigger for copd exacerbations, and exposure to lps induces p mapk activation in rat peritoneal macrophages and dendritic cells as well as an increase expression of inflammatory mediators. , glucocorticoid resistance in copd patients may also be related to the p mapk pathway through phosphorylated glucocorticoid receptor (gr) reducing gr translocation into the nucleus and dna binding, impairing the gr function. , the anti-inflammatory effects of corticosteroids are mediated by gr, and functional impairment of gr is an important mechanism of glucocorticoid resistance. copd and the pi k/akt pathways the phosphatidylinositol kinase (pi k) pathway is a major pathway regulating cell growth, proliferation, metabolism, survival and angiogenesis. serine/threonine kinase (akt), also known as protein kinase b, is an enzyme consisting of a ph domain, a kinase catalytic domain, and a regulatory domain that covalently attaches atp-phosphate groups to the serine/threonine of protein substrates to alter target protein activity. activated pi k phosphorylates phosphatidylinositol diphosphate to produce the secondary messenger phosphatidylinositol , , triphosphate, which binds the ph domains of akt and phosphoinositide dependent kinase- . akt undergoes a conformational change and is transferred to the plasma membrane, leading to akt activation. activated akt regulates cellular functions by phosphorylating various downstream factors including enzymes, kinases and transcription factors. , dysregulation of akt activity impacts on all these essential cellular processes, such as cell growth, survival and inflammation. the pi k/akt signalling pathway plays an important role in copd by regulating inflammatory cell activation, inflammatory mediator release and airway remodelling. the regulation of pi k/akt pathway in neutrophil restore some key copd neutrophil responses. pi k/ akt pathway regulates macrophage polarisation in emphysematous mice generated by cs exposure combined with intraperitoneal injection of cse. ecm proteins promoted proliferation, migration and adhesion of airway smooth muscle cells form rat models of copd through activation of the pi k/akt signalling pathway. ros activates pi k, initiating the pi k/akt signalling pathway. pi k/akt pathway plays an important role in the activation of nrf , which regulates oxidative stress and inflammation in copd. the persistent airway and lung inflammation of copd is related to a decreased histone deacetylase activity (mainly hdac ) caused by oxidative stress. up-regulation of pi kδ/akt signalling reduces the hdac activity, promoting the transcriptional activation of inflammatory genes. another study found that down-regulation of hdac is associated with glucocorticoid resistance. as the inflammatory signalling pathways closely associated with copd development have been elucidated, most candidate therapeutic drugs developed in recent years are molecular drugs targeting these signal transmitting substances. the following sections outline new copd treatment strategies (fig. ). oxidative stress plays a crucial role in the pathogenesis of copd. in the exhaled breath condensate of copd patients, the levels of oxidative stress markers such as hydrogen peroxide (h o ) and isoprostaglandin ( -ip) are significantly increased. through in vivo experiments, antioxidants have been shown to inhibit copd onset. n-acetylcysteine (nac) and other glutamines have been clinically tested in this regard. despite evidence of the beneficial role of nac in copd, its therapeutic efficacy in clinical management of copd has remained controversial due to its reduced bioavailability in an oral form and its acidic nature prohibiting its use in an inhaled form. in addition, the lack of assurance that there is an effective concentration of glutathione in the lung is another major reason for not achieving the desired therapeutic effect. other antioxidant enzymes, such as superoxide dismutase and glutathione peroxidase, have good antiinflammatory effects on smoking-induced lung inflammation in animal models, and clinical trials are underway. copd is also affected by oxidative stress and nitrosative stress. therefore, nitric oxide synthase inhibitors being developed for acute diseases may also be suitable to treat copd. the antioxidant transcription factor nrf downregulates inflammation-associated production of ros and reactive nitrogen species. nrf -deficient mice exposed to cs had more extensive emphysema and more pronounced airway inflammation than wild-type mice. as a small molecule nrf activator, sulforaphane increased the gene expression of nrf , reduced the level of ros, and prevented the damage of cse-treated alveolar epithelial cells. the natural product sulforaphane activated nrf in alveolar macrophage isolated from copd patients denitrify hdac and restore the sensitivity to the glucocorticoid dexamethasone in a glutathione-dependent manner. unfortunately, sulforaphane applied for weeks to patients with copd did not induce the expression of nrf genes or have an effect on oxidative stress, airway inflammation or lung function. resveratrol is a natural sirt activator. in the rat model of copd treated with resveratrol, serum il- and il- levels were decreased and lung inflammation was inhibited. in addition, resveratrol activation of sirt also downregulates the activity of mmp in fibroblasts in copd. in recent years, it has been found that srt is a compound that can activate sirt , which can improve lung function and reduce lung damage caused by cs (table ) . regulating the imbalance between proteases and their inhibitors has attracted much attention as a treatment for copd. mmps which degrade elastin are a target for drug development. nonspecific mmp inhibitors are mainly developed as anticancer agents, but they have been reported to cause side effects such as arthritis, so long-term use as a copd treatment drug may have hidden dangers. mmp- is a member of the mmp family and its endogenous inhibitor is timp- , which binds the carboxyl terminal of the catalytic centre of mmp- to form an enzyme-inhibitor complex through noncovalent bonding. both are key enzymes regulating ecm degradation and synthesis, and changes in their concentrations are closely related to an airway inflammation damage. through culturing balf cells of copd patients with healthy individuals, it was found that mmp- release by macrophages in copd patients was significantly increased while healthy control macrophages released more timps. selective inhibitors of mmp- are also being developed and have proven to be effective in treating copd in animal models, but have not been effective in clinical trials of copd. ne inhibitors are also a valuable potential therapeutic drug, which can not only protect the lung from ne-mediated tissue damage, but also control the exuberant inflammatory response. japan approved sivelestat (ono- ) for the treatment of ali and ards. however, many countries have not approved siveles for clinical use, due to the uncertainty of the randomised doubleblind trial results. other promising ne inhibitors have also been stopped for various reasons. azd ( weeks) combined with budesonide/formoterol has no effect on lung function, quality of life and lung function in copd patients (table ) . the levels of il- β, il- , tnf-α and il- are significantly increased in the sputum and serum of copd patients. they may also be a therapeutic target for copd. as a human anti-il- β monoclonal antibody, canakinumab ( -week treatment) showed no statistical analysis provided for lung function changes. the receptor inhibitor tocilizumab is an available il- inhibitor with confirmed efficacy in rheumatoid arthritis, fig. new molecular targeted drugs. based on the molecular mechanism of copd, many new molecular targeted drugs have been developing in recent years. antioxidants scavenge ros and inhibit oxidative stress in the lungs and reduce cellular damage and inflammation. protease inhibitors restore the balance between protease and anti-protease by inhibiting. proteases. cytokine and chemokine inhibitors play an important role in reducing the inflammatory response. adhesion molecule inhibitors can block inflammatory cells, which continuously migrate from the blood vessels to the tissue. pde inhibitors inhibit pde production to increase the camp activity in cells. in the occurrence and development of copd, the signalling molecules, such as nf-κb, mapk, pi k and vip help regulate inflammation and airway remodellings, and represent plausible targets for the development of therapeutic candidates. candidate drugs include inhibitors of p mapk, nf-κb and pi k, and vasoactive intestinal peptide (vip). the inhibitor of egfr reduces internalisation of egfr but does not reduce mucin stores. tgf-β inhibitor reduces a fibrotic airway remodelling and downregulates mmp expression, endothelin inhibitors prevent the progression of pulmonary hypertension in copd. adenosine a a receptor inhibits neutrophil superoxide production, phagocytosis, adhesion and cytokine release. macrolides reduces the inflammation of copd by regulating the pi k/akt-nrf pathway and control transcription factors such as nf-κb and ap- to inhibit the production of inflammatory cytokines. ppar agonists exert antioxidant and anti-inflammatory effects by downregulating nf-κb and other pro-inflammatory transcription factors but clinical trials in copd require further study. endogenous tnf-α plays an important role in the development of pulmonary fibrosis and causes a secondary interstitial lung disease. as anti-tnf-α therapies, the tnf-α antibody (infliximab) and soluble tnf-α inhibitor (etanercept) have been used as clinical drugs, mainly to treat inflammatory diseases such as rheumatoid arthritis; and the same clinical dose of the tnf-α antibody used in rheumatoid arthritis has a definite effect on bronchial asthma, but has not been confirmed in copd. in contrast, copd patients had significantly increased incidence of airway tumours and lung infections caused by tnf-α antibodies, presenting a difficult problem to be overcome with future anti-tnf-α treatments. inhibitors of the il- receptor cxc chemokine receptor (cxcr ) effectively block neutrophil infiltration in the lung tissue in animal models and clinical trials. cxcr inhibitors block neutrophil invasion and inhibit mucus production and airway remodelling. however, it should be noted that cxcr inhibition triggers side effects similar to those exhibited by the use of glucocorticoids, such as promoting bacterial/ fungal infection and delaying wound healing. currently, there are clinical trials in progress for the cxcr receptor antagonists in copd, bronchial asthma and cystic fibrosis. ccr has an affinity for multiple chemokines, including (mip- α/ ccl ) and regulated on activation, normal t-cell expressed and secreted (rantes/ccl ), which are both elevated in lungs of copd patients. , ccr antagonists have been developed and are in clinical trials for autoimmune diseases. ccr which is the only receptor for (mcp- /ccl recruits inflammatory cells to lungs in copd, and increases synthesis of muc ac and muc b. the levels of both ccr and mcp- /ccl mrna were increased in bronchial epithelium of copd patients. mcp- /ccl production upon cigarette smoke exposure were increased in a mouse model of copd, ccr inhibitors for copd have been studied, but statistical analysis not released. ltb is elevated to some extent in the balf, sputum, serum and lung tissues of copd patients, and is positively correlated with the copd severity. several inhibitors are under development, one of which has entered clinical trials, but no effective anti-inflammatory effect has been demonstrated. in recent years, a -lox inhibitor upstream of ltb has been under development for bronchial asthma, but current -lox inhibitors have problems such as lack of selectivity, structure-activity relationships, methaemoglobin formation, and poor efficiency and oral availability. it should be noted that inhibiting ltb biosynthesis at the level of -lox or flap removes the lta intermediate. however, the latter molecule is an important intermediate in the biosynthesis of anti-inflammatory lipoxins, potentially reducing the net anti-inflammatory effect. in addition, some lta h inhibitors are also being developed , because these have been suggested to block ltb production while preserving lta , allowing shunting into lipoxin a . this features may make lta h inhibitors superior therapeutic molecules as compared with -lox or flap inhibitors (table ) . in the inflammation process of copd, selectins are essential for the migration of inflammatory cells from the bloodstream into the pulmonary tissue. therefore, targeting these molecules may inhibit the inflammatory process of copd. although several selectin inhibitors have been tested in clinical trials for bronchial asthma protect the lung from ne-mediated tissue damage and control the exuberant inflammatory response azd ( weeks) combined with budesonide/ formoterol has no effect on lung function, quality of life and lung function in copd patients patients, they have not proven to be effective. bimosiamose, a pan-selectin antagonist, blocks the adhesion of neutrophils, eosinophils and lymphocytes in vitro, and has anti-inflammatory effect in animal models of lung inflammation. bimosiamose inhalation has good safety and tolerance for copd patients. it reduces the levels of il- and mmp- in the sputum and reduces the number of neutrophils, reduces airway inflammation and improves the lung function, thus warranting further testing. el is an antiselectin monoclonal antibody that recognises specific positions on the e and l selectins to inhibit cell adhesion. el is currently being developed as a therapeutic drug for acute exacerbation of copd. it is clear that further studies are required to demonstrate the true clinical benefits of bimosiamose and el in copd patients. because e, l, p selectins recognise and bind to epitopes containing the carbohydrate sle x of glycoprotein or glycolipidon on a cell surface. a clinical study of -o, -o desulfated heparin (odsh or pgx- ) which is a carbohydrate-based drug was performed in phase ii for copd. however, the trial has been terminated because the interim analysis showed that odsh had no effect on the safety of patients with acute exacerbation of copd (table ) . egfr and tgf inhibitor egfr regulates mucin stores in airway epithelium, which are significantly increased in copd. bibw is the inhibitor of egfr, and inhalation of bibw ( -week treatment) reduced internalisation of egfr but did not reduce mucin stores. inhibition of tgf-β signalling may also be a useful therapeutic strategy in copd. the bone morphogenic protein and activin membrane-bound inhibitor (bambi) is a transmembrane glycoprotein, which acts as a negative regulator of tgf β signalling. bambi is induced by members of the tgf family-²-catenin, smad and smad , acting as a pseudoreceptor. bambi expression as significantly stronger in copd patients and that increased plasma bambi levels in copd patients displayed excellent correlations with enhanced plasma tgf-β levels. the because the mechanisms regulating bambi expression are poorly understood, the clinical trail of bambi is not developed. in addition, small molecule antagonists which inhibit tgf-β receptor kinase or tgf-β activated pathways were studied, , although the long-term safety of such drugs might be a problem, particularly as tgf-β affects tissue repair and is a potent anti-inflammatory mediator (table ) . pde inhibitors pde inhibitors have a selective inhibitory effect on pde specifically expressed in inflammatory, airway smooth muscle and epithelial cells. its main biological effects are selective inhibition of pde , leading to increased camp levels in inflammatory cells, regulating the activity of inflammatory cells and regulating the release of inflammatory factors to exhibit antiinflammatory effects. they have been developed as new antiinflammatory drugs for copd and asthma since the s. the pde inhibitor roflumilast has been approved by the food and drug administration as a copd treatment. it was shown roflumilast reduced the diffuse emphysema induced by cs in mice as compared with that in the control group. other studies have found that roflumilast inhibits bleomycin-induced pulmonary fibrosis in rats and reduces pulmonary vascular remodelling. , clinical trials have proven that roflumilast relieves the symptoms of dyspnoea in copd patients and reduces the frequency of acute attacks. once-daily administration of roflumilast significantly improves forced expiratory volume in s and decreases exacerbations, particularly in patients with severe disease, , but has side effects such as nausea, vomiting and headache. there are mainly four subtypes of pde , a to d. in recent years, the antiinflammatory effect of pde inhibitors has been shown to be mainly related to pde b while pde d is related to side effects such as digestive tract symptoms. the development of new pde b subtype-specific agents is expected, and inhalants that reduce systemic side effects are also being developed. in addition, oher pde inhibitors is being developed now [ ] [ ] [ ] [ ] (table ) . endothelin signalling plays a major role in pulmonary hypertension secondary to copd. endothelin antagonises bosentan (treatment for months) can alleviate the condition of copd patients and prevent the progression of pulmonary hypertension. this effect is more significant in gold iii and iv patients. but for copd patients without pulmonary hypertension, bosentan will aggravate their hypoxaemia. at present, further research on the role of bosentan in patients with gold iii or iv copd and pulmonary hypertension in the acute exacerbation phase is ongoing, but its status is unclear (table ) . vasoactive intestinal peptide vasoactive intestinal peptide (vip) has been characterised as a vasodilatory peptide. it exerts a wide range of biological actions, such as bronchodilation, anti-inflammatory effects, via binding its receptor vpac or vpac to increase significantly camp, adenylate cylase and phospholipase c, which cause different downregulation on a variety of transcription factors. vpac receptor mrna is abundant in lung and t lymphocytes. vpac receptor is mainly distributed in the smooth muscle layer and the base of mucosal epithelium in lung. vpac was particularly elevated in alveolar macrophages of copd patients. vpac receptor was activated by vip, and inhibited the cseinduced cytotoxicity of rat lung alveolar l cells. increased serum vip levels are associated with acute exacerbation of copd patients. vip has significant therapeutic potential in the treatment of copd. how, it clinical application might be limited because of the short half-life of plasma after intravenous administration and the difficulty of routes. (table ) . adenosine a a receptor agonist adenosine is a natural purine nucleoside that is ubiquitous in human tissues and plays a key role in many biological processes, such as energy production and protein metabolism. at present, four subtypes (a , a a , a b and a ) of adenosine receptors have been cloned. the anti-inflammatory effect of adenosine is mainly attributed to occupancy of camp-elevating gs-protein-coupled , [ ] [ ] [ ] [ ] [ ] bosentan blocks endothelin receptor. bosentan ( months) can alleviate the condition of copd patients and prevent the progression of pulmonary hypertension. this effect is more significant in gold iii and iv patients. but for copd patients without pulmonary hypertension, bosentan will aggravate their hypoxaemia. , solithromycin decrease the production of proinflammatory cytokines and chemokines by epithelial and immune cells a macrolide antibiotic. no data of solithromycin ( days) collected for this outcome due to early termination of the trial (nct ) ppar agonists regulates function of multiple cells of the immune system. pparγ agonists includes troglitazone, rosiglitazone, and pioglitazone. pparα agonists includes clofibrate and fenofibrate. patients who took more than two thiazolidinediones ( . % rosiglitazone) had significantly less copd deterioration than patients receiving other diabetes drugs. results information of clinical trail (february, months) has been submitted to clinicaltrials. gov by the sponsor or investigator, but is not yet publicly available on clinicaltrials.gov (nct ) , a a-receptors. the key molecular mechanism is the suppression of nf-κb pathway activated by cytokines such as tnf-α and il- β. a a receptor plays an anti-inflammatory role in specific cells and various inflammation models. knockout of the a a receptor gene will cause mucus production, airway destruction and lung inflammation. currently, several adenosine a a receptor agonists have been proven effective in copd models, but there are cardiovascular side effects. a phase , randomised, double-blind study (nct ) assessed the safety of the selective adenosine a a receptor agonist, regadenoson, compared with placebo in subjects with asthma or copd, and the result showed randomised did not modify repeated forced expiratory volume in s (fev ) when compared to placebo. uk , , which is beneficial in the lungs of anaesthetised guinea pig without any obvious cardiovascular sideeffects. phosphorylated a a receptor agonists are under development to reduce adverse effects such as hypotension (table ) . macrolide antibiotics are secondary metabolites of a variety of actinomycetes bacteria. the molecule contains a - -membered macrolide structure, which has a wide range of functions. it has not only antibacterial function, but also anti-inflammatory effect, inhibition of mucus secretion and immune regulation. , the anti-inflammatory and immunomodulatory functions are mainly -ring and -ring. clinically, they are used for long-term treatment of chronic inflammatory lung diseases such as copd. the anti-inflammatory mechanism of macrolide antibiotics is complex and has not been fully elucidated. it may reduce the inflammation of copd by regulating the pi k/akt-nrf pathway and control transcription factors such as nf-κb and ap- to inhibit the production of inflammatory cytokines. animal models provided further evidence that clarithromycin has an inhibitory effect on the development of emphysema, and its dose is almost the same as the clinical dose. the potential benefit of a new antibiotic, solithromycin was studied for the long-term treatment of copd, but due to the early termination of the study, there were too few subjects and data collected to perform statistical analysis. other macrolides without anti-bacterial activity are being developed as anti-inflammatory drugs and clinical trials are expected in the future (table ) . ppar agonists peroxisome proliferator activated receptors (ppars) are ligandactivated nuclear hormone receptors belonging to the steroid receptor superfamily, including three recognised subtypes (pparα, pparγ and pparδ). the activation of pparγ and pparα may have anti-inflammatory and immunomodulatory effects. pparγ exert antioxidant and anti-inflammatory effects by down-regulating nf-κb and other pro-inflammatory transcription factors. cigarette smoke will down-regulate the expression of pparγ, and the level of pparγ in the lung tissues of copd patients is significantly lower than that of normal people. pparγ agonists, such as the thiazolidinediones, rosiglitazone and pioglitazone, have been shown to reduce lung inflammation in mouse models of tobacco smoke, and studies have found that treating model mice with thiazolidinedione can reverse emphysema. , in addition, pparγ agonists can also inhibit pulmonary fibrosis, which is expected to be a drug to prevent small airway fibrosis in copd. a retrospective epidemiological study showed that diabetes patients treated with pparγ agonists have a significantly reduced risk of copd exacerbation, but their risk of cardiovascular risk events has also increased. in addition, only large doses of thiazolidinediones can produce anti-inflammatory effects, which leads to speculation about the correlation of pparγ stimulation in copd. non-thiazolidinedione pparγ ligands are currently being studied to reduce potential cardiovascular risks. pparα agonists, such as fenofibrate, may have therapeutic potential in the treatment of systemic symptoms of copd (table ) . a japanese drug discovery company is developing a compound code named imd- , which is an ikk β inhibitor developed for the treatment of copd, but has no follow-up information posted since april . it is unclear whether study was performed. bms- is a highly selective ikk inhibitor with good pharmacokinetic characteristics. in the human airway smooth muscle cells, co-incubation with bms- markedly inhibited the nf-κb nuclear translocation induced by tnf-α and il- . ps- induce a dose-dependent inhibition of phosphorylated ikbα and nf-κb activation, and then reduces the expression of adhesion molecules, cytokines and chemokines on airway smooth muscle cells. a small molecule ikk inhibitor is under development as a therapy for inhibiting the nf-κb activity. the effectiveness of ikk inhibitors has been verified in animal models of copd; and clinical trials of ikk inhibitors in patients with bronchial asthma and joint rheumatism have also been conducted. ikk inhibitors are expected to be used as a new therapeutic drug for copd in the future following in-depth research. further developments include nf-κb "decoy" oligonucleotides and antisense and small interfering rna agents. , in addition, nf-κb-deficient mice have been reported to be more prone to sepsis, hence complications such as immunosuppression and infection susceptibility caused by long-term nf-κb inhibition must be considered (table ) . as a new type of anti-inflammatory drug, p mapk inhibitors have attracted much attention from researchers. currently, various small-molecule p mapk inhibitors have been developed and verified in animal models of smoking-induced pneumonia, proving their beneficial anti-inflammatory effects. inhibiting p mapk activation has been found to reduce the cs-induced airway smooth muscle cell proliferation, suggesting that p mapk inhibitors may reduce the progression of copd airway remodelling. p mapk inhibitors also reduce cytokine production by alveolar macrophages. in addition, there is evidence that corticosteroids cannot inhibit p mapk activation, and that p mapk inhibitors combined with corticosteroids enhance the inhibitory effect of corticosteroids on cytokines produced by macrophages in patients with copd mediated by lps. p mapk inhibitors have a unique advantage in patients with a poor hormone response. a days trial of p mapk inhibitor sb in patients with moderate stable copd reduced sputum neutrophils and plasma fibrinogen with improvement in forced vital capacity. the patients with moderate to severe copd receiving p mapk inhibitor ph for week decreased serum crp levels, and induced a significant increase of fev and a concomitant improvement in dyspnoea score. each subtype of p mapk has unique functions due to differential expression across tissue types and different regulatory kinases and downstream genes, hence their targeting comes with adverse effects. although some clinical trials are in progress, due to severe side effects such as those caused by an undesired pharmacological activity, suppression of the innate immune response to viral and bacterial infections, and damage to the central nervous system and liver, , these drugs remain challenging for a clinical application. there is a need to develop inhaled formulations and selective inhibitors of the α-δ subgroups. the inhaled narrow spectrum kinase (p α + src family) inhibitor (jnj /rv ) in patients with moderate to severe copd decreased serum crp levels as well as improved trough fev and dyspnoea index scores. however, p αmapk inhibitors block the upstream mapk kinase kinases, leading to hyperactivation of the transforming growth factor-activated kinase- and mixed-lineage kinase which then hyperactivate the jnk. therefore, other drugs that target more downstream substrates should be also developed (table ) . pi k inhibitors pi k is divided into three categories, namely classes i, ii and iii, among which class i pi k is most widely studied. class i pi k is a heterodimer composed of a regulatory subunit (p ) and a catalytic subunit (p ). there are four types of catalytic subunits: p α, p β, p δ and p γ, and while δ and γ subunits are limited to white blood cells, α and β subunits are widely distributed in various cells. pi k, especially pi k δ and γ subtypes, are closely related to a copd inflammation. pi k inhibitors reduce nitric oxide production by inhibiting carbon monoxide synthase. studies have shown that interruption of the pi k pathway improves severe copd protease imbalance. aerosolized tg - , a compound that selectively blocks pi kγ and pi kδ, inhibits pulmonary neutrophils induced by intranasal lps and smoke in mice with chronic obstructive pulmonary disease. as is a selective inhibitor of pi kγ, which reduces the migration of polymorphonuclear leucocytes in vitro and the infiltration of polymorphonuclear leucocytes in the lungs of mice with lps induced lung injury. the interventional therapy of tg - was successful even in steroid resistant copd induced by smoking in mice. various pi k inhibitors are currently being used in clinical trials, primarily for malignant tumours. , in recent years, inhaled pi kγ/δ inhibitors have been reported to inhibit pneumonia caused by smoking in animal models and have been especially effective and safe for patients with glucocorticoid contraindications. specific pi kδ inhibitors, gsk and rv are being developed, and studies on the effects of such inhibitors in copd are in progress. efficacy data remain limited. , in contrast, even selective p k subtype inhibitors have the risk of immunosuppression and secondary bacterial infections, and reducing the occurrence of side effects will be an important issue (table ) . trx is a multifunctional protein consisting of amino acids with a molecular weight of kda and a highly conserved cys-gly-pro-cys active site. trx exists in two forms: oxidised (trx-s ) and reduced (trx-(sh) ). trx-s can be reduced to trx-(sh) by the exchange reaction of -ss-and -sh under the action of thioredoxin reductase (trxr) and nicotinamide adenine dinucleotide phosphate (nadph). trx cooperates with trxr and nadph to form the trx system. trx catalyses the reduction of disulphide bonds and quenches ros by coupling with trx-dependent peroxidases or peroxiredoxins. in addition to its antioxidant effects, trx has a crucial role in the redox regulation of cellular signalling and activation. trx is involved in various redox-dependent cellular processes such as gene expression, signal transduction, cell growth, apoptosis and interacts with various target molecules. , under stress conditions, trx is released into the extracellular space where it exerts a cytoprotective effect and cytokine-like activities. trx expression in the sputum of copd patients is positively correlated with the degree of hypoxia. mice that overexpress human trx can effectively inhibit a cs-induced emphysema and pulmonary inflammation. intraperitoneal injection of trx suppress a smoke-induced murine pulmonary inflammation by inhibiting the production and release of cytokines, inflammatory mediators, chemokines and ros. trx inducer increases the trx expression in murine lung tissue and improves lung injury. recent research has also shown that inhaled trx also reduces a smoke-induced chronic lung injury. currently, clinical trials targeting acute lung diseases have entered the preparation stage. at the same time, as a pre-clinical trial of copd, intravenous infusion therapy for acute exacerbations, protein inhalation therapy for stable phase, and oral administration of inducers are also underway. adenosine a a receptor exert anti-inflammatory effect by enhancing camp regadenoson group ( months) occurred with higher incidence of dyspnoea, and unable to modify repeated fev when compared to placebo ((nct ). uk , is beneficial in the lungs of anaesthetised guinea pig without any obvious cardiovascular sideeffects. but uk- ( -week inhaled treatment) in dbpcrt showed no significant improvement in fev and quality of life parameters (nct ). , , progress in the mechanism and targeted drug therapy for copd wang et al. adjusting the redox balance trx plays an important role in maintaining the body's redox balance. trx can be used as an electron donor to reduce h o and tertiary butyl hydroperoxide. in addition, when the body's peroxidase reduces hydrogen peroxide, trx is also needed to provide a certain reduction equivalent. further, there are other redox systems similar to the trx system in the body, such as the glutathione (gsh) system. the trx system and the gsh system jointly control the redox system. the equilibrium state of the environment, and the trx and gsh systems cross each other to provide electrons and serve as a compensation system. , in addition, trx and thioredoxin-interacting protein (txnip), a negative regulator, constitute a redox-like protein compound (redoxisome) that regulates a variety of redox-sensitive signals and is essential for maintaining the intracellular and extracellular redox balance and monitoring inflammatory responses. without an oxidative stress, txnip is in a bound state with trx. when the intracellular ros content increases, trx and txnip are dissociated, and trx bind to ros. dissociated txnip combines with and activates the nlrp inflammasome to induce il- β expression in a nlrp -asc-caspase- -dependent manner, thus causing inflammatory reactions. this signalling complex may be a key regulatory mechanism for the body to regulate cellular redox balance and prevent the progression or exacerbation of stressinduced diseases. regulating the protease balance both endogenous and exogenous trx inhibit and improve a protease-induced emphysema. mmp- and mmp- play important roles in copd. oxidative stress upregulates the mmp- expression while trx inhibits mmp- via its antioxidant properties. , the mechanism may be inhibition of p mapk and jnk. in addition to inhibiting mmp, trx also inhibits its inhibitor, timp. studies have found that trx has a differential inhibitory effect on mmp- , mmp- , timp- and timp- , thereby regulating the mmp/timp balance. trx suppresses mmp and timp by reducing their activity but not degrading timp and mmp. , the activity of timp- , timp- or mmp- was not inhibited by a version of trx lacking a disulphide reductase activity or trx with a trxr deficiency. , this indicates that trx regulates the mmp/timp balance by differentially inhibiting the activities of timp and mmp, and this process depends on the redox active sites of trx and trxr. regulating inflammatory cells, cytokines and chemokines trx inhibits the migration and activation of inflammatory cells such as neutrophils, reduces the release of inflammatory factors, and reduces the inflammatory response. both in vivo and in vitro studies have shown that trx inhibits the chemotaxis of macrophages, lymphocytes, and neutrophils. , during copd development, the neutrophils and alveolar macrophages are activated to produce various inflammatory mediators, including il- β, il- , il- and tnf-α. trx significantly inhibits the production and release of il- β, il- , il- and tnf-α induced by lps in the human monocyte-derived macrophages. this is achieved by trx blocking the nf-κb pathway or inhibiting an inflammatory signal activation by cell surface molecules. , the specific mechanism of action has been thoroughly explained in our previous article. regulating adhesion factors and growth factors l-selectin (cd l) is a shedding molecule on neutrophils that plays a vital role in guiding neutrophils to adhere to the vascular endothelium and penetrate the blood vessels. trx inhibited the lpsinduced downregulation of l-selectin exfoliation on neutrophils and reduced the l-selectin attachment to endothelial cells whereas double-mutant trx c s/c s did not inhibit neutrophil adhesion to the endothelial cells. in a rat model of lps-induced inflammation, systemic trx significantly reduced neutrophil infiltration in the bronchus and lung tissues, but did not directly reduce the increased lps-induced icam- present on the endothelial cells. trx undergoes oxidation in response to egf. the local and specific oxidation of trx occurs during the ros signalling produced by egf stimulation. egfr signal transduction requires a special endoplasmic reticulum trx to control receptor expression on the cell surface. intracellular trx inhibits egfr synthesis and activation. tgf-β activates smad / , pi k/akt, erk / , gsk- β and/ or p mapk signalling to induce pulmonary fibrosis and emt. , trx inhibits the mpk -induced tgf-β function in a phosphorylation-dependent mannerm. trx inhibits bleomycininduced skin fibrosis by down-regulating tgf-β. trx overexpression inhibits airway remodelling by inhibiting tgf-β and egfr. regulating camp camp plays a protective role in copd inflammation through its effector proteins epac and pka. in animal models of brain injury, trx protected the astrocytes by activating camp-pka and inhibiting astrocyte apoptosis. down-regulating the trx gene inhibits the camp-pka pathway to cause apoptosis, exacerbating astrocyte damage caused by an oxygen-glucose deprivation/ reoxygenation in vitro. trx is necessary for the nerve growth factor (ngf) signalling through its camp responsive element to drive expression of c-fos, which has been hypothesised to be critical for the function of ngf. pka activity is inhibited by the hydrogen peroxide formed by insulin but activated by trx, which restores the newly formed -ss-bond of pka to the -sh group. we suggest that trx may also protect lung cells by acting on the camp-pka pathway in copd. regulating the nf-κb and mapk pathways trx suppresses the inflammatory response by regulating the nf-κb and mapk pathways. trx modulates nf-κb activity and plays different roles extracellularly and intracellularly. inhibiting the nuclear trx blocks the nuclear activities of nf-κb and ap- dependent transcription factors and reduces neutrophil invasion and tnf-α production. extracellular trx inhibits the production of p and p and promotes iκb synthesis by acting on cell membrane surface receptors to limit nf-κb activation and translocation into the nucleus, thereby blocking the nf-κb pathway. trx inhibits eotaxin-induced phosphorylation of extracellular signal-regulated kinase / and p by reducing the activation of erk / and p mapks. under normal conditions, trx binds to the n-terminal region of the apoptosis signal-regulating kinase (ask ). ask is a member of the mapk kinase family and elicits a wide variety of cellular responses to various types of stress by activating the jnk and p mapk pathways. under oxidative stress, trx separates from ask , activating ask . this indicates that trx acts as an upstream inhibitor of ask , and trx/ask signalling is an upstream modulator of p mapk. trx suppresses p mapk activation in the lps-stimulated neutrophils. in addition, ros exacerbates airway inflammation by activating inflammatory mediators and transcription factors, such as nf-κb, mapk and ap- . this suggests that trx regulates the p mapk pathway by removing ros. adjusting the pi k/akt signalling pathway the pi k/akt signalling pathway is a classic signalling channel that can be activated by various extracellular signals including growth factors, cytokines, and oxidative stress, and plays an important role in copd. trx inhibits the indomethacin-induced ros production and inhibits the expression of phosphorylated akt in rat gastric epithelial cells. in addition, trx deficiency reduces the expression of akt and pakt by no. the main activation signals of pi k/akt signalling are inhibited by trx, and downstream akt phosphorylation was also inhibited by trx. therefore, we suggest that trx likely plays an important role in the pi k/akt signalling pathway. improving glucocorticoid resistance copd is relatively resistant to modulation by corticosteroids; even high doses of glucocorticoid (gc) do not delay or inhibit copd progression. one mechanism of gc resistance is the impairment of gc sensitivity by the macrophage migration inhibitory factor (mif) via map kinase phosphatase- (mkp- ) inhibition. mif is part of a class of pleiotropic immunomodulatory factors with a unique structure that functions similar to chemokines and promotes inflammatory responses, directed cell migration, and release of other cellular inflammatory factors. mif may play a key role in the pathogenesis of airway inflammation. [ ] [ ] [ ] mif has at least two catalytic activities: tautomerase and oxidoreductase activities. the oxidoreductase activity of mif is closely related to the trx family. , - mkp- is an archetypal member of the dual specificity phosphatase family that inactivates the mapk activity in response to pro-inflammatory stimuli. - mkp- is induced by gc to mediate gc inhibition of erk, jnk and p mapk activities and cytokine production induced by proinflammatory stimuli such as lps or il- . [ ] [ ] [ ] it has recently been demonstrated that mif inhibits the gc-induced leucine zipper (gilz) expression via a unique set of effects on transcription factor expression and phosphorylation, and regulation by mif of mkp- and mapk activation are mediated through gilz (fig. ). fig. trx improves gc through mif. one gc resistance mechanism impaired by the mif is the loss of gc sensitivity via inhibition of mkp- . mkp- is induced by gc to mediate gc inhibition of erk, jnk and p mapk activities and cytokine production. mif inhibits gilz expression via a unique set of effects on transcription factor expression and phosphorylation. mkp- and mapk activation are regulated by mif via gilz. both intracellular and extracellular trx bind to mif and form a heterodimer to prevent the mif entry into cells and mif-induced glucocorticoid resistance fig. trx prevents and relieves copd pathogenesis through multiple molecular mechanisms. trx eliminates mif to improve glucocorticoid resistance and eliminates ros and inhibits neutrophil infiltration by regulating adhesion molecules to suppress the production of cytokines to reduce oxidative stress and inflammation. trx exerts its anti-oxidative and anti-inflammatory effects by regulating the nf-κb, mapk, pi k/akt and camp-pka pathways. trx also inhibits the airway neutrophil recruitment by down-regulating the expression of neutrophil l-selectin on circulating neutrophils. trx is subtle in regulating the balance between protease and antiprotease. trx has inhibitory effect on both, but it is asymmetric in its inhibition. trx has stronger inhibitory effects on over-generated proteases, thus maintaining the balance of the protease-antiprotease system. moreover, trx down-regulates the expression of egfr and tgf in the airway to reduce mucus secretion, airway remodelling and pulmonary fibrosis trx regulates mif expression levels and inhibits inflammation caused by mif. , in a mouse asthma model, transgenic overexpression of trx significantly reduced mif expression in the airway epithelial cells and reduced the number of mif-positive inflammatory cells in the lung parenchyma. trx inhibits mif production in human monocytes. mif has a specific affinity for trx; extracellular mif is internalised into cells exclusively by binding to trx on the cell membrane. exogenous trx and intracellular trx combine with mif to form a complex which affects the mif-induced inflammatory response. in addition, some studies have also demonstrated that trx directly bind to glucocorticoid receptor and enhance the cell's response to glucocorticoids. , although there are not the evidence showing the effect of trx on hdac , we suppose that trx may increase hdac activity by regulating cellular redox signalling, and we would like to prove this attractive hypothesis in our next studies. effects on the immune system trx has no inhibitory effect on the immune system while regulating inflammatory responses in various inflammation models. , , there is no significant difference in the population and differentiation of immune cells such as the mast cells, dendritic cells, and lymphocytes between trx overexpression and wt animals. oxidative stress promotes the th type immune response by inducing th cell apoptosis and th cell differentiation, breaking the th /th balance, and causing th airway inflammation. , after the ova challenge, il- expression in balf of trx-tg mice was significantly lower than that in wt mice, while serum levels of il- were comparable. this shows that trx inhibits local th cells to push the balance towards th and suppress local inflammation while having no effect on the th / th balance of the systemic immune system. bronchial ln (bln) cells isolated from the trx-tg mice produced an equal amount of th cytokines il- , il- and il- as the bln cells of wt mice after leaving the high trx environment. this shows that trx does not directly affect the th /th proliferation and differentiation, but rather inhibits inflammation by regulating the production and release of th /th cytokines. copd pathogenesis is mainly related to the overexpression of inflammatory mediators and cytokines, the activation of inflammatory signalling pathways, the protease/anti-protease imbalance, and the oxidation-antioxidation imbalance. these factors are interrelated and it is difficult to achieve the desired treatment results through a single target. owing to the overlapping function of molecular targeted inflammatory signals, the degree to which pathogenesis of copd can be prevented if only one pathway is inhibited remains unknown. at present, some drugs have been proven to be effective in animal tests; some are challenging to be used in clinical trials due to significant side effects while others continue to be in the hypothetical stage and have not been proven effective in treating copd. therefore, further studies of the functions and mechanisms of various target molecules are necessary, and their effectiveness and safety through must be evaluated through animal experiments and clinical trials. trx plays an important role in the treatment of copd (fig. ) . its mechanism of action is highly unified with the pathogenesis of copd, and it effectively inhibits the occurrence and development of copd through a variety of mechanisms. trx also improves the gc resistance of copd. whether used as a supplement to existing therapies or for patients with poor response to hormones, trx has unique advantages. therefore, we suggest that trx has good prospects in treating copd and may be an important drug for copd treatment in the future. copd: the dangerous underestimate of % alpha -antitrypsin deficiency accelerated ageing of the lung in copd: new concepts continuing to confront copd international patient survey: methods, copd prevalence, and disease burden in - relation of birth weight and childhood respiratory infection to adult lung function and death from chronic obstructive airways disease mild 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effects of the p mapk inhibitor sb- on blood biomarkers of inflammation in copd patients efficacy and safety of the oral p inhibitor ph- in chronic obstructive pulmonary disease: a randomised clinical trial phosphoinositide -kinase delta (pi kδ) in leukocyte signaling and function emerging pharmaceutical therapies for copd present status and tasks for future of point of care testing il- induces translocation of nf-kappab in cultured human bronchial smooth muscle cells we deeply appreciate prof. takashi inamoto for pointed advice and discussion for writing up this paper. competing interests: the authors declare no competing interests. open access this article is licensed under a creative commons attribution . international license, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the creative commons license, and indicate if changes were made. the images or other third party material in this article are included in the article's creative commons license, unless indicated otherwise in a credit line to the material. if material is not included in the article's creative commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. to view a copy of this license, visit http://creativecommons. org/licenses/by/ . /. key: cord- -vrnxucye authors: argano, christiano; scichilone, nicola; natoli, giuseppe; nobili, alessandro; corazza, gino roberto; mannucci, pier mannuccio; perticone, francesco; corrao, salvatore title: pattern of comorbidities and -year mortality in elderly patients with copd hospitalized in internal medicine wards: data from the reposi registry date: - - journal: intern emerg med doi: . /s - - - sha: doc_id: cord_uid: vrnxucye currently, chronic obstructive pulmonary disease (copd) represents the fourth cause of death worldwide with significant economic burden. comorbidities increase in number and severity with age and are identified as important determinants that influence the prognosis. in this observational study, we retrospectively analyzed data collected from the reposi register. we aimed to investigate comorbidities and outcomes in a cohort of hospitalized elderly patients with the clinical diagnosis of copd. socio-demographic, clinical characteristics and laboratory findings were considered. the association between variables and in-hospital, -month and -year follow-up were analyzed. among in-patients, ( . %) had a diagnosis of copd. patients with copd had more hospitalization, a significant overt cognitive impairment, a clinically significant disability and more depression in comparison with non-copd subjects. copd patients took more drugs, both at admission, in-hospital stay, discharge and -month and -year follow-up. comorbidities were more frequent in copd patients. cerebrovascular disease was an independent predictor of in-hospital mortality. at -month follow-up, male sex and hepatic cirrhosis were independently associated with mortality. ics-laba therapy was predictor of mortality at in-hospital, -month and -year follow-up. this analysis showed the severity of impact of copd and its comorbidities in the real life of internal medicine and geriatric wards. electronic supplementary material: the online version of this article ( . /s - - - ) contains supplementary material, which is available to authorized users. chronic obstructive pulmonary disease (copd) represents an important leading cause of morbidity and mortality with high economic and social costs: according to the who, copd is the fourth most common cause of death worldwide, and it is estimated to be the third by ; furthermore, the global burden of copd is expected to increase in the coming years, due to the prevalence of smoking and aging of the world population [ ] . comorbidities are an essential component of copd burden. some of these are related to aging, others may have the same underlying mechanisms (e.g. systemic inflammation) or share common risk factors (e.g. smoking exposure), but all of them are able to afflict prognosis [ ] . some comorbidities occur more frequently in copd patients, independently from pulmonary severity disease [ ] . they increase in number and severity with age and have a major impact on the patient's quality of life, hospitalization and mortality [ ] . in this sense, divo and colleagues identified twelve comorbidities associated with increased mortality [ ] . however, recommendations on management of respiratory diseases are based on evidence from studies with restrictive inclusion criteria or no representative enrollment [ , ] , thus not accounting for complicating effects from coexisting conditions and treatments. therefore, their management and prevention might provide benefit in reducing the global cost load especially since international recommendations on copd management do not systematically include the evaluation of comorbid conditions in the diagnostic approach or in the treatment decisions of the disease, thus focusing on isolated lung impairment rather than multimorbidity. given this background, the aim of this study was to assess comorbidities and outcomes in a cohort of elderly patients with the clinical diagnosis of copd, hospitalized in internal medicine and geriatric wards participating to the reposi (registro per lo studio delle polipatologie e politerapie simi) registry study. retrospectively, we analyzed the collected data within the frame of the reposi project in the recruitment weeks of , , and . reposi is an independent and collaborative register, organized by the italian society of internal medicine (simi) and the mario negri institute for pharmacological research. it involved the creation of a network of internal medicine and geriatric wards that collected information about polytherapy on elderly patients, affected by multiple diseases. patients were eligible for reposi if: ( ) they were admitted to one of the participating internal medicine wards during the index weeks chosen for recruitment (one in february, one in june, one in september, and one in december); ( ) their age was years or older; ( ) they gave informed consent. each ward had to enroll at least ten consecutive eligible patients during each index week recording data on socio-demographic details, the main reason for admission and comorbidities, diagnoses, treatment (including all drugs taken at hospital admission and recommended at discharge), clinical events during hospitalization and outcome. during those weeks, all participating centers had to complete the registration of all patients admitted, indicating those who were consecutively enrolled. for patients who were excluded, the reason had to be given. also, data on mortality or any new hospitalization were collected, with a telephone interview performed by a physician to the patient or his/her relatives, -and months after hospital discharge. then, a final database was created and checked by the mario negri institute for pharmacological research. the project's design is accessible at the related website [ ] . subjects were referred as having copd if a diagnosis of the disease was reported in previous medical charts, or whether the diagnosis was posed at admission, as judged by the clinician. given the nature of the study, the spirometric assessment was judged not to be a pre-requisite to confirm the diagnosis. socio-demographic variables such as age classes, marital status, living arrangement and need for assistance in daily living, were considered along with laboratory findings in patients with copd compared to the ones without it. the following clinical characteristics were evaluated: respiratory and non-respiratory disease distribution at hospital admission (according to international classification of diseases-ninth revision); cognitive status and mood disorders (by the short-blessed-test [sbt] [ ] and the geriatric-depression-scale [gds] [ ] ,respectively; performance in activities of daily living at hospital admission (measured by means of the barthel index [bi] [ ] ; severity and comorbidity index(assessed by the cumulative-illness-rating-scale cirs-s and cirs-c, respectively) [ ] , glomerular filtration rate (using the chronic kidney disease epidemiology collaboration-formula [ ] ), length of hospital stay, drugs prescriptions (at admission, discharge, at and months follow-up), destination at discharge, in-hospital and -month and -year mortality rate. the association between variables and in-hospital, -month and -year mortality was analyzed. quantitative variables were summarized as mean ( % confidence intervals), and categorical variables as percentage. patients with significant disability were selected according to a bi score of ≤ . fisher's exact-test for contingency tables, z test and non-parametric mann-whitney u test were used when appropriate. a multivariate logistic analysis was used to assess the relationship between variables and in-hospital, -month and -year follow-up mortality. variables were chosen according to the hosmer-lemeshow methodology [ ] . after univariate analysis, only variables with a p < . were included in the final model; then, through a backward process, variables were excluded until a significance level of p < . was reached for each variable. the application of hosmer-lemeshow test is a measure of how well the model fits the data without any choice of variables by researcher to put into the multivariate model. a two-tailed p < . was considered statistically significant. stata statistical software , release (stata-corp, college-station, tx-usa) was used for database management and all the analyses. during the recruitment period, out of inpatients were eligible for this analysis ( patients had missed variables); ( . %) presented with a diagnosis of copd. among them, % were male with a mean age of years. table shows the demographic characteristics and modifiable risk factors of the two study groups. interestingly, almost half of the copd in-patients had history of previous hospitalizations compared to only one-third of non-copd inpatients. a significantly higher proportion of copd subjects also showed history of alcohol consumption and were more often morbidly obese. in-patients with copd had a significantly higher cumulative illness rating scale for the evaluation of severity and comorbidity index (p < . for both comparisons). as shown in table , significant overt cognitive impairment was documented in almost half of in-patients with copd, while a quarter needed positioning of urinary catheter. in-patients with clinically significant disability (bi ≤ ) were . % in comparison with individuals without copd ( . %, p = . ). moreover, gds was shown to be more frequently abnormal (mean-score equal to . ). in addition, . % had a probable depression (gds > ) as opposed to non-copd individuals. copd patients took more drugs than those without copd, both at admission, at in-hospital stay, at discharge and at -and -year followup (table ) . overall, disease distribution showed that arterial hypertension, ischemic heart disease, atrial fibrillation, heart failure, chronic renal failure, peripheral artery disease, overt hypertensive heart disease, anemia, rheumatic diseases, prostatic hypertrophy, osteoporosis, pneumonia, gastroesophageal reflux disease, respiratory failure, and cholelithiasis were more frequent in copd patients ( table ) . as shown in table , subjects with copd had significantly longer hospital stay; in addition, higher rates of rehospitalization at -year after discharge were recorded. in-hospital and within -year mortality did not differ between the two groups. however, when we assessed independent predictors of mortality, running univariate analysis (see appendix) and then multivariate analysis ( fig. ) according to hosmer-lemeshow methodology, cerebrovascular disease and current ics-laba therapy were independently associated with in-hospital mortality. at -month follow-up, male gender, hepatic cirrhosis, and ics-laba therapy were predictors of mortality. at -year follow-up, ics-laba therapy was the only predictor of mortality. copd exacerbation did not represent an independent predictor of mortality in older hospitalized people even if % of patients with copd had exacerbation. in this observational study on the reposi registry, we assessed the distribution of comorbidities and the occurrence of outcomes in a population of elderly copd in-patients admitted to the internal medicine and geriatric wards, with the aim to evaluate whether copd subjects behave differently from non-copd individuals. overall, the current findings suggest that copd subjects are at higher risk of death within the first year from admission to the hospital. although comorbidities are increasingly identified as important factors of copd management and outcomes [ ] , studies specifically designed to evaluate the relationships between comorbidities and long-term outcomes in subjects with a diagnosis of copd admitted to an internal medicine ward are scarce [ ] , and this is also true for several chronic diseases [ ] . a recent study showed that the addition of comorbidities to age, bmi, blood markers and indexes such as smoking status, dyspnea assessment, airway obstruction produced a model, known as barc index, that performed better than established index scores in predicting -year mortality [ ] . our analysis showed that copd in-patients are more often older men, smokers or former smokers, and live with their relatives, in agreement with our previous findings [ ] . moreover, copd patients are severe obese fig. multivariate analysis in copd patients according to in-hospital, -month and -year mortality. or odds ratio, % ci % confidence interval, ics/laba inhaled corticosteroids and long-acting beta -agonists in combination, gfr glomerular filtration rate calculated by ckd-epi formula; gfr is referred to values every ml/ min; barthel index is referred to values every points; diastolic blood pressure is referred to values every mmhg. only the final model is shown according to hosmer-lemeshow methodology. for the selection of variables see appendix and statistical analysis section consistently with recent data that seem to confirm that obesity is more common in copd patients compared to subjects who do not have copd [ ] . interestingly, individuals with a diagnosis of copd had more frequent mood changes, indicating higher level of distress, in agreement with those from the nhanes study of . % of subjects with copd suffering from depression [ ] . shane et al. showed that up to % of patients with copd had clinically significant depressive symptoms, a proportion higher than that recorded in other chronic diseases such as stroke, diabetes, coronary heart disease, arthritis, hypertension, and cancer [ ] . similarly, copd patients showed worse cognitive impairment than non-copd patients; in the study by dodd et al., up to % of patients with copd exacerbation had features of cognitive impairment [ ] . a recent systematic review and meta-analyses outlined that one in four subjects with copd has mild cognitive impairment [ ] . in addition to affecting pharmacological treatment, comorbidities may impair the ability to use inhalation devices [ ] ; for example, cognitive impairments affect the ability to properly use the inhaled device, and anxiety and depression can reduce the adherence to treatment. it follows that the choice of the proper inhaler should also take into account the relative contribution of concomitant diseases in affecting the correct use of the device. it is commonly accepted that cognitive impairment and depression lead to progressive disability [ , ] , especially in oldest-old subjects [ , ] , thus potentially affecting short-and long-term outcomes. the current findings also show that the presence of anemia is associated with the frequency of exacerbations and increasing healthcare costs [ , ] . the phenomenon is relevant in clinical practice: indeed, cote et al. found that anemia was present in % of copd inpatients [ ] . the possible mechanism consists in persistent elevated interleukin levels, in particular il- , that interfere with the erythropoietin response [ ] . the current analysis highlighted that copd patients had a worse functional status than patients without copd; this is of clinical importance, given that hospitalized elderly patients affected by pneumonia with a clinically significant disability were already shown to have higher mortality risk [ ] . lanièce et al. found that severe disability was the most important predictor of early re-admission among elderly inpatients [ ] . recent data showed that male gender, previously hospitalized, polypharmacy (more than drugs), lower functional status and frailty, depression, heart diseases, copd, urinary tract infection were associated to a higher risk of hospitalization [ ] . moreover, heart failure, diabetes and stroke were associated with a prolonged hospital stay (> days) in hospitalized copd patients [ ] . the current findings on comorbidities distribution showed a significant prevalence of respiratory failure and respiratory conditions other than copd, as well as cardiovascular diseases, chronic renal failure, prostatic hypertrophy, rheumatic diseases, and gastroesophageal reflux disease. an interesting speculation on these findings comes from the theory of network medicine [ ] , based on which human diseases are not independent of each other, but rather the consequence of different biological processes that interact in this complex network, defined as "diseasome". in this regard, copd is among the best scenario in which multiple factors such as chronic inflammation, aging-related changes, altered immune response, increased oxidative stress, consequences of smoke exposure and physical inactivity are variably interwound. aging per se is characterized by chronic low-grade systemic inflammation, and is associated with multiple chronic conditions, including copd [ , , ] ; interestingly, a relationship among systemic inflammation, comorbidities and copd outcomes has been clearly documented [ ] . of note, ischemic heart disease, heart failure, myocardial infarction, diabetes, lung cancer, osteoporosis, metabolic syndrome, are all characterized by low-grade inflammation and frequently associated with copd [ ] . the question is whether, and to what extent, comorbidities affect mortality independent of lung disease. using data from the multicenter observational study eclipse, agusti and colleagues [ ] proposed the systemic inflammome, a network representation of systemic inflammation in individuals suffering from copd, which may account, in a proportion of subjects who are persistently inflamed, for significantly higher rates of all-cause mortality. the prevalence of comorbidities in patients with copd was assessed by divo and collaborators [ ] , who identified specific comorbidities significantly associated with increased mortality. the relative contribution of each comorbidity to mortality and the relationships among comorbidities led to the so-called "comorbidome". vanfleteren et al. [ ] identified five clusters of comorbidities: ''cardiovascular '', ''cachectic'', ''metabolic'' and ''psychological'' and ''less comorbidity'' . the authors however failed to find any association with mortality. our findings indicate that cerebrovascular disease significantly increased the risk of death during hospitalization. on the other hand, cirrhosis and men gender were significantly associated with -month mortality. these observations are in agreement with kim et al. that found a significant statistically association between copd and increased risk of stroke [ ] , and with divo et al. that found that the risk of death was strongly associated with different comorbidities including liver cirrhosis, suggesting a correlation with lifestyle and social behavior [ ] . these data were also confirmed by baty et al. that found a higher prevalence of alcoholic cirrhosis in their nationwide analysis of hospital admissions for copd in switzerland [ ] . moreover, our results are consistent with previous studies that identified comorbidities that were associated with copd progression and exacerbation frequency, poor quality of life, higher mortality and increase of costs management [ , , ] . the current analysis highlights the role of the ics-laba regular treatment, which was independently associated with in-hospital, -month and -year follow-up mortality. this result was unchanged even if variables such as copd exacerbation, heart failure, atrial fibrillation, ischemic heart disease, oral anticoagulants, anti-platelet drugs had been included into the model. in a recent meta-analysis, horita et al. found that patients treated with laba-lama had fewer exacerbations and a significantly lower risk of developing pneumonia in comparison with ics-laba [ ] . in addition, ernst et al. suggested a limit use of ics and ics-laba in copd patients on the basis of the evidence of adverse effects, especially severe pneumonia, leading to excess mortality [ ] . although the causes of mortality are not known, it cannot be excluded that chronic use of ics was responsible for severe adverse events in compromised subjects. the lack of data on the dosage or the class of corticosteroids does not allow to draw firm conclusions on the contribution of the active drug. similarly, it is plausible to hypothesize that laba variably influenced the outcome. a recent study showed the importance of bi as a strong predictor of -days, -and -month mortality in elderly patients with pneumonia [ ] . simonetti et al. found that pneumonia severity and low functional status are the main factors associated with mortality in elderly people with community acquired pneumonia [ ] . vitacca et al. suggested the utilization of a unique instrument, i.e. the bi-dyspnea, to provide a global assessment of disability evaluating both respiratory and motor impairment [ ] . formiga et al. demonstrated that a better functional status and a lower comorbidity conditions were independent predictors of mortality at -years in -year-old community-dwelling subjects [ ] . in the current study, disability did not enter the multivariate analysis as independent predictor of mortality, although the barthel score suggestive of physical impairment clearly distinguished the copd phenotype (fig. ) . a possible explanation for the apparent discrepancy between studies lies in the lack of information on the lung functional impairment, which may variably affect the ability to interact with daily activities. it is therefore logical to hypothesize that disability is one of the strongest predictors of mortality also in copd. further studies are needed to confirm it. with regard to the protective function of higher glomerular filtration rate, our data are consistent with those of singanayagam et al. who established that chronic renal failure was significantly associated with increased short-term mortality in patients with copd [ ] . a potential explanation lies in the glomerular damage by arterial stiffness along with hypoxic damage to tubules and interstitium as possible mechanisms in the relationship between copd and chronic renal failure [ ] . we found that blood pressure had a protective role regarding in-hospital mortality. our findings are in agreement with previous observations that showed a reverse association between higher blood pressure and mortality in oldest old patients [ , ] . moreover, recent analysis showed that in contrast to the general population, in frail elderly patients increased blood pressure is associated with reduced mortality. a possible explanation is that high blood pressure is necessary to maintain sufficient organ perfusion in a population of older subjects who are likely to have significant vascular damage [ , ] . regarding sex, our results are consistent with a previous study that showed in elderly hospitalized patients a male profile, smokers or former smokers, affected by copd, coronary artery disease and cancer responsible for re-hospitalization and higher mortality [ , ] . this observational study has some limits. first, there was no specific information about how the diagnosis of copd was formulated (gold criteria, radiological criteria), and the severity of copd was not taken into account. given the lack of spirometric confirmation, it cannot be excluded that a proportion of subjects actually suffered from chronic diseases other than copd. however, the observational nature of the design and the exploratory approach limit the weaknesses of the findings. second, the lack of information on the appropriateness of prescriptions, and the opportunity to exclude potential confounders that goes beyond the scope of the reposi study. the major strength of the study is the multicenter design of the reposi register and the large number of participating centers resulting in a comprehensive sample of the elderly patients hospitalized in internal medicine and geriatric wards. in conclusion, this study showed the impact of copd and its comorbidities in the real-world scenario of internal and geriatric wards, identifying factors that are linked with short-and long-term outcomes. the current findings strongly support that the management of copd patients should include identification and treatment of its comorbidities. this approach should be the first step for personalized care based on a multidimensional assessment of elderly patients affected by copd. clinical data monitoring and revision: carlotta franchi, laura cortesi, mauro tettamanti, gabriella miglio (istituto di ricerche farmacologiche mario negri irccs, milano) edoardo alessandro pulixi (azienda ospedaliera della provincia di lecco azienda ospedaliera policlinico sant'orsola-malpighi raffaella arnò (azienda ospedaliera universitaria policlinico s barbara brignolo ottolini (fondazione irccs cà granda ospedale maggiore policlinico costanza caccia dominioni (irccs policlinico san matteo di pavia mosè bartone (ospedale giovanni paolo ii lamezia terme, catanzaro, unità operativa chiara pes, alessandro delitala (azienda ospedaliera-universitaria di sassari policlinico umberto i, sapienza università di roma maria antonietta bleve (azienda ospedaliera "cardinale panico giordano sigon (fondazione irccs cà granda ospedale maggiore policlinico fondazione irccs cà granda ospedale maggiore policlinico giuliana ceriani (fondazione irccs cà granda ospedale maggiore policlinico tiziana tognin (asst di unità operativa complessa di medicina generale cesare poletto (dipartimento di scienze mediche policlinico umberto i, roma, smsc -medicina interna a e malattie metaboliche dell'osso) clinica san carlo casa di cura polispecialistica maria pasquale ospedale di monselice azienda ospedaliera universitaria, udine). nicola passariello, luca rinaldi (presidio medico di marcianise filippo alessandro montalto (azienda ospedaliera universitaria policlinico paolo giaccone azienda ospedaliera per l'emergenza cannizzaro azienda ospedaliera universitaria 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jurisdictional claims in published maps and institutional affiliations. key: cord- - f gvys authors: grabiec, aleksander m.; hussell, tracy title: the role of airway macrophages in apoptotic cell clearance following acute and chronic lung inflammation date: - - journal: semin immunopathol doi: . /s - - - sha: doc_id: cord_uid: f gvys acute and chronic inflammatory responses in the lung are associated with the accumulation of large quantities of immune and structural cells undergoing apoptosis, which need to be engulfed by phagocytes in a process called ‘efferocytosis’. apoptotic cell recognition and removal from the lung is mediated predominantly by airway macrophages, though immature dendritic cells and non-professional phagocytes, such as epithelial cells and mesenchymal cells, can also display this function. efficient clearance of apoptotic cells from the airways is essential for successful resolution of inflammation and the return to lung homeostasis. disruption of this process leads to secondary necrosis of accumulating apoptotic cells, release of necrotic cell debris and subsequent uncontrolled inflammatory activation of the innate immune system by the released ‘damage associated molecular patterns’ (damps). to control the duration of the immune response and prevent autoimmune reactions, anti-inflammatory signalling cascades are initiated in the phagocyte upon apoptotic cell uptake, mediated by a range of receptors that recognise specific phospholipids or proteins externalised on, or secreted by, the apoptotic cell. however, prolonged activation of apoptotic cell recognition receptors, such as the family of receptor tyrosine kinases tyro , axl and mertk (tam), may delay or prevent inflammatory responses to subsequent infections. in this review, we will discuss recent advances in our understanding of the mechanism controlling apoptotic cell recognition and removal from the lung in homeostasis and during inflammation, the contribution of defective efferocytosis to chronic inflammatory lung diseases, such as chronic obstructive pulmonary disease, asthma and cystic fibrosis, and implications of the signals triggered by apoptotic cells in the susceptibility to pulmonary microbial infections. understanding of the mechanism controlling apoptotic cell recognition and removal from the lung in homeostasis and during inflammation, the contribution of defective efferocytosis to chronic inflammatory lung diseases, such as chronic obstructive pulmonary disease, asthma and cystic fibrosis, and implications of the signals triggered by apoptotic cells in the susceptibility to pulmonary microbial infections. keywords efferocytosis . phosphatidylserine . apoptotic cell clearance . lung . airway macrophage . inflammation cellular turnover occurs as part of the normal homeostatic process and is vital for the contraction of cells recruited during an inflammatory response [ ] . as with most biological processes, it is becoming apparent that turnover of cells is regulated in a tissue-specific manner and this specificity is primarily driven by locally produced factors. for example, the unique microenvironment of the airspaces drives a distinct expression pattern of apoptotic cell recognition receptors on airway macrophages compared to tissue-resident macrophages from other anatomical locations [ ] . in the airways, cell turnover is primarily mediated by induction of apoptosis followed by engulfment of apoptotic cells by phagocytes, called 'efferocytosis'. the term 'efferocytosis' was coined to separate engulfment of apoptotic cells from other forms of phagocytosis and derived from the latin word 'effere' that translates as 'take to the grave'. while phagocytosis of pathogens requires initiation of an inflammatory response, removal of self-cells that undergo apoptosis is a tolerogenic process that prevents excessive inflammation and/or autoimmunity caused by the release of 'damage associated molecular patterns' (damps) from apoptotic cells that are not cleared in a timely manner and undergo secondary necrosis. to achieve this distinction, macrophages and other phagocytes utilise different sets of receptors to recognise microbial particles and cells undergoing apoptosis, activation of which subsequently leads to distinct cell activation programmes. whereas phagocytosis of pathogens triggers conserved pro-inflammatory signalling pathways, engulfment of apoptotic cells by phagocytes may promote the wound repair process, the production of factors to curtail inflammation or the secretion of growth factors to shape a developing tissue. efferocytosis therefore leads to different consequences and is a burgeoning focus of research, driven by the discovery of ever more apoptotic cell recognition receptors and, importantly, pathogens that use the apoptotic cell clearance process to facilitate their entry into host cells and/or subvert anti-pathogen immunity. the distinction between apoptotic and healthy cells is mediated primarily by the release of 'find-me' signals from apoptotic cells that include atp and utp [ ] , fractalkine (cx cl ) [ ] , lysophosphatidylcholine [ ] and sphingosine- -phosphate [ ] . in addition to recruitment, such soluble signals may also enhance the engulfment capacity of the responding cell. for example, apoptotic cell production of fractalkine induces milk fat globule-epidermal growth factor (mfg-e ) expression in phagocytes that enhances apoptotic cell clearance [ ] . apoptotic cells expose a variety of molecules on their cell surface that can be recognised by receptors on phagocytic cells. the precise composition of such 'eat-me' signals likely depends on whether apoptosis is occurring under homeostatic conditions or during inflammation and is tissue-and cell type-specific [ , ] . one of the best studied 'eat-me' signals is phosphatidylserine (ptdser) that in living cells is localised to the inner leaflet of the plasma membrane and is externalised upon induction of apoptosis [ ] . overexpression of ptdser enhances apoptotic cell engulfment, whereas ptdser blockade suppresses this process, leading to autoimmunity [ , ] . irreversible externalisation occurs when caspases inactivate flippase (atp c) that in healthy cells continually flips ptdser in the plasma membrane [ ] . at the same time, caspase-dependent activation of scramblases (such as xkr ), which non-specifically and bi-directionally scramble phospholipids in the plasma membrane, is also required for ptdser exposure on apoptotic cells [ ] . ptdser is transiently exposed on the surface of living cells that resist efferocytosis, suggesting that this signal alone may not be enough, or that prolonged interaction of ptdser receptors on phagocytes is required [ ] . oxidised low-density lipoprotein, calreticulin, annexin a , icam , c q and thrombospondin- (tsp ) are also implicated in efferocytosis [ ] . furthermore, healthy cells prevent engulfment by expressing cd and cd [ , ] or by ligating cd a that impedes macrophage function [ ] . a balance of efferocytosis-inducing and inhibitory signals may therefore determine apoptotic cell clearance. ptdser and other 'eat-me' signals exposed on apoptotic cells bind a plethora of receptors on phagocytic cells, a number of which have been identified in the lung (table ) . externalised ptdser is recognised directly by triggering receptor expressed by myeloid cells- (trem ) [ ] , cd [ ] , receptor for advanced glycation end products (rage) [ ] , stabilin- [ ] , brain-specific angiogenesis inhibitor- (bai ) [ ] and the family of t cell/transmembrane, immunoglobulin, and mucin (tim) receptors, which includes tim- , and [ , ] . other engulfment receptors require bridging molecules to link them to externalised ptdser. for example, integrin αvβ or αvβ requires mfg-e , while tyro , axl and mertk that form the tam receptor tyrosine kinase family [ ] require the bridging molecules protein s or growth arrest specific (gas ) [ ] . the n-terminal gla domains of protein s and gas bridge tam receptors to ptdser on the surface of apoptotic cells [ ] , whereas the c-terminal sex hormone-binding globulin-like domains bind and activate the tam receptor [ ] . there are also a number of receptors that recognise other externalised ligands including scavenger receptor class f, member (scarf ) and ldl receptorrelated protein- (lrp- , also known as cd ) that recognise c q and calreticulin, respectively, cd together with integrin αvβ or αvβ that recognises tsp- , cd that binds a modified form of the intracellular adhesion molecule icam , and lectin receptors that recognise altered sugars [ ] . the logic behind possessing so many receptors that can recognise apoptotic cells is not entirely clear. some, such as tim- , act as tethering receptors without any signalling consequences [ ] , similar to cd [ ] . different receptors may also act at different stages of efferocytosis [ ] or may preferentially clear cells in different locations. for example, trem and trem -l form a receptor-ligand pair connecting microglia with apoptotic neurons, directing removal of damaged cells to allow repair [ ] . it is also likely that an alternate outcome is required upon efferocytosis that requires linkage to different signalling components [ ] . with regard to the tam receptors, mertk is ubiquitously expressed on macrophages and even used as a defining marker for them. airway macrophages, however, unlike most other macrophages, constitutively express axl, possibly due to the local environment that is rich in granulocyte-macrophage colony-stimulating factor (gm-csf) [ ] . importantly, receptors that recognise apoptotic cells can also play a dual function: inducing the cytoskeletal rearrangements necessary to ingest the apoptotic cell and also transmitting an instructive signal [ ] . it is interesting to note that individual tam receptor family members use different molecules to bridge them to ptdser externalised on apoptotic cells: mertk and tyro are activated by both gas and protein s, whereas the sole ligand for axl is gas [ , ] . in the case of mertk and tyro , it is therefore possible that specific signals triggered by receptor ligation might differ depending on the bridging molecule, though this possibility remains to be verified experimentally. finally, further selectivity of response is afforded by co-operation of multiple receptors such as axl and lrp- on dendritic cells where axl tethers the apoptotic cell to dendritic cells, but lrp- is required to trigger internalisation [ ] . the receptors that mediate efferocytosis often have antiinflammatory signalling consequences that can change the phenotype and function of the ingesting cell. for example, engagement and activation of tam receptors inhibits signalling pathways triggered by cytokines and toll-like receptor ligands through induction of suppressor of cytokine signalling- and (socs- and ) [ , ] (see fig. a , b). the impact of apoptotic cell clearance on cell function depends on the cell type mediating efferocytosis, which in turn depends on tissue location. in the lung, efferocytosis is mediated predominantly by macrophages and airway epithelial cells, with most consequences studied in the former. in macrophages, efferocytosis increases the secretion of the antiinflammatory cytokines, transforming growth factor-β (tgf-β) and interleukin (il)- [ , ] , while inhibiting secretion of proinflammatory mediators such as tnf-α, il- , il- and leukotriene c [ , ] . il- production by macrophages upon apoptotic cell contact is, in part, dependent upon the scavenger receptor cd [ ] and tsp- , which links macrophages to apoptotic cells in cooperation with integrin αvβ [ ] . efferocytosis also upregulates prostaglandin e (pge ) and impairs fcrmediated phagocytosis [ , ] , and intratracheal instillation of apoptotic cells enhances the resolution of lpsinduced acute pulmonary inflammation [ ] . this change in function from pro-inflammatory to pro-resolution can be observed as a phenotypic switch from an m -to an m -like macrophage phenotype and includes the induction of peroxisome proliferator-activated receptor-γ (pparγ) [ ] . however, this is likely to be context-, cell-type-and tissue-dependent. for example, nitric oxide, but not il- , tgf-β or pge , mediates the immunosuppressive effects induced by apoptotic cell efferocytosis in dendritic cells [ ] . it is also interesting to note that efferocytosis by dendritic cells appears to be subset-specific. only cd + murine lung dendritic cells capture and present apoptotic cell-associated antigen in health and disease, whereas both the cd b hi and the cd + dendritic cells ingest and traffic latex beads or soluble antigen [ ] . whether this is due to selective expression of receptors recognising apoptotic cells or a phenotypic switch after ingestion is not currently known. therefore, clearance of apoptotic cells has profound influences on the ingesting cell. though the outcome has predominantly been studied for macrophages, other cell types, particularly dendritic cells, are also likely to be affected. [ ] and humans [ ] stabilin- not studied integrin αvβ or αvβ through mfg-e low αvβ expression in humans [ , ] confirmed in mice [ ] and humans [ ] tsp- cd (in complex with integrin αvβ or αvβ ) confirmed in humans [ , ] low expression in mice [ ] and humans [ ] altered sugars lectin receptors mannose receptor confirmed in mice [ ] and humans [ ] calreticulin lrp- /cd confirmed in mice [ ] and humans [ , ] c q scarf not studied bai brain-specific angiogenesis inhibitor- , icam intracellular adhesion molecule- , lrp- ldl receptor-related protein- , mfg-e milk fat globule-epidermal growth factor , ptdser phosphatidylserine, rage receptor for advanced glycation end products, tsp- thrombospondin- , scarf scavenger receptor class f, member , tim t cell/transmembrane, immunoglobulin, and mucin, trem triggering receptor expressed on myeloid cells- in any tissue, cell turnover is a natural homeostatic process and occurs predominantly by apoptosis before loss of plasma membrane integrity. timely removal of these apoptotic cells is critical to prevent autoimmune reactions to cellular constituents. however, the speed of turnover determines the requirements for the local phagocytic system in terms of its capacity to clear the accumulating apoptotic cells and is often governed by the local microenvironment and past inflammation history. in healthy murine and human lungs, airway macrophages make up % of cells retrieved by bronchoalveolar lavage [ , ] . they exist in a tolerant state due to interaction with proteins and receptors expressed by or secreted from the respiratory epithelium. furthermore, mucus bathing the epithelium contains surfactant proteins that dampen macrophage responsiveness in health [ ] . chimeric mouse experiments show that resident airway macrophages have an unusually prolonged life span with negligible turnover even at months in the absence of inflammation. this situation changes following their depletion during inflammation where replenishment from the periphery occurs, leading to a population of macrophages that are reported to have a shorter life span. airway macrophage removal by irradiation leads to replenishment from the periphery and a higher turnover rate of approximately days [ ] . however, the fate of resident airway macrophages following pulmonary infection is not entirely clear. one study shows that macrophages recruited to the fig. the many roles of apoptotic cell recognition and phagocytosis in immunity and infection. a efferocytosis leads to removal of apoptotic cells without release of their content. when apoptotic cells are not engulfed in a timely manner, they undergo secondary necrosis and release necrotic cell debris which subsequently causes uncontrolled inflammatory activation of the innate immune system by the released 'damage associated molecular patterns' (damps). b during apoptosis, cells expose phosphatidylserine (ptdser) on the outer leaflet of their membranes, which is recognised by specific receptors expressed on phagocytes. recognition of ptdser by tam receptors through bridging molecules gas and protein s triggers a signalling cascade which converges on upregulation of suppressor of cytokine signalling- and (socs ), which act as negative regulators of the immune response. activation of tam receptors by apoptotic cells inhibits production of proinflammatory cytokines, such as tnfα and il- , while promoting expression of factors that suppress inflammation and promote tissue repair, including il- and tgf-β. c some enveloped viruses express ptdser on their envelopes and use ptdser recognition receptors, such as tam and tim receptor families, to promote infection of the host cells and evade the immune response. d during microbial infections with intracellular pathogens, induction of apoptosis of infected cells is one of the strategies of the host immune system to facilitate pathogen clearance. for example, in case of mycobacterium tuberculosis (mtb) infections, necrosis of infected cells leads to dissemination of bacteria, whereas engulfment of infected cells undergoing apoptosis allows for pathogen destruction airways from the periphery during influenza infection contract by fas-dependent apoptosis, while the number of resident airway macrophages remains unchanged [ ] , whereas another implies significant ablation of resident airway macrophages followed by replenishment from the interstitial pool [ ] . discrepancy might arise from the use of intranasal dye (that becomes diluted on cell division) or the depletion by irradiation with the lung protected by lead. in order to track definitively the fate of airway macrophages following influenza infection, the flt -cre × rosa -lsl-yfp reporter mice would be useful as all bone marrow emigrants become yfp expressing and so mice do not require prior manipulation to distinguish resident versus recruited airway cells [ ] . like airway macrophages, epithelial cells similarly have a long half-life in health. using reporter mice where ciliated cells and their progeny can be tracked across their lifetime, a half-life of months in the trachea and months in the bronchioles and terminal bronchioles has been estimated [ ] . taken together, these observations indicate that in homeostasis relatively small quantities of apoptotic cells appear in the airways due to slow turnover of the main cell populations residing in the healthy lung. it is therefore not surprising that lung phagocytes efficiently clear these scarce apoptotic cells even when their efferocytic function is partly disrupted. for example, deletion of axl, which is highly expressed on murine airway macrophages, does not cause accumulation of necrotic cell debris and lung inflammation in the absence of accompanying infection despite significant impairment of the efferocytic function of airway macrophages [ ] . similarly, blockade of apoptotic cell uptake by airway epithelial cells through cell type-specific deletion of the small gtpase rac , which is required for efferocytosis mediated by several classes of engulfment receptors, does not affect the integrity and responses of the epithelial barrier without administration of exogenous apoptotic cells or induction of allergic airway inflammation [ ] . in health, apoptotic cells are essentially undetectable in the lung tissue [ ] , and immune cells infiltrating the airways which undergo apoptosis are rapidly cleared by airway macrophages in models of acute microbial infection-related lung inflammation [ ] . respiratory infections are therefore not associated with persistent accumulation of large quantities of apoptotic cells in the airspaces. however, increased numbers of dying cells are detected in the airspaces of patients with several aetiologically distinct chronic inflammatory lung diseases [ ] . although higher frequencies of apoptotic cells in these diseases might result either from elevated rates of apoptotic cell death or defects in apoptotic cell removal, experimental evidence suggests that reduced efficiency of efferocytosis, predominantly by airway macrophages, plays a key role in this pathological process [ , ] . the most comprehensive analysis of defects in apoptotic cell clearance has been performed in chronic obstructive pulmonary disease (copd), which is a chronic lung disease characterised by un-resolving inflammation due to accumulation of activated neutrophils and t cells causing small-airway obstruction, peribronchial fibrosis and/or destruction of airway walls (emphysema). these pathological processes lead to progressive destruction of lung parenchyma and, as a consequence, airflow limitation that is not fully reversible in patients with emphysema, and in other subtypes of copd [ ] . historically, lung pathology in copd was attributed to alterations in the protease/anti-protease balance and oxidative stress caused by cigarette smoking, which is the main risk factor for copd. however, there is evidence that indicates an important role of aberrant apoptosis and apoptotic cell clearance in the lung damage observed in copd [ ] . several reports demonstrate accumulation of apoptotic epithelial, endothelial and immune cells in the lungs of patients with copd and/or emphysema [ , , ] , and induction of structural airway cell apoptosis is sufficient to cause emphysematous changes in mice [ ] . in a series of elegant studies, hodge and co-workers demonstrate that increases in the numbers of apoptotic cells detected in the lungs of patients with copd can be attributed to significantly impaired efferocytic function of airway macrophages. uptake of apoptotic bronchial epithelial cells and neutrophils is significantly reduced in bronchoalveolar lavage macrophages from patients with copd compared to healthy controls [ , , ] , and this defect is more pronounced in copd patients who currently smoke [ ] . the observed reductions in efferocytic potential of airway macrophages in vitro correlate with the frequency of apoptotic bronchial epithelial cells isolated from bronchial brushings and are associated with altered expression of several proteins involved in apoptotic cell recognition and binding, including cd , cd and lrp- /cd [ ] . intriguingly, restoration of copd airway macrophage efferocytic function by the macrolide antibiotic azithromycin does not correlate with changes in expression of these molecules [ ] . instead, it depends on ptdser binding by airway macrophages [ ] , suggesting that deregulation of ptdser-recognising receptors or bridging molecules might be responsible for defective apoptotic cell removal in copd. neither tam nor tim families of ptdser recognition receptors have been studied in copd so far but, surprisingly, increased expression of mertk is observed on airway macrophages from cigarette smokers [ ] , which are also characterised by impaired apoptotic cell uptake compared to cells from healthy nonsmokers [ , ] . this observation indicates that upregulation of mertk is not sufficient to restore the efforocytic function of airway macrophages to normal levels and other ptdser receptors, such as axl, which is highly expressed on mouse airway macrophages [ ] , might play a more prominent role. apart from potential alterations in ptdser receptor expression and function, which require more detailed studies, several other mechanisms might be involved in efferocytosis defects observed in copd. significant impairment of apoptotic cell uptake by airway macrophages from smokers indicates an important role of oxidative stress caused by cigarette smoke components in this process [ , ] . in mice, cigarette smoke exposure, which is sufficient to induce emphysema [ ] , significantly suppresses efferocytosis by airway macrophages in vivo and in vitro, and this effect is reversible by treatment with antioxidants or overexpression of extracellular superoxide dismutase [ , ] . macrophage phagocytosis of apoptotic cells is also inhibited by the alarmin high mobility group protein- (hmgb ) [ , ] , and elevated levels of hmgb both in the airways and peripheral blood of patients with copd have recently been reported, negatively correlating with patient lung function [ , ] . since necrotic cells are the main source of extracellular hmgb , a positive feedback loop might exist in copd where apoptotic cells undergo secondary necrosis and release hmgb , which further impairs the efferocytic function of airway macrophages. this in turn would lead to accumulation of greater amounts of necrotic debris and perpetuation of chronic inflammation. finally, engulfment of apoptotic cells by macrophages is also regulated by the members of the collectin family of c-type lectins. the levels of mannose-binding lectin (mbl), which promotes apoptotic cell uptake in vitro [ ] , are reduced in the airways of patients with copd and correlate with impaired macrophage efferocytosis [ , ] . surfactant protein a (sp-a) and sp-d, on the other hand, play a more complex role in apoptotic cell recognition in the lung. while homeostatic interaction of sp-a or sp-d with signal inhibitory regulatory protein-α (sirpα) expressed on airway macrophages suppresses efferocytosis [ ] , opsonisation of apoptotic cells by sp-a or sp-d and interaction of this complex with lrp- /cd enhances apoptotic cell uptake [ , ] . the latter seems to play a more prominent role during chronic lung inflammation as sp-d levels are significantly reduced in patients with copd [ , ] , potentially contributing to efferocytosis defects. alternatively, downregulation of sp-d might represent a physiological response of the lung aimed at overcoming sirpα-dependent suppression of macrophage efferocytic function in the presence of large amounts of dead cells, which fail to efficiently remove apoptotic cells from the copd airways due to other phagocytosis defects. asthma is an obstructive airway disease characterised by hyper-responsiveness and chronic inflammation of the respiratory tract. while neutrophils are a predominant cell type in the lungs of copd patients, asthma represents eosinophildominant airway inflammation. initial priming of the adaptive immune system by airway allergens leads to the activation of tissue-resident mast cells, which release a broad array of inflammatory mediators promoting migration of eosinophils into the airways [ ] . products of eosinophil degranulation, including major basic protein, eosinophil cationic protein and reactive oxygen species, are cytotoxic to epithelial cells and cause airway damage and tissue remodelling. indeed, increased numbers of apoptotic epithelial cells have been detected in the lungs of patients with asthma compared to healthy individuals [ ] . apoptosis and subsequent uptake by phagocytes appear to be a predominant mechanism of eosinophil removal from the airways [ , ] , and glucocorticoids, which are commonly used to control inflammation in asthma, induce eosinophil apoptosis [ ] . these observations indicate that high efficiency of the phagocytic system is required for removal of large quantities of apoptotic eosinophils and bronchial epithelial cells from the airways of patients with asthma and raise the possibility that defects in efferocytosis might prevent resolution of lung inflammation. initial studies by hyunh et al. demonstrate that airway macrophages from patients with severe asthma contain reduced numbers of phagocytic bodies compared to healthy donors and patients with mild/moderate asthma and are defective in phagocytosing apoptotic jurkat t cells in vitro [ ] . failure of airway macrophages from patients with severe asthma to efficiently clear apoptotic cells is associated with reduced production of anti-inflammatory eicosanoids [ ] , suggesting that defects in efferocytosis might contribute to perpetuation of inflammation in asthma, not only through secondary necrosis of apoptotic cells, but also by reduced release of regulatory mediators that are normally produced upon recognition of apoptotic cells by airway macrophages. more recently, it has been shown that efferocytosis of apoptotic bronchial epithelial cells by airway macrophages isolated from induced sputum of patients with non-eosinophilic asthma is significantly reduced compared with patients with eosinophilic asthma, and the degree of uptake impairment is comparable to that observed in copd [ ] . this observation might partly explain the persistent neutrophilia and aberrant innate immune responses in this subgroup of patients [ ] . efferocytosis defects in asthma are associated not only with the subtype of airway inflammation but also with the bmi index: airway macrophages from obese patients with asthma, which typically suffer from more severe disease symptoms [ ] , are characterised by significantly reduced numbers of phagocytic bodies compared to non-obese asthmatics [ ] . notably, defective efferocytic function in obese asthmatics is not restricted to the site of inflammation as decreased uptake of beads mimicking apoptotic cells is also observed in peripheral blood monocytes isolated from these patients, correlating with reduced glucocorticoid responsiveness [ ] . while these reports provide clear evidence that removal of apoptotic cells is defective in asthma, in particular in certain disease subtypes, additional studies are needed to characterise the molecular mechanisms underlying the observed defects. even though potential changes in expression and function of receptors recognising apoptotic cells on airway macrophages have not been formally studied in asthma, it is important to note that the tim receptor family member tim- , which is preferentially expressed on specific lymphocyte populations, is an important susceptibility gene for allergic asthma [ ] . targeting tim- modulates airway inflammation in mouse models of airway hyper-responsiveness at least in part through tim- -dependent interaction of nkt cells with ptdser on the surface of apoptotic cells [ , ] . these observations suggest that recognition of ptdser by immune cells that do not phagocytose apoptotic cells also has profound effects on the development of chronic lung inflammation. they also indicate that future studies of molecules involved in apoptotic cell binding in asthma should not be restricted to analyses of airway macrophages as the main contributors to apoptotic cell clearance from the inflamed airways. interestingly, not only efferocytosis but also engulfment of bacteria by airway macrophages is impaired in asthma [ ] . this finding indicates that alterations in the intracellular molecular machinery regulating phagocytosis rather than changes in expression of receptors recognising apoptotic cells might be responsible for the observed phagocytosis defects. finally, while previous studies have solely focused on efferocytosis by airway macrophages, mounting evidence suggests that bronchial epithelial cells might be equally important in clearing apoptotic cells from the inflamed airways. even though epithelial cells are not professional phagocytes, they efficiently engulf apoptotic eosinophils, but not neutrophils [ , ] . animal studies demonstrate a critical role for airway epithelial cells in the removal of apoptotic cells from the inflamed lung and, as a consequence, control of inflammatory responses in the murine model of allergic airway hyper-responsiveness [ ] . future studies in humans are therefore necessary to characterise the relative contributions of airway macrophages and bronchial epithelial cells to defects in apoptotic cell removal in asthma and to identify therapeutic strategies which could restore and/or promote the efferocytic function of both cell types, as well as activate anti-inflammatory transcriptional programmes associated with apoptotic cell recognition. cystic fibrosis (cf) is a heritable disorder caused by mutation in the cf transmembrane conductance regulator (cftr) and characterised by severe pulmonary manifestations. impaired mucociliary clearance in cf patients prevents elimination of bacteria from the lung, leading to persistent neutrophilic inflammation and progressive, irreversible damage of the airways [ ] . similar to other lung diseases associated with chronic inflammation, both accumulation of apoptotic cells in the airways and reduced numbers of phagocytic bodies within sputum macrophages are observed in patients with cf compared to control patients with chronic bronchitis [ ] . mechanistically, degranulation products of immune cells are partly responsible for efferocytosis defects in cf as neutrophil elastase present in the airway fluid of cf patients selectively cleaves ptdser recognition receptors and suppresses apoptotic cell removal by airway macrophages [ ] . other potential mechanisms contributing to impaired apoptotic cell clearance in cf involve the release of hmgb which, similar to copd, is elevated in sputum samples from cf patients [ ] and effects of bacterial products on airway macrophages. pseudomonas aeruginosa infections are common in cf and represent an important cause of mortality in cf lung manifestations. in vitro, p. aeruginosa toxic metabolite pyocyanin and the polysaccharide alginate inhibit apoptotic cell uptake by macrophages [ , ] , though the relevance of this mechanism in patients has yet to be demonstrated. interestingly, animal studies indicate that airway epithelial cells in cf might also be deficient in phagocytic functions. while defective efferocytosis by airway macrophages in cf patients is a consequence of the ongoing inflammatory response and/or microbial infection, impaired apoptotic cell uptake by epithelial cells might be directly related to the lack of cftr expression. cftr-deficient epithelial cells express significantly increased levels of rhoa, which is a negative regulator of efferoctyosis, and rhoa inhibition restores their phagocytic function [ ] . it remains to be determined if a similar mechanism regulates bronchial epithelial cell efferocytosis in patients with cf. elevated levels of apoptotic cells and reduced frequencies of phagocytic bodies within bronchoalveolar lavage macrophages have also been reported in patients with idiopathic pulmonary fibrosis (ipf) [ ] . ipf is an interstitial lung disease characterised by epithelial injury that is followed by aberrant alveolar wound repair and scar formation, which ultimately lead to respiratory failure and death. ipf is frequently accompanied by chronic neutrophilic inflammation [ ] . interestingly, intratracheal instillation of apoptotic cells ameliorates fibrosis and inflammation in bleomycin-induced lung injury in mice [ , ] , indicating that signalling triggered by apoptotic cell recognition may play a protective role in lung diseases associated with dysregulated healing processes. the anti-fibrotic effects of apoptotic cells in this model are dependent on the induction of pparγ expression in airway macrophages and increased production of hepatocyte growth factor (hgf), which plays a key role in alveolar epithelial repair upon lung injury [ , ] . these observations suggest that defects in efferocytosis in ipf patients may be responsible not only for inefficient clearance of apoptotic cells but also for diminished production of factors that support tissue repair without fibrosis. collectively, the data from patients with asthma, copd, cf and pulmonary fibrosis indicate that defective apoptotic cell clearance in lung diseases is not specific for individual diagnoses but rather represents a general hallmark of chronic inflammation. although several mechanisms contributing to these defects have been proposed, it remains to be verified whether impairment of efferocytosis might be a direct cause of chronic inflammation, or is a consequence to the ongoing inflammatory processes that contributes to chronicity and prevents resolution. the latter model is supported by the observation that mice lacking the tam receptor axl do not develop spontaneous lung inflammation despite defects in apoptotic cell uptake by airway macrophages [ ] , but more detailed analyses of regulation and function of ptdser recognition receptors in the human lung are required. finally, because recognition of apoptotic cells by ptdser-recognising receptors activates downstream signalling pathways even without engulfment [ ] , future studies are needed to verify whether activation of transcriptional programmes triggered by recognition of apoptotic cells is also altered in chronic lung diseases and, if so, how they can be manipulated in the clinic by specific modulators of ptdser recognition receptors. while in sterile inflammation recognition of apoptotic cells by the immune system typically results in suppression of the ongoing inflammatory response, the complexity of this process and its biological effects greatly increase in the context of microbial infections. first, some enveloped viruses use ptdser receptors to promote their entry into the host cells and facilitate infection and immune evasion [ ] . the interaction between ptdser exposed on the surface of the viral envelope and members of the tam and tim receptor families expressed on the target cell enables proximity to specific entry receptors and enhances engulfment of the virus [ ] (fig. c) . the relevance of this process, called 'apoptotic mimicry', has recently been confirmed for a broad range of virions, including ebola and dengue viruses [ , ] . thus far, however, little is known about potential roles of this entry mechanism in pulmonary viral infections. the observation that the kinetics of influenza h n virus clearance was unaffected in axldeficient mice indirectly indicates that axl is not important for control of this infection [ ] , though axl-h n interaction has not been formally tested. similarly, although tim promotes internalisation and replication of several enveloped viruses, tim -mediated entry does not lead to a productive infection by influenza h n and severe acute respiratory syndrome (sars) coronavirus [ ] , arguing against an important role of apoptotic mimicry in viral lung diseases. second, many pathogens survive intracellularly, and phagocytosis of infected host cells undergoing apoptosis has diverse consequences for pathogen survival and immune response of the host [ ] . one of the main strategies of the immune system to control intracellular infections is through induction of apoptosis of infected cells, which are then engulfed and destroyed together with the pathogen by phagocytes (fig. d) . however, in some cases, efferocytosis of infected cells is used by intracellular pathogens, such as the parasite leishmania major, to evade the immune response and gain entry into the new cellular host [ ] . among pathogens important in respiratory diseases, the role of efferocytosis has been most thoroughly studied in the context of mycobacterium tuberculosis infections. m. tuberculosis infects macrophages and induces necrosis of the host cell to avoid clearance by the immune system and disseminate [ ] . interestingly, m. tuberculosis-infected mouse macrophages which die by apoptosis are rapidly efferocytosed by uninfected macrophages, leading to bacterial killing and elimination [ ] . this bactericidal effect is dependent on efferocytosis, as the uptake of naked m. tuberculosis does not allow for lysosome recruitment to the bacteriacontaining phagosome, and inhibition of apoptotic cell uptake with a tim- -blocking antibody prevents bacterial control in vitro and increases bacterial burden in the lungs in vivo [ ] . the observation that bactericidal activity of macrophages infected with streptococcus pneumoniae is dependent on induction of macrophage apoptosis suggests that a similar mechanism might be involved in controlling infection with this bacterium [ ] , though the involvement of efferocytosis in this process has not been formally proven. engulfment of macrophage-derived apoptotic vesicles also plays a critical, though indirect, role in the adaptive immune response against m. tuberculosis: annexin a -dependent uptake of apoptotic cells by dendritic cells is required for cross-presentation and generation of m. tuberculosis-specific cd t cell response and bacterial clearance from the lung [ ] . the antimicrobial role of apoptotic cell clearance in pulmonary infections is not restricted to bacteria as the influenza a virus induces apoptosis of epithelial cells upon infection and engulfment of influenza a-infected cells by macrophages is associated with reduction of viral titres [ ] . on the other hand, infection of macrophages with francisella novicida, a member of the francisellaceae family of intracellular bacteria which cause pulmonary inflammation associated with necrotic infiltrates in the lung, reduces their efferocytic function, potentially contributing to the accumulation of necrotic cell debris and exacerbation of disease [ ] . taken together, these studies suggest that efferocytosis is not only a constitutive function of macrophages required for maintaining immune homeostasis in health and during inflammatory response but also an important antimicrobial effector mechanism. however, it has to be noted that apart from bactericidal activity against specific pathogens, the antiinflammatory signal associated with apoptotic cell uptake by phagocytes might prevent the mounting of an efficient immune response in the context of other lung infections. prior exposure of mouse airway macrophages to apoptotic cells results in suppression of fcr-mediated phagocytosis and killing of bacteria, and intrapulmonary administration of apoptotic cells causes significant impairment of s. pneumoniae clearance from the infected lung [ ] . suppression of antimicrobial responses of airway macrophages is also augmented by glucocorticoids, which promote efferocytosis, and treatment of mice with apoptotic cells in the presence of glucocorticoids is associated with elevated bacterial burden in the lungs [ ] . even though validation of these observations in human systems is necessary, they clearly indicate that efferocytosis plays a dual role in lung infections: while efficient apoptotic cell uptake is required for resolution of the inflammatory response and elimination of certain intracellular pathogens, the antiinflammatory programmes activated upon prolonged exposure to apoptotic cells might increase susceptibility to secondary infections and infection-related exacerbations of chronic inflammatory lung diseases. in light of the importance of effercotysis in resolution of inflammation and the reported defects in apoptotic cell removal in chronic inflammatory lung diseases, it is not surprising that evaluation of potential therapeutic strategies aimed at enhancing apoptotic cell uptake gained a lot of attention in recent years [ , ] . strikingly, glucocorticoids, which are the most commonly used class of drugs in the treatment of asthma and copd, increase apoptotic cell engulfment by macrophages in vitro [ ] and restore the efferocytic function of airway macrophages from patients with severe asthma [ ] . upregulation of the tam receptor mertk [ , ] and downregulation of sirpα [ ] might be responsible for the pro-efferocytic activity of glucocorticoids in macrophages. however, it remains unknown whether promotion of apoptotic cell clearance significantly contributes to the antiinflammatory effects of glucocorticoids in patients with lung diseases. more systematic analyses of apoptotic cell accumulation and efferocytic functions of airway macrophages before and after glucocorticoid therapy in responders and nonresponders are therefore necessary to address this question. some classes of medications widely used in the clinic for other indications also promote efferocytosis. the antibiotic azithromycin increases phagocytosis of apoptotic cells by human airway macrophages in vitro [ , ] , and significant improvement of the efferocytic function of airway macrophages from copd patients after oral treatment with azithromycin has been reported [ ] . in light of recent evidence that azithromycin reduces the frequency of exacerbations in copd patients [ ] , it is tempting to speculate that at least part of the immunomodulatory activities of macrolide antibiotics can be attributed to their effects on apoptotic cell clearance. similarly, pparγ agonists, which are used as insulin sensitizers in diabetes mellitus, but also display broad antiinflammatory effects, promote efferocytosis by airway macrophages in vitro and ameliorate disease symptoms in animal models of pulmonary inflammation [ , ] . enhancement of apoptotic cell engulfment is also observed after treatment of macrophages from copd patients with simvastatin [ ] , a member of the statin family of cholesterol-lowering drugs, and retrospective studies suggested that statins might reduce the risk of copd exacerbations and mortality [ , ] . more recently however, in a large randomised clinical trial, simvastatin treatment had no effect on exacerbation rates in copd patients [ ] , though the efferocytic function of airway macrophages was not analysed in this study. it remains an open question if patients with copd can be stratified to identify a subgroup of patients that responds to statin treatment and whether this is related to effects on apoptotic cell clearance. finally, the observations that aberrant expression and activity of the tam receptor axl has an oncogenic function in haematological and epithelial malignancies triggered the interest in targeting the activity of ptdser recognition receptors, and a small molecule inhibitor of axl is currently in phase i clinical trials [ ] . however, preclinical studies indicate that pharmacological modulators of ptdser recognition receptors might have a significant impact on the immune system, especially in the context of lung immunopathology. in light of the critical role of axl in resolution of lung inflammation upon influenza infection [ ] , any attempts to target axl activity systemically should proceed with caution due to potential adverse events related to exaggerated inflammatory responses to respiratory infections. similar to axl, mertk signalling is also required for silencing of lung inflammation: inhibition of mertk proteolytic cleavage by the adam inhibitor tapi- restores mertk expression and attenuates inflammation during lps-induced lung injury [ ] , whereas administration of a mertk blocking antibody has the opposite effect [ ] . these results suggest that activating antibodies or compounds which prevent shedding of tam receptors could be beneficial in the context chronic lung diseases. indeed, tam receptors can be activated independently of apoptotic cell engulfment by specific antibodies [ , ] , though their effects have not been tested in models of lung inflammation. in that regard, it is noteworthy that activation of tam receptors leads to shedding of their extracellular domains and soluble forms of tam receptors can act as decoy receptors and suppress apoptotic cell engulfment by macrophages [ ] . although alterations in the levels of soluble tam receptors are noted in several pathologies [ , ] , their physiological role is still poorly understood. it remains unknown if administration of antibodies targeting tam receptors would cause their sequestration and what consequences it would have for the immune homeostasis of the lung. since the initial discovery of defects in apoptotic cell clearance in asthma and copd, great progress has been made in our understanding of the molecular mechanisms of efferocytosis and several new processes through which efferocytosis modulates host immune responses have been characterised (fig. ) . consequently, new questions have emerged regarding the role of apoptotic cell removal in lung homeostasis and the most important of them are listed in box . future studies addressing these questions, especially attempts to therapeutically manipulate efferocytosis in the clinic, should be designed in the context of the multiple roles of apoptotic cell phagocytosis in resolution of inflammation and microbial infections. box . future questions in apoptotic cell removal in the airspaces • does efferocytosis polarise airway macrophages to an m phenotype or are m polarised airway macrophages better at efferocytosis? • what is the impact of the tissue microenvironment on apoptotic cell recognition receptor repertoires and outcome of their ligation? • is homeostatic apoptotic cell clearance different in requirements and consequences to clearance of cells during inflammation? • what is the impact of the altered lung environment in asthma, copd and cf on apoptotic cell clearance? open access this article is distributed under the terms of the creative comm ons attribution . international license (http:// creativecommons.org/licenses/by/ . /), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the creative commons license, and indicate if changes were made. phagocytosis of apoptotic cells in homeostasis the axl receptor tyrosine kinase is a discriminator of macrophage function in the inflamed lung nucleotides released by apoptotic cells act as a find-me signal to promote phagocytic clearance cx cl /fractalkine is released from apoptotic lymphocytes to stimulate macrophage chemotaxis apoptotic cells induce migration of phagocytes via caspase- -mediated release of a lipid attraction signal apoptosis induces expression of sphingosine kinase to release sphingosine- -phosphate as a "come-and-get-me" signal fractalkine-induced mfg-e leads to enhanced apoptotic cell clearance by macrophages dangerous attraction: phagocyte recruitment and danger signals of apoptotic and necrotic cells the distribution and function of phosphatidylserine in cellular membranes masking of phosphatidylserine inhibits apoptotic cell engulfment and induces autoantibody production in mice in vivo recognition and clearance of red blood cells containing phosphatidylserine in their plasma membranes caspase-mediated cleavage of phospholipid flippase for apoptotic phosphatidylserine exposure xk-related protein and ced- promote phosphatidylserine exposure in apoptotic cells find-me and eat-me signals in apoptotic cell clearance: progress and conundrums the interaction between signal regulatory protein alpha (sirpalpha) and cd : structure, function, and therapeutic target apoptosis disables cd -mediated cell detachment from phagocytes promoting binding and engulfment human cd a binds to phosphatidylethanolamine and phosphatidylserine, and modulates the phagocytosis of dead cells overexpression of apoptotic cell removal receptor mertk in alveolar macrophages of cigarette smokers rage signaling by alveolar macrophages influences tobacco smoke-induced inflammation expression of high-mobility group box and of receptor for advanced glycation end products in chronic obstructive pulmonary disease azithromycin increases phagocytosis of apoptotic bronchial epithelial cells by alveolar macrophages smoking alters alveolar macrophage recognition and phagocytic ability: implications in chronic obstructive pulmonary disease trem- promotes macrophage survival and lung disease after respiratory viral infection priming of alveolar macrophages upon instillation of lipopolysaccharide in the human lung elastase-mediated phosphatidylserine receptor cleavage impairs apoptotic cell clearance in cystic fibrosis and bronchiectasis flow cytometric analysis of macrophages and dendritic cell subsets in the mouse lung phenotypic characterisation of alveolar macrophages and peripheral blood monocytes in copd azithromycin improves macrophage phagocytic function and expression of mannose receptor in chronic obstructive pulmonary disease role of surfactant proteins a, d, and c q in the clearance of apoptotic cells in vivo and in vitro: calreticulin and cd as a common collectin receptor complex clearance of apoptotic neurons without inflammation by microglial triggering receptor expressed on myeloid cells- cd b regulates the phagocytosis of apoptotic cells via phosphatidylserine recognition participation of the receptor for advanced glycation end products in efferocytosis rapid cell corpse clearance by stabilin- , a membrane phosphatidylserine receptor bai is an engulfment receptor for apoptotic cells upstream of the elmo/dock /rac module identification of tim as a phosphatidylserine receptor tim- and tim- glycoproteins bind phosphatidylserine and mediate uptake of apoptotic cells biology of the tam receptors the anticoagulation factor protein s and its relative, gas , are ligands for the tyro /axl family of receptor tyrosine kinases beginnings of a good apoptotic meal: the find-me and eat-me signaling pathways identification of the product of growth arrest-specific gene as a common ligand for axl, sky, and mer receptor tyrosine kinases the phosphatidylserine receptor tim- does not mediate direct signaling human cd mediates recognition and phagocytosis of apoptotic cells distinct roles for bai and tim- in the engulfment of dying neurons by microglia a role for trem ligands in the phagocytosis of apoptotic neuronal cells by microglia the resolution of inflammation: principles and challenges diversification of tam receptor tyrosine kinase function differential tam receptor-ligand-phospholipid interactions delimit differential tam bioactivities an axl/lrp- / ranbp complex mediates dc efferocytosis and antigen cross-presentation in vivo tam receptors are pleiotropic inhibitors of the innate immune response immunosuppressive effects of apoptotic cells interleukin- expression in macrophages during phagocytosis of apoptotic cells is mediated by homeodomain proteins pbx and prep- transcriptional and translational regulation of inflammatory mediator production by endogenous tgf-beta in macrophages that have ingested apoptotic cells tnf-alpha, il- , and il- expression is inhibited by gas in monocytes/macrophages macrophages that have ingested apoptotic cells in vitro inhibit proinflammatory cytokine production through autocrine/paracrine mechanisms involving tgf-beta, pge , and paf thrombospondin cooperates with cd and the vitronectin receptor in macrophage recognition of neutrophils undergoing apoptosis efferocytosis impairs pulmonary macrophage and lung antibacterial function via pge /ep signaling phosphatidylserinedependent ingestion of apoptotic cells promotes tgf-beta secretion and the resolution of inflammation ppargamma activation following apoptotic cell instillation promotes resolution of lung inflammation and fibrosis via regulation of efferocytosis and proresolving cytokines apoptotic cells induce immunosuppression through dendritic cells: critical roles of ifn-gamma and nitric oxide cd + pulmonary dendritic cells preferentially acquire and present apoptotic cell-associated antigen differential role of cd and cd on alveolar macrophages in the presentation of allergen to t lymphocytes in asthma alveolar macrophages: plasticity in a tissue-specific context the prolonged life-span of alveolar macrophages fas determines differential fates of resident and recruited macrophages during resolution of acute lung injury depletion of alveolar macrophages during influenza infection facilitates bacterial superinfections a lineage of myeloid cells independent of myb and hematopoietic stem cells ciliated epithelial cell lifespan in the mouse trachea and lung apoptotic cell clearance by bronchial epithelial cells critically influences airway inflammation endothelial cell death and decreased expression of vascular endothelial growth factor and vascular endothelial growth factor receptor in emphysema alveolar macrophages have a protective antiinflammatory role during murine pneumococcal pneumonia role of apoptosis in amplifying inflammatory responses in lung diseases impairment of phagocytosis of apoptotic cells and its role in chronic airway diseases efferocytosis and lung disease immunology of asthma and chronic obstructive pulmonary disease role of apoptosis in the pathogenesis of copd and pulmonary emphysema correlation of lung surface area to apoptosis and proliferation in human emphysema increased apoptosis of neutrophils in induced sputum of copd patients alveolar wall apoptosis causes lung destruction and emphysematous changes alveolar macrophages from subjects with chronic obstructive pulmonary disease are deficient in their ability to phagocytose apoptotic airway epithelial cells animal models of chronic obstructive pulmonary disease cigarette smoke-induced changes to alveolar macrophage phenotype and function are improved by treatment with procysteine cigarette smoke impairs clearance of apoptotic cells through oxidant-dependent activation of rhoa high mobility group protein- inhibits phagocytosis of apoptotic neutrophils through binding to phosphatidylserine hmgb inhibits macrophage activity in efferocytosis through binding to the alphavbeta -integrin high mobility group protein b (hmgb ) in asthma: comparison of patients with chronic obstructive pulmonary disease and healthy controls c q and mannose binding lectin engagement of cell surface calreticulin and cd initiates macropinocytosis and uptake of apoptotic cells therapeutic role for mannose-binding lectin in cigarette smoke-induced lung inflammation? evidence from a murine model oxidative stress decreases functional airway mannose binding lectin in copd surfactant proteins a and d suppress alveolar macrophage phagocytosis via interaction with sirp alpha surfactant protein a enhances alveolar macrophage phagocytosis of apoptotic neutrophils chronic obstructive pulmonary disease and inhaled steroids alter surfactant protein d (sp-d) levels: a cross-sectional study the immunology of asthma asthmatic bronchial epithelium is more susceptible to oxidant-induced apoptosis human alveolar epithelial cells engulf apoptotic eosinophils by means of integrin-and phosphatidylserine receptor-dependent mechanisms: a process upregulated by dexamethasone eosinophil apoptosis and the resolution of airway inflammation in asthma eosinophils in the lung-modulating apoptosis and efferocytosis in airway inflammation defective apoptotic cell phagocytosis attenuates prostaglandin e and -hydroxyeicosatetraenoic acid in severe asthma alveolar macrophages impaired macrophage phagocytosis in noneosinophilic asthma innate immune activation in neutrophilic asthma and bronchiectasis obesity and asthma: impact on severity, asthma control, and response to therapy obesity impairs apoptotic cell clearance in asthma tim- , a novel allergy and asthma susceptibility gene tim genes: a family of cell surface phosphatidylserine receptors that regulate innate and adaptive immunity apoptotic cells activate nkt 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tim-family proteins promote infection of multiple enveloped viruses through virion-associated phosphatidylserine the tim and tam families of phosphatidylserine receptors mediate dengue virus entry macrophages clean up: efferocytosis and microbial control evasion of innate immunity by mycobacterium tuberculosis: is death an exit strategy? efferocytosis is an innate antibacterial mechanism immunemediated phagocytosis and killing of streptococcus pneumoniae are associated with direct and bystander macrophage apoptosis annexin regulates dc efferocytosis and cross-presentation during mycobacterium tuberculosis infection virus clearance through apoptosis-dependent phagocytosis of influenza a virus-infected cells by macrophages defect in efferocytosis leads to alternative activation of macrophages in francisella infections glucocorticoidaugmented efferocytosis inhibits pulmonary pneumococcal clearance in mice by reducing alveolar macrophage bactericidal function glucocorticoids promote nonphlogistic phagocytosis of apoptotic leukocytes glucocorticoids induce protein sdependent phagocytosis of apoptotic neutrophils by human macrophages efficient clearance of early apoptotic cells by human macrophages requires m c polarization and mertk induction glucocorticoids relieve collectin-driven suppression of apoptotic cell uptake in murine alveolar macrophages through downregulation of sirpalpha fourteen-member macrolides promote the phosphatidylserine receptor-dependent phagocytosis of apoptotic neutrophils by alveolar macrophages azithromycin for prevention of exacerbations of copd antiinflammatory roles of peroxisome proliferator-activated receptor gamma in human alveolar macrophages the effect of peroxisome proliferator-activated receptorgamma ligands on in vitro and in vivo models of copd lovastatin enhances clearance of apoptotic cells (efferocytosis) with implications for chronic obstructive pulmonary disease statin use is associated with reduced mortality in copd statin use and risk of copd exacerbation requiring hospitalization simvastatin for the prevention of exacerbations in moderate-to-severe copd the tam family: phosphatidylserine sensing receptor tyrosine kinases gone awry in cancer upregulation of mer receptor tyrosine kinase signaling attenuated lipopolysaccharide-induced lung inflammation inhibiting mer receptor tyrosine kinase suppresses stat , socs / , and nf-kappab activation and enhances inflammatory responses in lipopolysaccharide-induced acute lung injury the axl receptor is a sensor of ligand spatial heterogeneity a soluble form of the mer receptor tyrosine kinase inhibits macrophage clearance of apoptotic cells and platelet aggregation plasma concentrations of gas (growth arrest specific protein ) and its soluble tyrosine kinase receptor saxl in sepsis and systemic inflammatory response syndromes increased plasma levels of the soluble mer tyrosine kinase receptor in systemic lupus erythematosus relate to disease activity and nephritis key: cord- -fvii nsv authors: mcnaughton, amanda; levack, william; mcnaughton, harry title: taking charge: a proposed psychological intervention to improve pulmonary rehabilitation outcomes for people with copd date: - - journal: int j chron obstruct pulmon dis doi: . /copd.s sha: doc_id: cord_uid: fvii nsv pulmonary rehabilitation (pr) is an important, evidence-based treatment that improves outcomes for people with copd. individualized exercise programmes aim to improve exercise capacity; self-management education and psychological support are also provided. translating increased exercise capacity into sustained behavioural change of increased physical activity is difficult. other unresolved problems with pr programmes include improving uptake, completion, response and sustaining long-term benefit. we offer a different perspective drawn from clinical experience of pr, quantitative and qualitative studies of singing groups for people with copd, and stroke rehabilitation research that gives psychological factors a more central role in determining outcomes after pr. we discuss take charge; a simple but effective psychological intervention promoting self-management––that could be used as part of a pr programme or in situations where pr was declined or unavailable. this may be particularly relevant now when traditional face-to-face group programmes have been disrupted by covid- precautions. people living with chronic obstructive pulmonary disease (copd) commonly carry substantial psychological morbidity along with their chest disease. , furthermore, psychological factors can influence uptake and outcomes of the most effective therapy available for people with copd -pulmonary rehabilitation (pr). , pr service providers aim to be "patient-centred" in their approach , and "empower patients" with both personalized exercise prescription, self-management education and psychological supports. pr audit reports also recommend services be responsive to people from ethnic minorities. these goals are challenging, especially as face-to-face pr services are likely to remain significantly disrupted in a covid- world. interventions that help people with copd self-manage their condition without face-to-face input would be a real advantage. "take charge" is a psychological intervention that potentially meets all these criteria. it is low-cost, requires minimal training and is effective as an adjunct to community rehabilitation for people after acute stroke -another group with significant psychological comorbidities that affect outcomes. it is also fully personcentred and of proven effectiveness in ethnic minority groups. with minor modifications from the version used in the stroke trials, take charge was used in a feasibility study for people with copd following acute exacerbations requiring hospitalization. the stroke study booklet and training manual are available, free to use (www.mrinz.ac.nz/programmes/stroke). in this article, we briefly describe the take charge intervention and evidence for benefit for people with stroke. we will draw parallels between the evidence concerning stroke rehabilitation and pulmonary rehabilitation, dominated in stroke by physical therapy approaches, and by exercise training in pr and suggest an alternative perspective based on hope, purpose and motivation. finally, we will propose options for using take charge for people with copd as part of pulmonary rehabilitation. although the abrupt onset of stroke requires a different model of rehabilitation from that of pulmonary rehabilitation (pr), pr and stroke rehabilitation (sr) share similarities. both are supported by overwhelming evidence of effectiveness. , nearly randomized controlled trials (rcts) confirm a significant reduction in mortality of patients managed in inpatient stroke and stroke rehabilitation units compared to management in general medical wards. both pr and sr are "black box" interventionsa complex mixture of components with considerable uncertainty as to which parts are critical to successful outcomes. finally, both pr and sr aim for behaviour change on the part of participants which is likely influenced by the nature and strength of the relationship between participants and health professionals; an unequivocally "psychological" variable. following on from the sr trials, coordinated, therapistled interventions are the recommended approach to stroke rehabilitation. , however, large randomized controlled trials aimed at optimizing the timing, dose and specific type of therapy-led intervention (compared to "usual care") have failed to show any additional benefit for patients at the level of independence or quality of life. this has led some to question the idea that the improved outcomes in the sr trials were solely the result of coordinated therapy. one alternative hypothesis is that sr has an important psychological component helping to increase motivation in the person with stroke. most of the sr rcts were conducted at a time when patients with stroke were managed on general medical wards, with no specific treatments apart from nursing care, and a significant expectation from health professionals, families and patients that this was a life-ending or life-changing event. a key component of stroke rehabilitation units was a shared enthusiasm for managing stroke, mobilizing patients and working with an expectation that there was "life after stroke". it is possible that patients (and their families) with this hope of a positive future, simply did not die as frequently as those without it. having hope could substantially affect engagement in physical therapy both in the hospital and at home, enhancing physical recovery. so enhancing personal motivation, in addition to a therapy-led rehabilitation approach, may improve outcomes, where a purely therapy-led approach does not. evidence to support this hypothesis comes from two large rcts involving participants after stroke, testing a psychological intervention aimed at increasing personal motivation. , the take charge intervention was tested in the early community phase of stroke rehabilitation, - weeks after acute stroke, in addition to usual community stroke rehabilitation. one of these studies was with participants from ethnic minority populations. this very brief intervention (one or two minute sessions in the person's home) uses simple images and prompts, to help the person look beyond their medical condition -in this case, strokeand transform from a "stroke person" into "the real 'me' who happens to have had a stroke" (see figure ). twelve months after stroke, people exposed to the take charge intervention in the taking charge after stroke (tacas) trial were performing significantly more advanced activities of daily living, were less likely to be dependent on another person for help, and reported better quality of life. these are the first trials of a specific stroke rehabilitation intervention that have shown a sustained benefit at the level of independence or quality of life. "taking charge" embraces four fundamental components: a sense of autonomy, a sense of purpose, a sense of competence or mastery and connectedness with others. these components have been extensively studied in the fields of education and psychology as part of self-determination theory. a facilitator, trained to be completely non-directive, guides the person through the taking charge booklet. the first three pages concentrate on sense of purpose, personal identity and hopes for the future, modified as necessary for the specific medical condition of interest (see figure ). further pages consider the issues of importance for the person (eg physical activity, mood, finances, supports, information, disease prevention) with a structure that allows them to break down their hopes for the future into "do-able" steps and identify their key support person/people. all ideas come from the person or their family, and the facilitator is trained not to provide 'helpful suggestions' ie this is all about the unique individual and is therefore fully person-centred. pr is also a complex intervention. exercise-training is a core component of pr programmes; guidelines indicate minimum levels of both dose and frequency, tailored to the individual, aiming to increase exercise capacity. , there is growing evidence of both the importance of increased physical activity as part of the efficacy of pr, and the substantial independent contribution this makes to health and survival. [ ] [ ] [ ] translating a personalized exercise programme into the sustained behavioural change of increased physical activity remains a significant challenge the first page of the take charge booklet from a feasibility study for people with exacerbations of copd requiring hospitalization showing the translation from the "taking charge" concept in figure to a specific medical condition, in this case, copd. the words "matua", "whaea", "koro", and "kuia" are in the māori language, with english equivalents of parent, mother, male and female elders/grandparents. for pr. this will be potentially more difficult in covid- pandemic environments. other problems with pr include gross under-utilization of pr (low rates of pr referral, uptake and completion) and considerable heterogeneity in patient responses to pr, as measured by exercise capacity, breathlessness scores, and health-related quality of life. , universal barriers to attendance include: travel and transport, depression, comorbidities, reduced perceived benefit, and socio-economic deprivation; others are patient or place-specific, eg ethnicity. , there is evidence that adaptive coping strategies to illhealth affect response to pr. but although anxiety ( %) and depression ( %) are common in patients with copd, there is no evidence that these conditions impact on rates of completion or response to pr. , , so how can we facilitate behaviour change to increase physical activity? various groups have studied the use of counselling, coaching and goal setting after pr, generally showing small improvements in physical activity. , the barriers and enablers to increasing physical activity for people living with copd are complex and varied, including physical, environmental and psychosocial factors. living with copd has social and psychological consequences besides physical constraints. anxiety, depression, impaired ability to work, problems with sexual function and limitations in social activities impact on wellbeing. an individual's symptoms of breathlessness, and level of disability are complex. the breathe oxford group argue that this is beyond the complicated pathophysiology, incorporating prior experiences and expectations as well as the personal perception of body signals. most pr programmes include an educational component usually concentrating on self-management, including how to manage breathlessness, medication adherence, inhaler technique, action plans for exacerbations and nutrition, as well as promotion of mental health and facilitation of advanced care plans. delivered as education, they are by definition health-professional-centred, and in terms of sustained behavioural change, their effectiveness is variable. , outside of pr, many non-pharmacological interventions have shown positive outcomes in terms of mood for people with copd, including home-based cognitive behavioural therapy, mindfulness, motivational interviewing and singing. [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] two randomized controlled trials of singing group interventions in copd report improvements in quality of life and reduction in anxiety, although not in lung function. , in our singing group study, there was a significant reduction in the hospital anxiety and depression scale (hads) anxiety score between baseline and one year, as well as a significant increase in mwt. one explanation for the improvement in mwt after singing group programmes is that participants are personally motivated -they attempt more themselves (autonomy), have realistic personal goals for improvement (competence/mastery), look forward to the activity and the future (purpose), and feel more socially connected -all components of take charge. in our qualitative study of a copd singing group, it was clear that social connection in a safe place was a key priority for participants, confirmed in other studies of pr. the participants in these studies appreciated the camaraderie of the singing group, with the once-weekly sessions at a community venue being a crucial part of their social schedule. many of the group overcame significant barriers -transport, weather, intermittent ill-health, exercise restriction -to attend at unexpectedly high rates ( %) over a full year. we think that the social connection component of the singing group, while at the same time doing something that is both challenging and enjoyable, was influential in maintaining the high attendance rate as well as the improved outcomes. the importance of social connection for health and wellbeing is well established. social isolation, loneliness, and living alone are associated with a - % increased likelihood of mortality in the general population, and there is no reason to think the copd population is any different. furthermore, in the general population, social isolation has a significant bidirectional relationship with depression and anxiety. it makes sense that the same should hold for people with copd. just as people with stroke managed on dedicated stroke rehabilitation wards may be more likely to hope (and believe) in a "life after stroke", we feel one of the key contributors to the consistent benefits of pr, cognitive behavioural therapy and community activities such as copd singing groups, is that involvement provides a person with copd the hope (and belief) in "life beyond copd". for people living with progressive dyspnoea and exercise limitation, often accompanied by social isolation, that hope may be the catalyst for engaging in physical and social activities that were previously thought "too hard". other evidence supports this view. arnold and colleagues showed that improvements in quality of life scores after pr were associated with increases in measures of self-efficacy and suggested that "focussing more explicitly on the enhancement of perceptions of personal control in copd patients may be an important aim of pulmonary rehabilitation". there is nothing stroke-specific about take charge and early qualitative work showed that patients with a range of medical conditions valued this idea. morgan and others have called for a more "person-centred" approach to the person with copd without being specific about how to go about this. take charge is such a person-centred intervention. a feasibility study using a modified take charge intervention for people with a recent exacerbation of copd requiring hospitalization is complete, and results are awaited. in that study, there was no problem modifying take charge for people with copd. building on that work, take charge could be tested as an adjunct to standard pr programmes, or for people who decline pr, as a standalone intervention. meantime, some services wanting to provide a validated tool for person-centred interaction, might choose to incorporate the take charge approach into existing pr programmes, at minimal cost. service configurations have changed dramatically with the advent of covid- , both for people with stroke and copd. although take charge has, so far, only been tested face-to-face, it is possible to deliver the facilitator input by telephone, video link or online chat with the person interacting with a hard copy of the booklet. in a covid- world of limited face-to-face interactions and restrictions on group activities, the built-in social interaction of a regular pr group or singing group will be diminished. there will be a greater onus on the individual with copd to undertake some or all components of a pr programme on their own. an intervention like take charge that explicitly encourages self-management, along with identification of key supporters would be a significant advantage. the psychological dimension of pr may be crucial to its effectiveness and enhancing that effect is worthy of further consideration by providers, audit authorities and researchers. a better understanding of this idea and trials of focussed psychosocial interventions may allow a broader range of effective interventions for people with copd. our view is we should help the person with copd get as much out of their life as they want rather than settling for self-management of their condition alone-ie to become "a person who happens to have copd" rather than remain a "copd patient". the take charge intervention is one option to help make this happen. the authors report no conflicts of interest in this work. anxiety disorders in patients with copd: a systematic review depression and anxiety in patients with copd the impact of anxiety and depression on outcomes of pulmonary rehabilitation in patients with differential response to pulmonary rehabilitation in copd: multidimensional profiling expanding pulmonary rehabilitation capacity. one size won't fit all personalized medicine and chronic obstructive pulmonary disease pulmonary rehabilitation for chronic obstructive pulmonary disease: has it peaked? socio-economic deprivation and the outcome of pulmonary 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stroke. cochrane database syst rev self-determination theory and the facilitation of intrinsic motivation, social development, and well-being pulmonary rehabilitation for chronic obstructive pulmonary disease. cochrane database syst rev british thoracic society guideline on pulmonary rehabilitation in adults physical activity is the strongest predictor of all-cause mortality in patients with copd: a prospective cohort study improving physical activity in copd: towards a new paradigm pulmonary rehabilitation and physical activity in patients with chronic obstructive pulmonary disease the covid- pandemic confronts the motivation fallacy within pulmonary rehabilitation programs pulmonary rehabilitation. an exercise in improvement -combined clinical and organizational audit rcp london whakawhanaungatanga: the importance of culturally meaningful connections to improve uptake of pulmonary rehabilitation by māori with copd -a qualitative study action plans and coping strategies in elderly copd patients influence the result of pulmonary rehabilitation: an observational study have we underestimated the efficacy of pulmonary rehabilitation in improving mood short-and long-term effects of a physical activity counselling programme in copd: a randomized controlled trial a patient-centered walking program for copd. chronic obstr pulm dis chronic breathlessness: re-thinking the symptom self-management in patients with copd: theoretical context, content, outcomes, and integration into clinical care self management for patients with chronic obstructive pulmonary disease efficacy of a minimal home-based psychoeducative intervention in patients with advanced copd: a randomized controlled trial mindfulnessbased cognitive therapy in copd: a cluster randomized controlled trial mindfulness and motivational interviewing: two candidate methods for promoting self-management singing teaching as a therapy for chronic respiratory disease-a randomized controlled trial and qualitative evaluation singing classes for chronic obstructive pulmonary disease: a randomized controlled trial sing your lungs out-a community singing group for chronic obstructive pulmonary disease: a -year pilot study sing your lungs out: a qualitative study of a community singing group for people with chronic obstructive pulmonary disease (copd) singing for adults with chronic obstructive pulmonary disease (copd). cochrane database syst rev loneliness and social isolation as risk factors for mortality: a meta-analytic review social disconnectedness, perceived isolation, and symptoms of depression and anxiety among older americans (nshap): a longitudinal mediation analysis what really matters to patients living with chronic obstructive pulmonary disease? an exploratory study the relationship between self-efficacy, functional exercise capacity and physical activity in people with copd: a systematic review and meta-analyses changes in personal control as a predictor of quality of life after pulmonary rehabilitation consequences of stroke, arthritis and chronic pain -are there important similarities? the international journal of copd is an international, peer-reviewed journal of therapeutics and pharmacology focusing on concise rapid reporting of clinical studies and reviews in copd. special focus is given to the pathophysiological processes underlying the disease, intervention programs, patient focused education, and self management protocols. this journal is indexed on pubmed central, medline and cas. the manuscript management system is completely online and includes a very quick and fair peer-review system, which is all easy to use. visit http://www.dovepress.com/testimonials.php to read real quotes from published authors. key: cord- -qr xynn authors: uzzaman, md. nazim; jackson, tracy; uddin, aftab; rowa-dewar, neneh; chisti, mohammod jobayer; habib, g m monsur; pinnock, hilary title: continuing professional education for general practitioners on chronic obstructive pulmonary disease: feasibility of a blended learning approach in bangladesh date: - - journal: bmc fam pract doi: . /s - - - sha: doc_id: cord_uid: qr xynn background: continuing medical education (cme) is essential to developing and maintaining high quality primary care. traditionally, cme is delivered face-to-face, but due to geographical distances, and pressure of work in bangladesh, general practitioners (gps) are unable to relocate for several days to attend training. using chronic obstructive pulmonary disease (copd) as an exemplar, we aimed to assess the feasibility of blended learning (combination of face-to-face and online) for gps, and explore trainees’ and trainers’ perspectives towards the blended learning approach. methods: we used a mixed-methods design. we trained gps in two groups via blended (n = ) and traditional face-to-face approach (n = ) and assessed their post-course knowledge and skills. the copd physician practice assessment questionnaire (copd-ppaq) was administered before and one-month post-course. verbatim transcriptions of focus group discussions with course attendees and interviews with three course trainers were translated into english and analysed thematically. results: forty gps completed the course (blended: ; traditional: ). the knowledge and skills post course, and the improvement in self-reported adherence to copd guidelines was similar in both groups. most participants preferred blended learning as it was more convenient than taking time out of their busy work life, and for many the online learning optimised the benefits of the subsequent face-to-face sessions. suggested improvements included online interactivity with tutors, improved user friendliness of the e-learning platform, and timing face-to-face classes over weekends to avoid time-out of practice. conclusions: quality improvement requires a multifaceted approach, but adequate knowledge and skills are core components. blended learning is feasible and, with a few caveats, is an acceptable option to gps in bangladesh. this is timely, given that online learning with limited face-to-face contact is likely to become the norm in the on-going covid- pandemic. provision of postgraduate training in family medicine is increasing in asia pacific, but rarely uses innovative online learning [ ] that could enhance access to continuing medical education (cme) essential for building and maintaining a high-quality primary care workforce [ ] . traditionally in bangladesh, post-graduate training involves face-to-face study, but shortage of physicians in many rural and semi-urban areas [ ] , mean that physicians often cannot leave their practices to attend several days of training. blended learning is a combination of face-to-face and online learning [ ] , which has become possible in bangladesh with recent substantial improvements in internet coverage, and may be a useful way to achieve cme [ ] . chronic obstructive pulmonary disease (copd) is an exemplar of a condition in which there are concerns that limited awareness of guideline recommendations amongst general practitioners (gps) [ , ] leads to misdiagnosis and inappropriate management [ , ] . copd affects an estimated million people worldwide [ ] and globally, is predicted to be the third leading cause of death by [ ] . although copd burden varies between countries, almost % of copd deaths occur in low-and middleincome countries (lmics) [ ] . the national copd guideline [ ] is not widely used in bangladesh. some clinicians follow global guidelines [ ] , however, substantial gaps exist between guideline recommendations and gps' practice. closing this gap is a priority research need for the international primary care respiratory group (ipcrg) [ ] . blended learning was introduced initially in undergraduate teaching [ ] [ ] [ ] [ ] and is now extending to postgraduate learning [ ] , though the concept is relatively new in bangladesh [ ] . an online component allows practitioners increased time and flexibility for study, wider and easier access to learning resources, and a higher level of autonomy in learning than in exclusively face-to-face courses [ , ] . management of copd requires acquisition of practical skills (spirometry; inhaler technique) necessitating a face-to-face component. therefore, we aimed to assess the feasibility of a blended learning approach to a copd cme course for gps in bangladesh. our mixed-methods feasibility study was conducted in june to august . quantitative data measured pre-post self-assessment of adherence to copd guidelines and qualitative focus groups and interviews explored trainee and trainers' perspectives of the blended learning. gps providing public and private primary healthcare services in bangladesh were invited to participate. gps in bangladesh have an mbbs (bachelor of medicine and surgery) are registered by the bangladesh medical and dental council, have at least two years' experience of clinical service but with no specialist post-graduate training. we excluded gps who had previously participated in post-graduate copd training at any time. the copd course, which was provided free of charge, was advertised nationally through the training management portal of the international centre for diarrhoeal disease research, bangladesh (icddr,b), and social media was used to disseminate the course advertisement. potential participants applied through the icddr,b portal. we screened applicants for eligibility, randomly selected participants who were randomly allocated (using a computer generated randomisation list) to either blended learning or the traditional face-to-face course. this was a feasibility study, so no sample size calculation was required [ , ] . resource availability allowed us to run two courses, so we allocated participants to each group. this is our normal group size, and is a sufficient sample size for assessing feasibility [ ] . the total training hours was h in both blended and traditional learning approaches and the courses contained the same content: components aimed at enhancing copd knowledge ( h) and skills ( h). a private facebook group was created to provide online learning support for both groups monitored by a tutor and for peer discussion. the tutors were gps with expertise in respiratory care and had considerable experience of delivering training. the learning approaches are summarised in table with further details in additional file . to assess how the training impacted on participants' practice and adherence to copd guidelines, the copd physician practice assessment questionnaire (copd-ppaq) was administered to all participants prior to starting training and after course completion. due to fellowship time restrictions, the copd-ppaq was administered only month after the course completed. this validated questionnaire is designed for the selfassessment by physicians of their implementation of key items (two domains: diagnosis and assessment; treatment and follow-up) of copd guidelines. the answers are globally reproducible [ ] . in line with the usual assessment on completion of icddr,b courses, skills were assessed by an oral examination and knowledge was assessed using a written multiple-choice questionnaire examination. following completion of training, all participants were examined on their copd knowledge and skills. from previous experience we anticipated that knowledge of copd and spirometry skills of gps with no prior copd training would be very low; we therefore did not assess this pretraining. all participants who completed the blended learning training were invited to participate in one of three focus groups facilitated by mnu supported by a note-taker. discussion addressed participants' perceptions of blended learning, preferences compared to previous experiences of face-to-face or online learning, advantages/ disadvantages of the blended learning. the three course trainers were interviewed individually to explore their views and opinions about the practicalities of delivering training using this approach (see additional file ). all discussions were digitally recorded and transcribed verbatim in the spoken language (bengali). the emotional context such as pauses, laughter, emphasis and non-verbal communication were included as notes in the transcripts to aid analysis. transcripts were translated (by mnu who led the focus groups) from bengali to english for analysis. examination scores, and copd-ppaq scores are expressed as percentages. summary statistics were calculated as means, proportions as necessary. stata statistical software (statacorp lp, college station, texas, usa) was used for data analysis. we used thematic analysis for the qualitative data [ ] using a coding framework developed by mnu in discussion with the other authors. the focus group discussions with trainees and interviews with trainers were analysed separately. this involved coding the whole data set and the codes were then synthesised into emerging themes which were combined into overarching themes including synthesised data from participants and tutors. the first author is a gp, employed by icddr,b, to deliver cme to healthcare professionals. he was involved in developing the learning materials, and facilitating training sessions which might have influenced the interviews/ focus groups and his interpretation of the data. to mitigate against this, themes were discussed within the multi-disciplinary author group. we received a total of online applications which were screened for eligibility. the commonest reasons for ineligibility were less than the minimum two years of clinical service (n = ), and already having specialised post-graduate training (n = ). did not provide complete information (eg. no qualification dates or experience) leaving eligible applicants. we randomly selected participants and allocated to each group. of the allocated participants, ( %) completed blended learning and ( %) traditional learning. the commonest reason for withdrawal in both groups was inability to take time out of practice. other reasons were illness, domestic or family responsibilities. most of the gps ( %) were between to years and half had - years' experience of patient care. almost half the participants of both groups were used to consulting with or more patients daily (table ) . the quantitative results are presented with the caveat that this was a feasibility study which was not powered to show a difference. detailed outcomes are therefore placed in additional files and without any statistical comparisons to avoid over interpretation. the overall end-of-course examination scores was similar in both groups, both for overall knowledge, and for assessment of skills. gps self-reported adherence to copd guidelines using copd-ppaq showed similar improvement in both groups. the self-assessment of key recommendations suggested that participants in both groups scored substantially better in all aspects of their practice except in smoking cessation and referral to specialist. eighteen of the blended learning course attendees (trainees) who completed the training participated in one of the three focus groups. they were aged - years and from nine districts of bangladesh. the location of their workplaces varied from three to over km from the training venue. the number of participants from urban, semi-rural and rural areas were nine, five and four respectively ( table ) . all trainees had previous experience of attending traditional training, half had participated in entirely online training and six had previous experience of a blended learning approach. interviews were conducted with the three trainers who were between and years of age. no further details are provided to maintain confidentiality of trainers. three main themes emerged in the analysis of both focus group discussions with trainees and interviews with course trainers. the themes and sub-themes are listed in table and described below. this was echoed by the trainers who were positive about the online resources being available ' hoursanytime, anywhere'. in contrast, one trainee preferred the traditional approach because it enabled him to focus on the topic for the duration of the course, whereas online learning could too easily be postponed. he also considered that the traditional approach was better for practical demonstrations (e.g. cardio-pulmonary resuscitation). one of the course trainers preferred the traditional approach, although he recognised that it was difficult for busy gps to be away from their practice. almost all the trainees felt confident of their knowledge and skills in diagnosing and managing copd patients after completing the training. most wished to participate in future courses using a blended approach and said they would recommend it to others. one participant was sufficiently confident in his acquired knowledge and skills that he felt he would be able to disseminate what he had learnt to staff in his practice. in contrast, a few participants felt that they did not get enough time to perform spirometry manoeuvres during "during practical session i expected more to learn about spirometer (how to operate the machine). however, we didn't have the scope to learn spirometer, especially with real patient". (trainee, p ) theme ii: educational advantages and disadvantages advantages of blended learning reasons provided for preferring the blended learning approach were the convenience of not having to relocate and the option to do some of the training in their own time which fitted around their practice work. reducing their physical presence in class was considered very helpful as it caused minimal interruption to their patient care. this view was particularly apparent in accounts from doctors who worked in rural areas and remote places where learning opportunities are limited, and staff resource is at a critically low level. "those of us who live in remote areas; the blended approach is a blessing for us which would allow us to add to our knowledge deficit quite a lot. those who stay centrally, get many opportunities to attend scientific seminars, cme (continued medical education) etc which we couldn't manage". (trainee, p ) in the blended learning approach, participants learned online before they attended face-to-face classes when they could solve the queries that had arisen while using the online resources. "we got learning contents in advance and were able to go through online. we know in advance what we will learn tomorrow. we solved our queries that arose during online learning when we were in faceto-face classes." (trainee, p ) a few participants said that blended was more attractive and interactive compared to a traditional approach or only online training. two of the trainers mentioned that the blended approach offered two-way learning with scope for providing better student support compared to either traditional or entirely online training. most of the trainees did not mention any generic drawbacks of the blended-learning approach. instead they discussed the weakness of the particular e-learning module they had used, and highlighted a few areas of the face-to-face classes which needed improving. some trainees found reading online content uncomfortable, mentioning that they were more comfortable with familiar paper rather than online documents. specifically, excessive screen exposure caused eye pain and headache to one of the trainees. although most participants completed the online module, a few mentioned that they had neglected the online learning either deliberately thinking that they would learn it from the faceto-face classes or procrastinating and not quite getting round to doing it in their busy schedules. "because of having the face-to-face part, we often have neglected the online part thinking that we have face-to-face classes"! (trainee, p ) apart from sharing the concern about the discomfort of online reading, trainers had some additional concerns about blended learning. one trainer was concerned that the online component might be considered as an extra pressure by some trainees. another trainer thought that the three-week gap between the online and face-to-face learning might increase participant dropout from the course. in addition, one of the trainers noted that unreliable internet access in some locations might limit the usefulness of the blended approach in bangladesh. in addition, this trainer was concerned that many physicians were not accustomed to using computers and if they only completed the minimum face-to-face tasks it might affect skill development of the trainees. almost all participants (trainees and trainers) thought the elearning module needed further development, with suggestions about more videos, animation, and quizzes with analytical questions to make it more interactive and attractive. opinions were divided about whether the contents were 'somewhat disorganised'. some trainees suggested including the content of the subsequent face-to-face classes in the e-learning module so that learning was reinforced. "practical sessions like inhaler techniques may be given online which would help us to learn better as we may not learn the technique in one face-to-face class. in future, if we get confused, we can watch the video and make our technique correct". (trainee, p ) most of the trainees wanted prompt feedback via the online platform rather than having to use a separate facebook group for this purpose. facebook was associated with social communication during leisure time and not as an effective medium for solving professional queries. indeed, some people noted that it was a distraction which wasted a lot of time. moreover, participants had only met once during the orientation class, so some did not feel sufficiently familiar with each other to be able to engage proactively in online group discussions. from a practical perspective they had to open facebook separately alongside the e-learning module which they found burdensome and although delegates tried it at least once, only delegates engaged in discussion. "yes, we had a facebook group [for solving queries]. but to me, when i logged on it, a lot of time went away unknowingly." (trainee, p ) a few trainees said that provision of a tutor for a scheduled online discussion would be helpful to solve queries and this would allow more time for practical tasks during face-to-face classes. two of the trainers with previous experience of online discussions, agreed and considered that the online discussion could help trainees to engage and learn more. "the provision of online discussion would help participants to learn more. even participants could ask question online which they couldn't understand in face-to-face classes". (trainee, p ) in contrast, some trainees considered that a fixed time for an online discussion was unlikely to be convenient for everyone, and reduced the flexibility that was an advantage of the online learning. they suggested that face-to-face classes were a better option for solving their queries. "i don't think we can align our time with the online tutor". (trainee, p ) "since we had the opportunity of face-to-face classes, here we didn't have the need of online classes". (trainee, p ) other trainees suggested that the e-learning platform should have a discussion board where a mentor would give his/her feedback, and everyone could see answers and learn accordingly. "i'd say that the online platform itself should keep an option of asking question […] a coordinator will reply to our queries in a particular time of a day". (trainee, p ) the majority of the trainees encountered challenges reading the online contents; only two participants did not have any problems. there were difficulties reading documents in full screen, sometimes a chapter showed as 'incomplete' even though it had been completed. a few trainees with previous experience of online courses suggested that chapters should be completed in order to qualify for the chapter accomplishment quiz. one trainee wanted the option of a mobile-based application along with the provision of offline access to the contents that they completed earlier for rereading as necessary. "mobile based app could be introduced where we can even get access without having internet connection [smiling]". (trainee, p ) almost all trainees shared that the practical sessions should involve "patients", if only for a short period of time. the practical classes were mostly device oriented. since we will apply our knowledge on patients, i think the practical classes need to be real patient-based which will make the course much more effective". (trainee, p ) the majority of the trainees thought that face-to-face classes would be more convenient if they were delivered days apart, preferably during weekends, so they would not need to leave their practice during working days. we all are busy, or it is difficult to manage leave for two-three consecutive days for face-to-face training. classes could be taken seven days apart and during weekend". (trainee, p ) two of the participants wanted an honorarium for participating in the course while one participant strongly opposed this issue. "we have been provided with food during training. if you could provide us some honorarium, that would be very good. after a certain age, we have more financial liabilities." (trainee, p ) in contrast, one trainer was concerned about the nonattendance of some participants suggesting that a course fee should be paid by the participants to make them more responsible. "this time we found that few participants didn't complete the course although there were many applicants who were very interested to attend the course. […..] one of the reasons might be that the participants didn't have to pay the course fee of their own". (trainer, t ) of the trainees allocated to each group, completed blended learning and completed the traditional faceto-face learning. inability to take time-out of practice was the commonest reason for attrition in both groups. the gain in knowledge and skills by the participants in both groups was similar. in addition, self-reported adherence to copd guidelines before and after training revealed similar improvement in both groups. all participants, except one trainer and one trainee, preferred the blended learning approach as it was more convenient within their busy work schedules. although a few participants 'neglected' the online modules, for most the online learning optimised the benefits of the face-toface sessions. there were a number of practical problems with internet connections and finding it 'uncomfortable' to read on-screen documents and most participants suggested improving interactivity. online support from tutors was valued, but embedded in the learning platform rather than using facebook which was associated with social interaction. a strength of our mixed method design is that it allowed triangulation of results; for example, the participants' perception of increased confidence in managing copd was matched by measured gains in skills and knowledge. the quantitative data will inform potential outcomes for a future evaluation of blended learning on copd and the qualitative data gave insights into both positive and negative perspectives. moreover, the practical suggestions and operational challenges will be helpful in refining future training. the examiners were aware of the allocation of both groups which risked biasing the quantitative outcomes, but the same examiners assessed participants from both groups ensuring consistency of assessment. blinded assessment was not possible within the resources of the study. we were aware of the impact of reflexivity, as the researcher conducting the focus groups and interviews (mnu) was also involved with training coordination and development of learning materials. involvement of a multidisciplinary author group unconnected with icddr,b or the course helped ensure a balanced interpretation of the data. although we achieved data saturation with respect to the trainee opinions, the limited number of trainers meant we only heard three perspectives. our aim was to assess the feasibility of the blended learning intervention, and the single location (dhaka) of the course and the small numbers limit generalisable, though our findings may be applicable to others working in similar settings in bangladesh or beyond. studies show that blended learning allows greater flexibility and responsiveness in adult learning processes [ , , ] . the addition of online learning overcomes limitations of time and space, reaches more students and supports instructional methods that may be hard to achieve without increased resources [ ] . some studies have found a mismatch regarding preferred learning approaches where trainers assumed that technology-based learning suited the trainees' style; however, trainees felt differently [ ] . in our study, trainees and trainers almost all agreed that blended learning overcame two limitations compared to entirely online or traditional learning. first, the e-learning component reduced the need for prolonged time out of practice to attend a course, and second, the prior online work optimised the learning of skills in the face-to-face class. a previous study with gps also found e-learning a useful way to gain knowledge and the face-to-face component a suitable way of transferring practical knowledge [ ] . furthermore, some participants in our study suggested blended learning was cost-effective [ ] as a substantial number of doctors could be trained within a short period of time [ ] . in contrast, a few trainees found it difficult to adapt their learning styles to a blended approach [ ] . some felt that provision of paper versions of the e-learning module would be helpful as they were accustomed to reading paper books [ ] . flexibility is generally seen as a strength as e-learning allows participants to learn at a convenient time [ ] . in our study, it was also viewed as a challenge because some gps found it difficult to schedule study time. also, some neglected online study hoping to catch-up in the face-to-face sessions. trainers living at a distance found it less efficient to schedule face-to-face classes involving long travel time for shorter meetings. the lack of a blended learning approach to cme in lmics may be associated with limited technological resources [ ] . echoing other studies that have highlighted poor access to technology as a barrier to the implementation of technology-enhanced teaching [ ] , our participants described annoying technical problems such as losing information on progress, or the need to switch between pages. the use of social media (in particular facebook) was associated with social communication and considered an ineffective way of interacting with fellow participants and solving queries though other studies have successfully used this approach [ ] . like several other studies, some trainees and trainers considered that, for productive interaction, it is important that tutors actively moderate online discussions [ ] [ ] [ ] . more patient involvement in skills development was wanted, and contributing to online modules could be a convenient way to incorporate patients. the dropout of participants ( in in our study) was another challenge. an outbreak of dengue fever in bangladesh was one factor and cultural context is also important. in lmics like bangladesh, food and honorarium are two important issues that need to be considered when developing education. government employees typically expect to receive an honorarium when they participate in any training. provision of accessible cme is central to maintaining the quality of primary healthcare and the morale of the workforce [ ] . in the context of copd, where underdiagnosis and inadequate management is common [ ] [ ] [ ] , our blended-learning course was a feasible approach to enhancing knowledge and skills of gps about copd. the observation by some of the participants that they were sufficiently confident in their learning to be able to pass on the knowledge to others in their practices is encouraging but needs further evaluation. 'train the trainer' programmes have been used successfully by the international primary care respiratory group [ ] , and blended learning offers the potential for online modules to be used to pass on knowledge. the flexible and practical blending of online and face-to-face learning has the potential to be used for cme of other long-term conditions in bangladesh and beyond. with some caveats, blended learning was an acceptable educational model and preferred by most of the busy gps in bangladesh. quality improvement requires a multifaceted approach, but adequate knowledge and skills are a core component; blended learning is a feasible option which could contribute to improved implementation of guideline recommendations. online cme was a novel approach in our lmic setting, but learning with limited face-to-face contact is likely to become the norm in the current covid- pandemic making this a timely message. received: june accepted: september the status of family medicine training programs in the asia pacific family medicine vocational training and career satisfaction in hong kong the health workforce crisis in bangladesh: shortage, inappropriate skill-mix and inequitable distribution blended learning: the convergence of online and face-to-face education. promising practices in online learning. north american council for online learning perceptions toward a pilot project on blended learning in malaysian family medicine postgraduate training: a qualitative study copd patients need more information about self-management: a cross-sectional study in swedish primary care copd management in primary care: is an educational plan for gps useful? diagnosing copd in primary care: what has real life practice got to do with guidelines? under-and over-diagnosis of copd: a global perspective chronic obstructive pulmonary disease (copd): key facts projections of global mortality and burden of disease from to national guidelines: asthma, bronichiolitis, and copd global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease the international primary care respiratory group (ipcrg) research needs statement teaching differential diagnosis in primary care using an inverted classroom approach: student satisfaction and gain in skills and knowledge improving education in primary care: development of an online curriculum using the blended learning model a blended learning approach to teaching basic pharmacokinetics and the significance of face-to-face interaction student perceptions of a virtual learning environment for a problem-based learning undergraduate medical curriculum blended learning for postgraduates; an interactive experience improving physicians' capacity for chronic obstructive pulmonary disease care through blended e-learning: a pilot study in the past, present and future of blended learning: an in depth analysis of literature amee guide : e-learning in medical education part : learning, teaching and assessment nuts and bolts of conducting feasibility studies information for authors: pilot and feasibility studies an audit of sample sizes for pilot and feasibility trials being undertaken in the united kingdom registered in the united kingdom clinical research network database the physicians' practice assessment questionnaire on asthma and copd using thematic analysis in psychology blended learning: strengths, challenges, and lessons learned in an interprofessional training program learning from focus groups: an examination of blended learning introducing an online community into a clinical education setting: a pilot study of student and staff engagement and outcomes using blended learning blended learning in cme: the perception of gp trainers blended learning: efficient, timely and cost effective building effective blended learning programs a new vision for distance learning and continuing medical education the role of blended learning in the clinical education of healthcare students: a systematic review the uses of information and communication (ict) in teaching and learning in south african higher education practices in the western cape : research : information and communication technologies facebook as a learning tool: perception of stroke unit nurses in a tertiary care what are the perceived benefits of participating in a computer-mediated communication (cmc) environment for distance learning computer science students? online discussion in blended courses at saudi universities blended learning in teacher education: an investigation across media global initiative for chronic obstructive lung disease. global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. gold executive summary prevalence and underdiagnosis of copd by disease severity and the attributable fraction of smoking report from the obstructive lung disease in northern sweden studies management, morbidity and mortality of copd during an -year period: an observational retrospective epidemiological register study in sweden (pathos) improving care for people with asthma: building capacity across a european network of primary care organisations-the ipcrg's teach the teacher programme publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations we gratefully acknowledge the contribution of mohammod rafiqul islam for online learning management system coordination. we are thankful to the trainers for their contribution in delivering the intervention. icddr,b acknowledges with gratitude the commitment of nihr global health research unit on respiratory health (respire) to its research efforts. icddr,b is also grateful to the governments of bangladesh, canada, sweden and the uk for providing core/unrestricted support. supplementary information accompanies this paper at https://doi.org/ . /s - - - .additional file . programme outline.additional file . topic guide for focus group discussion and interview. additional file . practice assessment of trained physicians using copd physician's practice assessment questionnaire (copd-ppaq). the qualitative data that support study findings may be available from the corresponding author on request.ethics approval and consent to participate ethics approval obtained from the international centre for diarrhoeal disease research, bangladesh (icddr,b) ethical review committee (pr- ) and sponsored by the academic and clinical central office for research and development (accord ac ). all participants provided written informed consent. not applicable.competing interests mnu, and au are involved with developing cme courses at icddr,b. the other authors declare no competing interests. key: cord- - kdc xk authors: hershenson, marc b. title: rhinovirus-induced exacerbations of asthma and copd date: - - journal: scientifica (cairo) doi: . / / sha: doc_id: cord_uid: kdc xk over the past two decades, increasing evidence has shown that, in patients with chronic airways disease, viral infection is the most common cause of exacerbation. this review will examine the evidence for viral-induced exacerbations of asthma and chronic obstructive lung disease and the potential mechanisms by which viruses cause exacerbations. attention will be focused on rhinovirus, the most common cause of respiratory exacerbations. exacerbations due to rhinovirus, which infects relatively few cells in the airway and does not cause the cytotoxicity of other viruses such as influenza or respiratory syncytial virus, are particularly poorly understood. while the innate immune response likely plays a role in rhinovirus-induced exacerbations, its precise role, either adaptive or maladaptive, is debated. because current treatment strategies are only partially effective, further research examining the cellular and molecular mechanisms underlying viral-induced exacerbations of chronic airways diseases is warranted. readers of this paper who care for patients with asthma will be familiar with the following scenario. a patient with recurrent cough and wheeze presents to the clinic for evaluation. the patient states that the only time she has respiratory symptoms is fall, winter, and spring following "colds. " she has no symptoms in the summer, or between colds. she denies she has asthma and does not feel the need to take inhaled steroids even though she has been prescribed them in the past. my response to this patient, and the premise of this review, is that many patients have asthma which is only triggered by viral upper respiratory tract infections. nevertheless, the role of viral infections in the exacerbation of asthma, chronic obstructive disease (copd), and other chronic airways diseases was almost completely ignored until the late s, when more sensitive methods of viral detection were developed. while the emphasis of allergic sensitization in the pathogenesis in asthma is strongly justified, serious exacerbations of this disease are more likely to relate to viral infection rather than allergen exposure (table ) . exacerbations constitute the major cause of morbidity and mortality in asthma and copd, and therefore vigorous attention towards the problem of exacerbations is warranted. what is the evidence for viral-induced exacerbations of asthma and copd, and why was the role of viral infection ignored for so long? it was once thought that rhinovirus and other cold viruses did not infect the lower airway. before the advent of polymerase chain reaction (pcr), viruses were rarely cultured from the bronchoalveolar secretions of immunocompetent individuals, even after experimental infection [ ] . early studies showed that replication of human rhinovirus (rv), the most prevalent respiratory virus, was temperature restricted, with optimal growth below body temperature, at ∘ - ∘ c [ ] [ ] [ ] . exacerbations of chronic airways disease following upper respiratory tract infections were explained by theories linking nasal (upper respiratory tract) and bronchial (lower respiratory tract) disease. the most common explanation was that nasal blockage and mouth breathing lead to inspiration of cold, dry, and unfiltered air, triggering an asthma attack. however, other workers in the field blamed a nasal-bronchial reflex mechanism involving trigeminal and vagal nerves (first proposed in ). [ ] [ ] [ ] [ ] . (this theory was also used to explain how nasal allergies promote asthma.) more recently, release of proinflammatory mediators from the nose and bone marrow into the circulation has been proposed [ ] . ( ) viral infection (most commonly rhinovirus) ( ) allergen exposure (tree, grass, and weed pollens; mold; animal dander; dust mites; and cockroach particles) ( ) exercise ( ) irritants including environmental tobacco smoke exposure, smoke from wood-burning appliances or fireplaces, strong odors from perfumes, cleaning agents, air pollution, and occupational dust or vapors ( ) medications (aspirin and other anti-inflammatory drugs, and beta blockers) ( ) changes in weather (cold air, changes in temperature, and humidity) ( ) gastroesophageal reflux ( ) sinusitis in contrast to the study showing temperature restriction, subsequent studies showed that many rv strains replicate at body temperature. [ , ] . for that matter, the temperature of the lower airways may decrease to - ∘ c during periods of increased minute ventilation (i.e., exercise) or cold temperature [ ] . however, it was the advent of pcr for the detection of respiratory viruses which really changed the understanding of exacerbations. pcr-based studies examining the prevalence of virus identification among various cohorts of patients with chronic airways disease consistently show a higher prevalence of viral infection during exacerbations. outpatient children who are sick with asthma exacerbations show anywhere from - % positivity for viral infection versus only - % of children who are well [ , ] . picornaviruses (primarily rv) were detected in % of cases, coronaviruses in %, influenza and parainfluenza viruses in %, and rsv in % [ ] . similar studies have been performed in hospitalized children, adult outpatients, and hospitalized adults [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . adults seem to show a slightly lower prevalence of viral infection during exacerbations. finally, to % of patients with copd exacerbations have virus identified by pcr versus to % of nonexacerbating subjects [ ] [ ] [ ] [ ] [ ] . across all of these studies, rv makes up approximately % of the viruses isolated ( table ). the prevalence of rhinovirus may be even higher depending on the time of year. a recent study detected on rv in % of all children admitted to an emergency room for acute asthma between january and july [ ] . together, these studies suggest that viral infections cause exacerbation of asthma and copd. additional information that viruses indeed cause attacks of chronic airways disease comes from an analysis of emergency department presentations for asthma and copd over the course of a calendar year. exacerbations of asthma in children peak after school return from summer vacation (in north america, the first week of september), consistent with an infectious cause [ ] . this "epidemic" of asthma exacerbations in children is primarily associated with fall rhinovirus it is now clear that rhinovirus can indeed infect the lower airways. following experimental infection, rv has been detected in the lower airways by immunostaining, pcr, and in situ hybridization for positive-strand viral rna [ ] [ ] [ ] [ ] . a study from the university of wisconsin [ ] was highly instructive. these investigators infected adult control and asthmatic subjects with rv and then stained biopsy tissue for rv capsid protein by immunohistochemistry. rv staining was clearly seen in the cytoplasm of cells in the epithelium ( figure ). however, staining was patchy and in some samples only or cells were positive. other investigators have similarly noted that rv infects relatively few cells in the airway [ , ] . researchers from imperial college, london [ ] performed in situ hybridization of biopsies from experimentally infected patients and found positive-strand viral rna in the epithelium. interestingly, there was also sparse staining of cells in the subepithelial layer (there was insufficient detail to determine cell type). until recently there was little evidence that rhinovirus replication occurred in the lower airways. however, the wisconsin group [ ] , examining sputum of experimentally infected controls and adults, showed persistence of viral rna up to days after infection; this duration of infection could only occur with viral replication. (nevertheless, the amount of viral replication in the airways remains uncertain.) also, patients with asthma who had an exacerbation following experimental infection had higher levels of viral rna in their sputum compared to asthmatics that did not experience an exacerbation, further evidence that viruses do indeed cause exacerbations. if indeed viral infections do cause exacerbations of asthma and copd (and the preponderance of evidence suggests that this is so), what is the proposed mechanism by which viruses cause exacerbations? rhinovirus, unlike influenza scientifica and other viruses, causes minimal cytotoxicity [ , ] . also, the amount of epithelial damage does not correlate with the severity of the symptoms, suggesting that symptoms are produced by processes independent of the severity of direct virus-induced damage to the epithelium. while selected studies have demonstrated cytotoxicity in various cell culture models [ ] , epithelial cell death is considered unlikely to contribute in vivo to rv-induced exacerbations of chronic airways disease. the current explanation is that rhinovirus infection induces the release of chemokines from airway epithelial cells, thereby attracting inflammatory cells to the airways. in patients with preexisting airway inflammation, the influx of additional inflammatory cells caused by rv infection would lead to additive or synergistic effects and an exacerbation of airways disease. there is ample evidence that rhinovirus infection induces airway epithelial cells to express proinflammatory chemokines. many studies of cultured airway epithelial cells show that rv increases expression of neutrophil-, eosinophil-, and t-cell-attracting chemokines, including cxcl , ccl , ccl , and cxcl [ , [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . a recent study by proud and colleagues [ ] examined the effect of experimental rhinovirus infection on nasal epithelial cell gene expression in situ. the most highly upregulated genes were those encoding chemokines (ccl , ccl , cxcl , cxcl , cxcl , cxcl , and ccl ). we have obtained similar results in the lungs of rv-infected mice (table ) . consistent with these results, experimental infections of asthmatic subjects have consistently shown increased number of airway neutrophils, lymphocytes and eosinophils [ , [ ] [ ] [ ] . a number of clinical studies suggest that rv potentiates preexisting allergic inflammation [ , , [ ] [ ] [ ] [ ] . however, the notion that viral infection simply augments asthmatic airway inflammation may not explain why asthmatics suffer manifestations of lower airways disease after colds while normal individuals do not. could asthmatics tissue was stained for rv capsid protein (red) and dapi, a nuclear stain. note that some cells are stained with rv and others are not. (c) tissue was stained with mouse igg, a negative control, and dapi. note the absence of red staining. antibody against rv and tissue blocks were generously provided by wai-ming lee, nizar jarjour, and jim gern (university of wisconsin figure : a mechanism to explain defective innate immunity in asthma. the differentiation of th and th t-helper cell lineages is mutually antagonistic. th cells produce il- which blocks th differentiation and th cells produce ifn-which blocks th differentiation. thus, individuals with an immune system skewed towards th tend not to produce eosinophils and ige-producing b cells, but not th cells. the relative lack of ifn-limits the antiviral response. airway epithelial damage [ , ] and mucus metaplasia, both of which occur in asthma, may provide rhinovirus with increased access to more readily infected basal cells [ ] and goblet cells [ ] , thereby increasing viral replication. interferon responses, which have been shown to affect the outcome respiratory viral infections in animal models, may also be deficient in patients with asthma. how might this be the case? it is well known that many allergic asthmatics show a skewing of their t cell differentiation towards the th phenotype. since the differentiation of th and th t-helper cell lineages is mutually antagonistic (e.g., il- blocks th differentiation) [ ] , allergic asthmatics with th polarization may have a deficiency in their interferon response ( figure ). during induced colds, asthmatic subjects with strong peripheral blood monocytes and sputum cell interferon gamma responses showed milder cold symptoms and more rapid viral clearance [ , ] . also following experimental rhinovirus infection, viral clearance and airway function correlate with blood and bronchoalveolar (bal) cd cell interferon gamma production [ ] . epithelial and bal cells from asthmatic subjects show reduced type i and type iii interferon responses to rhinovirus infection ex vivo [ , ] . together, these data suggest that asthmatics may be more susceptible for rv infection. on the other hand, other investigators have not found differences in interferon expression or viral clearance between controls and asthmatics. two groups have failed to show reduced interferon responses in cultured airway epithelial cells from subjects with asthma [ , ] . perhaps most importantly, a difference in viral copy number or titer between controls and asthmatics has not been demonstrated following experimental rv infection [ ] . to address the question of whether preexisting allergic airways disease alters the response to viral infection, and whether the interferon response to rhinovirus is required for viral clearance (or part of a maladaptive response to a relatively innocuous infection), we developed a mouse model of human rv infection [ ] [ ] [ ] [ ] [ ] [ ] . before describing this model, however, i like to say a little bit about the basic biology of rhinovirus. rv is an rna virus from the picornaviridae family. rhinovirus is composed of a single strand of positivesense rna enclosed in a small icosahedral capsid. there are greater than known serotypes of rhinovirus. the major subgroup ( serotypes) utilizes icam- as a receptor [ ] ; the minor group ( serotypes) uses the family of low density lipoprotein receptors (ldl-r, vldl-r, and ldl-r related protein) [ ] . other surface molecules, including tlr , may serve as a coreceptor and also be required for viral responses [ ] . rhinoviruses may also be classified not only on the basis of their host receptor but according to their resistance to antiviral drugs. according to this classification, there are type a viruses and type b viruses [ ] . a third group of rhinoviruses, type c, has recently been discovered [ ] [ ] [ ] . rhinoviruses have also been classified according to their genome sequences [ ] . interestingly, rv , a major group virus commonly used for experimental human infection, and rv , which has been used in animal models of rhinovirus infection (see below), are closely related. at this time, the only cell type conclusively shown to be infected by rv in humans is the airway epithelial cell. typically, rv infects small clusters of cells in the epithelial layer [ ] . rhinovirus is internalized by clathrin-mediated endocytosis [ ] [ ] [ ] [ ] . the endosome acidic ph triggers viral uncoating and rna insertion. rv replication occurs entirely in the cytoplasm. during viral replication, negative sense rna and doublestranded rna intermediates are formed. dsrna produced during viral infection represents an important stimulus for the host innate immune response. dsrna is recognized and engaged by three pattern recognition receptors, toll-like receptor (tlr)- , localized to the endosomal and plasma membranes, and cytoplasmic proteins rig-i, and mda- which are intracellular receptors for viral dsrna [ , ] . returning to the problem of animal models, major group viruses do not bind to murine cells, owing to a lack of homology between the human and mouse icam- . however, it was subsequently shown that minor group viruses infect la- mouse tracheal epithelial cells [ ] . we [ ] [ ] [ ] [ ] [ ] ] and others [ ] therefore infected mice with a minor group virus, rv b, by the intranasal route. because of as-yet undefined factors which limit viral replication in the mouse, infection is followed by a steady reduction in viral copy number and titer. however, careful studies of viral copy number show a spike in positive-strand vrna approximately hours after infection and a small amount of negative-strand vrna indicating viral replication. we also found a robust interferon response to infection, implying viral replication. immunofluorescence showed infection of airway epithelial cells and, interestingly, occasional subepithelial cells resembling monocytes. airways of infected mice showed neutrophilic inflammation which decreased with time, as well as subsequent lymphocytic infiltration, a pattern classically associated with viral infection. when we examined respiratory system resistance changes in response to methacholine administration, we found a small but significant increase in airways responsiveness in rhinovirus-infected mice which persisted at least four days after infection. interestingly, mice infected with uvirradiated replication-deficient virus showed modest airway inflammation and responsiveness one, but not four, days after infection. these data suggest that rhinovirus could induce a state of airways hyperresponsiveness without viral replication in the lungs, at least under some circumstances. consistent with this, uv irradiation inhibits but does not abolish major group rv-induced il- release in cultured airway epithelial cells [ , , ] . we next set out to develop a model of viral-induced asthma exacerbation [ ] . we employed a commonly used model of allergic airways disease. mice were treated with intraperitoneal and intranasal ovalbumin and then infected with rhinovirus. mice treated with ovalbumin alone demonstrated a significant increase in airways responsiveness, with respiratory system resistances higher than those obtained after rhinovirus infection. when we combined ovalbumin and rhinovirus treatments, airways hyperresponsiveness increased significantly over that generated by either ovalbumin or rhinovirus alone (figure ). this state of airways hyperresponsiveness persisted at least days after infection. when we examined airway inflammation, we found additive or synergistic increases in airway neutrophils, eosinophils, macrophages, lymphocytes, and chemokines such as ccl and ccl . we also found that the combination of ovalbumin and rhinovirus caused additive increases in the th cytokines il- and il- . when we performed immunohistochemistry to look for the source of ccl production, we expected to find ccl expression in rhinovirus-infected airway epithelial cells. however, to our surprise, we found that the main source of ccl was airway mononuclear cells. when we performed fluorescence microscopy using labeled antibodies against rhinovirus, ccl and cd , a macrophage surface marker, we confirmed ample colocalization of rv b, ccl , and cd , indicating ccl expression by cd -positive macrophages. while most cells were in the subepithelium, we also found cd -positive macrophages in the epithelial layer and the airway lumen. in follow-up studies, we also found colocalization of cd , rv b, and il- in subepithelial cells. several studies have examined the infection of monocytic cells by rhinovirus in vitro [ ] [ ] [ ] [ ] [ ] [ ] . however, the former data represent the first demonstration of rhinovirus infection of monocytes in vivo. at this point, we do not know whether colocalization represents replicative infection of airway macrophages, or simple phagocytosis of the virus. a small amount of viral replication has been noted in rvinfected peripheral blood monocyte-derived macrophages, but not in bal-derived macrophages [ , ] . to address this further, we isolated bronchoalveolar lavage macrophages from control and ovalbumin-sensitized and -challenged mice and infected them with rhinovirus ex vivo. macrophages from control mice showed ample th cytokine (tnf-, il- p ) expression in response to rv infection, but little or no th cytokine (il- , il- , ccl ) production. in contrast, bal cells from ovalbumin-sensitized and -challenged mice showed brisk th responses to ex vivo infection, but decreased th responses. this pattern of cytokine expression was consistent with a change in phenotype from m to alternatively activated m macrophages [ ] . we confirmed this by measurement of m markers such as arginase- , ym- , and mgl- . furthermore, flow cytometry showed high levels of cd b expression, indicative of exudative macrophages found after lung infection or injury. to determine the requirement of these macrophages for the observed airways hyperresponsiveness of rhinovirusinfected and ovalbumin-sensitized and -challenged mice, we depleted the macrophages using clodronate liposomes. administration of clodronate decreased the number of airway macrophages, but not neutrophils or lymphocytes. however the lungs of mice receiving clodronate showed reduced levels of ccl , eosinophils, il- , and airways responsiveness, demonstrating that macrophages are responsible for rv-induced airway responses in mice with preexisting allergic airways disease. the production of th cytokines by lung macrophages is consistent with recent work showing that, in addition to th helper t cells, innate immune cells may contribute to the production of th cytokines in asthma [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . finally, our unpublished experiments indicate that, under certain circumstances, m -polarized macrophages may also be targeted by rv infection. taken together, our data suggest that, rather than causing epithelial infection or damage, rv elicits asthma exacerbations by infecting inflammatory cells, in particular cells of the monocyte/macrophage lineage. but is there any evidence that rhinovirus infects inflammatory cells in humans? with the help of jim gern, nizar jarjour, and others from the university of wisconsin, we have begun to address this question. we obtained biopsy specimens from control and asthmatic subjects experimentally infected with rhinovirus. early unpublished results indicate colocalization of rv and cd in epithelial and subepithelial cells. returning to the question of antiviral innate immunity in asthma, we also employed our animal model to address this issue. does the inflammatory response to rhinovirus promote viral clearance and prevent more severe viral-induced disease? or is the inflammatory response to rhinovirus a maladaptive response to an innocuous stimulus, leading to exacerbations of lower airways disease? these questions have important ramifications for treatment. one often hears the statement that individuals "need to boost their immune response" to fight off colds or cold-induced asthma attacks. the imperial college group has championed the idea that the interferon response is deficient in asthmatics [ , ] , thereby explaining viral-induced exacerbations. in this case, boosting of the immune response with interferons might be helpful. to test the hypothesis that the immune response to rhinovirus may be counterproductive, we infected mice with defects in tlr and mda- [ ] , molecules which recognize double-stranded rna on the cell surface or in the cell cytoplasm, respectively. as noted above, these signaling pathways are responsible for double-stranded rnastimulated interferon production. our previous work showed that mda- , an rna helicase, is required for rhinovirusinduced interferon production in cultured airway epithelial cells [ ] . tlr knockout mice had normal interferon responses to rhinovirus infection. however, mda knockout mice showed a delay in type i interferon responses and a significant and persistent reduction in type iii interferon lambda production. however, despite these deficiencies, mda knockout mice showed only small increases in rv vrna and titer. further, rv-infected knockout mice showed less, rather than more, airway inflammation. similar results were found in rhinovirus-infected ovalbumin-sensitized and -challenged knockout mice. these data call into question the interferon requirement for rv clearance and suggest that the proinflammatory response to rhinovirus infection is indeed maladaptive. indeed, a recent study found that interferonlambda concentrations were higher in rhinovirus-infected infants with wheezing compared to those without wheezing [ ] . what about viral-induced copd exacerbations? since copd differs from asthma in several key respects, the pathogenesis of virus induced exacerbations may be different in this disease. copd differs from asthma in at least the following ways. the key trigger for copd is cigarette smoke rather than aeroallergens, air pollutants, or infection. copd encompasses two distinct processes, chronic bronchitis, and emphysema, which result in structural changes that limit airflow. the copd airway epithelium undergoes squamous metaplasia. in copd, macrophages and cd -positive cell play key roles rather than th cells, eosinophils, or mast cells. copd pathogenesis appears to be dominated by tgf-, tnf-, il- , and il- . the lower airways of to % of patients with copd are colonized by bacteria, particularly haemophilus influenzae, streptococcus pneumonia,and moraxella catarrhalis. [ , ] . finally, oxidative stress resulting either from inhaled oxidants or inflammatory cells plays a significant role. as mentioned above, about one half of copd exacerbations are associated with viral infections, the majority of which are due to rv [ ] [ ] [ ] [ ] [ ] . copd exacerbations may also be associated with the isolation of the new bacterial strain [ ] . thus, interactions between virus, bacteria, and host may play a role in the pathogenesis of copd exacerbations. recent studies by the imperial college london, in which patients with copd were experimentally infected with rhinovirus [ ] , have provided new information about rvinduced exacerbations in these patients. compared to controls, copd patients show increased sputum neutrophils in response to experimental rv infection. other investigators have shown increased neutrophils, eosinophils, macrophages, and lymphocytes in the airways of copd patients experiencing exacerbations [ ] [ ] [ ] [ ] [ ] [ ] [ ] . unlike asthma patients, copd patients experimentally infected with rv show increased sputum viral copy number versus controls, and viral load correlates with sputum neutrophils and interleukin- levels [ ] . bal cells from patients with copd show reduced interferon-alpha and -beta responses to rhinovirus infection ex vivo. together, these results provide ample evidence of altered innate immunity against viruses. these data reinforce in vitro data showing that exposure of lung cells to cigarette smoke extract reduces cxcl , interferon-beta, and rig-i expression in response to influenza virus infection [ ] . viral infection may also attenuate the antibacterial innate immune response in copd. for example, rhinovirus exposure impairs immune responses to bacterial products in human alveolar macrophages. we have shown that rv infection of mucociliary-differentiated airway epithelial cells cultured at air-liquid interface causes barrier dysfunction which allows translocation of haemophilus influenzae across the epithelium [ ] . we have also shown that elastase-and lps-treated mice with a lung phenotype similar to copd show delayed clearance of rhinovirus in vivo, similar to humans with copd [ ] . cystic fibrosis is a chronic airways disease with similarities to asthma and copd. cf may also be exacerbated by viral infection. for example, viruses were detected in % of patients with exacerbations of cystic fibrosis, compared to only % of patients in stable condition [ ] . rv has been identified in to % of cystic fibrosis patients with acute respiratory illness and was associated with increased respiratory symptoms, worse airway function and secondary bacterial infection, compared to uninfected patients [ ] [ ] [ ] [ ] . infancy: exacerbations of preexisting airways disease or a factor in asthma development? over the past decade, data from a birth cohort of highrisk infants with a positive family history of asthma (nicknamed the childhood origins of asthma, or coast) have shown that wheezing-associated illness with rv is the most important risk factor for asthma development [ , ] . the relative risk of asthma development in infants with wheezing associated with rhinovirus infection was far higher than that of infants with allergen sensitization or rsv infection alone. also, in infants hospitalized for respiratory infectionassociated wheezing, infection with rv was associated with asthma development [ ] in contrast to respiratory syncytial virus (rsv), which was negatively associated [ ] . together, these data suggest two possibilities, either that rv infection causes asthma, or that rv infections may simply reveal a preexisting tendency for asthma. more recent data suggest that the latter is likely; prospective characterization of the coast birth cohort demonstrated that allergic sensitization precedes hrv wheezing and that the converse is not true [ ] . also, it was recently shown that children developing asthma by age seven had a lung function deficit and increased bronchial responsiveness as neonates [ ] , suggesting that asthma precedes rv infection. if this is the case, then wheezingassociated illnesses due to rhinovirus are essentially viralinduced asthma exacerbations. is it possible that, under the right circumstances, for example, the appropriate genetic background and allergen exposure, rhinovirus infection in early life modulates the immune response, increasing the likelihood of asthma development? a positive family is a known risk factor for asthma development, and it has recently been found that infants of mothers with asthma are more likely to have severe respiratory tract infections with rv [ ] . to address this possibility, we infected baby mice with rhinovirus at to days of life. unlike mature mice, rhinovirus-infected neonatal mice showed mucus metaplasia and airways hyperresponsiveness which lasted for one month after infection [ ] . this is reminiscent of data from washington university st. louis in mature mice following infection with sendai virus [ ] . however, the finding of a developmental difference in response to rhinovirus, an infection that does not cause cytotoxic effects, warrants further investigation. studies using neutralizing antibody and an il- receptor knockout mouse showed that the effect of rv was dependent on il- . we also found increased production of il- by invariant natural killer t (inkt) cells. the notion that early rhinovirus infection could modulate future immune responses, leading to allergic airway inflammation, has been bolstered by the discovery of novel epithelial-derived cytokines which promote th differentiation. these cytokines, thymic stromal lymphopoietin (tslp), il- , and il- , play a key role in the maturation of th cells via dendritic cell (dc) activation [ ] [ ] [ ] [ ] [ ] [ ] , as well as the activation of mast cells and inkt cells [ ] . moreover, tslp, il- , and il- induce il- production by two novel innate effector leukocytes that mediate th immunity-type innate lymphoid cells (also called natural helper cells or nuocytes) [ ] [ ] [ ] [ ] [ ] [ ] [ ] and type myeloid cells [ ] . respiratory viral infections cause exacerbations of asthma and copd. this is evidenced by the increased identification of viruses in the respiratory tract during exacerbations compared to stable periods. also, epidemic cycles of asthma and copd exacerbations occur after school return and around the christmas holiday, consistent with an infectious cause. it has also been well demonstrated that viruses infect and replicate in the lower airways. finally, the severity of viralinduced exacerbations correlates with viral load. viral infection of the epithelium increases expression of chemokines, leading to influx of inflammatory cells and increased airway inflammation. innate immunity to viral infection may be decreased in asthma, owing to epithelial damage, mucus metaplasia, and immune system polarization towards a th phenotype. disease exacerbation in 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life predict asthma development in high-risk children rhinovirus-induced wheezing in infancy-the first sign of childhood asthma? predictors of asthma three years after hospital admission for wheezing in infancy evidence for a causal relationship between allergic sensitization and rhinovirus wheezing in early life influence of maternal asthma on the cause and severity of infant acute respiratory tract infections interaction between asthma and lung function growth in early life neonatal rhinovirus infection induces persistent mucous metaplasia and airways hyperresponsiveness persistent activation of an innate immune response translates respiratory viral infection into chronic lung disease nk cell deficiency predisposes to viral-induced th -type allergic inflammation via epithelial-derived il- overexpression of smad drives house dust mite-mediated airway remodeling and airway hyperresponsiveness via activin and il- beyond inflammation: airway epithelial cells are at the interface of innate and adaptive immunity il- -activated dendritic cells induce an atypical t -type response a role for tslp in the development of inflammation in an asthma model tlr -and th cytokine-dependent production of thymic stromal lymphopoietin in human airway epithelial cells differential role of thymic stromal lymphopoietin in the induction of airway hyperreactivity and th immune response in antigen-induced asthma with respect to natural killer t cell function this work is supported by nih grant hl . key: cord- - eygtr authors: ganesan, shyamala; comstock, adam t; sajjan, uma s title: barrier function of airway tract epithelium date: - - journal: tissue barriers doi: . /tisb. sha: doc_id: cord_uid: eygtr airway epithelium contributes significantly to the barrier function of airway tract. mucociliary escalator, intercellular apical junctional complexes which regulate paracellular permeability and antimicrobial peptides secreted by the airway epithelial cells are the three primary components of barrier function of airway tract. these three components act cooperatively to clear inhaled pathogens, allergens and particulate matter without inducing inflammation and maintain tissue homeostasis. therefore impairment of one or more of these essential components of barrier function may increase susceptibility to infection and promote exaggerated and prolonged innate immune responses to environmental factors including allergens and pathogens resulting in chronic inflammation. here we review the regulation of components of barrier function with respect to chronic airways diseases. the mammalian conducting airway can be broadly divided into two regions based on structure and function: the cartilaginous proximal airway starting from nasal cavities to bronchi and - generations of bronchioles, and non-cartilaginous distal airway consisting of terminal and respiratory bronchioles. luminal surfaces of the entire conductive airway tract are lined by a continuous layer of epithelial cells which vary in relative distribution, abundance, and cell type depending on the airway region in which they are found. the proximal airway through the bronchi is lined with pseudostratified epithelium and is made up of three major cell types: ciliated cells, non-ciliated secretory cells, and basal cells (fig. ) . as the bronchi branches into bronchioles and to terminal bronchioles the epithelium gradually changes from psuedostratified to simple cuboidal epithelium and the number of ciliated, goblet, and basal cells gradually decline and non-ciliated cells called clara cells becomes the major cell type. in the proximal airway and cartilaginous bronchioles, the invagination of epithelium forms submucosal glands, which are characterized by a variable proportion of ciliated cells, goblet cells, and serous cells. other minor cell types that are present in conducting airways are: ( ) chemosensory or brush cells which contains apical tufts of microvilli and are thought to play a role in regulation of both airway surface fluid secretion and breathing, , and ( ) pulmonary neuroendocrine cells which are typically tall and pyramidal in shape and extend from the basal lamina of the epithelium and possess microvilli. , ciliated cells account for over % of all epithelial cells in the conducting airway. approximately to cilia are found on the luminal surface of each ciliated cell, and in humans the length of the cilia ranges between μm in the proximal airways to . μm in the seventh generation of bronchi. a large number of mitochondria are present right below the apical surface and provide energy to the cilia for coordinated ciliary beating. ciliated cells are believed to be terminally differentiated and arise from basal or secretory cells. , however, recent studies have suggested a remarkable plasticity and differentiation potential for ciliated cells. after injury, ciliated cells dedifferentiate into squamous, cuboidal or columnar cells, thereby playing a role in restoration and regeneration of bronchial epithelium. the primary function of airway epithelium is to function as a physical barrier between the external environment and internal milieu. the three essential components that contribute to the barrier function of airway epithelium are: mucociliary escalators which trap and removes inhaled foreign particles from the airways, intercellular tight and adherens junctions that regulate epithelial paracellular permeability, and secreted antimicrobial products that kill inhaled pathogens. the major players that contribute to the mucociliary function of airway epithelium are mucus and cilia. while the mucus traps inhaled pathogens and other particulate material, coordinated beating of cilia sweeps the trapped material away from the lungs toward the pharynx. the efficient transport of mucus is dependent on the rate of ciliary beating as well as the hydration of mucus, which contributes to its viscoelastic properties. , in general, more hydrated mucus is cleared more efficiently from the lungs. the airway mucus contains more than proteins, and is secreted by both goblet cells and submucosal glands. the main component of airway mucus are mucins, which are high molecular weight glycoproteins that cross link to form the structural framework of the mucus barrier. , at least mucins are detected in human lungs. of these, muc ac and muc b are the predominant mucins in normal airways. muc ac is mainly produced by goblet cells, while muc b is predominantly produced by submucosal glands. , in healthy individuals, circadian rhythms regulate normal mucus secretion, principally through the vagal nerve. however in patients with inflammatory airway diseases, mucus hypersecretion from metaplastic and hyperplastic goblet cells contributes to obstruction of airways. various inflammatory mediators, such as tumor necrosis factor -α, il- β, il- , il- , neutrophil elastase, growth factors such as egf and tgf, and environmental factors such as cigarette smoke, allergens and microbial pathogens goblet cells have electron lucent granules which contain acidic mucin glycoproteins in the apical region of cytoplasm, and contain a condensed nucleus on the basal side giving the cells a unique shape. in normal conductive airways the ratio of goblet cell to ciliated cells is approximately : and this ratio increases under the conditions of chronic airway diseases, such as asthma, chronic obstructive pulmonary disease, and cystic fibrosis. the goblet cells secrete high molecular weight mucin glycoproteins into the airway lumen, which trap and remove foreign particles, thus protecting the epithelial surface. mucin secretion must be tightly regulated for normal functioning, as overproduction can block the airway and impair proper mucociliary clearance. serous cells are found at the distal ends of submucosal glands and resemble goblet cells morphologically, but their granule content is more electron-dense. serous cells secrete the bulk of glandular fluid in response to secretogogues that use camp and/or ca + as second messengers. the fluid secreted by these cells directly contributes to airway surface liquid (see later) volume, hydration of mucus released from goblet cells, , and innate immunity. basal cells are connected to the basement membrane via hemodesmosomes, providing the foundation for the attachment of ciliated and goblet cells to basal lamina, and also have the potential to regulate inflammatory responses, oxidant defense and transepithelial water movement. the most important feature of basal cells is their capacity to repopulate all the major cell types of conductive airway epithelium. [ ] [ ] [ ] basal cells are therefore thought to be the progenitor cells or the transient amplifying cells of the airway epithelium, but this is yet to be confirmed. the most prominent features of clara cells are the membrane-bound electron dense secretory granules. although these granules do not contain glycoprotein like in goblet cells, they secrete cc (or ccsp) protein which is used as a clara cell marker. , these cells also secrete surfactant proteins and antiproteinases that may protect bronchiolar epithelium. , clara impaired mucociliary clearance may also be a direct result of defective ciliary function as observed in patients with ciliary dyskinesia. although these patients have normal secretion of mucus, it is not cleared due to defective ciliary beating. on the other hand, in copd patients the impaired mucociliary function may be due to a combination of excessive mucus production, increased viscosity of mucus due to acquired dysfunction of cftr, and reduced ciliary beating. [ ] [ ] [ ] it has been shown that respiratory epithelial cells exposed to cigarette smoke extract or condensate showed shorter and % fewer cilia compared control cells. although mice exposed to cigarette smoke showed slight increases in ciliary beat frequencies at weeks and mo, it was significantly reduced at mo, and post-mortem examination revealed significant loss of tracheal ciliated cells. recently yaghi et al. provided direct evidence of suppressed ciliary beating in nasal epithelium from copd patients. such changes in number and function of cilia can significantly impair the mucociliary clearance function of airway epithelium. mucociliary dysfunction, in addition to causing obstruction of airways, may also promote recurrent and persistent respiratory infections as evidenced in patients with cystic fibrosis, ciliary dyskinesia, and copd. [ ] [ ] [ ] [ ] mucin glycoproteins have been shown to interact with several respiratory pathogens including pseudomonas aeruginosa, staphylococcus aureus, heamophilus influenzae, streptococcus pneumonia, burkholderia cenocepacia, influenza virus, adenovirus, and coronavirus. [ ] [ ] [ ] [ ] [ ] [ ] [ ] the bound pathogens which are cleared under normal conditions may persist in the airway lumen when the mucociliary clearance is impaired, and initiate an inflammatory response which can damage the airway epithelium. however, the impact of the interaction of mucin glycoproteins with pathogens in vivo is yet to be established. tight and adherens junctions located at the apicolateral border of airway epithelial cells also contribute significantly to the barrier function of conductive airway tract epithelium. like in other mucosal epithelium, paracellular permeability of airway epithelium is maintained through the cooperation of two mutually exclusive structural components: tight junctions and adherens junctions on the apicolateral membranes. while tight junctions regulate the transport of solutes and ions across epithelia, adherens junctions mediate cell to cell adhesion and promote formation of tight junctions. [ ] [ ] [ ] in normal airway epithelium, these intercellular junctions prevent inhaled pathogens and other environmental insults from injuring the airways, and also serve as signaling platforms that regulate gene expression, cell proliferation, and differentiation. , therefore, disassociation or sustained insults that affect junctional complexes will disrupt not only barrier function, but may also interfere with normal repair and differentiation of airway epithelium. airway epithelium is leaky, hyperproliferative, and abnormally differentiated in smokers and in patients with asthma and copd compared with airway epithelium in healthy smokers. [ ] [ ] [ ] [ ] infection with viruses or have all been shown to stimulate hypersecretion of mucus. [ ] [ ] [ ] [ ] [ ] [ ] therapies targeted to limit exaggerated mucus hypersecretion in addition to modulating mucociliary clearance in chronic airways disease may prevent airways obstruction. the rate of mucociliary clearance depends on the composition of the airway surface liquid (asl) lining the airway surface. asl is made up of two layers, an upper viscoelastic layer of mucins secreted by the goblet cells and submucosal glands, which floats on a lower periciliary layer containing large membrane-bound glyocproteins, as well as tethered mucins (muc- , muc- and muc- ). , the periciliary layer is relatively less viscous, approximately μm in height which corresponds to a length of outstretched cilia and acts as a lubricating layer for cilia to beat. , , hydration of asl is regulated by coordinated activity of chloride secretion (cl − ) and sodium (na + ) absorption channels. the combination of cl − secretion and reduced reabsorption of na + favors normal asl hydration and efficient mucociliary clearance. in normal airways, the coordinated functioning of atp-activated cystic fibrosis transmembrane conductance regulator (cftr), calcium-activated cl − channel (cacc), outwardly rectifying cl − channel (orcc), cl − channel (clc ), and epithelial na + channel (enac) regulate the asl hydration. cftr negatively regulates enac and therefore absent or dsyfunctional cftr increases enac activity leading to hyperabsorption of na + , an increased driving force for fluid reabsorption resulting in reduced asl depth and impaired mucociliary clearance as observed in the chronic airway disease cystic fibrosis. in cystic fibrosis patients this condition is further exacerbated by excessive mucus production due to goblet cell metaplasia and hyperplasia, and submucosal gland hypertrophy resulting in obstruction of airways. goblet cell metaplasia and hyperplasia are also observed in patients with other chronic airway diseases such as asthma and chronic obstructive pulmonary disease (copd), and is induced by the coordinated action of egfr and il- . - downstream of il- , several transcription factors, e.g., thyroid transcription factor (ttf)- , sam pointed domain-containing ets transcription factor (spdef), and forkhead transcription factor (fox)a , regulate goblet cell development downstream of il- . while both ttf- and foxa repress goblet cell metaplasia, , spdef promotes goblet cell metaplasia by downregulating foxa and ttf- . recently, increased spdef and decreased foxa expression has been shown to contribute to the development of goblet cell hyperplasia in mouse models of asthma. [ ] [ ] [ ] [ ] spdef not only promotes goblet cell hyperplasia but also upregulates the network of genes associated with mucus production. inhibition of aldose reductase or serpinb a, both of which are induced in asthma reduced spdef expression, attenuates development of goblet cell hyperplasia. , additionally, ttf- was significantly reduced in patients with asthma and mice deficient in ttf- were found to be prone to develop goblet cell metaplasia upon exposure to allergens. therefore, strategies to modulate activities of ttf- , foxa or spdef may attenuate goblet cell metaplasia and mucus production, thus improving mucociliary function in patients with asthma and other chronic airway diseases. however, our studies have not shown binding of rv to tight junction proteins. instead, rv-induced barrier dysfunction is dependent on ros generation. , oxidative stress constitutes a well-studied mechanism of tight junction breakdown, inducing tyrosine phosphorylation and dissociation of occludin from the tight junction complex. our on-going studies indicate that while normal differentiated airway epithelial cell cultures show restoration of barrier function at d post-rv infection, similarly differentiated copd cell cultures show barrier dysfunction up to d after rv infection (faris and sajjan, unpublished results). based on these preliminary observations, we speculate that rv infection in copd patients may further damage airway epithelium, and this may in turn promote airway remodeling, increase the risk for acquiring secondary infections and alter innate immune responses to infection or other environmental insults ultimately leading to progression of lung disease. therefore, strategies to inhibit barrier disruption or quickly restore barrier function after viral infection may prevent progression of lung disease in patients with copd and possibly in subjects with other chronic airways disease such as cystic fibrosis and asthma. adherens junctions are located just below the tight junctions and mechanically connect adjacent cells and initiate the formation and maturation of cell-cell contacts. the principal proteins in adherens junctions are type i transmembrane glycoprotein, epithelial cadherin (e-cadherin), β-catenin, and α-catenin. an extracellular domain of e-cadherin of adjacent cells forms homotypic, calcium dependent adhesions between epithelial cells. e-cadherin associates with the armadillo protein family member β-catenin and α-catenin, which then forms an interface with the microtubule network and actin cytoskeleton. , in addition, e-cadherin also regulates cell proliferation and differentiation by modulating egfr and β-catenin activities. under normal conditions, e-cadherin interacts and retains egfr in adherens junctions of airway epithelium, thus preventing egfr activation. [ ] [ ] [ ] dissociation of e-cadherin from the adherens junction complex or reduced expression of e-cadherin, each of which may occur during epithelial to mesenchymal transition, may cause uncoupling and redistribution of egfr from the adherens junction to the apical cell surface, where it is readily activated by egf ligands. excessive activation of egfr not only promotes cell proliferation, but also development of goblet cell metaplasia/hyperplasia. in fact, enhanced surface expression and phosphorylation of egf receptors in the airway epithelium has been observed in patients with asthma who show impaired mucosal barrier function. recently, we demonstrated that egf receptor phosphorylation is also increased in copd airway epithelial cells, which retains the phenotype of goblet cell hyperplasia. , β-catenin cooperates with e-cadherin to form adherens junctions. however, when dissociated from e-cadherin β-catenin translocates to the nucleus and activates canonical wnt/βcatenin signaling, thus promoting cell proliferation and suppressing cell-differentiation. , since cigarette smoke causes aberrant activation of canonical wnt/β-catenin signaling, , it is plausible that chronic cigarette smoke exposure decreases barrier function and facilitates invasion of airway epithelium by environmental allergens, pollutants, and pathogens. in asthma bacteria can also cause transient disruption of tight or adherens junctions. [ ] [ ] [ ] host factors, such as interferons and tumor necrosis factor-α expressed in response to infection may prolong tight junction disruption long after infection is cleared, enabling the passage of inhaled allergens and pollutants. , the formation of apico-lateral junctional complexes is closely related to cell polarization. recent gene arrays indicated the expression of two polarity complexes in airway epithelial cells: the crumbs (crb) complex and the partitioning defective (par) complex. the crb complex consists of the integral membrane protein crumbs and the scaffolding proteins, protein associated with lin seven (pals ), and pals -associated tight junction protein (patj). [ ] [ ] [ ] the crb complex plays a critical role in the formation of tight junctions, cell polarization, and ciliogenesis. decreased expression of crumbs delays formation of tight junctions and cilia. , depletion of pals leads to the loss of patj, disruption of cell polarity, decreased ter, and altered trafficking of e-cadherin. , coronavirus envelope protein e binds to pals , and ectoexpression of protein e delays tight junction formation in mdck cells. recently, we showed that crumbs is necessary for ciliogenesis in airway epithelial cells and is associated in the tip of mature cilia in mucociliary-differentiated bronchial airway epithelial cell cultures. the par complex is composed two scaffolding proteins, par and par , and atypical protein kinase c, but the molecular actions of the par complex in airway epithelial polarity are not known. tight junctions are composed of several transmembrane proteins (including occludin, multiple claudins, junctional adhesion molecule (jam)) and cytoplasmic scaffolding proteins containing pdz-domains (zonula occludens zo- , zo- , zo- ), cingulin, and mupp . transmembrane proteins in the junction connect the membranes of adjacent cells to make a tight seal, while scaffolding proteins anchor transmembrane proteins to the cytoskeleton. claudins function to regulate the paracellular permeability in airway epithelium, whereas occludin has been shown to regulate de novo assembly of tight junctions. although jam association with tight junctions is well studied, its function at tight junctions remains unclear. in recent years, the coxsackievirus and adenovirus receptor (car), which serves as a receptor for viruses, was also shown to be a transmembrane protein located in the tight junction and interacts with zo- in airway epithelial cells. further, car expression was shown to be required for formation of functional tight junctions and limits permeability of macromolecules. airway epithelial cells isolated from healthy smokers and patients with copd show reduced expression of occludin and claudins, which may contribute to the observed barrier dysfunction in these subjects. several respiratory viruses have been shown to increase permeability and decrease transepithelial resistance of airway epithelium by either interacting with tight junction proteins or by dissociating adherens junction complexes. coxsackievirus and adenovirus bind to car, inducing disassembly of the tight junction and reduction in transepithelial resistance (ter). , previously, we demonstrated that rhinovirus (rv) dissociates zo- , occludin, and claudin from the tight junctions and increases bacterial association and translocation across polarized airway epithelium. , , also been shown to decrease the expression defensin genes in the airways. herr et al. showed that hbd is significantly reduced in the pharyngeal wash and sputum of current or former smokers compared with non-smokers, and exposure of airway epithelium to cigarette smoke in vitro inhibited induction of hbd by bacteria. cathelicidins are another class of antimicrobial peptides and ll is the only human cathelicidin identified to date. ll binds to lipopolysaccharides and inactivates its biological function. overexpression of human ll in cystic fibrosis mouse models increased killing of p. aeruginosa and reduced the ability of this bacterium to colonize the airways. airway epithelial cells also generate oxidants such as nitric oxide (no) and hydrogen peroxide. three no synthases contribute to production of no in airway epithelia: the constitutively expressed nos and nos , and inducible nos . viral infections and pro-inflammatory cytokines induce expression of nos and defective nos expression is responsible for increased viral replication in cystic fibrosis, while overexpression of nos provides protection against viral infection. , recently we demonstrated that copd airway epithelial cells show a trend in decreased expression of nos and this was associated with impaired clearance of rhinovirus. extracellular hydrogen peroxide is produced by dual oxidase and . these belong to a family of nadph oxidases and are located in the plasma membrane and secrete hydrogen peroxide to the extracellular milieu. the dual oxidase-generated hydrogen peroxide in combination with thiocyanate and lactoperoxidase generates the microbicidal oxidant hypothiocyanite, which effectively kills both gram positive and gram negative bacteria. this innate defense mechanism is defective in cystic fibrosis airway epithelium due to impaired transport of thiocyanate. copd airway epithelial cells also show decreased expression of duox and , but their contribution to defective bacterial clearance in copd is yet to be determined. the three barrier functions of airway epithelial tract, mucociliary clearance, intercellular apical junctional complexes and antimicrobial products of airway function together to effectively clear inhaled pathogens, allergens and pollutants from the lungs. the intercellular apical junctional complex not only regulates paracellular permeability, but also separates proteins of basolateral surface from apical surface and promotes normal differentiation of airway tract epithelial cells. this is critical for regulation of secretion of mucus and antimicrobial proteins and peptides, and also for maintenance of viscosity and depth of asl, in which cilia beat. barrier function of airway tract epithelium is compromised in patients with chronic airways disease due to repetitive injury and abnormal repair leading to airway remodeling. understanding the molecular mechanisms of airway epithelial repair under normal and chronic disease conditions is necessary to develop therapies to prevent airway remodeling and promote normal epithelial repair. however, the field of airway epithelial repair is in its infancy, because airway epithelium is complex and comprises several cell types and the cells show remarkable however, allergens are thought to be primary stimulus responsible for airway remodeling. it was demonstrated that proteases present in the allergens disrupt not only tight junctions but also adherens junctions , and this could lead to both egfr activation and wnt/β-catenin signaling ultimately resulting in development of goblet cell metaplasia/hyperplasia. in addition to being a physical barrier, airway epithelium also acts as a biochemical barrier against invading pathogens. airway epithelial cells secrete a wide variety of antimicrobial substances such as enzymes, protease inhibitors, oxidants, and antimicrobial peptides, which accumulates in the asl and kill inhaled pathogens. lysozyme, an enzyme found in airway epithelial secretions, exerts antimicrobial effect against a wide range of gram-positive bacteria by degrading their peptidoglycan layer. lysozyme is also effective against gram-negative bacteria in the presence of lactoferrin, which disrupts the outer membrane, allowing lysozyme to gain access to the peptidoglycan layer. lactoferrin is an iron-chelator and inhibits microbial growth by sequestering iron which is essential for microbial respiration. lactoferrin also displays antiviral activity against both rna and dna viruses by either inhibiting binding of the virus to host cells or by binding to the virus itself. , lactoferrin levels increase in response to bacterial and viral infections. in clinically stable copd patients, lower levels of salivary lysozyme correlated with increased risk of exacerbations while reduced lysozyme levels in copd is thought to be due to degradation by proteases elaborated by bacterial pathogens or neutrophils. , epithelial cells produce protease inhibitors, such as secretory leukoprotease inhibitor (slpi), elastase inhibitor, α -antiprotease, and antichymotrypsin. these protease inhibitors mitigate the effects of proteases expressed by pathogens and recruited innate immune cells. maintaining the balance between antiproteases and proteases in the airway lumen during infection is pivotal in preventing lung inflammation and maintenance of tissue homeostasis. in copd patients, levels of slpi and lysozyme were shown to decrease with bacterial infection, while lactoferrin levels remain unchanged. this could be due to inactivation of slpi by proteases or decreased expression of slpi, but either way the end result under these conditions is an imbalance in the ratio of antiproteases to proteases in the airway lumen. therefore, neutralization of proteases would be beneficial in this situation. accordingly, administration of slpi decreased the levels of il- and elastase activity in airway secretion of cystic fibrosis patients, who also have reduced slpi in their airway lumen. human β defensins (hbd) are the most abundant antimicrobial peptides expressed on the surface of airway epithelium and are effective against a wide range of bacteria and viruses. 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adult cystic fibrosis patients, healthy individuals, and individuals with acute cold antiviral activities of lactoferrin antimicrobial peptides in the airway a possible role for lysozyme in determining acute exacerbation in chronic bronchitis in vitro evidence that human airway lysozyme is cleaved and inactivated by pseudomonas aeruginosa elastase and not by human leukocyte elastase effects of bacterial infection on airway antimicrobial peptides and proteins in copd in vivo suppression of interleukin- levels on the respiratory epithelial surface by aerosolization of recombinant secretory leukoprotease inhibitor key: cord- -ei b oqn authors: leung, j. m.; yang, c. x.; tam, a.; shaipanich, t.; hackett, t. l.; singhera, g. k.; dorscheid, d. r.; sin, d. d. title: ace- expression in the small airway epithelia of smokers and copd patients: implications for covid- date: - - journal: medrxiv doi: . / . . . sha: doc_id: cord_uid: ei b oqn introduction: coronavirus disease (covid- ) is a respiratory infection caused by the severe acute respiratory syndrome coronavirus (sarscov- ). this virus uses the angiotensin converting enzyme ii (ace ) as the cellular entry receptor to infect the lower respiratory tract. because individuals with chronic obstructive pulmonary disease (copd) are at increased risk of severe covid , we determined whether ace expression in the lower airways was related to copd and cigarette smoking. methods: using rnaseq, we determined gene expression levels in bronchial epithelia obtained from cytologic brushings of th to th generation airways in individuals with and without copd. we externally validated these results from two additional independent cohorts, which used microarray technologies to measure gene expression levels from th to th generation airways. results: in the discovery cohort (n= participants), we found that ace expression levels were increased by % in the airways of copd compared with non-copd subjects (copd= . ( . ) log counts per million reads (cpm) versus non-copd= . ( . ) cpm , p=. ). there was a significant inverse relationship between ace gene expression and fev % of predicted (r=negative . ; p= . ). current smoking also significantly increased ace expression levels compared with never smokers (never current smokers= . ( . ) cpm versus smokers= . ( . ) cpm, p= . ). these findings were replicated in the two external cohorts. conclusions: ace expression in lower airways is increased in patients with copd and with current smoking. these data suggest that these two subgroups are at increased risk of serious covid infection and highlight the importance of smoking cessation in reducing the risk. the world health organization (who) has declared coronavirus disease (covid- ) as a pandemic [ ] . covid- is caused by severe acute respiratory syndrome coronavirus- (sars-cov- ). covid- displays symptoms ranging from mild to severe (pneumonia) that can lead to death in some individuals [ ] [ ] [ ] . as of march , , there have been , laboratory-confirmed cases of covid- worldwide with , deaths worldwide [ ] . sars-cov- uses the angiotensin converting enzyme ii (ace- ) as the cellular entry receptor [ ] . while the virus can infect individuals of any age, to date, most of the severe cases have been described in those over the age of years and with significant comorbidities such as chronic obstructive pulmonary disease (copd) [ ] . here, we determined whether patients with copd have increased expression of ace- in bronchial epithelial cells in lower respiratory tract. patients undergoing bronchoscopy at st. paul's hospital (sph), vancouver, canada for clinical purposes were enrolled (table ). the protocol was approved by the university of british columbia/providence health care ethics board (ubc/phc reb h - ). all patients were required to be years of age or older, who underwent spirometry according to international guidelines [ ] . patients with copd were defined as those having a clinical diagnosis of copd made by a boardcertified respiratory physician and either a forced expiratory volume in second (fev )/forced vital capacity (fvc) < % or a clear evidence of emphysema on computed tomographic (ct) imaging on visual inspection. cytologic brushings were obtained in subsegmental airways ( th - th generation) of the lung that were unaffected by the patient's underlying clinical indication for bronchoscopy. total rna was extracted from cytologic brushings using the rneasy mini kit (qiagen, hilden, germany). transcriptome sequencing was performed on the novaseq (illumina, san diego, ca) at a sequencing depth of million reads. raw sequencing reads were quality controlled with fastqc [ ] and aligned to the gencode (version ) grch genome reference using star (spliced transcripts alignment to a reference) [ ] . after alignment, the data were quantified using rsem (rna-seq by expectation maximization) to obtain the read counts. limma voom [ ] was applied to normalize the counts to log counts per million reads (cpm), which was used in the downstream analysis. two cohorts were used for validation; the details of which are provided in a previous publication [ ] . first, we used datasets obtained from bronchial brushings of th - th generation bronchi collected at a single center using the u plus . microarray (denoted as the cornell . cc-by-nc-nd . international license it is made available under a author/funder, who has granted medrxiv a license to display the preprint in perpetuity. is the (which was not peer-reviewed) the copyright holder for this preprint . https://doi.org/ . / . . . doi: medrxiv preprint dataset) [ ] . second, we used dataset gse consisting of bronchial brushings from the th - th generation airways with gene expression profiles generated from the genechip human gene . st microarray [ ] . this dataset was denoted as british columbia cancer agency (bcca) cohort. we also determined protein expression of ace- in resected lung tissue specimens. these samples were obtained from current smokers with copd (mean±sd, fev /fvc ± %), non-smoker controls (fev /fvc ± %), and healthy current smokers (fev /fvc ± %). human lung tissue samples were obtained with informed consent from patients undergoing thoracic surgery as part of the james hogg lung registry (ubc/phc reb protocol h - ). formalin-fixed paraffin-embedded human lung tissues were stained with antibody against ace- (ab ; abcam) using the bond polymer refine red detection kit on the leica bond autostainer as previously described [ ] . airway epithelial-specific ace- protein intensity was quantified using the aperio imaging system with normalization to the length of the basement membrane (leica biosystem; concord, ontario). for the primary study population, log cpm of ace- was the principal outcome of interest. robust linear models were used to determine whether ) ace- was differentially expressed in patients with copd and in smokers after adjustment for age and sex and ) ace- expression was significantly correlated with lung function. all analyses were performed in r (version . . ). in the immunohistochemistry dataset, kruskal-wallis test with dunn's multiple comparisons test was used. table displays the demographic and clinical characteristics of the sph cohort. ace- expression in the epithelial cells was significantly increased in copd versus non-copd subjects (mean±sd of non-copd= . ± . versus copd= . ± . , p= . × - ; figure a ). there was a significant inverse relationship between ace- gene expression and fev % of predicted (r=- . ; p= . ; figure b) . interestingly, smoking status was also significantly related to ace- gene expression levels in airways of these participants with current smokers having a significantly higher gene expression than never smokers (never smokers= . ± . versus current smokers= . ± . , p= . ). former smokers had gene expression levels in-between that of never and current smokers (former smokers= . ± . ; figure c ). conditional on the smoking status, the association between ace- expression and copd was still significant (adjusted mean±se of non-copd: . ± . versus copd: . ± . , p= . ). next, we validated the above findings in: ) the cornell cohort (n= ) and ) british columbia cancer research agency (bcca) cohort (n= ). the average age of the cornell cohort was . (sd= . ) years with . % of the cohort being females. there were . % who were never smokers and . % who were current smokers at the time of the bronchoscopy. the average age of the bcca . cc-by-nc-nd . international license it is made available under a author/funder, who has granted medrxiv a license to display the preprint in perpetuity. is the (which was not peer-reviewed) the copyright holder for this preprint . https://doi.org/ . / . . . doi: medrxiv preprint cohort was . (sd= . ) years with . % of the cohort being females. all were heavy smokers with at least pack-years of smoking. of these, . % were current smokers at the time of the bronchoscopy and the remaining were former smokers. in both the cornell and bcca cohorts, current smokers had increased ace- gene expression levels in the airways compared with never smokers (in the cornell cohort; mean±sd of never smokers= . ± . versus current smokers= . ± . , p= . × - ) and with former smokers (in the bcca cohort; mean±sd of former smokers= . ± . versus current smokers= . ± . , p< × - ). in the bcca cohort, pre-bronchodilator fev was measured and it was significantly related to ace- gene expression level (r=- . ;p= . ). representative images of epithelial-specific ace protein expression in non-smokers, healthy smokers and smokers with copd are shown in figure d . ace- expression in the human small airway epithelium was significantly increased in copd compared to non-smokers but not in healthy smokers ( figure d ). there is a worldwide outbreak of covid- coronavirus. although most patients infected and diagnosed with cvoid- disease have mild symptoms, approximately % of individuals have demonstrated severe or critically severe disease including symptoms and signs of pneumonia, respiratory failure, septic shock and multi-organ failure. the estimated case-fatality rate is - % [ , ] . importantly, nearly all deaths have occurred in those with significant underlying chronic diseases including copd, and cardiovascular diseases [ ] . the reason for this observation is largely unknown. one possibility is differential expression of the ace- , which is the main receptor used by sars-cov- to gain entry into the host mucosa and cause active infection. here, we investigated gene expression levels of ace- in the airways of individuals with and without copd and found that copd and current smokers had significantly increased expression of ace- . importantly, gene expression levels of ace- were inversely related to individual's fev , suggesting a dose-dependent response. these findings were observed in different cohorts, indicating their generalizability and robustness. ace- is a type i transmembrane metallocarboxypeptidase with homology to angiotensin converting enzyme (ace). in contrast to ace, which converts angiotensin i to the active vasoconstrictor, angiotensin ii, ace- breaks down angiotensin ii to its metabolites including angiotensin-( - ) and angiotensin-( - ), which are potent vasodilators, and thus may be a negative regulator of the renin-angiotensin system [ ] . ace- is expressed in a variety of different tissues including both the upper and lower respiratory tract, myocardium and the gastrointestinal mucosa [ ] . although its role in human health and disease has not been fully elucidated, it appears to have an . cc-by-nc-nd . international license it is made available under a author/funder, who has granted medrxiv a license to display the preprint in perpetuity. is the (which was not peer-reviewed) the copyright holder for this preprint . https://doi.org/ . / . . . doi: medrxiv preprint important regulatory role in blood pressure and cardiac function. the physiologic role of ace- in the airways is largely unknown. however, in mice, ace- has been shown to protect animals from severe lung injury related to aspiration and sepsis [ ] . to our knowledge, our study is the first to demonstrate increased ace- expression in airways of current (but not former) smokers and those with copd. these results are also consistent with previous observations in small animals wherein smoke exposure has been shown to upregulate both the expression and activity of ace- in the airways [ , ] . while the up-regulation of ace- may be useful in protecting the host against acute lung injury, chronically, this may predispose individuals to increased risk of coronavirus infections, which uses this receptor to gain entrance into epithelial cells. this may in part explain the increased risk of viral respiratory tract infection in active smokers and virus-related exacerbations in those with copd. there were limitations to the study. first, the study was cross-sectional and as such, we could not determine whether interventions such as inhaled corticosteroids or bronchodilators (for those with copd) could modulate ace- gene expression in the airways. second, as receptor expression is one of many host factors that govern infection risk among individuals, the precise attributable risk (for coronavirus infections) imposed by cigarette smoking and copd is uncertain. third, although the airway epithelia is the major source of entry for covid- , the virus can gain host entry through other ports including gastrointestinal mucosa, which was not evaluated in this study. fourth, we did not have access to upper airway tissues, which may also become infected with sars-cov- . in summary, active cigarette smoking and copd up-regulate ace- expression in lower airways, which in part may explain the increased risk of severe covid- in these sub-populations. these findings highlight the importance of smoking cessation for these individuals and increased surveillance of these risk subgroups for prevention and rapid diagnosis of this potentially deadly disease. . cc-by-nc-nd . international license it is made available under a author/funder, who has granted medrxiv a license to display the preprint in perpetuity. is the (which was not peer-reviewed) the copyright holder for this preprint . https://doi.org/ . / . . . doi: medrxiv preprint the red box indicates the median and the interquartile range. the p-value was obtained from the robust linear model abbreviations: ace- , angiotensin converting enzyme ii; copd, chronic obstructive pulmonary disease; cpm, counts per million reads . cc-by-nc-nd . international license it is made available under a author/funder, who has granted medrxiv a license to display the preprint in perpetuity. is the (which was not peer-reviewed) the copyright holder for this preprint . https://doi.org/ . / . . . doi: medrxiv preprint abbreviations: ace- , angiotensin converting enzyme ii; copd, chronic obstructive pulmonary disease; cpm, counts per million reads ace- gene expression in airway epithelia is inversely related to fev % predicted (p= . ) . cc-by-nc-nd . international license it is made available under a author/funder, who has granted medrxiv a license to display the preprint in perpetuity. is the (which was not peer-reviewed) the copyright holder for this preprint . https://doi.org/ . / . . . doi: medrxiv preprint figure c . a violin plot of ace expression in small airways of never, former and current smokers in the st. paul's hospital cohort. the red box indicates the median and the interquartile range. the p-value was obtained from the robust linear model. abbreviations: ace- , angiotensin converting enzyme ii; cpm, counts per million reads . cc-by-nc-nd . international license it is made available under a author/funder, who has granted medrxiv a license to display the preprint in perpetuity. is the (which was not peer-reviewed) the copyright holder for this preprint . https://doi.org/ . / . . . doi: medrxiv preprint figure d . protein staining of ace airways of individuals with and without copd human kidney slide was the positive control for ace- . in airways, most of the protein expression was noted in the epithelial layer, most pronounced in those with copd. abbreviations: ace- , angiotensin converting enzyme ii; ns, non-smoker non-smoker µm human kidney healthy smoker copd . cc-by-nc-nd . international license it is made available under a author/funder, who has granted medrxiv a license to display the preprint in perpetuity. is the (which was not peer-reviewed) the copyright holder for this preprint . https://doi.org/ . / . . . doi: medrxiv preprint clinical characteristics of coronavirus disease in china feng z. early transmission dynamics in wuhan, china, of novel coronavirus-infected pneumonia characteristics of and important lessons from the coronavirus disease (covid- ) outbreak in china: summary of a report of cases from the chinese center for disease control and prevention clinical characteristics of hospitalized patients with novel coronavirus-infected pneumonia in standardization of spirometry fastqc: a quality control tool for high throughput sequence data star: ultrafast universal rna-seq aligner voom: precision weights unlock linear model analysis tools for rna-seq read counts widespread sexual dimorphism in the transcriptome of human airway epithelium in response to smoking threshold of biologic responses of the small airway epithelium to low levels of tobacco smoke a dynamic bronchial airway gene expression signature of chronic obstructive pulmonary disease and lung function impairment. american journal of respiratory and critical care angiotensin-converting enzyme is an essential regulator of heart function quantitative mrna expression profiling of ace , a novel homologue of angiotensin converting enzyme angiotensin-converting enzyme protects from severe acute lung failure alternative roles of stat and mapk signaling pathways in the mmps activation and progression of lung injury induced by cigarette smoke exposure in ace knockout mice role of angiotensin-converting enzyme (ace) and ace in a rat model of smoke inhalation induced acute respiratory distress syndrome key: cord- -i ck oo authors: kouri, andrew; gupta, samir; yadollahi, azadeh; ryan, clodagh m.; gershon, andrea s.; to, teresa; tarlo, susan m.; goldstein, roger s.; chapman, kenneth r.; chow, chung-wai title: chest reviews: addressing reduced laboratory-based pulmonary function testing during a pandemic date: - - journal: chest doi: . /j.chest. . . sha: doc_id: cord_uid: i ck oo abstract to reduce the spread of sars-cov- , many pulmonary function testing (pft) laboratories have been closed or have significantly reduced their testing capacity. as these mitigation strategies may be necessary for the next - months to prevent recurrent peaks in disease prevalence, fewer objective measurements of lung function will alter the diagnosis and care of patients with chronic respiratory diseases. pfts, which include spirometry, lung volumes, and diffusion capacity measurement, are essential to the diagnosis and management of patients with asthma, copd, and other chronic lung conditions. both traditional and innovative alternatives to conventional testing must now be explored. these may include peak expiratory flow devices, electronic portable spirometers, portable exhaled nitric oxide measurement, airwave oscillometry devices, as well as novel digital health tools such as smartphone microphone spirometers, and mobile health technologies along integration of machine learning approaches. the adoption of some novel approaches may not merely replace but could improve existing management strategies and alter common diagnostic paradigms. with these options come important technical, privacy, ethical, financial, and medicolegal barriers that must be addressed. however, the covid- pandemic also presents a unique opportunity to augment conventional testing by including innovative and emerging approaches to measuring lung function remotely in patients with respiratory disease. the benefits of such an approach have the potential to enhance respiratory care and empower patient self-management well beyond the current global pandemic. as of june nd, there are over . million confirmed cases of covid- globally, and many countries have implemented broad and extraordinary public health strategies in hopes of "flattening the curve". one important consequence of these strategies has been the widespread suspension of non-urgent healthcare services, such as non-urgent outpatient in-person consultations and routine diagnostic testing. this has resulted in the full or partial closure of most pulmonary function testing (pft) laboratories, in keeping with guidance provided by the american thoracic society. this guidance is founded primarily on concerns that the testing performed in these laboratories, which includes spirometry, lung volume, and diffusion capacity measurement, present a higher risk of sars-cov- transmission compared to other diagnostic tests, given the potential for aerosol formation and coughing during the testing of patients with lung disease. though these and other societal measures have resulted in some success in slowing the spread of sars-cov- , modeling at both local and national levels has suggested that current policies will likely need to be maintained for as long as months in order to prevent a deadly rebound. , for pft laboratories, this implies continued closure versus limited reopening with strict pre-visit viral testing, personal protective equipment use, and cleaning protocols -either scenario leading to a significant reduction in testing capacity compared to historical norms. although the provisional diagnosis and management of chronic respiratory diseases with limited access to objective measures of lung function may be feasible in the short term, sustained reductions in testing will almost certainly lead to sub-optimal care for many. furthermore, the inability to diagnose new conditions objectively, for example occupational asthma, may worsen long term outcomes. as such, it is important to address this issue as soon as possible. as with the decrease in in-person consultations, virtual and digital technologies may play an important role going forward, but it is vital to consider the technical, administrative, ethical, and financial implications that will arise as newer technologies replace, complement or augment conventional pulmonary function testing. pulmonary function testing is essential to the care of respiratory disorders. it is used to diagnose lung disease, monitor disease course and the effect of therapeutic interventions, determine perioperative risk, and assess prognosis. reduced access to pfts over the next - months would affect the nearly half a billion children and adults worldwide who live with asthma and chronic obstructive pulmonary disease (copd), the two most common chronic respiratory conditions, as well as those who will be under-and over-diagnosed during that time period due to reduced testing. in both children and adults with asthma, respiratory symptoms correlate poorly with lung function measurements and cannot be used to infer underlying pulmonary function and pathophysiology. , the results of pfts have also been shown to change physicians' treatment plans in as many as % of patients with asthma, and are a strong independent predictor of exacerbation risk. with copd, pfts are critical for diagnosis, for assessing the impact of pharmacologic and non-pharmacologic interventions, and for prognosis, as deteriorating function is associated with increased exacerbations, hospitalization, and risk of death. pfts are equally vital in preventing misdiagnosis of asthma and copd, which can result in the unnecessary, potentially harmful, and costly use of respiratory medications in patients who will not benefit from them. [ ] [ ] [ ] as many as one third of patients receiving anti-asthma therapy in canada are found not to have the disease when objective measures of lung function are used diagnostically. the overdiagnosis and misdiagnosis of copd may be even worse, with estimates of overdiagnosis in primary care ranging from % to %. objective measurement of lung function has also been shown to reduce the problem of gender bias in copd. beyond asthma and copd, many other chronic respiratory conditions rely on the objective measurements of lung function to guide diagnosis, management, and prognostication. guidelinebased care of patients with cystic fibrosis, interstitial lung disease, and pulmonary hypertension, for example, depends on regular access to pft results. [ ] [ ] [ ] [ ] access to reliable pulmonary function data is particularly critical for lung transplant patients when weekly monitoring with spirometry is the gold standard care during the first months post-transplant when the risk of acute graft rejection is highest. though some respiratory sub-specialists have already provided guidance as to how care should be adjusted while deferring non-essential pfts, it is not yet clear how long this new paradigm of care will be effective in avoiding negative health outcomes, especially as increasing numbers of patients have their testing postponed. to prevent undue harm to both patients and technicians in communities with high prevalence of covid- , many healthcare facilities have restricted laboratory-based pfts to "essential" cases where results will influence immediate treatment decisions. however, this has the secondary effect of further limiting the information available to clinicians who must already manage patients without physical examinations, since many have now moved almost exclusively to virtual care for outpatient visits. without this information, management decisions are being made based on history alone. this may be adequate for routine follow-up of some patients with stable respiratory disease but is challenging for new patients and follow-up patients whose clinical status has changed. though pft laboratories may gradually open as covid- numbers plateau and begin to decrease, infection control requirements will likely still reduce testing capacity for a long time. similar concerns around infection control and testing capacity will also adversely affect traditional alternatives to in-laboratory testing such as office-based spirometry, as current international recommendations do not distinguish between healthcare settings when assessing the risks of aerosol generating procedures, and even the use of spirometer filters does not eliminate the need for enhanced infection control measures. , , alternatives to laboratoryand office-based pfts may be sought in existing approaches as well as innovative technologies. home measurement of peak expiratory flow (pef) using an inexpensive portable handheld device is already a guideline-recommended option to facilitate patient self-management in asthma and in the diagnosis of occupational asthma, but its role is less well defined in copd. , , many studies have investigated the potential for pef to be used as a surrogate for pfts in the diagnosis and management of patients with asthma and copd, but the results have been mixed. some research has shown that pef, in combination with other tools such as validated patient questionnaires, can be used to help diagnose copd when spirometry is not easily available, [ ] [ ] [ ] [ ] and may be helpful in copd prognostication independent of spirometry. however, other work in both diseases has shown that agreement between pef (a purely effortdependent measure) and spirometry can be highly variable, and may lead to inappropriate clinical decision making if relied on exclusively, particularly in children and in cases with either very mild or severe airway obstruction. [ ] [ ] [ ] [ ] additionally, studies in children with asthma have shown that self-recorded peak flow is often inaccurate and adherence levels low, and similar concerns may extend to adults. thus, while pef may continue to be used by patients with asthma already familiar with its measurement and tracking, it is unlikely to suffice as a long-term replacement for pfts across chronic respiratory diseases. given the potential for aerosol generation during the forced exhalation maneuver required for pef measurement, patients using this technique to monitor their respiratory status at home should also be counselled on measures to avoid infecting other members of their household while using their flowmeter. a more sophisticated alternative to pef measurement is the use of portable spirometers. as a home-based measurement, it minimizes the exposure risk of forceful expiratory measurements and cough in the laboratory or office setting. many of these devices are now commercially available and in addition to providing more accurate objective measurements of lung function compared to pef, most are now also designed to pair with and download results onto personal mobile devices or computers, facilitating transmission to and monitoring by healthcare professionals. electronic portable spirometers have been studied and found to be comparable to conventional laboratory spirometry in several chronic respiratory conditions, such as asthma and copd, cystic fibrosis, idiopathic pulmonary fibrosis, and post-lung and hematopoietic stem cell transplant monitoring. [ ] [ ] [ ] [ ] [ ] [ ] [ ] indeed, the ability of patients to monitor spirometry weekly, more frequently than is feasible using laboratory-based measurements, offers advantages in some settings where early detection of problems is important -pulmonary fibrosis monitoring and lung transplant surveillance are two established examples. , limitations of these devices include cost, which can range from $ to over a $ usd, lack of feedback on quality of the breathing maneuvers in many devices, variable reporting of accuracy levels (though some devices claim to meet american thoracic society standards for spirometry and include global lung function initiative reference equations), and the need to validate results against reference standards when starting them for new patients. additionally, most of these devices are only able to provide spirometry readings, and cannot aid in lung volume or diffusion capacity measurement. given these limitations, clinicians considering electronic portable spirometers must select the most appropriate devices available locally, ideally balancing price, accuracy, and features that support correct and safe usage. with the correct device-patient match, portable spirometers may present a valuable in-home alternative to pfts for monitoring patients with known chronic lung conditions, augmenting virtual care with important physiologic data. their use could also offload the testing demand on pft laboratories and outpatient clinics, allowing them to focus their limited capacity on new diagnoses and more urgent testing. as with flowmeter use, patients using portable spirometers at home should be counselled on measures to avoid potentially infecting other members of their household. the fraction of exhaled nitric oxide (feno) has been studied extensively in asthma, but also in other respiratory diseases, as a non-invasive biomarker that can supplement or potentially replace conventional spirometry in diagnosis and management decisions. [ ] [ ] [ ] [ ] unlike spirometry, measurement of feno does not require forceful expiratory maneuvers and is not prone to trigger cough. feno may be particularly useful in identifying asthma characterized by type airway inflammation, and may help guide treatment initiation decisions in these patients. , guidelines do not currently recommend using feno alone in either the diagnosis or ongoing management of asthma across different phenotypes. however, increased use of the technology could see revision of these paradigms. at present, laboratory-based measurements are used to diagnose asthma by demonstrating evidence of variable airflow obstruction. such an approach is fraught with difficulty, as patients with mild asthma seldom demonstrate bronchodilator responsiveness at times of randomly scheduled laboratory visits. in fact, operating characteristics of exhaled no measurement for asthma diagnosis were clearly superior to those of spirometry with bronchodilator testing in a recent review. moreover, traditional challenge studies are not only cumbersome to carry out, but also produce variable responses in different subpopulations of patients with asthma and depending on the challenge used. arguably, recognizing and managing airways inflammation is a more important treatment decision in asthma than the decision to use albuterol for symptoms, and exhaled nitric oxide has been suggested as a predictor of inhaled corticosteroid responsiveness is patients with asthma or asthma-like symptoms. institutions familiar with feno testing may thus consider using this technology as a potentially safer (i.e. less likely to generate aerosols) method in inpatient and outpatient settings for diagnosing and following patients with asthma characterised by type airway inflammation. portable handheld devices that can measure feno are also available, and could be a useful remote monitoring option in patients with eosinophilic asthma in the future, though strategies to ensure appropriate technique and quality standards will be required. however, the high cost of portable devices, requirement for patient coaching, and lack of validation for feno in different asthma phenotypes and across other chronic respiratory diseases means it is unlikely to provide an adequate long-term substitute for pfts. oscillometry is emerging as an alternative form of pulmonary function testing that offers some advantages over conventional pfts. it has been shown to be more sensitive than spirometry in early diagnosis of copd, , to correlate better with respiratory symptoms and asthma control , as well as in identifying spirometrically silent episodes of biopsy-proven acute graft rejection following lung transplant. however, there is a dearth of normal reference values for oscillometry due to its relative infancy when compared to conventional pfts, though this is anticipated to improve with recent publications of technical and interpretation guidelines. , as oscillometry is conducted under normal tidal breathing and does not require forced expiratory efforts, it may also have infection control advantages over spirometry, being less likely generate aerosol and minimizing potential sars-cov- transmission. furthermore, oscillometry can be easily conducted in the very young, the elderly and those with physical or cognitive impairment. oscillometry may also be a useful endpoint in methacholine or other challenge studies, obviating the need for forceful maneuvers (although challenge-induced cough remains a potential hazard). lastly, remote home monitoring with portable oscillometry is available and likely to provide more reliable readings than portable spirometry, as coaching, a crucial component for quality control in spirometry, is not needed for oscillometry. one barrier to the broader use of oscillometry is the high cost of the limited portable devices available (for example, the tremoflo ® device from thorasys) , though some of this may be recouped over time given the increased volume of testing permitted by oscillometry, and staff training is considerably simpler than with traditional spirometry. , [ ] [ ] [ ] novel digital health alternatives a growing body of literature is exploring the potential to turn existing mobile devices and smartphones into portable electronic spirometers using their built in microphones, supplemented with machine learning techniques. , pilot studies of these "smartphone spirometers" in healthy subjects and patients with asthma and copd have demonstrated reasonable levels of agreement between resulting values and traditional spirometry, particularly with the fev /fvc ratio. [ ] [ ] [ ] [ ] [ ] though rigorous clinical evaluation and validation of these innovative approaches against laboratory-based pulmonary function testing has not been done and they cannot be considered a current alternative during the covid- crisis, their low cost and capacity for broad dissemination and digital integration offer considerable promise. is not a direct substitute for formal pulmonary function testing but may contribute to improved management outcomes if implemented during the covid- pandemic. in asthma care, mhealth applications supporting patient self-management through education, medication reminders, symptom monitoring, and action plan provision have been shown to improve asthma control, medication and action plan adherence, and quality of life. , similar mhealth interventions for copd have been associated with decreased hospitalization risk. importantly, many mhealth self-monitoring technologies are able to facilitate the transmission of clinical data to healthcare professionals, which could enhance the virtual and remote-patient monitoring and management currently taking place. these types of mhealth solutions may be leveraged in patients with established respiratory diagnoses and relationships with mhealth-savvy health care professionals, but are likely less useful in new patient assessments or cases of diagnostic uncertainty. additionally, it is important to note that mhealth in asthma and copd is an emerging research field, and long-term studies of clinical effectiveness are still lacking. , another innovative approach to enhance remote and virtual monitoring is the use of machine learning algorithms with telemonitoring data. in copd for example, machine learning techniques have been combined with sociodemographic, clinical, and physiologic telemonitoring data to predict acute exacerbations of copd with high sensitivity and specificity. [ ] [ ] [ ] as these technologies mature, they may become particularly useful in centers with established telemonitoring programs in helping clinicians to identify which patients are at higher risk of clinical deterioration, allowing triaging of limited pft resources. however, as with all applications of machine learning with healthcare data, interpreting clinical applicability, generalizability, and the potential for algorithmic bias must be carefully addressed. our present concern is to maintain the usual management standards of patients with chronic respiratory disease until conventional lung function laboratories are able to re-open. however, as new technology is developed and validated, we may find our management strategies improved. convenience is one obvious advantage of remote patient-measured pulmonary function options. patients, especially those living in underserviced areas, may be spared the need for frequent office visits and laboratory-based studies if equally useful measurements can be generated at home. more frequently monitored lung function at home or in the workplace also offers obvious advantages in the management of difficult asthma, for example. the benefits of weekly home spirometry for monitoring patients with interstitial lung disease, post-transplant patients, and those with cystic fibrosis have already been demonstrated and seems likely to replace at least some of the quarterly clinic visits now employed. , , , additionally, many of the non-remote options reviewed such as in-laboratory feno and airwave oscillometry currently offer a lowerrisk alternative to pfts in the short-term, as they are less likely to generate aerosols, but they may also prove to be viable longer-term alternatives as more research is dedicated to their validation across respiratory conditions. one important question that remains with the proposed use of alternative and/or portable pulmonary function testing technologies is what criteria would warrant confirmation with in-laboratory testing. while some options such as feno have established cut-offs, interpretation guidelines for other options such as airwave oscillometry have only recently been published and have yet to be incorporated into computer-based interpretation algorithms. , clinicians will have to be mindful of emerging evidence when using any pft alternative and incorporate other sources of clinical information into their decision making. however, any signals of deterioration from the options suggested could equally prove useful in the triaging of limited in-laboratory pft resources. see table for a summary of reviewed alternatives and their limitations. though the covid- pandemic presents an opportunity to study and explore the potential alternatives to conventional pfts in managing the care of patients with chronic respiratory diseases, these alternatives are not without their own unique challenges. integrating many of the proposed remote alternatives into existing care workflows and electronic health records that are already struggling to cope with the massive shift to virtual care would be challenging. privacy and equity issues would need to be carefully addressed, particularly when dealing with interventions that interact with patients' personal digital devices as well as when considering the costs of various alternatives. technical support for both patients and healthcare workers may be needed with new technologies and devices. remuneration systems would need to be adjusted to recognize the technical and professional components involved in the introduction of new and advancing technologies, and to compensate for potential loses in hospital revenue associated with decreased laboratory testing. this is already occurring to some extent, as the us administration has enacted several regulatory changes to support expanded remuneration for remote patient monitoring and telehealth services. finally, the use of novel technological solutions may herald unanticipated or new medicolegal implications which will require consideration. in the face of serious limitations to the availability of conventional laboratory and office-based pulmonary function testing that are likely to persist for at least the next - months, respiratory clinicians, researchers, and administrators must begin to consider how alternatives to conventional pfts could be integrated into the care of patients with chronic respiratory diseases to provide the best possible quality of care. though no current individual alternative is sufficient to replace conventional testing in all patients, many of the options reviewed may provide acceptable and actionable physiologic information to improve clinical management. examples include the use of portable electronic spirometry and mhealth self-monitoring technologies in patients with asthma and copd, as well as portable oscillometry for monitoring patients postlung transplant. the covid- pandemic provides a unique opportunity for the respiratory community to implement existing alternatives to pfts and to engage in the rigorous clinical evaluation of new digital solutions and systems that may enhance the management of those with respiratory diseases, while being mindful of the importance of privacy and autonomy to our patients. table . summary of evidence for pft alternatives during a pandemic peak expiratory flow measurement use in asthma : -diagnosis of variable expiratory airflow limitation (diurnal variation, response to therapy, variation between visits) -diagnosis of occupational asthma and workexacerbated asthma -short-term and long-term self-monitoring (i.e. use in asthma action plans) use in copd [ ] [ ] [ ] [ ] [ ] [ ] : -diagnosis, in combination with validated patient questionnaires -prognostication results less reliable in children, and in patients with very mild or severe airways obstruction. may also be adherence issues, particularly in children but also in adults. remote follow-up in patients diagnosed with [ ] [ ] [ ] [ ] [ ] [ ] [ ] an interactive web-based dashboard to track covid- in real time pulmonary function laboratories: advice regarding covid- impact of non-pharmaceutical interventions (npis) to reduce covid mortality and healthcare demand projecting the transmission dynamics of sars-cov- through the postpandemic period workplace interventions for treatment of occupational asthma. cochrane database syst rev covid- and health care's digital revolution standardization of spirometry world health organization. chronic respiratory diseases global initiative for asthma. global strategy for asthma management and prevention asthma symptoms do not predict spirometry spirometry can be done in family physicians' offices and alters clinical decisions in management of asthma and copd global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease reevaluation of diagnosis in adults with physician-diagnosed asthma factors associated with 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applications in self-management of patients with chronic obstructive pulmonary disease: a systematic review and meta-analysis of their efficacy living with asthma and chronic obstructive airways disease: using technology to support self-management -an overview machine learning for copd exacerbation prediction ensemble machine learning for the early detection of copd exacerbations improving prediction of risk of hospital admission in chronic obstructive pulmonary disease: application of machine learning to telemonitoring data key challenges for delivering clinical impact with artificial intelligence trump administration makes sweeping regulatory changes to help u.s. healthcare system address covid- patient surge authors' contributions: an initial draft of this paper was prepared by a.k., and all authors contributed to the editing and final draft of the work. a.k acts as the guarantor of this work. key: cord- -ekvzaae authors: mcmanus, terence e.; marley, anne-marie; baxter, noreen; christie, sharon n.; o'neill, hugh j.; elborn, j. stuart; coyle, peter v.; kidney, joseph c. title: respiratory viral infection in exacerbations of copd date: - - journal: respir med doi: . /j.rmed. . . sha: doc_id: cord_uid: ekvzaae background: patients with copd have frequent exacerbations. the role of respiratory viral infection is just emerging. we wished to determine prospectively the incidence of viral infection in exacerbated and stable copd patients as well as smokers who do not have airways obstruction. methods: stable and exacerbated copd patients were recruited along with a group of patients who had smoked but who did not have any airways obstruction. spirometry was performed and sputum specimens were tested for a range of different respiratory viruses using pcr. results: one hundred and thirty-six patients with exacerbations of copd, stable copd patients and non-obstructed smokers were recruited. a respiratory virus was detected in % of exacerbations, % of stable copd patients and % of non-obstructed smokers, p < . . rhinovirus was most frequently detected. the symptom of fever was associated with virus detection, p < . . infection with more than one virus was only found in the exacerbated copd patients. conclusion: respiratory viral infection is associated with exacerbations of copd. rhinovirus was the most common infecting agent identified and in two cases human metapneumovirus was also detected. dual infections were only seen amongst those patients admitted to hospital with acute exacerbations of copd. viruses were more commonly detected in those with more severe airways disease. patients with copd have frequent exacerbations which lead to increased airway inflammation and often subsequent hospitalization. bacteria are associated with approximately % of exacerbations. , a number of studies have identified viral infections of the respiratory tract as precipitating agents. studies using serology and viral culture identified respiratory viruses in % of patients during acute exacerbations of copd. with the development of more sensitive molecular tests the role of viruses in copd has been better defined. walsh et al. identified several common respiratory viruses in a cohort of patients with copd or congestive cardiac failure. viruses were identified by serology and viral culture methods. significant outcomes in terms of hospitalisation were seen for respiratory syncytial virus (rsv) and influenza a infected patients. greenberg et al., using serology and viral culture, showed that in % of cases of hospitalisation of copd patients a virus was detected and that the mean time to return to symptomatic baseline was weeks. the most common viruses identified were of the picornavirus classification (rhinoviruses). several studies have used pcr for the diagnosis of viral infection. initially, in seemungal et al. examined patients with copd when stable and subsequently during an exacerbation. ten of exacerbations were associated with rhinovirus infection. higher symptom scores and sputum interleukin- levels were seen with rhinovirus exacerbations. seemungal et al. went on to show respiratory viral infection in % of exacerbations of copd. viral infection was associated with a more severe exacerbation, and in patients who had a higher frequency of exacerbations, i.e. those with the poorest lung function. patients were reviewed in convalescence at e weeks. the majority ( %) of these viruses were rhinovirus (i.e. % of copd exacerbations). plasma il- levels were elevated in all exacerbations, and levels were significantly increased in the virus positive group when comparison was made with those in whom no virus was detected. rohde et al. used pcr to detect viruses in patients with exacerbations of copd. a respiratory virus was detected in % of cases in comparison to % of control subjects with stable copd. the majority of viruses detected were picornaviruses. the most recent study from beckham et al. combined specimens obtained for two previous studies for analysis by pcr. they detected a respiratory viral infection in % of acute respiratory illnesses. respiratory viral infection in copd patients during exacerbation has been associated with longer median symptom recovery time in comparison to exacerbations in which a viral agent was not identified ( days versus days respectively). the hypothesis tested in the present study was that acute respiratory viral infection is implicated in the pathogenesis of copd exacerbations. the aims of the present study were to examine respiratory specimens for the presence of respiratory viruses in patients with copd whilst stable and also during exacerbations. this study was approved by the queen's university belfast ethics committee and all patients gave written consent. the patient groups described in this paper have been described in other related publications. patients hospitalised with exacerbations of copd were recruited within h of presentation over a -year period. a further group of stable copd patients were also recruited. stability was defined as no change in respiratory symptoms or alteration in therapy in the previous weeks. patient's symptoms were recorded in a binary format. spirometry was performed, the best of reproducible readings was taken (vitalograph spirometer, vitalograph, buckingham, uk). spirometry was repeated after nebulised beta agonist (salbutamol . mg). any patients with significant improvement in fev (> ml/ %) were excluded. those patients with a history of bronchiectasis, neoplastic process or other serious concomitant disease were excluded. copd and assessment of severity was classified according to the gold criteria. exacerbation of copd was classified according to the gold criteria with symptoms of increased dyspnoea, increased cough or increased sputum production. stable copd was classified according to the gold criteria without any symptoms of exacerbation or changes in treatment within the last weeks. sputum samples were obtained either by spontaneous production or following nebulised hypertonic saline. briefly, ml of % saline was nebulised via an air driven nebuliser. every min spirometry was repeated to measure fev , and nebulisation continued if fev had not fallen by more than %. this was continued up to min. all sputum expectorated was collected. all samples were processed within h. specimens were mixed with volumes of . % dithiothreitol (sigma, poole, uk) and shaken in an orbital incubator (gallenkamp, loughborough, uk) for min at c followed by the addition of volumes of phosphate buffered saline and shaken for a further min. the resulting suspension was then filtered through mm nylon gauze (lockertex, warrington, uk) and spun down at  g for min. after removing the supernatant the cell pellet was resuspended in lysis buffer (qiagen, crawley, uk). total nucleic acid extraction was performed on ml of sputum sample suspended in lysis buffer (qiaamp dna blood mini kit). extracted samples were screened for common respiratory viruses (rhinovirus, human metapneumovirus, influenza a h and h , influenza b, rsv a and b, coronavirus e, adenovirus and parainfluenza , and ) using an eight-well multiplexed, nested pcr system (fig. ). a positive control was used for each set of patient's tests. mastermix and pcr cycling conditions are listed in the supplementary material(appendix a and a respectively). tests results were accepted as being valid when the positive control tested positive with correct sized product(s). a positive result was noted when second (or first and second) round products were noted and confirmed as being the correct size. indeterminate test results were repeated. this method allowed rapid testing of clinical specimens for multiple viruses with sensitive and specific assays. a power calculation was performed to determine study group sizes. assuming a respiratory virus detection rate of % amongst copd patients during exacerbations and % detection when stable a power calculation was performed using epiinfoä version . using a confidence value of % with a power of % and a : ratio of group sizes, patients with copd exacerbations and stable copd subjects were required. normally distributed data were presented as mean ae standard deviation, whilst non-parametric data were expressed as median and inter quartile ranges. normally distributed continuous variables were compared by t-test; otherwise the differences were assessed by the mannewhitney utest. for discrete variables frequencies and percentages were reported and groups compared using the chi squared test. a significance level of % was chosen. statistical analysis was carried out using spss (chicago, il) version . . a total of subjects were recruited in this study (table ) ; were seen during an acute exacerbation, and were recruited when stable. an additional non-obstructed smokers with a fev and fvc within the normal range were recruited. patient characteristics are shown in tables and ; the exacerbated and stable copd groups were of similar age, sex, fev , tobacco use, baseline mrc score, inhaled steroid and body mass index (bmi) and pack years of tobacco use. crp and white cell count (wcc) were significantly elevated during exacerbation when compared to stable copd patients. crp levels were . mg/dl ( . e . mg/dl) at exacerbation and . mg/dl ( . e . mg/dl) in stable patients (p < . ). the wcc increased from . ae . to . ae .  /l in exacerbations of copd (p < . ). similarly the neutrophil count increased from . ae . to the majority of patients described symptoms of increased dyspnoea, cough along with increased sputum volume and purulence during exacerbations ( table ). the presence of fever was associated with the identification in the same patient, p < . . the majority of patients were mrc score during exacerbations. respiratory viruses were detected in sputum and nasal/ throat swabs in of ( %) patients during exacerbations of copd and of ( %) stable copd patients (p < . ) ( table ). the viruses detected (table ) were rhinovirus ( %), adenovirus ( %), parainfluenza ( %), influenza a h ( %), rsv b ( . %), metapneumovirus ( . %), coronavirus ( %) and rsv a ( %). there were dual infections in six cases however these were all confined to the exacerbated copd group. a respiratory virus was more frequently detected during exacerbations in patients with more severe airways disease, p < . (table ). no associations were seen between viral infection and patient sex or medication (use of theophylline or inhaled steroid therapy). the main findings of this study were that respiratory viruses were more frequently detected during acute exacerbations of copd in patients admitted to hospital and that crp levels correlated with exacerbation and duration of hospital stay. this study was performed over a -year period in order to avoid bias due to seasonality. the detection rate of respiratory viruses during exacerbations of copd in this study ( %) is comparable to results obtained by seemungal lower detection rates may be related to time of sampling as patients presenting to hospital had developed symptoms for a median of days prior to admission. this is the first study to prospectively analyse this range of respiratory viruses in patients recruited during exacerbation of copd. the most common infecting agent was rhinovirus in keeping with previous studies, e however we also detected a high rate of adenoviral infection which has not previously been reported. this is in keeping with the findings of coyle et al. who demonstrated that adenovirus is more commonly detected using pcr than conventional immunofluorescence and virus culture techniques. previous investigators have related adenoviral infection to subsequent latent infection in the form of adenovirus e a and that it may be important in the pathogenesis of copd. metapneumovirus was discovered in and initially detected in young children with a respiratory tract illness. it was subsequently found to play a role in communityacquired respiratory tract illness with . % of patients presenting with 'influenza-like illness' testing positive. beckham et al. tested specimens from patients during exacerbations of copd and when stable for metapneumovirus but all patients were negative. rohde et al. found metapneumovirus to be present in . % of patients during acute exacerbations of copd and none of the stable copd patients in keeping with the findings of this study. the detection of human metapneumovirus in this study confirms its role as a respiratory pathogen in adult patients with copd. the study showed relatively lower detection rates of influenza virus compared to other studies. e this may be related to improved vaccination amongst this group of at risk individuals and it may also reflect that during recruitment for this study there was no influenza epidemic. there was also a lower incidence of rsv infection ( cases). previous investigators have suggested that it is more common. some have suggested that it is present in low copy numbers. it is possible that a more sensitive realtime pcr assay is required in order to detect it. however a recent study suggests that rsv accounted for . % of copd admissions in hospitalised patients. this is the first study to also include a group of patients from the same community who do not have respiratory disease (non-obstructed smokers). there were similar detection rates of respiratory viruses in the stable copd ( . %) and nos groups ( . %) supporting previous findings which found respiratory viral infection to be present in asymptomatic individuals. the frequency of detection in these groups suggests that copd patients do not have a higher carriage rate of viral infections to nos but a larger study is required in order to confirm this. one of the weaknesses of this study was that patients were recruited following admission to hospital. in some cases there may be several days between infection, development of symptoms and presentation. depending on the duration of viral infection prior to seeking medical help there may be some cases in which patients present late and thus viral replication is decreasing, resulting in a reduced detection rate. this may lead to an underestimation of the prevalence of viral infection in these patients. recent publications also suggest that rsv detection is increased with the use of real-time pcr assays. all respiratory viral assays in this study utilized nested pcr technology and not real-time pcr methods. detection of respiratory viruses by pcr may in fact relate to airway colonization or viral persistence. however, several of the patients were seen at different time points during this study and the same virus was not detected by repeat sampling suggesting that those testing positive using the pcr screen were experiencing an acute viral infection. another possible confounding factor is that patients with copd experience exacerbations in which no precipitating agent can be identified. these episodes may be related to the progressive nature of this disease process rather than an acute event. thus the true role of respiratory viral infection in exacerbations may be underestimated. a possible area of bias was that all patients recruited were hospitalized. thus selection bias may have been imposed in that those patients admitted to hospital tended to have particular types of respiratory viral infection or that respiratory viral infection only precipitated an exacerbation and subsequent hospital admission in patients with severe copd. another potential source of bias is the seasonality of respiratory viral infection. we addressed this issue by recruiting patients during all months of the year over a -year period. other potential sources of bias include patient selection; those patients most ill and requiring non-invasive ventilation were too ill to participate in the study. thompson et al. have published data linking influenza and rsv infection with increased mortality in the elderly. there are increased admissions in older people in winter. fleming showed that acute respiratory infections are associated with hospitalisation and increased mortality. it reinforces the health service implications of winter infection and increased exacerbations of copd. it is also noteworthy that the peak death rate is in patients diagnosed with acute respiratory disease. influenza has been linked with increased health care use by the elderly and there is an excess mortality particularly in the elderly. this paper highlights the impact of respiratory viral infection on health care resources. it supports the use of influenza vaccination in patients with underlying respiratory disease in order to reduce exacerbations and hospital admissions. in conclusion this study supports the hypothesis that respiratory viral infection is associated with exacerbations of copd. rhinovirus was the most common infecting agent identified and in two cases human metapneumovirus was also detected. dual infections were only seen amongst those patients admitted to hospital with acute exacerbations of copd. the development of multiplexed real-time pcr assays will enable this technology to be utilized in an acute diagnostic setting. relation of sputum inflammatory markers to symptoms and lung function changes in copd exacerbations bacterial infection in chronic obstructive pulmonary disease bacterial infection and the pathogenesis of copd infectious etiology of acute exacerbations of chronic bronchitis respiratory syncytial and other virus infections in persons with chronic cardiopulmonary disease respiratory viral infections in adults with and without chronic obstructive pulmonary disease detection of rhinovirus in induced sputum at exacerbation of chronic obstructive pulmonary disease respiratory viruses, symptoms, and inflammatory markers in acute exacerbations and stable chronic obstructive pulmonary disease respiratory viruses in exacerbations of chronic obstructive pulmonary disease requiring hospitalisation: a case-control study respiratory viral infections in patients with chronic, obstructive pulmonary disease coming together: the ats/ers consensus on clinical pulmonary function testing global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: national heart, lung, and blood institute and world health organization global initiative for chronic obstructive lung disease (gold): executive summary antibiotic therapy in exacerbations of chronic obstructive pulmonary disease a touchdown nucleic acid amplification protocol as an alternative to culture backup for immunofluorescence in the routine diagnosis of acute viral respiratory tract infections role of latent viral infections in chronic obstructive pulmonary disease and asthma a newly discovered human pneumovirus isolated from young children with respiratory tract disease human metapneumovirus as a cause of community-acquired respiratory illness relevance of human metapneumovirus in exacerbations of copd respiratory syncytial virus infection in elderly and high-risk adults pcr detection of viral nucleic acid in fatal asthma: is the lower respiratory tract a reservoir for common viruses? latent adenoviral infection in the pathogenesis of chronic airways obstruction mortality associated with influenza and respiratory syncytial virus in the united states the contribution of influenza to combined acute respiratory infections, hospital admissions, and deaths in winter the impact of influenza-associated respiratory illnesses on hospitalizations, physician visits, emergency room visits, and mortality staff and patients of the mater hospital belfast. this study was supported by a unrestricted grants from astrazeneca, boehringer ingelheim and the mater hospital. no conflicts of interest declared. key: cord- -vxaqizkj authors: bouquet, jerome; tabor, david e.; silver, jonathan s.; nair, varsha; tovchigrechko, andrey; griffin, m. pamela; esser, mark t.; sellman, bret r.; jin, hong title: microbial burden and viral exacerbations in a longitudinal multicenter copd cohort date: - - journal: respir res doi: . /s - - - sha: doc_id: cord_uid: vxaqizkj background: chronic obstructive pulmonary disease (copd) is a heterogeneous disease characterized by frequent exacerbation phenotypes independent of disease stage. increasing evidence shows that the microbiota plays a role in disease progression and severity, but long-term and international multicenter assessment of the variations in viral and bacterial communities as drivers of exacerbations are lacking. methods: two-hundred severe copd patients from europe and north america were followed longitudinally for years. we performed nucleic acid detection for respiratory viruses and s ribosomal rna gene sequencing to evaluate the bacterial microbiota in sputum samples collected at stable, acute exacerbation and follow-up visits. results: similar viral and bacterial taxa were found in patients from the usa compared to bulgaria and czech republic but their microbiome diversity was significantly different (p < . ) and did not impact exacerbation rates. virus infection was strongly associated with exacerbation events (p < e- ). human rhinovirus ( . %), coronavirus ( . %) and influenza virus ( . %) constitute the top viral pathogens in triggering exacerbation. moraxella and haemophilus were -fold and . -fold more likely to be the dominating microbiota during an exacerbation event. presence of proteobacteria such as pseudomonas or staphylococcus amongst others, were associated with exacerbation events (or > . ; p < . ) but more strongly associated with exacerbation frequency (or > . ; p < e- ), as confirmed by longitudinal variations and biotyping of the bacterial microbiota, and suggesting a role of the microbiota in sensitizing the lung. conclusions: this study highlights bacterial taxa in lung sensitization and viral triggers in copd exacerbations. it provides a global overview of the diverse targets for drug development and explores new microbiome analysis methods to guide future patient management applications. chronic obstructive pulmonary disease (copd) is defined by airflow limitation but encompasses several lung diseases. this heterogeneity includes differences in clinical characteristics, source of inflammation, response to therapies and causes of exacerbation [ ] . as copd progresses, exacerbations become more frequent and more severe. exacerbation rates reflect an independent susceptibility phenotype [ ] , which could be mediated by host factors [ ] , environmental factors [ ] , viral infections and/or the bacterial microbiome [ , ] . infections are predominant causes of copd exacerbations, with approximately half reported to be caused by bacterial infections including non typeable haemophilus influenzae (nthi), moraxella catarrhalis, streptococcus pneumoniae, or pseudomonas aeruginosa, and the other half by viral infections, primarily human rhinovirus (hrv), but also influenza virus, coronavirus and respiratory syncytial virus (rsv) to name a few [ , ] . bacteria and viruses are also frequently isolated in the airways of stable copd patients [ ] [ ] [ ] . the advent of culture-independent testing has suggested viral persistence [ ] and colonization of the lower airways with a resident bacterial microbiota [ ] , implicating a role for the microbiota in disease pathogenesis, progression and treatment outcome of lung diseases [ ] . studies of the microbiome provide a new framework to understand host-pathogen interactions, which can also yield new markers for patient diagnosis and management. microbiota diversity is seen as a potential biomarker in cases where a single pathogenic organism reduces community complexity such as in bacterial vaginosis [ ] , or crohn's disease [ ] . lung microbial dysbiosis in copd is characterized by decreased diversity [ ] [ ] [ ] , which may contribute to altered immune response to environmental insults [ ] . dysbiosis at the time of copd exacerbation contributes to increased disease severity [ ] and higher -year mortality rates [ ] . geography could also be a potential covariate in copd patients microbiota. the gut microbiota has been shown to be geographically variable [ ] . previous studies in different conntries have evaluated the copd microbiota [ , ] , but the effect of geographical variations has not yet been evaluated in a single study in relation to disease severity. the present cohort stems from a study on the incidence of viral infections in copd [ ] . patients were enrolled in europe and north america and followed up for up to rsv seasons, with scheduled wellness visits and unscheduled illness visits. to further our understanding of copd exacerbation dynamics, we retrospectively evaluated the sputum bacterial microbiota from a subset of this study. the goals were to identify differences in patients with higher rates of exacerbations, to assess geographical differences in the microbiota between europe and the usa, and to determine the influence of viral infections on microbiota diversity and the frequency of exacerbations. the patient cohort is part of an observational study on the incidence of acute respiratory illness (ari) or events leading to the worsening of cardiorespiratory status in copd (clinicaltrials.gov, nct ) [ ] . the protocol was approved by independent institutional review boards, and all subjects signed written informed consent at enrollment. the study population included adults ≥ years of age with copd, recruited at sites in bulgaria, sites in czech republic, and sites across the usa from fall to spring (fig. a) . cohort from bulgaria and czech republic showed similar characteristics, and are analyzed jointly as europe for fig. sampling timeline and composition. (a) timeline from oct to may , copd patients were enrolled and sampled during scheduled wellness visits (blue arrows), and any unscheduled visits (red and purple arrows) within days of an acute exacerbation or exacerbation follow-up visit. samples were considered stable if collected days post-hospitalization or ari. dotted arrows correspond to samples collected at scheduled wellness visits that incidentally corresponded to acute exacerbation events ( . %) and exacerbation follow-up visits ( %). piecharts represent the proportion of patients from europe and usa (b), the proportion of samples collected at each disease state (c) and the proportion of samples associated with antibiotics (abx) and inhaled corticosteroids (cs) taken in the past days (d) ease of representation. subjects had scheduled wellness visits in may and october each year to obtain sputum and clinical data (fig. a) . unscheduled illness visits to collect sputum and clinical data were performed when a subject experienced an ari or acute exacerbation of copd symptoms, and during follow-up illness visits. samples were considered stable if collected at least days from the last day of hospitalization or from the last ari or acute exacerbation event if it did not require hospitalization. acute exacerbation samples were collected within h of an event, additional samples were collected - days after an acute exacerbation event during unscheduled visits (fig. a, c) . patients were characterized with a frequent exacerbator phenotype if they experienced or more exacerbation events per year. no investigational drug was administered in the study. the subject's physician prescribed and recorded all treatment deemed necessary to provide adequate supportive care. samples collected to days following treatment were considered treatment associated (fig. d) . spontaneous rather than induced sputum collection was possible in this severe copd study subset following a standardized collection visit [ ] . subjects were asked to gargle with water immediately prior to sputum collection to reduce the number of oral bacteria [ ] . subjects were asked to cough deeply and expectorate into a cup, mixed : with cold transport media and kept at - °c or below [ ] . the genmark respiratory virus panel (genmark diagnostics, inc. carlsbad, ca) was used to detect common respiratory viruses from all sputum samples. rsv detection was confirmed by rt-pcr as previously described [ ] . additionally, rt-pcr using primers against hrv vp -vp [ ] was used to detect human rhinovirus subtypes. bacterial genomic dna was extracted at a single central lab using the zymobiomics dna kit (zymo, california, usa) following manufacturer's instructions. the v hypervariable region of the s rrna gene was pcr amplified [ ] and sequenced using illumina miseq platform along with negative controls, zymobiomics microbial community and dna standards, and a phix library for quality control. s rrna gene sequences were analysed using qiime version . [ ] . dada software package [ ] , wrapped in qiime , was used for correcting sequences and obtained annotated sequence variants (asvs). taxonomy was assigned using a naïve bayes classifier [ , ] that was trained on the greengenes database version . clustered at % identity [ ] v sequences. alignment was performed with mafft [ ] , masked and used in fasttree [ ] to build the phylogenetic tree. alpha-diversity metrics [ ] , beta diversity metrics [ ] , and principal coordinate analysis (pcoa) were estimated after samples were rarefied to sequences per sample. significant features of interest were re-tested using non-rarefying alpha [ ] and beta diversity estimates [ ] . analysis of composition (ancom) was used for differential taxa abundance calculations [ ] on nonrarefied data. ancom account for the structure of the data and controls for the false discovery rate. microbiota profiles were clustered into biotypes using the biotyper package in r [ ] . longitudinal microbiota variations at stable time points were assessed by calculating the median weighted unifrac distance [ ] for patients with at least stable samples. patients were categorized into the bottom and top quartile of within-patient stable samples median unifrac distances, respectively. associations of the microbiota and viral components with demographics and clinical data were calculated in r using fisher's test for categorical variables, welsh's ttest for comparison of means in continuous variables, and chi-squared test to compare expected frequencies. odds ratio were calculated using questionr package in r [ ] . associations of microbial diversity with demographics and clinical data were calculated with qiime 's diversity plugin using grouped and pairwise kruskal-wallis test corrected for false discovery rate for analysis of alpha diversity, and permanova following permutations for analysis of beta diversity distances. the cohort was composed of patients, from europe (bulgaria and czech republic) and from the usa ( fig. and table ). all but patients presented with severe or very severe copd. patients from europe and the usa were matched by age, sex, and gold stage. at enrollment, their forced expiratory volume as a percent of predicted (fev %) and their comorbidities (congestive heart failure, diabetes, hypertension and malignancy) were similar between europe and the usa. the usa patients had significantly higher smoking history in pack-years and longer copd duration. the number of exacerbations per year and the number of frequent exacerbator phenotype, defined as or more exacerbations/year, was higher in the usa compared to europe, but not statistically significant (table ) . a total of sputum samples were collected from these patients over years, with similar proportions of samples collected at acute exacerbation in europe ( . %) and in the usa ( . %) (supplementary table ). approximately and % of samples were associated with antibiotic and corticosteroid treatment, respectively. significantly more samples collected in the usa were associated with antibiotic treatment (supplementary table ). analysis of bacterial taxa in sputum samples shows phyla commonly observed in the lung microbiota, with firmicutes, proteobacteria and bacteroidetes representing a majority (> %) of the phyla identified (fig. a) . prevotella, veillonella, streptococcus and haemophilus represented the most prevalent (> %) bacterial genera (fig. a) . samples from european patients had more bacteroidetes and less proteobacteria overall than samples from the usa patients. within the phylum firmicutes, the usa patients had more streptococcus than veillonella compared to european patients (fig. a) . microbiota predominant with prevotella, streptococcus and veillonella were found in a majority of samples ( / ; . %) (fig. b) . prevotella, streptococcus and veillonella represented the majority of the microbiota in samples collected at stable states, haemophilus and moraxella were predominant in acute exacerbation samples, and pseudomonas was prevalent in exacerbation follow-up samples (fig. b ). viral testing on sputum samples showed that . % of sputum samples were positive for at least one virus, with hrv found in the largest proportion of samples ( . %), followed by coronavirus ( . %) and influenza virus ( . %) (fig. c ). all viruses, except for adenoviruses, were detected more frequently at acute exacerbation ( . %), than at follow-up visits ( . %) or stable ( . %) (fig. c ). there were no significant differences in viral incidence between europe and the usa, with the exception of coronavirus hku , influenza b virus and rsv a (supplementary table ). alpha diversity metrics such as the number of observed asv, shannon evenness, or faith phylogenetic diversity (pd) indexes, represent the mean number of taxons in a , and their respective shannon diversity index. * p < . , **p < . , *** p < . , lower and higher statistical significant diversity compared to the average are noted in red and blue, respectively. hmpv, human metapneumovirus sample, sometimes weighted by the phylogenetic relatedness. overall, samples from the usa patients had significantly lower shannon diversity index than those from europe (fig. a) , even when corrected for antibiotic use or clinical sites (supplementary fig. and ) . years of severe copd and smoking pack-years were associated with differences in microbiota diversity but not as significantly as geography (supplementary table ). no significant differences in the number of observed asvs and in faith pd index were observed at exacerbation compared to stable samples (supplementary table ). prevotella-predominant microbiota showed the highest alpha diversity, while samples predominant with escherichia, haemophilus, and pseudomonas had the lowest alpha diversity (fig. b ). there were no significant differences in microbial diversity between samples infected or not with a virus, or between samples infected with different viruses (fig. c) . beta diversity are metrics such as weighted unifrac and robust aitchison pca used for comparing microbiota communities resulting in distance matrices. here, principal coordinate visualization of weighted unifrac distance supports the above conclusions, showing some differences in geography and predominant bacteria but not affected by the type of viral infection ( supplementary fig. ). these results were also supported by testing non-rarefied alpha and betadiversity estimates, with geography (p < . ) and dominant bacterial genus (p < . ), but not viruses (p > . ) being associated with significant changes in diversity (data not shown). the odds ratio of an acute exacerbation event and frequent exacerbations (≥ events/ year) was calculated for demographic and clinical data, viral infections and abundance of certain bacterial taxa in the lung microbiota (fig. ). viral infections were more strongly associated with an exacerbation event than with frequent exacerbations. parainfluenzaviruses (piv), influenza b virus and rsv b had the highest odds ratio of an exacerbation event (fig. a) . interestingly, influenza b virus was negatively correlated with frequent exacerbations, as it was only detected in patients that exacerbated infrequently. bacteria were more strongly associated with exacerbation frequency than with exacerbation events. presence or higher abundance of enterococcus, lactobacillus, moraxella, pseudomonas, staphylococcus and streptococcus was correlated with frequent exacerbations. neisseria, prevotella and veillonella were significantly associated with a lower exacerbation frequency (fig. b) . interestingly, top quartile abundance odds ratio of the genus haemophilus was not associated with higher exacerbation rate. this effect, however, seemed mediated by h.parainfluenzae. we noted that differential abundance of only bacterial taxa were significantly associated with exacerbation events, while taxa were associated with exacerbation frequency ( supplementary fig. ) , with high e.coli, lactobacillus, and staphylococcus in stable samples as potential predictors of frequent exacerbation ( supplementary fig. ). patients with hypertension had a significantly higher odds ratio of being frequent copd exacerbators (fig. c) . other comorbidities did not significantly influence exacerbation frequency. we quantified temporal variability of the sputum microbiota at stable state within individual subjects. for patients with more than longitudinal stable samples, we calculated their median weighted unifrac distances and categorize the top and bottom quartile patients into consistent and variable microbiota over time (fig. a) . patients with a more variable sputum microbiota (median weighted unifrac > . ) were more likely to have a higher relative abundance of bacillus, escherichia, lactobacillus, moraxella, and staphylococcus ( fig. and supplementary fig. ). microbiota variability in seemingly stable disease state were associated with higher exacerbation frequency and frequent viral infections (fig. b) . longitudinal sampling also enabled the assessment of recurrent viral infections by the same viral species, strain or subtype in consecutive samples. viruses were detected in to consecutive samples from patients (fig. ) . the time beween consecutive samples ranged from days to year. viruses that were detected within - weeks of sampling corresponded most probably to a typical single infection, and these included the detection of coronavirus oc , hrv a, piv , rsv a and b. viruses that were detected in the same patient over days apart may correspond to chronic or recurrent infections, with adenovirus c, coronavirus hku , hrv a, hrv b and hrv c detected. eighteen out of ( %) samples from these patients corresponded to acute exacerbation events, and / ( %) patients were frequent exacerbators (fig. ) . we sought to define common microbiota clusters and their association with clinical characteristics. microbiota in stable samples could be separated into biotypes, as indicated by the highest calinski-harabasz (ch) index following iterative partitioning-around-medoids clustering analysis over the jensen-shannon distance. betweenclass analysis showed major clusters, biotype represented by neisseria and veillonella, and biotype represented by streptococcus and rothia (fig. a) . samples with high relative abundance of streptococcus/rothia (biotype ) were found in greater proportion in usa patients, which was associated with longer history of copd and less frequent detection of viruses at stable visits (fig. a) . samples at acute exacerbation visits could be separated into biotypes, characterized by a high relative abundance of either prevotella (biotype ), streptococcus (biotype ), or haemophilus (biotype ) fig. risk factors of copd exacerbations. adjusted odds ratio of (a) viral infections (b) bacterial abundance (top/bottom quartile) and (c) demographics and clinical history features to be associated with acute exacerbation events or patients with frequent exacerbations (≥ events/ year). significance are presented in red (positive association) and green (negative association). orange dots represent non-significant odds ratio. horizontal bars represent the % confidence interval. genera names are in bold and species italicized (fig. b) . streptococcus and haemophilus were found in a majority of usa samples, and associated with longer copd duration, higher exacerbation frequency, antibiotics and corticosteroid use, but did not significantly correlate with higher viral infections (fig. b) . exacerbation follow-up samples were more diverse and could be optimally clustered into biotypes. biotype was characterized by a high relative abundance of pseudomonas and significantly associated with longer copd duration and antibiotic use. biotype was characterized by a high relative abundance of streptococcus or rothia and was significantly associated with higher exacerbation frequency. other biotypes were not significantly associated with clinical characteristics (fig. c) . biotyping shows that microbiota profile diversity is dynamically dependent on disease state. understanding of the presence and role of both bacterial and viral pathogens over time in the heterogeneous and dynamic copd disease [ ] is needed for patient treatment and management. the characterization of the s rrna gene microbiota and respiratory viruses from a longitudinal and international cohort of severe copd patients described in this study provides the largest survey to date on their complex associations with copd patients are particularly susceptible to respiratory infections [ ] . hrv was identified as the most prominent agent in respiratory tract infections in this cohort of copd patients. viral characterization is of particular importance as few reports exist on the diversity of respiratory viral agents in copd [ ] and viral diversity should be accounted for when designing new treatments. in particular, the newly described hrv c was detected in of , samples ( of patients) in the present cohort, which was reported only once previously [ ] . we detected viruses in % of stable samples. asymptomatic viral infections in copd patients are common [ ] . however, the role of these asymptomatic infections in disease progression is unclear. most respiratory viruses tested here showed highly significant positive odds ratio with exacerbation events, but lower significance in regards to exacerbation frequency. this may indicate that viral infections alone do not sensitize the lung to repeat exacerbations as much as the bacterial microbiota. interestingly, similar trends have been shown in asthma where respiratory viral infections in early life resulted in microbiome changes and hypersensitivity predisposition that can lead to asthma [ , ] . repeat viral detection were more frequent in patients with frequent exacerbator phenotype, but the number was small, and contradicting reports exist on the repeated detection of a single virus in copd [ ] . further complete viral genomic characterization will be needed to understand the nature of viral infection. with the advent of culture-independent techniques, it appears that all microbiomes harbor potential bacterial pathogens as characterized here and elsewhere [ ] , but that only a portion of them will develop exacerbation-prone phenotypes, a phenotype that appears independent of disease gold stage yet linked to microbiota diversity [ ] . it was previously observed that microbiota diversity in the copd lung correlated with disease severity but not disease state [ ] . here, microbiota diversity alone was not correlated with frequent exacerbations, but was highly correlated with certain bacterial taxa dominating the microbiota. microbiota predominant with escherichia, pseudomonas or streptococcus, showed significantly lower alpha diversity and significant positive odds ratio with the frequent exacerbation phenotype, suggesting a role of the microbiota in sensitizing the copd lung to acute exacerbations. this study was limited in disease severity metrics with the exception of baseline evaluation and sampling of events. longitudinal monitoring of symptoms scales would help to better understand the relation of certain bacteria to not only exacerbation frequency, but also the symptom severity and copd progression. the use of biotyping has been seldom used in respiratory microbiota research [ ] and not yet explored in copd. a complex resident bacterial community could be identified in all copd sputum samples and categorized into , and biotypes at stable, acute exacerbation and exacerbation follow-up visits, respectively. biotype at stable state was associated with higher viral infections, while biotypes and at acute exacerbation were associated with high exacerbation frequency. these findings are interesting because they mirror another study showing the partitioning of copd exacerbation samples into cytokine profile clusters [ ] with associations to specific ratios of proteobacteria, firmicutes and bacteroidetes that highlighted the heterogeneity of exacerbation profiles in copd patients. during exacerbation follow-up visits, biotype with a high relative abundance of pseudomonas was found over-represented in samples associated with antibiotics use. antibiotic treatment inadequacy is the cause for secondary infection or the emergence of multi-drug resistant p.aeruginosa [ ] . new targeted treatments, such as monoclonal antibodies, could be useful in such settings [ ] . the principal novelty of this study cohort was the long term patient follow-up. we were able to collect several sputum samples per patient at stable state over the course of years and studied the copd microbiota longitudinally. the lung microbiome is inherently variable, shaped by a process of inhalation and elimination [ ] . the lung microbiome is also personal, with large interpatient variability [ ] . previously, it was shown that microbial dysbiosis from stable to exacerbated state correlated with greater exacerbation severity [ ] . here, patients with greater microbiota variability at stable state correlated with higher exacerbation frequency. proteobacteria such as pseudomonas and moraxella were more abundant in patients with more variable microbiota at stable state. interestingly, p.aeruginosa and m.cattharalis are prominent causes of exacerbations [ ] , but their role in stable disease is less clear [ ] . it was previously shown that chronic colonization with p. aeruginosa occurs more frequently in more severe copd patients [ ] and that m.catarrhalis asymptomatic colonization was associated with a greater frequency of a sputum iga response than exacerbation [ ] . our results suggest that dysbiotic burden at stable state by pseudomonas, moraxella and others might sensitize the lung to further exacerbations and viral infections. pseudomonas and moraxella, like many opportunistic proteobacteria, are pro-inflammatory [ , ] . imbalanced inflammation can improve p.aeruginosa's fitness [ ] , allow the acquisition of new m.cattharalis strains [ ] , leading to exacerbation and possibly infections from other pathogens in a coupled cycle of inflammation and dysbiosis [ ] . microbiology clinical testing in copd patients is most often performed at exacerbation or follow-up visits. patients might benefit from clinical monitoring of these bacteria at stable state to assess their presence and/or growth which could lead to potential future exacerbations. we also noted geographical differences in copd lung microbiota. geographical differences in gut microbiota have previously been noted [ ] , but not yet in the lung. there were significant differences in alpha and beta diversity between the usa and europe, but not within countries or sites. microbiota diversity in the usa was lower and although frequent exacerbator phenotypes were more common than in europe, the difference was not significant. usa patients tended to have samples with high relative abundance of streptococcus (biotype ) and haemophilus (biotype ) associated with the frequent exacerbator phenotype. s.pneumoniae and h.influenzae are commonly associated with exacerbations [ ] , and should also be considered as potential risk factors in the frequent exacerbator phenotype. significantly more samples collected in the usa were associated with antibiotics use, but this alone did not explain differences in diversity. this observational study included a variety of standard-ofcare medications, doses and timings precluding precise treatment effect modeling on the microbiota. clinical trials exploring current and novel treatment modalities will lead to better patient management and antibiotics stewardship as reviewed elsewhere [ ] . predominance of haemophilus was over-represented in acute exacerbation samples (figs. and ), as noted in previous studies [ , , , , ] . however, interestingly, using odds ratio (fig. ) or ancom (suppplementary fig. a ) over haemophilus abundance, h.influenzae was high but not significantly associated with acute exacerbation event, whereas h.parainfluenzae was significantly higher at stable state. differences in haemophilus abundance compared to other studies might be due to the type of sputum collected, transportation media, extraction protocol or an effect of the sample size. although h.parainfluenzae can be the cause of respiratory infection in healthy subjects, it has not been associated with exacerbation in copd [ ] . h.parainfluenzae could compete for niche resources leading to overgrowth of the more pathogenic h.influenzae. previous work has shown that h.influenzae competes with s.pneumoniae [ ] and that patients colonized by nthi and acquiring hrv have more frequent and severe exacerbations [ ] . here, streptococcus species could not be resolved using s rrna v region, and although speciation of haemophilus was attempted, further validation using targeted pcr or whole genome sequencing will be necessary to ensure correct discrimination. to note, constant improvements in s databases can also affects taxonomic resolution. silva database [ ] version updated in classified reads into more genera (n = ) compared to greengenes version . updated in (n = ). however, bacterial taxa discussed in this study showed less than % variations in read classification between the database classifiers (data not shown), and conclusions were unchanged. speciations and typing of bacteria and viruses are critical to understanding their pathogenicity and complex relationships. greater taxonomic resolution will be achieved using updated databases and more comprehensive techniques like shotgun metagenomics. in summary, our study provides a broad survey of viruses and bacteria colonizing severe copd patients, providing clinicians with potential targets for clinical testing and patient treatment. it demonstrates that viral infections are strongly associated with acute exacerbation events, and that particular components of the microbiota are associated with higher exacerbation frequency. geographic and longitudinal differences in the lung copd microbiota exist and were correlated with exacerbation outcomes. stable state longitudinal microbiota monitoring and biotyping could lead to the identification of potential biomarkers indicative of future exacerbations from bacterial sensitization. comprehensive microbiota profiling and respiratory viral detection will be useful in the development of anti-microbial agents for therapeutic intervention or for better patient management. supplementary information accompanies this paper at https://doi.org/ . /s - - - . additional file : table s . sample characteristics. table s . statistical significance of alpha and beta microbiota diversity metrics against demographic and clinical variables using qiime 's diversity plugin. figure s . shannon diversity following antibiotic 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challenge for personalized medicine clinical and molecular epidemiology of human rhinovirus c in children and adults in hong kong reveals a possible distinct human rhinovirus c subgroup factors associated with symptomatic rhinovirus infection in patients with copd early-life respiratory viral infections, atopic sensitization, and risk of subsequent development of persistent asthma role of the airway microbiome in respiratory infections and asthma in children longitudinal profiling of the lung microbiome in the aeris study demonstrates repeatability of bacterial and eosinophilic copd exacerbations the nasopharyngeal microbiota of children with respiratory infections in botswana antibiotic treatment adequacy and death among patients with pseudomonas aeruginosa airway infection treatment efficacy of medi in pseudomonas aeruginosa blood stream infection and acute pneumonia rabbit models the role of the microbiome in exacerbations of chronic lung diseases analysis of the lung microbiome in the "healthy" smoker and in copd lung microbiology and exacerbations in copd bronchial microbiome of severe copd patients colonised by pseudomonas aeruginosa moraxella catarrhalis in chronic obstructive pulmonary disease: burden of disease and immune response inflammation: a double-edged sword in the response to pseudomonas aeruginosa infection moraxella catarrhalisacquisition, airway inflammation and protease-antiprotease balance in chronic obstructive pulmonary disease lower airway bacterial colonization patterns and species-specific interactions in chronic obstructive pulmonary disease influence of the lung microbiota dysbiosis in chronic obstructive pulmonary disease exacerbations: the controversial use of corticosteroid and antibiotic treatments and the role of eosinophils as a disease marker haemophilus influenzae and haemophilus parainfluenzae in chronic obstructive pulmonary disease inhibitory and bactericidal effects of hydrogen peroxide production by streptococcus pneumoniae on other inhabitants of the upper respiratory tract a prospective, observational cohort study of the seasonal dynamics of airway pathogens in the aetiology of exacerbations in copd the silva and "all-species living tree project (ltp)" taxonomic frameworks publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations we would like to thank the study participants and the site investigators authors' contributions mte and mpg conceived the original study cohort. jb, det, brs, hj conceived the present study design. det and jss conducted viral testing. det and at conducted a microbiota pilot study. jb and vn conducted microbiota experiments. jb performed computational and statistical analyses. jb wrote the manuscript with critical revisions from det, jss, brs and hj. all authors read and approved the final version of the manuscript. this study was fully funded by astrazeneca.availability of data and materials data underlying the findings described in this manuscript may be obtained in accordance with astrazeneca's data sharing policy described at https:// astrazenecagrouptrials.pharmacm.com/st/submission/disclosure ethics approval and consent to participate this observational study is registered under nct at clinicaltrials.gov. the protocol was approved by independent institutional review boards, and all subjects signed written informed consent at enrollment. all authors are employees and share holders of astrazeneca. key: cord- -yywxmioq authors: boixeda, ramon; rabella, nuria; sauca, goretti; delgado, maria; martínez-costa, xavier; mauri, montserrat; vicente, vanessa; palomera, elisabet; serra-prat, mateu; capdevila, josep antón title: microbiological study of patients hospitalized for acute exacerbation of chronic obstructive pulmonary disease (ae-copd) and the usefulness of analytical and clinical parameters in its identification (virae study) date: - - journal: int j chron obstruct pulmon dis doi: . /copd.s sha: doc_id: cord_uid: yywxmioq purpose: respiratory infection is the most common cause for acute exacerbation of chronic obstructive pulmonary disease (ae-copd). the aim of this work was to study the etiology of the respiratory infection in order to assess the usefulness of the clinical and analytical parameters used for copd identification. patients and methods: we included patients over a period of years. the etiology of the respiratory infection was studied by conventional sputum, paired serology tests for atypical bacteria, and viral diagnostic techniques (immunochromatography, immunofluorescence, cell culture, and molecular biology techniques). we grouped the patients into four groups based on the pathogens isolated (bacterial versus. viral, known etiology versus unknown etiology) and compared the groups. results: a pathogen was identified in patients. the pathogen was identified through sputum culture in patients, seroconversion in three patients, and a positive result from viral techniques in patients. no significant differences in identifying etiology were observed in the clinical and analytical parameters within the different groups. the most cost-effective tests were the sputum test and the polymerase chain reaction. conclusion: based on our experience, clinical and analytical parameters are not useful for the etiological identification of copd exacerbations. diagnosing copd exacerbation is difficult, with the conventional sputum test for bacterial etiology and molecular biology techniques for viral etiology providing the most profitability. further studies are necessary to identify respiratory syndromes or analytical parameters that can be used to identify the etiology of new ae-copd cases without the laborious diagnostic techniques. chronic obstructive pulmonary disease (copd) is associated with significant morbidity and mortality, with the world health organization estimating its rise from being the fifth to the third leading cause of death by . the overall prevalence of copd in spain is estimated to be . %. copd is a slow, progressive disease, with patients experiencing episodes of acute deterioration known as exacerbations, which increase in frequency and severity with disease progression. the causes of acute exacerbations of copd (ae-copd) are multifactorial. half of the ae-copd cases are attributed to respiratory infections ( %), but exacerbations are also associated with pollution, temperature changes, allergens ( %), and other comorbidities ( %) such as heart failure and pulmonary thromboembolism. in several studies, the presence of bacteria in ae-copd has been associated with purulence of the sputum and the presence of inflammatory markers. , in recent years, emerging new diagnostic techniques have revealed a relationship with respiratory viruses. [ ] [ ] [ ] [ ] in addition, the etiology of respiratory infections in ae-copd patients differs according to the geographic area. currently, ae-copd patients are treated with antibiotics as the first line of defense, depending on the severity of the copd and the severity of the exacerbation itself. with the emergence of multidrug resistance and increased economic spending on antibiotic therapy, numerous studies have assessed the benefit of antibiotic treatment, , recommending a short course of antibiotic treatment for slight exacerbations. similarly, biological markers such as procalcitonin have been proposed as markers for antibiotic administration in the ae-copd, allowing a reduction in antibiotic prescriptions. the identification of respiratory viruses as a cause for ae-copd may help reduce the use of antibiotics. therefore, it is important to find clinical and analytical parameters that could guide us in identifying the etiology of new ae-copd cases, especially considering the laborious diagnostic techniques currently used for diagnosis. the aims of our study were to identify the etiology of respiratory infections in patients hospitalized for ae-copd using different diagnostic tests and to evaluate the usefulness of the clinical and analytical parameters of the diagnostic process. we included patients who were consecutively admitted to the hospital of mataró with ae-copd between april , and march , . copd was defined according to the global initiative for chronic obstructive pulmonary disease (gold) criteria, with patients exhibiting compatible spirometry measurements and a smoking history of at least ten packs/year. a diagnosis of acute exacerbation (ae) was assumed when a minimum of two anthonisen criteria were present. any patient with copd decompensation that was caused by a noninfectious disease was excluded from the study, assuming that the selected patients presented with an upper or lower respiratory tract infection. identification was made based on the respiratory infection and dyspnea admission diagnoses from the international statistical classification of diseases, ninth revision, clinical modification (icd- -cm) , ( , , , , . , , , , . , . ), excluding the patients who had a known cause of respiratory failure that was different from infectious exacerbation (heart failure, pulmonary thromboembolism, pneumonia). finally, the patients who met the inclusion criteria and none of the exclusion criteria (severe immunosuppression, the need for mechanical ventilation or admittance to the intensive care unit, arrival from a nursing home, or a terminal stage of the disease) were asked for their informed consent. the study was approved by the consorci sanitari del maresme ethics committee of the hospital of mataró. upon admission, a complete clinical history and physical exam were performed. each patient's demographic and l ifestyle characteristics, baseline dyspnea (based on the dyspnea scale from the medical research council ), exacerbation history, history of pneumonia, and hospital admissions during the previous year were evaluated. the contact with family members at home suffering from an upper respiratory tract infection was collected. we obtained information on each patient's upper respiratory tract (nasal congestion, rhinorrhea, and sneezing), lower respiratory tract (cough and expectoration), and constitutional symptoms (dysthermia, fever, chills, asthenia, anorexia, headache, arthromyalgia, and impaired consciousness). upon admission, the severity of the exacerbation was classified (depending on the presence of respiratory failure, severe cyanosis, baseline dyspnea deterioration, the utilization of accessory muscles, the worsening of blood gas levels, and a blood ph , . ), as were the severity of copd (according to the gold criteria) and copd prognosis (according to the body mass, airflow obstruction, dyspnea, and exercise capacity [bode] multidimensional index). vital signs and anthropometric data were collected from each patient, and a chest radiograph was taken to rule out pneumonia. baseline spirometry measurements were collected, and each patient's treatment before and during hospitalization for ae-copd was recorded. submit your manuscript | www.dovepress.com a baseline blood gas reading, a complete cell blood count (cbc), and basic biochemistry readings (ast, alt, creatinine, urea, glucose, and electrolytes) were collected from each patient upon arrival to the emergency room. a routine blood analysis that included total protein and a protein profile was performed the following day. upon hospital admission, the sputum was collected upon spontaneous expectoration in a conventional manner with or without using mucolytic agents. sputa were collected before starting antibiotic treatment at the hospital. the sputa were cultured only if the quality criteria were met in a sputum gram stain (, epithelial cells and . polymorphonuclear leukocytes). sera were collected from patients at admission and weeks after the initial collection for a second paired serology. passive agglutination techniques were used to detect mycoplasma pneumoniae, and microimmunofluorescence was used to detect chlamydia species. the npl and the nasal exudate that were collected hours after admission were used for viral detection. the different techniques that were performed are detailed below. immunochromatography was used to rapidly detect antigens from influenza viruses a and b or respiratory syncytial virus (rsv). the binaxnow influenza a and b ® and binaxnow rsv ® tests (binax inc, scarborough, me) were used according to the manufacturer's instructions. immunofluorescence techniques were used to detect influenza viruses a and b, adenovirus, parainfluenza virus, and rsv. the replication of influenza viruses a and b, adenovirus, parainfluenza, rhinovirus, and rsv was detected in cell culture. we determined the presence of nucleic acids from influenza viruses a and b, rsv a and b, parainfluenza , , , and , coronaviruses e and oc , rhinovirus, and metapneumovirus. the realaccurate™ respiratory rt-pcr kit (pathofinder, maastricht, netherlands) was used for the nucleic acid and respiratory virus amplification test, and the qiaamp viral rna mini kit (qiagen iberia sl, madrid, spain) was used to extract rna from clinical samples. the realaccurate™ respiratory rt-pcr kit (pathofinder) consists of ready-to-use solutions that contain primers and taqman probes that were used in accordance with the conditions set by the manufacturer. in a control visit performed one week after admission or coinciding with hospital discharge, we recorded the evolution of the episode with regards to clinical symptoms, physical examination, and treatment. in conjunction with the earlier episode evaluation, we identified cases of treatment failure (identified as the persistence of hemodynamic alterations, respiratory failure, severe adverse effects, or a lack of treatment response). the length of hospital stay and possible complications were also included. the data were collected in a microsoft access database and analyzed using spss for windows, version . (ibm corporation, armonk, ny). the qualitative variables are expressed as counts and percentages, while the quantitative variables are expressed as means and standard deviations or interquartile range. comparisons between means were performed using the student's t-test for independent samples or the mann-whitney u test for variables that did not meet the criteria of normality. for comparisons of proportions, the chi-square or fisher's exact test was used. in all cases, we considered values of p , . to indicate significant differences. to study the relationship between the analytical and clinical parameters and the etiology of ae-copd, three groups were categorized. group contained patients for whom a virus was detected with diagnostic tests, group included the patients who exhibited the detection of bacteria only, and group contained patients with unknown etiologies. during the study period, consecutive patients were admitted to the hospital with a diagnosis of respiratory infection and dyspnea according to icd- -cm guidelines. we included patients based on the inclusion and exclusion criteria. in six patients with the clinical criteria for chronic bronchitis, spirometry was not performed in the follow-up. finally, of the remaining patients were submit your manuscript | www.dovepress.com dovepress dovepress excluded because the follow-up spirometry readings were not compatible with an infection. thus, we studied patients with ae-copd of a probable infectious origin who met the inclusion criteria and had no other causes of acute decompensation (figure ). the demographics of the patients and the baseline characteristics of ae-copd are presented in tables and . the patients were hospitalized in the following departments: internal medicine ( . %), pneumology ( . %), and the short stay unit ( . %). over the course of two years, the admissions peaks coincided with seasonal variations, exhibiting two annual peaks (spring and winter) (figure ) . a total of pathogens were isolated. of these, were bacterial and were viral. of the sputum samples surveyed, were grampositive, were gram-negative, and contained polymorphonuclear cells without bacteria. in addition, ziehl-neelsen staining was performed in samples, all of which had a negative result. the culture results were positive in patients (table ) , with higher numbers of patients exhibiting h. influenzae and p. aeruginosa. we obtained two positive serologies for mycoplasma pneumoniae ( . %) and one for chlamydia pneumoniae ( . %). an npl was collected from all patients to detect a possible viral etiology. we identified a positive result in patients and found herpes virus type- in two patients. the detection of herpes virus type- was attributed to contamination. so then, we identified a positive result from viral techniques in patients. an etiological agent was identified in of the patients ( . %), and an unknown ae-copd etiology was assigned to patients ( . %). a bacterial agent was identified as the etiological agent in patients ( ( . %), e. coli plus influenza a virus and p. aeruginosa plus coronavirus. the efficiencies of the diagnostic tests are shown in table . we compared the characteristics of the patients using bacterial and viral isolation. when we assessed the clinical and analytical parameters of ae-copd according to etiological diagnoses, no significant differences were observed, with the exception of the lymphocyte count for the patients whose ae-copd was attributed to a virus (table ) . we obtained statistically significant differences between the analytical datasets for the patients with known and unknown etiologies. in patients with an unknown etiology, we observed a greater decrease in the ph and po in the baseline arterial blood gas upon arrival at the emergency room, as well as a greater leukocytosis and increased heart rate ( table ) . the evaluation of ae-copd after a week of hospital admission revealed clinical improvement in the majority of patients ( . %). treatment failure was observed in seven patients ( . %), and no positive changes were observed in three patients ( . %). treatment failure was evidenced by the worsening of respiratory failure in three patients, severe adverse effects in two patients, and a lack of treatment response in four patients. only one patient died during hospitalization. this prospective observational study of patients admitted for ae-copd (vir-ae) included a -year follow-up period and was intended to identify the infectious etiology of copd exacerbations (whether viral or bacterial), as well as to describe the clinical features and analytical variables used to differentiate the cause of exacerbation. an infectious cause was identified in of the patients included in this study ( . %). a bacterial etiology was identified in patients, a viral infection was observed in patients, and two patients had mixed etiology. a higher sensitivity was observed with the conventional sputum analysis and the polymerase chain reaction technique (pcr) for the npl analysis. the clinical and laboratory variables that were evaluated for the diagnosis were practically the same for the bacterial and viral etiology cases, with the exception of a relative lymphocyte count that was lower in the group with viral etiology and a longer hospitalization period in patients with bacterial infections. we attributed the longer hospital stay to parenteral treatment after finding multiresistant bacteria in some patients with bacterial etiology. other studies have identified clinical symptoms such colds or a sore throat upon the isolation of rhinovirus, or even when rhinorrhea was associated with a bacterial etiology. however, we have not identified any clinical symptom as indicative of a viral etiology in this study, probably because of the sample size. we have also identified a greater involvement of baseline arterial blood gas (a decrease in ph and po ) in the group with an unknown etiology, as well as increased leukocytosis and heart rate, which could mean that a bronchospasm component contributes to the ae-copd within this group. in addition to bronchospasm, other causes of ae-copd such as heart failure or pulmonary thromboembolism were likely to be excluded from our study due to the fact that we only selected a population with a highly suspicious respiratory infection. similarly, we excluded patients coming from residential centers, patients admitted to the hospital in the days prior to their current admission, and patients transferred from the intensive care unit in order to eliminate any hospital-acquired infections. this comprehensive selection of patients may limit the external validity of our results. we observed a mean age of years (range - years) and a smoking history in all of our patients ( . % were active smokers), which is probably due to the high percentage of men in our study. the diagnosis of copd exacerbation is a matter of debate. the most frequent cause of copd exacerbation is considered to be viral or bacterial bronchial infection. this fact is based on the regular presence of purulent coughing and bacterial isolation from the cough of more than half of the patients with exacerbations. in addition, up to % of patients with stable copd had evidence of bronchial bacterial colonization in the absence of ae-epoc. however, authors such as sethi et al have demonstrated that pathogen colonization is not responsible for the exacerbation, as for haemophilus, where infection with an additional bacterial strain is necessary to elicit an exacerbation. the identification of a bacterial etiology for ae-copd is primarily obtained through the study of sputum. we obtained sputum in % of patients, which shows the difficulty of obtaining it in clinical practice. a mixed respiratory flora was obtained in % of these patients and was diagnostic in . %, with the samples exhibiting a predominance of h. influenzae and p. aeruginosa. it is important to note that our patients had severe copd exacerbations that caused respiratory failure and required hospital admission. h. influenzae and p. aeruginosa were detected mainly in the patients with severe copd, which could explain the inability to isolate bacteria such as pneumococcus and viruses, as severe copd benefits the enterobacteria and p. aeruginosa. the routine use of serology is not useful for the diagnosis of acute mycoplasma pneumoniae or chlamydia infection. from the point of view of viral etiology, pcr techniques have been performed on the bronchial exudate of copd streptococcus pneumoniae ----- haemophilus influenza ----- moraxella catarrhalis ----- pseudomonas aeruginosa respiratory syncytial virus -- in our study, the result was lower, as we detected a virus in % of all the ae-copd cases, with little evidence of influenza virus in our sample. this could be explained due to the fact that an influenza epidemic was not identified during the study period. the discrepancies between our data and the data from other studies could also be explained by the different samples and techniques used. for example, higher percentage were obtained of sputum samples than npl samples ( % and %, respectively). in reference to the literature, we probably could have obtained better results by analyzing the sputum rather than obtaining the npl for virological diagnostic techniques. even so, based on the results obtained, we can state that viral infections could be the cause of ae-copd. we should have this in mind at the time of prescribing antibiotics, especially in a slightly sick patient who presents no purulent sputum. viral disease has a seasonal distribution, and therefore, efforts to confirm the diagnosis in routine clinical practice notes: data are expressed as number (%) unless otherwise indicated. *we compared the patients with known diagnostic ( as bacterial, as viral, as mixed viral and bacterial, and as mycobacterium spp.) and unknown diagnostic. abbreviations: ae-copd, acute chronic obstructive pulmonary disease exacerbation; crp, c-reactive protein; nat, nucleic acid amplification test; paco , partial pressure of carbon dioxide; po , partial pressure of oxygen; post-bd fev , post-bronchodilator forced expiratory volume in the first second; sato , saturated oxygen; sd, standard deviation; u/l, units per litre. submit your manuscript | www.dovepress.com dovepress dovepress are to be reserved for situations in which viruses are present in the community; otherwise, this diagnosis could lead to a significant economic cost. rapid viral antigen detection with immunochromatography tests has a low diagnostic sensitivity, is not very useful, and is too expensive to be used in nonepidemic situations. in conclusion, we stress that differentiating the etiology of ae-copd on the basis of clinical and laboratory data is difficult in common clinical practice. in our experience, the most profitable diagnostic tests to identify the possible cause of the acute decompensation of a patient with copd are the conventional sputum test for bacteria and molecular biology techniques for viruses. prevalence of copd in spain: impact of undiagnosed copd on quality of life and daily life activities toward a consensus definition for copd exacerbations outcomes following acute exacerbation of severe chronic obstructive pulmonary disease exacerbations of chronic obstructive pulmonary disease: when are bacteria important? bacterial infection in chronic obstructive pulmonary disease. a study of stable and exacerbated outpatients using the protected specimen brush respiratory viral infections in adults with and without chronic obstructive pulmonary disease respiratory viruses, symptoms, and inflammatory markers in acute exacerbations and stable chronic obstructive pulmonary disease respiratory viruses in exacerbations of chronic obstructive pulmonary disease requiring hospitalisation: a case-control study infections and airway inflammation in chronic obstructive pulmonary disease severe exacerbations prevalence of viral infection detected by pcr and rt-pcr in patients with acute exacerbation of copd: a systematic review diagnosis and management of chronic obstructive pulmonary disease: joint guidelines of the spanish society of pulmonology and thoracic surgery (separ) and the latin antibiotics in chronic obstructive pulmonary disease exacerbations. a meta-analysis antibiotics for exacerbations of chronic obstructive pulmonary disease short-course antibiotic treatment in acute exacerbations of chronic bronchitis and copd: a meta-analysis of double-blind studies antibiotic treatment of exacerbations of copd: a randomized, controlled trial comparing procalcitonin-guidance with standard therapy the global initiative for obstructive lung disease home page antibiotic therapy in exacerbations of chronic obstructive pulmonary disease catàleg de diagnòstics i procediments positive predictive value of icd- -cm codes to detect acute exacerbation of copd in the emergency department usefulness of the medical research council (mrc) dyspnoea scale as a measure of disability in patients with chronic obstructive pulmonary disease the body-mass index, airflow obstruction, dyspnea, and exercise capacity index in chronic obstructive pulmonary disease microscopic and bacteriologic analysis of expectorated sputum identifying viral infections in vaccinated chronic obstructive pulmonary disease (copd) patients using clinical features and inflammatory markers bacteria and exacerbations of chronic obstructive pulmonary disease chronic obstructive pulmonary disease. : the aetiology of exacerbations of chronic obstructive pulmonary disease new strains of bacteria and exacerbations of chronic obstructive pulmonary disease detection of rhinovirus in induced sputum at exacerbation of chronic obstructive pulmonary disease system of influenza surveillance in spain low sensitivity of rapid diagnostic test for influenza the authors report no conflicts of interest in this work. this project was funded by a mataró tv foundation grant ( ).our thanks to the pneumology department of the hospital de mataró for its assistance with this research and agustí viladot for the bibliographic revision. submit your manuscript here: http://www.dovepress.com/international-journal-of-copd-journalthe international journal of copd is an international, peer-reviewed journal of therapeutics and pharmacology focusing on concise rapid reporting of clinical studies and reviews in copd. special focus is given to the pathophysiological processes underlying the disease, intervention programs, patient focused education, and self management protocols.this journal is indexed on pubmed central, medline and cas. the manuscript management system is completely online and includes a very quick and fair peer-review system, which is all easy to use. visit http://www.dovepress.com/testimonials.php to read real quotes from published authors. key: cord- - mk h qf authors: takamoto, hiroki; nishine, hiroki; sato, shohei; sun, guanghao; watanabe, sadao; seokjin, kim; asai, masahito; mineshita, masamichi; matsui, takemi title: development and clinical application of a novel non-contact early airflow limitation screening system using an infrared time-of-flight depth image sensor date: - - journal: front physiol doi: . /fphys. . sha: doc_id: cord_uid: mk h qf obstructive pulmonary diseases, such as diffuse panbronchiolitis (dpb), asthma, chronic obstructive pulmonary disease (copd), and asthma copd overlap syndrome (acos) trigger a severe reaction at some situations. detecting early airflow limitation caused by diseases above is critical to stop the progression. thus, there is a need for tools to enable self-screening of early airflow limitation at home. here, we developed a novel non-contact early airflow limitation screening system (eafl-ss) that does not require calibration to the individual by a spirometer. the system is based on an infrared time-of-flight (tof) depth image sensor, which is integrated into several smartphones for photography focusing or augmented reality. the eafl-ss comprised an nm infrared tof depth image sensor ( × pixels) and custom-built data processing algorithms to visualize anterior-thorax three-dimensional motions in real-time. multiple linear regression analysis was used to determine the amount of air compulsorily exhaled after maximal inspiration (referred to as the forced vital capacity, fvc(eafl)(–ss)) from the tof-derived anterior-thorax forced vital capacity (fvc), height, and body mass index as explanatory variables and spirometer-derived fvc as the objective variable. the non-contact measurement is automatically started when an examinee is sitting cm away from the eafl-ss. a clinical test was conducted with copd patients ( / m/f, – years) as typical airflow limitation cases recruited at st. marianna university hospital and healthy volunteers ( / m/f, – years). the eafl-ss was used to monitor the respiration of examinees during forced exhalation while sitting still, and a spirometer was used simultaneously as a reference. the forced expiratory volume in s (fev %(eafl)(–ss)) was evaluated as a percentage of the fvc(eafl)(–ss), where values less than % indicated suspected airflow limitation. leave-one-out cross-validation analysis revealed that this system provided % sensitivity and % specificity. further, the fev (eafl)(–ss) values were closely correlated with that measured using a spirometer (r = . , p < . ). hence, eafl-ss appears promising for early airflow limitation screening at home. obstructive pulmonary diseases, such as diffuse panbronchiolitis (dpb), asthma, chronic obstructive pulmonary disease (copd), and asthma copd overlap syndrome (acos) trigger a severe reaction at some situations. detecting early airflow limitation caused by diseases above is critical to stop the progression. thus, there is a need for tools to enable self-screening of early airflow limitation at home. here, we developed a novel non-contact early airflow limitation screening system (eafl-ss) that does not require calibration to the individual by a spirometer. the system is based on an infrared time-of-flight (tof) depth image sensor, which is integrated into several smartphones for photography focusing or augmented reality. the eafl-ss comprised an nm infrared tof depth image sensor ( × pixels) and custom-built data processing algorithms to visualize anterior-thorax three-dimensional motions in real-time. multiple linear regression analysis was used to determine the amount of air compulsorily exhaled after maximal inspiration (referred to as the forced vital capacity, fvc eafl−ss ) from the tof-derived anterior-thorax forced vital capacity (fvc), height, and body mass index as explanatory variables and spirometer-derived fvc as the objective variable. the non-contact measurement is automatically started when an examinee is sitting cm away from the eafl-ss. a clinical test was conducted with copd patients ( / m/f, - years) as typical airflow limitation cases recruited at st. marianna university hospital and healthy volunteers ( / m/f, - years). the eafl-ss was used to monitor the respiration of examinees during forced exhalation while sitting still, and a spirometer was used simultaneously as a reference. the forced expiratory volume in s (fev % eafl−ss ) was evaluated as a percentage of the fvc eafl−ss , where values less than % indicated suspected airflow limitation. leave-one-out cross-validation analysis revealed that this system provided % sensitivity and % specificity. further, the fev eafl−ss values were closely correlated with that measured using a spirometer (r = . , p < . ). hence, eafl-ss appears promising for early airflow limitation screening at home. diffuse panbronchiolitis (dpb), asthma, chronic obstructive pulmonary disease (copd), and asthma copd overlap syndrome (acos), all known as typical obstructive pulmonary diseases, trigger a severe reaction including death for some situations (laucho-contreras et al., ) . spirometry is useful for early detection of these diseases with airflow limitation, although it is not designed for home-use. early airflow limitation detections are critical to stop the disease progression. here, we developed a novel home-use non-contact early airflow limitation screening system (eafl-ss) using an infrared timeof-flight (tof) depth image sensor (integrated into several smartphones) that does not require calibration to the individual by a spirometer. idiopathic inflammatory becomes a cause of dpb, which is frequently found in east asia. dpb is a disease associated with respiratory bronchioles (akaba et al., ) . respiratory bronchioles without treatment in early stage causes severe obstructive respiratory disorder, bronchiectasis, and death. asthma is a syndrome of lung dysfunction involving airflow obstruction. the decrease of expiratory volume in s (fev ) is observed in patients with asthma. while, the number of deaths from copd is increasing worldwide, and more than % of copd-related deaths occur in low-and middle-income countries (world health organization [who], ). patients with severe copd require home oxygen therapy, which drastically degrades their quality of life. copd is characterized by a persistent airflow limitation that is usually progressive. early intervention, such as smoking cessation, it is particularly important to change the natural history of copd. however, the noticeable symptoms (cough, sputum, and dyspnea) are not common in the early stages of copd. thus, early detection is crucial to effectively prevent the progression of copd. in physiologically point of view, copd is diagnosed by the fev /forced vital capacity (fvc) ratio (the global initiative for chronic obstructive lung disease [gold], ). as for covid- hospitalized patients, copd is the second risk factor (next to malignant tumor) of reaching to the composite end points (admission to intensive care unit, invasive ventilation, or death) (guan et al., ) . spirometric measurements, especially the forced expiratory volume in s evaluated as a percentage of the forced vital capacity (fev %), are the gold standard in airflow limitation screening and fev % values less than % indicate suspected airflow limitation. however, a conventional spirometer with a disposable mouthpiece can only be utilized for early airflow limitation screening with the help of a healthcare professional. we have previously developed various medical screening systems, including respiratory measurement devices, such as a household-use major depressive disorder screening system and infection screening systems, including a pediatric pneumonia monitor using a doppler radar that determines a respiratory curve and estimates the respiration rate (matsui et al., ; sun et al., sun et al., , sun et al., , dagdanpurev et al., dagdanpurev et al., , . a noncontact respiratory monitoring method using a fiber-grating vision sensor has been developed to evaluate the pulmonary functions of patients with airflow limitation (tsujimura et al., ) . this method successfully determined tidal volume with precision equivalent to that of a spirometer. however, this method requires several laser markers projected on the chest wall and related large-scale equipment. soleimani et al. ( ) achieved accurate lung function measurement using a depth image sensor, but the proposed method required preliminary calibration using a spirometer for every new examinee. to facilitate screening for airflow limitation at home without the help of healthcare professionals, we developed a novel noncontact eafl-ss that does not require initial calibration. it relies only on an infrared tof depth image sensor, which is integrated into several types of smartphones. the eafl-ss monitors the three-dimensional ( d) motions of the anterior-thorax region of an examinee in real-time and derives a respiratory volume curve using multiple linear regression analysis (figure ) . in contrast to the fiber-grating vision sensor, the tof depth image sensor of the eafl-ss is small ( . cm × . cm × . cm) and does not require any markers on the chest wall. furthermore, unlike the system developed by soleimani et al. ( ) the eafl-ss does not require calibration to the individual using a spirometer. instead, a multiple linear regression analysis was used to achieve early airflow limitation screening without calibration to the individual by deriving a volume curve from the d motion of the anterior thorax measured by the tof depth image sensor and the examinee's somatotypes [including height and body mass index (bmi)]. in addition, the distance from the eafl-ss to the examinee was confirmed automatically to allow the accurate determination of a volume curve without calibration to figure | exterior design of the early airflow limitation screening system (eafl-ss), which includes an nm infrared time-of-flight (tof) depth image sensor for three-dimensional anterior-thorax motion measurement and an lcd display to provide instructions to the user. the individual. a liquid crystal display (lcd) is used to direct the examinee to sit in an upright position, and the contact-free measurement is automatically started when an examinee is sitting cm away from the eafl-ss. here, we report the development and clinical testing of the eafl-ss with copd patients as typical airflow limitation cases and healthy subjects. the results were evaluated via leave-one-out cross-validation analysis (loocv). an eafl-ss prototype is shown in figure . the prototype comprises a tof depth image sensor, an -inch lcd, and a built-in personal computer. the tof depth image sensor (camboard pico flexx, from pmd technologies ag, siegen, germany), with built-in nm infrared illumination of , ( longitudinal × lateral pixels), a viewing angle of • in the longitudinal direction by • in the lateral direction, and depth resolution of mm) is mounted at the center of a funnellike indent in the eafl-ss and perpendicular to the ground (figure ) . the tof depth image sensor monitors the motion of the anterior thorax of an examinee in real-time by measuring the respective round-trip times of nm infrared light reflected from the anterior-thorax region in each of the , pixels. the depth data determined by the infrared light flight time at each pixel is then transferred to the built-in personal computer via usb . at a frame rate of hz. the data processing algorithm of the eafl-ss is outlined in figure . the eafl-ss instructs the examinee via the lcd to sit cm away from the device. the eafl-ss automatically begins capturing d depth images of the examinee's anterior thorax when the tof depth image sensor senses that the examinee is in the correct sitting position. an automatic chest bounding box detection algorithm (ostadabbas et al., ) was used to extract the thorax region in the captured images (figure ) . the anterior-thorax depth image was binarized to eliminate background and other points more than cm away from the initial sitting position. then, the thorax region in the captured images was determined by removing the non-thorax region (i.e., neck and head) using this algorithm. the sampling and figure | data processing algorithms incorporated in the eafl-ss. the system automatically creates a three-dimensional moving image of the examinee's anterior thorax to derive a respiratory curve corresponding to the extracted anterior-thorax region of interest (roi). analysis software was written using labview, a graphical block diagram programming language (national instruments, austin, tx, united states). the eafl-ss measures the d movement of the anterior thorax using a tof depth image sensor (figures , ) . because the depth image sensor of the eafl-ss is mounted in front of an examinee, it cannot measure the posterior-thorax motions. hence, to estimate the forced vital capacity (fvc eafl−ss) using a single tof depth image sensor, multiple linear regression analysis was conducted to determine fvc eafl−ss from the fvc anterior−thorax derived from the tof depth image sensor, somatotype data (i.e., height and bmi) as explanatory variables and the spirometerderived fvc spirometer as the objective variable: ( ) thus, the eafl-ss-derived volume curve, volume(t) eafl−ss , was determined by multiplying the anterior-thorax volume curve by the fvc eafl−ss /fvc anterior−thorax ratio (figure ) . then, loocv analysis was used to evaluate the eafl-ss performance without initial calibration. the area of each pixel is determined by its distance from the eafl-ss. thus, the d anterior image was reconstructed after area correction of each pixel using the following equation: where s ij is the pixel area of the tof depth image sensor ( ≤ i ≤ , ≤ j ≤ ), and d ij is the distance between the eafl-ss and the thorax surface corresponding to each pixel; • and • are the vertical and horizontal solid angles (transverse area at a distance), respectively. a gaussian filter ( × ) was adopted to remove the high-frequency components of artifacts. the d anterior-thorax image shows alteration, which is synchronous with the timing of exhalation ( figure a ) and inhalation ( figure b) . where z ij (t) is the change in distance from the tof depth image sensor for a specific pixel (i, j) during a sampling duration of . ms (i.e., one sample at a sampling rate of hz), and roi ij is when s ij is included within the roi and when s ij is beyond the roi. the volume anterior−thorax (t) of a healthy examinee is shown in figure . fvc anterior−thorax (eq. ) corresponding to effort respiration is determined from the peak-to-peak amplitude of the volume anterior−thorax (t). each examinee was requested to make an effort to inhale and exhale without moving his or her body. the eafl-ss can measure anterior-thorax movement through light clothing, such as t-shirt, polo shirt and blouse, but participants were asked to remove any thick clothing (such as coats or sweaters). using the eafl-ss and a spirometer (chestgraph hi- , chest m.i., inc., tokyo, japan) as a reference simultaneously, the following respiratory parameters were determined: the forced expiratory volume in s (fev eafl−ss , fev spiriometer ), which is an important parameter to determine the severity of airflow limitation, the amount of compulsorily exhaled air amount after maximal inspiration, (fvc eafl−ss , fvc spirometer ), which is referred as the fvc, and the fev value as a percentage of the fvc value (fev . % eafl−ss , fev . % spirometer ), which is an indicator of airflow limitation if it is less than %. to evaluate these respiratory indices without initial calibration, loocv analysis was conducted. the height and bmi of each examinee were recorded. measurements for patients and healthy volunteers were conducted by a pulmonologist based on the ats/ers guideline. make were requested to sit on a chair cm away from the eafl-ss. the eafl-ss automatically initiated the measurement when the examinee sat down cm away from the sensor. after three normal respirations, the examinee was asked to make an effort to inhale and exhale without moving his or her body. the measurement time was s. a spirometer as a reference was used simultaneously at the same time as eafl-ss measurement. all measurements were conducted in sitting position. the eafl-ss-derived volume curve, volume eafl−ss (t), was determined by multiplying the y-axis of anteriorthorax volume curve by the ratio fvc eafl−ss/ fvc anterior−thorax (figure ) . volume eafl−ss (t) and the respiratory curve measured by the spirometer, volume spirometer (t), as a reference are shown in figure . the changes observed in the noncontact-derived volume curve (volume eafl−ss (t)) were similar to those in the contact-derived volume curve (volume spirometer (t)). to enhance the utility of the eafl-ss, it needs to be effective without preliminary calibration using a spirometer before every measurement. therefore, we adopted loocv analysis to determine the fev eafl−ss , fvc eafl−ss , and fev . % eafl−ss of each examinee without using his or her spirometry results. loocv analysis was previously used in our small-scale study to evaluate a respiratory-related infection screening system (yao et al., ) . fev eafl−ss , the index to determine airflow limitation severity, and fvc eafl−ss were significantly correlated with fev spirometer (figure a ) and fvc spirometer (figure b) , respectively (fev eafl−ss : r = . , p < . ; fvc eafl−ss: r = . , p < . ). fev . % eafl−ss can be used to determine airflow limitation: airflow limitation is suspected when fev . % eafl−ss is less than %. fev . % eafl−ss was significantly correlated with fev . % spirometer (r = . , p < . ), as shown in figure c ). the similarities of bland and altman plots (fev , fvc, and fev . %) between first and second measurements revealed the repeatability of measurements (figures a-c) . features of patients with airflow limitation and healthy volunteers are shown in table . using fev . % eafl−ss , eafl-ss achieved % sensitivity and % specificity (figure ) . receiver operating characteristic (roc) curve is shown in figure . early airflow limitation screening system achieved % sensitivity and % specificity in airflow limitation screening. the proposed system succeeded to measure fev % (fev /fvc) and fev without touching examinees using only tof depth image sensor without conducting preliminary calibration via a spirometer. fev % and fev are two dominant parameters to determine airflow limitations induced by asthma, copd, and acos. "fev % < %" is an indicator of asthma, although it may improve spontaneously or by treatment. this value is also required for copd diagnosis and is usually presented in acos patients. "fev < % predicted" is compatible with asthma diagnosis and is an indicator of severity and future events including death for copd and acos patients. the predicted values for fev are calculated from age, race, height, and gender for healthy people (the global initiative for chronic obstructive lung disease [gold], ) . chronic obstructive pulmonary disease, one of obstructive pulmonary disease, which is frequently induced by chronic smoking, is the third leading cause of death in the world (world health organization [who], ) . it is important to screen for copd to diagnose it at an early stage and to recommend changes in daily habits to copd patients. copd treatment is mainly treated only after it becomes figure | fev . % eafl−ss values observed in patients with airflow limitation and healthy volunteers (eafl-ss determines an examinee to have airflow limitation when fev . % eafl−ss is less than %). symptomatic, but a standard therapy has not been established. therefore, early airflow limitation screening is important to inform recommendations to people with the disease to improve their daily habits. eafl-ss appears promising for early at-home detection of airflow limitation induced by early stage mild copd but not severe copd. soleimani et al. ( ) achieved accurate fev and fvc measurements using a depth image sensor. however, that method required preliminary calibration using a spirometer for each new examinee. in contrast, the eafl-ss successfully estimated the fev and fvc without calibration by using an equation derived from multiple linear regression analysis with explanatory variables (i.e., combinations of somatotype parameters (height and bmi) and fvc anterior−thorax derived from the d thorax tof motion image). loocv analysis revealed that the eafl-ss can be used to accurately determine the fev and fvc without initial calibration using a spirometer. in recent years, tof depth image sensors have been built into several types of smartphones. therefore, a smartphone loaded with the eafl-ss data processing algorithm can be used as a portable eafl-ss for personal use at home, for home care, and during sick visits. early airflow limitation screening system automatically creates a d anterior-thorax motion image (figure ) . one of the co-authors of this study, mineshita, reported that unilateral bronchial obstruction can be diagnosed and assessed based on the asynchrony in airflow between the left and right lungs, which is induced by a unilateral obstruction ( ). thus, eafl-ss has the potential to be used to diagnose unilateral lung obstruction by creating d asymmetric left and right thorax motion images. a conventional spirometer cannot be used for this purpose (mineshita et al., ) . a limitation of the present study is the small sample size of patients and healthy volunteers. therefore, future studies should involve more participants to further validate the accuracy of the fev -derived airflow limitation severity screening. the preliminary results of this study indicate our system to be a promising device for early airflow limitation screening either at home or in the workplace without the need for initial calibration. all datasets presented in this study are included in the article/supplementary material. the study was approved by tokyo metropolitan university hino campus ethics committee ht and tm designed the research and wrote the manuscript. ks and sw contributed to exterior design and development of system. hn and mm supervised the medical aspects of respiratory measurements and performed clinical testing. gs, ss, and ma contributed to the signal processing and image processing methods. all authors reviewed the manuscript. this study received funding from huawei innovation research program. the funder was not involved in the study design, collection, analysis, interpretation of data, the writing of this article or the decision to submit it for publication. the supplementary material for this article can be found online at: https://www.frontiersin.org/articles/ . /fphys. . /full#supplementary-material video s | anterior-thorax three dimensional moving image of a healthy volunteer captured by infrared time of flight (tof) depth image sensor. video s | the flow of data processing. depth image ⇒ anterior-thorax three dimensional moving image ⇒ respiration curve corresponding to anterior-thorax. frontiers in physiology | www.frontiersin.org coexistence of diffuse panbronchiolitis and sarcoidosis revealed during splenectomy: a case report a novel machine-learning-based infection screening system via - seasonal influenza patients' vital signs as training datasets development and clinical application of a novel autonomic transient response-based screening system for major depressive disorder using a fingertip photoplethysmographic sensor diagnosis of disease of chronic airflow limitation, asthma, copd, and asthma-copd overlap syndrome global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease china medical treatment expert group for covid- . comorbidity and its impact on patients with covid- in china: a nationwide analysis asthma copd overlap syndrome: an approach to a real -world endotype in obstructive lung disease a novel screening method for influenza patients using a newly developed noncontact screening system left and right lung asynchrony as a physiological indicator for unilateral bronchial obstruction in interventional bronchoscopy a vision-based respiration monitoring system for passive airway resistance estimation remote, depth-based lung function assessment clinical evaluation of the newly developed infectious disease/fever screening radar system using the neural network and fuzzy grouping method for travellers with suspected infectious diseases at narita international airport clinic an infectious disease/fever screening radar system which stratifies higher-risk patients within ten seconds using a neural network and the fuzzy grouping method an objective screening method for major depressive disorder using logistic regression analysis of heart rate variability data obtained in a mental task paradigm evaluation of a new fiber-grating vision sensor for assessing pulmonary functions in healthy and copd subjects multiple vital-sign-based infection screening outperforms thermography independent of the classification algorithm key: cord- -ygfnkgqp authors: fujita, yu; takeshita, fumitaka; kuwano, kazuyoshi; ochiya, takahiro title: rnai therapeutic platforms for lung diseases date: - - journal: pharmaceuticals (basel) doi: . /ph sha: doc_id: cord_uid: ygfnkgqp rna interference (rnai) is rapidly becoming an important method for analyzing gene functions in many eukaryotes and holds promise for the development of therapeutic gene silencing. the induction of rnai relies on small silencing rnas, which affect specific messenger rna (mrna) degradation. two types of small rna molecules, i.e. small interfering rnas (sirnas) and micrornas (mirnas), are central to rnai. drug discovery studies and novel treatments of sirnas are currently targeting a wide range of diseases, including various viral infections and cancers. lung diseases in general are attractive targets for sirna therapeutics because of their lethality and prevalence. in addition, the lung is anatomically accessible to therapeutic agents via the intrapulmonary route. recently, increasing evidence indicates that mirnas play an important role in lung abnormalities, such as inflammation and oncogenesis. therefore, mirnas are being targeted for therapeutic purposes. in this review, we present strategies for rnai delivery and discuss the current state-of-the-art rnai-based therapeutics for various lung diseases. traditional surgery, bivas-benita et al. reported that no mortality occurred as a result of the use of the endotracheal technique. endotracheal applications are currently being used by many practitioners in the pulmonary field [ , ] ; this is useful for studying pulmonary drug delivery in mice. however, the approach is more complex in humans because an artificial path for the delivery of drugs into the lungs is used. therefore, the method is being used in animal models to test and evaluate its reliability for possible clinical applications. intratracheal route: under anesthesia, the trachea is exposed surgically, and a tube or needle is inserted through an incision made between the tracheal rings. complications, such as vascular injury and air leakage, are possible due to the tracheotomy. (b) endotracheal route: sirnas are sprayed directly from the mouth into the lungs using a microsprayer ® aerolizer (penn-century, philadelphia, pa, usa) and a laryngoscope. it is important to maintain a clear view of the trachea during the procedure. intranasal delivery is another common method of pulmonary drug application in animal studies. in many studies, in vivo success has been demonstrated in delivering sirnas to the lungs intranasally [ , , ]. an experimental setup of intranasal delivery by spray or droplet is simple and painless for the animal. although the success in delivering sirnas intranasally in rodents cannot be completely extrapolated to human use because of the significant differences in lung anatomy [ ] , this approach has potential for the clinical application of sirnas. phase ii clinical trials have been initiated for the treatment of respiratory syncytial virus (rsv) infection, making use of intranasal application of naked chemically modified sirna molecules that target viral gene products [ , ] (see section . . . for details). intranasal entry has long been used to administer small molecules, such as proteins, for systemic delivery. because the nasal mucosa is highly vascularized, delivery of a thin epithelium of medication across the surface area can result in rapid absorption of the medication into the blood. therefore, sirnas administered intranasally might be deposited in the nose, and some of them may be unable to reach the lower respiratory tract. in fact, it has been reported that intranasal application of unformulated sirnas resulted in lower delivery efficiency and homogeneous pulmonary distribution than that achieved with intratracheal application [ ] . the intranasal method is suitable for some lung diseases, such as upper respiratory infection by rsv, and it also has potential for systemic delivery rather than pulmonary delivery of sirnas. therefore, it is important to consider the route of administration in animal studies when assessing the delivery and therapeutic efficacy of a formulation for pulmonary delivery. careful choice of efficient delivery in response to the condition of lung diseases is necessary. the use of aerosols to deliver medication to the lungs has a long history. administration by inhalation is a popular and non-invasive method of delivering agents into the lungs. there are several inhalation devices available for the delivery of drugs into the lungs. metered dose inhalers (mdis) and dry powder inhalers (dpis) are the most common modes of inhaled delivery. mdis are the most commonly used inhalers for several lung diseases, such as asthma, bronchitis, and chronic obstructive pulmonary disease (copd), and a spacer is an external device that is attached to an mdi to allow for better drug delivery by enhanced actuation and inhalation coordination. for most mdis, the propellant is one or more gases called chlorofluorocarbons (cfcs). although cfcs in drugs are safe for patients to inhale, they are harmful to the environment. therefore, further development of inhalable sirnas may not be the best way forward. dpis are devices that deliver medication to the lungs in the form of dry powder. the use of dpis has already shown promise for the in vivo delivery of therapeutic macromolecules such as insulin [ ] and low-molecular-weight heparin [ ] ; thus, it could be a better device for delivering sirnas to the lungs. the advantages of dpis are improved stability and sterility of biomolecules over liquid aerosols and propellant-free formation. although drugs are commonly delivered to the lungs by inhalation, most in vivo studies using sirnas have relied on intratracheal or intranasal delivery. the reason could be the difficulty in formulating inhalable sirnas and maintaining the stability during the delivery process. a suitable carrier is also needed to protect nucleic acids from degradation due to shear force and increased temperature during the drying process. the use of spray-drying as a technique for engineering dry powder formulations of sirna nanoparticles, which might enable the local delivery of biologically active sirna directly to the lung tissue, has been demonstrated [ , ] . in the future, the technique is desirable to estimate the in vivo study on sirna therapy for inhalation. in the long term, we anticipate that there will be more sophisticated devices for clinical use and that those currently being developed will be more suitable. there are two main barriers to efficient pulmonary sirna delivery to the cells of the lung. the first is the complex, branched anatomy of the lungs and biomechanical barriers, such as the mucus layer covering the airway cells [ , ] (figure ) . a remarkable feature of the respiratory tract is its high degree of branching. airway consists of respiratory bronchioles, alveolar ducts, and alveolar sacs. all of these structures bear alveoli, the tiny air sacs in which the gas exchange takes place. it is generally acknowledged that the critical factor for efficient sirna delivery depends on the properties of rnai drug particles in terms of size, charge, shape, velocity and density. for efficient pulmonary sirna delivery, the particles must be deposited in the lower respiratory tract. deposition in the airway is affected by the particle size and patient's pulmonary function. a particle size between - μm is found to be the most appropriate for deposition at the lower respiratory tract [ ] . in addition, the presence of mucus and surfactant proteins, the mucociliary clearance actions, and phagocytosis by macrophages present major barriers to targeted pulmonary delivery. therefore, delivery systems usually require delivery vectors, and these vectors need to be designed in order to maximize the sirna deposition to the diseased area of the respiratory tract. besides, the extracellular barriers to sirna delivery also depend on physiological features of the respiratory tract, which may change with the disease stage and characteristics of the patient. at the active stage of lung disease, the physiological conditions of the airways might change and have significant impact on the efficiency of the pulmonary delivery system. during infection, inflammation, and allergic reaction, there is an increase in mucus secretion along with the impaired mucociliary clearance [ ] . moreover, asthma and copd are both chronic inflammatory conditions of the lung associated with structural "remodeling" that is inappropriate to the maintenance of normal lung function [ ] . the airway wall thickness, the high viscosity, and the composition of the mucus layer might be altered in patients who have inflammatory lung diseases. figure . extracellular barriers to pulmonary sirna delivery. the anatomical feature of the respiratory tract is its high degree of branching. the mucus lines the respiratory epithelium from the nasal cavity to the terminal bronchioles. the deposited particles on the ciliated epithelial cells are rapidly cleared by the mucociliary clearance actions. mucus and mucociliary clearance of mucus-trapped particles is a pulmonary defense mechanism as a physiological barrier. in the alveolar, clara cells and type ii alveolar cells secrete on the surface of the alveolar epithelium, forming a thin layer of pulmonary surfactants. the surfactants act as the main barrier for sirna delivery because they reduce the transfection efficiency. in addition, the macrophages located in the alveoli rapidly engulf the foreign particles by phagocytosis. the particles taken up into the macrophages are subsequently degraded inside the cells. these factors present major barriers to targeted pulmonary delivery. the second is the airway cell membrance and its intracellular barriers ( figure ). for efficient gene silencing in the lungs, sirnas must be delivered to their site of action, be stable, enter the target cells, and be present in the cytoplasm at sufficient concentration. once the sirnas reach the target cells, they must be trafficked into the cytoplasm and taken up by argonaute (ago) /rna-induced silencing complex (risc), which degrades mrnas and, subsequently, suppresses the sequence-specific gene expression. for efficient endocytosis to occur, particles should be under nm in size. particles within this size range could also avoid macrophage uptake and delayed lung clearance [ ] . the physicochemical properties of sirnas also play a significant role in crossing the biological membrane. despite their small size, the negative charge and chemical degradability of sirna molecules prevent them from readily crossing biological membranes. therefore, efficient sirna delivery approaches need to overcome this limitation by facilitating cellular uptake. one of the main functions of a delivery vector is to facilitate the cellular uptake of sirnas [ ] . the electrostatic complexation of sirna molecules with cationic lipids and polymers helps to mask their net negative charge. the positively charged sirna carrier complex interacts with anionic proteoglycans on the cell membrance, forms an endocytic vesicle, and enters the cells by endocytosis [ ] . after cellular internalization, the sirna carrier complex in endocytic vesicles is transported along microtubules to lysosomes that are co-localized with the microtubule-organizing center. to avoid lysosomal degradation, sirnas must escape from the endosome into the cytoplasm, where they can associate with the rnai machinery. endosomal escape is a major barrier for efficient sirna delivery [ , ] . the endosomal entrapment and lysosomal degradation of sirna and carriers contribute to the low transfection efficiency and is a major difficulty for delivery vectors. an ideal delivery agent should protect sirnas from enzymatic degradation, facilitate cellular uptake, and promote endosomal escape inside the cells with negligible toxicity. multiple approaches for the delivery of sirnas have been reported, ranging from the relatively simple direct administration of saline-formulated sirnas to lipid-based and polymer-based nanoparticle approaches and sirna conjugation and complexation approaches [ ] . the negative charge and chemical degradability of sirnas under physiologically relevant conditions make its delivery a major challenge. accordingly, the delivery of sirnas usually requires a vector or carriers for their transfection into the target cells. in general, both viral and non-viral vectors are being assessed for sirna delivery to lung cells. some viral vectors, such as retroviruses and adenoviruses, have been demonstrated to mediate gene silencing in an in vitro lung model [ ] and to induce rnai in a range of animal tissues [ ] . recently, guo et al. showed that lentivirus-mediated sirna was used to specifically knock down the expression of nuclear protein (nupr ) in vivo, which resulted in inhibited tumor growth [ ] . however, viral-based delivery has several disadvantages. the immune response to viruses not only impedes gene delivery but also has the potential to cause severe complications [ ] . recent well-documented cases, such as the death of jesse gelsinger due to complications related with an adenoviral delivery vector, highlight this problem [ ] . in addition, some viral vectors may insert their genome at random positions in the host chromosome, which eventually restrict the gene function [ ] . . intracellular barriers to pulmonary sirna delivery. barriers to cellular internalization are dependent on the surface properties of sirna and carriers (e.g., charge and size). after sirnas are successfully taken into the target cells by endocytosis, the main barriers for delivering sirnas to its site of action are the endosomal entrapment and lysosomal degradation of sirna and carriers. to direct target-gene silencing, the sirnas need to escape from the endosome into the cytoplasm, where they associate with the ago /rna-induced silencing complex (risc) to direct the cleavage of mrnas bearing complementary binding sites. as an alternative to viral vectors, non-viral vectors, including lipid and polymer-based vectors, have been generally used for the delivery of sirnas to the lungs due to their reduced toxicity [ ] . ongoing research into the transfection of primary cells and whole organisms with sirna using non-viral transfection agents has produced some promising results. lipid-based delivery vectors are successfully used to deliver sirna in vitro and in vivo [ ] . cationic lipids are composed of positively charged head, a linker and hydrophobic. in general, lipid-based complexes are easy to formulate and good transfection efficacy is achieved due to interaction with negative charged cell membrance. many commercial sirna transfection agents are lipid-based delivery system, some of which are also employed for pulmonary delivery-dharmfect [ ] , oligofectamine [ ] , lipofectamine [ ] and transit-tko [ ] . similarly, cationic polymers have also been assessed for sirna delivery to lung cells. cationic polymer polyethylenimine (pei) is widely used for sirna delivery [ , ] . pei is considered as the gold standard for in vitro gene delivery and its transfection efficiency depends on the molecular weight and degree of branching. on the other hand, lipid-based vectors can also induce toxicity and non-specific activation of inflammatory cytokine and interferon responses [ , ] . although polymer-based vectors elicit a relatively less strong immune response than lipid-based vectors, effective sirna delivery to a local area in lung diseases requires more attention to the development of non-toxic delivery vectors. an important point for sirna-mediated inhibition of gene expression is whether the observed effects are specific rather than due to off-target effects and free from potential interferon responses [ , ] . interestingly, some studies have shown that it was possible to administer "naked sirnas" to mice and down-regulate an endogenous or exogenous target without inducing an interferon response [ ] . the term "naked sirnas" refers to the delivery of sirnas without any delivery vectors. naked sirnas are degraded by serum endonucleases and are usually removed by glomerular filtration, resulting in a short plasma half-life of < min. thus, some studies of systemic delivery of naked sirnas have failed to achieve the downregulation of the targeted gene [ , ] . in contrast, there have also been some successes of locally delivering naked sirnas to the lungs [ , , , ] . a few of them reported that the use of delivery vectors showed no significant difference in gene silencing efficiency compared to that of naked sirnas [ , ] . indeed, in one clinical trial, the delivery of naked sirnas for the treatment of rsv has been used [ , ] . this successful evidence can be because that naked sirnas for clinical applications are highly chemically modified to prevent nuclease-induced degradation and presumably minimize immune stimulatory effects. although it is unclear how the naked sirnas cross the cell membrane, gain access to the cytoplasm, and remain intact to perform their biological action, both animal and human trials have been conducted successfully, showing the efficacy of naked sirnas (aln-rsv ) that were administered intranasally. this explanation has not been confirmed, but the physiological damage of respiratory epithelial cells caused by viral infection may have possibly influenced the mystery. the active change in airway epithelial cell membrance caused by infectious disease might affect cellular internalization. naked sirna delivery has some advantages, such as simple formation and the absence of toxicity or inflammatory responses that are usually associated with delivery vectors. nevertheless, the advantage of naked sirnas over delivery vectors in the treatment of lung diseases is controversial [ , ] . further in vivo investigations about both naked sirnas and non-viral vectors are required. lung disease is a major cause of death, and diminished quality of life is responsible for the suffering of many patients. various lung diseases make life extremely difficult for the patients, and severe cases of these lung diseases can result in death. the high death rates associated with lung cancer are partially due to the fact that it is unfortunately difficult to cure. above all, copd is the fourth-leading cause of death in most industrialized countries and is predicted to become third by [ ] . therefore, decisive action is needed to stem the rising health and economic burden this represents. chronic lung diseases, such as copd and asthma, are disorders of the airways largely related to the presence of persistent inflammation. the approval of inhaled corticosteroids pioneered a new generation of therapy in treating chronic inflammatory diseases. this was the first time that an anti-inflammatory product was available to reduce the characteristic lung inflammation in airways and the associated obstruction. corticosteroids are still an important therapeutic intervention. however, they are used with limitations in copd and moderate to severe asthma. likewise, the treatment of various refractory lung diseases also depends on systemic corticosteroid therapy. many of these patients also suffered various side effects from systemic corticosteroid use, such as weight gain and uncontrolled hyperglycemia. treatment of lung disease using cell-specific targeting as well as rnai techniques represents a novel strategy and could possibly provide new opportunities in nanomedicine. pulmonary applications of sirna in in vivo conditions are frequently studied and often result in clinical trials [ , ] . the findings of recent clinical studies of pulmonary rnai therapeutics are discussed. since the discovery of rnai, the therapeutic potential of sirnas has been rapidly recognized. in , the first human clinical trial of rnai-based therapy was initiated for the treatment of age-related macular degeneration with a sirna targeting vegf-receptor delivered intravitreally [ ] . many studies have been conducted over the past few years that involve the delivery of sirnas to the lungs for the treatment of various lung diseases. delivery to the lungs will be most important to moving sirna technology into the clinic. a number of sirna-based therapies are being evaluated in clinical trials for the treatment of different conditions, including lung diseases such as asthma and rsv infection. table is a summary of clinical trials of sirna-based therapeutics [ ] . sirna shows potential for the treatment of various pulmonary viral infections, and it has been reported that sirna-based therapeutics can also be used in the treatment of influenza [ ] , parainfluenza virus [ ] , severe acute respiratory syndrome (sars) [ ] , and rsv [ ] . above all, rsv is the most promising therapeutic target of sirnas. rsv is a common cause of serious respiratory infections in infants and children. it also produces significant morbidity and mortality in adult immunocompromised or elderly populations [ ] . an rsv vaccine is not available, and the only approved antiviral therapy for rsv is undesirable for pediatric patients due to its potential teratogenicity and limited effectiveness. thus, a safe and efficacious rsv therapy has long been awaited for both pediatric and adult patients. rnai-based therapy has shown promising effects in murine models of rsv infection [ ] . the sirna, aln-rsv , is directed against the mrna encoding the n-protein of rsv that exhibits specific in vitro and in vivo anti-rsv activity. it is delivered without a delivery vector as a nasal spray and targets the upper respiratory tract instead of the lower lung area. aln-rsv has undergone complete phase i intranasal and inhalation studies in healthy adults and has been found to be generally well tolerated [ ] . additionally, aln-rsv has been evaluated in a randomized, double-blind, placebo-controlled phase ii trial in lung transplant patients with rsv respiratory tract infection [ ] . the administration of aln-rsv to rsv infected lung transplant patients was safe and well tolerated and associated with a statistically significant improvement in symptoms. based on these results, a larger multinational, randomized, double-blind phase iib trial of aln-rsv has been initiated in lung transplant patients to confirm and extend these findings. cancer is a major target of rnai-based therapy, as oncogenes, mutated tumor suppressor genes, and several other genes contributing to tumor progression are potentially important targets for gene silencing by rnai. lung cancer is one of the most frequent tumors worldwide with regard to incidence rates and mortality. patients with lung cancer are commonly diagnosed at an advanced stage of the disease and have limited therapeutic options. although the knowledge regarding the genetic and molecular basis of lung cancer has regularly increased, the median survival rates of individuals with advanced lung cancer are still poor. rnai-based therapy is an attractive strategy for the development of more effective anticancer therapies with reduced treatment-related toxicity. the major advantage of rnai therapeutics in cancer might be the simultaneous targeting of multiple genes belonging to different cellular pathways that are involved in tumor progression. the simultaneously inhibition of several genes would also minimize the risk of drug resistance normally encountered with small molecule-based therapies, involving sirnas and mirnas. there have already been significant improvements in sirnas for primary or metastatic lung cancer treatment by targeting oncogenes such as akt [ ] , wilms tumor (wt ) [ ] , overexpressed genes such as the insulin-like growth factor receptor (igf- r) [ ] , nupr [ ] and ezh [ ] . some of these studies have successfully shown the efficacy of rnai-based therapy through intrapulmonary administration of sirnas with non-viral vectors. although strategies to minimize off-target and nonspecific immune stimulatory effects must be devised, these data suggest that the silencing of the target gene with sirnas is an attractive strategy for the prevention and treatment of primary and metastatic lung cancer. there are currently some clinical trials in progress estimating the safety and efficacy of sirna-based drugs for cancer treatment. atu , a sirna-lipoplex targeted against protein kinase n (pkn ), prevented lung metastasis in a phase i trial of various cancer models [ ] . pkn is a downstream effector of the phosphoinositide -kinase (pi k) signaling pathway [ ] , which regulates diverse cellular responses, including development, growth, and survival [ ] . recently, pkn has also been considered as a suitable therapeutic target for modulating tumor angiogenesis because loss of function analysis with atu in cultured primary endothelial cells showed an essential role of pkn for endothelial tube formation and migration [ ] . atu can be considered as a potential sirna for preventing lung metastasis and might be suitable for preventing hematogenous metastasis combined with conventional cancer therapy. inflammatory lung disease, also called copd, includes a wide range of lung ailments. these related diseases include asthma, pulmonary fibrosis, and chronic bronchitis. they are influenced by a combination of environmental, genetic, and epigenetic components [ ] . copd is a chronic inflammatory disease of the airways. this disease is hallmarked by airflow that is not fully reversible. systemic and local airway inflammation has been implicated in the pathogenesis of copd [ ] . copd is mainly associated with tobacco smoking, and recent studies investigating the pathophysiology of emphysema have demonstrated that cigarette smoke can cause cells to enter cellular senescence. smoking might cause cells to senesce due to dna damage through increased cell turnover, which in turn leads to accelerated telomere shortening [ ] . lately, a lot of studies have investigated the role of cellular senescence in the development and progression of copd [ ] . although several medication classes, including inhaled corticosteroids, are used for copd treatment, none of these medications have been shown to significantly improve long-term lung function during the progression of the disease. current interventions that have been shown to improve mortality in copd are cessation of smoking and delivery of supplemental oxygen when hypoxemia is present. many people are developing copd, and the cause of this condition is complicated and not thoroughly understood. one key factor is genetic susceptibility. some studies have shown a large genetic contribution to the variability in pulmonary function and copd [ , ] . polymorphisms in multiple genes have been reported to be associated with copd [ ] , such as transcription factor [e.g. nuclear factor-kappa b (nfκb)] [ ] , extracellular matrix (e.g., matrix metalloproteinase- (mmp- )) [ , ] , cytokines [e.g. tumor necrosis factor (tnf)-α] [ ] , chemokines [e.g. interleukins (il)- , il- receptor and chemokine receptor (ccr) ] [ , ] , and apoptosis (e.g., caspase- and vascular endothelial growth factor (vegf)) [ , ] . many of these have been identified as possible targets for therapeutic intervention using molecule inhibitors or antagonists. although several new treatments that target the inflammatory process are now in clinical development, such as tnf-α inhibitors and i-kappab kinase complex (ikk ) inhibitors [ , ] , clinical trials with sirnas have never been performed in copd. the delay of drug development for copd might be due to the relatively recent emergence of research addressing the molecular basis of copd. furthermore, more research is needed to understand the essential molecular mechanisms about the pathogenesis of copd and to develop monitoring techniques to support the development of rnai therapies. currently, no available treatments reduce the progression of copd or suppress the inflammation in small airways and lung parenchyma. the rnai-based approach for the key molecules also has potential implications for the treatment of copd. asthma is also a chronic inflammatory disease of the airways characterized by variable and recurring symptoms and reversible airflow obstruction. the world health organization estimates that million people are currently affected and that, by the year , another million will be affected by the disease [ ] . inhaled corticosteroids are very effective in mild asthma because they improve symptoms and decrease exacerbations. however, in moderate and severe asthma, inhaled corticosteroids have important therapeutic limitations. although corticosteroids remain an important therapeutic intervention for inflammatory lung diseases, their use is not always completely effective and is associated with side effects. due to such limitations, it is clear that there is a need for new types of medications that can treat and improve the prognosis of moderate to severe asthma. many target genes have been identified that participate in the pathogenesis of asthma. the most promising targets include genes coding for cytokines (il- , il , and il- ), cytokine and chemokine receptors (il- receptor and ccr ), and tyrosine kinases [spleen tyrosine kinase (syk) and lck/yes-related novel tyrosine kinase (lyn)], as well as for transcription factors [signal transducers and activators of transcription (stat ), stat , gata , and nfκb] that are involved in asthma [ , , ] . the genes that have been assessed as sirna targets for the treatment of asthma in preclinical models are reported [ ] . currently, in a clinical trial for asthma, excellair tm (zabecor, bala cynwyd, pa, usa), a sirna that targets syk, is being used. the kinase is involved in signaling from a b cell receptor and is a key regulator of downstream signaling cascades that ultimately lead to the activation of several pro-inflammatory transcription factors. it has been reported that antisense oligonucleotides administered by aerosol were potent to decrease syk expression, mediator release from alveolar macrophages, and syk-dependent pulmonary inflammation [ ] . moreover, inhibition of inflammatory mediators was shown in a study using sirna targeting syk in airway epithelial cells [ ] . following the successful results of the company's phase i clinical trial, a phase ii trial for its asthma drug candidate excellair tm has already been initiated. some of the current treatments for asthma and other inflammatory conditions, such as tnf-α inhibitors or leukotriene inhibitors, inhibit only one of the mediators of inflammation. in contrast, sirna targeting syk seeks to inhibit an initial signaling step of inflammation and, thereby, prevent the release of multiple inflammatory mediators. overall, recent progress of sirnas to the lungs has also improved the therapeutic feasibility of rnai for inflammatory lung diseases. the rapid progress will put sirna-based therapeutics on a fast track to the clinic. mirnas are small endogenous noncoding rnas that regulate gene expression by repressing translation or promoting the degradation of their target mrna. mirnas regulate gene expression by binding to the ′ untranslated region (utr) of their target mrnas and mediating mrna degradation or translational inhibition. in the human genome, transcripts of approximately % of all mrnas are estimated to be targeted by mirnas [ ] . according to their function, mirnas play an important role in cellular processes as development, proliferation, and apoptosis of pulmonary pathologies [ ] . a growing number of mirnas have been shown to be involved in different lung diseases. this evidence makes mirnas a promising technology for current and future therapeutic development. we discuss the role of some mirnas in various lung diseases as well as the possible future of these discoveries in clinical applications. table shows the summary of mirnas in therapeutic development. at this point, a mirna-based therapy has already entered a phase ii clinical trial. there is evidence that upregulation or downregulation of mirnas is critical for lung homeostasis and, thus, may contribute to the development of pathological pulmonary conditions. many studies have focused on the role of mirnas in inflammatory lung diseases, such as copd [ , ] , pulmonary fibrosis [ ] [ ] [ ] [ ] , and asthma [ ] [ ] [ ] [ ] (table ) . [ ] [ , ] the pathogenesis of copd is attributed to not only chronic inflammation in the airways but also systemic inflammation [ ] . cigarette smoking is the main risk factor for the development of copd. smoking has been shown to cause biological change in the gene expression of the lungs [ ] , and there are some reports about smoking-related mirnas [ , , ] . however, there are few reports that focus on the mirnas related to the pathogenesis of this disease with systemic inflammatory components. recent study on pulmonary fibroblasts of copd patients presents less expression of mir- a after stimulation with proinflammatory cytokines when compared with non-copd subjects with similar smoking histories [ ] . the downregulation of mir- a resulted in a prolonged mrna half-life of cyclooxygenase- , thus increasing prostaglandin e in fibroblasts from copd subjects. moreover, ezzie et al. researched the difference of mirna profiles expressed in the lungs of smokers with and without copd. they concluded that mir- and mir- a were the most affected mirnas in subjects with copd [ ] . yet, copd is a complex, multi-component, and heterogeneous disorder with a number of different pathological processes and subgroups with their own characteristics and natural history [ ] . a better understanding of the complexity of the disease and potential clinical relevance of the identified mirnas is needed. pulmonary fibrosis can be caused by an identifiable irritation to the lungs, but, in many cases, the cause is unknown, and the therapeutic possibilities are limited. cigarette smoking is one of the most recognized risk factors for the development of pulmonary fibrosis. this disorder is mainly accompanied by increased expression of the key fibrotic mediator transforming growth factor β (tgf-β) and other cytokines produced at the lesion of active fibrosis [ ] . recently, it was reported that mirnas may play an important regulatory role in the pulmonary fibrotic change in the lungs. the downregulation of let- d in idiopathic pulmonary fibrosis (ipf) resulted in increased collagen deposition and alveolar septal thickening [ ] . in addition, liu et al. reported that the oncogenic mir- was found to be upregulated in ipf patients and in the murine lungs with bleomycin-induced fibrosis [ ] . although these mirnas may be potential therapeutic targets because their expression is related to the regulation of tgf-β, the factor is necessary but not sufficient for pathologic fibrosis of the lungs. pulmonary fibrosis is also a complicated illness that can have many different causes. focus on the role of mirnas in asthma has recently increased. asthma is an inflammatory disease of the airway that is characterized by an abnormal response of t helper- (th )-type cd +t lymphocytes against inhaled allergens [ ] . in a different asthmatic mouse model, there was an observed increase in the expression of mir- in the lungs [ ] . this report might contribute to the understanding of the inflammatory mechanism in the airway through the inhibition of il- , favoring the th lymphocyte response. a toll-like receptor (tlr )-induced th lymphocyte induces high expression of mir- , and selective blockade of mir- suppressed the asthmatic phenotype [ ] . in addition, airway remodeling is a characteristic feature of asthma and has important functional implications. rodriguez et al. have shown that mir- is related to the development of inflammatory infiltration into the lung and airway remodeling [ ] . thus, some studies present a functional connection between mirna expression and asthma pathogenesis and suggest that targeting mirnas in the airways may lead to anti-inflammatory treatments for allergic asthma. despite the evidence from experimental models, the expression profiling of mirnas in airway biopsies from patients with mild asthma before and after treatment with inhaled corticosteroids and in healthy volunteers revealed no differences in mirna expression [ ] . further investigations about the role of mirnas related to asthma pathogenesis are required. although the basic evidence of mirna biology is still providing new insights, applications of mirna-based therapy for inflammatory lung diseases are less advanced than those for lung cancer [ ] . one reason for this could be that the disease heterogeneity is caused by the effects of many environmental air pollutants, including smoke and volatile organic compounds. the presence of several risk factors makes the understanding of the pathogenesis of inflammatory lung diseases complicated. understanding the role that mirnas play in the modulation of gene expression, leading to sustain the pathogenesis of lung diseases, is important for the development of new therapies that focus on the prevention of disease progression and symptom relief. given the significant roles that mirnas play in multiple pathways of lung carcinogenesis, increasing efforts are dedicated to the research and development of mirna-based therapies, including restoring functions of tumor suppressive mirnas or inhibiting oncogenic mirnas. the development of mirna-based therapies for lung cancer is growing prosperously with the help of new rnai technologies. compared to sirna-based therapies, which are already in clinical trials, mirnas are less toxic and have the potential to target multiple genes. the difficulty associated with mirna delivery is mainly equal to that of sirnas. the critical problems for the development of this therapy are effective delivery into target sites, potency of the therapy, and elimination of off-target effects [ ] . there are two strategies as the therapeutic applications of mirnas for lung cancer [ ] . one strategy is mirna replacement therapy, which involves the re-introduction of a tumor suppressor mirna mimic to restore a loss of the function. mirna mimics are synthetic rna duplexes designed to mimic the endogenous functions of mirnas with chemical modifications for stability and cellular uptake. the concept of mirna replacement therapy is most exemplified by the let- mirna. let- is a tumor-suppressor mirna in non-small-cell lung cancer that inversely correlates with the expression of the ras oncoprotein, a key cancer gene [ ] . intranasal administration of let- mimic into mouse models of lung cancer significantly reduced tumor growth, suggesting that mirna replacement therapy is indeed promising [ , , ] . another mirna that shows the value of mirna replacement is provided by mir- a [ , ] . local and/or systemic delivery of a synthetic mir- a mimic led to accumulation of mir- a in the tumor tissue and inhibition of lung tumor growth. lately, ling et al. also showed that tumor suppressor mir- exhibited anti-lung cancer activity through post-transcriptional regulation of erbb [ ] . thus, therapeutic mirna mimics have a powerful potential by attacking multiple genes relevant to several diseases. however, it is necessary to pay attention to the potential toxicity in normal tissues under conditions in which the therapeutic delivery of mirna mimics will lead to an accumulation of exogenous mirnas in normal cells [ ] . although the assumptions are well founded, there is still insufficient evidence for toxicity caused by mirna mimics. indeed, several in vivo studies failed to reveal side effects caused by the mirna mimics and suggested that delivery of mirna mimics to normal tissues was well tolerated [ , ] . it will be important to research mirna mimic-induced effects in normal cells and to carefully assess toxicity before using them in clinical practice. the second strategy is directed toward a gain of function and aims to inhibit oncomirs by using anti-mirnas. chemical modifications, such as '-o-methyl-group and locked nucleic acid (lna), would increase oligo stability against nucleases [ ] . antisense oligonucleotides contained in these modifications are termed antagomirs or "lna-antimirs" [ , ] . they are oligonucleotides with sequences complementary to the endogenous mirna and inhibit the specific mirna function. an lna-antimir against mir- has been shown to effectively silence mir- in non-human primates [ ] , and the findings support the potential of these compounds as a new class of therapeutics. moreover, it has also been reported that anti-mir- delivered into lung tumor xenografts in mice led to inhibited tumor growth [ ] . relative to studies on mirna mimics, studies with antisense oligonucleotides have shown effective evidence with naked oligonucleotides. this illustrates the potential of chemical modifications of oligonucleotides to improve their stability, resistance to rnase, and pharmacologic properties. therefore, inhibition of mirna function by chemically modified antimir oligonucleotides has become an important and widely used approach. recent data from the first phase ii study in patients with chronic hcv infection treated with the lna-modified antimir- showed that this compound was well tolerated and provided continuing viral suppression. an increasing number of studies have examined the therapeutic potential of mirnas. recently, the evidence of roles for mirnas in determining drug resistance has emerged [ ] . cytotoxic and molecular target drugs have been widely used in the treatment of advanced lung cancer; unfortunately, many cases are still refractory to chemotherapy. in this situation, combining mirna mimics or antimir with chemotherapy may potentiate the efficacy of the cancer treatment in the future. in addition, mirnas related with cancer stem cells may significantly broaden the field of mirna-based therapy and suggest that mirnas can be potential tools to kill cancer cells associated with therapy resistance, recurrence, and metastasis [ , ] . hence, the main challenge is the successful delivery and chemical modifications of the therapeutic mirnas to the target tissue without harming normal tissues. rnai-based approaches provide a promising therapeutic modality for the treatment of various lung diseases. one of the greatest challenges in rnai-based therapy continues to be the delivery method of the therapeutic sirnas and mirnas to the target cells. pulmonary delivery applications are very attractive, since they tend to be non-invasive, are locally restricted, and can be administered by the patient. a realistic therapeutic intervention, such as aerosolization, can enhance drug delivery to the site of action and decrease systemic exposure of the patient to the therapy, thereby reducing off-target effects. the advancement of pulmonary sirna delivery to the clinic illustrates that rnai-based therapy holds a central place in the future treatment of lung diseases. on the other hand, mirnas have the opportunity to target multiple genes in a fine-tuned manner, and the mirna-based therapy will provide an attractive anti-tumor and anti-inflammatory approach for various lung diseases. in particular, anti-mirna therapy by chemically modified antimir oligonucleotides has become a potential therapy for lung diseases because the oligonucleotides can be successfully delivered without delivery vectors. increased evidence has indicated that mirnas fulfill causative roles in a variety of lung diseases and have prompted investigations into their potential as therapeutic targets. further understanding of the detailed mechanisms of rnai-based therapy and investigations of more effective delivery methods are required for future development. these novel approaches could open new avenues for various lung diseases and improve the clinical outcome of the patients. strategies for silencing human disease using rna interference rnai therapeutics: a potential new class of pharmaceutical drugs small interfering rna inhibits hepatitis b virus replication in mice rnai suppresses polyglutamine-induced neurodegeneration in a model of spinocerebellar ataxia confirming the rnai-mediated mechanism of action of sirna-based cancer therapeutics in mice chemical modification of sirna sirna and isrna: two edges of one sword targeted delivery of antisense oligodeoxynucleotide and small interference rna into lung cancer cells poly(ester amine)-mediated, aerosol-delivered akt small interfering rna suppresses lung tumorigenesis poly(beta-amino ester) as a carrier for si/shrna delivery in lung cancer cells inhibition of non-small cell lung cancer cell proliferation and tumor growth by vector-based small interfering rnas targeting her /neu rodriguez-padilla, c. wt gene silencing by aerosol delivery of pei-rnai complexes inhibits b -f lung metastases growth inhibition of influenza virus production in virus-infected mice by rna interference using sirna in prophylactic and therapeutic regimens against sars coronavirus in rhesus macaque intrapulmonary delivery of xcl -targeting small interfering rna in mice chronically infected with mycobacterium tuberculosis effective treatment of respiratory alphaherpesvirus infection using rna interference a randomized, double-blind, placebo-controlled study of an rnai-based therapy directed against respiratory syncytial virus rna interference: new therapeutics in allergic diseases emerging oligonucleotide therapies for asthma and chronic obstructive pulmonary disease suppression of plasminogen activator inhibitor- by rna interference attenuates pulmonary fibrosis development and preclinical efficacy of novel transforming growth factor-beta short interfering rnas for pulmonary fibrosis pulmonary delivery of therapeutic sirna the lung as a route for systemic delivery of therapeutic proteins and peptides spray drying of sirna-containing plga nanoparticles intended for inhalation design of an inhalable dry powder formulation of dotap-modified plga nanoparticles loaded with sirna silencing of fas, but not caspase- , in lung epithelial cells ameliorates pulmonary apoptosis, inflammation, and neutrophil influx after hemorrhagic shock and sepsis in vivo gene silencing (with sirna) of pulmonary expression of mip- versus kc results in divergent effects on hemorrhage-induced, neutrophil-mediated septic acute lung injury nonviral sirna delivery to the lung: investigation of peg-pei polyplexes and their in vivo performance intratracheal versus intravenous liposomal delivery of sirna, antisense oligonucleotides and anticancer drug attenuation of fibrosis in vitro and in vivo with sparc sirna rnai-mediated suppression of constitutive pulmonary gene expression by small interfering rna in mice intratracheal instillation as an exposure technique for the evaluation of respiratory tract toxicity: uses and limitations non-invasive pulmonary aerosol delivery in mice by the endotracheal route pulmonary vaccine delivery inhibition of respiratory viruses by nasally administered sirna noninvasive delivery of small inhibitory rna and other reagents to pulmonary alveoli in mice immunological and toxicological implications of short-term studies in animals of pharmaceutical aerosol delivery to the lungs: relevance to humans evaluation of the safety, tolerability and pharmacokinetics of aln-rsv , a novel rnai antiviral therapeutic directed against respiratory syncytial virus (rsv) clinical evaluation of inhaled insulin inhalable lactose-based dry powder formulations of low molecular weight heparin extracellular barriers in respiratory gene therapy nanodelivery in airway diseases: challenges and therapeutic applications expression of respiratory mucins in fatal status asthmaticus and mild asthma remodeling in asthma and chronic obstructive lung disease polymeric nanocarriers for drug delivery to the lung nonviral delivery of synthetic sirnas in vivo rapid crossing of the pulmonary endothelial barrier by polyethylenimine/dna complexes delivery of sirna therapeutics: barriers and carriers cellular sirna delivery using cell-penetrating peptides modified for endosomal escape delivering silence: advancements in developing sirna therapeutics gene silencing by adenovirus-delivered sirna effect of adenovirus-mediated rna interference on endogenous micrornas in a mouse model of multidrug resistance protein gene silencing lentivirus-mediated rnai knockdown of nupr inhibits human nonsmall cell lung cancer growth in vitro and in vivo cancer gene therapy: challenges and opportunities us gene therapy in crisis rnai-dependent and -independent antiviral phenotypes of chromosomally integrated shrna clones: role of vasp in respiratory syncytial virus growth non-viral sirna delivery to the lung lipid-based systemic delivery of sirna protection against lethal influenza virus challenge by rna interference in vivo fibronectin induces cell proliferation and inhibits apoptosis in human bronchial epithelial cells: pro-oncogenic effects mediated by pi -kinase and nf-kappa b full deacylation of polyethylenimine dramatically boosts its gene delivery efficiency and specificity to mouse lung cationic liposome-mediated delivery of sirnas in adult mice lipidic systems for in vivo sirna delivery expression profiling reveals off-target gene regulation by rnai induction of an interferon response by rnai vectors in mammalian cells lack of interferon response in animals to naked sirnas rnai-mediated gene-targeting through systemic application of polyethylenimine (pei)-complexed sirna in vivo systemic delivery of rafsirna using cationic cardiolipin liposomes silences raf- expression and inhibits tumor growth in xenograft model of human prostate cancer pulmonary gene silencing in transgenic egfp mice using aerosolised chitosan/sirna nanoparticles a combinatorial library of lipid-like materials for delivery of rnai therapeutics immunologic aspects of chronic obstructive pulmonary disease drug delivery trends in clinical trials and translational medicine: challenges and opportunities in the delivery of nucleic acid-based therapeutics suppression of ocular neovascularization with sirna targeting vegf receptor the us national institutes of health respiratory syncytial virus infection in elderly and high-risk adults rna interference therapy in lung transplant patients infected with respiratory syncytial virus down-regulation of igf-ir using small, interfering, hairpin rna (sirna) inhibits growth of human lung cancer cell line a in vitro and in nude mice ezh silencing with rnai enhances irradiation-induced inhibition of human lung cancer growth in vitro and in vivo atu , a liposomal small interfering rna formulation targeting protein kinase n , inhibits cancer progression pkn is required for malignant prostate cell growth downstream of activated pi -kinase cellular function of phosphoinositide -kinases: implications for development, homeostasis, and cancer the stability of mrna influences the temporal order of the induction of genes encoding inflammatory molecules inhaled and systemic corticosteroids in chronic obstructive pulmonary disease cigarette smoke induces senescence in alveolar epithelial cells senescence in chronic obstructive pulmonary disease identifying targets for copd treatment through gene expression analyses targeting the nf-kappab pathway in asthma and chronic obstructive pulmonary disease neutrophil elastase contributes to cigarette smoke-induced emphysema in mice pathobiology of cigarette smoke-induced chronic obstructive pulmonary disease tumor necrosis factor-alpha gene polymorphism in chronic bronchitis characterization of cigarette smoke-induced inflammatory and mucus hypersecretory changes in rat lung and the role of cxcr ligands in mediating this effect comprehensive gene expression profiling of rat lung reveals distinct acute and chronic responses to cigarette smoke inhalation alveolar wall apoptosis causes lung destruction and emphysematous changes inhibition of vegf receptors causes lung cell apoptosis and emphysema copd: current therapeutic interventions and future approaches p mapk inhibitors, ikk inhibitors, and tnfalpha inhibitors in copd chronic respiratory disease-asthma sirna as a therapy for asthma targeting allergic airway diseases by sirna: an option for the future? antisense-and rna interference-based therapeutic strategies in allergy aerosolized syk antisense suppresses syk expression, mediator release from macrophages, and pulmonary inflammation syk tyrosine kinase participates in beta -integrin signaling and inflammatory responses in airway epithelial cells many roads to maturity: microrna biogenesis pathways and their regulation micrornas in lung diseases regression of murine lung tumors by the let- microrna development of a lung cancer therapeutic based on the tumor suppressor microrna- the microrna mir- a inhibits prostate cancer stem cells and metastasis by directly repressing cd dysregulation of micrornas after myocardial infarction reveals a role of mir- in cardiac fibrosis therapeutic silencing of microrna- in primates with chronic hepatitis c virus infection control of stress-dependent cardiac growth and gene expression by a microrna mir- family regulates postnatal mitotic arrest of cardiomyocytes microrna- promotes palmitate-induced apoptosis in cardiomyocytes by down-regulating sirt microrna- delays als progression and promotes regeneration of neuromuscular synapses in mice defective erythroid differentiation in mir- mutant mice mediated by - - zeta downregulation of the serum response factor/mir- axis in the quadriceps of patients with copd microrna expression in induced sputum of smokers and patients with chronic obstructive pulmonary disease mir- mediates fibrogenic activation of pulmonary fibroblasts and lung fibrosis inhibition and role of let- d in idiopathic pulmonary fibrosis mir- is a major regulator of genes associated with pulmonary fibrosis participation of mir- in pulmonary fibrosis requirement of bic/microrna- for normal immune function microrna- is up-regulated in allergic airway inflammation and regulates il- p expression antagonism of microrna- suppresses the effector function of th cells and the development of allergic airways disease down-regulation of mir- a contributes to up-regulation of rhoa in bronchial smooth muscle cells gene expression networks in copd: microrna and mrna regulation reduced mir- a increases prostaglandin e( )in chronic obstructive pulmonary disease fibroblasts identification of keratinocyte growth factor as a target of microrna- in lung fibroblasts: implication in epithelial-mesenchymal interactions downregulation of microrna expression in the lungs of rats exposed to cigarette smoke micrornas as modulators of smoking-induced gene expression changes in human airway epithelium copd as a lung disease with systemic consequences--clinical impact, mechanisms, and potential for early intervention transcriptomic studies of the airway field of injury associated with smoking-related lung disease copd, a multicomponent disease: implications for management asthma and allergic inflammation microrna expression profiling in mild asthmatic human airways and effect of corticosteroid therapy micrornas in inflammatory lung disease--master regulators or target practice? artificial micrornas as sirna shuttles: improved safety as compared to shrnas in vitro and in vivo the promise of microrna replacement therapy ras is regulated by the let- microrna family the let- a microrna protects from growth of lung carcinoma by suppression of k-ras and c-myc in nude mice the let- microrna reduces tumor growth in mouse models of lung cancer nanoparticles modified with tumor-targeting scfv deliver sirna and mirna for cancer therapy tumor suppressor mir- suppresses lung cancer cell progression through post-transcriptional regulation of erbb silencing of micrornas in vivo with "antagomirs lna-mediated microrna silencing in non-human primates regression of a lung cancer tumors by anti-mir- vector role of microrna in anticancer drug resistance microrna mir- inhibits human pancreatic cancer tumor-initiating cells this work was supported in part by a grant-in-aid for the third-term the authors declare that there are not conflicts of interest to report. key: cord- - gl xe w authors: rady, w.; abouelela, a.; abdallah, a.; youssef, w. title: role of bronchoscopy during non invasive ventilation in hypercapnic respiratory failure date: - - journal: egyptian journal of chest diseases and tuberculosis doi: . /j.ejcdt. . . sha: doc_id: cord_uid: gl xe w abstract introduction non invasive positive pressure ventilation (nippv) is the first line treatment for hypercapnic acute respiratory failure (arf) secondary to copd exacerbation in selected patients. limited data exist supporting the use of fiberoptic bronchoscopy (fob) during this clinical setting. the aim of this study is to assess the role of fob during nippv in patients with decompensated copd acute exacerbation. methods this study is a randomized prospective case control pilot study carried out on patients - admitted to critical care units at alexandria university hospital, egypt - suffering from hypercapnic arf secondary to copd exacerbation with kelly matthay score from to . all patients received nippv. patients were divided randomly into equal groups: group i (cases) ( patients) was subjected to additional intervention of early fob during the first – h from admission while group ii (control) ( patients) received the conventional treatment and nippv only. outcome parameters measured were changes in abg data, duration of nippv, rate of its success, icu stay and mortality as well as the safety of fob and possible complications. results no significant difference was detected between the groups regarding the baseline characteristics. no serious complications happened from fob, and oxygen desaturation happened in / patients ( %), tachycardia in / patients ( %). in group i, patients ( %) were successfully weaned from nippv versus patients ( %) in group ii (p = . ). total duration of nippv was . h in group i versus . h in group ii (p = . ). length of icu stay was . days in group i versus . days in group ii (p = . ). only patient died in group i versus patients in group ii (p = . ). conclusion the early application of fob during nippv in patients with arf due to copd exacerbation was shown to be safe. significant improvement in the outcome of patients who underwent fob was noticed in terms of improved abg data, shorter duration of nippv, higher percentage of success and shorter icu stay while no significant difference was detected in mortality. the american thoracic society, european respiratory society, and the british thoracic society have each defined copd using slightly different wordings and approaches over the past years.the global initiative for chronic obstructive lung disease (gold) a report produced by the national heart, lung, and blood institute (nhlbi) and the world health organization (who) defines copd as a preventable and treatable disease with some significant extrapulmonary effects that may contribute to the severity in individual patients. its pulmonary component is characterized by airflow limitation that is not fully reversible. the airflow limitation is usually progressive and associated with an abnormal inflammatory response of the lungs to noxious particles or gases [ ] . the global initiative for chronic obstructive lung disease (gold)a report produced by the national heart, lung, and blood institute (nhlbi) and the world health organization (who) -defines an exacerbation of chronic obstructive pulmonary disease (copd) as an acute increase in symptoms beyond normal day-to-day variation .this generally includes an acute increase in one or more of the following cardinal symptoms: cough increases in frequency and severity, sputum production increases in volume and/or changes character, and dyspnea increases [ ] . it is estimated that - percent of exacerbations are due to respiratory infections (mostly bacterial like haemophilus influenzae, moraxella catarrhalis, streptococcus pneumoniae, pseudomonas aeruginosa and enterobacteriaceae and viral like rhinoviruses. influenza, parainfluenza, coronavirus, and adenovirus), percent are due to environmental pollution, and percent are of unknown etiology [ ] . some copd exacerbations of unknown etiology may be related to other medical conditions, such as myocardial ischemia, heart failure, aspiration, or pulmonary embolism [ ] . patients with copd who present to the hospital with acute worsening of dyspnea should be evaluated for potential alternative diagnoses, such as heart failure, pulmonary thromboembolism, and pneumonia. this was illustrated in an autopsy study of patients with copd who died within h of admission for a copd exacerbation .the primary causes of death were heart failure, pneumonia, pulmonary thromboembolism, and copd in , , , and percent, respectively [ ] . noninvasive positive pressure ventilation (nippv) refers to mechanical ventilation delivered through a noninvasive interface, such as a face mask, nasal mask, or nasal prongs; it is more comfortable allowing expectoration, eating, speech and prevents rebreathing than full face mask. the face mask is generally preferred over a nasal mask or nasal prongs during the initiation of niv for several reasons. most patients with acute respiratory failure are mouth breathers; therefore, niv delivered by a nasal mask results in a large air leak through the mouth and a worse outcome. the nasal air passages offer significant resistance to airflow, which can mitigate the beneficial effects of nippv if a low level of positive airway pressure is used. there are two principal forms used: pressure support ventilation (psv) and bilevel positive airway pressure (bipap). psv is the most common mode chosen by clinicians who want to maximize patient comfort and synchrony. both provide positive airway pressure during the respiratory cycle, but bipap offers pressure in a biphasic manner, with higher pressures during inspiration than expiration. studies in patients with obstructive lung disease indicate that low-level cpap offsets the detrimental effects of auto-positive end-expiratory pressure, which are caused by gas trapped in alveoli at end expiration and decreases inspiratory work of breathing. the addition of inspiratory pressure support to cpap (or bipap) generally improves tidal volume in proportion to the amount of pressure applied .both cpap and bipap have been used as an alternative to intubation in patients with a variety of respiratory conditions, including congestive heart failure with pulmonary edema and copd, avoiding the complications associated with endotracheal intubation. it improves numerous clinical outcomes and is the preferred method of ventilatory support in many patients with an acute exacerbation of copd complicated by hypercapnic acidosis [ , ] . nippv has physiologic benefits. respiratory mechanics measured after the initiation of nippv demonstrate a decreased respiratory rate, an increased tidal volume, and increased minute ventilation. in addition, the arterial oxygen tension (pao ) tends to increase as the paco decreases. the pressure support level should be increased until patient's respiratory rate is below breaths per min because this respiratory rate indicates that the inspiratory effort has been reduced to a reasonable level. however, the expiratory effort of patients with copd may increase when the pressure support is increased, which makes selection of the optimal pressure support level difficult [ ] . flexible fiberoptic bronchoscopy (fob) has become an indispensable tool in the optimal management of intensive care unit (icu) patients with both diagnostic and therapeutic goals. its safety and usefulness, in well-trained hands with appropriate precautions, have led to its increasing use even in unstable and mechanically ventilated patients. currently, rigid bronchoscopes are not often used except for the management of massive hemoptysis, removal of tracheobronchial foreign bodies, laser photoresection for obstructing endobronchial tumours, dilatation of tracheobronchial strictures and placement of airway stents [ , ] . in bronchoalveolar lavage (bal), the fob is wedged into a subsegmental bronchus and multiple aliquots ( - ml) of saline are instilled into that lung segment and then withdrawn by suction. the centrifuged bal fluid is stained for opportunistic pathogens and cultured. although ml was once considered the maximum, recent literature demonstrates that lavage volumes of up to ml are well tolerated. patients should not eat or drink anything - h before procedure. also you to try avoid any aspirin, ibuprofen, or other blood-thinning drugs before procedure. after procedure, your gag reflex will return. however, until it does, patients should not eat or drink anything. to test if the gag reflex has returned, place a spoon on the back of your tongue for a few seconds with light pressure. if patient does not gag, wait min and try it again [ ] . so, the aim of this work is to assess the role of early fiberoptic bronchoscopy during non invasive ventilation in acute exacerbation of copd patients in terms of effectiveness and safety. this prospective case control study was carried out on patients, suffering from hypercapneic acute respiratory failure as a result of acute exacerbation of chronic obstructive pul-monary disease (copd), receiving non invasive mechanical ventilation admitted consecutively to critical care units at alexandria university main hospital. patients were divided into two groups: group i (cases): patients received conventional medical treatment plus early fiberoptic bronchoscopy during non invasive ventilation. group ii (controls): patients received only conventional medical treatment and noninvasive ventilation. all copd patients met all the following criteria while breathing oxygen via a venturi mask. a) ph less than . and (paco ) above mmhg. b) (pao )/(fio ) ratio less than . c) dyspnea at rest with respiratory rate (rr) above breaths/min. d) use of accessory respiratory muscles. e) mild hypercapneic encephalopathy kelly matthay score [ ] between & . f) inability to spontaneously clear airways from excessive secretions, as expressed by the lowest score of an arbitrary cough efficiency scale evaluated by the nurses on the basis of the volume of the expelled sputum after three hard coughing efforts ( = less than ml; = between and ml and; = more than ml). patients were divided into two groups: group i (cases): patients received medical treatment and early fiberoptic bronchoscopy within h of starting non invasive ventilation. group ii (control): patients received only medical treatment and non invasive ventilation. all patients received medical therapy consisting of: ) controlled oxygen therapy. ) nebulized bronchodilator (salbutamol and anticholinergic drugs). ) intravenous corticosteroids. ) antibiotic strategy was based on empirical intravenous administration of levofloxacin plus b-lactam (for penicillin-allergic patients: levofloxacin plus aztreonam or carbapenem), unless some risk factors for pseudomonas aeruginosa were identified (ciprofloxacin plus anti-pseudomonal b-lactam). antibiotic-therapy was later adjusted according to the results of bacterial cultures [ ] . ) subcutaneous low-molecular weight heparin; and therapy for comorbidities if necessary. ) anti stress ulcer. non invasive ventilation was delivered in a pressure support (ps) mode with positive end-expiratory pressure (peep) or pressure controlled mode (bipap) via a well-fitting full-face mask with the addition of a heated humidifier [ ] . ps or inspiratory positive airway pressure (ipap) was initially set at cm h o and then titrated up to achieve an expiratory tidal volume of - ml/kg and a respiratory rate below breaths/ min to a maximum of cm h o depending on clinical and arterial blood gases (abgs) response and patient tolerance. peep or expiratory positive airway pressure (epap) was always set at up to cm h o to achieve optimal ventilation and oxygenation. back-up rr is set at a - breaths/min. fio was initially set at . - . then titrated down till reaching . or arterial oxygen saturation ranging between % and %. the time from initiation of niv to the bronchoscopy procedure was recorded. following bronchoscopy all patients remained on noninvasive ventilatory support for at least two hours. before, during and after bronchoscopy, level of conscious, the electrocardiogram, arterial blood pressure, pulse oximeter and ventilatory parameters (fio , ventilator mode, inspiratory and expiratory pressures, tidal volume, and respiratory rate) were continuously monitored. arterial samples were drawn for blood gas analysis from the arterial line at baseline, before and h after procedure. ventilator settings were adjusted to optimize ventilatory support. the fraction of inspired oxygen (fio ) was increased to % just before and throughout the procedure. fob was performed after the patients had adapted to nippv. a swivel connector (t-adapter) was inserted between the ventilator tubing and the mask to allow the insertion of the bronchoscope. sedation was achieved in all cases using midazolam ranging from . mg up to mg in incremental doses to achieve conscious sedation, before and after the insertion of the bronchoscope and can be repeated every three to five minutes according to patient tolerance. topical anesthesia of the nasopharynx ( % lidocaine spray solution) and larynx ( ml of % lidocaine hydrochloride were instilled via the bronchoscope channel to the laryngeal, tracheal and bronchial mucosa, not exceeding an overall dose of mg) was performed before advancing the bronchoscope into the tracheobronchial tree. firstly, a careful suction of bronchial secretions was performed to fully clear airways. then, the tip of the fob was wedged into the bronchial sub segment. bronchoalveolar lavage (bal) was performed by sequential instillation of five aliquots of ml saline solution at room temperature. the retrieved fluid was sent immediately to the microbiology laboratory for microscopic analysis and culturing. the isolated bacteria with a count of cfu/ml or more of the bal fluid were considered as etiological agents of infection. the duration of bronchoscopy was defined as the time from insertion until removal of the bronchoscope from the tracheobronchial tree [ , ] . after the bronchoscopic procedures, the fio decreased in order to maintain arterial oxygen saturation measured by the pulse oximetry (spo ) at - %. routine chest physiotherapy was done to facilitate expectoration. electrocardiogram, spo , and noninvasive blood pressure were monitored continuously. abgs were sampled as follows: at baseline, before, and at the end of fbo; and subsequently as clinically indicated. weaning nippv was applied continuously at least during the first - h. once clinical status and abgs had improved, nippv was administered intermittently with sessions lasting two to six hours three times daily. then ps or ipap was reduced progressively. nippv weaning was considered successful within three days of ventilation or more when all the following criteria are met for longer than h while breathing with oxygen (fio . ): ph above . , spo above %, rr less than breaths/min, fully conscious, efficient cough with a significant amount of sputum, radiographic improvement of chest infection and stable hemodynamic status [ ] . failure of nippv trial was considered if at least one of the following criteria for intubation was met: cardiac arrest or severe hemodynamic instability; respiratory arrest or gasping; and/or worsening of abgs or worsening of sensorium level during nippv. comparison between the two groups of the study regarding the abg data, the success of nippv in avoiding invasive mechanical ventilation, the duration of nippv, length of icu stay and mortality were recorded and analyzed statistically using appropriate statistical tests. this comparative case control prospective study was conducted on patients admitted to the critical care medicine department &respiratory intensive care unit in alexandria main university hospital by acute exacerbation of chronic obstructive pulmonary disease (copd) and fulfilling the criteria for application of non invasive positive pressure ventilation (nippv). patients were randomly assigned into two equal groups by allocated randomization: group i (cases): patients received conventional medical treatment plus early fiberoptic bronchoscopy during non invasive ventilation. group ii (controls): patients received only conventional medical treatment and noninvasive ventilation. comparison between the two studied groups according to arterial blood gases at different periods at admission, patients were initially managed with repeated sittings of bronchodilator nebulizer through a face mask with o flow - l/min, ph in group i ranged between . and . with a mean value of . ± . while in group ii, ph ranged between . and . with a mean value of . ± . with no statistical difference between both groups (p . ). six to twelve hours from admission during niv (before bronchoscopy), ph in group i ranged between . and . with a mean value of . ± . while in group ii, ph ranged from . to . with a mean value of . ± . with no significant statistical difference between both groups (p . ). - h from admission during niv ( h after bronchoscopy in group i), improvement of ph in group i ranged between . and . with a mean value of . ± . which was significantly better than values in group ii, as ph ranged from . to . with a mean value of . ± . (p . ). at admission on face mask with o flow - l/min, pco in group i ranged between . and . mmhg with a mean value of . ± . mmhg while in group ii, pco ranged between . and . mmhg with a mean value of . ± . mmhg with no statistical difference between both groups (p . ). six to twelve hours from admission during niv (before bronchoscopy), pco in group i ranged few complications developed during fob procedure. desaturation of arterial blood (sao less than %) displayed on the monitor occurred in / patients ( %). increased heart rate more than beats/minute occurred only in / cases ( %). ventilator settings before and after fob among group i inspiratory positive airway pressure (ipap) before fob ranged between . and . cm h o with a mean value of . ± . while after fob, it ranged between . and . with a mean value of . ± . with a significant statistical difference (p < . ). expiratory positive airway pressure (epap) before fob was ranging from . to . cm h o with a mean value of . ± . while after fob, it was significantly less as it ranged between . and . with a mean value of . ± . (p < . ). frequency before fob was ranging between and breaths per minute with a mean value of . ± . which was significantly less after fob, as it ranged between and with a mean value of . ± . (p < . ). also fraction of inspired oxygen (fio ) showed a significant decrease after the bronchoscopy as it was ranging from % to % with a mean value of . ± . before fob versus - % with a mean value of . ± . after fob (p < . ). outcome was evaluated as regards success of weaning from niv, total duration of niv in succeeded cases, length of icu stay, and mortality rate during hospitalization. in group i, cases ( %) have been successfully weaned from nippv while only cases( %) failed on nippv and intubated while in group ii , cases ( %) have been successfully weaned from nippv while cases ( %) failed on nippv and intubated with a significant statistical difference in favor of group i (p = . ). total duration of niv in succeeded cases in group i ranged between . and . h with a mean value of . ± . while in group ii, it ranged from . to . h with a mean value of . ± . with a significant statistical value between both groups (p . ). as regards the length of intensive care unit (icu) stay in group i, it ranged between . and . days with a mean value of . ± . while in group ii it ranged from . to . days with a mean value of . ± . with a significant statistical value between both groups (p . ). only one case ( %) in group i died versus cases ( %) in group ii with no significant statistical value between both groups (p = . ). alert, follows complex three-step command (i.e., take a sheet of paper, tear it into four pieces and place three pieces in one pile) alert, follows simple commands (show me two fingers) lethargic, but arousable and follows simple commands stuporous, i.e., only intermittently follow simple command even with vigorous attempts to arouse patient comatose, brain stem intact comatose with brain stem dysfunction table comparison between the two studied groups according to o index at different periods of follow up. bacteriological study of the bal revealed no growth in / cases ( %) while / cases ( %) had positive findings. staphylococcus auerus in cases, pseudomonas aeuroginosa was found in cases while candida was found in cases. escherichia coli, proteus, and klebsiella were found only once in different patients. arterial blood gases' analysis showed an almost similar baseline ph with a mean value of . ± . in group i versus . ± . (p . ) in group ii. relative improvement in the ph was noticed in a similar pattern in both groups after the application of nippv (before bronchoscopy) as mean value of ph in group i improved to . ± . while in group ii, the mean value became . ± . with no significant statistical difference between both groups (p = . ). significant difference in ph was noticed in favor of group i after the bronchoscopy as the mean value of ph was . ± . which was significantly better than values in group ii, as ph mean value was . ± . (p = . ). these changes in ph after the application of the bronchoscopy are comparable to the study done by scala et al. [ ] as ph was initially . improved to . after application to nippv, it remained . during bronchoscopy and improved significantly to . after bronchoscopy (p < . ). scala et al.'s study was the first study performed to assess the role of fob during nippv in patients with decompensated copd while the main difference that the control group in that study was patients on invasive mechanical ventilation and community acquired pneumonia was the etiology of decompensation in both studied groups. similar changes were noticed in the pco as the initial mean value in mmhg was . ± . improved to . ± . after application of nippv, with significant further improvement after the bronchoscopy to . ± . in group i while in group ii the readings were . ± . , . ± . and . ± . , respectively. significant difference was detected only in the third readings (after doing the bronchoscopy in group i and nearly at the same time in group ii) with p = . * . comparing these results with scala et al.'s [ ] results, we can observe a similarity in the two studies in the trend of pco in mmhg as it was , and in the initial setting, during nippv and after fiberoptic bronchoscopy, respectively. the oxygenation index was low in both groups at the baseline with mean values of . ± . and . ± . in group i and ii, respectively, and then it started to show some improvement in both groups after the application of the nip-pv. significant improvement in oxygenation was seen in group i compared to group ii after doing bronchoscopy in group i as the mean value was . ± . in group i versus . ± . in group ii (p . ). the baseline readings are comparable to scala et al.'s [ ] study as it was then increased to during nippv, but in contrast to the present study pao /fio dropped after bronchoscopy to . this can be explained by the different timing of sampling post bronchoscopy in the two studies as we preferred to postpone the sampling in the current study h post bronchoscopy as long as no significant drop in oxygen saturation was recorded by oximetry to avoid recording the immediate relative desaturation which is expected after bronchoscopy which may mask the real improvement in oxygenation after clearing the secretions from the lung during bronchoalveolar lavage. besides the etiology of decompensation in scala study was community acquired pneumonia while in my study was different factors including upper and lower respiratory tract infections, environmental factors, atopy, discontinuation of maintenance medical treatment, and another medical illness. considering the limited data on the application of fob during nippv in copd patients, it was very important to record the complications related to fob in group i of the study to validate the safety of the procedure in this specific setting and compare it to overall rates of fbo related complications in other studies. few complications developed during fob procedure. desaturation of arterial blood (sao less than %) displayed on the monitor occurred in / patients ( %) but it was not clinically significant to prevent the completion of the procedure and it was temporary for few minutes and easily manageable through temporary increase in ps or ipap on nippv and enhancing the procedure. another complication was encountered in the form of increased heart rate more than beats /minute which occur in only / cases ( %) and it was mostly related to the light sedation as it disappeared with the administration of extra doses of sedative drugs. however, no significant side effects as vomiting, cardiovascular events, pneumothorax and bronchospasm happened during the procedure. the lack of major complications is consistent with previous reports, which clearly demonstrated the feasibility and safety of fbo plus bal performed under the assistance of nippv in patients with severe hypoxemic and hypercapnic arf who should have to be otherwise intubated to allow such invasive procedures [ ] [ ] [ ] [ ] [ ] . this was also in agreement with a feasibility study done by hans jo¨rg baumann et al. [ ] to assess the safety of fob in patients with acute hypoxemic respiratory failure requiring nippv, the average duration of bronchoscopy was . ± . min (range . - . min). in all cases bronchoscopy was completed without subsequent complications. two patients developed transient sao values below % during the procedure, the minimum sao was % (tables - ) . the application of fob in group i patients provided an additional benefit apart from the drainage of copious secretions and clearing the airway which is the provision of early accurate sampling of tracheal and alveolar secretions for microbiological examination. this analysis was greatly helpful to reach an accurate diagnosis and started a targeted antibiotic , we can notice that the same organisms were isolated from both studies with the only exception of the streptococcus pneumonia which was not isolated from the current study although it is known to be the first causative organism for community acquired pneumonia and the second common organism in acute exacerbation after haemophilus influenza bacteria. this finding might be explained as a high proportion of patients in the present study were initially admitted to the hospital in the medical wards and shifted to critical care areas after developing decompensated respiratory failure and they might have got gram negative hospital acquired infections during their stay in addition to the preceding intake of oral antibiotic before admission which may alter classical pattern of microorganisms. analysis of the nippv settings before and after the application of fob showed significant improvement in all parameters after the procedure in the form of decrease in epap, ipap, respiratory rate and fio ( table ) with p value < . for all parameters. these findings demonstrate the clear benefit of the fob as a synergetic tool with nippv to minimize the work of breathing and oxygen requirement which was subsequently reflected in the form of lower ventilator setting. this beneficial effect was mainly due to clearance of secretions and also due to recruiting the partially atelectatic alveoli by washing of mucous plugs. in group ii, cases ( %) have been successfully weaned from nippv while cases ( %) failed and required intubation and mechanical ventilation. most of them failed due to accumulation of secretions with subsequent deterioration of the abg findings and depressed consciousness level. comparing this failure rate ( %) with another study also done by raffaele scala et al. [ ] in on patients with acute respiratory failure, nippv failed in of patients ( . %) which is near to our study. in another study done by carlucci a et al. [ ] studying noninvasive versus conventional mechanical ventilation, patients out of patients ( % of all niv patients) eventually required endotracheal intubation while in group i of the present study, the failure rate on nippv is significantly less than group ii as only patients failed out of patients ( %). in scala et al.'s [ ] study which is the only study done to assess the effect of early fbo during nippv, the technique failed in of patients ( %). the discrepancy between the ratios in the two studies cannot be explained due to the small number of patients which make any statistical analysis or correlation unreliable. besides the etiology of decompensation in scala study was community acquired pneumonia while in my study was different factors which were less medically serious than pneumonia. the total duration of niv in succeeded cases in group i ( patients) ranged between . and . h with a mean value of . ± . while in group ii ( patients), it ranged from . to . h with a mean value of . ± . with a significant statistical value between both groups (p . ) denoting the possible beneficial effect of fob in facilitation of faster weaning after removing the secretions and improvement of blood gases. the duration of nippv in group ii is more or less comparable to raffaele scala et al.'s [ ] study as nppv was delivered for a median duration of . h ( . to h) (mean duration for the first day, . h [sd, . h]) for a median duration of . days. in another study done by carlucci aetal [ ] the mean length of niv according to the reason for mechanical ventilation was . days (range: - days) in hypoxemic arf, . days (range: - days) in hypercapnic arf, and . days (range: - days) in pulmonary edema (tables and ). the length of intensive care unit (icu) stay in group i was significantly shorter in group i compared to group ii (p . ). this is explained by the faster improvement in patients of group i and less incidence of intubation and mechanical ventilation which definitely lead to the prolongation of icu stay in group ii .comparing the length of icu stay in group ii where we apply nippv without fob with another similar matching group of nippv in carlucci a et al. [ ] study, a high degree of similarity exists as the length of stay in the present study was ranging from . to . days with a mean value of . ± . days while it was . ± . days in the nippv group in the other study. only one case ( %) in group i died versus cases ( %) in group ii with no significant statistical difference between both groups (p = . ). comparing the mortality in group i to the mortality in scala et al.'s [ ] study, where out of patients ( %) died, it was found that it is much less in our study. this can be attributed to the etiology of decompensation in scala study was community acquired pneumonia while in my study was different factors less in severity. however, the interpretation of data in this limited number of patients is unreliable. the mortality in group ii ( %) came in agreement with most of the studies applied on nippv for hypercapnic respiratory failure, as an example the mortality in carlucci a et al. [ ] study was % ( out of patients). minor change in this percentage of mortality between different studies can be understood in the light of different levels of care and experience in different centers as well as different baseline characteristics of the studied groups of patients. finally, it is obvious that the application of fob was safe and beneficial for patients in the present study in terms of outcome and also in reducing the economic burden of patient care by reducing the number of patients who need invasive mechanical ventilation as well as shorter stay in icu. however, the selection of patients -managed by nippv in whom application of fbo will be beneficial remains a clinical decision to be done by the treating physician based on the overall clinical condition of the patient and his initial response to treatment on nippv and also the available resources and the skills of the physician in the provision of fob with minimal risk of complications. with the application of more randomized clinical trials on the role of bronchoscopy in the setting of ahrf, a clear consensus and precise guidelines might develop in the future emphasizing its application as a standard of care during nippv. the limitations of the study are related mainly to the limited sample size of patients ( cases and controls). however, this can be explained by the difficult recruitment of patients fulfilling the matching criteria to be involved in the study as the patients were recruited over a period of months, considering also the novelty of the research as it was the first time -to the best of our knowledge -to investigate the role of fbo during nippv in aecopd patients as scala et al.'s [ ] study published in did not compare between two groups of patients of nippv as we did. the control group in scala et al.'s [ ] study was patients on invasive ventilation. we totally agree that this study was very important and a pioneer but we are claiming that our study design and objectives are more reasonable and the results we reached in our pilot study can be considered a preliminary cornerstone and starting point for further investigations in the same topic through a multicenter study to provide adequate sample size in a reasonable duration. another limitation is related to some technical difficulties in the early provision of fbo during the course of nippv as we were planning to do the procedure within the first h from the patient admission. however, the unavailability of skilled personnel to do the bronchoscopy in a safe way in many times delayed the procedure to - h more than the initial plan, all patients who underwent bronchoscopy later than h from admission were omitted from the study. in another study done by hans jo¨rg et al. [ ] on the role of the fob in patients with acutehypoxemic respiratory failure requiring nippv the median duration of continuous niv prior to bronchoscopy was . h. the last considered limitation in the present study is the unavailability of the sedative drug dexmedetomidine (precedex) in the egyptian market which would be definitely a better choice to provide adequate and safe sedation during fob without compromising the respiration or cardiovascular stability of the patients. however, with the provision of titrated sedation of midazolam under the supervision of highly experienced intensivists, we were able to provide adequate sedation during bronchoscopy with no serious complications [ , ] . global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: executive summary . global initiative for chronic obstructive lung disease (gold) standards for the diagnosis and treatment of patients with copd: a summary of the ats/ ers position paper copd exacerbations. : aetiology antibiotic therapy in exacerbations of chronic obstructive pulmonary disease utilization of noninvasive ventilation in acute care hospitals: a regional survey increased use of noninvasive ventilation in french intensive care units effects of noninvasive ventilation on pulmonary gas exchange and hemodynamics during acute hypercapnic exacerbations of chronic obstructive pulmonary disease bronchoscopy in the intensive care unit bronchoscopy: common problems and solutions bronchoscopy prevalence and severity of neurological dysfunction in critically ill patients. influence on need for continued mechanical ventilation medicine consensus conference: definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis full and partial ventilatory support. the significance of ventilator mode continuous positive airway pressure during fiberoptic bronchoscopy in hypoxemic patients. a randomized double-blind study using a new device noninvasive versus conventional ventilation to treat hypercapnic encephalopathy in copd early fiberoptic bronchoscopy during noninvasive ventilation in patients with decompensated chronic obstructive pulmonary disease due to communityacquired-pneumonia noninvasive positive pressure ventilation via face mask during bronchoscopy with bal in high-risk hypoxemic patients continuous positive airway pressure during fiberoptic bronchoscopy in hypoxemic patients. a randomizeddouble-blind study using a new device fiberoptic bronchoscopy during nppv in patients with chronic obstructive lung disease with hypoxemia and hypercapnia fiberoptic bronchoscopy during noninvasive positive pressure ventilation delivered by helmet noninvasive mechanical ventilation for diagnostic bronchoscopy using a new face mask: an observational feasibility study fiberoptic bronchoscopy in patients with acutehypoxemic respiratory failure requiring noninvasive ventilation -a feasibility study noninvasive positive pressure ventilation in patients with acute exacerbations of copd and varying levels of consciousness epidemiologic survey icu sedation after coronary artery bypass graft surgery: dexmedetomidine-based versus propofol-based sedation regimen calming patients agitation with dexmedetomidine none. key: cord- -y vkpuv authors: nan title: global initiative for chronic obstructive lung disease strategy for the diagnosis, management and prevention of chronic obstructive pulmonary disease: an asia–pacific perspective date: - - journal: respirology doi: . /j. - . . .x sha: doc_id: cord_uid: y vkpuv abstract: chronic obstructive pulmonary disease (copd) is a major public health problem and its prevalence and mortality are increasing throughout the world, including the asia–pacific region. to arrest these worldwide trends, the global initiative for chronic obstructive lung disease (gold) expert panel's global strategy for the diagnosis, management, and prevention of copd was published in . based on recently published clinical trials, the gold statement was updated in . the asia–pacific copd roundtable group, a taskforce of expert respirologists from the asia–pacific region, has recently formulated a consensus statement on implementation of the gold strategy for copd in the asia–pacific region. the key issues identified by the copd roundtable group for comment are: (i) where there is no access to spirometry, diagnosis of copd could be suspected on the basis of history, symptoms and physical signs; (ii) inhaled bronchodilators are the preferred regular treatment for copd in the region, but oral bronchodilators may be considered if the cost of inhaled bronchodilators is a barrier to treatment; (iii) the use of an metered dose inhaler with spacer in place of a nebulizer is recommended in the treatment of acute airflow obstruction in patients with copd; (iv) influenza vaccination is recommended for all patients with copd in communities where there is a high likelihood of severe acute respitory syndrome; and (v) simplified pulmonary rehabilitation programmes should be established in areas where comprehensive programmes are unavailable. physical exercise training and education on smoking cessation should be core elements of any rehabilitation program. in summary, the copd roundtable group supports implementation of the gold strategy for the diagnosis, management and prevention of copd in the asia–pacific region, subject to the additions and modifications to the guidelines suggested above. chronic obstructive pulmonary disease (copd) is a major public health problem throughout the world. a world health organization (who)/world bank study estimated the worldwide prevalence of copd in to be . / in men and . / in women. , copd was estimated to be the sixth most common cause of death globally, and the twelfth most common cause of burden of disease worldwide. furthermore, copd is expected to increase in prevalence and mortality over the coming decades. for example, of the four leading causes of death in the usa, copd is the only one that continues to increase in prevalence. copd is also projected to be the fifth greatest cause of worldwide burden of disease in , and the third most common cause of death internationally. copd is associated with huge economic costs. in the uk for example, copd accounts for % of all working days lost, and in the usa, the estimated annual cost of copd is over us$ billion. relatively little is known about the prevalence, morbidity and mortality of copd in developing countries, including those in the asia-pacific region. a recent study in thailand estimated the prevalence of copd in to be per people at risk (smokers aged ≥ years), but this estimate is based on the number of people hospitalized with copd and, therefore, represents only the prevalence of moderate to severe disease. a who/world bank study, , which estimated the prevalence of copd in different areas of the world (using informed expert opinion or extrapolations from comparable regions where published data were lacking), suggested that the prevalence of copd in china in was . / in males and . / in females. these estimates have been challenged by recent reports of an overall copd prevalence of . % ( per people aged ≥ years) in three regions of china. the who/world bank study also estimated a copd prevalence of . / in males and . / in females in for 'other asia and islands' (an amalgam of countries and island states in the asia-pacific region). , furthermore, data from that study were used to extrapolate a copd prevalence figure of . % ( per people) for the entire asian population. these estimates, which are not necessarily based on actual epidemiological data, do not provide reliable information about the precise prevalence of copd in the asia-pacific region. this in turn means that governments are unaware of the regional economic and human impact of copd, and are, therefore, unable to plan effective strategies for reducing the burden of disease. large-scale, population-based, epidemiological studies are logistically difficult and expensive to conduct. an alternative method for assessing copd prevalence that makes use of a well-validated computerized tool for predicting prevalence on the basis of local copd risk factor data (prevalence of smoking, exposure to biomass fuel, air pollution, high-risk occupations etc.) has shown that the overall pre-valence of clinically significant copd amongst adults ≥ years old in the asia-pacific region is approximately . %. these data suggest that copd is a more significant problem in the region than has been previously realised. furthermore, trends in risk factors (increased incidence of smoking, greater longevity with associated increased risk of succumbing to chronic diseases such as copd, and increased exposure to environmental pollution) suggest that the prevalence of copd in the asia-pacific region is likely to increase over coming years. in , an international group of copd experts met to discuss the development of a global initiative for chronic obstructive lung disease (gold). cosponsored by the us national institutes of health (heart, lung, and blood institute (nhlbi)) and who, the gold expert panel consisted of health professionals from around the world with expertise in respiratory medicine, epidemiology, socioeconomics, public health, and health education. the model for this initiative was the global initiative for asthma (gina), an international strategy for developing comprehensive evidence-based guidelines on asthma control and management, using a committee of experts. the gold expert panel agreed that the objectives of gold should be to increase awareness of copd (amongst governments, public health officials, healthcare workers, and the general public), improve prevention and management of the disease, decrease copd morbidity and mortality, and encourage new research into the disease. in , the gold expert panel conducted a workshop to review existing copd guidelines and advances in understanding of the disease, the ultimate aim being to prepare a consensus guidelines document/global strategy for the diagnosis, management, and prevention of copd. this was published, in both full workshop report and executive summary forms, early in . updated gold guidelines, , based on clinical research published from june to march that has had an impact on the management of copd, were published in july . these reports present evidence-based guidelines on copd diagnosis and management, and, importantly, include grades (a, b or c) for the weight of scientific evidence supporting each recommendation. the gold strategy presents a copd management plan divided into four components: (i) assessment and monitoring of disease; (ii) reduction of risk factors; (iii) management of stable copd; and (iv) management of exacerbations. information and recommendations presented in the gold report are based on 'best-validated current concepts of copd pathogenesis and the available evidence on the most appropriate management and prevention strategies'. the content of the report was developed by experts in copd research and clinical management, then extensively reviewed by other experts, scientific societies, the nhlbi and who, before publication. gold guidelines are to be audited after implementation to assess the impact of the programme on outcomes. the updated gold guidelines include the following changes: (i) the classification system has been modified to: i = mild, ii = moderate, iii = severe, iv = very severe; (ii) for moderate to very severe copd, the use of regular treatment with long-acting bronchodilators, including tiotropium, rather than short-acting bronchodilators is recommended (evidence level a); (iii) inhaled glucocorticosteroids are recommended only in patients with copd of severity iii and frequent exacerbations (evidence level a); (iv) rehabilitation programmes should be ≥ months in duration (evidence level b); and (v) nurse-administered home care represents an effective and practical alternative to hospitalization in selected patients with exacerbations of copd without acidotic respiratory failure. while the gold recommendations are intended to have universal applicability, the expert panel drew attention to some possible difficulties in the implementation of gold recommendations in developing countries. thus, the gold expert panel noted: that 'reproducible and inexpensive exercise-testing methodologies . . . suitable for use in developing countries need to be evaluated and their use encouraged'; that 'spirometers need to be developed that can ensure economical and accurate performance when a relatively untrained operator administers the test'; and that 'methods and strategies for implementation of copd management programs in developing countries will require special attention'. thus, the gold expert panel acknowledged that some aspects of the gold guidelines may require amendments to ensure their relevance, applicability and usefulness in developing countries. in the asia-pacific region, this task has been taken up by the asia-pacific copd roundtable group. the copd roundtable group is a taskforce of expert respirologists from the asia-pacific region that has met - times per year since july . the copd roundtable group has the support of the asia-pacific society of respirology (apsr) and is supported by an educational grant from boehringer ingelheim and pfizer. the main objectives of the copd roundtable group are to: (i) increase awareness of copd in the region; (ii) assess the regional relevance and applicability of the gold guidelines and facilitate their implementation; (iii) identify copd-related problems specific to the region for discussion and resolution; (iv) stimulate regional collaborative research into copd. as noted above, however, one of the main reasons for the establishment of the copd roundtable group was to facilitate regional implementation of gold guidelines; to this end, the roundtable group has developed a consensus statement on the implementation of the gold strategy for copd in the asia-pacific region. the relevance and practicality of the gold recommendations for the region were considered by the copd roundtable group at several meetings. during this review process, roundtable members focused on the implications of implementing the gold strategy in their own countries, taking into account both local published data and members' experience of copd diagnosis, management and prevention in the region. on the basis of these deliberations, the copd roundtable group concluded that implementation of gold recommendations would be very useful in the asia-pacific region. particular strengths of the gold strategy identified by the roundtable included: (i) the emphasis on the need for spirometry in the diagnosis and assessment of copd; and (ii) the inclusion of a disease severity classification which recognized the importance of intervention at a presymptomatic disease stage. the copd roundtable group also endorses the gold guidelines on smoking cessation and in view of the immense burden of smokingrelated copd in the asia-pacific region believes that greater efforts to achieve smoking prevention and cessation should be encouraged in this part of the world. in addition, the copd roundtable group identified that some aspects of the gold guidelines require amendment to suit the needs of the region. these amendments are discussed below. the gold document unequivocally identifies spirometry as the gold standard for the diagnosis and assessment of copd because it is the most reproducible, standardized, and objective way of measuring airflow limitation. specifically, a fev to fvc ratio of < %, together with a postbronchodilator fev of < % predicted, confirms the presence of an airflow limitation that is not fully reversible. gold also states that 'health care workers involved in the diagnosis and management of copd patients should have access to spirometry'. , the copd roundtable group fully supports this recommendation and encourages the use of spirometry for the diagnosis and assessment of copd patients in the asia-pacific region. however, the roundtable group also notes that, for a number of reasons (e.g. costs, inaccessibility, lack of awareness, lack of technical knowledge etc.), spirometry is unavailable to large numbers of patients in many asian countries. the gold guidelines state: 'where spirometry is unavailable, the diagnosis of copd should be made using all available tools'. therefore, for the asia-pacific region, the copd roundtable group recommends addition of the following statement to the gold guidelines relating to the diagnosis and assessment of copd. where there is no access to spirometry, the diagnosis of copd could be suspected on the basis of history, symptoms and physical signs. if spirometry is not available, peak flow measurements can be used to exclude asthma but not to diagnose copd. a forced expiratory time (fet, which is the time taken for an individual to forcefully exhale through an open mouth, from total lung capacity until airflow becomes inaudible. the time taken to exhale should be recorded with a stopwatch; ≥ s is abnormally prolonged) † > s is a good guide to the presence of an fev /fvc ratio < % (i.e. obstructive disease). while chest x-rays are not recommended for diagnosing copd, they can be useful for excluding other common diseases that can give rise to airway obstruction (e.g. tuberculosis, bronchiectasis, lung cancer etc.). because there is very little correlation between peak flow measurement and symptoms in longitudinal studies of copd patients and copd patients can have improvements in symptoms and quality of life without improvements in lung function, the group does not recommend the use of serial measurements of peak flow to assess or monitor any response to therapy. the mrc dyspnoea scale, while not used for diagnosis of copd, is a functional scale that is useful for assessing shortness of breath and disability, and can assist in the evaluation of disease severity. gold recommends inhaled bronchodilators as the preferred option for symptomatic management in stable copd, either as regular treatment or on an asneeded basis. , bronchodilator therapy prevents symptoms or reduces their severity, but does not modify the decline in lung function in copd. inhaled bronchodilator therapy is preferred over oral therapy because lower doses are needed to achieve a therapeutic response, and because adverse effects are less likely to occur, and resolve more rapidly after treatment withdrawal. the copd roundtable group supports the promotion of inhaled therapy as the preferred route of bronchodilator delivery for copd patients in the region. however, the roundtable group also notes that, in some asia-pacific settings, where the cost of therapy is not reimbursed and the patient has limited financial resources, oral bronchodilator treatment may be less expensive and is, therefore, an appropriate alternative to inhaled therapy. while emphasising that inhaled bronchodilators remain the preferred option (as stated in gold), the copd roundtable group recommends addition of the following statement to the gold guidelines relating to use of bronchodilators in the treatment of stable copd. wherever possible, copd patients should receive bronchodilator therapy via the inhaled route. however, oral bronchodilators ( b -agonists, theophylline) may be appropriate if the cost of inhaled bronchodilators is a barrier to treatment. the gold report notes: when treatment is given by the inhaled route, attention to effective drug delivery and training in inhaler technique is essential. copd patients may have more problems in effective coordination and find it harder to use a simple metered dose inhaler (mdi) than do healthy volunteers or younger asthmatics. it is essential to ensure that inhaler technique is correct and to recheck this at each visit. patients who have been prescribed drugs using mdi and have trouble mastering inhaler technique should attempt to use a spacer with the mdi. the copd roundtable group notes that use of spacers results in more efficient delivery of bronchodilator to the lungs compared to use of the mdi alone, particularly in patients who have not mastered the correct inhaler technique. furthermore, this approach is as effective as nebulized drug delivery in patients who have been taught how to use a spacer plus a mdi correctly. in these patients, alternative inhaler devices may also be tried to optimize the benefits of inhaled therapy. for example, dry powder inhalers (dpi) are breath activated and do not require the same level of hand-and-mouth coordination as mdi, so some copd patients may find these easier to use. for these reasons, the copd roundtable group recommends addition of the following statements to the gold guidelines relating to use of bronchodilators in the treatment of stable copd. patients who have difficulty mastering inhaler technique with the mdi should try the use of a spacer with the mdi. different types of spacers and inhaler devices should be experimented with in an attempt to identify a device that the patient can use easily and effectively. as with inhaler technique, patients require training in how to use a spacer effectively. this approach is more convenient than recommending treatment with a nebulizer. nebulizers may not be available for many copd patients in the asia-pacific region because they are expensive, require set-up, a power source and filling with a nebulizer solution. furthermore, in areas that are affected by severe acute respiratory syndrome (sars), it is thought that the risk of transmission of the virus may be reduced by the use of spacer devices. the asia-pacific region was severely affected by an epidemic of sars caused by a new coronavirus, with far-reaching health, societal and economic costs. the epidemic peaked in february to may . while the epidemic of sars has now been brought under control, the who warns that in the absence of a vaccine and a cure the possibility of a seasonal recurrence cannot be ruled out. it is important that sars is differentiated from other respiratory diseases, particularly from the 'triggers or mimics' of an acute exacerbation of copd. currently, there is no gold standard for diagnosis, which usually encompasses suspicion, isolation and then empirical use of antibiotics and supportive treatment. sars is thought to be transmitted via droplets and close contacts. however, airborne and other modes of transmission cannot be excluded. for this reason it is recommended that nebulized treatment in patients with copd be avoided. the use of spacer devices may help to reduce this risk. the use of an mdi with spacer in place of a nebulizer is recommended in the treatment of acute airflow obstruction in patients with copd in an attempt to reduce the risk of droplet transmission of respiratory infection such as sars. sars should be considered in the differential diagnosis of an acute exacerbation of copd and if sars is suspected the patient should be triaged accordingly. it is recommended that bronchodilator treatment should not be delayed or denied in patients with copd. in treating patients who are experiencing an acute exacerbation it is important to ensure that the bronchodilator dosage is adequate and titrated at frequent intervals based on patient response, when using a spacer instead of a nebulizer. it is recommended that appropriate ventilatory support should not be delayed or denied in patients with copd. the burden of suspected sars should be reduced by influenza vaccination of copd patients. the gold expert panel cites category a evidence that influenza vaccination can reduce serious illness and death in copd patients by approximately %. in light of this evidence, gold recommends vaccination against influenza for all patients with copd. vaccines that contain killed or live, inactivated viruses should be used since these have been shown to be more effective in elderly patients with copd. the gold guidelines add that influenza strains are adjusted annually for appropriate effectiveness and should be given once (in autumn) or twice (in autumn and winter) each year. , the copd roundtable group notes that influenza vaccination is not routinely offered to copd patients in asia, but is given by some pulmonologists or in response to patient requests. furthermore, a review of the literature shows that there is a knowledge gap with respect to use of influenza vaccination in the region, particularly in patients with copd. in early deliberations there were some reservations regarding vaccination of copd patients. however, this has been reevaluated in the context of new information from recent clinical trials of the efficacy of influenza vaccination and the sars epidemic within the asia-pacific region. [ ] [ ] [ ] with these considerations in mind, the copd roundtable group recommends addition of the following statements to the gold guidelines relating to influenza vaccination in patients with copd. influenza vaccination is highly recommended for all copd patients within the asia-pacific region where there could be a recurrence of sars which mimics the clinical presentation of influenza. patients should be vaccinated - months prior to the anticipated peak incidence of influenza. while the copd roundtable group recommends vaccination of all patients with copd in communities where there is a high likelihood of sars, there remain some issues regarding the implementation of influenza vaccination for copd patients in the asia-pacific region, for the following reasons: (i) low surveillance data from tropical countries; (ii) apparent lack of bimodal seasonality in tropical countries; (iii) uncertainty of appropriate frequency or timing of vaccines; (iv) the presence of two potential vaccine formulations to coincide with influenza strains emerging in february and september; (v) limited efficacy data on vaccination in tropical countries; and (vi) lack of cost-effectiveness and cost-savings studies. in countries with bimodal peaks or a relative lack of seasonality of influenza infection, the choice of when to vaccinate is left to physicians. gold lists the main goals of pulmonary rehabilitation programmes in patients with copd as reduction of symptoms, improved quality of life, and increased physical and emotional participation in everyday activities. these goals are achieved by attending to problems such as exercise deconditioning, social isolation, depression/other mood disturbances, muscle wasting, and weight loss. since these problems particularly affect patients with stage ii (moderate), stage iii (severe) or stage iv (very severe) copd, gold recommends that patients in these subgroups should be enrolled in pulmonary rehabilitation programmes. , however, the gold guidelines also point out that category a evidence indicates that copd patients at all stages of disease benefit (in terms of exercise tolerance and symptoms of dyspnoea and fatigue) from exercise training programmes. , as noted in the gold document, pulmonary rehabilitation has been carefully evaluated in a large number of clinical trials. these have yielded category a evidence that pulmonary rehabilitation improves exercise capacity, reduces perceived intensity of breathlessness, improves health-related quality of life, reduces the number of hospitalizations and days in hospital, and reduces anxiety and depression associated with copd. there is also category b evidence that pulmonary rehabilitation improves arm function with strength and endurance training of the upper limbs, provides benefits that extend well beyond the immediate period of training (provided home exercise training is continued after the programme ends), and improves survival in patients with copd. the gold guidelines also note that pulmonary rehabilitation programmes ideally involve several types of health professionals. however, significant benefits can also be attained by more limited personnel, so long as the healthcare professionals concerned are aware of the needs of individual patients. the updated gold guidelines recommend a duration of ≥ months for pulmonary rehabilitation. a comprehensive pulmonary rehabilitation programme includes: exercise training : as assessed by to -min sessions of bicycle ergometry, treadmill exercise, walking tests etc., at up to % peak oxygen consumption or until symptoms intervene, on a daily to weekly basis. nutrition counselling : nutritional state is an important determinant of symptoms, disability and prognosis in copd, with both overweight and underweight patients potentially having problems. how-ever, nutritional therapy without an accompanying exercise regimen may not be helpful. education : while education of the patient is a component of most pulmonary rehabilitation programmes, its specific contribution to the improvements seen after pulmonary rehabilitation remain unclear. the gold guidelines also emphasize that baseline and outcome assessments should be made for each participant in a pulmonary rehabilitation programme so that individual gains can be quantified and appropriate areas targeted for improvement. assessments should include history and physical examination, pre-and post-bronchodilator spirometry, exercise capacity, health status and the impact of breathlessness, inspiratory and expiratory muscle strength, and possibly lower limb strength in patients with muscle wasting. the copd roundtable group recognizes that pulmonary rehabilitation is one of the most effective management strategies for patients with copd. therefore, its use and benefits should be promoted to copd patients, healthcare professionals, funding agencies, and governments in the region. unfortunately, comprehensive pulmonary rehabilitation programmes, as described in gold, are beyond the means of many asian healthcare systems and, therefore, unavailable to most patients in the region. indeed, the difficulties of providing pulmonary rehabilitation programmes in developing countries, with reduced resources available for healthcare, may be better appreciated when it is considered that in a developed country such as canada, < % of the copd population per annum has access to pulmonary rehabilitation programmes. physicians in the asia-pacific region who are unable to refer copd patients to established pulmonary rehabilitation programmes are unlikely to be able to organize the complex, multidisciplinary types of programmes described in the literature. however, they may be able to organize the 'next best' alternative, that is, less complicated programmes which include only the most important components of pulmonary rehabilitation. minimum elements of pulmonary rehabilitation which could be made available in simplified programmes involving limited numbers and types of healthcare professionals include: (i) basic exercise tests, for example, -min walking distance tests; (ii) regular (daily if possible) exercise, for example, walking to a symptom-limited maximum, then resting, then continuing to walk until min of exercise has been completed; and (iii) educating patients about how to minimize exposure to other copd risk factors, such as smoking, indoor air pollution due to biomass fuels and occupational hazards. the above measures, which could be included in simplified pulmonary rehabilitation programmes, would be expected to benefit copd patients who do not have access to more intensive and complete programmes. on this point, it is pertinent to note that pulmonary rehabilitation programmes conducted in the home have been associated with benefits for copd patients. , with the above considerations in mind, the copd roundtable group recommends addition of the following statements to the gold guidelines relating to pulmonary rehabilitation in patients with copd. although there is limited evidence within the region, simplified pulmonary rehabilitation programs which include the crucial elements of regular exercise training and patient education have been found to be workable and are recommended. exercise training programs involving simple, structured elements (a baseline -min walking test to determine workload requirements, followed by regular sessions of walking for min and, ideally, upper limb exercises) are pivotal to the success of a pulmonary rehabilitation program. patient education initiatives may be undertaken by trained physiotherapists to improve patient awareness of the importance of smoking cessation in the management of copd. such initiatives will aid in enhancing patient co-operation and improving rapport between the patient and physiotherapist. the gold strategy for the diagnosis, management and prevention of copd is an important initiative which is relevant and useful for the asia-pacific region. the copd roundtable group agrees with the content and recommendations of the gold strategy, and supports implementation of the programme as a means of helping to prevent copd and improving diagnosis and management of the disease in the region. the only respects in which the views of the copd roundtable group diverge from those of the gold guidelines are expressed in the specific modifications outlined in the text above. as noted, the copd roundtable group statement on the gold guidelines represents the consensus view of members of the group. before publication, however, the statement was presented as a 'working document' for discussion/feedback at the october meeting of apsr in taipei. clarification of some of the key messages articulated by the copd roundtable group may be warranted to avoid misinterpretation. with regard to spirometry, the roundtable group is keen to emphasize both the key role of this tool for diagnosing and assessing copd, and the pressing need for greater availability of spirometers in the region. the roundtable group urges that the gold recommendations on this issue be used to mount pressure not only on regional governments and health funding agencies to finance wider access to spirometry in the region, but also on manufacturers to provide cheap but efficient spirometers. however, economic considerations are not the only barriers to use of spirometry in asian countries; others include lack of demand for/recognition of the need for spirometric testing (by patients, healthcare professionals, and health administrators/ policymakers), lack of technical knowledge and expertise in the use of spirometers, and inappropriate emphasis on reporting, diagnosing and managing symptoms (as opposed to lung function) in patients with copd. for these reasons, it is vital to note that the copd roundtable group recommends that a diagnosis of copd can be suspected on the basis of symptoms, physical signs and history only when spirometry is unavailable. the other important implication of this statement is that diagnosis of copd by repeat peak expiratory flow measurements or chest x-ray appearances in these circumstances is not recommended. similarly, none of the other recommendations made by the copd roundtable group should be interpreted as contravening gold recommendations. the roundtable group notes that the inhaled route is the preferred means of bronchodilator delivery for copd patients. oral bronchodilators should only be used when there is no affordable inhaled alternative for the patient. similarly, the roundtable group agrees that enrolment of copd patients in 'standard' pulmonary rehabilitation programmes is the preferred option, and one which should be promoted as much as possible, but suggests that participation in a simplified programme is better than no pulmonary rehabilitation at all. with respect to experimenting with spacers before using nebulizers, this is also consistent with the discussion of bronchodilator therapy presented in the full workshop report of the gold strategy. this approach should be tried in patients who are unable to master inhaler technique with a mdi. health professionals caring for copd patients should take the time to educate patients about correct inhaler technique and to check on correct technique during follow-up consultations. in some countries such as the philippines, there is a high rate of nebulizer use, and this has prompted the copd roundtable group to include a specific endorsement of the use of spacer devices before resorting to nebulization. finally, gold recommends influenza vaccination for all patients with copd, and in light of the recent sars epidemic the copd roundtable group supports this recommendation. however, because of limited evidence regarding influenza vaccination within the asia-pacific region, the roundtable group suggests that in countries which lack seasonality of influenza, the choice of vaccination should be left to physicians. adherence to copd guidelines has been shown to not only improve clinical outcomes but also to lower healthcare costs in a us teaching hospital setting. while findings from studies conducted in developed countries cannot automatically be extrapolated to healthcare systems in developing countries, the copd roundtable group considers that implementation of the gold strategy for prevention, diagnosis and management of copd in the asia-pacific region would confer similar types of clinical and economic benefits. it is hoped that the additions and modifications to the gold guidelines suggested by the copd roundtable group will further enhance the applicability and usefulness of these guidelines in the region. finally, the copd roundtable group acknowledges that there is a need for regional studies evaluating these consensus recommendations. clinical data, for example, on the efficacy of pulmonary rehabilitation programmes and the diagnosis of copd with or without spirometry, will lend support to and enable further refinement of this consensus statement. evidence-based health policylessons from the global burden of disease study the global burden of disease: a comprehensive assessment of mortality and disability from diseases, injuries and risk factors in and projected to global mortality, disability, and the contribution of risk factors: global burden of disease study economic burden of chronic obstructive pulmonary disease. impact of new treatment options chronic obstructive pulmonary disease: new opportunities for drug development american lung association fact sheet: chronic obstructive pulmonary disease (copd) chronic obstructive pulmonary diseases in thailand: incidence, prevalence, present status and future trends the impact of tobacco on lung health in china chronic obstructive pulmonary disease: a prevalence estimation model asia-pacific countries and regions: projections based on the copd prevalence estimation model global initiative for asthma. global strategy for asthma management and prevention. nhlbi/who workshop report. national institutes of health. national heart, lung and blood institute, publication no. - global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease hurd ss for the gold scientific committee. global strategy for the diagnosis, management and prevention of copd update global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease canadian thoracic society copd guidelines: summary of highlights for family doctors comparison of the effectiveness of inhaler devices in asthma and chronic obstructive airways disease: a systematic review of the literature overview on sars in asia and the world who says sars outbreak is over, but fight should go on sars: hospital infection control and admission strategies evidence-based to acute exacerbations of copd influenza vaccination for the - season: recommendations in the context of concern about sars update : preparing for the next influenza season in a world altered by sars acute respiratory illness in patients with copd and the effectiveness of influenza vaccination: a randomized controlled study pulmonary rehabilitation programs in canada: national survey a simple pulmonary rehabilitation program improves health outcomes and reduces hospital utilization in patients with copd unconditional educational grants from boehringer ingelheim and pfizer covered the costs of the group's meetings and the writing of the consensus statement. the deliberations of the group were free of any influence from the funding companies. members of the asia pacific copd roundtable group have acted as consultants for several pharmaceutical companies, including boehringer ingelheim and pfizer, and have spoken at meetings sponsored by pharmaceutical companies, including boehringer ingelheim and pfizer. key: cord- -r jqmes authors: althani, asma; bushra, sumbul; shaath, noor; sattar, hisham a. title: characterisation of winter respiratory viral infections in patients with asthma and copd in qatar date: - - journal: arch virol doi: . /s - - - sha: doc_id: cord_uid: r jqmes respiratory viruses in patients with chronic obstructive pulmonary disease (copd) or asthma have not been characterised in qatar. this study aimed to identify the most common viral strains responsible for respiratory tract infections in asthma/copd patients (without exacerbations) in qatar during the winter season ( - ). nasal swabs from patients with asthma/copd and respiratory symptoms were evaluated for common viruses. adult patients ( with asthma and with copd) were enrolled. viral infections were present in out of patients ( %). cough and wheezing were the most common symptoms. rhinovirus was the most common causative agent, followed by coronaviruses. our findings confirm previous reports of rhinovirus prevalence in respiratory tract infections in asthma/copd. a countrywide survey to confirm our findings is warranted. abstract respiratory viruses in patients with chronic obstructive pulmonary disease (copd) or asthma have not been characterised in qatar. this study aimed to identify the most common viral strains responsible for respiratory tract infections in asthma/copd patients (without exacerbations) in qatar during the winter season ( ) ( ) . nasal swabs from patients with asthma/copd and respiratory symptoms were evaluated for common viruses. adult patients ( with asthma and with copd) were enrolled. viral infections were present in out of patients ( %). cough and wheezing were the most common symptoms. rhinovirus was the most common causative agent, followed by coronaviruses. our findings confirm previous reports of rhinovirus prevalence in respiratory tract infections in asthma/copd. a countrywide survey to confirm our findings is warranted. respiratory viruses in patients with underlying lung diseases such as chronic obstructive pulmonary disease (copd) or asthma are associated with exacerbations and excess morbidity and mortality. murphy et al. reported that influenza in patients with asthma can cause acute exacerbations, whereas in patients with copd, it can lead to respiratory distress [ ] . other common respiratory viruses, especially rhinoviruses, cause the majority of exacerbations in children and adults with asthma [ ] . johnston et al. carried out a study in the uk to investigate the role of viral infections in acute exacerbations of asthma in schoolchildren, and they reported that the most commonly identified virus type in this population was rhinovirus [ ] . in one of the earlier studies using pcr to detect respiratory viruses in adults, a respiratory virus was found in % of exacerbations ( % rhinoviruses) [ ] . rhinovirus infection has also been associated with nearly half of all chronic obstructive pulmonary disease (copd) exacerbations [ ] . furthermore, the presence of two or more viral agents may contribute to the severity of exacerbations. wilkinson et al. have reported that a total of % of copd exacerbations in the uk were associated with the bacterial pathogen haemophilus influenzae, and rhinovirus was identified in % of exacerbations [ ] . however, higher bacterial loads were observed in exacerbations with both rhinovirus and h. influenzae, thus suggesting that interaction between these pathogens may contribute to exacerbation severity [ ] . other viruses have also been implicated in exacerbation of asthma and copd symptoms. for example, ko et al. reported that the most prevalent viruses detected during acute exacerbations of copd in hong kong were influenza a virus and coronavirus [ ] . much of the morbidity, mortality, and excess health-care utilisation associated with asthma and copd are related to exacerbations [ ] . identifying viral aetiology associated with respiratory tract infections in asthma and copd is useful for the development of strategies for the prevention and treatment of infections leading to exacerbations in this vulnerable population. there is little data on the frequency of respiratory viruses in the middle east, particularly in qatar. in this study, we sought to determine the burden of respiratory viruses in adult patients with asthma/copd in qatar, using real-time reverse transcription polymerase chain reaction (rt-pcr). the objective of this study was to identify viral strains responsible for respiratory tract infection in asthma/ copd adult patients who visited the chest clinic in qatar during the winter season from october to march (corresponding to the annual peak in respiratory infections in qatar) in order to identify the viral pathogens involved. during october -march , adults with copd or asthma, seeking care at the chest clinic of the hamad medical corporation, qatar, with symptoms of upper respiratory tract infection were eligible for participation. all patients were outpatients at the time of recruitment. patients with lower respiratory tract infections were excluded. all of the patients were assessed clinically by the recruiting physician to ensure the absence of other significant respiratory diseases. all patients had at least five symptoms of respiratory tract infection (table ) but otherwise were stable and had no exacerbation of copd/asthma at the time of sample collection. the most common symptoms in all patients were dry cough and wheezing. medicines taken for asthma/ copd by the patients were not recorded in our study. routine testing for bacteria was not performed, because the primary objective of the study was to examine the frequency of viral pathogens that cause respiratory tract infections. nasal swabs were collected from the sample population (to detect any upper respiratory tract viruses) and sent to the health science department at qatar university for processing. the study protocol was approved by the research committee of hamad medical corporation. all study participants signed informed consent forms according to the recommendations of the hamad medical corporation research committee, which approved the study. nasal swabs were collected from the patient population. an aliquot of processed samples was frozen at - °c for subsequent rna extraction and polymerase chain reaction (pcr). rna extraction from the frozen samples was performed using a standard extraction kit ( the primers and probe were used at a concentration according to the manufacturer's instructions (ftd respiratory pathogen samples, mikrogen tm ). for all pcr amplifications positive and negative controls were included. as positive controls, the positive controls provided in the kit were used. negative controls were carried out with water instead of rna. pcr runs were carried out according to the standard taqman Ò pcr profile. amplification of target dna and detection of pcr products were performed using an abi machine. amplification of the target sequence was detected as an increase in fluorescence above a baseline with no or little change in fluorescence. in order to analyse the data, the reporter (fam) fluorescence was automatically normalised to a passive reference to avoid the measurement of non-pcrrelated fluorescence. a threshold was set above the baseline, and the threshold cycle value (ct) was defined as the cycle number at which the fluorescence passes the fixed threshold and a statistically significant increase in fluorescence is first detected. data analysis was performed using statistical software (spss version . ; spss; chicago, il, usa) to calculate correlations and/or significance of the data. a value of p \ . was considered statistically significant. a total of adult patients ( females and males) were enrolled: patients of arab origin and patients of non-arab origin. all patients were aged c years (average age of asthma patients = yr [ranges; n = for - yr; n = for - yr; n = for [ yr]; average age copd patients = yr [ranges n = for - yr; n = for - yr; n = for [ yr). the majority of the patients had asthma ( asthma patients vs. patients with copd). none of the copd patients and of the asthma patients had received an influenza vaccine over the last two years. fourteen of the asthma patients and five of the copd patients were smokers. table both groups of patients with viral infections and those without viral infections shared the same symptoms, with cough and wheezing being the most common in both groups (table ). however, among the patients suffering from viral infection, those infected with rhinovirus had the most severe symptoms compared with other viruses (results not shown here). dry cough was the predominant symptom among patients with rhinovirus (n = ) and coronavirus infections (n = ). chi square analysis demonstrated that the correlation between the symptoms and the presence of the virus was non-significant (p c . ). no significant relationship was observed between specific symptoms and age or ethnic origin. rhinoviruses and coronaviruses usually cause self-limited and harmless upper respiratory illnesses. however, these viruses have been associated with exacerbations in patients with asthma and copd. our study is the first in qatar to analyse the clinical aetiology of respiratory tract viral infections in adult patients from all age groups with asthma or copd. however, it is important to note that our study did not investigate the viral aetiology in patients with exacerbations. all patients were stable at time of recruitment and sample collection. to our knowledge, there are no other studies in which the frequency of respiratory viruses in adults with asthma/copd in the middle east has been reported. rhinovirus was the most common viruses identified, followed by coronaviruses. the copd sample was too small to allow any specific conclusions regarding viral aetiology. however, in the copd population, the corona viruses were the most common viral infectious agents. viral infections in our sample population were identified in out of patients. the low detection rate could reflect lower sensitivity of detection in older age groups or with nasal swabs compared with paediatric groups or with nasopharyngeal samples. it may also be that other pathogens are involved in respiratory tract infections affecting middle eastern populations. for example, metapneumovirus has been shown to affect adults with respiratory tract infections and wheezing in this region [ ] [ ] [ ] . cough and wheezing were the most predominant clinical manifestations in the present study in patients at baseline, with and without viral infections. we found that the distribution of viral infections did not correlate with the age and ethnic background of the patient. however, the effects of smoking were difficult to evaluate due to the small number of smokers in the population. in the last several years, respiratory virus infections have been identified in [ % of wheezing episodes in adults [ , , ] . furthermore, in several studies, rhinovirus has been identified as the most common respiratory virus associated with asthma exacerbations, and coronavirus is the second most frequent [ , ] . our findings in the qatari population corroborate data from previous studies and present the first of such studies in qatar, albeit in adult asthma and a minority of copd patients with no exacerbations [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . it is possible that the aetiology of viral infection would differ if samples were analysed during an exacerbation. furthermore, while most studies have focused on the paediatric population, this is one of the few studies that examines viral aetiology in adults. there are several potential shortcomings of the current study. the sample size is quite small and may not be an accurate representation of the qatari asthmatic population. larger studies are needed to verify the current data. the number of copd patients was markedly smaller than that of asthma patients. this was mainly because patients with asthma may be more concerned for their health, especially when they suffer from upper respiratory tract infections (urtis), and go to the hospital, while copd patients may not consider their symptoms very serious. indeed, there is very poor education and awareness of copd in qatar among physicians and patients. in addition, there is a large population of copd smoker patients in qatar who are not aware of their disease status. larger numbers of copd patients must be enrolled in order to determine viral aetiology more accurately in this population. furthermore, an equal number of females and males also need to be included in future studies. another potential shortcoming is that a control population was not included in the study; therefore, the frequency of rhinovirus or coronavirus infections in populations hospitalised with non-respiratory conditions or in asymptomatic populations or non-asthmatic or non-copd populations with respiratory tract infections cannot be determined. finally, this study was limited to the ''winter season'' in qatar, and it may be that the infection pattern changes throughout the year. longer-term studies are needed to determine this. the morbidity associated with rhinovirus and coronavirus infections, especially in high-risk populations such as patients with asthma or copd, suggest that these infections should be a target for prevention or treatment strategies. in addition, the relatively low number of viruses found in our sample population may point towards other pathogens (viral or bacterial pathogens not investigated here) that may be implicated in causing urtis in patients in qatar. in patients with and without viral infections, dry cough and wheezing were the most common symptoms efficacy and safety of inhaled zanamivir for the treatment of influenza in patients with asthma or chronic obstructive pulmonary disease: a double-blind, randomized, placebo-controlled, multicentre study acute exacerbations of asthma: epidemiology, biology and the exacerbation-prone phenotype community study of role of viral infections in exacerbations of asthma in - year old children ireland, dc respiratory viruses and exacerbations of asthma in adults respiratory viruses, symptoms, and inflammatory markers in acute exacerbations and stable chronic obstructive pulmonary disease effect of interactions between lower airway bacterial and rhinoviral infection in exacerbations of copd a -year prospective study of the infectious etiology in patients hospitalized with acute exacerbations of copd how viral infections cause exacerbation of airway diseases respiratory tract viral infections in inner-city asthmatic adults study of human metapneumovirus-associated lower respiratory tract infections in egyptian adults human metapneumovirus in hospitalized children in amman prevalence of human metapneumovirus (hmpv) in children with wheezing in shiraz-iran acknowledgments the authors would like to thank all nurses in the chest clinic of hamad general hospital in qatar for their help in sample collection; dr. r. singh, biostatistician at hamad medical corporation; and ehssan othman for coordinating the project. the authors would like to acknowledge support of dr. sabah allawati, from medcommz ltd., in providing editorial support for this article. the medical research department at hmc and the research office of qatar university provided financial support to carry out this study. no competing financial interests exist for any of the authors. key: cord- -h ib authors: falsey, ann r; walsh, edward e; esser, mark t; shoemaker, kathryn; yu, li; griffin, m pam title: respiratory syncytial virus–associated illness in adults with advanced chronic obstructive pulmonary disease and/or congestive heart failure date: - - journal: j med virol doi: . /jmv. sha: doc_id: cord_uid: h ib background: respiratory syncytial virus (rsv) is recognized as a serious pathogen in people with chronic cardiopulmonary conditions. immunoprophylaxis might be considered for adults at high‐risk for frequent and severe rsv infection. thus, we studied the incidence of rsv‐related medically attended acute respiratory illness (mari) in adults with severe chronic obstructive pulmonary disease (copd) and/or congestive heart failure (chf). methods: subjects ≥ years of age with gold class iii/iv copd and/or american heart association class iii/iv chf and exposure to children ≥once per month were recruited. subjects were evaluated over . to . years for rsv‐associated mari, defined as polymerase chain reaction (pcr) and/or seroresponse. results: four hundred forty‐five subjects were enrolled between october and may . overall, rsv infections were documented by pcr or serology for a cumulative incidence of . %. of these, ( . %) subjects had protocol‐specified rsv‐mari for an incidence of . / patient‐seasons. all‐cause mari was common ( . / patient‐seasons) with rhinovirus most commonly identified. conclusion: rsv infection was common in adults with severe copd and/or advanced chf. given the severity of underlying cardiopulmonary diseases in the study population, most illnesses were surprisingly mild. thus, active immunization rather than passive immunoprophylaxis with monoclonal antibodies may be a more cost‐effective strategy. obstructive pulmonary disease (copd) and congestive heart failure (chf) affect millions of people worldwide and have been identified as risk factors for severe rsv infection. , [ ] [ ] [ ] [ ] [ ] in addition, these patients may present primarily with symptoms of decompensated heart failure or acute exacerbation of copd (aecopd), and the role of viral infection is unappreciated. although molecular diagnostic testing has markedly improved the recognition of rsv and other respiratory viruses in these settings, adult rsv remains an underrecognized problem. the most effective means of preventing infectious diseases is vaccination because this approach can be deployed to protect the largest at-risk group possible. presently, a successful rsv vaccine remains elusive, while passive immunoprophylaxis with a monoclonal antibody, palivizumab, in high-risk infants has been shown to reduce rsv hospitalizations. although all older adults are at increased risk of more severe rsv infection, certain subgroups such as those with severe copd or chf may be at even greater risk and could potentially benefit from passive immunoprophylaxis if infection rates and severity are found to be substantial. there are limited data available on the incidence of rsv infection in adults with class iii or iv copd and/or chf. this observational study was designed to collect data in a high-risk population of adults with exposure to children who might exhibit both high rates of infection and severe illness when infected with rsv. this was a prospective and observational study conducted across multiple consecutive rsv seasons to determine the incidence rate of medically attended acute respiratory illness (mari) or events leading to worsening cardiorespiratory status in adults with severe copd and/or advanced chf associated with rsv and other viral infections. fifty-seven sites in nine countries (bulgaria, canada, czech republic, france, germany, italy, russia, sweden, and the united states) in the northern hemisphere participated in the study from fall through spring . the protocol was approved by independent institutional review boards, and all subjects signed written informed consent at enrollment. the study population included adults ≥ years of age with severe copd (global initiative for chronic obstructive lung disease stage iii/ iv) and/or chf (new york heart association class iii/iv or american college of cardiology-american heart association stage c/d) and had expected exposure to children (< years of age) at least once a month. an acute respiratory illness (ari) was defined as new onset or worsening of at least two of the following respiratory symptoms (sore throat, nasal congestion or discharge, hoarseness, cough, sputum, wheezing, dyspnea, and pleuritic chest pain) or one respiratory symptom and ≥ systemic symptoms (feverishness, fatigue, headache, and myalgia). worsening cardiorespiratory events were defined as follows: aecopd: worsening of ≥ major symptoms (dyspnea, sputum volume, and sputum purulence) for ≥ consecutive days; or worsening of any one major symptom together with anyone minor symptom (sore throat, cold, fever without other cause, or increased cough or wheeze) for ≥ consecutive days. worsening of chf was defined as a change in ≥ symptom or sign (pulmonary edema, dyspnea, weight gain ≥ pounds, pedal edema, jugular venous distension, and tachycardia and tachypnea) beyond normal day-to-day variation and warranting medication changes. mari was considered any illness where a subject sought outpatient, inpatient, or over-the-phone medical consultation for ari or worsening cardiorespiratory status. subjects were considered to have per protocol rsv-mari if they had a positive reverse transcriptase polymerase chain reaction (rt-pcr) during the acute phase of illness and/or a ≥ -fold increase in rsv-specific serum antibody in the period surrounding the health care visit. three different pcr assays were used to test for rsv in nasal and sputum samples. these included the genmark respiratory viral panel (www.genmarkdx.com) that tests for common respiratory viruses and subtypes, an m gene-based pcr assay and an assay that detects rsv f and n genes. serology: rsv-specific antibodies were measured at enrollment, at the time of mari (acute), approximately days after illness (convalescent) and each october and may. serum antibodies were measured using an rsv neutralizing antibody assay and a -plex rsv f, ga, gb, and n-specific igg electrochemiluminescent (ecl) assay on the mesoscale discovery platform. an rsv seroresponse was defined as > -fold rise in neutralizing antibody titer or to any rsv antigen in the ecl assay over seasonal baseline or between samples. continuous variables were summarized by descriptive statistics, including mean, standard deviation, median, and range. confidence intervals were two-sided unless otherwise stated. the primary endpoint objective of the study was to determine the incidence rate of inpatient and outpatient rsv-mari across multiple consecutive rsv seasons. primary endpoint analysis and secondary outcomes (allcause mari and death) were performed with adjustment for individual subject follow-up time. four hundred fifty-three subjects were enrolled in the study between an inverse relationship between serum rsv antibody levels and incidence of rsv-mari was observed ( figure ). higher antibody levels to each of the rsv antigens were associated with a lower incidence of rsv-mari, and the relationship was most clearly seen in season possibly due to more subjects with rsv-mari and available serology in season versus season ( vs , respectively). season was not included because subjects were being enrolled throughout the year, and preseason blood was not available for many subjects. in addition to the subjects with per protocol rsv-mari, an additional rsv infections were also identified. of these, had for all viruses, the addition of sputum testing resulted in ( . %- . %) increased viral detections during illness (table ) . for severe illness and hospitalizations in prior studies. , , [ ] [ ] [ ] however, in our population of adults with class iii/iv copd and chf, it was surprising that illnesses were not as severe as expected. in a previous study of high-risk adults with copd and chf of varying stages including mild or moderate disease, the rate of rsv-mari was . / person-seasons, similar to the rate of . observed in this study. in that study, % of high-risk patients were hospitalized and % died when infected with rsv. when all rsv infections, including serologic diagnoses in this study, were considered, % of rsv-infected subjects were hospitalized and there were no deaths. notably, % of infected patients either were asymptomatic or had a mild illness that did not require any medical intervention. regular exposure to children required for participation in this study may have led to higher infection rates ( %- . %) compared with those observed in previous surveillance and vaccine studies ( %- %). , one explanation for lack of severe illness in this very frail population might be that regular exposure to children resulted in recent rsv infections before the study leading to increased protective baseline immunity. attention. influenza with abrupt illness onset and fever tends to drive patients to seek medical attention within several days. the typical rsv illness begins with a cold and progresses over several days to dyspnea and wheezing. the average time to seek medical attention is - days by which time virus may no longer be detectable in the upper airways. , in addition, because rsv infection in adults represents reinfection, a rapid amnestic antibody response may obscure a rise in antibody if acute sera collection is delayed. finally, because the analysis of acute and convalescent sera is not possible in patients that die, results may have been biased toward milder illness. in summary, rsv, as well as other respiratory viruses, led to significant morbidity in high-risk persons with cardiopulmonary disease. the finding that rsv can result in relatively mild disease in patients with very advanced copd and chf highlights the incomplete understanding of disease pathogenesis in adults. given our results, immunoprophylaxis with an rsv monoclonal antibody of a select high-risk adult population may not be practical. however, given the overall burden of rsv in older adults, programs to develop vaccines for active immunization may be a feasible approach. we would like to thank the study participants and the site investigators listed as follows: marc afilalo/canada, andreea a r falsey served as an advisor for sanofi pasteur, pfizer, novavax, and gilead sciences. e e walsh provides consultative advice to clinical and epidemiologic features of respiratory syncytial virus respiratory syncytial virus infection in elderly and high-risk adults rates of hospitalizations for respiratory syncytial virus, human metapneumovirus, and influenza virus in older adults mortality associated with influenza and respiratory syncytial virus in the united states medically attended respiratory syncytial virus infections in adults aged >/= years: clinical characteristics and outcomes risk factors for severe respiratory syncytial virus infection in elderly persons high morbidity and mortality in adults hospitalized for respiratory syncytial virus infections respiratory viral infections in adults with and without chronic obstructive pulmonary disease global and regional estimates of copd prevalence: systematic review and meta-analysis epidemiology and risk profile of heart failure can analysis of routine viral testing provide accurate estimates of respiratory syncytial virus disease burden in adults? the impact-rsv study group. palivizumab, a humanized respiratory syncytial virus monoclonal antibody, reduces hospitalization from respiratory syncytial virus infection in high-risk infants comparison of the genmark diagnostics esensor respiratory viral panel to real-time pcr for detection of respiratory viruses in children the burden of hospitalized lower respiratory tract infection due to respiratory syncytial virus in rural thailand development and pilot study of a dualtarget rsv assay to detect and subtype respiratory syncytial virus in nasal swab samples development of electrochemiluminescent serology assays to measure the humoral response to antigens of respiratory syncytial virus consequences of immature and senescent immune responses for infection with respiratory syncytial virus influenza-and rsvassociated hospitalizations among adults risk factors for respiratory syncytial virus illness among patients with chronic obstructive pulmonary disease winter viruses: influenza-and respiratory syncytial virus-related morbidity in chronic lung disease comparison of the safety and immunogenicity of respiratory syncytial virus (rsv) vaccinesnonadjuvanted vaccine or vaccine adjuvanted with alum-given concomitantly with influenza vaccine to high-risk elderly individuals an adjuvanted, postfusion f proteinbased vaccine did not prevent respiratory syncytial virus illness in older adults humoral and mucosal immunity in protection from natural respiratory syncytial virus infection in adults diagnosis of respiratory syncytial virus infection: comparison of reverse transcription-pcr to viral culture and serology in adults with respiratory illness the diagnosis of viral respiratory disease in older adults detection of respiratory viruses in sputum from adults by use of automated multiplex pcr update on human rhinovirus and coronavirus infections virus-induced exacerbations in asthma and copd respiratory viruses, symptoms, and inflammatory markers in acute exacerbations and stable chronic obstructive pulmonary disease a prospective, observational cohort study of the seasonal dynamics of airway pathogens in the aetiology of exacerbations in copd clinical impact of human coronaviruses e and oc infection in diverse adult populations human coronavirus and acute respiratory illness in older adults with chronic obstructive pulmonary disease viral shedding and immune responses to respiratory syncytial virus infection in older adults yield of sputum for viral detection by reverse transcriptase pcr in adults hospitalized with respiratory illness respiratory syncytial virus-associated illness in adults with advanced chronic obstructive pulmonary disease and/or congestive heart failure ar falsey, mp griffin, and mt esser participated in the study design, collection, analysis and interpretation of data and the writing of this report. ee walsh participated in collection and analysis of data and reviewed the manuscript. k shoemaker and l yu provided statistical analysis. ar falsey and mp griffin are the guarantors of the paper and take responsibility for the integrity of the work as a whole, from inception to published article. http://orcid.org/ - - - key: cord- -w ne fn authors: schrumpf, jasmijn a.; van der does, anne m.; hiemstra, pieter s. title: impact of the local inflammatory environment on mucosal vitamin d metabolism and signaling in chronic inflammatory lung diseases date: - - journal: front immunol doi: . /fimmu. . sha: doc_id: cord_uid: w ne fn vitamin d plays an active role in the modulation of innate and adaptive immune responses as well as in the protection against respiratory pathogens. evidence for this immunomodulatory and protective role is derived from observational studies showing an association between vitamin d deficiency, chronic airway diseases and respiratory infections, and is supported by a range of experimental studies using cell culture and animal models. furthermore, recent intervention studies have now shown that vitamin d supplementation reduces exacerbation rates in vitamin d-deficient patients with chronic obstructive pulmonary disease (copd) or asthma and decreases the incidence of acute respiratory tract infections. the active vitamin d metabolite, , -dihydroxy-vitamin d ( , (oh)( )d), is known to contribute to the integrity of the mucosal barrier, promote killing of pathogens (via the induction of antimicrobial peptides), and to modulate inflammation and immune responses. these mechanisms may partly explain its protective role against infections and exacerbations in copd and asthma patients. the respiratory mucosa is an important site of local , (oh)( )d synthesis, degradation and signaling, a process that can be affected by exposure to inflammatory mediators. as a consequence, mucosal inflammation and other disease-associated factors, as observed in e.g., copd and asthma, may modulate the protective actions of , (oh)( )d. here, we discuss the potential consequences of various disease-associated processes such as inflammation and exposure to pathogens and inhaled toxicants on vitamin d metabolism and local responses to , (oh)( )d in both immune- and epithelial cells. we furthermore discuss potential consequences of disturbed local levels of (oh)d and , (oh)( )d for chronic lung diseases. additional insight into the relationship between disease-associated mechanisms and local effects of , (oh)( )d is expected to contribute to the design of future strategies aimed at improving local levels of , (oh)( )d and signaling in chronic inflammatory lung diseases. vitamin d is a pleiotropic hormone that is well-known for its role in the regulation of calcium and phosphate homeostasis and bone mineralization. the vitamin d receptor (vdr) acts as the receptor for the active form of vitamin d, i.e., , dihydroxy-vitamin d [ , (oh) d], and is expressed in nearly all tissues and cell-types and regulates a large number of genes (∼ . - % of the total genome) ( , ) . as a result, vitamin d affects many additional processes including cell proliferation and differentiation, apoptosis, dna repair, ion transport, metabolism, cell adhesion, and oxidative stress responses ( , ) . vitamin d deficiency [serum -hydroxy-vitamin d [ (oh)d] < nmol/l; (oh)d is the main circulating form of vitamin d and its levels are used to assess vitamin d status in the clinic ( , ) affects more than % of the children and adults worldwide and is a major cause of bone diseases such as rickets and osteoporosis ( ) . increasing evidence has indicated that vitamin d deficiency is also associated with various other diseases such as cancer, cardiovascular disease, alzheimer's disease and muscle myopathy, as well as several immune-related diseases such as type diabetes, multiple sclerosis, inflammatory bowel disease (ibd), psoriasis and chronic inflammatory lung diseases including asthma, cystic fibrosis (cf), and chronic obstructive pulmonary disease (copd) ( ) ( ) ( ) ( ) . several studies have now shown that vitamin d deficiency is prevalent in copd patients and inversely correlated with lung function and severity of the disease ( ) ( ) ( ) ( ) ( ) . it is currently unknown whether vitamin d deficiency is a cause or consequence of copd, since many copd patients have low physical activity levels and spend most time indoors ( ) . there are however studies suggesting that low (oh)d levels are associated with development of copd, based on observed associations between polymorphisms in the vitamin d binding protein (vdbp), (oh)d serum levels and copd severity ( , , , ) . in addition, one study in mice showed that maternal vitamin d deficiency can impair lung -development, -structure andfunction in the offspring and suggests that even before birth, maternal (oh)d serum levels are important for a healthy lung development ( ) . this might be relevant, since associations have been found between lower childhood lung function and development of copd later in life ( ) . the link between maternal (oh)d status and asthma development is however much clearer, since two recent randomized controlled trials (rcts) have shown that maternal vitamin d supplementation reduces the risk of childhood asthma/recurrent wheeze ( ) . this might be explained by the fact that multiple vitamin d-regulated genes are transcriptionally active during alveolar maturation and a number of these genes are differentially expressed in asthma ( ) . additionally, this protective effect was linked to the gggenotype of the q functional snp rs , which is associated with lower expression of ormdl and increased sphingolipid metabolism ( ) . moreover, maternal circulating (oh)d levels affect the gut microbiota and can therefore indirectly modulate immune responses in the lung via the gutlung-axis ( ) . also later in life, optimal (oh)d levels remain crucial for keeping the lungs healthy. for example, heulens et al. showed that subacute and chronic cigarette smoke (cs) exposure decreased lung function and promoted early signs of emphysema and airway inflammation in vitamin d-deficient mice compared to vitamin d-sufficient animals ( ) . similarly in an elastase-induced copd mouse model, topical administration of vitamin d in the lungs counteracted alveolar damage and improved lung function ( ) . yet in humans, it is still unclear whether vitamin d status influences copd development and disease progression. taken together, these observations suggest an important role for vitamin d during fetal and childhood lung maturation, and indicate that sufficient (oh)d levels might contribute to protection against development of childhood asthma and possibly copd at older age. systemic levels of biologically active , (oh) d are tightly regulated to preserve sufficient levels of calcium (ca + ) and phosphate (po − ) for optimal bone mineralization, whereas in mucosal tissues locally produced (autocrine) , (oh) d levels and signaling can be elevated or decreased upon exposure to inflammatory mediators, pathogens or inhaled toxicants ( ) . this could be important, since the inflamed airway mucosa of patients suffering from chronic inflammatory lung diseases is constantly exposed to these disease-associated factors ( , , ) . impaired local levels of , (oh) d and vdr signaling might have consequences for disease pathogenesis and progression. dysregulated host defenses as found in patients with chronic inflammatory airway diseases include aberrant immune responses, altered microbiome composition, impaired epithelial barrier function, and aberrant secretion of host defense molecules ( ) ( ) ( ) . adequate , (oh) d levels may provide protection against these dysregulated processes by maintaining the integrity of the mucosal barrier and promotion of killing of pathogens (e.g., via the induction of the antimicrobial peptide [amp] hcap /ll- ) and via the modulation of both innate and adaptive immune responses ( , , ) . in this review, we first discuss the effects of these disease-associated factors on local synthesis and availability of , (oh) d and , (oh) d-induced responses in the lung mucosa. in the second part of the review we will describe the mechanistic links between vitamin d deficiency and the pathogenesis of chronic inflammatory lung diseases such as asthma, cf and copd, and discuss recent evidence related to the protective effects of vitamin d on copd and on copd exacerbations. vitamin d enters the circulation either via food intake (plantbased: vitamin d /animal-based: vitamin d ) or as a result of its synthesis in the skin by uvb radiation. it subsequently binds to the vdbp ( , ) , after which this complex is transported to the liver where it is converted by vitamin d- hydroxylases (cyp ri and cyp a ) into (oh)d. however, recent studies showed that also other cell types such as airway epithelial cells, keratinocytes, intestinal epithelial cells, and monocytes/macrophages express cyp ri and cyp a , and thus are able to (locally) convert vitamin d into (oh)d ( , ) . this inactive (oh)d needs to be converted into the active , (oh) d by -hydroxyvitamin d- α-hydroxylase (cyp b ) in the kidney and in other cells, including several immune-and epithelial cells ( ) ( ) ( ) ( ) ( ) ( ) ( ) . , (oh) d regulates expression of several genes by binding the nuclear vdr, which heterodimerizes with the retinoic acid receptor (rxr) to interact with vitamin d response elements (vdres) that are present on the promoter region of these genes ( , ) . vdr is most abundantly expressed in intestinal enterocytes, pancreatic islets, renal distal tubules and osteoblasts, but is also present at lower levels in most other tissues and several other epithelial-and immune cells ( ) ( ) ( ) ( ) ( ) . expression of vdr is classically regulated by , (oh) d, growth factors and hormones such as fgf- and pth, respectively, circulating calcium levels, bile acids, transcriptional co-activators/repressors, and genetic-and epigenetic modifications, which is tissue specific ( ) ( ) ( ) ( ) . , (oh) d regulates its own negative feedback by several mechanisms, including induction of expression of the catabolic enzymes -hydroxyvitamin d- -hydroxylase (cyp a ) and cyp a ( , ) . cyp a is expressed in most tissues and converts both (oh)d and , (oh) d into , (oh) d or , (oh) d and , , (oh) d or , , (oh) d, respectively (dependent on whether cyp a hydroxylates at c- or at c- ). these are further converted into metabolites that have been found to be excreted into the bile (summarized in figure ) ( , , ) . cyp a is mainly expressed in the liver and small intestines and contributes to the metabolic clearance of (oh)d and , (oh) d by converting (oh)d into β, (oh) d, and , (oh) d into frontiers in immunology | www.frontiersin.org , r, (oh) d or , s, (oh) d ( ). expression of both cyp b and cyp a in the kidneys is tightly regulated to maintain optimal ca + -and po − levels in the circulation, which are important for bone mineralization ( ) . in short, in response to low ca + levels, parathyroid hormone (pth) is secreted by the pituitary glands, which in turn reduces ca + excretion and reabsorption of po − ( ). pth further induces expression of cyp b and represses expression of cyp a in the kidneys ( ) . this will increase the levels of , (oh) d in the circulation, which promotes intestinal ca + and po − absorption ( ) . these elevated circulating ca + and po − levels will subsequently induce expression of fibroblast growth factor (fgf- ) in osteocytes and osteoblasts and impair secretion of parathyroid hormone (pth) by the parathyroid glands ( ). in the kidneys, fgf- suppresses expression of cyp b and induces expression of cyp a , thereby inhibiting the synthesis and promoting degradation of , (oh) d ( ). these complex mechanisms that explain how vitamin d and its metabolic enzymes maintain sufficient ca + and po − levels in the circulation are more extensively discussed by quarles et al. ( ) . in summary, it has become increasingly evident that the effects of vitamin d are not limited to homeostasis of ca + and po − and bone mineralization, because several extra-renal cells such as airway epithelial cells and immune cells express the vdr and are capable of converting circulating (oh)d into the active , (oh) d metabolite. local levels and activity of , (oh) d are in part determined by expression of vdr and the equilibrium between the vitamin d metabolic enzymes cyp b and cyp a . it is important to realize that mucosal expression of cyp a , cyp b and also vdr can be affected by several disease-associated inflammatory mediators, toxicants and pathogens, summarized in table . as a consequence of this, the local availability of , (oh) d and/or vdr signaling in tissues such as the inflamed airways of patients that suffer from chronic inflammatory airway diseases might be reduced. chronic lung diseases are characterized by airway inflammation and impaired respiratory host defense, which is illustrated by the increased susceptibility for respiratory infections and exacerbations ( , , ) . furthermore, exposure to inhaled toxicants such as cigarette smoke and air pollutants are associated with disease pathogenesis and exacerbations in copd, cf and in asthma patients ( ) ( ) ( ) . it would therefore be of great interest to investigate these effects on local , (oh) d levels and on , (oh) d-mediated respiratory host defense in the airway mucosa. studies in airway epithelial cells have shown that exposure to uv-inactivated non-typeable haemophilus influenzae (nthi) increased expression of the coga- a (colon cancer epithelial cell line) trophoblasts tnf-α; il- β; il- cyp a ↑ macrophages macrophages (derived from thp- ) macrophages (derived from thp- ) t cells t cell activators (anti-cd /anti-cd ; pha; pma/ionomycin) other hand, in the bronchial cell line beas- b expression of vdr was decreased after infection with respiratory viruses such as human rhinovirus (hrv) and respiratory syncytial virus (rsv) ( ) . collectively, these studies have shown in airway epithelial cells that respiratory viral-and bacterial infections can either promote or impair , (oh) d synthesis and responses. a local airway inflammatory milieu can also exert differential effects on , (oh) d synthesis and signaling, dependent on the type of inflammatory mediators that are predominantly present. we have shown in differentiated primary airway epithelial cells that th cytokines such as il- and il- , enhance expression of cyp b and expression of hcap /ll- upon (oh)d treatment, which suggests that a th -inflammatory environment, as found in allergic airway inflammation, increases the conversion of (oh)d into the active , (oh) d ( , ) . the observation that levels of both , (oh) d and hcap /ll- were increased in bronchoalveolar lavage (bal) after allergen challenge is in line with this proposed mechanism ( ) . this effect of th cytokines was in contrast to the effects (chronic) exposures to the proinflammatory cytokines il- β, tnf-α and il- a that strongly increased the expression of the (oh)d-and , (oh) d-degrading cyp a , even in absence of its inducer , (oh) d ( ). furthermore, shortterm exposures to tgf-β , a pleiotropic growth factor which is elevated in the lungs of copd, cf and asthma patients, also increases the expression of cyp a ( ) . as a consequence, , (oh) d-mediated expression of the amp hcap /ll- was impaired, which was likely the result of the enhanced degradation of both (oh)d and , (oh) d by this enzyme ( , ) . in addition to pathogens and cytokines, exposure to inhaled toxicants such as cigarette smoke (cs) and particulate matter (pm) may also alter expression or activity of vdr and cyp b . studies have demonstrated that cigarette smoking or exposure to cs extract (cse) decreases expression of cyp b and inhibited membrane bound (m)vdr translocation to the cell membrane in airway epithelial cells and a cells (an alveolar tumor cell line), respectively ( , , ) . this inhibition reduces the conversion of (oh)d to , (oh) d and , (oh) d-mediated gene expression as well as nongenomic actions of , (oh) d-membrane associated, rapid response steroid-binding (marrs)-signaling ( , , ) . this adverse effect of cigarette smoking on the synthesis and effects of , (oh) d in airway epithelial cells was recently confirmed in vivo by vargas buonfiglio et al. who demonstrated that vitamin d supplementation increased antimicrobial activity in apical surface liquid (asl) in the airway of healthy non-smokers, but not in smokers ( ) . on the other hand, exposure to pm increases the expression of both cyp b and vdr in airway epithelial cells, thereby possibly promoting the synthesis and effects of , (oh) d ( ). it is however important to consider that several retrospective and observational studies have demonstrated that air pollution is an independent risk factor for developing vitamin d deficiency ( ) . in conclusion, exposure to cs, tgf-β and presence of a proinflammatory milieu appeared to most strongly decrease local presence and signaling of , (oh) d in airway epithelial cells. igm/anti-cd /il- ) cyp b ↑ vdr ↑( ) whereas, various studies show that exposure to proinflammatory stimuli most likely affects local (oh)d and , (oh) dlevels and reduces the effects of (oh)d and , (oh) d in (airway) epithelial cells, the opposite appears to be the case for immune cells. in monocytes, macrophages and neutrophils, effects on , (oh) d synthesis and antimicrobial responses upon (oh)d treatment were generally enhanced by these proinflammatory stimuli as illustrated by increased expression of both vdr and cyp b ( , , ( ) ( ) ( ) ( ) . it is therefore tempting to speculate that this apparent increase in antimicrobial responses upon (oh)d treatment in immune cells in an inflammatory environment may serve as a second line of defense and compensate for the enhanced epithelial degradation of (oh)d and , (oh) d during inflammation. inhaled toxicants may also affect , (oh) d availability and responsiveness of immune cells. this is illustrated by two recent studies studying the effects of cigarette smoke on the human monocyte/macrophage-like cell line thp- . one study showed that treatment with cigarette smoke extract (cse) increased the expression of vdr without enhancing , (oh) d responses ( ), while the other study -that focused on the effects of benzo[a]pyrene (bap) (a component produced by cigarette combustion)-demonstrated that , (oh) dmediated cyp a expression was induced, which was found to further enhance degradation of , (oh) d ( ). in summary, proinflammatory stimuli generally increased the effect of (oh)d and , (oh) d on immune cells, whereas more studies are needed to fully determine the impact of exposure to cigarette smoke and other inhaled toxicants. whereas, these studies provide evidence that inflammation and inhaled toxicants may affect (oh)d and , (oh) d metabolism and responsiveness in epithelial cells and immune cells, it is not clear whether this has an impact on these events in lung tissue of patients with chronic lung diseases. although evidence is limited, we can speculate that levels of , (oh) d and responses are also affected by disease-associated factors in mesenchymal cells that are present in the lung mucosa. one study that showed in a bleomycin fibrosis model and in primary lung mouse fibroblasts that tgf-β reduced expression of the vdr might support this assumption ( ) . it is currently insufficiently studied whether exposures to disease-associated factors promote or impair levels of , (oh) d and responses in immune-, mesenchymal and epithelial cells combined to give a better reflection of the in vivo situation. interestingly, one study did already show that nasal cyp b -and , (oh) d-levels are both reduced in chronic rhinosinusitis (crs) patients with nasal polyps as compared to crs-patients without nasal polyps, whereas no difference was found in circulating , (oh) dlevels ( ) . since most other studies were performed in vitro using monocultures of epithelial cells or immune cells, more complex models are needed to delineate this. therefore, animal models or preferably more complex animal-free cell culture models using co-cultures or organs-on-chips models of primary fully differentiated epithelial cells, airway-derived fibroblasts or smooth muscle cells and immune cells could be considered in future studies. after discussing altered (oh)d and , (oh) d metabolism and responsiveness in the inflamed airway mucosa, it is important to consider the possible consequences of these inflammation-induced changes in the airway mucosa keeping in mind the pleotropic effects of , (oh) d that were introduced earlier. in several cells, tissues and organs, , (oh) d regulates multiple cellular processes that affect normal and malignant cell growth and differentiation ( , ) . , (oh) d displays furthermore protective effects on mucosal host defense by maintaining the integrity of the epithelial barrier, inhibition of epithelial-to-mesenchymal transition (emt), stimulating production of amps and modulating both innate-and adaptive immune functions ( , , ) . in addition, , (oh) d maintains both energetic and survival homeostasis in the mucosal epithelium through the modulation of stress and damage responses, including clearance of disturbing and stressful agents ( , ) (figure ). in chronic inflammatory lung diseases, epithelial barrier function is impaired, and as a consequence the susceptibility toward respiratory infections is increased ( ) . there is increasing evidence that , (oh) d promotes epithelial barrier integrity or protects against epithelial barrier destruction. in cells of the bronchial epithelial cell line hbe, , (oh) d inhibited csemediated reduction of the epithelial barrier and expression of ( ) . only the first study that used a more severe mouse model with higher levels of inflammation and edema found an effect of vitamin d on epithelial barrier function. since inflammation is detrimental for epithelial barrier integrity ( ) , it cannot be excluded that the main protective effects of , (oh) d on the epithelial barrier in the first study by shi et al. were in fact exerted through inhibition of inflammation rather than via direct induction of cell junction proteins. , (oh) d might also promote epithelial barrier function through its ability to increase expression of cystic fibrosis transmembrane conductance regulator (cftr) in airway epithelial cells ( ) . cftr maintains optimal asl-and mucus hydration, volume and ph that support mucociliary clearance and activity of amps ( ) . moreover, cftr is also affected in the airways of smokers and copd patients ( ) . in summary, these studies indicate that , (oh) d promotes both the integrity and function of the epithelial barrier and might additionally protect against epithelial damage by dampening inflammatory responses. the loss of epithelial barrier function with a decrease in epithelial polarization and cell-junction proteins and a gain of expression of mesenchymal markers is a hallmark of emt ( ) . emt is primarily involved in development, wound healing and stem cell differentiation, and tgf-β signaling plays a major role in this process ( ) . elevated tgf-β levels are found in the lungs of patients with chronic inflammatory lung diseases and this was associated with cigarette smoking, inflammation and fibrosis ( , ) . there are indications that , (oh) d counteracts various pathways leading to emt. in mouse models and in airway epithelial cell lines, vitamin d supplementation and , (oh) d, respectively, has been shown to inhibit emt and fibrosis, in particular when this process is induced by tgf-β ( , ( ) ( ) ( ) ( ) . in addition to maintenance of the epithelial barrier and inhibition of fibrosis as discussed in the previous paragraphs, vitamin d is also actively involved in respiratory host defense by a variety of mechanisms ( , ) . , (oh) d is an important inducer of amps, which are mostly cationic peptides that have a broad-spectrum antimicrobial activity, the ability to modulate immune responses and to promote epithelial wound repair and angiogenesis ( ) . hcap /ll- is likely to be the most prominent amp that is induced by , (oh) d and is expressed in several types of mucosal epithelial cells and immune cells such as monocytes and neutrophils ( , , ) . in macrophages and intestinal epithelial cells, , (oh) d also increases expression of human β-defensin- (hbd- ), whereas in keratinocytes expression of both hbd- and human β-defensin- (hbd- ) is increased by , (oh) d ( ) ( ) ( ) ( ) . collectively these data show that amps are modulated by , (oh) d in mucosal tissues, which could have impact on susceptibility to both bacterial and viral infections and on the composition of the microbiota, which will be discussed in the next section. diseases such as copd and asthma are characterized by chronic inflammation, a low-grade and prolonged inflammation that may result in destruction and aberrant repair of surrounding tissue by growth factors, proteases and cytokines that are released at the site of inflammation ( ) ( ) ( ) . cumulative data suggest that vitamin d exerts anti-inflammatory effects via its actions on both innate and adaptive immune responses. upon viral infection or exposure of pro-inflammatory stimuli such as poly(i:c) or pm, , (oh) d attenuates induced expression of cytokines and chemokines e.g., via inhibition of nuclear factor (nf)-κb or oxidative stress, respectively, in (airway) epithelial cells ( , , ) . furthermore, , (oh) d increases expression of the soluble decoy receptor for il- (sst ) by airway epithelial cells, which in turn inhibits the actions of the type alarmin il- ( ) . taken together, these findings suggest that on the one hand , (oh) d protects against infections by enhancing epithelial barrier function and production of amps, and on the other hand , (oh) d induces tolerance and dampens proinflammatory responses in various cell types of the airway mucosa. thereby, , (oh) d may prevent exaggerated inflammatory responses and further damage to the mucosal tissue, qualities that are very relevant in the context of chronic inflammatory (lung) diseases (figure ) . copd is considered to be a disease of accelerated aging lungs, underscored by markers of aging being increased in these patients partly as a result of oxidative stress ( ) . evidence that , (oh) d may protect epithelial cells from oxidative stress was provided by pfeffer et al. who demonstrated that , (oh) d increased expression of the antioxidant gene g pd in airway epithelial cells. furthermore, , (oh) d increased the ratio of reduced to oxidized glutathione and decreased the formation of -isoprostane after exposure to pm ( ) . the induction of klotho by , (oh) d might be another , (oh) d-mediated anti-aging mechanism ( ) . klotho is an anti-aging protein that is mainly expressed in the kidney, brain and in the lung by airway epithelial cells and exerts its protective effects through the inhibition of inflammation, insulin/igf- signaling and activation of forkhead transcription factor (foxo) signaling, which enables removal of reactive oxygen species (ros) ( ) ( ) ( ) . expression of klotho is impaired in the airways of smokers and further decreased in the airways of copd patients and in cultures of the bronchial epithelial cell line hbe after cse exposure ( ) . these studies suggest that , (oh) d may protect against aging via inhibition of oxidative stress and possibly via its ability to restore klotho expression (figure ) . however, direct evidence showing that , (oh) d indeed increases expression of klotho in airway epithelial cells is currently lacking. in addition to providing protection against oxidative stress and aging, data from studies using intestinal epithelial cells suggest that , (oh) d may also promote cellular survival via the induction of autophagy and reduction of apoptosis ( , ) . in chronic inflammatory lung diseases, aberrant activation of autophagy plays a role in disease pathogenesis ( ) . a recent study showed that club cells and autophagy-related proteins were both decreased in copd patients and that these proteins were important for club cell structure and function in airways ( ) . however, the effects of , (oh) d on autophagy in the airway mucosa of chronic inflammatory lung diseases are still unclear and need to be further evaluated ( ) . clearly vitamin d has pivotal actions in host defense that are relevant in the context of chronic inflammatory lung diseases, in which vitamin d deficiency may be prevalent. strategies to promote local levels of , (oh) d or use it as a treatment itself could be therefore of interest. here, we will discuss the latest clinical evidence accompanied with functional in vitro and animal studies that may explain the effects of vitamin d supplementation on typical hallmarks of chronic airway diseases. currently, inhaled corticosteroid (ics)-use with or without long acting bronchodilators is the most frequently used treatment for copd and asthma patients . however, the response to corticosteroids is not always effective in many copd patients and in patients with steroid resistant (sr)-asthma ( ) . there are several complex mechanisms that underlie the resistance to corticosteroids in both copd and sr-asthma that include but are not limited to genetic background, impaired glucocorticoid receptor binding, t helper type cell (th )-inflammation and oxidative stress (e.g., from air pollution or smoking) and decreased numbers of il- secreting regulator t cells (tregs), which normally prevent skewing toward th -inflammation ( ) . direct evidence of the ability of , (oh) d to reverse sr was provided by a study showing that ex-vivo stimulation https://goldcopd.org ( ). with , (oh) d promoted generation of il- -secreting tregs which restored sensitivity toward corticosteroids in cd + t cells that were derived from sr-asthma patients ( ) . a further potential treatment role of , (oh) d was elegantly illustrated by studies that showed that vitamin d deficiency is associated with decreased steroid responsiveness in asthmatics and by the fact that several potential underlying mechanisms of sr such as oxidative stress and th -mediated inflammatory responses could be reversed by vitamin d treatment ( , ( ) ( ) ( ) ( ) ( ) ( ) . interestingly, the corticosteroid dexamethasone was shown to increase expression of the (oh)d and , (oh) d degrading enzyme cyp a in renal cells and osteoblasts ( ) , which suggests a bidirectional interaction between corticosteroids and , (oh) d and could further limit , (oh) d levels for patients. additional research is needed to determine if vitamin d may also improve corticosteroid responsiveness in copd. exacerbations are a major burden for copd patients, they accelerate decline in lung function and frequently result into hospital admissions ( , ) . exacerbations are often triggered by pollutants or by bacterial-and/or viral infections ( , , ) . copd patients generally have lower serum (oh)d levels than age-and smoking-matched controls, which is associated with more and more severe exacerbations ( , ) . several in vivo and in vitro studies have provided evidence that explain the protective effects of vitamin d on exacerbations in copd patients and this will be discussed accordingly. first of all, pfeffer et al. showed that (oh)d and , (oh) d reduce the production of proinflammatory cytokines in part via the ability to enhance antioxidant responses in airway epithelial cells that were exposed to pm ( ) . this was also demonstrated in human dcs that were matured in presence of pm, where treatment with , (oh) d counteracted the expansion of proinflammatory il- a + and ifn-γ + th . cells ( ) . in line with this, bolcas et al., showed that vitamin d supplementation counteracted the development of airway hyperresponsiveness and accumulation of th /th cells in mice that had been repeatedly exposed to both diesel exhaust and house dust mite allergens ( ) . vitamin d could therefore exert a protective role in air pollution-triggered exacerbations. in addition to its protective effects against pollutants, there is also increasing evidence that , (oh) d may enhance clearance of respiratory viral infections that account for - % as underlying cause of exacerbations in copd patients ( ) . infections with respiratory viruses such as hrv, coronaviruses and to a lesser extend respiratory syncytial virus (rsv) and (para)influenza virus are present during exacerbations and may predispose the host toward secondary bacterial infections that can eventually lead to uncontrolled bacterial outgrowth, more severe exacerbations and neutrophilic inflammation ( , ) . two recent in vitro studies showed that acute exposure to relatively high doses ( - nm) of , (oh) d reduced hrv-infection in undifferentiated cultures of airway epithelial cells ( , ) . in those models, , (oh) d most likely interfered with viral replication by increasing expression of interferon-stimulated genes and expression of hcap /ll- , which has been shown to have direct antiviral activity ( , , ) . in fully differentiated airway epithelial cells, treatment with lower concentrations of , (oh) d ( nm) during epithelial differentiation had no effect on acute hrv infection ( ) . as for other viruses than hrv, both hansdottir et al. and telcian et al. showed that , (oh) d did not decrease rsv infection in airway epithelial cells, but did reduce virus-induced inflammatory responses ( , ) . in addition, two other studies reported in influenza (h n and h n )-infected a cells comparable findings ( , ) . moreover, inhibitory effects of , (oh) d on poly(i:c)-induced inflammatory responses were furthermore confirmed in primary airway epithelial cells hansdottir et al. and by our group ( , ) . up to now, the afore mentioned studies suggest that higher doses of , (oh) d might be protective against hrv-infections in undifferentiated airway epithelial cells only, whereas for other respiratory viral infections , (oh) d mainly reduces inflammatory responses without affecting viral clearance. however, more studies are needed, especially in differentiated airway epithelial cells using multiple hrv-serotypes that use different receptors for infection to verify if , (oh) d indeed is capable of promoting hrvclearance. there is more consensus about , (oh) d reducing virus-induced inflammatory responses and this may certainly help to alleviate the burden of exacerbations in copd ( , ) . in addition to viral infections, also bacterial infections are associated with copd exacerbations and account for ∼ % of all exacerbations ( ) . due to improved study design and sampling techniques from the lower airways using bronchoscopy in recent decades, the causative role of bacteria in copd-related exacerbations has become clear ( ) . this was additionally supported by sethi et al., who found that acquisition of a new strain of pathogenic bacterial species into the airways was linked to copd exacerbations ( ) . recent developments in assessing the airway microbiota using s rrna sequencing techniques further demonstrated that during exacerbations, the relative abundance of haemophilus, pseudomonas, and moraxella was increased and the microbial composition was shifted toward the proteobacteria phylum ( ) . the ability of , (oh) d to promote antibacterial activity was recently demonstrated in cultures of airway epithelial cells. in differentiated airway epithelial cells, we have shown that both (oh)d and , (oh) d treatment enhances epithelial expression of hcap /ll- and antibacterial activity against nthi, a gram-negative bacterium, which is associated with copd exacerbations ( , ) . in addition, yim et al. demonstrated that , (oh) d treatment increased expression of the amp hcap /ll- and killing of pseudomonas aeruginosa and bordetella bronchiseptica, which are both gram-negative bacteria ( ) . these observed antibacterial effects of , (oh) d on airway epithelium in vitro were recently confirmed in vivo by vargas buonfiglio et al. the authors demonstrated that vitamin d supplementation increased antimicrobial activity against the gram-positive staphylococcus aureus in asl in healthy non-smokers and was dependent on presence of hcap /ll- ( ) . in murine airways, studies showed no effects of , (oh) d on the expression of defb or mcramp (the murine homolog for camp) ( ) . this can be explained by the fact that both the promotors of mcramp and defb lack vdres, suggesting that mice might not be suitable for studying the role of , (oh) d in amp-mediated host defense in infection ( ) . indeed, niederstrasser et al. showed no effects of vitamin d deficiency on the susceptibility of mice to pulmonary infection with streptococcus pneumoniae or pseudomonas aeruginosa ( ) . however, in a recently developed mouse model by lowry et al., who transfected mcramp knockout mice with the human camp gene, topical vitamin d treatment increased expression of camp and promoted antibacterial effects on the mucosa of the skin ( ) . there are also multiple other murine studies that demonstrate protective effects of vitamin d on bacterial infections in the gut, indicating that , (oh) dmediated antibacterial effects are additional modulated by other mechanisms such as via enhancement of epithelial barrier integrity ( , ) . in conclusion, these observations show that , (oh) d promotes protection against pollutants and enhances clearance of viral-and bacterial infections (both gram-positive and negative bacteria) in combination with a dampening effect on exaggerated immune responses and these features might explain why vitamin d (deficiency) is linked to copd exacerbations. there are strong indications that modulation of immune responses and antibacterial activities by , (oh) d and/or , (oh) d-regulated amps as well as autophagy have implications for the composition of the microbiota at the epithelial mucosa of the airways and the gut ( ) . evidence for a role of amps in regulating the composition of the microbiota in the gut came from a variety of studies, including those showing that paneth cell-derived defensins may modulate the composition of the microbiome ( ). this notion is further supported by observations showing that many commensal gut bacteria are protected from killing by amps such as the , (oh) d-inducible hcap /ll- and hbd- , whereas pathogens are in general more sensitive ( ) . alterations in the gut microbiota have been linked to many diseases of the gut such as ibd but also with diseases affecting the lungs such as copd and asthma, implicating an important role for the so-called gut-lung axis ( , ) . the mechanisms that explain how gut microbiota affect lung health and disease are complex and include the production of short chain fatty acids (scfas). scfa have a wide range of effects on both immune and structural cells, and the effect of scfa produced in the intestine on lung immunity may in part be explained by modulation of myeloid cells in the bone marrow, which subsequently migrate to the airways and modulate local immune responses ( ) . microbiota that are diverse, rich and contain a higher abundance of scfaproducing species within these populations are considered to be associated with health ( ) . in the gut there is strong evidence that both vitamin d deficiency and/or supplementation affect composition of the adult and infant microbiota ( , ) , specifically in relation to disease ( ) . however, due to the limited number of rcts and small sample sizes, the precise effects on the microbiota and the mechanisms involved in this are still unclear ( ) . alterations in the lung microbiota are also observed in copd and asthma patients and are likely the result of environmental exposures, airway remodeling, infections and treatments such as the use of antibiotics. this may contribute to disease pathogenesis through altered epithelial innate and adaptive immune responses that damages the airway epithelial barrier and provokes further changes in the lung microbiome that accumulates with increasing disease severity ( , ) . to date only studies describe a possible influence of vitamin d on composition of the microbiota in the airways ( , ) . toivonen et al. showed an association between low serum (oh)d levels and reduced richness of the nasopharyngeal microbiota and bronchiolitis severity in patients with low (oh)d levels ( ) , whereas in another study vitamin d supplementation decreased the abundance of staphylococcus aureus, staphylococcus epidermidis and corynebacterium species in sputum samples in vitamin d-deficient cf patients compared to sufficient cf patients ( ) . in summary, there is evidence that alterations in the airway or gut microbiota can affect chronic airway disease and that these changes could be related to both vitamin d deficiency and/or supplementation. however, due to the limited number of rcts and small sample sizes more rcts are needed in larger patient populations. the above described protective and therapeutic possibilities of vitamin d, together with observations that many copd patients are vitamin d deficient, suggest that copd patients might benefit from vitamin d supplementation. as discussed elsewhere in this review, the link between circulating (oh)d levels and the number of exacerbations has been extensively studied ( ) . so far however, only rcts have investigated the effect of vitamin d supplementation in the context of copd: only out of rcts showed that vitamin d supplementation reduces the number of exacerbations ( ) ( ) ( ) ( ) . however, in a post-hoc analysis, selecting those patients that were vitamin d deficient, exacerbations were indeed reduced after vitamin d supplementation. jolliffe et al. summarized these rcts and performed a recent individual participant data meta-analysis and concluded that vitamin d supplementation is only protective against exacerbations in copd patients with baseline serum (oh)d levels < nmol/l ( ) . these important findings suggest that exacerbations in this specific subset of copd patients are connected to vitamin d deficiency and this part can be resolved with supplementation. in summary, the protective effects of vitamin d in patients suffering from copd are most prominent in those with vitamin d deficiency and this would indicate that serum levels (oh)d in these patients should always be determined before considering using vitamin d supplementation. since only rcts with relatively small patient populations have been conducted in both vitamin d-sufficient and -deficient copd patients, more rcts are needed, especially in vitamin d-deficient patients. currently, a multicenter rct is being conducted by rafiq et al. in a group of vitamin-deficient copd patients ( (oh)d < nmol/l), which may reveal whether vitamin d supplementation is indeed protective against exacerbations in this group ( ) . in addition to the effects of vitamin d supplementation in copd patients, the effects of vitamin d supplementation has also been extensively investigated in other lung diseases (which have associations with vitamin d deficiency) such as asthma, cystic fibrosis, upper respiratory tract infections. most rcts that investigated the effects of vitamin d supplementation were performed in acute respiratory tract infections (artis) and asthma. a recent meta-analysis that assessed the effects of vitamin d supplementation in rcts ( , participants) showed that indeed vitamin d supplementation was protective against atris and this effect was again more profound in patients with vitamin d deficiency (oh)d < nmol/l at baseline ( ) . a recent meta-analysis in asthma that included a total of randomized controlled trials ( , participants), indicated that vitamin d supplementation reduced the rate of asthma exacerbations and increased lung function, especially in patients with vitamin d insufficiency ( (oh)d < nmol/l) ( ) . interestingly, in asthma patients that were supplemented with vitamin d, the frequency of respiratory infections was reduced, and this effect was related to the increase of hcap /ll- ( ) . cf patients with vitamin d deficiency had a higher rate of exacerbations as compared to patients with sufficient (oh)d levels ( ) . however, only one recent multicenter rct was conducted and indicated that vitamin d supplementation did not affect the number of exacerbations in cf patients with serum (oh)d concentrations between and . nmol/l ( ) . in summary, the protective effects of vitamin d supplementation in patients suffering from copd, asthma or artis are most prominent in those with vitamin d deficiency and this would indicate the importance of establishing serum levels (oh)d in these patients as supplementation could reduce unnecessary aggravated disease pathology as a result of this deficiency. many drivers of copd pathogenesis such as chronic exposure to noxious particles and gases, which are present in cs and air pollution, proteolytic enzymes, cytokines and chemokines that are released by infiltrating inflammatory cells, are known to harm the epithelial barrier and cause aberrant remodeling of the airway epithelium with important functional consequences for e.g., host defense. a dysfunctional epithelial barrier increases the susceptibility toward bacterial and viral infections, which are important triggers of copd exacerbations and these exacerbations contribute importantly to disease progression. sufficient local levels of , (oh) d may provide partial protection against these effects by reducing the effects of oxidative stress induced by exposure to inhaled oxidants or those derived from recruited inflammatory cells. , (oh) d furthermore protects against impairment of epithelial barrier function by promoting the integrity of the epithelial barrier, and by modulating both innate and adaptive immune responses. protection against the detrimental effects of both bacterial and viral infections is provided by the ability of , (oh) d to promote of antiviral responses, induce expression of amps and modulate of inflammatory responses. taken together, these activities suggest that , (oh) d may provide protection against development and progression of copd, and against disease exacerbations. in addition, the local inflammatory milieu as well as the chronic exposure to noxious particles and gases, which are present in cs and air pollution, may negatively affect synthesis and signaling of , (oh) d. here we discussed recent in vitro studies that demonstrated that disease-associated factors such as inflammation and exposure to cs and air pollution could interfere with , (oh) d signaling and its degradation and activation by affecting expression of vdr, cyp a and cyp b , respectively. these findings indicate that , (oh) d levels and its activities on airway mucosa might be impaired especially in patients with copd with exposures to cigarette smoke and cytokines such as tnf-α, il- β, il- a and tgf-β . this suggests that even in patients with sufficient (oh)d serum levels the local activity of , (oh) d in the lungs can be improved. we have to start generating more information on both systemic and local , (oh) d levels and gene expression signatures related to (oh)d and , (oh) d metabolism or responses in copd (and other chronic inflammatory diseases that are related to vitamin d deficiency), both at baseline and after vitamin d supplementation. this information could lead to improved treatment strategies that enhance local efficacy of , (oh) d, using e.g., specific cyp a -inhibitors such as vid ( ) . alternatively, degradation by cyp a could be prevented by using , (oh) d analogs that are insensitive to cyp a -mediated degradation, such as sulfone and sulfoximine derivatives, that also act as a vdr agonist ( ) . a third option is to entail the use of combination treatment with vitamin d and anti-inflammatory or certain anti-fibrotic drugs that target cytokines/proteins that are known to potentially decrease local levels and signaling of , (oh) d by inducing expression of cyp a ( , , ) . when considering such strategies, it should be noted that these may enhance the calcemic side effects and lead to unwanted inhibition of the immune system. we therefore need to carefully analyze the preclinical in vivo and in vitro studies and balance the pros and cons of the different strategies. in conclusion, future studies in copd and but also in other chronic inflammatory diseases that are related to vitamin d deficiency, should be designed with more focus on assessing and improving local levels of , (oh) d. these new insights may lead to the development of new treatment strategies, such as those targeting cyp a to enhance local , (oh) d resulting in improved homeostasis and protection of the airway mucosa in patients with 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interest.copyright © schrumpf, van der does and hiemstra. this is an open-access article distributed under the terms of the creative commons attribution license (cc by). the use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. no use, distribution or reproduction is permitted which does not comply with these terms. key: cord- -j u ga authors: sapey, elizabeth; bafadhel, mona; bolton, charlotte emma; wilkinson, thomas; hurst, john r; quint, jennifer k title: building toolkits for copd exacerbations: lessons from the past and present date: - - journal: thorax doi: . /thoraxjnl- - sha: doc_id: cord_uid: j u ga in the nineteenth century, it was recognised that acute attacks of chronic bronchitis were harmful. years later, it is clearer than ever that exacerbations of chronic obstructive pulmonary disease (ecopd) are important events. they are associated with significant mortality, morbidity, a reduced quality of life and an increasing reliance on social care. ecopd are common and are increasing in prevalence. exacerbations beget exacerbations, with up to a quarter of in-patient episodes ending with readmission to hospital within days. the healthcare costs are immense. yet despite this, the tools available to diagnose and treat ecopd are essentially unchanged, with the last new intervention (non-invasive ventilation) introduced over years ago. an ecopd is ‘an acute worsening of respiratory symptoms that results in additional therapy’. this symptom and healthcare utility-based definition does not describe pathology and is unable to differentiate from other causes of an acute deterioration in breathlessness with or without a cough and sputum. there is limited understanding of the host immune response during an acute event and no reliable and readily available means to identify aetiology or direct treatment at the point of care (poc). corticosteroids, short acting bronchodilators with or without antibiotics have been the mainstay of treatment for over years. this is in stark contrast to many other acute presentations of chronic illness, where specific biomarkers and mechanistic understanding has revolutionised care pathways. so why has progress been so slow in ecopd? this review examines the history of diagnosing and treating ecopd. it suggests that to move forward, there needs to be an acceptance that not all exacerbations are alike (just as not all copd is alike) and that clinical presentation alone cannot identify aetiology or stratify treatment. in the nineteenth century, it was recognised that acute attacks of chronic bronchitis were harmful. years later, it is clearer than ever that exacerbations of chronic obstructive pulmonary disease (ecopd) are important events. they are associated with significant mortality, morbidity, a reduced quality of life and an increasing reliance on social care. ecopd are common and are increasing in prevalence. exacerbations beget exacerbations, with up to a quarter of in-patient episodes ending with readmission to hospital within days. the healthcare costs are immense. yet despite this, the tools available to diagnose and treat ecopd are essentially unchanged, with the last new intervention (non-invasive ventilation) introduced over years ago. an ecopd is 'an acute worsening of respiratory symptoms that results in additional therapy'. this symptom and healthcare utility-based definition does not describe pathology and is unable to differentiate from other causes of an acute deterioration in breathlessness with or without a cough and sputum. there is limited understanding of the host immune response during an acute event and no reliable and readily available means to identify aetiology or direct treatment at the point of care (poc). corticosteroids, short acting bronchodilators with or without antibiotics have been the mainstay of treatment for over years. this is in stark contrast to many other acute presentations of chronic illness, where specific biomarkers and mechanistic understanding has revolutionised care pathways. so why has progress been so slow in ecopd? this review examines the history of diagnosing and treating ecopd. it suggests that to move forward, there needs to be an acceptance that not all exacerbations are alike (just as not all copd is alike) and that clinical presentation alone cannot identify aetiology or stratify treatment. 'next to avoiding a fatal issue, our efforts must be directed to prevent the case going on to chronic bronchitis, especially in those who have had previous attacks'. r douglas powell, london ( ) an exacerbation of chronic obstructive pulmonary disease (copd) is defined as 'an acute worsening of respiratory symptoms that results in additional therapy'. the word exacerbation has a latin root; stemming from the verb exacerbare meaning 'to provoke to anger' and the oxford english dictionary defines an exacerbation as 'the process of making a problem, bad situation, or negative feeling worse'. this accurately reflects the negative impact copd exacerbations (ecopd) have on patient quality of life, lung function decline and mortality. in the uk, national audit data highlight the high mortality and readmission rates (and thus healthcare costs) associated with ecopd. exacerbations impact on patients' quality of life and even a single exacerbation is associated with an increase in mean annual forced expiratory volume (fev ) decline. the early identification, provision of appropriate treatment and subsequent prevention (or ideally, primary prevention) of exacerbations has to be a central strategy for copd care. we use clinical symptoms to diagnose an exacerbation of copd, based on the triad of increased breathlessness, increased sputum volume and/ or increased sputum purulence. these criteria are essentially unchanged over the last years, finessed with clinical investigations such as a chest radiograph, arterial blood gas, ecg, a full blood count and sputum culture (all available since - ). [ ] [ ] [ ] [ ] [ ] in stark terms, our diagnostic approach to copd exacerbations has not fundamentally changed for almost years. we have no copd-specific biomarkers and the diagnosis is often one of exclusion. this is in contrast to many other acute presentations of chronic diseases, such as a myocardial infarction (mi) in ischaemic heart disease, where specific and sensitive diagnostic toolkits including biomarkers, imaging and interventions have revolutionised care pathways and patient outcomes. such disparity in advancement raises the question of why copd is so far behind other common, debilitating and progressive chronic diseases which are associated with acute flares of symptoms. why do we not have a better diagnostic and treatment toolkit for ecopd? perhaps to move forward, we need to examine the past. in , douglas powell identified cold weather, upper respiratory tract infections and pollution as an important causes of (acute) bronchitis, observing that 'dusty employments…dusty winds (and) irritating fogs' bring on typical attacks. today, the most important listed triggers of exacerbations of copd include viral and/ or bacterial tracheobronchial infection and inhalation of environmental irritants. in a study of hospitalised (and thus severe) exacerbations of copd, bacteria or viruses were identified in % using quantitative culture and pcr. bacteria were present in % of patients, most commonly haemophilus influenzae, streptococcus pneumoniae, moraxella the variability of inflammation in sputum in one patient with copd. a spontaneous sputum sample was collected over hours post waking and following mouth rinsing procedures daily for days (visits - ), and then twice weekly for further weeks (visits , ; , ; , ) in a patient with moderate severity copd in the stable state who had been an ex-smoker for years. a differential cell count was performed and cytokines were measured in sputum sol phase. each marker is the concentration of that mediator on the visit day. neutrophil (pmn) / ml (red circles), myeloperoxidase (mpo) mg/ml (green square); tnfα pm (cerise triangle): il nm (cyan triangle); ltb nm (black diamond). adapted from sapey et al. copd,chronic obstructive pulmonary disease; tnf, tumour necrosis factor. catarrhalis; staphylococcus aureus and pseudomonas aeruginosa, in descending order of prevalence. viruses were found in %, with rhinoviruses, influenza viruses, respiratory syncytial viruses, parainfluenza viruses and coronaviruses most commonly identified, again in descending order of prevalence. viral infections are important in copd, associated with frequent exacerbations, a higher total symptom burden at presentation and a longer period before symptom recovery, perhaps reflecting the lack of specific therapies available. coinfection (bacterial and viral) is common (seen in % of severe exacerbations), associated with increased lung and systemic inflammation, longer hospitalisation and more severe lung disease. the role of air quality is of increasing interest. short-term exposure to major air pollutants (trioxygen (o ), carbon monoxide, nitrogen dioxide, sulphur dioxide, particulate matter (pm) and pm . ) is associated with respiratory risk but a recent systematic review concluded that these pollutants were also associated with risk of exacerbation. other identified triggers and/or risk factors for exacerbation include discontinuation and poor adherence with medications, poor nutritional and lower socioeconomic status and dynamic hyperinflation. these causative triggers and predisposing factors have been consistently identified across the literature, but studies also highlight alternative pathologies which might account for symptoms, including thromboembolic disease and mi (identified in % and % of suspected copd exacerbations, respectively), suggesting comorbidity is important. the treatment of exacerbations has remained short-acting bronchodilators and corticosteroids with or without antibiotics for years, almost irrespective of the underlying cause. however, with global concerns about antibiotic use and an increasing number of clinical trials of new or repurposed therapeutics given at the time of exacerbation, identifying the exacerbation trigger has never felt more relevant. can clinical evaluation alone help identify the cause? from the late s onwards, a body of evidence supported the concept that the presence of purulent sputum at exacerbation presentation was indicative of a bacterial exacerbation (eg stockley et al, ) and this has been used ever since as a potential biomarker for bacterial infections. however, there are concerns about the ability of patients to self-report sputum colour without training or a colour chart to refer to daniels et al and in some studies, sputum colour could not differentiate between a viral or bacterial aetiology. a landmark study in suggested that exacerbations could be stratified using inflammatory profile. here, % of exacerbations were associated with bacteria, % with a virus, most commonly rhinovirus, % with a significant sputum eosinophilia and % with no significant inflammation (termed pauci-inflammatory). of note, these groupings did not reflect differences in symptom burden, clinical presentation or sputum colour, which could not differentiate between causes, meaning clinicians could not predict what the cause or inflammatory profile of the exacerbation was using standard clinical evaluation alone. this has important but perhaps predictable implications for clinical practice. moving forward, as with other acute presentations of chronic disease, we should not rely on clinical symptoms, signs or non-specific investigations to direct a stratified approach to exacerbation treatment. given copd is an inflammatory disease, the immune response may provide aetiological insight. in engel hypothesised that the structural lung damage described in chronic bronchitis and emphysema might be caused by repeated infections, with multiple acute insults leading to long-term lung damage. in , morgan suggested that there were differences in the acute and chronic inflammation seen in the bronchial tree and surmised that these differences may influence patient outcome and require different treatments. fifty years on from this observation, how far has our understanding of the inflammatory basis of acute exacerbations of copd progressed? there is a substantial and convincing body of evidence that airway inflammation is prevalent in stable copd and is fundamental to its pathogenesis with studies suggesting relationships with disease severity and inflammatory burden. however, pulmonary inflammation varies greatly between individuals and within individuals with copd even when clinically stable and this heterogeneity has proven challenging in biomarker evaluation or inflammation-targeted therapeutic intervention. figure provides an example of the variability of the inflammatory profile of spontaneous sputum inflammation day to day in one patient with copd. as shown, although some mediators share a common pattern of change (if one mediator is up, others are up and vice versa), not all do (eg, on visit , tumour necrosis factor (tnf)α has increased, but leukotriene b (ltb ) and interleukin- (il ) have decreased) and this suggests that the variability in mediators does not only reflect dilution of the sample, but true variability in inflammatory pattern. there appears to be a further amplification of inflammation during exacerbation in many (but not all) patients. once an insult (bacterial, viral or environmental) sufficiently activates the resident immune cells of the airways, it appears to trigger a cascade of inflammatory mediators. this in turn recruits a wave of activated immune cells to the airways, which are predominantly neutrophils but also include eosinophils, monocytes and cd +t cells and these cells have the potential to cause significant disruption and damage when they enter tissue en masse. for example, activated neutrophils release proteinases during migration through complex tissues, degranulation, frustrated where local host defences are overwhelmed, non-resident immune cells, predominantly neutrophils, but also t cells, b-cells and eosinophils are recruited into the lung tissue, following chemokines secreted by epithelial and endothelial cells and resident immune cells. fibroblasts may be activated by growth factor releases from macrophages and epithelial cells. . recruited and resident immune cells are able to release cytotoxic granular contents, reactive oxygen species and proteinases into the tissue and these have been causally associated with the development of mucus secretion, but also emphysema and small airways remodelling, leading to progression of the underlying copd. phagocytosis and neutrophil extracellular traps (net) formation. the concentration of proteinases initially far exceed and thus overwhelm their inhibitors leading to degradation of structural lung proteins including elastin and collagen causing bystander tissue damage and cleavage of enzymes, cytokines, receptors and opsonins including components of the complement cascade and immunoglobulins. while tissue damage is heightened in exacerbations of copd, tissue repair is blunted, effecting the structural integrity of the airways. this inflammatory cascade also results in systemic inflammation, with increases in acute phase proteins such as fibrinogen and c reactive protein (crp). relationships have been described between the degree of pulmonary and systemic inflammation in some studies, a potential link between the multimorbid diseases associated with copd and copd exacerbations (see later). these processes are illustrated in figure . copd severity (definable by a number of measures, but commonly by fev in one second (fev ) at one timepoint) is not synonymous with copd activity (the trajectory of lung function decline or exacerbation frequency). some patients have mild copd by fev which is rapidly progressing or with frequent exacerbations and vice versa. while hypothetically attractive, studies have not consistently linked disease activity (such as exacerbation frequency) to the presence of increased airways inflammation in the stable state. however, the presence of potentially pathogenic bacteria on sputum culture is associated with exacerbation frequency and there is a clear relationship with bacteria and inflammation which supports the concept of inflammatory burden increasing the susceptibility to exacerbations. it is likely that some studies have been underpowered to assess differences in inflammation or have failed to include patients with high exacerbation frequencies, which is understandable given the challenges of recruiting these unstable patients to research studies. there is an association between inflammation and exacerbation outcome. symptom resolution corresponds to abating inflammation and continuation of symptoms or recurrence of exacerbation corresponds to sustained inflammation, suggesting a causal relationship between inflammatory load and host experience. while it is attractive to assume that all exacerbations of a certain aetiology might share the same inflammatory profile and burden, the complexity of host, environment and exacerbation trigger interactions within copd are likely to produce patterns with greater subtlety than that. however, just as with stable copd, within copd exacerbations there might be phenotypes or 'treatable traits' which could help focus therapeutic choices. immune cell function might provide mechanistic insight. it has been proposed that some frequently exacerbating copd patients might experience a 'triple innate immune system hit' which could increase their susceptibility to bacterial exacerbations. first, the frequent exacerbator phenotype has been associated with a reduced ability of airway macrophages to phagocytose bacteria. theoretically, this would lead to increased neutrophil recruitment and in this group neutrophilic inflammation is commonly described. second, studies suggest the accuracy of neutrophil targeting is impaired in copd and associated with heightened bystander tissue damage. third, airway macrophages and monocytes from the frequent exacerbator phenotype are less able to clear dead and dying neutrophils (and eosinophils via efferocytosis, resulting in cell necrosis and localised inflammation and tissue damage). neutrophilic inflammation is corticosteroid resistant in copd but promisingly, studies have identified potential therapeutic targets to improve impaired cellular functions. nrf activators increase macrophage phagocytosis and pi k inhibitors have been shown to increase neutrophil migratory accuracy in vitro as well as reducing inflammation with pi k inhibitors under assessment in early phase studies as a potential therapy during copd exacerbations. due to advancements initially in asthma care, trials of therapies in those copd patients with an eosinophil signal are well underway (with studies currently listed on the clinicaltrials. gov website). results to date suggest that this trait is associated with a good treatment response to oral steroids at exacerbation and inhaled steroids in the stable state, with studies of specific antieosinophil therapies (including mepolizumab) showing promise in selected patient groups. furthermore, studies of community-treated exacerbation suggest that there is no advantage in treating adults without an eosinophil signal with oral prednisolone, as this provides no symptomatic benefit and an increase risk of harm. in hospitalised ecopd, studies suggest that oral corticosteroids and shorter courses appear adequate, with no benefit using high-dose intravenous therapy. excessive use of oral corticosteroids is associated with harm, which is especially clear in studies of patients on long-term maintenance but also potentially raises concerns about uncontrolled and/or unsupported use of 'rescue packs'. of note, a recent cochrane review concluded that there was no evidence of benefit from self-management interventions (including rescue packs) to reduce all-cause hospital admission, all-cause hospitalisation days, emergency department visits, general practitioner visits, dyspnoea scores, the number of copd exacerbations or all-cause mortality although more research was needed. however, the provision of a rescue pack for patients with exacerbations remains a recommendation from the national institute for health and care excellence in the revised guideline published in december (based on expert opinion). these studies begin to highlight that there are different types of copd exacerbations, with different responses to treatment and that a 'one size fits all' approach for both treatment and prevention is overly simplistic. to further advance inflammation-based treatments, a toolkit is needed to match exacerbation aetiology with host response and therefore treatment. in other words, we need to phenotype exacerbations. the value of phenotyping exacerbations of copd is to derive patterns for treatment response or to enhance our understanding of underlying mechanisms. a frequently used, yet rudimentary classification of an exacerbation phenotype is the categorisation as 'infective' or 'non-infective' exacerbations of copd. this is commonly used to direct treatment with antibiotics and systemic corticosteroids, respectively but does not inform underlying mechanisms, likely treatment response or if the exacerbation severity and outcomes are the same. recent advances which exploit developments in biomarker identification, mediator discovery and molecular diagnostics, for example in microbial detection, have furthered our understanding of the exacerbation event. there has been great interest in studying systemic plasma samples in copd to provide insight into the pathogenesis of exacerbations. one such study included exacerbating patients (unselected, of any aetiology), assessing preselected inflammatory mediators. of these, crp, interleukin- , myeloid-progenitor inhibitory factor , pulmonary and activation-regulated chemokine, adiponectin and soluble intracellular adhesion molecule- were significantly elevated at the exacerbation event. however, no plasma mediator alone provided a robust predictive tool for diagnosing an exacerbation event. crp combined with a major symptom (dyspnoea, sputum purulence or sputum volume) improved diagnostic accuracy but no mediator/symptom combination predicted clinical severity or recovery. this result may reflect that the study included 'all comers' with an exacerbation (all aetiologies) and therefore might have been underpowered to find predictive biomarkers if the biomarkers varied by aetiology or host response. to address this, further studies utilised differing approaches to identify phenotypes of exacerbations. the first attempts to investigate biomarkers in virus-associated exacerbations as a specific phenotype were made from the east london cohort. in this study, human rhinovirus (hrv) infection was examined in healthy controls and copd patients at stable state and during exacerbation. baseline cxcl (interferon gamma inducible protein ) was higher in copd than controls, but at exacerbation, there was an increase in serum cxcl in hrv positive exacerbations, correlating with sputum hrv virus load, and no increase in hrv negative exacerbations. a combination of 'cold' symptoms and serum cxcl at exacerbation was associated with a roc of . in predicting an hrv-associated exacerbation of copd. the studies described so far tested preformed hypotheses to identify associations between inflammatory profiles and exacerbation. in the first study of its kind, the beat-copd study employed cluster analysis using mediators sampled from the airways to determine biologically distinct exacerbation groups. four biological exacerbation phenotypes were described, mapping on to inflammation, independent of each other but clinically indistinguishable. sputum interleukin β (il β) was found to be most sensitive for bacteria-associated exacerbations (proinflammatory cluster, receiver operating characteristic curve (roc) . ), serum cxcl was (again) most sensitive for virus-associated exacerbations (th cluster, roc . ) and peripheral blood eosinophils (th cluster, roc . ) was the most sensitive for sputum eosinophilic-associated exacerbations. an independent validation cohort of subjects confirmed that sputum il β, serum cxcl and peripheral blood eosinophils these studies highlight four potential exacerbation phenotypes which might provide robust treatment pathways in time. . bacterial in origin, il- β as a biomarker, neutrophilic inflammation. . viral in origin, with cxcl as a biomarker. . eosinophillic in origin and as a biomarker. pauci-inflammatory. these appear to be biologically different even when clinically indistinguishable. however, while our understanding of each of these phenotypes needs to be improved, we understand very little at all about the so-called pauci-inflammatory exacerbation. indeed, it is unclear whether this represents copd at all or the acute presentation of a related comorbidity which may also cause or exacerbate breathlessness and a cough. the recognition and gravitas of comorbidities in copd has built over the last decade or more. whether the presence of comorbidities is based on self-report or systematically sought, they are common and affect mortality. exacerbations represent a period with multiple insults to both the lung and systemically. such insults include the aetiological factor itself (pathogen or environmental), lung physiological changes and additional work of breathing, hypoxia, periods of inactivity (which can effectively be prolonged periods of 'bed rest' during an in-patient admission), with a study suggesting that an acute medical admission is associated with a median step count of per day (iqr - ), dehydration, malnutrition, the therapies prescribed and their side effects (eg, oral corticosteroids and hyperglycaemia and antibiotics and gastrointestinal disturbance) and then the sequelae of these factors including systemic inflammation, hypo and hypernatraemia/kalaemia and altered sympathetic drive. figure summarises the complex relationships between comorbidity and exacerbations in copd. there is a significant and complex interplay between the exacerbation and the comorbid condition including the impact of comorbidities on the exacerbation itself; how an exacerbation contributes to comorbid disease; the prognostic role of comorbid disease and the subclinical presentation of a comorbid condition at the time of an exacerbation. cardiovascular disease highlights the interplay and is the most studied comorbidity in this context. patients presenting to hospital with a copd exacerbation have a host of comorbid conditions and the presence of a comorbid condition and the systemic manifestation of that figure comorbidity and copd exacerbations. there are many stressors during copd exacerbations which can predispose to or exacerbate comorbidities and the multimorbidity patients experience. this figure is a schematic of some of these factors, but is not exhaustive and each stressor can influence the other, irrespective of placement in the figure. stressor include the direct effects of infection and inflammation, dyshomeostasis including hypo and hypernatraemia, kalaemia and glycaemia, hypoxia and hypercapania. organ dysfunction is common, especially of cardiac and renal origin. patients are placed on short courses of oral corticosteroids and physical activity is reduced (and can equate to bed rest in some patients), both contributing to sarcopenia and osteopenia. copd, chronic obstructive pulmonary disease. comorbidity increases the duration of an exacerbation. coexistent ischaemic heart disease leads to far greater number of symptomdays per year, while an increased blood glucose in hospitalised patients leads to a longer stay and is associated with a higher risk of death. mi is more likely in the period following presentation with an exacerbation [ ] [ ] [ ] and there is evidence of increase platelet aggregation, increased arterial stiffness as well as myocardial injury as evidenced by cardiac biomarkers at the time of a copd exacerbation. the fact that comorbid disease may present subclinically at the time of the exacerbation is also important to consider, be it as a differential or as a further contributing factor to the symptoms and challenges of managing the condition. in a prospective case series, one in patients presenting to hospital with an exacerbation of copd had criteria that would meet diagnosis of a mi. impaired cognitive function is evident, if assessed, in a large proportion of patients at the time of discharge from a hospitalised exacerbation, with no evidence of recovery months later. prognostically, comorbidities present a greater risk of hospitalisation, particularly in the presence of lower lung function, as well as increased all-cause readmissions related to multimorbidity and older age. in the eclipse study (evaluation of copd longitudinally to identify predictive surrogate end-points), the best predictor of exacerbations was a former history of them. in addition, however, a history of reflux and heartburn was a further independent factor. the presence of acute kidney injury and lower limb muscle cross-sectional area at the time of exacerbation requiring hospitalisation are both prognostic of death. the prognostic copd exacerbation score such as the validated decaf score ("dyspnoea, eosinopenia, consilidation, acidaemia and atrial fibrillation" score predicting in-patient mortality) and the pearl score ("previous admissions, emrcd score, age, right-sided heart failure and left sided heart failure" score predicting -day readmission and mortality) include cardiac comorbidity in their calculations. patients deemed as frequent exacerbators are more likely to be depressed or have coexistent cardiovascular disease or osteoporosis. it is unclear if some events labelled exacerbations are actually a presentation of a comorbid condition (and studies suggest that clinicians are less likely to diagnose mi or pulmonary embolus (pe) if there is a concomitant diagnosis of copd, ) perhaps the so-called pauci-inflammatory exacerbations, or whether the comorbidity is exacerbating the copd. there remains a role for more timely identification of comorbid disease and addressing the contributing factors. the role of systematic identification of certain comorbidities and of preventative strategies, both pharmacologically and lifestyle-based are topics for ongoing discussion and research. in the meantime, opportunity exists to ensure optimal treatment for those with identified comorbid disease, such as ensuring beta-blockers are prescribed in those who meet the criteria or that hyperglycaemia or hyperlipidaemia are adequately addressed. despite a greater understanding of the biology and complexity of copd exacerbations, this has not (yet) translated into novel therapies to treat exacerbations. there has been no new intervention to treat copd exacerbations since the widespread adoption of non-invasive ventilation to treat exacerbations with hypercapnoeic respiratory failure in the early s. from the first introduction of guidelines such as gold in , the therapy for an exacerbation is unchanged. as described below, despite being commonly used, there remain significant research knowledge gaps in determining which exacerbations do and do not require treatments with antibiotics and corticosteroids. systemic corticosteroids were first used in rheumatological disease during the late s. despite evidence in the late s that many hospitalised patients were being treated with systemic corticosteroids, it was only at the turn of the millennium that small randomised clinical trails (rcts) first documented clinical efficacy, suggesting benefit on lung function and outcomes such as length of hospital stay. around the same time, the first small outpatient trials of steroids at exacerbation reported, with modest benefits confirmed in a larger rct. later it was defined that short course ( days) treatment was as effective as longer day courses, and without the need to taper dose. with a greater emphasis on exacerbation phenotyping, more recent studies have documented the ability to safely withhold steroids in exacerbations without an eosinophil signal. however, the practicality of achieving this at point-ofcare, and the optimal blood eosinophil cut-off to guide steroid therapy remain to be determined, and there are ongoing trials in the area. given the toxicity associated with repeated courses of corticosteroids, the need for effective novel anti-inflammatory agents is also great. disappointingly, there is no evidence of benefit with the anti-tnf agent entanercept or roflumilast, for example. anthonisen's rct demonstrated the superiority of antibiotics over placebo in exacerbations presenting with at least two of the three cardinal symptoms of increased breathlessness, sputum volume and sputum purulence. importantly, this had been conducted in patients with copd, rather than just those with chronic bronchitis. however, the placebo response rate was high, likely reflecting viral pathogens as a common cause of exacerbation, and more recent studies have not shown a benefit of antibiotics in other outcomes such as prolonging the time to next exacerbation. biomarkers such as sputum colour and procalcitonin have been suggested as strategies to better guide antibiotic therapy, but there remains unmet need to better define which exacerbations do and do not benefit from antibiotic therapy. it is also notable that there are no effective interventions to treat (or prevent) rhinovirus infections, thought to be the single the most common cause of a copd exacerbation. salbutamol has been available since the late s, with ipratropium following in the s. these replaced the non-selective β adrenoreceptor agonist isoprenaline. there are no good data on long-acting bronchodilator drugs at the time of exacerbation. the s audit referred to above highlighted the widespread use of theophyllines (in % of patients), and use of respiratory stimulants such as doxapram in the management of hospitalised exacerbations. use of theophylline has reduced, while respiratory stimulants have been replaced by non-invasive ventilation for the management of hypercapnoeic respiratory failure in the respiratory ward environment, following initial studies in the early s . models of care have changed, with the recognition that earlier access to treatment for exacerbations can be associated with faster recovery and reduced risk of hospital admission. however, the risks and benefits of patient-held rescue packs remain to be definitely established. research to develop new interventions at exacerbation of copd is hampered by robust outcome measures to assess exacerbation recovery. changes in lung function are not patient centred, and changes in symptoms scores not validated. 'clinical recovery' and 'treatment failure' are subjective constructs, while studies have also examined effects of exacerbation treatment on the time to the next event given that exacerbations cluster in time, with a high-risk period for a second event in the period following recovery from a first. we have at least made progress in prevention of exacerbations, though even when used optimally there seems to be a ceiling of reduction at around %. effective interventions (outlined in table ), alone and in combination, include non-pharmacological approaches such as pulmonary rehabilitation, and pharmacological approaches the mainstay of which remains long-acting bronchodilators with or without inhaled corticosteroids and, in selected cases, prophylactic antibiotics. for patients remaining hypercapnic following a hospitalised exacerbation, domiciliary non-invasive ventilation significantly reduces the risk of rehospitalisation (with an absolute risk reduction of % in a recent landmark study). similar to strategies to better target exacerbation treatment, there is also now emerging evidence on how better to target exacerbation prevention interventions, including the optimal use of inhaled corticosteroids. thus, while exacerbation prevention strategies are incompletely effective, the challenge here is rather selecting the right combination of interventions for the right patient at the right time, rather than the absence of effective prevention strategies. in , r douglas powell advised that our management aims should be to save life and prevent further episodes of then acute and chronic bronchitis, now copd. we still have a long way to go to achieve this. exacerbations of copd are still associated with significant mortality, morbidity, readmission and poor life quality. there have been no real advancements in routine care since the s. there is considerable unmet need for novel strategies to identify, treat and prevent exacerbations, and a pressing need to better use existing therapies. this remains a major challenge. how do we move forward? copd as a disease concept has always raised the question of 'lumping or splitting'; is this one disease or many? innovation in asthma care has provided a path which perhaps copd should follow. asthma phenotypes and now endotypes provide clinically blurred but biologically distinct clusters with an emerging arsenal of treatments for those with the most difficult to manage symptoms. the concept of 'treatable traits' has gained considerable momentum in stable copd, and perhaps now the same concept should be tested further in exacerbations. we are beginning to see some differences in biological signals across exacerbation aetiologies and host responses. to build on this, we need to continue with more stratified studies of ecopd, learning from the fruitful experience of focusing on those with an eosinophilic signal, but this time using poc testing to characterise and test treatments in (eg) viral or pauci-inflammatory exacerbations. this will provide more information about aetiology, but to personalise treatment, this must be incorporated into a holistic understanding of the impact of the hosts comorbidity and immune responses. from these data, we could build our ecopd toolkit, which we hypothesise might include poc identification of bacterial or viral pathogen (ensuring that the correct antibacterial or viral therapy is used and thus reducing redundant therapy), blood biomarkers to identify or exclude an eosinophil (corticosteroid use or avoidance) or cardiac (acute coronary syndrome, heart failure) or neutrophilic treatment pathway and a measure of acuity and respiratory compromise. by exploring these ideas, we may be able to introduce a stratified approach to treatment and prevention, which might, finally, really impact on these debilitating and costly events, to the benefit of our patients. contributors all authors wrote the manuscript and all contributed to the manuscript equally. funding e sapey was funded by the medical research council, grant number mr/ r / . other authors received no specific grant for this work from any funding agency in the public, commercial or not-for-profit sectors. no, there are no competing interests for any author. global strategy for the diagnosis, management and prevention of chronic obstructive pulmonary disease effect of exacerbations on quality of life in patients with chronic obstructive pulmonary disease: a year follow up study acute exacerbations and lung function loss in smokers with and without copd the impact of exacerbation frequency on mortality following acute exacerbations of copd: a registry-based cohort study copd: who cares when it matters most? national chronic obstructive pulmonary disease (copd) audit programme: outcomes from the clinical audit of copd exacerbations admitted to acute units in effect of a single exacerbation on decline in lung function in copd a treatise on the disease of the chest and on mediate auscultation. (translated by j forbes) de la numeration des globules rouges du sang ueber die form des menschlichen electrocardiogramms the determination of gases in blood and other solutions by vacuum extraction and manometric measurement. i notes on xrays ueber die isolierte farbung der schizomyceten in schmitt-und trockenpraparaten on consumption, on certain diseases of the lungs and pleura infection in the pathogenesis and course of chronic obstructive pulmonary disease infections and airway inflammation in chronic obstructive pulmonary disease severe exacerbations respiratory viruses, symptoms, and inflammatory markers in acute exacerbations and stable chronic obstructive pulmonary disease major air pollutants and risk of copd exacerbations: a systematic review and meta-analysis adherence to inhaled therapy, mortality and hospital admission in copd socioeconomic status, race and copd health outcomes physiological changes during symptom recovery from moderate exacerbations of copd venous 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infarction and stroke following exacerbation of copd risk of myocardial infarction (mi) and death following mi in people with chronic obstructive pulmonary disease (copd): a systematic review and meta-analysis exacerbations of chronic obstructive pulmonary disease and cardiac events. a post hoc cohort analysis from the summit randomized clinical trial increased platelet activation in patients with stable and acute exacerbation of copd cardiovascular risk, myocardial injury, and exacerbations of chronic obstructive pulmonary disease cognitive dysfunction in patients hospitalized with acute exacerbation of copd prevalence and outcomes of diabetes, hypertension and cardiovascular disease in copd audit programme: outcomes from the clinical audit of copd exacerbations admitted to acute units in england susceptibility to exacerbation in chronic obstructive pulmonary disease acute kidney injury in stable copd and at exacerbation bedside assessment of quadriceps muscle by ultrasound after 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of chronic obstructive pulmonary disease: a prospective randomised controlled trial controlled trial of oral prednisone in outpatients with acute copd exacerbation outpatient oral prednisone after emergency treatment of chronic obstructive pulmonary disease short-term vs conventional glucocorticoid therapy in acute exacerbations of chronic obstructive pulmonary disease: the reduce randomized clinical trial tnfα antagonists for acute exacerbations of copd: a randomised double-blind controlled trial randomized double-blind controlled trial of roflumilast at acute exacerbations of chronic obstructive pulmonary disease antibiotic therapy in exacerbations of chronic obstructive pulmonary disease doxycycline for outpatient-treated acute exacerbations of copd: a randomised double-blind placebo-controlled trial hospital procalcitonin testing and antibiotic treatment of patients admitted for chronic obstructive pulmonary disease exacerbation randomised controlled trial of nasal ventilation in acute ventilatory failure due to chronic obstructive airways disease early therapy improves outcomes of exacerbations of chronic obstructive pulmonary disease temporal clustering of exacerbations in chronic obstructive pulmonary disease effect of home noninvasive ventilation with oxygen therapy vs oxygen therapy alone on hospital readmission or death after an acute copd exacerbation: a randomized clinical trialeffect of home niv on outcomes after acute copd exacerbationeffect of home niv on outcomes after acute copd exacerbation small copds": copd should be an orphan disease asthma phenotypes: the evolution from clinical to molecular approaches global initiative for chronic obstructve lung disease. global strategy for prevention, diagnosis and management of copd key: cord- - qdrshz authors: scully, crispian title: respiratory medicine date: - - journal: scully's medical problems in dentistry doi: . /b - - - - . - sha: doc_id: cord_uid: qdrshz ●. upper respiratory infections are commonplace, especially in young people, and are often contagious; ●. lower respiratory infections are often contagious and some are potentially fatal; ●. asthma is common and may be life-threatening; ●. chronic obstructive pulmonary disease is common and disabling; ●. tuberculosis worldwide is an important infection, affecting people with hiv/aids or malnutrition particularly; ●. lung cancer is common and usually has a poor prognosis. • upper respiratory infections are commonplace, especially in young people, and are often contagious the respiratory tract consists of the upper respiratory tract (urtnose, paranasal sinuses, pharynx and larynx; discussed in ch. ) and the lower respiratory tract (lrt): the respiratory airways (trachea, bronchi and bronchioles) and lungs (respiratory bronchioles, alveolar ducts, alveolar sacs and alveoli), discussed in this chapter. protective mechanisms in the respiratory tracts include a mucociliary lining. particles or pathogens are trapped in the mucus and driven by ciliary action (the ciliary elevator) to the pharynx. mucociliary trans port declines with age but any effect on clinical infection has not been proved. lymphoid tissues of the waldeyer ring (adenoids, palatine and lingual tonsils) are important in developing an immune response to pathogens. however, the best respiratory defence mechanism is the cough reflex, the components of which include cough receptors, affer ent nerves, the cough centre, and efferent nerves and effector muscles. impairment of any of these -as may be seen in older patients or those with conditions associated with lowered consciousness (e.g. sedative use and neurological disease) -can weaken protection. dysphagia or impaired oesophageal motility may exacerbate the tendency to aspi rate foreign material. the alveolar defence mechanisms include mac rophages, immunocytes, surfactant, phospholipids, immunoglobulin g (igg), ige, secretory iga, complement components and factor b; many immune defects manifest with recurrent respiratory infections. lung function is vital to gas exchange -the blood absorbs oxygen and releases carbon dioxide. normal gas exchange requires adequate alveolar ventilation, normal ventilation/blood flow relationships and adequate alveolar-capillary membrane surface area. breathing (ven tilation) depends on respiratory drive, which reacts to the respiratory load. this process requires work and results in gas exchange. oxygen is transported in combination with haemoglobin in erythro cytes and a small amount dissolved in plasma. the oxyhaemoglobin dissociation curve is sigmoidal; once the oxygen saturation falls below %, the amount of o transported to the tissues and brain falls rapidly. high temperatures, acidosis, raised co and raised , diphosphoglycerate ( , dpg) levels encourage oxygen offloading, whereas fetal haemoglobin and carboxyhaemoglobin have the con trary effect. chronic hypoxaemia (e.g. at high altitudes) stimulates release of erythropoietin from the kidneys, with a rise in red cell pro duction, and raised , dpg. athletes have abused erythropoietin to gain competitive advantage (ch. ). the most common lrt disorders are asthma and chronic obstructive pulmonary disease (copd). respiratory disorders are common, and are often caused or aggravated by tobacco smoking. they may significantly affect general anaesthesia (ga) and conscious sedation (cs), since they are often a contraindica tion to use of benzodiazepines, opioids, ga agents and other respira tory depressants. impaired gas exchange leads to laboured breathing and can cause significant incapacity. features include cough, sputum production, wheeze, dyspnoea, chest pain, cyanosis, fingerclubbing ( fig. . ) , use of accessory muscles of respiration with indrawing of the intercostal spaces (hyperinflation), and abnormalities in chest shape, movements, respiratory rate and breath sounds. cough may be a feature of any respiratory problem but, if chronic, may herald serious disease -for example, copd, cancer or infec tion such as tuberculosis. mucoid or mucopurulent sputum is often a feature ( fig. . ); purulent sputum indicates acute bronchitis, bronchiectasis or lung abscess. blood (haemoptysis) or bloodstained sputum, though common in acute infections (especially in preexisting copd), bronchiectasis and pulmonary embolism, may herald an even more serious condition -for example, possibly one due to carcinoma or tuberculosis. wheezing is caused by airways obstruction and is a typical sign of asthma or copd. breathlessness (dyspnoea) is distress ing, and may be caused by respiratory or cardiovascular disease, or by anaemia, and is particularly ominous if it persists at rest. excessive resistive load, such as in asthma, copd and cystic fibro sis, impairs airflow. elastic load increases because of, for example, interstitial fibrosis, muscle paralysis and obesity. diagnosis of respiratory disorders is from the clinical features sup ported by imaging (especially chest radiography). spiral computed tomography (ct) can now scan the lungs in a quick - second breathhold and therefore, instead of producing a stack of individual ct slices, which may be misaligned due to patient movement or breathing in between slices, provides highresolution three dimensional images. respiratory function tests can measure individual components of the respiratory process. spirometry is the basic screening test for assess ing mechanical load problems, the quantification involving determi nation of the vital capacity (vc) -slow vital capacity (svc) and/or forced vital capacity (fvc) -and the speed of maximal expiratory flow (mef; fig. . ). in health, about % of a normalsized vc is expelled in second (fev ). the peak flow meter, which measures the peak expiratory flow rate (pefr; the earliest portion of forced expiration), is a simple measure of airflow obstruction, when the fev is a much smaller fraction of the vc. in lung restriction, the diminished vc can be mostly expelled in about second. serial meas urements (e.g. in asthma) provide valuable information about disease progress. the reversibility of airways obstruction is usually assessed by spirometry before and after use of a bronchodilator agent. arterial blood gas analysis yields considerable information about gas exchange efficiency. arterial hypoxaemia in adults is defined as pao below . kpa breathing room air, although it is not usually treated as clinically important unless below kpa, when oxygen saturation will be % or less (table . ). arterial carbon dioxide tension (paco ) is used as an inversely pro portional index of 'effective' alveolar ventilation. hence, a high paco is taken to indicate poor alveolar ventilation. alveolar hypoventila tion (raised paco ) with a normal ph probably represents a primary ventilatory change present long enough for renal mechanisms to compensate, as in chronic ventilatory failure. ventilation/blood flow relationships are most simply assessed by considering the size of the difference between the amounts of oxygen and carbon dioxide in the blood and in the air; the differences are small if the lungs are work ing efficiently. disparity between ventilation/blood flow ratios results in abnormally wide differences -and then alveolar-arterial po and arterial-alveolar pco gradients will be abnormal. alveolar capillary surface area is assessed by measuring the uptake of carbon monoxide -usually abnormal in diffuse interstitial inflam matory and fibrotic processes and in emphysema. assessing bronchial reactivity and the exercise response can help evaluate breathlessness. simple exercise testing provides information about overall fitness and the appropriateness of cardiorespiratory responses. radionuclide lung scanning, blood gas analysis and sputum cytology or culture are sometimes needed in addition. management can include oxygen administration by mask or nasal cannula (figs . and . ) . lrt disorders can cause significant incapacity and are often a con traindication to ga, and even to cs. asthma is common, affecting - % of the overall population; it is on the increase, particularly in childhood, with a frequency of up to % in some highincome countries. asthma usually begins in childhood or early adult life; about half the patients with asthma develop it before age years. bronchial hyperreactivity causes reversible airway obstruction from smooth muscle constriction (bronchospasm), mucosal oedema and mucus hypersecretion. there are two main types, extrinsic (allergic) and intrinsic asthma (table . ). extrinsic (allergic) asthma, the main childhood type, may be pre cipitated by allergens in animal dander, feathers or hair, drugs (e.g. nonsteroidal antiinflammatory drugs [nsaids] and some antibiot ics), food (e.g. eggs, fish, fruit, milk, nuts), house dust (mite allergens) or moulds. patients frequently have or develop other allergic diseases, such as eczema, hay fever and drug sensitivities. extrinsic asthma is associated with ige overproduction on allergen exposure, and release of mast cell mediators (histamine, leukotrienes, prostaglandins, bradykinin and platelet activating factor), which cause bronchospasm and oedema. about % of asthmatic children lose their asthma or improve by adulthood. intrinsic asthma is usually of adult onset and not aller gic, but appears rather to be related to mast cell instability and airway hyperresponsivity. triggers include emotional stress, gastro oesophageal reflux or vagally mediated responses. either type of asthma can be triggered by: infections (especially viral, mycoplasmal or fungal); irritating fumes (e.g. traffic or cigarette smoke); exercise (possibly due to cold air); weather changes; emotional stress; foods (e.g. nuts, shellfish, strawberries or milk) or additives (such as tartrazine); and drugs (e.g. aspirin and other nsaids, beta blockers and angiotensinconverting enzyme inhibitors [aceis]). in wellcontrolled patients with asthma, clinical features may be absent. during an asthmatic episode, symptoms may include dysp noea, cough and paroxysmal expiratory wheeziness with laboured expiration. the frequency and severity of attacks vary widely between individuals (table . ). patients may become distressed, anxious and tachycardic, have reduced chest expansion and be using accessory respiratory muscles to increase their ventilatory effort. nasal polyps are common, especially in aspirinsensitive asthmatics. children with asthma initially suffer from repeated 'colds' with cough, malaise and fever, often at night. asthma is typically diagnosed when the patient has more than one of the following -wheeze, cough, difficulty breathing and chest tightness -particularly if these are frequent and recurrent; are worse at night and in the early morning; occur in response to, or are worse after, exercise or other triggers, such as exposure to pets, cold or damp air, or with emotions or laughter; or occur without an association with colds. there is often: ■ a personal history of atopic disorder ■ a family history of atopic disorder and/or asthma ■ widespread wheeze, heard on chest auscultation ■ a history of improvement in symptoms or lung function in response to adequate therapy. a prolonged asthmatic attack, which is refractory to treatment, may lead to lifethreatening status asthmaticus (persisting for more than hours). failure of the patient to complete a sentence, indrawing of the intercostal muscles, a rapid pulse, a silent chest and signs of exhaustion are suggestive of impending respiratory arrest. diagnosis of asthma is from the clinical history and presentation, based on recognizing a characteristic pattern of episodic symptoms in the absence of an alternative explanation. investigations include a chest radiograph (to exclude other diagnoses, such as a pneumo thorax), spirometry (serial pefr), skin tests and blood examination (usually eosinophilia, raised total ige and specific ige antibody concentrations, which may help identify allergens). occasionally, a histamine or methacholine challenge is used if the diagnosis is unclear. in children with an intermediate probability of asthma, who can perform spirometry and have evidence of airways obstruction, assess the change in fev or pefr in response to an inhaled bronchodilator (reversibility) and/or the response to a trial of treatment for a speci fied period; if there is significant reversibility, or if a treatment trial is beneficial, a diagnosis of asthma is probable. management includes patient education, smoking cessation advice, avoidance of identifiable irritants and allergens, and use of drugs. home use of peak flow meters allows patients to monitor progress and detect any deterioration that may require urgent modification of treatment. treatment should be based on the amount by which peak flow is reduced (a pefr diary should be kept). drugs used for asthma management (table . ) include oxygen, shortacting β agonists (sabas; such as salbutamol), corticosteroids, leukotriene receptor antagonists and omalizumab (a recombinant humanized monoclonal antiige antibody that reduces the antigen specific ige). inhaled longacting β agonists (labas) may be needed ( fig. . ). deaths from asthma are usually a result of failure to recognize dete rioration or reluctance to use corticosteroids. other factors that have been studied include: ■ air pollution -there is an association between air pollution and aggravation of existing asthma ■ allergen avoidance -there is no consistent evidence of benefit ■ breast-feeding -there is evidence of a protective effect in relation to early asthma ■ electrolytes -there is no consistent evidence of benefit ■ fish oils and fatty acid -there is no consistent evidence of benefit ■ house dust mites -measures to reduce the numbers of house dust mites do not affect asthma severity ■ immunotherapy -allergenspecific immunotherapy is beneficial in allergic asthma ■ microbial exposure -there is insufficient evidence to indicate that the use of probiotics in pregnancy reduces the incidence of childhood asthma ■ modified milk formulae -there is no consistent evidence of benefit pets -there are no controlled trials on the benefits of removing pets from the home ■ tobacco -exposure to cigarette smoke adversely affects quality of life, lung function, need for rescue medications and longterm control with inhaled steroids. there is an association between maternal smoking and an increased risk of infant wheeze ■ weight reduction -there is an association between increasing body mass index and symptoms of asthma. elective dental care should be deferred in severe asthmatics until they are in a better phase; this can be advised by the patient's general practitioner. asthmatic patients should be asked to bring their usual medica tion with them when coming for dental treatment. local anaesthe sia (la) is best used; occasional patients may react to the sulphites present as preservatives in vasoconstrictorcontaining la, so it may be better, where possible, to avoid solutions containing vasoconstric tor. adrenaline (epinephrine) may theoretically enhance the risk of arrhythmias with betaagonists and is contraindicated in patients using theophylline, as it may precipitate arrhythmias. relative analgesia with nitrous oxide and oxygen is preferable to intravenous sedation and gives more immediate control. sedatives in general are better avoided as, in an acute asthmatic attack, even ben zodiazepines can precipitate respiratory failure. ga is best avoided, as it may be complicated by hypoxia and hyper capnia, which can cause pulmonary oedema even if cardiac function is normal, and cardiac failure if there is cardiac disease. the risk of post operative lung collapse or pneumothorax is also increased. halothane or, better, enflurane, isoflurane, desflurane and sevoflurane are the preferred anaesthetics, but ketamine may be useful in children. allergy to penicillin may be more frequent in asthmatics. drugs to be avoided, since they may precipitate an asthmatic attack (see later), include those listed in box . . acute asthmatic attacks may also occasionally be precipitated by anxiety; it is important to attempt to lessen fear of dental treatment by gentle handling and reassurance. even routine dental treatment can trigger a clinically significant decline in lung function in approximately % of asthmatics. acute asthmatic attacks are usually selflimiting or respond to the patient's usual medication, such as a betaagonist inhaler, but status asthmaticus is a potentially fatal emergency (ch. ). there may be complications caused by the antiasthmatic drugs (table . ). gastrooesophageal reflux is not uncommon, with occasional tooth erosion. periodontal inflammation is greater in asthmatics than in those without respiratory disease. persons using steroid inhalers may develop oropharyngeal candidosis or, occasionally, angina bullosa haemorrhagica. guidelines on the management of asthma may be found at: http://www.sign.ac.uk/guidelines/fulltext/ /index.html, http:// www.nice.org.uk/guidance/qualitystandards/indevelopment/asthma. jsp and http://www.britthoracic.org.uk/portals/ /guidelines/ asthmaguidelines/qrg % .pdf (all accessed september ). churg-strauss syndrome (css) is a rare, potentially fatal, systemic vasculitis similar to polyarteritis nodosa (pan), characterized by severe asthmalike attacks with peripheral eosinophilia, and intravas cular and extravascular granuloma formation with eosinophil infiltra tion and skin lesions in %. cardiopulmonary involvement is the main cause of death. css is diagnosed if at least of the criteria listed in box . are positive. the year survival of untreated css is %. combination treatment with cyclophosphamide and prednisolone (prednisone) provides a year survival of %. management problems relating to patients with css may include res piratory impairment and corticosteroid treatment (ch. ). chronic obstructive pulmonary disease (copd; chronic obstructive airways disease, coad) is a common, chronic, slowly progressive, irre versible disease (most frequently a combination of chronic bronchitis and emphysema), characterized by breathlessness and wheeze (airways obstruction), cough and sputum. chronic bronchitis is defined as the excessive production of mucus and persistent cough with sputum production, daily for more than months in a year over more than consecutive years. it leads to production of excessive, viscous mucus, which is ineffectively cleared from the airway, obstructs and stag nates, and becomes infected, usually with streptococcus pneumoniae, moraxella catarrhalis and haemophilus influenzae. patchy areas of alveolar collapse can result. emphysema is dilatation of air spaces dis tal to the terminal bronchioles with destruction of alveoli, reducing the alveolar surface area available for respiratory exchange. copd is now the preferred term for conditions with airflow obstruction because of a combination of airway and parenchymal damage; patients were previ ously diagnosed as having chronic bronchitis or emphysema. copd is characterized by airflow obstruction -defined as an fev / fvc ratio reduced to less than . . if fev is % or more, a diagno sis of copd should only be made if there are respiratory symptoms (e.g. dyspnoea or cough). the airflow obstruction is not fully revers ible, does not change significantly over months, and is usually progres sive in the long term. the most important causes of copd include cigarette smoking, environmental pollution, dusts, chemicals or occupational exposures to various substances. exposure to smoke from home cooking or heating fuels may contribute. deficiency of the antiproteolytic enzyme alpha antitrypsin is a rare cause of emphysema. there is often significant airflow obstruction before the person is aware of it and so copd typically remains undiagnosed until patients are in their fifties. differentiation from asthma is important (table . ). a diagnosis of copd should be considered in patients over the age of who have a risk factor (e.g. smoking) and exertional breath lessness, chronic cough, regular sputum production, frequent winter 'bronchitis' or wheeze. clinical judgment is based on history, physical examination, confirmation of airflow obstruction using spirometry (postbronchodilator spirometry) and assessment of the severity of dyspnoea (tables . and . ). copd is characterized by breathlessness and wheeze (airways obstruction), cough and an early morning mucoid sputum production. to investigate symptoms that seem disproportionate to spirometric impairment progressive dyspnoea, low oxygen saturation, carbon dioxide accumu lation (hypercapnia) and metabolic acidosis mean that patients may ultimately become dyspnoeic at rest ('respiratory cripples'), especially when recumbent (orthopnoea), and eventually develop respiratory failure, pulmonary hypertension, right ventricular hypertrophy and rightsided heart failure (cor pulmonale). two clinical patterns of copd are recognized: ■ 'pink puffers' -patients with emphysema who manage to maintain normal blood gases by hyperventilation, and are always breathless but not cyanosed; rather they are pink from vasodilatation ■ 'blue bloaters' -patients with chronic bronchitis who lose their co drive, fail to maintain adequate ventilation and become both hypercapnic and hypoxic with central cyanosis, cor pulmonale and oedema (for these patients, the respiratory drive is from the low po and thus oxygen administration is contraindicated) (table . ). the diagnosis of copd is based upon clinical history and presen tation. investigations include a chest radiograph (which may show hyperinflated lung fields with loss of vascular markings); arterial blood gases (which should be measured if pulse oximetry shows oxygen satu ration less than %); spirometry; and lung function tests. fev is reduced in all cases (fev of less than % signifies severe copd) and the flow-volume curve shows a typical pattern, with reduced flow rates at mid and lowerlung volumes. a ratio of fev :fvc of less than % confirms airways obstruction. patients with copd and their family should be educated about the disease, and about required lifestyle changes and medication. nondrug therapy includes: stopping smoking (nicotine replacement therapy or bupropion may help); exercise by pulmonary rehabilitationof proven benefit; weight loss (improves exercise tolerance); and vaccination (pneumococcal and influenza vaccines). drug therapy includes shortacting bronchodilators (anticholinergic drugs [ipra tropium bromide]) and β agonists (salbutamol) to treat the reversible component of airway disease; corticosteroids (inhaled or systemic); and antibiotics (amoxicillin, trimethoprim or tetracycline). mucolytics, such as carbocisteine, reduce acute exacerbations by almost onethird. longterm oxygen therapy (ltot) reduces mortality. people with stable copd who remain breathless or have exacerba tions, despite using shortacting bronchodilators, should be offered the following as maintenance therapy: ■ if fev is % of predicted or more: use either a longacting β agonist (laba) or longacting muscarinic antagonist (lama). ■ if fev is less than % predicted: either a laba with an inhaled corticosteroid (ics) in a combination inhaler, or a lama. offer a lama in addition to a laba plus ics to people with copd who remain breathless or have exacerbations, despite taking laba plus ics, irrespective of their fev . provide pulmonary rehabilitation for all who need it; noninvasive ventilation (niv) is the treatment of choice for persistent hyper capnic ventilatory failure during exacerbations not responding to medical therapy. the frequency of exacerbations should be reduced by appropriate use of inhaled corticosteroids and bronchodilators, and vaccinations. bronchodilators (shortacting β agonists [saba] and shortacting muscarinic antagonists [sama]) should be the initial empirical treat ment for the relief of breathlessness and exercise limitation. ics have potential adverse effects (including nonfatal pneumonia) in people with copd. offer a oncedaily lama in preference to fourtimes daily sama to people with stable copd who remain breathless or have exacerbations, despite using shortacting bronchodilators as required, and in whom a decision has been made to commence regular maintenance bronchodilator therapy with a muscarinic antagonist (see above). most patients -whatever their age -are able to acquire and main tain an adequate inhaler technique. bronchodilators are usually best administered using a handheld inhaler device (including a spacer device if appropriate). patients with distressing or disabling dyspnoea, despite maximal therapy using inhalers, should be considered for nebulizer therapy. they should be offered a choice between a face mask and a mouth piece to administer their nebulized therapy, unless the drug specifically requires a mouthpiece (for example, anticholinergic drugs). some patients with advanced copd may require maintenance oral corticosteroids when these cannot be withdrawn following an exacer bation. these individuals should be monitored for the development of osteoporosis and given appropriate prophylaxis. theophylline should only be used after a trial of saba and laba, and only to those who are unable to use inhaled therapy, as there is a need to monitor plasma levels and interactions. the dose of theo phylline prescribed should be reduced at the time of an exacerbation if macrolide or fluoroquinolone antibiotics (or other drugs known to interact) are given. there is insufficient evidence to recommend prophylactic antibiotic therapy in the management of stable copd. mucolytic drug therapy should be considered in patients with a chronic cough productive of sputum. if patients remain symptomatic on monotherapy, their treatment should be intensified by combining therapies from different drug classes, such as: ■ β agonist and theophylline ■ anticholinergic and theophylline. inappropriate oxygen therapy in people with copd may depress respiration. ltot is indicated in patients with copd who have a pao of less than . kpa when sta ble, or a pao greater than . kpa and less than kpa when stable, and one of: secondary polycythaemia, nocturnal hypoxaemia (oxygen saturation of arterial blood [sao ] of less than % for more than % of the time), peripheral oedema or pulmonary hypertension. to reap the benefits of ltot, patients should breathe supplemental oxygen for at least hours per day. to ensure that all those eligible for ltot are identified, pulse oximetry should be available in all health care settings. the assessment of patients for ltot should comprise the measurement of arterial blood gases on two occasions at least weeks apart in patients who have a confident diagnosis of copd, who are receiving optimum medical management and whose copd is stable. patients should be warned about the risks of fire and explosion and told not to smoke when using oxygen. ambulatory oxygen therapy should be considered in patients on ltot who wish to continue oxygen therapy outside the home, and who have exercise desaturation, are shown to have an improvement in exercise capacity and/or dyspnoea with oxy gen, and are motivated to use oxygen. adequately treated patients with chronic hypercapnic respiratory failure who have required assisted ventilation during an exacerbation, or who are hypercapnic or acidotic on ltot, should be referred to a specialist centre for consideration of longterm niv. advanced emphysema is occasionally treated with sur gery -excision of large acquired bullae or, rarely, lung transplantation. patients with copd who need dental care can be classified as follows: ■ patients at low risk -experience dyspnoea on effort but have normal blood gas levels. these patients can receive all dental treatment with minor modifications. ■ patients at moderate risk -experience dyspnoea on effort, are chronically treated with bronchodilators or recently with corticosteroids, and pao lowered. a medical consultation is advised to determine the level of control of the disease before any dental treatment. ■ patients at high risk -have symptomatic copd that may be end stage and poorly responsive to treatment. with these patients, a medical consultation is essential before any dental treatment is carried out. patients with copd are best treated in an upright position at midmorning or early afternoon, since they may become increasingly dyspnoeic if laid supine. it may be difficult to use a rubber dam, as some patients are mouthbreathers and not able to tolerate the additional obstruction. la is preferred for dental treatment, but bilateral mandibular or palatal injections should be avoided. patients with copd should be given relative analgesia only if absolutely necessary, and only in hospital after full preoperative assessment. cs with diazepam and midazolam should not be used, as benzodiazepines are respiratory depressants. patients should be given ga only if absolutely necessary, and intravenous barbiturates are contraindicated. secretions reduce airway patency and, if lightly anaesthetized, the patient may cough and contaminate other areas of the lung. postoperative respiratory complications are more prevalent in patients with preexisting lung diseases, especially after prolonged operations and if there has been no preoperative preparation. the most important single factor in preoperative care is cessation of smok ing for at least week preoperatively. respiratory infections must also be eradicated; sputum should first be sent for culture and sensitivity, but antimicrobials such as amoxicillin should be started without await ing results. the medical management of copd should be optimized prior to surgery. the ultimate clinical decision about whether or not to proceed with surgery should rest with a consultant anaesthetist and consultant surgeon, taking account of comorbidities, functional status of the patient and necessity for the surgery. composite assessment tools, such as the american society of anesthesiologists (asa) scoring system, and not just lung function, are the best criteria for the assessment of patients with copd before surgery. those taking corticosteroids should be treated with appropri ate precautions (ch. ). interactions of theophylline with other drugs, such as adrenaline (epinephrine), erythromycin, clindamycin, azithro mycin, clarithromycin or ciprofloxacin, may result in dangerously high levels of theophylline. ipratropium can cause dry mouth. guidelines for the management of copd may be found at: http:// publications.nice.org.uk/chronicobstructivepulmonarydisease cg (accessed september ). respiratory viruses usually spread by touch or airborne transmission and the very small particles ( - . micrometres) can avoid the upper respiratory tract defences and the mucociliary elevator to reach the lung alveoli. a range of viruses can cause lower respiratory tract infections (lrtis ; table . ). some viruses (e.g. influenza and respiratory syncytial) can spread from the upper to the lower respira tory tract via infection of the respiratory epithelium and can lead to bacterial superinfection and pneumonitis (pneumonia). mycoplasmal (atypical) pneumonia and tuberculosis (tb) may be direct infections. epidemics of a potentially fatal severe acute respiratory syndrome (sars) have been caused by a coronavirus that originated in china and spread worldwide; h n bird influenza also arose as an epidemic; and a similar epidemic, but of swine influenza (h n ), emanated from mexico (see later). bacterial infections, such as pneumonia or lung abscess, can also result from material aspirated into the lungs, and are usually unilat eral. those who aspirate more than others have, as a result, more frequent lrti and this is seen in alcohol and other drug abusers, as well as comatose patients. exogenous penetration and contamination of the lung can result from trauma (e.g. a stab wound or road traffic accident) or surgery. entamoeba histolytica can occasionally cause pneumonia -by direct extension from an amoebic liver abscess (table . ). patients with endocarditis, or septic pelvic or jugular thrombo phlebitis, may experience lrti acquired haematogenously and then it is often bilateral. immunocompromised persons (e.g. those with human immunode ficiency virus/acquired immune deficiency syndrome [hiv/aids] and transplant recipients) and people with bronchiectasis or cystic fibrosis are also susceptible to respiratory infections by a range of opportun istic microbes. pneumocystis jiroveci (p. carinii), for example, is a com mon cause of potentially fatal pneumonia in immunocompromised patients -especially those with hiv/aids (chs and ). clinical features of lrti vary according to the part of the respiratory tract mainly affected: ■ bronchiolitis causes rapid respiration, wheezing, fever and dyspnoea -but is restricted mainly to infants. ■ bronchitis causes cough, wheezing and sometimes dyspnoea. ■ pneumonia causes cough, fever, rapid respiration, breathlessness, chest pain, dyspnoea and shivering. antimicrobial therapy is indicated, particularly for pneumonia. antivirals have not been highly effective. oxygen may be needed. pneumococcal vaccine is indicated for older people. the majority of lrtis are severe illnesses, and are contraindications to all but emergency dental treatment. ga is hazardous and absolutely contraindicated. dental treatment should be deferred until recovery, or be limited to pain relief. influenza is mainly a communitybased infection transmitted in house holds and communities. healthcareassociated influenza infections can arise in any healthcare setting, most commonly when influenza is also circulating in the community. influenza is a contagious disease caused by influenza virus types a, b or c. type a has two main subtypes (h n and h n ); it causes most of the widespread influenza epidemics and can occasionally be fatal. type b viruses generally cause regional outbreaks of moderate severity, and type c viruses are of minor significance. a person can spread influenza starting day before they feel sick and for another - days after symptoms start. influenza can be pre vented or ameliorated by vaccination each autumn; this is especially indicated for older people and those with cardiorespiratory disease. influenza attacks virtually the whole respiratory tract; symptoms appear suddenly after - days and include fever, sore throat, nasal congestion, headache, tiredness, dry cough and muscle pains (myalgia). most people recover in - weeks but infection can be lifethreatening, mainly because primary influenzal viral pneumonia can lead to sec ondary bacterial pneumonia or can exacerbate underlying conditions (e.g. pulmonary or cardiac disease). the old and very young, and those with chronic disorders, are more likely to suffer complications, such as pneumonia, bronchitis, sinusitis or otitis media. influenza has also been followed by depression, encephalopathy, myocarditis, myositis, pericarditis, reye syndrome and transverse myelitis. rest, maintenance of fluid intake, analgesics, antipyretics, and avoid ance of alcohol and tobacco help relieve symptoms. aspirin must never be given to children under the age of years who have 'flulike symptoms, and particularly fever, as this can cause reye syndrome. zanamivir (an antiviral that works against influenza types a and b) can shorten the symptoms by approximately day, if treatment is started during the first days of illness. other antiviral drugs include amantadine, oseltamivir and rimantadine; they may be helpful but their use is restricted mainly to immunocompromised persons, since they can cause adverse effects. influenza can be a severe contagious illness so all but emergency den tal treatment should be deferred until recovery. ga is hazardous and absolutely contraindicated. influenza type a subtype h n can cause an illness known as 'avian influenza' or 'bird 'flu' in birds, humans and many other animal spe cies. hpai a(h n ) -'highly pathogenic avian influenza virus of type a of subtype h n ' -is the causative agent and is enzootic in many bird populations, especially in southeast asia. it has spread globally and resulted in the deaths of over people and the slaughter of mil lions of chickens. a vaccine that could provide protection (prepandrix) has been cleared for use in the european union. h n is a more recent emergent infection, similar in many respects. swine influenza is common in pigs in the midwestern united states, mexico, canada, south america, europe (including the uk, sweden and italy), kenya, china, taiwan, japan and other parts of eastern asia. transmission of swine influenza virus from pigs to humans is not com mon, but can produce symptoms similar to those of influenza. a outbreak in humans ('swine 'flu') was due to an apparently new strain of h n arising from a reassortment produced from strains of human, avian and swine viruses. it can pass from human to human. antiviral agents such as oseltamivir may help. vaccines are now available. an outbreak of a lifethreatening febrile respiratory infection appeared in , originating from guangdong, china, and was named severe acute respiratory syndrome (sars). caused by a newly recognized coronavirus (sarsassociated coronavirus, sarscov), sars spread via close contact to many countries across the world. according to the world health organization, people worldwide became sick with sars during the course of the first recognized outbreak and died. the incubation period of - days is followed by a high fever (above . °c), malaise, headache and myalgia. some people also experience mild upper respiratory symptoms and, after - days, lower respiratory signs -a dry cough and dyspnoea, potentially progressing to hypox aemia. sars can cause a pneumonia with a mortality approaching %, particularly in older or immunocompromised people. artificial ventilation has been needed in - % of cases. antiviral agents, such as oseltamivir or ribavirin, may help. inactivated vaccines, virally and bacterially vectored vaccines, recombinant protein and dna vaccines, as well as attenuated vaccines, are under development. sars is a severe illness, and all but emergency dental treatment should be deferred until recovery. ga is hazardous and absolutely contraindicated. for all contact with suspect sars patients, careful hand hygiene is important, including handwashing with soap and water; if hands are not visibly soiled, alcoholbased handrubs may be used as an alternative to handwashing. if a suspected sars patient is admitted to hospital, infection control personnel should be notified immediately. infection control measures (www.cdc.gov/ncidod/hip/iso lat/isolat.htm; accessed september ) should include standard precautions (e.g. hand hygiene): healthcare personnel should wear eye protection for all patient contact; contact precautions (e.g. gown and gloves for contact with the patient or their environment); and airborne precautions (e.g. an isolation room with negative pressure relative to the surrounding area and use of an n filtering disposable respirator for persons entering the room). pneumonia is classed as 'primary' if it occurs in a previously healthy individual, and is usually lobar; it is called 'secondary' if it follows some other disorder, such as previous viral respiratory infections, aspir ation of foreign material, lung disease (bronchiectasis or carcinoma), depressed immunity (e.g. alcoholism or immunosuppression), or aspir ation of oral bacteria ( pneumonia causes cough, fever, rapid respiration, breathlessness, chest pain, dyspnoea and shivering. complications can include lung abscess or empyema (pus in pleural cavity). it is important to avoid alcohol and tobacco, but use analgesics and antipyretics to relieve the symptoms. broadspectrum antimicrobi als given promptly and empirically usually include a macrolide (azithromycin, clarithromycin or erythromycin), quinolone (moxiflox acin, gatifloxacin or levofloxacin), or doxycycline for outpatients. for in patients, cefuroxime or ceftriaxone plus a macrolide is used. prophylaxis includes immunization against influenza and pneumococci. pneumonia is a severe illness and all but emergency dental treatment should be deferred until recovery. ga is hazardous and absolutely contraindicated. ventilatorassociated pneumonia (vap) is discussed later. legionellosis is a bacterial respiratory infection caused by one of the family legionellaceae, gramnegative aerobic bacilli, ubiquitous in water and soil but particularly preferring warm aquatic environments. the term legionnaire's disease was coined as a result of an outbreak of the previously unrecognized respiratory disease in an american legion meeting in philadelphia in , but it is now recognized worldwide, many infections being contracted during travel abroad, particularly to spain, turkey and some other mediterranean areas. legionella bacteria can be found in natural freshwater environments, usually in insufficient numbers to cause disease. legionella grow best in warm water, as in hot tubs, cooling towers, hot water tanks, large plumbing systems, or the airconditioning systems of large buildings. though there are over legionellaceae, most infections are caused by legionella pneumophila. disease is contracted by inhalation of contaminated mist or vapour, mainly (approximately %) through aerosolization of infected water in airconditioning systems, hotwater systems, humidifiers, nebulizers, showers and spa pools. outbreaks have mostly been linked to aerosol sources in the community, cruise ships and hotels, with the most likely sources being whirlpool spas, air conditioning units in large buildings, potable (drinking) water systems, and water used for bathing. risk factors include: ■ exposure to: recent travel with an overnight stay outside of the home (outbreaks of travelassociated legionellosis are infrequently identified but more than % of cases are thought to be associated with recent travel) whirlpool spas recent repairs or maintenance work on domestic plumbing ■ systemic illhealth: alcohol use chronic kidney disease diabetes immune defects liver disease malignancy smoking. illness mainly affects males over , smokers, heavy drinkers, older people and the immunocompromised. also vulnerable are travellers, especially middleaged and older tourists, and conference or business groups, possibly because of tiredness or age. many young people have been exposed to infection and become seropositive, but remained healthy. there is no evidence of persontoperson transmission of legionellosis. legionellosis manifests as one of two clinical syndromes (table . ). legionnaire's disease is typically a lobular type of pneumonia, which can be fatal but is fortunately rare; infection can range from discrete patches of inflammation and consolidation to involvement of whole lobes. pontiac fever is milder and usually subsides rapidly, often with out treatment. people who should be tested for legionnaire's disease include those with pneumonia in the following groups: because legionella is commonly found in the environment, clinical isolates are necessary to interpret the findings of an environmental investigation. diagnosis can be by rapid urine molecular testing for l. pneumophila antigen, and culture of respiratory secretions on selective media. sensitivity and specificity of the diagnostic tests are shown in table . . pontiac fever is a selflimited illness; most cases recover within week and few benefit from antibiotic treatment. overall mortality in legionnaire's disease may be as high as %, and over % in older people and up to % in the immunocompromised. erythromycin is standard treatment; cephalosporin is an alternative. legionella species are present in roughly twothirds of potable water samples collected from domestic and institutional taps and drinking fountains, and from a similar percentage of dental units, but water from these dental units often has higher bacterial concentrations (ch. ). there are reports of legionella infections in dental unit water lines, and antibodies and occasionally frank infection demonstrated in dental staff; at least one patient appears to have contracted and died from infection emanating from a dental practice. prevention is crucial, involving (ch. general aspects tuberculosis (tb) , an infection caused by mycobacteria, affects approxi mately onethird of the world's population ( . billion people); it is a major global health problem, some million people dying from it annu ally. tb disproportionately affects the poorest persons in both high income and developing countries. in highincome countries, most human tb arises from mycobacterium tuberculosis, transmitted from person to person through the air. tb usually affects the lungs initially (pulmonary tb) but can also involve brain, kidneys, spine and other parts. from victorian times to about the second world war, mycobacterium bovis infection from infected cows' milk (bovine or btb) was a major cause of morbidity and mortality; it was clinically and pathologically indistin guishable from infection caused by m. tuberculosis. cattletesting and a slaughter programme became compulsory in and, by the s, the incidence of tb in cattle had been substantially reduced. tuberculosis from m. bovis in cows' milk was virtually eliminated in highincome countries by the tuberculin testing of cattle and pasteurization of milk. in the developing world, many cattle still have tb, and btb is still seen. btb has also increased in highincome countries over the last two dec ades and an infection rate of up to % in badgers -and transmission to cattle -may explain this. tb is not spread by touch or by drinking glasses, dishes, sheets or clothing. it is usually transmitted by infected sputum, typically from close contacts such as family members, but is unlikely to be transmit ted between normal social contacts. tb can present an occupational risk to healthcare professionals, including dental staff. one outbreak of drugresistant tb in new york involved at least patients, most of whom contracted tb in one of hospitals; nearly % of the patients were also hivpositive, and most were young males of hispanic or african heritage. tb has been transmitted between pas sengers during longhaul airline flights. the risk of transmitting tb though air circulation is now low because the highefficiency particu late air (hepa) filters on newer commercial aircraft are of the same type as those used in hospital respiratory isolation rooms; indeed, the number of times air is cleaned each hour exceeds the recommendation for hospital isolation rooms. subsaharan africa has the highest rates of active tb per capita, driven primarily by the hiv epidemic. the absolute number of cases is highest in asia, with india and china having the great est burden of disease globally. in the usa and most western european countries, the majority of cases occur in foreignborn residents and recent immigrants from countries in which tubercu losis is endemic. immunocompromised people -such as diabetics and severely immuno deficient patients, like those with hiv/aids (about % of south africans with hiv/aids also have tb) -and patients in prisons or institutions are at risk. tb also mainly affects medically neglected persons, such as vagrants, alcoholics, intravenous drug abusers or older homeless people. the main groups at increased risk for infection therefore include people who are resourcepoor or immunoincompetent, especially: tb in developing countries is particularly widespread and is increasing, the highest rises in incidence being in southeast asia, subsaharan africa and eastern europe. in highincome countries, the incidence is also rising, probably because of worsening social deprivation, homelessness, immigration, hiv infection and intra venous drug abuse. it is now as common in london as in the devel oping world, and is seen especially in immigrants, such as those from the indian subcontinent, africa and south asia. this increase appears to be a result of the development of tb disease in individu als who may have been infected for some time and of new infections acquired in the uk, or as a result of travel to other countries where tb is common. london accounted for the highest proportion of cases in the uk in ( %), followed by the west midlands region ( %); % of these were born outside the uk and mainly originated from south asia and subsaharan africa. in , there was a rise in the number of tb cases compared to , as well as an increase in drug resistance. more information on tb, including statistics, can be found at: http:// www.hpa.org.uk/publications/infectiousdiseases/tuberculosis/ and http://www.tbfacts.org/tbstatistics.html (both accessed september ). initial infection with tb is usually subclinical. about % of those infected develop overt disease; of these, half will manifest within years (primary tb), while the remainder will develop postprimary disease. inhaled mycobacteria may cause subpleural lesions (primary lesion) and lesions in the regional lymph nodes (primary complex). body defences usually localize the mycobacteria, though these remain viable; infected persons are not obviously ill and are unlikely to know they are infected (latent ; table . ). latent tb infection (ltbi) usu ally becomes active only after many years, if body defences become weakened (box . ). however, active tb can develop shortly after mycobacteria enter the body, if body defences are impaired such as in ageing, drug or alcohol abuse, or hiv/aids. also, in massive infec tions, acute active tb can result, typically causing a chronic productive cough, haemoptysis, weight loss, night sweats and fever. erythema nodosum may be associated. extrapulmonary tb is less common; it may appear as glandular involvement in the neck or elsewhere, and is less infectious than pulmonary tb. lymph node tb may lead to lymphadenopathy, caseation of the nodes and pressure symptoms -for example, on the bronchi. postprimary tb follows reactivation of an old primary pulmonary lesion and results in features ranging from a chronic fibrotic lesion to fulminating tuberculous pneumonia. the pulmonary lesions may extend and lead to a pleural effusion. reactivation or progression of primary tb may also result in widespread haematogenous dissemina tion of mycobacteria -'miliary tb'. multiple lesions may involve the central nervous system, bones, joints, and cardiovascular, gastrointes tinal and genitourinary systems. clinical presentation in tb is thus variable, depending on the extent of spread and the organs involved. as it frequently passes unrecog nized for so long, the mortality is high. similar illnesses to tb may also be caused by atypical (nontuber culous) mycobacteria, such as m. avium complex (mac; see below). the diagnosis of tb is suggested by the history and confirmed by physical examination, a massively raised erythrocyte sedimentation rate (esr), positive tuberculin skin tests (tsts; mantoux or heaf test for a delayed hypersensitivity reaction to protein from m. tuberculosis [purified protein derivative; ppd]) and chest imaging. hypersensitivity develops with - weeks of infection and can be detected by conversion of the tst from negative to positive, but tsts are neither % sensi tive nor specific. a positive mantoux reaction indicates previous immu nization (bcg; bacille calmette-guérin -live attenuated m. bovis) or current infection -not necessarily disease. chest radiography may show scarring and hilar lymphadenopathy. computed tomography (ct) may show areas of calcification or highlight a tuberculous abscess. smears and culture of sputum, blood, laryngeal swabs, bronchoalveolar lavage, gastric aspirates or pleural fluid may be tested for mycobacteria. polymerase chain reaction (pcr) techniques have greatly acceler ated the diagnosis and speciation, though ziehl-neelsen, auramine or rhodamine microbial stains are still used. the mycobacteria growth indicator tube (mgit) system gives results as early as - days. blood assay for m. tuberculosis (bamt) may be positive by interferongamma release assay (igra). some % of people over years have a positive igra. the igra can be used in place of (but not in addition to) tst. igras measure the immune reactivity to m. tuberculosis. white blood cells from most persons that have been infected with m. tuberculosis will release interferongamma (ifnγ) when mixed with m. tuberculosis antigens. a positive test result sug gests that m. tuberculosis infection is likely; a negative result suggests that infection is unlikely. latent infection (ltbi) can be diagnosed with either a tuberculin skin test or an igra (more specific). igra gives a result within hours and should be used biological therapy is given, such as for rheumatoid arthritis or inflammatory bowel disease. prior bcg vacci nation does not cause a falsepositive igra test result. more informa tion on the igra is available at: http://www.cdc.gov/tb/publications/ factsheets/testing/igra.htm (accessed september ). active tb is diagnosed by sputum microscopy and culture in liquid medium with subsequent drugsusceptibility testing. nucleic acid people who should be tested for tb include those who have symp toms, those who have had close daytoday contact with active tb disease (family member, friend or coworker), those who have hiv infection or aids, those with lowered immunity, those who are required to for employment or school, and those about to be treated with biological agents. the top priority of tb control programmes is to identify and give complete treatment to all patients with active disease. tb is a notifi able disease and contact tracing is an important aspect of limiting spread. treatment with antibiotics is indicated for people who are sick with tb, those infected but not sick, and those who are close contacts of infectious tb cases. treatment for 'symptomatic sputumpositive' patients, which should be instituted as soon as possible, is combination chemotherapy, usually isoniazid plus rifampicin plus pyrazinamide or ethambutol for months, with continuation of daily isoniazid and rifampicin for a further months. treatment for 'asymptomatic' patients who are believed to have been infected by contacts, but are not unwell, includes isoniazid for months or isoniazid and rifampicin for months. rifapentine is a longacting rifampicin used once weekly. fluoroquinolones (moxifloxacin) may also act against tb. there may be resistance to one or more than one antibiotic. currently, given the potential risk of drugresistant tb being present, treatment is usually started with isoniazid, rifampicin, pyrazinamide and ethambutol (or a quinolone such as gatifloxacin or moxifloxacin) for months, then isoniazid and rifampicin for months. all antituberculous drugs (table . ) have potentially serious adverse effects and require careful monitoring. if patient compliance is considered to be poor, directly observed therapy (dot), where drugs are dispensed by and taken in the presence of a healthcare profes sional, may be indicated. new drugs are on the horizon. immunization using bcg is advocated for schoolchildren, highrisk individuals and healthcare professionals -although its efficacy has been questioned. new vaccines are in development. chemoprophylaxis with isoniazid and rifampicin is indicated in a number of situations (box . ) . tb can become resistant to the drugs used to treat it particularly when the drugs are misused or mismanaged. this may occur, for example, when: in some developing countries, approximately % of cases are multi ple antibioticresistant; this is termed multidrugresistant tuberculosis (mdrtb); in the uk, only a small minority currently fall into this category but the number of cases is increasing. mdrtb is defined as resistance to rifampicin and isoniazid; it may be atypical in presenta tion and the infection disseminates. more than % of people with tb worldwide have mdrtb, and eastern europe has a high prevalence. mdrtb is seen mainly in people with hiv/aids and in hiv/aids and in africans. bedaquiline, is a new antitubercular agent the first active agent against tuberculosis to be registered since . extensively drugresistant tuberculosis (xdrtb) is a rare type of mdrtb, not only resistant to isoniazid and rifampin, but also to any fluoroquinolone and at least one of three injectable secondline drugs (i.e. amikacin, kanamycin, or capreomycin). xdrtb is of special concern for immunocompromised people (e.g. with hiv/aids), who are more likely to develop tb, and have a higher risk of death if they do develop it. xdrtb is most often encountered in people from eastern europe, russia and africa. it has been transmitted in healthcare facilities and is now seen worldwide. it is essentially untreatable, though capreomycin has been used effectively to treat mdrtb in hivpositive individuals. totally drugresistant tb was reported initially in - in india, iran and italy; it is spreading, despite denials, and is most disquieting. chronic ulcers, usually on the tongue dorsum, are the main oral manifestation of tb. they result from coughing of infected sputum from pulmonary tb, including in hivinfected persons with tb, but are rare and such cases (usually middleaged males) may result from neglect of symptoms or default from treatment. occasionally, the diagnosis is made from biopsy of an ulcer after granulomas are seen microscopically. acidfast bacilli are rarely seen in oral biopsies, even with the help of special stains, so unfixed material should also be sent for culture if possible. tuberculous cervical lymphadenopathy is the next most common form of the infection and is particularly com mon among those from south asia. most tb lymphadenitis is pain less, with several enlarged, matted nodes, but systemic symptoms are present only in a minority and only about % have pulmonary mani festations on radiography (fig. . ) . diagnosis relies on tuberculin testing, which can be positive in both tuberculous and non tuberculous mycobacterial cervical lymphadenitis. any person with lymphadenop athy and recent conversion from a negative to positive tuberculin test should be suspected of having mycobacterial infection, and this should prompt biopsy (e.g. fineneedle aspiration biopsy) for culture or histo logical confirmation. pcr will improve diagnosis, as culture must wait - weeks for a result. oral complications of antitubercular therapy are rare, but rifabutin and rifampicin can cause red saliva. pulmonary tb is of high infectivity, as shown by cases of tuber culous infection of extraction sockets and cervical lymphadenitis in patients treated by an infected member of staff at a dental clinic. dental staff who themselves were hivpositive, working in a dental clinic for hivinfected persons in new york, have died from tb con tracted occupationally. transmission of mdrtb between two dental workers may have occurred in an hiv dental clinic. infection control is thus important, so staff with tb are usually precluded from their occupation until treated. management of a patient with tb depends upon the level of poten tial infectivity (table . ) . patients with open pulmonary tb are con tagious, and dental treatment is thus best deferred until the infection has been treated. treatment with appropriate drugs for weeks drasti cally reduces the infectivity of patients with pulmonary tb. if patients with open pulmonary tb must be given dental treatment, special pre cautions should be used to prevent the release of mycobacteria into the air, to remove any that are present and to stop their inhalation by other persons. reduction of splatter and aerosols, by minimizing cough ing and avoiding ultrasonic instruments, and use of a rubber dam, are important. improved ventilation, ultraviolet germicidal light, new masks and personal respirators, and other personal protective devices, such as hepa filters, are indicated ( fig. . ) . mycobacteria are very resistant to disinfectants, so that heat sterilization must be used. la is safe and satisfactory. relative analgesia is contraindicated because of the risk of contamination of the apparatus. ga is also contraindicated for dental treatment because of the risk of contamina tion of the anaesthetic apparatus and because of impaired pulmonary function. aminoglycosides, such as streptomycin, enhance the activity of some neuromuscular blocking drugs and in large doses may alone cause a myasthenic syndrome. possible drug interactions are shown in table . . other factors, such as alcoholism or intravenous drug use (ch. ), hepatitis (ch. ) or hiv disease (ch. ), may also influence dental management. mycobacteria other than tuberculosis (mott) are widely distributed in water, soil, animals and humans, and rarely cause disease. severe mott infections have been seen, however, in individuals predisposed because of defects in the interleukin (il ) and interferongamma (ifngamma) pathways. mycobacterium abscessus, a bacterium found in water, soil and dust, has been known to contaminate medications and products, including medical devices. healthcareassociated m. abscessus can cause a vari ety of infections, usually of the skin, but it can also cause lung infec tions in persons with various chronic lung diseases and is increasingly recognized as an opportunistic pathogen in cystic fibrosis (cf) patients persontoperson transmission of atypical mycobacteria is not important in acquisition of infection, except for skin infections. on rare occasions, mott skin infections have followed tattooing with contaminated tattoo inks. many people become infected with and har bour mott in their respiratory secretions without any symptoms or evidence of disease. individuals with respiratory disease from mott do not readily infect others and, therefore, do not need to be isolated. mott are generally not infectious to others. infection with m. abscessus is usually caused by injections of con taminated substances or by invasive medical procedures employing contaminated equipment or material. infection can also occur after accidental injury where the wound is contaminated by soil. there is very little risk of transmission from person to person. mac complex, m. scrofulaceum and m. kansasii are possible causes of tuberculous cervical lymphadenitis. mac may also infect the lungs (similar to tb), skin or lymph nodes. lung disease is also caused occasionally by m. kansasii, mainly in middleaged and older persons with underlying chronic lung conditions. m. fortuitum and m. chelonae may cause skin and wound infections and abscesses, frequently associated with trauma or surgery. m. marinum may cause 'swimming pool granuloma', a nodular lesion that may ulcerate, usually on an extremity. m. ulcerans may produce chronic ulcerative skin lesions, usually of an extremity. m. abscessus skin infections present with swollen and/ or painful areas that are usually red, warm and tender to the touch, and which can also develop into boils or pustules. other features of m. abscessus infection are fever, chills, muscle aches and malaise. cervical lymphadenitis due to mac, m. scrofulaceum and m. kansasii may affect otherwise healthy young children, most commonly pre school females who have unilateral cervical lymphadenopathy, typically in the submandibular or jugulodigastric nodes, and they may form a 'cold abscess'. mott is the usual cause in children under years but tb is more common in older patients. absence of fever or tuber culosis, a positive tuberculin test and failed response to conventional antimicrobials are highly suggestive of mott, but definitive diagnosis is by smear, culture or pcr of biopsy material obtained by fineneedle aspiration or removal of nodes. treatment is based on results of laboratory testing, which should identify the appropriate antibiotic. preventive treatment of close contacts of persons with disease caused by mott is not needed. most mott are resistant to standard antitubercular medication and, though it is possible that clarithromycin or clofazimine may have some effect, excision of affected nodes is the usual recommended therapy. water from dental units may contain mott species; mycobacterial proliferation in biofilms may explain the extent of this contamination (ch. ). aspiration syndromes are conditions in which foreign substances are inhaled into the lungs and which can have consequences ranging from asphyxia to infection and lung abscess. dental restorations or frag ments of teeth, plaque, gastric contents and other materials may be aspirated, especially if material enters the pharynx, and particularly if the cough reflex is impaired for any reason. most commonly, aspiration syndromes involve oral or gastric contents associated with gastrooesophageal reflux disease (gord), swallowing dysfunction (ch. ), neurological disorders and structural abnormalities, such as a pharyngeal pouch. cricopharyngeal dys function involves cricopharyngeal muscle spasm or achalasia of the superior oesophageal sphincter, and can be seen in infants who have a normal sucking reflex but have incoordination during swallowing, pos sibly secondary to delayed development or cerebral palsy. anatomical disorders, such as cleft palate, pharyngeal pouch, oesophageal atresia, tracheooesophageal fistula, duodenal obstruction or malrotation, and motility disorders, such as achalasia, may have an aspiration risk. infirm older patients are also at risk of aspiration, especially if they are bedbound or have neurological disorders. isolated superior laryngeal nerve damage, vocal cord paralysis, cerebral palsy, muscular dystrophy and riley-day syndrome (familial dysautonomia) are all associated with increased risk of aspiration. ventilatorassociated pneumonia (vap), as defined by the centers for disease control and prevention (cdc), is present when the chest radiograph shows new or progressive infiltrate, consolidation, cavitation or pleural effusion in conjunction with either new onset of purulent sputum or change in character of sputum, and an organism isolated from blood, or the isolation of an aetiological agent from a specimen obtained via suction aspiration through an endotracheal or tracheostomy tube. the major route for acquiring endemic vap is oropharyngeal colo nization by endogenous flora or by exogenously acquired pathogens from intensive care units. vap is the most commonly reported health careacquired infection in patients receiving mechanical ventilation, with prevalence rates consistently in the - % range. mortality rates in vap are at least double those in patients without vap, ranging from % to % when the infection is caused by a multidrugresistant gramnegative pathogen. the healthcare infection control practices advisory committee of the cdc has developed guidelines for the prevention of vap. these include strategies aimed at preventing aspiration of contaminated oral or gastric material (e.g. raising the head of the bed and draining subglottic secretions), and interventions to alter bacterial coloniza tion of stomach (e.g. stress ulcer prophylaxis and selective digestive decontamination) and mouth. oral hygiene, suctioning and the provi sion of moisture to lips and oral mucosa, plus toothbrushing, may be important in prevention of vap. there are also strategies for manag ing ventilator circuits (e.g. replacement of ventilator circuits, use of closed rather than open suction, and use of heat moisture exchange as opposed to heated circuit technology). lung abscess is a localized infection leading to cavitation and necro sis. while some cases result from aspiration of foreign material, most develop from pneumonia caused by infection with staph. aureus or klebsiella pneumoniae. bronchial obstruction by carcinoma is another important cause. symptoms resemble those of suppurative pneumonia. there is a risk of infection spreading locally or leading, via septicaemia, to a brain abscess. diagnosis rests mainly on the chest radiograph, which may sometimes show cavitation or a fluid level. antimicrobial chemotherapy, postural drainage and relief by bronchoscopy of any obstruction are indicated. a wellrecognized cause of lung abscess is inhalation of a tooth or fragment, a restoration or rarely, an endodontic instrument. when undertaking endodontics or cementing restorations, such as inlays or crowns, a rubber dam or other protective device should always be used to avoid the danger of inhalation. lung abscesses may also result from aspiration of oral bacteria, particularly anaerobes, especially in infirm older patients or those who are intubated. the other main dangers in dentistry are with ga, particularly if an inadequate throat pack has been used. patients who inhale tooth frag ments or dental instruments must have chest radiographs (lateral and posteroanterior) and, if necessary, bronchoscopy. loeffler syndrome appears to be an allergic reaction, usually to the parasitic worm ascaris lumbricoides, or drugs such as sulphonamides. it manifests with pulmonary infiltrates (and abnormal chest radio graph) and eosinophilia (eosinophilic pneumonia). the disease usually clears spontaneously. sarcoidosis, so named because skin lesions resembled a sarcoma, is a multisystem granulomatous disorder, seen most commonly in young adult females in northern europe, especially in people of african heritage. the aetiology is unclear but propionibacterium acnes and p. granulosum have been implicated and associations have been reported with exposure to inorganic particles, insecticides, moulds and occupations such as firefighting and metalworking. serum sam ples contain antibodies directed against mycobacterium tuberculosis antigens. sarcoidosis is associated with hladrb and dqb , and a butyrophilinlike (btnl ) gene on chromosome . thelper (th ) cells release il and ifnγ, and augment macrophage tumour necrosis factor alpha (tnfα) release. cd regulatory t cells cause a limited impairment of cellmediated immune responses (partial anergy) but no obvious special susceptibility to infection. sarcoidosis affects the thorax in %, but has protean manifestations and can involve virtually any tissue (table . ). sarcoid most typi cally causes löfgren syndrome (fever, bilateral hilar lymphadenopathy, arthralgia and erythema nodosum, especially around the ankles; figs . and . ). other common presentations may include pulmonary infiltration and impaired respiratory efficiency, with cough and dyspnoea in severe cases, or acute uveitis, which can progress to blindness. susceptibility to lymphomas has been suggested but not confirmed. because of its vague and protean manifestations, sarcoidosis is under diagnosed. in the presence of suggestive clinical features, helpful investigations include: chest radiography (enlarged hilar lymph nodes); raised serum angiotensinconverting enzyme (sace ; table . ) in acute disease (this is insensitive, nonspecific and a poor guide to therapy); positive gallium citrate or gadolinium or positron emis sion tomography (pet) scans; labial salivary gland or transbronchial biopsy (for histological evidence of noncaseating epithelioid cell granulomas) -except in löfgren syndrome, which is a classical clini cal diagnosis. fdeoxyglucose pet is helpful in identifying sites for biopsy. nonspecific findings may include mild anaemia, leukopenia, eosinophilia, hypergammaglobulinaemia, raised esr and low serum albumin. hypercalcaemia is common because of extrarenal produc tion of active vitamin d and can result in renal damage. alkaline phosphatase, 'nucleotidase, lysozyme and adenosine deaminase levels are raised in hepatic sarcoidosis. evidence of impaired delayed hypersensitivity reactions to some antigens may be useful. kveim skin tests are not now used. half the patients with sarcoidosis remit within years and about % remit by years. patients with only minor symptoms usually need no treatment but corticosteroids, sometimes with azathioprine, methotrexate, tetracyclines, hydroxychloroquine, infliximab or etaner cept, are given if there is active organ disease (ocular disease, progres sive lung disease, hypercalcaemia or cerebral involvement). biopsy of the minor salivary glands frequently shows noncaseating granulomas and association with other features of sarcoidosis, par ticularly hilar lymphadenopathy. this is an important diagnostic find ing that may obviate more invasive procedures. sarcoidosis can involve any of the oral tissues but has a predilection for salivary glands. asymptomatic swelling of the parotid glands or cervical nodes, and less frequently the lips, may accompany systemic disease. superficial or deepseated red submucosal nodules may develop intraorally and on the lips. nontender, wellcircumscribed, brownishred or violaceous nodules with superficial ulceration have also been reported. the oral and lip lesions may occasionally precede systemic involvement. there is enlargement of the major salivary glands in about % of cases; some have xerostomia, and the association of salivary and lacri mal gland enlargement with fever and uveitis is known as uveoparotid fever (heerfordt syndrome). salivary swelling may also be seen with out other features of heerfordt syndrome. the salivary gland swellings usually resolve on treatment of sarcoidosis but this may take up to years. facial palsy and other cranial neuropathies may be seen. there is also an association with sjögren syndrome, when ssa and ssb serum autoantibodies are found. rarely there is an association of thyroiditis with addison disease, sjögren syndrome and sarcoidosis (tass syndrome). there is a group of patients who have histologi cal features of sarcoid in one or more sites in the mouth, such as the gingivae, but no systemic manifestations. a few of these patients may ultimately develop other more or less systematized disease but the majority probably have isolated lesions. such cases, where no exog enous cause for the granulomatous reaction can be found, are regarded as having 'sarcoidlike' reactions (orofacial granulomatosis) and treat ment is unnecessary. however, patients should be kept under observa tion for as long as possible. management of patients with systemic sarcoidosis may include con sideration of respiratory impairment, uveitis and visual impairment, renal disease, jaundice or corticosteroid treatment. la is safe and satisfactory. cs is contraindicated if there is any res piratory impairment. ga should only be given in hospital. lung cancer is the most common cancer in highincome countries in males and most frequently affects adult urban cigarettesmokers. bronchogenic carcinoma accounts for % of all primary lung cancer and has also become increasingly common in women (because of increased tobacco use), to the extent that the mortality rate for the two sexes has become almost equal. metastases from cancers elsewhere are also frequently found in the lungs. recurrent cough, haemoptysis, dyspnoea, chest pain and recurrent chest infections are the predominant features. local infiltration may cause pleural effusion, lesions of the cervical sympathetic chain (horner syndrome), brachial neuritis, recurrent laryngeal nerve palsy or obstruction of the superior vena cava with facial cyanosis and oedema (superior vena cava syndrome). there are many nonmetastatic extrapulmonary effects of bron chogenic (or other) carcinomas -for example, weight loss, anorexia, fingerclubbing, neuromyopathies, thromboses (thrombophlebitis migrans), muscle weakness, various skin manifestations and ectopic hormone production (of antidiuretic hormone, adrenocorticotropic hormone, parathyroid hormone and thyroidstimulating hormone). metastases from bronchogenic cancer are common and typically form in the brain (which may manifest with headache, epilepsy, hemi plegia or visual disturbances), liver (hepatomegaly, jaundice or ascites) or bone (pain, swelling or pathological fracture). the diagnosis is based on history and physical examination, supported by radiography, ct and magnetic resonance imaging (mri), sputum cytology, bronchoscopy and biopsy. spiral ct appears to detect tumours at an early stage. the overall year survival rate is only %. radiotherapy is the most common treatment. only some % of patients are suitable for surgery but, even then, the year survival is only about %. chemotherapy has been disappointing, except in smallcell carcinomas. dental treatment under la should be uncomplicated. cs should preferably be avoided. ga is a matter for specialist management in hospital, as patients often have impaired respiratory function, espe cially after lobectomy or pneumonectomy. this, along with any muscle weakness (myasthenic syndrome, eaton-lambert syndrome) that can make the patient unduly sensitive to the action of muscle relaxants, makes ga hazardous. oral cancer may be associated with lung cancer, and vice versa, or develop at a later stage (ch. ). such synchronous or metachronous primary tumours must always be ruled out. metastases can occasionally affect the orofacial region and cause enlargement of the lower cervical lymph nodes, epulislike softtissue swellings or labial hypoaesthesia or paraesthesia in the jaw. soft palate pigmentation is a rare early oral manifestation. lung cancer is a fairly common cause of death in dental techni cians, but it is unknown whether this is due to smoking alone or to dust inhalation. cystic fibrosis (cf) is one of the most common fatal hereditary dis orders. inherited as an autosomal recessive trait, with an incidence of about in births, it is the most common inherited error of metabolism and is seen mainly in people of european descent. the gene responsible is on chromosome q. cf is caused by defects in the cystic fibrosis transmembrane conductance regulator (cftr), a protein that appears to be part of a cyclic adenosine monophosphate (camp)regulated chloride channel, regulating cl − and na + transport across epithelial membranes, and ion channels and intracellular fluid flow in sweat, digestive and mucus glands. the basic defect in cf is abnormal chloride ion transport across the cell membrane of nearly all exocrine glands. the blockage of salt and water movement into and out of cells results in the cells that line the lungs, pancreas and other organs producing abnormally thick, sticky mucus that can obstruct the airways and various glands, especially in the respiratory tract and pancreas. involved glands (lungs, pancreas, intestinal glands, intrahepatic bile ducts, gallbladder, submaxillary and sweat glands) may become obstructed by this viscid or solid eosino philic material. recurrent respiratory infections result in a persistent productive cough and bronchiectasis, with the lungs becoming infected with a variety of organisms including staph. aureus, haemophilus influenzae, pseudomonas aeruginosa, strep. pneumoniae, burkholderia cepacia, and sometimes mycoses or mycobacteria. mycobacterium abscessus is a nontuberculous mycobacterium increasingly recognized as an opportunistic pathogen in cf patients. viral infections, such as mea sles, can have severe sequelae. pancreatic duct obstruction leads to pancreatic insufficiency, with malabsorption and bulky, frequent, foulsmelling, fatty stools. gallstones, diabetes, cirrhosis and pancreatitis may result. sinusitis is very common. growth is frequently stunted. the mutations can also cause con genital bilateral absence of the vas deferens, so fertility is impaired in most males with cf. in women, fertility may be impaired by viscid cervical secretions, but many women have carried pregnancies to term. most patients have a high concentration of sodium in their sweat (also reflected in the saliva); a sweat test showing sodium and chloride values of more than mmol/l is considered positive, between and mmol/l equivocal, and less than mmol/l negative. physiotherapy and postural drainage are crucially important. clearance of sputum is helped by water aerosols and bronchodila tors (terbutaline or salbutamol), but mucolytics such as carbocisteine, methyl cysteine and dornase alfa are of questionable effectiveness. treatment with ivacaftor, a cftr potentiator, improves chloride transport through the ion channel. amoxicillin and flucloxacillin are effective prophylactic antimicrobi als and may be given by aerosol. vaccination against measles, whoop ing cough and influenza is important. a low fat intake, adequate vitamins and oral pancreatic enzyme replacement (pancreatin) are also necessary. doublelung or heart-lung transplantation may eventually become necessary. sinusitis is very common; most cf patients have recurrent sinusitis and nasal polyps. the major salivary glands may enlarge and hyposali vation sometimes occurs. the lowfat, highcarbohydrate diet and dry mouth may predispose to caries. enamel hypoplasia and black stain may be seen, and both dental development and eruption are delayed. tetracycline staining of the teeth was common but should rarely be seen now. pancreatin may cause oral ulceration if held in the mouth. la is satisfactory but cs is usually contraindicated because of poor respiratory function. ga is contraindicated if respiratory function is poor. lung disease, such as bronchiectasis, liver disease and diabetes, may complicate treatment. bronchiectasis is dilatation and distortion of the bronchi. causes include: ■ congenital defects, which should be considered in all patients include cystic fibrosis, kartagener syndrome, alpha antitrypsin deficiency, collagen defects (e.g. marfan syndrome) there is no identifiable underlying cause in about % of adults and % of children. the damaged and dilated bronchi lose their ciliated epithelium and therefore mucus tends to pool, causing recurrent lrtis, typically with strep. pneumoniae, haemophilus influenzae or pseudomonas aeruginosa. overproduction of sputum, which is purulent during exacerbations, a cough (especially during exercise or when lying down) and finger clubbing are typical features, with recurrent episodes of bronchitis, pneumonia and pleurisy. haemoptysis is not uncommon. in advanced bronchiectasis, chest pain, dyspnoea, cyanosis and respiratory failure may develop. complications may include cerebral abscess and amyloid disease. chest radiography and pulmonary function tests are required. high resolution ct (hrct) is useful. postural drainage is important. antimicrobials, such as amoxicillin, cephalosporins or ciprofloxacin, are given for acute exacerbations and for longterm maintenance treatment. ga should be avoided where possible and is contraindicated in acute phases. workers exposed to airborne particles may develop pulmonary disease (pneumoconiosis), which ranges from benign (e.g. siderosis) to malig nant, as in mesothelioma from asbestosis (see appendix . ), but any pneumoconiosis can cause significant incapacity. ga may be contraindicated; the physician should be contacted before treatment. berylliosis may be a hazard in some dental technical laboratories, when lung cancer is more frequent. respiratory complications following surgical operations under ga include segmental or lobar pulmonary collapse and infection. they are more common after abdominal surgery or if there is preexistent respiratory disease or smoking (see also ch. ), and can be signifi cantly reduced by smoking cessation, preoperative physiotherapy and bronchodilators, such as salbutamol. if postoperative pulmonary infection develops, sputum should be sent for culture, and physiotherapy and antibiotics should be given. the common microbial causes are strep. pneumoniae and haemophilus influenza; in this case, suitable antibiotics include amoxicillin and erythromycin. hospital infections may include other microorganisms, such as mrsa, klebsiella, pseudomonas and other gramnegative bacteria. inhalation (aspiration) of gastric contents can cause pulmonary oedema and may be fatal (mendelson syndrome); it is most likely if a ga is given to a patient who has a stomach that is not empty, has a hiatus hernia or is in the last trimester of pregnancy. prevention is by ensuring the stomach is empty preoperatively; if it is not, an anaes thetist should pass an endotracheal tube. antacids or an h receptor blocker, such as cimetidine or ranitidine, may be given by mouth pre operatively to lower gastric acidity. if gastric contents are aspirated, the pharynx and larynx must be carefully sucked out. systemic corticosteroids have been recommended but probably do not reduce the mortality. respiratory distress in premature infants may be caused by immaturity of surfactantproducing cells, when the alveoli fail to expand fully; this necessitates endotracheal intubation for many weeks. it may, in turn, result in midface hypoplasia, palatal grooving or clefting, or defects in the primary dentition. the same oral effects may be seen with prolonged use of orogastric feeding tubes. the degree to which subsequent growth corrects these deformations is currently unknown, though the palatal grooves typically regress by the age of years. using soft endotracheal tubes does not obviate this problem and, at present, the best means of avoiding palatal grooving appears to be the use of an intraoral acrylic plate to stabilize the tube and protect the palate. acute respiratory distress syndrome (ards) is a sequel to several types of pulmonary injury and some infections, including those with oral viridans streptococci. patients with endstage pulmonary disease are considered for potential transplantation, usually using a lung from a braindead organ donor. a combination of ciclosporin, azathioprine and glucocorticoids is usu ally given for lifelong immunosuppression to prevent a tcell, alloim mune rejection response. inhaled nitric oxide modulates pulmonary vascular tone via smooth muscle relaxation and can improve ventilation/perfusion matching and oxygenation in diseased lungs. early graft failure following lung transplantation has been described by various investi gators as reimplantation oedema, reperfusion oedema, primary graft failure or allograft dysfunction. pathologically, this entity is diffuse alveolar damage. see also chapter . a meticulous presurgery oral assessment is required and dental treatment must be undertaken with particular attention to establishing optimal oral hygiene and eradicating sources of potential infection. dental treatment should be completed before surgery. for months after surgery, elective dental care is best deferred. if surgical treat ment is needed during that period, antibiotic prophylaxis is probably warranted. cardiopulmonary transplantation (heart and lung transplantation) is the simultaneous surgical replacement of the heart and lungs in patients with endstage cardiac and pulmonary disease, with organs from a cadaveric donor. all transplant recipients require lifelong immunosuppression to pre vent a tcell, alloimmune rejection response. see also chapter . a meticulous presurgery oral assessment is required and dental treatment must be undertaken with particular attention to establishing optimal oral hygiene and eradicating sources of potential infection. dental treatment should be completed before surgery. for months after surgery, elective dental care is best deferred. if surgical treat ment is needed during that period, antibiotic prophylaxis is probably warranted. national institutes of health: national institute of allergy and infectious diseases healthcare infection control practices advisory committee guideline for the prevention of healthcare associated pneumonia nosocomial pneumonia: state of the science extensively drugresistant tuberculosis as a cause of death in patients coinfected with tuberculosis and hiv in a rural area of south africa a review of the possible role of oral and dental colonization on the occurrence of health careassociated pneumonia: underappreciated risk and a call for interventions reducing ventilatorassociated pneumonia through advanced oraldental care: a month study apic infection control and applied epidemiology: principles and practice sepp. ventilatorassociated pneumonia and oral care: a successful quality improvement project guidelines for preventing the transmission of mycobacterium tuberculosis in healthcare settings a randomized trial of dental brushing for preventing ventilatorassociated pneumonia pneumonia associated with a dental unit waterline the pathogenesis of ventilatorassociated pneumonia: its relevance to developing effective strategies for prevention aspects of human disease chronic obstructive pulmonary disease (copd) aspects of human disease in vitro antibacterial activities of oral care products against ventilatorassociated pneumonia pathogens the impact of a simple, lowcost oral care protocol on ventilatorassociated pneumonia rates in a surgical intensive care unit intermittent suction of oral secretions before each positional change may reduce ventilatorassociated pneumonia: a pilot study current trends and newer concepts on diagnosis, management and prevention of respiratory tract infections key: cord- -swkcdvx authors: becerra-diaz, mireya; song, mason; heller, nicola title: androgen and androgen receptors as regulators of monocyte and macrophage biology in the healthy and diseased lung date: - - journal: front immunol doi: . /fimmu. . sha: doc_id: cord_uid: swkcdvx androgens, the predominant male sex hormones, drive the development and maintenance of male characteristics by binding to androgen receptor (ar). as androgens are systemically distributed throughout the whole organism, they affect many tissues and cell types in addition to those in male sexual organs. it is now clear that the immune system is a target of androgen action. in the lungs, many immune cells express ars and are responsive to androgens. in this review, we describe the effects of androgens and ars on lung myeloid immune cells—monocytes and macrophages—as they relate to health and disease. in particular, we highlight the effect of androgens on lung diseases, such as asthma, chronic obstructive pulmonary disease and lung fibrosis. we also discuss the therapeutic use of androgens and how circulating androgens correlate with lung disease. in addition to human studies, we also discuss how mouse models have helped to uncover the effect of androgens on monocytes and macrophages in lung disease. although the role of estrogen and other female hormones has been broadly analyzed in the literature, we focus on the new perspectives of androgens as modulators of the immune system that target myeloid cells during lung inflammation. the immune system is essential for maintaining homeostasis within tissues and organs and protecting them against threats, such as harmful pathogens or cancerous transformation ( ) . it comprises both innate and adaptive components. the innate immune system is made up of the innate lymphoid (innate lymphoid cells [ilcs] , natural killer cells [nks] , and lymphoid tissue inducers [lti] ) and innate myeloid subsets ( , ) . the innate immune system consists of a network of immune cells and molecules that provide rapid, first-line defense against pathogens. in contrast, the adaptive immune response, made up of b and t lymphocytes ( ), takes days or even weeks to become established ( ) . innate immune cells express pattern recognition receptors that recognize unique and conserved pathogen-associated molecular patterns such as lipopolysaccharide (lps), viral ssrna, and fungal β-glucan ( ) . b and t cells have evolved to recognize a finer repertoire of self-and nonself-antigens that facilitate pathogen-specific actions, immunologic memory generation, and host immune homeostasis regulation ( ) . to accomplish this, the adaptive immune response involves a tightly regulated interplay between t and b lymphocytes and antigen-presenting cells of the myeloid lineage, such as dendritic cells (dcs), monocytes, and macrophages ( ) . myeloid cells arise from the bone marrow. the type and magnitude of the immune response is influenced by biological sex and age ( ) , and therefore differs between males and females. sex differences in the function of the immune system arise from both genetic (chromosomal) sex differences and differences mediated by the action of male and female sex hormones. because the concentration of sex hormones changes over the lifespan and throughout the course of the menstrual cycle in women, the function of the immune system also changes during different stages of life. innate myeloid immune cells, like other cell types, express sex hormone receptors and are responsive to sex hormones ( ) . sex hormones are synthesized from cholesterol through a defined enzymatic cascade, predominately in the gonads and the adrenal glands ( ) . sex hormones are also produced in other tissues, including the brain, placenta, mammary glands, liver, and adipose tissue ( ) ( ) ( ) . in addition to driving sexual development of egg and sperm production, sex hormones are responsible for the development of male and female secondary sexual characteristics, like breast development and growth of facial hair, that occur during puberty ( ) . androgens include testosterone, dihydrotestosterone (dht), androstenedione, androstenediol, and dehydroepiandrosterone (dhea), with dht being the most potent ( ) . the concentration of androgens in circulation is about seven-fold higher in adult men than in adult women ( , ) . estradiol and progesterone are the predominant female sex hormones ( ) synthesized by the ovaries and adrenal glands. both male and female sex hormones are bound to the plasma proteins, albumin and sex hormone binding globulin (shbg), and only a small percentage exists as free hormone ( - %). thus, the bioavailability of sex hormones is regulated by their biosynthesis and also the amount of albumin and shbg. importantly, sex hormones mediate not only anatomic differences between women and men but also direct sex differences in immune responses, leading to different risks for immunologic diseases ( ) . overall, women have a greater risk for autoimmune diseases (such as systemic sclerosis and systemic lupus erythematosus) ( ) , whereas men are more likely to die of infectious and parasitic diseases ( ) . moreover, men have a greater risk of non-reproductive cancers ( ) ( ) ( ) . both gender and sex are important mediators of these and other health and disease differences observed between men and women. while gender refers to the array of socially constructed roles, attitudes, personality traits, and behaviors, sex represents a biological characteristic of an individual ( ) , including the hormonal milieu and chromosome complement ( ) . in general, estrogens are considered to have proinflammatory properties and androgens are thought to have anti-inflammatory properties ( ) . in the united states ( ) and worldwide ( ) , relevant evidence highlights important epidemiologic sex differences in incidence, susceptibility, and severity of a number of diseases that affect the respiratory tract. in this review, we will focus on how male sex hormones, the androgens, modulate the response of myeloid cells in the lung and how this modulation impacts the outcome of different diseases of the lung. biological sex mediates differences in the incidence and pathophysiology of lung diseases. these differences arise from sex differences in the structure and function of the lung itself, and also in the immune cells that populate the lung and are recruited to it during inflammation. before birth, the female lung has several structural advantages over the male lung. surfactant is produced earlier, and, although the female lung is smaller, it has more alveoli per unit area. neonatal females have higher expiratory flow rates than do male neonates when corrected for size. thus, male sex is a major risk factor for the development of respiratory distress syndrome, bronchopulmonary dysplasia in neonates ( ) ( ) ( ) ( ) , and asthma in childhood ( , ) . in addition to the contribution of structural differences of the lung between the sexes, sex differences in lung function and lung diseases are also dependent on the action of sex hormones. we have summarized some broad concepts that define how testosterone and estrogen affect lung macrophage function and how this may contribute to the outcome of particular lung diseases in figure . as testosterone rises after puberty, the immunosuppressive effects of this hormone on protective immune responses to infectious diseases in males can worsen pulmonary disease. this would be exemplified by tuberculosis or influenza. some of these effects are a result of androgen effects on critical inflammatory macrophage functions although the effects on the adaptive immune system also have a significant contribution to the overall outcome. thus, testosterone appears to play a key immunoregulatory role in lung macrophages. testosterone's immunoregulatory properties also appear to be dependent on the amount of cellular expression of ar and on the concentration of the hormone. low concentrations of testosterone have been noted in patients with asthma, copd, and tuberculosis. low testosterone may also be linked to insufficient control of tissue-damaging inflammatory responses seen in copd and pulmonary fibrosis. estrogen tends to promote wound healing responses in macrophages. dysregulation of wound healing responses and overactive tissue remodeling macrophages in the lung could be broadly used to describe the th response in allergic asthma, which is worse in women. cancer could also be considered an aberrant wound healing response driven by m -like tumor associated macrophages. we have highlighted here how sex hormones contribute to changes in lung macrophage function that contribute to lung disease. however, it should be pointed out that not every sex difference in lung disease is due to direct effects on macrophages but on the broader coordinated immune response as a whole. figure | sex differences in lung diseases discussed in this review and how they may be connected to the effects of androgens (and estrogens) on inflammatory macrophages in the lung. asthma in boys than in girls. with the onset of puberty, male and female sex hormones and their effects on the structural cells of the lung and on the immune system contribute to the incidence of asthma ( , ) . the incidence and severity of asthma are greater in adult women than in adult men ( , ) and greater in female than in male mice ( , ) . female sex hormones, such as estrogen, appear to worsen asthma, although a straightforward correlation between amount of female sex hormone and asthma symptoms has not been concluded. androgens have multiple immunoregulatory and bronchodilatory functions and may contribute to, or be biomarkers for, better lung function in men ( ) . accordingly, serum testosterone is low in men with moderate to severe asthma ( ) ( ) ( ) . in one study, each ng/dl increase in serum testosterone correlated with a % ( % ci, %- %; p = . ) decrease in the likelihood of having asthma ( ) . on the other hand, high concentrations of testosterone and cyclic amp in sputum of asthmatic women during the luteal phase of the menstrual cycle were thought to play a role in premenstrual exacerbations ( ) . the idea that sex hormones may be a causal factor in asthma was significantly strengthened by a recent study of , adults that quantified serum sex hormones and asthma outcomes ( ) . that study showed that low testosterone in both women and men was associated with an increased incidence of asthma. the other interesting finding was that higher testosterone was protective against asthma in obese women. obesity is a risk factor for asthma ( ) ( ) ( ) . therefore, how high body mass index (bmi) and circulating sex hormones together affect asthma requires further investigation. another androgen, dehydroepiandrosterone (dhea), also known as androstenolone, is an endogenous steroid hormone and one of the most abundant circulating steroids in humans. it is a precursor for the synthesis of both testosterone and estrogen. dhea is sulfated at the c β position into dhea-s by the action of the sulfotransferase enzymes sult a and sult e in the adrenal glands. the amount of dhea-s in the circulation is ∼ - times those of dhea. dhea became of interest to the asthma field because women with severe asthma had very low concentrations of dhea-s ( ) and dhea-s concentration correlated with lung function ( ) . interestingly, dhea-s is suppressed by oral or inhaled glucocorticoids, the mainstay therapy for asthma ( ) . human dhea peaks at around age and then follows an age-dependent decline until they reach prepubertal concentrations. reduced secretion of dhea with age has been related to a number of age-associated conditions. replacement of dhea has been considered as a possible therapeutic that could activate protective responses in an aging immune system. dhea is known to downregulate th -inflammatory cytokines while upregulating il- synthesis ( , ) in concanavalin a-stimulated peripheral blood mononuclear cells from adult males with atopic dermatitis ( , ) . thus, it was hypothesized that it would be a useful treatment for atopic diseases including asthma and the results of the clinical trials for dhea in asthma patients show promise. the results are discussed in a later section titled "effects of androgen exposure on monocytes, macrophages in humans with lung disease". sex differences also have been reported in chronic obstructive pulmonary disease (copd), a heterogeneous, chronic, and progressive respiratory disorder that includes chronic bronchitis and emphysema ( ) . chronic exposure of the airways to insults, such as cigarette smoke, leads to epithelial cell injury, destruction of pulmonary capillary vasculature, acceleration of epithelial cell senescence, and airway remodeling. the loss of lung compliance ultimately leads to copd ( , ) . copd was previously thought to affect mostly elderly men, primarily because of the higher prevalence of smoking in men. however, as smoking rates increased in women, the number of copd cases in women exceeded that of men ( ) . these differences are not only based on gender, as women develop more severe copd with earlyonset disease (< years) and have greater susceptibility to copd with lower tobacco exposure ( ) . moreover, increasing age in female smokers leads to a faster annual decline in forced expiratory volume in the first second when compared to that of male smokers, even when they smoke fewer cigarettes ( ) . similarly, pulmonary fibrosis is another lung disease that manifests sex differences ( ) , with men being more affected than women ( , ) . it is characterized by destruction of the pulmonary parenchyma and deposition of extracellular matrix with alterations in phenotype of both fibroblasts and alveolar epithelial cells ( ) . the lungs are also the target of respiratory viruses such as influenza a ("flu"), respiratory syncytial virus, and coronaviruses, such as severe acute respiratory syndrome and the middle east respiratory syndrome. the viruses infect the airway epithelial cells and cause damage to the epithelial barrier by themselves or as a result of the immune response to the viral infection. sex differences have been noted in the immune response to influenza a virus and to the influenza vaccine. in general, women have a more robust protective immune response to influenza virus and vaccine than do men. although this elevated response is helpful in clearing virus, women of reproductive age also experience higher mortality and hospitalizations ( ) ( ) ( ) ( ) ( ) , possibly from collateral tissue damage to the lungs. the vigorous immune response in women also means that women experience more adverse events after vaccination ( ) . indeed, a systems biology approach identified that high testosterone was correlated with a blunted response to the flu vaccine in men ( ) . as testosterone wanes in elderly men, mortality increases ( ) . since the male immune response to the virus is also less robust, the incidence of seasonal flu is generally higher in men than in women in developed countries, according to the world health organization ( ). it is not yet known how fluctuations in sex hormones across the menstrual cycle and lifespan affect the immune system's response to the influenza virus in humans. mouse studies have revealed that estrogen is protective at high, but not low, concentrations ( , ) . on the other hand, testosterone replacement in gonadectomized or aged male mice enhanced survival rates ( ) . despite these findings in mouse models, studies examining the effect of sex hormones on cellular and molecular mechanisms in human immune cells during influenza infection are lacking. like influenza infection, tuberculosis (tb), a lung disease caused by mycobacterium tuberculosis, exhibits notable sex differences in the number of cases worldwide, with men being almost twice as frequently affected than women ( , ) . both sex and gender differences impact the incidence of tb. although tb affects less women than men in adulthood ( ) , women in their economically active years ( - years old) have a higher tb incidence compared to women in other age groups ( ) . this indicates that factors associated with gender, such as exposure to the bacteria, are important in this disease. however, because male predominance does not occur in children, this suggests that biological factors such as male sex hormones also play a significant role ( ) . this is supported by a study of medically castrated men who experienced a significantly smaller proportion of death from tb, . % compared to . % in intact men ( ) . understanding how androgens lead to the greater susceptibility of men to tb is critical, as tb is still one of the leading fatal infectious diseases worldwide and may also may favor the development of other diseases, such as lung cancer ( ) . lung cancer is a very complex disease that depends on a number of variants such as sex, gender, race, and socioeconomic status ( ) . the development of lung cancer is also related to environmental factors, such as pollution due to industrialization and urbanization ( ) . an additional gender-associated risk factor, significantly linked to developing lung cancer, is cigarette smoking ( ) . historically, more men develop lung cancer and suffer lung cancer-associated deaths compared to women ( ) . however, the incidence of lung cancer has changed notably in both women and men. in men, lung cancer incidence started to increase in the s and started to decrease in the early s, while in women, the mortality rates and incidence began to rise in the s ( ) . changes in smoking habits in the last several decades with a rise in the number of women who smoke correlate with an increase in the incidence of lung cancer in this demographic group ( ) . smoking is definitely a key factor in the development of lung cancer; however, recent studies show a higher incidence of lung cancer in young women compared to young men ( , ) , even when the prevalence of cigarette smoking among young women has approached but not exceeded that among men ( ) . this suggests that the higher incidence of lung cancer in women is not explained simply by gender differences in smoking habits: a deeper analysis of differences mediated by sex, such as greater sensitivity to tobacco smoke in women is warranted ( , ) . furthermore, men and women develop different specific types of lung cancer. malignant mesothelioma is more common in men, while women develop more adenocarcinoma ( ), particularly non-small cell lung cancer (nsclc) ( ) . women have a superior survival rate for lung cancer compared to men ( ) . tumor-associated macrophages are critical in tumor progression yet how androgens influence macrophage behavior in lung cancer and in responses to treatment must be addressed more deeply to develop better therapies and increase survival rates in men. the lungs are a primary interface with the external environment. the delicate structures needed for gas exchange make them susceptible to damage from invading pathogens and toxic molecules. some insults to the lung can lead to the development of chronic conditions such as allergic asthma. as a protective mechanism, alveolar macrophages clear the air space of infectious, toxic, or allergenic particles to maintain homeostasis in the alveoli. thus, alveolar macrophages have a dual function as inflammatory cells, phagocytosing and killing inhaled bacteria or viruses, and also as controllers of the inflammatory immune response, minimizing alveolar damage. resident alveolar macrophages are seeded embryonically from yolk sac and fetal liver monocytes ( ) ( ) ( ) . in asthma and other lung diseases, recruited alveolar macrophages derived from blood monocytes can turn into pathogenic cells, worsening the condition ( , ) . mouse alveolar macrophages are characterized by high surface expression of siglec f and produce tgfβ. tgfβ both supports am development ( ) and their maintenance of immune homeostasis by induction of tregs and suppression of b and t cell proliferation. another important function of am is the clearance of surfactant. am from male and female mice respond differently to surfactant protein a (sp-a) ( , ) . sp-a acts as an opsonin and is important in clearance of pathogens. sex differences in am responses to surfactant could affect bacterial clearance and regulate the production of proinflammatory mediators. the molecular mechanisms that mediate these differences and how sex hormones change this important am function is an open question. in the human lung, there appears to be more diversity in the subtypes of lung macrophages compared to mice. the main determinant of the frequency of subtypes of macrophages in humans appears to be their anatomical location within the lung. am are the predominant immune cells in the lung airways (bronchi and bronchioalveolar space). flow cytometric panels have employed hla-dr, cd , cd , and cd to differentiate between am, im and monocytes. human am were identified as large, highly autofluorescent cd -cd + cells that also express cd , cd , and marco ( , ) . there appear to be two populations of am distinguished by either high or low expression of cd . more recent approaches to characterize the macrophage populations in the lung involve single-cell transcriptomic analysis ( , ) . although macrophages show a large variation in the transcriptional phenotype, expression of marco, ccl , apoc , apoe, pparg, and mrc was found in macrophages from healthy donors ( , ), while chi l , marcks, il rn, pla g , mmp , and spp were highly expressed in macrophages from pulmonary fibrosis patients ( ) . thus, a second contributor to diversity is likely the activation state of the cells. there are no data that describe sex differences in human am responses and the effect of sex hormones on these cells. from our mouse and human mdm studies, we would predict that androgens augment the immune homeostatic functions of these cells in the male lung. further work is still needed to standardize characterization of the different subpopulations of human lung macrophage populations and their role in maintaining healthy lung function and in disease. interstitial macrophages (ims), are another macrophage population found in the lung. they are a minor population of monocyte-derived macrophages ( ) , which comprise - % of lung macrophages ( ) and are localized in the lung parenchyma ( ) . ims contribute to maintaining homeostasis through the spontaneous release of il- , a cytokine that dampens inflammation ( ) . ims can prevent the development of aberrant type allergic responses triggered by inhaled allergens ( ) and have been related to reduction of asthma ( , ) . different subpopulations of ims have been found in the lung; however, their characterization has not arrived at a consensus due to difficulties in their identification and isolation. in the mouse lung, different subpopulations of ims have been described based on the expression of surface markers. one report described three different subpopulations of ims based on the differential expression of proinflammatory cytokines, chemokine ligands, mhc-ii, cd c, cd , and lyve- ( ); other group identified two subpopulations, based on similar markers but including cx cr ( ) . moreover, ims subpopulations can be also described based on the different anatomic locations these cells populate inside the mouse lung parenchyma ( ) . further work is needed to better characterize and define the different im populations, as the different subtypes may have different functions during the inflammatory process. smaller in size than their am counterparts, human ims express more of the monocytic marker cd than am, perhaps suggesting their monocytic origin, and have lower expression of cd than human am. the responses of im to androgen will depend on their expression of ar which has not been measured. this will be a challenge due to difficulties in clearly identifying this population (and its subpopulations) from the monocytic, am and other myeloid populations in the lung. monocytes are produced in the bone marrow along with a number of other myeloid cells. myeloid cells originate from common pluripotent hematopoietic stem cells and represent the major subset of white cells in circulation ( ) . these cells comprise basophils, neutrophils, eosinophils, dcs, monocytes, and macrophages, among others ( ) . monocytes are released into circulation, then blood monocytes are recruited into inflamed tissue and can mature into macrophages or dendritic cells. there are two main subsets of mouse monocytes, "classical" or ly c high monocytes that originate directly from ly c + precursors, and "non-classical" or ly c low monocytes that derive from ly c high monocytes ( ). the origin of ly c low monocytes was demonstrated by sunderkotter, et al. by tracking the maturation of dii-labeled ly- c high monocytes into dii-labeled ly c low monocytes ( ) . this process depends on the transcription factor nr a , which regulates the development and survival of ly c low monocytes ( ). these two monocyte subsets mirror the human cd + classical and cd + non-classical monocyte populations, respectively ( ) . ly c high monocytes highly express the chemokine receptor cc-chemokine receptor (ccr ), whereas ly c low monocytes highly express cx cr ( ) . importantly, ccr expression is required for ly c + monocyte egress from the bone marrow into the circulation and entry into noninflamed and inflamed tissues ( ) ( ) ( ) from the blood ( ). as monocytes migrate into tissue, they mature into macrophages developing unique, tissue-dependent morphology and functions ( ) . they lose expression of ly c and gain expression of mhc class ii, becoming more efficient antigen-presenting cells ( ) . some authors have proposed the concept of "tissue monocytes, " which are monocytes that can enter non-lymphoid organs without obligatory differentiation into macrophages. therefore, monocytes are much more than simply precursors for macrophages. in human lungs, monocytes, which can be both beneficial and pathogenic in a variety of pulmonary diseases ( ) , are present at steady state ( ) . multiple-color cytometric analysis on cells obtained from different anatomical locations of the lung of healthy subjects (non-smokers with normal lung function and absence of disease or infection) revealed that while intermediate monocytes (cd + cd + ) are more frequent in the airways, classical monocytes (cd + cd − ) are more frequent in blood ( ) . moreover, the different monocyte subsets produced tnfα to different degrees upon stimulation with tlr ligands ( , , and / ). thus, the anatomic location where samples are obtained should be considered and reported when working with human bronchoscopies, as this may alter the type and abundance of monocytes and macrophages found. accurate identification of monocytes in the lung compartments in humans has been a challenge because monocytic "contamination" from the blood vessels ( , ) . overcoming this challenge, desch et al. performed a flow cytometric phenotyping study and identified two additional lung monocyte populations by analyzing lungs obtained from donors who died of non-pulmonary causes ( ) . cd + cd − cd c − cd a − intravascular monocytes were similar to cd + blood monocytes and cd + cd + cd c − cd a − monocytes were described as tissue "monocytes." these studies highlight that we are just at the beginning of understanding the complexity of lung monocyte subtypes and their functions depending on the inflammatory state of the lung. other myeloid populations, like dcs, occupy the lung parenchyma at steady state, and their relative numbers change during inflammation. we refer readers to previous excellent reviews in this journal that cover the importance of dcs in immune responses in the lung and how they are affected by sex differences. therefore, we will not discuss dcs here ( , ( ) ( ) ( ) ( ) ( ) . polarization is a very important effector characteristic observed in monocytes and macrophages. polarization refers to the change in phenotype and function of monocytes and macrophages as they are exposed to different inflammatory milieus or factors in the tissue microenvironment. to understand the effects of the differing inflammatory or tissue environments on monocyte-macrophage phenotype and function, researchers have used cytokines and other factors in vitro to mimic different inflammatory and tissue microenvironments. monocytes and macrophages stimulated with interferon-γ, lps, tnfα, interleukin (il)- , and granulocyte-macrophage colonystimulating factor promote a pro-inflammatory macrophage phenotype denoted as m polarization. the activation state was also known as "classical" activation. m -polarized macrophages mediate immunity to intracellular infections, such as viruses and bacteria, and they are generally considered tumoricidal ( ) ( ) ( ) ( ) . m macrophages accomplish these functions by inducing production of nitric oxide, reactive nitrogen intermediates, reactive oxygen species, and hydrogen peroxide ( ) ( ) ( ) . in contrast, activation of macrophages with il- or il- , as in extracellular parasitic infections and allergic reactions, leads to m polarization or "alternative" activation of macrophages ( ) . m macrophages produce inflammatory mediators and chemokines, such as chitinase-like proteins ( ), il- ( ) , ccl , ccl , ccl , and ccl , which activate th cells and promote eosinophil infiltration into the lungs ( , ) . in allergic asthma, a th -inflammatory response to inhaled allergens drives lung macrophages toward an m phenotype. increased number and percent of m macrophages have been correlated with asthma severity and a decline in lung function in humans and mouse models ( ) ( ) ( ) . similarly, m macrophages are the predominant subset seen in pulmonary fibrosis and are responsible for fibrogenesis ( ) . during copd, the number of macrophages in airways, lung parenchyma, bronchoalveolar lavage fluid, and sputum increases ( , ) . this increase may occur as a result of enhanced monocyte recruitment from circulation in response to chemokines such as ccl and cxc-chemokine ligand- , which are increased in the sputum and bronchoalveolar lavage fluid of patients with copd ( ) . unlike in allergic asthma and pulmonary fibrosis, macrophages in copd are polarized toward an m profile ( ) . in addition to affecting men and women differently, another commonality of copd is that macrophages both in the alveolar space and in lung tissue present an altered activation phenotype. different concentrations of cytokines (tnf-α, il- β, il- , il- , il- ) and chemokines (ccl , ccl , ccl , ccl , ccl , il- , cxcl , and cxcl ) are found comparing smokers to healthy subjects ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) . thus the external provoking stimulus uniquely shapes macrophage phenotype and function. while the m /m designations are useful for in vitro studies with stimulation with defined cytokines, the in vivo phenotype of macrophages exists on a spectrum somewhere in between these two well-defined opposing phenotypes or does not fit the paradigm at all. for example, m and m markers can exist simultaneously within the same cell in some cases ( ) ( ) ( ) . the key factors dictating the macrophage phenotype or activation state are the stage of the immune response and the soluble factors and interactions in a particular tissue microenvironment. for example, the lung environment is rich in gm-csf, tgfβ, and pparγ and is critical for development of mature ams after birth in both mice ( , , ( ) ( ) ( ) ( ) ( ) and humans ( ) ( ) ( ) ( ) ( ) ( ) . furthermore, interactions between cd on type ii alveolar epithelial cells and cd r on the surface of the am deliver regulatory signals to the am to prevent proinflammatory signaling and macrophage activation ( ) . thus, macrophage nomenclature has evolved as our understanding of the phenotypes and functions of different types of tissue resident macrophages, recruited monocytes and monocyte-derived macrophages advances. in-depth studies of the effects of androgens and other sex hormones on tissue macrophage plasticity and phenotype have yet to be carried out. because androgens are lipophilic steroid hormones, they can easily diffuse across cell membranes without the need for receptor-mediated import ( ) . androgens in circulation are found mostly bound to sex hormone-binding globulin and albumin ( ) . free (unbound) steroid sex hormones can signal through two different mechanisms: the classical ar, located in the intracellular compartment, and the membrane, or nonclassical, ar ( ) . androgen binding to classical and nonclassical ars mediates genomic and non-genomic androgen effects, respectively ( ) . upon androgen binding, the classical ar undergoes a conformational change and dissociates from heat-shock and other chaperone proteins. an androgen-ar complex is formed that translocates to the nucleus, dimerizes, and binds to androgen responsive elements that modulate the transcription of target genes ( ) . importantly, it has been reported that the androgen-ar complex can also mediate nongenomic changes ( ) by causing calcium flux and by activating second messenger pathways including erk, akt, and mapk, at least in cell lines ( ) ( ) ( ) . whereas, genomic modulation may need hours or days ( ), non-genomic modulation can occur within seconds to minutes after androgen exposure, does not involve the complex binding to dna, and therefore does not affect transcription of target genes ( ) . dhea has no known unique receptor and is not a direct ar agonist. it affects immune function but, because it can interact with other sex hormones, it has been difficult to establish its mechanisms of action. most studies of androgen-ar complex-mediated gene expression have been carried out in the context of male reproductive tissue in prostate cancer (pca) ( ) ( ) ( ) . as previously discussed, immune cells are responsive to sex hormones, and almost all immune cells express sex hormone receptors ( ) . mouse monocytes, macrophages ( ) , and dcs ( ) express both classical and non-classical ars although the vast majority studies do not specifically dissect the role of the two types of ar on the outcomes being measured in the study. because recent literature has described how sex steroids modulate the functions of dcs ( , , ), we will not discuss it here. we will focus on the importance of androgen-ar regulation of monocyte and macrophage function and how androgen-ars modulate monocytes and macrophages in lung diseases. androgen receptor expression in mouse and human monocytes and macrophages is summarized in table . in general, the expression of the mrna and protein for classical ar has been assessed, often by non-quantitative means, and non-classical ars have not been measured. we have summarized the outcomes of many studies on mouse and human monocyte-macrophages responses in the presence of androgens in figure . in general, monocyte-macrophage exposure to androgen results in a reduction of pro-inflammatory responses (boxed and shaded in green). it is possible that the reduction in inflammation by androgen may be due to ar suppression of estrogen/erα-driven pro-inflammatory responses. ar was demonstrated to inhibit erα activity by binding eres in breast cancer cells ( ) . whether this indirect mechanism accounts for the broad immunosuppressive effects of androgens in normal untransformed immune cells is not known. in keeping with reduced pro-inflammatory responses, we found that androgen enhanced il- -induced m polarization of bone marrow derived and alveolar macrophages in vitro and macrophage-specific deficiency of ar diminished m polarization of lung macrophages in vivo ( ) . in some cases, however, inflammatory responses are increased by androgens (boxed and shaded in red). the different responses may be due to different types of tissue macrophages or experimental system. monocyte-macrophage responses are dependent on the concentration of the hormone, expression of ar, and upon the inducing stimuli to which the macrophage is exposed. the majority of in vitro studies examining the effects of androgens on monocytes and macrophages have not clearly acknowledged or separated the effect of androgen on membrane ars and nonclassical ar signaling from that of classical ars. therefore, we have to assume that the studies described in the section below are a result of classical ar activity unless explicitly investigated or stated. determining how non-classical ar signaling and androgen-independent activation of ar affects monocyte and macrophage function is a gap in our knowledge that must be addressed in future studies. androgens modulate the expression of proinflammatory molecules such as tnfα in mouse monocytes and macrophages. in , lai et al. ( ) demonstrated that lps-induced production of tnfα was decreased in bmm lacking classic ars. moreover, they found that ar, in the presence of dht, induced tnf-α promoter activity ( ) . on the other hand, several reports have suggested the contrary. in one study that used splenic macrophages from midline laparotomy trauma-hemorrhaged mice, dht suppressed tnf-α production from lps-stimulated cells ( ) . this effect was also observed in the mouse macrophage cell line j ( ) , in which testosterone inhibited tnf-α production. in addition, testosterone also decreased expression of the proinflammatory molecule nitric oxide in response to lps in the mouse macrophage cell lines raw . ( ) and j ( ) , but it enhanced the expression of il- in the latter. other molecules important in monocyte-macrophage functions are also affected by androgens. for example, the expression of ccr was enhanced in mouse monocytes by androgens and thereby enhanced chemotaxis ( ) . however, suppressing ar with sirna in prostate cells increased macrophage recruitment via ccl upregulation, which might promote prostate cancer ( ) . phagocytosis was increased by testosterone in rat peritoneal macrophages at − m but not at concentrations lower or higher than − m ( ). cytotoxicity of raw macrophages to the mouse prostate cancer cell line, tramp c , was enhanced by dht alone ( ) . this was attributed to enhanced expression of the m polarization markers, trail and tnf-α, in the macrophages. testosterone ( , , and nm) induced apoptosis in mouse bmm through fas-fasl ( ) and activation of caspase , and poly (adp-ribose) polymerase ( ) . in terms of m polarization of macrophages, we showed recently that in vitro exposure of bmm to dht prior to il- stimulation enhanced chi l and arg gene expression, as well as production of ym ( ) . androgen amplified the m phenotype by increasing il- -mediated m polarization. our results were similar to those found in response to il- in the raw cell line ( ) . this enhanced m macrophage polarization correlated with decreased tlr expression and sensitivity to a tlr -specific ligand observed in testosterone-treated raw cells ( ) . taken together, these observations suggest that androgens and ars can either promote or suppress inflammatory properties of mouse macrophages, depending on the external environmental conditions, ar expression, and concentration of hormone. overall, androgens are more likely to reduce polarization of m macrophages. this could represent an important mechanism by which inflammatory pathways are downregulated in males. the opposite effects seen in different inflammatory contexts highlight the need for a deeper and broader study of the androgen/armediated modulation of monocytes and macrophages, as these cells participate in both the initial and late phases of immune responses in a variety of diseases. most of the studies analyzing the role of ar have focused on prostate cancer, primarily in transformed cell lines ( - ) but macrophages are vital in cancer development and metastasis ( ) . furthermore, it is important to consider that opposing effects could result from differential activation of either classical or non-classical (arindependent) effects ( , ) which have been rarely studied to date. androgens affect a number of key monocyte and macrophage functions. studies of androgen receptor function in human monocytes and macrophages have focused primarily on the roles of male sex and sex hormones in promoting atherosclerotic foam cell formation ( ) and inhibiting cutaneous wound healing ( , ) . foam cells are a type of macrophage localized in the blood vessel walls where they engorge cholesterol ( ). foam cells exhibit enhanced inflammatory cytokine secretion and cause atheroma, contributing to cardiovascular disease ( , ). the effect of androgen on monocytes and macrophages in other immune-mediated human diseases where monocytes and macrophages play a role has been neglected. the degree of ar expression in monocytes and macrophages is likely the primary determinant of responsiveness, although most studies examining responses to androgens do not quantify ar expression (see table ). the expression or action of androgens on non-classical ars in human monocytes and macrophages has yet to be examined carefully. most studies assume that the outcomes that are measured are a result of the activity of classical ar. sex differences in ar content may also play a role in responsiveness. this fact highlights the importance of considering the sex of cells in all in vitro studies to accurately assess how sex hormones affect the responses of monocytes and macrophages. apoptosis was significantly greater in human thp- cells cultured for days with nm testosterone than in control cells or cells treated with estradiol (e ), owing to a reduction in proliferating cell nuclear antigen, induction of poly-adp ribose polymerase-cleaved, an increase in iκb-α, and a decrease in phosphorylated iκb-α ( ) . e , in contrast, promoted cell survival. other studies noted concentration-and time-dependent regulation of apoptosis in thp- cells, with an increase in the proto-oncogene bax and fas ( ) . androgen exposure inhibited proliferation of the human monoblastic leukemia cell line u , depending on the concentration and time of exposure ( ) . cell cycle arrest occurred at the g /m phase, although another study measured no effect of testosterone on pma-differentiated u cells ( ) . how testosterone regulates apoptosis and survival of untransformed primary human monocytes and mdms has not been well-studied. toxicity was observed when monocytes were differentiated into macrophages over days in the presence of . mg/ml androgen, but not at lower concentrations of the hormone ( ) . testosterone reduced the viability of monocytes from a healthy control and a patient with systemic lupus erythematosus in a concentration-dependent fashion ( , ) . these two studies highlight the importance of concentration in studies of sex hormones. an additional example is the finding that e enhances tnf-α secretion from antigen-stimulated t-cells at low concentrations and inhibits secretion at high concentrations ( ) . il- β-induced nf-κb activation is also inhibited at high but not at low e concentrations ( ) . hence, it is important to carry out in vitro studies of sex hormone responses over a wide range of physiologic concentrations of sex hormones. in general, androgens have a suppressive effect on proinflammatory cytokine expression in monocytes and mdms. this finding is consistent with the idea that the immune system of females produces cytokines in response to pathogens and insults more robustly than that of males. monocyte or mdm expression of tnf-α, il- β, il- , and il- is reduced in the presence of testosterone ( ) ( ) ( ) . many studies in this field have relied on human cell lines, such as thp- and u , with or without pma-induced differentiation into macrophages, and differentiated hl- cells, although primary monocytes and mdms have been used in a few cases ( , ) . another immunoregulatory function of testosterone is the upregulation and secretion of c inhibitor (c inh) from monocytes ( ) . c inh is a kda plasma protein whose main function is inhibition of the complement system to prevent spontaneous activation. thus, testosterone keeps complement activation in check. another mechanism by which testosterone limits inflammation is by decreasing the generation of reactive oxygen species generation from differentiated hl- cells. interestingly, the production of reactive oxygen species in response to zymosan, but not lps, was inhibited by testosterone ( ) . in terms of allergic immune responses, metabolism of arachidonic acid into inflammatory leukotrienes (lts) via the -lipoxygenase ( -lo) pathway is sex-dependent in human monocytes. pergola et al. ( ) reported that primary human peripheral blood monocytes from women synthesize more -lo product than do the same cells from men. α-dht ( nm) suppressed lt synthesis in female cells to the levels observed in males. erk activation by androgens reduced phospholipase d activity in monocytes and impaired -lo product formation by reducing active diacylglycerides. the other branch of arachidonic acid metabolism is the cyclooxygenase (cox) pathway, which generates prostaglandins. prostaglandin e (pge ), one of the most abundant cox products produced by the airway epithelium and smooth muscle ( , ) , can either stimulate or suppress immune cell function. testosterone reduced pge production in monocytes obtained from heparinized peripheral blood of healthy adults and incubated for h with lps ( ) . a few studies have examined the effect of dhea on human monocytes and macrophages. in the presence of lps, dhea induced il- and tnf-α production by primary human monocytes and il- and tnf-α production by thp- cells ( ) . in these experiments, dhea counteracted the effects of cortisol and the glucocorticoid receptor on lps-induced il- and tnf-α by inducing expression of the scaffolding protein rack (receptor for activated c kinase ) in thp- cells and primary human monocytes ( ) . rack is involved in multiple signal transduction cascades, including the mapk, protein kinase c, and src signaling pathways. rack shuttles proteins around the cell, anchors proteins at particular locations, and is involved in cell migration ( ) . in contrast, dhea added to alveolar macrophages lavaged from non-smoking asbestos workers significantly reduced superoxide anion release in vitro ( ) , consistent with its role in dampening th inflammation ( ) . therefore, the effect of dhea on monocytes and macrophages may be stimulus-dependent and needs more in-depth investigation. the formation of foam cells (lipid-filled macrophages) is generally associated with the pathogenesis of cardiovascular diseases, such as atherosclerosis. however, foam cells are also found in patients with silicosis ( ) and other fibrotic lung diseases ( ) and in tuberculosis. alveolar macrophages take up extracellular and intracellular lipids in response to inhaled silica, vaping products ( ) , and mycobacterium tuberculosis ( ) . furthermore, the metabolism of fatty acids by macrophages by β-oxidation for sustained energy production is a key feature of the functional phenotype of macrophages with a pro-resolving, tissue reparative (m ) phenotype. therefore, we have included how androgens modulate foam cell formation and lipid handling in macrophages as part of this discussion. macrophages from men and those exposed to testosterone favor the processes of lipid handling and foam cell formation, supporting evidence that atherosclerosis is a male-dominant disease when age is taken into account ( ) . atherosclerotic plaques composed of a number of different immune cells form in blood vessel walls. in advanced stages of atherosclerosis, macrophages in plaques take up oxidized low-density lipoprotein (ldl), creating foam cells. eventually, cholesterol crystals accumulate, trigger inflammation and plaque rupture. the role of sex in the inflammatory events of atherosclerosis has been reviewed elsewhere ( ) . in vitro studies have sought to ascertain how testosterone promotes these processes by utilizing primary mdms. in mdms from healthy men, androgen treatment was shown to upregulate genes involved with lipoprotein processing, transporter proteins, cell-surface adhesion, and other pathways, but none of these genes were upregulated in female macrophages ( ) . the marked sex specificity of androgen effects on human macrophage gene expression is most likely related to sex differences in mdm ar expression. similarly, treatment of mdms with modified and native ldl led to changes in expression of mrnas involved in homeostatic regulation of lipid metabolism, depending on the sex of macrophage donors ( ) . functionally, androgen-treated mdms from men but not women accumulate cholesteryl esters ( ) . male macrophages exhibit increased rates of lysosomal acetylated ldl degradation and upregulated expression of scavenger receptor class b type i ( ), increasing high-density lipoprotein ( )-induced cholesterol efflux. the expression of ar in monocytes/macrophages also upregulates lectin-type oxidized ldl receptor molecules that are involved in foam cell formation ( ) . however, corcoran et al. ( ) observed no effect of testosterone on cholesterol content or efflux from mdms of healthy male and postmenopausal female donors (age - years). because their study used healthy donors, it is possible that the absence of other health-related factors, such as smoking, poor health, and genetic risk factors for coronary heart disease in the healthy blood donors may have produced these results. chemotaxis of thp- cells was diminished when androgen receptor was knocked down by sirna suggesting a role for ar in migration of monocytes ( ) . the authors identified tnf-α as a key ar-regulated molecule important in monocyte migration. in contrast, a handful of studies have tested the effect of testosterone on primary human monocyte phagocytosis and migration, but no effect was found ( , ( ) ( ) ( ) . testosterone did not change the cytotoxic capacity of monocytes from male donors (age range - years) to lyse red cells sensitized with igg antibodies ( ) . most studies that have used mouse models to investigate sex differences in lung diseases have focused on the role of estrogen and estrogen receptors ( ) ( ) ( ) . the importance of androgen and ars in lung disease has been poorly studied. earlier studies were directed at modulating monocyte and macrophage functions unconnected to ar function, as years ago it was believed that mouse macrophages did not express classical ars ( ) . nevertheless, recent studies have examined sex differences in mouse models of allergic asthma, copd, and influenza. we and others have reported sex differences in mouse models of allergic lung inflammation ( , , , ) . some of the observed differences have been clearly attributed to the effect of androgens. we showed that dht reconstitution of castrated male mice reduced overall lung inflammation ( ) . a reduction of total serum ige and total immune cell recruitment to the lungs, specifically eosinophils, revealed the regulatory effect of androgens on several cell types. however, the unexpected enhancement of the production of the canonical m macrophage marker involved in eosinophil recruitment ( , ) , ym , by dht in alveolar macrophages ( ) showed that androgens have a regulatory or an activating effect depending on the cell type. we demonstrated that deletion of classical ars on monocytes and macrophages (ar flox lysmcre mice) resulted in reduced inflammation (less eosinophil recruitment to the alveolar space), along with less mucus production and lung cell infiltrate, despite no differences in serum testosterone level between arsufficient and ar flox lysmcre mice ( ) . this finding indicates the importance of androgens as modulators of m macrophage polarization and the critical role of these cells in allergic lung inflammation. other recent studies have shown that testosterone has an anti-inflammatory role in a mouse model of allergic lung inflammation induced by house dust mite but focused on other cell types in lung, such as th ( ) and ilc cells ( , ) . similarly, high concentrations of androgens in circulation have been related to a decrease in the expression of tnfα and other proinflammatory cytokines, such as il- and il- β, in rodent macrophage cell models and in human monocytes ( , , , , ) . how androgen and ars impact functions on ims still needs to be studied. at the time this review was written, no reports on ar expression in ims were found. however, we hypothesize that as ims are derived from blood monocytes ( ) , but once in the tissue they develop an intermediate size and phenotype between monocytes and am ( , ) , their expression of ar could be somewhere in between. therefore, androgen and ars could regulate the functions and activation of these cells. this requires further study, as ims are a constitutive macrophage population in the lung, and may play a role mediating sex differences in lung diseases. mouse models have also shown that sex differences affect copd. in , tam et al. ( ) reported that smokeinduced copd is characterized by small airway remodeling in female but not male mice and that ovariectomy before smoke exposure ameliorates the disease. another study focusing on α- antitrypsin deficiency, the leading genetic cause of emphysema, also uncovered a higher susceptibility of female mice for this condition ( ) . however, these studies did not determine if androgens mediate resistance to copd, or if the key to the observed sex differences is ovarian sex hormones. thus, the role that androgens play in copd and copd models remains unclear. mouse studies that have focused on sex differences in influenza showed that at moderate influenza virus a (iav) loads, morbidity, mortality, and the associated inflammatory response is greater in female than in male mice, but that mortality is similar at higher loads ( , , ) . the role of sex hormones was well-addressed in these studies. high levels of estrogen in estrogen-reconstituted female mice protected against lethal iav doses ( ), whereas the lower estrogen levels in intact females were associated with greater inflammatory responses and increased morbidity after infection. similar observations were made after progesterone replacement ( ) . in males, a decrease in androgen levels after castration increased morbidity and pathology upon iav infection, but replacement of testosterone or dht reduced morbidity, mortality, and inflammation ( , ) . these findings suggest that although estrogen may be protective or detrimental, depending on concentration, androgens may suppress inflammation in a broader way. gonadectomy studies in mice have been used to uncover the role of androgens in tb. similar to observations in castrated men, castrated male mice that displayed greater pro-inflammatory responses in the lung (more tnf-α, ifn γ, il- , inos, and il- ) than intact males. ifn-γ-activated macrophages (m macrophages) control of tb infection in both human and mouse ( ) . ovary removal in females did not impact susceptibility to tb ( ) , suggesting that testosterone is responsible for male susceptibility to tb. we previously reported that dht enhances m macrophage polarization through ar ( ) . therefore, we speculate that the greater male susceptibility to tb could be at least in part mediated by enhanced m responses that are poorly protective and decrease protective proinflammatory macrophage responses. formal studies to address this idea as well as how androgen effects on other key immune cell players in tb are needed. how androgens affect monocyte and macrophage biology in lung cancer models in mice has not been well-studied. monocytes and macrophages are important cellular players in tumorigenesis. tumor-associated macrophages (tams) can be classified into two phenotypes that are either pro-inflammatory and tumoricidal (m -like) or promote tumor growth and suppress anti-tumor immune responses (m -like) ( ) ( ) ( ) . as mentioned previously, sex hormones augment m macrophage polarization, thus, play an important role in lung carcinogenesis. the greater overall incidence of lung cancer in men could be explained by an enhanced m polarization by androgens ( ) . on the other hand, estrogen has been shown to induce tumor angiogenesis ( ) . estrogen signaling though the camp, mapk, and akt pathways with the consequent phosphorylation of erk and egfr signaling, along with the enhanced expression of cmyc and cyclin d, results in nsclc cell proliferation ( ) . mouse models must therefore address the role of androgens on monocytes and macrophage function in the establishment and progression of lung cancer in male and female animals. few studies have examined the effect of sex hormones on peripheral blood monocytes and lung macrophages from men and women with asthma or the other lung diseases we have discussed here. in women with asthma, dominance of m macrophages in airways and lung tissue has been documented ( ) and a connection between female sex and female sex hormones surmised. there is a paucity of literature regarding how introducing or depleting exogenous sex hormones (such as in female-to-male transgender individuals receiving testosterone supplementation or women with estrogen blockade) affects the function of blood monocytes and lung macrophages in men and women with asthma. most studies correlate concentrations of sex hormones with either inflammatory markers, such as cytokines or chemokines in serum and other fluids, or with lung function measurements. we will summarize below the small number of studies in which androgen concentrations were manipulated in humans and the effects on monocyte or macrophage function. hypogonadism in men refers to a deficiency in testosterone production from the testes that results from testicular, hypothalamic, or pituitary abnormalities. klinefelter's syndrome in men, which is a result of additional x-chromosomes (e.g., xxy), is the most common cause of hypogonadism. testosterone replacement therapy is the primary treatment option to restore physiologic testosterone levels, typically in the range of to ng/dl. in general, exogenously administered testosterone has a suppressive effect on the proinflammatory immune response from monocytes. for example, spontaneous production of proinflammatory cytokines (il- β, il- , and tnfα) ex vivo was reduced or completely absent in the monocytes and dcs from men with type- diabetes who had partial androgen deficiency and were treated for months with testosterone replacement. this suppression was maintained for more months after testosterone withdrawal ( ) . testosterone replacement therapy also is associated with a reduction or complete abrogation of spontaneous ex vivo production of inflammatory cytokines by antigen-presenting cells ( ) . on the other hand, the circulating monocytes from hypogonadal men treated with testosterone replacement therapy exhibited significantly upregulated expression of cd b at baseline compared to monocytes from healthy controls. this was also seen after stimulation with cpg oligodeoxynucleotides to mimic bacterial dna exposure ( ) . membrane expression of cd b, also known as lysosome-associated membrane protein (lamp) , is indicative of release of lysosome and/or phagolysosome contents into the extracellular medium, a mechanism that may be involved in killing and/or digesting target cells. these data suggest that testosterone increases the inflammatory function of these cells, an effect that would contrast with its typical role as an immunosuppressant. the immune system of individuals with klinefelter's syndrome provides unique insight into the genetic contribution of the x-chromosome and that of diminished testosterone to sex differences in different diseases. men with klinefelter's syndrome have an increased risk of developing autoimmune diseases, particularly those that are typically female-dominant, such as rheumatoid arthritis and systemic lupus erythematosus ( ) . as might be predicted due to the negative effect of lower concentration of testosterone on lung function, men with klinefelter's syndrome are more likely to be diagnosed with pulmonary diseases, such as copd and pneumonia ( ) . asthma is also reported in these individuals ( ) ( ) ( ) and it was successfully controlled with long-acting β-agonists and oral testosterone replacement in one case report ( ) . at the cellular level, however, cytokine production in stimulated whole blood from klinefelter's men was similar to that of women ( ) . these data suggest that the effect of the additional x-chromosome was more dominant than the reduction in circulating androgen in klinefelter's men. in the same study, however, purified monocytes showed the opposite response: cytokine production from the monocytes of healthy and klinefelter's men was similar and less robust than that from the monocytes of women. this observation led to the opposite conclusion-that androgen plays a more important role in monocyte cytokine production than does chromosomal complement. pcos is a disease characterized by hyperandrogenism, amenorrhea, and polycystic ovaries. the cystic folliclesovarian theca cells-produce testosterone that causes significant elevations in serum concentrations of testosterone, androstenedione, dhea, and dhea-s. in women with pcos, serum testosterone is in the range of - ng/dl ( - nmol/l) ( ), compared with a range of - ng/dl in healthy, ovulatory women ( ) . this endocrinopathy is associated with metabolic disorders, such as dyslipidemia, insulin resistance, metabolic syndrome, and cardiovascular complications. immune function is impaired in women with pcos, leading to increased secretion of autoantibodies and increased risk of type diabetes, asthma, and thyroid disease ( ) . because androgens downregulate the inflammatory responses that contribute to asthma, one might hypothesize that women with pcos would have less asthma. however, htet al. ( ) found that asthma prevalence was . % in women with pcos compared to only . % in women without pcos (p = . ). women both with and without pcos who had asthma tended to have a higher bmi than those without asthma ( ) . after multivariable analysis, the authors concluded that both pcos and high bmi were independently associated with asthma ( ) . it is therefore possible that testosterone contributes to the chronic inflammatory state that accompanies high bmi and that the metabolic dysfunction overpowers the protective effects of testosterone on asthma development. few cellular and molecular studies have endeavored to uncover mechanisms that explain the association between asthma and pcos. at the cellular level, circulating monocytes from women with pcos expressed the receptor for advanced glycation endproducts (rage) more strongly than monocytes from healthy control women ( ) . ages are involved in the pathogenesis of a number of chronic lung diseases, ranging from cystic fibrosis to asthma. rage can also bind other alarmins, such as the s a /a heterodimer (calprotectin) or the high-mobility group box (hmgb) protein. both of these ligands have been implicated in the pathogenesis of allergic asthma ( , ) , as they induce cell proliferation or apoptosis, inflammation, collagen synthesis, and cell migration in many different cell types. the concentration of age proteins and testosterone correlated positively, even after controlling for bmi and other metabolic function tests ( ) . taken together these two studies suggest that monocytes from women with pcos would be more responsive to rage ligands. this heightened responsiveness could promote cellular inflammatory responses that contribute to asthma pathogenesis. studies are needed to examine how the increased testosterone in women with pcos affects circulating monocytes and lung macrophages to increase asthma prevalence in this group. testosterone has been administered therapeutically for asthma. in an early study, asthmatic women were given testosterone either daily for days over weeks or daily for days over or more weeks. although the number of participants in the study was small, % saw improved symptoms, with % reporting no asthma attacks up to months later ( , ) . no studies have examined the effect of exogeneous testosterone administration on blood monocytes or lung macrophages in men and women with asthma. testosterone deficiency is also present in patients with copd ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) . in a clinical study of exercise and testosterone injection in men with copd, the interventions did not significantly alter pulmonary function or blood gas variables ( ) . on the other hand, a retrospective study of two large cohorts of men who commenced testosterone replacement therapy within months of a copd diagnosis showed a . - . % decrease in hospitalizations, dependent on age ( ) . more work is needed to understand how testosterone and its signaling pathways can be harnessed to alleviate lung disease without affecting reproductive systems or having unwanted metabolic effects. asthmatic patients have decreased serum concentration of dhea and dhea-s ( ) ( ) ( ) . therefore, some clinical trials have tested whether dhea-s supplementation reduces asthma. men and women with poorly controlled moderate-to-severe asthma were given nebulized dhea-s for weeks. this treatment led to a statistically significant improvement in the asthma control questionnaire (acq) and trends toward better asthma symptom scores and more symptom-free days and nights ( ) . oral dhea for weeks improved lung function in asthmatic women with low dhea-s < µg/dl ( ) . however, neither of these clinical studies examined the cellular component of the disease pre-or post-intervention. dhea and dhea-s are also lower in patients with copd than in healthy controls, and copd leads to pulmonary hypertension (ph). dhea supplementation improved the -min walk test, pulmonary hemodynamics, and the diffusing capacity of the lungs for carbon monoxide of patients with ph-copd ( , ) . the therapeutic potential of dhea is currently being investigated in patients with ph in the ediphy (effects of dhea in pulmonary hypertension) trial. however, outcome measures of this trial do not include examination of the immune cells or the effect of dhea treatment on those cells. analysis of immune cell function would add important cellular mechanistic insight to these types of trials and help uncover some of the widespread effects of this hormone on the immune system. modulation of monocyte and macrophage function mediated by the interaction of androgen and ar has been examined mostly by correlative studies in humans following lifespan changes in sex hormones or using hormonal manipulation in mouse models of lung disease. most human-based reports are merely descriptive or correlative and do not consider variables such as age, bmi, and phase of the menstrual cycle as key modulators of circulating sex hormone concentrations. taking these factors into account should be encouraged if we are to gain a better understanding of the impact of sex hormones in health and disease. analyses of the function of immune cells from male and female healthy controls and patients with lung diseases are needed to unlock how sex hormones alter the biology of the innate and adaptive immune response. studying the role of sex hormones as modulators of the immune system is complex because they interact with other hormonal systems and with one another, and because of the nearly ubiquitous expression of sex hormone receptors in most cells of the body. males and females have all types of sex steroids, although in different circulating concentrations. in humans, changes in the concentration of sex steroids have implications for lung health and may contribute to disease by affecting the function of the immune system. female sex hormones have been more widely studied as immune system modulators than have androgens. more focus in the future must be directed to how androgens affect the immune system and the interaction between male and female sex steroids in immune function. historically, animal models have used only males as study subjects, leaving females aside out of concern for the variability in results introduced by sexually mature adult females with active estrous cycles. as a result, biomedical and preclinical research has neglected to reflect more than % of the world's population. this omission had some notable negative consequences: eight of ten drugs withdrawn by the fda between and had significant health risks to women ( ) . it was not until that the nih addressed this oversight with its requirement to include sex as a biological variable in all research studies ( ) . the practices of using only male animals, not clearly reporting the sex (and age) of the animals used, and mixing male and female results have obscured a proper understanding of how sex and sex hormones influence normal biology and that of disease states. moreover, many reports comparing sex as a variable lack strict controls on culture conditions in vitro, which can alter the results. for example, if investigators fail to appreciate that animal serum or ph indicators, such as phenol red, may act as a source of steroids or sex hormone receptor agonists and do not clearly report their use, the interpretation and reproducibility of the experiments can be diminished. we strongly advocate for the use of hormone-free serum or animal serum replacements (for human cell studies) and use of culture medium that does not contain sex steroid receptor agonists. moreover, rigorous experimentation should include careful and detailed reporting of cell culture conditions, donor sex and age for cell studies, accurate age and sex in animal work (adherence to arrive guidelines), and separate male and female results. here, we have highlighted the importance of sex hormones as modulators of monocytes and macrophages and the important role of these innate immune cells in lung diseases where sex differences are apparent. these cells are part of a larger response that includes the adaptive immune system as well as the structural cells of the lung that are all affected by the action of sex steroids. as such, how innate cells like monocytes and macrophages shape the pulmonary immune response and how they resolve lung inflammation differently in the male and female lung and in the presence of different sex steroids needs intensive study. uncovering the cellular and molecular mechanisms will be crucial for finding new ways to treat different lung diseases depending on the sex of the patient. mb-d, ms, and nh wrote and revised the manuscript, interpreted the literature, approved and are accountable for all aspects of the final version. all authors contributed to the article and approved the submitted version. funding nih (nhlbi) r hl (to nh). dept of defense cdmrp w xwh- - - (to nh). overview 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results of a -week, randomized, double-blind, placebo-controlled study dhea) improves pulmonary hypertension in chronic obstructive pulmonary disease (copd): a pilot study association of adrenal hormone metabolites and mortality over a -year follow-up in copd patients with acute exacerbation sex as an important biological variable in biomedical research sex as a biological variable: a -year progress report and call to action key: cord- -wurzy k authors: van der merwe, rené; molfino, nestor a title: challenge models to assess new therapies in chronic obstructive pulmonary disease date: - - journal: int j chron obstruct pulmon dis doi: . /copd.s sha: doc_id: cord_uid: wurzy k chronic obstructive pulmonary disease (copd) is a major cause of morbidity and mortality. current therapies confer partial benefits either by incompletely improving airflow limitation or by reducing acute exacerbations, hence new therapies are desirable. in the absence of robust early predictors of clinical efficacy, the potential success of novel therapeutic agents in copd will not entirely be known until the drugs enter relatively large and costly clinical trials. new predictive models in humans, and new study designs are being sought to allow for confirmation of pharmacodynamic and potentially clinically meaningful effects in early development. this review focuses on human challenge models with lipopolysaccharide endotoxin, ozone, and rhinovirus, in the early clinical development phases of novel therapeutic agents for the treatment and reduction of exacerbations in copd. the global initiative for chronic obstructive lung disease defines chronic obstructive pulmonary disease (copd) as a … common preventable and treatable disease characterized by persistent airflow limitation that is usually progressive and associated with an enhanced chronic inflammatory response in the airways and the lung to noxious particles or gases. exacerbations and comorbidities contribute to the overall severity in individual patients. exacerbations are associated with increased airway and systemic inflammation, which lead to airway wall edema, sputum plugging, and bronchoconstriction. copd remains a major global health and economic burden that is expected to be the third leading cause of death, and the fifth leading cause of disability by . in , copd accounted for $ . billion in health care expenditures in the united states alone ($ . billion in direct health care expenditures, $ . billion in indirect morbidity costs, and $ . billion in indirect mortality costs). in europe, copd accounts for . billion euros in health care spending a year. pharmacological therapy is used to control symptoms, as well as to reduce exacerbations, and to improve exercise tolerance. ambulatory copd patients are currently treated with long-acting bronchodilators and inhaled corticosteroids, along with systemic corticosteroids during exacerbations. there is a pressing need to develop novel approaches for the treatment of copd and the prevention or reduction of acute exacerbations of copd. existing therapies give partial benefits either by incompletely improving airflow limitation or reducing acute exacerbations, hence the need for newer, more effective therapies. evidence that existing medications reduce lung function decline in the long term has been inconclusive. the torch study investigated the effects of combined salmeterol plus fluticasone, either component alone, and placebo, on the rate of postbronchodilator forced expiratory volume in second (fev ) decline. the investigators found that salmeterol plus fluticasone reduced the rate of fev decline by ml/year compared with placebo. despite this large study, a meta-analysis conducted by soriano et al concluded that inhaled corticosteroids showed a significant improvement in lung function decline compared with placebo at months, however, after months there was no significant difference between placebo and inhaled corticosteroid treatment. one of the main challenges in developing new therapeutic agents for the treatment or prevention of acute exacerbations of copd is that their potential success cannot be entirely known until the investigational therapies enter relatively large phase ii studies, assessing clinical outcome over a -to -month period or longer. , this article reviews the experimental challenges that can be performed relatively early in drug development for the treatment of copd in order to obtain preliminary signals of safety and efficacy in humans. these challenge models are representative of the local inflammatory response caused by an exacerbation of copd; however it is important to note that these models do not reflect the actual exacerbation milieu. the models chosen are those models that have successfully been used to date in copd drug development. depending on the dose given during inhalation, these challenge models may also cause local and systemic inflammation, thus making them ideal for assessing the inflammatory processes in the lungs during an exacerbation and the potential therapeutic benefit of novel agents, as they mimic the local inflammatory response in the lung during an exacerbation. lipopolysaccharide (lps) is a macromolecular cell wall surface antigen of gram-negative bacteria. it is made up of three components: the o antigen (or o polysaccharide) side chain, the core oligosaccharide, and the lipid a moiety. lps is an extremely biologically active substance and has been used for many years in preclinical and clinical research, due to its role in activating many transcription factors. in the serum, lps binds to a lipid-binding protein, which facilitates the association between lps and cd on the cell membranes. this in turn facilitates the transfer of lps to the trl /md complex ( figure ) . this triggers a signaling cascade in macrophage lineage and endothelial cells, resulting in the secretion of proinflammatory cytokines and nitric oxide, and the activation of complement and the coagulation systems that contribute to characteristic features of inflammation, and with excessive stimulation, "endotoxic shock." in monocytes and macrophages, lps triggers the production of powerful inflammatory mediators including cytokines (eg, interleukin [il]- , il- , il- , tumor necrosis factor [tnf]-α and platelet-activating factor), which stimulate production of prostaglandins and leukotrienes. in addition, lps activation results in enhanced macrophage phagocytic and cytotoxic activity. activation of alternative complement pathway factors c a and c a induce histamine release, and affect neutrophil chemotaxis and accumulation. kinin activation releases bradykinins and other vasoactive peptides, which cause hypotension. the release of these mediators and subsequent systemic response make lps a powerful research tool in evaluating inflammatory pathways. healthy subjects inhaling endotoxin show a systemic and pulmonary inflammatory response, recruiting neutrophils and macrophages to the lung tissue. inhalation of nebulized doses (up to µg) of lps via a dosimeter in healthy volunteers, leads to an increase in temperature, blood c-reactive protein (crp), blood and sputum neutrophils, blood monocytes and lymphocytes, and blood and sputum proinflammatory mediators, including: il- , tnfα, myeloperoxidase (mpo), matrix metalloproteinase- , il- , il- β, monocyte chemotactic protein- , and macrophage inflammatory protein- β. , bronchial segmental instillation induces an early phase response ( - hours), resulting in a statistically significant increase in neutrophils, tnf, il- β, il- r antagonist, il- , and granulocyte colony-stimulating factor. neutrophils, macrophages, and monocytes increase - hours post instillation. , intranasal lps challenge may be the least invasive and best tolerated model. clinical symptoms are minimal; however, very little or no data have been published to date using this model. further validation of the intranasal model needs to be performed to compare it to the lps inhalation challenge model, to better understand the relevance of the lps-triggered nasal inflammation to the phenomena that occur in the central and distal airways in copd. many of the effects of exogenous lps can be blocked by medications. in one study, pretreatment with oral prednisolone or cilomilast had no effect on the local lps-induced inflammatory response in the lung; pretreatment with prednisolone alone significantly inhibited the lps-induced crp response. cilomilast attenuated the increase in crp, but not significantly. similarly, in another study, subjects who received simvastatin - mg demonstrated a reduction in neutrophils, mpo, tnfα, matrix metalloproteinase- , - , and - in the bronchoalveolar lavage fluid (balf), as well as a reduction in plasma crp, versus placebo. hohlfeld et al used lps to show that roflumilast reduced the influx of total cells, neutrophils, and eosinophils into the airways of healthy subjects after segmental challenge with endotoxin, with statistical significance. it is important to remember that inhaled lps challenge is a model of acute neutrophilic inflammation and not a model of copd. the model can be used to understand the biological effects of compounds that inhibit the lps pathway (table ) . ozone (o ) is a major component of urban environmental air pollution. it is formed in the troposphere from primary precursor pollutants. in the presence of light, no is cleaved by sunlight to no figure ). in epidemiological studies, o levels have been associated with exacerbations of asthma, copd, and pneumonia. [ ] [ ] [ ] experimental o exposure in healthy human subjects is known to elicit a reversible impairment in lung function, as well as acute proximal airways neutrophilic inflammation, and an increase in the concentration of several cytokines and mediators of inflammation within the airways. in the first reported study of the inflammatory effects of low-level o exposure ( ppb o for . hours) in healthy volunteers, there were statistically significant increases in polymorphononuclear neutrophils, prostaglandin e , lactate dehydrogenase, il- , α -antitrypsin, and decreased phagocytosis via the complement receptor. this is similar to a more recent study with low-level exposure to o at ppb for . hours, in which there were increased airway neutrophils, monocytes, and dendritic cells, as well as modifications of the expression of cd , hla-dr, cd , and cd on monocytes. in another study examining whether circulating cd b plays a role in the inflammatory response following inhaled o exposure, volunteers underwent controlled exposure to o ( ppb for hours) and to clean air on two separate occasions. induced sputum collected from subjects exposed to o revealed marked neutrophilia, and increased expression of mcd on airway macrophages and monocytes. circulating cd b levels also predicted the magnitude of the airway neutrophil response following inhaled o exposure. a number of different classes of therapeutic agents have been studied in the o challenge model in healthy volunteers. therapeutic classes include corticosteroids (administered orally and by inhalation) and nonsteroidal anti-inflammatory drugs. more recently, studies investigating the effects of cxc chemokine receptor (cxcr) , antagonists have been reported. [ ] [ ] [ ] [ ] [ ] holz et al conducted a double-blind, double-dummy, placebo-controlled, three-period crossover study. eighteen healthy subjects, who had been shown at screening to produce more than a % increase in sputum neutrophils in response to exposure to ppb o , were randomly assigned to receive alternating single orally inhaled doses of fluticasone mg, mg of prednisolone orally, and placebo at least weeks apart. compared with placebo, pretreatment with inhaled or oral corticosteroids resulted in a significant reduction of sputum neutrophils, by % and %, respectively. this was associated with statistically significant reductions in sputum mpo, by % for inhaled corticosteroids and % for oral steroids. compared with placebo, there was a mean reduction in sputum il- levels, by % after inhaled corticosteroids and % after oral corticosteroids. similar results were obtained in a study conducted by alexis et al. in subjects receiving fluticasone . mg and mg, sputum neutrophilia was significantly reduced by % and %, respectively. the following inflammatory markers were also significantly reduced in a dose-dependent manner in subjects receiving fluticasone: cd b, mcd , cd , cd , hla-dr, and cd on sputum monocytes. serum clara cell protein levels (a marker of pulmonary damage) were significantly increased post-o challenge. schelegle et al pretreated healthy volunteers with indomethacin, which was shown to significantly reduce o -induced decrements in fev and forced vital capacity, when compared to no drug or placebo. this was associated with reductions in subjective symptoms of cough, shortness of breath, and throat tickle on indomethacin treatment, suggesting that cyclooxygenase products play a partial role in subjective symptoms associated with o exposure. hazucha et al demonstrated a similar reduction of o -induced decrements in fev and forced vital capacity following singledose treatment with either mg or mg of ibuprofen compared to placebo, which was associated with reduced post-o balf levels of prostaglandin e , thromboxane b , and il- . sch is a novel, selective, oral cxc chemokine receptor antagonist that inhibits neutrophil activation and modulates neutrophil trafficking in animal models. eighteen healthy o responders (. % increase in sputum neutrophils) underwent o challenge tests ( ppb, hours intermittent exercise) hour after the last treatment dose, and sputum was induced at hours postchallenge following sch treatment. the o challenge resulted in statistically significantly lower sputum neutrophil counts ( . × ml − ) compared with prednisolone ( . × ml − ; p = . ) or placebo ( . × ml − ; p = . ). comparable results were obtained for total cell count, percentage of sputum neutrophils, and for il- and myeloperoxidase in sputum supernatant. post challenge, sch inhibited neutrophilia in peripheral blood, but significantly less than in sputum. gaga studies in copd have been conducted using o concentrations in the range of - ppb with . - minutes of exercise every minutes, aiming to maintain a ventilatory rate of between - l/min. [ ] [ ] [ ] in a study of nine subjects with copd and ten age-matched controls, gong et al found an increase in specific airway resistance and a statistically significant decrease in fev in the copd subjects versus the age-matched controls. in summary, o challenge has been well tolerated in healthy volunteers and in older subjects, as well as subjects with asthma or copd. the o -challenge model potentially provides critical decision-making data in understanding whether new compounds have the desired biological effect in healthy volunteers and patients with copd; hence it can de-risk decisions to move forwards into large phase ii safety and efficacy trials. rhinovirus is responsible for the common cold and is spread through infected respiratory secretions from one person to another. human rhinovirus (hrv) replicates at °c- °c and thus has been linked to upper airway infections, where mucosal surfaces are cooler. evidence exists that hrv is not limited to the upper airways. gern et al hrv binds to intracellular adhesion molecule (icam)- , the major hrv receptor. the low-density-lipoprotein receptor binds to a minor group of hrv (hrv ). the gene for icam- maps to human chromosome , as do the genes for a number of other picornavirus receptors. several studies have shown induction of proinflammatory genes implicated in neutrophil activation following rhinovirus induction of bronchial epithelial cells (eg, il- regulated by nf-κβ signaling pathways and groα). [ ] [ ] [ ] rhinovirus infection of epithelial cells leads to the release of proinflammatory cytokines and chemokines including il- and il- . chemokines attract inflammatory cells (eg, neutrophils, eosinophils). these cells release toxic products, stimulating mucus production and leading to tissue damage, with possible long-term loss of lung function. some mediators, such as endothelin- , have a direct effect in causing bronchoconstriction and vasoconstriction, resulting in airflow obstruction and impaired gas exchange. healthy subjects, subjects with asthma, and subjects with allergic asthma have been intensively studied in clinical trials inoculating them with rhinovirus or other rhinovirus serotypes. [ ] [ ] [ ] these studies demonstrated that rhinovirus infection of the lower airways is common after experimental inoculation. several studies looking at causes of exacerbations in copd have shown that viruses account for up to % of exacerbations, and that hrv is numerically the most important virus type. , [ ] [ ] [ ] [ ] [ ] [ ] figure depicts the total viral and hrv exacerbation rate in seven exacerbation studies. other viruses associated with acute exacerbations of copd are coronavirus, influenza a and b, parainfluenza, adenovirus, and respiratory syncytial virus. , [ ] [ ] [ ] [ ] [ ] to develop a model of viral exacerbation in subjects with copd, mallia et al conducted a virus dose-escalating study infecting four copd subjects with rhinovirus. in this study, the median tissue culture infective dose (tcid ) of rhinovirus was administered by the inhaled route using a nebulizer, to elicit a copd exacerbation. although there was a decrease in fev ( %) and peak expiratory flow ( %) maximal on day , there was not a statistically significant increase in total sputum cell count or peripheral neutrophil count. symptoms of cold and lower respiratory tract symptoms, as well as lung function changes that are characteristic of viral-induced exacerbations of copd, were observed. there was an increase, although not statistically significant, in the proinflammatory cytokines il- and il- . in another study, there were significant increases in total respiratory scores in both copd subjects and submit your manuscript | www.dovepress.com dovepress dovepress healthy controls. peak expiratory flow fell by . ml in the controls (p = not significant) and by . ml (p , . ) in the copd patients. peripheral white cell counts and neutrophils increased in both groups. sputum neutrophil count also increased in the copd patients but not in the controls. more recently, both the upper and lower symptom scores were found to be significantly higher in the copd subjects. in this study, ten of the infected copd subjects met the criteria defining an exacerbation of copd. subjects in the copd group demonstrated significant decreased peak expiratory flow from baseline, while those in the control group did not. the blood and sputum showed a significant increase in peripheral neutrophils in the copd subjects but not the controls. however, crp was significantly increased in both groups on day . subjects in the copd group had significantly increased sputum neutrophil elastase levels over baseline on days and , as well as il- levels on day . sputum neutrophil elastase levels were significantly higher in subjects with copd, compared with control subjects on days - . to date, only one laboratory has published on this model and as such, the data should be interpreted with caution. the main advantage of this model is that it will give a clear understanding and insight into the molecular and cellular inflammatory processes that take place during a viral-associated exacerbation of copd. there are no published data to date on the effect of pharmacological interventions in this model. the rhinovirus challenge model has the potential for use as a preclinical and clinical tool to identify and investigate novel drug targets and establish whether new therapeutic agents have potential clinical utility. these include (but are not limited to) targets against soluble icam- and thus inhibit interaction of hrv with icam- , , inhibitors of rhinovirus rna-dependent rna polymerases d, activators of retinoic acid-inducible gene , inhibitors of rhinovirus capsid protein vp- and inhibitors of different rhinovirus proteases (eg, a, c). , currently, this is the only model that reflects the underlying mechanism of viral exacerbations of copd. the use of challenge models has the potential to significantly inform early decision making, before embarking on longterm phase ii and iii clinical trials designed to test interventions that may treat or avert exacerbations of copd. although challenge models are good predictive models of acute exacerbations of copd, there are ethical considerations associated with inducing exacerbations in subjects with copd. therefore, safety boards may be advised to only consider subjects with mild copd for inclusion in these studies. healthy subjects could be used as an alternative, when determining the effects of a developmental drug's mechanism of action on lung inflammation. the lps and o models have been used successfully in healthy subjects. [ ] [ ] [ ] , , [ ] [ ] [ ] as these models represent the local inflammation in the lung during an exacerbation, and test the mechanism of action of potential novel drugs, these data may be used for future decision making. the lps challenge model is the best validated model in subjects with copd. pharmaceutical companies have used lps models as a means to establish proof of principle early during the clinical development process, because they are relatively simple to perform and have few adverse events. this model is cost effective because it can be conducted in healthy subjects, who are easy to recruit. lps challenge data, whether positive or negative, can provide valuable information to aid investment decision making. one disadvantage of the lps model is that it is a model of lung inflammation, but not of the disease state, thus preclinical validation of the developmental drug's effects on lps pathways is essential. for anti-inflammatory targets that are involved in the tolllike receptor , nf-κβ pathway, the lps challenge model is the model of choice. despite the longstanding knowledge and understanding of the adverse effects of o on pulmonary biology, the use of o as a challenge model to assess the potential of new drugs for the prevention of acute exacerbations in copd, is relatively new. the model has been shown to be safe and to have few side effects in healthy volunteers, and in patients with asthma and copd. , , , additionally, it is reliable and reproducible. it has been used successfully to generate biological effect and systemic effect for fluticasone and the cxcr antagonists, sch and sb- . , a limitation of the o model is that it has yet to be determined whether inhibition of neutrophilia translates into clinical benefits for patients with copd. preliminary data indicate that inhibition of the neutrophil response following o challenge may be associated with beneficial changes in system scores obtained in subjects with copd. challenge with rhinovirus to elicit mild exacerbations in subjects with copd appears to be safe and well tolerated, but only a few copd subjects have been exposed to this model. the observation that fev does not always return to baseline after inducing an exacerbation in copd subjects may call to question the feasibility of using the challenge in a broader population of patients with copd, in addition to raising ethical considerations. this remains an exciting model with a great deal of potential, as rhinovirus models are good predictive models of viral-induced acute exacerbations of copd. in order for pharmaceutical companies to succeed in the copd arena, innovative approaches to clinical trial design and conduct are required that will generate critical, highquality proof of efficacy and biologic target engagement data to support early investment decision making, early drug termination, and facilitation of better-informed decisions regarding those drugs in which proof of effect has been clearly demonstrated. challenge models in copd, which expose fewer individuals for short periods of time to eliciting agents, may serve as surrogate of potential efficacy and thus may help early decision making and reduction in clinical development timelines. global initiative for chronic obstructive lung disease. global strategy for the diagnosis, management and prevention of copd chronic obstructive pulmonary disease (copd) fact sheet key facts effect of pharmacotherapy on rate of decline of lung function in chronic obstructive pulmonary disease: results from the torch study a pooled analysis of fev decline in copd patients randomized to inhaled corticosteroids or placebo salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease for uplift study investigators. mortality in the -year trial of tiotropium (uplift) in patients with chronic obstructive pulmonary disease bacterial endotoxins: chemical structure, biological activity and role in septicaemia lps/tlr signal transduction pathway dose-response relationship to inhaled endotoxin in normal subjects inhaled endotoxin in healthy human subjects: a dose-related study on systemic effects and peripheral cd + and cd + t cells local inflammatory responses following bronchial endotoxin instillation in humans evaluation of oral corticosteroids and phosphodiesterase- inhibitor on the acute inflammation induced by inhaled lipopolysaccharide in human available at: http:// clinicaltrials.gov/ct /show/nct ?term=nct &ran k= roflumilast attenuates pulmonary inflammation upon segmental endotoxin challenge in healthy subjects: a randomized placebo-controlled trial blunting airway eosinophilic inflammation results in a decreased airway neutrophil response to inhaled lps in patients with atopic asthma: a role for cd health effects of air pollution air pollution in asthma: effect of pollutants on airway inflammation committee of the environmental and occupational health assembly of the ozone-induced airway inflammation in human subjects as determined by airway lavage and biopsy exposure of humans to ambient levels of ozone for . hours causes cellular and biochemical changes in the lung low-level ozone exposure induces airways inflammation and modifies cell surface phenotypes in healthy humans responses of subjects with chronic obstructive pulmonary disease after exposures to . ppm ozone validation of the human ozone challenge model as a tool for assessing anti-inflammatory drugs in early development fluticasone propionate protects against ozone-induced airway inflammation and modified immune cell activation markers in healthy volunteers indomethacin pretreatment reduces ozone-induced pulmonary function decrements in human subjects sch , a novel cxcr antagonist, inhibits ozone-induced neutrophilia in healthy subjects no effect of inhaled budesonide on the response to inhaled ozone in normal subjects effects of cyclo-oxygenase inhibition on ozone-induced respiratory inflammation and lung function changes sch , a novel treatment option for severe neutrophilic asthma sb- , a novel cxcr selective antagonist, inhibits ex-vivo neutrophil activation and ozone-induced airway inflammation in humans short-term respiratory effects of . ppm ozone exposure in volunteers with chronic obstructive pulmonary disease the acute effects of . ppm ozone in patients with chronic obstructive pulmonary disease response to ozone in volunteers with chronic obstructive pulmonary disease responses of older men with and without chronic obstructive pulmonary disease to prolonged ozone exposure detection of rhinovirus rna in lower airway cells during experimentally induced infection the major human rhinovirus receptor is icam- members of the low density lipoprotein receptor family mediate cell entry of a minor-group common cold virus role of p mitogen-activated protein kinase in rhinovirus-induced cytokine production by bronchial epithelial cells rhinovirus induction of the cxc chemokine epithelial-neutrophil activating peptide- in bronchial epithelium low grade rhinovirus infection induces a prolonged release of il- in pulmonary epithelium quantitative and qualitative analysis of rhinovirus infection in bronchial tissues rhinoviruses infect the lower airways lower airways inflammation during rhinovirus colds in normal and in asthmatic subjects respiratory viruses in exacerbations of chronic obstructive pulmonary disease requiring hospitalisation: a case-control study infections and airway inflammation in chronic obstructive pulmonary disease severe exacerbations a -year prospective study of the infectious etiology in patients hospitalized with acute exacerbations of copd effect of interactions between lower airway bacterial and rhinoviral infection in exacerbations of copd viral pathogens in acute exacerbations of chronic obstructive pulmonary disease a one-year prospective study of infectious etiology in patients hospitalized with acute exacerbations of copd and concomitant pneumonia rhinovirus infections in chronic bronchitis: isolation of eight possibly new rhinovirus serotypes role of infection in chronic bronchitis infectious agents associated with exacerbations of chronic obstructive bronchopneumopathies and asthma attacks respiratory viruses, symptoms, and inflammatory markers in acute exacerbations and stable chronic obstructive pulmonary disease respiratory viral infections in adults with and without chronic obstructive pulmonary disease an experimental model of rhinovirus induced chronic obstructive pulmonary disease exacerbations: a pilot study an experimental model of virus induced chronic obstructive pulmonary disease exacerbation experimental rhinovirus infection as a human model of chronic obstructive pulmonary disease exacerbation comparative antirhinoviral activities of soluble intercellular adhesion molecule- (sicam- ) and chimeric icam- /immunoglobulin a molecule efficacy of tremacamra, a soluble intercellular adhesion molecule , for experimental rhinovirus infection: a randomized clinical trial genetic clustering of all human rhinovirus prototype strains: serotype is close to human enterovirus regulation of innate antiviral defenses through a shared repressor domain in rig-i and lgp for pleconaril respiratory infection study group. efficacy and safety of oral pleconaril for treatment of colds due to picornaviruses in adults: results of double-blind, randomized, placebo-controlled trials implications of the picornavirus capsid structure for polyprotein processing purification and partial characterization of poliovirus protease a by means of a functional assay acute lps inhalation in healthy volunteers induces dendritic cell maturation in vivo this review is part of a dissertation for a master's degree (rvdm) at the university of surrey, uk. editorial assistance was provided by lourdes briz and carrie lancos, medimmune, llc. sponsorship: this manuscript was sponsored by medimmune. conflict of interest: rvdm is an employee of medimmune; nam is a former employee of medimmune. submit your manuscript here: http://www.dovepress.com/international-journal-of-copd-journalthe international journal of copd is an international, peer-reviewed journal of therapeutics and pharmacology focusing on concise rapid reporting of clinical studies and reviews in copd. special focus is given to the pathophysiological processes underlying the disease, intervention programs, patient focused education, and self management protocols.this journal is indexed on pubmed central, medline and cas. the manuscript management system is completely online and includes a very quick and fair peer-review system, which is all easy to use. visit http://www.dovepress.com/testimonials.php to read real quotes from published authors.international journal of copd : key: cord- -yfh d io authors: su, yu-ching; jalalvand, farshid; thegerström, john; riesbeck, kristian title: the interplay between immune response and bacterial infection in copd: focus upon non-typeable haemophilus influenzae date: - - journal: front immunol doi: . /fimmu. . sha: doc_id: cord_uid: yfh d io chronic obstructive pulmonary disease (copd) is a debilitating respiratory disease and one of the leading causes of morbidity and mortality worldwide. it is characterized by persistent respiratory symptoms and airflow limitation due to abnormalities in the lower airway following consistent exposure to noxious particles or gases. acute exacerbations of copd (aecopd) are characterized by increased cough, purulent sputum production, and dyspnea. the aecopd is mostly associated with infection caused by common cold viruses or bacteria, or co-infections. chronic and persistent infection by non-typeable haemophilus influenzae (nthi), a gram-negative coccobacillus, contributes to almost half of the infective exacerbations caused by bacteria. this is supported by reports that nthi is commonly isolated in the sputum from copd patients during exacerbations. persistent colonization of nthi in the lower airway requires a plethora of phenotypic adaptation and virulent mechanisms that are developed over time to cope with changing environmental pressures in the airway such as host immuno-inflammatory response. chronic inhalation of noxious irritants in copd causes a changed balance in the lung microbiome, abnormal inflammatory response, and an impaired airway immune system. these conditions significantly provide an opportunistic platform for nthi colonization and infection resulting in a “vicious circle.” episodes of large inflammation as the consequences of multiple interactions between airway immune cells and nthi, accumulatively contribute to copd exacerbations and may result in worsening of the clinical status. in this review, we discuss in detail the interplay and crosstalk between airway immune residents and nthi, and their effect in aecopd for better understanding of nthi pathogenesis in copd patients. the lungs are vital organs involved in gas exchange between the vascular system and the external environment, thus they are greatly exposed to the environment-derived microorganisms, including fungi, viruses, and bacteria. the bronchial tree and parenchymal tissues of the lungs, that until recently were considered as sterile, are colonized by phylogenetically-diverse microbes. the genera of firmicutes, bacteroidetes, and proteobacteria are the most common phyla identified and represent % of the total bacterial microbiome in the healthy airway ( , ) . the majority of the lung microbiota belongs to the normal flora that play an important role in the pulmonary epithelial integrity, colonization resistance, and homeostasis of the immune system in the respiratory tract ( ) . a small fraction of them are, however, potentially pathogenic microorganisms that are involved in a variety of lung diseases, as exemplified by the genus haemophilus. non-typeable haemophilus influenzae (nthi) is a gram-negative coccobacillus that are commonly residing in the human airways. uniquely and yet unexplained, nthi is a commensal when colonizing the nasopharynx or throat, but pathogenic in the lower airways triggering a robust inflammatory response [for reviews see ( , ) ]. nthi is considered a potential opportunistic pathogen as it frequently infects the lower respiratory tract of lungs with structural damage as a consequence of non-infectious lung diseases or mechanical injuries. moreover, nthi occasionally causes bronchitis and pneumonia ( ) . in addition, lower airway colonization by nthi has been associated with disease progression of several more or less non-infectious lung diseases such as bronchiectasis ( ), cystic fibrosis ( ) , interstitial lung diseases ( , ) , but mostly in chronic obstructive pulmonary disease (copd) ( , ) . copd is a severe inflammatory lung disease characterized by airflow limitation with a range of pathological changes. both genetics and environmental factors trigger the onset of copd, however, microbes including nthi play an important role in the acute exacerbations. this review describes the disease progression of copd in the context of host immuneinteractions linked to nthi, and the overall impact in disease exacerbation. copd is the third leading cause of morbidity and mortality worldwide expected to affect more than million people by ( , ) . according to the global initiative for chronic obstructive lung disease (gold), copd is a pulmonary disease that is manageable, but significant exacerbations and co-morbidities may, however, contribute to the overall severity in individual patients ( ) . copd is characterized by chronic airflow limitation of the peripheral airways with a range of pathological changes in the lung that are not fully reversible, and usually become progressively worse over time. the progression of copd is associated with an abnormal inflammatory response of the lung to noxious particles or gases. from a pathological point of view, copd comprises a group of pulmonary abnormalities related to the inflammatory reaction of the airways, alveoli, and pulmonary vessels ( ) ( ) ( ) ( ) . these include (i) pulmonary emphysema, (ii) chronic bronchitis, and (iii) disease in the small airways. the pulmonary abnormalities progressively affect all parts of the lung, resulting in increased resistance of the conducting airways and thus chronic airflow obstruction that eventually will lead to a declined lung function. emphysema is a permanent loss of elastic lung recoil caused by elastolytic destruction and enlargement of the alveolar wall distal to the terminal bronchioles. this consequently results in the loss of alveolar attachments to the small airways and thus limitation of airflow and gaseous exchanges. chronic bronchitis is characterized by consecutive and chronic cough with expectorations that last for more than months within years. it is associated with inflammation of the bronchial walls with increased inflammatory infiltrates, hyperplasia of goblet cells, hypertrophy of tracheobronchial submucosa, increased mucous secretion and, finally, dilatation of the airway ducts (airways of about - mm in internal diameter). the majority of the ciliated epithelium lining the airways are also either compromised or dysfunctionnal, and may be replaced by nonciliated squamous epithelial cells. small airway diseases, on the other hand, involve hyperplasia and metaplasia of mucosal glands and goblet cells, hypersecretion of intraluminal mucus, macrophage bronchiolitis, and accumulation of lymphocytes in the small bronchioles (airways of ∼ mm or less in diameter and terminal bronchioles). in addition, distortion, fibrosis, stenosis, tortuosities, hyperplasia, and hypertrophia of the small airway smooth muscles also contribute to the loss of elasticity in the lung parenchyma. although copd mainly affects the lungs, it also produces significant extrapulmonary consequences as a results of an escalated inflammatory response orchestrated by airway cells and immune mediators ( , ) . the comorbidities are commonly seen in copd patients despite the actual mechanism responsible for the systemic inflammation remains to be elucidated. the development of copd is multifactorial, with cigarette or tobacco smoking being the primary cause of copd ( , ) . other risk factors that may promote the onset and progression of copd includes prolonged occupational exposure to particles/gases in mining and textile industries, air pollution resulting from biomass combustion, and bronchial hyperresponsiveness ( , , ) . the variability of copd incidences among smokers is also explained by a genetic predisposition, such as α -antitrypsin deficiency and cutis laxa [mutation of the elastin gene (eln)] ( , ) . the α -antitrypsin deficiency is caused by deleterious homozygous mutations in serpina which contributes to - % of copd cases. the deficiency results in increased neutrophil elastase activity that ultimately leads to the degradation and collapse of the alveoli. importantly, meta-analyses of genome-wide association studies (gwas) and other genotyping studies have revealed that multiple single nucleotide polymorphism (snps) in at least genes from different pulmonary genomic loci are associated with copd susceptibility ( ) ( ) ( ) ( ) . airway epithelium exposed to cigarette or tobacco smoke has compromised tight junctions and delayed epithelial wound repair ( ) ( ) ( ) ( ) . moreover, cigarette smoke alters basal cell differentiation and subepithelial extracellular matrix (ecm) composition, and thus causes airway remodeling (i.e., goblet cell hyperplasia and small airway squamous metaplasia) ( ) ( ) ( ) . this results in mucus hypersecretion, impaired mucocilliary clearance, and airway obstruction. tobacco or cigarette smoke also enhances proliferation and ecm deposition by activating the extracellular signal related kinase (erk) and the p signaling pathway ( ). the alteration of major ecm components are widespread in all lung compartments in copd patients with a total increase of type i and iii collagens, fibronectin, and laminin in parallel with reduced concentrations of proteoglycans, perlecan decorin, versican, biglycan, tenascin and elastin ( , ). cigarette induced-overexpression of matrix metalloproteases (mmps- , , , , , and ) and elastase has also been reported, and may contribute to the airway tissue destruction and fibrosis ( - ). in addition, harmful volatile chemicals derived from cigarette smoke (i.e., acetaldehyde, acrolein, and crotonaldehyde) are prone to form carcinogen adducts with dna and various proteins (i.e., apoliprotein e and surfactant protein a). they also dysregulate airway epithelial ion transport, disrupt the phagocytic activity of airway phagocytes, and diminish the airway surface liquid volume ( - ). numerous proteomics and transcriptomic analyses have unveiled the crucial impact of cigarette or tobacco smoke and copd disease progression on airway gene expression ( , ). the differential gene expression studies were done using copd experimental models or clinical samples [i.e., bronchial epithelial cells, sputum, plasma, blood, and bronchoalveolar lavage (bal) fluid]. collectively, most of the altered genes are involved in oxidative stress, xenobiotic metabolism, antioxidant responses, dna repair, ecm remodeling, inflammatory responses, and immune defenses, which the latter two are our major interest of discussion in this review. the omics data aid in the increased knowledge of molecular mechanisms in copd. they may reflect the dynamic response and attempts by the airway epithelial cells to repair the cytotoxic injury primarily triggered by inhaled irritants. deleterious and irreversible alterations occurring and interfering with the airway epithelial homeostasis and immune defense may promote copd development and progression. notably, gene alterations in phagosomal-and leukocyte transendothelial migration pathways (ltm) are significantly correlated with the level of t cells and airway obstruction in smokers ( ). the ltm, however, were found to be further dysregulated in copd patients. hence, in addition to clinical/physiology variables, a number of gene products with significant differential gene expression may be targeted as specific proteomic signatures or biomarkers for early copd detection, patient monitoring, disease subgrouping, and finally treatment selection ( , ). tobacco or cigarette smoke regulates airway gene expression via two main mechanisms, by altering the status of (i) chromatin remodeling, and (ii) dna methylation of the target genes (figure ) ( - ). chromatin remodeling is a result of a disrupted balance in histone acetylation/deacetylation ( ). excessive activation of more than transcription factors including nf-κb, and lipoprotein peroxidation products (peroxinitrite, acrolein, and hne from tobacco smoking) contributes to such anomaly. nf-κb is a key inflammatory and redox-sensitive transcription factor that plays a direct role in cigarette smoke-induced airway inflammation. nf-κb has been described as a "smokesensor" due to its sensitive activation by tobacco residues ( ). stimulation of multiple signaling cascades [p mitogenactivated protein (mapk) kinases, mitogen and stress-activated kinase (msk ), protein kinase c zeta (pkcζ), and iκb kinase (ikk) complex (ikkα, ikkβ, and nemo)] by tobacco residues promotes the activation and nuclear translocation of transcription factor nf-κb rela/p ( , - ). this is followed by a complex formation of nf-κb/cbp-p [coactivator, crebbinding protein (cbp) or cbp/p ] at target dna sequences. it should be noted that cbp/p also has intrinsic histone acetyltransferase (hat) activity. subsequent acetylation and phosphorylation of the subunit p in the nf-κb/cbp-p complex by the activated msk /pkcζ-signaling pathways (and other different kinases), and cbp/p , respectively, are required for the full activation of nf-κb ( , , ). this enhances the dna binding affinity of the complex. histones h and h in the chromatin complex of target sequences are then being acetylated (histone h at lys ; h at lys and lys ) and phosphorylated (histone h at ser ) by the subunit cbp of the nf-κb/cbp-p complex, and the activated msk and pkcζ, respectively. the hyperacetylated core histones, however, fail to be neutralized or deacetylated by a dysfunctional histone deacetylase (hdac ). peroxinitrite nitrates the tyrosine residues of the hdac and causes inhibition of activation and reduced expression of the protein. of note, peroxinitrite is a by-product generated from the immune cell-derived nitrite oxide (no) and reactive oxygen species (ros) of cigarette smoke ( , ). cigarette or tobacco smoke disturbs the dna methylation status of target genes through several mechanisms. firstly, dna damage caused by cigarette smoke stimulates the dna methyltransferase (dnmt) to actively induce cpgs methylation at the damaged site ( ). the hypermethylation is prone to introduce error of methylation in some target genes, resulting in reduced gene expression. secondly, activation of nicotine signaling pathway by tobacco smoke causes camkii/iv and erk/mapk pathway activation that subsequently induces the activity of cbp to suppress the expression of dnmt . this may result in reduced dna methylation and thus altered level of gene repression by dnmt ( - ). finally, enhanced activities of transcription factors such as hypoxia inducible factor due to the high level of carbon monoxide and hypoxia have also been reported to influence airway gene expression ( ) . consequently, the combinatorial effect from both aberrant acetylation of histone and dna methylation promotes the transformation of chromatin from a condensed structure to an activated open conformation. this facilitates irregular accessibility of dna for transcription machineries, hence figure | cigarette and tobacco smoke has several effects on gene regulation. nicotine and other compounds in the smoke alter gene expression by two pathways, firstly, chromatin remodeling (left) and secondly, dna methylation (right). chromatin remodeling involves activation of kinases signaling pathways, activation and nuclear translocation of transcription factor nf-κb (rela/p ), and complex formation with cbp/p on specific dna sites. cbp/p is intrinsically a histone acetyltransferase (hat). subunit p is further phosphorylated at ser and ser , respectively, by msk and pkcζ, whereas cbp acetylates p at lys . the phosphorylation and acetylation enhance the interaction within the nf-κb/cbp/p complex while stabilizing the dna binding of nf-κb. the complex of nf-κb/cbp/p then modifies the histones through cbp-mediated acetylations of histone h (at lys ) and h at lys and lys , and phosphorylation of h at ser by msk and pkcζ. this results in the structure change of chromatin, from a condensed structure (repressed) to an activated open conformation. the transcription of target genes is therefore increased. in the second mechanism, several side effects resulting from cigarette smoking such as dna damage and nicotine signaling could trigger the hypermethylation or decreased methylation of target dna. this may lead to dna methylation anomalies and thus altered dna expression. resulting hypoxia due to high concentrations of carbon monoxide also contributes to altered gene expression. the aberrant gene expression by cigarette smoke mostly occurs in pro-inflammatory genes with resulting increased production of inflammatory mediators, and amplified inflammation in the copd lung upon exposure. irregular gene expression by various cell types in the airway. the mechanisms reported are responsible for increased expression of nf-κb-dependent proinflammatory gene products [i.e., il- β, il- , il- , ccl- cyclooxygenase (cox)- , and mip- /cxcl ] in both pulmonary structural cells (bronchial, small airway, and alveolar epithelial cells) and immune cells (alveolar macrophages), increased vegf and inos in nasal fibroblasts and lymphocytes (jurkat t cells), respectively, and decreased activity of antioxidant transcription factor nrf and α -antitrypsin in bronchial epithelial cells ( , , , , - , [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . these may contribute to the anatomical anomalies in the airway and excessive inflammatory responses among smokers during the course of copd. copd is associated with chronic inflammation in the peripheral airways orchestrated by both innate and adaptive immune responses that are interconnected via dendritic cells ( ) . increasing numbers of inflammatory cells (neutrophils, macrophages, t and b lymphocytes, mast cell, eosinophils, and dendritic cells) and inflammatory mediators are accumulated in the airway lumen/wall in the lung parenchyma ( , ) . these immune cells and inflammatory mediators can hence be detected in the sputum and bal fluid of copd patients. the level of accumulation is positively correlated with disease severity. an increasing number of studies using animal models and clinical tissues have reported the nature of excessive airway inflammatory responses in copd. despite this, the heterogeneity in symptoms progression among copd patients remain unexplained. the overall mechanism of copd inflammatory immune response is depicted in figure . the first line of defense in the lung-the innate immunity and inflammasome lung structural cells (epithelial and endothelial cells, fibroblasts, and airway smooth muscle cells) are activated by inhaled irritants through the stimulation of several pattern recognitions receptors (prrs), with toll-like receptor (tlr)- being reported as the key player in most of the inflammatory responses ( ) ( ) ( ) ( ) . this causes an increased expression and release of an array of pro-inflammatory mediators and chemokines through the oxidative pathway by the activated bronchial epithelial cells and immune cells (alveolar macrophages). the inflammatory mediators [(interleukin (il)- β, il- , il- , il- , c-x-c motif chemokine ligand (cxcl) , granulocyte-macrophage colonystimulating factor (gm-csf), granulocyte-colony stimulating factor (g-csf), tumor necrosis factor (tnf)-α, fibroblast growth factor and (fgf / ), transforming growth factor (tgf)-β , c-c motif chemokine ligand (ccl) , ccl , and thymic stromal lymphopoietin (tslp)] act on recruited immune cells and resident cells to initiate a series of innate immune responses ( , ( ) ( ) ( ) ( ) ( ) . meanwhile, activated alveolar macrophages, which are usually patrolling the lung parenchyma, further release more pro-inflammatory mediators and chemokines [il- β, il- , il- , il- , tnf-α, ccl , cxcl , cxcl (ena- ), cxcl , cxcl , cxcl , ccl , leukotriene b (ltb )], ros, elastolytic enzyme [matrix metalloprotease protein (mmp)- ,− , and− ; and cathepsin-k,-l, and -s], gm-csf, and g-csf ( , , ) . the enhanced levels of ccl and cxcl result in recruitement of blood monocytes expressing ccr and cxcr (receptors for ccl and cxcl , respectively), to the lung and differentiate locally into macrophages. interestingly, there are higher expression levels of the ccr and cxcr found on blood monocytes in copd subjects ( ) . this may explain the rapid recruitment and excessive accumulation of monocyte-derived interstitial macrophages in the lung tissue of copd patients ( , ) . upregulation of neutrophil chemoattractors (ltb , cxcl , cxcl , il- , and tnf-α) induces a massive migration of circulating neutrophils into the lung parenchyma ( ) . the transmigration of blood neutrophils occurs through adherence of the granulocytes to e-selectin of endothelial cells that is found to be upregulated in copd ( ) . this results in airway neutrophilia in several copd patients ( , , ) . the recruited neutrophils (to the lung) are then activated to secrete granule proteins [myeloperoxidase (mpo) and neutrophil lipocalin] while releasing its own il- for further neutrophilic recruitment and amplification of the inflammation ( ) . in addition to the macrophage-derived proteases, neutrophils also secrete serine proteases [neutrophil elastase (ne), cathepsin g, proteinase- , mmp- , and mmp- ] that are associated with serious alveolar destruction in emphysema ( ) . the protease activity may be further enhanced in conditions with genetic deficiencies or suppressed expression of α -antitrypsin by tobacco smoke. in addition, ne, cathepsin g, and proteinase- are involved in the stimulation of mucus secretion from submucosal glands and goblet cells, resulting in airway mucus hypersecretion and airway obstruction in copd ( ) . the nlrp (nlrp : nucleotide-binding domain, leucinerich-containing family, pyrin domain-containing- or nod-like receptor protein ) inflammasome is a cytosolic multi-protein complex (consisting of the inflammation sensor protein nlrp , adapter protein asc, and the effector protein caspase- ) ( ). the nlrp inflammasomes are involved in the copd airway inflammation by regulating the production of pro-inflammatory cytokines il- α, il- β, and il- . these cytokines are important for neutrophil survival and activation of t helper (th) cells ( ) . interestingly, local airway nlrp inflammasome activation is positively correlated with acute exacerbations and lower airway microbial colonization in copd patients ( , ) . moreover, in an elastase-induced emphysema model, the nlrp inflammasome is activated in addition to hyperproduction of mucin muc ac by diesel extract particles, extracellular atp, and inflammatory protein s ( , ) . the adaptive immunity is initiated at a later stage, and is recognized by the increased number of t and b lymphocytes and pulmonary dendritic cells. dendritic cells are the major antigen-presenting cells (apc) in the airways, and link the innate and adaptive immunity. circulating dendritic cells (expressing receptors ccr and ccr ) are recruited to the airway via dendritic chemoattractants ccl and ccl released by activated airway epithelial cells in response to cigarette smoke ( , ) . dendritic cells act by endocytosis of inhaled irritants that subsequently are processed into antigen peptides during maturation and further migration to lymph nodes. uncommitted t lymphocytes are thereafter primed by the presented antigen. these important cells are activated by il- released from dendritic cells for subsequent commitment into antigen-specific t cell lineages, i.e., t helper (th ; cd + cd + ) cells, whereas immature dendritic cells in the airway promote th differentiation ( , ) . interestingly, in copd patients, pulmonary th and cytotoxic t cells (tc; cd + cd + ) express more cxcr receptors compared to healthy individuals ( , ) . this enhances their migration toward chemoattractants cxcl , cxcl , and cxcl that are actively released by alveolar macrophages in copd subjects. activated cd + t cell subset type (tc ) releases perforins, granzyme b, and tnf-α to induce alveolar cells apoptosis, contributing to the emphysema ( ) . in parallel, pulmonary th t cells are activated by alveolar macrophage-derived il- and il- to secrete il- a and il- causing neutrophilic inflammation ( , ) . inflammatory cytokines are also released by type figure | non-typeable h. influenzae-dependent immune responses in the lower airway of copd patients result in inflammation. airway epithelium exposed to cigarette or tobacco smoke display an increased permeability with compromised tight junctions, and airway remodeling (goblet cell hyperplasia and small airway squamous metaplasia). cigarette smoke causes the activation of airway epithelium and alveolar macrophages. the activated airway structural and resident immune cells release an array of chemotactic factors responsible for recruitment of inflammatory and immune cells to the lung. activated epithelium produces tgf-β and fgf that triggers the production of ecm molecules by fibroblasts. increased deposition of ecm causes progression of fibrosis and air flow limitation. the chemokines cxcl and il- , and ltb attract the circulating neutrophils through the receptors cxcr and blt , respectively. meanwhile, cxcl and ccl targeting the receptors cxcr and ccr on blood monocytes are also released. recruited blood monocytes differentiate into macrophages in the airway tissue. activated alveolar macrophage and epithelium cell also release inflammasome ( l- β and il- ) for neutrophils survival and activation of helper t cells th . the chemokine il- are released by macrophages to attract t helper cell subset th , and ilc . both th and ilc will release il- and il- that will act on the alveolar epithelium to release cxcl and il- for enhanced recruitment of neutrophils, resulting in neutrophilic inflammation. activated neutrophils are thereafter degranulated and release myeloperoxidase (mpo), lipocalin, neutrophil elastase (ne), cathepsin-g (cg), proteinase- (prot- ), and matrix metalloprotease (mmp) and . the granulated products are proteolytic and elastilolytic to aveolar, causing alveolar destruction and emphysema. in addition, ne, cg, and prot- are also targeting goblet cells and submucosal glands to induce hypersecretion of mucus. dendritic cells carrying the receptors ccr and ccr are recruited to airway tissue via chemottractants ccl and ccl . the dendritic cells uptake the antigen (smoke residues), and present the antigens to the naïve t cells at lymph nodes. uncommitted t lymphocytes are thereafter primed to the presented antigen and activated by il- derived from dendritic cells (professional antigen presenting cells; apc). mature/activated t cells expressing receptor cxcr are chemotactic toward cxcl , cxcl , and cxcl and are recruited to the lung tissue. cytotoxic cd + t cell subtype tc releases perforin and granzyme b resulting in epithelial apoptosis contributing to emphysema progression. for the humoral immune response, b cells are activated by th , enter the circulation via high-endothelial venule (hev)-like vessel and transported to lung tissue, and organized into lymphoid follicles at peripheral airway. b cell-derived plasma cells from lymphoid follicles release iga, and secreted into airway lumen as secretory iga (siga) via the polymeric immunoglobulin receptor. mucosal antibodies play an important role to eradicate pathogens and noxious antigens via immune exclusion. however, the airway defense by siga is diminished by nthi iga protease that degrade the antibodies. tlr and tlr of the airway phagocytes and epithelium following exposure to cigarette smoke are not responding to p and los of nthi. this results in defective phagocytosis and delayed bacterial clearance from the airway. the suppressed tlr induction in t cells has also lead to th predominant immune response, with low production of ifn-γ and reduced t cell-mediated immune killing of nthi. moreover, nthi downregulates foxp of tregs and thus impairs the anti-inflammatory/pro-inflammatory balance of tregs. the extensive immunosuppressive activity by tregs diminishes the response of effector t to (continued) figure | nthi stimulation. lastly, plasma cells from copd patients fail to produce nthi-specific antibodies and compromised immunoglobulin class switching. the impairment of the host immune response in copd toward nthi infection are labeled in blue. in total, nthi infection in copd lung adversely reduces the production of il- β, il- , il- , cxcl- , il- , tnf-α, antimicrobial peptide (amp), and ifn-γ. this may explain the inefficient eradication of airway pathogens in copd patients whereby persistent nthi infection concomitantly escalates the inflammation and thus exacerbation in copd. innate lymphoid cells (ilc ) ( ) . the ilcs are involved in the homeostasis of lung immunity and are regulated by epithelially produced il- and tslp ( , ) , and are further stimulated in response to cell damage. the accumulation of b lymphocytes in the peripheral airway and within lymphoid follicles is associated with airway autoimmunity in the progression of copd ( ). airway tissue damage in conjunction with impaired t-regulatory cells (tregs), both related by cigarette smoke, contributes to the formation of autoantibodies against airway components. autoantibodies against elastin, epithelial, endothelial, carbonylated, and citrullinated proteins are found in the circulation of copd patients ( ) ( ) ( ) ( ) ( ) ( ) . the generation of autoantibodies might activate plasma exudate-derived complement components resulting in a chronic inflammation, and consequently damage of the airways with emphysema progression ( ) ( ) ( ) ( ) . from a physiological point of view, a modulated inflammatory process is important for a protective and optimal immune response. however, the prolonged airway inflammation in copd as a results of impaired homeostasis leads to serious side effects since it amplifies the tissue damage and impairs the local immune defenses. the abrogated local immune system may make the airways of copd patients susceptible for opportunistic or recurrent infections by viruses and bacteria that in turn might exacerbate the disease. acute exacerbations of copd (aecopd) are episodes of acute symptom worsening that usually are associated with both respiratory (increased airway inflammation) and non-respiratory (system inflammation/co-morbidities) effects ( ) ( ) ( ) . the typical symptoms of an aecopd include increased production of purulent sputum, dyspnea, cough, wheezing, and symptoms of a cold that may last from days up to weeks ( , , ) . it commonly occurs in patients with advanced copd and results in additional therapy based on the level of exacerbations. exacerbations are classified in three levels according to gold. there is the mild disease that can be treated with short acting bronchodilators (sab); moderate disease with sab combined with antibiotics and/ or oral corticosteroids; and finally severe exacerbations with acute respiratory failure which requires emergency room visit and eventually hospitalization ( , ) . aecopd is a complex yet multifactorial consequence of copd. most of the exacerbations could be triggered by infectious (up to %) or non-infectious agents (∼ %) (aecopd with known etiology), whereas up to % of cases are of unknown etiology ( , ) . respiratory tract infections are the major causes for aecopd with known etiology and are mainly attributed to infections by viruses, bacteria, and atypical bacteria (not detected with conventional gram-staining) ( , , ) . non-infectious causes of aecopd include air pollution, environmental factors, meteorological effects, and comorbidities of the patients, all of which are partially contributing to copd exacerbations ( , , ) . respiratory viral infections are often the primary cause in the infection-dependent aecopd, and virus was identified as single or multiple infecting strains from up to % of copd patients with exacerbations recorded between years - ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) . the most common infecting viruses are, by far, human rhinovirus, influenza virus a, and respiratory syncytial virus, whereas parainfluenza virus, coronavirus, echovirus, human metapneumovirus, and adenovirus are considerably rare. bacterial infections contribute to an average of % of infective acute exacerbations with a prevalence being reported ranging from to % ( , , ( ) ( ) ( ) . the most commonly pathogenic bacterial species isolated from the lower airway of copd patients during aecopd are nthi, moraxella catarrhalis, streptococcus pneumoniae, staphylococcus aureus, pseudomonas aeruginosa, and klebsiella pneumoniae ( , , , , ( ) ( ) ( ) ( ) . it has been suggested that infection with new strains of the infecting species, rather than a new species, is highly associated with an increased risk of exacerbation ( , , ) . atypical bacteria that cause exacerbations are chlamydia spp., legionella pneumophilia, and mycoplasma spp. in contrast to viral infections that are diagnosed in - % of copd patients with stable disease and increase to . - % during copd exacerbations, bacterial colonization in the airways are more common with the same species during both stable disease ( - %) and exacerbations ( . - %) ( , , , , , ( ) ( ) ( ) ( ) . hence the precise or direct role of bacterial infection as the primary cause in triggering aecopd remains controversial although a significantly increased bacterial load is observed during exacerbation in several patients. this further suggests that bacteria might be more involved as secondary invaders after an initial viral infection. viral infections have been reported to cause several physiological changes in the lung that in turn facilitates secondary bacterial invasion. the mechanism of bacterial superinfection has been described for h. influenzae, s. pneumoniae, s. aureus, and many other airway pathogens ( ) ( ) ( ) . firstly, viral infections destroy the tight junctions of the airway epithelial barrier while inducing epithelium apoptosis. this results in the onset of airway epithelium lining repair whereby the sloughed off dead cells would become a rich nutrient source for growth of infecting bacteria. the damaged epithelium lining also enables bacterial adherence to the exposed basement membrane and ecm. secondly, the demolished ciliated clearance as a result of the virus-damaged airway epithelium lining further promotes bacterial colonization and subsequent epithelial transmigration into deeper tissues ( ) ( ) ( ) . lastly, viral infections are also detrimental to the airway immune defense by causing degradation of antimicrobial peptides (amp), and by triggering ifn-γ secretion by immune cells. this results in suppressed macrophage and neutrophil responses to infecting bacteria, and thus enables bacterial evasion of the airway immune defense ( ) ( ) ( ) ( ) . nevertheless, viral and bacterial coinfection have greater impact in the aecopd airway inflammatory responses than bacteria or virus infection alone ( , ) . this is in parallel with the co-isolation of both respiratory viruses and bacteria from to % of aecopd patients ( , , , ( ) ( ) ( ) ( ) ( ) . infective aecopd is also attributed to impaired functions of amp, macrophages, and neutrophils triggered by inhaled irritants such as tobacco smoke. expression of microbialinduced amp (human β-defensin ) is suppressed in airway epithelial cells when exposed to cigarette smoke ( , ) . both the alveolar and monocyte-derived macrophages in patients with copd are defective in phagocytosis of bacteria such as h. influenzae and s. pneumoniae ( , ) , and in efferocytosis of apoptotic neutrophils and epithelial cells. in addition, neutrophils from copd patients are aberrant in chemotactic response with defective accuracy ( ) . all these factors contribute to the failure to resolve inflammation in copd leading to facilitated chronic microbial colonization, also during exacerbations. the low number of cultivable bacteria found in healthy individuals previously led to the conclusion that healthy and normal lungs are virtually sterile. this hypothesis is currently being revised, since the introduction of s rdna based molecular diagnostics has shown that even healthy lungs have a distinct microbial community, different from that seen in the upper respiratory tract ( , ) . this has led to the concept of a core human lung microbiome which can be altered in copd stable disease and during exacerbations ( ) . the role of the lung microbiome in the pathogenesis of copd by influencing host immune response has also been suggested ( , ( ) ( ) ( ) ( ) ( ) ( ) . the stability of the lung microbiome has profound impact on maintaining local immune homeostasis ( ) . according to the "vicious circle" hypothesis, airway inflammation and impaired immune defenses caused by either viral infections or irritant inhalation have ecological influence on the airway microenvironment and growth conditions that would eventually lead to dysbiosis of the lung microbiota ( , ) . the changed lung microbiome would then cause a maladaptive immunological response resulting in further inflammation and damage of the lung immune defenses, and additional alteration of the lung microbiome. the chain of events thus generates a vicious circle that contributes to copd progression and exacerbation. several studies have documented that copd progression from stable state to an exacerbation could induce microbiota shift in the lower airway (bronchioles), sputum, and throat ( , ( ) ( ) ( ) ( ) ( ) ( ) ( ) . alteration in the microbiome complexity or richness is associated with the inflammatory process and changes in ecm protein expression in the lung, as observed in copd ( , ) . declined diversity in the lung microbiome has been reported to be related to disease severity, inflammation and decreased lung functions in copd. this includes the increased emphysematous destruction, bronchial tissue remodeling, lymphoid follicle formation, elevated autoantibodies, and il- a production, and finally increased neutrophil extracellular traps (net) formation in the airway of animal models or aecopd patients ( ) ( ) ( ) ( ) . it has recently been reported that lung microbiome diversity is also associated with genetic factors. mannose-binding lectin (mbl) deficiency has also been associated with disease severity and exacerbations in patients with cystic fibrosis and bronchiectasis ( ) . however, copd patients with a genetic deficiency in mbl are less susceptible to haemophilus spp. colonization, lowering the risk of exacerbations while their lung microbiota is more diverse than normal copd patients ( ) . in this review we will focus on nthi, one of the dominant genera that is relatively abundant in the total copd-dependent lung microbiome, due to its role of infection in copd immunological responses ( , , - , , - ) . the microbiology of h. influenzae has recently been reviewed in detail by our group and others ( , , ) . it is a gramnegative coccobacillus that commonly colonizes the human nasopharynx, and is typed as capsulated (type a-f) or nonencapsulated strains (nthi). h. influenzae may cause both invasive and mucosal disease ( ) . since the introduction of capsule polysaccharide conjugate vaccines against type b (hib), nthi dominate, followed by capsule type f (hif) ( , ) . mucosal infections, including acute otitis media, sinusitis, and exacerbations in copd, are nowadays mainly associated with nthi. there has also been a significant shift in the epidemiology of severe invasive disease, from hib infections in small children to nthi in adults ( , ) . the most common principal infection focus by h. influenzae is now community acquired pneumonia (cap), whereas the incidence of historically common diagnoses such as meningitis and epiglottitis have significantly decreased ( , ) . patients with underlying conditions, notably copd, seem to be at higher risk for invasive infections ( ) . there is consensus that h. influenzae is one of the key bacterial pathogens involved in pathogenesis of both stable copd disease and acute exacerbations ( ) . however, the relative abundance and significance of nthi in copd varies between different studies. several factors, such as sampling methodology, choice of microbiological analysis and, if the patient has a stable disease or an exacerbation, or has been subject to previous antibiotic therapies, tend to affect the outcome of the studies ( ) . common sampling methods from the lower respiratory tract include both bronchoscopy techniques such as protected specimen brush (psb) and collection of bal fluid as well as non-invasive methods like sputum sampling ( ) . all of these methods, particularly sputum, are to some extent subject to the risk of contamination from the normal microbial flora of the oro-and nasopharynx, which might reduce their specificity ( ) . however, several studies still show a distinct association between lower respiratory tract samples and clinical parameters in copd patients, making the information valuable ( ) . cultivable bacteria are seldom found in the lower airways of healthy individuals ( ) , whereas copd patients show bacterial growth in - % of cases even during stable disease ( table ) . on top of that, several studies have shown a significant increase in the proteobacteria phylum, which includes haemophilus spp., in individuals with both stable disease and aecopd ( table ) . nthi is consistently one of the predominating bacterial species isolated in those cultures; other important pathogens include s. pneumoniae, m. catarrhalis, and p. aeruginosa ( ) . during aecopd, the bacterial load is increased even further, and nthi continues to be the predominating species ( ) . furthermore, acquisition of a new nthi strain has, in one study, been linked to the onset of aecopd ( ) . moreover, the growth and dominance of h. influenzae following rhinovirus infection was observed in the sputum microbiome of patients with copd ( ) . the chronic inflammation that characterizes copd pathogenesis causes significant changes to the pulmonary tissue. the lower respiratory tract of patients suffering from this disease is marked by epithelial denuding, hypersecretion of mucus, disproportionate phagocyte presence and imbalances in antioxidant/oxidants ( ) . this altered milieu selects for specific bacterial species that are genetically equipped to competently address these environmental stressors ( , , ) . nthi is the most common pathogen isolated from the sputum of copd patients, and the primary cause of exacerbations ( ) , indicating a unique ability to colonize and persist in the chronically inflamed lower respiratory tract. in recent years, great efforts have been made in understanding how nthi colonizes the pulmonary tissue. in addition to the regular arsenal of virulence factors associated with nthi ( ), the bacterial pathogen undergoes specific adaptations to increase its fitness in the copd setting. specific genetic islands that include ureabcefgh, lic b, hgba, iga, hmw , and hmw have been reported to be enriched in nthi strains isolated from copd patients compared to commensal nthi ( ) . these genes are involved in raising the ph of the environment, lipooligosaccharide (los) synthesis, iron uptake, immune evasion, and attachment to host tissue. the validity of these findings is strengthened by previous work identifying upregulation of many of the same bacterial gene products during growth in copd sputum ( ) . moreover, peroxiredoxinthioredoxin, an antioxidant enzyme, was found to be one of the most enriched proteins in nthi during growth in copd sputum, suggesting that the bacteria upregulate oxidative stress-countermeasures when facing oxidative imbalances in the diseased lung ( ) . oxidative stress resistance has previously been shown to be vital for nthi survival in infection models ( ) . in a seminal investigation by pettigrew et al., wholegenome sequencing (wgs) was conducted to follow the in vivo adaptation of nthi to the copd environment over time ( ) . several interesting findings were reported in this work. firstly, the median duration of persistence by the pathogen was found to be days, but it could persist in patients for up to as many as , days. secondly, slipped-strand mispairing-mediated phase variation was identified as the primary genetic adaptation to the niche. poignantly, the genes affected by the regulation mechanism encoded for (among others) the hmw adhesins, los biosynthesis, and iron uptake, that is, the same processes identified in the previous studies as important for copd adaptation ( , ) . thirdly, and somewhat surprising, it was observed that a very limited number of genes were gained/lost during persistent colonization, meaning that selection for strains that thrive in the inflamed lower airways occurs at the very onset of colonization. finally, the authors reported that genetic changes occurred in of the investigated vaccine antigens during persistent infections, a fact that might be taken into consideration for potential vaccine development against nthi. another virulence factor that has been reported by murphy and co-workers to play a pivotal role for nthi survival in copd settings is iga-protease, a hydrolytic enzyme that cleaves secretory iga (siga) antibodies in the mucosal epithelium ( ) ( ) ( ) . four genes encode for the same number of different variants of the endopeptidase with various cleavage site specificities: two igaa (igaa and igaa ) and two igab (igab and igab ). the igaa is present in all nthi whereas igab is present in ∼ % of the strains ( ) . the igab gene has been reported to be more prevalent in copd exacerbation-causing strains, although the in vivo expression levels did not differ from asymptomatic colonization strains that also carried the gene ( ) . however, iga-protease b and b have been found to promote the intracellular survival of nthi in human epithelial cells, providing a secondary function (in addition to hydrolysis of iga antibodies) that could facilitate nthi growth in inflamed environments ( ) . while a majority of the persistent nthi strains that dwell in copd patients continuously express one or more variants of the enzyme, it has recently been found that a phase variation to an off-state can occur via slipped-strand mispairing over time ( ) . this suggests that during certain conditions, there is a fitness benefit in not expressing iga in the airways of copd patients, albeit the specifics of this process are currently unknown. another interesting aspect of nthi colonization of copd patients is with regard to biofilm formation ( ) . nthi strains that colonize the eustachian tube causing otitis media are known to build up biofilms in situ ( ) . however, strains isolated from copd patients tend to have significantly diminished ability to form biofilm compared to invasive strains or those isolated from otitis media patients ( ) , suggesting that this mechanism is not important for survival in the copd niche. as biofilms tend to protect the bacterial community from external assaults, these findings could indicate that the hypermucoid milieu in the copd airways is severely impaired in its ability to deliver an apt immune response for optimal clearance of residing microorganisms. in light of this impairment, biofilm formation might not be necessary for nthi to persist in this particular environment. infections with nthi have also been shown to reduce cellular levels of e-cadherin, a protein required for tight junction formation and epithelial cell integrity in human cells ( ) . considering that perturbations in the epithelial cell barrier caused by the loss of e-cadherin is a common symptom of copd, nthi-mediated exacerbations likely contribute to this step of copd pathogenesis. the subsequent denuding of the epithelium could facilitate microbial colonization of the basal lamina, a well-established virulence mechanism employed by nthi and other pathogens ( ) . it is currently unknown which bacterial virulence factor(s) that induce the reduction of e-cadherin levels in the host. in summary, investigations from recent years show that the environment of the lower respiratory tract of copd patients selects for nthi strains that can upregulate adhesins, modify los biosynthesis pathways, increase antioxidant stress responses and cellular invasion strategies, and, finally, trigger tolerance against acidic ph. these important colonization mechanisms thus provide researchers with viable targets for developing novel therapies. nthi is a commensal in the nasopharyngeal site but is often associated with strong inflammatory responses in the lower respiratory airways, especially in patients with copd, bronchiectasis, cystic fibrosis, pneumonia, or idiopathic pulmonary fibrosis ( , ) . colonization and subsequent infection of nthi in the lower airways of copd patients elicits episodes of immune responses orchestrated by both the innate and adaptive immunity. nthi infection is thus commonly associated with inflammation that is mainly mediated by transcription factor nf-κb-dependent production of proinflammatory mediators. the activation of nf-κb requires induction of cross-signaling networks and cascades via activation of prrs (pattern recognition receptors) of host innate immune cells ( ) . unresolved or prolonged (chronic) inflammation or failure to restore the homeostatic inflammatory status potentially contributes to exacerbations. this is clearly shown in murine copd simulation models with nthi-triggered inflammation ( - ). mice exposed to nthi lysates display inflamed airways loaded with increased levels of inflammatory mediators and phagocyte infiltrates. moreover, multiple exposures to bacterial lysates which may represent a chronic nthi infection caused extremely high infiltration of phagocytes and lymphocytes in the airways of this particular mouse model. in addition, the airway walls of the infected animals were also thickened due to increased collagen deposition (fibrosis) that reflects the typical copd features. the host immune response and specific interactions during nthi infection in copd is summarized in figure . the epithelium and alveolar macrophages are predominant cell types in the airway compartment. they comprise the first line of defense in the cellular immune response against potential inhaled pathogens and antigens. the sensing of bacteria, and particularly nthi in the lower airways is initiated via prrs expressed on innate immune cells and endothelium in addition to epithelial cells ( ) ( ) ( ) . tlrs are prrs that sense stimulation by nthiderived pathogen-associated molecular patterns (pamps), and play a primary role in initiating effector cellular responses and intracellular signaling for nf-κb activation ( ) . among the different tlrs, most of the studies on nthi infection have by far been focused on tlr and . lipoproteins including nthi p , and los are potent immunomodulators for activation of tlr and tlr , respectively, and has been described in several studies on airway epithelial cells and alveolar macrophages ( ) ( ) ( ) ( ) . interaction of nthi lipoprotein p with tlr on human epithelial cells [type ii alveolar a and human middle ear epithelial cells (hmee)] causes nf-κb-dependent activation via two distinct tlr-signaling pathways, that is, the nf-κb translocation-dependent, and -independent pathways ( ) . the nf-κb nuclear translocation-dependent pathway requires activation of nf-κb-inducing kinase ikk complex. in the second pathway, the mkk / -p mapk signaling cascade is recruited for direct nuclear phosphorylation, and thus activation of nf-κb. the branching of both pathways may occur at the tgf-β activated kinase (tak ) signaling junction. nthi stimulation via tlr and downstream activation of p mapk/nf-κb-dependent pathways result in expression of cox- and prostaglandin (e ) (pge ) that promote inflammatory responses ( ) . tlr stimulation by nthi los also contributes to the activation of nf-κb via two signaling pathways, the primary activating pathway of myd cascade and the alternative pathway of toll/il- r domain-containing adapter-inducing interferon-β (trif). both pathways activate nf-κb through phosphorylation and degradation of inhibitor iκbα ( , ) . nthi-tlr signaling mediates an effective innate immune response that leads to upregulation of tnf-α, il- β, il- , macrophage-inflammatory protein (mip)- α, mip- , and neutrophil infiltration in the airways of mice. the tlr response promotes efficient pulmonary clearance of bacteria in tlr expressing animals compared to cd /tlr knockout mice ( , ) . a recent study by jungnickel et al. revealed that, in parallel with the infection-induced pulmonary neutrophilic inflammation, nthi-dependent stimulation of both tlr and tlr in a transgenic mouse [(kras la ) with oncogenic kras allele in the lung epithelium] additionally promotes the proliferation of kras-induced early adenomatous lesion in the lung in an tlr-dependent manner ( ) . the association or role of nthi-induced airway inflammation in lung cancer progression, however, is not supported by another recent cohort study showing the lack of differences in nthi specific-antibodies between cancer-and non-cancer copd patients ( ) . lastly, dectin- and the epidermal growth factor receptor (efgr) pathway also have proinflammtory effects upon interaction with nthi ( , ) . activation of the dectindependent proinflammatory response requires nthi-induced phosphorylation of the dectin- hem-immunoreceptor tyrosinebased activation motif (hemitam) ( ) . direct activation of efgr in alveolar cells and hmee by nthi-derived egflike factor has been shown to contribute to nf-κb activation. the efgr-dependent nf-κb activation is mediated via an nf-κb nuclear translocation-independent pathway, which involves both mkk / -p and pi k/akt signaling pathways ( ) . surprisingly, the interaction of efgr and nthi also results in negative regulation and suppression of the induction of tlr via the src-mkk / -p α/β map kinase-dependent signaling cascade, and this in turn may facilitate nthi infection ( ) . the actual components of nthi that exhibit the egf-like factor activity have, however, yet to be defined. the efgrdependent negative regulation of tlr may thus suggest a novel mechanism targeted by nthi for immune evasion by attenuating the responses of host prr, despite the contradicted role of efgr in proinflammatory and innate immune responses of the airway epithelium ( ) . nthi infection also upregulates the nrlp -inflammasome during nthi-induced inflammation in the airway epithelium and alveolar macrophages, leading to increased secretion of il- β and il- , and thus neutrophilic influx to the lung ( ) . some of the endogenous inflammatory mediators that are produced in response to nthi infection, including tnf-α, il- α, and tgf-β , may act synergetically with nthi on the airway epithelial and immune cells. the synergetic interaction drives a positive feedback loop to amplify the nf-κb transcriptional activity on proinflammatory genes and further augments airway inflammation. the synergetic activation of nf-κb by nthi and tnf-α in hmee and normal human bronchial epithelial (nhbe) cells occurs via nf-κb nuclear translocation-dependent and independent pathways. the latter pathway involves mapk/extracellular signal regulated kinase kinase kinase (mekk )-dependent activation of mapk kinase / -p mapk pathway ( ) . however, the synergetic action of nthi with tgf-β is mediated by another mechanism which involves smad / -protein kinase a (pka)-p -dependent signaling cascade. the pathway components, pka and p , phosphorylates residue ser and acetylates lys of the nf-κb subunit p , respectively. this results in enhanced dna-binding activity of nf-κb ( ) . the synergetic action of nthi with both tnf-α and tgf-β enhances the production of tnf-α, il- β, and il- from airway epithelial cells and interstitial polymorphonuclear infiltrates. recently, it has been reported that co-infection of human rhinovirus and nthi on the airway epithelial cells (nhbe cells and the beas- b cell line) also results in synergetic induction of ccl and il- , albeit the exact mechanism remains to be elucidated ( ) . of note, activated macrophages also release increased concentrations of tnf-α and il- α ( ) , further enhancing the inflammatory synergetic effect of surrounding immune cells. finally, il- α acts synergetically with nthi to upregulate the expression of amp β-defensin (defb- ) via the p /mapk pathway ( ) . of note, il- α could also act individually to upregulate the expression of defb- via the src-dependent mek / -erk / signaling pathway ( ) . taken together, the synergetic action may aid in the expansion of the inflammatory response and in some cases worsen the clinical outcome. alveolar macrophages located in the air-parenchyma interface are the primary professional phagocytes in the lung ( , ) . these cells are responsible for infection eradication through its phagolysosomal machinery while releasing a plethora of inflammatory cytokines and chemokines for promoting a local inflammatory response and recruitment of neutrophils. neutrophils are the first responder cells recruited from circulation to the airway for efficient killing of pathogens through an array of microbicidal strategies ( , ) . during nthi lung infection, both alveolar macrophages and neutrophils are the main innate immune cells involved in the pulmonary bacterial clearance through phagocytosis. they are also an important source of cytokine secretion required for induction of other immune cells and enhanced bacterial killing. eradication of nthi by alveolar macrophages involves adhesion or contact, phagocytosis and phagolysosomal processing of bacteria, in addition to secretion of tnf-α. phagocytic clearance of nthi by alveolar macrophages is orchestrated through actin polymerization, plasma membrane lipid rafts, and phosphatidylinositol -kinase (pi k) signaling cascade upon induction of macrophage prrs by nthi ( ) . interestingly, in response to nthi infection, human alveolar macrophages, and blood neutrophils produce extensive amount of intracellular and extracellular ros as a component of the antimicrobial defense. this leads to the formation of macrophage and neutrophil extracellular traps (mets and nets, respectively), with co-expression of mmp- for enhanced bacterial killing ( , ) . nevertheless, the overexpression of mmps may adversely result in a protease imbalance and contribute to alveolar emphysematous destruction and bronchiectasis in copd ( ) . moreover, excessive endogenous ros production could also introduce airway oxidative stress that is detrimental by causing chronic inflammation and tissue damage in the lung, and thus contributing to the copd exacerbation ( , ) . the net formation is elicited mainly by nthi los in addition to other haemophilus pamps ( ) . several studies by king et al. have revealed that t cellmediated adaptive immune responses against nthi airway infection in patients with idiopathic bronchiectasis and copd has been predominated by a th /tc response ( ) ( ) ( ) . the activated t cells produce reduced level of the cd ligand and ifn-γ, and increased levels of tnf-α, il- , and il- , as well as altered igg subclass production by plasma cells. it is to be noted that the th /tc -mediated immune response is less effective in suppressing nthi infection. redirecting the th /tc -mediated immune response to th /tc dominant (which is more protective) by adding the th /tc mediators (cd ligand and ifn-γ) has helped to restore the t cellmediated immune killing of nthi ( ) . however, a separate study in a copd mouse model by lu et al. reported that nthi infection causes increased production of airway type interferon ( -ifn) ( ) . it was further reported that dna of nthi acts as a pamp in stimulating the sting/tbk /irf pathway, and thus the production of -ifn. the impact of the bacterial dnainduced -ifn in host immune/inflammatory response, which may potentially induce a th /tc response requires further investigations. copd patients also have abnormally higher number of treg cells, myeloid-derived suppressor cells (mdsc), and exhausted effector t cells (pd- + ) than healthy individuals ( , ) . cigarette smoke-induced anti-inflammatory activity of tregs in a copd model is further suppressed by nthi infection. the pathogen causes downregulation of foxp (biomarker of tregs), and thus impairs the anti-inflammatory/pro-inflammatory balance of tregs ( , ) . this may lead to the extensive immunosuppressive activity by tregs on the proliferation of nthi p -specific effector t cells, causing a diminished response of effector t cells to sputum il- and il- induction, and increased levels of il- and tgf-β ( , ) . recently, it has been reported that mucosal-associated invariant t cells (mait) from copd patients are more effective in response to nthi stimulation and thus produce increased levels of ifn-γ, -, to -fold more than the copd th (cd + ) and tc (cd + ) cells ( ) . however, the pulmonary mait cell immune responses are compromised in the presence of corticosteroids that are commonly used for the treatment of copd. this may potentially prone the t cell-mediated immunity to a th /tc response in copd patients treated with corticosteroids ( ) . interestingly, antigen-specific th cells from nthi-immunized non-copd mice model recognize both homologous and heterologous strains of nthi, and are able to confer protection upon adoptive transfer ( ) . however, it is unclear whether the th cell which is prone to the inflammatory response could be "trained" to counteract the nthi infection in copd patients, particularly during exacerbations. during the systemic humoral immune response in nthiinfected copd patients, greater concentrations of nthi-specific igg, iga, igm, and ige serum antibodies are produced compared to non-infected controls ( , ( ) ( ) ( ) . some of the nthispecific serum immunoglobulins are specific to p , p , and p ( , , ) . however, decreased mucosal antibodies associated with siga deficiency, or decreased total igg in the small airways have been reported in copd patients, and might be associated with disease severity ( , ) . importantly, nthi-specific mucosal siga has been found to be lower in the airways of nthi-infected copd patients than the non-colonized patients ( , ) . the epithelial polymeric immunoglobulin receptor (pigr) is essential for the generation of mucosal siga. it is, however, downregulated in copd patients with a positive correlation to disease severity and increased level of tgf-β ( ) . the combinatorial effects of downregulated plgr and elevated tgf-β contribute to an impaired mucosal iga immunity in copd patients. a mouse model lacking the pigr ( −/− ) is therefore devoid of siga and are susceptible to airway stimulation by an nthi lysate resulting in increased inflammation and airway neutrophilia. interestingly, introduction of exogenously added siga mitigated the airway inflammation ( ) . nthiinfected copd patients with greater airway inflammation have also decreased nthi-specific mucosal igg in the bal fluid compared to the non-colonized patients ( ) . interestingly, the phenomenon with decreased nthi-specific antibodies seems to be restricted to the airways, since the specific serum antibodies are not affected. therefore, the reduced mucosal igg is unlikely to be associated with hypogammaglobulinemia (igg deficiency), despite the latter was reported as a contributing factor in nthi infection ( ) . decreased airway iga might be attributed to the expression of iga proteases by nthi. the bacterial iga protease degrades the local airway iga during airway colonization to avoid immune exclusion by siga ( , ) . reduced mucosal antibodies might promote host immune evasion and resistance to complement-mediated killing of nthi, thus enable persistent colonization of nthi in the airways of copd patients, in addition to a plethora of various other virulence mechanisms ( , , ) . in a cohort study of stable copd patients, augmented airway inflammation and plasma fibrinogen, but not systemic inflammation, were found to be constantly correlated with the increased bacterial load ( ) . higher numbers of nthi has a greater impact than s. pneumoniae and m. catarrhalis in triggering inflammatory responses as measured by the augmented levels of inflammatory cytokines in sputum including il- , mpo, and l- β. the increased inflammatory response in affected patients is potentially attributed to the persistent colonization of nthi in the lower airway ( , ) . the compromised innate immune response in copd, particularly the decreased microbicidal activity, has been regarded as one of the culprits for persistent airway colonization by nthi, and is highly associated with copd exacerbations (figure ). whilst the role of macrophage extracellular traps (met) for killing of nthi remains unknown, it has been reported that blood neutrophils and net from copd patients are defective in the killing of planktonic or biofilm/net-entrapped nthi, respectively ( , , ) . a series of studies by berenson et al. revealed that alveolar macrophages derived from copd patients are basically dysfunctional in eradication of nthi ( , ( ) ( ) ( ) . intriguingly, tlr and tlr expressed on alveolar macrophages from copd patients are intrinsically unresponsive to the potent immunomodulatory lipoprotein p and los, respectively. this causes decreased los/p -induced expression of tlrs, reduced nf-κb nuclear activation and consequently diminished il- , tnf-α, and il- β responses by alveolar macrophages from copd patients. the compromised tlr expression and signaling potentially contribute to the defective complement-dependent and independent phagocytosis of nthi. the defective phagocytosis is greater for nthi than for m. catarrhalis, and correlates with disease severity. interestingly, the phagocytosis disability was not detected in monocyte-derived macrophages in copd. in contrast, however, taylor et al. reported that monocyte-derived macrophages from copd patients are also defective in phagocytosis of nthi and s. pneumoniae. the author also suggested that the defective monocytederived macrophages are not attributed to the alteration in cell surface tlr or tlr expression, macrophage receptor with collagenous structure (marco), cd , cd or the mannose receptor ( ) . the unresponsive tlr and tlr in copd alveolar macrophages to nthi lipoprotein and los might be explained by the recently reported phenomenon of tlr tolerance ( ) . repetitive stimulation of copd alveolar macrophages with the same tlr ligands, pam csk and lps desensitizes the tlr and tlr , respectively, and generates tlr tolerance. moreover, the repetitive tlr stimulation further reduced the production of tnf-α, ccl , and il- without affecting the constantly augmented level of il- and il- in alveolar macrophages. this may provide alternative explanations for diminished immune responses against the recurrent/repetitive infection by nthi. the intrinsically reduced expression of tlrs in copd patients may also contribute to the impaired pulmonary immune response thus facilitating nthi persistent colonization. expression of tlr or tlr are found to be lower on sputum neutrophils, alveolar macrophages, nasal epithelium, and t cells in copd patients despite high concentrations of il- and mmp- ( ) ( ) ( ) ( ) . the lack of the more protective th /tc immune response in copd patients against nthi infection might be attributed to upregulated antagonists (a , irak-m, and myd s) of the myd /irak/mapk signaling pathway in copd t cells ( ) . it should be noted that the myd /irak/mapk pathway is required for expression of tlr in th , whereas production of ifn-γ in th /tc is tlr -dependent via the tlr /trif/ikke/tbk signaling pathway. the antagonists prevent the nthi los-induced tlr expression in th and tc and thus a reduced secretion of ifn-γ. in addition, unusual high numbers of tregs in copd patients have also contributed to effector t cell dysfunction or a th /tc predominant immune response ( ) . however, freeman et al. reported that tc (cd + ) cells from copd patients have increased expression of tlr , tlr , tlr , tlr , and tlr / as well as tc cytokines (ifnγ and tnf-α) compared to healthy individuals that may imply the auto-aggressive response of lung tc cells in copd lung inflammation ( ) . however, the copd tc cells can only be stimulated by ligands for tlr / (pam csk ) yet tolerant to other agonists, indicating the dysfunctional tlrs or tlr tolerance on t cells despite their high level of receptor expression. inversely, peripheral blood neutrophils isolated from copd patients have increased expression of tlr , tlr , and nlrp ( , ) . nevertheless, the increased tlrs expression might not improve the microbicidal ability of copd peripheral neutrophils probably due to the inaccurate responses to cytokines ( ) . in addition, certain types of snps (snps) in tlr and tlr have also been associated with decreased lung function, enhanced inflammatory responses and increased immune cell infiltration in copd ( ) . interestingly, the diminished il- responsiveness of copd alveolar macrophage to nthi infection has a strong association with the carriage of tlr (t c) polymorphism instead of tlr (arg gln), tlr (thr ile; asp gly), and tlr (t c) ( ) . the carriage of tlr (t c) is also positively correlated with diminished lung function. of note, the activation of tlr -signaling cascade in pro-inflammatory cytokine response requires stimulation from microbial dna ( ) . the microbicidal malfunction in both innate and adaptive immune cells is also potentially linked to the deleterious effect of tobacco smoke, the major risk factor for copd. it has been reported that, exposure of tobacco or cigarette smoke can impair phagocytosis/engulfment of nthi by alveolar macrophages isolated from copd patients ( , ) . moreover, the chemical exposure also suppressed the tlr-induced tnfα, il- , and il- production in copd alveolar macrophages that have been pre-stimulated with tlr , , or ligands (pam csk , lps, or phase i flagellin, respectively), or whole nthi bacteria ( ) . this may potentially delay the macrophagedependent bacterial clearance. the suppressive effect of cigarette smoke in macrophage-dependent phagocytosis is due to the suppression of the pi k signaling cascade which is required for optimal phagocytic activity and movement ( ) . meanwhile, the cigarette smoke also inhibits the activation of the p -erk signaling pathway and p /nf-κb, thus dampens the nthi losinduced cytokine production of copd alveolar macrophages ( ) . the diminished alveolar macrophage responsiveness could also be related to anticholinergic agents used by copd patients that results in lower concentrations of nthi-induced tnfα ( ). nevertheless, the impaired phagocytosis of nthi by copd alveolar macrophages could be improved in the presence of nuclear erythroid related factor and microrna mir- ( , ) . interestingly, in addition to the constant exacerbated inflammatory effect observed in different murine model studies, gaschler et al. observed a rapid pulmonary clearance of nthi in mice upon exposure to cigarette smoke, and this was positively correlated with an increased neutrophilia in the animal bal fluid ( , ( ) ( ) ( ) . however, in other copd animal studies, cigarette smoke also impaired the il- production that has a potential anti-bacterial activity while delaying the airway clearance of nthi ( ) ( ) ( ) . interestingly, il- might play a protective role in copd exacerbation as supplementation of il- manages to restore the homeostasis of airway immune response and improve nthi clearance ( ) . the increased airway neutrophilia might be due to the enhanced production of pulmonary il- triggered by cigarette smoke ( , , , ) . this may imply the important microbicidal role of neutrophils (neutrophilia) in compensating the copd-or cigarette smoke-associated dysfunctional alveolar macrophages ( , ) . however, such compensation may not be adequate to provide optimal immune defense to eradicate persistent nthi lower airway colonization, since the cigarette smoke also has profound suppressive effect on the host adaptive immunity, thus constantly risking the copd patients to episodes of exacerbation and relapsed infection. in adaptive immunity, cigarette smoke impairs the antigen-specific b and t cells responses to nthi infection. it suppresses the secretion of ifnγ and il- by nthi-specific t cells. antibody production by b cells has also been attenuated, with lower levels of specific anti-p antibodies and compromised igg , igg a, and iga class switching ( , ) . a recent and some previous cohort studies revealed that the level of airway antimicrobial cathelicidin (hcap /ll- ) in copd patients increase gradually from the stable disease to exacerbation states ( , ) . moreover, higher levels of cathelicidin are positively associated with nthi airway colonization, sputum neutrophilia, and higher concentrations of il- , particularly in the nthi-infected copd patients. of note, cathelicidin and other amps play important roles in the innate immune defense against different pathogens and persist immunomodulatory properties ( ) ( ) ( ) . ironically, it is plausible that the increased level of cathelicidin could diminish or alter the balance in lung microbiota, and the immune/inflammatory response. this might contribute to the "vicious circle, " thus considerably increasing the risk for nthi infection during copd exacerbations ( , ) . moreover, the microbicidal property of cathelicidin could be compromised by the inflammatory conditions in the airway, such as low ph, or the effect of cigarettes that causes peptide citrulination and modification ( , ) . finally, expression of amps (human beta defensin and s a ) by copd airway epithelium in response to nthi infection, is also disturbed by cigarette smoke. the insulted airway cells have also a reduced expression of tlr and il- , and impaired nthi-induced nf-κb activation ( , ) . thus, a large body of evidence exists on the deleterious effects of tobacco smoke. antibiotic treatment of aecopd has been shown to significantly reduce the risk of treatment failure, especially for in-patients with severe exacerbations and patients requiring intensive care ( ) . the efficacity of antibiotic treatment for out-patients with exacerbations is less clear ( , ) . recommendations on which empirical treatment to use for aecopd varies between different countries, but common antimicrobial agents that are frequently used as definitive therapy against nthi include aminopenicillins (with or without a beta-lactamase inhibitor), tetracyclines, trimethoprimsulfamethoxazole, and fluoroquinolones. in addition, the clinical and laboratory standards institute (clsi) has developed clinical breakpoints for the macrolides azithromycin and clarithromycin ( ) , whereas the european committee on antimicrobial susceptibility testing (eucast) have not set any clinical breakpoints against this class of antibiotics due to lack of clinical data ( ) . one study shows that nthi frequently develops resistance to macrolides during prolonged treatment and that treatment failure may occur, making fluoroquinolones more reliable for eradication in copd-patients ( ) . as for aminopenicillins, resistance is also common, with up to - % of nthi isolates expressing beta-lactamases and an additional - % of the isolates having amino acid substitutions in penicillin-binding protein (pbp ), which reduces their susceptibility to these agents ( , ) . the fraction of isolates expressing beta-lactamases has been stable during the last years, whereas an increase has been seen in isolates displaying altered pbp ( , ) . this is worrisome, since some of these amino acid substitutions also confer resistance to third generation cephalosporins ( ) . moreover, there seems to be a correlation between isolates expressing altered pbp and increased invasiveness. studies have shown that strains that express a mutated pbp with certain key amino acid substitution have a significantly higher rate of invasion of bronchial epithelial cells compared to strains with a wild type pbp ( ) . however, when such mutated pbp was cloned into a susceptible wild type strain, invasion efficacy did not increase, suggesting that pbp is only indirectly linked to invasion ( ) . besides using antibiotics for acute management of copd exacerbations, some studies have considered the use of continuous prophylactic antibiotics in the management of patients with copd ( ) . there is some evidence that continuous administration of macrolide antibiotics would prevent future exacerbations in a selected population of the most severely ill patients, but a cochrane review revealed no support for a reduced all-cause mortality or less hospital readmissions ( ) . however, more recent studies have shown a significant decrease in both the frequency of exacerbations and hospitalizations when long-term azithromycin treatment was chosen ( ) . the fact that macrolide antibiotics display not only antimicrobial effects, but also have anti-inflammatory and immunomodulatory properties, has made them interesting to use as prophylactic therapy ( ) . it has been shown that azithromycin inhibits mucus hypersecretion in the respiratory tract by significantly inhibiting tnf-α induction of the muc ac mucin secretion from human nasal epithelial cells ( ) . more specifically, it has been shown that azithromycin can reduce the nthi-dependent induction of muc ac expression by suppressing the transcription factor activator protein- ( ) . apart from affecting mucus secretion, it also seems that low-dose azithromycin has the ability to improve phagocytosis of bacteria by airway macrophages ( ) . one study showed that azithromycin concentrations that were unable to kill nthi still increased the uptake rate of the bacteria into alveolar macrophages by enhancing their phagocytic function ( ) . however, the risk of development of antimicrobial resistance limits the use of low-dose azithromycin solely for its immunological properties. this has triggered an interest in finding new macrolide substances that lack antibiotic effect and solely interact with the airway immune system ( ) . the considerable clinical problems caused by nthi with regard to copd exacerbations and otitis media has prompted the scientific community to investigate whether a vaccine can be developed against the pathogen ( , , ) . the search has been intensified due to a steady increase in antibiotic resistance and a trend of more invasive infections caused by nthi over the last decade ( ) . whereas, a highly efficient glycoconjugate vaccine has previously been developed against hib, an identical strategy cannot be employed against nthi due to the lack of a polysaccharide capsule. vaccine developments efforts have thus been concentrated on identifying nthi surface structures that are immunogenic, have low antigenic variability, and are conserved across this genetically highly heterogeneous species. several promising vaccine candidates have been identified in the last years, as excellently reviewed elsewhere ( , ). two of these antigens, fused into one protein, protein e-pila, are together with protein d currently being tested by glaxosmithkline in a phase iib proof-of-concept clinical trial (randomized, observer-blind, placebo-controlled, and multicentric) for infection prophylaxis in copd patients ( - years old) ( ) . notably, the m. catarrhalis ubiquitous surface protein a (uspa ) is also included in the vaccine so that an immune response against both exacerbation-causing pathogens could be elicited by the same preparation. this clinical study (nct ) is the only one currently being conducted on nthi (and m. catarrhalis) according to clinicaltrials.gov, and as the investigations are on-going, the results are currently unknown. due to an increase in the difficulty to treat nthi infections, an efficient and protective nthi vaccine likely considerably raises the quality of life of copd patients. since nthi-mediated exacerbations contribute to the progression of the disease and a steady deterioration of the pulmonary capacity of those patients, prevention against nthi infections potentially slows down the debilitating effect of the disease. it is therefore critical to continue this line of research until such a vaccine has been obtained. it could also be worth targeting non-conventional structures with a vaccine, such as the secreted enzymes urease and iga protease that have proven important for nthi infections in copd patients in several studies ( ) . copd is a multifaceted airway disease. several factors influence the clinical outcome of copd. importantly, the crosstalk between intrinsic factors (the stability and integrity of the airway immune response and structure in addition to hereditary factors), and the extrinsic factors (lung microbiome, viral and bacterial infections, meteorological factors, and noxious inhalation) determines the fate of lower airway opportunistic infection by h. influenzae. intriguingly, nthi has been one of the most isolated pathogens at both stable and exacerbation states of copd. such persistent airway colonization of nthi costs virulence fitness to counteract with the bactericidal effect of the host immune response. adversely, the impaired defense mechanisms in copd are not only unable to protect the lung structure from inhaled physical assaults, but they also fail to suppress nthi infection. the disoriented immune response in copd instead allows the pathogen to cause more harm and inflammation in the airways. the currently used bronchodilator and inhaled corticosteroid therapies have limited efficacy in preventing disease progression in copd. moreover, the inhaled corticosteroid therapies might have side effects that may weaken the immune response. hence, more investigations are needed to garner a more adequate knowledge regarding the variabilities in immune networking of copd. this knowledge will be an important platform for a more efficient drug design. in addition, a vaccine targeting nthi is another important approach in controlling the infective exacerbations in copd as the antibiotic treatment is also getting dampened by the emergence of nthi antibiotic resistance. y-cs coordinated and drafted the major part of the manuscript, and prepared the figures; fj participated in the literature study of virulence and vaccine research of nthi; jt prepared the review section for nthi epidemiology in copd and antibiotic studies; y-cs and kr edited and critically revised the manuscript. all authors read and approved the final manuscript. topographical continuity of 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in chronic obstructive pulmonary disease subjects relationship between azithromycin susceptibility and administration efficacy for nontypeable haemophilus influenzae respiratory infection nonantibiotic macrolides restore airway macrophage phagocytic function with potential anti-inflammatory effects in chronic lung diseases vaccines for nontypeable haemophilus influenzae: the future is now we thank the following funding agencies for their financial support during the preparation of the manuscript. they are the alfred Österlund, the anna and edwin berger, the swedish medical research council (grant number k - x- - - , www.vr.se), the physiographical society (forssman's foundation and, endowments for the natural sciences, medicine and technology), skåne county council's research and development foundation, and heart lung foundation (kr: grant number , www.hjart-lungfonden.se). the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.copyright © su, jalalvand, thegerström and riesbeck. this is an open-access article distributed under the terms of the creative commons attribution license (cc by). the use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. no use, distribution or reproduction is permitted which does not comply with these terms. key: cord- -xnos iud authors: ritchie, andrew i.; wedzicha, jadwiga a. title: definition, causes, pathogenesis, and consequences of chronic obstructive pulmonary disease exacerbations date: - - journal: clin chest med doi: . /j.ccm. . . sha: doc_id: cord_uid: xnos iud acute exacerbations of chronic obstructive pulmonary disease (aecopd) are episodes of symptom worsening which have significant adverse consequences for patients. exacerbations are highly heterogeneous events associated with increased airway and systemic inflammation and physiological changes. the frequency of exacerbations is associated with accelerated lung function decline, quality of life impairment and increased mortality. they are triggered predominantly by respiratory viruses and bacteria, which infect the lower airway and increase airway inflammation. a proportion of patients appear to be more susceptible to exacerbations, with poorer quality of life and more aggressive disease progression than those who have infrequent exacerbations. exacerbations also contribute significantly to healthcare expenditure. prevention and mitigation of exacerbations are therefore key goals of copd management. acute exacerbations of chronic obstructive pulmonary disease (aecopds) are episodes of symptom worsening that have significant adverse consequences for patients. the important causes of exacerbations include airway bacteria, viruses, and pollution; however, the interplay of these triggers must also be considered. it is recognized that defects in immunity and host defense lead to more frequent aecopds. greater frequency of exacerbations is associated with accelerated lung function decline, quality-of-life impairment, and increased mortality. furthermore, as the incidence of chronic obstructive pulmonary disease (copd) increases, exacerbations place a greater burden on health care systems, accounting for more than million unscheduled attendances per year in the united states. the direct costs of copd treatment in the united states are greater than $ billion per year, , with exacerbations estimated to account for % to % of these health care costs. exacerbations are also important outcome measures in copd, with acute treatment targeting accelerated recovery, whereas long-term maintenance therapy is designed to prevent and reduce their frequency and severity. although half of the patients treated in the community recover to their baseline symptoms by days, a study of the time course found that, despite treatment, % had still not fully recovered by weeks. moreover, in a small proportion of exacerbations, symptoms never returned to the baseline level. consequently, a substantial number of copd exacerbations can be prolonged, which culminates in greater morbidity associated with such an event. a key audit examining hospital admissions showed that more than one-quarter of patients experience another event during the following weeks. in a cohort of patients with moderate to severe copd followed up after exacerbation, % had a recurrent event within days of the first (index) exacerbation. such events are therefore complex, and an initial exacerbation seems to increase the susceptibility to a subsequent exacerbation. these recurrent events are associated with substantially increased mortality and this has driven financial incentives for health care services aiming to avoiding hospital readmission. , exacerbations definition aecopds are transient periods of increased symptoms of dyspnea, sputum purulence, and sputum volume, but they may also encompass minor symptoms of nasal blockage/discharge, wheeze, sore throat, cough, fever, chest tightness or discomfort, fatigue/reduced energy, sleep disturbance, or limited physical activity. copd exacerbations are associated with several features, including increased airway inflammation, mucus hypersecretion, and gas trapping. there is a degree of controversy over the precise definition of exacerbation events. the global initiative for chronic obstructive lung disease (gold) document aecopd definition slightly differs from this as "an acute worsening of respiratory symptoms that results in additional therapy." this definition requires the patient to seek or use treatment and is an example of a health care use (hcu) exacerbation in which the patient or clinician decides whether treatment is warranted. the disadvantage with only considering this definition is that it risks not accounting for important events in certain key scenarios; for example, those of lesser severity that do not trigger increased treatment use, where respiratory deterioration with an alternative cause is misdiagnosed, or events in resource-poor areas with a lack of access to treatment or clinicians. the alternative to an hcu definition is to measure the increase in symptoms and to classify an exacerbation when this change crosses a threshold (regardless of whether the patient receives treatment). this approach has been widely accepted in research, using several validated patient-reported outcome (pro) tools such as symptom/treatment diary cards and questionnaire tools such as the exact (exacerbations of chronic obstructive pulmonary disease tool) and cat (the copd assessment test). when implemented, it was discovered that a large number of events are unreported and untreated. studies using symptom-based definitions typically report an incidence of exacerbations that is approximately twice as high as with hcu definitions. one reason for this is that the method captures additional milder events that the hcu definition does not. although unreported exacerbations are milder than reported events, they do not seem to be inconsequential. however, the science of measuring symptoms is challenging, both in the collection of (daily) data and in their analysis. analysis challenges include defining the threshold for exacerbation, ceiling effects, and how and when to reset the baseline symptom level in the event of incomplete exacerbation recovery. two of the most extensively validated pros in exacerbation studies are the exact and cat, which seem to be valuable in the assessment of exacerbation frequency, duration, and severity and have been qualified as an exploratory end point by both the us food and drug administration (fda) and the european medicines agency (ema). a particular strength of the exact is its ability to detect unreported events, and, in the attain (aclidinium to treat airway obstruction in copd patients), comparing a long-acting muscarinic antagonist with placebo, unreported (untreated) symptom (exact)-defined events had the same medium-term health consequences as reported (treated) hcu exacerbations. moreover, the trial intervention reduced the rate of both symptom (exact)-defined and hcu events. however, a challenge with interpreting pros such as the exact tool is the discordance between hcu exacerbations and symptom (exact)-defined events, with discrepancies found in both observational studies and clinical trials. a major challenge is the heterogeneous nature of the clinical presentation, and alternative causes for acute deterioration, such as heart failure, pneumothorax, pulmonary emboli, or anxiety, must be considered. traditionally, infective exacerbations are thought to be driven by infection of the airway lumen (bronchi/bronchioles), whereas pneumonia represents alveolar infection. however, it is likely that these distinct processes overlap. a chest radiograph is not routinely performed during a copd exacerbation, and consolidation may be missed if it is early in the infective process, or through the insensitivity of the test. the latest gold guidelines define exacerbation severity by the treatment that is required. mild: treatment with short-acting bronchodilators only moderate: treated with short-acting bronchodilators plus antibiotics and/or oral corticosteroids severe: requires either hospitalization or a visit to the emergency department and may also be associated with respiratory failure. exacerbations are airway inflammatory events that are triggered by infection in most cases. respiratory viral infections are the predominant cause, although bacterial infections and environmental factors such as air pollution and ambient temperature trigger or worsen these events. , although early studies focused on bacteria as the primary cause of exacerbations, the development of highly specific molecular diagnostic techniques has highlighted the importance of viruses as key triggers for exacerbations. [ ] [ ] [ ] the primary role of different exacerbation triggers and important aspects of their interplay, including viral-bacterial fig. . overview of aecopd. egf, endothelial growth factor; ena, epithelial-derived neutrophil-activating peptide; icam- , intercellular adhesion molecule ; il, interleukin; ip, interferon g-induced protein; i-tac, interferoninducible t-cell alpha chemoattractant; gm-csf, granulocyte-macrophage colony-stimulating factor; gro, growth-regulated oncogene; mmp, matrix metalloproteinase; rantes, regulated upon activation, normal t cell expressed and presumably secreted; tgf, transforming growth factor; th, t helper; tnf, tumor necrosis factor; vegf, vascular endothelial growth factor. coinfection, deficient host response to bacteria, and the lung microbiome in exacerbation are described here (fig. ) . it has long been observed that the frequency of aecopd doubles in winter months, , with more than % of exacerbations preceded by coryzal symptoms (table ) . , , viruses earlier studies using culture-based methods underestimated the prevalence of respiratory viruses during copd exacerbations. however, with the advent of polymerase chain reaction (pcr) methods, the detection of viruses in copd exacerbations increased to % to %. the wide variations in virus detection are likely to be the consequence of whether patients were sampled at true onset of symptoms or sampling was delayed. additional factors could include variation in the range of viruses tested for, sensitivity of the assays, the study period (eg, winter vs yearlong, variation in virus epidemics; eg, respiratory syncytial virus [rsv]), population (eg, community vs inpatient, uptake of the influenza vaccine), and sampling method (eg, nasopharyngeal swabs, sputum). in studies where patients reported exacerbation symptoms at onset, there is a greater prevalence of viral infection, because viral load is higher at exacerbation onset , and may therefore be undetectable by the time patients present to hospital. , , , , , rhinoviruses are the most prevalent in most of these studies, accounting for up to % of all exacerbations. influenza viruses and rsvs are also commonly detected, being identified in up to % and % of aecopds respectively. parainfluenza viruses, human metapneumoviruses, coronaviruses, and adenoviruses are detected, but less frequently. importantly, viral aecopds are associated with more severe symptoms, greater airflow limitation, and delayed recovery compared with exacerbations where no virus is detected. , the greater incidence of rhinovirus in induced sputum, as opposed to nasal aspirates at exacerbation, further supports the theory that naturally occurring rhinovirus drive most exacerbations. although these studies have shown an association between respiratory virus infection and exacerbations, they do not prove causation because pcr detects viral nucleic acid but it cannot prove the presence of live, replicating virus. consequently, secondary causes cannot be excluded. however, in , mallia and colleagues provided novel evidence of a causal relationship between respiratory virus infection and exacerbations in patients with copd through their experimental rhinovirus infection in patients with mild copd. in their human model, they showed clearly that respiratory viruses produce symptoms that are typical of an exacerbation, confirming that respiratory viruses can infect the lower airway and contribute to inflammatory changes. chronic viral infection is another key aspect to examine when considering the role played by viruses such as rsv. although rsv infection has been seen at exacerbation, whether it alone drives the event is not entirely clear, because this virus is found incidentally within the airways of patients with copd at stable state where it is associated with increased airway inflammation. latent expression of adenoviral e a protein in alveolar epithelial cells can potentiate the effects of lung inflammation induced by cigarette smoke. it is therefore plausible that chronic viral infection could contribute to disease severity in copd, and further work is required to understand how viruses detected in the stable state relate to exacerbations. it is not fully understood why patients develop an exacerbation following respiratory virus infection but never smokers do not often go on to develop significant lower respiratory symptoms. furthermore, there is a subgroup of copd that seems to be more susceptible to infection, irrespective of disease severity (the frequent-exacerbator phenotype). copd is associated with substantial changes in innate immunity that are likely to be relevant in the pathogenesis of exacerbations. tobacco smoking impairs mucociliary clearance, and the rhinovirus binding receptor intercellular adhesion molecule (icam- ) is upregulated by bronchial epithelial cells in copd. alveolar macrophages, which are numerous and form a first line of defense in the respiratory tract, are defective in copd, with impairments in their ability to phagocytose bacteria , and clear dead and dying cells compared with alveolar macrophages from healthy smoking and nonsmoking controls. in the human experimental rhinovirus infection model, mallia and colleagues found nasal lavage viral load was significantly higher in patients with copd following rhinovirus infection compared with age-matched healthy controls. because all subjects were inoculated with the same virus dose, this suggests impairment in the immune response that controls viral replication in copd. this finding supports the work by hurst and colleagues, who earlier showed that exacerbation frequency was related to cold acquisition rather than the propensity to develop an exacerbation following a cold. the most abundant cells in the airway are bronchial epithelial cells (becs) and alveolar macrophages. interferon (ifn) deficiency has been observed in these important cells and, therefore, proposed as a potential mechanism of increased susceptibility to rhinovirus infection. respiratory viruses such as human rhinovirus (hrv) replicate within the respiratory epithelium triggering the production of type i (fn-a, ifn-b) and type iii ifns (ifn-l), which limit viral replication, protein synthesis, and protein trafficking ( table ) . however, ifn deficiency remains controversial in copd. mallia and colleagues found that bronchoalveolar lavage (bal) cells of subjects with copd had a deficient ifn-b response to ex vivo infection with hrv- , but did not identify any deficiency in bec responses. in contrast, hsu and colleagues recently showed impaired ifn responses to influenza virus in becs from copd. these findings are supported by a study that showed a decrease in expression of ifn stimulated genes in the induced sputum of copd participants compared with healthy controls. however, schneider and colleagues and baines and colleagues showed increased ifn-l responses to hrv- and hrv- b infection of copd becs respectively compared with healthy controls. further studies of ifn induction in response to viral infection in epithelial and bal cells in copd are clearly needed because this is a potential therapeutic target. viral infection in copd also leads to the production of disease-relevant proinflammatory cytokines such as interleukin (il)- (cxcl ), il- , chemokine ligand (ccl /rantes), tumor necrosis factor alpha (tnf-a), and ifn-g-induced protein (ip- /cxcl ) via the nuclear factor kb pathway leading to the recruitment of neutrophils, macrophages, natural killer cells, t cells, and dendritic cells at the site of infection enhancing viral clearance. importantly, the magnitude of this response is greater in patients with copd compared with healthy controls , , and may explain how increased airway inflammation contributes to lower airway symptoms in copd exacerbations. in general, exacerbations become both more frequent and more severe as the severity of the underlying copd increases, , although the reason some patients with copd experience more frequent exacerbations than others remains unclear. the evaluation of copd longitudinally to identify predictive surrogate endpoints (eclipse) cohort study identified a distinct frequentexacerbator phenotype. this group, irrespective of disease severity, was more susceptible to exacerbations and could be identified by a previous history of or more exacerbations in a preceding year. there is some indirect evidence that an increased susceptibility to virus infection may be a characteristic of frequent exacerbators. in studies of naturally acquired virus-induced copd exacerbations, virus infection was detected more commonly in exacerbation-prone patients. , alveolar macrophages taken from such patients (defined as having had an exacerbation during a -year period) and exposed to bacteria or tolllike receptor ligands ex vivo showed impaired induction of cxcl /il- and tnf-a, compared with macrophages from patients who were exacerbation free for a year. nevertheless, the description of frequent exacerbators remains essentially clinical and further studies are warranted to elucidate differences in the immune responses and conclusively provide an underlying mechanism to explain this phenotype. bacteria are also extremely important in the pathogenesis of copd exacerbations. studies using traditional sputum culturing techniques have isolated bacteria in % to % of exacerbations of copd. studies have also shown that bacterial colonization is common in copd and is associated with greater airway inflammation and increased risk of exacerbation. , , however, it remains unclear from these studies whether exacerbations occur because of the acquisition of new bacterial strains or an outgrowth of preexisting bacteria. the microbiome changes during chronic obstructive pulmonary disease exacerbations in up to % of aecopds showing the hallmarks of a bacterial cause, the causative pathogens are not recovered from respiratory samples by traditional culture methods. the application of microbiome techniques, which are culture independent, is giving rise to a new understanding of the interaction between the host and the millions of microorganisms that are present on bodily surfaces. studies identifying bacteria based on s ribosomal rna gene sequences have shown that the lungs of healthy people and patients with copd are colonized by rich, complex bacterial communities. [ ] [ ] [ ] recently, researchers have begun to highlight the shifts in microbial communities during copd exacerbations ( table ) . one of the first longitudinal studies, by huang and colleagues, found that the sputum microbiome did not show any significant changes in the key characteristics of community richness, evenness, and diversity. however, substantial taxonomic composition variation was seen during exacerbations, with an increase in proteobacteria the larger copd-map and aeris longitudinal studies found no significant change in shannon diversity or core taxa abundancies at exacerbation, however, both studies suggested that exacerbations result from dysbiosis caused by changes in preexisting bacteria in the lung rather than complete removal or appearance of a novel species. , overall, these findings suggest that, although the bacteria cultured at exacerbation undoubtedly drive events, enrichment of taxa closely related to a dominant pathogen could also contribute to pathogenesis. therefore, exacerbations can be considered polymicrobial infections. a study of the microbiome following experimental rhinovirus infection also showed an outgrowth in haemophilus and neisseria that were present in lower numbers before rhinovirus infection. these changes were correlated with increased neutrophil concentration and neutrophil elastase levels, and were not observed in the healthy control group. these findings support the hypothesis that the bacteria identified at exacerbation are not newly acquired but are caused by an outgrowth of preexisting bacteria that have experienced newly favored conditions. both the beat-copd cohort and copd-map cohorts identified distinct microbiome compositions between bacterial and eosinophilic exacerbations, suggesting that these are stable exacerbation phenotypes. the aeris study found that individuals with concomitant bronchiectasis had a greater abundance of haemophilus. it suggested that frequent exacerbators may have greater dysbiosis compared with infrequent exacerbators, thus providing a potential mechanism by which aecopds arise. events treated by antibiotics alone led to a reduction in the relative abundance of proteobacteria, whereas treatment with corticosteroids alone led to an enrichment of multiple taxa, including members of bacteroidetes, firmicutes, and proteobacteria. , this finding was supported by an earlier study of tracheal aspirates from intubated patients in whom the investigators observed that bacterial communities became less diverse as the duration of intubation and antibiotic administration increased, suggesting that microbial communities are influenced by therapeutic interventions. when both steroids and antibiotics were used to treat an exacerbation, a mixed effect on the airway microbiome was seen. a current hypothesis is that bacteria enter the lower respiratory tract by microaspiration during sleep or inhalation. in healthy lungs, pathogens either fill an ecological niche or are eradicated with minimal inflammation by the innate immune response. however, in patients with copd, a combination of defective innate immunity including impaired mucociliary clearance and variation in antigenic structure among strains allow these bacteria to persist and proliferate. a complex host-pathogen interaction in the lower airway determines this outcome. in a mouse model, h influenzae strains associated with copd exacerbations induced greater airway neutrophil recruitment compared with colonizationassociated strains. exacerbation-associated m catarrhalis strains interact differently with primary human airway epithelial cells, showing greater adherence and eliciting more il- . sputum immunoglobulin (ig)a levels, representing the mucosal host response to the infecting strain, were greater with colonization, whereas the systemic serum igg host response was larger during exacerbations. it is thought that a robust mucosal immune response diminishes bacterial interaction with the airway epithalamium, resulting in less airway inflammation, thus favoring colonization. recent studies focusing on the immune response to bacterial infection have shown the development of specific antibodies to important species, including h influenzae, m catarrhalis, s pneumoniae, and p aeruginosa following exacerbations. some of these show bactericidal and opsonophagocytic function, thereby aiding bacterial clearance. [ ] [ ] [ ] however, the multitude of strains may result in recurrent exacerbations with the same species and also creates a challenge for effective vaccine development. coinfection with bacteria and viruses is common, occurring in % to % of exacerbations. , , the dynamics of viral and bacterial infection have been examined by hutchinson and colleagues, who collected respiratory samples from patients with copd at exacerbation onset, and also to days later: % of patients who had a virus detected at exacerbation onset went on to have a bacterial infection. george and colleagues reported that, when hrv was detected at exacerbation onset, % of patients developed a bacterial infection at days. mallia and colleagues found comparable results in experimental rhinovirus infection in copd, with % of patients with copd showing bacterial infection in their sputum at day compared with only % in healthy volunteers. those who developed a bacterial infection had prolonged respiratory symptoms and delayed recovery compared with those in whom bacteria were not detected. exacerbations with coinfection with viruses and bacteria are associated with greater airflow limitation, increased airway inflammation, and delayed exacerbation recovery. , however, mechanisms underpinning how hrv infection leads to a secondary bacterial infection have not been fully elucidated. possible mechanisms include viral impairment of macrophage response to bacteria [ ] [ ] [ ] leading to a reduction in neutrophil recruitment and bacterial clearance or, alternatively, an upregulation of adhesion molecules in the bronchial epithelium. however, further work is needed to understand the complex pathogen-host interactions to direct further therapeutics. copd is characterized by aberrant airway inflammation. a further increase in airway inflammation is seen in most exacerbations, but this process is not uniform and inflammation is related to exacerbation cause. frequent exacerbators also show greater inflammation, and exacerbation nonrecovery is associated with persistent inflammation and a shorter time to the next exacerbation. traditionally, airway eosinophilia and t-helper cell type (th ) inflammation has been considered associated with allergic airway disorders such as asthma, and airway neutrophilia with copd. however recent studies have reported that % to % of patients with copd show sputum eosinophilia in the stable state. [ ] [ ] [ ] the spiromics (subpopulations and intermediate outcome measures in copd study) cohort has found that sputum eosinophilia at stable state is associated with more severe disease and increased exacerbation frequency. interventional studies additionally suggest that high blood eosinophilia level at stable state might predict a better treatment response to inhaled corticosteroid use and could therefore be used to guide therapy. , acute exacerbations may be associated with further enhancement of eosinophilic airway inflammation, with up to % of copd exacerbations being associated with sputum eosinophilia. , although there is biological plausibility for viral infection leading to sputum eosinophilia, studies of exacerbations to date have been conflicting. , , as a result, despite the considerable interest in the role of sputum and blood eosinophilia at stable state as biomarkers for disease outcome and steroid responsiveness, further work is needed to evaluate the significance of increased th inflammation during copd exacerbations. copd exacerbations associated with bacterial pathogens show significantly more airway neutrophilic inflammation compared with nonbacterial episodes. furthermore, the exacerbation severity and degree of airway bacterial concentration are related to the degree of neutrophilic inflammation. , important mediators of this airway neutrophilia in bacterial exacerbations include il- , leukotriene b , and tnf-a. , studies examining bacterial exacerbations have identified an il- b signature comprising tnf-a, granulocyte colony-stimulating factor (growthregulated oncogene-a), il- , cluster of differentiation (cd) ligand, and macrophage inflammatory protein (mip- ). il- a has been associated specifically with h influenzae exacerbations. neutrophil degranulation and necrosis can cause significant damage related to the release of neutrophil elastase and matrix metalloproteinases. clinical resolution of the symptoms of exacerbation is associated with a consistent decrease in mediators of neutrophilic airway inflammation, whereas nonresolving exacerbations show a sustained level of exaggerated airway inflammation. studies from experimental infections also indicate that viral infection induces airway neutrophilic inflammation and innate inflammatory meditators such as il- b, granulocyte colony-stimulating factor (gm-csf), cxcl /il- , and tnf-a. , , macrophages alveolar macrophages play a key role in the host defense against invasive pathogens by removing bacteria from the lung by phagocytosis, mediating inflammatory responses. there is increasing evidence of macrophage dysfunction in copd. alveolar macrophages and monocyte-derived macrophages show impaired phagocytosis of h influenzae, s pneumoniae, and escherichia coli compared with healthy controls. , , bewley and colleagues also found that phagocytosis of h influenzae was impaired in subjects with copd with a history of exacerbations. alveolar macrophages of exacerbation-prone subjects with copd also showed impaired production of inflammatory cytokines cxcl and tnf-a in response to h influenzae compared with nonexacerbation-prone subjects with copd, implicating macrophage dysfunction as a potential mechanism responsible for increased exacerbation frequency in copd. macrophages from patients with copd stimulated ex vivo with respiratory virus produce less ifn compared with healthy subjects. however, in vitro studies have not necessarily supported this, with similar and even increased ifn released by cells taken from patients with copd. in a murine model of copd, ifn-a and ifn-b responses as a result of virus infection were reported as deficient in study and viral clearance was impaired ; conversely, another study reported reduced ifn-l (but not in ifn-b) and no difference in virus load. therefore, it remains unclear whether production of ifn in response to virus infection is impaired in patients with copd. a reliable and objective biomarker of an aecopd would be invaluable to aid in reliable diagnosis and guide appropriate treatment. the patient samples most investigated are serum or plasma, although sputum, urine, or exhaled breath may also contain useful biomarkers. several studies have shown that the levels of a variety of immunoinflammatory cells and molecules are increased during exacerbations in respiratory samples, including exhaled breath, sputum, bronchoalveolar lavage, and bronchial biopsy ( table ). a viral exacerbation is suggested with a history of coryzal symptoms and can subsequently be confirmed by pcr from a respiratory sample. however, a reliable biomarker would be invaluable for guiding therapy and antibiotic stewardship (see tables and ). to date, serum cxcl (ip- ) seems the most promising, with bafadhel and colleagues reporting a cutoff of pg/ml to distinguish viral from nonviral exacerbations, giving a specificity of % and sensitivity of %. quint and colleagues reported an area under the curve for serum ip- alone of . ( % confidence interval, . - ) for detecting a human rhinovirus infection at exacerbation. other biomarkers have been investigated, with levels of il- , monocyte chemoattractant protein- (mcp- ), and tnf-a all being increased in viral-associated aecopd compared with viral-negative subjects and controls. procalcitonin has also been used to try to detect viral-associated aecopd, but the evidence so far is equivocal. bafadhel and colleagues suggested that a useful biomarker for determining bacterial-associated aecopd was sputum il- b, with a cutoff of pg/ml having a specificity of % and sensitivity of %. the serum biomarker best suited for distinguishing a bacterial cause in this study was c-reactive protein (crp) at a cutoff of mg/l, having a specificity of % and sensitivity of %. dal negro and colleagues also found that high sputum tnf-a level was associated with pseudomonas-related exacerbations, and, in those subjects without high tnf-a level, high levels of il- and il- b in the sputum distinguished bacterial from viral and noninfective exacerbations. an electronic nose used in the detection of cardinal volatile organic compounds has recently been used in a pilot study to distinguish bacterial from viral aecopd, although development and proof of concept are needed before this technology can play a role in outpatient diagnostics. a danish study investigating biomarkers indicative of frequent exacerbators discovered that simultaneously increased fibrinogen, crp, and white blood cell counts indicated an increased risk of frequent exacerbation. increased plasma fibrinogen level in patients at risk of frequent exacerbation has also been replicated in further studies. , the fda has gone on to qualify fibrinogen as an end point of exacerbations and mortality. high levels of serum surfactant protein d have been shown to predict exacerbations when at their highest levels. however, the most comprehensive study to date, which included patients and examined markers, in separate cohorts (spiromics and copdgene), found no biomarker showed a significant relationship to exacerbation frequency in either cohort (after adjustment for recognized confounders: age, gender, percentage predicted forced expiratory volume in second [fev ], smoking and health status [quality of life], and self-report of gastroesophageal reflux). lung function decline several studies have now shown that copd exacerbations affect disease progression. donaldson and colleagues showed that patients with a history of frequent exacerbations show accelerated decline, at around %, whereas kanner and colleagues also showed that episodes of respiratory infections affect fev decline. however, some of the earlier studies did not show a relationship between exacerbations and fev decline. [ ] [ ] [ ] a review by silverman suggested that this heterogeneity could be caused by the general/unselected or chronic bronchitis/ higher bnp levels indicate a more severe exacerbation and a longer hospital stay , plasma fibrinogen fibrinogen increases during copd exacerbation ( . g/l sd . ), and then returns to the patient's baseline over a period of to wk , this process is associated with a concurrent increase in il- a large meta-analysis of more than , participants indicated that a -g/l increase in plasma fibrinogen resulted in a . -fold increase in copd-specific mortality il- il- has been shown to be a better predictor of mortality than both crp and plasma fibrinogen urine metabolomics few biomarkers isolated from the urine are clinically useful in aecopd one study that shows promise for the future has indicated that certain metabolomics can be used to differentiate copd from asthma with a > % accuracy sputum eosinophilia sputum eosinophil levels have been found to negatively correlate with bacterial load at exacerbation serum peripheral blood eosinophil count at a cutoff of % is likely to be the best measure of sputum eosinophilia, with bafadhel et al reporting a specificity of %, sensitivity of % exhaled nitric oxide several studies of aecopd show an increase, with showing an increase of . ppb (À . to . ppb) at exacerbation , abbreviations: bnp, brain natriuretic peptide; crp, c-reactive protein; iqr, interquartile range; pct, procalcitonin; sd, standard deviation. data from refs. , , , [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] emphysema populations studied in the early, negative studies in contrast with the copd patient populations studied in the later, positive studies. a recent copdgene study showed that the effect of exacerbations on decline was greatest in patients with mild (gold stage ) copd, with each event associated with an additional ml/y decline. on occasion, lung function following an exacerbation does not fully recover, and then a group of patients who experience frequent exacerbations (because they have more events) are likely to have a faster lung function decline than patients who have zero or few exacerbations. according to the latest global burden of disease study estimates for , copd accounted worldwide for . million deaths. exacerbations are the predominant cause of mortality, and soler-cataluñ a and colleagues showed that aecopds requiring hospitalization are independently associated with mortality (after adjusting for confounding variables such as age, fev , body mass index, and charlson comorbidity index), and that the mortality risk increases with exacerbation frequency. a canadian mortality study showed that rates after the first hospitalized copd exacerbation were % at $ years and % at $ years. the mortality risk peaks sharply in the first days after hospitalization and gradually declines over the subsequent months. with every new hospitalized exacerbation, the risk of death increased, and the interval between hospitalizations decreased over time. for aecopds requiring hospitalization, patients with older age, higher arterial paco , prolonged oral corticosteroid use, or admission to intensive care unit are more likely to die. in a large analysis of a uk primary care population, rothnie and colleagues show a clear association between both the increasing frequency and the severity of aecopds and mortality. the relationship between copd exacerbations and health-related quality of life was first reported by seemungal and colleagues, , , exacerbations also worsen patients' mental health with an increase in anxiety and depression and feelings of fatigue. hospital admission and readmission for acute exacerbations have a particularly negative impact on quality-of-life scores. , physical activity acutely at exacerbation, patients spend less time outside of their homes, and patients who experience frequent exacerbation have a faster decline in time spent outdoors compared with infrequent exacerbators. peripheral muscle weakness also deteriorates during an aecopd. patients who maintain physical activity at a low level reduce the risk of hospital admission for copd by % (p . ) compared with little or no physical activity aecopds are episodes of symptom worsening that have significant adverse consequences for patients. exacerbations are highly heterogeneous events associated with increased airway and systemic inflammation and physiologic changes. the frequency of exacerbations is associated with accelerated lung function decline, quality of life impairment, and increased mortality. they are triggered predominantly by respiratory viruses and bacteria, which infect the lower airway and increase airway inflammation. a proportion of patients seem to be more susceptible to exacerbations, with poorer quality of life and more aggressive disease progression than those who have infrequent exacerbations. exacerbations also contribute significantly to health care expenditure. prevention and mitigation of exacerbations are therefore key goals of copd management. global strategy for the diagnosis, management, and prevention of chronic obstructive lung disease report. gold executive summary copd exacerbations: defining their cause and prevention relationship between exacerbation frequency and lung function decline in chronic obstructive pulmonary disease effect of exacerbation on quality of life in patients with chronic obstructive pulmonary disease severe acute exacerbations and mortality in patients with chronic obstructive pulmonary disease the epidemiology and economics of chronic obstructive pulmonary disease the clinical and economic burden of chronic obstructive pulmonary disease in the usa the economic impact of exacerbations of chronic obstructive pulmonary disease and exacerbation definition: a review standards for the diagnosis and treatment of patients with copd: a summary of the ats/ers position paper time course and recovery of exacerbations in patients with chronic obstructive pulmonary disease temporal clustering of exacerbations in chronic obstructive pulmonary disease inflammatory changes, recovery and recurrence at copd exacerbation clinical audit indicators of outcome following admission to hospital with acute exacerbation of chronic obstructive pulmonary disease antibiotic treatment of exacerbations of copd: a randomized, controlled trial comparing procalcitoninguidance with standard therapy understanding why patients with copd get readmitted: a large national study to delineate the medicare population for the readmissions penalty expansion antibiotic therapy in exacerbations of chronic obstructive pulmonary disease detection and severity grading of copd exacerbations using the exacerbations of chronic pulmonary disease tool (exact) acute exacerbations of pulmonary diseases. european respiratory society usefulness of the chronic obstructive pulmonary disease assessment test to evaluate severity of copd exacerbations patient-reported outcomes for the detection, quantification, and evaluation of chronic obstructive pulmonary disease exacerbations characterisation and impact of reported and unreported exacerbations: results from attain major air pollutants and risk of copd exacerbations: a systematic review and meta-analysis guidelines for the management of adult lower respiratory tract infections-full version pathogenesis of viral infection in exacerbations of airway disease role of infection in chronic bronchitis new strains of bacteria and exacerbations of chronic obstructive pulmonary disease seasonality and determinants of moderate and severe copd exacerbations in the torch study seasonal distribution of copd exacerbations in the prevention of exacerbations with tiotropium in copd trial epidemiological relationships between the common cold and exacerbation frequency in copd exacerbation of chronic obstructive pulmonary disease respiratory syncytial virus, airway inflammation, and fev decline in patients with chronic obstructive pulmonary disease amplification of inflammation in emphysema and its association with latent adenoviral infection susceptibility to exacerbation in chronic obstructive pulmonary disease smoking is associated with shortened airway cilia upregulation of adhesion molecules in the bronchial mucosa of subjects with chronic obstructive bronchitis defective macrophage phagocytosis of bacteria in copd phagocytic dysfunction of human alveolar macrophages and severity of chronic obstructive pulmonary disease alveolar macrophages from subjects with chronic obstructive pulmonary disease are deficient in their ability to phagocytose apoptotic airway epithelial cells the airway epithelium: soldier in the fight against respiratory viruses impaired antiviral stress granule and ifn-b enhanceosome formation enhances susceptibility to influenza infection in chronic obstructive pulmonary disease epithelium reduced sputum expression of interferonstimulated genes in severe copd increased cytokine response of rhinovirusinfected airway epithelial cells in chronic obstructive pulmonary disease novel immune genes associated with excessive inflammatory and antiviral responses to rhinovirus in copd inflammatory response in acute viral exacerbations of copd copd exacerbations: definitions and classifications impaired innate immune alveolar macrophage response and the predilection for copd exacerbations infection in the pathogenesis and course of chronic obstructive pulmonary disease relationships among bacteria, upper airway, lower airway, and systemic inflammation in copd a persistent and diverse airway microbiota present during chronic obstructive pulmonary disease exacerbations analysis of the lung microbiome in the "healthy" smoker and in copd microbiome diversity in the bronchial tracts of patients with chronic obstructive pulmonary disease airway microbiome dynamics in exacerbations of chronic obstructive pulmonary disease sputum microbiome temporal variability and dysbiosis in chronic obstructive pulmonary disease exacerbations: an analysis of the copdmap study longitudinal profiling of the lung microbiome in the aeris study demonstrates repeatability of bacterial and eosinophilic copd exacerbations outgrowth of the bacterial airway microbiome after rhinovirus exacerbation of chronic obstructive pulmonary disease chronic obstructive pulmonary disease j topic j nice lung microbiome dynamics in copd exacerbations. eur respir the role of the bacterial microbiome in lung disease haemophilus influenzae from patients with chronic obstructive pulmonary disease exacerbation induce more inflammation than colonizers moraxella catarrhalis acquisition, airway inflammation and protease-antiprotease balance in chronic obstructive pulmonary disease moraxella catarrhalis in chronic obstructive pulmonary disease host-pathogen interaction during pneumococcal infection in patients with chronic obstructive pulmonary disease strain-specific immune response to haemophilus influenzae in chronic obstructive pulmonary disease systemic and upper and lower airway inflammation at exacerbation of chronic obstructive pulmonary disease rhinovirus infection induces degradation of antimicrobial peptides and secondary bacterial infection in chronic obstructive pulmonary disease rhinovirus exposure impairs immune responses to bacterial products in human alveolar macrophages viral inhibition of bacterial phagocytosis by human macrophages: redundant role of cd human rhinovirus impairs the innate immune response to bacteria in alveolar macrophages in chronic obstructive pulmonary disease rhinovirus attenuates non-typeable hemophilus influenzaestimulated il- responses via tlr -dependent degradation of irak- rhinovirus enhances various bacterial adhesions to nasal epithelial cells simultaneously stable copd: predicting benefit from high-dose inhaled corticosteroid treatment copd exacerbation severity and frequency is associated with impaired macrophage efferocytosis of eosinophils sputum eosinophilia and short-term response to prednisolone in chronic obstructive pulmonary disease: a randomised controlled trial association of sputum and blood eosinophil concentrations with clinical measures of copd severity: an analysis of the spiromics cohort blood eosinophil counts, exacerbations, and response to the addition of inhaled fluticasone furoate to vilanterol in patients with chronic obstructive pulmonary disease: a secondary analysis of data from two parallel randomised controlled trials blood eosinophils and inhaled corticosteroid/long-acting b- agonist efficacy in copd viral infections in allergy and immunology: how allergic inflammation influences viral infections and illness airway eosinophilia in chronic bronchitis during exacerbations oxidative and nitrosative stress and histone deacetylase- activity in exacerbations of chronic obstructive pulmonary disease neutrophil adhesion molecules in experimental rhinovirus infection in copd altered macrophage function in chronic obstructive pulmonary disease impaired alveolar macrophage response to haemophilus antigens in chronic obstructive lung disease differential effects of p , mapk, pi k or rho kinase inhibitors on bacterial phagocytosis and efferocytosis by macrophages in copd elastaseand lps-exposed mice display altered responses to rhinovirus infection analysis of viral infection and biomarkers in patients with acute exacerbation of chronic obstructive pulmonary disease the expression of il- , tnf-a, and mcp- in respiratory viral infection in acute exacerbations of chronic obstructive pulmonary disease the use of serum procalcitonin as a diagnostic and prognostic biomarker in chronic obstructive pulmonary disease exacerbations: a literature review update a two-stage logistic model based on the measurement of pro-inflammatory cytokines in bronchial secretions for assessing bacterial, viral, and noninfectious origin of copd exacerbations diagnosing viral and bacterial respiratory infections in acute copd exacerbations by an electronic nose: a pilot study biomarkers for predicting copd exacerbations fibrinogen and copd: now what? chronic obstr pulm dis blood fibrinogen as a biomarker of chronic obstructive pulmonary disease biomarkers in airway diseases biomarkers predictive of exacerbations in the spiro-mics and copdgene cohorts lower respiratory illnesses promote fev decline in current smokers but not ex-smokers with mild chronic obstructive pulmonary disease the progression of chronic obstructive pulmonary disease is heterogeneous: the experience of the bode cohort effect of pharmacotherapy on rate of decline of lung function in chronic obstructive pulmonary disease: results from the torch study a long-term follow-up of respiratory symptoms and ventilatory function in a group of working men exacerbations in chronic obstructive pulmonary disease: do they contribute to disease progression? acute exacerbations and lung function loss in smokers with and without copd impact of prolonged exacerbation recovery in chronic obstructive pulmonary disease global, regional, and national deaths, prevalence, disabilityadjusted life years, and years lived with disability for chronic obstructive pulmonary disease and asthma, - : a systematic analysis for the global burden of disease study long-term natural history of chronic obstructive pulmonary disease: severe exacerbations and mortality mortality and mortality-related factors after hospitalization for acute exacerbation of copd natural history of chronic obstructive pulmonary disease exacerbations in a general practice-based population with chronic obstructive pulmonary disease effect of exacerbations on quality of life in patients with chronic obstructive pulmonary disease: a year follow up study impact on patients' health status following early identification of a copd exacerbation impact of anxiety and depression on chronic obstructive pulmonary disease exacerbation risk risk factors of readmission to hospital for a copd exacerbation: a prospective study determinants and impact of fatigue in patients with chronic obstructive pulmonary disease exacerbations and time spent outdoors in chronic obstructive pulmonary disease muscle force during an acute exacerbation in hospitalised patients with copd and its relationship with cxcl and igf-i influence of season on exacerbation characteristics in patients with copd seasonal variations in exacerbations and deaths in patients with copd during the tiospir((r)) trial serum ip- as a biomarker of human rhinovirus infection at exacerbation of copd an experimental model of rhinovirus induced chronic obstructive pulmonary disease exacerbations: a pilot study lymphocyte subsets in experimental rhinovirus infection in chronic obstructive pulmonary disease a systematic review of diagnostic biomarkers of copd exacerbation c-reactive protein in outpatients with acute exacerbation of copd: its relationship with microbial etiology and severity serum inflammatory biomarkers and clinical outcomes of copd exacerbation caused by different pathogens procalcitonin to guide antibiotic administration in copd exacerbations: a meta-analysis high plasma brain natriuretic peptide levels in stable copd without pulmonary hypertension or cor pulmonale calistru pi. european respiratory journal significance of nt-pro-bnp in acute exacerbation of copd patients without underlying left ventricular dysfunction acute exacerbations of chronic obstructive pulmonary disease are accompanied by elevations of plasma fibrinogen and serum il- levels inflammatory biomarkers improve clinical prediction of mortality in chronic obstructive pulmonary disease metabolomic profiling of asthma and chronic obstructive pulmonary disease: a pilot study differentiating diseases blood and sputum eosinophils in copd; relationship with bacterial load exhaled nitric oxide as a biomarker in copd and related comorbidities effects of exacerbations and seasonality on exhaled nitric oxide in copd bronchial microbiome of severe copd patients colonised by pseudomonas aeruginosa key: cord- -ws qesns authors: sin, don d. title: covid- in copd: a growing concern date: - - journal: eclinicalmedicine doi: . /j.eclinm. . sha: doc_id: cord_uid: ws qesns nan as of august , , over million people around the world have been infected with severe acute respiratory syndrome coronavirus (sars-cov- ), the virus responsible for the coronavirus disease (covid- ) pandemic [ ] . the case-fatality rate is between . % and % with most dying from respiratory failure related to diffuse alveolar damage, vascular thrombosis or pulmonary edema [ ] . to date, , individuals worldwide have succumbed to the disease [ ] . there is considerable debate on whether (or not) chronic obstructive pulmonary disease (copd), a common airway disease that affects % of individuals over years of age [ ] , is a risk factor for covid- . a recent review of the epidemiological literature revealed wideranging prevalence ( . À %) of copd among patients with covid- . however, these previous studies may have suffered from several important methodological limitations including small sample sizes and ascertainment bias. the study by attaway et al. addresses some of these limitations and provides important data that fill in critical gaps in knowledge [ ] . using a large and robust cleveland clinic covid- registry, the investigators abstracted data on patient characteristics including co-morbidities on all laboratory confirmed cases of covid- at their center. of the , symptomatic patients, who were tested for covid- , ( . %) had copd. interestingly, after adjustment for covariates, the investigators found no significant differences in the rate of sars-cov- positivity between copd and non-copd patients. however, significantly higher rates of hospitalization (adjusted odds ratio of . ), icu admissions (adjusted odds ratio of . ) and invasive mechanical ventilation (adjusted odds ratio of . ) were observed in copd patients infected with the virus (versus non-copd patients). these data are remarkably consistent with those by guan et al., who in laboratory confirmed hospitalised patients from hospitals in china showed that copd patients were . times more likely to experience icu admissions, invasive mechanical ventilation or death [ ] . together, these data suggest that copd is a risk factor for severe covid- that leads to hospitalization and icu admission. how does copd increase the risk of severe covid- ? although the exact mechanisms have not been fully worked out, there are several intriguing possibilities. the first point of host engagement for sars-cov- is usually the nasal mucosa, which contains an abundance of a protein called angiotensin converting enzyme- (ace- ) [ ] . the virus uses this protein as its receptor to gain entry into epithelial cells. once in, the virus usurps the cellular machinery of the host to produce a myriad of daughter virions, which are ultimately released into the extracellular milieu, causing infection of adjacent cells and propagation of the virus into more distal parts of the respiratory tract. without ace- , infection is aborted and ace- expression levels in lungs are associated with increased severity of covid- . it is now well established that patients with copd have increased expression of ace- in the lower respiratory tract, which is further amplified by active smoking [ , ] . this may increase the risk for severe covid- . another possibility is that patients with copd often demonstrate perturbations in the renin-angiotensin-aldosterone system with up-regulation of ace and angiotensin ii [ ] that may be exacerbated during acute sars-cov- infection, leading to acute pulmonary hypertension and pulmonary edema. another consideration is pharmacotherapy. copd patients are often prescribed inhaled medications such as inhaled corticosteroids (ics). provocatively, in the paper by attaway et al., they showed that those patients who tested positively for sars-cov- were . times less likely to have used corticosteroids at the time of testing than those who tested negatively ( . % vs . %, p < . ) [ ] . although these data cannot be considered definitive owing to important methodological limitations such as confounding by indication and severity, they raise the possibility that corticosteroids may offer some protection against covid- . thus, during this pandemic, patients with copd should be encouraged to use their prescribed inhalers as they did prior to the pandemic. long-acting bronchodilators are first line therapies for copd, followed by the addition of ics for those who are frequent exacerbators and during significant exacerbations, they should be managed with antibiotics and oral corticosteroids [ ] . for exacerbations directly related to sars-cov- infection, they should be treated with systemic dexamethasone, especially if they require supplemental oxygenation or invasive mechanical ventilation. under these settings, the use of dexamethasone has been shown to reduce doi of original article: http://dx.doi.org/ . /j.eclinm. . . pulmonary vascular endothelialitis, thrombosis, and angiogenesis in covid- global strategy for the diagnosis, management, and prevention of chronic obstructive lung disease: the gold science committee report covid- and copd sars-cov- infection in the copd population is associated with increased healthcare utilization: an analysis of cleveland clinic's covid- registry comorbidity and its impact on patients with covid- in china: a nationwide analysis sars-cov- receptor ace gene expression and raas inhibitors ace- expression in the small airway epithelia of smokers and copd patients: implications for covid- serum levels of raas components in copd dexamethasone in hospitalized patients with covid- À preliminary report key: cord- -yclnl n authors: read, r. c. title: infection in acute exacerbations of chronic bronchitis: a clinical perspective date: - - journal: respiratory medicine doi: . /s - ( ) - sha: doc_id: cord_uid: yclnl n abstract acute exacerbations of chronic bronchitis (aecb) is an important cause of death and morbidity in developed countries and also has significant economic impact. the disease is characterized by increased dyspnoea, sputum volume and sputum purulence; the most commonly associated pathogens are haemophilus influenzae, streptococcus pneumoniae and moraxella catarrhalis. h. influenzae and s. pneumoniae express virulence determinants that directly and indirectly impair mucociliary clearance and incite other consequences that are permissive to microbial persistence. regarding the use of antibiotics, there is currently a lack of large-scale clinical trials that are sufficiently powerful to provide good evidence-based information. nonetheless, antimicrobial chemotherapy has repeatedly been shown to confer benefit in patients with moderately severe features of aecb. simple clinical criteria can be used to identify patients in whom there is a higher likelihood of treatment failure or mortality during aecb. these include significant cardiopulmonary co-morbidity, frequent exacerbations, advanced decline in lung function, malnutrition or other generalized debility, advanced age (> years) and concurrent treatment with corticosteroids. in such patients, an aggressive antimicrobial approach to aecb may be warranted in order to prevent clinical failure or representation. from a clinical perspective, appropriate drugs include those that are stable to β-lactamases, are bactericidal against causative pathogens, penetrate diseased lung tissue in high concentrations and have a good safety profile. ( ) , [ ] [ ] [ ] [ ] [ ] [ ] topical reviews infection in acute exacerbations of chronic bronchitis: a clinical perspective introduction chronic obstructive pulmonary disease (copd) is characterized by irreversible airflow obstruction due to chronic bronchitis or emphysema; this is defined as a ratio of forced expiratory volume in set: forced vital capacity (fevi: fvc) of less than %. patients are subject to acute exacerbations in which there is an acute decline in fev,, often in association with increased dyspnoea, and production of increased quantities of sputum which may be purulent. recent epidemiological data from the u.s.a. show that copd affects an estimated million individuals and is the fifth most common cause of death ( ) . development of respiratory failure during an acute exacerbation of copd occurs in those whose stable airway function is severely impaired ( ) . however, respiratory failure is not the only cause of death in this group; as acute exacerbation of copd can also result in death due to other causes, such as acute myocardial infarction ( ) . the role of infection in aecb is a contentious issue. bacteria and neutrophils are frequently identified in the sputum of patients with aecb, but it is unclear whether they have a causal relationship with the development of exacerbations, or whether bacterial counts are merely allowed to increase as a result of the acute impairment of mucociliary clearance. studies with antibiotics have revealed a positive, but small effect compared to placebo, in patients with aecb. in the interests of targeting therapy to those who need it most, there are some data that allow us to identify patients who do not benefit from antimicrobial therapy, and others for whom it is probably a mandatory component of management. within the trachea, bronchi and medium to small airways of the lung, the respiratory mucosa is normally sterile. during the evolution of copd in an individual patient, there is a gradual increase in mucus production, depressed ciliary function and epithelial cell injury. bacteria that are not normally present in the airway below the larynx are then able to colonize the diseased epithelium ( ). the association of purulent sputum in chronic bronchitis with haemophilus influenzae and streptococcus pneumoniae was convincingly demonstrated by may ( ) . these pathogens, of course, are common colonizers of the upper respiratory tract and they can be recovered from the lower airways even c harcourt publishers ltd r. c. read during stable copd ( ). monso et al. ( ) performed bronchoscopic sampling by protected specimen brush (psb) of the lower airways of outpatients with stable copd and compared this with patients with acute exacerbations of copd. this showed that the prevalence of lower airway bacterial colonization in outpatients with stable copd is high ( %), mainly due to h. infruenzae in s. pneumoniae, whilst exacerbated copd is associated with a higher yield ( . %) of these pathogens and higher numbers of organisms. in patients with more severe aecb, psb will retrieve a wider range of bacteria including gramnegative enteric bacilli, pseudomonas sp. and stenotrophomonas sp. ( ) . therefore at the very least, even if infection with bacterial pathogens is not the cause of acute exacerbations, they are clearly flourishing in the lower airways in some of these patients, in association with an inflammatory infiltrate (as evidenced by a yield of neutrophils in sputum). molecular typing of strains of h. influenzae isolated from sputum of patients with copd has demonstrated that a single strain may persist for many months within the lower respiratory tract mucosa of these patients, and remains present even if there have been acute exacerbations of copd which have been treated with antibiotics ( ). this suggests that haemophilus infuenzae exists in a state of equilibrium with the host defences, which is lost during exacerbations. during antimicrobial therapy, the equilibrium is restored though the microbe is not eradicated. during chronic colonization there is likely to be a constant balancing act between the host and its bacterial colonizers. on the one hand, host defences include cough, ciliary beating, mucus containing secreted immunoglobulin and lactoferrin, and alveolar macrophages. on the other hand, microbes have adapted to avoid rapid clearance, gain nutrients and survive in the respiratory tract sufficiently to grow and disseminate to other hosts. in the case of haemophilus injluenzae, the factors which enable the organism to achieve these aims include the production of a polysaccharide capsule, pili, lipopolysaccharide, outer membrane proteins, iron-regulated proteins and factors toxic to ciliary activity (reviewed by read and finch) ( ). the pathogens associated with exacerbations of copd have been summarized by ball ( ) in summary, bacteria are present within the lower airways in most patients with stable copd. in most cases of aecb, there is evidence of increased inflammation in the lower airways together with an increase in bacterial numbers. whether the latter is cause or effect has not been elucidated. table . the studies assessed in this meta-analysis differed in terms of the main outcomes measured (symptom score, days of illness, etc.) so it was able only to report a crude overall effect size relative to placebo, and the effect on peak expiratory flow (pef), which was reported in the majority of the studies. overall, the meta-analysis demonstrated a modest but statistically significant benefit from antibiotic therapy (overall effect size . compared with placebo, % ci: . - . ). the peak expiratory flow improved by a small amount ( . min-' compared with placebo). none of the studies assessed included any quality of life outcomes. the largest of the studies assessed, by anthonisen et al. ( ) , stratified patients according to the severity of their illness and was able to demonstrate the largest effect size in those patients with the most severe exacerbations. antibiotics gave the greatest benefit in terms of resolution of symptoms and avoidance of deterioration, in those patients who had two or more of the following features, increased dyspnoea, increased sputum volume and increased sputum purulence. in europe, the commonest antimicrobials used in aecb include the aminopencillins (u.k. and france), the macrolides (spain), tetracyclines (germany) and third generation cephalosporins (italy) ( ). both the european respiratory society ( ) and the american thoracic society ( ) have produced guidelines for the management of copd. these endorse the judicious use of simple and inexpensive antimicrobial therapy based on individual clinical assessment by physicians. the british thoracic society has recommended antibiotic therapy if any two of worsening dyspnoea, increased sputum volume or increased sputum purulence are present ( ) . the major pathogen, haemophilus injeuenzae, is demonstrating rising resistance to the aminopenicillins which is mainly due to production of p-lactamases. in the u.k., prevalence of resistant h. infuenzae ranges from % ( ) . both of the major /?-lactamases are plasmid-mediated and transferable, and so their prevalence is expected to rise with increased use of aminopenicillins in the community. erythromycin has virtually no activity against haemophilus injluenzae, but clarithromycin has better activity, though this is based on a study which demonstrated that % of h. influenzae isolates had a mic of pg ml-' or less ( ) . azithromycin has better in vitro activity than the other macrolides ( ). moraxella catarrhalis demonstrates almost universal production of p-lactamases and is also resistant to trimethoprim (reviewed by amyes and gemmell) ( ) . resistance to p-lactams amongst streptococcus pneumoniae isolates is due to a stepwise mutation of the penicillinbinding proteins. there is controversy regarding the impact of penicillin resistance of pneumococci on the management of patients with respiratory tract infection. patients with pneumonia treated with high dose penicillin and subsequently shown to be infected with penicillin-resistant pneumococci, showed no increase in severity of outcome compared to patients with sensitive strains ( ) . however, the effect of penicillin resistance amongst pneumococci on outcomes in community-treated aecb, where lower doses of oral agents are generally used, has not been investigated. pneumococcal resistance is associated with childcare facilities, hospital facilities, antibiotic use and immunocompromise ( ) . importantly, long-term treatment with low doses of p-lactam antibiotics has recently been shown to contribute to the selective pressure promoting pharyngeal carriage of penicillin-resistant strains of s. pneumoniue ( ) . the potential implications of this for patients with aecb treated in the community are obvious. identifying those patients most likely to benefit from antibiotic therapy with regard to patients presenting to their general practitioner with cough, it is possible to identify patients for whom no benefit will accrue from the use of antibiotics. these include patients with acute bronchitis and otherwise good respiratory health ( , ) . a recent meta-analysis of double-blind placebo-controlled trials of antibiotics in patients presenting with acute cough demonstrated that neither resolution of cough nor clinical improvement was significantly hastened by antibiotic therapy ( ) . regarding patients with copd, the trial of anthonisen et al. ( ) showed that patients with more than two of (i) increased dyspnoea, (ii) increased sputum volume and (iii) increased sputum purulence can benefit from antibiotic therapy, whilst those patients with only one of these features are unlikely to benefit. with such a heterogeneous population, it is possible that positive benefit from antibiotics in the more severe subgroups has been diluted out in the studies of antibiotic therapy in patients with aecb. the majority of patients presenting to their community physician with aecb do not fulfil these simple clinical criteria and are therefore unlikely to benefit from antimicrobial therapy. there is a strong case for targeting antibiotic therapy in patients with more severe manifestations of aecb. the major determinants of the survival over the long-term in patients with aecb are age and the degree of airways obstruction (fevi < %) ( ) . co-existing cardiopulmonary disease such as ischaemic heart disease, and also diabetes, have been linked to poor outcome in copd patients ( ) . use of oral corticosteroids has also been linked to poor outcome ( ) . seneff et al. ( ) demonstrated that amongst patients admitted to intensive care units with aecb, variables associated with hospital mortality included age, severity of respiratory and non-respiratory organ system dysfunction, and hospital length of stay before intensive care unit (icu) admission. these factors imply a worse prognosis of an infective aecb. although each of these factors is associated with a poorer outcome of copd, their effects are not necessarily mediated through infection. prescott et al. ( ) investigated patients who had died from an aecb and determined whether their death was directly linked to infection on clinical grounds. the only historical risk factor that was associated with an infective 'death' was the presence of chronic mucus hypersecretion. despite this reservation, a strong argument to target therapy at those patients with manifestations of disease associated with a poor prognosis can be made. future studies should determine whether use of antimicrobial therapy in these patients affects clinical outcome, quality of life measurements and the likelihood of hospital admission. of further importance, economically, and in terms of quality of life, is the failure of outpatient management resulting in patients needing to return to their physician. one study has determined that these patients can be identified. those with co-existing cardiopulmonary disease, or who have a history of recurrent exacerbations (> per year) are at greatest risk of failing therapy and needing a return visit ( ) . appropriate antimicrobial therapy in patients with aecb table suggests appropriate antimicrobial therapy in patients with aecb. the majority of patients presenting to their general practitioner will not require antibiotic therapy. these are patients with acute bronchitis and simple chronic bronchitis with reasonable lung function and less than two of the three of the 'anthonisen criteria'. patients who are ambulant and relatively well with no co-existing illnesses, but who present with two or more 'anthonisen criteria' can probably be managed by simple therapy with ,&lactams, for example an aminopenicillin, which is cheap and likely to be efficacious in this group. however, local data may point to a high prevalence of filactamase-secreting h. injkenzae, in which case therapy with antibiotics that are stable to p-lactamase is logical. these include co-amoxiclav, the quinolones and modern macrolides (clarithromycin or azithromycin). in patients with advanced age, or with cardiopulmonary comorbidities or moderately to severely impaired lung function (fevi < %), it would seem logical to treat infection with more sophisticated antibiotics in order to ensure microbiological clearance. particularly in those patients with recurrent exacerbations, infection with a p-lactamase-secreting h. injiuenzae is more likely. in addition, these patients are more likely to be infected with unusual pathogens such as the gram-negatives such as enterobacteriaceae and staphylococcus aureus. in these patients the use of advanced antimicrobials such as co-amoxiclav, quinolones and modern macrolides would seem logical. this has no current evidence basis, and trials to determine whether they have an effect on clinical outcome should be conducted, though some have argued that this will be difficult ( ) . us bureau of the census. statistical abstract of the united states pathophysiology of chronic obstructive pulmonary disease acute respiratory tract infections and risk of first time acute myocardial infarction interaction of non-typable haemophilus infruenzae of human respiratory mucosa in vitro the bacteriology of chronic bronchitis bacteriological findings in trans-tracheal aspirates from patients with chronic bronchitis and bronchiectasis bacterial infection in chronic obstructive pulmonary disease bronchial microbial patterns in severe exacerbations of r.c. read the copd guidelines group of the standards of care committee of the bts. bts guidelines for the management of chronic obstructive pulmonary disease. management of acute exacerbations of copd antimicrobial susceptibility of community-acquired lower respiratory tract bacterial pathogens isolated in the u.k. during the - cold season spectrum and mode of action of azithromycin, a new -membered ring macrolide with improved potency against gramnegative organisms antibiotic resistance resistance to penicillin and cephalosporin and mortality from severe pneumococcal pneumonia in management of infections caused by antibiotic resistant streptococcus pneumoniae low dosage and long treatment duration of plactam what will it take to stop physicians from prescribing antibiotics in acute bronchitis? quantitative and systematic review of randomised control trials comparing antibiotic with placebo for acute cough in adults prognosis in chronic obstructive pulmonary disease the natural history of chronic bronchitis survival of patients with chronic obstructive pulmonary disease receiving longterm domiciliary oxygen therapy hospital and one-year's survival of patients admitted to intensive care units with acute exacerbations of chronic obstructive pulmonary disease chronic mucus hypersecretion in copd and death from pulmonary infection acute infective exacerbations of chronic bronchitis is an objective assessment of antibiotic therapy in exacerbations of chronic bronchitis possible? key: cord- -bch v authors: singanayagam, aran; joshi, priya v; mallia, patrick; johnston, sebastian l title: viruses exacerbating chronic pulmonary disease: the role of immune modulation date: - - journal: bmc med doi: . / - - - sha: doc_id: cord_uid: bch v chronic pulmonary diseases are a major cause of morbidity and mortality and their impact is expected to increase in the future. respiratory viruses are the most common cause of acute respiratory infections and it is increasingly recognized that respiratory viruses are a major cause of acute exacerbations of chronic pulmonary diseases such as asthma, chronic obstructive pulmonary disease and cystic fibrosis. there is now increasing evidence that the host response to virus infection is dysregulated in these diseases and a better understanding of the mechanisms of abnormal immune responses has the potential to lead to the development of new therapies for virus-induced exacerbations. the aim of this article is to review the current knowledge regarding the role of viruses and immune modulation in chronic pulmonary diseases and discuss avenues for future research and therapeutic implications. chronic diseases are the leading cause of death worldwide and the third most common group of chronic diseases are chronic pulmonary diseases that account for an estimated four million deaths annually [ ] . the most prevalent diseases of the respiratory tract are chronic obstructive pulmonary disease (copd), asthma, tuberculosis and lung cancer, and the most common genetic disease is cystic fibrosis (cf). copd is estimated to be the fourth leading cause of mortality by [ ] and an estimated million people suffer from asthma. copd, asthma and cf are all chronic inflammatory conditions but their etiology and pathogenesis differ markedly. copd and asthma are believed to be caused by exposure to relevant environmental agents (mainly cigarette smoke and aeroallergens, respectively) in patients with a susceptible genetic background, whereas cf is caused by mutations in the cf transmembrane regulator gene. the typical clinical course of these conditions is of chronic symptoms that are punctuated by periods of increased symptoms termed 'acute exacerbations'. acute exacerbations are now recognized to be significant events in the course of the disease and have enormous implications for patients, their caregivers and for healthcare providers. exacerbations accelerate disease progression, impair quality of life, cause significant morbidity for patients and are the major cause of mortality. in addition they are the major drivers of excess healthcare costs as they often result in unscheduled healthcare visits, treatment costs and above all hospitalizations. therefore, preventing exacerbations is a major therapeutic goal in all three diseases and one that has not been achieved with currently available treatments. despite the differences between copd, asthma and cf, all three have in common that respiratory virus infections are a major trigger of acute exacerbations. an important mechanism underlying this may be impaired host immune responses to virus infection and a better understanding of these mechanisms has the potential to lead to the development of new therapies that may be beneficial in different chronic pulmonary diseases. the aim of this article is to review the current knowledge regarding the role of viruses and host immune responses in asthma, copd and cf, and discuss avenues for future research and therapeutic interventions. although this article primarily focuses on acute exacerbations of chronic respiratory diseases, virus infection has also been implicated in the induction of asthma. asthma is strongly related to a genetic predisposition to develop allergic reactions to aeroallergens. however, not all individuals with atopy develop asthma and, therefore, it has been proposed that other environmental factors may act as 'triggers' to the development of asthma in genetically susceptible individuals. one such factor that has attracted much research interest is respiratory virus infections, in particular infection with respiratory syncytial virus (rsv). in the majority of cases rsv causes a self-limiting upper respiratory tract infection, but in infants under the age of one year it can cause a more serious infection of the lower respiratory tract -bronchiolitis -and studies have linked rsv bronchiolitis with an increased frequency of subsequent wheezing and asthma [ ] . recently, it has been reported that rhinovirus (rv) infection is also related to the development of asthma [ ] . however, these studies are unable to ascertain the direction of the relationship between viral infections and asthma, that is, whether infections cause asthma or infections occur more frequently in individuals predisposed to asthma. recent evidence has emerged supporting the later hypothesis. a study using data on hospitalization due to rsv infection for all twins born in denmark between and found that rsv hospitalization and asthma were positively associated but that a model in which asthma 'causes' rsv hospitalization fitted the data significantly better than a model in which rsv hospitalization 'causes' asthma [ ] . a study of the temporal relationship between sensitization to aeroallergens and viral wheeze showed that allergic sensitization led to an increased risk of wheezing illnesses but viral wheeze did not lead to increased risk of subsequent allergic sensitization [ ] . therefore, the link between asthma and virus infection may be due to genetically determined alterations in airway or immune responses that predispose infants both to infection and asthma, rather than virus infections causing asthma [ ] . this will be discussed later in light of recent developments regarding innate immune responses in asthma but it is clear that the relationship between respiratory virus infections and the induction of asthma is complex and requires further study. asthma is the most common chronic respiratory disease affecting up to % of adults and % of children in the western world [ ] . the global initiative for asthma (gina) defines asthma as 'a chronic inflammatory disorder of the airways in which many cells and cellular elements play a role. the chronic inflammation is associated with airway hyperresponsiveness that leads to recurrent episodes of wheezing, breathlessness, chest tightness, and coughing, particularly at night or in the early morning. these episodes are usually associated with widespread, but variable, airflow obstruction within the lung that is often reversible either spontaneously or with treatment'. this definition refers to the key physiological marker of asthma -reversible airflow obstruction, and the key pathological characteristic -airways inflammation. the characteristic pattern of inflammation of allergic diseases and also in asthma involves eosinophils, mast cells and t helper lymphocytes (th ) and a wide range of inflammatory mediators. asthma exacerbations are episodes characterized by progressive increase in shortness of breath, cough, wheezing and chest tightness, or some combination of these, and increased airflow obstruction that is manifested by reductions in measurements of lung function such as peak expiratory flow (pef). acute exacerbations are a common occurrence in asthma and the social and economic burden of asthma exacerbations is substantial, due to both the direct costs of healthcare utilization and the indirect costs associated with lost productivity. current therapies for asthma consist of bronchodilator and antiinflammatory medications, the mainstay of which are inhaled β -agonists and inhaled corticosteroids, respectively. these are highly effective in relieving symptoms and reduce exacerbations by approximately % in clinical trials [ ] . however, in 'real life' surveys of asthmatics a significant proportion of patients continue to experience acute exacerbations despite therapy and, therefore, prevention/treatment of exacerbations remains a major unmet clinical need in asthma [ ] [ ] [ ] . it has long been recognized that viral respiratory tract infections are triggers for exacerbations of asthma in both adults and children but early studies reported low detection rates of viruses in asthma exacerbations casting doubt on this association. the development of highly sensitive and specific molecular diagnostic techniques using polymerase chain reaction (pcr) technology led to a reappraisal of the role of virus infections in asthma. studies using pcr detected viruses in approximately % to % of asthma exacerbations in school-aged children and % to % of exacerbations in adults. although respiratory virus infection can be detected in stable asthma patients detection rates are consistently lower than in exacerbated patients [ , ] . therefore, these studies suggest that the majority of asthma exacerbations are associated with respiratory virus infections and that the low detection rates in earlier studies were a consequence of diagnostic methods with a low sensitivity. the most common viruses detected in these studies were rv. rvs are members of the picornaviridae family and are the most common cause for the common cold in both children and adults. more than serotypes exist. virus typing classified rvs into rv-a and rv-b groups based on susceptibility to anti-viral drugs and on genetic sequence similarity. more recently a newly identified group termed rv-c has been identified based purely on sequencing data [ ] . other respiratory viruses have been detected in subjects with asthma exacerbations including influenza, rsv, coronaviruses, human metapneumoviruses, parainfluenza viruses (piv) and adenoviruses. however, in a recent study in children the only virus type significantly associated with asthma exacerbations was rv [ ] . the risk of exacerbation following virus infection is influenced by other factors such as allergy and environmental pollution. allergen sensitization, exposure to sensitizing allergens, and respiratory virus infection act in a synergistic manner to significantly increase the risk of hospitalization with acute asthma in both adults [ ] and children [ ] . the presence of high ambient levels of nitric oxide(no) is also associated with an increased risk of exacerbation following rv infection [ ] . following discovery of the role of rv in asthma exacerbations research attention has focused on the mechanisms of susceptibility to virus infection in asthmatics. rv infection in healthy individuals results in a predominantly upper respiratory symptom syndrome ('common cold'), whereas in asthmatics infection results in lower respiratory symptoms and airflow obstruction ('acute exacerbation'). a study of co-habiting partners discordant for the presence of asthma demonstrated that asthmatics do not have a higher frequency of rv infections but have more severe lower respiratory symptoms and changes in airway physiology [ ] . similar results have been reported in experimental rv infection studies in asthmatics and nonasthmatic control subjects [ ] . therefore, it would appear that the consequences of virus infection in asthmatics are more severe than in non-asthmatics. understanding the mechanisms underlying increased disease severity is crucial to developing new strategies to treat virus-induced exacerbations. most research into virus-induced asthma exacerbations has focused on rv as these are the most common viruses detected in asthma exacerbations and well-characterized models of rv infection exist both in vitro and in vivo. rvs primarily enter and replicate in epithelial cells in the respiratory tract and trigger a cascade of immune and inflammatory responses. following viral entry into a cell, uncoating of the virus leads to the release of viral rna that is recognized by pattern recognition receptors including toll-like receptors (tlr)- , - and - , and the cytosolic rna helicases, retinoic acid inducible gene i (rig-i) and melanoma differentiation-associated protein- (mda- ) [ , ] . the interactions between ligand and receptor trigger signaling cascades ultimately resulting in the activation of transcription factors such as interferon regulatory factor (irf)- and- , nuclear factor-b (nf-b) and activating transcription factor (atf ). these activated transcription factors translocate to the nucleus and induce transcription of the type i interferons (ifn-α and -β) and pro-inflammatory cytokines including interleukin (il)- /cxcl , il- , epithelial-derived neutrophilactivating peptide (ena- /cxcl ) and ifn-γinduced protein kda (ip- /cxcl ) [ ] [ ] [ ] [ ] [ ] . ifn-α and -β have both a direct antiviral effect through inhibition of viral replication in cells and an indirect effect through stimulation of innate and adaptive immune responses. the direct antiviral activity of type i ifns is mediated by various mechanisms including blocking viral entry into cells, control of viral transcription, cleavage of rna and blocking translation. these effects are mediated through the up-regulation of interferon stimulated genes (isgs) and the production of antiviral proteins. the indirect antiviral effect is mediated through induction of natural killer cell cytotoxicity [ ] , up-regulation of the expression of major histocompatibility complex (mhc- ) on cells and up-regulation of co-stimulatory molecules on antigen-presenting cells. therefore, a robust interferon response is central to effective antiviral responses and resolution of virus infections. recently a novel class of interferons termed type iii interferons, or interferonlambda (ifn-λ) has been described. the type iii ifns consist of ifn-λ , , (respectively, il- , il- a and il- b) [ ] . the ifn-λs utilize a different receptor than ifn-α/β but appear to have functional similarities, however much more is known about the mechanism of action of ifn-α/β. the pro-inflammatory mediators and cytokines induced by rv infection lead to chemoattraction of inflammatory cells such as neutrophils, lymphocytes and eosinophils. this inflammatory response contributes to virus clearance but is also responsible for the pathology induced by rv infections. the balance between antiviral and inflammatory responses following virus infection is likely to determine the clinical outcome of the infection. an effective antiviral response rapidly controls viral replication with a minimal inflammatory response and limited clinical illness. if antiviral responses are inadequate this is likely to result in uncontrolled viral replication, greater inflammatory response and more severe clinical illness ( figure ). the evidence that clinical illness following virus infection is more severe in asthmatics has stimulated research into possible dysregulation of antiviral and inflammatory responses in asthmatics. in wark et al. examined the kinetics of virus replication in bronchial epithelial cells obtained from asthmatics and healthy volunteers and reported that viral replication is increased in cells from asthmatics compared to non-asthmatic subjects [ ] . this was the first report indicating that the innate immune response to virus infection may be impaired in asthma. furthermore, the authors demonstrated that production of ifnβ was impaired in asthmatics and administration of exogenous ifn-β resulted in restoration of a normal antiviral response, and this was confirmed in a subsequent study [ ] . deficient ifn-β production by bronchial epithelial cells [ ] , as well as deficient ifn-α production by peripheral blood mononuclear cells [ ] [ ] [ ] and dendritic cells [ ] has also been reported in asthma. our group has also shown that ifn-α and ifn-β production by alveolar macrophages is impaired in asthmatics (manuscript submitted). furthermore, deficient ifn-λ production by epithelial cells and alveolar macrophages in asthmatics has also been reported and related to clinical outcomes following experimental rv [ ] . however, other groups have not reported deficient ifn induction in epithelial cells from asthmatics [ , ] . in experimental rv infections virus loads were higher and virus shedding prolonged in asthmatics but this was not statistically significant [ , ] . therefore, although interferon deficiency is an exciting new mechanism underlying increased severity of virus infection in asthma it has not been conclusively demonstrated to occur in all asthmatic subjects studied. the studies in question were small with different experimental conditions such as cell culture techniques and virus dose. it is also possible that interferon deficiency occurs in some asthmatics only and it may also be related to disease severity, disease control or degree of atopy. further studies with more subjects and careful patient selection and characterization are required to provide answers to these ongoing research questions. up-regulation of interferonstimulated genes if interferon production in response to virus infection is impaired in asthmatics what are the possible molecular mechanisms underlying this? the discovery that ifn-α, ifn-β and ifn-λ are all deficient suggests that it is not a genetic defect as ifn-α and ifn-β are on different genetic loci than ifn-λ. a key family of proteins regulating both interferon production and allergic inflammation are the suppressor of cytokine signaling family (socs), and one member of this family, socs , is a potent negative regulator of type i and type ii interferons and of th inflammation [ , ] . socs is induced by type ii cytokines such as il- [ ] and, therefore, persistent th inflammation may result in chronic up-regulation of socs and impaired interferon responses, but this hypothesis requires further investigation. in vitro infection of airway epithelial cells with rv induces the production of inflammatory mediators and this has also been reported in vivo in both experimental and naturally-acquired viral infections. chemokines and cytokines such as il- , il- and regulated on activation, normal t-cell expressed and secreted (rantes) have been detected during virus infections in asthmatic patients [ ] [ ] [ ] [ ] [ ] . however it remains unclear whether the inflammatory response following virus infection differs quantitatively or qualitatively in asthmatics. one experimental rv infection study reported increased nasal lavage levels of il- and il- β in asthmatics [ ] but not in control subjects; however, another study reported no differences in il- , il- , il- and granulocyte-monocyte-colony stimulating factor (gm-csf) levels in either nasal lavage or sputum between asthmatics and nonasthmatics [ ] . increased sputum levels of il- but not rantes or il- have been reported in asthmatics [ ] . these conflicting results highlight the need for further studies evaluating the inflammatory profile (preferably in the lower airway) in well-characterized patients and nonasthmatic controls following virus infection. many of the inflammatory mediators produced are chemoattractants and, therefore, following virus infection inflammatory cells are recruited to the lungs. a number of different inflammatory cells have been identified in both naturally-occurring and experimental virus infections in asthma. although stable asthma is characterized by eosinophilic inflammation, a number of studies have identified neutrophils as the key inflammatory cell in virus-induced asthma exacerbations [ , [ ] [ ] [ ] . neutrophils release bioactive mediators such as the protease neutrophil elastase that have effects such as stimulation of mucous production and, therefore, are likely key contributors to the pathogenesis of asthma exacerbations. another key cell involved in immune and inflammatory responses in the lungs is the macrophage. there is evidence that rvs can infect macrophages and that in asthmatics macrophage responses to virus infection are altered. our group has reported that rvs infect macrophages and induce tnf-α production [ ] and that production of the cytokine il- , that plays a key role in linking innate and adaptive antiviral immune responses and promoting t cell anti-viral immune responses, is impaired in asthmatics [ ] . as described previously, macrophage production of ifns in response to virus infection is also impaired in asthma [ ] . therefore, there is evidence of impaired antiviral responses in asthmatics in macrophages as well as respiratory epithelial cells. increased lymphocyte numbers in bronchoalveolar lavage (bal) and bronchial biopsies in experimental rv infection in asthmatics has been reported, with increases in cd +, cd + and nk cells [ , ] . abnormalities of the acquired immune system in stable asthma have been well described with skewing of acquired immune responses towards a th profile. as robust antiviral responses require an adequate th response it is possible that in diseases such as asthma with predominant th cells antiviral immunity is impaired. impaired levels of the th cytokines il- , - , - and ifn-γ have all been reported in asthma [ , [ ] [ ] [ ] . in human experimental rv infection lower respiratory symptoms, bronchial hyperreactivity, reductions in blood total and cd + lymphocytes and virus load are related to deficient ifn-γ, il- or il- responses and to augmented il- , il- , and il- responses [ , ] . sputum ifn-γ/il- messenger rna ratio following virus infection is inversely related to both peak cold symptoms and the time to viral clearance [ ] . therefore, augmented th and deficient th immune responses are associated with greater clinical illness following rv in asthma. the identification of impaired innate immunity in asthma suggests a possible mechanism not only for virus-induced asthma exacerbations but also for the link between respiratory virus infections and the subsequent development of asthma. it is possible that infants who will develop asthma in later life have impaired immune responses from birth and, therefore, are more likely to develop more severe disease manifestations (for example, bronchiolitis) following respiratory virus infection. most studies to date have focused on the role of the acquired immune system and identified reduced ifn-γ production as a significant risk factor both for subsequent wheezing illness and allergic sensitization [ ] [ ] [ ] . no studies have investigated innate immune responses in infants prior to the development of symptomatic asthma but impaired ifn-α production has been reported in older children with atopic asthma [ ] . in conclusion there is evidence that both innate and acquired immune responses in asthmatics are impaired and this may be a key mechanism underlying virusinduced asthma exacerbations and the link between virus infections and the subsequent development of asthma in infants. further studies are needed to determine whether these deficiencies are common to all asthmatics, whether they represent a specific asthma phenotype and how they relate to conventional measures of asthma control. another important research question is whether new interventions targeting the interferon pathways can prevent asthma exacerbations and even potentially prevent the development of asthma in infants. chronic obstructive pulmonary disease (copd) is the most common chronic respiratory condition in adults. the global initiative for obstructive lung disease (gold), a collaboration between the world health organization and the national heart lung and blood institute, defines copd as 'a preventable and treatable disease with some significant extrapulmonary effects that may contribute to the severity in individual patients. its pulmonary component is characterized by airflow limitation that is not fully reversible. the airflow limitation is usually progressive and associated with an abnormal inflammatory response of the lung to noxious inhaled particles or gases' [ ] . the main etiological agents linked with copd are cigarette smoking and biomass exposure and the inflammatory response consists of neutrophils, macrophages and cd + t cells and, therefore, differs from the allergic inflammation seen in asthma. pulmonary inflammation is further amplified by oxidative stress and excess proteases released by inflammatory cells recruited to the lung. as in asthma, acute exacerbations are a common occurrence in copd and become more frequent as the disease progresses [ ] . exacerbations are a major cause of morbidity, mortality and healthcare costs and accelerate decline in lung function [ ] and quality of life [ ] in copd patients. historically, bacterial infections have been considered the predominant infectious etiology, however epidemiological data showing a greater frequency of exacerbations in the winter months [ ] and frequent coryzal symptoms preceding exacerbations suggest a causal role for viruses [ ] . older studies using cell culture and serologic diagnostic tests detected viral infection in only approximately % to % of exacerbations [ , ] . however, these diagnostic methods have low sensitivity for virus detection especially for rvs that are the most common cause of upper respiratory tract infections. more recent studies using modern pcr-based techniques have allowed a re-evaluation of the importance of viruses in copd exacerbations and these studies have shown the presence of viruses in % to % of exacerbations [ ] [ ] [ ] [ ] . a recent systematic review evaluated weighted mean prevalence of respiratory viruses detected by pcr in patients with acute exacerbations of copd. eight studies were included with an overall prevalence of . %, with picornaviruses including rvs being the most frequently detected pathogen, followed by influenza, parainfluenza, rsv and adenoviruses [ ] . although these studies have higher detection rates they are likely to have underestimated the role of viral infections in copd exacerbation as they evaluated patients at the time of presentation to healthcare services which often occurs considerably later than the onset of exacerbation and by which time virus may no longer be detectable. although viruses are frequently detected in copd exacerbations, their presence during exacerbations does not prove a definite causative role. experimental infection using rv provides a novel tool for investigating relationships between virus infection and exacerbations. such studies have been previously conducted in asthma and yielded important insights into the mechanisms linking virus infection to exacerbations in asthma. a recent study from our group reported the first experimental rv infection study in copd [ ] . copd patients and nonobstructed controls were infected with rv with sequential measurement of symptoms, lung function, inflammatory markers and virus load. following rv infection, copd subjects developed symptomatic colds followed by the typical lower respiratory symptoms of an acute exacerbation. symptoms were accompanied by objective evidence of airflow limitation and airways inflammation and inflammatory markers correlated with virus load. virus was detected in airway samples prior to the onset of symptoms and viral clearance was followed by symptom resolution and return of inflammatory markers to baseline levels. therefore, this study directly links respiratory virus infection to lower respiratory symptoms, airflow obstruction and airways inflammation in copd and provides novel evidence supporting a causative role for rv infection in copd exacerbations. much less is known regarding mechanisms of virusinduced exacerbations in copd compared to asthma. in the experimental infection study, symptoms, airflow obstruction and airways inflammation were more severe in the copd subjects compared to non-obstructed controls [ ] . therefore, as is the case in asthma it would appear that clinical illness following rv infection is more severe in copd subjects, but the mechanisms underlying this are poorly understood. copd exacerbations are associated with increased levels of inflammatory mediators including tumor necrosis factor-alpha (tnf-α) [ ] , il- [ , ] , il- [ ] , and leukotriene b [ ] and inflammatory cells such as neutrophils [ , ] and eosinophils [ ] . however, few studies have examined the inflammatory response specific to virus-induced exacerbations. virus infection has been associated with high levels of il- [ , ] and ip- [ , ] and papi et al. reported that elevated sputum eosinophils were only seen in exacerbations in which a virus was present [ ] . others have reported that the presence of rv is not associated with significant airway inflammation [ ] and that only exacerbations associated with purulent sputum (presumed bacterial infection) are associated with airways inflammation [ ] . from the data available no clear conclusions can be drawn regarding the inflammatory response to virus infection in copd and there are no studies comparing the effects of naturally-occurring virus infections in copd patients and non-copd controls. there is evidence from animal models that the inflammatory response to virus infection may be exaggerated in copd. in a mouse model of copd utilizing intranasal administration of lipopolysaccharide and elastase, infection with rv resulted in increased levels of tnf-α and il- compared to control mice [ ] . this was accompanied by increased airway hyper-responsiveness and increased mucus production. similarly, in the human copd rv challenge study, increased levels of il- and neutrophil elastase were reported in copd subjects when compared to non-obstructed controls [ ] . these studies suggest that copd is associated with an exaggerated inflammatory response to viral infection and this may explain the increased severity and duration of symptoms seen in these patients. in vitro studies have shown that cigarette smoke impairs release of ifn-β and ifn-α [ ] . bal cells from copd patients infected ex vivo with rv demonstrated deficient induction of ifn-β with similar trends for deficient induction of ifns-α and -λ, associated with deficiency of the interferon stimulated gene cxcl [ ] . similar findings have been reported in a mouse model where persistence of rv, increased airways inflammation and deficient induction of ifns-α, -β and -γ were reported in copd mice compared to controls [ ] . however in vitro rv infection of epithelial cells from copd patients resulted in higher virus load and increased inflammatory mediators, but no differences in interferon production compared to cells from control subjects [ ] . further studies examining the role of interferon deficiency in viral exacerbations are required as this may lead to potential future therapeutic application of interferon therapy in reducing exacerbation severity in copd. rvs bind to cells via intercellular adhesion molecule- (icam- , major group rvs) or members of the low-density lipoprotein receptor family (minor group rvs). icam- is upregulated on the bronchial epithelium of patients with copd [ , ] and, therefore, it is possible that increased icam- levels may permit greater virus binding and increased viral entry into epithelial cells in copd patients. the majority of studies have detected viruses at a greater frequency during acute exacerbations compared to the stable state. one study indicated that rsv is detected in nasal lavage at a similar frequency of around % in the stable state and during exacerbations [ ] . this was followed by a similar study reporting detection of rsv in about % of sputum samples, with detection being related to greater airway inflammation and to a faster decline in lung function [ ] . however, other studies have not reported increased rsv detection in stable copd [ , ] . a study comparing virus loads between infants with acute respiratory infections and adult copd patients found that virus loads were -fold higher in the infants, suggesting low-grade virus infection in copd [ ] . the disparity between these findings is likely to be due to a combination of factors including differing sensitivity of the pcr techniques used, differences in severity of copd patients included or differences in the populations studied [ ] . latent infection by adenovirus has also been proposed to be involved in the pathogenesis of copd. lung tissue from copd patients has been demonstrated to carry more group c adenoviral dna than matched nonobstructed smokers [ ] . latent adenoviral infection in combination with cigarette smoke exposure in a guinea pig model caused an increase in lung volumes, airspace volume and reduced surface to volume ratio compared to smoke exposure alone [ ] . additionally, adenovirus detection has been shown to be similar in exacerbated and stable copd patients [ ] . some authors have postulated that the presence of rsv and adenovirus in stable copd may contribute to the pathogenesis of the disease as there are some common pathologic features between respiratory viral infection and copd including a predominance of cd + t lymphocytes. however, this remains a largely unproven hypothesis. cystic fibrosis (cf) is an autosomal recessive disease caused by mutations in the gene for the cystic fibrosis transmembrane regulator (cftr) protein. defective cftr function leads to abnormal transport of chloride and sodium across the pulmonary epithelium, resulting in viscous secretions in the lungs, recurrent bacterial infections and progressive loss of lung function. pulmonary involvement is the most common manifestation of the disease and respiratory failure the most common cause of death. respiratory infections are the leading cause of morbidity, decline in lung function and hospitalizations due to acute exacerbations. the major cause of infectious complications in cf has always been considered to be bacterial infection, with pseudomonas aeruginosa the most common organism detected. there has been relatively little research on the role of virus infections in cf but recent studies have suggested that viruses have a significant impact on the cf patient. the role of respiratory viruses in cf exacerbations is likely to have been under-appreciated in the past because older studies investigated only one virus type and the detection methods used were not sufficiently sensitive. newer pcr techniques have helped to improve detection and it is now becoming clear that viruses are implicated in exacerbations in cf. previous studies using serology, culture and immunoflourescence detected viruses in % to % of exacerbations in cf patients [ ] [ ] [ ] [ ] . in contrast, studies using pcr for virus detection have reported detection rates of % to % [ ] [ ] [ ] . a number of different viruses have been detected in cf patients with the most common being rvs, influenza and rsv. the incidence of viral infections in children with cf is not elevated in comparison to healthy children but the severity of clinical illness associated with infection is greater [ ] . viral infections are associated with deterioration in lung function and more severe clinical illness indicating that they contribute to disease progression thus demonstrating the clinical importance of research within this field [ , ] . the mechanisms of viral-induced cf exacerbations and increased clinical illness are poorly understood with conflicting results from published studies. some authors have reported increased production of pro-inflammatory cytokines and chemokines by epithelial cells obtained from cf patients compared to healthy controls [ , ] . however, others have failed to detect any differences in cytokine production between cf and normal cells [ , ] . these differences may be due to different viruses used (rv, rsv, piv) and differences in cell culture techniques, but it remains unclear whether the cf epithelium is intrinsically pro-inflammatory in response to virus infection. another mechanism that has been postulated is a deficiency in antiviral innate immune responses in cf cells. increased replication following piv infection of cf cells has been reported and this was corrected by administration of ifnα [ ] . ifn responses were not impaired but induction of nitric oxide synthase (nos ) was impaired in cf. nos is required for production of no that has potent antiviral effects and, therefore, impaired no synthesis may be one mechanism of impaired antiviral host responses in cf. our group has reported reduced ifn-β and ifn-λ production and reduced isgs in cf epithelial cells [ ] and, therefore, ifn deficiency may be relevant to cf as well as in asthma and copd. holtzman has proposed that 'hypersusceptibility' to virus infection, via defective interferon pathways, is a unifying pathway in asthma, copd and now cf [ ] . both bacterial and virus infections are common in cf and copd and, therefore, co-infections are likely to be common. there is now increasing evidence that both viral and bacterial infections can modulate host immune responses and increase susceptibility to subsequent infection. there is abundant evidence from both human studies and animal models that influenza infection impairs antibacterial immunity and this can result in secondary bacterial pneumonia [ , ] . however, much less is known regarding the effect of other respiratory viruses, such as rvs, on susceptibility to bacterial infection. in vitro studies have reported that rv infection increases bacterial adhesion to epithelial cells [ ] [ ] [ ] and impairs macrophage immune responses to bacterial products [ ] . we have found that experimental rv infection in copd is followed by secondary bacterial infection in % of patients and this is related to deficiency of the antimicrobial peptides elafin and secretory leukoprotease inhibitor (slpi) (submitted manuscript). there are also studies indicating that virus-bacteria interactions influence host immune responses in cf. chattoraj et al. reported that rv infection of cf cells liberates planktonic bacteria from biofilm [ ] . planktonic bacteria express virulence factors and stimulate inflammatory responses more readily compared to biofilm bacteria and this was manifested by increased cytokine responses. evidence is also emerging that bacterial infection can increase susceptibility to viral infection. infection of epithelial cells by haemophilus influenzae (a common organism in copd) increases susceptibility to infection by rv, possibly by up-regulation of icam- [ ] . cf cells infected with mucoid p.aeruginosa and then with rv produced less ifn and viral loads were higher compared to cells infected with the rv alone [ ] . this effect was not seen in normal epithelial cells infected with pseudomonas and was related to the inhibition of akt phosphorylation and irf- activation -both prerequisites for the ifn response to rv infection. it is widely acknowledged that the main infectious cause of asthma exacerbations is virus infection and it is believed that bacteria play only a minor role. however, a recent study using culture-independent molecular methods for bacterial detection reported that the bacterial flora in the airways of asthmatics is closer to that of copd patients than of non-asthmatics [ ] . the role of bacteria in asthma exacerbations needs to be revisited as virus-bacterial interactions may play a role in the pathogenesis of asthma exacerbations. this is a fertile area for further research. our knowledge of the interactions between respiratory viruses and bacteria, and how these influence host immune responses in pulmonary diseases, is still at an early stage. further research is required to understand better these complex relationships and to explore the implications they may have for the development of new therapies. there is now convincing data implicating respiratory viruses as a major cause of acute exacerbations in asthma, copd and cf. in all these conditions there is evidence that host immune responses to virus infection are impaired, but whether this occurs through a common mechanism, or whether mechanisms differ between the different diseases is unclear. further research is needed to elucidate the exact mechanisms of increased susceptibility to virus infection in pulmonary diseases, the interactions between viruses and bacteria and how these impact on host immune responses. a better understanding of these mechanisms has the potential to lead to the development of novel therapies that will reduce the impact of acute exacerbations in chronic pulmonary diseases. list of abbreviations atf: activating transcription factor; bal: bronchoalveolar lavage; cf: cystic fibrosis; cftr: cystic fibrosis transmembrane regulator; copd: chronic obstructive pulmonary disease; ena- : epithelial-derived neutrophilactivating peptide ; icam- : intercellular adhesion molecule; ifn-α: interferon-alpha; ifn-β: interferon-beta; ifn-λ: interferon-lambda; ifn-γ: interferon-gamma; il: interleukin; ip- : ifn-γ-induced protein- ; irf: interferon regulatory factor; isg: interferon stimulated genes; mda- : melanoma differentiation-associated protein- ; nf-κb: nuclear factor-kappa b; no: nitric oxide; nos : nitric oxide synthase ; pcr: polymerase chain reaction; pef: peak expiratory flow; piv: parainfluenza virus; rantes: regulated on activation: normal t-cell expressed and secreted; rig-i: retinoic acid inducible gene i; rsv: respiratory syncytial virus; rv: rhinovirus; slpi: secretory leukoprotease inhibitor; socs: suppressor of cytokine signaling family; th / : t helper / ; tlr: toll-like receptors; tnf-α: tumor necrosis factor-alpha - . the global burden of chronic diseases: overcoming impediments to prevention and control projections of global mortality and burden of disease from to respiratory syncytial virus bronchiolitis in infancy is an important risk factor for asthma and allergy at age wheezing rhinovirus illnesses in early life predict asthma development in high-risk children exploring the association between severe respiratory syncytial virus infection and asthma: a registry-based twin study evidence for a causal relationship between allergic sensitization and rhinovirus wheezing in early life respiratory syncytial virus and asthma: still no final answer the global burden of asthma: executive summary of the gina dissemination committee report effect of inhaled formoterol and budesonide on exacerbations of asthma. formoterol and corticosteroids establishing therapy (facet) international study group characterization of the severe asthma phenotype by the national heart, lung, and blood institute's severe asthma research program real-world evaluation of asthma control and treatment (react): findings from a national web-based survey clinical management of asthma in : the asthma insights and reality in europe (aire) study use of polymerase chain reaction for diagnosis of picornavirus infection in subjects with and without respiratory symptoms multiplex molecular detection of respiratory pathogens in children with asthma exacerbation a diverse group of previously unrecognized human rhinoviruses are common causes of respiratory illnesses in infants prevalence of viral respiratory tract infections in children with asthma synergism between allergens and viruses and risk of hospital admission with asthma: case-control study study of modifiable risk factors for asthma exacerbations: virus infection and allergen exposure increase the risk of asthma hospital admissions in children personal exposure to nitrogen dioxide (no ) and the severity of virus-induced asthma in children frequency, severity, and duration of rhinovirus infections in asthmatic and non-asthmatic individuals: a longitudinal cohort study rhinovirus-induced lower respiratory illness is increased in asthma and related to virus load and th / cytokine and il- production co-ordinated role of tlr , rig-i and mda in the innate response to rhinovirus in bronchial epithelium the rna helicase rig-i has an essential function in double-stranded rna-induced innate antiviral responses rhinovirus stimulation of interleukin- in vivo and in vitro: role of nf-kappab corticosteroids and beta agonists differentially regulate rhinovirusinduced interleukin- via distinct cis-acting elements proud d: human airway epithelial cells produce ip- (cxcl ) in vitro and in vivo upon rhinovirus infection rhinovirus stimulation of interleukin- in vivo and in vitro. evidence for nuclear factor kappa b-dependent transcriptional activation doublestranded rna activates rantes gene transcription through cooperation of nuclear factor-kappab and interferon regulatory factors in human airway epithelial cells natural killer cells in antiviral defense: function and regulation by innate cytokines ifn-lambdas mediate antiviral protection through a distinct class ii cytokine receptor complex asthmatic bronchial epithelial cells have a deficient innate immune response to infection with rhinovirus exogenous ifn-beta has antiviral and anti-inflammatory properties in primary bronchial epithelial cells from asthmatic subjects exposed to rhinovirus diversity in the bronchial epithelial cell response to infection with different rhinovirus strains impaired virus-induced interferon-alpha release in adult asthmatic patients atopic phenotype in children is associated with decreased virus-induced interferon-alpha release toll-like receptor function is reduced in adolescents with asthma counterregulation between the fcepsilonri pathway and antiviral responses in human plasmacytoid dendritic cells role of deficient type iii interferon-lambda production in asthma exacerbations rhinovirus-induced modulation of gene expression in bronchial epithelial cells from subjects with asthma in vitro susceptibility to rhinovirus infection is greater for bronchial than for nasal airway epithelial cells in human subjects similar colds in subjects with allergic asthma and nonatopic subjects after inoculation with rhinovirus- suppressor of cytokine signaling (socs) inhibits type i interferon (ifn) signaling via the interferon alpha receptor (ifnar )-associated tyrosine kinase tyk 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clinical and biologic significance rhinovirus replication in human macrophages induces nf-kappabdependent tumor necrosis factor alpha production lower airways inflammation during rhinovirus colds in normal and in asthmatic subjects the role of il- deficiency in the pathogenesis of virus-induced asthma exacerbations reduced production of interleukin by interferon gamma primed alveolar macrophages from atopic asthmatic subjects reduced interleukin- levels in bal specimens from patients with asthma compared to patients with sarcoidosis and healthy control subjects relationship of upper and lower airway cytokines to outcome of experimental rhinovirus infection reduced interferon gamma production and soluble cd levels in early life predict recurrent wheezing by year of age low ifn-gamma production in the first year of life as a predictor of wheeze during childhood bidirectional interactions between viral respiratory illnesses and cytokine responses in the first year of life the gold scientific committee: global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. nhlbi/who global initiative for chronic obstructive lung disease (gold) workshop summary evaluation of copd longitudinally to identify predictive surrogate endpoints (eclipse) investigators: susceptibility to exacerbation in chronic obstructive pulmonary disease the lung health study research group: lower respiratory illnesses promote fev( ) decline in current smokers but not ex-smokers with mild chronic obstructive pulmonary disease: results from the lung health study effect of exacerbation on quality of life in patients with chronic obstructive pulmonary disease seasonality and determinants of moderate and severe copd exacerbations in the torch study respiratory viruses, symptoms, and inflammatory markers in acute exacerbations and stable chronic obstructive pulmonary disease association of viral and mycoplasma pneumoniae infections with acute respiratory illness in patients with chronic obstructive pulmonary diseases infections with viruses and mycoplasma pneumoniae during exacerbations of chronic bronchitis infections and airway inflammation in chronic obstructive pulmonary disease severe exacerbations respiratory viruses in exacerbations of chronic obstructive pulmonary disease requiring hospitalisation: a case-control study biopsy neutrophilia, neutrophil chemokine and receptor gene expression in severe exacerbations of chronic obstructive pulmonary disease epidemiology of respiratory viruses in patients hospitalized with near-fatal asthma, acute exacerbations of asthma, or chronic obstructive pulmonary disease prevalence of viral infection detected by pcr and rt-pcr in patients with acute exacerbation of copd: a systematic review experimental rhinovirus infection as a human model of chronic obstructive pulmonary disease exacerbation granulocyte inflammatory markers and airway infection during acute exacerbation of chronic obstructive pulmonary disease airway inflammation during stable and acutely exacerbated chronic obstructive pulmonary disease inflammatory changes, recovery and recurrence at copd exacerbation changes in bronchial inflammation during acute exacerbations of chronic bronchitis inflammatory response in acute viral exacerbations of copd detection of rhinovirus in induced sputum at exacerbation of chronic obstructive pulmonary disease serum ip- as a biomarker of human rhinovirus infection at exacerbation of copd acute exacerbations of copd: identification of biological clusters and their biomarkers relationships among bacteria, upper airway, lower airway, and systemic inflammation in copd elastase-and lps-exposed mice display altered responses to rhinovirus infection effect of sidestream and mainstream smoke exposure on in vitro interferon-alpha/beta production by l- cells increased cytokine response of rhinovirus-infected airway epithelial cells in chronic obstructive pulmonary disease upregulation of adhesion molecules in the bronchial mucosa of subjects with chronic obstructive bronchitis respiratory syncytial virus, airway inflammation, and fev decline in patients with chronic obstructive pulmonary disease evaluation of a quantitative real-time pcr for the detection of respiratory syncytial virus in pulmonary diseases respiratory syncytial virus persistence in chronic obstructive pulmonary disease latent adenoviral infection in the pathogenesis of chronic airways obstruction emphysematous lung destruction by cigarette smoke. the effects of latent adenoviral infection on the lung inflammatory response acute and latent adenovirus in copd association of respiratory viral infections with pulmonary deterioration in patients with cystic fibrosis infective respiratory exacerbations in young adults with cystic fibrosis: role of viruses and atypical microorganisms effect of respiratory virus infections including rhinovirus on clinical status in cystic fibrosis the effect of respiratory viral infections on patients with cystic fibrosis severe viral respiratory infections in infants with cystic fibrosis the role of respiratory viruses in cystic fibrosis rhinovirus c and respiratory exacerbations in children with cystic fibrosis. emerg infect dis impaired innate host defense causes susceptibility to respiratory virus infections in cystic fibrosis prevalence and impact of respiratory viral infections in young children with cystic fibrosis: prospective cohort study australian respiratory early surveillance team for cystic fibrosis: innate inflammatory responses of pediatric cystic fibrosis airway epithelial cells: effects of nonviral and viral stimulation interleukin- production by cystic fibrosis nasal epithelial cells after tumor necrosis factor-alpha and respiratory syncytial virus stimulation lack of an exaggerated inflammatory response upon virus infection in cystic fibrosis impaired type i and type iii interferon induction and rhinovirus control in human cystic fibrosis airway epithelial cells hypersusceptibility to respiratory viruses as a shared mechanism for asthma, chronic obstructive pulmonary disease, and cystic fibrosis insights into the interaction between influenza virus and pneumococcus the innate immune rheostat: influence on lung inflammatory disease and secondary bacterial pneumonia rhinovirus enhances various bacterial adhesions to nasal epithelial cells simultaneously effects of rhinovirus infection on the adherence of streptococcus pneumoniae to cultured human airway epithelial cells rhinovirus disrupts the barrier function of polarized airway epithelial cells rhinovirus exposure impairs immune responses to bacterial products in human alveolar macrophages rhinovirus infection liberates planktonic bacteria from biofilm and increases chemokine responses in cystic fibrosis airway epithelial cells hershenson mb: h. influenzae potentiates airway epithelial cell responses to rhinovirus by increasing icam- and tlr expression pseudomonas aeruginosa suppresses interferon response to rhinovirus infection in cystic fibrosis but not in normal bronchial epithelial cells disordered microbial communities in asthmatic airways all the authors contributed equally to writing the manuscript. all authors read and approved the final manuscript. pre-publication history key: cord- -iclruwmx authors: webley, wilmore c.; hahn, david l. title: infection-mediated asthma: etiology, mechanisms and treatment options, with focus on chlamydia pneumoniae and macrolides date: - - journal: respir res doi: . /s - - -z sha: doc_id: cord_uid: iclruwmx asthma is a chronic respiratory disease characterized by reversible airway obstruction and airway hyperresponsiveness to non-specific bronchoconstriction agonists as the primary underlying pathophysiology. the worldwide incidence of asthma has increased dramatically in the last years. according to world health organization (who) estimates, over million children and adults worldwide currently suffer from this incurable disease and , die from the disease each year. it is now well accepted that asthma is a heterogeneous syndrome and many clinical subtypes have been described. viral infections such as respiratory syncytial virus (rsv) and human rhinovirus (hrv) have been implicated in asthma exacerbation in children because of their ability to cause severe airway inflammation and wheezing. infections with atypical bacteria also appear to play a role in the induction and exacerbation of asthma in both children and adults. recent studies confirm the existence of an infectious asthma etiology mediated by chlamydia pneumoniae (cp) and possibly by other viral, bacterial and fungal microbes. it is also likely that early-life infections with microbes such as cp could lead to alterations in the lung microbiome that significantly affect asthma risk and treatment outcomes. these infectious microbes may exacerbate the symptoms of established chronic asthma and may even contribute to the initial development of the clinical onset of the disease. it is now becoming more widely accepted that patterns of airway inflammation differ based on the trigger responsible for asthma initiation and exacerbation. therefore, a better understanding of asthma subtypes is now being explored more aggressively, not only to decipher pathophysiologic mechanisms but also to select treatment and guide prognoses. this review will explore infection-mediated asthma with special emphasis on the protean manifestations of cp lung infection, clinical characteristics of infection-mediated asthma, mechanisms involved and antibiotic treatment outcomes. incidence and etiology of childhood and adult onset asthma asthma incidence is highest in childhood and thereafter decreases and remains stable at~ - new cases per per year throughout late adolescence and adulthood [ ] . in adult populations, the prevalence of active cases of childhood-onset asthma (coa) and adult-onset asthma (aoa) are approximately equal, or favor aoa [ ] . reasons for this counterintuitive prevalence ratio include ( ) the propensity for coa to remit more frequently than aoa and ( ) the greater number of years of adulthood in which to accrue new cases [ ] . of relevance to clinical management and population disease burden is the wide range of asthma severities, from mild intermittent to severe persistent; the most severe % of cases account for % of health care utilization and morbidity [ ] . robust population-based data indicate that around half of adults with asthma remain suboptimally controlled, even when treated with currently available anti-inflammatory medications, and~ % of adults with active asthma are severely uncontrolled [ ] [ ] [ ] . these data indicate the need for novel therapies that are effective in the most severe and treatment-resistant cases of asthma that account for the majority of morbidity, mortality and health care utilization. the emerging evidence that a wide variety of microbes are present in the lower airway and may play a role in asthma pathogenesis suggests that manipulating the airway microbiome may be a novel approach towards this goal. studies confirm the existence of an infectious etiology mediated by chlamydia pneumoniae (cp) [ ] and possibly other viral [ ] , bacterial [ ] and fungal [ ] microbes. among the various infections associated with asthma, the obligate intracellular respiratory pathogen cp is of particular interest, as it is associated with both asthma severity and treatment resistance [ ] [ ] [ ] . although this review focuses on cp we will discuss mycoplasma pneumoniae (mp) briefly under treatment (section v). it is possible that microbes such as cp and mp that have been implicated in recurrent wheeze and asthma etiology may serve as cofactors for viral infections, but certainly appear to act independently in asthmatic disease. the etiology of asthma remains unknown and is almost certainly multifactorial. many "triggers" for asthma attacks are well known (e.g., allergens, viral respiratory infections, fumes, cold air, exercise) but underlying mechanisms for why some exposed individuals develop asthma while most do not remain elusive [ ] . genetic studies have failed to locate a unique "asthma gene" and instead point towards complex multifactorial genetic and environmental factors [ ] . a currently popular paradigm, the "hygiene hypothesis," posits that the increased incidence of allergies (hayfever and eczema) and asthma noted in recent decades, is associated with less exposure to childhood infections and bacterial products (e.g., endotoxin). emerging evidence supports the hygiene hypothesis for hayfever and eczema but not for asthma which appears instead to be related to infections throughout the life cycle [ ] [ ] [ ] . the host lung and gut microbiome as they relate to asthma are active areas of research [ ] . yet it must be pointed out that studies of bacterial rrna may fail to detect cp due to low copy numbers or sampling problems due to deep tissue intracellular locations for this species [ , ] . an increasing number of studies have now confirmed that the host microbiome has a significant impact on the risk of asthma development. a study published in by hilty and colleagues using s rna clone-library sequencing showed that when compared with healthy controls, patients with asthma had significantly more pathogenic proteobacteria and fewer bacteroidetes [ ] . careful assessment of both healthy controls and asthmatic patients has confirmed the presence of bacterial communities. however, the bacterial burden was significantly greater in patients with asthma than in the healthy controls [ ] . the microbial burden was even greater in asthmatics with greater bronchial reactivity upon methacholine challenge. these patients showed marked improvement in bronchial reactivity to methacholine after weeks on clarithromycin. importantly, greater bronchial reactivity also correlated with greater relative abundance of members of certain bacterial communities known to exhibit characteristics that contribute to asthma pathophysiology, including species capable of inducing nitric oxide reductase, produce sphingolipids or have the ability to metabolize steroid compounds [ , ] . a recent study showed that -month old infants who had positive oropharynx cultures of streptococcus pneumoniae, moraxella catarrhalis, or haemophilus influenzae showed increased susceptibility for development of childhood asthma [ , ] . another recent study concluded that the nasopharyngeal microbiome within the first year of life was a determinant for infection spread to the lower airways and predicted the severity of accompanying inflammatory symptoms, as well as risk for future asthma development. the authors showed that early asymptomatic colonization of the nasopharynx with streptococcus was a strong asthma predictor [ ] . these authors also demonstrated that antibiotic usage disrupted this asymptomatic colonization and prevented asthmatic onset [ ] . these findings support the hypothesis that colonization of the developing airway by certain microbes (both viral and bacterial) can significantly alter the airway architecture and overall immune function, influencing how the airway responds to a variety of insults [ ] . these findings also suggest that antimicrobial agents may represent an effective therapeutic tool with the potential to curtail both the duration and severity of asthma exacerbations initiated by a variety of microbes and exposes the limitation of the hygiene hypothesis in this regard [ ] . the microbiome studies cited here have not specifically targeted cp and mp in upper airways. studies that have specifically tested for these atypical organisms have reported positive detection [ , ] . intracellular detection of cp in adenoid tissue of symptomatic children was extremely common [ ] and raises questions regarding a potential for cp-microbiome interactions. infections in early life can act either as inducers of wheezing or as protectors against the development of allergic disease and asthma. many young children have wheezing episodes associated with early-life respiratory infections. the infections most likely to be associated with these wheezing episodes include respiratory syncytial virus (rsv), human rhinovirus (hrv), human metapneumovirus, parainfluenza viruses and coronavirus [ ] . the hygiene hypothesis has proposed that, for some infants, frequent early life infections may protect against asthma [ ] and this certainly appears to be the case for most infants, as wheezing episodes with respiratory infections diminish as the child ages. however, for others, early-life wheezing episodes may mark the beginning of asthma. regarding established asthma, many types of viral respiratory infections have been shown to have a significant influence. in fact, viral respiratory infections are diagnosed in % of episodes of asthma in both children and adults [ , ] . the question then remains; what factors determine if a viral respiratory infection provokes the onset of chronic asthma? factors appear to include the type of virus and the viral infectious dose as well as host susceptibility factors leading to inflammation, airway cellular infiltration with neutrophils and eosinophils or the presence of allergens in the airway and their interactions with the host immune system. if this combination of host and pathogen factors results in airway inflammation and hyperresponsiveness, the outcome could be asthma. could cp play a key role in this complex scenario? a clue to the answer to this question was found in a secondary analysis [ ] of data from a community-based pediatric viral respiratory infection study that identified viral infections in - % of exacerbations [ ] . one hundred and eight children with asthma symptoms completed a -month longitudinal study in which exacerbations were recorded, and cp pcr and cp-specific secretory iga (cp-siga) antibodies were measured both during exacerbations and during asymptomatic periods. cp pcr detections were similar between the symptomatic and asymptomatic episodes ( % v %, respectively). children reporting multiple exacerbations remained cp pcr positive (p < . ) suggesting chronic infection. cp-siga antibodies were more than seven times greater in subjects reporting four or more exacerbations compared to those who reported just one (p < . ). the authors suggested that immune responses to chronic cp infection may interact with allergic inflammation to increase asthma symptoms [ ] . notably, mp was not found to be important in this study. emerging evidence links cp infection with both de novo asthma (asthma onset during/after an acute lower respiratory tract infection in a previously non-asthmatic individualalso referred to as the "infectious asthma" syndrome) and with asthma severity [ , , , ] . this section will review what is known about cp in asthma initiation and severity, and the multiple experimentally established mechanisms that might mediate these associations. therapeutic implications are reviewed in section v. de novo wheezing during an acute lower respiratory tract infection is remarkably common [ ] . most of these wheezing episodes appear to resolve without chronic sequelae but sometimes chronic asthma develops. surprisingly, clinical studies report that asthma onset after an acute respiratory illness is exceedingly common (up to % of adult-onset asthma cases [ ] . this strong temporal association of respiratory infections and asthma onset has been confirmed in a population-based study [ ] . the most reliable way to establish whether a specific respiratory pathogen can initiate asthma would be to perform large, long-term prospective microbiological and clinical cohort studies of the general (non-asthmatic) population. such a study would be very expensive and has not yet been undertaken. a second approach would be to perform prospective studies in selected non-asthmatic patients exhibiting "risk factors" for asthma in clinical settings [ ] . if the selected "risk factors" do indeed identify people at higher likelihood of developing the "infectious asthma" syndrome, this type of study might be feasible. characteristics associated with cp/mp biomarkerpositive "infectious asthma" include patients with severe, treatment-resistant asthma, exhibiting a neutrophilic airway inflammation or test pcr positive for cp or mp. it should however, be noted that there is currently no test or set of tests that will definitively diagnose who will benefit maximally from azithromycin treatment. factors that predict risk in non-asthmatics for developing the "infectious asthma" syndrome include a previous history of self-limited lower respiratory tract illnesses such as acute bronchitis (often with wheezing) and/or pneumonia [ , , ] . other risk factors may be operative but are poorly understood at this time. over a -year time period, hahn et al. [ ] collected prospective cp microbiologic testing and clinical data on patients with de novo wheezing. nine of these subjects exhibited an acute bronchitic illness and one had community-acquired pneumonia. all met serological criteria for an acute primary (n = ) or secondary (n = ) cp infection. of the nine patients with acute bronchitis and wheezing, four improved without treatment and five progressed to chronic asthma. the patient with pneumonia was treated with a traditional short course of a macrolide with resolution of pneumonic infiltrate, yet developed chronic bronchitis and cp was isolated by culture from his sputum months later. this type of study has not been replicated but raises several questions. cp is well known to cause protean manifestations of acute respiratory illness; these observations suggest that cp may also be capable of causing protean manifestations of chronic respiratory conditions (e.g., asthma, chronic bronchitis and copd, reviewed in [ ] ). whereas some of the cp infected patients with de novo wheezing resolved their acute illness without treatment, others developed chronic sequelae; identification of underlying protective and promoting factors might help address the current asthma pandemic. once established, cp-associated asthma has been linked with increased severity in several studies. cook et al. [ ] first identified cp biomarkers in what they referred to as "brittle asthma" (asthma that was hard to control and more severe than average). an accumulating body of evidence supports the association of cp infection with asthma severity [ , , ] and with steroid resistant asthma [ ] . multiple mechanisms support the biologic plausibility of these associations (reviewed in [ ] ). exposure to cigarette smoke is an established factor tied to steroid resistance in asthma [ ] . similar to cigarette smoke, cp induces pulmonary bronchial epithelial ciliostasis [ ] . additionally cp infects alveolar macrophages and lung monocytes leading to enhanced production of tnf-α, il- β, il- and il- ; infects human bronchial smooth muscle cells to produce il- and basic fibroblast growth factor (with potential effects on bronchial hyper reactivity and lung remodeling that have yet to be thoroughly investigated); and chronic infection exposes tissues to chlamydial heat shock protein (chsp ) and bacterial lipopolysaccharide (lps) that have been associated with increased inflammation and asthma (reviewed in [ ] ). lastly, cp-specific ige has been demonstrated to be strongly associated with severe persistent asthma ( % of cases) [ ] and other chronic respiratory illnesses in children severe enough to justify undergoing bronchoscopy [ ] . whereas exposure to recognized allergens can be mitigated, exposure to unrecognized bacterial "allergens" may result in chronic unrelenting exposures that could contribute to severity [ , ] . it may prove difficult or even impossible to unravel exactly which mechanism(s) contribute to producing an "infectious asthma" phenotype. in regard to the involvement of cp in asthma pathogenesis, the controversy of whether the association is causal or coincidental can be settled in two ways: ( ) patients diagnosed with asthma can be treated with the aim of evaluating the effects of antibiotics in ameliorating asthma symptoms compared to untreated of placebo controls and ( ) animal models can be performed to evaluate the role of cp in asthma initiation and/or exacerbation. experimental animal inoculation studies may help to elucidate mechanisms underlying cp asthma pathogenesis. over the past three decades, animal models of asthma have been extensively utilized to elucidate mechanisms of the disease, determine the activities of genes of interest, investigate cellular pathways and predict the safety and efficacy of various drugs being considered for asthma treatment. initial murine models of chlamydial lung infections were carried out in adult mice and seemed to closely represent acute human asthma. these studies utilized the mouse pneumonitis biovar of c. trachomatis (mopn) since it is well known as a natural mouse pathogen [ ] and would therefore represent the best choice for investigating host-pathogen interactions in this context. these early studies recorded extensive lung consolidation after days of airway infection and found significant airway inflammation characterized by neutrophil infiltration in airway exudates [ ] . these early studies also confirmed that multiple reinfections were required to induce symptoms of chronic asthma and that a th immune response contributing ifn-γ and subsequently activated macrophages was necessary to clear the infection [ , ] . more recently, many studies have utilized neonatal mouse models for infectious asthma since early studies demonstrate that neonatal t cell immune responses in both mice and human are skewed toward a th cellular phenotype as a result of placental immune pressure. these th cells are much less effective in the immune response compared to their adult counterparts [ , ] . horvat, et al. later demonstrated that neonatal chlamydial lung infection induced mixed t-cell responses that drive allergic airway disease (aad) using a balb/c mouse model with ovalbumin to induce aad [ ] . further work from this group confirmed that chlamydial infection in neonatal and infant, but not adult mice, exacerbated the development of hallmark features of asthma in ovalbumin-induced allergic airways disease models. some of these notable features include increased mucus-secreting cell numbers, il- expression, and airway hyperresponsiveness [ ] . studies from our own lab confirm that early-life chlamydial airway infection induces a th immune response, both airway eosinophilia and neutrophilia, and permanent alteration of lung structure and function with concomitant enhancement of the severity of allergic airways disease in later life [ ] . we confirmed that neonatally infected mice never cleared the infection, showed dissemination to the liver and spleen through the peripheral circulation, and the development of chlamydia-specific ige antibodies in the infected neonates but not adult controls [ ] . recently, hansbro et al. completed work using a bone marrow chimera reconstitution that clearly demonstrated that infant lung infection results in lasting alterations in hematopoietic cells, leading to increased severity of aad later in adult life [ ] . a significant study by kaiko et al. [ ] , demonstrated that infection of bone marrow-derived dentritic cells (bmdc) promoted th immunity and airways hyperreactivity in a mouse model. intratracheal passive transfer of infected bmdc but not uninfected control bmdc into naïve balb/c mice resulted in increased il- and il- in the bal fluid [ ] . these animals also showed significant increases in airways resistance and a reduction in airways compliance compared to their uninfected counterparts. these are hallmarks of asthma and further confirm the role of chlamydial infection in asthma initiation and pathology, at least in mice. a further set of experiments by schröder et al. [ ] demonstrated that adoptive transfer of lung dendritic cells from cp infected mice, but not from uninfected mice, produced eosinophilic airway inflammation after challenge with an exogenous allergen (human serum albumin) that was dose-, timing-, and myd -dependent. taken together, these findings suggest it is plausible that cp infection solely of lung dendritic cells may be sufficient to induce an asthma "phenotype" that may demonstrate characteristics that are both "infectious" and "allergic". these animal model studies have added significantly to our understanding of the mechanisms involved in the inflammatory process of chlamydial infection leading to asthma initiation and exacerbation. it also appears that the damage caused by chlamydial airway infections over time leads to an exaggerated airway repair or airway wall remodeling. the major features of this type of response include epithelial cell shedding, goblet cell hyperplasia, hypertrophy and hyperplasia of the airway smooth muscle bundles, basement membrane thickening and increased vascular density through angiogenesis [ ] . the functional and mechanical consequences of this type of aberrant repair leads to bronchial wall thickening which can uncouple the bronchial wall from the surrounding parenchyma, significantly enhancing airway narrowing and severe obstruction [ ] . this type of airway damage might prove irreversible even with long-term inhaled steroid treatment. moreover, it is well documented that corticosteroid use drives cp out of a persistent state into active replication, since corticosteroids negatively impact several aspects of cell-mediated immunity while favoring the shift from a th towards a th immune response [ ] . this shift in response significantly impedes the ability of the host to eradicate intracellular pathogens like cp and may lead to the release of chsp which exacerbates the inflammatory process [ ] . there is also evidence that cp infection may promote airway remodeling by decreasing the ratio of mmp to timp secreted by inflammatory cells, and by altering cellular responsiveness to corticosteroids [ ] . see fig. the concept that asthma is a syndrome with different underlying etiologies is well accepted. the use of the word "phenotype" to describe asthma subtypes based primarily on the inflammatory composition of respiratory secretions and/or peripheral blood is more problematic. the original definition of "phenotype" referred to relatively stable somatic manifestations of underlying genetics (such as eye color) whereas current asthma inflammatory "phenotyping" is based on cross sectional sampling of a dynamic physiologic process (host inflammatory response) and does not account for the fact that inflammatory composition is not necessary a fixed characteristic [ ] . in the context of a review that focuses on chlamydial infection we are reluctant to place too much emphasis on asthma phenotypes based on inflammatory cell compositions because well described host responses to acute, sub-acute and chronic chlamydial infections involve a wide array of inflammatory cells (including eosinophils, neutrophils and monocytes) the composition of which varies significantly at different temporal stages of the infection [ ] . we have commented on some fairly well defined asthma categories but even these can change over time (e.g., mild asthma can become severe, stable asthma can become uncontrolled). the dynamic and often unpredictable nature of asthma symptomatology is one of the factors that make asthma research so challenging. historically asthma was categorized as either allergic or non-allergic but this distinction was put into question as early as the s [ ] . an early report of the association between cp and asthma did find independent associations of cp biomarkers, clinical allergy and asthma [ ] yet in the clinical setting there is overlap between atopy and cp infection [ ] . the animal models described earlier indicate that cp can promote both asthma and atopy, thus an absolute distinction between these two categories as indicators of differing underlying etiologies may not be warranted. macrolide treatment trials that examine subgroup responses are one approach to examining the predictive value of this and other subgroups. asthma has also been characterized as either "eosinophilic" or "neutrophilic" based on the cellular composition of respiratory secretions or bronchoalveolar lavage fluid (balf) [ ] . simpson et al. [ ] performed an rct of a macrolide (clarithromycin) in severe refractory asthma in adults and reported no overall benefit in the group as a whole. however, there was a positive effect in the pre-specified subgroup of patients with "neutrophilic" asthma as defined by sputum il- and neutrophil numbers. the predictive power of these findings is limited since it is unclear whether sputum composition is stable over time in severe refractory asthma (or any asthma, for that matter). the majority of people with asthma can be well controlled with conventional guideline-based anti-inflammatory treatments (mainly inhaled steroids, sometimes in combination with an inhaled long-acting bronchodilator) [ ] . nevertheless, a significant minority of people with asthma is not well controlled by guideline treatments [ , ] . the proportion of all people with "refractory" asthma (asthma that is not responsive to guideline therapies) has been estimated at between and % but the contribution of refractory asthma to asthma morbidity and mortality is considerably greater, as the most severe % of asthma cases account for % of asthma morbidity and health care costs [ ] . if patients with the "overlap syndrome" (asthma and copd) are included, the numbers of people with refractory disease increases significantly [ ] . of the various novel therapies under consideration for refractory asthma [ ] , macrolides appear to be one of the most promising. a metaanalysis of randomized, controlled trials (rcts) of macrolides for the long term management of asthma in both adults and children found positive effects on peak expiratory flow rate (pefra measure of pulmonary function), asthma symptoms, asthma quality of life (aql), and airway hyper responsiveness (ahr), but not on forced expiratory flow rate in s (fev ) [ ] . the updated cochrane review of rcts [ ] reported positive benefits on asthma symptoms and fev but not on aql (ahr and pefr were not analyzed). a joint european respiratory society/american thoracic society (ers/ats) guideline on severe asthma recommends against the use of macrolides ("conditional recommendation, very low quality evidence") [ ] . the ers/ats guideline states "this recommendation places a relatively higher value on prevention of development of resistance to macrolide antibiotics, and relatively lower value on uncertain clinical benefits." the inconsistent findings of the meta-analyses, along with the uncertainties surrounding the clinical benefits of macrolides, underscore the need for higher quality evidence. this section adds some evidence not included in the meta-analyses, reviews what is known about macrolide side effects (including the clinical consequences of resistance) and suggests research approaches to obtain better evidence. we conclude with some provisional recommendations for clinicians who may be approached by patients with new-onset, uncontrolled and/or refractory asthma who are asking for macrolide treatment. current evidence for all asthma treatments is limited due to selection bias initiated by researchers, clinicians, and even asthma patients themselves. researcher bias. the academic literature is replete with asthma efficacy studies lacking in generalizability [ ] . the efficacy trials on which current asthma treatment guidelines are based systematically exclude > % of people with asthma encountered in the general clinical population [ , ] . only pragmatic effectiveness trials, with minimal exclusions, are able to provide evidence applicable to the general population [ ] . clinician bias. a recent trial of azithromycin for acute exacerbations of asthma (aza-lea) is notable because over % of patients with an exacerbation were not eligible for enrollment primarily because they had received an antibiotic from a treating clinician [ ] . an accompanying editorial speculated that one possible reason for the negative results of azalea was that clinicians were somehow able to identify and treat likely candidates, making them ineligible for the research [ ] . be that as it may, azalea is an example of asthma research made less informative due to nonresearcher clinician behavior. patient bias. hahn et al. [ ] performed a pragmatic trial of azithromycin for asthma (azmatics) in which the likely candidates excluded themselves from randomization. this unanticipated event occurred because azmatics was an internet-based trial; people with severe, refractory asthma identified themselves as likely candidates and contacted the pi for enrollment; but upon learning that they had a % chance of receiving placebo, they opted out of randomization in favor of receiving a comparable azithromycin prescription from their personal clinician [ ] . rather than lose data on this "open-label" (ol) group, the study protocol was altered to include a third (ol) arm. randomized results were similar to azalea (negativesee fig. ); however, ol subjects exhibited large and unprecedented improvements in symptoms and quality-of-life (qol) that persisted long after treatment was completed (figs. & ) . because the ol group was not randomized, these results do not appear in any meta-analysis of rcts; nevertheless they strongly suggest that future macrolide rcts should focus on the severe end of the asthma spectrum, as also recommended by others [ , , ] , and preferably engage patient populations that are unlikely to want to opt out of randomization. macrolide mechanisms of action in asthma are thought to be directly anti-inflammatory, indirectly anti-inflammatory (i.e., antimicrobial), or both. it is difficult to invoke direct anti-inflammatory macrolide effects as responsible for large clinical benefits persisting to months after treatment completion. antimicrobial effects, against specific respiratory pathogens or against the general lung microbiome, remain likely possibilities. circumstantial evidence suggests that macrolide treatment effects may, at least in part, be attributable to antimicrobial actions against chronic atypical infections [ , ] . this issue is by no means settled and requires further research that may be challenging given the selection biases noted above coupled with likely low sensitivity of lung sampling leading to false negative diagnosis of, for example, chronic cp lung infection [ ] . fig. azithromycin improves asthma symptoms and patient quality of life. subjects with severe refractory asthma treated with azithromycin (open label) had fewer persisting asthma symptoms a and greater asthma quality of life b than groups with lesser asthma severity randomized to azithromycin or to placebo [ ] azithromycin is generally well tolerated and is widely used for a variety of acute respiratory illnesses. concerns about adverse effects of azithromycin include development of antibiotic resistance, sudden cardiac death, hearing loss and effects on the host mcrobiome. development of resistance is a possibility whenever antibiotics are used; azithromycin is no exception. however, there are no reports of patient harm from resistant organisms in any cardiorespiratory trial performed to date [ ] . rather, the only detectable clinical effects of azithromycin in these trials were decreased incidences of sinusitis, acute bronchitis and pneumonia, and less use of other antibiotics [ , ] . sudden cardiac death attributable to azithromycin ( in prescriptions in high cardiac risk patients) was plausibly documented in an epidemiologic study of a medicaid population in tennessee [ ] . the same risk was also present for a quinolone (levofloxacin). subsequent population-based studies in average risk populations showed no increased risk of sudden death [ , ] . mild hearing loss was reported in an excess of < % of heart disease subjects randomized to mg azithromycin once weekly for months [ , ] . hearing test changes leading to discontinuation of azithromycin occurred in . % of severe copd subjects randomized to mg azithromycin daily for year [ ] . the clinical significance of these hearing test changes is unclear. notably, it is likely that daily azithromycin dosing is unnecessary [ ] and may lead to increased adverse events [ ] . the prolonged half-life of azithromycin within cells, including within immune system cells, allows weekly dosing and may be preferable to daily dosing when targeting either immune cells or intracellular pathogens such as cp. although largely speculative at this time, it appears that macrolide effects against the lung microbiome may be potentially harmful or helpful in asthma. segal et. al. reported that an week treatment with azithromycin did not alter bacterial burden but reduced α-diversity [ ] . they also observed significant reduction in certain pro-inflammatory cytokines, which might explain the non-specific anti-inflammatory effects proven beneficial in copd and asthma [ ] . published findings from slater et al. that specifically evaluated azithromycin effects on the lung microbiome revealed a significant reduction in bacterial richness in the airway microbiota [ ] . importantly, reductions were most significant in three pathogenic genera: pseudomonas, haemophilus and staphylococcus [ ] . overall, available data suggest that azithromycin treatment of severe asthma, while controversial, may benefit those with confirmed atypical bacterial infection [ ] . resistance, adverse events including sudden death, hearing loss and changes in host microbiome should be monitored in future pragmatic trials. protean manifestations of chronic cp infection, that may include asthma, chronic bronchitis, copd, and the "overlap syndrome" (asthma and copd) argue in favor of pragmatic trials with broad inclusion criteria that include patients with lung multi-morbidity. at least nine domains distinguish pragmatic (or effectiveness) trials from explanatory (efficacy) trials (table ) [ ] . in the context of future rcts of macrolides for asthma, we fig. asthma quality of life (aql) improvement scores at months ( months after completing azithromycin). the minimum clinically important score is ≥ . ; a score of . is considered a large important change [ ] propose that the most important pragmatic domains are ( ) broad eligibility to account for the protean clinical manifestations of both chronic reactive/obstructive lung disease and cp infections as discussed previously and ( ) a comprehensive patient-centered primary outcome. asthma exacerbations are a current popular choice as a primary outcome because they are clinically relevant [ ] . however, exacerbations are only one of many outcomes that are important to asthma patients [ ] . compared to exacerbations, asthma quality-of-life (qol) more comprehensively measures patient-important outcomes. qol includes, but is not limited to, the adverse effects of exacerbations on patient well-being [ ] and qol has proven robust in the sole pragmatic macrolide-asthma trial performed to date [ ] (figs. and ). many patients in this pragmatic trial [ ] had significantly decreased asthma qol at study entry and large important improvements in qol after azithromycin, but did not experience exacerbations. this significant subgroup would have been either possibly ineligible for inclusion or not counted as successes in a trial using exacerbations as the primary outcome. pragmatic trials primarily ask does this treatment work? explanatory trials primarily ask what is the mechanism? addressing target groups/mechanisms in pragmatic trials of macrolides is desirable and possible as secondary aims by specifying a priori hypotheses coupled with subgroup analyses. we recommend studying a wide array of biomarkers using this approach. it is notable that rcts of macrolides have been performed and/or macrolides are being recommended in the treatment of many chronic lung conditions (diffuse pan-bronchiolitis, cystic fibrosis, bronchiectasis, copd, post-transplant bronchiolitis obliterans) [ , ] . a planned trial will test the effectiveness of azithromycin in patients with the "overlap syndrome" (asthma-copd) [ ] . it is time to add asthma to the growing list of chronic respiratory conditions that are being evaluated by robust macrolide rcts that are pragmatic in nature. in the meantime, patients with severely uncontrolled and/or refractory asthma, or new-onset asthma are increasingly searching the internet for new information and are sometimes better informed than their doctor about current evidence regarding macrolides for asthma (hahn: personal observations). pending more robust data from asthma rcts that have yet to be performed, how should practicing clinicians respond when such patients request macrolide treatment? as stated above, the ers/ats guidelines on severe asthma recommend against the use of macrolides, albeit with caveats that the evidence for this recommendation is weak and provisional [ ] . informal guidelines from a pulmonology research group state that they recommend macrolide treatment only for confirmed diagnoses of atypical lung infection [ ] . from a practical standpoint, their recommendation limits treatment only to those who have undergone bronchoscopy; even then the diagnostic sensitivity is likely to be less than perfect due to sampling issues discussed earlier. both these recommendations have met resistance from patients who have read and understood the evidence (hahn: personal communication). we offer a third alternative recommendation, repeated word for word from the conclusion of the sole practice-based pragmatic trial of azithromycin for asthma conducted to date [ ] : "pending further randomized trials, given the relative safety of azithromycin and the significant disease table proposed design for a randomized trial of azithromycin for the long-term management of asthma. seven of nine precis- [ ] domains are recommended as pragmatic and two as explanatory domain pragmatic or explanatory? a comments eligibility. who is selected to participate in the trial? pragmatic exclusions only for safety; comorbidities included. recruitment. how are participants recruited into the trial? pragmatic recruited from practice sites (emergency rooms, clinics). setting. where is the trial being done? pragmatic performed at the practice site. organization. what expertise and resources are needed to deliver the intervention? no extraordinary expertize required. flexibility: delivery. how should the intervention be delivered? total weekly oral dose can be administered on any schedule desired. flexibility: adherence. what measures are in place to make sure participants adhere to the intervention? adherence encouraged by frequent contacts by the research team and monitored by patient report and pill count. follow-up. how closely are the participants followed-up? explanatory -monthly study visits to collect non-routine information (e.g., spirometry, biomarkers, qol) primary outcome. how relevant is it to participants? pragmatic outcome is patient-centered (see text for discussion). to what extent are all data included? pragmatic intention-to-treat. a precis- grades on a scale from (extremely explanatory) to (extremely pragmatic). column presents recommendations for which end of the spectrum is emphasized burden from severe refractory asthma, prescribing prolonged azithromycin therapy to patients with uncontrolled asthma may be considered by managing clinicians, particularly for patients who have failed to respond to conventional treatment and as an alternative to instituting immunomodulatory agents". interested clinicians and others wishing more information on patient experiences, scientific evidence and treatment alternatives are referred to a book on the subject [ ] . evidence supports a complex interaction between host genetics/immune response and environmental factors (e.g., viral infections, microbiome) in the development, exacerbation and severity of asthma. emerging evidence from animal models and human studies points to chlamydia pneumoniae (cp) as a key player in this complex scenario. future research is required to unravel the quantitative contribution of cp to asthma pathogenesis, and pragmatic treatment trials are recommended to investigate 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asthma chronic infection and severe asthma the precis- tool: designing trials that are fit for purpose the role of macrolides in asthma: current evidence and future directions measuring quality of life in asthma role of long term antibiotics in chronic respiratory diseases long-term macrolide treatment for chronic respiratory disease rofumilast or azithromycin to prevent copd exacerbations (reliance) the role of atypical infections and macrolide therapy in patients with asthma not applicable. not applicable. data sharing is not applicable to this article as no datasets were generated or analyzed during the current study. authors' contributions ww initiated the writing of the manuscript and contributed to the sections highlighting basic research and animal models. dh contributed to sections dealing mainly with clinical analyses, treatment and clinical trials. however, both authors contributed to its multiple revisions and formatting. both authors read and approved the final manuscript. ww is an associate professor of microbiology at the university of massachusetts amherst and director of the premed/prehealth advising center. he was the first to show a direct link between cultivable c. pneumoniae in the lower airway and pediatric asthma severity. ww has carried out animal model studies confirming a link between early life airway infection with c. pneumoniae and reactive airway disease. the authors declare that they have no competing interests. figures and were reproduced by permission of the american board of family medicine. ethics approval and consent to participate not applicable.• we accept pre-submission inquiries • our selector tool helps you to find the most relevant journal submit your next manuscript to biomed central and we will help you at every step: key: cord- -f iu sje authors: ko, fanny w.; chan, ka pang; hui, david s.; goddard, john r.; shaw, janet g.; reid, david w.; yang, ian a. title: acute exacerbation of copd date: - - journal: respirology doi: . /resp. sha: doc_id: cord_uid: f iu sje the literature of acute exacerbation of chronic obstructive pulmonary disease (copd) is fast expanding. this review focuses on several aspects of acute exacerbation of copd (aecopd) including epidemiology, diagnosis and management. copd poses a major health and economic burden in the asia‐pacific region, as it does worldwide. triggering factors of aecopd include infectious (bacteria and viruses) and environmental (air pollution and meteorological effect) factors. disruption in the dynamic balance between the ‘pathogens’ (viral and bacterial) and the normal bacterial communities that constitute the lung microbiome likely contributes to the risk of exacerbations. the diagnostic approach to aecopd varies based on the clinical setting and severity of the exacerbation. after history and examination, a number of investigations may be useful, including oximetry, sputum culture, chest x‐ray and blood tests for inflammatory markers. arterial blood gases should be considered in severe exacerbations, to characterize respiratory failure. depending on the severity, the acute management of aecopd involves use of bronchodilators, steroids, antibiotics, oxygen and noninvasive ventilation. hospitalization may be required, for severe exacerbations. nonpharmacological interventions including disease‐specific self‐management, pulmonary rehabilitation, early medical follow‐up, home visits by respiratory health workers, integrated programmes and telehealth‐assisted hospital at home have been studied during hospitalization and shortly after discharge in patients who have had a recent aecopd. pharmacological approaches to reducing risk of future exacerbations include long‐acting bronchodilators, inhaled steroids, mucolytics, vaccinations and long‐term macrolides. further studies are needed to assess the cost‐effectiveness of these interventions in preventing copd exacerbations. chronic obstructive pulmonary disease (copd) is a common disease worldwide - with significant morbidity and mortality, and incurs intensive expenditure of healthcare resources. the literature of acute exacerbation of copd (aecopd) is fast expanding. this review focuses on several aspects of aecopd including epidemiology in the asia-pacific region, diagnostic approach including investigations and acute management of exacerbations. the evidence for nonpharmacological interventions for patients who have had a recent exacerbation is reviewed, and treatments to reduce future risk of exacerbations are discussed. the copd poses a major health and economic burden in the asia-pacific region, as it does worldwide. in a recent population-based survey conducted in nine asia-pacific territories, the prevalence of copd was estimated at . %. of patients with copd, % had at least one exacerbation in the previous year, and % required hospitalization. a study from hokkaido, japan, reported an exacerbation frequency ranging from . to . events per person per year. patients with exacerbations in the first year of the study had more frequent aecopd during follow-up and worse quality of life (qol). the copd is one of the leading causes of mortality worldwide, and acute exacerbations contribute substantially to this. copd was the fifth leading cause of death in and will rank third by . in hong kong, copd ranked as the third leading cause of respiratory death, after respiratory infection and cancer. a japanese study of patients admitted with copd as the primary condition or comorbidity found a higher mortality in patients with older age, male gender, lower body mass index (bmi), more severe dyspnoea, lower level of consciousness and worse activities of life. a new zealand study of patients with aecopd requiring hospitalization found that the curb score ( to , and to ) was associated with increasing -day mortality rate ( . %, . % and . %, respectively). impairment of working ability or early retirement in copd patients due to physical disability contributes to a substantial socioeconomic loss and health expenditure. a survey in of copd patients ( % male) performed in rural areas of xuzhou, china, found that a high proportion of patients ( %) required hospitalization due to respiratory symptoms, with a total indirect economic loss estimated at yuan ($us ). these patients were found to have poor knowledge about copd, and the treatment given during both the stable and acute exacerbation states did not match international standards, which could partly explain the high exacerbation rate. the triggering factors of aecopd include infectious and noninfectious precipitants. however, up to % of aecopd is of unknown aetiology. infections respiratory tract infections, either viral or bacterial, are major causes of aecopd. the true prevalence depends on the definition of the individual study. a study in south korea estimated that up to % of aecopd cases had a precipitating respiratory tract infection, based on compatible infective symptoms and computed tomography findings. a prospective study from australia estimated that % of the aecopd was due to respiratory infection based on positive microbiological results, irrespective of radiological findings. in a systematic review involving the asia-pacific countries, the weighted mean prevalence of respiratory viral infections in aecopd was %. significant geographical variation in viral prevalence was noted in this review, with influenza virus being the most common in asia, while picornavirus was more common in australia, europe and north america. other relatively common causative viruses included respiratory syncytial virus, coronaviruses, parainfluenza, adenovirus and human metapneumovirus. , when compared with noninfective aecopd, those with viral infection had a more severe clinical course, as reflected by longer length of hospital stay, deterioration of lung function and worse hypoxaemia. multiple studies have also found that aecopd due to viral infection is more common in the spring and winter seasons. , , bacterial infections bacterial infection is a major cause of infective aecopd, with prevalence ranging from % to %. , [ ] [ ] [ ] pseudomonas aeruginosa, klebsiella pneumoniae and haemophilus influenzae were the three most common pathogens identified in mainland china and taiwan. , in hong kong and australia, h. influenzae, p. aeruginosa and moraxella catarrhalis were the major pathogens. , the most common causative microbes from a korean study were streptococcus pneumoniae, p. aeruginosa and k. pneumoniae. although more than % of the pseudomonas strains were susceptible to common antipseudomonal antibiotics in china, pseudomonal infection itself was associated with poor clinical outcome in a study in taiwan. a diverse range of bacterial pathogens is implicated in aecopd, and hence, a wide variability of antibiotics resistance patterns has been observed in different countries in the asia-pacific region. standard antibiotic therapy recommended by copd guidelines in western countries may not be directly applicable in the asia-pacific region. continuous surveillance of the prevailing organisms and their antibiotic resistance pattern is warranted. co-infection by virus and bacteria at the time of aecopd is not uncommon, ranging from % to %. an australian study found that aecopd patients with co-infection had a lower forced expiratory volume in s, a longer length of hospital stay and higher likelihood of hospital readmission. noninfectious causes of aecopd including air pollution, meteorological effect and comorbidities of the patients such as pulmonary embolism and heart failure always need to be considered. in the asia-pacific region, outdoor air pollution is an important cause of aecopd. the exact prevalence varies when different pollutants are taken into account. although well accepted, the causal relationship between air pollution and aecopd is difficult to establish, as most of the studies have focused on the temporal relationship between the two. these studies should be interpreted with caution due to variable definitions and study designs. an increase in air pollutants such as sulphur dioxide (so ), , nitrogen dioxide (no ), - ozone (o ), , small-diameter particulate matter (pm) . , , , pm and coarse pm ( . - -μm aerodynamic diameter) increases the risk of aecopd and/or hospitalizations, with either immediate harmful effects or a time lag of several days. mortality rate increases from % to % with an increase in concentrations of pm . , pm , and no . , in hong kong, with the introduction of restrictions on the sulphur content in fuel oil in july , there was an immediate fall in ambient so , leading to a significant decline in allcause and respiratory disease mortality. the relationship between carbon monoxide (co) exposure and aecopd is not straightforward. recent data from tian et al. from hong kong showed a reduction in hospitalization for copd and respiratory tract infections after short-term exposure to ambient co. , the effect was robust even after the adjustment of other pollutants, weather variables and the lag days of co exposure. the protective effect may be secondary to an acute protective effect from respiratory tract infection, a reduction in sputum eosinophils or improvement of bronchial responsiveness. however, the direct clinical effect of co exposure on the rate of aecopd remains to be confirmed. second-hand smoking and exposure to biomass fuel combustion are major sources of indoor air pollution. exposure to second-hand smoke was associated with increased risk of visits to emergency department by patients with copd and a greater risk of hospitalization in a study from san francisco, usa. however, similar studies are not available in the asia-pacific region. there is as yet little information on the effect of exposure to combustion of biomass fuels on symptoms or exacerbations of patients with copd. a lower ambient temperature, even with a decrease of °c , can lead to aecopd. the effect is more marked when there is a significant drop ( °c) in ambient temperature. winter season and low humidity are confirmed triggers for aecopd , and hospital admissions in cities such as hong kong and shanghai, and the lag effect could be as long as days. the peak seasons for aecopd were spring and autumn from a study in hokkaido, japan. it appears that the seasons associated with aecopd differ among cities. besides temperature as a seasonal factor, viral infection and air pollution can also interact with seasonal effects to influence risk of developing aecopd. the effect of air pollutants on the risk of aecopd is also dependent on the ambient temperature. , , the detrimental effect of lower temperature on aecopd can be potentiated by a concomitant increase in no , o and so levels. increased barometric pressure, greater hours of sunshine and lower levels of humidity have been associated with increased risk of aecopd. a study from new zealand has shown that the use of long-term humidification therapy, with humidified, fully saturated air at °c and a flow rate of - l/min, can lead to significantly fewer exacerbation days, increased time to first exacerbation and reduced exacerbation frequency for chronic airway diseases, including copd. other causes and comorbidities a recent korean study has shown that noninfectious causes of aecopd included pulmonary embolism ( %), congestive heart failure ( %) and discontinuation of copd medications ( %). causes could not be identified in % in this study, which did not assess other potential noninfectious causes including air pollution, meteorological effect and comorbidities of the patients. the prevalence of venous thromboembolism ranged from % to % , [ ] [ ] [ ] [ ] in the screened aecopd population, depending on the study objective and method of screening. acute exacerbations of copd are characterized by a worsening of the patient's respiratory symptoms, dyspnoea, cough and/or sputum, more than the usual day-to-day variations and requiring changes to their medication. depending on its severity, an aecopd may be managed in primary care or as an outpatient or, if severe, may require hospitalization. after initial history and examination, a number of investigations may be useful in assessing the aetiology, severity and complications of an aecopd ( table ). the selection of investigations will depend on the clinical setting in which the patient is being treated (e.g. primary care, emergency department or hospital), with fewer investigations needed in primary care if the patient has a mild to moderate exacerbation, compared with more intensive workup if the patient is hospitalized with a severe exacerbation and respiratory failure. other biomarkers of the bacterial aetiology of exacerbations have been tested in studies, but none is yet in routine clinical practice. the use of serum procalcitonin, which is a marker of bacterial infection, to guide prescription of antibiotic therapy was tested in a randomized controlled trial (rct). in this study, noninferiority of the procalcitonin-guided approach, compared with the standard guideline-based approach, was not conclusively proven. with the development of molecular, cultureindependent techniques, it is now evident that the healthy lung has its own site-specific population of microbes and is not a sterile organ as previously thought. the community composition of microbial flora can be determined by sequencing the variable hot topics on acute exacerbation of copd regions of the s gene, which encodes bacterial ribosomal ribonucleic acid. according to the 'vicious cycle' paradigm, chronic bacterial infection in the airways may drive inflammation, with significant implications for the pathogenesis and progression of copd, including impact on exacerbations. , alterations in the lung microbiome in copd exacerbations several small studies have sampled the airway microbiome during aecopd. experimental infection with rhinovirus increased the total bacterial load in sputum samples of patients with copd, with 'outgrowth' and dominance of h. influenzae occurring at to weeks after viral infection, which suggests that acute viral infection changes the community composition of the lung microbiome. a complex microbiome with diverse bacterial communities has been demonstrated both in endotracheal aspirates from mechanically ventilated patients with severe aecopd and in sputum samples obtained from patients experiencing a moderate exacerbation. bacterial community composition may be relatively stable in sputum samples at the start of an exacerbation and during recovery over months. however, other studies have found that the structure and diversity of both bacterial and fungal genera in the sputum microbiome can change rapidly each day, as shown in hospitalized copd patients with a severe exacerbation. similarly, we have observed dynamic and rapid changes of the airway microbiome in a study of cystic fibrosis (cf) patients hospitalized for antibiotic therapy during an acute exacerbation. in the cf population, there was an increase in microbial diversity and a reduction in the relative abundance of pseudomonas by day of intravenous antibiotics, but by days to of the admission, bacterial community composition had returned to pretreatment levels. whether similar changes occur in the lung microbiome with treatment during an aecopd is not clear, but a recent small study (six patients only) suggests that this may indeed be the case. overall, these studies illustrate the dynamic nature of the lung microbiome during and after exacerbations of lung diseases that are characterized by chronic bacterial infection in the airway. however, most studies have been conducted in only small numbers of patients, and further investigation is needed to determine the relationship between composition of the lung microbiome and risk of aecopd and progression. moreover, adequately powered studies are required to determine whether restoration of the diversity of the microbiome with treatment may serve as a biomarker of recovery from exacerbation and how this relates to subsequent re-exacerbation rates and long-term lung function decline. continuous prophylactic antibiotics, especially macrolides, have been shown to reduce the frequency of aecopd. as yet, no studies have examined the effects of long-term antibiotics on the copd microbiome; however, several studies have measured changes in airway bacterial load. in a -week rct of stable copd patients with neutrophilic airway inflammation, treatment with azithromycin tended to reduce the frequency of severe exacerbations and decreased sputum neutrophil counts and neutrophil chemokine (cxcl ) levels. total bacterial load was reduced fold with azithromycin, but this change did not reach statistical significance. in a -week study of patients with copd, there was no change in airway bacterial load (measured by s quantitative polymerase chain reaction (qpcr)) with the use of azithromycin, pulsed moxifloxacin or doxycycline (compared with placebo). despite no apparent reduction in bacterial load in these initial reports, characterization of changes in the airway microbiome remains an important goal in patients using long-term antibiotics, because beneficial changes in the community dynamics of the microbiome could occur, but without appreciable change in total bacterial load. more detailed, prospective studies of the lung microbiome and its impact on exacerbations are required. inhaled bronchodilators (short-acting β agonists and short-acting muscarinic antagonists) are effective in the treatment of aecopd. several methods of administration are available in the acute setting, including wet nebulizers and metered dose inhalers (mdi) with spacer device. nebulizers and mdi with spacers have demonstrated equal efficacy in relieving acute airflow obstruction, with no significant difference in length of hospital stay. a recent cochrane review found no difference in outcomes for nebulizers and mdi with spacers in patients with acute asthma; a similar appraisal of the evidence specific to copd patients is awaited. in addition to clinical endpoints, the relative lung distribution of salbutamol appears to be similar for nebulizer versus mdi with spacer. there are theoretical benefits in favour of mdi with spacers, including faster administration, improved cost-effectiveness and increased opportunity for inhaler technique education. nebulizers are known to generate aerosols, which may be important in the transmission of infection. the familiarity of staff and patients with each delivery method may vary, and patient factors including reduced level of consciousness or severe dyspnoea may be relevant, necessitating an individually tailored decision. for patients receiving mechanical ventilation, there is currently insufficient evidence to support one delivery method over the other. the use of systemic corticosteroid in the treatment of aecopd is well established, based on its effectiveness in suppressing airway inflammation. a prolonged course and high-dose systemic corticosteroids can give a longer and better anti-inflammatory effect. however, steroid use is associated with many adverse events, especially with the cumulative dose due to the recurrent nature of aecopd. there is currently no consensus on the standard regimen of systemic corticosteroids, in regard to dose, route and duration for aecopd. the recommended steroid regimens by the global obstructive lung disease (gold) guideline and respiratory societies in the asia-pacific region are shown in table . [ ] [ ] [ ] [ ] studies suggest that use of oral corticosteroids at low dose is as effective as intravenous corticosteroids given at high dose, while minimizing the risk of adverse effects. the reduction in the use of corticosteroids in exacerbated copd (reduce) trial showed that a -day course of oral corticosteroids was not inferior to a -day course in terms of exacerbation recurrence but with a shorter length of hospital stay. a cochrane review suggested that a short course, to days, of systemic corticosteroids does not lead to increase in treatment failure or risk of relapse of aecopd. data regarding the use of systemic corticosteroids are limited in the asia-pacific region. a turkish study comparing efficacy between oral steroid and intravenous methylprednisolone found that the improvement of blood gas parameters, symptom scores, length of stay and readmission due to aecopd were comparable with these two treatments. however, the group receiving intravenous methylprednisolone had more events of recurrent aecopd requiring attendance to emergency department, hyperglycaemia and worsened blood pressure control. the scarcity of data is also indirectly reflected by the inconsistent corticosteroids regimens noted in a taiwanese observational study of aecopd. there have been relatively few studies of the use of nebulized corticosteroids for exacerbations, as an alternative to systemic steroids. given that bacteria are implicated in a substantial proportion of exacerbations (as discussed earlier in epidemiology), antibiotics are frequently used in the acute management of inpatients or outpatients with an aecopd. broad-spectrum antibiotics covering common respiratory pathogens, based on local guidelines and microbial patterns, are recommended for patients who are experiencing at least two symptoms that are consistent with a greater likelihood of bacterial infection such as an increase in sputum purulence or volume and dyspnoea. examples of commonly prescribed antibiotics include amoxycillin (with or without clavulanic acid), a macrolide or tetracycline, or a respiratory quinolone. oral antibiotics are preferred, although intravenous antibiotics can be used oral prednisolone mg/day × days jrs oral prednisolone - mg/day × - days tsanz oral prednisolone - mg/day × days (tapering dose required for those receiving > days) mts oral corticosteroids, no longer than days, dose not specified pccp oral prednisolone hot topics on acute exacerbation of copd if there is impaired mental state, swallowing difficulty, severe exacerbation or coexistent pneumonia. the optimal duration of antibiotic treatment is not certain from the available evidence, although antibiotics are usually recommended for days. despite the widespread use of antibiotics for aecopd in clinical practice, a cochrane systematic review of trials ( participants) of antibiotics versus placebo for aecopd found inconsistent benefit for the use of antibiotics, depending on the clinical setting and severity of the exacerbation. for hospitalized patients, the pooled results showed that antibiotics reduced the risk of treatment failure (relative risk of . ). in contrast, for outpatient treatment, the quality of evidence for benefit was generally low and was not statistically significant when the analysis was restricted to currently available antibiotics (as opposed to antibiotics used in older studies). for patients admitted to intensive care units (icu), there was high quality evidence from trial which showed a statistically significant effect on mortality. a retrospective clinical audit in an australian hospital found that inpatient antibiotic regimens frequently diverged from published clinical guidelines and that discordance was associated with longer length of stay and greater healthcare costs. oxygen supplemental oxygen therapy is often required in the treatment of aecopd. the thoracic society of australia and new zealand has produced endorsed guidelines for acute oxygen use. to avoid the consequences of hypoxaemia and hyperoxaemia, supplemental oxygen should be titrated to target oxygen saturations of - % in patients with copd or other chronic respiratory diseases. pulse oximetry should be employed routinely, and consideration given to arterial blood gas measurement. patients with high or increasing fio requirements may require close observation or admission to a high dependency unit/icu facility. where nebulizers are used for administration of bronchodilators, an air-driven nebulizer is preferred. , noninvasive ventilation one of the major breakthroughs in treating aecopd patients in the last few decades is the application of noninvasive ventilation (niv) for acute hypercapnic respiratory failure. use of niv effectively unloads the respiratory muscles and reduces the effort on the work of breathing. niv reduces intubation rate, overall mortality due to respiratory failure and rates of invasive mechanical ventilation-related complications. based on the evidence from studies in the asia-pacific region and western countries, niv is now recommended by clinical guidelines as first-line treatment for acute type respiratory failure due to aecopd. , - the criteria for initiation of niv include respiratory acidosis (arterial ph ≤ . and/or partial arterial carbon dioxide concentration (paco ) ≥ . kpa or mm hg), severe dyspnoea with clinical signs indicating fatigue of respiratory muscles, increased work of breathing or both. these signs include retraction of the intercostal spaces, use of respiratory accessory muscles and paradoxical movement of the abdomen. when niv is used together with effective pharmacological treatment, many patients will demonstrate recovery and be able to be weaned from niv, with mean duration of use ranging from to days. [ ] [ ] [ ] regarding adverse effects, the use of niv has been linked to claustrophobia, skin abrasion over the application site of the mask interface, gastric distension and pneumonia, although the incidence of pneumonia is less common than with invasive mechanical ventilation. which patients with aecopd should be hospitalized? high-risk aecopd patients are best managed in hospital, to aim to prevent the high rates of morbidity and mortality. the various admission criteria of the gold guidelines and from three asia-pacific respiratory societies are listed in table . the criteria can be generally divided into three categories: severe copd symptoms: increase in shortness of breath and increased frequency of exacerbation development of new complications: pulmonary hypertension, carbon dioxide retention (reduced alertness), haemodynamic instability or arrhythmia inadequate outpatient treatment expected: advanced age, failed initial medical or outpatient management and insufficient home support unfortunately, death is not an uncommon outcome for hospitalized aecopd patients. the mortality rate ranged from % to % in the asia-pacific region based on different cohorts , , [ ] [ ] [ ] and was as high as % for patients requiring icu admission. increasing age , , , and impaired respiratory gas exchange were risk factors for in-hospital mortality. acidotic ph, high paco and low partial arterial oxygen concentration were all associated with higher inhospital mortality. , , other risk factors include abnormal clinical findings (increased dyspnoea, long-term use of corticosteroids and high acute physiology and chronic health evaluation (apache) ii score. there are few prospective cohort studies on the long-term prognosis for discharged aecopd patients in the asia-pacific region. the -day mortality rate has been estimated to be around . %. , the -year mortality rate was % to % in patients not requiring niv support or icu care. , , , for patients who required niv support or icu care during the index hospitalization, the -year mortality rates were % and %, respectively, with a very high overall mortality rate of % at years after discharge. cardiovascular comorbidity is common among copd patients. in an italian study of hospitalized aecopd patients, % had arterial hypertension, % had chronic heart failure, and % had ischaemic heart disease. only a limited number of studies have been conducted in the asia-pacific region regarding the cardiovascular comorbidity in aecopd patients. a study from australia observed that cardiovascular events contributed to % of long-term mortality following the first episode of aecopd. a study from italy found that in patients admitted to the hospital for aecopd, cardiac troponin elevation emerged as an independent predictor of increased risk of allcause mortality. it is not certain whether aecopd increases cardiac stress and exacerbates cardiac comorbidity, therefore leading to excessive mortality related to cardiovascular events during or after an aecopd. antibiotics antimicrobial action adverse effects of specific antibiotics, antibioticassociated diarrhoea, candidiasis and antibiotic resistance (repeated or prolonged use) oxygen therapy improve gas exchange risk of carbon dioxide retention with hyperoxia and adverse effects of delivery methods (e.g. dry nasal passages with nasal prongs) niv improve respiratory acidosis and decrease respiratory rate, work of breathing, severity of breathlessness, complication such as ventilator-associated pneumonia and length of hospital stay, mortality and intubation claustrophobia, skin abrasion over the application site of mask interface, gastric distension and pneumonia support patient with respiratory failure (usually when niv failed or not suitable) ventilator-associated pneumonia, barotrauma and failure to wean to spontaneous ventilation niv, noninvasive ventilation. hot topics on acute exacerbation of copd treatment approaches for aecopd are summarized in table . there is recent strong interest in the nonpharmacological interventions for patients who have recently experienced an aecopd. as this is a high-risk group of patients, studies of intervention strategies both during inpatient stay and shortly after discharge have been undertaken, with the aim of decreasing readmission rates and improving qol. these interventions include disease-specific self-management, pulmonary rehabilitation, early medical follow-up, home visits by respiratory health workers, integrated care programmes and telehealth-assisted hospital at home. self-management describes formalized patient education programmes aimed at teaching skills and providing support for health-promoting behaviour. a cochrane review has found that self-management interventions (in the absence of supervised exercise) are effective in patients with copd and are associated with improved health-related qol, a reduction in respiratory-related and all-cause hospital admissions, and improvement in dyspnoea. however, heterogeneity among interventions, study populations, follow-up time and outcome measures have made it difficult to formulate clear recommendations regarding the most effective form and content of selfmanagement in copd. in the only study that has recruited patients immediately following an aecopd ( patients with aecopd after hospital discharge from centres in spain and belgium), intervention consisted of an individually tailored care plan upon discharge that was shared with the primary care team, as well as accessibility to a specialized nurse case manager through a web-based call centre. the intervention resulted in lower rates of hospitalization and readmissions, although there was no difference in mortality at -month follow-up. another systematic review that examined the effects of self-management alone delivered during hospitalization for an aecopd or within month of hospital discharge found no effects on mortality rate, depressive symptoms, primary care usage or exercise capacity. minimal effects were found on self-efficacy, anxiety symptoms and health-promoting behaviour. self-management interventions delivered immediately post-aecopd vary widely, and outcome measures are inconsistent. such variations have made it difficult to draw strong recommendations regarding effectiveness. further studies on self-management interventions, preferably delivered by trained healthcare professionals to selected patients with structured follow-up, are required. a cochrane review of nine small heterogeneous trials of peri-hospitalization and early post-hospitalization pulmonary rehabilitation showed wide-ranging benefits including a significantly reduced risk of readmission. an rct in hong kong showed that an early rehabilitation programme for weeks following aecopd led to improvement in qol for up to months but did not reduce healthcare utilization at year. although pulmonary rehabilitation appears useful for post-hospitalization copd patients, a recent observational study reported that only % of people completed a post-hospitalization pulmonary rehabilitation programme over a -month period. from the patient perspective, a common reason for nonparticipation in pulmonary rehabilitation is transport difficulties, particularly in the immediate post-discharge setting where patients often feel too ill and/or breathless to engage. as treatment guidelines have recommended sessions of exercise training to be effective, this may be a difficult task for many patients without adequate social support. a recent study noted that comorbidities do not seem to preclude patients with copd from obtaining significant and clinically meaningful improvements in functional exercise capacity and health status following pulmonary rehabilitation. complex patients with copd and comorbidities thus should not be excluded from pulmonary rehabilitation. encouraging patients immediately post-aecopd to participate in pulmonary rehabilitation and obtaining the resources required for a pulmonary rehabilitation programme remain critical challenges in the care of copd patients. early clinic follow-up by pulmonologists appears to reduce exacerbation-related rehospitalization rates of copd patients. a retrospective cohort study in israel of patients discharged from hospital following treatment of aecopd found that early clinic followup by a pulmonologist within a month from hospital discharge could reduce exacerbation-related rehospitalization rates within days from discharge. another retrospective cohort study using data of medicare beneficiaries in the usa involving patients admitted for aecopd found that a follow-up visit with their primary care physician or pulmonologist within days of discharge could lower rates of emergency room visits and readmission in patients with copd. additional rct are needed to assess the beneficial effects of the specific components of care in the early clinic consultation for these patients who are recently discharged after an aecopd. a cochrane review analysing data of copd patients from nine rct that provided interventions by an outreach nurse (visiting patients in their homes, providing support and education, monitoring health and liaising with physicians) found that outreach nursing programmes for copd improved diseasespecific health-related qol. however, the effect on hospitalizations was heterogeneous, reducing hot topics on acute exacerbation of copd admissions in one study but increasing them in others. among these studies, only one study involved patients with recent aecopd, and this study also included other patients with congestive heart failure. another study involved patients who had experienced aecopd within the past months. there are currently inadequate data to recommend this service for patients shortly post-aecopd. a recent meta-analysis of data from trials involving people, with a follow-up ranging from to months, has shown that integrated disease management of copd improved disease-specific qol and exercise capacity, and reduced hospital admissions and hospital days per person. the trials included in this meta-analysis varied greatly with participants being treated in all types of healthcare settings (mostly primary or secondary with one trial in tertiary care) and with different programmes. the studies included in this metaanalysis consisted of stable copd patients who had received a programme provided by caregivers from at least two disciplines, with two different components (e.g. exercise, education or self-management) and with a duration of at least months. no rct has specifically assessed the effect of a comprehensive programme with multidisciplinary input for patients who have had a recent admission for aecopd. however, there are studies suggesting that a post-aecopd rehabilitation programme and self-management may help to decrease exacerbations and improve the qol of patients. , ko et al recently reported an audit of patients undergoing a -week comprehensive copd care programme shortly post-aecopd and found that patients had a reduction in hospital admissions at year after the programme compared with the year prior to the commencement of programme. further studies are needed to assess if integrated disease management for patients shortly after aecopd can help to decrease readmissions. the cost-effectiveness of these labour-intensive programmes should also be assessed. treatment of aecopd at home may lead to fewer readmissions in comparison with conventional hospital treatment. however, this is not suitable for all copd patients as many aecopd patients are too unwell to be managed at home, at least initially. mortality, in addition to patients' or relatives' satisfaction, is not significantly altered by either method of care in this group of selected patients who can be considered for receiving home care. with advancement in technology, telemedicine is expanding in its application. a recent rct compared the effects of home-based telehealth hospitalization with conventional hospitalization in patients with severe aecopd. the study found that home-based telehealth hospitalization was noninferior to conventional hospitalization when the noninferiority margin was set at % of the control group's risk of readmission. the data suggest that a subgroup of patients with severe copd may be treated for acute exacerbation at home using telehealth, without the physical presence of health professionals but with a proper organizational 'backup'. further studies are needed to assess patient selection, and the safety and cost-effectiveness of such approaches. in particular, the population in the asia-pacific region may have education levels and socioeconomic conditions that are different from those of other countries. evidence-based clinical guidelines for copd include recommendations for interventions targeted at preventing exacerbations, including a range of inhaled, oral and injectable medicines that reduce the frequency of copd exacerbations. inhaled long-acting β agonists, alone or in combination with inhaled corticosteroids, and inhaled long-acting muscarinic antagonists all reduce exacerbation rates. the oral phosphodiesterase- inhibitor, roflumilast, is associated with fewer exacerbations in copd patients with a phenotype of chronic bronchitis and history of prior exacerbations. oral mucolytic agents such as n-acetylcysteine also reduce acute exacerbations. vaccination against both influenza and pneumococcal infections is advocated as part of overall care of copd patients. a checklist of recommendations can help to remind clinicians about the importance of preventing future exacerbations, especially at the time of hospital discharge. despite such treatment recommendations, aecopd still occurs frequently and is associated with significant morbidity and mortality. there is thus an urgent need for more effective strategies to prevent exacerbations. macrolide antibiotics have shown promise in other chronic lung diseases, prompting recent interest in prophylactic use in patients with copd. nine rct have reported the effects of prophylactic macrolide antibiotics on risk of exacerbations of copd. , [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] furthermore, two systematic reviews found a statistically significant reduction in copd exacerbations with the use of long-term macrolides. , in the cochrane systematic review of herath and poole, covering five of the studies, the number needed to treat to prevent one exacerbation was eight. in the meta-analysis of ni et al, the unadjusted risk ratio of an acute exacerbation with macrolide treatment was . ( % confidence interval: . - . ; p < . ). subgroup analysis suggests that months of macrolide therapy is the minimum treatment duration necessary to demonstrate significant reductions in copd exacerbations. , although these pooled analyses demonstrated a statistically significant improvement in total score for the st george respiratory questionnaire with macrolide use, this failed to reach the minimal clinically important difference. , frequency of hospitalization and all-cause mortality did not differ between macrolide and placebo groups. , these systematic reviews suggest that more studies are required to determine optimal treatment regimen hot topics on acute exacerbation of copd (dose, individual agent and duration) and that patient selection needs to be further explored as perhaps subpopulations of patients with copd may derive greater benefit. adverse effects are an important concern given that patients with copd are generally older with associated multimorbidities, and the potential for increased antimicrobial resistance needs to be considered. in summary, while emerging evidence suggests that continuous macrolide therapy reduces exacerbation frequency in copd, there are many questions that remain to be addressed before this treatment can be routinely recommended in clinical practice. the challenge is to identify the patients with copd who will benefit the most from macrolides while minimizing the risk of adverse effects. the aecopd poses a major health and economic burden to society. infectious etiologies that are related to aecopd involve a wide variety of viruses and bacteria. environmental factors including air pollution and meteorological effects also influence the rate of aecopd. the approach to diagnostic tests for aecopd consists of characterizing gas exchange, infection and inflammation. acute management typically involves use of bronchodilators, antibiotics and/or systemic steroids and, if severe, oxygen and niv. further studies are needed to assess the different types of nonpharmacological interventions available shortly post-aecopd, as well as pharmacotherapy to reduce future risk of exacerbations, for identification of the efficacious components and overall cost-effectiveness. fwk is a honorary clinical associate professor at the chinese university of hong kong and a consultant of the prince of wales hospital, hong kong. her clinical work is in the field of adult respiratory medicine, and involves studying different aspects of copd including etiologies and predictors for exacerbations, pulmonary rehabilitation, comorbidities and management programmes. kpc is a resident of the respiratory division of the prince of wales hospital, hong kong. his clinical work is in the field of adult respiratory medicine, and research work in the field of airway diseases in particular in the predictors for exacerbation, comorbidities and management of copd. dsh is a stanley ho professor of respiratory medicine at the chinese university of hong kong and a honorary consultant physician at the prince of wales hospital, hong kong. his research interests include clinical management of common airway diseases and emerging severe acute respiratory infections. jrg is a respiratory advanced trainee and a research scientist at the prince charles hospital, and a phd student at the university of queensland, brisbane, australia. dwr is a thoracic and cystic fibrosis physician at the prince charles hospital, an associate professor in the school of medicine, the university of queensland, and the team head of lung inflammation and infection, qimr berghofer medical research institute, brisbane, australia. iay is a thoracic physician and director of thoracic medicine at the prince charles hospital and a professor at uq thoracic research centre, school of medicine, the university of queensland, brisbane, australia. his clinical work is in the field of thoracic medicine, and his research team is studying gene-environmental interaction in 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nationwide population-based study is elevated troponin associated with in-hospital mortality in emergency department patients admitted with chronic obstructive pulmonary disease? in-hospital and -year mortality of patients treated in the icu for acute exacerbation of copd: a retrospective study prospective outcomes in patients with acute exacerbations of chronic obstructive pulmonary disease presenting to hospital: a generalisable clinical audit d-dimer as a prognostic biomarker for mortality in chronic obstructive pulmonary disease exacerbation biochemical markers of cardiac dysfunction predict mortality in acute exacerbations of copd cardiac troponin-i predicts long-term mortality in chronic obstructive pulmonary disease comorbidity and gender-related differences in patients hospitalized for copd. the ecco study five-year outcome in copd patients after their first episode of acute exacerbation treated with non-invasive ventilation cardiac troponin elevation predicts all-cause 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rehabilitation following hospitalization in patients with copd: can it reduce readmissions? statement on pulmonary rehabilitation objectively identified comorbidities in copd: impact on pulmonary rehabilitation outcomes the association between hospital readmission and pulmonologist follow-up visits in patients with copd outpatient follow-up visit and -day emergency department visit and readmission in patients hospitalized for chronic obstructive pulmonary disease home care by outreach nursing for chronic obstructive pulmonary disease outcome evaluation of a randomized trial of the phoenixcare intervention: program of case management and coordinated care for the seriously chronically ill a randomized, controlled trial of an intensive community nurse-supported discharge program in preventing hospital readmissions of older patients with chronic lung disease integrated disease management interventions for patients with chronic obstructive pulmonary disease copd care programme can reduce readmissions and inpatient bed days hospital at home for acute exacerbations of chronic obstructive pulmonary disease home-based telehealth hospitalization for exacerbation of chronic obstructive pulmonary disease: findings from "the virtual hospital" trial prevention of acute exacerbations of copd effect of roflumilast on exacerbations in patients with severe chronic obstructive pulmonary disease uncontrolled by combination therapy (react): a multicentre randomised controlled trial twice daily n-acetylcysteine mg for exacerbations of chronic obstructive pulmonary disease (pantheon): a randomised, double-blind placebo-controlled trial implementing clinical guidelines for chronic obstructive pulmonary disease: barriers and solutions erythromycin and common cold in copd the effect of oral clarithromycin on health status and sputum bacteriology in stable copd long-term erythromycin therapy is associated with decreased chronic obstructive pulmonary disease exacerbations long-term azithromycin use in patients with chronic obstructive pulmonary disease and tracheostomy effect of months of erythromycin treatment on inflammatory cells in induced sputum and exacerbations in chronic obstructive pulmonary disease azithromycin for prevention of exacerbations of copd azithromycin and cough-specific health status in patients with chronic obstructive pulmonary disease and chronic cough: a randomised controlled trial azithromycin maintenance treatment in patients with frequent exacerbations of chronic obstructive pulmonary disease (columbus): a randomised, double-blind, placebo-controlled trial prophylactic antibiotic therapy for chronic obstructive pulmonary disease (copd) prophylactic use of macrolide antibiotics for the prevention of chronic obstructive pulmonary disease exacerbation: a meta-analysis we acknowledge the patients and staff who have contributed to our research programmes. we are grateful for funding support from respiratory research fund of the chinese university of hong kong key: cord- - sjxi et authors: maremanda, krishna p.; sundar, isaac k.; li, dongmei; rahman, irfan title: age-dependent assessment of genes involved in cellular senescence, telomere, and mitochondrial pathways in human lung tissue of smokers, copd, and ipf: associations with sars-cov- covid- ace -tmprss -furin-dpp axis date: - - journal: front pharmacol doi: . /fphar. . sha: doc_id: cord_uid: sjxi et background: aging is one of the key contributing factors for chronic obstructive pulmonary diseases (copd) and other chronic inflammatory lung diseases. here, we determined how aging contributes to the altered gene expression related to mitochondrial function, cellular senescence, and telomeric length processes that play an important role in the progression of copd and idiopathic pulmonary fibrosis (ipf). methods: total rna from the human lung tissues of non-smokers, smokers, and patients with copd and ipf were processed and analyzed using a nanostring platform based on their ages (younger: < years and older: > years). results: several genes were differentially expressed in younger and older smokers, and patients with copd and ipf compared to non-smokers which were part of the mitochondrial biogenesis/function (hspd , fen , cox , cox , ucp & ), cellular senescence (pcna, pten, klotho, cdkn c, tnks , nfatc & , gadd a), and telomere replication/maintenance (parp , sirt , nbn, tert, rad , slx , hat ) target genes. interestingly, nox and tnks were increased in the young ipf as compared to the young copd patients. genes in the mitochondrial dynamics and quality control mechanisms like fis and rhot were decreased in young ipf compared to their age matched copd subjects. ercc and gadd b were higher in young copd as compared to ipf. aging plays an important role in various infectious diseases including the sars-cov- infection. lung immunoblot analysis of smokers, copd and ipf subjects revealed increased abundance of proteases and receptor/spike protein like tmprss , furin, and dpp in association with a slight increase in severe acute respiratory syndrome coronavirus (sars-cov- ) receptor ace levels. conclusions: overall, these findings suggest that altered transcription of target genes that regulate mitochondrial function, cellular senescence, and telomere attrition in the pathobiology of lung aging in copd and ipf is associated with alterations in sars-cov- ace -tmprss -furin-dpp axis as pharmacological targets for covid- . aging is an important factor influencing the overall lung health and function (wahba, ; skloot, ) . lung function declines with age after lung maturation. evidences suggest that a significant contribution of various environmental factors influence the aging lung (rojas et al., ) . according to the behavioral risk factor surveillance system (brfss) data from , . % (age-adjusted) us adults were reported to have chronic obstructive pulmonary disease (copd) (wheaton et al., ) . further, there has been an increasing reports of young copd population visiting for different hospital services (gershon et al. ) . aging influences many chronic lung diseases, such as copd, idiopathic pulmonary fibrosis (ipf), and asthma. also chronic lung diseases like asthma and ipf share some of the common yet distinct features compared to copd (maghsoudloo et al., ) . environmental stress factors like smoking remains a common influencing factor for the disease progression in all these three cases. cigarette smoke (cs) is one of the strongest contributing risk factors in the pathogenesis of copd along with the decline in lung function (rahman and adcock, ) . cellular senescence is a process of irreversible cell cycle arrest, having both beneficial and harmful effects depending on the cell state (birch et al., ) . cs plays a role in advancing the lung aging by altering the process of cellular senescence (nyunoya et al., ) . several factors including oxidative stress influence the process of cellular senescence. telomeres and mitochondria play a major role in influencing the process of cellular senescence and are often associated with maintaining the lung cellular health (liu et al., ; passos and von zglinicki, ; birch et al., ) . earlier reports from our laboratory and others have shown that smoking and copd is associated with the mitochondrial damage and dysfunction, altering the process of cellular metabolism and function (ahmad et al., ; lerner et al., ) . similarly, telomere dysfunction was also associated with smoking and copd (morla et al., ; de-torres et al., ) . mitochondrial and telomere dysfunction also play a causative role in the progression of ipf (povedano et al., ; molina-molina and borie, ; zank et al., ) . several molecular mechanisms were identified in relation to cs causing copd pathogenesis and associated complications (putcha et al., ) . cs alters several key cellular functions, among them the crucial genes related to mitochondrial function, cellular senescence, and telomeric length were selected in the current study to observe for any differential changes among young and old age groups categorized as non-smokers, smokers, and copd groups. our previous studies showed independent contributions of these canonical signaling pathways and how they contribute toward the development of premature lung aging in chronic lung diseases, such as copd/emphysema yao and rahman, ; ahmad et al., ; rashid et al., ) . accumulating evidence suggest the close relationship of all these three pathways in influencing lung aging and disease (lee et al., ; saretzki et al., ; passos and von zglinicki, ) . senescent cells are found in many age-related/chronic diseases (tchkonia and kirkland, ) . studies from our laboratory showed that mice from different age group when exposed to chronic air and cs influence the process of lung inflammation and senescence. chronic cs exposure in lung epithelial cells and mice increases several markers of cellular senescence (nyunoya et al., ; fujii et al., ) . recently, it was reported that serum from copd patients can induce senescence in lung epithelial cells (kuznar-kaminska et al., ) , giving strength to the importance of this area that needs to be explored further. several dna damaging agents present in smoke, which may activate the dna damage response, thereby influencing telomere function leading to accumulation of senesced cells. however, recent meta-analysis suggests that even though smokers are associated with shorter telomere length, the study implicates that smoking does not accelerate the telomere attrition in leucocytes (bateson et al., ) . smoking and copd conditions altered the expressions of many key genes involved in the above three crucial pathways of cellular maintenance. the current study was undertaken to determine the changes in genes related to mitochondrial biogenesis and function, telomere function, and cellular senescence with respect to their age in human lungs. this study is important in unraveling some of the potential biomarkers to differentiate and follow the course of aging in copd. keeping in view the importance of these genes in both copd and ipf, we have also made comparisons between the similar age grouped copd and ipf subjects, using the same set of gene panels. aging is one of the key components, which decides the subject's susceptibility to various diseases and infections presumably due to inflammaging (gardner, ) . the recent pandemic of severe acute respiratory syndrome coronavirus (sars-cov- ) was thought to affect more elderly people especially men (bonafe et al., ; koff and williams, ; sargiacomo et al., ) . men with age-related comorbidities have a higher coronavirus disease (covid- ) mortality rate (zhao et al., ) . comorbidities like cardiovascular disease, diabetes, and chronic respiratory diseases present a high mortality rate (emami et al., ) . studies involving the role of lung aging and senescence play an important role in understanding the role of the multiple players involved in combating sars-cov- infection and can discover potential druggable targets. considering the important role played by some of the crucial receptors and targets in covid- (hoffmann et al., ) , we determined the protein expression of sars-cov- receptor angiotensin converting enzyme (ace ) and aiding proteases like transmembrane protease serine protease- (tmprss- ) and spike protein convertase furin in lung homogenates of non-smokers, smokers, copd, and ipf subjects. we also examined the levels of dipeptidyl peptidase (dpp ), the receptor for the middle east respiratory syndrome coronavirus, (mers-cov) (seys et al., ) . rigorous and unbiased approaches were used to ensure full and detailed reporting of both methods and analyzed data. the current study was approved for the procurement of the human lung tissues as de-identified tissues by the materials transfer agreement and procurement (institutional review board, irb), and laboratory protocols by the institutional biosafety committee, ibc of the university of rochester medical center, rochester, ny, with project code: drai protocol: , date of approval and irb/ibc approvals / / and / / , and / / and / / , university material transfer agreement (mta) signed on the above dates as well. patients' data or patients are not directly involved in this study as the lung tissues were procured from several agencies (see below). all patients/subjects were of age and above. all methods were carried out in accordance with relevant guidelines and regulations of the university of rochester, rochester, ny. the human peripheral lung tissues from non-smokers, smokers, and copd/ipf were procured/obtained from the ndri (national disease research interchange; the samples were collected from patients with various cause of deaths reported such as cardiac arrest or trauma/accidents, for most of the samples lower peripheral lung lobes were used or as supplied), ltrc (lung tissue research consortium of the national heart lung blood institute, nhlbi), and department of medicine and pathology, and of the university of helsinki hospital, finland as described in our previous reports . the clinical characteristics of the subjects used in the current study are given in table . the subjects were broadly classified into two age groups: young age (≤ years) group, old age (> years) group, as per previous studies (sanchez-salcedo et al., ) . although there were some co-morbid conditions reported for the specimens from copd patients (which were on various medications), the tissues were assigned to different groups based on the age, smoking status (current/ex-smokers), and lung disease status (normal vs. smoker's, normal vs. copd) reported during the procurements of the specimens. as described in the above samples, the following samples were obtained in the same way for further disease-wise comparison. additional comparisons were made between copd ( additional samples from above groups were added in addition to the samples mentioned in table ) and ipf lung samples ( in young ipf, in old ipf) based on their age to determine for the changes in the same custom gene panel (supplementary table ). total rna was extracted from the human lung tissues stored at − °c or in rnalater, using direct-zol rna miniprep plus kit (zymo research, r ) according to the manufacturer's instructions. rna concentration was measured using a nanodrop (thermo fisher scientific, usa). various genes involved in mitochondrial biogenesis and function, telomere replication and maintenance, and cellular senescence pathways were included in the custom code sets (supplementary table ). the code set contained a total of genes including reference genes (abcf , hprt, polr b, rplp , ldha, gusb) for gene normalization (supplementary table ). the code sets were identified by overlapping the existing panels of the above cellular pathways and the distinct genes were used as described in the code sets. the samples were sent for analysis and processed through the nanostring ncounter system (nanostring technologies seattle, wa, usa). a total of -ng rna was submitted after adjusting the samples to a minimum of µg/µl as per the requirements. selected mrna (prepared as mentioned above), which were found to be significantly and differentially altered were further validated for their expression using qpcr (three samples per group, run in duplicates) used in the study as described earlier (maremanda et al., ) . the primers were obtained from bio-rad as described below with catalog numbers along with pcr conditions (initial denaturation at °c min followed by cylces at °c s and °c min, fluorescence intensity was measured during the end of °c incubation, melting curve analysis was performed after this reaction ( °c for s, and then . °c for s until °c total protein assayed by bicinchoninic acid (bca) method were isolated from the lung homogenates of non-smokers, smokers, copd, and ipf in ripa buffer with protease inhibitors, which were reduced and separated using the pre-made polyacrylamide gels (bio-rad) (maremanda et al., ) . the transferred membranes were probed for some of the important protein involved in the covid- , like tmprss (ab ), furin (ab ), dpp (ab ), and ace (ab ). all the antibodies used in the current study were procured from the abcam and were used at : dilution in blocking buffer. the relative expression and equal loading as assessed using the ponceau s staining or b-actin after stripping of the blots. imaging was done using bio-rad chemidoc and blots were analysed using image lab densitometry. nanostring mrna counts were first normalized using the nanostringnorm function in the statistical analysis software r (version . . ) on log transformed data. geometric mean of reference genes was used to remove the technical variation and background expression. differential analysis was conducted using linear models in the limma (version . . ) package (r/bioconductor) after adjusting for the gender difference. comparison among different experimental groups were performed using linear contrasts within the linear model framework; moderated t statistics was used to determine the differences in the gene expression levels between groups with empirical bayes approach. the benjamini-hochberg procedure was used to adjust the p values to control the false discovery rates at %. the analyzed data was represented in the graphs as y-axis showing the negative log p-value and x-axis representing log fold change across each pairwise comparisons as described previously . the significantly altered gene data were shown as dot plot representation. four random samples from each age group were used for comparisons among non-smokers, smokers, and copd groups (as given in supplementary table ) . comparisons with ipf includes all the samples as mentioned in the table and supplementary table . overall, the study consisted of lung tissue samples from different sources as mentioned above. the collected tissues were classified into six different groups based on age, the smoking and disease status. further, comparative gene analysis was also done based on the smoking and disease status irrespective of the age. there were no genes in common that were changed in any of the comparisons involving all the three groups, i.e., non-smokers, smokers, and copd. first, we analyzed differentially expressed transcript levels among young non-smokers vs. young smokers, young smokers vs. young copd and young non-smokers vs. young copd (figure ) . we found five genes were differentially expressed in young non-smokers vs. young smokers' pairwise comparison. out of five genes, the transcript levels of four genes (nfatc , nfatc , gadd a, and cdkn a) were decreased and one gene (parp ) was increased in the young smokers as compared to young non-smokers group (figures and a ). next, we compared genes differentially expressed in young smokers vs. young copd pairwise comparison. out of five genes, transcript levels of one gene (sirt ) was decreased and the remaining four genes (rad , cdkn c, cox , and klotho) were significantly increased in young smokers as compared to the young copd group (figures a and b) . finally, we found six genes differentially expressed among young non-smokers vs. young copd group pairwise comparison. out of six genes, the transcript levels of two genes cdkn c and klotho that belong to cellular senescence panel were decreased in the young copd as compared to young nonsmokers group. while the transcript levels of the remaining four genes parp , sirt , tert, and slx were increased in the young copd as compared to the young non-smokers group (figures a and c) . overall, four genes parp , sirt , klotho, and cdkn c were among the common target genes that were differentially expressed in the young copd group as compared to young non-smokers and young smokers groups. here, we analyzed differentially expressed transcript levels among old non-smokers vs. old smokers, old smokers vs. old copd, and old non-smokers vs. old copd groups. out of seven genes, we found three genes igf , cox , and rif were decreased and the remaining four genes nfatc , nfatc , rad , and pcna were increased in old smokers as compared to old non-smokers group ( figures b and a) . the transcript levels of igf , parp , pten, nbn, hspd , and rif were decreased and gar was increased in old smokers as compared to old copd group ( figures b and b ). only two genes were affected among old nonsmokers and old copd group; rpa and pcna were increased in old copd as compared to the old non-smokers group ( figures b and c) . overall, a total of three genes as mentioned above (igf , rif , and pcna) were among the common targets that were found to be differentially expressed in old smokers as compared to old non-smokers and the old copd groups. we then analyzed differentially expressed genes among young non-smokers vs. old non-smokers, young smokers vs. old smokers, and young copd vs. old copd pairwise comparisons. transcript levels across different age groups were performed to better understand, whether age influences the measured outcomes in the current study. accordingly, we found that nine genes were significantly elevated in young non-smokers as compared to old non-smokers group (pcna, nfatc , acd, gsk b, hat , ucp , cdkn a, cdkn c, and sirt ; figures c and a) . although, young smokers show increased transcript levels of parp , ucp , and e f genes but decreased levels of nfatc , nfatc , myc, and gadd a as compared to the old smokers group as seen in figures c and b . additionally, two genes (tnsk and pten) were decreased in the young copd group as compared to the old copd group. the transcript levels of gar , tert, h ax, and fen tend to increase in the younger copd group as compared to the old copd group (figures c and c) . interestingly, we noted that transcript levels of nfatc was decreased in lungs of old nonsmokers, but increased in lungs of old smokers. we performed grouped analysis of differentially expressed transcripts (comparisons without considering the age factor (young or old) among non-smokers, smokers and patients with copd groups (e.g., young non-smokers with old non-smokers group, young smokers with old smokers group, and young copd and old copd group; n = /group; figures and a) . results indicated that smokers show decreased foxo and increased rad levels as compared to non-smokers group ( figure a ). while decreased parp and increased rad levels were observed in smokers as compared to copd group ( figure b ). in patients with copd klotho was decreased and parp and slx genes were increased as compared to nonsmokers group ( figure c) . furthermore, these comparisons revealed that smokers have significantly higher levels of rad expression compared to both non-smokers and copd groups. whereas, copd patients showed significantly higher levels of parp as compared to both non-smokers and smokers groups. pairwise analysis of young non-smokers vs. young ipf showed significantly altered genes, which were given in table . comparisons between old non-smokers and old ipf showed significantly altered genes, as listed in table along with their observed level of significance. the gene comparisons among these groups were given in figure b . as detailed above both copd and ipf are chronic age related diseases that severely alter lung function and share certain common features for the disease occurrence and progression. here, we compared the altered gene levels related to the same pathways among copd and ipf subjects as detailed above. there was no change in any of the genes analyzed in comparisons between young ipf (n = ) and old ipf (n = ). while, genes were found to be altered in the comparisons between young copd vs. young ipf, as indicated in table . a total of genes were altered in comparisons between old copd vs. old ipf as shown in table . some of the differentially expressed mrna targets predicted using nanostring were selected for qpcr analysis. the expression trends of these selected genes matches with the trend observed using the nanostring mrna analysis with varied levels of fold changes (figure ). combined gene analysis for parp which matches with the trend as given in figure . the results clearly indicate that the genes validated using qpcr are in agreement and significant across all the pairwise comparisons made. western blots analysis (figures and , and supplementary figures and ) revealed a significant increase in the protein levels of tmprss protease (which plays a crucial role in the processing of the sars-cov- proteins) in copd subjects as compared to smokers and non-smokers. similarly, the levels of another important protease/convertase furin, which cleaves the spike protein of sars-cov- , was also increased in smokers and copd subjects, with a significant expression in copd subjects. ace , cellular receptor for sars-cov- binding, was found to be increased in smokers as compared to the rest of the groups. the samples were also further probed for the expression of dpp , another crucial protein which plays an important role in mers-cov binding. the dpp expression was found to be significantly higher in smokers as compared to copd and nonsmokers. these results indicate that the levels of proteases, which aid in the processing and binding of the viral spike proteins were highly expressed in copd and smokers. the expression results showed varied protein intensities in smokers and copd for tmprss and dpp in the lungs, which may suggest a varied aging is associated with the decline in lung function, and copd is a disease of aging (rojas et al., ; wheaton et al., ) . nonetheless, there is growing evidence of copd in younger subjects, which needs thorough and careful phenotypic characterization for potential markers to understand the cause and progression of disease. the current study examined the changes in gene expression in the lungs of non-smokers and smokers and patients with copd/ipf. the study included age as an influencing factor independent of lung disease status. the extracted rna was processed and analyzed using the sophisticated nanostring ncounter analysis platform. nanostring has several advantages in simultaneous estimation of the several gene levels in a single sample with low amounts of sample input (eastel et al., ; goytain and ng, ) . we have successfully used this platform to report changes in gene expression using different gene set panels in our earlier studies sundar et al., ). in the current study, the custom designed panel included genes from three different pathways addressing the mitochondrial biogenesis and function, telomere function, and cellular senescence, which play a major role in the lung inflammation and copd development. most chronic diseases, like copd, are associated with the mitochondrial dysfunctions. several reports claim the causal role of mitochondrial dysfunctions in the initiation and progression of smoking associated copd (bialas et al., ; ryter et al., ; zhang et al., ) . we have previously reported the presence of mitochondrial dysfunctions in cs-induced lung damage models and in human lungs (ahmad et al., ) . further, we along with others have reported that telomere dysfunction is also seen in copd patients and smoking plays a crucial role in influencing telomere genes (liu et al., ; morla et al., ; ahmad et al., ) . assessment of all these three pathway related genes in the same subjects throws light on the involvement and coordination of complex processes in smoking-related chronic lung disease such as copd. pairwise comparisons revealed that a total of genes were altered among the young and old subjects. cdkn a (p ), a cyclin-dependent kinase (cdk), plays a vital role in cellular senescence and proliferation and was reported to be increased in smokers and copd subjects (chiappara et al., ) . further, p disruption attenuated cs-induced lung inflammation in mice (yao et al., ) . in the current study, there was a figure | quantitative pcr validation of the selected genes, which were found to significantly and differentially altered across various pairwise comparisons. the values were deduced based on -ddct method. the genes represented were found to be significant in their pairwise comparisons (p < . ). student t-test was used to compare the level of significance in pairwise comparisons, while anova was used for multiple comparisons. reduced expression in the p levels in the young smokers compared to non-smokersin accordance with the previous reports, where cdkn c (p ), along with p was decreased in aging lungs of mice (park and chung, ) . among the other important targets klotho, sirt , parp , and pcna were altered in the current study. copd patients has reduced klotho expression as compared to non-smokers, in accordance with previous reports (gao et al., ) . in similar lines, parp was also elevated in the copd subjects compared to smokers and non-smokers, as reported earlier (hwang et al., ; dharwal and naura, ) . we have reported that tert levels were altered in mice (young and old) exposed to chronic cs . accordingly, the current results demonstrates that tert levels were significantly increased in copd patients, but this gene may be influenced in a different way in humans, as younger copd patients has higher tert levels compared to older ones. nuclear factor of activated t cells c (nfatc ) levels were significantly higher in aged smokers as compared to younger ones. earlier reports claim that nfatc levels were increased by nicotine/smoking (frazer-abel et al., ) . it was also reported that nfatc enhances tumor-initiating phenotypes in lung adenocarcinoma (xiao et al., ) . these observations were opposite in non-smokers, as they age the levels of nfatc decreased. this suggests that nfatc may be used as a potential marker related to cs-induced lung damage. among the other important genes that were altered and are crucial in the maintenance of these three pathways are acd, which is related to tpp gene and coordinates with its function was elevated in copd (else et al., ; ahmad et al., ) . fen could be a novel biomarker for copd which was increased in the young copd group as compared to the old copd group. prior studies showed mutation in fen linking lung cancer progression in an age-dependent manner in mice exposed to benzo[a]pyrene which is present in tobacco smoke (wu et al., ; ahmad et al., ) . pairwise comparisons between non-smokers and ipf subjects revealed changes in some important genes like parp , pcna, fen , cdkn b, nfatc , and gadd b, as discussed in the above comparisons. however, the directionality of the changes varied between groups, which may be attributed to the small sample size in the study and the heterogeneity in the samples used. further comparisons were also made between the expression profiles of the young ipf and old ipf with their age matched copd subjects. interestingly, some of the well characterized genes in ipf like nox and tnks were increased in the young ipf as compared to the young copd patients (hecker et al., ) . mitophagy is a well-known phenomenon occurring in both copd and ipf and regulates the mitochondrial related damage response toward the disease figure | western blot analysis of the crucial targets involved in covid in non-smokers, smokers, and copd subjects. five samples per groups were used to probe for the tmprss , furin, ace , and dpp . data were shown as mean ± sem (n = /group). level of significance were indicated as **p < . and ***p < . across the groups. (hara et al., ; ryter et al., ) . genes participating in the mitochondrial dynamics and other quality control mechanisms like fis and rhot were found to be decreased in young ipf compared to their age matched copd subjects. ercc (excision repair cross-complementation group ) was also found to be high in young copd as compared to ipf. earlier reports claim that ercc gene is strongly associated with copd subjects (de andrade et al., ) . some of the common gene targets like gadd b needs further attention and characterization especially in the chronic lung diseases like copd and ipf. recent biomarker identification study indicated gadd b in their list of genes that can be targeted in chronic diseases like asthma, ipf, and copd (maghsoudloo et al., ) . several studies indicate that the patients with underlying chronic disease conditions like diabetes, hypertension, and copd are more prone to covid- infections and have higher chances of the hospitalization rates and mortality (emami et al., ; koff and williams, ; zhao et al., ) . several crucial mechanisms and targets were reported to increase this susceptibility in these patients (hoffmann et al., ). in the current study, we have determined the expression of four such important protein targets reported to play an important role in sars-cov- covid- . as anticipated, copd and ipf patients in our study have higher levels of tmprss proteins in the lungs, suggesting the ideal condition for the processing of the viral protein and attachment to its receptor ace . ace receptor abundance expression was slightly increased in smokers, copd, and ipf subjects (leung et al., ) . furin, another crucial protease in covid- infection, was also found to be higher in smokers, copd, and ipf as compared to the non-smokers. we have also assessed the levels of dpp in the same samples and found that dpp was significantly higher in the smokers as compared to non-smokers and copd. dpp was found to play an important role in the entry of mers-cov, acts as its receptor (belonging to the similar class of beta coronaviruses) in humans, and was also suggested to play an important role in covid- infections (bassendine et al., ) . in agreement with recent reports (seys et al., ) , suggesting that smokers and copd have higher dpp , our findings suggest increase in dpp in smokers, but to our surprise we didn't find any increase in copd subjects. this may suggest a different mechanism in smokers and copd, which required further studies. nevertheless, the varied abundance of different sars-cov- covid- proteins suggest cell-specific effects for viral entry in smokers and copd/ipf subjects. this may be used as pharmacological targets in attenuating covid- infections. figure | western blot analysis of the crucial targets involved in covid in non-smokers and ipf subjects. five samples per groups were used to probe for the tmprss , furin, and ace . data were shown as mean ± sem (n = /group). level of significance were indicated as *p < . and ***p < . across the groups. in conclusion, our study provides a novel direction showing a crucial and interdependent association with different cellular pathways, e.g., mitochondrial, telomere, and cellular senescence in association with sars-cov- covid- proteins. whilst the study provides several differential gene expression patterns in non-smokers, smokers, and copd/ipf, there is a limitation regarding the small sample size and past smoking history in terms of their stratifications for further analyzing the data and their interpretations. it remains to be seen the alterations seen in various genes will have direct bearing on susceptibility to covid- infections in smokers, and patients with copd and ipf. nonetheless, this human study provides useful and valuable information in terms of approach and identifying targets involved in various cellular processes linking with age and copd and ipf disease progression with pharmacological targets in covid- infections. the raw data supporting the conclusions of this article will be made available by the authors, without undue reservation, to any qualified researcher. the current study was approved for the procurement of the human lung tissues as de-identified tissues by the materials transfer agreement and procurement (institutional review board, irbc), and laboratory protocols by the institutional biosafety committee, ibc of the university of rochester medical center, rochester, ny, with project code: drai protocol: , date of approval and irb/ibc approvals / / and / / , and / / and / / , university material transfer agreement (mta) agreements signed on the above dates as well. written informed consent was not provided because the human peripheral lung tissues from non-smokers, smokers, and copd/ipf were procured/obtained from the ndri (national disease research interchange) and ltrc [lung tissue research consortium of the national heart lung blood institute (nhlbi)]. km: experiments, data analyses, writing, and editing the manuscript. is: data analyses and editing the manuscript. dl: data analyses and editing the manuscript. ir: concept, design, obtained funding, writing, and editing the manuscript. this study was supported by the nih r hl , r hl , and r es (all ir). dl is supported in part by the university of rochester ctsa ul tr of the nih. this manuscript has been released as a pre-print at the following pre-print servers medrxiv with https://www.medrxiv.org/ content/ . / . . . v and researchsquare with https://www.researchsquare. com/article/rs- /v . the supplementary material for this article can be found online at: https://www.frontiersin.org/articles/ . /fphar. . /full#supplementary-material supplementary table | pre-selected genes belonging to the mitochondrial biogenesis and function pathway with their annotations. supplementary table | determined genes with raw and normalized counts based on nano string analysis for non-smokers, smokers, and copd comparisons. supplementary table | determined genes with raw and normalized counts based on nano string analysis for non-smokers, smokers, copd and ipf comparisons. impaired mitophagy leads to cigarette smoke stress-induced cellular senescence: implications for chronic obstructive pulmonary disease shelterin telomere protection protein reduction causes telomere attrition and cellular senescence via sirtuin deacetylase in chronic obstructive pulmonary disease covid- and co-morbidities: a role for dipeptidyl peptidase (dpp ) in disease severity? smoking does not accelerate leucocyte telomere attrition: a metaanalysis of longitudinal cohorts the role of mitochondria and oxidative/antioxidative imbalance in pathobiology of chronic obstructive pulmonary disease mitochondria, telomeres and cell senescence: implications for lung ageing and disease inflamm-aging: why older men are the most susceptible to sars-cov- complicated outcomes the role of p waf /cip in large airway epithelium in smokers with and without copd age-dependent of transcriptomics in smokers, copd, and ipf copd as a disease of immunosenescence genetic variants associated with the risk of chronic obstructive pulmonary disease with and without lung cancer telomere length, copd and emphysema as risk factors for lung cancer parp- inhibition ameliorates elastase induced lung inflammation and emphysema in mice application of nanostring technologies in companion diagnostic development tpp /acd maintains genomic stability through a complex role in telomere protection prevalence of underlying diseases in hospitalized patients with covid- : a systematic review and meta-analysis nicotine activates nuclear factor of activated t cells c (nfatc ) and prevents cell cycle entry in t cells insufficient autophagy promotes bronchial epithelial cell senescence in chronic obstructive pulmonary disease klotho expression is reduced in copd airway epithelial cells: effects on inflammation and oxidant injury the effect of aging on susceptibility to infection trends in copd prevalence, incidence and health services use in younger adultsp nanostring ncounter technology: high-throughput rna validation mitochondrial quality control in copd and ipf. cells reversal of persistent fibrosis in aging by targeting nox -nrf redox imbalance sars-cov- cell entry depends on ace and tmprss and is blocked by a clinically proven protease inhibitor cigarette smoke-induced autophagy is regulated by sirt -parp- -dependent mechanism: implication in pathogenesis of copd covid- and immunity in aging populations -a new research agenda serum from patients with chronic obstructive pulmonary disease induces senescence-related phenotype in bronchial epithelial cells aging-and smokingassociated alteration in the relative content of mitochondrial dna in human lung mitochondrial redox system, dynamics, and dysfunction in lung inflammaging and copd ace- expression in the small airway epithelia of smokers and copd patients: implications for covid- scaffold hopping approach on the route to selective tankyrase inhibitors mitochondrial dysfunction leads to telomere attrition and genomic instability identification of biomarkers in common chronic lung diseases by coexpression networks and drug-target interactions analysis age-dependent assessment of genes involved in cellular senescence, telomere and mitochondrial pathways in human lung tissue of smokers, copd and ipf: associations with sars-cov- covid- ace -tmprss -furin-dpp axis age-dependent assessment of genes involved in cellular senescence, telomere and mitochondrial pathways in human lung tissue of smokers, copd and ipf: associations with sars-cov- covid- ace -tmprss -furin-dpp axis protective role of mesenchymal stem cells and mesenchymal stem cell-derived exosomes in cigarette smoke-induced mitochondrial dysfunction in mice clinical implications of telomere dysfunction in lung fibrosis telomere shortening in smokers with and without copd cigarette smoke induces cellular senescence age-dependent changes of p (kip ) and p (cip /waf ) expression in skeletal muscle and lung of mice mitochondria, telomeres and cell senescence mice with pulmonary fibrosis driven by telomere dysfunction comorbidities and chronic obstructive pulmonary disease: prevalence, influence on outcomes, and management oxidative stress and redox regulation of lung inflammation in copd lung cellular senescence is independent of aging in a mouse model of copd/emphysema aging and lung disease. clinical impact and cellular and molecular pathways mitochondrial dysfunction as a pathogenic mediator of chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis disease progression in young patients with copd: rethinking the fletcher and peto model mitoq counteracts telomere shortening and elongates lifespan of fibroblasts under mild oxidative stress covid- and chronological aging: senolytics and other anti-aging drugs for the treatment or prevention of corona virus infection? dpp , the middle east respiratory syndrome coronavirus receptor, is upregulated in lungs of smokers and chronic obstructive pulmonary disease patients the effects of aging on lung structure and function dna methylation profiling in peripheral lung tissues of smokers and patients with copd genetic ablation of histone deacetylase leads to lung cellular senescence and lymphoid follicle formation in copd/emphysema aging, cell senescence, and chronic disease: emerging therapeutic strategies influence of aging on lung function-clinical significance of changes from age twenty chronic obstructive pulmonary disease and smoking status -united states high risk of benzo [alpha]pyrene-induced lung cancer in e d fen mutant mice nfatc enhances tumor-initiating phenotypes through the nfatc /sox /aldh axis in lung adenocarcinoma role of histone deacetylase in epigenetics and cellular senescence: implications in lung inflammaging and copd disruption of p attenuates lung inflammation induced by cigarette smoke, lps, and fmlp in mice sirt protects against emphysema via foxo -mediated reduction of premature senescence in mice idiopathic pulmonary fibrosis: aging, mitochondrial dysfunction, and cellular bioenergetics association of urine mitochondrial dna with clinical measures of copd in the spiromics cohort the impact of copd and smoking history on the severity of covid- : a systemic review and meta-analysis key: cord- -z l vdsr authors: río, francisco garcía; clau, luis borderías; macario, ciro casanova; celli, bartolomé r.; sanglás, joan escarrabill; mangado, nicolás gonzález; torrent, josep roca; romero, fernando uresandi title: air travel and respiratory disease date: - - journal: archivos de bronconeumología ((english edition)) doi: . /s - ( ) - sha: doc_id: cord_uid: z l vdsr nan in recent years there has been a progressive rise in the number of people who travel by air. according to data from the international civil aviation organization, million people traveled by air in and, despite problems related to security restrictions and severe acute respiratory syndrome (sars), it is anticipated that the number of passengers will increase annually by . % until . more than million air traffic operations were handled during in airports managed by the spanish aviation authority (aeropuertos españoles y navegación aérea, aena), representing travel by million passengers. those figures correspond to a % increase in the number of passengers since , with an annual increase of %. in addition, advances in the monitoring and treatment of many chronic respiratory diseases have allowed changes in the lifestyle of patients. thus, patients are now able to consider leisure and professional activities that were not possible some years ago. although adverse respiratory events as a result of air travel are not common, this form of transport does present potential risks. data from airline companies forming part of the international air transport association (iata) show that between and there were deaths in flight, corresponding to . deaths per million passengers or . deaths per million takeoffs. respiratory complications represented the third highest known cause of death ( %) after cardiac causes ( %) and deaths due to cancer ( %). in addition, it was noteworthy that while there was prior knowledge of the presence of heart disease in only % of deaths due to cardiac events, there was prior knowledge in % of those due to respiratory disease, suggesting that there are problems in the assessment of patients prior to the flight or in their in-flight care. aside from fatal events, respiratory symptoms are responsible for a good proportion of the emergencies that occur on board aircraft. analysis of all cases in which the first-aid kit was used on commercial aircraft belonging to the iata between august and july showed that chest pain and dyspnea were of the most common causes, along with loss of consciousness. , likewise, % of passengers who required medical assistance had a known medical condition associated with the episode that occurred on board the aircraft, further indicating the importance of careful assessment prior to flight. along similar lines, a service offering the assistance of experts by radio during in-flight emergencies received calls in , of which % corresponded to respiratory problems. , thus, respiratory problems may represent up to % of in-flight emergencies. in response to this situation, various guidelines and recommendations have been prepared by scientific societies or the airline companies themselves. , [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] however, little scientific information supported by a high level of evidence is available in this field, meaning that the majority of the recommendations are based solely upon expert consensus. in fact, in recent years, conflicting results have been reported using the regimens recommended in previous guidelines. furthermore, there is a local problem generated by differences in the legislation and the wide range of criteria, resources, and attitudes of the different airline companies. the aim of these guidelines is to define assessment protocols for patients with chronic respiratory disease intending to travel by plane that are adapted to the situation in spain and the most recent available data. in addition, the guidelines aim to establish specific recommendations for the most common respiratory diseases. extensive information is available on respiratory physiology during air travel in both healthy individuals and patients. , - , - some of those detailed reviews of francisco garcía río a (coordinator), luis borderías clau, b ciro casanova macario, c bartolomé r. celli environmental conditions and their control are published by the airlines themselves and are available on the internet. , it is worth remembering that the atmosphere surrounding the earth's crust is made up of different layers or strata: the troposphere, the stratosphere, the mesosphere, the thermosphere, and the exosphere. the layer closest to the earth is the troposphere, which extends from sea level to m ( feet) at the poles and to m ( feet) at the equator (appendix ). today's commercial aircraft fly within this zone. atmospheric pressure depends on the column of air above the measurement point; consequently, the higher the altitude, the lower the pressure. since the reduction in atmospheric pressure is logarithmic (figure ), at lower levels small changes in altitude produce substantial changes in pressure. thus, at m ( feet) the atmospheric pressure is less than half that at sea level. the composition of the troposphere is constant and contains approximately % nitrogen and % oxygen. since the partial pressure of a gas is a function of its concentration and the total pressure, oxygen tension is directly dependent upon altitude and drops exponentially as altitude increases ( figure ). this hypoxia is the cause of the limitations and risks faced by mountaineers and also of acclimatization problems in high-altitude populations. in addition, adaptation to this type of environment is affected by the amount of exercise that is performed. in terms of the physiologic response of the human body, the atmosphere can be divided into zones: the physiologic zone, the physiologically deficient zone, and the zone equivalent to space. the physiologic zone is where the human body is well adapted and where the oxygen level is sufficient to maintain normal processes. this zone extends from sea level to an altitude of m. nevertheless, rapid changes in altitude within this zone can cause minor problems due to the expansion of gases trapped within the body. the physiologically deficient zone extends from to m. in that zone, the reduction in barometric pressure causes a critical environmental hypoxia, necessitating the use of supplementary oxygen at higher altitudes. from a physiologic point of view, space begins at an altitude of m. in this zone, the low ambient pressure means that humans are unable to survive even with supplementary oxygen and they require pressurized suits. above m the barometric pressure is lower than the vapor pressure of water at ºc and body fluids evaporate. commercial aircraft generally fly at an altitude of around to m ( - feet). , , if the internal pressure of the aircraft were to be directly dependent upon the external atmospheric pressure the environment would be incompatible with life. consequently, aircraft must be pressurized, that is, have elevated pressure compared with that of the external environment. to achieve this, they take ambient air and compress it. since the gas heats up in this process, it must subsequently be cooled. the pressure is controlled according to the quantity of air injected and through the use of escape valves set to the desired pressure. to support the pressure difference, the structure of the aircraft must be reinforced and that increases its weight. as a result of both the increased weight and the additional energy required to compress the air, cabin pressurization increases aircraft fuel consumption and thereby decreases their independence. the pressurization system used by commercial aircraft is known as isobaric. initially, as the aircraft climbs in altitude, it maintains the same ambient pressure as its environment, and then, from a certain altitude, it maintains a constant (isobaric) pressure, irrespective of changes in altitude. many military aircraft employ a different system known as differential-isobaric pressurization, which imposes fewer structural requirements and thereby saves weight. due to the technical limitations mentioned and the cost, aircraft pressure is not maintained at that of sea level but rather at an intermediate pressure; that pressure depends on the type of aircraft but is usually approximately equivalent to that of an altitude of m. altitude, the atmospheric oxygen tension is equivalent to breathing . % oxygen at sea level. although international legislation establishes that minimum cabin pressure should correspond to an altitude of m ( feet), the pressure does not remain constant throughout a flight. in a large series of measurements performed during commercial flights, it was determined that the conditions within aircraft cabins usually correspond to an altitude of to m ( - feet) above sea level. , , survival in the event of a sudden reduction in cabin pressure necessitates the use of oxygen masks (obligatory equipment on commercial flights). it is also important to note that at an altitude of m a person will lose consciousness in to seconds. the degree of pressurization also depends on the type of plane. the old concorde was pressurized at a comfortable level corresponding to an altitude of m ( feet). the current tendency for new models of aircraft, whether manufactured by boeing or airbus, is to pressurize at this more comfortable, safer pressure. however, the new airbus is expected to carry around passengers with a cabin pressure equivalent to an altitude of more then m ( feet) for up to hours. in addition to the difficulties caused by changes in barometric pressure, the external environment presents additional problems for commercial flights. the concentration of ozone, which is very low at sea level, increases with altitude and peaks in the stratosphere. ozone, which is important to filter ultraviolet radiation, is toxic to the respiratory system, even at concentrations below part per million (ppm), which can be reached at some common flight altitudes. to manage this problem, planes have catalytic ozone converters installed to reduce the concentration of the gas. the regulations of the federal aviation administration establish a maximum mean concentration of . ppm and a maximum peak concentration of . ppm. the temperature falls by approximately ºc for every m increase in altitude, necessitating warming of the air inside the cabin. this air normally has a low humidity ( %), which can cause problems for some individuals. most commercial aircraft recirculate approximately % of the air to improve humidity and energy efficiency. the air must be filtered to retain particles smaller than . µm in diameter using highefficiency particulate air (hepa) filters similar to those used in hospital operating theaters. in addition to particles in suspension, this system is considered effective for the retention of bacteria, fungi, and even viruses released during speech, coughing, or sneezing ( figure ). the air is renewed to times per hour, although this may vary according to the model and the zone of the plane. the cabin ventilation system generates transverse airflow and is able to renew the air more effectively than in buildings with air conditioning. complex electronic systems with sensors located throughout the cabin control the temperature and regulate valves in order to maintain a temperature that is as homogeneous as possible. finally, it is worth mentioning that the carbon dioxide content of this filtered and conditioned air is usually very low ( ppm). the partial pressure of inspired oxygen (pio ) is a function of the atmospheric pressure and the vapor pressure of water. as the vapor pressure of water at the same body temperature remains stable with altitude, pio will decrease with altitude (hypobaric hypoxia). breathing ambient air at m ( feet) is equivalent to breathing . % oxygen at sea level, meaning pio falls from mm hg at sea level to mm hg at m. , in healthy subjects, this can represent a reduction in pao from to mm hg, , , which is usually well tolerated and does not produce symptoms. however, in patients with chronic respiratory diseases and some degree of baseline hypoxemia, the reduction in pio during the flight can cause more marked reductions in oxyhemoglobin saturation. [ ] [ ] [ ] acute exposure to a hypobaric environment triggers hyperventilation, which is essentially induced by stimulation of peripheral chemoreceptors and is usually mediated by an increase in tidal volume. it also generates an increase in cardiac output to compensate for the residual systemic hypoxia. this increase is mainly mediated by tachycardia and is usually proportional to the drop in oxygen saturation. the increased pulmonary perfusion caused by the rise in cardiac output is associated with hypoxic vasoconstriction of the pulmonary artery and increased systolic pulmonary pressure. as a consequence of the increase in pulmonary vascular resistance, there is a redistribution of pulmonary blood flow and an increase in perfusion of certain areas of the lungs compared with the situation at sea level. altitude is also associated with limitation of oxygen diffusion from the atmosphere into the pulmonary capillaries as a consequence of the interaction of various factors. both the reduced pio and the reduction in affinity of hemoglobin for oxygen in conditions of low pao lead to a more marked drop in the oxygen content of the pulmonary capillaries than at sea level. finally, the transit time of blood through the pulmonary capillaries is shortened due to the tachycardia caused by the altitude and this limits the time available to establish an adequate oxygen equilibrium. the net result is an increase in the alveolar-arterial oxygen difference. , , in addition, the oxyhemoglobin saturation is significantly reduced during physical exercise in a hypobaric environment. exercise at high altitudes also increases the alveolar-arterial oxygen difference in subjects who normally reside at sea level, while it does not affect those native to high altitudes. studies performed using the multiple inert gas elimination technique have shown that hypobaric hypoxia is associated with a greater heterogeneity in the ventilation-perfusion ratio and a limitation of diffusion that together worsen hypoxemia as exercise intensity increases. limited diffusion secondary to reduced pio appears to exert the greatest influence on blood gas alterations during exercise in a hypobaric environment. additionally, the interstitial edema caused by extravasation of fluids into the extravascular space appears to potentiate the ventilation-perfusion imbalance. the changes described have few consequences in healthy subjects, who might only note a slight increase in tidal volume and heart rate. however, hypobaric hypoxia represents a risk for some patients with chronic respiratory disease, in whom it can aggravate preexisting hypoxemia and favor the development of cardiovascular complications. in fact, it is recognized that hypoxia reduces the ischemic threshold in men with exerciseinduced ischemic heart disease as well as favoring some atrial arrhythmias and being associated with ectopic ventricular beats as a result of increased sympathetic activity. with increasing altitude, barometric pressure is reduced and gases expand if they are trapped in the body, unable to escape. this phenomenon is explained by boyle's law, which establishes that the volume of a gas is inversely proportional to the pressure: although the expansion of the trapped gases is limited, it occurs rapidly, and in healthy subjects can cause discomfort in organs such as the ear, paranasal sinuses, teeth, and gastrointestinal system. in patients with respiratory diseases, and even in young, apparently healthy individuals with small apical bullae, the phenomenon can generate more serious problems. [ ] [ ] [ ] [ ] ears. air trapping can occur in the ears due to partial or complete obstruction of the eustachian tube, which normally equalizes air in the middle ear with the outside. this can occur both during ascent and descent and is also one of the main problems associated with underwater diving. it can be the result of a chronic intrinsic or acquired obstruction or an acute process caused by an infection or allergic reaction. with increasing altitude, the air expands and exerts a pressure on the tympanic membrane, which expands outward. when a pressure increase of to mm hg is reached, a small bubble of air is expelled into the nostrils and is sometimes accompanied by a small noise. upon descent, the reverse situation occurs. the external pressure increases and the tympanic membrane is pressed inwards. it is much more likely for obstruction to occur in this situation since the eustachian tube functions less effectively in this direction. this air block can produce sounds, nausea, and pain in the ears that is sometimes very intense, particularly if the finally phase of the descent occurs very rapidly. a useful maneuver to prevent this obstruction involves repeated swallowing of saliva. consumption of liquids or food can also help. if the condition persists, gentle valsalva maneuvers are recommended. paranasal sinuses. the paranasal sinuses can present similar problems to those experienced in the ear. in this case, the obstruction may be due to chronic lesions such as polyps or to acute problems such as mucus generated in response to infections or allergies. in general, the problem appears during descent and in % of cases affects the frontal sinuses. the pain can become very intense. [ ] [ ] [ ] [ ] barodontalgia. some subjects may experience dental pain, mainly during ascent to between and m. it was initially thought that small pockets of air trapped during dental restoration or other manipulations were the cause of the problem. however, it has not been possible to confirm that hypothesis, despite the association of symptoms with different types of dental complaints. gastrointestinal tract. the gastrointestinal tract usually contains some quantity of gas, and consequently, gastrointestinal discomfort is common during air travel. nevertheless, such problems are of minor significance at the cabin pressures reached during commercial air travel. lungs. in healthy subjects without structural abnormalities there are usually no problems of this type associated with the lungs since pulmonary gas pressure is rapidly equalized with the ambient pressure. nevertheless, some young, apparently healthy subjects may have apical bullae, which can burst during ascent and cause a pneumothorax. in some cases this may be a tension pneumothorax and become serious. given that the gas in the body cavities is saturated with water vapor, the expansion caused by increased altitude is greater than that calculated according to boyle's law. given that body temperature remains constant, in the case of bullae or closed pneumothorax the increase in volume can be calculated with the following formula: ∆volume= pressure of gas at sea level-water vapor pressure if it is assumed that the gas pressure is mm hg at sea level and mm hg at an altitude of m, and that water vapor pressure remains constant at mm hg, it can be estimated that the volume of trapped gas will increase by . % during ascent. the problem is much more severe in patients with chronic obstructive pulmonary disease (copd), since those patients usually have regions of emphysema that are poorly connected with the exterior or separated from it and can cause rupture and pneumothorax, in addition to the problems generated by hypoxia. airline companies usually recommend that individuals do not fly within weeks of the resolution of a spontaneous pneumothorax, although the scientific evidence supporting this recommendation is very limited. if the pneumothorax has been treated surgically or by pleurodesis with talc it is highly unlikely that there will be a relapse during flight. diving and flight. a particular problem may occur following scuba diving activities. dissolved nitrogen can accumulate in the tissues (residual nitrogen) during scuba diving, particularly when diving is deep and repeated. during ascent, that nitrogen may be released and give rise to symptoms of decompression, which in some cases can be severe. in general, it is recommended that individuals do not fly within hours following scuba diving, and that they abstain longer periods if diving required decompression breaks. tables and computer programs are available that can help determine the amount of residual nitrogen and the recommended delay before flying. [ ] [ ] [ ] [ ] as mentioned, cabin humidity is usually less than % to %. this can cause skin dryness and discomfort in the eyes, mouth, and nostrils. the dehydration caused by a long flight can also be significant in patients with bronchiectasis. if nasal irritation is particularly acute, use of a hypertonic saline spray is recommended. prolonged immobility, particularly in a sitting position, contributes to the accumulation of blood in the legs, and this can cause swelling, tightness, and discomfort in the lower limbs. in turn, immobility can favor the development of deep vein thrombosis (dvt). for some subjects, the aircraft environment and the flight itself can trigger increased anxiety, which can lead to an exaggerated perception of some respiratory symptoms or contribute to the deterioration of an existing respiratory condition. it is difficult to establish definitive guidelines based on currently available information. in fact, a wide variety of procedures are used for the assessment of patients with respiratory disease. in a review of in-flight requests for oxygen, information on oximetry or spirometry results were only available in % of cases. furthermore, a survey of specialists in respiratory medicine in england and wales revealed that they followed highly diverse criteria in prescribing use of oxygen in flight. in any case, to establish a medical opinion on risk in air travel, the type, reversibility, and degree of functional impairment caused by the disease must be assessed along with the tolerance of the patient for the predicted flight altitude and the length of exposure. although all patients with chronic respiratory disease may benefit from a clinical assessment prior to undertaking air travel, such assessment should be considered obligatory in those situations shown in table . the following procedures should be considered in this preliminary examination: -medical history, in which special attention should be paid to recognizing all cardiorespiratory disease, with particular interest in comorbidity that could be worsened with hypoxemia (cerebrovascular disease, ischemic heart disease, heart failure). it is also important to assess dyspnea and other respiratory symptoms and compile previous experiences of the patient on other flights. -measurement of oxyhemoglobin saturation by pulse oximetry (spo ) or arterial blood gas analysis, following a period of rest sufficient to guarantee stability of the recordings. in the case of clinical suspicion of hypercapnia, blood gas analysis should obviously be performed. -forced spirometry , and single-breath determination of the diffusing capacity of the lung for carbon monoxide (dlco). -walk test. the medical departments of some airlines propose walking for m as a way to assess tolerance of flight conditions. in such a test, the aim is to verify that the patient is capable of walking m without limitation due to dyspnea. although it is a crude procedure that has not been sufficiently validated, it allows an estimate to be made of the cardiorespiratory reserve by assessing the increase in ventilation and cardiac output in response to exercise. in principle, there is no reason to use a m walk test in place of the minute walk test, which is commonly used in many patients with respiratory disease and is well standardized. criteria for concern should be the inability of the patient to continue walking for minutes, a distance covered of less than m, or the development of severe dyspnea (score of more than on the borg scale). garcÍa pressure of gas at m-water vapor pressure -incremental cardiorespiratory exercise test. the incremental exercise test is not recommended for the systematic assessment of all patients, although it could be useful if the results of simulated altitude-induced hypoxia were unclear. it has been confirmed that a peak oxygen consumption (vo max) greater than . ml/min/kg in patients with moderate or severe copd is associated with a pao of greater than mm hg during the flight. that relationship between vo max and pao was confirmed in the first and fourth hour of flight in a study involving patients with severe copd. in fact, in a multivariate analysis, pao at sea level and vo max were selected as independent predictors of pao during the first hour of flight. however, in the fourth hour the only independent variable associated with vo max was pao . identification of at-risk patients. the information collected in the aforementioned procedures should allow identification of patients who should not fly (table ) along with those in whom the hypoxemia in flight could prove dangerous. in general, it is accepted that patients with acute respiratory failure should not fly. this should also apply to patients with sputum-positive tuberculosis. in the case of patients who are negative for the human immunodeficiency virus (hiv), it would be necessary to have taken antituberculosis treatment for at least weeks. in hiv-positive patients, negative sputum stains or a negative sputum culture are required during the course of the treatment. passengers with respiratory symptoms who come from areas of local transmission of sars should also be prohibited from flying, as should contacts of probable or confirmed cases of sars who have been exposed within the last days. patients with undrained pneumothorax, subcutaneous or mediastinal emphysema, or a pulmonary contusion, or who have undergone a major thoracic surgical procedure in the last weeks are also considered to have a respiratory contraindication for air travel. most current guidelines only consider the results of pulse oximetry or baseline arterial blood gas analysis in screening for patients at risk of developing severe hypoxemia. , [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] in fact, pao greater than mm hg or spo above % are usually considered acceptable for air travel in the majority of cases. , however, in recent years it has been shown that screening based on pao or spo alone are insufficient. for instance, a study was performed in which in-flight hypoxemia was assessed in a group of patients with copd who had a resting pao of more than mmhg, without hypercapnia, and a forced expiratory volume in second (fev ) less than % of reference. in % of the patients, pao was less than mm hg at an altitude of m and % had a pao of less than mm hg. what was even more noteworthy in that study was that % of the patients had a pao less than mm hg when they undertook lowintensity exercise similar to that necessary to walk along the aisle of the cabin or to go to the bathroom. similar findings have been obtained in patients with interstitial disease. figure shows a proposed algorithm for patient assessment. in those patients who receive home oxygen therapy, it is recommended that the oxygen flow be increased during the flight, usually by to l/min. in other patients, in-flight hypoxemia should be estimated if they have a pao less than mm hg or an spo less than %, if the forced vital capacity (fvc) or dlco is less than % of reference, or if other risk factors are present ( table ) . based on the level of hypoxemia during air travel in healthy subjects, a pao of more than to mm hg has been arbitrarily considered acceptable. [ ] [ ] [ ] [ ] [ ] consequently, it is important to estimate the pao during the flight, since below mm hg provision of supplementary oxygen during the flight is recommended. pao at altitude can be estimated in ways: through the use of prediction equations or with a hypoxia-altitude simulation (hypoxic challenge) test. absolute acute respiratory failure sputum-positive tuberculosis passengers from areas with recent local outbreaks of severe acute respiratory syndrome (sars) with respiratory symptoms contacts of probable or confirmed cases of sars who have been exposed in the last days undrained pneumothorax thoracic surgery within the last weeks lung contusion subcutaneous or mediastinal emphysema relative resolution of a spontaneous pneumothorax in the last weeks major thoracic surgery within the last weeks scuba diving in the last hours (table ) . , [ ] [ ] [ ] [ ] [ ] [ ] [ ] some of them allow pao to be determined for any given altitude based on values obtained at sea level ( figure ). , in most cases, the equations were established for patients with copd and the measurements of pao at altitude were performed in hypobaric chambers or following altitude simulation via respiration with a fraction of inspired oxygen (fio ) of %. the accuracy improves when measurements of fev , or fev /fvc are included. in addition, greater accuracy is obtained when they are applied to copd patients with an fev less than % of reference. despite the simplicity of equations to estimate in-flight hypoxia and their widespread availability, they also have drawbacks. the most important is the consequence of their very large % confidence interval, which is ± . mm hg, mainly due to the use of very small samples in their calculation. it is notable that in patients with severe copd differences have been detected between the actual pao during the flight and that estimated in the equation of gong et al of - ± mm hg (range, - to mm hg). in almost all cases, patient series used to develop the equations have involved healthy men or men with copd, meaning that accurate information on women is lacking. nor have flight duration and cabin conditions been considered. in addition, the equations have not been validated with another hypoxia test repeated after the test used to generate them. it is possible that equations that include fev underestimate the severity of hypoxemia triggered by altitude in hypercapnic patients, since some authors have demonstrated that pao at altitude is inversely proportional to paco at sea level. in the same way, equations that use fev or fev /fvc in healthy subjects probably overestimate pao at altitude. it is also likely that the cause of the hypoxemia should be taken into account. for instance, hypoxemia as a result of shunt is affected very little by altitude, while that caused by ventilation-perfusion imbalance is highly dependent upon pio . , recently, a specific prediction equation that includes dlco was developed for patients with restrictive disease. another equation relevant to patients with copd or interstitial disease has also been proposed. in addition, in recent years models have incorporated paco , both for healthy subjects and patients with copd. in the light of available data, the equation published by muhm would be the most recommendable in healthy subjects and patients with copd, while that of christensen et al would be advisable for patients with restrictive disease. hypoxia-altitude simulation test. although hypobaric hypoxia is the ideal method to estimate the degree of hypoxemia during a commercial flight, it can not be used in ordinary clinical practice due to the limited availability of hypobaric chambers (appendix ). as an alternative, it is recommended to resort to the isobaric hypoxia-altitude simulation (hypoxic challenge) test, initially described by gong et al. this test assumes that respiration of a hypoxic gas mixture at sea level (normobaric hypoxia) simulates the hypobaric hypoxia characteristic of higher altitude. the maximum altitude corresponding to cabin pressure ( m) can be simulated by respiration of a mixture of % oxygen in nitrogen. no specific preparation is required for the test. it is recommended that the test be performed without interruption of the patient's usual medication, attempting to avoid changes in the dose or intervals of the medication. once patients are seated, they can be made to breathe a hypoxic gas mixture using a douglas bag, a plethysmography chamber, or a venturi mask. the most traditional and simple method is to ask the subject to breathe the gas mixture contained in a to l douglas bag, which is filled with % oxygen and nitrogen as a carrier using pressurized cylinders. in this case, the patients can breath through a mouthpiece with a nose clip, or through a face mask with a valve to prevent rebreathing. , the second option involves filling a sealed plethysmography chamber with a gas mixture ( % oxygen in nitrogen) that can be kept constant by introducing oxygen or nitrogen through a port. this procedure has the advantage of not requiring a mask or mouthpiece and also allowing titration of the oxygen flow required to correct the hypoxemia by administration of oxygen through nasal prongs within the hypoxic environment of the chamber. however, while the patient remains in the chamber it is not possible to obtain samples of arterial blood and monitoring is therefore limited to spo . as a third possibility, a venturi mask can be used in which oxygen is replaced with nitrogen as the carrier gas. it has been confirmed with various devices that a venturi system at % generates an fio of %, while % produces an fio of %, both in healthy subjects and patients with copd. however, it must be remembered that not all commercial models based on the venturi principle are able to administer oxygen with an error of less than %, as claimed in their specifications. in addition, the fio can be reduced if the inspiratory flow of the patient exceeds the total flow generated by the apparatus. although its role is more limited, the dead space inside the mask also affects the concentration of oxygen provided. it is also necessary to consider that nitrogen is % less dense than oxygen, meaning that the carryover capacity for air through the venturi system is lower than that of oxygen, thereby making the fio achieved less accurate. thus, it appears reasonable to suggest that if this system is used to administer the hypoxic gas mixture then fio should be monitored simultaneously. during the test, the patient will be asked to breathe at tidal volume and the test will be ended after minutes , or when a stable situation is achieved, defined as the absence of variability in spo (± %) or heart rate (± beats per minute) for at least minutes. it is recommended that spo be monitored continuously and that arterial blood gas analysis be performed at the beginning and end of the test. in terms of pulse oximetry, it should not be forgotten that true oxygenation can be slightly overestimated in smokers, given that the technique does not discriminate between oxyhemoglobin and carboxyhemoglobin. furthermore, most pulse oximeters display a certain degree of inaccuracy and variability in the saturation range between % and %. therefore, spo should only be used to monitor the test, while interpretation of the test results should be based on pao . in both healthy subjects and patients with copd, the hypoxic challenge test provides a measure comparable to that obtained by simulating the same altitude in a hypobaric chamber. the relationship between isobaric hypoxia and hypobaric hypoxia appears not to be affected by the age or the sex of the subjects. in turn, it has also been demonstrated that there is a good correlation between the pao obtained during simulation of altitude-induced hypoxia and that determined during flight, although this correlation is weakened when the interval between the measurements is longer than months. in terms of safety, the tolerance of hypoxic challenge is good and only mild side effects such as tachycardia, dyspnea, vertigo or nausea, headache, and sleepiness have been described. hypoxic challenge offers certain advantages over prediction equations. it provides a more accurate assessment of the individual's response to hypoxia. in addition, it allows assessment of the possible effects of hypoxia, such as symptoms or electrocardiographic (ecg) abnormalities. although initial studies involved continuous ecg monitoring, , few arrhythmias related to hypoxia were identified and all of them were benign; consequently, systematic ecg monitoring is not recommended. however, it may be considered on an individual basis in patients with cardiovascular comorbidity. despite these considerations, hypoxic challenge is a procedure that also presents limitations. it does not reproduce cabin conditions of pressure or air density. however, in order for reduced air density or flow turbulence to generate an increase in fev or a reduction in work of breathing, altitudes of more than m are required, suggesting that these factors will have little influence. in addition, the potential beneficial effect of the reduced air density will never be greater than the negative effect caused by the reduction in pio , the increase in lung elasticity and air trapping, and the poor distribution of ventilation. , the length of the flight is also not taken into account during hypoxic challenge. however, changes in arterial blood gases during a flight lasting hours have recently been analyzed in patients with copd. it has been demonstrated that when patients remain seated pao falls until cruising altitude is reached and then remains stable for the rest of the flight. there is less consensus regarding the application of these recommendations in children with respiratory diseases. little information is available on physiologic changes at altitude in children. in addition, the spectrum of disease can be very broad. in premature babies with acute viral respiratory infection there is a greater risk of apnea due to immaturity of the breathing pattern. in that case, environmental hypoxia can increase the risk of apnea and it is therefore recommended that infants do not fly until months after the date for full-term birth. on the other hand, some children with cystic fibrosis are better adapted to a hypoxic environment, probably through changes in the dissociation characteristics of hemoglobin. as a result, the current recommendation considers that children with an fev less than % of reference for cystic fibrosis or other chronic lung disease should undergo a hypoxic challenge test and that if spo is less than % during the test then provision of oxygen during the flight should be prescribed. , the most recommendable route for administration of the hypoxic gas mixture in children is breathing in a plethysmography chamber. supplementary oxygen is recommended during air travel for patients who have an estimated in-flight pao of less then mm hg obtained with prediction equations or, preferably, a hypoxic challenge test ( figure ). , the criteria on which this cutoff is based are arbitrary. since healthy individuals can reach a pao of to mm hg at cabin altitude, mm hg was considered to represent the lower limit for a clinically acceptable pao . therefore, that cutoff is based on expert consensus and does not have scientific support. patients with an estimated pao greater than mm hg could fly without a requirement for supplementary oxygen. finally, the group of patients with an estimated pao between and mm hg should be assessed on an individual basis. in this case, if there is serious deterioration of resting lung function, marked exercise limitation in either the walk test or the incremental cardiorespiratory exercise test, or comorbidity, provision of oxygen during the flight could also be recommended ( figure ). oxygen is usually provided during the flight through nasal prongs. in patients with severe copd subjected to conditions of hypobaric hypoxia similar to those in the cabin of a commercial aircraft, it has been shown that provision of oxygen through nasal prongs at a rate of l/min produces a greater increase in pao than when administered using a venturi mask at % or %. in fact, ventimask systems may favor dilution of ambient air at relatively low flow rates. an oxygen flow of l/min appears sufficient to correct the hypoxemia in most cases. it has been confirmed that provision of oxygen through nasal prongs at l/min in healthy subjects and patients with obstructive or restrictive disease who breathe an ambient fio of % achieves an spo similar to that recorded when they breathe at an fio of %. in restrictive diseases, a flow rate of l/min also appears to be sufficient to maintain adequate oxygenation during the flight, although when the patient moves about the aircraft it may be advisable to increase the flow to l/min, so long as an extension is available. finally, provision of supplementary oxygen should be considered a safe and effective procedure for the management of many patients with chronic respiratory diseases who undertake a journey by air. , , for example, it has recently been described that provision of oxygen during flights of up to km allowed a group of patients with severe lung disease to reach their destinations satisfactorily. in that study, only a few episodes of near fainting were observed due to insufficient oxygenation when going to the bathroom without supplementary oxygen. consultation prior to air travel. however, the response of physicians cannot currently be clear and robust, since there is insufficient scientific evidence and many elements remain to be clarified. in general, the first recommendation for a patient with copd and hypoxemia would be to avoid air travel and look for other means of transport. this indication might have been valid some years ago but it is currently insufficient for many patients, since it may affect their quality of life and in some cases their work. in fact, a small survey performed in the united states of america on patients with severe copd showed that each year approximately in traveled by air. however, those results cannot be extrapolated to spain, where the proportion is likely to be lower. as for other diseases, it is accepted that patients with copd should maintain a pao of more than mm hg during a flight. , , with this threshold, no problems have been observed in studies involving hypoxic challenge and it seems reasonable given the clinical experience accumulated in patients with copd treated by continuous home oxygen therapy. however, this level is arbitrary and no studies have analyzed its possible consequences in periods of time closer to those of flights, although flight duration appears to have less effect than the altitude reached. despite the potential impact of copd, few studies have addressed the problem of hypoxemia at high altitude during air travel in this setting. furthermore, the studies performed have involved small samples of patients without severe hypoxemia, the majority eucapnic, and without significant cardiovascular comorbidity. , , , , the results of those studies indicate that patients can have reductions in pao of up to mm hg when they reach an in-flight altitude of m ( feet). this situation is not uncommon in normal flights, and although the incidence of medical problems appears minimal in the general population, , the same is not true of copd patients, in whom symptoms and the requirement for in-flight medical assistance are more common. nevertheless, these events do not normally appear to be particularly serious, and when they are, they are usually cardiovascular in origin. , although the interpretation of these data may be erroneous due to the limitations of their collection, it is also possible that the tolerance of hypoxemia in patients with copd (without other factors that could alter oxygen transport such as heart disease or anemia) is greater than might be expected. according to current knowledge, it could be recommended that all patients with moderate or severe copd who wish to travel by air should be clinically assessed, with attention to the following elements: ) ruling out the presence of exacerbation or that the patient is in an early phase of recovery from an exacerbation, ) identifying the treatment being taken, and ) reducing comorbidity. once clinical stability has been confirmed and treatment optimized, arterial blood gas analysis and spirometry should be performed in the days prior to flying. the values obtained for pao must be adjusted to sea level; in some regions of spain that may imply an increase of up to mm hg. in order to simplify the assessment, the following algorithm could be recommended in response to the presence of hypoxemia ( figure ): . pao > mm hg. in general, patients with this pao will not present severe hypobaric hypoxemia, making systematic estimation of in-flight pao unnecessary. nevertheless, the presence of symptoms (dyspnea or chest pain) during previous flights should be assessed, and if they are present, oxygen support at low flow rates ( - l/min) should be recommended. it also seems wise to extend that treatment option to those cases and in which the in-flight cabin pressure corresponds to an altitude of greater than m ( feet) and the patient has very severe copd (fev ≤ %), where limitations may be present in the mechanisms of compensation for hypoxemia, or diseases that alter oxygen transport. . pao = - mm hg. an estimate of in-flight pao should be made using a prediction equation or, preferably, hypoxic challenge. prescription of oxygen at low flow rates is recommended in the following situations: -estimated in-flight pao less than mm hg -flights in which the cabin pressure corresponds to an altitude greater than m ( feet) -presence of cardiovascular comorbidity and/or anemia . pao < mm hg. patients in this situation usually already receive continuous home oxygen therapy. the goal would be maintenance of the same oxygen levels during the flight, necessitating an increase of to . l/min over the patient's usual oxygen support. such treatment should not normally create problems in eucapnic copd patients, in whom a tendency toward hypocapnia due to hyperventilation has been observed. however, in the presence of hypercapnia, prior assessment of variations in gas exchange following increased oxygen support should be undertaken. it is important to mention that patients who are not receiving continuous home oxygen therapy have a lower sense of the severity of the disease and a substantial proportion may not consult their doctor prior to undertaking air travel. thus, improved treatment education should be developed for this patient population. alongside preflight planning based on pao , other general measures to prevent deterioration of hypoxemia include the following: -avoid excessive physical effort: do not carry weight and reserve a seat close to the bathroom. however, this should not be a contraindication for the necessary movement of the lower limbs to prevent dvt -avoid sleep -do not eat large meals it is advisable for airline companies to have trained staff available who are able to monitor spo in patients who require oxygen during the flight (spo between % and % could be acceptable). in addition, they might be able help to detect abnormalities in heart rhythm, which although rare, show a high between-individual variability. this monitoring is essential if the patient has to travel urgently whilst clinically unstable. while awaiting new studies that improve upon the substantial limitations in our understanding, the overall message is that all patients with copd should be assessed by their pneumologist prior to air travel. supplementary oxygen should be provided for those patients whose estimated in-flight pao is less than mm hg, taking particular care with those who have cardiovascular comorbidity. commercial flights represent a favorable environment for the spread of pathogens transported by passengers or flight personnel, as was shown during the recent outbreak of sars. few studies or data are available on this topic and it is difficult to quantify the global repercussions, which may be underestimated, since almost all of the diseases involved have incubation periods that are shorter than the length of the trip, some of the diseases are treated as trivial processes, and the studies that have been performed have included a significant proportion of passengers who could not be located. the international health regulations adopted worldwide in to limit the spread of disease are in the process of revision. , recently, the world health organization (who) published guidelines on infectious diseases and air travel. risk factors. the respiratory infections that have been the object of the greatest interest are pulmonary tuberculosis, sars, and infections caused by the influenza virus. since the microorganisms responsible for those infections are mainly transmitted through the air, the risk of transmission during flights is affected by duration, the proximity of the index case, and the cabin ventilation, in addition to the pathogenic characteristics, the epidemiology of the infection in each region, and the immune status of the subject. the use of appropriate filters and correct recirculation of air in the plane reduces the risk of infection. although the safety of hepa filters in protection against viruses has been questioned, a more serious concern is the absence of legislation obliging their use in most countries. hepa filters were found not to be used on % of flights carrying more than passengers in the usa, and that figure is considerably higher in small planes that undertake local flights. based on the cases analyzed and studies involving mathematical models, individuals seated in either of the rows of seats closest to the affected passenger are at the highest risk for transmission of mycobacterium tuberculosis and if ventilation is doubled, the risk is reduced by half. the probability of transmission is also reduced to almost zero in passengers seated rows from the zone of infection. , however, this "safe distance" does not apply in the case of a patient with sars, who could infect any other healthy passenger seated in the next rows. studies performed by the who have failed to demonstrate that air recirculation by itself facilitates transmission of infectious disease on board aircraft. however, it should be confirmed that the cabin ventilation system functions correctly and continuously while passengers are on board, independently of whether or not the plane is in flight or held on the runway, as inadequate functioning clinical calls have recently been made in scientific journals and in the general media for serious consideration to be given to regulations on the use of hepa filters and for an increase in the number of checks made on aircraft by the authorities. , tuberculosis. a third of the world's population is infected by m tuberculosis, and consequently, it is the most extensively studied model of transmission during air travel. evidence is available that transmission from smear-positive individuals is more common during long flights (longer than hours) and can affect both the passengers and crew members. seven episodes of possible tuberculosis transmission during airplane journeys have been studied, of the episodes corresponding to strains resistant to isoniazid and rifampicin. possible transmission of the infections (mantoux conversion) to other passengers or crew members could only be established in of the episodes, although it was not possible to demonstrate development of the disease as a result of exposure during a commercial flight in any of the cases. , in the remainder, the studies found no evidence of transmission, were inconclusive, , or the likelihood of transmission was considered very low. in all of the cases, the index patient had substantial radiographic involvement and sputum stains revealed acid-fast bacilli with positive sputum cultures. despite the fact that acquisition of the disease and possibly transmission of the infection is less likely than in other modes of transport, a great deal of anxiety has been generated among the public, health authorities, and airline companies, and consequently, the who has published guidelines with a protocol that ends with a series of recommendations for passengers, physicians, health authorities, and airlines (appendix ). severe acute respiratory syndrome. the epidemic outbreak of sars, for which the causative agent is a coronavirus, is the most recent and representative example of a disease transmitted by a very small number of travelers to other countries and continents within a few weeks. studies showed that in of the flights investigated for carrying patients infected with the sars virus transmission of the virus to other passengers was likely to have occurred. . - the majority of the patients who were infected had been seated in the rows closest to the index case, although at least in flight lasting hours (hong kong-beijing) an outbreak occurred that affected a high percentage of passengers seated up to rows from the index case and subsequently in more than secondary cases. possible explanations for that outbreak have been sought, and although no conclusive results have been obtained, it has been suggested to have occurred mainly through aerial transmission from a direct or indirect contact, that some of the passengers were infected prior to the flight, or that it occurred as a result of defective cabin ventilation. the cabin crew may have an increased risk of acquiring the disease due to their movement through the aircraft. the who developed a series of recommendations and guidelines, which included a series of measures that should be followed by all countries (appendix ) . , once those measures were put into practice, no new cases of long-distance propagation of the disease were identified. influenza. epidemic infection with the influenza a virus appears between the months of october and april in the northern hemisphere and between may and september in the southern hemisphere. in a recent study undertaken in switzerland, almost % of passengers who suffered fever during a journey to subtropical or tropical regions had a significant antibody titer against influenza viruses when they returned and in more than % it was possible to demonstrate a seroconversion of more than times the initial titer. the most common pathogens in fever episodes outside the periods of local epidemic were influenza viruses. that source may be the cause of some of the limited outbreaks that occur during the nonepidemic period. , other viruses such as influenza b and parainfluenza also have demonstrated pathogenic capacity. , as in conventional epidemic outbreaks, a series of risk factors affect acquisition of infection, such as age over years, presentation of comorbid conditions, and close contact with the index case, meaning that tourism in groups can facilitate infection. nevertheless, only studies have reported infection during air travel. , , the passengers seated in the rows closest to the index case were the most often affected, although given the high infectiousness of the virus, between % and % of the passengers was possible in flights lasting longer than hours and up to % of secondary familial contacts developed the disease. suspension or failure of the ventilation system favors disease transmission, as demonstrated in a flight in which an individual with flu infected % of the passengers. some countries recommend flu vaccination for those passengers undertaking journeys to the southern hemisphere during the summer and who were not vaccinated during the previous year. some microorganisms that do not produce respiratory symptoms, or at least are not associated with respiratory conditions as the principal symptoms, are nevertheless transmitted through the airways. among them, meningococcus and measles virus are the most noteworthy as a result of their infectiousness, morbidity and mortality. between and , cases were studied of patients with meningococcal disease who had traveled by plane during the infectious period without evidence of a single secondary case. nevertheless, given the severity of the disease, it is advised that individuals seated near the index case begin prophylactic treatment in the hours following the case being reported, so long as less than days have elapsed since the contact. , the measles virus is highly contagious, with up to % of exposed individuals developing the disease, and cases have been described of transmission during air travel. [ ] [ ] [ ] [ ] currently, the vaccination schedule in the different autonomous communities of spain includes vaccination against meningococcus from the age of years and measles from months, making the risk of transmission of those diseases presumably minimal, although individuals without antibodies or those from other countries who have not been vaccinated could be affected. no epidemic outbreaks have been reported for the virus that causes the common cold, but this absence is presumably due to the high frequency of the disease and the difficulties associated with investigating it. one study found no evidence that the air recirculation system in the cabin aided appearance of symptoms of infection in the upper airways. there is currently a great deal of concern regarding spread of the avian flu virus (h n ). this virus has a shorter incubation period and is more contagious than the sars virus. the usa has prepared a national plan to prevent the spread of outbreaks through the establishment of a series of specific health measures in airports. in addition to an increase in the number of health care workers, medical consulting rooms have been built that allow the health of passengers to be assessed and isolation rooms created to establish a quarantine area in international airports. those facilities are in permanent contact with the centers for disease control and prevention (cdc) and have access to passenger information for all flights in order to identify contacts of a possible index case. to date, the benefits of such a strategy have not been demonstrated and it is quite unlikely that it would prevent or slow an epidemic caused by introduction of the influenza or sars virus. detection of individuals with the disease exclusively in the destination airport would only have consequences for the detection of individuals who developed the clinical features during the flight and of contacts, thereby making the sensitivity low. most experts are in favor of strategies similar to those followed in the sars outbreak, including monitoring to detect individuals with symptoms in the departure airport, in an effort to prevent individuals with the disease from boarding the flight. [ ] [ ] [ ] [ ] if a case of infection with the avian influenza virus is confirmed, isolation measures similar to those followed for patients and contacts with sars must be established, treatment with neuraminidase inhibitors should be initiated immediately, and in contacts, prophylactic measures with those drugs should be started during the first hours. if a specific vaccine is available it should be immediately administered to contacts. the who has established a global plan in which these elements are considered. , recently, a series of recommendations and considerations were prepared on the management of exposure to an infectious disease during commercial air travel : -although passenger transport companies can refuse to transport individuals with a disease, they cannot undertake systematic examination in an effort to identify ill passengers. -early diagnosis is necessary to establish measures for the other passengers. -governments have the legal authority, in accordance with international law, to establish controls on passengers with transmissible diseases for which declaration is obligatory. -the authorities may establish measures to quarantine passengers who arrive at their airports. -physicians must identify those subjects who are not in a good enough state of health to travel by air and inform them of how a flight might affect their health. -prevention is the best course of action and postponement of the journey should be advised. -hand washing reduces the risk of transmission of contagious diseases and should be performed as a matter of course during travel and always prior to eating. -the mouth and nose should be covered in the event of sneezing or coughing and hands should be washed afterwards to protect others. -in the case of a passenger with suspected sars during the flight, a us national institute for occupational safety and health n mask should be provided and an isolation zone established in the aircraft. survival and quality of life have improved in patients with cystic fibrosis, making it not uncommon for them to want to go on holidays and even undertake work that may involve air travel. few studies have assessed the effects of commercial flights on patients with cystic fibrosis. there is some disagreement regarding estimation of the level of hypoxemia in those patients. although in a study performed in a small group of patients aged between and years, hypoxic challenge predicted with a high level of sensitivity and specificity the development of desaturation during the flight, later studies have not confirmed those findings. a study undertaken by the same group that contained a larger number of subjects and involved longer flights ( - hours) contradicted the earlier findings and showed that an fev less than % of reference better identified patients who desaturated than did the results of hypoxic challenge. only a small percentage of the patients who displayed reductions in spo to below % presented symptoms and required oxygen supplementation. however, it should be noted that the patients included in those studies were stable, had disease that was not very advanced, and were younger than other groups of patients with cardiac or respiratory diseases for whom reduction of pao to below mm hg necessitates the implementation of oxygen therapy during the flight. this would explain the greater tolerance of hypoxia seen in patients with cystic fibrosis, confirmed both in acute exposure in hypobaric chambers and during time at altitude. in addition, in patients with cystic fibrosis, the results of hypoxic challenge are particularly variable over time and can change within a few weeks. , consequently, the decision to have a cystic fibrosis patient use oxygen therapy during a flight should not be based exclusively on hypoxic challenge tests but also on clinical parameters and the degree of bronchial obstruction. other recommendations to consider in patients with cystic fibrosis who intend to travel by air are summarized in table . some authors have described an increase in exacerbations following a holiday, , related to poorer management of the disease. correct compliance with treatment and, in particular, physiotherapy improves the conditions in which the return flight is undertaken and reduces the likelihood of complications. the estimated incidence of venous thromboembolic disease (vtd) in the general population is per person-years. the pathogenesis of dvt was first described by virchow in , and the description remains valid today. it is based on a triad formed by stasis of venous blood flow, damage to the vascular endothelium, and hypercoagulability. these circumstances coincide in acquired-transient or persistent-or congenital conditions defined as risk factors, present in approximately % of patients with vtd. extended journeys have been associated with an increased incidence of vtd and have been included in the list of risk factors. , in , the term "economy class syndrome" was coined following the description of cases of vtd after flights in economy class. the aim was to highlight that the limited space within which to stretch the legs during an extended period of time reduces venous return and favors stasis of venous blood flow. this situation is not exclusive to air travel in economy class. it has also been described in business class and in other forms of travel, such as cars and buses, involving long periods of time with the lower limbs flexed and at rest. apart from venous stasis, there is a lack of agreement regarding other factors associated with air travel that could contribute to dvt such as dehydration, favored by the low humidity of the cabin and in some cases increased by the diuretic effect of coffee or alcoholic drinks, and the hypobaric hypoxia associated with pressurized cabins. dehydration could predispose to dvt as a result of hemoconcentration and blood hyperviscosity, although this hypothesis has not been confirmed. it has been observed in experimental studies that hypobaric hypoxia favors activation of clotting , and reduces physiologic fibrinolytic activity of endothelial cells ; however, those results have not been reproduced in subsequent studies. incidence and risk of vtd. studies addressing the incidence and risk of thrombosis associated with long-distance flights have employed a variety of different methods and yielded disparate results. for passengers with a high risk of thrombosis due to the presence of additional risk factors the incidence of vtd appears to be high, from % to %. , in patients at low or moderate risk the incidence drops to between % and %. , most of the vtd events that were identified were asymptomatic dvt that exclusively affected the venous territory of the calf, although the screening method used in almost all of the studies involved venous compression ultrasound with or without doppler, raising questions over the results due to the limited sensitivity of the technique for distal clots. the influence of other individual risk factors appears to be decisive in generating dvt. the incidence of pulmonary embolism has been assessed in cohort studies. [ ] [ ] [ ] according to data collected in paris airports between and , the incidence of this entity has increased. significant differences have been described in incidence rates according to distance traveled, ranging from . per passengers for distances of less than km to . cases per passengers in flights of more than km. differences were also seen according to distance traveled in a study performed at madrid barajas airport. in flights lasting more than hours the incidence of pulmonary embolism was . per passengers and in flights lasting to hours it was . per passengers, while no cases were observed in flights lasting less than hours. consequently, hours has been considered the cutoff for recommending general measures for the periodic movement of the limbs. the relative risk of vtd is difficult to establish due to the heterogeneity of the studies. , , considering only air travel, the risk is not clear (odds ratio, . ), and consequently, it could not be considered as an independent risk factor. however, in passengers with additional risk factors for thrombosis, the odds ratio increased in all studies to represent a -fold to -fold higher risk of vtd. recently, it has been demonstrated that the immobility during a flight lasting more than hours increases the levels of certain markers of clotting in subjects without risk factors for thrombosis, but it remains to be established whether this represents an increased risk of vtd. prophylactic measures. patients must be assessed individually and the presence of other risk factors for venous thrombosis identified (table ) in order to adopt prophylactic interventions. classification of the risk as moderate or high in these circumstances is not well established. it seems reasonable to extrapolate the impact of each of these factors on vtd. general measures. adequate hydration, regular movement of the lower limbs, and avoiding keeping the legs bent for long periods of time are the measures recommended by most experts. these measure are recommended for general application in flights lasting more than hours. drink lots of liquids to avoid noxious effects of the dry cabin air on the secretions and mucosa of the airway if the patient uses a nebulizer, some airlines allow the patient's own nebulizer to be used or provide one for long-haul journeys if possible, physiotherapy exercises should be performed during stopovers on long journeys compression stockings. in passengers at high risk of thrombosis, compression stockings, generally knee length and with a pressure of to mm hg have proven to be effective in reducing the incidence of vtd; [ ] [ ] [ ] ; no adverse effects are associated with their use and they are well tolerated. prophylactic drug treatment. the use of acetylsalicylic acid and low molecular weight heparins has been tested in passengers at high risk of thrombosis. a dose of mg acetylsalicylic acid for days proved to be ineffective and caused gastrointestinal discomfort in % of subjects. in contrast, a single dose of enoxaparin, both at a therapeutic weight-adjusted dose and as a high-risk prophylactic dose, administered to hours prior to the flight reduced the incidence of dvt without side effects. the general conclusions on vtd and air travel are summarized in table . few studies have addressed the effects of air travel on patients with respiratory diseases who present respiratory failure or severe abnormalities in control of ventilation. issues that must be taken into account in relation to air travel in such patients, in addition to the characteristics and length of the flight, are the following: ) the total length of the journey (flight time plus predicted waiting time and risk of unexpected delays), ) travel from the airport to the final destination, ) logistic aspects such as provision of oxygen or the feasibility of charging the batteries of the apparatus or a wheelchair during the flight and at the destination, and ) the altitude of the destination point and the length of time the individual will remain there. most patients can travel despite limitations, so long as the journey is sufficiently prepared and no elements are left to chance. in general, an increase in oxygen flow of to l is recommended in patients who receive home oxygen therapy. it is also essential to know the conditions of each airline company prior to embarking upon a journey, both in terms of the transport and provision of oxygen and in relation to the accessories required by the patient (wheelchair, ventilator) and the requirement to travel with an escort. some companies allow the passenger to carry small oxygen bottles (a maximum of bottles less than . m long and mm in diameter), but other companies do not accept transport of oxygen, although they allow the use of some oxygen concentrators, according to very strict regulations, so long as the user has sufficient batteries available to last the entire duration of the flight. cases have been described of patients with kyphoscoliosis or neuromuscular diseases in whom long air journeys generated right heart failure, presumably linked to the hypoxia maintained during the flight. from a theoretical point of view, in patients with nonhypercapnic restrictive disease (caused by involvement of the parenchyma), who present a risk of hypoxia during the flight, oxygen would be indicated to reduce the impact of hypoxemia on pulmonary hypertension. in patients with restrictive diseases who use mechanical ventilation (for extrapulmonary involvement), it is recommendable that they carry the apparatus with them during the flight, even if they only use it at night. clearly, patients with continuous ventilation should carefully assess the journey since they will need to use the ventilator throughout the travel period, including during airport transfers. from a logistic perspective, it is very important to confirm the hand luggage that the patient can carry, especially in relation to wheelchairs, the ventilator, and the spare battery. in the case of patients with severe disability, most airlines require the presence of an escort and consider that person can take responsibility for there are few reports in the literature on the impact of air travel in patients with sleep apnea-hypopnea syndrome (sahs). some complications have been associated with long journeys followed by a period at altitude. all patients with sahs should avoid consumption of alcohol immediately before and during the flight. patients in a severe condition should employ continuous positive airway pressure (cpap) during long flights. to this end, they should have a dry cell battery available for use as an energy source for the equipment. although the low humidity of the air in aircraft cabins may favor the development of bronchospasm due to loss of water from the bronchial mucosa, asthma attacks during air travel are thought to be rare. in addition, it is sometimes difficult to differentiate them from dyspnea due to hyperventilation or panic. more recently, a higher incidence of episodes of bronchospasm requiring treatment during flight has been described. patients with controlled asthma and no respiratory failure do not present problems for air travel, although they should ensure that they have their medication to hand. patients with severe asthma with frequent exacerbations and serious attacks should ensure that the disease is well controlled prior to the day of the flight. since , the emergency medication in most aircraft includes bronchodilators, both in pressurized cartridges and for injection. however, in case of an attack, patients are recommended to take their normal rescue medication. patients with primary tumors or metastases can generally fly safely. nevertheless, it may be necessary to consider measures to alleviate hypoxemia or pain. pneumothorax is a contraindication for air travel. a patient will only be allowed to fly when the lung has been completely reinflated. the patient should not be allowed to fly until hours after pleural drainage has been withdrawn and with a radiograph performed hours after completion of drainage to confirm resolution of the pneumothorax. optionally, some airline companies may accept transport of a passenger with a pleural drain. in that case, since it is difficult to guarantee continuous aspiration during the flight, it is recommended that a heimlich valve be used. in exceptional cases it may be necessary to evacuate a pneumothorax during the flight. this should only be done by trained staff and when the cabin pressure corresponds to sea level. simple rib fractures do not usually present problems during the flight, particularly when there is no lung damage or prior pulmonary disease. the main problem associated with such fractures is pain, which can reduce ventilation. therefore, it is important that adequate analgesia is guaranteed during the flight. multiple fractures may cause thoracic instability and, in that case, the requirement for specialized transport should be considered. flights should be postponed in all patients with acute respiratory failure due to lung contusion until lung function returns to normal. , likewise, mediastinal or subcutaneous emphysema constitutes a contraindication for travel on commercial flights. in any of those situations, if air travel is essential an air ambulance is required. although individual assessment is necessary, as a general rule patients are advised not to fly until at least weeks after the operation. patients with respiratory diseases who require oxygen on board or some form of health care during the flight are the association between venous thromboembolic disease (vtd) and air travel is weak. the clearest risk is for presentation of asymptomatic deep vein thrombosis (dvt) restricted to the calf area. symptomatic episodes of vtd, including fatal pulmonary thromboembolism, are rare. the risk is increased in journeys lasting more than hours in patients with additional risk factors. regular movement of the legs and hydration should be a general recommendation. in passengers with other risk factors for venous thromboembolism, the decision to implement other prophylactic measures should be made on an individual basis. knee-length compression stockings are effective and reduce the incidence of dvt. low molecular weight heparins are effective in patients at high risk of thrombosis. in general, a single high-risk prophylactic dose of low molecular weight heparin appears to be sufficient but should be assessed on an individual basis. aspirin is ineffective and should not be recommended. considered as ill patients who require medical authorization (medical fitness for air travel [meda] case). all patients who report such a condition must be informed when making the reservation of the process that needs to be followed in order to obtain medical authorization, of the limitation and requirements that exist, of the number of escorts required, and of the cost of the service requested. in turn, they must complete the incad/medif form provided by the company (appendix ), based on iata recommendations, and send it by fax to the medical department of the airline company to receive authorization and initiate the corresponding procedures. oxygen is normally supplied through a mask, although patients may use their own nasal prongs. three sources of oxygen can be used in aircraft. if cabin pressure is lost, passengers may receive oxygen through masks located above their seats. however, this oxygen source, which has a limited duration, cannot be used for provision of supplementary oxygen to sick patients during the flight. the most common practice is to use cylinders with a capacity of cubic feet. at a flow rate of l/min, those cylinders can provide oxygen for hours, , making it important to estimate the number of cylinders that the patient will need based on the flow prescribed and the length of the journey. recently, the american department of transportation approved the use of portable oxygen concentrators, which can be used during takeoff and landing and while moving inside the cabin. this equipment can also help the patient while moving inside the plane and in the terminal. to date, the only approved models are manufactured by inogen (www.inogen.net) and airsep (www.airsep.com). it should be noted that most companies do not allow the use of liquid oxygen on board. if the patient wishes to transport a portable liquid oxygen system it must be checked in empty and filled on arrival at the destination. in general, in-flight oxygen is administered at flow rates of or l/min, and exceptionally, at l/min. the medical department of the airline company may require that the patient be accompanied by an escort trained in the used of the oxygen therapy system. in most cases, provision of oxygen during the flight is a service paid for by the passenger. as a guide, from january the spanish airline iberia charges € per flight and requires at least hours notice prior to departure of the flight or hours in the case of emergencies. in more exceptional cases, some companies may insist that a second seat is purchased for the oxygen source. previous experiences of travel with patients requiring oxygen therapy or mechanical ventilation show that the main problems arise during transfer of the patients. in general, most companies only provide oxygen during the period of time inside the plane or during transfer between planes of the same company. if oxygen is required during boarding or while waiting in the airport, the passenger should inform the medical services of the company to organize specialized transport, such as ambulance transfer to the plane. transport with oxygen during the flight does not represent an exceptional situation. data from the airline iberia indicate that persons require supplementary oxygen in flight each year. it is also possible to use cpap equipment or ventilators during flights. in that case, patients should carry their own equipment, since it is not provided by airlines. it is important to mention that, since the great majority of commercial aircraft do not have plug sockets in the cabin, the patient should carry a dry cell battery to independently power the equipment. permission to use cpap or a ventilator on board must also be requested when making the reservation and requires authorization by the medical department of the company. in general, an escort is not required for the use of cpap, obtain a report of the clinical condition of the patient that includes the most recent functional assessment and treatment. this is essential if the stay is for a number of weeks and the destination does not have the usual health care resources. in countries in which smoking is still allowed inside the aircraft, the patient must be seated in a nonsmoking area. avoid excessive alcohol consumption prior to and during the flight, especially in cases of apnea-hypopnea syndrome and risk of venous thromboembolic disease. move around during long flights, unless oxygen is required. if oxygen is required, it should be used if possible while moving inside the plane (with an extension to allow movement). prophylactic measures should be taken to reduce the risk of thromboembolism. carry required medication, especially rescue inhalers, in hand luggage. if medication is checked with baggage, ensure that it is not affected by the extreme conditions in the hold. use spacer chambers rather than nebulizers. if continuous positive airway pressure is required on a long-haul flight, carry a dry cell battery, which must be switched off prior to landing. patients who require a ventilator must be able to tolerate temporary disconnection of the apparatus during takeoff and landing. the requirement for oxygen or any other form of medical assistance must be indicated when the reservation is made, at least hours. prior to departure. if necessary, assistance must be organized with the medical department of the company to transfer the patient within the airport. whereas mechanical ventilation usually demands the presence of an assistant trained in its use. patients who are completely dependent on a ventilator and cannot tolerate temporary disconnection of the equipment during takeoff and landing, or in the event of other occurrences, cannot fly in commercial aircraft. in such cases, the use of air ambulances is necessary. nevertheless, there is a marked diversity in the regulations, availability, cost, and ease of oxygen provision during air travel, making it advisable for patients or their representatives to determine the criteria established by the company with which they intend to fly. this information can be obtained directly from travel agencies, when making a reservation, or via the webpage of the british lung foundation. finally, all patients with respiratory diseases who intend to fly are advised to consider certain general recommendations ( table ) and even to access specific information sources for patients. [ ] [ ] [ ] . individuals with tuberculosis (tb) with the possibility of between-individual transfer, such as sputum-positive patients, must postpone their journey until they are no longer a potential source of transmission. . if the history of a patient with tb who could transmit the disease shows that he or she has recently undertaken a journey by air (eg, within the last months), the physician should immediately inform the health authorities in the declaration of the tb case. . the health authorities should immediately contact the airline company if the person has undertaken a journey lasting at least hours in a commercial aircraft during the last months. for the airline companies . airline companies should work closely with health authorities in the provision of information to passengers and flight crew who may have been exposed to mycobacterium tuberculosis as well as in the identification of those passengers who should be informed. airline companies should cooperate closely with health authorities in the provision of information to passengers and flight crew who may have been exposed to m tuberculosis as well as in the identification of those passengers who should be informed. airline companies should require the home and work addresses and telephone numbers of passengers so that they can be informed in the event of potential health risks (exposure to m tuberculosis or other infectious diseases, exposure to toxins, etc). airline companies should ensure that all crew receive appropriate training in first aid and the use of universal precautions regarding exposure to biologic fluids. all aircraft must be equipped with emergency medical supplies (including gloves, masks containing high efficiency particulate air [hepa] filters, and biohazard bags). . airline companies must have prearranged access to physicians with experience in transmissible disease who are available for subsequent consultation by health authorities. records of all diseases and medical emergencies must be kept for at least years. . long delays should be reduced to a minimum and hepa filters should be installed and maintained at maximum efficiency ( . % at . µm). centro travel by air: health considerations flying with respiratory disease inflight deaths during commercial air travel. how big a problem? utilization of emergency kits by air carriers. oklahoma city: faa civil aeromedical institute response capability during civil air carrier inflight medical emergencies. oklahoma city: faa civil aeromedical institute british thoracic society standards for care committee. managing passengers with respiratory disease planning air travel: british thoracic society recommendations expert care, everywhere managing passengers with respiratory disease planning air travel: british thoracic society recommendations standards for the diagnosis and care of patients with chronic obstructive pulmonary disease the canadian thoracic society standards committee. recommendations for 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congenital kyphoscoliosis following intercontinental air travel assisted ventilation at home. . oxford: medical publications emergencies in the air responding to medical events during commercial airline flights viajar con oxígeno. reflexiones a propósito de la primera reunión internacional de pacientes con déficit de alfa- antitripsina a comparative analysis of arranging in-flight oxygen aboard commercial air carriers air travel with a lung condition safe flying for people with lung disease medical guidelines for airline passengers the authors would like to thank dr fernando merelo de barberá, head of aerospace medicine at iberia, and dr francisco ríos tejada, head of the department of aerospace medicine at the aerospace medicine training center, for advice on preparation of the manuscript. . establish a screening system organized by the authorities in the affected regions in which all passengers are assessed by health workers at the point of departure. in case of suspicion during the flight, isolation measures should be taken for subjects who are suspected to carry the disease (provision of an exclusive bathroom, covering the mouth and nostrils of the patient with an appropriately protective mask) and the health authorities at the destination point should be informed about the suspicion. . management of contacts. contacts are considered as all individuals seated in the rows closest to the index case and all those who have had close contact with the index case prior to or during the journey. if the affected individual is a member of the cabin crew, all passengers are considered contacts. it is obligatory for the health authorities to identify and locate the whereabouts of those individuals for the following days and to contact the health authorities immediately if they develop any symptoms. . the aircraft should be disinfected according to world health organization guidelines. key: cord- -wm krxve authors: koslik, hayley j.; joshua, jisha; cuevas-mota, jazmine; goba, daniel; oren, eyal; alcaraz, john e.; garfein, richard s. title: prevalence and correlates of obstructive lung disease among people who inject drugs, san diego, california date: - - journal: drug alcohol depend doi: . /j.drugalcdep. . sha: doc_id: cord_uid: wm krxve background: pulmonary tissue damage leading to obstructive lung disease (old) could result from intravenous administration of insoluble particles found in illicit drugs. this study described the prevalence and identified correlates of old among people who inject drugs (pwid). methods: in - , a community-based cohort of pwid who had injected within the past month were enrolled in a study to assess hiv, hepatitis c virus (hcv) andmycobacterium tuberculosis (mtb) infections and their related risk factors. data were obtained through face-to-face interviews, serological testing and spirometry. baseline data were used for a cross-sectional analysis of the prevalence and correlates of old, defined as fev /fvc < . . univariate and multivariable logistic regression were used to identify factors associated with old. results: among participants who had complete spirometry and interview results, the mean age was . years, . % were male, . % were black, . % smoked cigarettes and . % had old. few ( . %) pwid with old reported a previous diagnosis of copd although many ( . %) reported related symptoms. black race (aor = . , %ci: . , . ), pack-years smoked (aor = . / years, %ci: . , . ), and duration of injection drug use (aor = . , %ci: . , . ) were independently associated with old after controlling for age. conclusions: the prevalence of old was high in this cohort and associated with black race and cigarette smoking—known risk factors. in addition, old prevalence increased with greater duration of injection drug use, suggesting a link between cumulative exposure to injected insoluble particles and old. further examination of these adulterants and lung pathology are needed. obstructive lung disease (old) is a group of conditions characterized by episodic or persistent airflow limitation that makes breathing difficult, which may be partially irreversible (global initiative for chronic obstructive lung disease, ). these conditions include chronic obstructive pulmonary disease (copd) and asthma, and are characterized by symptoms of shortness of breath, chest tightness, wheezing, cough, and mucus production. among united states (u.s.) adults, the number of physician-diagnosed copd and asthma cases annually is a staggering . and million, respectively (office of disease prevention and health promotion, ), and globally the number has reached and million cases, respectively (world health organization (who), , ). copd is the fourth leading cause of death in the u.s. (heron, ) and remains the third leading cause of death worldwide (world health organization (who), ). mortality outcomes for individuals with copd vary by patient phenotype (whether there is overlap with asthma, moderate/severe exacerbations with chronic bronchitis or j o u r n a l p r e -p r o o f emphysema, etc.), but is predominantly due to disease progression (golpe et al., ) . old costs the u.s. healthcare system an estimated $ billion annually in copd-related expenditures -$ billion going to direct healthcare costs, and the rest to indirect costs, such as patients' inability to work or time taken off from work (guarascio et al., ) -and $ . billion per year in asthmarelated expenditures (office of disease prevention and health promotion, ). the leading risk factor for copd is cigarette smoking (bhatt et al., ) , but studies have also reported associations with older age (de marco et al., ) , low socioeconomic status (wheaton et al., ) , human immunodeficiency virus (hiv) infection (drummond et al., ) and history of pulmonary tuberculosis (byrne et al., ) . copd has been found to be associated with injection drug use (crothers et al., ) , although this could be confounded by the very high prevalence of smoking among people who inject drugs (pwid) (clarke et al., ) . to date, only one study has assessed old specifically among pwid (horyniak et al., ) . in addition to factors such as age, gender, lower education and history of childhood respiratory illness being associated with copd among non-smokers (lamprecht et al., ) , there is evidence to suggest that the risk of old among pwid might not be entirely attributable to smoking (ward et al., ) . one hypothesis is that non-soluble contaminants added to illicit drugs by dealers to increase their volume, or excipients added to oral prescription medications as binders or to help them dissolve faster, may become lodged in the alveoli when they are injected intravenously, causing lung pathology (gotway et al., ) . for example, pulmonary fibrosis and granulomas, in addition to emphysema and pulmonary hypertension, have been reported with injection of talc-containing j o u r n a l p r e -p r o o f drugs (griffith et al., ; paré et al., ) . other drug excipients like microcrystalline cellulose, crospovidone (an insoluble, hygroscopic powder contained in pills to help them dissolve), and starch have also been reported to lead to pulmonary complications when injected (fields et al., ; ganesan et al., ; lamb and roberts, ; nguyen et al., ) ; however, these may be less likely than talc to enter the lungs as they tend to be larger in size (kringsholm and christoffersen, ) . considering these mechanisms, certain injection drug-related factors (e.g., type of drugs injected, frequency and duration of injection drug use) may increase exposure to adulterants, thereby contributing to the increased risk of old among pwid. the primary objectives of this study were to measure the prevalence of old among pwid in san diego, ca, and to identify pwid-specific correlates of old in this population after controlling for known risk factors. it was hypothesized that old would be independently associated with factors related to injection drug use. due to the reported lack of access to healthcare (chitwood et al., ) and/or the over-utilization of emergency department care in this population (kerr et al., ) , a secondary analysis evaluated whether there was an association between utilization of healthcare in pwid and old. the present study used baseline data from the study of tuberculosis, aids, and hepatitis c risk (stahr ii) cohort for a cross-sectional analysis of the prevalence and correlates of old among pwid. stahr ii was a prospective cohort study in which community-recruited pwid who had injected at least once in the prior month (actively injecting) were enrolled in - , and j o u r n a l p r e -p r o o f followed for two years through semi-annual follow-up visits to determine the prevalence, incidence, and risk factors for mycobacterium tuberculosis (mtb), hiv, and hepatitis c virus (hcv) infections among pwid in san diego, ca. stahr ii methods were published in detail elsewhere (robertson et al., ) . the stahr ii study protocol was approved by an institutional review board at the university of california san diego, and all participants provided written informed consent. the current analysis also received a non-human subjects research determination from san diego state university's human research protections program. study participants were recruited through targeted sampling, which consisted of street outreach and posting flyers in areas where pwid generally gather (e.g., syringe exchange program sites), print and online advertising (e.g., local newspaper, craigslist), as well as through participant referrals (robertson et al., ) . eligible participants were at least years old, spoke english or spanish, had illicitly injected drugs in the past days, were non-institutionalized (i.e., hospitalized, incarcerated or in-patient substance use treatment), and resided in san diego county without plans to move away in the next months. old status (yes/no) was determined at baseline by spirometry using a forced expiratory volume per second/forced vital capacity (fev /fvc) ratio without the use of bronchodilators. spirometry j o u r n a l p r e -p r o o f was repeated three times in the same visit and then averaged according to american thoracic society recommendations ( ) . old was defined as a fixed ratio fev /fvc value < . based on global initiative for chronic obstructive lung disease (gold) cut-offs (güder et al., ) . computer-assisted personal interviews were conducted at baseline by trained interviewers in a private setting and lasted an average of - minutes. interviews collected information about potential correlates and known risk factors for old including socio-demographics (i.e., age, gender, race/ethnicity, homelessness), smoking status, lifetime and recent drug use and injection behaviors, symptoms and previous diagnosis of respiratory illness, and healthcare utilization. due to the non-linear relationship between age and risk of old, age (collected in years) was categorized for this analysis as a binary variable (< years and  years) for consistency with other studies as this is the age that copd symptoms typically begin (national heart lung and blood institute) and copd prevalence increases (ntritsos et al., ) . eight individuals reported being transsexual/transgender and were grouped by their preferred binary gender (male/female). since prior studies found only black race to be associated with old compared to other races (chatila et al., ; drummond et al., ) , race was dichotomized for this analysis (black/non-black). for descriptive purposes, a non-binary race variable (asian, black, hispanic, other, white) was reported. self-perceived homelessness was queried, "in the past months, have you ever thought of yourself as homeless?" (yes or no). to obtain cigarette smoking status, participants were asked about lifetime history of smoking ("have you ever smoked at least cigarettes in your entire life?" [yes/no]), and current smoking status ("do you smoke cigarettes now?" [yes/no]). responses to these questions were used to create a "cigarette smoking status" variable (never smoker, former smoker, current smoker). packyears of smoking among former and current smokers was calculated as the number of cigarettes smoked per day times the number of years smoked divided by . participants were also asked if they had ever used marijuana or hash (yes/no). to examine injection drug use practices, participants were asked to specify the number of years they had been injecting drugs (continuous) and the specific types of drugs (e.g., heroin, cocaine, methamphetamine) they had injected, smoked, or inhaled in their lifetime (yes/no). types of heroin injected (black tar, white powder, brown powder, other) were assessed among those who reported injecting heroin in the past months. the main reasons for not seeking medical care in the past months, if applicable, were grouped into categories due to small sample sizes (visit not expected to be helpful, avoidance of bad news; fear of hostility, disrespect, or arrest; too embarrassed, ashamed, tired, sleepy, lazy, depressed, ill, weak, sick, or busy to go; transportation issues; no insurance, too expensive; or other). questions also queried whether participants had received professional help for drug or alcohol use in their lifetime (yes/no), and if yes, the type of professional help received (drugs only, alcohol only, both), and the number of times help was received (continuous). respiratory-related symptoms and previous diagnoses were also assessed. j o u r n a l p r e -p r o o f following the interview, participants received pre-test counselling and serologic testing for hiv (uni-gold recombigen, trinity biotech plc, bray, ireland), hcv (oraquick®, orasure technologies, bethlehem, usa) and mtb (quantiferon-tb gold in-tube, qiagen, hilden, germany) infection using commercially-available assays (described elsewhere) (horyniak et al., ) . post-test counselling and referrals for care were also provided depending on test results. descriptive statistics were calculated for all variables. for skewed data we report medians and interquartile ranges (iqrs) instead of means. bivariate associations were assessed between old and other covariates using chi-square tests for categorical variables and t-tests or wilcoxon rank sum tests for continuous variables, and simple logistic regression. covariates with a p-value< . in bivariate analysis or supported by the literature as potential risk factors for old were included in multivariable analyses. collinearity was assessed using tolerance (< . ) and variance inflation (> ) statistics. a backwards stepwise regression procedure was used to determine factors independently associated with old. pack-years smoked, age, and race were kept in models examining correlates of old to control for known risk factors (chatila et al., of the stahr ii participants, ( . %) had complete baseline spirometry and interview data for this analysis. fifty-five participants had missing spirometry results because of either recent surgery or participant refusal precluded measurement. most participants were years of age or older ( . %), male ( . %), and non-black ( . %). overall, the mean number of years injecting drugs was . (standard deviation [sd]  . ) and the median number of times injected in the past six months was (iqr - ). the most common drugs ever injected were heroin ( . %), methamphetamine ( . %), and cocaine ( . %) (lesser used drugs not shown and are available from the authors). the overall prevalence of old was . % (n= ). on bivariate analysis (table ) , we found that having old was associated with age greater than (p= . ), black race (p= . ), higher smoking intensity (median pack-years: . vs . , p= . ), and longer duration of injection drug use (mean years: . vs . , p< . ). we did not observe statistically significant associations between old and other socio-demographics, type of drug injected, frequency of injecting in the past months, behavioral factors and hiv, hcv or mtb infection. compared to pwid without old (table ) , a greater proportion of pwid with old reported shortness of breath (p= . ) or a physician diagnosis of emphysema (p< . ) or other lung diseases (p= . ). although . % of pwid with old reported respiratory symptoms, only . % reported physician-diagnosed emphysema. pwid with old were more likely to see a doctor or healthcare provider (p= . ) and marginally more likely to report healthcare utilization in the past months in terms of emergency department visits (p= . ) and having healthcare j o u r n a l p r e -p r o o f coverage/insurance (p= . ). the main reason for not seeking medical care when needed differed between groups, with pwid with old more often reporting that the "visit [was] not expected to be helpful, avoidance of bad news" (p= . ) and "fear of hostility, disrespect or arrest" (p= . ). no other respiratory symptoms or illnesses or healthcare utilization variables were associated with old. in multivariable logistic regression analysis adjusting for age, pack years smoked, and black race ( smoking history, with a % increase in the odds of old for every pack-years smoked (aor= . , % ci: . , . ). this study found the prevalence of old to be . % among pwid in san diego, ca. black race, pack-years smoked, and duration of injection drug use were independently associated with old after adjusting for age. although pwid with old have increased need for healthcare, access to and utilization of health services were not associated with old in this study. the observed prevalence of old in this study is similar to that found among current and former pwid in baltimore, md ( . %) (drummond et al., ) . the prevalence among pwid is much higher than the general population where the prevalence of copd is approximately . % (world health organization (who), ). this finding highlights the disparity faced by pwid potentially due to behavioral, economic, and environmental factors. factors that might account for this disparity include a high prevalence of current smokers (clarke et al., ) , high rates of hiv (alcabes and friedland, ; morris et al., ) and mtb infection byrne et al., ) , socioeconomic disadvantage (wheaton et al., ) , and delayed detection and/or treatment of old due to healthcare stigma or limited access (drummond et al., ; neale et al., ) . our findings provide further evidence that old disproportionately affects pwid, and a multilevel approach is needed to address the disparity. our findings provide novel information about old among pwid. nearly the entire cohort smoked cigarettes, and consistent with the evidence in a smoking population (jaen diaz et al., ) , packyears smoking was independently associated with old status. the fact that smoking was nearly ubiquitous in this cohort was a relative strength of the study in that it allowed for assessment of other correlates of old. black race was found to be independently associated with old. black race has been previously identified as a risk factor for early-onset copd, defined as age < years (foreman et al., ) . the older age category in this study included those considered for earlyonset copd in the prior study, which may explain the high prevalence of old among blacks in this cohort. higher prevalence of old among blacks may occur because of greater vulnerability to the effects of tobacco smoking (dransfield et al., ) . despite smoking fewer cigarettes per day, blacks with emphysema showed similar lung impairment to their white counterparts in the national emphysema treatment trial (chatila et al., ) . duration of injection drug use was also independently associated with old status. this comports with the hypothesis that exposure to non-soluble particles in illicit drugs or medications meant for oral use might increase the risk for old, because injection duration is a proxy for cumulative exposure to excipients. the specific drug type or administration route (injected, smoked, or inhaled) was not associated with old. without knowing the type or quantity of contaminants and lifetime frequency of exposure, it is difficult to assess whether specific drugs increase the risk of old. assuming all drugs contain some contaminants, it is also the case that lack of specificity between drugs may mask any association. this hypothesis merits further investigation in a larger sample that more precisely measures the quantities and types of contaminates injected over time. old is often not recognized among pwid in healthcare settings (drummond et al., ) , despite our finding no association between old and healthcare variables in this study. less than half of this cohort ( . %) reported receiving healthcare in the past months and a similar proportion ( . %) reported not going to see a doctor or healthcare provider even if they perceived the need to go. while % of pwid in baltimore had a diagnosis of old or emphysema from a physician (drummond et al., ), only . % and . %, respectively, had these diagnoses among those with old in our cohort; however, . % reported shortness of breath (dyspnea) suggesting that old is underdiagnosed among pwid in san diego, ca. dyspnea is one of the most commonly reported symptoms of copd and is part of its pathophysiology (anzueto and miravitlles, ) . despite experiencing symptoms indicative of old (i.e. dyspnea), few in this cohort sought primary care. pwid with old were less likely to seek care because they expected their visit to be unhelpful, they would receive bad news, or they would be mistreated. prior studies report less access to healthcare among pwid compared to the general population (chitwood et al., ) , which could result in underutilization of primary healthcare services. aside from the obstacles j o u r n a l p r e -p r o o f perceived by pwid, healthcare providers also cite that insufficient education on the "unique and demanding nature of pwids" (lang et al., ) as an additional obstacle to care. in addition, pwid may over-utilize emergency department care for injection-related complications (kerr et al., ; raven et al., ) . a slight trend of over-utilization was seen in those with old; participants only reported on emergency department visits in the past months, which might have attenuated this finding. specialized treatment programs however were heavily utilized with nearly % having received substance use treatment in their lifetime. screening for old remains important in this underserved population, and better access to healthcare is crucial. the sars-cov- virus responsible for a pandemic of novel coronavirus disease (covid- ) that began in disproportionately affects older individuals, particularly those with underlying immunosuppressive conditions and lung disease such as copd (chinese center for disease control and prevention, ). mortality rates for covid- are reportedly higher for those with chronic respiratory diseases ( . % vs . % overall) (chinese center for disease control and prevention, ). our findings suggest that pwid should be considered an additional high-risk group for developing complications from covid- due to the high prevalence and underdiagnoses of old. pwid are also thought to be at higher risk of infection, transmission, and complications from the virus due to the high prevalence of homelessness and incarceration, which make it difficult to maintain social distancing and adequate hygiene precautions. more research is needed to understand the associations between covid- case outcomes and a history of substance abuse as well as the impact caused by the global pandemic (national institute on drug j o u r n a l p r e -p r o o f abuse (nida), ). clinicians need to be aware of the special challenges in caring for pwid and not postpone rehabilitation efforts (ornell et al., ) . this study had limitations that should be taken into consideration when interpreting the findings. it did not measure the types and quantities of potential contaminants found in the drugs injected by participants. therefore, duration of injection drug use and frequency of injection in the last months were used as proxies for cumulative exposure to these contaminants. further research is needed to verify whether injecting contaminants caused old. factors such as second-hand smoke, air pollution, occupational dust or fumes, and other lung irritants were not measured, and might contribute to the overall burden of old in this population. as this study was cross-sectional, we cannot infer temporality of the associations. lastly, this study relied on self-report of drug use and healthcare-related factors, potentially leading to misclassification due to recall problems. however, we have no reason to expect that misclassification differed by old status; therefore, misclassification would tend to bias our results toward null findings. old prevalence was high in this cohort of pwid and consistent with findings from pwid elsewhere (drummond et al., ) . we also found a high prevalence of previously undiagnosed and untreated old in symptomatic pwid. while prior research found a relationship between injection drug use and old, this study was the first to address whether injection-related factors were associated with old in a cohort made up entirely of pwid. this study is also the first to identify an association between duration of injection drug use and old, although the mechanisms for this association need further exploration. it is unclear whether an accumulation of exposure to excipients in the drugs or another factor contributed to this relationship. future research is needed that more precisely measures exposure to injected particles. smoking also continues to be an important contributor to old in pwid. thus, smoking cessation programs in this population remain extremely pertinent. the study of tuberculosis, aids and hepatitis c risk (stahr ii) was funded by the national institutes of drug abuse (nida) grant #r da (pi: richard s. garfein). the study of tuberculosis, aids and hepatitis c risk (stahr ii) was funded by the national institutes of drug abuse (nida) grant #r da (pi: richard s. garfein). the funding source had no involvement in the study design, the collection, analysis and interpretation of data or in the writing of the report and in the decision to submit the article for publication. dr. garfein received a grant from the national institutes of health to conduct this study. chitwood, d.d., mcbride, d.c., french, m.t., comerford, m., injection drug use and human immunodeficiency virus infection pathophysiology of dyspnea in copd mycobacterium tuberculosis infection among persons who inject drugs in smoking duration alone provides stronger risk estimates of chronic obstructive pulmonary disease than pack-years tuberculosis and chronic respiratory disease: a systematic review advanced emphysema in african-american and white patients: do differences exist? pulmonary embolization of microcrystalline cellulose in a lung transplant recipient early-onset chronic obstructive pulmonary disease is associated with female sex, maternal factors, and african american race in the copdgene study embolized crospovidone (poly[n-vinyl- -pyrrolidone]) in the lungs of intravenous drug users 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addiction starch and talc emboli in drug addicts' lungs copd in never smokers: results from the population-based burden of obstructive lung disease study qualitative investigation of barriers to accessing care by people who inject drugs in saskatoon, canada: perspectives of service providers hiv and chronic obstructive pulmonary disease: is it worse and why? national heart lung and blood institute covid- : potential implications for individuals with substance use disorders barriers to accessing generic health and social care services: a qualitative study of injecting drug users pulmonary effects of iv injection of crushed oral tablets: "excipient lung disease gender-specific estimates of copd prevalence: a systematic review and meta-analysis office of disease prevention and health promotion the covid- pandemic and its impact on substance use: implications for prevention and treatment long-term follow-up of drug abusers with intravenous talcosis medicaid patients at high risk for frequent hospital admission: real-time identification and remediable risks evaluating the impact of mexico's drug policy reforms on people united states: a binational mixed methods research agenda talcosis associated with iv abuse of oral medications: ct findings employment and activity limitations among adults with chronic obstructive pulmonary disease -united states chronic obstructive pulmonary disease (copd) the top causes of death abbreviations: iqr: interquartile range. sd: standard deviation. hcv: hepatitis c virus. hiv: human immunodeficiency virus. mtb: mycobacterium tuberculosis *p-values were based on chi-square test, t-test, or simple logistic regression. a : ≥ % of cell sizes < **participants that are "missing" or "n/a" were excluded from the analysis. values are shown for reporting purposes *p-values were based on chi-square test don't know" or "refuse to answer" were excluded from the analysis. values are shown for reporting purposes. a variables are descriptive only and were not considered for multivariable analysis. b treatment includes rehabilitation center the authors are grateful to the study participants for sharing their stories and making this research possible. j o u r n a l p r e -p r o o f key: cord- -uskyldv authors: miravitlles, marc title: tratamiento farmacológico de las agudizaciones infecciosas de la epoc date: - - journal: archivos de bronconeumología doi: . /s - ( ) - sha: doc_id: cord_uid: uskyldv las agudizaciones de la enfermedad pulmonar obstructiva crónica (epoc) son episodios frecuentes y potencialmente graves, que dejan un impacto permanente en la calidad de vida y en la función pulmonar de los pacientes. hasta un % de las agudizaciones tiene una etiología bacteriana, en ocasiones asociada a infección vírica. la tasa de fracaso del tratamiento ambulatorio de las agudizaciones alcanza el - % y la gravedad de la enfermedad de base es el principal factor de riesgo de fracaso. la colonización bacteriana persistente es un factor de riesgo de agudizaciones frecuentes y graves, y de más rápida progresión de la epoc. por este motivo el tratamiento antibiótico de las agudizaciones debe perseguir no sólo la curación clínica, sino también la mejor erradicación posible para acelerar la recuperación y prevenir las recaídas. nuevos ensayos clínicos han demostrado que el antibiótico que consigue una mejor erradicación puede prolongar el tiempo sin síntomas de agudización. exacerbations of chronic obstructive pulmonary disease (copd) are frequent and potentially serious episodes that permanently affect patients’ quality of life and lung function. up to % of exacerbations are caused by bacteria, sometimes associated with viral infection. outpatient treatment of exacerbations is unsuccessful in - % of patients and the main risk factor for this lack of success is the severity of the underlying disease. persistent bacterial colonization is a risk factor for frequent and severe exacerbations and for rapid progression of copd. therefore, antibiotic treatment should aim to achieve not only the resolution of symptons but also the best eradication possible to hasten recovery and prevent recurrences. new clinical trials have demonstrated that the antibiotic that best achieves bacterial eradication can prolong exacerbation-free periods. la enfermedad pulmonar obstructiva crónica (epoc) en una enfermedad crónica, progresiva e invalidante, producida por el consumo de tabaco . su curso progresivo se ve a menudo agravado por períodos de aumento de los síntomas, particularmente de la tos, la disnea y la cantidad y purulencia del esputo. estos episodios son lo que conocemos por agudizaciones. la mayoría de estas agudizaciones están producidas por infecciones bronquiales: bacterianas, víricas o mixtas . la definición de agudización es difícil y no hay criterios clínicos universalmente aceptados, aunque la combinación de síntomas descrita por anthonisen et al (incremento de la disnea y de la producción y purulencia del esputo) ha sido ampliamente utilizada. en cualquier caso, se debe evitar la confusión entre la definición de agudización y la de agudización infecciosa. los citados criterios de anthonisen et al se han utilizado para establecer la probabilidad de etiología bacteriana y la necesidad de un antibiótico, pero no deben emplearse para definir la agudización, pues infravaloraría la frecuencia de agudizaciones no infecciosas, que no cursan con combinaciones de los síntomas mencionados. para la definición de agudización se han propuesto enfoques distintos: uno basado en síntomas de infección; otro, en síntomas generales, y un tercero basado en la utilización de recursos . las ventajas e inconvenientes de cada uno de ellos se resumen en la tabla i. la definición basada en síntomas de infección deriva del trabajo mencionado de anthonisen et al . desde su publicación en , los criterios llamados "de anthonisen" o "de winnipeg" se han utilizado para decidir la necesidad o no de un tratamiento antibiótico de la agudización. sin embargo, conviene recordar que los pacientes que participaron en dicho estudio tenían una epoc moderada-grave, con un valor medio de volumen espiratorio forzado en el primer segundo (fev ) de tan sólo un %; por este motivo sus resultados no pueden curso de enfermedad pulmonar obstructiva crÓnica (epoc) unidad . aspectos terapÉuticos las agudizaciones de la enfermedad pulmonar obstructiva crónica (epoc) son episodios frecuentes y potencialmente graves, que dejan un impacto permanente en la calidad de vida y en la función pulmonar de los pacientes. hasta un % de las agudizaciones tiene una etiología bacteriana, en ocasiones asociada a infección vírica. la tasa de fracaso del tratamiento ambulatorio de las agudizaciones alcanza el - % y la gravedad de la enfermedad de base es el principal factor de riesgo de fracaso. la colonización bacteriana persistente es un factor de riesgo de agudizaciones frecuentes y graves, y de más rápida progresión de la epoc. por este motivo el tratamiento antibiótico de las agudizaciones debe perseguir no sólo la curación clínica, sino también la mejor erradicación posible para acelerar la recuperación y prevenir las recaídas. nuevos ensayos clínicos han demostrado que el antibiótico que consigue una mejor erradicación puede prolongar el tiempo sin síntomas de agudización. drug treatment of acute infective exacerbations of copd aplicarse a los pacientes con función pulmonar normal o próxima a la normalidad, incluso aunque presenten una agudización de tipo i o ii (con o de los síntomas antes enumerados, respectivamente). estudios más recientes han intentado definir nuevos criterios de agudización infecciosa. la combinación de un resultado negativo en la tinción de gram, una disminución poco importante de la función pulmonar durante el episodio y una historia de menos de agudizaciones el año previo fue un % predictiva de una etiología no bacteriana de la agudización, mientras que la presencia de las características tuvo un valor predictivo positivo del % . sin embargo, a excepción del número de agudizaciones previas, las otras características muy raramente pueden verificarse en la práctica cotidiana. la búsqueda de marcadores biológicos de agudización ha suscitado gran interés. hurst et al estudiaron hasta posibles marcadores en suero de pacientes en fase estable y durante una agudización. el marcador más selectivo fue la proteína c reactiva, pero por sí sola, sin la utilización de alguno de los síntomas de agudización, no fue lo suficientemente sensible ni específica para diagnosticar una agudización. otros estudios han confirmado que la determinación de la proteína c reactiva no es lo bastante sensible ni específica para diagnosticar una etiología bacteriana en la infección respiratoria baja . otra molécula candidata es la procalcitonina. en un estudio aleatorizado se utilizó la concentración plasmática de procalcitonina para decidir el tratamiento antibiótico, comparado con la práctica clínica habitual. los pacientes del grupo de procalcitonina recibieron significativamente menos antibióticos que los del grupo de tratamiento habitual, pero cabe destacar que la evolución a largo plazo fue peor en los pacientes del grupo de procalcitonina que recibieron menos antibióticos. por el tamaño reducido de la muestra (tan sólo pacientes con agudización de la epoc) no es posible extraer conclusiones definitivas . llegados a este punto cabe afirmar que los síntomas clásicos de agudización son insustituibles para el diagnóstico de la agudización y que los criterios de anthonisen son los que mejor nos aproximan a la etiología bacteriana. la única aportación significativa ha sido la confirmación de que el cambio de color del esputo o su aspecto purulento es el mejor signo de infección bacteriana , . este hallazgo, junto a la alteración de la función pulmonar, debe servir para orientar la posible etiología y guiar el tratamiento antibiótico empírico [ ] [ ] [ ] . los mecanismos de defensa pulmonar están alterados en los pacientes con epoc. por este motivo las bacterias pueden adherirse al epitelio bronquial y proliferar; es lo que conocemos como "colonización bronquial". diversos estudios realizados con técnicas diagnósticas sensibles y específicas, como el cepillado bronquial protegido, han demostrado que entre un y un % de los pacientes con epoc estable pueden estar colonizados por microorganismos potencialmente patógenos . por este motivo el aislamiento en el esputo de un microorganismo potencialmente patógeno durante una agudización no puede considerarse la prueba definitiva de su papel etiológico. en cualquier caso, la carga bacteriana durante las agudizaciones es superior a la encontrada en pacientes colonizados en fase estable , , lo que apoya la participación decisiva de las bacterias en el desarrollo de las agudizaciones. la colonización bacteriana de las vías aéreas se ha relacionado directamente con la frecuencia y con la gravedad de las agudizaciones, y también con la evolución de la epoc. los pacientes colonizados por haemophilus influenzae presentan más agudizaciones, a igual grado de deterioro de la función pulmonar, que los sujetos que no se encuentran colonizados por microorganismos. además, los pacientes con epoc en quienes se identificó este patógeno en fase estable presentaron más síntomas y un esputo más purulento en el momento de la agudización que las personas no colonizadas . pero la evidencia más importante de la influencia de la colonización bronquial en la evolución de la enfermedad se detalla en un estudio realizado en pacientes con epoc grave, que fueron controlados durante más de un año. los resultados mostraron que el incremento de la carga bacteriana bronquial y los cambios en las cepas bacterianas aisladas durante el seguimiento se asociaban de forma significativa e independiente con un aumento de la inflamación de las vías aéreas y, más importante aún, con una pérdida acelerada de la función pulmonar . por tanto, las bacterias colonizadoras de las vías aéreas pueden afectar y modificar la historia natural de la epoc por mecanismos diferentes pero complementarios: por una parte, la colonización por sí misma desencadenaría una reacción inflamatoria bronquial, que sería la responsable del incremento del daño inflamatorio y del deterioro de la función pulmonar; por otra, la colonización bron- quial crónica actuaría como un factor que predispondría a la aparición de un número superior de agudizaciones de mayor gravedad. la mayor frecuencia de agudizaciones también se ha asociado de forma significativa con una pérdida acelerada de función pulmonar ( fig. ) . para explicar la etiopatogenia de la infección bacteriana durante las agudizaciones existen teorías: el cambio de las cepas colonizantes y el aumento de la carga bacteriana. según la primera, cuando una nueva cepa bacteriana alcanza el epitelio bronquial, aumenta la probabilidad de que se desarrolle una agudización, ya que no hay una respuesta específica de anticuerpos frente a la nueva cepa. se basa en estudios de sethi et al , que observaron que la adquisición de una nueva cepa se asociaba con una odds ratio de , (intervalo de confianza del %, , - , ) para presentar una agudización. no obstante, en su estudio tan sólo un % de las agudizaciones se asoció a un cambio de cepa, por lo que otro mecanismo debe explicar el restante %. la segunda teoría se basa en que existe una relación muy estrecha entre colonización y agudización, ya que podría tratarse de pasos sucesivos del mismo proceso. esta hipótesis está sustentada por estudios que han demostrado que los pacientes con agudizaciones frecuentes presentan concentraciones significativamente mayores de las bacterias patógenas aisladas que los mismos pacientes en fase estable y, además, las especies bacterianas son las mismas en ambas circunstancias , . al parecer sería precisa una concentración elevada de bacterias en las secreciones respiratorias para desencadenar una agudización; es lo que podemos denominar "concentración umbral o dintel". cuando la carga bacteriana supera este valor, aparecerán los síntomas de agudización. el tratamiento antibiótico podría reducir la carga bacteriana por debajo del dintel y eliminar los síntomas, pero al cesar la presión antibiótica los microorganismos volverían a proliferar y producir una nueva agudización; es lo que se conoce como "la teoría cuantitativa de la agudización" o del fall and rise (fig. ) . hay una serie de factores que pueden modificar el dintel de aparición de los síntomas de agudización bacteriana en la epoc (tabla ii). no erradicó la cepa causante; en cambio, en caso de recaídas tardías podríamos usar el mismo antibiótico que en la agudización anterior, ya que no está relacionado con un mal resultado del anterior tratamiento. en la figura se resumen estas posibilidades. según las evidencias publicadas, algo más del % de las agudizaciones podrían atribuirse a infecciones respiratorias , aunque este número asciende hasta el - % en pacientes graves . h. influenzae es la bacteria aislada con mayor frecuencia en todas las series, seguido de streptococcus pneumoniae, moraxella catarrhalis y pseudomonas aeruginosa , . las infecciones virales, particularmente por los virus de la gripe, paragripal, rhinovirus y adenovirus, provocan, solas o combinadas con bacterias, hasta el % de los episodios de agudización infecciosa (tabla iii). con frecuencia coexisten la infección vírica y la bacteriana, sobre todo en pacientes graves o de edad avanzada, y se ha observado que la coinfección se asocia a una mayor gravedad de la inflamación bronquial y de los síntomas, así como a un mayor deterioro de la función pulmonar . por desgracia, las manifestaciones clínicas no permiten identificar la causa de la agudización debido a que tanto las agudizaciones de origen vírico como bacteriano muestran los mismos síntomas clínicos y similar respuesta inflamatoria , . se ha observado que el grado de deterioro funcional respiratorio de los pacientes con epoc puede indicar la presencia de diferentes microorganismos potencialmente patógenos en las muestras de esputo en el curso de una agudización [ ] [ ] [ ] . en la epoc leve-moderada, es decir, con un fev superior al %, el cultivo de esputo es poco efectivo y en muchos casos no se aíslan microorganismos potencialmente patógenos, mientras que los pacientes que presentan un deterioro funcional grave, . la mayoría de los pacientes con epoc agudizada van a ser tratados de forma ambulatoria. estudios realizados en atención primaria indican que menos de un % de las agudizaciones precisa tratamiento hospitalario . el tratamiento ambulatorio de la agudización se basa en pilares fundamentales: broncodilatadores, corticoides y antibióticos. en esta revisión se tratará de forma exclusiva el tratamiento antibiótico. la elección razonada de un antibiótico debe basarse en aspectos: a) conocimiento de las especies bacterianas causantes de la infección bronquial; b) conocimiento de la prevalencia de la resistencia antibiótica de los diferentes agentes causales en una comunidad, y c) características y factores de riesgo del paciente , . anteriormente se han mencionado los microorganismos causales más frecuentes y su relación con el deterioro funcional pulmonar. respecto a las resistencias, es importante tener en cuenta las que presentan h. influenzae y s. pneumoniae a los antimicrobianos clásicos (tabla iv). la importancia de la resistencia a la penicilina en infecciones por s. pneumoniae va unida también al hecho de que es muy común que estas cepas presenten también resistencia a otros antimicrobianos usados en el tratamiento de la infección neumocócica, como macrólidos, tetraciclinas o cotrimoxazol . en cuanto a h. influenzae conviene remarcar que la serie más amplia publicada en españa señalaba una resistencia del , % frente a las penicilinas ya en , con diferencias importantes entre los hospitales analizados, que oscilaron entre el , y el , % . la resistencia a las cefalosporinas oscila entre el y el %, y a los macrólidos puede llegar a ser del % . los factores de riesgo del paciente con agudización de la epoc se han descrito en diversos estudios , - y en su mayoría coinciden con los llamados "factores mo-dificadores del dintel de agudización" (tabla ii). la importancia de modificar el tratamiento antibiótico según los factores de riesgo del huésped viene determinada por la alteración importante que presentan estos pacientes en sus mecanismos de defensa y la posibilidad de que desarrollen insuficiencia respiratoria en caso de que el antibiótico no actúe de forma rápida y eficaz. un tratamiento antibiótico menos enérgico en un paciente sin factores de riesgo puede tener éxito gracias a la aportación de las defensas del paciente, pero esto puede no ser cierto en pacientes más comprometidos , . por este motivo, en el tratamiento antibiótico son importantes otras variables, como la tasa de erradicación bacteriológica, la rapidez de acción y la prevención de recaídas. si no logramos la erradicación tras el tratamiento antibiótico, se corre el riesgo de provocar la perpetuación de una colonización residual en pacientes que han superado el episodio de agudización. además, la mayor erradicación bacteriológica se acompañará de una prolongación del tiempo hasta la próxima agudización . las nuevas fluoroquinolonas presentan mayor actividad frente a s. pneumoniae, aunque conservan el mismo perfil de actividad frente a los otros patógenos respiratorios. entre ellas, actualmente están comercializadas en nuestro país el levofloxacino y el moxifloxacino. de estas , el moxifloxacino es la más activa frente a neumococo y el levofloxacino se hallaría entre ésta y las quinolonas anteriores , . la erradicación conseguida con moxifloxacino sobre h. influenzae es significativamente superior a la conseguida con macrólidos . nuevos ensayos clínicos han demostrado que en pacientes con epoc el tratamiento con una fluoroquinolona como el moxifloxacino se acompaña de una tasa de curación significativamente superior y una reducción significativa del riesgo de recaída, comparado con el tratamiento considerado estándar . por este motivo, en pacientes de edad avanzada con una alteración moderada o grave de la función pulmonar las fluoroquinolonas deben ser el tratamiento antibiótico de primera línea , . estos beneficios no se han demostrado de forma concluyente en pacientes con enfermedad leve, jóvenes o con bronquitis crónica sin obstrucción al flujo aéreo , ; en estos casos el antibiótico de elección en nuestro medio será amoxicilina-ácido clavulánico. por último, las nuevas fluoroquinolonas también han demostrado una mayor rapidez de resolución de los síntomas en pacientes con epoc y un fev menor del % . como ejemplo, en la figura se muestra el algoritmo de decisión del tratamiento antibiótico de la guía clínica elaborada por la sociedad española de neumología y cirugía torácica y la sociedad española de geriatría y gerontología (separ-seeg) . en pacientes graves debemos tener en cuenta la posibilidad de infección por p. aeruginosa, que viene determinada por el número de tandas previas de antibióticos recibidas y por una alteración funcional respiratoria con un fev inferior al % o a , l , , . también aumenta el riesgo de infección pseudomónica la demostración de bronquiectasias. en estos casos se recomienda tratamiento por vía oral con dosis altas de ciprofloxacino. sin embargo, en estos pacientes es muy importante po- der disponer de un cultivo de esputo y adecuar el tratamiento en función del resultado del antibiograma y de la evolución clínica. hay otras opciones antibióticas potencialmente útiles en el tratamiento del paciente con epoc agudizada, pero de las que se dispone de una experiencia limitada. el cefditorén pivoxil es una cefalosporina oral, con un buen espectro de actividad antibacteriana y estable frente a betalactamasas. sus características lo convierten en un buen candidato para el tratamiento de pacientes sin factores de riesgo. no obstante, los datos existentes sobre su efectividad clínica son limitados y la dosis recomendada para las agudizaciones de la bronquitis crónica ( mg veces al día durante días) puede ser excesivamente baja para pacientes con epoc y/o con algún factor de riesgo. esta dosis recomendada se ha estudiado exclusivamente en pacientes con bronquitis crónica de más de años . carecemos de información sobre su eficacia clínica y bacteriológica a estas dosis en pacientes con epoc y distintos factores de riesgo. otra posibilidad es el tratamiento con dosis elevadas de amoxicilina para lograr superar la baja susceptibilidad de algunas cepas de s. pneumoniae y conseguir reducir la duración del tratamiento. la administración de amoxicilina-ácido clavulánico a dosis de . / mg veces al día durante días se ha demostrado que es tan eficaz desde el punto de vista clínico y bacteriológico como el tratamiento durante días con el mismo compuesto a dosis de / mg veces al día, sin diferencias en su tolerabilidad . obviamente, los nuevos tratamientos van destinados a reducir la duración de la antibioterapia para mejorar el cumplimiento y restituir la función lo antes posible. hay experiencias puntuales dirigidas a reducir la duración del tratamiento más allá de los días. la formulación de levofloxacino mg utilizada una vez al día durante días se ha demostrado equivalente a azitromicina durante días en pacientes mayores de años con bronquitis crónica no complicada . no obstante, es importante resaltar que en estos casos se echa de menos un grupo de comparación con placebo. por último, la máxima reducción de la duración del tratamiento antibiótico sería la administración de una dosis única. esta estrategia se ha ensayado con azitromicina en microesferas en administración única de g. esta nueva preparación permite administrar una dosis elevada por vía oral, que proporciona una mayor concentración pico plasmática y mayor área bajo la curva de h. en un ensayo clínico comparativo en pacientes fumadores o exfumadores mayores de años y con agudizaciones tipo i de anthonisen, la azitromicina en microesferas en dosis única fue bien tolerada y equivalente desde el punto de vista clínico y bacteriológico a mg de levofloxacino al día durante días . en resumen, debemos aplicar el tratamiento antibiótico que se ha mostrado más eficaz y con mejor capacidad de erradicación, especialmente cuando nos encontremos frente a pacientes con algún factor de riesgo. en la tabla v se resumen las características que debe reunir el antibiótico ideal para el tratamiento de las agudizaciones de la epoc. también debemos intentar siempre prescribir el tratamiento más corto que haya demostrado su eficacia y, por último, iniciar el tratamiento lo antes posible para lograr mejorar los resultados clínicos las agudizaciones frecuentes suponen un impacto permanente sobre el estado de salud de los pacientes con epoc , , . por este motivo no es de extrañar que, si preguntamos a pacientes con epoc qué esperan del tratamiento antibiótico de las agudizaciones, su respuesta sea conseguir la curación lo antes posible y, sobre todo, evitar la recurrencia . el tratamiento antibiótico eficaz es el que permitirá la mejor tasa de curación y el alivio más rápido de los síntomas, y también el que prolongará el tiempo hasta la recaída . además del tratamiento antibiótico hay otras estrategias destinadas a prevenir la aparición de agudizaciones; básicamente el mejor tratamiento de la epoc estable, desde el punto de vista farmacológico y no farmacológico (rehabilitación), contribuye a disminuir la frecuencia de agudizaciones . desde la perspectiva de la infección bronquial hay otras alternativas al tratamiento erradicador de la agudización; entre ellas destacan las destinadas a incrementar la capacidad defensiva del paciente. las vacunas con extractos bacterianos de administración oral pueden ser úti-les para reducir el número, la gravedad y/o la duración de las agudizaciones en pacientes con epoc, aunque por desgracia la mayoría de los estudios realizados con estos compuestos son de escasa calidad . la vacuna antigripal ha demostrado su utilidad a la hora de disminuir la frecuencia de agudizaciones, y la vacuna antineumocócica con serotipos es eficaz para prevenir la neumonía en pacientes con epoc menores de años y en aquéllos con obstrucción grave al flujo aéreo ; no obstante, es eficaz y está recomendada para la prevención de la neumonía y la enfermedad invasiva por neumococo en mayores de años tengan o no epoc, por lo que debe administrarse a todos los pacientes con epoc . el tratamiento con un inmunoestimulante oral, el am (inmunoferón ® ), ha demostrado restablecer los defectos en la actividad de las células fagocíticas y los linfocitos t presentes en la epoc , . este efecto podría tener un papel importante en la defensa frente a la colonización y la infección en la epoc. un ensayo clínico de doble ciego, aleatorizado y controlado con placebo en pacientes con epoc demostró que los tratados con am tenían una mejoría significativa de su estado de salud tras meses de tratamiento comparado con placebo, y se observó una tendencia a un mayor número de pacientes sin agudización en el grupo de am , pero sin alcanzar la significación estadística (el , frente al , %; p = , ). la corta duración del estudio, tan sólo meses, no permitió comprobar de forma inequívoca el efecto de am sobre la reducción de las agudizaciones . para acabar, merece la pena comentar que las últimas tendencias en la prevención de las agudizaciones incluyen la utilización de antibióticos de forma profiláctica en pacientes con epoc moderada-grave. aunque no es un tratamiento nuevo, pues se utilizó hace ya algunos años de forma empírica , la aparición de nuevos antibióticos y los conocimientos sobre las interacciones entre bacteria y huésped han llevado al diseño de nuevos ensayos clínicos aleatorizados y controlados con placebo, con objeto de evaluar la eficacia del tratamiento antibiótico en pacientes estables administrando tandas repetidas a lo largo de un año para la prevención de agudizaciones . en un plazo no muy largo podremos disponer de resultados que contestarán algunas preguntas, pero seguro que abrirán muchos interrogantes más acerca del uso de los antibióticos en pacientes estables con epoc grave. hasta entonces debemos concentrar nuestros esfuerzos en proporcionar el mejor tratamiento antibiótico posible a nuestros pacientes agudizados para conseguir lo que se ha denominado el círculo virtuoso, esto es, eliminar el máximo de bacterias lo antes posible para lograr la preservación del órgano (fig. ). tabla v características del antibiótico ideal en la agudización de la epoc antibiotic therapy in exacerbations of chronic obstructive pulmonary disease what is an exacerbation of copd? clinical predictors of bacterial involvement in exacerbations of chronic obstructive pulmonary disease use of plasma biomarkers at exacerbation of chronic obstructive pulmonary disease diagnostic value of c reactive protein in infections of the lower respiratory tract: systematic review effect of procalcitonin-guided treatment on antibiotic use and outcome in lower respiratory tract infections: cluster-randomised, single-blinded intervention trial relationship of sputum color to nature and outpatient management of acute exacerbations of copd bronchoscopic validation of the significance of sputum purulence in severe exacerbations of chronic obstructive pulmonary disease infective exacerbations of chronic bronchitis. relation between bacteriologic etiology and lung function group of bacterial infection in copd. relationship between bacterial flora in sputum and functional impairment in patients with acute exacerbations of copd sputum color as a marker of acute bacterial exacerbations of chronic obstructive pulmonary disease microbiologic determinants of exacerbation in chronic obstructive pulmonary disease bacterial infection in chronic obstructive pulmonary disease. a study of stable and exacerbated outpatients using the protected specimen brush relationship between bacterial colonisation and the frequency, character, and severity of copd exacerbations airway bacterial load and fev decline in patients with chronic obstructive pulmonary disease relationship between exacerbation frequency and lung function decline in chronic obstructive pulmonary disease new strains of bacteria and exacerbations of chronic obstructive pulmonary disease the biology of bacterial colonisation and invasion of the respiratory mucosa exacerbations of chronic obstructive pulmonary disease: when are bacteria important? the efficacy of oral ciprofloxacin vs. clarithromycin for the treatment of acute bacterial exacerbations of chronic bronchitis clinical significance of the infection-free interval in the management of acute bacterial exacerbations of chronic bronchitis short-term and long-term outcomes of moxifloxacin compared to standard antibiotic treatment in acute exacerbations of chronic bronchitis strain specific response to haemophilus influenzae in chronic obstructuve pulmonary disease epidemiology of chronic obstructive pulmonary disease exacerbations wedzicha ja. detection of rhinovirus in induced sputum at exacerbation of chronic obstructive pulmonary disease effect of interactions between lower airway bacterial and rhinoviral infection in exacerbations of copd bacterial infection in exacerbated copd with changes in sputum characteristics factors associated with relapse after ambulatory treatment of acute exacerbations of chronic bronchitis. a prospective multicenter study in the community appropriate outpatient treatment of acute bacterial exacerbations of chronic bronchitis health status and costs of exacerbations of chronic bronchitis and copd: how to improve antibiotic treatment antimicrobial resistance in respiratory tract pathogens: results of an international surveillance study antimicrobial susceptibility of , haemophilus influenzae isolates from respiratory tract infections in spain. results of a -year ( - ) multicenter surveillance study. spanish surveillance group for respiratory pathogens factors associated with increased risk of exacerbation and hospital admission in a cohort of ambulatory copd patients: a multiple logistic regression analysis antibiotics are associated with lower relapse rates in outpatients with acute exacerbations of copd patients hospitalized for copd have a high prevalence of modifiable risk factors for exacerbation highlights on the appropriate use of fluoroquinolones in respiratory tract infections moxifloxacin in respiratory tract infections eradication of h. influenzae in aecb: a pooled analysis of moxifloxacin phase iii trials compared with macrolide agents en: separ-segg (sociedad española de geriatría y gerontología), editores. guía de buena práctica clínica en geriatría: enfermedad pulmonar obstructiva crónica. madrid: elsevier farma antibiotic treatment and factors influencing short and long term outcomes of acute exacerbations of chronic bronchitis levofloxacin versus clarithromycin in copd exacerbations: focus on exacerbation-free interval on behalf of the impac study group. speed of recovery from acute exacerbations of copd after treatment with antimicrobials: results of a two-year study clinical and bacteriological efficacy in treatment of acute exacerbations of chronic bronchitis with cefditoren-pivoxil versus cefuroxime-axetil efficacy and safety of pharmacokinetically enhanced amoxicillin-clavulanate at , / milligrams twice daily for days versus amoxicillin-clavulanate at / milligrams twice daily for days in the treatment of acute exacerbations of chronic bronchitis incumplimiento del tratamiento con antibióticos en infecciones agudas no graves patient stratification in the management of acute bacterial exacerbation of chronic bronchitis: the role of levofloxacin mg acute exacerbation of chronic bronchitis: expanding short-course therapy early therapy improves outcomes of exacerbations of chronic obstructive pulmonay disease exacerbations impair quality of life in patients with chronic obstructive pulmonary disease. a two-year follow-up study exacerbations, hospital admissions and impaired health status in chronic obstructive pulmonary disease patient's perception of exacerbations of copd -the perceive study copd exacerbations. : prevention steuere-stey c. oral bacterial vaccines for the prevention of acute exacerbations in chronic obstructive pulmonary disease and chronic bronchitis clinical efficacy of anti-pneumococcal vaccination in patients with copd chronic obstructive pulmonary disease: national clinical guideline on management of chronic obstructive pulmonary disease in adults in primary and secondary care. managing stable copd defective natural killer and phagocytic activities in chronic obstructive pulmonary disease are restored by glycophosphopeptical (inmunoferon) treatment with am restores defective t-cell function in copd patients treatment with the immunomodulator am improves the health-related quality of life of patients with copd prophylactic antibiotic therapy for chronic bronchitis (cochrane review) placebo-controlled, double-blind trial of chronic, intermittent pulse therapy of moxifloxacin to prevent acute exacerbations in copd patients with chronic bronchitis: baseline data chronic obstructive pulmonary disease (copd) exacerbation and inflammation of the respiratory tract: clinical implication, prognostic consequences, and therapeutic strategies key: cord- -d oj cw authors: lee, jinju; kim, hun sik title: the role of autophagy in eosinophilic airway inflammation date: - - journal: immune netw doi: . /in. . .e sha: doc_id: cord_uid: d oj cw autophagy is a homeostatic mechanism that discards not only invading pathogens but also damaged organelles and denatured proteins via lysosomal degradation. increasing evidence suggests a role for autophagy in inflammatory diseases, including infectious diseases, crohn's disease, cystic fibrosis, and pulmonary hypertension. these studies suggest that modulating autophagy could be a novel therapeutic option for inflammatory diseases. eosinophils are a major type of inflammatory cell that aggravates airway inflammatory diseases, particularly corticosteroid-resistant inflammation. the eosinophil count is a useful tool for assessing which patients may benefit from inhaled corticosteroid therapy. recent studies demonstrate that autophagy plays a role in eosinophilic airway inflammatory diseases by promoting airway remodeling and loss of function. genetic variant in the autophagy gene atg is associated with asthma pathogenesis, and autophagy regulates apoptotic pathways in epithelial cells in individuals with chronic obstructive pulmonary disease. moreover, autophagy dysfunction leads to severe inflammation, especially eosinophilic inflammation, in chronic rhinosinusitis. however, the mechanism underlying autophagy-mediated regulation of eosinophilic airway inflammation remains unclear. the aim of this review is to provide a general overview of the role of autophagy in eosinophilic airway inflammation. we also suggest that autophagy may be a new therapeutic target for airway inflammation, including that mediated by eosinophils. autophagy is an essential process that maintains cellular homeostasis and cell function by delivering cytosolic constituents, including organelles, denatured proteins, or invading pathogens, to lysosomes for degradation and amino acid recycling ( ) ( ) ( ) . through autophagy, cells eliminate damaged or harmful components, thereby ensuring survival after exposure to stressors such as hypoxia, ros, dna damage, aggregated proteins, damaged organelles, or intracellular pathogens ( ) . aberrant regulation of autophagy can result in cancer ( ) , neurodegenerative disease ( ) , and myopathies ( ) . generally, autophagy is categorized into different types: macroautophagy, chaperone-mediated autophagy, and microautophagy ( ) . usually, macroautophagy is regarded as "autophagy"; we also referred it as autophagy in this review. autophagy is a dynamic process associated with the formation of autophagosomes, which are double-membrane cytoplasmic vesicles that engulf cellular components. the core proteins involved in autophagosome formation are autophagy-related genes (atg), which comprise sub-groups: ) the atg /unc- -like kinase complex, which regulates initiation of autophagy; ) the ubiquitin-like protein (i.e., atg and atg /microtubule-associated protein light chain [lc ] conjugation system), which assists elongation of the autophagic membrane; ) the class iii pi k/vacuolar protein sorting complex i, which participates in the early stages of autophagosome formation; and ) transmembrane proteins (i.e., atg /mammalian atg and vacuole membrane protein ), which may contribute to the delivery process via major steps: induction of autophagosomes and fusion of autophagosomes with lysosomes ( , ). autophagy regulates immunity by eliminating invading pathogens, regulating recognition of innate pathogens, playing roles in ag presentation via mhc class ii molecules, and controlling b-and t-cell development ( ) . t-cells lacking atg , atg , atg , or beclin- showed impaired proliferation and increased cell death ( ) . furthermore, autophagy dysfunction is related to various inflammatory diseases, including inflammatory bowel disease ( ) , asthma ( ), and chronic rhinosinusitis (crs) ( - ). for example, formation of double-membrane autophagosomes in fibroblasts from severe asthmatic patients has been observed by electron microscopy ( , ) , and genetic variants of the autophagy gene atg are associated with promotion of airway remodeling and loss of lung function in childhood asthma ( ) . eosinophils are a major type of inflammatory cell that play an important role in airway inflammatory diseases, including asthma ( ) ( ) ( ) . among the many proinflammatory molecules, il- is involved in eosinophil-mediated inflammation. il- promotes the differentiation, survival, trafficking, activation, and effector functions of eosinophils ( ). migration of eosinophils, especially to the lungs, is regulated by chemokines such as ccl (regulated on activation, normal t cell expressed and secreted [rantes]), ccl (mcp ), ccl (eotaxin ), ccl (mcp- ), ccl , ccl , and ccl , which bind to ccr ( , ) . eosinophils with inflammatory lesions in the lungs produce and release a variety of proinflammatory mediators, including basic proteins (major basic protein, eosinophil cationic protein [ecp], eosinophil peroxidase, eosinophil-derived neurotoxin), cytokines (il- , il- , il- , il- , il- , il- , il- , il- , and il- ) , chemokines (ccl , ccl , and ccl ), growth factors (tnf and tgf-α/β) ( , ) . these proteins contribute to sustained inflammation ( ) and tissue damage ( , ) . for example, tgf-β produced by eosinophils in asthma patients is implicated in tissue remodeling through fibroblast proliferation and increased production of collagen and glycosaminoglycans ( , ) . although evidence suggests that autophagy and eosinophils play important roles in immune responses and airway inflammation, few studies have examined the association between autophagy and eosinophils in inflammatory diseases. here, we focus on the role of autophagy in eosinophilic airway inflammation, and suggest modulation of autophagy as a promising therapeutic approach to treat eosinophilic inflammatory diseases. asthma is a chronic airway disease characterized by airway hyperresponsiveness (ahr) and inflammation caused by molecular and cellular responses ( ) . various types of inflammatory cell are involved in the pathogenesis of asthma, including dendritic cells, mast cells, eosinophils and lymphocytes ( ) . asthma is typically associated with an imbalance between th and th pathways; over-driven th -mediated inflammation leads to airway inflammation and asthma ( ) . in such situation, eosinophils play important roles in augmenting ahr, mucus production, and airway remodeling in allergic asthma by producing il- and leukotrienes from eosinophil lipid bodies ( , ) . blood eosinophil counts correlate with the severity of allergic asthma ( ), and electron microscopy reveals large numbers of eosinophils in the bronchial mucosa of patients with severe allergic asthma ( ). accordingly, the current focus of asthma treatment is the use of anti-inflammatory drugs such as inhaled corticosteroids. however, these drugs often failed to control asthma in some patients ( ). recent studies suggest that asthma pathogenesis is largely heterogeneous and complex, which is not simply driven by allergenspecific th lymphocytes as expected in allergic asthma. some patients were characterized by the upregulation of ifn-γ, il- , and neutrophils in their lungs, in which airway neutrophilia correlated with asthma severity ( - ). furthermore, consistent with the role of il- in neutrophil recruitment, th cells promoted neutrophilic inflammation, and contributed to the development of ahr in concert with th cells in asthma animal models ( ) . thus, a novel therapeutic target for treating diverse types of asthma, including eosinophilic asthma, is needed. recent studies suggest that autophagy is a promising candidate. poon et al. ( ) showed that a single-nucleotide polymorphism (snp) rs g>a of atg correlated significantly with a reduction in pre-bronchodilator forced expiratory volume- s (fev ) in asthmatic patients ( table ) . they also used electron microscopy to show that fibroblasts and epithelial cells in bronchial biopsy tissue from asthmatic patients harbored more double-membrane autophagosomes than tissue from a healthy subject ( ) . martin and colleagues ( ) rs ) of atg are associated with childhood asthma ( table ). these findings were tested in a murine model of asthma (table ) ( , ) . inhibition of autophagy by intraperitoneal injection of -methyladenine ( -ma) and intranasal knockdown of atg led to a marked improvement in ahr, the number of infiltrating eosinophils, il- levels in bronchoalveolar lavage fluid, and histological inflammatory features ( ) . however, suzuki et al. ( ) showed that deficiency of cd c-specific autophagy promotes neutrophilic airway inflammation in a murine asthma model. they found that impaired autophagy induced th polarization, resulting in refractory asthma ( ) . although they demonstrated a role for autophagy in neutrophilic airway inflammation, but not eosinophilic inflammation, the results suggest that autophagy plays an important and diverse role in asthma. in addition, recent studies demonstrated that autophagy plays a crucial role in airway remodeling in airway smooth muscle (asm) cells ( table ) . ghavami et al. ( ) showed that autophagy is a regulator of fibrogenesis induced by tgf-β in primary human atrial myofibroblasts (hatmyofbs). tgf-β promoted collagen- and fibronectin synthesis in hatmyofbs, which correlated with autophagic activation in these cells. autophagy inhibition by atg deficiency or treatment with bafilomycin-a (baf-a ) and -ma decreased the fibrotic effect of tgf-β ( ) . mcalinden et al. ( ) investigated the correlation between autophagy activation and asthma airway remodeling; human asthmatic tissues showed thickened epithelium, greater lamina propria depth, and increase in asm bundles with higher expression of beclin and atg along with reduced p compared with non-asthmatic controls. they also showed that tgf-β induces upregulation of airway remodeling markers, collagen- and smad / phosphorylation (pro-fibrotic signaling) along with the increased expression of beclin- and lc b-ii (a marker of autophagosome formation) in asm cells, which was reversed by an autophagy inhibitor, chloroquine (cq). cq also prevented accumulation of collagen in the lung of murine asthma models ( ) . furthermore, autophagy is a critical mediator of asthma exacerbations due to viral infection as well as allergic asthma ( ). viral infection is associated with exacerbation of acute asthma. rhinovirus, severe respiratory syncytial virus, influenza viruses, coronaviruses, and adenoviruses are often detected in the airways of asthma patients ( ). treatment with baf-a inhibited vacuolar-type h+-atpase-mediated degradation of sequestered material and blocked autophagy flux by interfering with late-stage autophagosome-lysosome fusion in lung epithelial cells, resulting in growth inhibition of influenza a viruses ( ) . an experimental model based on mouse hepatitis virus (mhv), a prototype coronavirus used in replication and function studies, revealed that autophagy is required for viral replication, particularly for the formation of double membrane vesicle-bound mhc replication complexes ( ) . further study revealed that a coronavirus non-structural protein expressed by the mhv and severe acute respiratory syndrome coronavirus activates autophagy by generating autophagosomes independently of starvation ( , ). thus, given its significant impact on asthma pathogenesis, further studies are needed to investigate the role of autophagy in the context of different cell types and to establish a therapeutic strategy for its regulation. pollution is a main cause of copd; indeed, approximately % of smokers suffer from this disease ( ) . copd differs from asthma in that the main characteristic is irreversible airflow obstruction ( , ) . the physiological abnormalities that characterize copd are emphysema and obliteration of small airways ( ) . although emphysema can occur independently of small airway narrowing, and vice versa, these pathologies usually coexist in copd ( ) . narrowing of the small airways is caused by inflammation, increased airway muscle mass and fibrosis in the airway wall, and accumulation of inflammatory mucus exudates in the lumen ( ) . although the major inflammatory cells involved in copd are cd + t cells, neutrophils and macrophages, some patients have eosinophil involvement (similar to that in asthma) ( ) . as mentioned before, eosinophils migrate in response to cytokines (il- in particular) and specific chemokines (such as eotaxin i and rantes). exacerbation of copd is triggered by persistent inflammation, which is itself caused by eosinophil-derived proinflammatory mediators such as basic proteins, cytokines, and growth factors ( ) . recent studies demonstrate an association between autophagy and copd ( table ) ( ) ( ) ( ) . chen et al. ( ) showed that expression of lc b-ii, atg , atg , atg , and atg is higher in individuals with copd than in those without, and that treatment of primary human bronchial epithelial cells with aqueous cigarette-smoke (cs) extract induces lc b-ii. they also demonstrated a regulatory role for lc b during epithelial cell apoptosis in a cs-induced lung cell injury model ( , ) . apoptosis is implicated in the pathogenesis of copd. treatment of epithelial cells with cs extract initiates the extrinsic apoptosis pathway, which involves assembly of the fas-dependent death-inducing signaling complex (disc) and activation of caspase- ; it also induced expression and conversion of the autophagic regulator lc b, increased autophagosome formation, and increased caspase- activation. sirnamediated knockdown of autophagic proteins beclin- or lc b in epithelial cells inhibits assembly of the fas-dependent disc ( , ) . moreover, apoptotic indices and emphysema development were reduced markedly in lc b knock-out mice exposed to cs ( ) . the mechanism by which cs induces autophagy in epithelial cells is unclear; however, oxidative stress is a possible link that connects copd to autophagy. oxidative stress can damage lipids, proteins and dna, and also activate autophagy ( ) . furthermore, it is recognized as a major factor that predisposes an individual to developing copd ( ) . various types of inflammatory cell including eosinophils and structural cells produce ros in the airways of a copd patient ( , ) . treatment with the antioxidants such as n-acetyl-lcysteine reverses starvation-induced autophagosome formation (which is associated with intracellular ros production) in cultured cells ( ) . h o -induced autophagic cell death can be prevented by knockdown of atg such as beclin- , atg , and atg ( ) . indeed, exposure to cs induces pro-oxidant states in several cell types, including epithelial cells ( ) . in addition, chemical inhibitors of nadph oxidase, a membrane-dependent source of ros, inhibit cs extract-induced activation of lc b ( ) . the evidence cited above suggests that increased activation of autophagic pathways may trigger or exacerbate copd. thus, resolution of autophagy should be studied with respect to alleviating copd. autophagy and eosinophilic airway inflammation https://immunenetwork.org for more than wk ( ). it is commonly categorized into groups based on the presence or absence of nasal polyps (nps): chronic rhinosinusitis with nasal polyps (crswnp) and chronic rhinosinusitis without nasal polyps (crssnp) ( ) . the groups show distinct inflammatory patterns. whereas crssnp is characterized by type inflammation with increased levels of ifn-γ in the inflamed sinus mucosa and low ecp/myeloperoxidase ratios, crswnp is typically characterized by type inflammation, which is associated with a typical th -skewed eosinophilic inflammation with high il- and ecp concentrations in the polyps ( , ) . il- is a potent activator and survival factor for eosinophils. several reports show that eosinophilic inflammation is dominant in patients with severe refractory crs ( , ) . however, recent findings in eastern asia countries showed that crswnp can be classified into eosinophilic and non-eosinophilic type ( ) . np from caucasian patients are mainly eosinophil-dominant with robust th response (> %), whereas np from asian patients (korea, japan, and china) are characterized by less infiltration of eosinophils but are largely neutrophil-dominant (> %) with mixed th or th type inflammation ( ) ( ) ( ) ( ) ( ) . of interest, np from asian patients born and resided in the united states appears non-eosiniphil-dominant, suggesting the contribution of genetic factors to eosinophilic inflammation in np ( ) . another core pathologic feature of crs is elevated prostaglandin d (pgd ) levels. upregulation of pgd in nps correlates strongly with the number of mast cells that mainly produce pgd and play an important role in orchestrating eosinophil infiltration in patients with crs ( ) ( ) ( ) . also, expression of pgd synthase is increased in patients with crswnp and correlates positively with eosinophilic inflammation ( ) . however, it is unclear why these pathologic features occur in crs. previous reports suggest that autophagy plays an important role in crs (table ) ( , ). chen et al. ( ) showed that expression of lc protein fell markedly, but akt/mtor signaling (a negative regulator of autophagy) was activated, in nps from patients with crswnp but not in individuals with normal nasal mucosa. in addition, they demonstrated a negative correlation between autophagy and nps; also, formation of lc puncta (an alternative indicator of autophagy) decreased in np-derived fibroblasts ( ). in another report, wang et al. ( ) showed that np tissues are deficient in autophagy and that cyclooxygenase (cox- ) is negatively regulated by autophagy in np-derived fibroblasts. lc and cox- (a common indicator of inflammation) were analyzed by immunoblotting in fresh tissues from nps and control nasal mucosa. lc expression was decreased, while cox- expression increased significantly, in fresh np tissues compared with control nasal mucosa ( ). in addition, cox- expression by np-derived fibroblasts and nasal mucosa-derived fibroblasts was reduced by starvation-induced autophagy and by overexpression of lc ; however, it increased upon inhibition of autophagy by -ma ( ). choi et al. ( ) used a murine model of crs (mice in which atg is conditionally deleted in a myeloid cell-specific manner) to show that disruption of autophagy in crs is linked to dysregulation of pgd production and eosinophilic inflammation ( table ) . indeed, more severe exacerbation of crs was induced in myeloid cell-specific atg -deficient mice than in wild-type mice with increased infiltration of eosinophils and production of pgd ( ). in addition, depletion of autophagy-deficient macrophages alleviated eosinophilic inflammation and pgd dysregulation significantly ( ). these findings suggest a critical role of autophagy in exacerbating eosinophilic inflammation and in the pathologic features associated with crs. also, it suggests the possibility that autophagy may be a valuable therapeutic target for resolution of eosinophilic inflammation in crs. undoubtedly, the role of eosinophils in airway inflammation is important. here, we describe the importance of autophagy in asthma, copd, and crs, focusing on eosinophil-mediated airway inflammations. snp rs g>a of atg correlates significantly with loss of pre-bronchodilator fev in asthmatic patients. inhibition of autophagy in a murine asthma model improves ahr, reduces the number of infiltrating eosinophils, and reduces il- levels in bronchoalveolar lavage fluid. in addition, autophagy is a potential link between virus infection and asthma. however, deficiency of cd c-specific autophagy promotes neutrophilic inflammation in a murine asthma model. these results suggest that autophagy plays different roles depending on the cell type and/or the disease model employed. thus, further studies are necessary if autophagy is to be targeted successfully to treat asthma. with respect to copd, autophagy is an important regulator of epithelial cell apoptosis, which contributes to the pathogenesis of copd. cs extract induces not only apoptosis pathway, e.g., disc and caspase- , but also activates lc b, autophagosome formation and, eventually, caspase- in epithelial cells. these pathways are inhibited either by sirnamediated knockdown of beclin- or lc b, or by an inhibitor of autophagy such as -ma. indeed, autophagosome formation is higher in copd patients than in healthy controls. it is suggested that oxidative stress is a critical mediator of apoptosis in copd. exposure to cs induces pro-oxidant-mediated stress in epithelial cells. chemical inhibitors of nadph oxidase, a membrane-dependent source of ros, inhibit cs extract-induced activation of lc b and apoptosis. these data implicate autophagy as an important regulator of epithelial cell apoptosis and in the pathogenesis of cs-induced copd. autophagy is also linked to eosinophilic inflammation in crs. crswnp is associated with a typical th -skewed eosinophilic inflammation, with high il- and ecp levels in nps. another core pathologic feature of crs is increased expression of pgd . upregulation of pgd in nps correlates strongly with the number of mast cells, which produce pgd and play an important role in orchestrating eosinophil infiltration in patients with crs. although it is not clear how these factors are linked, we provide evidence that autophagy is a key mediator. observational studies suggest that autophagy is involved in crs. for example, expression of lc protein correlates negatively with np development and expression of cox- . in addition, increased eosinophilic inflammation and pgd production induce more severe crs in myeloid cell-specific atg -deficient mice than in wild-type mice. these findings reveal the critical role of autophagy in exacerbating crs. although autophagy plays diverse roles, either protective or detrimental, in chronic airway inflammatory (depending on the type of cell affected and the disease model used), it holds promise as a novel therapeutic target. however, the molecular mechanism underlying disease pathogenesis is not clear. in addition to its role in regulating eosinophilic or neutrophilic inflammation, autophagy has a broad effect on diverse th responses, likely by controlling innate immune cells. autophagy-deficient macrophages promote production of the th cytokine ifn-γ during galn/lps-induced liver injury ( ) and dextran sulfate sodiuminduced colitis ( ) . autophagy-deficient myeloid cells also promote th responses during mycobacterium tuberculosis infection ( ) , as well as th responses during eosinophilic crs ( ). these results suggest that autophagy is a versatile immune modulator that will require careful modulation to achieve therapeutic benefit. thus, further studies are needed to demonstrate how autophagy contributes to the pathogenesis of various airway inflammatory diseases, and to establish an appropriate therapeutic strategy dependent of the unique context of different diseases. autophagy in immunity and inflammation why is autophagy important in human diseases? autophagy and inflammasomes mechanisms and biological functions of autophagy in diseased and 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oxidative stress and autophagy oxidative stress in copd autophagy in cigarette smoke-induced chronic obstructive pulmonary disease reactive oxygen species are essential for autophagy and specifically regulate the activity of atg oxidative stress induces autophagic cell death independent of apoptosis in transformed and cancer cells airway mucosal inflammation in copd is similar in smokers and ex-smokers: a pooled analysis european position paper on rhinosinusitis and nasal polyps . a summary for otorhinolaryngologists chronic rhinosinusitis pathogenesis pathogenesis of chronic rhinosinusitis: inflammation immunopathology of chronic rhinosinusitis clinical and biological markers of difficult-to-treat severe chronic rhinosinusitis pathogenesis of eosinophilic chronic rhinosinusitis classification of chronic rhinosinusitis according to a nasal polyp and tissue eosinophilia: limitation of current classification system for asian population differentiation of chronic sinus diseases by measurement of inflammatory mediators different types of t-effector cells orchestrate mucosal inflammation in chronic sinus disease distinct immunopathologic characteristics of various types of chronic rhinosinusitis in adult chinese histological and immunological features of noneosinophilic nasal polyps subclassification of chronic rhinosinusitis with nasal polyp based on eosinophil and neutrophil increased noneosinophilic nasal polyps in chronic rhinosinusitis in us secondgeneration asians suggest genetic regulation of eosinophilia measurement of inflammatory mediators of mast cells and eosinophils in native nasal lavage fluid in nasal polyposis role of mast cells and basophils in chronic rhinosinusitis correlation between the prostaglandin d( )/e( ) ratio in nasal polyps and the recalcitrant pathophysiology of chronic rhinosinusitis associated with bronchial asthma role of prostaglandin d and e terminal synthases in chronic rhinosinusitis macrophage autophagy limits acute toxic liver injury in mice through down regulation of interleukin- β autophagy deficiency in myeloid cells increases susceptibility to obesity-induced diabetes and experimental colitis autophagy protects against active tuberculosis by suppressing bacterial burden and inflammation key: cord- - l rsa authors: choi, juwhan; oh, jee youn; lee, young seok; hur, gyu young; lee, sung yong; shim, jae jeong; kang, kyung ho; min, kyung hoon title: the association between blood eosinophil percent and bacterial infection in acute exacerbation of chronic obstructive pulmonary disease date: - - journal: int j chron obstruct pulmon dis doi: . /copd.s sha: doc_id: cord_uid: l rsa introduction: the use of antibiotics is based on the clinician’s experience and judgment, and antibiotics may often be overused in the treatment of acute exacerbations of chronic obstructive pulmonary disease (aecopd). eosinophils have been studied as biomarkers of bacterial infection and prognostic factors in chronic obstructive pulmonary disease and aecopd. thus, the purpose of this study was to determine whether eosinophils could be used to determine bacterial infection in aecopd events. methods: we retrospectively analyzed the medical records of patients admitted to korea university guro hospital for aecopd between january and may . data pertaining to baseline characteristics, results of previous pulmonary function tests, treatment information during the admission period, and history of pulmonary treatment were collected before admission. results: a total of aecopd events were eligible for inclusion and were divided into two groups based on the eosinophil count: those involving eosinophil counts of less than % ( events) and those involving counts of % or more ( events). in univariate analysis, the only bacterial pathogen identification events and bacterial-viral pathogen co-identification events were significantly more frequent in the group with eosinophil counts of less than % (p= . and p= . , respectively). in logistic regression analysis, the rates of only bacterial pathogen identification [odds ratios = . ; % confidence interval, . – . ; p= . ] and bacterial-viral pathogen co-identification [odds ratios= . ; % confidence interval, . – . ; p= . ] were higher in the group with eosinophil count less than %. conclusion: in conclusion, eosinophil counts of less than % are potential indicators of a bacterial infection in aecopd events. eosinophils could thus serve as a reference for the use of antibiotics in aecopd treatment. chronic obstructive pulmonary disease (copd) is an airway and lung disease that impairs the immune lung defense system making it susceptible to bacterial infections. , copd patients may experience acute exacerbations due to these bacterial infections. the global initiatives for chronic obstructive lung disease (gold) guideline recommend the use of antibiotics when a bacterial infection is suspected in events of acute exacerbations of chronic obstructive pulmonary disease (aecopd). the gold guideline also suggests that symptoms such as increase in dyspnea, sputum volume, and sputum purulence are the criteria for antibiotic usage. since these symptoms are not presented as absolute numerical values, the use of antibiotics is based on clinical experience and judgment. hence, antibiotics are often overused and stray from the gold guidelines, as reported by a study conducted in europe. to solve this problem, various biomarkers that distinguish bacterial infections have been studied, which include c-reactive protein (crp) and procalcitonin. however, crp commonly elevates in viral infections and hence cannot specifically distinguish bacterial infections. , procalcitonin is useful for distinguishing bacterial infections but is expensive and less accessible. therefore, we need a biomarker that can specifically distinguish bacterial infections, while being cost-effective and user-friendly. it is known that eosinophils are lowered in pneumonia and other infectious diseases caused by bacteria. [ ] [ ] [ ] eosinophils are a simple test that can be easily measured and are inexpensive to use in the clinical field. thus, the purpose of this study was to determine whether eosinophils could be used to determine bacterial infection in aecopd events. we retrospectively reviewed and analyzed the medical records of aecopd events in patients admitted in the korea university guro hospital from january to may . we searched our electronic medical records database using keywords such as "copd" and "acute exacerbation". this study was approved by our institutional review board (kugh - ). this study was a retrospective study, so patient consent was not necessary, and we maintained patient confidentiality with the declaration of helsinki. copd was diagnosed based on the gold guidelines, where a ratio of forced expiratory volume in the first second (fev ) to forced vital capacity was less than % in post-bronchodilator spirometry prior to admission, and aecopd was defined as "an acute event characterized by a worsening of the patient's respiratory symptoms that is beyond normal day-to-day variation and leads to a change in medication". , all the patients were older than years. patients were excluded ) if the cause of admission was not aecopd, for example, acute heart failure, acute pulmonary edema, acute pulmonary embolism, pneumothorax, or arrhythmia; or ) if they had a co-morbidity that could affect the eosinophilic count, for example, cancer, allergic disorder, autoimmune disease, or hematologic disease; or ) if they had no clinical data, such as pulmonary function test (pft), laboratory test, and culture test results. medical records were reviewed and analyzed for the following data: age, gender, smoking history, comorbidities, treatment information during admission period, laboratory test, culture test, polymerase-chain-reaction (pcr) assay, previous pft, and pulmonary-related treatment before admission. laboratory test, culture test, and pcr assay were conducted within hrs after admission. blood, sputum, and urine culture were conducted for identification of the bacterial infection. sputum pcr assay was conducted for identification of viral infection. sputum pcr assays were performed using nasopharyngeal aspiration by a trained doctor. and sputum pcr assay can detect influenza virus, respiratory syncytial virus, parainfluenza virus, coronavirus, rhinovirus, enterovirus, adenovirus, bocavirus, and metapneumovirus. we defined "maintenance oral steroid" as using steroid for more than three weeks and "short-term oral steroid use" as using steroid for three weeks or less. data were analyzed by spss software (spss for windows, spss inc., chicago, il, usa). data were reported as mean ± standard deviation or number and percent of each group. we divided the two groups with respect to eosinophil count of %. continuous variables were compared using the mann-whitney test or independent t-test, while categorical variables were compared using the chi-square test or fisher`s exact test. variables with p-value < . on univariate analysis were tested in logistic regression analysis. when analyzing logistic regression analysis, white blood cell (wbc) and crp were converted into binary variables based on the optimal cut-off values, and these optimal cutoff values were calculated using receiver operating characteristic. the cut-off values of wbc and crp were , . cells/mm and . mg/l, respectively. the logistic regression analysis was assessed by the hosmer-lemeshow test, with p-value < . considered statistically significant. multivariate analysis was performed in three different models. model- analyzed only bacterial pathogen identification, bacterial-viral pathogen co-identification, and laboratory findings (wbc, crp). model- analyzed all other factors that were statistically significant in the univariate analysis except for the nopathogen identification factor. model- analyzed the age and gender along with the factors of model- . with respect to the exclusion criteria, only aecopd events were eligible. out of these, events with eosinophil counts less than % and events with eosinophil counts of % or more were analyzed. table shows baseline characteristics of the total events and the two groups. there were statistically significant differences between the two groups: length of hospital stay (p< . ), experience of intensive unit care (p= . ), wbc (p< . ), eosinophil percent (p< . ), eosinophil count (p< . ), crp (p< . ), and fev (liters) (p= . ). there were no statistically significant differences in the other factors (p-value for all other variables > . ) ( table ) . we analyzed any past treatment associated with pulmonary conditions before admission. there was a statistically significant difference between the two groups for maintenance oral steroid (p= . ), but no statistically significant differences in the other factors were noted (p-value for all other variables > . ) ( table ) . we classified all events into four groups according to bacteria or virus identification: only bacterial pathogen identification, only viral pathogen identification, bacterial-viral pathogen co-identification, and no-pathogen identification. the only bacterial pathogen identification events and bacterial-viral pathogen co-identification events were significantly more frequent in the group with eosinophil counts of less than % (p= . and p= . , respectively). the no-pathogen identification events were significantly more frequent in the group with eosinophil counts of % or more (p< . ). the frequency of only viral pathogen identification events did not show any statistically significant difference between the two groups (p= . ; table ). in all multivariate models, the only bacterial pathogen identification events and bacterial-viral co-identification events showed statistically significant differences between the two groups (table ). table shows odds ratio, % confidence interval, and p-value by logistic regression analysis. this study was the first to analyze whether bacterial infections can be differentiated based on the eosinophil percent of % in aecopd patients in korea. our results showed that only bacterial pathogen identification events and bacterial-viral pathogen coidentification events are significantly more frequent in groups with eosinophil counts of less than %. since some studies used eosinophil percent of % as a cut-off value to predict the prognosis and treatment response in copd, we also used the same cut-off value. for example, some studies analyzed the prognosis of steroid inhaler response and treatment in copd based on the % value, , while some analyzed the pneumonia risk and stability in stable copd based on the % value. , eosinophils, which make up - % of the total wbcs, have several receptors on their cell surface and secrete various cytokines and mediators. research in eosinophils was initially focused on helminth infection and allergic disorders. as research progressed, it was found that eosinophils performed various functions in the human body such as regulation of innate and adaptive immunity and responses to infection and inflammation. , since animal studies showed that eosinophil count decreased with acute bacterial infection, eosinophils have been studied as a marker of bacterial infections. , the reason for the decrease in peripheral eosinophils count in acute bacterial infection was the accumulation of eosinophils at the inflammatory site and inhibition of egress from the bone marrow. additionally, bacterial infection in lungs affects the cytokine and chemokine release from the airway smooth muscle cells (asmc). bacterial infections activate human asmc to release c-x-c motif chemokine (cxcl)- that increases neutrophil recruitment. on the other hand, bacterial infections inhibit the release of eotaxin- that is proven to induce blood eosinophilia in studies on mice. many studies have been conducted on the relationship between eosinophil and copd and aecopd. in copd analysis, it was thought that sputum eosinophilia could be indirectly predicted by the peripheral blood eosinophils, and blood or sputum eosinophil count were inversely related to the bacterial load. in aecopd analysis, eosinopenia is predicted to have a poor prognosis. eosinopenia group based on eosinophil count of /mm is associated with long hospital day and high mortality. our results suggested that the eosinopenia group showed an increase in the mortality rate and duration of hospitalization because the rate of bacterial infection was higher than the eosinophilia group. studies on the relationship between eosinophils and viral infection have shown heterogeneous results. there have been studies of the relationship between viral infections and eosinophil in children and infants, but not with copd. although these studies were not conducted for copd patients, it was reported that respiratory viral infections showed various cytokines and eosinophil activation depending on the type of virus. , furthermore, in the murine asthma model study, airway eosinophil infiltration increased following a rhinovirus infection unlike that in the control mice. in conclusion, eosinophil is expected to show various patterns depending on the virus type and airway reactivity. however, additional studies are needed because of the lack of studies in copd patients. biomarkers should be such that they are quick and easy to perform, and cost-effective despite medical and economic levels. however, crp and procalcitonin are difficult to perform in all hospitals, including primary care hospitals. on the other hand, eosinophil test, belonging to complete blood count test, is easily accessible anywhere and is inexpensive. a disadvantage of using eosinophil as a biomarker is that there are many factors that affect eosinophils, such as hematologic disorders, cancer, allergy diseases, medications, and steroids. in this study, patients with diseases that could affect eosinophil were initially excluded and the use of inhaled corticosteroids or oral steroid was analyzed using univariate and multivariate analysis. in pulmonary-related treatment before admission, the use rate of β oral agonist was high. korean copd patients prefer oral medicines over inhalers. also, previous epidemiological studies on the use of medications in copd patients in korea show a low use rate of inhalers. because there was no difference in the use rate of β oral agonist between the two groups, we think that it will not affect the results of the study. this study had several limitations. first, it had a retrospective design and was a single center study. we wanted to analyze other biomarkers like procalcitonin, but only half the patients were tested for procalcitonin and hence, could not evaluate the procalcitonin together. second, colonization and contamination could not be distinguished in the analysis of isolation. to compensate for this as much as possible, we also analyzed the condition bronchiectasis that was known to be highly colonized, and the difference between the two groups was not apparent. additionally, culture test and pcr assay were performed by trained doctors. third, we could not analyze the effect of the steroid dose and type. in the inhaled corticosteroids group, different doses and different kinds of inhalers were used, and the dose varied between and mg in the oral steroid use group. fourth, eosinophil may be affected by various conditions and diseases. although eosinophil has the advantage of being cheap and easy to use in practice, it is dangerous to decide alone by eosinophil percent whether to use antibiotics in aecopd. it would be useful to use it as a reference. although this study was a retrospective and singlecenter study, we analyzed various factors in a largescale group, and multiple factors that affected eosinophil count were analyzed. however, an additional large-scale multicenter, randomized control study will be required to demonstrate our results better. eosinophil count of % may be an indicator to distinguish various bacterial infections in aecopd patients. furthermore, by predicting the presence or absence of bacterial infection, a more reliable antibiotic treatment can be determined. copd, chronic obstructive pulmonary disease; aecopd, acute exacerbation of chronic obstructive pulmonary disease. the international journal of copd is an international, peer-reviewed journal of therapeutics and pharmacology focusing on concise rapid reporting of clinical studies and reviews in copd. special focus is given to the pathophysiological processes underlying the disease, intervention programs, patient focused education, and self management protocols. this journal is indexed on pubmed central, medline and cas. the manuscript management system is completely online and includes a very quick and fair peer-review system, which is all easy to use. visit http://www.dovepress.com/testimonials.php to read real quotes from published authors. submit your manuscript here: https://www.dovepress.com/international-journal-of-chronic-obstructive-pulmonary-disease-journal defective phagocytosis in airways disease oxidative stress-mediated inkt-cell activation is involved in copd pathogenesis copd exacerbations: causes, prevention, and treatment global strategy for the diagnosis, management and prevention of chronic obstructive lung disease report: gold executive summary antibiotic therapy in exacerbations of chronic obstructive pulmonary disease antibiotic prescription for copd exacerbations admitted to hospital: european copd audit c-reactive protein level and microbial aetiology in patients hospitalised with acute exacerbation of copd c-reactive protein levels predict bacterial exacerbation in patients with chronic obstructive pulmonary disease effect of procalcitonin-guided treatment on antibiotic use and outcome in lower respiratory tract infections: cluster-randomised, single-blinded intervention trial blood and sputum eosinophils in copd; relationship with bacterial load blood eosinophil count and pneumonia risk in patients with chronic obstructive pulmonary disease: a patient-level meta-analysis experimental observations on the eosinopenia induced by acute infection copd exacerbations: defining their cause and prevention blood eosinophil counts, exacerbations, and response to the addition of inhaled fluticasone furoate to vilanterol in patients with chronic obstructive pulmonary disease: a secondary analysis of data from two parallel randomised controlled trials blood eosinophils and inhaled corticosteroid/long-acting beta- agonist efficacy in copd stability of blood eosinophil count in patients with copd in the uk clinical practice research datalink weller pf, goetzl ej. the human eosinophil: roles in host defense and tissue injury the eosinophil the eosinophil in infection eosinopenia of acute infection: production of eosinopenia by chemotactic factors of acute inflammation behavior of eosinophil leukocytes in acute inflammation. ii. eosinophil dynamics during acute inflammation differential regulation of ccl- /eotaxin- and cxcl- /il- by gram-positive and gram-negative bacteria in human airway smooth muscle cells neutrophil activation induced by artinm: release of inflammatory mediators and enhancement of effector functions relationship between interleukin- and eotaxin in regulating blood and tissue eosinophilia in mice peripheral blood eosinophils: a surrogate marker for airway eosinophilia in stable copd eosinopenia as a marker of mortality and length of stay in patients admitted with exacerbations of chronic obstructive pulmonary disease different cytokine profile and eosinophil activation are involved in rhinovirus-and rs virus-induced acute exacerbation of childhood wheezing a comparison of cytokine responses in respiratory syncytial virus and influenza a infections in infants the effect of rhinovirus on airway inflammation in a murine asthma model possible health effects of noise induced cortisol increase this study was supported by a korea university guro hospital grant (o ). all authors contributed to data analysis, drafting and revising the article, gave final approval of the version to be published, and agree to be accountable for all aspects of the work. the authors report no conflicts of interest in this work. key: cord- -eeldyj u authors: graziani, desirée; soriano, joan b; del rio-bermudez, carlos; morena, diego; díaz, teresa; castillo, maría; alonso, miguel; ancochea, julio; lumbreras, sara; izquierdo, josé luis title: characteristics and prognosis of covid- in patients with copd date: - - journal: j clin med doi: . /jcm sha: doc_id: cord_uid: eeldyj u patients with chronic obstructive pulmonary disease (copd) have a higher prevalence of coronary ischemia and other factors that put them at risk for covid- -related complications. we aimed to explore the impact of covid- in a large population-based sample of patients with copd in castilla-la mancha, spain. we analyzed clinical data in electronic health records from january to may by using natural language processing through the savana manager(®) clinical platform. out of , copd patients, had a diagnosis of covid- . the proportion of patients with covid- in the copd population ( . %; % ci . – . ) was significantly higher than in the general population aged > years ( . %; % ci . – . ); p < . . compared with copd-free individuals, copd patients with covid- showed significantly poorer disease prognosis, as evaluated by hospitalizations ( . % vs. . %: or . ; % ci . – . ) and mortality ( . % vs. . %: or . ; % ci . – . ). patients with copd and covid- were significantly older ( vs. years), predominantly male ( % vs. %), smoked more frequently, and had more comorbidities than their non-copd counterparts. pneumonia was the most common diagnosis among copd patients hospitalized due to covid- ( %); % of patients showed pulmonary infiltrates suggestive of pneumonia and heart failure. mortality in copd patients with covid- was associated with older age and prevalence of heart failure (p < . ). copd patients with covid- showed higher rates of hospitalization and mortality, mainly associated with pneumonia. this clinical profile is different from exacerbations caused by other respiratory viruses in the winter season. chronic obstructive pulmonary disease (copd) is one of the most prevalent chronic diseases, one of the main diagnoses in hospital admissions (especially during winter), and the fourth leading cause of death worldwide. importantly, one of the main factors underlying the negative impact of the disease in patients and health systems is copd exacerbation [ ] . in turn, these exacerbations are primarily caused by respiratory viral infections (especially during epidemic periods), which have a direct effect on the symptomatology and favor bacterial superinfections [ , ] . copd exacerbations worsen the prognosis of the disease by increasing mortality when associated with hospitalizations [ ] . caused by coronavirus- (sars-cov- ), the clinical manifestation of covid- varies from mild to very severe symptoms and can lead to death in some patients [ , ] . since the onset of the covid- pandemic, the severity of the disease has been associated with pre-existing comorbidities, namely cardiovascular diseases, diabetes mellitus, and hypertension. in contrast with the reported burden of influenza epidemics in copd patients, the impact of covid- in these patients seems to have been less evident; however, copd patients usually present a fragile situation and a lower respiratory functional reserve [ , ] . covid- severity and mortality have also been associated with patient's age. although the virus can infect individuals of all ages, the majority of severe cases to date have been described in people older than years and with significant comorbidities [ , ] . the prevalence of copd also increases markedly with age, with most diagnoses occurring in patients aged and older. indeed, patients over years old frequently present with more than one chronic disease, especially in the endocrine-metabolic and cardiovascular spheres. several observational and case-control studies have confirmed a higher prevalence of cardiovascular diseases in copd patients than in the general population, possibly due to the coexistence of common risk factors or an associated pathogenic mechanism [ ] . although there are large discrepancies in the studies that have evaluated the relationship between copd and cardiovascular disease, copd patients undoubtedly have a higher prevalence of coronary ischemia and other risk factors that may worsen the prognosis of covid- [ ] . based on the above, it is crucial to characterize the evolution of sars-cov- infection in copd patients and identify the impact of copd and associated comorbidities in the patient's evolutionary course. the combination of real-world data (rwd) with big data analytics and artificial intelligence has the potential to increase our understanding of covid- in a timely manner. using such methods, this study aims to reuse the clinical information contained in the electronic health records (ehrs) of the population with copd and covid- to (a) describe the clinical characteristics of patients with copd and covid- and (b) to assess the influence of copd and related comorbidities and treatments in the prognosis of covid- . this was a multicenter, non-interventional, retrospective study using free text data captured in the ehrs of patients diagnosed with copd and covid- . the study period was january- may . we followed the strengthening the reporting of observational studies in epidemiology (strobe) guidelines for reporting observational studies [ ] . clinical data from a total of , , patients with available ehrs throughout the community of castilla la-mancha (spain) were collected from all available departments, including inpatient, outpatient, emergency room, and primary care. natural language processing (nlp) and artificial intelligence (ai) techniques were used to extract and analyze the information in ehrs. the software used (savana manager ® ) is a powerful multilingual, free-text analysis engine capable of interpreting the content in clinical records, regardless of the system in which they operate. the software can capture numerical values and physician's notes and translate them into usable variables, thus allowing the reuse of information included in large-scale collections of clinical records; therefore, the processed free-text information captured in ehrs is treated as big data. the methodology used to generate the study database has four distinct phases for data extraction and aggregation, namely (a) acquisition: the acquisition of data is the responsibility of the healthcare center, in close collaboration with the staff of savana information technology. following the general data protection regulation (gdpr) of the european union, data are extracted, anonymized, and transferred to savana; (b) integration: in this phase, data are integrated into the database; (c) nlp processing: using the ehread ® technology developed by savana, nlp techniques are implemented to analyze and extract the unstructured, free-text information written in millions of ehrs. the output of nlp processing is a synthetic patient database, as the software creates a patient database from scratch. this ensures that this information is protected and makes traceability to individual patients impossible; (d) validation: this process consists of a medical validation carried out by doctors and researchers. the terminology used by savana is based on multiple sources, such as snomed ct [ ] . this terminology includes codes, concepts, synonyms, and definitions used in clinical documentation. it also includes symptoms, diagnoses, body structures, and substances. due to the novel methodological approach of this study, we complemented our clinical findings with an evaluation of savana's performance. this evaluation aims to verify the precision of the system by identifying records that contain mentions of copd, covid- , and its related variables. the results of the annotations were used to generate the gold standard and to calculate savana's performance. the performance of the system is calculated in terms of the standard metrics for precision (p), recall (r), and its harmonic mean f-score [ ] : precision = tp/(tp + fp). this parameter gives us an indicator of the precision of the information that the system retrieves. recall = tp/(tp + fn). this parameter gives us an indicator of the amount of information that the system retrieves. f-score = × precision × recall/(precision + recall). this parameter provides us with a general performance indicator for information retrieval. in all cases, tp is the number of true positives (i.e., records retrieved successfully), fn is the number of false negatives (i.e., records incorrectly not retrieved), and fp is the number of false positives (i.e., records recovered incorrectly). the search terms for copd and covid- have been previously described [ , ] . for the linguistic evaluation of the variable "copd", we obtained precision, recall, and f-scores of . , . , and . , respectively; these metrics indicate that patients with copd were properly identified within the target population. ehread identified covid- with a precision of . , a recall of . , and an f-score of . ; again, these results indicate that within our population with copd, covid- cases were accurately identified. for all statistical analyses, spss software (v . ) was used. categorical variables are reported as absolute frequencies and percentages, while continuous variables are presented using mean and standard deviation. for the assessment of statistical significance of numerical variables, we used t-tests for independent samples or anovas. to measure the relative distribution of patients assigned to different categories of qualitative variables, we used chi tests. in all cases, a p value for statistical significance was set at . . the study was compliant with legal and regulatory requirements and the research practices described in the ich guide to good clinical practice, the declaration of helsinki in its latest edition, good pharmacoepidemiology practices, and local regulations. since this is a retrospective and observational study using anonymous patient data, informed consent does not apply to the present study. all actions were taken following the code of good data protection practices for big data projects of the european data protection authority and the european gdpr. the study has been approved by the ethics and research committee of the university hospital of guadalajara (spain). a total of , patients with a diagnosis of copd were attended by the health system of castilla la-mancha (spain) between january and may . among these, patients were diagnosed with covid- . the patient flowchart is depicted in figure . the percentage of patients diagnosed with covid- in the copd population ( . %; % ci . - . ) was significantly higher than in the general population older than years, ( . %; % ci . - . ); p < . . covid- diagnosis was confirmed by pcr in ( %) of patients; in the remaining cases, diagnosis was based on rapid serological tests or clinical, radiological, and/or analytical evaluation, considering the reduced availability of pcr testing in the study area between march and may . the demographic and clinical characteristics of covid- patients with and without copd are shown in table . compared with copd-free patients with covid- older than years, patients with both covid- and copd were older ((mean age ± sd) ± years vs. ± years (p < . )) and predominantly male. furthermore, these patients showed a higher prevalence of comorbidities and a worse prognosis, as evaluated by hospitalizations ( . % vs. . %: or . ; % ci . - . ) and mortality rate ( . % vs. . %: or . ; % ci . - . ) ( table ) . the percentage of patients diagnosed with covid- in the copd population ( . %; % ci . - . ) was significantly higher than in the general population older than years, ( . %; % ci . - . ); p < . . covid- diagnosis was confirmed by pcr in ( %) of patients; in the remaining cases, diagnosis was based on rapid serological tests or clinical, radiological, and/or analytical evaluation, considering the reduced availability of pcr testing in the study area between march and may . the demographic and clinical characteristics of covid- patients with and without copd are shown in table . compared with copd-free patients with covid- older than years, patients with both covid- and copd were older ((mean age ± sd) ± years vs. ± years (p < . )) and predominantly male. furthermore, these patients showed a higher prevalence of comorbidities and a worse prognosis, as evaluated by hospitalizations ( . % vs. . %: or . ; % ci . - . ) and mortality rate ( . % vs. . %: or . ; % ci . - . ) ( table ) . in castilla-la mancha, the covid- pandemic began in march . at that time, there were hardly any other viral infections, including influenza. to assess the burden of covid- in patients with copd, we compared the clinical characteristics and outcomes of patients with copd and covid- during the study period with existing data from copd patients during the last two winter seasons. although patients' characteristics (including comorbidities) were similar in the two periods, covid- was associated with poorer prognosis in terms of hospitalization and mortality (table ) . the main diagnosis of copd patients with covid- requiring hospital admission was pneumonia ( % of patients); % of hospitalized patients had pulmonary infiltrates, in turn suggestive of pneumonia and heart failure. in patients who died, the distribution of patients with pneumonia and heart failure were % and %, respectively, similar to non-copd patients with covid- who died ( % had pneumonia and pulmonary infiltrates with different diagnosis, mainly heart failure or acute respiratory distress syndrome). in the copd population with covid- , those who died were older ( ± years vs. ± years; p = . ) and had a higher incidence of heart failure than those who did not die from the disease; no other prognostic factor was identified (table ) . table . impact of comorbidities on the mortality of patients with copd. copd-covid- regarding pharmacological treatment, most patients were under treatment with bronchodilators, namely beta agonists and anticholinergics (table ); a significantly greater use of both drugs was observed in those patients who died. on the other hand, the elevated rates of inhaled steroids use in both patient groups forbid further assessment of differences regarding the use of these agents and mortality. finally, we did not observe any differences in covid- -related mortality rates based on use of cardiovascular drugs. table . impact of treatments on the mortality of patients with copd. ( january- may ) finally, in table , our finding observed in the crude analysis of an association with death in covid- patients with copd is further confirmed. the increased mortality risk of covid- patients with copd versus those without copd is sustained in several multivariate analyses adjusted by covariates, and very consistently, sequentially with or and % ci of . ( . - . ) adjusted by sex and age (model ); of . ( . - . ) when we also added the two most relevant comorbidities, that is heart failure and high blood pressure (model ); and of . ( . - . ) when we added all single comorbidities in a full model (model ). since the who declared the covid- outbreak a global pandemic, clinicians have aimed at determining the impact of the disease on patients with chronic diseases, especially of pulmonary and cardiovascular nature. although the frequency and severity of covid- has been associated with pre-existing comorbidities such as heart disease, arterial hypertension, and diabetes. surprisingly and "against all prognosis", however, healthcare data show that the incidence of covid- in copd patients has been relatively low [ ] . this trend was already observed from the onset of the pandemic; a study that evaluated hospitalized patients with covid- in china revealed a low incidence in patients with copd, with a total of cases [ ] . however, copd was linked with a higher risk for poor disease outcome (composite endpoint including admission to an intensive care unit, invasive ventilation, or death), reflected by a hazard ratio (hr) of ( % ci - . ), after adjusting for age and smoking. in this study, the comorbidity of copd as a risk factor was exceeded only by malignancy (hr . , % ci . to . ) [ ] . subsequently, a systematic review and meta-analysis showed that, although the prevalence of copd in covid- cases was low, sars-cov- infection was associated with high rates of severity and mortality in patients with copd [ ] . in our study, we have confirmed that the impact of covid- in copd patients has been relatively limited. plausible underlying reasons for this include remission of the seasonal flu period, an absence of exposure to environmental factors due to isolation, the significant drop in contamination, and better control of the disease by complying with the treatments conscientiously "out of fear". our results, however, indicate that patients with copd are at a higher risk of sars-cov- infection doubling the infection rates observed in the general population over years of age. this increased risk has also been described in a concise meta-analysis showing that copd is associated with a significant, five-fold increased risk of severe covid- infection; of note, this analysis is focused on the chinese population and there was substantial variability among the included studies [ ] . although a greater risk associated with covid- in copd patients seems clear, it is difficult to accurately determine the extent to which copd itself or associated comorbidities affect the higher prevalence of covid- and its prognosis. in our study, copd patients were older and had more comorbidities. these factors could have been critical in the reported higher rates of admissions and mortality. although it is not possible to accurately assess the impact of comorbidities in copd [ ] in a cross-sectional study, there is no doubt that copd patients are at higher risk for covid- , showing a higher incidence of the disease and worse prognosis (as determined by higher hospitalization and mortality rates). our multivariate analyses presented in table adds strength to our finding of an increased risk of death, ranging from % to %, in covid- patients with copd versus those without copd. please note that in the full model , some individual comorbidities were associated with nominal increases, but not statistically significant increased risks, such as stroke, ischemic heart disease, ischemic heart disease, and sleep apnoea, as well as smoking with an odds ratio (or) of . % confidence interval (ci) ( . - . ), likely due to mathematical collinearity of these comorbidities in multimorbid patients. given the scarcity of pcr tests for sars-cov- at the onset of the covid- pandemic, regional protocols established the performance of multiple pcr tests for respiratory viruses in all patients who were hospitalized for respiratory symptoms. the results of these tests allowed us to confirm the near absence of other viral infections, including influenza, during the covid- pandemic. this allowed us to compare the differential impact of covid- in copd patients by comparing data during this period with data from the last two winter seasons. although both populations showed similar age and comorbidities, covid- caused a higher rate of hospitalizations and in-hospital mortality. most patients admitted for covid- presented pulmonary infiltrates compatible with sars-cov- pneumonia and, in some cases, with associated heart failure; this finding markedly differed from patients with copd exacerbation due to other viral causes. these data indicate that patients who were admitted into a hospital or died from covid- have different clinical profiles compared to those with winter viral exacerbations. thus, these differences must be taken into account so we can adapt to a scenario where both clinical profiles can coexist. as faust comments in a recent article [ ] , many hospitals in areas hard-hit by covid- (as is the case in our study population) have had an unprecedented overload and demand for hospital resources during the crisis that have never been seen before, even during the worst flu season. although the interaction that may exist between sars-cov- and other viruses is unknown, the scenario can be further complicated by their simultaneous presentation. the treatment of patients with chronic diseases have been another highly discussed topic with regards to the newly identified pandemic. faced with the initial alarm regarding the deleterious potential of certain drugs such as ace inhibitors or arbs, our data do not confirm a negative impact of these drugs in patients with copd and related comorbidities that justify their use. these data are consistent with other series in the general population [ , ] . in patients with copd and asthma, although there is still very little scientific evidence, the treatment with inhaled glucocorticoids (igc) could have a "protective effect" against covid- since they may decrease the expression of the ace receptor genes and the tmprss transmembrane protease genes, both key for the virus to enter cells and make copies of itself [ ] . previous clinical data in patients with asthma support this hypothesis in our population [ ] . however, since most copd patients were under treatment with igcs, it was not possible to evaluate the specific effect of igcs in our population. since the prescription of beta agonists and anticholinergics is guided by symptoms, the observed greater use in patients who died may simply be related to increased severity of the disease. perhaps one of the most controversial topics around covid- is the association between smoking and the manifestation of the disease. although a protective effect of nicotine was initially suggested, several meta-analyses have confirmed that smoking increases the risk of severe covid- and mortality; these results are not consistent, however [ , ] . as is the case with the present study (where we were not able to determine with precision whether smokers were still active tobacco users or the intensity of exposure) the exact duration of smoking was not reported in most studies included in these meta-analyses. both copd and tobacco smoke can up-regulate ace- expression in lower airways, which in part may explain the increased risk of severe covid- in this population [ ] . the results presented here must be interpreted in light of some strengths and limitations. data were extracted from the public health system of castilla-la mancha, with a population of , , inhabitants. specifically, we analyzed data from the sescam health system, which operates the savana manager ® clinical platform with available data since . the information obtained from , , patients with available ehrs available during the study period is verifiable and includes the clinical management of all patients without any type of bias. this differs from other databases, where limited reliability has generated controversy [ ] . importantly, since we collected information from the entire population, reproducibility of the results does not apply. on the other hand, the results reported for some variables rely on the quality of the data captured in the clinical reports, which in many cases may not include all the clinical information for a given patient. since this is not a study based on a strict registry of variables, the information that was not adequately documented was excluded from further analyses [ , ] . in this study, we included covid- cases both confirmed with pcr or serological tests and those exclusively diagnosed based on clinical criteria (i.e., symptoms, imaging, and laboratory results). however, it should be noted that pcr and other rapid laboratory tests for the detection of sars-cov- were not used routinely in spain during the onset of the pandemic. furthermore, this decision is supported by reports questioning the clinical validity and high sensitivity of symptom and image-based identification of patients with covid- , especially in the early stages of the disease [ ] [ ] [ ] . finally, diagnoses for viral infections analyzed in previous winter seasons were mostly based on clinical evaluations, without specifications regarding the type of virus in most cases. the data, which spans two annual periods, are nevertheless representative of copd exacerbations due to viral processes during the winter season. in conclusion, the results of this study confirm a higher incidence of covid- in copd patients and higher rates of hospital admissions and mortality, mainly associated with pneumonia. this clinical profile is different from that observed during winter exacerbations caused by other respiratory viruses. overall, our data support the implementation of specific plans in this population with close monitoring of copd patients in sceneries at risk for covid- . global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease epidemiology of chronic obstructive pulmonary disease exacerbations acute exacerbation 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corticosteroids the impact of copd and smoking history on the severity of covid- : a systemic review and meta-analysis ace- expression in the small airway epithelia of smokers and copd patients: implications for covid- a global information extraction and terminology expansion framework in the medical domain extracting information from the text of electronic medical records to improve case detection: a systematic review diagnosis of the coronavirus disease (covid- ): rrt-pcr or ct? detection of sars-cov- in different types of clinical specimens correlation of chest ct and rt-pcr testing in coronavirus disease (covid- ) in china: a report of cases this article is an open access article distributed under the terms and conditions of the creative commons attribution (cc by) license the authors declare no conflict of interest. key: cord- -xn anxj authors: olloquequi, jordi title: covid‐ susceptibility in chronic obstructive pulmonary disease date: - - journal: eur j clin invest doi: . /eci. sha: doc_id: cord_uid: xn anxj in the middle of december , chinese health authorities detected a series of pneumonia cases caused by an unknown agent in wuhan, the capital of hubei province. the causative agent was soon identified as a new strain of human‐infecting coronavirus( ), firstly named novel coronavirus ( ‐ncov) and later renamed as severe acute respiratory syndrome coronavirus (sars‐cov‐ ). the infection disease caused by sars‐cov‐ , known as coronavirus disease (covid‐ ), varied from asymptomatic or common cold‐like symptoms such as dry cough, fever and tiredness to severe dyspnea and respiratory failure( ). in the middle of december , chinese health authorities detected a series of pneumonia cases caused by an unknown agent in wuhan, the capital of hubei province. the causative agent was soon identified as a new strain of human-infecting coronavirus , firstly named novel coronavirus ( -ncov) and later renamed as severe acute respiratory syndrome coronavirus (sars-cov- ). the infection disease caused by sars-cov- , known as coronavirus disease (covid- ), varied from asymptomatic or common cold-like symptoms such as dry cough, fever and tiredness to severe dyspnea and respiratory failure . this initial outbreak alarmingly spread through china and other countries, and barely three months later, the world health organization (who) formally declared covid- a global pandemic . as of august , there have been more than , , cases and , deaths by covid- worldwide . like in other infectious diseases, certain population groups have been reported to suffer a higher risk of severe clinical course of covid- . among them, patients with hypertension and diabetes seem the most significant, comprising the . % and . % of patients in critical conditions, respectively , . to a lesser extent, patients with coronary heart disease and cerebrovascular disease have also been repeatedly reported in severe cases, while older adults are the age group with highest mortality rates by covid- , this article is protected by copyright. all rights reserved reasonable to expect that patients with chronic respiratory diseases are also in the population risk group. indeed, who acknowledges that conditions that increase oxygen needs or reduce the ability of the body to use it properly will put patients at higher risk of serious lung conditions such as pneumonia . chronic obstructive pulmonary disease (copd) is a leading cause of death and disability globally, characterized by persistent respiratory symptoms and airflow limitation due to airway inflammation and/or alveolar abnormalities . the global initiative for chronic obstructive lung disease (gold) recognizes copd patients amongst the worst affected by covid- . in the present review, the available evidence pointing to copd patients as more prone to suffer a severe covid- clinical course is discussed, and the pathophysiological mechanisms linking both diseases are explained ( figure ). copd emerges from a complex interaction between genetic predisposition and environmental factors. while over independent genetic associations with lung parameters defining copd and with copd risk have been described , cigarette smoking is by far the main environmental risk factor for copd. hence, between and % of smokers develop copd, whereas to % of copd patients are smokers or ex-smokers , . to date, no definitive evidence on whether ever-smokers are at an increased risk of covid- . however, who argues that tobacco users may be at higher risk of sars-cov- infection, since smoking implies repetitive hand-to-face contact and often sharing of mouth pieces and hoses, all of which could facilitate the virus entry . in turn, a recent study on , covid- patients reported that . % of current smokers died or suffered a severe clinical condition compared to only . % among never-smokers . moreover, . % of severe cases were eversmokers compared to . % of milder cases . in this sense, a recent systematic review by vardavas and nikitara concluded that smoking is most likely associated with negative progression and adverse outcomes of covid- . on the other hand, a meta-analysis conducted by lippi and henry based on data from chinese patients suggests that active smoking is not significantly associated with covid- severity . in spite of this contradictory data, the deleterious effects of cigarette smoking on lung defenses are wellknown , . smoking impairs the mucociliary clearance, alters humoral response to antigens and affects alveolar macrophages responsiveness, thus increasing the susceptibility to respiratory infections - . moreover, it has also been reported that cigarette smoking decreases the number and cytotoxic activity of natural killer (nk) cells, one of the main lines of defense against viral infections , . it is not strange, thus, to find increased death rates this article is protected by copyright. all rights reserved from influenza and pneumonia among smokers , . cigarette smoking is also associated with a systemic inflammatory pattern . importantly, it has been shown that the immune changes found in copd patients are an amplification of those present in smokers who do not develop copd , . in addition, these pulmonary and systemic alterations persist after smoking cessation , . hence, an impaired response against sars-cov- or other pathogens could be expected despite current smoking status in copd patients. although the molecular basis for the amplification and "chronification" of these alterations remains obscure, it is accepted that both genetic and epigenetic factors are involved . in this sense, a recent study from mostafaei and colleagues used machinebased learning algorithms to find novel genes associated with copd . they identified candidate genes whose expression was significantly regulated by smoking and/or copd. among the most significant, the authors stressed the novel prkar b gene, which encodes an important protein kinase in camp signaling, a protective factor in the lung and copd. interestingly, prkar b expression was significantly downregulated in copd patients who smoked more than packs per year . in addition to cigarette smoking, other risk factors for copd development could also be related with covid- incidence and prognosis. for instance, exposure to smoke coming from biomass burning (biomass smoke, bs), which affects billion people worldwide, has also been recognized as one of the main risk factors for copd, especially among non-smokers . importantly, like tobacco smoke (ts), bs has been shown to alter pulmonary defenses, and this effect could conceivably also be enhanced and sustained in copd patients . in this regard, although copd caused by bs and ts present some differential hallmarks, patients with double exposure have worse blood oxygenation . in any case, the impact of bs on lungs is supported by several epidemiological studies reporting increased risks of acute respiratory infections (aris) in people exposed to this environmental pollutant , . also, in vitro studies confirm that bs exposure alters or impairs antiviral response of lung cells , . although no study is available yet on the risk of sars-cov- infection and bs exposure, a recent report from investigators of university of harvard reported an increased mortality rate by covid- associated to long-term exposure to pm . , one of the main components of bs . suffering from respiratory infections during childhood also been long recognized as a risk factor for copd development . however, whether this infancy infections are involved in copd development per se or are a consequence of previous factors determining an impaired lung function is a subject of debate. hence, although it has been reported that respiratory syncytial virus infection (rsv) or a history of pneumonia during childhood this article is protected by copyright. all rights reserved are associated to impaired lung function and risk of developing copd - , it has also been demonstrated that people born with a diminished airway function are more likely to suffer copd symptoms and subsequent viral infections [ ] [ ] [ ] . in any case, there is no doubt that subjects who develop copd are at an increased risk of suffering respiratory infections, a matter of importance in the context of covid- pandemics. this subject is discussed in the next section. although copd is mainly a chronic disease, a substantial number of patients suffer from exacerbations, defined as acute and sustained worsenings of the patient's condition from stable state and beyond normal day-to-day variations, requiring medication changes or hospitalization . exacerbations arise from several risk factors and triggers, being viral infections one of the most important causes . hence, viruses are responsible for a half to two-thirds of copd exacerbations , while these pathogens are also identified in over % of all stable copd patients, being associated to worse clinical outcomes . picornaviruses, influenza a, rsv and parainfluenza are among the most detected viruses in copd exacerbations . regarding the incidence of coronaviruses infection in copd patients, the available data is scarce. notwithstanding, a study assessing the presence of sars-cov through rt-pcr in patients with mild to moderate copd reported no trace of infection . by contrast, another study reported presence of coronavirus in . % of stable copd patients , whereas several coronaviruses were associated to multiple respiratory and systemic symptoms, as well as with hospitalizations, in a cohort of , copd patients . the fact that copd patients could be more susceptible to respiratory infections is sustained by mounting evidence. thus, in vitro and in vivo studies have demonstrated that patients with copd have increased viral titer and copy numbers after rhinovirus infection than control subjects [ ] [ ] [ ] . moreover, an upregulation of intercellular adhesion molecule- (icam- ), which is the rhinovirus major group receptor, has been reported in airways and parenchyma of copd patients , . likewise, seys and co-workers showed an upregulated expression of dipeptidyl peptidase iv (dpp ), a type ii transmembrane glycoprotein that serves as receptor for middle east respiratory syndrome coronavirus (mers-cov), in copd patients . interestingly, both dpp mrna and protein levels were inversely correlated with lung function and diffusing capacity. the authors concluded that increased dpp expression could partially explain why copd patients are more susceptible to mers-cov . regarding covid- , a recent paper by leung and co-workers investigated the expression of angiotensin this article is protected by copyright. all rights reserved converting enzyme ii (ace- ) in the lower tract of copd patients , since this transmembrane metallocarboxypeptidase has been shown to act as the doorway that allows sars-cov- into the lungs . the authors reported that copd patients show an increased airway gene expression of ace- compared to control subjects and ace- were inversely related to fev , suggesting a dose-dependent response . hence, these findings reinforce the idea of a higher risk for sars-cov- in subjects with copd. finally, it has been shown that viral infection may increase the number of bacteria in the lower airways and even facilitate a subsequent bacterial infection in copd . indeed, to % of copd patients hospitalized for exacerbations present viruses and bacteria coinfection, and these coinfections increase the severity of the exacerbations [ ] [ ] [ ] . hence, one may anticipate that copd patients with covid- are at higher risk to develop a more severe pneumonia. the increased susceptibility to respiratory infections leading to disease severity may reflect a defective immunity in copd . indeed, both the innate response to pathogens and the role of adaptive immune system to such challenges are impaired in copd, which can result in recurrent infections , , . hence, despite increased numbers of alveolar macrophages have been reported in copd patients, their phagocytic ability is reduced as compared to smokers without copd [ ] [ ] [ ] . moreover, alveolar macrophages of patients with copd also exhibit an altered capacity to secrete proinflammatory mediators and proteases, express surface and intracellular markers, induce oxidative stress and engulf apoptotic cells . in turn, some studies have found reduced numbers and impaired maturation of dendritic cells in copd patients [ ] [ ] [ ] . in addition, interferon (ifn) signaling, which plays a key role in the innate antiviral response is also impaired in copd. thus, mallia and co-workers reported a reduced production of ifn-β in broncoalveolar lavage (bal) cells from subjects with copd after rhinovirus infection . recent results from our research group also showed a significative reduction expression of ifn-β and its main transcription factor, irf- , in lung epithelium and alveolar macrophages of copd patients . this reduction was also observed in pulmonary mrna levels of these immune mediators. since ifn-β has proven to inhibit coronavirus replication , , copd patients could be especially susceptible in front of covid- . regarding adaptive immunity, a downregulation of the epithelial polymeric immunoglobulin receptor (pigr) has been observed in copd patients . pigr is essential for generation of mucosal siga, an effective virus-neutralizing molecule , and its reduction was positively correlated to copd's severity . on another front, this article is protected by copyright. all rights reserved cd + t cells are critical for respiratory viral clearance and provide protection against secondary infections influenza virus in subjects with copd . interestingly, they found a downregulation of the t cell receptor signaling molecule cd (ζ-chain) in lung cd + of these patients compared with smokers and healthy controls. they also observed a reduced t-cell cytotoxicity and an upregulation of programmed cell death protein- (pd- ), which renders immunosuppressive actions on cd + cells . in another study, the same research group demonstrated that the impaired cytotoxic activity of cd + t cells was paralleled by a reduced proportion of cd + t cytotoxic cells in lung tissue from copd patients . in addition to cytotoxic t cells, other t subtypes seem to be altered in copd. regulatory t cells (tregs) are a subtype of lymphocytes that express the transcription factor foxp , which, among other functions, have been shown to limit the extent of tissue damage that occurs during a virus infection , . importantly, copd patients exhibit decreased numbers of pulmonary treg cells, as well as reduced levels of foxp mrna and lung interleukin secretion than controls . collectively, these findings indicate a characteristic immune dysfunction in copd that could impact on the pulmonary anti-viral defense. finally, it is noteworthy that the impaired immune response is not only restricted to pulmonary cells of copd patients. interestingly, a recent paper by agarwal and co-workers have demonstrated that human peripheral blood mononuclear cells (pbmc) from copd patients have a reduced ability to metabolize carbohydrate or fatty acids, suggesting a metabolic impairment in systemic immune cells in copd . moreover, the neutrophil-to-lymphocyte ratio (nlr) is increased both in stable and exacerbated copd patients , .this is particularly relevant, since a recent paper by liu and coworkers has shown that nlr is an independent risk factor for the in-hospital mortality for covid- . the study, which was performed on covid- patients, reported that subject in the highest tertile had a . -fold higher risk of mortality (or= . ; % ci, . to . ; p = . ) after adjustment for potential confounders, when compared with patients in the lowest tertile . so far, information on covid- incidence and clinical course on copd patients is scarce. a recent metaanalysis by lippi and henry have reported that copd is associated with a significant, over five-fold risk of severe covid- infection . however, the reported prevalence of copd in patients diagnosed with covid- is surprisingly low. hence, the prevalence of chronic respiratory disease and copd in two cohorts of chinese this article is protected by copyright. all rights reserved covid- patients has been only . % ( , patients studied) and . % ( patients studied) , respectively. moreover, in the usa population, chronic respiratory diseases were comorbidities in . % of covid- patients . in this regard, a group of investigators leaded by dr. Àlvar agustí recently published a paper suggesting that the use inhaled corticosteroids could reduce the risk of infection or of developing covid- symptoms, since previous in-vitro studies have shown that these drugs are capable of suppressing coronavirus replication . the same authors, however, warned about the fact that systemic corticosteroids were counterproductive to treat sars , . in this respect, it has also been shown that fluticasone propionate, an inhaled corticosteroid, impairs innate and acquired antiviral immune responses leading to delayed virus clearance and increases pulmonary bacterial load during virus-induced exacerbations in a murine model of copd exacerbation . in six months, the covid- pandemic has spread to more than countries and now the main focus of infection is centered in north and south america. consequently, governments and institutions work relentlessly to stop the spread of the sars-cov- worldwide, while trying to manage the sanitary, economic and social crisis we are facing. since a vaccine against this coronavirus has not yet been discovered, the most important thing is to take steps to stop its spread and to protect those people at highest risk of infection or developing a more serious clinical course. while hypertension and diabetes are the two comorbidities most clearly related to covid- susceptibility, available data regarding copd is contradictory. it is probable that copd-patients are underrepresented in intensive care settings due to their pre-existing poor prognosis and decisions to limit the treatment to palliative care in situations of poor prognosis. peoples in risk groups are advised to self-isolate, and most severe copd-patients most probably do not move out of their homes due to the limits of the disease for their performance in general. therefore, the incidence of covid- may be lower in copd-patients. nevertheless, substantial evidence points to copd patients as a particularly susceptible group to sars-cov- infection and to a worst prognostic. indeed, most copd patients are or, at least, have been exposed to noxious gases or pollutants capable of altering pulmonary defenses during many years. also, the immune dysfunction observed in copd may cause increased susceptibility to respiratory viral infections and an impaired inflammatory response against these challenges. finally, it is noteworthy that sars survivors showed a this article is protected by copyright. all rights reserved significative impairment of pulmonary function months after recovery . if the same is confirmed for covid- patients, a serious impact in the clinical course and quality of life in those with copd as comorbidity could be expected, since they already have a diminished lung function. in any case, more research in larger patient groups will bring more data on copd and covid- severity and associations of immune dysfunction in copd with covid- risk. it would be important to know whether the patients are more prone for severe infection due to impaired immune responses and whether the clinical picture of the disease and the cytokine storm differ in these patients. also, genotyping and complete phenotyping (including serological, radiological and histopathological assessment) will help to understand the mechanistic insights of the susceptibility to covid- . in light of all these facts, copd patients should be considered as a high-risk group in covid- . hence, sanitary authorities must apply specific mechanisms to monitor and assess patients with copd in the context of the current pandemic. none to declare. lippi g, henry bm. active smoking is not associated with severity of coronavirus disease (covid- a novel coronavirus from patients with pneumonia in china evaluation and treatment coronavirus (covid- ) who declares covid- a pandemic potential interventions for novel coronavirus in china: a systematic review covid- and the cardiovascular system are patients with hypertension and diabetes mellitus at 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pulmonary disease exacerbation oxidative and nitrosative stress and histone deacetylase- activity in exacerbations of copd upregulation of adhesion molecules in the bronchial mucosa of subjects with chronic obstructive bronchitis. american journal of respiratory and critical care medicine the main rhinovirus respiratory tract adhesion site (icam- ) is upregulated in smokers and patients with chronic airflow limitation (cal) dpp , the middle east respiratory syndrome coronavirus receptor, is upregulated in lungs of smokers and chronic obstructive pulmonary disease patients ace- expression in the small airway epithelia of smokers and copd patients: implications for covid- . the european respiratory journal a pneumonia outbreak associated with a new coronavirus of probable bat origin effect of interactions between lower airway bacterial and rhinoviral infection in exacerbations of copd infections and airway inflammation in chronic obstructive pulmonary disease severe exacerbations viral, 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lung: the role of cytotoxic cd + t cells role of regulatory t cells during virus infection the role of regulatory t cells in immunopathogenesis and immunotherapy of viral infections antielastin autoimmunity in tobacco smoking-induced emphysema systemic immuno-metabolic alterations in chronic obstructive pulmonary disease (copd) neutrophil-to-lymphocyte ratio in chronic obstructive pulmonary disease: a retrospective study neutrophil-to-lymphocyte ratio as an independent risk factor for mortality in hospitalized patients with covid- chronic obstructive pulmonary disease is associated with severe coronavirus disease (covid- ). respiratory medicine. : . . team. tncpere. the epidemiological characteristics of an outbreak of clinical characteristics of patients infected with sars-cov- in wuhan preliminary estimates of the prevalence of selected underlying health conditions among patients with coronavirus disease -united states do chronic respiratory diseases or their treatment affect the risk of sars-cov- infection? sars: systematic review of treatment effects corticosteroid suppression of antiviral immunity increases bacterial loads and mucus production in copd exacerbations impact of severe acute respiratory syndrome (sars) on pulmonary function, functional capacity and quality of life in a cohort of survivors histopathology and genetic susceptibility in covid- the author would like to thank dr. jack white for helping with the literature revision and ms. marta chmielewska for linguistic advice. this article is protected by copyright. all rights reserved this article is protected by copyright. all rights reserved key: cord- -anrzcsrt authors: nan title: . jahrestagung der Österreichischen gesellschaft für pneumologie date: - - journal: wien klin wochenschr doi: . /s - - - sha: doc_id: cord_uid: anrzcsrt nan patientencharakteristik, anamnese, symptome: eine -jährige patientin wurde nach plötzlichem auftreten von dyspnoe, tachypnoe und rechtsthorakalen schmerzen mit ausstrahlung in den rechten oberbauch vorstellig. die anamnese bezüglich traumas oder chronischen vorerkrankungen war unauffällig. diagnostik und diagnose: die blutgasanalyse zeigte eine hypoxie. laborchemisch fand sich lediglich eine isolierte, milde leukozytose. die thoraxauskultation ergab rechtsseitig verminderte atemgeräusche. die computertomografie des thorax wies einen rechtsseitigen hinteren zwerchfelldefekt mit intrathorakaler hernierung des kolon ascendens und rechtsseitigen pneumothorax mit mediastinalshift nach links aus. bildgebend bestand mithin der verdacht auf eine kolonperforation und eine bochdalek-hernie. differentialdiagnostik: obwohl bochdalek-hernien bei erwachsenen selten sind, müssen sie differentialdiagnostisch bei patienten mit dyspnoe berücksichtigt werden. eine intrathorakale kontamination nach bakterieller translokation oder hohlorganperforation kann zur entwicklung von pleuraempyemen führen. die sorgfältige intraoperative lavage und drainage der thoraxhöhle hat deshalb in diesen fällen große bedeutung. therapie: es erfolgte eine notfalllaparotomie, welche die diagnose bestätigte. ein cm langer zwerchfelldefekt mit inkarzeriertem und perforiertem kolon ascendens wurde erkannt. unter erweiterung der bruchpforte konnte das kolon nach intraabdominell reponiert werden. aufgrund von ischämischen veränderungen sowie der kolonperforation wurde eine rechtsseitige hemikolektomie mit anlage einer seit-zu-seit ileotransversostomie erforderlich. nach ausgedehnter abdomineller und transdiaphragmaler thorakaler lavage wurde eine bülaudrainage platziert, zwerchfelldefekt und bauchdecke wurden mittels naht verschlossen. am . postoperativen tag wurde aufgrund eines rechtsseitigen pleuraempyems nach diagnostischer vats eine anterolaterale thorakotomie mit anschließender pleuradekortikation zur sanierung erforderlich. die patientin erholte sich letztlich gut und wurde am . postoperativen tag nach hause entlassen. patientencharakteristik, anamnese, symptome: im juli wird eine -jährige patientin vom niedergelassenen pneumologen an unsere abteilung überwiesen. die aufnahme erfolgt aufgrund einer vor ca. zwei wochen suspizierten pneumonie, welche mit amoxicillin-clavulansäure behandelt wurde. im aufnahmegespräch berichtet die patientin über deutliche abgeschlagenheit und belastungsdyspnoe (stiegen steigen) bei bisher altersentsprechend sehr guter leistungsfähigkeit. in der anamnese sind eine atypische pneumonie vor einem jahr, eine primär biliäre cholangitis (ed im rahmen der pneumonie) und eine substituierte hypothyreose auffällig. in den von uns initial erhobenen laborbefunden zeigen sich moderat erhöhte entzündungsparameter (crp , mg/ dl, leukozyten , g/l), woraufhin die antibiotische therapie auf azithromycin mg umgestellt wird. eine durchgeführte computertomographie des thorax zeigt bipulmonale fleckige milchglastrübungen, peribronchovaskuläre verdichtungen mit teils positivem pneumobronchogramm und hiläre sowie mediastinale lymphadenopathie. zur abklärung der dementsprechend im raum stehenden differenzialdiagnosen einer sarkoidose, vaskulitis bzw. eines lymphoms werden eine bronchoskopie mit transbronchialer lymphknotenbiopsie (lk l, lk r, lk und lk r) und detaillierte laborchemische untersuchungen durchgeführt. diagnostik und diagnose: im verlauf kommt es zu einer verschlechterung der nierenfunktion (creatinin , mg/dl) und einer proteinurie ( , g/l), ansteigenden entzündungsparametern (crp, leukozyten, bsg) und einem positiven ergebnis für mpo-anca ( iu/ml). die histopathologische aufarbeitung der lymphknotenbiopsien zeigt ausgeprägte reaktive zell-und kernveränderungen ohne hinweis für eine infiltration mit malignen zellen. die erhobenen befunde erhärten den verdacht auf eine mpa-anca-assoziierte vaskulitis mit pulmonaler und renaler beteiligung. die patientin wird an die universitätsklinik für nephrologie transferiert, wo komplikationslos eine nierenbiopsie durchgeführt wird. hierbei zeigt sich das histologische bild einer pauci-immunen glomerulonephritis mit halbmondbildungen und schlingennekrosen in % der glomeruli, vereinbar mit der diagnose einer mpo-ancaassoziierte vaskulitis. therapie: nach entsprechender aufklärung der patientin beginnen wir mit der therapie mit rituximab mg (aktuell zwei gaben erhalten, dritte gabe geplant) sowie methylpred-therapie: im rahmen einer rechtsseitigen thorakotomie erfolgte eine offene wedge-resektion des oberlappen sowie mittellappens rechts, wobei sich intraoperativ histologisch der verdacht einer lymphominfiltration ergab. die fistulierung zur speiseröhre wurde mittels vena azygos-patch gedeckt und übernäht. eine protektive endoluminale vac-anlage konnte bereits am . postoperativen tag entfernt werden. histologisch bestätige sich ein aggressives non-hodgkin-lymphom der b-zellreihe, speziell eines diffusen großzelligen b-zell-lymphoms (zentroblastisch-polymorph), nicht-keimzentrumstyp nach hans-klassifikator. von onkologischer seite wurde einer therapie mittels r-chop initiiert bei postoperativ chirurgisch unauffälligem status. allergie mit biss background: lung transplantation is the ultimate treatment option for patients with end-stage respiratory diseases but bears the highest mortality rate among all solid organ transplantations due to chronic lung allograft dysfunction (clad). the mechanisms leading to clad remain elusive due to insufficient understanding of the complex post-transplant adaptation processes. here, we aimed to better understand the processes preceding clad, and investigate their association with future changes in allograft function. methods: we performed an exploratory cohort study in patients, including broncho-alveolar lavage samples from lung donors and recipients (after transplantation). we analyzed the alveolar microbiome using s rrna sequencing, the cellular composition using flow-cytometry, and conducted metabolome and lipidome profiling. results: we established distinct temporal dynamics for each of the analyzed data sets. comparing matched donor and recipient samples, we revealed that recipient-specific as well as environmental factors, rather than the donor microbiome, shape the long-term lung microbiome. we further discovered that the abundance of certain bacterial strains correlated with underlying lung diseases even after transplantation. a decline in forced expiratory volume during the first second (fev ) is a major characteristic of lung allograft dysfunction in transplant recipients. by using a machine learning approach, we could accurately predict future changes in fev from our multi-omics data, whereby microbial profiles showed a particularly high predictive power. conclusions: broncho-alveolar microbiome, cellular composition, metabolome and lipidome show specific temporal dynamics after lung transplantation. the lung microbiome can predict future changes in lung function with high precision. über eine anterolaterale thorakotomie rechts im . icr inklusive adäquate onkologische lymphadenektomie position rechts bis i the authors marked with an asterisk (*) are the corresponding authors. abstracts Ögp conclusions: patients with copd are insufficiently evaluated for cad due to overlapping symptoms. current cad risk scores for stable chest pain appear inappropriate for patients with copd. background: oncologic patients are regarded the population most at risk of developing a severe course of covid- due to the fact that malignant diseases and chemotherapy often weaken the immune system. in the face of the ongoing sars-cov- pandemic, how particular patients deal with this infection remains an important question. in the period between the th and th of april , a total of patients were tested in one of seven oncologic outpatient clinics for sars-cov- , regardless of symptoms, employing rt-qpcr using bgi real-time fluorescent rt-pcr kit for detecting -ncov on applied bioscience abi instruments. results: of patients, seventy-eight ( . %) were tested positive of sars-cov- . only one of the patients who tested positive developed a severe form of covid- with pneumonia (curb- score of ), and two patients showed mild symptoms. fourteen out of asymptomatic but positively tested patients received chemotherapy or chemo-immunotherapy according to their regular therapy algorithm (+/- weeks of sars-cov- test), and of ( . %) positive tested patients received glucocorticoids as co-medication. none of the asymptomatic p current symptom-based risk scores for stable coronary artery disease evaluation are not applicable in copd patients background: cardiovascular diseases are arguably the most important comorbidity in patients with chronic obstructive pulmonary disease (copd). despite an increased prevalence of coronary artery disease (cad) in copd patients, there are no dedicated diagnostic recommendations. we investigated whether copd patients receive adequate primary evaluation of cad despite overlapping symptoms. methods: patients with copd, who underwent invasive coronary angiography (ica), were retrospectively matched (for age, bmi and cardiovascular risk factors) with patients without functional lung diseases. quality and onset of symptoms prior to ica were documented and individual patients' pre-test probabilities according to esc guidelines were calculated. endpoints were delay of ica referral after symptom onset and clinical outcome, defined as subsequent revascularization. results: mean delay between symptom onset and ica was . ± . months in copd patients compared to . ± . months in the control group (p < . ). copd patients had a lower rate of typical chest pain ( . % vs. . %, p = . ), and dyspnoea only ( . % vs. . %, p = . ). sub-analysis of gold grades revealed an incremental delay with increasing copd severity: gold : . ± . months; gold : . ± . months; gold : . ± . months and gold : . ± . months. furthermore, the revascularization rate increased with higher pre-test probability for the control group, but not for patients with copd gold - . abstracts background: chronic thromboembolic pulmonary hypertension (cteph) is characterized by severe pulmonary artery hypertension and presence of sleep-disordered breathing (sdb) with associated hypoxemia which could further contribute to the severity of hypertension adversely affecting the outcome. limited data are available on the prevalence of sdb in cteph and so far, the effect of balloon pulmonary angioplasty (bpa) on sdb has not been evaluated. we hypothesized that subjects with cteph have a high prevalence of sdb, both obstructive and central sleep apnea with associated hypoxemia, which could improve with bpa. methods: consecutive patients with cteph underwent treatment-naïve and post-bpa polygraphy (nasal-pressure-sensor, thermistor, thoracoabdominal-excursion-sensors, pulse oximeter; alice pdx, philipps®) and hemodynamic and echocardiographic assessments. results: before bpa, prevalence of sdb (defined as an apnea-hypopnea index (ahi) > per hour) was %: patients infected patients showed unexpected complications due to the sars-cov- infection during the cancer treatment. conclusions: these data clearly contrast the view that patients with an oncologic disease are particularly vulnerable to sars-cov- and suggest that compromising therapies could be continued or started despite the ongoing pandemic. moreover, the relatively low appearance of symptoms due to covid- among patients on chemotherapy and other immunosuppressive co-medication like glucocorticoids indicate that suppressing the response capacity of the immune system reduces disease severity. background: for the further crisis management of the corona pandemic and the socio-economic impact on society, a strategy that allows selective isolation measures is particularly important. so far, it has been assumed that patients suffering from covid- develop antibodies that provide immunity and are thus protected from a reinfection with sars-cov- . this also forms the basis of the assumption that rapid vaccine development will lead to rapid control of the pandemic. in the present study, we analyzed the antibody development of oncology patients days after positive rt-qpcr testing for sars cov . methods: rt-qpcr and anti-sars-cov -antibody methods from bgi (mgieasy magnetic beads virus dna/rna extraction kit) and roche (elecsys anti-sars-cov- immunoassay) were used, respectively, according to the manufacturers' specifications. results: surprisingly, in only of individuals with a confirmed history of covid- antibody development was detected. despite of multiple testing, these patients did not develop antibodies in subsequent tests. conclusions: first analyses indicate that patients may benefit from inpatient pr after hospitalization due to covid- . symptoms of dyspnea, cough, depression, and anxiety decreased significantly over the course of the pr, whereas quality of life significantly increased. pr could therefore play an important role in dealing with the pandemic. follow-up assessments three and six months after the pr are currently ongoing. background: fatigue is among the most common symptoms in covid- patients and about % still suffer from persistent fatigue months later [ ] . some studies discuss a possible link to obstructive sleep apnea syndrome (osas) [ ] , however, no studies have been published in covid- patients after discharge. therefore, we examined covid- patients for the presence of osas within weeks after acute hospital discharge during inpatient pulmonary rehabilitation. methods: from may until july we screened all eligible covid- patients for osas using polygraphy. if the screening revealed an apnea-hypopnea index (ahi) of ≥ , further diagnostics using polysomnography were conducted. furthermore, we assessed the sleepiness using the epworth sleepiness scale (ess) and the body-mass-index (bmi). results: patients were eligible for the study, of which were willing to participate. mean age was . (range: - ), % were female, and mean bmi was . (range: . - . ). only four patients had an ahi < , whereas eleven fulfilled the criteria for an at least moderately severe osas (ahi ≥ ). the ahi was significantly correlated with the bmi (r = . , p < . ) but not with the ess (r = - . , p = . ). a positive airway pressure therapy was indicated in eight patients ( %); five agreed to the therapy ( %). conclusions: according to our data, rates of osas are extraordinarily high in patients after hospitalization due to covid- . this could be an explanation for frequently mentioned symptoms of tiredness and attention deficit. yet, further studies are needed to examine a possible causal association and correlations to other common symptoms, such as cognitive impairment or sleep disturbances. ( %) without sdb, ( %) with predominantly obstructive sleep apnea (osa; ahi = ), and ( %) with predominantly central sleep apnea (csa; ahi = ). osa was associated with male-gender, obesity and overnight fluid-shifts, whereas csa with worse right ventricular end-diastolic diameter. patients with sdb had significantly higher oxygen-desaturation index (odi) and tendency for worse desaturation than those without sdb. after bpa, mean ahi and odi decreased by % (p = . ) and % (p = . ). in osa patients, ahi decreased from to (p = . ) and in csa patients from to (p = . ). along with improvement in sdb, nocturnal desaturation decreased (time-below- % from % to % of time-in-bed, p = . ). conclusions: this is the first study of the effects of bpa on sdb in cteph. we found high prevalence of sdb, both osa and csa, in consecutive subjects underdoing bpa, and report that bpa significantly improved sleep-disordered breathing and nocturnal desaturations. future randomized controlled trials are needed to determine if effective treatment of sdb improves central hemodynamics, morbidity and mortality of patients with cteph. pulmonary rehabilitation following covid- -first short-term results regarding symptoms, quality of life, and psychological burden of disease background: even though many studies have been published on covid- within the last months, little is known about the results of pulmonary rehabilitation (pr) following a severe infection. therefore, the current study examines the changes of wellbeing through inpatient pr after covid- . methods: we surveyed patients at the beginning (t ) and the end (t ) of inpatient pr following hospitalization due to covid- . we assessed respiratory symptoms (dyspnea, cough, and phlegm expectoration) and pain with symptom rating scales, fatigue with the brief fatigue inventory (bfi), quality of life with the euroqol-questionnaire (eq- d-sl), and symptoms of depression and anxiety with the patient health questionnaire (phq-d). results: from the beginning of may until the end of june , patients were eligible, of which patients could be included in the study and completed all t and t assessments (mean age: . ; . % female; . % after invasive ventilation). at t the participants were heavily burdened and dyspnea on exertion was by far the most common and burdensome impairment. over the course of the pr (mean treatment duration: days; range: - days), the data revealed improvements in all mentioned outcomes. dependent samples t-tests revealed statistical significance in all variables, except for pain (p = . ) and phlegm expectoration (p = . ). effect sizes ranged from small (d = . , p < . for dyspnea at rest) to large abstracts background: patients with repaired congenital diaphragmatic hernia (cdh) often suffer from obstructive airway disease. nitrogen multiple breath washout (n -mbw) is a sensitive method to detect ventilation inhomogeneity and peripheral airway pathology with higher sensitivity than conventional spirometry. we set out to obtain detailed information about peripheral airway pathology by n -mbw in addition to conventional lung function testing. methods: we prospectively compared school-aged children following cdh repair and healthy controls using spirometry, body plethysmography and n -mbw. group analyses were made using t-test and mann-whitney-u test, as appropriate. matching criteria included age, gender and level of physical activity. results: (median [iqr] age [ - ] years, f:m = : ) former patients and matched healthy controls ( [ - ] years, f:m = : ) were included. mean lung clearance index (lci) was highly similar in both groups ( . vs. . ; p = . ). slope of conducting airways (scond) was significantly higher ( . vs. . ; p = . ) in cdh patients. fev ( vs. %pred; p = . ), mef ( vs. %pred; p = . ), mef ( vs. %pred; p = . ) and fef - ( vs. %pred; p = . ) were significantly lower in cdh patients. rv ( vs. %pred; p = . ), rv/tlc ratio ( vs. %pred; p = . ) and airway resistance (reff ) ( vs. %pred; p = . ) were significantly higher in cdh patients, whereas there was no significant difference in tlc ( vs. %pred; p = . ) and fvc ( vs. %pred; p = . ). three cdh patients had lci and eight scond values above the upper limit of normal (healthy controls: two and three, respectively). according to conventional lung function testing, / former patients showed an obstructive, none a restrictive pattern and six had normal lung function. fev % correlated significantly positively with mef %, mef % and fef - % and negatively with rv/tlc ratio. conclusions: we found significant airway obstruction in both central and peripheral airways and hyperinflation in patients with congenital diaphragmatic hernia compared to healthy controls. central sleep apnea in pacing-induced cardiomyopathy background: sleep disordered breathing, in particular central sleep apnea (csa) is common in heart failure patients, but its role in pacing induced cardiomyopathy has not been studied yet. in this study entitled upgrade, we set out to evaluate the effect on sleep architecture and sleep disordered breathing in picm patients receiving biventricular pacing. methods: presence of csa was assessed by single-night polysomnography (psg) in picm patients within one month after left ventricular lead implantation (with biventricular stimulation still not activated). csa was diagnosed in half of patients (n = ). patients with moderate or severe csa were randomized to cardiac resynchronisation therapy (crt) versus right ventricular pacing (rvp) in a double-blinded cross-over design and re-scheduled for a follow up psg - months, after repeated assessment of sleep and crossing-over another psg was conducted - months later. results: crt led to a significant increase in left ventricular ejection fraction and significant reduction in left ventricular end systolic volumes and n-terminal pro brain natriuretic peptide plasma levels, whereas no significant effect was observed with ongoing rvp. csa was significantly improved after . ( . - . ) months of crt: apnea hypopnea index (ahi) decreased from . ( . - . ) events per hour at baseline to . /h ( . - . ) by crt (p < . ). central apnea index decreased from . /h ( . - . ) at baseline to . /h ( . - . ) after crt activation (p < . ). ongoing rvp yielded only a minor improvement in ahi and central apnea index. pre-existent csa did not affect structural response rate and had no impact on mid-term follow up (median . years). conclusions: csa is highly prevalent in patients with picm. crt upgrading significantly improves csa leading to a similar outcome in picm patients without pre-existent csa. upgrade is an investigator-initiated independent clinical trial, supported by the Önb jubiläumsfondsprojekt nr. . this study was further supported by an unlimited scientific grant from the boston scientific investigator sponsored research , named severe acute respiratory syndrome coronavirus (sars-cov- ), was observed in wuhan (china) for the first time and subsequently spread rapidly across the globe. the lung is the virus' primary target organ, but many other organs are affected, too. in consequence, therapy focuses on both, pulmonary and systemic symptoms. at present, there is no established pharmacological treatment for covid- available, however, many studies are currently on their way. treatment is based on local (i. e. inhalation) and systemic therapy, often in ventilated patients. prerequisites for inhalation therapy are measures to prevent infection of health care personnel, use of adequate systems for drug administration and compounds suitable for pulmonary delivery. we reviewed publications on covid- treatment for strategies for save inhalation therapy of ventilated/non-ventilated patients and compounds used in clinical studies. strategies for inhalation administration differ in respect of disease severity and use of personnel protective equipment is essential. in mild-disease patients, asthma/copd treatment is preferred by pmdis/dpis, if necessary. jet/mesh nebulizers can be used with mouth pieces/nasal cannulas (no face masks to avoid aerosol spread) and one-way filters/valves. in ventilated patients, mesh nebulizers with filters should be used. physical therapy/suctioning should not be combined with aerosol therapy (avoidance aerosol spread). numerous compounds/biomolecules are under study for inhalation treatment of covid- , e. g. interferons (with/without systemic administration of antivirals, such as ribavirin, lopinavir, ritonavir), sargramostim (gm-csf), aviptadil (synthetic vasoactive intestinal polypeptide), das (recombinant sialidase), pul (immunostimulant, tlr / / agonist), budesonide, nitrogen oxide and hydrogen. in summary, inhalation therapy is important for treatment of pulmonary symptoms of covid- . strategies for pulmonary drug delivery differ in respect to disease severity (e. g. mild symptom patients vs. ventilated patients). various pharmacological compounds/biomolecules are under study. however, up to now there is no established inhalation treatment of covid- . ual basis. recent studies show that hs can improve health even in cf babies. methods: the surveys provide information about acceptance, reason and frequency of - % hs application using a jet or vibrating membrane nebuliser (vmn; eflow®rapid) in children ≤ years. the online questionnaires address healthcare professionals in paediatric cf centres in the uk and german speaking countries (dach). in the uk and in dach paediatric cf centres participated in the survey. from both regions, a total of healthcare professionals responsible for almost cf children ≤ years of age responded. results: secretolysis by hs in children ≤ y is rated excellent, very good, or good by . % in uk and by % in dach. the tolerability is reported excellent to good by . % (uk)/ % (dach). in both surveys approx. % of caregivers declare to use vmn in cf patients ≤ y and less than % in infants ≤ y. caregivers satisfaction regarding the ease of inhalation with vmn in infants ≤ y is rated excellent to good by . % (uk)/ % (dach) and in the group - y by % (uk and dach). conclusions: the results of the survey reveal that in children ≤ years nebulized hs for secretolytic therapy is general practice and well tolerated by this age group. they are consistent with the latest recommendations in the official cf guidelines for children, which confirm the benefits of using hs. in addition, the data also reflect the trend in the uk, where the annual report of the uk cf registry refers that the use of hs in young children is increasing every year. expression patterns of heat shock protein in patients with thymic epithelial tumors regarding the world health organization classification background: thymic epithelial tumors (tets) are rare malignancies with unique association to the paraneoplastic syndrome myasthenia gravis (mg). heat shock protein (hsp ) harbour great potential as cancer biomarker and hsp inhibitors approach clinical cancer therapy. methods: to investigate hsp tissue expression patterns, we analysed tumor tissues of completely resected tet patients (n = ; thymomas and thymic carcinomas (tcs)), regular thymic tissue of six mg patients, and four patients without mg, background: pulmonary hemodynamics during exercise may help to identify early pulmonary vascular disease in systemic sclerosis (ssc). whether they are of prognostic relevance in this subset of patients is unknown. we tested the association between pulmonary heamodynamics at rest and peak exercise with all-cause mortality in patients with ssc. methods: all ssc patients with resting mpap < mm hg and at least -year follow-up data who underwent symptomlimited exercise right heart catheterization between april and december , were analyzed. age-adjusted cox-regression analyses were performed to assess the association between pulmonary hemodynamics and mortality. ]) turned out as age-independent predictors of mortality. in contrast, resting pulmonary hemodynamics (mpap, pulmonary arterial wedge pressure, co, pvr and tpr) were not associated with age-adjusted mortality. conclusions: in this study assessing the prognostic relevance of pulmonary exercise hemodynamics in patients with systemic sclerosis, pvr and tpr at peak exercise as well as mpap/co-slope and tpg/co-slope turned out as age-independent predictors of all-cause mortality. clinical survey with hypertonic saline ( - %) and the eflow®rapid in cf children below years of age mnt: % a: % ab: % b : . % and b : . b : % tc: . %). we detected hsp expression in centroblasts, but not centrocytes, of germinal centres in % of mg patients with fth. all lymphoid follicles of myasthenic patients expressed hsp protein. hassall's corpuscles showed no hsp expression in every tissue sample. we did not detect thymic hsp expression in four patients with regular thymic morphology or five patients with tth. conclusions: hsp expression data propose high potential for hsp as an additional immunohistochemical marker for mnt, who-b thymoma, and tc or as a possible candidate molecule for targeted therapy. caution is warranted in tet patients with mg overexpressing hsp . later-line treatment with lorlatinib in alkand ros -rearrangement-positive nsclc: a retrospective, multicenter analysis background: anti-fibrotic medication is effective in progressive fibrosing interstitial lung diseases (ild), but a subgroup of fibrotic ild patients also benefits from immunomodulatory therapies. additional to high-resolution computed tomography (hrct), blood and broncho-alveolar lavage (bal) biomarkers could help to identify such phenotypes. methods: hrct of subsequent single-center ildboard patients (mean age (standard deviation ) years, % male), were evaluated for radiological findings considered noninflammatory (reticulation including honeycombing (ret), traction bronchiectasis (tbr), emphysema (emp)) or active inflammatory (consolidations (con), ground glass opacities (ggo), noduli (ndl), mosaic attenuation (mos)) in distinct lung regions. each resulting score was further graded as minimal ( - regions involved), medium ( - ) and extensive ( - ). associations between blood and bal biomarkers and radiological finding scores were evaluated using spearman correlation coefficients, kruskal-wallis tests were used for significance testing between the graded subgroups. results: blood neutrophil, lymphocyte and eosinophil fraction, neutrophil-lymphocyte ratio (nlr) and bal lymphocyte fraction consistently showed opposite correlations for inflammatory versus non-inflammatory hrct finding scores. blood lymphocyte fraction significantly differed by the graded extent of ggo (p = . ) and con (p = . ), eosinophil count by tbr (p = . ) and nlr by con (p = . ). c-reactive protein significantly related to ggo (p = . ) and con (p = . ), while ldh showed multiple significant positive associations with ret (p = . ), tbr (p < . ), ggo (p = . ) and mos (p = . ). in bal fluid, lymphocyte fraction had a significant interaction with ggo (p = . ). conclusions: biomarkers from peripheral blood and bal may have the potential to differentiate predominantly noninflammatory or fibrotic from active inflammatory radiological ild patterns. the german severe asthma registry: obesity is associated with asthma parameters abstracts (sgrq-c) was used. furthermore, we asked, independent from each other, the patient as well as the treating physician to estimate the global health status of the patient (excellent, good, fair, poor, very poor). inclusion criteria were a physician's diagnosis of copd and age ≥ years. subjects with a history of lung surgery, lung cancer or copd exacerbation within the last four weeks were excluded. results: pulmonologists and general practitioners participated and enrolled , copd patients. of those patients did not fulfill the gold criteria for copd (fev / fvc ≥ . ) and were excluded due to missing data. finally, patients ( . % men; mean age . ± . (se) years; mean fev %pred. . ± . (se)) were analyzed. in . % of study participants, patients and physicians disagreed on the global health status. in . % it was estimated better by the physician than by the patient (overrated patients), and in . % it was underrated. multivariate regression analysis indicated that overrated patients had a statistically significant better lung function (fev ), less exacerbations and a lower total sgrq-c score compared to underrated patients. conclusions: in stable copd outpatients, treated by pulmonologists and general practitioners, the global health status, most likely indicating the burden of copd, tends to be overestimated by physicians in patients with milder airway obstruction and less exacerbations and underestimated in patients with more severe airway obstruction and frequent exacerbations. this discordant perception of global health might severely affect treatment options. lowering of mean pulmonary artery pressure is a prognostic marker in pulmonary hypertension background: treprostinil (tre), a prostacyclin analog, is effective for the treatment of pulmonary arterial hypertension and non-operable chronic thromboembolic pulmonary hypertension (cteph). we hypothesized that a greater change of hemodynamics is of prognostic value. therefore, we evaluated effects of first-line subcutaneous (sc) tre in patients with severe pulmonary hypertension (ph) and analyzed the prognostic value of hemodynamic response at year on treatment. methods: data was prospectively collected from patients with pre-capillary ph in who functional class iii or iv, mean right atrial pressure of mm hg, and/or cardiac index ≤ . liters/min/m . patients received first-line sctre. dose adjustments were performed individually according to clinical symptoms and side effects. results: between and patients were treated with first-line sctre. all patients were classified as non-lowrisk at baseline ( mwd > , who functional class i or ii, right atrial pressure < mm hg and cardiac index ≥ . l/min/m ). ( %) patients underwent double lung transplantation, and ( . %) died of any cause. overall survival rates at , , , and years were %, %, % and %. the strongest predictor of outcome was change in mpap after one year of sctre. change in mpap - . ± . mm hg (p = . ) was associated with the best subsequent survival of . ± . years. obesity is a risk factor for asthma severity. this study aims to evaluate associations of obesity with severe asthma parameters in the german severe asthma registry including patients ( ± yrs, % female, bmi ± kg/m², % obese (bmi ≥ kg/m²)), treated with anti-ige-and with anti-il (r) antibodies. the same proportion of obese patients received biologics as non-obese patients, but obese patients were more frequently on lama therapy ( % vs. % p = . ), had more exacerbations ( . ± /y vs. . ± /y, p = . ), worse quality of life and more often uncontrolled asthma ( % vs. %, p < . ), as reflected by worse acq ( . ± . vs. . ± . ), act ( ± vs. ± ) and maqlq scores ( . ± . vs. . ± . ; all p < . ). obesity was associated with less blood eosinophils ( % vs. %, p < . ), more neutrophils ( . ± . g/l vs. . ± . g/l, p = . ) and lower lung function parameters: fev ( . ± . l vs. ± . l, p = . ) and fvc ( . ± l vs. . ± l, p < . ). non-obese patients were more often non-smokers ( % in non-obese vs. % in obese, p < . ). conclusions: in our severe asthma cohort, obesity represents a specific phenotype of severe asthma that is significantly associated with exacerbations, worse quality of life, lower blood eosinophil numbers, as well as lower fev , and fvc. discordant perception of global health between copd outpatients and their physicians -real world data from the clara project of pulmonary exercise hemodynamics with all-cause mortality in patients with normal or mildly elevated pulmonary arterial pressure (pap) at rest. methods: patients with unexplained dyspnea and/or suspected pvd undergoing exercise right heart catheter (rhc) at our ph-clinic were retrospectively analysed. exercise rhc was performed in case of a resting mpap < mm hg. in a first step, dichotomized resting-, submaximal-and maximal exercise hemodynamic variables were analysed using multivariate cox regression, adjusted for sex and age, to identify prognostic cut-offs. best cut-off for each variable was defined as the cut-off score with the smallest p-value. in a second step, the relevance of cut-offs, derived from the first model, was assessed using a multivariate model also accounting for age, sex, cardiopulmonary comorbidities, smoking history, and pulmonary resting hemodynamics. results: patients were included ( % female, age: ± yr, mpap: ± mm hg). median observational-time was . yr (iqr: . - . ) with n = ( %) mortality events. mpap/ cardiac ouput (co)-slope, transpulmonary gradient (tpg)/coslope and pulmonary arterial wedge pressure (pawp)/co-slope turned out as sex and age independent predictors of mortality. best cut-offs were found at . mm hg/l/min (mpap/coslope), . mm hg/l/min (tpg/co-slope) and . mm hg/l/ min (pawp/co-slope). in the second model, correcting for age, sex, cardiopulmonary comorbidities, smoking history and pulmonary resting hemodynamics, mpap/co-slope (hr: . , %ci: . - . ; p = . ), tpg/co-slope (hr: . , %ci: . - . ; p = . ) and pawp/co-slope (hr: . , %ci: . - . ; p = . ) remained significant predictors of allcause mortality. conclusions: in patients with normal or mildly elevated pap at rest, pulmonary pressure/co-slopes are predictors of allcause mortality, independent from age, sex, cardiopulmonary comorbidities and resting pulmonary hemodynamics. of the annual average of insured patients . to . % claimed an ao medication. distribution of the age groups - , - , - and > years was . , . , . and . %, respectively. based on diagnoses (hospital and sick leave data), age (< years) and drug patterns an asthma cohort was selected ( % of patients with ao). annual relative prevalence of selected drug groups is presented in fig. . from to the reduction in reliever drugs is associated with an increase in controller medication, in particular, combinations of inhaled corticosteroids (ics) and formoterol (f). subgroup analyses show that this pattern is consistent in differently defined asthma cohorts, not present in a copd cohort and more marked in asthma patients seen by a respiratory specialist. two large studies on the single inhaler treatment (sit) concept were presented and in sit was introduced in the gina report. conclusions: change in asthma treatment recommendation was effectively translated into practice in burgenland. pulmonary pressure/flow slopes during exercise as independent predictors of mortality in patients at risk for pulmonary hypertension philipp douschan* , , vasile foris , , alexander avian , teresa sassmann , , horst olschewski , , gabor kovacs , background: patients with early pulmonary vascular disease (pvd) typically show an abnormal hemodynamic response to exercise. however, it is unknown whether pulmonary exercise hemodynamics are of prognostic relevance in patients with early pvd, independent from pulmonary resting hemodynamics. the aim of this study was to assess the association fig. | p abstracts of extrafine beclomethasone-dipropionate, formoterol-fumarate and glycopyrronium (bdp/ff/ g, trimbow® / / µg) in patients with copd. methods: a prospective, multicenter nis was conducted over weeks in pulmonary and general practices in austria in / . eligible patients with copd had an indication for treatment with bdp/ff/g according to the summary of product characteristics. in addition to tolerability, lung function, exacerbation rate, symptom scores and copd assessment test (cat) were recorded. results: patients (male %, mean age years) with moderate to very severe airflow limitation (gold grade - : . %) and persistent symptoms (gold b: . %, gold d: %) according to the gold report were included. by end of weeks, lung function parameters (fev , fev %, and fvc; p < . ) and symptoms (cough, sputum and shortness of breath; p < . ) improved significantly compared to baseline. a clinically-relevant improvement from baseline in cat score was observed at week and persisted at week in gold b (from . to . points; p < . ) and gold d (from . to . points; p < . ) patients. a significant reduction of moderate and severe exacerbations over the study period was also observed ( . % and . % respectively; p < . ). by end of weeks, . % continued on the treatment. there were adverse reactions reported, of which were non-serious (e. g. oral mycosis) and five were serious, but none of which were deemed drug-related. conclusions: results of this study support the tolerability and effectiveness of bdp/ff/g in patients with copd in a realworld setting. patients treated with extrafine bdp/ff/g experienced an improvement in lung function, symptom control and reduction in exacerbations. tests for diagnostics of covid- -principles and approvals of commercially available tests rüdiger siekmeier* , tanja grammer , winfried märz , , in december an unknown viral infection was firstly described in a local fish and wild animal market in wuhan/ china which was identified as a novel coronavirus infection by the chinese center for disease control and prevention (ccdc) on jan. th and announced as -new coronavirus disease ( -ncov, now covid- ) by the world health organization (who) on feb. th . rapidly spreading across the globe up to begin of august at least million of infections and deaths were reported worldwide. therefore, there was an urgent need of laboratory tests. in our analysis we looked for commercially available covid- tests. at july th at least commercially available tests were described (https:// www. dx.com/coronavirus-test-tracker-launched-covid- -tests). of these, are based on pcr methods (mostly pcr, qpcr) (with federal drug agency (fda; very most) or center of disease control (cdc; few) emergency use authorization background: patients with acute exacerbations of copd do not only suffer from physical symptoms but also from psychological distress and stress. as pharmacological interventions showed only limited effectiveness in targeting the latter, a need for alternative treatment options emerges. in other chronic conditions, mindfulness interventions are effective in reducing psychological distress and stress. however, research on mindfulness interventions in copd is still scarce and not focusing on exacerbations. therefore, the present study reviewed the existing literature and explored the acceptability, feasibility, and implementation of mindfulness interventions focusing on exacerbations in copd patients. methods: firstly, literature examining mindfulness interventions in copd patients was reviewed. secondly, a qualitative and explorative study using semi-structured interviews was conducted. the sample consisted of copd patients ( % women; m = . years, sd = . ) hospitalised after an acute exacerbation. data were analysed using thematic analysis. results: the literature review yielded eight studies, providing preliminary evidence for the feasibility and effectiveness of mindfulness interventions in copd patients. the qualitative analysis revealed five main findings: ( ) patients express an openness and need for new treatment approaches. ( ) mindfulness is difficult to differentiate from other mind-body concepts. ( ) implementation conditions are crucial for patient's interest. ( ) limitations of the application of interventions must be considered. ( ) not interested patients differ from interested ones. conclusions: hospitalized copd patients showed a strong interest in new treatment approaches like mindfulness interventions. focusing on mindfulness interventions during exacerbations seem acceptable and feasible. future studies investigating those are needed and should consider implementation conditions, patients' needs and physical limitations. background: systemic sclerosis is a chronic autoimmune disease characterized by inflammation and tissue remodelling. increases in the expression and of the ap- transcription factor fra- has been shown in the skin of these patients. in mice ectopic overexpression of fra- leads to a systemic sclerosis phenotype, strongly affecting the skin and lung. fra- transgenic mice show pronounced pulmonary inflammation, vascular remodelling and lung fibrosis. although, the role of several immune cells such as macrophages, b and t lymphocytes has been investigated, the contribution of innate lymphoid cells (ilc) to disease pathogenesis remains elusive. the focus of this study was to determine the development and function of ilc and their role in scleroderma. methods: multi-colour flow cytometry was used to evaluate the inflammatory cell landscape in fra- transgenic mice in a time dependent manner. primary cells were isolated and functional assays e. g. apoptosis (caspase activation) and proliferation (ki staining and cell counts) were performed in vitro. results: pronounced changes in the inflammatory profile of the lung were observed in a time dependent manner, with increased numbers of t cells and eosinophils and reduced ilc. similar changes were also reflected in the blood, spleen and liver. isolated ilc exhibited decreased proliferation and functional activity. importantly, reduced numbers and function of ilc was already observed before the first signs of lung fibrosis, as assessed by collagen deposition and lung function measurements. conclusions: this early dysregulation suggests that ilc play an important role in the development of lung fibrosis in scleroderma and restoration of ilc could prevent the progression of the disease. (eua)/with ce-mark/with eua and ce-mark: ( pending)/ / ) serving as gold standard for virus diagnostics after sampling of nasal/throat swabs in acute infection or other molecular methods (isothermal amplification ( / / ), crispr ( / / ), sequencing ( / / ) and others ( / / ). more tests ( / / ) are based on immunological antigen detection of virus peptides after sampling of nasal/throat swabs in acute infection which are typically poct tests based e. g. on immunofluorescence-based lateral flow technology or chromatographic digital immunoassay providing results in a few minutes. tests ( ( pending, revoked)/ / ) allow measurement of immunoglobulines igm, iga and igg alone/in combination in blood samples and provide information on the immune status after convalescence. analytical principles of these are different and some (e. g. lateral flow assays) serve for rapid diagnostics. in summary, number and quality of tests rapidly increased. recent development is based on regulatory guidelines (e. g. https://www.gov.uk/government/publications/how-testsand-testing-kits-for-coronavirus-covid- -work) and includes also combined tests for discrimination against other diseases (e. g. influenza). serum tumor maker dynamics as predictive biomarkers in nsclc chemo-immunotherapy and mono-immunotherapy maintenance -a retrospective cohort study department of pulmonology, johannes kepler university linz, linz, austria objectives: to evaluate serum tumor markers (stm) as biomarkers for treatment, monitoring and prognosis in advanced non-small cell lung cancer (nsclc) treated with chemoimmunotherapy. methods: patients having received platinum-based doublet chemotherapy (cht) and pd- /pd-l -directed immune checkpoint inhibitor (ici) combination therapy were retrospectively followed. carcinoembryonic antigen (cea), carbohydrate antigen - (ca - ), cytokeratin- fragments (cyfra - ) and neuron specific enolase (nse) were routinely measured at nsclc diagnosis. the marker with the highest relative elevation was defined "leading stm", its change was assessed between cht-ici initiation as well as first mono-ici maintenance therapy and the respective subsequent restaging. corresponding computed tomography (ct) evaluations were analyzed according to response evaluation criteria in solid tumors (recist). for both cht-ici and ici-maintenance phase, stm and recist response were evaluated regarding progression-free (pfs) and overall survival (os) in kaplan-meier analyses. results: among cht-ici patients ( % women, mean age years), median pfs was months (m; , ) and median os was m ( ,/). pfs was significantly (p = . ) longer, when stm concomitantly decreased ( m ( , ; n = )) vs. m ( , ; n = ). in the ( . %) patients who received mono-ici maintenance, stm decrease was associated with significantly (p < . ) longer pfs ( m ( ,/; n = ) vs. . m ( , ; n = )). median os was not reached in most subgroups in both treatment phases. patients with radiologically stable or progressive disease and concomitant stm decrease vs. increase had similar pfs in the cht-ici setting ( m ( , ; n = ) vs. . ( , ; n = )), but longer pfs in the mono-ici maintenance setting ( m ( , ; n = ) vs. m ( , ; n = )). employing a retrospective approach, we collected and analyzed data of all patients with advanced non-small-cell lung cancer who received ici monotherapy with atezolizumab, nivolumab or pembrolizumab at the kepler university hospital linz between may and december . kaplan-meier analyses were used to evaluate pfs and os. uni-and multivariate cox-regression analyses were calculated to show the impact of influencing variables. results: of patients, persons died ( . %). regarding to the male patients, died ( . %). for female patients it was out of ( . %). kaplan-meier analyses showed no significant difference for pfs (median length , months, p = . ) or os (median length months, p = . ) between men and women. with regards to gender related predictors of outcome like pd-l expression or ecog-score, we observed considerable differences: pd-l expression could be shown a significant predictor for pfs and ecog status predicted os in men. however, we could not verify any significant predictors for female patients. conclusions: in our retrospective research covering participants, we could not verify the higher chance of survival among male patients, frequently mentioned in previous studies. the finding that we could not verify any significant predictors for female patients shows the necessity for further research in that field especially in women. background: endothelial cells (ec) represent a key cell type in the homeostatic regulation of vascular and lung function, including vasoreactivity, coagulation, immune processes and barrier function. disturbances in ec function have been associated with development and progression of pulmonary hypertension, both in its idiopathic form or associated with interstitial lung disease. however, it is not clear whether these functional changes are associated with altered ec composition. methods: we performed single cell rna sequencing on pulmonary arteries isolated from donors and pulmonary hypertension patients. bioinformatics analysis was conducted to gain unbiased insight into ec heterogeneity at the single cell level. multiplex immunofluorescence staining was combined with confocal imaging of lung tissue samples to assess the spatial heterogeneity of pulmonary artery ec. results: our data revealed that ec in adult human pulmonary arteries are composed of three major populations. each population was characterized by enrichment in a specific set of biological processes determining their distinct functional roles. background: systemic sclerosis (ssc) is an autoimmune disorder leading to fibrosis of skin and other internal organs. one ssc hallmark is severe vasculopathy with impaired vascular permeability and tone as an early disease manifestation. pulmonary complications are the main cause of mortality in patients, but treatment options are still limited. pirfenidone is approved for the treatment of idiopathic pulmonary fibrosis (ipf), however its effectiveness in ssc-pf is still unknown. here, we investigated the effectiveness of pirfenidone in a preclinical ssc-pf model, the fra- transgenic (tg) mouse. methods: fra- tg and wild-type (wt) control mice received either standard or pirfenidone supplemented diet. pulmonary function testing, fibrosis quantification, inflammatory cell profiling of bronchoalveolar lavage (bal) and lung tissue as well as transcriptome analysis of lung homogenates was performed. using in vitro electric cell impedance sensing measurements pirfenidone effects on endothelial cell permeability were analysed. results: compared to wt mice, tg mice had decreased lung function and elevated levels of inflammatory cells in bal and lung. pirfenidone exacerbated this phenotype further by increasing collagen deposition and worsening lung function. these functional and structural changes were associated with significantly higher lung tissue and bal inflammation, characterized by predominant eosinophilic infiltration in pirfenidone-treated tg mice. of note, pirfenidone did not alter lung function, collagen deposition or inflammation in wt mice. transcriptomic profiling indicated the activation of inflammatory cell recruitment and extravasation pathways with significant downregulation of the endothelial cell barrier protein ve-cadherin. further, pirfenidone led to decreased resistance of pulmonary microvascular endothelial cell monolayers in vitro. conclusions: pirfenidone was associated with significant deterioration of lung function and elevated inflammatory infiltrates in the lungs of ssc mice. our study shows that this effect might be due to disturbances of endothelial cell integrity upon pirfenidone treatment especially in diseases with a predisposed vasculature such as ssc. background: there is a growing interest in metabolic profiling of pulmonary arterial hypertension (pah) due to current findings suggesting significant metabolic changes causing pulmonary arterial remodeling and linking pah to insulin resistance. such findings may have major impact on future diagnostic and therapeutic strategies for pah. however, most of the studies have enrolled patients with severe disease whose reduced physical activity may have a profound effect on insulin sensitivity. we aimed to directly measure insulin sensitivity in ipah patients by applying the gold standard method botnia-clamp. methods: we assessed insulin sensitivity in five non-diabetic, normal weight patients with severe idiopathic pah and preserved physical activity in comparison to their age-, sex-, and body composition matched non-diabetic healthy controls. for assessing insulin sensitivity, the hyperinsulinemic-euglycemic (botnia) clamp was performed in a simultaneous pairwise matched-control manner. results: in this study we detected no indication of insulin resistance in patients characterized by manifest ipah but no major limitations in their daily physical activity. both ipah and control groups displayed normal efficacy of glycemic control. the botnia clamp measurements showed no differences in insulin response or insulin sensitivity in any of the ipah patients when compared to their healthy controls and also the comparison of the groups showed no significant differences. in ipah, the whole-body glucose disposal capacity in response to insulin infusion showed the same characteristics as in healthy controls. conclusions: this study does not support insulin resistance to be a primary cause of pulmonary vascular remodeling in ipah. multiplex imaging analysis confirmed in situ relative frequencies of ec populations and revealed their characteristic spatial distribution throughout the pulmonary artery tree. arteries in pulmonary hypertension patients displayed altered composition of ec population characterized by the diminished presence of one cell cluster. conclusions: in this study, we have revealed ec heterogeneity in the human pulmonary arteries at a single cell resolution and uncovered evidence for their distinct functional specification. cellular therapy aimed at restoration of the affected cluster or expression of their key genes could serve as a potential therapeutic option in treatment of pulmonary hypertension. clinical relevance of exercise hemodynamics and right ventricular function in copd patients asthma may have consulted the internet for self-medication advice. methods: on july , we queried google trends for the terms "coronavirus asthma", "-copd", "-hypertension", "-diabetes" and "-cancer", all representing pre-existing conditions constituting a major risk for covid- . when further exploring the health-seeking behavior of patients affected by asthma and/ or copd during the covid- outbreak, we focused on those therapeutic approaches with the highest rsv world-wide and thus comparable. results: we observed highest rsv for "coronavirus asthma" followed by "coronavirus diabetes" and "coronavirus cancer", "coronavirus hypertension" ranked fourth together with "coronavirus copd". paralleling the world-wide covid- outbreak, highest rsv was seen for the topics "salbutamol", "montelukast", "ipratropium bromide", "beclometasone", and "flucticasone propionate", encompassing mainly relievers, followed by inhaled corticosteroids (ics). conclusions: despite other risk factors like hypertension having been largely debated in the media, our analysis revealed highest search volumes for asthma. considering the gina guidelines in which the authors explicitly state that asthma treatment should no longer be based solely on short-acting bronchodilators, our data clearly indicates a fail in reaching asthma patients with respective fundamental changes in therapy. even more alarming is the high search volume for montelukast, since the fda released a boxed warning for montelukast in march because of serious neuropsychiatric side-effects. our findings emphasize the urgent need of spreading guidelines and respective updates in a timely manner more intensively in order to reach the general public-especially in a world with an ongoing, potentially life-threatening pandemic. is there a difference in local disease control between a vats and thoracotomy approach? most studies suggest a similar outcome, but nodal upstaging as a quality parameter is frequently reported to be higher in thoracotomy patients. if more positive lymph nodes are missed by vats, pn in these patients should result in a higher failure rate of local disease control. in this study we analyze the difference of vats to open thoracotomy regarding above mentioned parameters. methods: the institutional database was queried. exclusion criteria were pathologic nodal positive status, metastatic disease, tumour size > cm, adjuvant/neoadjuvant therapy. patients were included. the vats cohort included patients, the thoracotomy cohort patients. results: a vats approach in patients with pathologic n disease did not show a significantly higher rate for local or lymph node recurrence compared to thoracotomy ( . % vs. . %; p = . ). there was no difference in disease-free and overall survival comparing the two groups. comparing the location of recurrence, thoracotomy patients showed a significantly higher rate of metastatic disease ( . % vs. . %; p = . ), beneficial effects of multidisciplinary rehabilitation in post-acute covid- tionnaire related to covid- specific symptoms was filled out by all participants. results: , subjects participated ( , lead participants, , household members). the projected number of cases according to age and sex for vienna is , cases ( . %). the cumulative number of positive tested cases in vienna until may th was , . hence, the projected number is . to . times larger than the observed cases. the relative risk of seropositivity by age was highest for children aged - years [rr . (ci . - . )] and lowest for subjects years and older [rr . (ci . - . )]. half of the infected subjects developed no or mild symptoms. in a multivariate analysis (fig. ) taste and smell disturbances were most strongly related to sars-cov- -specific antibody positivity. the infection probability within households with one confirmed sars-cov- -specific antibody-positive person was %, about times higher than the general ambulatory infection risk. conclusions: prevalence rates in vienna are low ( . %) with the highest seroprevalence in young children and lowest in older (≥ years) inhabitants. taste and smell disturbances are very prevalent in covid- infected persons and can guide clinicians in diagnosis-and decision making of covid- . distribution and prognostic significance of gluconeogenic and glycolytic phenotypes in nonsmall cell lung cancer background: skin prick test (spt) is a minimal invasive diagnostic test, identifying type-i-sensitization, which is associated with symptoms as wheezing, atopic dermatitis and rhinitis. prevalence data vary between countries from . %- . %. data about the prevalence in austria are scarce. moreover, associated factors for positive spt have only been investigated in specific age-(e. g. children or adults only) and subgroups (e.g asthmatics).therefore, our aim was to investigate the prevalence of positive spt in a general austrian population, to define associated factors and compare the prevalence and associated factors between childhood and adulthood. methods: data was obtained from the lead study, an observational, population-based cohort. we included . participants with a valid spt and analyzed two age groups separately: childhood ( - yrs; n = ) and adulthood ( - yrs, n = ). multivariate regression model was used to identify factors associated with positive spt including socioeconomic status, allergic and/or respiratory diseases, lung function, body composition, lifestyle habits, smoking exposure, pet exposure, and family history. results: in our study the overall prevalence of a positive spt is . % and is higher in male compared to female in all age pins (fig. ) . house dust mite and grasses mix are the most prevalent allergens. factors positively associated with positive spt in childhood are doctor's diagnosed allergy or asthma and diagnosed parental allergy; in adulthood are doctor's diagnosed allergy or asthma, diagnosed parental allergy, and high socioeconomic status. smoking (current, former and secondhand) is ally, glycolytic and gluconeogenic gene expression was inferred from the cancer genome atlas (tcga) datasets. results: pck was preferentially expressed in the lung adenocarcinoma subtype, while glut expression was higher in squamous cell carcinoma. glut and pck were inversely correlated, glut showing preferential expression in larger tumors while pck was highest in smaller tumors. however, a mixed phenotype showing the presence of both, glycolytic and gluconeogenic cancer cells was frequent. in lung adenocarcinoma, pck expression was associated with significantly improved overall survival compared to glycolytic or mixed tumors, while the opposite was found for glut . pck / expression was enhanced in metastases compared to primary tumors. the metabolic tumor microenvironment and the -dimensional context play an important role in modulating both pathways, since pck expression preferentially occurred at the tumor margin and hypoxia differentially regulated glycolysis and gluconeogenesis in nsclc cells in vitro. conclusions: glycolysis and gluconeogenesis are activated in nsclc in a tumor size and oxygenation dependent manner and show a differential correlation with outcome. the frequent co-activation of gluconeogenesis and glycolysis in nsclc should be considered in potential future therapeutic strategies targeting cancer cell metabolism. abstracts assays showed significantly reduced migration of rgs -/-neutrophils towards chemokines with preserved intra-cellular calcium signaling. importantly, the attenuated neutrophil migration was associated with activated rhoa, suggesting rhoa as a predominant negative regulator of neutrophil transmigration. conclusions: our findings demonstrate the efficacy of silenced rgs for suppressing neutrophilic hyperinflammation in two different animal models. the specific effects of rgs loss might provide an option for a novel therapeutic intervention in inflammatory lung diseases with recurrent exacerbations, without compromising infection defense mechanisms. endothelial dysfunction following enhanced tmem a activity in human pulmonary arteries background: endothelial dysfunction is one of the hallmarks of different vascular diseases, including pulmonary arterial hypertension (pah). ion channelome changes have long been connected to vascular remodelling in pah, yet only recently the focus shifted towards ca +-activated cl-channels (cacc). the most prominent member of the cacc tmem a has been shown to contribute to the pathogenesis of idiopathic pah (ipah) in pulmonary arterial smooth muscle cells, however its role in the homeostasis of healthy human pulmonary arterial endothelial cells (paecs) and in the development of endothelial dysfunction remains underrepresented. methods: using healthy donor (n = ) and ipah (n = ) lungs, we analysed the expression of tmem a in primary human paecs. ipah was mimicked with selective adenoviral overexpression encoding tmem a tagged with mcherry. tmem a activity was investigated by patch clamp. live cell ca + imaging was applied to detect changes in ca + homeostasis. paec proliferation, apoptosis, tube-formation, wound healing assay, no production and measurements of paecs metabolic state addressed functional consequences of increased tmem a activity. the role of endothelial tmem a in the tone of pulmonary arteries ex vivo was investigated by wire myography. results: here we report enhanced tmem a activity in ipah paecs. upon tmem a overexpression in healthy primary human paecs in vitro and in human pulmonary arteries negatively associated with positive spt in adulthood, but not in childhood. conclusions: our study in an austrian general population identified that . positive spt is highly prevalent, . is more prevalent in male, . the main allergens observed are grasses mix and house dust mite, and . there is a difference in factors associated with spt in childhood vs adulthood. neutrophil recruitment in the acute inflammatory phase of interstitial lung disease is determined by rgs methods: data was obtained from the austrian lead study, an observational, population-based cohort study. adults aged - years with valid lf and metabolic data, including waist circumference (wc) for central obesity, and dxa scan for vat (n = . ) were included in this analysis. lf was assessed by spirometry pre-and post-bronchodilation (bd). abnormal lf was defined as fev pre bd<lln (gli) and further divided into obstructive (fev pre<lln + fev /fvc post<lln) and restrictive (fev pre<lln + fev /fvc post≥lln + fvc post<lln) pattern. regression models were performed analysing the association between mets components (idf ) and abnormal, obstructive, and restrictive lf pattern (corrected for age, sex, smoking status). results: fig. shows odds ratios of mets components and vat associated with impaired lf pattern. increased vat was associated with both, obstructive (or . [ . - . ]) and restrictive (or . [ . - . ]) lf pattern, while increased wc was not. conclusions: vat showed a consistent association with lf impairment independent of the type of impairment, in contrast to the different components of the mets. in december an unknown viral infection was firstly described in a local fish/animal market in wuhan/china. it was identified as a novel coronavirus infection by the chinese center for disease control and prevention (ccdc) on jan. th and announced as -new coronavirus disease ( -ncov, now covid- ) by the world health organization (who) on feb. th . the disease rapidly spreads across the globe (begin of august at least million of infections and deaths reported worldwide) and until now no specific treatment has been described. therefore, measures for disease prevention (e. g. vaccines, rapid testing, control of viral transmission by masks/face shields, gloves, digital monitoring/social ex vivo, we demonstrate the functional consequences of the augmented tmem a activity: alterations of ca + dynamics and enos activity as well as decreased no production, paecs proliferation, wound healing, tube-formation and acetylcholine-mediated relaxation of human pulmonary arteries. we propose, that erk / pathway is specifically affected by elevated tmem a activity, leading to these pathological changes. conclusions: with this work we introduce increased tmem a activity in the outer cell membrane of human paecs important for the development of endothelial dysfunction in ipah. metabolic syndrome and visceral adipose tissue (vat) are associated with obstructive and restrictive lung function impairment background: malignant pleural mesothelioma (mpm) is a highly aggressive tumor with dismal outcome and thus, investigating reproducible pretreatment parameters to assess benefit from treatment modalities and to estimate survival is of outmost importance. this study aims to identify potential serum prognostic biomarkers in a large retrospective cohort of a high-volume institution. methods: we performed a retrospective analysis of the clinical records, serum parameters at diagnosis, and longterm outcome of patients with pathologically diagnosed mpm between and . previously published prognostic serum biomarkers were tested and validated and, in consequence, the prognostic value of an inflammatory serum marker score (vmis-vienna mesothelioma inflammation score) was investigated. results: in total, patients ( male, . %) were included. median age was years (iqr - ). median overall survival (os) for all cases was months ( % ci; . - . ). survival was % at year, % at years, and % at years. median os and disease-free survival (dfs) of patients undergoing multimodality treatment including surgery was months ( % ci; . - . ) and months ( % ci; . - . ), respectively. the optimal cut-off values for pretreatment neutrophil-to-lymphocyte ratio (nlr), serum fibrinogen and crp were . , . mg/dl and . mg/dl, respectively. univariate analysis revealed that age (p = . ), ecog status (p = . ), tumor stage (p = . ), histologic subtype (p = . ), type of treatment (p < . ), nlr (p < . ), fibrinogen (p < . ) and crp (p < . ) were significantly associated with os. accordingly, the vmis (consisting of pretreatment nlr, fibrinogen and crp) was highly associated with os (score vs. , hr . , p = . ; score vs , hr . , p < . ). in multivariate analysis, vmis (p = . ), histologic subtype (p = . ), and the type of treatment (p = . ) were independently associated with os. conclusions: vmis was found to be an independent prognostic score in mpm helping to stratify patients into different treatment groups. methods: we performed a retrospective analysis of all inpatients aged < years, who were admitted to our department between january and december for suspected or confirmed tuberculosis (tb) infection, for the presence of otb. results: we were able to identify four paediatric cases with otb (cohort: inpatients, . %) (fig. ) . three patients suffered from posterior ( fig. ) and one from anterior uveitis associated with tb. two patients were diagnosed with pulmonary ultra wide-field fundus photography of the right eye shows two (one at the temporal inferior and one at the nasal superior vessel arcades) yellowish choroidal granulomas with ill-defined borders and substrantial elevation. there seems to be a serous retinal detachment around the granulomas (case # ) abstracts tb after being referred by the ophthalmologist, the remaining showed ocular involvement in the setting of disseminated tb. all patients were treated with systemic corticosteroids and anti-tuberculosis therapy (att). patients received topical steroids additionally, one of whom (case # ) also received steroids intravitreally once for persisting macular oedema. visual acuity remained normal in two patients. conclusions: despite a higher incidence of extrapulmonary tb in the paediatric age group in general ( ), otb was uncommon in our cohort. when disseminated disease is suspected or ocular symptoms are noted in paediatric tb patients, a detailed ophthalmological examination is imperative. lung transplantation for acute respiratory distress syndrome patients: a single center experience background: acute respiratory distress syndrome (ards) is a rapidly progressive lung disease with a high mortality rate. although lung transplantation (ltx) remains the only lifesaving option for certain end-stage pulmonary diseases, ards as indication for ltx is discussed controversially and only limited data are available. for example, in the eurotransplant region, only patients transplanted for ards are documented. since we have followed a liberal approach of accepting ards patients for ltx, we reviewed retrospectively the outcome of this particular patient cohort in our center. methods: from / to / at total of patients transplanted for ards were identified. demographic and clinical data of these patients were collected and analysed. results: eight/ patients were listed and transplanted while on extracorporeal membrane oxygenation (ecmo). the remaining patients could be initially successfully weaned from ecmo but remained respirator dependent. the median mechanical ventilation time and median length of ecmo was . ( . - . ) and . ( - ) days before ltx. primary graft dysfunction (pgd) grades at hrs were % (n = ), two patients were classified as pgd ungradable (due to prophylactically prolonged ecmo). length of icu and hospital stay was ( . - ) and ( . - ) days. the -day mortality was % and -year survival rate was calculated as . % (fig. ) . one patient developed chronic lung allograft dysfunction (clad) and received re-transplantation years after the primary procedure. the median follow up time was ( . - ) days. conclusions: lung transplantation is feasible in carefully selected ards patients. given the lack of alternative treatment options it provides acceptable long-term results. investigating prognosis in malignant pleural mesothelioma: the vienna mesothelioma inflammation score (vmis) including pretreatment neutrophil-to-lymphocyte ratio, fibrinogen, and crp is independently associated with overall survival background: malignant pleural mesothelioma (mpm) is a highly aggressive tumor with dismal outcome and thus, investigating reproducible pretreatment parameters to assess benefit from treatment modalities and to estimate survival is of outmost importance. this study aims to identify potential serum prognostic biomarkers in a large retrospective cohort of a high-volume institution. methods: we performed a retrospective analysis of the clinical records, serum parameters at diagnosis, and longterm outcome of patients with pathologically diagnosed mpm between and . previously published prognostic serum biomarkers were tested and validated and, in consequence, the prognostic value of an inflammatory serum marker score (vmis-vienna mesothelioma inflammation score) was investigated. results: in total, patients ( male, . %) were included. median age was years (iqr - ). median overall survival (os) for all cases was months ( % ci; . - . ). survival was % at year, % at years, and % at years. median os and disease free survival (dfs) of patients undergoing multimodality treatment including surgery was months ( % ci; . - . ) and months ( % ci; . - . ), respectively. the optimal cut-off values for pretreatment neutrophil-to-lymphocyte ratio (nlr), serum fibrinogen and crp were . , . mg/dl and . mg/dl, respectively. univariate analysis revealed that age (p = . ), ecog status (p = . ), tumor stage (p = . ), histologic subtype (p = . ), type of treatment (p < . ), nlr (p < . ), fibrinogen (p < . ) and crp (p < . ) were significantly associated with os. accordingly, the vmis (consisting of pretreatment nlr, fibrinogen and crp) was highly associated with os (score vs. , hr . , fig. | v survival curve from - (n = ) abstracts Ögp p = . ; score vs , hr . , p < . ). in multivariate analysis, vmis (p = . ), histologic subtype (p = . ), and the type of treatment (p = . ) were independently associated with os. conclusions: vmis was found to be an independent prognostic score in mpm helping to stratify patients into different treatment groups. surgical management and risk analysis of primary malignant pulmonary and chest wall sarcomasretrospective results from a high-volume center katharina sinn , berta mosleh , richard hritcu , györgy lang , jose matilla , konrad hoetzenecker , shahrokh taghavi , walter klepetko , thomas klikovits , mir alireza hoda Ögp background: postoperative pain management after videoassisted thoracoscopic surgery (vats) is still a heavily debated topic, which may affect patients' pain, need of opioids, and postoperative length of stay (los). this study aims to analyse the effects of an additional intercostal catheter (icc) in comparison to a single shot intraoperative intercostal nerve block (ssinb) alone. methods: all patients receiving an anatomic vats resection from / - / were analysed. icc placement at our department was initiated in september . patients with misplacement of the icc were analysed in the ssinb group. exclusion criteria for analysis was a prolonged los because of postoperative complications not related to pain-management protocol (one hiatal hernia with oesophageal perforation, one hematologic comorbidity requiring further workup). the icc cohort included patients, the ssinb cohort patients. results: pain scores on the first postoperative day, after chest drain removal and highest pain score measured did not differ between the two groups (p = . / . / . ). in four patients ( . %), icc showed a primary non-function. the overall amount of opioids (piritramide, . mg vs. . mg; p = . ) as well as the duration of opioid usage ( . days vs. . days; p = . ) was significantly less in the icc cohort. the icc cohort showed a significantly shorter postoperative los of . (mean, range - ) days in comparison to . (mean, range - ) days (p = . ). chest drain duration was significantly shorter in the icc cohort ( . days vs. . days; p = . ). there was no difference in comorbidities (coronary artery disease, diabetes mellitus, copd; p = . / . / . ), age, gender or postoperative complications (p = . / . / . ). conclusions: pain management with icc reduces the amount of opioids and number of days with opioids patients' require to achieve sufficient analgesia while at the same time reduces the postoperative los and chest drain duration. in conclusion, icc is an effective tool in postoperative pain management. analysis of pain management after anatomic vats resection in austrian thoracic surgery departments persistent symptoms in patients after acute covid- covid- and obstructive sleep apnea sars-cov- -specific antibody seroprevalence in a general population -the viennese lead covid- study background: pulmonary hypertension (ph) is a frequent complication of copd and is associated with poor survival. however, pulmonary and right ventricular hemodynamics and their association with physical capacity in copd patients with out-of-proportion dyspnea is unknown. in this study we hypothesized that copd patients show abnormal hemodynamics during exercise, associated with impaired exercise capacity.methods: out of outpatients with unexplained dyspnea, copd patients with mpap < mm hg and age and sex matched controls without copd and mpap < mm hg, who underwent right heart catheterization at rest and during symptom-limited ergometer exercise, were compared.results: we analyzed copd patients ( ± yr, fev : ± %) and controls ( ± yr, fev : ± %). in copd, resting mpap and pvr were slightly elevated (median: (iqr: - ) vs. ( - ) mm hg, p = . and . ( . - . ) vs. . ( . - . ) wu, p = . ). at peak exercise, mpap and pvr were markedly elevated ( ( - ) vs. ( - ) mm hg, p = . and . ( . - . ) vs. . ( . - . ) wu, p = . ), whereas pulmonary vascular compliance (pvc) and right ventricular output reserve ( . ( . - . ) vs. . ( . - . ) mm hg, p = . and ( . ( . - . ) vs. . ( . - . ) ml/mm hg, p = . ) were significantly reduced. mpap/co-slope ( . ( . - . ) vs. . ( . - . ) mm hg/l/min, p = . ) and transpulmonary gradient (tpg)/co-slope ( . ( . - . ) vs. . ( . - . ) mm hg/l/ min, p = . ) were significantly steeper in copd. compared to controls, copd patients had worse exercise performance (peak oxygen uptake (vo ) ( ( - ) vs. ( - ) %predicted, p < . ). moreover, peak vo was significantly correlated with peak exercise mpap (p = . , r = - . ), pvr (p = . , r = - . ), pvc (p = . , r = . ), pulmonary arterial stiffness index (p < . , r = - . ), rv output reserve (p = . , r = . ), mpap/co-slope (p = . , r = - . ) and tpg/coslope (p = . , r = - . ).conclusions: in copd, pulmonary and right ventricular hemodynamics are markedly changed as compared to patients without copd. these findings are strongly associated with exer-abstracts backgroud: the corona virus disease (covid- ) pandemic increases the demand for post-acute care in patients after a severe disease course. various longterm sequelae are expected and physical and rehabilitation medicine (prm) is challenged to support the recovery both physically and mentally. the aim of this study was to explore dysfunctions and outcome of covid- survivors after early post-acute rehabilitation.methods: this study analysed the rehabilitative outcomes of a subgroup of patients included in a prospective observational multicenter study to investigate long-term sequelae in patients hospitalized for sars-cov- infection.results: a total of subjects discharged after severe to critical covid- infection underwent an individualized, multiprofessional treatment plan. despite a high proportion of patients requiring mechanical ventilation with consequent symptoms of post intensive care syndrome, indices of performance status and pulmonary parameters improved significantly.conclusions: covid- survivors show varying degrees of physical and psychological dysfunctions in the early period of recovery after hospital discharge. in this phase, patients strikingly benefit from multidiscinplinary inpatient rehabilitation, but the course of residual impairments remains unclear. assessing self-medication for obstructive airway disease during covid- using google trends background: inhibition of glycolysis has been considered as a therapeutic approach in aggressive cancers including lung cancer. abbreviated gluconeogenesis, mediated by phosphoenolpyruvate carboxykinase (pepck), was recently discovered to partially circumvent the need for glycolysis in lung cancer cells. however, the interplay of glycolysis and gluconeogenesis in lung cancer is still poorly understood.methods: we analyzed the expression of glut , the prime glucose transporter, and of pck and pck , the cytoplasmic and mitochondrial isoforms of pepck, in samples of nonsmall cell lung cancer (nsclc) and in nsclc metastases using tissue microarrays and whole tumor sections. spatial distribution was assessed by automated image analysis. addition-most likely due to a longer follow-up time. other clinical factors did not differ between groups.conclusions: vats lobectomy does not result in a higher rate of local disease recurrence, suggesting adequate lymph node dissection with this approach. other factors than the surgical technique might be responsible for nodal upstaging, therefore nodal upstaging should no longer be used as a quality marker for lymph node dissection.background: acute exacerbation of interstitial lung disease (ild) is associated with a poor prognosis and high mortality. the regulator of g protein signaling (rgs ) is present in the lung as well as in neutrophils. however, the potential of rgs to limit neutrophilic hyperinflammation and thus disease progression in acute exacerbation has not been explored so far.methods: to investigate the functional relevance of rgs invivo, we examined the acute inflammatory bleomycin response phase of pulmonary fibrosis utilizing rgs knock out (rgs -/-) and wild type (wt) mice at age - weeks (equivalent to adult age in humans). the lipopolysaccharide (lps)-induced acute lung injury model was used as a second model. the in-vivo studies were extended with analysis of the chemokine levels in the lung, the migratory behavior of the neutrophils obtained from wt and rgs -/-animals and the downstream pathways in-vitro.results: in the acute phase of pulmonary fibrosis, rgs -/mice had preserved lung function as compared with wt mice which showed significant combined ventilatory disorders. analysis of specific immune cell subpopulations in bronchoalveolar lavage fluid (balf) and lung tissue showed a significant attenuation in the total cell number in the balf of rgs -/-animals, predominantly made up of neutrophils and lowered myeloperoxidase (mpo) enzymatic activity in lung tissue. a similar picture was seen in the lps lung injury model. our in-vitro abstracts background: cystic fibrosis (cf) leads to airway colonisation with pathogens. the significance of colonisation with fungi is not entirely clear, and epidemiological data regarding colonisation with fungi are somewhat contradictory. candida albicans and aspergillus fumigatus have been most frequently reported, with colonisation rates between - % and - %, respectively.methods: we analysed results of sputum cultures from paediatric and adult patients of our centre taken between and . modified culture methods had been used for fungal cultures. to determine chronic colonisation we applied modified leeds criteria.results: , sputum specimens from patients were analysed. of , isolated pathogens, , ( . %) were fungi cultivated from , / , specimens ( . %). / ( . %) patients were at least colonised once. colonisation rates with fungi did not change significantly between ( / ; . %) and ( / ; . %). some species seem to be associated with chronic colonisation while others do not (fig. ) .conclusions: almost all patients showed colonisation with one or more fungi. the proportions of patients already colonised in childhood and over many years were very high. some species were detected at much higher rates than previously reported. these differences are more likely due to culture methods and the long observation period than to differences in cohorts. adequate culturing methods are crucial to study the impact of fungal-colonisation in cf patients.contact tracing (apps)) are of great importance. we analysed a rapidly increasing number of publications investigating virus transmission by aerosols and the role of masks/shields for prevention. in brief, infectious aerosols are produced by coughing, sneezing, speaking and even normal breathing of infected individuals demonstrating the role of the lung as an "aerosol generator". in aerosol the virus is stable for hours and coughing/sneezing in contrast to normal breathing can transport aerosol for a distance of about meters. half lifetimes of viable virus are h (aerosol, copper-surface), h (cardboard) and h (plastic-surface) underlining the need of masks/shields and adequate disinfection. a major number of professional masks/ face-shields were developed, e. g. n mask, surgical mask, face-fitting mask, mit face shield differing strongly in respect to their properties for filtering and infection prevention; however, comparative head-to-head studies are missing. in summary, masks/face shields play an important role for prevention of covid- infection. however, there are differences in respect to type of the masks/face shields and their indication for use, e. g. general population, health care workers and the use should be combined with other methods of disease prevention. airway colonisation with fungi in cystic fibrosis patients results: patients with a median age of years were identified. the most common histology was ewing-sarcoma (n = , %). ( %) patients underwent neoadjuvant therapy ( % cht, . % rt, . % immunotherapy). median tumor size at diagnosis was . cm (range, to cm). extended resection was necessary in % (n = ), intraoperative use of ecmo in patient. postoperative complications were observed in patients ( %). adjuvant therapy was administered in ( %) patients ( . % cht, . % rt, % chrt). -day mortality was . %. there was no significant difference in overall survival (os) or disease free survival (dfs) between ps and cws (p = . and p = . ) or in type of histology (ewing sarcoma vs others, p = . and p = . ). -year os and dfs were % and %, median os was not reached. median dfs was . months. patients requiring extended resection (> involved anatomical structures) had a trend for impaired os (hr . , p = . ) and significantly worse dfs (hr . , p = . ).conclusions: radical resection of primary malignant ps and cws offers good long-term outcome with low complication rate despite extended resections. however, extent of disease and subsequent necessity for extended resection is an unfavorable factor for long-term survival. background: the ests eurolung scores were established to predict postoperative morbidity and mortality in patients undergoing anatomic lung resections. since its introduction, the eurolung scores have been updated once and an easy-touse and free-of-charge smart phone app has been created. so far, the scores have not been validated in other patient cohorts. herein we aimed to elaborate the accuracy of the various eurolung scores in our vats cohort. methods: the eurolung scores were calculated for a consecutive cohort of patients scheduled for vats lobectomy. postoperative complications, as defined and used by the eurolung scores, were then analyzed in this prospectively maintained database.results: overall, the observed complication rate was . % in the vats lobectomy database. the eurolung predicted a mean risk of morbidity of . % with a weak eta correlation (η) (eurolung : η = . ; parsimonious eurolung : η = . ; parsimonious eurolung : η = . ). a better coherence was observed with the parsimonious eurolung ( ; . %) and the current parsimonious eurolung ( ; . %). binary logistic regression analysis of the included parameters showed that extended resections and ppofev % were associated with increased complications in the eurolung scores. -day mortality was . % (predicted mortality according to eurolung : . %, parsimonious eurolung : . %) and was associated with ppofev % for both scores and coronary artery disease for the eurolung score only. the eurolung showed a larger area under the roc curve than the parsimonious eurolung ( . vs. . ). again, only a very weak eta correlation between predicted and observed mortality was found for the eurolung (η = . ) and the parsimonious eurolung ( ) (η < . ).conclusions: even though predicted and observed morbidity/mortality rates were comparable in our cohort the scores were not useful to predict the individual risk in this vats cohort. therefore, the scores should not be used to permit or refuse surgical therapy. initial experience with intercostal catheter for postoperative pain management in vats background: postoperative pain and its management influences patients' rehabilitation, postoperative complications and quality of life. despite its impact there are no uniform guidelines. different centers seem to use various strategies for pain management. in this study we aim to analyze pain management regimens after vats lobectomy used in austrian thoracic surgery units with a special interest in opioid usage and strategies to avoid opioids.methods: a questionnaire was designed to assess the current use of regional anesthesia, post-operative pain medication and characteristics of individual pain management regimens. the questionnaire was sent to all thoracic surgery units in austria, with nine out of twelve departments returning them.results: pain management varied between all centers. all departments use regional anesthesia perioperatively. four out of centers use epidural analgesia or an intercostal catheter for postoperative regional anesthesia in at least % of patients. two departments follow an opioid restrictive regimen, depending on visual analogue scale (vas) and two administer opioids on a fixed schedule. three out of departments use nsaids on a fixed schedule. the most used medication is metamizole ( out of centers; on a fixed schedule, two depending on vas) followed by piritramid ( out of centers; none as a fixed prescription). all centers reported that their regimen is standardized (with centers basing it on an in-house standard) and all assessed their patients pain scores on a regular basis.conclusions: there is no standardized postoperative pain management regimen after anatomic vats resections. there seems to be a trend towards prolonged postoperative regional anesthesia to reduce opioid consumption in some centers. a further prospective study is in preparation to evaluate the feasibility of opioid-free postoperative pain management and its impact on quality of life. perioperative mortality and morbidity following pneumonectomy for severe inflammatory disease of the lung background: some cases of severe pulmonary inflammation are not amenable to conservative treatment. if pneumonectomy is required in highly septic and instable patients the inherent risk of the procedure increases further. in a retrospective study we analysed these patients comparing them to elective pneumonectomy in patients with malignant disease.methods: during the last years patients (age: . +/- . years; males: , females ) underwent pneumonectomy. of these cases had underlying severe inflammatory disease (central necrotizing abscess or pulmonary gangrene with accompanying empyema) whereas had resection for malignant tumours. abstracts results: the inflammatory group was significantly younger ( . +/- . vs. . +/- . years; p = . ) and had a significantly lower bmi ( . +/- vs. . +/- . ; p = . ) than the malignant group. there were no differences concerning cigarette or alcohol consumption or copd, coronary artery disease or peripheral arterial occlusive disease. both the rate of severe perioperative complications ( . % vs. . %) and of perioperative death ( . % vs. . %) were significantly higher in patients with inflammatory disease (p = . ). in spite of the high perioperative mortality rate of pneumonectomy in inflammatory disease, -years survival rate ( . % vs. . %) showed no statistically significant difference between the two groups.conclusions: though sometimes required as a life-saving procedure in severe inflammation of the lung, pneumonectomy in such conditions carries a high perioperative morbidity and mortality. if the first months after pneumonectomy are survived however, the prognosis of this subgroup is fair. problem at the pneumonectomy stump. salvage by myoplastic closure background: for primary closure when material is lacking and for the treatment of bronchial stump dehiscence following pneumonectomy a variety of methods such as pericardial or omental flap as well as myoplastic techniques have been advocated. we present our experience with myoplasty for closure of the main bronchus stump.methods: retrospective analysis of pneumonectomies within the last years (age: . +/- . years; males: , females ). in patients ( . %) problems at the bronchial stump were present ( on the right and on the left side), thereof primary impossibilities of direct closure and secondary dehiscences.results: in one case dehiscence occurred one day after pneumonectomy, in the remaining patients dehiscence became evident after a mean of . days ( - days). the impossibilities of direct closure of the stump derived from necrosis and fistula following bifurcational stenting in lung cancer, from lack of viable bronchial tissue during completion pneumonectomy following left-sided sleeve resection and from bronchial necrosis in aspergillosis. closure of the stump was done by pedicled pectoralis major flap in , by pedicled diaphragmatic flap in and by pedicled sternoleidomastoideus flap in one patient. if deemed necessary, second-look procedures and/or thoracostomy and vac were additionally used. one patient did not survive his septic condition and died within days ( . %). the overall years survival rate was %.conclusions: pedicled myoplastic flaps provide reliable closure even in detrimental cases of dehiscence of the main bronchus stump.publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. key: cord- - rupk u authors: van rijn, anneloes l.; van boheemen, sander; sidorov, igor; carbo, ellen c.; pappas, nikos; mei, hailiang; feltkamp, mariet; aanerud, marianne; bakke, per; claas, eric c. j.; eagan, tomas m.; hiemstra, pieter s.; kroes, aloys c. m.; de vries, jutte j. c. title: the respiratory virome and exacerbations in patients with chronic obstructive pulmonary disease date: - - journal: plos one doi: . /journal.pone. sha: doc_id: cord_uid: rupk u introduction: exacerbations are major contributors to morbidity and mortality in patients with chronic obstructive pulmonary disease (copd), and respiratory bacterial and viral infections are an important trigger. however, using conventional diagnostic techniques, a causative agent is not always found. metagenomic next-generation sequencing (mngs) allows analysis of the complete virome, but has not yet been applied in copd exacerbations. objectives: to study the respiratory virome in nasopharyngeal samples during copd exacerbations using mngs. study design: nasopharyngeal swabs from patients from the bergen copd exacerbation study ( – ) were analysed by mngs and in-house qpcr for respiratory viruses. both dna and rna were sequenced simultaneously using an illumina library preparation protocol with in-house adaptations. results: by mngs, / samples tested positive. sensitivity and specificity, as compared with pcr, were % and % for diagnostic targets ( / and / , respectively). additional viral pathogens detected by mngs were herpes simplex virus type and coronavirus oc . a positive correlation was found between cq value and mngs viral normalized species reads (log value) (p = . ). patients with viral pathogens had lower percentages of bacteriophages (p< . ). no correlation was found between viral reads and clinical markers. conclusions: the mngs protocol used was highly sensitive and specific for semi-quantitative detection of respiratory viruses. excellent negative predictive value implicates the power of mngs to exclude any pathogenic respiratory viral infectious cause in one test, with consequences for clinical decision making. reduced abundance of bacteriophages in copd patients with viral pathogens implicates skewing of the virome during infection, with potential consequences for the bacterial populations, during infection. a a a a a chronic obstructive pulmonary disease (copd) is characterized by exacerbations with high morbidity and mortality, and over million patients suffer from this disease worldwide [ ] . a copd exacerbation is an acute event leading to worsening of the respiratory symptoms and is associated with a deterioration of lung function [ ] . exacerbations are mainly associated with infections, of which a large part is caused by viruses ( - %) [ ] [ ] [ ] [ ] . however, in part of the exacerbations an etiologic agent is not detected. current routine virus diagnostics is based on polymerase chain reactions (pcr) and inherently the number of detectable pathogens is restricted to the ones included in the assay. rare, mutated and pathogens with an uncommon clinical presentation will be missed, along with new and currently unknown ones. over the last decades, several previously unidentified viruses have been discovered as respiratory pathogens, including metapneumovirus [ ] , middle-east respiratory syndrome coronavirus [ ] and human bocavirus [ ] . metagenomic next generation sequencing (mngs) is an innovative method, which enables the detection of all genomes in a given sample. proof of principle studies have shown that mngs on respiratory samples can confirm and extend pcr results and deliver typing and resistance data at the same time [ ] [ ] [ ] [ ] [ ] . the performance of mngs in the clinical diagnostic setting, especially the positive and negative predictive value, has not yet been elucidated and is likely to differ per clinical syndrome and sample. previous data from reports on s rrna analysis from the respiratory tract have led to increased insight in the microbiome in patients with copd [ ] . changes in bacterial populations have been associated with exacerbation events and clinical phenotypes [ ] . however, these studies are intrinsically limited to analysis of the bacterial part of the microbiome. so far only a few studies using shotgun metagenomics have focussed on the respiratory virome in children with acute respiratory infections [ , ] . in this study, we analyse the composition of the virome in adult patients with exacerbations of copd. the aim of this study was to correlate the respiratory virome in copd patients as found by mngs with qpcr and clinical data. patients with copd were included in the bergen copd exacerbation study (bces) between and in bergen, norway [ ] . all patients lived in the haukeland university hospital district. baseline data taken during the first visit while in the stable state included amongst others exacerbation history, medications, comorbidities, spirometry and global initiative for chronic obstructive lung disease (gold ) categorisation. patients were given a telephone number to a study nurse, whom they would contact in case of an exacerbation. patients with an exacerbation according to a predefined set of symptoms were scheduled for an appointment with a study physician the next working day. during exacerbations, nasopharynx swabs were sampled and two different markers for the severity of the exacerbation were scored. after an exacerbation a control visit was scheduled. during the study period patients had at least one exacerbation and in total exacerbations were included in bces, of which exacerbation samples were tested in the current study. nasopharyngeal samples were frozen and stored at - ˚c. in total nasopharyngeal samples of patients at the time of exacerbation were selected based on the availability of other samples (outside the current focus) and sent to the leiden university medical center (the netherlands) for further testing. the viral respiratory panel covered by the multiplex real-time pcr (qpcr) developed in our laboratory consists of coronavirus e, coronavirus hku , coronavirus nl , coronavirus oc , influenza a, influenza b, human metapneumovirus, parainfluenza - (differentiation with probes), respiratory syncytial virus, and rhinovirus [ ] . total nucleic acids (na) were extracted directly from μl clinical sample, using the total nucleic acid extraction kit on the magnapure lc system (roche diagnostics, almere, the netherlands) with μl output eluate. nucleic acid amplification and detection by real-time pcr was performed on a biorad cfx thermocycler, using primers, probes and conditions as described previously [ ] . cq values were normalized using a fixed baseline fluorescence threshold. the metagenomics protocol used has been described and optimized for simultaneously rna and dna detection previously [ ] . in short, internal controls, equine arteritis virus (eav) for rna and phocid herpesvirus- (phhv) for dna (kindly provided by prof. dr. h.g.m. niesters, the netherlands), were spiked in μl of the virus transport medium in which the nasopharyngeal swab was stored. nucleic acids were extracted directly from μl clinical sample using the magnapure dna and viral na small volume extraction kit on the mag-napure system (roche diagnostics, almere, the netherlands) with μl output eluate (an updated version of the isolation method used for qpcr, tested previously [ ] ). extraction buffer was used as negative control (for extraction, library preparation, and sequencing). for library preparation, μl of nucleic acids were used, using the nebnext ultra™ directional rna library prep kit for illumina , with several in-house adaptations to the manufacturers protocol in order to enable simultaneous detection of both dna and rna. the following steps were omitted: poly a mrna capture isolation, rrna depletion and dnase treatment step. this resulted in a single tube per sample throughout library preparation containing both dna and rna. metagenomic sequencing was performed on an illumina nextseq sequencing system (illumina, san diego, ca, usa), and approximately million bp paired-end reads per sample were obtained. after quality pre-processing, sequencing reads were taxonomically classified with centrifuge [ ] using an index constructed from ncbi's refseq and taxonomy databases (accessed february ) with reference nucleotide sequences for the viruses, bacteria, archaea, fungi, parasites, and protozoa. reads with multiple best matches were uniquely assigned to the lowest common ancestor (k = centrifuge setting; previously validated [ ] ). both negative and positive results were confirmed using genomedetective website [ ] version . (accessed december -january ) and horizontal coverage (%) was determined using genomedetective. read counts were normalized, dividing the rawread count by the total number of reads in the sample and by the (average) genome size, and multiplied by ^ (to achieve comprehensible read counts in the same order of magnitude as the raw read counts). for samples with dubious or inconclusive classification results a de novo assembly was performed. pre-processed short reads assigned to a higher taxonomic level of a suspected viral target were extracted and de novo assembled with spades version . . [ ] into longer stretches of contiguous sequences (contigs). the resulting contigs were then run against the blast ncbi's nucleotide (nt) database (accessed ) using blastn . . [ ] . after identification of a putative target sequence, all the reads from the original sample were mapped against the identified best blast hit for further confirmation using bwa . . software package [ ] . sensitivity, specificity, positive and negative predictive values were calculated based on pcr positive and pcr negative target results of samples. correlation between qpcr cq value and logarithm of normalized numbers of mngs viral reads was tested with population pearson correlation coefficient. potential correlations of mngs data with clinical variables were tested as follows. cq value/ viral reads and clinical parameters (exacerbation severity, duration of exacerbation or decrease/increase in forced expiratory volume in second (fev , control visit compared to baseline) were tested with one-way anova and kruskal-wallis test when appropriate (depending on distribution). comparison of the percentage of phages of all viral reads (after subtraction of the internal control eav and phhv reads) between mngs virus positive samples and negative samples was tested with mann-whitney u test, comparison with clinical parameters with kruskal-wallis test. diversity of the virome in different patient groups was characterized by shannon diversity index (h) and tested with welch two sample t-test. statistical analyses were performed using ibm spss statistics version software for windows < . were considered statistically significant. prior to inclusion all subjects received written and oral information and signed informed consent. the bces study was approved by the regional ethical committee in western norway (rek-vest, case-number . ). the performance of this study, including mngs, was approved by the medical ethics review committee of the leiden university medical center (cme number b . ); no additional consent was necessary. in total patients with exacerbations were included with a median of one exacerbation per patient (range - ). baseline patient characteristics and exacerbation characteristics are shown in tables and respectively. of the samples, ( %) tested positive with in-house pcr: ( %) were rhinovirus positive, three influenza a, two coronavirus nl , one coronavirus oc , two parainfluenza and one parainfluenza . cq values ranged from - (table ). a median of million ( , , - , , ) sequence reads per sample were obtained. of the million reads, approximately % were homo sapiens reads, % were bacterial and . % viral (table ) . a median of % of the reads could not be assigned to sequences in the centrifuge index database (ncbi refseq). of the qpcr positive samples, tested positive with mngs, resulting in a sensitivity of mngs of %. only one sample, that was rhinovirus positive by qpcr (cq ), could not be detected by mngs ( table ) . coverage of reference genomes was high ( - %) with the exception of three samples: % coverage of rhinovirus c ( , , mapped reads, accession ay . ). a coverage plot of all reads against this reference strain (fig ) showed good horizontal and vertical coverage (read coverage depth ). the original oc qpcr amplification appeared to have been inhibited, and repeated oc qpcr confirmed the positive mngs result (cq ). sensitivity, specificity and predictive value. the sensitivity, specificity and predictive values of mngs were calculated based on pcr positive and pcr negative target results of samples and the normalized read counts (table ). calculations were made using different cut-off values of respectively � , � and � normalized read counts. with a cutoff of � , the sensitivity was % and specificity % and the positive predictive value (ppv) increased to %. the negative predictive value (npv) was % for all cut-off levels. a roc curve (fig ) , using youden's index [ ] demonstrated that the optimal sensitivity and specificity were achieved using a cut-off of reads ( % ( / ) and % ( / ) respectively). typing mngs provides additional typing data, as compared to qpcr. of the rhinoviruses detected with mngs, ( . %) were rhinovirus a, ( . %) rhinovirus b and ( . %) rhinovirus c. the three influenza viruses were assigned to be h n strains by mngs. in order to analyse the semi-quantitative quality of the mngs assay, the number of the normalized sequence reads (log) mapping to qpcr target viruses (species level) as obtained with mngs were compared to the cq values of qpcr. a significant negative correlation was found (fig ; pearson correlation coefficient ρ = - . , p = . ). the following markers were tested for potential associations with clinical severity of exacerbation (exacerbation severity, self-reported exacerbation severity), length of exacerbation and a decrease/increase in fev (control visit compared to baseline): mngs pathogen positive versus negative exacerbation (qpcr targets), the number of normalized reads (log, cutoff of � normalized reads) for the different target viruses (species level). no correlation was found between these markers and the different disease severity parameters (results not shown). overall proportions of normalized read counts of viral families (excluding eav and phhv control reads, cut-off of � normalized reads) detected by mngs per patient are shown in fig . patients with viral pathogens (pcr target viruses) had significantly reduced proportions of bacteriophages when compared to patients without viral pathogen: % and % bacteriophages respectively (p< . ) bacteriophage reads vs. all viral reads, normalized reads excluding eav and phhv control reads. the shannon diversity scores for bacteriophages (normalized reads, cut-off of � normalized reads) were comparable for copd exacerbations of viral aetiology in pcr positive versus negative patients (fig ) . shannon diversity (normalized reads, excluding internal controls) was significant lower for all viral reads (p< . ) and eukaryotic viruses (p = . ) in patients with viral pathogens (pcr target viruses positive). no significant association was found between the diversity scores, nor the percentage of bacteriophages, and the following parameters: disease severity, length of exacerbation, number of exacerbations during the study period, difference in fev , gold stage, smoking, crp level, and the virus species (results not shown). the most prevalent phyla were proteobacteria, firmicutes actinobacteria and bacteroidetes, see fig . the normalized bacterial read count of the most prevalent phyla was not significantly different between patients with a pcr-target virus positive and pcr-target negative patients. pathogenic bacterial species detected with an abundance of > % of the bacterial reads were: h. influenza (five samples); m. catarrhalis ( samples); s. pneumoniae (one sample); and the respiratory virome in copd patients s. aureus (one sample). no apparent association with bacteriophages was found, or was a high abundance of bacteriophages associated with copd exacerbations of viral cause. the raw sequence data of the samples, after removal of human reads have been deposited to sequence read archive database (http://www.ncbi.nlm.nih.gov; accession number srx -srx ). in this study, the respiratory virome in patients with copd exacerbations was analysed with both mngs and qpcr, and combined with clinical data. the incidence of viral pathogens was % with both mngs and qpcr. mngs failed to detect one rhinovirus with low load (cq ) and pcr failed to detect one betacoronavirus oc ( reads), due to one of the limitations of pcr, i.e. inhibition of amplification. one additional viral pathogen, not present in the respiratory pcr panel, was detected: herpes simplex virus , found by others to be associated with copd [ ] . the incidence of viral pathogens was comparable to that in previous publications ( - %) [ , , ] . the viral pathogen with the highest incidence was rhinovirus, followed by influenza, coronaviruses and para-influenza viruses. interestingly, subtyping data was readily available by mngs, accentuating the high resolution of mngs, with rhinovirus (rv) species a and c being most frequent, followed by rv-b. rv-c was first identified in and associated with high symptom burdens in children and asthmatics [ , ] . recently, an asthma-related cadherin-related family member (cdhr ) gene variant [ ] was associated with greater rv-c receptor display on pulmonary cell surfaces of children and adults, and associated with higher susceptibility to severe virus-triggered asthma episodes [ , ] . in line, romero-espinoza et al detected predominantly rv-c in children with acute asthma exacerbations by mngs [ ] . the significance of rv-c infection in the adult population is less well studied. although rv-c has been previously associated with exacerbations of copd [ , ] , to our knowledge, to date, cdhr polymorphisms have not yet found to be associated with copd. the sensitivity, specificity and positive and negative predictive values of mngs were high: %, %, % and %, respectively, when encountering a cut-off of � normalized reads, with a detection limit of approximately cq . the high negative predictive value implicates the potential of mngs to exclude the most prevalent viral respiratory infections in one test. the potential to exclude any infectious cause, both viral and bacterial, would have significant consequences for starting and/or continuation of antimicrobial or, at the other end of the spectrum, immune-modulating treatment. the normalized viral species sequence read count might give an indication of the viral burden and the clinical relevancy of the detected virus. although in our dataset we could not find any correlation with disease severity, several paediatric studies demonstrated a correlation between virus load and severity in respiratory infections [ ] [ ] [ ] [ ] . further analysis with a larger number of infected patients and/or a different spectrum of exacerbation severity will be needed to demonstrate or exclude such an association in copd patients. furthermore, the complete respiratory virome showed a high bacteriophage abundance that could be linked to the absence of viral pathogens. lower bacteriophage abundance may be the result of viral expansion. hypothetically, a healthy virome size and diversity fits a certain size and diversity of bacteriophages, while during viral infection, pathogens predominate the virome. alternatively, others have hypothesized that viral and microbial diversity may play a role in infection susceptibility and the development of acute and chronic respiratory diseases [ ] . our results indicate that virome dysbiosis may be accompanied by bacteriome dysbiosis, though no significant differences were detected in line with other reports [ , ] . however, these studies don't compare between copd exacerbation with and without viral infections. others have found a higher phage abundance in a patient with severe copd when compared with one patients with moderate copd and healthy controls, dna sequencing, in line with the hypothesis of a state of dysbiosis that increases with disease progression [ ] . in copd patients, viral infections have been suggested to trigger bacterial overgrowth and infections [ , ] , demonstrating the significance of viral-bacterial interactions. moreover, hypothetically, bacteriophages play a role in the horizontal gene transfer of bacterial virulence factors. the most abundant bacterial phyla detected in this study were comparable with other reports. although the percentage of proteobacteria was relatively high when compared to other studies of the nasopharyngeal microbiome, our swabs are sampled during copd exacerbations [ , ] . study of the lower airways by means of e.g. protected brushes during bronchoscopy is needed for further analysis of bacterial and viral (sub)populations including comparison with pcr and culture results. studies comparing the respiratory virome during stable disease and exacerbations are needed to determine a potential correlation between the virome/bacteriome during stable state and disease progression or exacerbation frequency. in the current study, most respiratory pathogens detected were rna viruses. this is in line with previous literature [ , , ] . however, it must be noted that, despite the fact that a wide range of dna viruses have been detected with the current protocol (dna bacteriophages with high abundance, herpes simplex virus, bocavirus, anelloviruses, cmv, ki polyomavirus [ ] ), we cannot exclude suboptimal detection of some dna viruses. furthermore, highly divergent viruses with sequences deviating from their representative ncbi refseq sequences may have been missed, as has been described by others [ ] . however, bioinformatic classification using alternative databases (both genomedetective and local databases) did not result in additional findings. though mngs renders the possibility to detect all viruses in direct respiratory material, this revolutionary method is not yet used as routine accredited diagnostic procedure for pathogen detection. before mngs can be implemented as a routine diagnostics, the optimal protocol must be defined and analysis and interpretation of the metagenomic data must be standardized, followed by external quality assessment. this study demonstrates good performance of our mngs protocol, in line with other studies [ , , , ] and seems to overcome some of the current thresholds for implementation in clinical diagnostics. the mngs protocol used was highly sensitive and specific for semi-quantitative detection of respiratory pathogenic viruses. excellent negative predictive value implicates the potential of mngs to exclude a known viral infectious cause in one test, with consequences for clinical decision making. reduced abundance of bacteriophages in copd patients with viral pathogens implicates skewing of the virome, and speculatively the bacterial population, during infection. management and prevention of exacerbations of copd copd exacerbations: defining their cause and prevention copd exacerbations. : aetiology the role of viral infections in exacerbations of chronic obstructive pulmonary disease and asthma. therapeutic advances in respiratory disease a newly discovered human pneumovirus isolated from young children with respiratory tract disease isolation of a novel coronavirus from a man with pneumonia in saudi arabia cloning of a human parvovirus by molecular screening of respiratory tract samples exploring the potential of next-generation sequencing in detection of respiratory viruses genomic characterization of a newly discovered coronavirus associated with acute respiratory distress syndrome in humans unbiased parallel detection of viral pathogens in clinical samples by use of a metagenomic approach metagenomic sequencing complements routine diagnostics in identifying viral pathogens in lung transplant recipients with unknown etiology of respiratory infection. plos one metagenomic sequencing for combined detection of rna and dna viruses in respiratory samples from paediatric patients. biorxiv lung microbiome dynamics in copd exacerbations metagenomic analysis of viral genetic diversity in respiratory samples from children with severe acute respiratory infection in china characterization of the viral microbiome in patients with severe lower respiratory tract infections, using metagenomic sequencing systemic inflammatory markers in copd: results from the bergen copd cohort study performance of different mono-and multiplex nucleic acid amplification tests on a multipathogen external quality assessment panel metagenomic sequencing for combined detection of rna and dna viruses in respiratory samples from paediatric patients centrifuge: rapid and sensitive classification of metagenomic sequences genome detective: an automated system for virus identification from high-throughput sequencing data spades: a new genome assembly algorithm and its applications to single-cell sequencing basic local alignment search tool fast and accurate short read alignment with burrows-wheeler transform understanding diagnostic tests : receiver operating characteristic curves the human virome protein cluster database (hvpc): a human viral metagenomic database for diversity and function annotation frequent detection of human rhinoviruses, paramyxoviruses, coronaviruses, and bocavirus during acute respiratory tract infections masstag polymerase-chain-reaction detection of respiratory pathogens, including a new rhinovirus genotype, that caused influenza-like ill a genome-wide association study identifies cdhr as a susceptibility locus for early childhood asthma with severe exacerbations cadherin-related family member , a childhood asthma susceptibility gene product, mediates rhinovirus c binding and replication genetic association of the functional cdhr genotype with early-onset adult asthma in japanese populations unbiased detection of respiratory viruses by use of rna sequencing-based metagenomics: a systematic comparison to a commercial pcr panel we thank our generade project partners floyd wittink, wouter suring (hogeschool leiden), danny duijsings (baseclear) and christiaan henkel (leiden university). we also like to thank tom vreeswijk, lopje höcker and mario van bussel (kml, lumc) for help with the pre-sequencing experiments and jeroen laros (human genetics, lumc) for help with the bioinformatics. we thank caroline brouwer for technical assistance (kml, lumc). key: cord- -ji cet authors: duarte de araújo, antónio manuel silva; correia-de-sousa, antónio jaime botelho title: copd: will there be room for nebulisers after the current covid- pandemic? date: - - journal: nan doi: . /j.opresp. . . sha: doc_id: cord_uid: ji cet nan founding: the authors have no founding to declare. inhaled medication is the mainstay of chronic obstructive pulmonary disease (copd) management and therapeutic success depends on the maintenance of a correct inhalation technique. however, there is a growing evidence concerning misuse of hand-held inhalers as a common clinical problem worldwide. in clinical practice, up to % of patients can present inhalers' mishandling. in the largest study assessing the use of inhalers in real-life, - % of patients presented at least one error, depending on the type of inhalers they used, and, in a more recent study, handling errors were observed in more than % of demonstrations. in previous published papers, a significant inhalers' misuse was also confirmed in a portuguese cohort of copd patients. , moreover, the functional progression of copd and the aging process, reducing inspiratory muscle function, decreases the patient's ability to generate sufficient inspiratory flow, limiting at least the use of dry-powder inhalers properly. in patients with severe copd and limited inspiratory capacity it is often necessary to introduce metered dose inhalers with or without a spacer in order to provide the necessary treatment to the patient. this has several limitations as many of the more recent copd treatment drugs are not available in such devices. nebulisers are the oldest devices developed to produce aerosols and deliver inhaled medication, and they are regularly used at home, when elderly people are unable to handle portable inhalers correctly. they are known to present significant disadvantages: lack of portability, lack of chemical stability of some drugs, lengthy administration time, significant waste of medication, health care professionals and caregivers' exposure to aerosolised medication, and the lack of the definition regarding the optimal doses required. their high costs and the need for daily cleaning are other usual drawbacks. they are not regularly recommended for chronic disease management in copd, because there is no evidence of superiority of nebulisers in patients who are able to use portable inhaler devices properly. however, when prescribed, patients are usually satisfied with nebulised therapy, and it is often preferred by those who have been recently hospitalised. in recent years, nebulised drug delivery has significantly evolved. nebulisers became more portable, lighter and battery-powered, and more silent in operation. breath-enhanced and breath-actuated technologies improved the efficiency of jet nebulisers by reducing the loss of medication to the environment and the exposure of caregivers. recent developments, the vibrating mesh and the adaptive aerosol delivery technologies provide precise and reproducible doses, reduces the losses of aerosol, during expiration, and allows a deeper aerosol deposition in the lungs, together with a shorter treatment duration. they can also give feed-back to the patient and to the caregiver that the prescribed dose was delivered. however, they are even more expensive, their cleaning more difficult, and they need a more complex initial learning period. another common limitation for the use of nebulisers has always been the reduced availability of drugs, or their associations, that can be used in these devices. currently, the most frequently used are short-acting β -agonists, short-acting muscarinic antagonists and budesonide. twice-daily nebulised formoterol fumarate, a long-acting β agonist (laba), was proven to be effective and welltolerated in copd treatment, and arformoterol, another laba, can also be useful as a nebulised maintenance therapy for copd. two different long-acting muscarinic antagonists, a soluble glycopyrrolate bromile formulation and revefenacin, are nebulised therapies already approved by the us foods and drugs administration, respectively for twice-and once-daily maintenance therapy of copd. in the future, a dual inhibitor of phosphodiesterase and phosphodiesterase enzymes, developed for use as nebulisation, could be used as maintenance therapy for copd patients, because of the bronchodilator and anti-inflammatory related effects. in a recent systematic review and meta-analysis, high doses of nebulised budesonide during hospitalisation, seemed to be non-inferior to systemic corticosteroids, in the treatment of copd acute exacerbations. nebulised corticosteroids can also be preferable versus oral prednisolone in patients with diabetes mellitus or with heart failure, because of the mineralocorticoid effects and fluid retention related to systemic corticosteroids. a subgroup of copd patients is known to present chronic bronchial infection, and the use of antibiotics can be associated with reduction of bacterial load. low doses of nebulised antibiotics can provide higher tissue concentration with fewer bacterial-resistance related issues. however, a possible bronchial hyperesponsiveness can occur. copd patients suffering from severe α -antitrypsin (aat) deficiency commonly present an emphysema phenotype, and accelerated disease progression. intravenous aat can be administered to protect the lungs from inflammatory destruction and to reduce the development of emphysema. more recently, nebulized aat can be delivered directly to the lungs, leading to aat levels three times higher than those reached by intravenous administration. because the increased risk of infection transmission via aerosols during treatment with nebulisers, there has been a progressive shift from the use of nebulisers to metered-dose inhalers with valved holding chambers. however, nebulisers remain widely used in hospital setting and in ambulatory clinics. the current covid- pandemic demands greater infection control precautions, and many national and international guidelines recommend against the use of nebulised therapies, as an infection control measure. some authors advise that nebuliser treatments should be performed only if absolutely necessary, and in negative pressure environments . although there is no evidence regarding whether nebulisations are related to sars-cov- transmission , it was previously associated with the risk of transmission of sars in a honk-kong hospital. in a systematic review of articles published in all languages from / / to / / , tran et al found two studies describing an association between nebulisations and risk of sars transmission . because it is not clear how significant is the role of nebulisers in the spread of sars-cov- , and there are no reviews or trials investigating this association, recommendations were established based on general principles and previous case reports, related to other viruses. probably in the future, inhaled medication delivered by portable devices will continue to be largely preferred. due to the current awareness that nebulisations may potentially aerosolise respiratory pathogens, nebulisers will be significantly deprescribed, and relief medication will preferably be administered using metered-dose inhalers with valved holding chambers. however, in face of the recent developments related both to nebulisers and new drugs developed to be administered by nebulisation, there will probably be a room for the use of nebulizers in the future, both for copd exacerbations and maintenance therapy. device errors in asthma and copd: systematic literature review and meta-analysis. npj primary care respiratory medicine assessment of handling of inhaler devices in real life: an observational study on patients in primary care chronic obstructive pulmonary disease exacerbation and inhaler device handling: reallife assessment of patients copd: analysing factors associated with a successful tratment copd: misuse of inhaler devices in clinical practice the global initiative for chronic obstructive lung disease (gold) a review of nebulized drug delivery in copd efficacy and safety of rpl , a dual pde and pde inhibitor, in healthy volunteers and in patients with asthma or chronic obstructive pulmonary disease: findings from four clinical trials nebulized corticosteroids in the treatment of copd exacerbations: systematic review, meta-analysis and clinical perspective chronic respiratory infection in patients with chronic obstructive pulmonary disease: what is the role of antibiotics? efficacy and safety of inhaled α -antitrypsin in patients with severe α -antitrypsin deficiency and frequent exacerbations of copd respiratory support for adult patients with covid- aerosol generating procedures and infective risk to healthcare workers: sars-cov- -the limits of the evidence aerosol generating procedures and risk of transmission of acute respiratory infections to healthcare workers: a systematic review founding: the authors have no founding to declare.conflicts of interest: the authors have no conflict of interest to declare.references: key: cord- -iivry ou authors: tsoumakidou, maria; siafakas, nikolaos m title: novel insights into the aetiology and pathophysiology of increased airway inflammation during copd exacerbations date: - - journal: respir res doi: . / - - - sha: doc_id: cord_uid: iivry ou airway inflammation increases during acute exacerbations of copd. extrinsic factors, such as airway infections, increased air pollution, and intrinsic factors, such as increased oxidative stress and altered immunity may contribute to this increase. the evidence for this and the potential mechanisms by which various aetiological agents increase inflammation during copd exacerbations is reviewed. the pathophysiologic consequences of increased airway inflammation during copd exacerbations are also discussed. this review aims to establish a cause and effect relationship between etiological factors of increased airway inflammation and copd exacerbations based on recently published data. although it can be speculated that reducing inflammation may prevent and/or treat copd exacerbations, the existing anti-inflammatory treatments are modestly effective. exacerbations are a cardinal feature of the natural history of moderate and severe chronic obstructive pulmonary disease (copd) [ ] . patients with frequent exacerbations have significantly lower quality of life and increased morbidity and mortality rates [ ] [ ] [ ] [ ] . although the effect of copd exacerbations on lung function has been questioned in the past, recent evidence suggests that exacerbations accelerate long-term decline in lung function, specifically in smokers [ ] [ ] [ ] . the mechanism of this acceleration remains largely unknown. treatment decisions for copd patients are frequently made according to exacerbation rates. in the ats/ers guidelines it is stated that patients with frequent exacerbations should be initiated a trial of inhaled steroids [ ] . systemic steroids should be administered during acute copd exacerbations, both in the inpatient and outpatient setting. these treatment strategies indicate the central role of inflammation in the pathogenesis of exacerbations. although evidence for increased inflammation on copd exacerbations has been reviewed previously, there has been little focus on why inflammation increases and which the consequences of this increase are [ , ] . investigating further these important questions may help establish a cause and effect relationship between inflammation and copd exacerbations. the primary aim of this review is to summarize emerging explanations for why inflammation is increased during copd exacerbations. for practical purposes an attempt is made to categorize aetiological factors of increased inflammation into extrinsic or intrinsic, as it can be seen in table . a secondary aim is to try to explain how increased inflammation is associated with the pathophysiology of copd exacerbations. bacterial infections are generally considered to be the most common causes of copd exacerbations. it is estimated that more than % of all exacerbations are of bacterial origin [ , , ] . accordingly, antibiotics should be administered in inpatients and outpatients with acute copd exacerbation and changes in sputum characteristics suggestive of bacterial infection [ ] . the most common bacteria connected to copd exacerbations are non-typable h. influenzae, s. pneumoniae, and m. cattarhalis [ , , ] . the same bacteria often colonize the nasal mucosa and pharynx of healthy individuals, but in smokers and in patients with copd impaired mucocilliary clearance and innate immunity allow these pathogens to colonize the lower airways [ ] . copd exacerbations may be triggered by the acquisition of a new bacterial species or by an increase in the absolute number of the same bacteria that colonize the airways or by the acquisition of a different strain from the same bacterial species [ ] [ ] [ ] . airway bacteria initiate airway inflammation through several interconnecting mechanisms. the surface of bacteria allows the complement system to be activated through the alternative pathway, while specific surface molecules of the bacteria, called pathogen-associated molecular patterns (pamps), bind to pattern recognition receptors on a variety of leukocytes and initiate signalling pathways that lead to the activation of nf-κb and production of proinflammatory cytokines [ ] . once activated, innate immunity can trigger both cell-mediated and antibodymediated adaptive immune responses. this cascade of events leads to increased blood flow to tissue, increased temperature, redness and swelling which characterize inflammation. a significant number of studies in stable copd patients suggest that airway bacterial infections are associated with increased airway inflammation ( ) ( ) ( ) ( ) . finding a relationship between bacteria and inflammation on stable copd adds weight to the argument that bacteria may play a causative role in airway inflammation during copd exacerbations. soler et al used protected specimen brush and bronchoalveolar lavage sampling to determine inflammatory cell counts, levels of cytokines concentrations and microbial patterns in stable copd patients and found that increased neutrophils and tumour necrosis factor-alpha (tnfalpha) levels may be related to bronchial colonization [ ] . increased tnf-alpha, as well as myeloperoxidase (mpo) and interleukin- (il- ) levels have been specifically related with h. influenzae infection, as shown by bresser et al [ ] . however, in that study all mediators were measured in frozen sputum and mpo and il- levels were only retrospectively compared to non-infected patients. in fresh sputum samples from copd patients r. stockley and his group demonstrated that mpo, neutrophil elastase (ne) activity, il- and ltb levels are positively related to sputum bacterial load [ ] . moreover, the type of organism affected sputum mpo levels and ne activity; mpo levels were relatively increased in the presence of ps. aeruginosa compared to h. influenzae and to m. catarrhalis. there have been also reports for decreased secretory leukocyte protease inhibitor (slpi) in sputum samples from copd patients colonised with bacteria [ , ] . upper airways inflammation in copd is also increased when there is bacterial colonization [ ] . all these results taken together suggest that bacteria are [ ] . this discrepancy may be due to differences in sputum induction time or in sputum processing or in the assays used for the detection of fluid-phase mediators. another intriguing hypothesis is that different strains of the same pathogens may induce different levels of inflammation and subjects taking part in different studies might have been infected by different strains of h. influenzae. it was recently shown that h. influenzae strains isolated from copd patients during exacerbation induce more inflammation than strains of the same pathogen isolated from colonizers [ ] . the close association between airway infections and increased inflammation during copd exacerbations has been further confirmed by a report of increased systemic inflammation in infected patients during exacerbation [ ] . consistent with these observations, airway inflammation can be decreased with treatment of the infection. early evidence came from a relatively small study, which showed that neutrophilic mediators' levels may decrease after treatment of bacterial exacerbations [ ] . gompertz et al confirmed that there are significant decreases in neutrophilic inflammatory mediators after treatment of purulent exacerbations [ ] . most importantly, white et al studied patients with bacterial exacerbations and demonstrated a significant fall in sputum leukotriene b (ltb ) levels and an increase in slpi levels in patients in whom bacteria were eradicated, but not in those in whom bacteria persisted on stable state [ ] . moreover, mpo and ltb levels were significantly lower and slpi levels significantly higher in patients with treated compared to patients with untreated bacterial infections on stable state. in conclusion, three major findings support the hypothesis that bacterial infections are actively implicated in the mechanisms of increased airway inflammation during copd exacerbations: ) bacterial infections increase airway inflammation in colonized stable copd patients ) bacterial-positive exacerbations show increased inflammation (particularly of neutrophilic type) compared to bacterial-negative exacerbations and ) eradication of bacteria after a bacterial exacerbation is accompanied by a significant decrease in airway inflammation. a summary of these findings is presented in table . b viral infections respiratory viruses are important triggers of copd exacerbations. initial studies using serology and cell cultures for detecting viral infections suggested that % of copd exacerbations are related to viral infections [ ] [ ] [ ] . later studies using the more sensitive method of reverse transcriptase polymerase chain reaction showed that %- % of copd exacerbations may be secondary to viral infection [ , ] . rhinoviruses, picornaviruses, respiratory syncytial virus, influenza a and b and coronaviruses are more frequently detected [ , ] . possible mechanisms of viral-induced inflammation have been described. the airway epithelial cell is the principal host cell for most respiratory viruses [ ] . viral replication in the epithelial cell triggers intracellular signalling pathways, including activation of nfκb, which leads to increases in the secretion of multiple cytokines and recruitment of multiple leukocytes to the airways [ ] . antigen presenting cells are of particular importance, because binding of viruses to these cells induces innate and adaptive immune responses and t lymphocyte activation [ ] . there is convincing data that viruses induce inflammation in asthma [ ] . in animal models of emphysema, latent adenoviral infection amplifies the emphysematous destruction and increases the inflammatory response [ ] . in stable copd latent adenoviral infection has been associated with severe emphysema and increased inflammation [ ] . the group of j wedzicha showed that viral infections might be implicated in the mechanisms of increased airway and possibly systemic inflammation during copd exacerbations. plasma il- and fibrinogen levels were higher during viral than non-viral exacerbations, although the difference just failed to reach statistical significance [ ] . however, in that study viruses were detected in nasal samples and it has been shown that in copd patients respiratory viruses are detected more frequently in induced sputum than in nasal lavage [ , ] . when rhinovirus infection was detected in induced sputum samples a significant correlation was demonstrated between rhinovirus infection and increased sputum il- levels on copd exacerbations [ ] . further to these observations, two recent studies showed that viral airway infections during copd exacerbations are related to airway eosinophilia [ , ] . this new find-ing may be of particular clinical importance as airway eosinophilia could be used as an indicator of viral infection during an exacerbation. the important role of eosinophils in the pathogenesis of copd exacerbations is further supported by studies in bronchial biopsies and sputum samples, which show increased eosinophil numbers and eosinophil mediators in copd patients during exacerbations [ ] [ ] [ ] [ ] [ ] [ ] . eosinophils may be actively involved in the pathogenesis of viral-induced copd exacerbations through the release of destructive enzymes, reactive oxygen species and inflammatory mediators. c atypical bacteria atypical pathogens with potential importance in acute exacerbations include m. pneumoniae, c. pneumoniae and legionella spp. considerable confusion exists in the literature regarding the significance of these potential pathogens in acute exacerbations of copd [ ] . this is partly due to differences in the techniques used to detect the presence of atypical infections. when a fourfold increase in antibody titter or a positive culture or rt-pcr is used, m. pneumoniae and legionella are rare and c. pneumoniae infection may be involved in up to % of copd exacerbations [ , [ ] [ ] [ ] . moreover, chronic colonization with c. pneumoniae may be associated with a higher rate of copd exacerbations [ ] . c. pneumonia infection can amplify inflammation in the airways of copd patients by stimulating the production and expression of cytokines, chemokines and adhesion molecules [ ] . however, clear evidence showing a direct relationship between increased inflammation and c. pneumoniae infection during copd exacerbations is yet lacking [ ] . epidemiologists have linked ambient particulate air pollution (pm) exposure with exacerbations of pre-existing pulmonary diseases, such as copd [ ] . pm-mediated enhancement of airway inflammation is a central pathogenetic mechanism by which pm exposure leads to exacerbation of inflammatory pulmonary diseases [ ] [ ] [ ] . it has been suggested that pm exposure induces lung inflam-mation by an increase in reactive oxygen species [ , ] . to the best of our knowledge there are no in vivo studies on the effect of pm exposure on airway inflammation in copd patients. there is also lack of information on airway inflammation during pm exposure induced copd exacerbations, which may be due to difficulties in defining such exacerbations. trolox equivalent antioxidant capacity is decreased in patients presenting with acute exacerbation of copd [ ] . recent reports suggest that -isoprostane levels are increased in exhaled breath condensate of copd patients during exacerbations, while levels of the antioxidant enzyme glutathione(gsh) in bronchoalveolar lavage fluid are decreased [ , ] . oxidative stress may be closely associated to increased inflammation during exacerbations [ , ] . oxidant stimuli induce cellular expression of inducible nitric oxide synthase and heme-oxygenase- (ho- ) and increase nitrotyrosine formation. we have shown that there is increased ho- expression and nitrotyrosine formation in the airways of copd patients during severe exacerbations relatively to stable state and that this is accompanied by an increase in indices of neutrophilic inflammation, i.e. neutrophil numbers, mpo and il- levels [ ] . evidence for a close association between oxidative stress, airway neutrophilia and increased il- during severe copd exacerbations is also supported by drost et al [ ] . a certain limitation in the study by drost et al is the fact that different patients were examined on exacerbation and on stable state. oxidative stress induces the transcription of various inflammatory factors, such as nuclear factor-kappab (nf-κb) and activator protein- (ap- ) [ ] . it has been shown that nf-κb dna binding in sputum inflammatory cells is increased during copd exacerbations [ ] . other investigators have reported increased nuclear localisation of p , which is a signal of nf-κb activation, in sputum macrophages during copd exacerbations [ ] . nf-κb is important for transcription of il- gene and oxidative stress may induce or amplify airway neutrophilia by inducing the transcription of il- gene [ ] . in support of this hypothesis both we and drost et al have found increased il- levels and neutrophil numbers associated with increased oxidative stress on severe copd exacerbations [ , ] . activated neutrophils and other inflammatory cells can in turn release reactive oxygen species and increase airway oxidative stress. because oxidative stress can induce inflammation and vice versa, it is not clear which of the two, oxidative stress or inflammation, is primarily involved in the mechanisms of copd exacerbations-[the chicken and egg problem]. alterations in innate and adaptive immunity are implicated in copd pathogenesis [ ] . evidence favouring participation of the adaptive immune response in copd includes the several reports of increased numbers of tlymphocytes, specifically cd +ve t-cells with a "type "profile [ ] [ ] [ ] [ ] . it is still unknown whether these alterations are triggered by cigarette smoking, viral infections, or there is a genetic predisposal. we have recently shown that cd +ve t lymphocytes may mediate their destructive effects in copd through increased perforin expression and cytotoxic activity [ ] . it would be reasonable to assume that lymphocytes may be implicated in the mechanisms of increased inflammation during copd exacerbations. according to our observations changes in lymphocyte subpopulations occur during severe copd exacerbations [ ] . in specific, there is a further increase in cd +ve t cells and this is rather associated with increased cd +ve type cells compared to type . this finding suggests that tc and tc responses may fluctuate in relation to the different phase (exacerbation versus stable state) of the disease in the same patient. similar observations have been made in other inflammatory diseases [ ] . a relative increase of tc versus tc cells may result in impaired immunity, increased susceptibility to viral infections and increased inflammation [ ] [ ] [ ] . although saetta et al also found increased t cell numbers in endobronchial biopsies from chronic bronchitis patients on mild exacerbations, no difference was detected in cd or cd +ve cell numbers [ ] . this discrepancy may be attributed to the fact that we examined sputum samples (not biopsies) from copd patients (not chronic bronchitis) on severe exacerbation (not mild exacerbation). moreover, saetta et al compared different patients on exacerbation and on stable state, which could be a limitation in their study. however, finding increased t cell numbers still adds evidence to the argument that immune responses may be involved in the mechanisms of increased airway inflammation during copd exacerbations. it would be logical to assume that small increases in airway inflammation in patients with already increased baseline levels of inflammation can easily trigger a copd exacerbation. this presumes the existence of an inflammatory threshold, above which exacerbation occurs. in relation to this hypothesis, bhowmik et al showed that copd patients with frequent exacerbations (≥ episodes/ year) have increased baseline sputum il- and il- levels [ ] . however, it was not examined whether this was related to bacterial colonization, as bacterial colonization can increase airway inflammation and exacerbation rates. the same group also showed faster rises over time in plasma fibrinogen and sputum il- in patients with frequent exacerbations [ ] . on the contrary, gombertz et al did not detect any difference in neutrophilic mediators (including il- ) between frequent (≥ episodes/year) and infrequent exacerbators [ ] . interestingly, when patients with bronchiectasis were excluded from the analysis, slpi was found to be lower in copd patients with frequent exacerbations, which suggests that copd patients with bronchiectasis may represent a distinct group. fujimoto et al also report no difference in baseline il- and markers of eosinophilic inflammation between stable and unstable copd patients [ ] . however, results between this and other studies are not comparable due to lower exacerbation rates (mean episode/year) in the unstable copd group in this study. in conclusion, data relating baseline airway inflammation to exacerbation frequency are rather controversial. part of the existing confusion may be due to significant heterogeneity among copd patients and to the existence of several factors, like bacterial colonization and bronchiectasis that may increase airway inflammation. in particular, copd patients with bronchiectasis may represent a distinct group characterized by higher rates of bacterial colonization, increased baseline levels of airway inflammation and longer symptom recovery times at exacerbation [ ] . episodes of copd exacerbations are characterized by an acute increase in a patient's baseline dyspnoea, cough and/or sputum production [ ] . severe exacerbations are also associated with worsening of pulmonary gas exchange that may lead to hypoxemia with or without hypercapnia [ ] . in order to support a role for airway inflammation in copd exacerbations the mechanisms which are induced by airway inflammation need to be related to the symptoms and pathophysiology of exacerbations. increased airway inflammation induces many pathologic changes on the airways. accumulation of inflammatory cells in the airway mucosa by itself causes airway wall thickening. inflammatory cells can release potentially harmful mediators, such as proteases and reactive oxygen species [ ] . neutrophil and eosinophil products, like mpo, ne and eosinophilic cationic protein (ecp), have been found increased on exacerbations, and can cause inflammatory damage and increased permeability of the bronchial mucosa, resulting in airway oedema and protein exudation [ , , , ] . inflammatory mediators, like ecp, can also induce bronchoconstriction by increasing achetinocholine release from parasynmpathetic nerves, while others, like ne, increase mucus secretion [ , ] . furthermore, mediators of inflammation enhance coughing [ ] . potentially harmful mediators may be released not only by inflammatory cells but also by resident cells. for example, endothelin (et)- , which has been found increased on exacerbations, can be released by epithelial cells and stimulates mucus secretion and bronchial hyperesponsiveness [ ] . the cascade of the above events leads to significant airway narrowing and increased airway secretions, while the patient suffers from increased cough, sputum, and/or increased dyspnea. the mechanisms of dyspnea are not entirely understood yet, but may be also associated with excessive airway narrowing and dynamic hyperinflation due to increased inflammation [ ] [ ] [ ] . a brief summary of the pathophysiologic events that may link airway inflammation to the symptoms of copd exacerbations and to respiratory failure is given in figure . airway narrowing, caused by increased inflammation, leads to expiratory flow limitation and dynamic hyperinflation. dynamic hyperinflation in turn increases work of respiratory muscles and oxygen consumption, resulting in decreased mixed venous oxygen tension [ ] . airway narrowing also increases ventilation/perfusion inequality, because a greater proportion of blood flow is diverted through lung units with low v'/q' ratios [ ] . the combi-schematic presentation of the main pathophysiologic events of copd exacerbations, starting from increased airway inflamma-tion figure schematic presentation of the main pathophysiologic events of copd exacerbations, starting from increased airway inflammation. nation of increased ventilation/perfusion inequality and decreased mixed venous oxygen tension significantly worsen gas exchange in patients with severe copd exacerbations. increased airway inflammation would be also expected to increase lung tissue oxygen demand and oxygen consumption. in patients with acute lung injury no relation has been found between pulmonary oxygen consumption and lung inflammation, but there is no relevant data in copd exacerbations [ ] . despite the increasing recognition of the importance of airway inflammation in the development of copd exacerbations, there is still confusion regarding the role of anti-inflammatory strategies in the prevention and treatment of copd exacerbations [ , ] . there are studies showing a beneficial effect of inhaled steroids in preventing copd exacerbations and systemic steroids in treating acute exacerbations, however the overall benefits for copd patients in these studies are generally modest [ ] [ ] [ ] . considering that inflammation in stable copd is steroid resistant, this should not come as a great surprise [ ] . although the majority of copd patients respond modestly to steroid therapy, there might be subgroup of patients, those with eosinophilic pattern of inflammation during exacerbations that may benefit the most from steroid administration. there is already evidence that stable patients with high sputum eosinophil counts are steroid responsive, but there is no relevant data on copd exacerbations [ , ] . identifying patients that may benefit from systemic steroid administration during exacerbations is of great importance, due to the serious adverse events frequently observed with this kind of treatment [ ] . other drugs with anti-inflammatory properties, like methylxanthines and mucolytic agents seem not to be effective on copd exacerbations [ ] . b-agonists are mainly administered as bronchodilators, although they may also have an anti-inflammatory role [ ] . novel drugs aimed at inhibiting targets, including no synthase, phosphodiesterase , proteases and various inflammatory mediators have not been tested during exacerbations yet. it has been long postulated that airway inflammation may be increased during copd exacerbations and this may be involved in the pathophysiology of exacerbations. there is now sufficient data to support such a hypothesis. firstly, there are accumulating observations for increased inflammation during copd exacerbations. secondly, specific aetiological factors for this increase have been identified. thirdly, possible mechanisms that may link airway inflammation with the pathophysiology of exacerbations have been unmasked. despite significant advances in our understanding of the role of inflammation in copd exacerbations, the existing anti-inflammatory treatments remain modest and there is little overall benefit for the patient. further research is needed to target therapies to the appropriate patient populations and to develop new therapeutic strategies. the natural history of chronic airflow obstruction effect of exacerbations on quality of life in patients with chronic obstructive pulmonary disease: a year follow up study wedzicha ja: effect of exacerbation on quality of life in patients with chronic obstructive pulmonary disease course and prognosis of chronic obstructive lung disease. a prospective study of patients relationship between exacerbation frequency and lung function decline in chronic obstructive pulmonary disease lower respiratory illnesses promote fev( ) decline in current smokers but not 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corticosteroids for acute exacerbations of chronic obstructive pulmonary disease corticosteroid resistance in airway disease sputum eosinophilia and short-term response to prednisolone in chronic obstructive pulmonary disease: a randomised controlled trial bradding p: sputum eosinophilia and the short term response to inhaled mometasone in chronic obstructive pulmonary disease. thorax effect of beta-agonists on inflammatory cells the author(s) declare that they have no competing interests.publish with bio med central and every scientist can read your work free of charge key: cord- -cfjrwt authors: girkin, jason; maltby, steven; singanayagam, aran; bartlett, nathan; mallia, patrick title: chapter in vivo experimental models of infection and disease date: - - journal: rhinovirus infections doi: . /b - - - - . - sha: doc_id: cord_uid: cfjrwt abstract human and animal models continue to play a crucial role in research to understand host immunity to rhinovirus (rv) and identify disease mechanisms. human models have provided direct evidence that rv infection is capable of exacerbating chronic respiratory diseases and identified immunological processes that correlate with clinical disease outcomes. mice are the most commonly used nonhuman experimental rv infection model. although semipermissive, under defined experimental conditions sufficient replication occurs to induce host immune responses that recapitulate immunity and disease during human infection. the capacity to use genetically modified mouse strains and drug interventions has shown the mouse model to be an invaluable research tool defining causal relationships between host immunity and disease and supporting development of new treatments. used in combination the insights achieved from human and animal experimental infection models provide complementary insights into rv biology and yield novel therapeutic options to reduce the burden of rv-induced disease. that deliberately expose humans to an infectious agent are required, when there are more than enough naturally acquired infections to yield sufficient subjects for studies. despite the ubiquity of viral colds there are a number of factors that make studies of naturally acquired infections problematic. although rvs are the commonest etiological agents of viral colds there are several other viral causes (and nonviral causes of upper airway symptoms), and the clinical syndromes caused by different virus types are indistinguishable. , other factors contributing to variability in naturally acquired infections include different routes of inoculation (eye, nasopharynx, direct contact, aerosol, etc.), different inoculation doses, variability in the perception of symptoms leading to differences in time to presentation and host factors (immune status, smoking, age, etc.) that influence viral pathogenicity. further, the heterogeneous nature of naturally occurring infections requires that large patient numbers are needed to identify statistically significant effects of treatment. therefore human experimental infection studies are an attractive proposition as they allow for a known etiological agent to be administered at a standard dose, route of inoculation, and time point to a selected group of recipients with similar characteristics (e.g., age, smoking history, health/disease, and antibody status). detailed follow up can be carried out in a controlled clinical setting with sample collection at defined time points in relation to the time of infection. as the clinical syndrome induced by rv challenge in young healthy volunteers is benign and self-limiting, experimental rv infection in this group is relatively uncontroversial. perhaps the only risk to subjects was the possibility of additional infectious agents present in the inoculum and good manufacturing practice (gmp)-prepared stocks are now required by regulators for experimental infection studies in humans to contravene this risk. studies in healthy volunteers have been central to establishing the key aspects of the biology of rv infection including routes of acquisition of infection, À clinical symptoms, , inflammatory and immune responses, involvement of the lower airway, , and correlates of immune protection of rv infection. virus challenge studies have also been used in healthy volunteers to evaluate a vast array of potential treatments. however, none of these studies have led to the licensing of a single treatment for the common cold. À licensing approval was sought for an antiviral drug, pleconaril, for the treatment of rv infection. approval was denied by the food and drug administration as the adverse effects outweighed the benefits in healthy subjects with self-limiting colds. the lack of approval of any antiviral treatments casts doubt on whether continued investment in viral challenge studies is justified. however, the recognition that rv infection is associated with more severe clinical manifestations in people with chronic lung diseases such as asthma and copd provided a new impetus to research and a new direction to human experimental infection studies. up until the early s the prevailing view was that rv infection resulted in a self-limiting, mild upper respiratory tract syndrome only. there were occasional reports of rv infection associated with more severe clinical illness such as pneumonia but both scientific and pharmacological research tended to be focused on other respiratory viruses such as influenza and respiratory syncytial virus, as these were considered to be more serious human pathogens. colds had long been associated with asthma exacerbations but early studies investigating virus infection in asthma and copd exacerbations reported low detection rates. À the consensus was that asthma exacerbations were predominantly triggered by allergen exposure and copd exacerbations by acute bacterial infection. the development of highly sensitive and specific molecular diagnostic techniques using polymerase chain reaction (pcr) technology led to a revolution in viral diagnostics and a reevaluation of the role of respiratory viruses in a range of clinical syndromes. this was particularly pertinent to human rvs, which are either difficult or impossible to culture (e.g., rv-c strains) and due to the large number of serotypes diagnostic serology testing is not feasible. pcr-based diagnostic tests have a much greater sensitivity for the detection of rvs and studies using pcr revealed that the range of clinical illness associated with rv infection was much broader than previously recognized and included more severe disease syndromes such as pneumonia, bronchiolitis, acute rhinosinusitis, and influenza-like illness. in addition rvs could be detected in most asthma exacerbations, and in a substantial proportion of copd exacerbations. asthma is estimated to affect million people worldwide and copd affects . million people and was the cause of . million deaths in . much of the enormous morbidity, mortality, and healthcare costs associated with asthma and copd are related to acute exacerbations. therefore the recognition that rvs are a major cause of asthma and copd exacerbations stimulated new interest in their biology and treatment. as part of this research investigators considered whether experimental infection studies in humans could be extended from healthy volunteers to patients with asthma and copd. respiratory viruses can be detected in up to % of asthma exacerbations in children and %À % of exacerbations in adults, , À with rvs the commonest virus detected. the recognition of the role of rvs in asthma exacerbations stimulated research into their biology in an attempt to develop treatments for virus-induced exacerbations. this research included investigating whether experimental rv infection could be used in people with asthma in the same way it had been used in healthy individuals. the first experimental rv challenge of subjects with asthma was carried out in at dalhousie university, canada. of the volunteers inoculated, became infected but only had $ % decrease in forced expiratory volume in second (fev ) and an increase in airway hyperreactivity (ahr). the authors felt that these findings suggested "that other viral pathogens may play a more important role in precipitating asthma attacks." it is unclear why this study failed to induce features of asthma exacerbations but it would be almost another decade before further experimental rv infection studies in people with asthma were attempted. experimental infection studies in allergic (nonasthmatic) subjects suggested that rv infection could induce changes in lower airway physiology similar to that seen in asthma. , in an experimental infection study from the university of southampton, united kingdom included a small group of people with allergic asthma and reported that upper respiratory symptoms were more severe in atopic subjects but did not report on lower airway symptoms or physiology. concurrently a study using pcr to detect viruses in naturally acquired asthma exacerbations strongly supported a role for rv. subsequent studies were carried out by research groups in the united kingdom, the netherlands, À and the united states , in volunteers with mild, intermittent asthma. these studies demonstrated that rv infection induced airway obstruction, , increased ahr, À , and airway inflammation , , À and rv could be detected in the lower airways, , thereby supporting a causative role for rvs in asthma exacerbations. having established that respiratory viruses are a trigger for asthma exacerbations, research focused on investigating why rvs cause a benign, self-limiting illness in healthy subjects but result in more severe manifestations in people with asthma. a study of naturally acquired infections in cohabiting couples discordant for asthma suggested that people with asthma were not more susceptible to virus infection but had more lower respiratory tract symptoms. airway inflammation during naturally acquired infections was greater in people with asthma compared with those without asthma but the number of subjects in this study was small and the viruses detected were different between the two groups. viral challenge studies are ideally suited to addressing this research question as people without asthma matched for characteristics such as age and gender can be infected simultaneously. most of the earlier infection studies did not include a control group of healthy volunteers and therefore could not address the question as to whether host responses to infection differ in people with asthma. studies that did include nonasthmatic controls produced somewhat inconsistent results with one study reporting no differences in lower airway inflammatory cells, another reporting increased nasal inflammatory mediators in asthma and discrepant results regarding virus-induced respiratory symptoms. , these divergent results were likely related to differences in sampling methods and timing, antibody status of subjects, and choice of healthy controls (e.g., atopic vs nonatopic). the first study to show clear differences between subjects with and without asthma in their responses to rv infection was published in . in this study, rv challenge induced more respiratory symptoms, greater lung function impairment, increased bronchial hyperreactivity, and eosinophilic and neutrophilic lower airway inflammation in asthmatic compared with normal subjects with direct correlations between loss of lung function and the degree of neutrophilic, eosinophilic inflammation, and nasal viral load. in addition, the study provided insights into potential mechanisms of differential responses to viral infection in people with asthma. despite being infected with the same dose of virus, postinoculation virus loads tended to be higher in the asthmatic subjects compared with the healthy controls, suggesting that antiviral immunity may be impaired in people with asthma with subsequent failure to control viral replication. virologic and clinical outcomes were related to deficient interferon (ifn)-γ and interleukin (il)- responses and to augmented t-helper type (t h ) responses (il- , il- , and il- ), indicating that excessive t h or impaired t h (or il- ) immunity may be important mechanisms. when infected with rv in vitro, alveolar macrophages and bronchial epithelial cells from subjects with asthma demonstrated deficient production of ifnβ and ifnλ, and this was related to the severity of virus-induced asthma exacerbations. other reports subsequently confirmed that ifn production is deficient in asthma, , but this finding has not been replicated in all studies. À it may be that this phenomenon only occurs in a subset of people with asthma, or that it is seen in more severe or poorly controlled asthma. such patients were not initially included in challenge studies as these were limited to mild, wellcontrolled asthma not requiring inhaled corticosteroids. in rv challenge was shown to be safe in a small group of people with wellcontrolled asthma requiring long-term use of inhaled corticosteroids. a larger study confirmed this and reported significantly more upper and lower respiratory symptoms, greater reduction in peak expiratory flow and fev , increased viral loads, increased bronchoalveolar lavage (bal) eosinophils, and increased nasal il- , il- , and il- in subjects with moderate asthma using inhaled corticosteroids. this study also identified novel mediators of virus-induced asthma exacerbations including il- , il- , and il- . poor asthma control was associated with more severe virus-induced exacerbations, greater t h inflammation and higher virus load. therefore responses to virus infection may differ depending on asthma severity and control, which may account for some of the discrepant results in earlier experimental infection studies. these successful viral challenge studies should pave the way for further studies in subjects with moderate asthma that should reveal new insights into the pathogenesis of exacerbations that may not have been obtained from studies in mild asthma. the evidence that emerged from research, including experimental infection studies, that asthma is associated with deficient ifn responses led to the development of inhaled ifnβ as a treatment for asthma exacerbations. a clinical trial of inhaled ifnβ reported that treatment can reduce the severity of virus-induced exacerbations in a subgroup of patients assessed with more severe asthma. the development of inhaled ifn as a novel asthma treatment is a clear demonstration of the potential of experimental rv infection studies to contribute to the discovery of new treatments for virus-induced asthma exacerbations. the global initiative for obstructive lung disease defines copd as "a common preventable and treatable disease, characterized by persistent airflow limitation that is usually progressive and associated with an enhanced chronic inflammatory response in the airways and the lung to noxious particles or gases. exacerbations and comorbidities contribute to the overall severity in individual patients." acute exacerbations of copd are the major drivers of morbidity, mortality, and healthcare costs in copd and prevention of exacerbations a major unmet need. acute bacterial infection was believed to be the main cause of copd exacerbations and this is reflected in the widespread use of antibiotics in copd exacerbations. , although copd exacerbations are preceded by upper respiratory symptoms in up to two-thirds of cases, virus detection rates in the pre-pcr era were low. , as with asthma, the role of viruses in copd exacerbations was reexamined using pcr-based detection methods. although detection rates of respiratory viruses in copd exacerbations are more variable than in asthma, respiratory viruses can be detected in %À % of copd exacerbations, with rvs the predominant virus type detected. À despite this emerging evidence implicating respiratory viruses in a significant proportion of copd exacerbations, both scientific and clinical research continued to focus on bacterial infection. as evidence of this, it was almost two decades after the first experimental rv infection study was carried out in asthma that a similar study in copd was attempted. despite the excellent safety record of experimental infection studies in asthma, caution was warranted in repeating these studies in copd as there are major differences between these two populations. copd patients are older, current or ex-smokers, and have impaired lung function with irreversible airflow obstruction. all these factors have the potential to result in a more severe response to experimental rv challenge, compared with the younger, nonsmoking patients with relatively normal baseline lung function recruited to the asthma infection studies. the first experimental infection study in copd was a small pilot study published in that established the safety of rv infection in four patients with moderate airflow obstruction (fev %À % predicted) and not using regular inhaled therapy. the subjects developed symptoms consistent with a copd exacerbation following rv inoculation, together with objective markers of exacerbation with falls in lung function and increases in upper airway inflammatory markers. all the subjects recovered completely without treatment and no adverse events were reported. subsequently the same research group carried out two larger studies of experimental rv infection in subjects with copd and non-copd control subjects. , these studies replicated the findings of the pilot study, wherein rv infection manifested in cold symptoms, lower respiratory symptoms consistent with exacerbations of copd, including airway inflammation and worsened airflow obstruction. , these studies provided important causal evidence linking virus infection to copd exacerbations. studies from naturally acquired infection were supportive of this link but do not provide definitive evidence as pcr evaluation detects viral nucleic acid and therefore does not prove the presence of live virus and samples are only collected after exacerbation onset. respiratory virus nucleic acid can also be detected in copd patients with stable disease, although is usually elevated during copd exacerbations. in experimental infection models, rv was present in airway samples prior to exacerbation onset, virus load increased in parallel with the increase in symptoms, airflow obstruction and inflammation, and clearance of virus was associated with exacerbation resolution. , strong correlations were observed between virus load and airway neutrophil numbers, neutrophil elastase, il- , il- , and tumor necrosis factor-alpha (tnfα), granulocyte macrophage colony stimulating factor, most of which of also correlated with levels of epigenetic regulator, histone deacetylase and these inflammatory responses were greater in patients with copd. in these studies, rv infection is the sole experimental agent responsible for increased inflammatory markers in patients with copd, providing strong evidence that rv infection directly causes exacerbations in copd patients. another advantage of virus challenge studies over naturally acquired infections is the ability to carry out detailed and repeated lower airway sampling during the course of the exacerbations, including the use of bronchoscopy. this has provided a wealth of mechanistic data regarding the pathogenesis of virus-induced exacerbations including the presence of inflammatory mediators, , inflammatory cells, , , oxidative and nitrosative stress, and impaired antiviral ifn responses. a novel observation that emerged from these studies was that secondary bacterial infections occurred in % of experimental virus-induced exacerbations, whereas coinfection was rarely reported in naturally acquired exacerbations. analysis of the respiratory microbiome following experimental rv infection suggest that secondary infection occurs due to an outgrowth of previously present airway bacteria. potential mechanisms of secondary bacterial infection include reduced antimicrobial peptides and increased glucose in the airways. a subsequent study of naturally acquired exacerbations sampling at multiple time points during exacerbations confirmed the validity of this observation. therefore although the numbers of copd subjects recruited to virus challenge studies to date is small, rv infection appears to be safe in this population and replicates the features of naturally acquired infection. further studies including larger numbers of patients are needed to validate these findings and further investigate the mechanisms of virus-induced exacerbations in copd. since the first studies in healthy volunteers, experimental rv infection has been extended to patients with asthma and copd and has contributed enormously to expanding our understanding of the biology of rv infection and how it affects patients with chronic airway diseases. a summary of the key findings from human experimental infection studies in people with asthma and copd is provided in table . . these studies have tended to have a narrow focus on rv infection and host immune responses. it is clear from both in vivo and in vitro studies that there are interactions between respiratory virus infections and other factors that exacerbate asthma and copd such as bacteria, allergens, and air pollution. these factors have been somewhat neglected in viral challenge studies and are a promising field of future research that is starting to be addressed. , as mentioned previously, the use of the viral challenge model in asthma is much further advanced compared with copd. one study identified ifn-deficiency in copd but this has not been replicated. with the development of inhaled ifn as a therapy option for asthma, the role of ifn in copd requires urgent further investigation. other areas of future research include the effects of virus infection on novel pathways such as lipidomics and metabolomics in asthma and copd. respiratory viruses have also been identified as triggers of exacerbations in other airway diseases such as cystic fibrosis , and bronchiectasis , and there is evidence of impaired antiviral immunity in these diseases. experimental infection studies may help to define the role of virus infection in these patient populations. aa exposed to allergen placebo, aa exposed to rv, aa exposed to rv and allergen perhaps the most promising use of the virus challenge model will be to accelerate the process of drug development. , virus challenge studies have been used to evaluate the effects of existing asthma therapies on virus-induced exacerbations. , recently the first study using viral challenge to evaluate a novel, unlicensed drug in asthma was also published. although these studies had negative results they demonstrate the potential of the viral challenge model in drug development. the key to successful drug development is the identification of clinically relevant mechanisms of rv infection or immunopathology that can be experimentally manipulated for therapeutic benefit. this is where human experimental rv infection is complemented by work in animal models. there are a number of options for modeling human rv infection in animal models and they provide the ability to investigate specific disease components and mechanisms that would be otherwise impossible in humans. human experimental infection models have the advantage of identifying disease correlates, but the degree of experimental manipulation possible is extremely limited and the safety and effectiveness of interventions must first be evaluated in animals. animal models have proven useful for mechanistic studies across a range of diseases. models of rv infection have been reported in several animal species, including mouse, cotton rat, and nonhuman primates. each of these experimental systems provides its own advantages and disadvantages and a substantial contribution to the knowledge base of the biology of rv infection. animal models provide a range of benefits to complement human experimental approaches. experimental animals can be readily manipulated to induce consistent disease outcomes, such as the induction of allergic airway disease (aad) to model asthma or cigarette smokeÀinduced copd. animal models have less variability than human populations providing more consistent experimental outcomes and statistical power in intervention studies. experimental environment, exposures (e.g., previous infection history), endpoints, and interindividual variability can be controlled. further, a broad array of tools are available to characterize disease outcomes, including reagents, genetically modified animal strains, experimental protocols, and assessment techniques (e.g., lung function testing). sample tissues can be easily isolated at experimental endpoints, which are difficult or impossible to sample in humans (e.g., lung tissues, draining lymph nodes, bone marrow). further, animal models serve as a valuable preclinical system for the assessment of novel interventions, to provide proof-of-principle safety and efficacy findings prior to exposure of healthy human volunteers. mice in particular have been extensively used to model disease, including virus infection and exacerbations of asthma and copd. À as a result, a wealth of tools and techniques are available to study immune mechanisms and pathophysiology in mice. well-characterized protocols and reagents support the induction of disease states and allow detailed characterization of immune responses (e.g., fluorescently tagged monoclonal antibodies to quantify immune cell subsets). a range of transgenic and knockout mouse strains are available that allow for the careful dissection of relevant disease mechanisms. further, reagents are available to assess the effects of novel interventions on disease outcomes (e.g., blocking antibodies and various forms of innate immunity activators; see chapter : emerging therapeutic approaches). the expansion of mouse rv infection models has paralleled our understanding of rv biology in humans. initial approaches focused on understanding the effects of rv infection in isolation, identifying the mechanisms and cell types mediating lung pathology. increasingly complex experimental models are now being used to characterize long-term effects of infection on airway function and the effects of rv infection on preexisting airway disease (e.g., asthma exacerbations). À one of the biggest developments in mouse rv infection models was the protocol for isolation of highly purified, concentrated (high titers) of rv from henrietta lacks (hela) immortalized human epithelial cell lines and later, the intracellular adhesion molecule (icam- ) transfected rhabdomyosarcoma cell lines. , prior to this, clarified infected hela cell lysates were used for in vitro experiments. some investigators also used infected hela cell lysates in mouse models. efforts to improve the quality and validity of the model made use of a partial purification protocol to generate viral stocks. for mouse models of rv infection or exacerbations, the refined, high-titer, rv purification protocol is the gold standard. a major barrier that hindered the early development of mouse models was the species specificity of rv infection. "major-group" rv strains, which make up approximately % of all rv strains, enter the cell through binding of icam- . , rv binding to icam- is limited to human and chimpanzee and does not occur in other species, including mouse. as a result, major-group rv strains cannot infect mouse cells and fails to replicate or induce pathology in mouse models. early attempts to develop rv mouse models failed to detect sufficient viral replication to induce disease. a major advance enabling the development of mouse rv infection models was the initial recognition that the minor-group rv-a , which use the host cell receptor low-density lipoprotein receptor, can infect the mouse epithelial cell line la- . this recognition suggested that minorgroup rv viruses (e.g., rv-a ) may be useful to model infections in mice in vivo. indeed, inoculation of wild-type balb/c mice with rv-a induced lung pathology, mucus production, and inflammatory cytokine production. notably, rv infection was also sufficient to induce exacerbations of preexisting asthma in sensitized and challenged mice (as discussed in more detail below). an alternate approach was also sought to allow modeling of majorgroup rv infection in mice. the same study by tuthill et al. demonstrated that transfection of la- cells with a chimeric icam- receptor containing the human extracellular receptor domains allowed infection and replication by the major-group virus rv-a . this finding provided the basis for developing a transgenic mouse strain expressing a chimeric mouseÀhuman icam- receptor. chimeric receptor expression in hu-icam tg mice is sufficient to support in vivo infection with rv-a , resulting in airway inflammation, mucus production, viral replication, and inflammatory cytokine production. of note, the hu-icam tg mouse was generated by random insertion of a chimeric transgene and little is known about the transgene insertion site within the genome. use of this transgenic strain requires additional experimental considerations (e.g., genotyping and use of heterozygous animals in experiments), which has limited its broad utility. additional variations have also been reported in the literature, which aim to broaden the available mouse models. genetic rv-a variants have been generated by serial passage through mouse embryonic fibroblasts in vitro and lung epithelial cells in vivo, which exhibit increased growth in mouse cells. inoculation of balb/c mice with the rv-a / m m variant [ plaque forming units (pfu)] allowed for recovery of virus from mouse lung after hours, when mice were also pretreated with intranasal hydrochlorous acid to increase epithelial permeability. successful use of mouse models also depended on the development of streamlined rv isolation protocols that have allowed consistent and rapid isolation of virus stocks, to limit variability between experiments. the current gold-standard protocols for rv isolation, rv-a infection of wild-type balb/c mice, and the infection of transgenic mice expressing chimeric mouseÀhuman icam- receptor with rv-a are published and readily available. a range of studies have assessed the effects of primary rv infection in mice, contributing to our understanding of the mechanisms underlying disease pathogenesis. studies have used similar protocols, typically performing intranasal inoculation of b À tcid (tissue culture infective dose in % of culture, a titration of infection units of pathogens that do not form plaques in culture) rv-a and assessing responses over week following infection in balb/c or c bl. mice. in the initial publication by bartlett et al., intranasal inoculation of wildtype balb/c mice with tcid rv-a induced a range of disease features similar to human disease. rv infection induced airway inflammation characterized by increased neutrophil numbers at and hours postinfection and increased lymphocyte numbers persisting for -week postinfection. tissue pathology was characterized by perivascular and peribronchial inflammation, increased mucus production, and elevated inflammatory cytokine production (including mip- , kc, mip- α, ip- , rantes, itac, il- , il- β, ifnα/β/λ/γ). furthermore, rv infection resulted in the development of an rv-specific adaptive antibody response by days postinfection. further studies have provided insights into the effects of rv infection alone in mice. following inoculation of wild-type c bl/ mice with tcid rv-a , detectable rv positive-and negative-strand rna were recovered from the lung, indicative of active viral replication and viral rna was detectable up to days postinfection. the study also noticed a small increase in airway neutrophils and lymphocytes in the presence of uv-inactivated rv-a , although uv-inactivated rv-a (and major-group virus rv- ) failed to induce inflammatory cytokine production. rv-a infection also increased airway responsiveness to methacholine challenge at days and postinfection. inoculation with rv-a or uv-inactivated rv-a induced pi k activation in airway epithelial cells and pretreatment with the pi k inhibitor ly in vivo dampened neutrophilic inflammation and inflammatory cytokine production (kc, mip- , mip- α, ifnγ). inoculation of c bl/ mice with rv-a ( tcid ) leads to discontinuous expression of zonula occludens- , suggesting that infection disrupts airway epithelial barrier function. rv infection also stimulated il- production and release into the airways, which is dependent on type i ifn production and stimulates activation of natural killer (nk) and cd t cell responses. treatment with an il- Àil- ra complex increased expression of il- , il- rα, ifnγ, and cxcl and stimulated increased nk, cd , and cd t cell recruitment and activation. ccl and irf- are the most upregulated lung transcripts following rv-a infection. blocking ccl or irf- function reduced lung neutrophil and macrophage accumulation and ifn responses and blocking ccl also reduced ahr. this publication also delineated ahr from inflammatory infiltrates showing instead a relationship between classical proinflammatory transcription factors (nfκb) and ahr. as alluded to previously, the use of knockout mice in particular has provided insights into a number of mechanisms regulating rv-induced pathology. key roles for neutrophils and the neutrophil chemokine receptor cxcr in mediating rv-induced pathology were identified. inoculation of cxcr / mice with rv-a ( . tcid ) resulted in reduced airway neutrophil numbers, reduced inflammatory cytokine production (tnfα, mip- , kc), decreased mucus production, and decreased cholinergic responsiveness, with no alteration in viral load, compared with wild-type control animals. further, antibody depletion of neutrophils and infection of tnfr / mice also reduced ahr, compared with control animals. these findings provide evidence for a role of neutrophilic inflammation, potentially via tnfα production, on downstream pathology following rv infection. roles for pattern recognition molecules have been demonstrated for mda , toll-like receptor (tlr ) and tlr . infection of mda / mice resulted in delayed type i ifn (ifnα/β) and suppressed type iii ifn expression, with a slight early increase in viral load in the lung. in contrast, inoculation of tlr / mice resulted in normal ifn responses and no difference in viral yield. both mda / and tlr / mice had reduced neutrophil numbers, inflammatory cytokine production (cxcl , cxcl , ccl , cxcl ) and airways responsiveness, compared with wild-type controls. differing roles for nfκb signaling pathways in rv-induced inflammation and type i inf responses in antiviral immunity have been demonstrated. disruption of nfκb signaling in p / mice resulted in reduced neutrophil numbers and inflammatory cytokine production (cxcl , cxcl , cxcl ), while ifn production and viral loads are unaltered. in contrast, ifnar / mice have unaltered neutrophilic inflammation, a persistent increase in lymphocyte numbers and cytokines ccl , cxcl , and cxcl , with reduced ifnα production and increased viral load. a pathogenic role for the proinflammatory molecule muc has also been demonstrated, with increased expression of antiviral genes (mx , ip- ), reduced neutrophil inflammation and viral load in muc / mice following rv-a inoculation ( pfu). studies using tbet / mice (a key regulator of t h cell differentiation) have also demonstrated the key role for t h -polarized t cells in the response to rv infection. tbet / mice developed a t h / t h -polarized immune response to rv infection ( tcid ) with increased il- and il- a production, deficient nk cell responses, and decreased neutralizing antibody development. cd t cells contributed to increased airway eosinophil numbers and mucus production following rv infection in tbet / mice. studies using tslp receptor-deficient mice (tslpr / ) demonstrated that rv-a infection interferes with tolerance to an inhaled allergen, via a mechanism requiring tslp, il- , and activation of ox l on lung dendritic cells. after observing increased levels of the tnf super family member protein, tnfsf (trail or cd ) production over a time course of rv-a infection in mice, girkin et al. compared rv-a infection in tnfsf / mice to wild-type balb/c mice and observed an almost complete ablation of inflammatory responses to rv-a . following rv infection, peribronchiolar inflammation and lung histopathology were reduced in tnfsf / mice; neutrophil and lymphocytes in bal remained at baseline; and cd t cells, cd t cells, nks, plasmacytoid dendritic cells (pdcs), and myeloid dendritic cells were all reduced in flow cytometry of total lung cells. tnfsf / mice were protected from rv-induced ahr, and failed to develop rv-induced exacerbations of allergic airways disease. an interesting proviral effect of trail was also identified whereby tnfsf / mice had reduced viral load and anti-trail antibodies reduced viral load (whereas recombinant trail administration increased viral load) in beas b cells infected with rv-a in vitro. this effect on viral load was independent of ifn responses and may be associated with an unidentified role of apoptosis in rv replication, which remains to be explored. some studies have assessed the effect of primary rv infection on clinically relevant sequelae, including secondary bacterial infection and the effects of premature birth on infection. exposure of epithelial cells in culture to rv-a resulted in increased bacterial attachment and translocation through an epithelial monolayer (nontypeable haemophilus influenzae (nthi), pseudomonas aeruginosa, staphylococcus aureus), suggesting a potential mechanism underlying secondary bacterial infections following viral infection. a subsequent study demonstrated that primary inoculation with rv-a ( tcid ) delayed the clearance of nthi in vivo, associated with suppressed chemokine production (kc, mip- ) and neutrophilic inflammation through a tlr -mediated mechanism. the model has also been used to assess immune alterations relevant to premature birth and bronchopulmonary dysplasia, risk factors for viral-induced exacerbations. exposure of neonatal mice to hyperoxia ( % oxygen) in early life increased inflammatory cytokine expression (il- , ifnγ, tnfα, ccl , ccl , ccl ) and suppressed early ifn responses following rv-a infection ( pfu) at days of age. one study has also assessed the effect of rv infection timing on subsequent development of aad. inoculation of -day-old mice with rv-a and subsequent induction of house dust mite (hdm)-induced allergic airways disease had additive effects with increased neutrophilia and ahr in female mice, although rv inoculation had no additional impact in male mice. these studies extend the use of rv infection in mice to new areas, including mechanisms of early life infection susceptibility, to mechanisms of secondary bacterial infection/compromised antimicrobial immunity and experimental exploration of clinical risk factors associated with increased likelihood to develop virus-induced exacerbations of respiratory diseases. mouse models are valuable tools for the preclinical testing of novel treatments. several studies have used the mouse rv infection model to assess intervention strategies, including vaccine development and drug treatment. primary inoculation of balb/c with rv-a ( tcid ) rapidly induced circulating rv-specific igg antibody production within days, which binds capsid protein vp and those antibodies were crossreactive to another minor strain rv (rv- ). repeated rv infections were necessary to induce rv-specific iga responses and neutralizing antibodies, but administration of cpg or subcutaneous immunization with freund's adjuvant promoted neutralizing antibody development and may inform potential vaccine strategies. pretreatment with the plant flavanol quercetin before and during rv-a infection effectively reduced viral replication, inflammatory cytokine production (kc, mip- , tnfα, ccl , ifnα, and ifnλ ), and ahr. treatment with the cancer therapeutic gemcitabine ( , -difluorodeoxycytidine) reduced rv load, inflammatory cytokine levels (tnfα, il- β), and reduced lung lymphocyte numbers. treatment with corticosteroid therapy (fluticasone proprionate) suppressed ifn responses to rv and reduced airway inflammation, leading to increased mucus production and reduced antimicrobial responses. effects on viral load, mucin production, and antibacterial response could be reversed by administration of recombinant ifnβ. despite promising findings in mouse models, quercetin has not entered clinical trials for the treatment of rv infection, likely due to a previous randomized community clinical trial in that showed little benefit of quercetin supplementation on upper respiratory infections. these findings may highlight the limitation of mouse models, which (while valuable) do not always fully recapitulate human disease mechanisms. animal models to study rv-mediated exacerbations of airway disease have also been developed. these models combine experimental rv infection with models of airways disease, including asthma, copd, and chronic rhinosinusitis. models of asthma typically consist of administration of a sensitizing agent [e.g., ovalbumin (ova) or hdm] and subsequent challenge in the airways to induce an eosinophilic, allergic airways disease. copd is typically induced by prolonged and repeated exposure of mice to cigarette smoke or treatment with elastase. after airways disease is established, mice are then inoculated with rv to induce disease exacerbations. these models are explained and expanded upon in the following sections. researchers have also used double-stranded rna (dsrna) administration as a surrogate for virus infection to exacerbate preexisting disease (reviewed in refs. [ , ] ). however, these approaches fail to model the complexity of virus infection and are beyond the scope of the current book chapter. many studies have characterized the effects of rv infection on preexisting asthma and have provided insights into the immune cell types involved, key molecules, and responses to potential therapies. in the initial report of an rv (rv-a ) exacerbation model, ova-sensitized and challenged balb/c mice were inoculated with rv-a during the allergen challenge phase. the combination of virus and allergen challenge increased airway neutrophil, eosinophil, and lymphocyte numbers; increased cytokine production (il- , il- , and ifnγ), increased ahr; and increased mucus gene expression. subsequent studies have identified key functional roles for macrophages, gamma-delta (γδ) t cells, dendritic cell subsets, and neutrophils in rv-induced immunopathology. in a similar model, rv-a inoculation into ova-sensitized/challenged mice increased macrophage lung infiltration and eotaxin- /ccl expression. eotaxin was expressed by pulmonary macrophages in the lung after combined virus infection and allergen challenge. further, macrophage depletion or antieotaxin treatment reduced rv-induced airway eosinophilia and ahr. macrophage activation state also modulates the response to rv infection in allergen sensitized/challenged mice and shapes the resulting pattern of inflammation. rv infection in asthma exacerbation models induced an il- expressing macrophage population, with m polarized phenotype. depletion of il- -producing cells in cd b-dtr mice or ccr / mice reduced airway inflammation and ahr. interestingly, while rv infection of ova-treated wild-type mice contributes to mixed neutrophilic and eosinophilic airway inflammation and m macrophage phenotype, il- r / mice exhibit neutrophil inflammation alone and increased m polarization of pulmonary macrophages but still have exacerbated airway responses. γδt cells dampen exacerbation responses. γδt cells are increased in rv-induced asthma exacerbation models and blocking responses with anti-γδtcr antibody worsened exacerbations with increased ahr, and increased numbers of t h cells and eosinophils, with no effect on virus load. pdcs were recruited to the lung during rv-induced inflammation and subsequently promoted t h responses in the lung draining lymph nodes, in a process mediated by il- . depletion of pdcs with an antibody or treatment with anti-il- reduced eosinophil numbers, decreased lung pathology, reduced cytokine production (il- , il- ), and reduced ahr. functional roles for neutrophils, and neutrophil extracellular traps (nets), have also been provided in rv-induced asthma exacerbation models. chronic low-dose hdm exposure and rv infection have additive effects on neutrophilia and induce ahr. a more recent study demonstrated that rv infection in an hdm-mediated asthma model results in double-stranded dna release into the airways and administration of genomic dna alone was sufficient to mimic characteristic components of rv-induced exacerbations. further, blocking neutrophil elastase or degrading nets by applying dnase into the airways reduced eosinophil and lymphocyte numbers, tissue pathology, and cytokine production (il- , il- ). a number of studies have highlighted the functional roles of specific molecules in rv-induced mouse exacerbation models, as potential therapeutic targets to validate in patient populations. in addition to roles during rv infection alone highlighted above, mda and tlr are also involved in rv-induced exacerbations. mda / and tlr / mice have decreased inflammatory responses and ahr, while mda / also had decreased ifn responses (ifnβ/λ /λ ). midline (a e ubiquitin ligase) is upregulated in an hdm-induced model, and short interfering rnaÀmediated inhibition prior to rv inoculation reduced neutrophil numbers and mucus production production. the monocyte chemotactic protein ccl is produced by epithelial cells and macrophages following rv-induced exacerbation and administration of an anti-ccl antibody reduced eosinophil numbers and ahr. foxa -overexpressing transgenic mice produce excess mucus in their airways and rv infection increased foxa expression. in foxa -deficient mice (foxa / ), rv clearance is increased, with increased ifnβ activation. il- expression is also increased in rv-induced exacerbations and blocking the il- receptor reduced type cytokine production (il- , il- , il- , il- , il- , tslp), mucus production, and numbers of eosinophils, neutrophils, t cells, and innate lymphoid type cells. combining dsrna administration with rv-a inoculation worsened preexisting allergic airways disease. repeated dsrna administration after ova sensitization/ challenge resulted in neutrophilic lung inflammation and tissue pathology and combined dsrna and rv-a inoculation increased expression of tslp, tnfα, and ifnλ in the lung. key roles for pattern recognition receptors have also been demonstrated in rv asthma exacerbation models. hdm-allergic tlr / mice had a decreased antiviral response, with reduced ifn release (ifnα/β/λ /λ /λ ) and increased virus replication, associated with increased eosinophil and lymphocyte numbers, increased il- and ccl , and ahr. administration of ifn or transfer of wild-type tlr -competent pdcs could restore antiviral responses and reduce disease exacerbation. ova-allergic tlr / mice also had reduced macrophage, neutrophil, and eosinophil numbers and suppressed ahr after rv inoculation. bone marrow transfer experiments demonstrated that tlr / bone marrow could protect from exacerbations, while transfer of wild-type bone marrow restored responses in tlr / mice. transfer of wild-type macrophages into tlr / mice could also restore exacerbations. as previously mentioned, a role for trail has also been demonstrated, with hdm-allergic trail-deficient mice (tnfsf / ) protected from rv-induced ahr and induction of airway inflammation. rv-induced asthma exacerbation models have also been used to assess the responses to existing therapies and as preclinical models for novel therapies. treatment of hdm-allergic mice with the long acting beta- agonist salmeterol reduced ahr and eosinophil numbers during rv exacerbation, and limited chemokine levels (ccl , ccl , cxcl ) through modulation of pp a. the findings of this study were focused on pp a as a novel therapeutic target rather than promoting salmeterol monotherapy (which was associated with adverse events and tolerance to β -agonists with chronic salmeterol use ). an approach to block majorgroup rv virus infection was assessed through administration of antihuman icam- antibody, which prevented entry of rv-a and rv- and reduced neutrophil and lymphocyte numbers, cytokine production (il- , il- , il- , ccl , ccl ), mucus production, and virus load in human transgenic mice in an ova-allergic model. treatment with a nontoxic anthraquinone derivate reduced rv-induced ahr, neutrophil, and eosinophil airway inflammation; inflammatory cytokine production; and mucus hypersecretion while also boosting type ifn response and reducing viral yields, with associated decreased akt, hif- α, and vegf production. treatment with an antiinflammatory vap- /ssao inhibitor, pxs- a, or the macrolide antibiotic azithromycin also reduced neutrophil numbers and pxs- a reduced ahr following rv-a inoculation in hdm-allergic mice. . . mouse chronic obstructive pulmonary disease exacerbation models rv also plays an important role in virus-induced exacerbations of copd. several studies have assessed the effects of rv inoculation in animal models of copd. exposure to elastase and lipopolysaccharide (lps) once per week for weeks induces features of copd, including airway inflammation, goblet cell metaplasia, and altered lung function. addition of rv-a led to persistence of viral rna ( . days postinfection), deficient ifn responses (ifnα/β/γ) and increased ahr, lung volume, cytokine production (tnfα, il- , il- ), and mucus production, compared with elastase/lps administration alone. a subsequent study attempting to replicate the elastase/lps model of copd found that a single elastase treatment followed by rv-a inoculation was enough to increase airway neutrophil and lymphocyte numbers, increased inflammatory cytokine production (tnfα, cxcl , ccl ), mucus hypersecretion, and ahr. in the same elastase-induced model, fluticasone proprionate treatment reduced ifn responses, increased viral load, suppressed airway immune cell numbers (lymphocytes and neutrophils), suppressed inflammatory cytokines (il- , tnfα), and increased mucus production, following rv-a exacerbation. the differences in the experimental approaches required to elicit an rv-induced exacerbation in these different studies is likely due to the quality of virus inoculum used by the different investigators, which as explained previously, is influenced by purification approach. the first study used only crude virus-infected cell lysates, whereas the later study employed a highly purified virus inoculum. several studies have also reported on rv infection in a cigarette smo-keÀinduced copd model. in an initial study, weeks of cigarette smoke exposure resulted in increased viral persistence, neutrophilia, and increased mucus production following rv infection. subsequent studies demonstrated that goblet cell gene expression was reduced following treatment with a gamma-secretase inhibitor (gsk l , ) to limit notch activation. further, supplementation of feed with quercetin reduced rvinduced lung inflammation (including neutrophilia), goblet cell metaplasia, and ahr. to our knowledge, only one study has assessed the effect of rv infection in a chronic sinusitis model. a mouse model of chronic allergic rhinosinusitis was induced by weeks of repetitive nasal ova challenges. increased rv-a yields were reported in the nasal tissue of mice with rhinosinusitis, although inflammatory cytokine production and histopathology were unaffected. this study served to illustrate the range of additional diseases where rv infection has been shown to be relevant in human populations where animal models are available for future research (e.g., cystic fibrosis). a limited number of studies reported the use of rv infection in other animals, namely cotton rats and nonhuman primates. we note that historical studies assessing "rv" infection in other animal species are referring to genetically distinct viral genera and should not be confused with human rv (e.g., equine rv and bovine rv). for example, while human rv and equine rv were both originally assigned to the rhinovirus genus, they have been reclassified into enterovirus and apthovirus, respectively. equine rv has subsequently been renamed "equine rhinitis virus." the cotton rat (sigmodon hispidus) is a recognized model for human respiratory infection, particularly for respiratory syncytial virus, as well as adenoviruses, parainfluenza virus, measles, and human metapneumovirus (reviewed in ref. [ ] ). to date, two studies have reported on rv infection in cotton rats, providing evidence that cotton rats are partially permissive to rv major-group infection. intranasal inoculation of rv-a ( pfu) into cotton rats induced lower respiratory histopathology, increased mucus production, and induction of inf-activated genes. immunization with live rv-a -induced high levels of circulating antibodies and protected from subsequent infection, while prophylactic transfer of anti-rv-a serum also protected from disease. further, this protection was transferred effectively from mother to newborn, limiting viral yields in subsequently infected progeny. in a later study, the same group provided evidence that infection with rv-b ( pfu) induced similar disease pathology. furthermore, immunization with rv-b provided protection from subsequent infection with either rv-b (an rv-b group virus) or rv-a (an rv-a group virus), demonstrating some degree of crossreactivity to very different major-group viruses. chimpanzees and gibbons are the only nonhuman primates that support rv infection, although rv infection has also been reported in the vervet monkey cells, with consistent infection requiring high dose exposure. initial rv infection studies in chimpanzees were reported in , using rv-b and rv-a and in gibbons in . subsequent studies in chimpanzees and gibbons assessed the antiviral effects of drug treatments on rv infection, using bis-benzimidazole and triazinoindole, respectively. , administration of soluble truncated form of human icam- can prevent subsequent infection in chimpanzees. however, it has been noted that neither chimpanzees nor gibbons develop "cold" symptoms following rv infection and the high costs and logistics of these studies has limited further progress. chimpanzees are an endangered species and require considerable resources and facilities for research. current chimpanzee research is limited to the united states and gabon. however, the national institutes of health in the united states have indicated that they are seeking to eliminate the use of chimpanzees in research. all but one species of gibbon are endangered. thus clinical research using nonhuman primates in the future to characterize rv infection are likely to be limited or nonexistent. as rv does not normally infect rodents, an attenuated mengovirus infection model has been proposed as an alternative option to model rv infection. mengovirus also belongs to the picornaviridae family and normally causes systemic infection in rodents. using an attenuated mengovirus, intranasal inoculation of pfu into rats increased airway neutrophil and lymphocyte numbers, induced lung tissue pathology, and increased expression of cxcl and ccl . a subsequent report using a genetically attenuated mengovirus vmc( ) in mice also induced lower respiratory tract infection with increased lung neutrophil and lymphocyte numbers, expression of cxcl , cxcl , cxcl , il- a, infs, and chemokines cxcl and ccl . other respiratory virus infections are associated with acute exacerbations of asthma and copd, including respiratory syncytial virus, influenza, human coronavirus, human parainfluenza virus, human metapneumoviruses, and adenoviruses. animal models for these infections have largely been limited by the specificity of viruses to humans. it is unclear to what extent the mechanisms causing pathology differ between different viruses (or between strains of the same virus). a detailed discussion of the disease processes induced by each of these different virus infections is beyond the scope of this chapter. a detailed analysis of the relevant disease mechanisms in each infection setting is necessary to inform our understanding of disease exacerbations and ideally to identify common mechanisms between viruses that can be targeted for therapy. no animal model can completely recapitulate naturally occurring human rv infection. while animal models provide important insights into disease mechanisms, it is important to also recognize their limitations. there are recognized limitations of mice as models of human respiratory disease. these include differences in response/symptoms between other species and humans. there are differences in respiratory tract architecture in human, nonhuman primate, and mouse airways. they range from dichotomas (each airway splits into two), trichotomas (airways split into threes), or monopodial branching (central airway continues while subordinate airways branch out) with differences in airflow inhomogeneities covered in detail by miller et al. there are also differences in mucus production processes in mouse compared with human airways. the short lifespans of laboratory animals do not capture the life-course of human disease, mice do not naturally develop asthma or copd, and most current models of asthma represent eosinophilic, allergic patterns of disease. it remains unclear to what extent the current models and pathophysiology truly reflect human disease (particularly considering recognized heterogeneity of the human population). rv has evolved for efficient replication in the human respiratory tract. due to the decreased efficiency of rv entry into nonhuman epithelial cells (and likely differences in the nuances of cellular machinery required for replication), a high amount of viral load is required to elicit a biological response to rv in laboratory animals (e.g., tcid in mouse vs À tcid in experimental human infection models). human rv strains also demonstrate limited viral replication and different replication kinetic between mouse and man. these differences highlight the importance of confirming findings in relevant patient cohorts/samples and the utility of using human experimental models in parallel with animal models. this point is not purely for academic consideration. more so, it is important to take into consideration clinical trial design and outcomes. for example, mouse models highlighted the key relevance of il- in asthma pathology through use of knockout mice and antibody blockade. however, the initial randomized control trial assessing anti-il- therapy (mepolizumab) in a broad asthma population failed to demonstrate any clinical effect. it was not until subsequent trials limited recruitment to patients with demonstrable eosinophilic asthma (a patient subset that is more closely modeled by the experimental mouse system) that clinical improvements were observed. , . . future directions for animal models in a similar way to experimental human infection models, there has been a narrow focus in animal models. in mice, focus has largely been on rv infection alone with a growing body of literature assessing asthma exacerbations. while difficult to model in mice, rv-induced copd exacerbations models are emerging through use of elastase administration and cigarette smokeÀinduced copd. a summary of key findings from mouse models of rv-induced exacerbations of airway disease is presented in table . . limited studies have reported on rv effects or potential interventions in these models. as with human experimental infections, animal infection models may also be relevant to an expanding array of diseases in the future (e.g., cf, bronchiectasis). to date, there has been limited assessment across different rv strains in both animal and human studies. the primary focus of rv models has been on rv-a in mice, or rv-a and rv-a in human, possibly due to the availability of these strains and the ease of growing these strains in cell culture. in particular (due to its relatively recent discovery), rv-c infection has yet to be assessed in animal models. there has so far been difficulty in generating sufficient quantities of rv-c for research purposes (particularly at infectious titers required for mouse models). with the recent establishment of a suitable cell line (e hela cells) that supports rv-c replication this gap in the literature will likely be rectified. elastase/lps rv-a nil deficient antiviral immunity increased inflammation exaggerated ahr increased mucin expression as is the case for the majority of human virusÀmouse infection models, the mouse is semipermissive to rv infection and as such a high-titer inoculum is required to induce prolonged replication and robust, reproducible host immune responses. a mouse-adapted rv strain (rv- bm) has been generated by serial passage in mouse epithelial cells (la- cells) though this mouse-adapted virus has only been characterized in vitro with primary mouse tracheal epithelial cells and has not yet been tested in vivo. the clinical translation of novel therapies identified in animal models for the treatment of rv infection in humans is yet to come to fruition. however, there are multiple molecules currently in the drug development pipeline, ranging from virus-targeting molecules, drugs targeting host factors of the viral replication cycle, and biologics such as innate immune stimulators and cytokine blocking monoclonal antibodies, all of which are elaborated on in chapter , emerging therapeutic approaches. there are significant opportunities for further research in both human and nonhuman models, including assessment of infections in various unexplored disease backgrounds that are exacerbated by rv infection (e.g., cystic fibrosis) and expansion of studies using newly identified rv strains (e.g., rv-c strains). human and mouse rv experimental infection models effectively complement each other and have contributed immensely to our understanding the mechanisms shaping rv-induced pathology. human experimental rv challenge studies have shed light on the biology of rv infection and the mechanisms associated with rv-induced exacerbations of chronic respiratory diseases. mouse models of rv infection in particular are readily manipulatable to identify cause and effect between specific molecules and disease outcomes for preclinical testing. an excellent example of how human and mouse models complement each other is the growing understanding of the disease mechanisms during rvinduced asthma exacerbations. human experimental infection revealed a potential role for induced type immunity following rv infection in individuals with asthma. , subsequent mouse model studies have demonstrated a causal role for rv-induced type immune effector molecules in exacerbations, , , , allowing preclinical assessment of the efficacy and safety of novel therapies. findings from these studies have not yet resulted in the development of approved therapies for rv infections, cold symptoms, or exacerbations of respiratory diseases associated with rv infection. however, the wealth of knowledge derived from experimental rv infections has broadened our understanding and identified many potential therapeutic approaches. can we distinguish respiratory viral infections based on clinical features? a prospective pediatric cohort compared to systematic literature review the viral etiology of 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of a mouse model for human rhinovirus infection mouse respiratory epithelial cells support efficient replication of human rhinovirus mouse models of rhinovirus-induced disease and exacerbation of allergic airway inflammation selection of rhinovirus a variants adapted for growth in mouse lung epithelial cells rhinovirus disrupts the barrier function of polarized airway epithelial cells il- complexes induce nk-and tcell responses independent of type i ifn signaling during rhinovirus infection ccl and irf- mediate hallmark inflammatory and ifn responses following rhinovirus b infection cxcr is required for neutrophilic airway inflammation and hyperresponsiveness in a mouse model of human rhinovirus infection mda and tlr initiate proinflammatory signaling pathways leading to rhinovirus-induced airways inflammation and hyperresponsiveness defining critical roles for nf-kappab p and type i interferon in innate immunity to rhinovirus muc regulates lung rhinovirus infection and inflammation 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airway inflammation in balb/ c mice effects of an interleukin- blocking monoclonal antibody on eosinophils, airway hyper-responsiveness, and the late asthmatic response mepolizumab for prednisonedependent asthma with sputum eosinophilia mepolizumab for severe eosinophilic asthma (dream): a multicentre, double-blind, placebo-controlled trial mutations in vp and a proteins improve binding and replication of rhinovirus c in hela-e cells temperature-dependent innate defense against the common cold virus limits viral replication at warm temperature in mouse airway cells key: cord- - y ieamp authors: cameron, robert j.; de wit, deo; welsh, toni n.; ferguson, john; grissell, terry v.; rye, peter j. title: virus infection in exacerbations of chronic obstructive pulmonary disease requiring ventilation date: - - journal: intensive care med doi: . /s - - -x sha: doc_id: cord_uid: y ieamp objectives: we aimed to characterise and quantify the incidence of common infectious agents in acute exacerbations of chronic obstructive pulmonary disease (copd) requiring ventilation, with a focus on respiratory viruses. design: an epidemiological study conducted over years. setting: a -bed intensive care unit (icu). participants: icu patients over years of age with a primary diagnosis of copd exacerbation requiring non-invasive ventilation (niv) or ventilation via endotracheal tube (ett). materials and methods: nasopharyngeal aspirates (npa) and posterior pharyngeal swabs (ps) were tested for viruses with immunofluorescence assay (ifa), virus culture (vc) and polymerase chain reaction (pcr). paired virus and atypical pneumonia serology assays were taken. blood, sputum and endotracheal aspirates were cultured for bacteria. results: episodes in patients were recorded. twenty-three ( %) died within days. a probable infectious aetiology was found in patient episodes ( %). a virus was identified in cases ( %), being the sole organism in cases ( %) and part of a mixed infection in cases ( %). a probable bacterial aetiology was found in cases ( %). there was no statistically significant difference in clinical characteristics or outcomes between the group with virus infections and that without. conclusion: forty-six ( %) of the patients with copd exacerbation requiring mechanical ventilation had a probable viral pathogen. prodromal, clinical and outcome parameters did not distinguish virus from non-virus illness. pcr was the most sensitive whilst virus culture was the least of virus assays. electronic supplementary material: the electronic reference of this article is http://dx.doi.org/ . /s - - -x. the online full-text version of this article includes electronic supplementary material. this material is available to authorised users and can be accessed by means of the esm button beneath the abstract or in the structured full-text article. to cite or link to this article you can use the above reference. abstract objectives: we aimed to characterise and quantify the incidence of common infectious agents in acute exacerbations of chronic obstructive pulmonary disease (copd) requiring ventilation, with a focus on respiratory viruses. design: an epidemiological study conducted over years. setting: a -bed intensive care unit (icu). participants: icu patients over years of age with a primary diagnosis of copd exacerbation requiring non-invasive ventilation (niv) or ventilation via endotracheal tube (ett). materials and methods: nasopharyngeal aspirates (npa) and posterior pharyngeal swabs (ps) were tested for viruses with immunofluorescence assay (ifa), virus culture (vc) and polymerase chain reaction (pcr). paired virus and atypical pneumonia serology assays were taken. blood, sputum and endotracheal aspirates were cultured for bacteria. results: episodes in patients were recorded. twenty-three ( %) died within days. a probable infectious aetiology was found in patient episodes ( %). a virus was identified in cases ( %), being the sole organism in cases ( %) and part of a mixed infection in cases ( %). a probable bacterial aetiology was found in cases ( %). there was no statistically significant difference in clinical characteristics or outcomes between the group with virus infections and that without. conclusion: forty-six ( %) of the patients with copd exacerbation requiring mechanical ventilation had a probable viral pathogen. prodromal, clinical and outcome parameters did not distinguish virus from non-virus illness. pcr was the most sensitive introduction chronic obstructive pulmonary disease (copd) is defined as the presence of progressive, incompletely reversible obstructive lung disease from diffuse causes, including chronic bronchitis, emphysema and small airways disease. some - % of approximately patients presenting annually with exacerbations of copd are admitted to our intensive care unit (icu) for ventilatory assistance with either bilevel non-invasive positive pressure ventilation (niv) or ventilation via an endotracheal tube (ett). despite several studies in the unventilated population [ , , , , , ] , and two studies in ventilated copd patients [ , ] , the viral aetiology of many copd exacerbations remains unclear. over respiratory viruses [ ] have been shown to cause upper and lower respiratory tract infections via inflammatory and neural mediators [ ] . of these, influenza types a and b (inf a, b), parainfluenza types , and (para , , ), rhinovirus (rv), adenovirus (av), respiratory syncytial virus (rsv), coronavirus (cov) [ , ] and, less commonly, human metapneumovirus (hmpv) [ ] , and enterovirus (ev) [ , ] have been shown to play significant roles in airway infections. we hypothesised that viral infections may be associated with a significant disease burden in patients with exacerbations of copd admitted to icu for ventilatory support. we aimed to investigate the incidence of these viruses. we also sought other known biological and atypical pathogens responsible for copd exacerbations to build up as complete a microbiological profile as possible. any patient over the age of years requiring mechanical ventilation for an exacerbation of copd within h of admission to hospital was considered for the study. these patients were admitted to the icu for ventilatory support. we defined copd as baseline fev < % predicted with incompletely reversible obstructive spirometry as per american thoracic society/ european respiratory (ats/ers) copd consensus guidelines [ ] . in the absence of prior spirometry, we assessed a smoking history of at least pack years, physical examination, review of previous hospital records, chest radiograph changes suggestive of copd, exclusion of other major co-morbidities as a primary cause of chronic breathlessness and chronic reduction in exercise tolerance to make the diagnosis of copd. icu admission for ventilatory support was considered when, despite optimal medical therapy and oxygen administration, there was acidosis (ph < . ), hypercapnia (paco > mmhg), increasing respiratory distress and/or worsening fatigue or reduced consciousness [ ] . the decision to mechanically ventilate was made by the attending icu specialist based upon past history and current clinical and radiological information. each patient was assessed for either niv or endotracheal intubation using the guidelines of the british thoracic society [ ] . patients were excluded from the study who themselves elected not to have mechanical ventilation, or who were not mechanically ventilated because they were not expected to survive due to the severity of their underlying copd or concurrent illnesses, after consultation with either themselves, if capable and conscious, or with their relatives/care givers. patients with asthma completely reversible with bronchodilators, those less than years old, those with restrictive lung disease or surgery or trauma within the previous weeks and those admitted to general wards before icu admission for more than h (and therefore at risk of a hospital-acquired infection) were excluded. the presence of clinical pneumonia or the finding of chest radiograph changes did not exclude patients, as virus infections are well recognised to cause pneumonic changes [ ] . the study was conducted between july and november . approval for the study was obtained from our hospital ethics committee and consent obtained from patients or their next-of-kin. the duration of prodromal symptoms of increased cough, worsening dyspnoea, increased quantity or discolouration of sputum or increased wheeze was estimated from the start of their symptomatic deterioration. prior smoking history, exercise tolerance, baseline functional capability and the presence of other co-morbidities were recorded. treatment prior to hospital admission was listed, including home oxygen, corticosteroid therapy and antibiotics in the previous days. baseline clinical parameters, blood results, apache ii score and arterial blood gas prior to commencement of mechanical ventilation were noted. every effort was made to exclude other causes of respiratory failure, such as respiratory depressants, uncontrolled oxygen therapy, pulmonary embolism, increased atmospheric pollution, acute left ventricular failure and pneumothorax by using careful history taking, clinical acumen, radiology, angiography and echocardiography where appropriate. full blood count, chemistry, blood cultures and chest radiography were performed on admission to hospital. sputum specimens were collected on admission, if possible, or within h of hospital admission, and viral nasal and pharyngeal specimens were taken after patient stabilisation and enrolment in the study. sputum for bacterial analysis was collected via endotracheal tube suction in intubated patients and by spontaneous or voluntary cough from patients who received niv. all other specimen collection was identical. nasopharyngeal aspirate (npa) and posterior pharyngeal swab (ps) (copan venturi transystem, italy) were collected from all patients. immunofluorescence assay (ifa), either direct (merifluor bioscience, cincinnati, ohio) or indirect (chemicon international, temecula, ca), and virus culture (vc) were performed on the npa. virus culture only was performed on the ps and polymerase chain reaction (pcr) on both specimens. all patients were routinely treated with bronchodilators and empirical antibiotics for at least days, changed or ceased according to the subsequent microbiological profile. all patients received physiotherapy when clinically stable. new chest radiograph changes on admission implied pneumonic change or collapse which was not present on previous chest films (if available) or which was clearly abnormal and had the hallmarks of a primary pulmonary pathological process. whether changes were new or chronic was agreed by consensus between a thoracic physician and an intensivist. we have defined a probable pathogen as "the most likely biological agent(s) to have caused the exacerbation of copd". acute serological titres for inf a and b, para , and , rsv, av, chlamydia, legionella and mycoplasma antibodies were followed weeks later with a paired convalescent titre. a fourfold rise in titre signified a probable causative agent. virus nucleic acid extraction with or without reverse transcriptase and amplification was performed on npa and ps samples. pcr detection was performed for inf a and b, para , and and rsv types a and b (hexaplex assay) and human ev, hmpv, cov, rv and av (real-time pcr). appendix in the electronic supplementary material (esm) contains further details. a positive pcr viral assay was considered evidence for a probable virus pathogen. a screening genus-specific chlamydia assay (both igg and iga) was initially performed. for the purpose of this study, seroconversion of either or both igg and iga between acute and convalescent sera was considered evidence of acute chlamydia genus infection. a single acute or convalescent specimen with either iga, or iga and igg present was indicative of probable recent infection with chlamydia. a positive igg without iga was not considered evidence of recent chlamydia infection. sputum processing was performed using standard laboratory media. microscopy of gram stain smears as well as identification of all significant isolates was reported. sputum samples were considered non-representative of a lower respiratory tract specimen if there were fewer than neutrophils per high-power field or more than squamous epithelial cells per low-power field. the significance of a culture result was based on the quality of the sputum and whether the culture matched the smear result [ ] . identified bacteria were defined as probable pathogens if the predominant growth of a potential respiratory pathogen was obtained in the presence of gram stain microscopy showing profuse organisms with a consistent morphotype. other bacterial isolates were considered as commensals or improbable pathogens. statistical analysis was performed using r (version . . ) (www.r-project.org). categorical variables were analysed using the chi-squared test or fisher's exact test as appropriate, depending on whether numbers in the contingency tables satisfied the chi-squared test assumptions. continuous variables were analysed using the mann-whitney u-test for non-normally distributed variables or the unpaired ttest for normally distributed variables. a p value of < . was considered significant. of potential participants ( potential episodes), a total of were not entered in the study for the following reasons: participation was declined ( ); death before inclusion ( ); enrolment more than h after hospital admission ( ); or failure to meet the criteria for the diagnosis of copd ( ). two patients were admitted twice with separate episodes. three patients were included in this study without hypercarbia > mmhg. the indications for niv in these cases were a combination of hypoxia (po < ) in spite of adequate oxygen therapy, ph < . and symptomatic relief. of the patients ( episodes), ( %) died within days of admission. the mean apache ii score was (range - ) ( table ) . less than % of the patients had recent or any pre-morbid spirometry values, and these data were therefore omitted in reporting. convalescent serological follow-up of initial viral and atypical titres was %. we were unable to obtain a sputum specimen suitable for bacterial analysis in / patient episodes ( %). all these patients received niv. a probable infectious aetiology was found in episodes ( %). a virus was the probable pathogen in cases ( %), being the sole organism in cases ( %) ( table ) and part of a mixed infection in cases ( %) ( table ). virus cultures for herpes simplex virus type (hsv ) were positive in cases ( %). six hsv cases also had another probable pathogen identified and the remaining two had no distinguishable clinical or radiological features that identified hsv as a probable pathogen. these eight hsv results were therefore not included as probable pathogens. ( ) only two other viral cultures were positive, one for inf a and one for rv, both of which correlated with a positive pcr. inf a was the most common organism in cases ( %) with ( %) rv, ( %) cov, ( %) hmpv and ( %) ev. twenty-four ( %) of episodes occurred in the australian summer and autumn months from december to may, whilst the bulk of exacerbations, / ( %), occurred in the winter and spring months between june and november (p = . ). figure shows the seasonal breakdown. there were two discrete clusters of influenza a that occurred each within a -week period, both in early spring and separated by years, and comprising / ( %) of the a probable bacterial aetiology was found in cases ( %) ( table ) , being a sole agent in cases ( %) and in a mixed infection in a further ( %) ( table ) . haemophilus influenzae was the most common bacterium in / cases ( %). chlamydia species were the only atypical organisms found, being the sole aetiology in cases ( %) and in mixed infections ( %). mixed infections constituted ( %) of all cases (table ) . there was no statistically significant difference between the group with probable viral aetiology and those without a viral aetiology in length of prodrome, initial clinical parameters, apache ii score, changes on chest radiograph, length of stay or mortality (table ). there are only two other published series of infective agents in ventilated copd patients [ , ] . a subsequent study also examined the outcomes of treatment in one of these initial series [ ] . all patients in the soler study [ ] and all in the fagon study [ ] were intubated, facilitating protected brush and bronchoalveolar lavage specimens. no bronchoscopic specimen collection was performed on the smaller subset of intubated patients in our study, where patients ( %) received niv alone, with ( %) receiving both niv and ett and only ( %) being intubated without niv. the collection of appropriate respiratory samples has been complicated by the introduction of niv as an accepted modality for the treatment of severe copd exacerbations, as niv patients may not produce suitable sputum. fibre-optic bronchoscopy may not be easily tolerated by these patients, in spite of the use of modified face masks [ ] . inducement of sputum specimens with hypertonic saline, although an effective method of sample collection in unintubated patients [ , ] , may induce or worsen bronchospasm and was not considered a practicable option in our cohort with initial respiratory instability. bacteria grown from sputum or endotracheal aspirate may not be representative of the pathogenic organism that is causing the exacerbation [ , , ] , with up to half of stable copd patients colonised by a potential bacterial pathogen [ , ] . to reduce this possibility, we examined our sputum specimens for the presence of neutrophils and correlated the gram stain with culture in an effort to determine whether the organism was a commensal or a probable pathogen [ ] . twenty-five ( %) of the patients received antibiotics within the days prior to icu admission. of these , ( %) had a positive bacterial culture (all h. influenzae). the possibility that recent antibiotic therapy may have reduced the bacterial yield in the other episodes must be considered. both soler [ ] and fagon [ ] focused primarily on the bacterial yield. fagon did not investigate for viruses. soler obtained serology for chlamydia, mycoplasma, legionella, inf, para, rsv and hsv. av, hmpv, cov, ev and rv were not sought. soler found potential pathogens in % of cases, compared with % in our study, and community-acquired bacteria in % of cases in his cohort, against % in our study. fagon found bacteria in / ( %) of protected brush specimens, predominantly haemophilus and streptococcus species. soler did not find significant clinical or outcome differences between the bacteria-positive and -negative groups, whilst fagon noted significantly greater pyrexia on presentation in the bacteria-positive group, but in no other parameters. protected brush specimens may well increase the overall yield of bacteria, whilst ensuring the false-positive rate is minimised. the limited range of viruses sought and the lack of pcr assay may well have underrepresented virus incidence ( %) in soler's study, compared with % in ours. he found atypical organisms in % of cases, compared with our %. with adequate follow-up serology in only % of the survivors in our study, this may account for the paucity of proven atypical organisms. some % of cases were polymicrobial in soler's study, compared with % in ours. the mechanisms for viral upper respiratory tract infections (urtis) causing lower respiratory tract infection (lrti) symptoms include cytokine and paracrine release, altered cell-mediated immunity and lymphocyte recruitment [ ] , neurohormonal reflexes and direct epithelial damage of the lower respiratory tract [ , , , ] . we may therefore assume that the recovery of common viruses from the upper respiratory tract samples (npa and ps) reflects a probable viral aetiology for lower respiratory tract symptoms. a lower sensitivity for viral diagnosis than for direct bronchoscopic sampling of lower respiratory tract specimens is possible [ , , ] . a virus aetiology has been implicated in non-ventilated copd exacerbations in between and % of cases [ , , , ] , with the most common virus detected in each series varying due to seasonal variation, method of virus detection and influenza vaccination status. infa [ , ] , rsv [ , , ] , cov [ ] and rv [ , , , ] were the most frequently detected viral pathogens in more recent studies of copd exacerbations. in our study, inf a, para , rsv and rv were most often detected ( table ). one study suggests that patients with evidence of virus infection during copd exacerbations have greater symptom severity at onset than those with non-virus exacerbations, and a significantly longer median time to symptom recovery [ ] . we did not find this in our study, with no significant differences in prodromal symptoms, length of icu and hospital stay or mortality observed between virus and non-virus exacerbations. our study is the first to use pcr to detect viruses in ventilated copd patients. pcr was the most sensitive method for virus detection, with virus culture the least sensitive. garbino reports a % virus culture positivity from bronchoalveolar lavage (bal) specimens in a group of hospitalised patients with lrtis, whilst reverse transcriptase pcr (rt-pcr) identified a virus in % of the same specimens [ ] . this may be because the presence of only small quantities of virus is not detectable by culture. most viral pathogens are more difficult to culture after more than h of illness and pcr is able to detect infection for a longer period due to its high sensitivity. pcr is consistently associated with high detection rates in other studies of the copd exacerbation population, with a - % virus yield [ , , ] . a rising antibody titre over weeks is considered strong evidence for a probable virus or atypical pathogen, but is obviously not possible in deceased patients or those lost to follow-up. whilst a useful epidemiological tool, it provides a retrospective diagnosis and therefore cannot affect clinical decisions in the critically unwell. we used new genetic techniques to enhance the diagnostic yield and provide a more accurate picture of the role of viral infection (see appendix , esm). however, most cases were diagnosed by rt-pcr alone. this heavy re-liance on rt-pcr to establish a diagnosis of viral infection may be too sensitive, detecting small amounts of residual viral nucleic acid without other clinical evidence of viral infection. extensive precautions were taken against contamination in our study, and negative pcr controls showed no evidence of false positivity. respiratory viruses may be commensal in stable copd patients. seemungal found respiratory viruses more often in the sputum and nasal lavage of patients with exacerbations of copd ( %) than of patients with stable copd ( %) [ , ] . latent sequences of common respiratory viruses such as adenovirus [ , ] have been detected by pcr. it has been well demonstrated that copd patients may excrete rsv for extended periods of time [ ] , so one cannot be absolutely certain that the rsv demonstrated in our study was necessarily pathogenic. for other viruses, persistent colonisation is not well described and it is reasonable to assume that they played a pathogenic role. quantitative real-time pcr may allow differentiation between latent or former infection and current infection. advances in the availability and rapidity of molecular sequencing may also allow changes in infectious agent serotype or antibiotic resistance to be discerned [ , ] . there is no evidence to date to suggest that treatment with antiviral agents in this subset of copd patients with virus exacerbations requiring ventilatory support will significantly alter the course of their acute illness. it is nevertheless important to have a better understanding of the pattern of disease in order to target more efficiently any potential treatments. the early detection of virus infection by pcr is in its infancy, but the development of more sophisticated anti-viral agents may allow early targeting of virus pathogens. a probable virus pathogen was found in cases ( %) and a probable bacterial aetiology was found in cases ( %) in this study of ventilated copd exacerbation patients. no prodromal or initial clinical parameters distinguished viral from non-viral illness in our study. there were no significant differences between virus and non-virus exacerbations in ventilation time/length of stay or -day mortality. niv made protected specimen collection more difficult than in intubated patients, which may have decreased the bacterial and viral yield. pcr offered a more detailed view of the spectrum of virus illness in this group of patients, including previously unsought viruses 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acute exacerbations and stable chronic obstructive pulmonary disease lower respiratory viral illnesses: improved diagnosis by molecular methods and clinical impact impact of respiratory virus infections on persons with chronic underlying conditions epidemiology and treatment of chronic bronchitis and its exacerbations respiratory viral infections in adults respiratory viral infections in adults with and without chronic obstructive pulmonary disease rapid and sensitive routine detection of all members of the genus enterovirus in different clinical specimens by real-time pcr key: cord- -ar cnsa authors: rouadi, philip w.; idriss, samar a.; naclerio, robert m.; peden, david b.; ansotegui, ignacio j.; canonica, giorgio walter; gonzalez-diaz, sandra nora; rosario filho, nelson a.; ivancevich, juan carlos; hellings, peter w.; murrieta-aguttes, margarita; zaitoun, fares h.; irani, carla; karam, marilyn r.; bousquet, jean title: immunopathological features of air pollution and its impact on inflammatory airway diseases (iad) date: - - journal: world allergy organ j doi: . /j.waojou. . sha: doc_id: cord_uid: ar cnsa air pollution causes significant morbidity and mortality in patients with inflammatory airway diseases (iad) such as allergic rhinitis (ar), chronic rhinosinusitis (crs), asthma, and chronic obstructive pulmonary disease (copd). oxidative stress in patients with iad can induce eosinophilic inflammation in the airways, augment atopic allergic sensitization, and increase susceptibility to infection. we reviewed emerging data depicting the involvement of oxidative stress in iad patients. we evaluated biomarkers, outcome measures and immunopathological alterations across the airway mucosal barrier following exposure, particularly when accentuated by an infectious insult. the presence in the air of one or more natural or anthropogenic substances at a concentration, or location, for a duration, above their natural levels with the potential to cause an adverse health effect defines air pollution. indoor air pollution refers to chemical, biological, and physical exposure of air pollutants in homes, schools, and workplaces. similar to indoor air pollution, ambient (outdoor) air pollution can result from chemical substances or biologically derived contaminants modified by climate change or human activity such as bioaerosols and aeroallergens. air quality guidelines endorsed by the world health organization (who) aim to provide clean air in and around the home. air pollution reduced life expectancy in by year and months on average worldwide. who has linked . million deaths globally in to household cooking using coal, wood and biomass stoves. outdoor air pollution in the same year caused an estimated . million deaths. in inflammatory airway disease (iad) patients an estimated - % increased risk in asthma-related mortality was commensurate with a rise in ambient pollutant concentrations such as no , pm . , or ozone when computed few days prior to asthma death. similar but smaller increments in chronic obstructive pulmonary disease (copd)-related mortality were attributed to pollution and ranged from . % to . %. in the respiratory tract, air pollution can impact wellness in healthy people and patients with iad, irrespective of their atopic status. hence, the airway mucosal barrier may be disrupted by immunopathological mechanisms resulting from effects of pollution and iad. the co-occurrence of iad phenotypes (allergic rhinitis, and chronic rhinosinusitis, copd and asthma) within an individual increases the likelihood of pollutant induced exacerbation of disease or infection. we reviewed the following iads in relation to air pollution. allergic rhinitis (ar), is an ige mediated inflammatory disease generated by a spectrum of outdoor aeroallergens like pollens or indoor aeroallergens such as dust mites, cockroaches, cat allergens, or molds. crs represents multiple overlapping rhinosinusitis phenotypes with different endotypes. asthma is characterized by chronic atopic or non-atopic inflammation of the airway with superimposed episodes of acute exacerbations. the majority of exacerbations are triggered by respiratory viral infections, most commonly human rhinovirus. , other triggers include allergens and atmospheric pollutants. , copd, another chronic inflammatory airway disease, is characterized by airflow limitation and cough. acute exacerbation of copd, like in the upper airway, can be triggered by infection and inhalation of irritants. , chemical pollutants are health-damaging atmospheric aerosol and non-aerosol particles originating from a variety of natural (eg, volcanic eruptions) or anthropogenic sources (eg, biomass burning, fossil fuel combustion, or traffic related particles). primary pollutants such as particulate matter (pm) and volatile organic compounds are aerosol particles directly emitted as solid or liquid droplets in the air. in the atmosphere, natural gasto-particle conversion can culminate in secondary chemical pollutant particles like are ozone and pm. particularte matter (pm) is a mixture of solid and liquid particles suspended in indoor and outdoor air. their source, size, classification, and airway distribution patterns are well described. [ ] [ ] [ ] various human indoor activities cause resuspension and deposition of particles in indoor air, a process governed primarily by the effective size of the particle. this can range from hours for pm to several months for -mm particulate pollutants. pm . broadly represents around % of the total mass of pm and can be inhaled more deeply into the lungs, with a portion depositing in the alveoli and entering the pulmonary and systemic circulation. the submicron pm family, ultrafine particles and nanoparticles, due to their small size, have a relatively large surface area allowing a greater proportion of compounds to be displayed at the surface such as metals and organic compounds. , they cannot be taken by macrophages and can escape phagocytosis. when retained in the lungs, the ensuing inflammation can result in asthma and lung fibrosis; , yet they can allocate to distant organs through systemic circulation resulting in different toxicological phenotypes such as diabetes and heart disease. [ ] [ ] [ ] the adverse health effects of pm are not uniform since pm is not a single entity; rather its constituents and their proportion in ambient air can change from one geographical location to another depending on the type of emissions inherent to each area. volatile organic compounds (vocs) and formaldehyde vocs are primary pollutants located mainly indoors and include benzene, toluene, xylenes, terpenes, and polycyclic aromatic hydrocarbons. they produce a secondary pollutant, formaldehyde, by an indoor chemical reaction between ozone or nitrogen oxide and terpene. formaldehyde appears to be associated with a higher risk of nasopharyngeal carcinoma and leukemia. the primary domestic, - microbial, and socio-cultural sources of vocs , are well elaborated. diesel exhaust represents the most important local contributor to ambient air pollution and has been classified by who as carcinogenic to humans. it is a complex mixture of chemicals and metals stratified into fractions: a solid fraction (made of a soot of carbon core, metals, and their oxides), a gaseous fraction (made of nitrogen, oxygen, and polycyclic aromatic hydrocarbons -pahs), and a liquid fraction where pahs can adsorb into soot or water droplets. , ultrafine particles, nitrogen oxide, and pm (in the range of . mm) can be produced also by internal combustion of diesel engines. metal elements include chromium, magnesium, zinc, and lead and are associated with engine emissions and abrasion of tires and brake pads. vanadium and nickel are tracers of long-range transport from the use of heavy fuel oil. the relatively large surface area of diesel exhaust particles (deps) permits many of these chemicals and metals to attach to its core. thus, most of the deleterious effects of deps are due to chemicals that are adsorbed onto their surface. ozone and nitrogen oxide (nox) to date, ozone is considered the most damaging air pollutant in terms of adverse effects on human health, vegetation, and crops. [ ] [ ] [ ] [ ] [ ] [ ] it produces short-and long-term effects on cardiorespiratory function. recent evidence suggests there is no threshold concentration below which there are no effects on health. ground-level ozone is formed in the atmosphere by a complex reaction of its precursors, nitrogen oxide (nox), carbon monoxide, and volatile organic compounds in the presence of sunlight. background ozone concentrations are strongly correlated with the increased global nox emissions derived from human-generated fossil fuel combustion and biomass burning. tobacco smoke (tbs) tobaco smoke (tbs) emits a wide range of gases, aerosolized liquids, and fine particulate matter including voc and formaldehyde, nitrogen oxide, pm . , and nicotine. , tbs is estimated to cause approximately , excess deaths per year, and it can contribute to % of all cancer deaths. among other actions, tbs can induce dna damage, change in sputum (mucin) quality, and depressed antioxidant and antimicrobial activity in smokers and among copd patients. , household dust household dust represents a convenient means to sample respiratory exposure to pollutants. in one study, the respirable fraction of dust constituted less than % of the total weight of dust surrounding us, and on scan electron microscopy consisted of large flakes (> mm diameter) to which are adherent smaller particles. the median aerodynamic diameter of respirable dust particles allows their deposition both in the nose and lungs. the chemical composition of these flakes suggests household dust might be an important carrier vehicle of organic pollutants into the airways in addition to its intrinsic risk of oxidative stress. allergens can pollute indoor and outdoor air and exacerbate ar and asthma. indoor allergenic pollutants can be derived from skin scales of pets (eg, cats, dogs), urine of rodents (eg, mice), molds, or from fecal material of arthropods such as house dust mites and cockroaches. outdoor allergens are aeroallergens originating from grasses, trees, weeds, or molds. outdoor pollen also modulates indoor aeroallergen concentration. the concentration of aeroallergens in the indoor environment is governed by complex bioaerosol dynamics. for example, airborne cat allergen (fel d ) is mostly associated with large particles (> mm), but around / of fel d are carried on particles less than micra in diameter. thus fel d can be deposited in the alveoli but most importantly suspended for several days in the air favoring distribution of the allergen in the environment. [ ] [ ] [ ] also, the groups of mite allergens listed in the who nomenclature of allergens are composed of particles ranging in diameter from to mm. hence, they can become airborne upon disturbance and can be carried on house dust that becomes a vector for exposure. how dust mite allergen particles can induce and volume , no. , month trigger asthma in lower airways remains to be determined. the diversity and functioning of the normal microbiome are crucial for maintaining the health of the host. while the effects of pm on human health are well established, the impact of infectious particles on bacterial ecosystems has been overlooked. in vitro studies suggest black carbon, a major component of pm, is strongly implicated in predisposition to respiratory infectious diseases, , and induces structural and functional changes in the biofilms of both streptococcus pneumonia and staphylococcus aureus. this is manifested by increase in biofilm thickness and tolerance to degradation by proteolytic enzymes, thereby promoting colonization of the respiratory tract. similarly, evidence suggests indoor and outdoor dust modifies microbial growth, virulence, and biofilm formation of opportunistic pathogens. by exposing opportunistic bacteria (pseudomonas aeruginosa, escherichia coli, and enterococcus faecalis) to progressively increasing concentrations of indoor and outdoor dust, a differential growth pattern of pathogens was noted. this was commensurate with increased biofilm formation and sensitivity to oxidative stress following hydrogen peroxide challenge. consequently, the detrimental impact of particulate pollutants on human health is not only due to direct effects on the host but also may involve the effect on bacterial behavior in the host. oxidative stress is a disproportionate generation of free radicals beyond the body antioxidant capacity. it translates into a non-ige mediated th airway inflammation following exposure to a pollutant. in brief, reactive oxygen species (ros), generated naturally as by-product of cell growth and metabolism, can be produced following pollutant exposure. , ros include oxygen radicals (eg, superoxide, hydroxyl, hydroperoxyl) and certain non-radicals (eg, h o , ozone, singlet oxygen) that are easily converted into radicals. ros have a pivotal role in cell signaling in the oxidation/reduction cascades following exposure and ultimately generation of anti-oxidant mechanisms thru nrf- , activator protein , and nuclear factor-kappa b. [ ] [ ] [ ] [ ] antioxidants are scavengers of ros and can be enzymatic or non-enzymatic systems, constitutive or de novo synthesized by activated gene expression, according to ros load. the inflammatory phase of oxidative stress involves cytokines-and chemokines-mediated activation and recruitment of inflammatory cells secondary to direct effect of pollutants on airway epithelial cells. this can propagate oxidative stress further and augment the inflammatory response and tissue damage. alternatively, ros can contribute directly to cell injury and apoptosis by disrupting cellular and nuclear membranes in the epithelial barrier wall and altering the function of cellular enzymes. , a different mechanism by which environmental pollution can trigger disease in the nose is via a neurogenic mechanism. another component of oxidative pathway is the exposure-driven adjuvant effect on atopy where environmental pollution acts as an exacerbating factor for allergic airway disease by enhancement of allergic airway hypersensitivity in atopic individuals. the evidence emerges from experimental protocols involving inhalation of pollutants and allergen challenge which show pollutants can act synergistically to heighten the allergic response with increased expression of th inflammatory biomarkers. , this is in contrast to healthy individuals which express either th or a mixed th /th profile in controlled exposure studies. epidemiological studies suggest pollution modulates ar, [ ] [ ] [ ] [ ] [ ] [ ] [ ] rhinosinusitis, and asthma. , other studies suggest a positive association between exposure and prevalence of ar and asthma , [ ] [ ] [ ] [ ] in children and adults predominately in reports on short-term exposure and residential proximity studies to sources of traffic pollution. , however, other long-term exposure studies provided evidence to the contrary. [ ] [ ] [ ] this could be due to differences in study design, methods of exposure assessment, and complex nature of studied pollutants. inin-vivovivo studies in both human and animal models suggest pollutant exposure induces inflammatory changes in normal, chronically diseased and allergic nasal and sinonasal tissues ( table ). the cytokine profile of affected tissues suggests activation of the oxidative inflammatory pathways. [ ] [ ] [ ] moreover, there is compelling evidence for involvement of oxidative stress inflammatory pathways following pollutant exposure in the pathogenesis of rhinitis, crs, and asthma irrespective of atopic status. this stems from an abundance of literature on oxidative stress biomarkers studied under natural or experimental allergen exposure both in seasonal and perennial ar described in table . in fact, dust mite or ragweed allergic patients exposed to diesel exhaust particlesdeps in climate chamber expressed higher nasal symptom scores following dust mite or ragweed challenge, respectively, when compared to nonexposed but allergen-challenged patients. , also in the lower airways, short-term natural increase in ambient air ozone was associated with deteriorating lungh function tests in atopic asthmatics despite use of proper asthma controller therapy. similarly, an ozone exposure protocol revealed atopic asthmatics expressed depressed spirometry testing results compared to healthy volunteers. along with this, climate chamber studies revealed (ozone) exposure of healthy or allergic asthmatics induces a neutrophilic or a mixed neutrophilic and eosinophilic inflammatory profile in the lower airways, respectively. furthermore, gene expression profiles of sputum cells recovered from healthy volunteers and allergic asthmatic patients also confirmed significant difference in inflammatory response to ozone exposure. analysis of biomarkers activity greatly improved our understanding of cascade and signal pathways involved in atopic and non-atopic phenotypes of airway disease following exposure. although most oxidative stress biomarkers require tissue specimen collection, some studies suggest an analysis of biomarkers can be determined non-invasively in exhaled breath condensates or blood. [ ] [ ] [ ] [ ] [ ] [ ] natural allergen exposure reverses oxidative and antioxidative status compared to asymptomatic period, with a persistent oxidative state outside pollination season in allergic patients when compared to healthy controls. ar and asthma comorbidity in children does not seem to augment oxidative stress markers compared to ar alone, although adult patients with seasonal ar and asthma manifest an exaggerated stress response during natural allergen exposure compared to ar alone. clinically, oxidative stress correlates with nasal symptom scores in children with perennial ar and can predict ar severity independent of total ige. additionally, ros status does not correlate with atopic skin sensitization in children with perennial ar. furthermore, dust mite challenge in asthmatics or sensitized mice resulted in oxidative damage to nucleic acids as well as lipids and proteins and subsequently triggered dna repair pathways. further blockage of dna repair proteins resulted in increased production of dna double-strand breaks and cell apoptotic enzymes suggesting importance of dna repair in suppressing airway inflammation. endogenous antioxidant response in atopic respiratory diseases is complex and oxidative stress response to anti-inflammatory drugs isare poorly understood. antioxidant enzymes mostly studied in atopic respiratory diseases include heme oxygenase and , , nadph oxidases, catalase, , superoxide dismutase, , , dual oxidases and (in crs patients), paraoxonase, and glutathione peroxidase. , antioxidant activity can also be measured by serum thiol-sh and total antioxidant status ( table ). in this respect, evidence suggests oxidative stress decreases antioxidant enzyme activity or total antioxidant status in atopic children , , or in human in vitro controlled exposure studies, whereas other studies present evidence to the contrary. for example, heme oxygenase antioxidant (iso)enzyme- activity was preferentially increased in a human in vitro model of perennial ar, and upregulated in a human exposure model of copd aggravated by infection; ; also dual oxidase antioxidant (iso) enzymes showed preferential upregulation in different phenotypes and endotypes of crs. , contrary to this, antioxidant enzymes can be downregulated in asthma and rhinitis irrespective of atopic status, and in vitro animal exposure models challenged by an infectious insult. importantly, genetic polymorphism in antioxidant/ detoxifying genes like gstm and gstp can alter oxidative stress response in patients with copd and those with ar following exposure. , exogenous (dietary) antioxidants are scavengers of oxygen free radicals and can act on different levels of defensive antioxidation pathways. , epidemiologic, in vivo , and in vitro studies suggest a beneficial role of exogenous antioxidants in patients with iad or in controlled exposure studies of healthy sinonasal epithelial cells. however, lack of clinical trials data clearly supporting their efficacy, in addition to their potential role in skewing th /th balance towards a th -type immunity as suggested in vitro, renders their indication restricted to special situations such as over exposure to environmental pollutants, among others. nacetylcysteine maintains a potent antioxidant effect in in vitro studies or in ovalbuminsensitized rats by downregulating tumor necrosis factor-alpha in recruited inflammatory cells. along these lines, intranasal steroids can exhibit an exogenous antioxidant regulatory role in seasonal ar by decreasing exhaled breath condensates of leukotriene b and -isoprostane, although no effect was seen on exhaled carbon monoxide and nitrogen oxide. in another study involving children with ar and asthma, no effect of topical nasal steroid therapy was noted on measured lipid peroxidation oxidative stress biomarkers and antioxidant enzymes. data on potential antioxidant effect of inhaled steroids in adult asthmatics is scarce. epidemiological studies suggested prior intake of oral or inhaled steroids in adult asthmatic patients had no effect on asthma control, as measured by clinical symptoms and fev testing, with pm and ozone exposure. other similar studies noted increased consumption of asthma controller therapy (bronchodilators, inhaled corticosteroids, or both) with pm or no exposure in adults. moreover, in children inhaled steroid therapy downregulated induced expression of heme oxygenase- in non-smoking patients with bronchiectasis but had no effect on exhaled carbon monoxide. furthermore, desloratadine can exert an antioxidant effect in children with perennial ar by increasing antioxidant enzyme activities (catalase and superoxide dismutase) and decreasing lipid peroxidation marker (malonaldehyde) although no effect was seen on total antioxidant status. when compared to placebo, fexofenadine improved nasal symptom scores in ragweed ar patients following ragweed challenge and dep controlled exposure. the majority of controlled human exposure studies to ambient pollutants have been conducted in climate chambers on healthy individuals. [ ] [ ] [ ] [ ] for example, relative to clean air, mixtures of vocs increased ratings of nasal irritation, odor intensity and cognitive symptoms (memory loss, dizziness), and a two-fold increase in polymorphonuclear cells in nasal lavage immediately following exposure. similar studies using different pollutants showed no detectable effects on nasal symptom scores or markers of nasal inflammation. , additionally, healthy subjects exposed to room air, nanoparticles, or o /terpene showed no significant changes in inflammatory biomarkers in blood, sputum or nasal secretions and pulmonary function tests. however, only nanoparticles exposure increased significantly high frequency variability in heart rate, thereby indicating a shift in autonomic balance to a more parasympathetic tone. low level ozone exposure in healthy subjects resulted in increased sputum production of airway inflammatory cells such as neutrophils, monocytes, and dendritic cells, and modification of cell surface phenotypes of antigen presenting cells. using a similar protocol the reported decrement in lung spirometry testing (fev ) of healthy subjects was associated with increased neutrophilic airway inflammation following exposure; the latter likely being more pronounced in healthy individuals with gstm null genotype. more importantly, comparing healthy controls to atopic asthmatics, exposure to high levels of ultrafine particles in a climate chamber was associated with a small but significant fall in arterial oxygen saturation, a fall in forced expired volume over s (fev ) the morning after exposure, and a transient slight decrease in low frequency (sympathetic) power during quiet rest. these controversial results can be related partly to the nature and concentration of the investigated pollutant or its experimental duration of exposure keeping in mind brief exposure to a single pollutant in a climate chamber does not reflect chronic exposure to multiple pollutants in real life. controlled exposure studies in atopic patients involving allergen challenge revealed more consistent results. for example, dust mite allergic patients reported worsening nasal symptom scores following intranasal dust mite challenge and dep exposure commensurate with increased histamine levels in nasal washes, all suggestive of induced mast-cell degranulation. similarly, controlled exposure studies in ragweed allergic patients challenged with dep and ragweed outside their pollen season reported higher total nasal symptoms scores or increased levels of specific ige and expression of th inflammatory cytokines, when compared to ragweed challenged alone. taken together, controlled airway exposure studies to ambient pollutants in healthy individuals show small but significant negative health effects whereas exposure studies in allergic patients support the role of pollutants in increasing atopic airway hypersensitivity. large scale translational studies are needed to correlate the bio-cellular toxic effects of pollution with epidemiological studies. signal and cascade pathways triggered across the airway mucosal barrier at first encounter of pollutants are complex (see fig. ). airway mucosal cells can recognize pollutants through an epithelial toll-like receptors (tlr)-mediated mechanism either directly or indirectly by the intermediary of pattern recognition receptors (see below). more precisely, pollutants such as pm, cigarette smoke, and ozone can present themselves directly to subclasses of surface tlrs, namely tlr and tlr , which can serve as ligands for these pollutants. alternatively, pollutants can be bound to pattern recognition receptors, a collective conglomerate of receptors which encompasses tlrs and normally can recognize conserved molecular structures derived from microbial agents or released by damaged nonmicrobial cells. once triggered, pattern recognition receptors and tlrs attract antigen presenting cells and leukocytes to the site of inflammation resulting in priming of the airway to subsequent mucosal infectious insults. afterwards, when eventuated by an infectious challenge, alveolar macrophages mount a heightened inflammatory response aimed at containing and clearing bacteria while producing minimal collateral tissue damage. , the immunological "storm" resulting from co-exposure and infection is studied in different clinical models of respiratory cells and also in patients with iad such as copd ( table ) . another signal pathway is mediated by submucosal innate lymphoid cells (ilcs) which can differentiate into adaptive subsets. ilc s relates to immune reactions in crs without nasal polyps, copd, and some viral and bacterial infections; whereas ilc s becomes important in regulating type immunity and some helminthic and viral infections. , other immunologic and antimicrobial responses to pollutant exposure modulate expression of host defense peptides and antiviral mechanisms, impair mucus production crucial for capturing pollutants or weaken tight junctions essential for the epithelial airway defense barrier. , epidemiological studies suggest indoor and outdoor air pollution increase the risk of respiratory tract infections in both pediatric - and adult populations. , , , for example, morbidity of the recent covid- pandemic disease has been linked partly to air pollution. [ ] [ ] [ ] [ ] also, air pollution can aggravate the severity of asthma caused by respiratory viral infections. moreover, in vitro studies suggest air pollution may suppress innate and adaptive immunity and increases susceptibility to bacterial and viral respiratory infections in both human and animal clinical models, following short-or long-term exposure (see table ). for example, in the upper airways diesel exhaust exposure increased the number of human nasal epithelial cells infected by influenza a virus in vitro the proposed mechanism was enhancement of virus attachment and entry into respiratory cells mediated by radical oxygen species, despite increased antiviral interferon-dependent signaling and interferon-stimulated gene expression by dep exposure. also, in vitro rrhinovirus (rv) infectivity following nitrogen oxide and ozone exposure in human respiratory epithelial cells loss of low-level dep-exposed mdmf along their differentiation into macrophages likely due to dysfunctional (loss of mitochondrial membrane electrical potential and lysosomal function) and phenotypic (tlrmediated reduction in cd and cd surface marker expression) structural changes in mdmf of healthy exposed individuals. this can likely contribute to inflammation in copd by decreased mdmf proinflammatory cytokines (cxcl ) production. resulted in increased icam receptor expression (receptor for rv ) and pro-inflammatory il- cytokine production. in another combined human and animal model, activated nasal airway microbial proteins at the surface mucosal liquid, which include lysozyme, human cathelicidin antimicrobial peptide, and human b defensins, were attenuated following (pm) exposure and staphylococcus aureus infection. the ensuing impaired bacterial killing resulted from adsorption and electrostatic interactions between either pollutant or bacteria with activated microbial proteins leading to the depletion of the latter. the literature on the lower airways exceeds that on the upper airways. in this respect, susceptibility to infections following exposure was examined at several stages of immunological alterations triggered in host cells. starting with the epithelial barrier level, an initial in vivo pm exposure of bronchial epithelial cells in mice followed by experimental infection with pseudomonas aeruginosa resulted in decreased levels of an epithelial ciliary marker (b tubulin) and a non-ciliary epithelial (clara cells) marker, and their gene expression/transcription regulator, all suggesting airway remodeling is a contributing factor to the impaired bacterial clearance. furthermore, an initial infection with pseudomonas aeruginosa induced an epithelial antimicrobial peptide human beta defensin ; but as the model was pre-exposed to pm, induction of human beta defensin was suppressed and a cell senescence biomarker (sa-b-gal) was upregulated in an ros-dependent process. also, in an in vitro human model, a pm-enhanced susceptibility to streptococcus pneumoniae infection was heightened by increased bacterial adhesion and penetration into bronchial epithelial cells. this was mediated by a receptor for platelet-activating factor, a putative receptor for pm-stimulated pneumococcal adhesion to airway cells. on a submucosal level, macrophages and monocytes play a central role in phagocytosis. the study of immunopathological alterations in phagocytosis has shown inconsistent results. for example, in an exposure (pm)-infectious animal model, impaired streptococcus pneumoniae clearance and phagocytosis resulted from decreased macrophages internalization of bacteria, although increased binding of microbe to surface of macrophages was reported. in a similar model increased susceptibility to staphylococcus aureus infection resulted from depressed phagocytosis index and abnormal natural killer cell response. also, in another animal exposure model increased infectivity to listeria monocytogenes resulted from decreased ros-induced nitric oxide production by alveolar macrophages. in contrast, natural (chronic) pm exposure of human bronchoalveolar lavage fluid decreased macrophage cytokine (cxcl ) release and downregulated induced phagosomal oxidative burst. per contra, no impairment in macrophage redox potential, proteolysis or phagocytosis was observed likely due to the experimental chronicity of exposure. additionally, in an analogous model using high levels of the same pollutant (pm), the impaired antimicrobial defense resulted from defective macrophage activation of t cells by class ii þ major histocompatibility complex and subsequent decrease in interferon-g production, but unaltered phagocytic activity. interestingly, no increase of neutrophils and tnf-a levels was observed in bronchoalveolar lavage following exposure and infection suggesting acute exposure to relatively high level of pm does not trigger a classic or sustained inflammatory response. besides suggesting interference with innate immunity, exposure studies suggest further alterations in adaptive immunity as evidenced by immunopathological relationships between antigen presenting cell cytokines, the corresponding sensitized t cells subsets, and recruited neutrophils (see table ). as such, a listeria monocytogenes-mediated suppression of macrophages immune response upon low dose dep exposure manifested as "dysfunctional" production of macrophages-derived cytokines. this was associated with downregulation of innate protective cytokines (e.g. il- b, tumor necrosis factor-a, il- , il- and interferon-g), suppression of adaptive cd and cd t cell immune response, and upregulation of macrophage bactericidal anti-inflammatory cytokines (il- and il- ). other examples of altered cytokine release include the pro-inflammatory besides the role of cytokines in fine tuning extent of inflammation in these models, t cell subsets like t cytotoxic (cd þ ) and regulatory t cells (treg) in addition to neutrophils have been studied. dep exposure in rats increased susceptibility to listeria monocytogenes infection by attenuating t cell mediated immunity, namely cd þ t helper lymphocytes and cd þ t cytotoxic cells; pm exposure in neonatal mice resulted in depression of adaptive response to influenza virus a infection and by an increased expression in treg cells and il- in lung tissues. interestingly, the induced immunosuppressive effect was reversed by treg depletion and restored by either treg transfer or recombinant il- treatment. furthermore, airway neutrophilia, which is instrumental in bacterial clearance, has been studied in inin-vitrovitro infectious exposure model in relationship to th and th proinflammatory cytokine release. the concomitant increase in bronchoalveolar lavage fluid il- with airway neutrophilia, and their attenuation in il- "knock out" mice following exposure and infection suggested the importance of il- in inducing neutrophil-mediated airway inflammation. also, decreased induction of il- a-mediated airway neutrophilia following exposure and infection in il- r mice compared with wild-type controls also suggests il- signaling is required in il- aexacerbated neutrophilia. moreover, in an in vivo exposure-infectious animal model modulated by interferon-g priming to mimic viral infection, an impaired pm-mediated bacterial phagocytosis correlated with activation of genes encoding neutrophil-recruiting chemokines and increased histopathology suggestive of severe pneumonia. still, in an animal in vivo model, exposure followed by lps infection induced cytokine changes in the lung suggestive of a th /th imbalance and manifested by increased expression of il- among others, and a concordant decrease in ifn-g expression. the infectious-exposure model is an attractive tool to explore immunopathological alterations in copd patients or in laboratory cells exposed to secondhand smoking. in a mice model, weeks secondhand smoking pre-exposure was followed by infection with non-typeable haemophilus influenza which is a pathogen commonly implicated in acute exacerbation of copd. the model revealed increased number of immune cell infiltrates except for macrophages, and a suppressed induction of a robust adaptive immune response manifested as decreased ifn-g. also, a downregulated t cell adaptive response manifested by decreased bacterial clearance and diminished efficiency of specific antibody subclass switching, both mitigated by anti-viral vaccination. in a similar animal model examining the immunological effect of antibiotic therapy, cigarette smoke exposure followed by streptococcus pneumoniae infection resulted in recruitment of macrophages and monocytes in lung tissue and alveolar fluid reportedly to confine infection to the lung; also a decreased number of neutrophils but a differential increase in neutrophil-mediated antimicrobial peptide, myeloperoxidase. antibiotic therapy had no effect on mice survival rate but reduced lung injury and induced a differential change of cytokine levels in bronchoalveolar lavage fluid most importantly downregulation of th and th inflammatory cytokines. human in-vitro pre-exposure and infectious models are designed to mimic acute exacerbations in stable but exposed copd patients. dep exposure followed by non-typeable haemophilus influenza infection did not compromise mucosal barrier function in copd or healthy patients. however, epithelial endoplasmic reticulum activity was markedly disrupted in copd patients, manifested by depressed gene expression of the integrated stress response markers in an ros-mediated process. in another model, macrophages differentiating from locally recruited monocytes in lungs of copd patients were pre-exposed to low level dep and subsequently challenged with tlr agonists or heat killed e.coli. this resulted in structural and functional changes in innate and adaptive immune system consisting of mitochondrial and lysosomal dysfunction in macrophages, decreased expression of their surface recognition markers, loss of macrophage differentiation, and reduction in proinflammatory cytokine production (e.g.il- ). the majority of exposure-infection human and animal models have examined immunological alterations following long-term (weeks) and lowdose pre-exposure periods which best mimics real-life outdoor pollutant exposure or indoor secondhand smoking relevant to copd. nevertheless, other models which studied brief and short-term (hours to days) exposure periods have yielded mixed results. for example, one-week diesel exhaust pre-exposure of mice in vivo decreased pseudomonas aeruginosa clearance from bronchial epithelial cells, whereas in the same model a six-months pre-exposure did not. also, in an in vivo model, mice were pre-exposed to pm for day (short term) or weeks (long term), later infection with influenza virus a and survival rate was assessed over the ensuing days following contamination. short-term exposure improved mice survival rate and triggered a robust immune response whereas long-term exposure did not, reportedly mediated by macrophage cytokine gene expression regulator kdm a. to model secondhand smoking exposure or for recent initiation of active smoking, mice were exposed to brief ( h per day for days) low dose of side stream cigarette smoke or to prolonged ( . weeks) high dose cigarette smoke, respectively, and later inoculated with streptococcus pneumonia. surprisingly, brief exposure did not show significant survival benefit whereas prolonged exposure in mice did, reportedly due to diminished propagation of bacteria into the systemic circulation during chronic exposure. finally, in a mice model examining only chronic secondhand smoking exposure and its impact on non-typeable haemophilus influenza antimicrobial response, weeks secondhand smoking preexposure, theoretically mimicking mainstream smoking, compromised the ability of host t cellmediated adaptive immune system to mount an effective response against non-typeable haemophilus influenza infection. taken together, these models suggest exposure impairs innate and adaptive immunity against airway microbial infections. limitations inherent to the design of these models compel a careful interpretation of results taking into consideration the response to infectivity of animal host cells, the duration and intensity , , , of pollutant pre-exposure, and the nature of microbial agents used for contamination. we reviewed evidence for the involvement of oxidative stress pathways and their nature in healthy individuals and patients with inflammatory airway diseases following exposure to a spectrum of important chemical, allergic and infectious air contaminants. when comparing exposure clinical models in patients with ar, crs, and allergic asthma, the signal and cascade pathways can generate important oxidative and anti-oxidative markers and induce specific changes in adaptive and innate immune system. thus, exposure can amplify the inflammatory process in patients with ar, crs, and allergic asthma supporting evidence that, at least in atopic individuals, exposure can increase airway hypersensitivity. when accentuated by an infectious insult, pre-exposure clinical models in patients with inflammatory airway diseases show specific immunopathological alterations at mucosal and submucosal levels of the airway epithelial barrier and ultimately in the adaptive immune system. the resultant increased susceptibility to infection can be due to either increased infectivity of microbial agents or to a ros-mediated direct effect of pollutant on host immune defense cells. the complex nature and composition of chemical air pollutants and their aerodynamic properties is reflected in conflicting epidemiological and experimental results on exposure and its impact on health. also, the oxidative stress-mediated immunopathological changes have highlighted important antioxidant markers, which can be therapeutically bio-engineered. since there is no clear 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diesel exhaust particle exposure in vitro alters monocyte differentiation and function biochemical and biophysical research communications down-regulating pulmonary macrophage kdm a and mediates histones modi fi cation in il- and ifn-b promoter regions cigarette smoke-mediated inflammatory and oxidative responses are strain-dependent in mice the importance of antioxidants which play the role in cellular response against oxidative/nitrosative stress: current state a review of the epidemiological evidence for the ' antioxidant hypothesis human and animal research not applicable. not applicable.availability of data and materials not applicable. we attest that all authors contributed significantly to the creation of this manuscript.-philip rouadi and samar idriss initiated the work, contributed substantially to the conception and design of the study, the acquisition, analysis, and interpretation of data. -philip rouadi supervised the manuscript.ethics committee approval not applicable. all authors agreed to the publication of this work. the authors have nothing to declare relative to this paper. key: cord- -yu n eur authors: wesseling, geertjan title: occasional review: influenza in copd: pathogenesis, prevention, and treatment date: - - journal: int j chron obstruct pulmon dis doi: nan sha: doc_id: cord_uid: yu n eur influenza viruses cause respiratory tract infections that in patients with underlying lung diseases such as chronic obstructive pulmonary disease (copd) are associated with exacerbations and excess morbidity and mortality. typically, influenza b is associated with relatively mild, local outbreaks, whereas influenza a is the cause of world-wide pandemics. upon infection, two antigens present on the viral surface, hemagglutinin and neuraminidase result in human immunity, but since many subtypes of these antigens exist that vary over time, immunity in the population is blunted. vaccination is advocated in high-risk groups including patients with underlying (lung) diseases and in the elderly, and needs to be repeated annually with vaccines expected to cover the expected change in viral antigenicity. when started early, antiviral drugs, especially neuraminidase-inhibitors can be prescribed in adjunct to nonspecific interventions in an attempt to shorten disease duration and to prevent complications in case of an influenza infection. currently, the effectiveness of antiviral drugs specifically in patients with copd has not been proven. it is believed that the risk of a pandemic outbreak of infl uenza is growing. three pandemics occurred in the th century; most recently in which resulted in millions of deaths worldwide. a new outbreak may have similar devastating results and is likely to affect elderly people, patients with reduced immunity, and patients suffering from chronic diseases such as chronic obstructive pulmonary disease (copd). chronic obstructive pulmonary disease is characterized by largely irreversible progressive airfl ow limitation. this airfl ow obstruction is associated with an infl ammatory process in the bronchial mucosa. most patients are current or ex-smokers. many patients have one or more exacerbations per year, which are associated with an accelerated decline in lung function and decreased quality of life (nhlbi ) . exacerbations are responsible for over half of the direct disease-related costs of care. viral infections including infl uenza, respiratory syncytial virus (rsv), and many other viruses are important causes of exacerbations, excess morbidity and mortality in copd (wedzicha ; wilkinson et al ) . during seasonal outbreaks of viral infections, patients with copd are at risk for respiratory illness-related hospitalizations, irrespective of age or disease severity (gorse et al ) . prevention and early treatment of exacerbations are therefore believed to be an important target in the management of copd. inhaled steroids may reduce the number and the severity of exacerbations in patients with severe airfl ow obstruction and frequent exacerbations, but the effects are limited (burge et al ; jones ). inhaled bronchodilators may have similar effects. annual infl uenza vaccination is recommended in most copd guidelines and neuraminidase inhibitors are available for the treatment of infl uenza. evidence of the role of infl uenza viruses in the pathogenesis of copd and as a cause of exacerbations is discussed in this review and current recommendations for prevention and treatment of infl uenza in patients with copd are summarized. the infl uenza virus belongs to the orthomyxovirus group. the infl uenza virus is a spherical or fi lamentous enveloped virus. virus strains are characterized by different hemagglutinin (h) and neuraminidase (n) subclasses. hemagglutinin, a surface glycopeptide, aids attachment of the virus at specifi c receptor sites on the walls of susceptible host cells and facilitates entry of viruses into the cell. the enzyme neuraminidase facilitates cell penetration by pinocytosis and stimulates the release of viruses from the host cell by budding through the cell membrane (matrosovich et al ) . the virus exists in two main forms: a and b. infl uenza a is generally responsible for epidemics and pandemics. infl uenza b causes milder, generally more localized and less severe outbreaks, eg, in schools or in camps. a lesser known c form rarely causes disease in humans. h subtypes (h -h ) and nine n subtypes (n -n ) have been identifi ed for infl uenza a viruses. new antigenic variants of infl uenza a develop at irregular intervals through the process of antigenic shift, whereas point mutations in infl uenza a and b viruses result in changes in amino acids in the h and the n glycoproteins responsible for humoral immunity, resulting in antigenic drift (zambon ) . these changes render the individual's immune response less able to combat new variants. as a result, major shifts in antigenic profi les of the viruses can cause epidemics. the immune system is less blunted by the minor antigenic drifts that cause less severe outbreaks (stamboulian et al ) . in the appearance of infl uenza a type h -n was associated with over million deaths. the worldwide pandemic that occurred in was the result of the emergence in hong kong of infl uenza h -n . minor antigenic drifts have since then caused smaller outbreaks in various areas of the world. avian fl u, caused by h -n , has emerged in and re-emerged in - and represents a major change in viral surface antigens, and transmission to humans has been shown to be a serious threat (beigel et al ) . infl uenza is thought to occur in approximately % of the world's population annually. in most cases infl uenza is an acute febrile respiratory disease that occurs in annual outbreaks of varying severity. the incubation period of infl uenza is to days. infl uenza typically causes extensive destruction of airway epithelial cells (hers ) . symptoms start abruptly and consist of fever, shivering, and diffuse pains in the extremities. many patients present with early, prominent systemic symptoms and have headache, soreness of the throat, and dry cough that can persist for several weeks (monto et al ) . mortality can be high in the elderly especially in patients with chronic respiratory or cardiac diseases. recovery can take up to months and secondary bacterial infections are common, particularly with streptococcus pneumoniae and haemophilus infl uenzae. staphylococcus aureus superinfections can cause pneumonia that has a mortality of up to % (brundage ) . in otherwise healthy individuals, treatment consists of paracetamol, bed rest, and suffi cient oral intake of fl uids (wiselka ) . in patients with copd, as in patients with heart or kidney diseases, early treatment with appropriate antibiotics is recommended (nathan et al ) . in susceptible persons, usually smokers, exposure to inhaled noxious particles and gases results in infl ammation in the bronchial mucosa, lung parenchyma, and pulmonary vasculature (nhlbi ) . other processes believed to be of importance are an imbalance of proteinases and antiproteinases and oxidative stress. many cells and mediators are involved in the pathogenesis of infl ammation in copd. with time this infl ammation can result in structural changes in the bronchial wall and destruction of lung parenchyma or emphysema, and consequently in irreversible airfl ow obstruction and gas exchange abnormalities. host factors are believed to be important in the pathogenesis of the characteristic infl ammation in copd, as are viruses (proud and chung-wai ) . also, host behavior in response to viruses and possible aberrant antiviral host responses may infl uence the persistence of infl ammation following exposure to viruses. in stable copd latent respiratory viruses, such as rsv or adenoviruses have been associated with accelerated lung function decline, independent of smoking status, exacerbation frequency, and lower airway bacterial load (mallia and johnston ) . rsv may also be associated with systemic infl ammation. whether other viruses, such as different infl uenza strains, have similar effects in stable copd is at present unknown. it has been shown that respiratory viruses, such as rsv and also infl uenza viruses, enter into the bronchial epithelial cells where they can replicate and result in epithelial cell destruc-tion and necrosis. this results in increased permeability of the mucosa, which allows other pathogens and irritants to penetrate, leads to neurogenic infl ammation by substance p and bradykinin, m -and β -receptor dysfunction, and contributes to bronchial hyperresponsiveness (wilkinson et al ) . airway hyperresponsiveness causes excessive airway narrowing in copd patients. viruses are not only involved in the infl ammation of stable copd, but they also can trigger exacerbations (rohde et al ; wedzicha ) . exacerbations are commonly defi ned as events in the natural course of the disease characterized by a change in the patient's baseline dyspnea, cough and/or sputum that is beyond normal day-to-day variation, is acute in onset, and may warrant a change in regular medication in patients with underlying copd (nhlbi ) . respiratory viruses are considered to be amongst the most important triggers of exacerbations. between % and up to % of copd exacerbations have been found to be associated with symptomatic colds precipitated by viruses (seemungal et al ; wedzicha ) . of these, rhinovirus and enteroviruses, both belonging to the picornavirus group of rna viruses, stand out. coronavirus, adenovirus, rsv, infl uenza a and b, and parainfl uenza viruses have been linked with copd exacerbations and often multiple viruses can be detected (rohde et al ) . various mechanisms are believed to be involved in the way viruses induce or aggravate exacerbations. rhinoviruses attach to airway epithelium cells through intercellular adhesion molecule- (icam- ) and thereby cause infl ammatory cell recruitment and activation. also, viral infections were found to be associated with increased oxidant stress, the activation of nuclear factor κb, and the expression of stress-response genes (wedzicha ) . the proportion of exacerbations related to isolation of infl uenza virus differs between studies and is probably infl uenced by the number of copd patients that receive infl uenza vaccination (gorse et al ) . infl uenza infections are cause of excess morbidity and mortality in copd and may affect the progression of the disease. in older studies and in populations that received no infl uenza vaccination, the hospitalization rates for acute exacerbations of copd are substantially higher in the infl uenza season than in the noninfl uenza season (simonsen et al ) . considering the infl uence of different respiratory viruses in stable copd and the important role of viral infections in exacerbations, vaccination is a potentially effective way to reduce morbidity and mortality caused by exacerbations. unfortunately, signifi cant variation within the major virus types causing disease limits the success of vaccination programmes. since infl uenza viruses display antigenic shift and drift, new vaccines must be developed at regular intervals. in response to the arrival of new pandemic strains, new vaccines must be made available in suffi cient quantities. the effectiveness of the vaccines, usually inactivated virus vaccines containing virus strains ( type a and type b) depends on the similarity between the strains in the vaccine and the virus strains likely to circulate in the upcoming winter. protection occurs through circulating antibodies to h and n or stimulation of cytotoxic t-cell responses. protection by infl uenza vaccination is only effective in % of patients and only lasts for one year (who ) . new vaccines must be prepared each year to cover the expected change in antigenicity. as a consequence, by defi nition supplies are limited in case of an emerging epidemic. obviously, the benefi t of vaccination is largest in epidemic years when the vaccine strain is similar to the epidemic strain. currently, all standards and guidelines therefore recommend annual infl uenza vaccination in all patients with copd as a cost-effective intervention, in spite of the fact that there are no randomized studies of infl uenza vaccinations in patients with copd (nhlbi ) . evidence to support this recommendation largely stems from observational studies in elderly subjects. in a large cohort study of nearly , elderly patients, vaccination resulted in a reduction of % in the numbers of hospitalizations for all respiratory conditions and a reduction of about % in all-cause mortality compared with nonvaccinated subjects (nichol et al ) . in subjects with chronic lung diseases, vaccination resulted in a % reduction in hospitalizations and a % decrease in death rates during infl uenza seasons (nichol et al ) . a meta-analysis of published effects of infl uenza vaccination by gross and colleagues ( ) showed a % reduction in respiratory illnesses, a % reduction in hospitalizations, a % reduction in all cause deaths, and a % reduction in pneumonia in vaccinated subjects. in a randomized clinical trial, wongsurakiat and colleagues ( ) demonstrated that infl uenza vaccination is highly effective in the prevention of acute respiratory illness related to infl uenza virus infection, regardless of severity of copd, comorbid diseases, age, gender, or smoking status. from their extensive review of the literature and the limited number of studies specifi cally performed in copd patients, published in the format of a cochrane review, poole and colleagues ( ) concluded that administration of an inactivated infl uenza vaccination has a clinically important and signifi cant effect in reducing exacerbations, caused by infl uenza, occurring three or more weeks after vaccination, and probably an effect on the total number of exacerbations in copd patients. in epidemic years, when the proportion of exacerbations caused by infl uenza is higher, this effect is likely to be greater. only limited data on the effects of infl uenza vaccination on number or duration of hospitalizations, mortality, or outcomes in terms of lung function have been reported. they also concluded that there was no evidence of an increase in early exacerbations (poole et al ) . yet, in the experience of many clinicians, transient increases in symptoms may occur in the weeks after vaccination. chronic obstructive pulmonary disease patients are susceptible to unfavorable outcomes in case of an infl uenza infection. vaccination can help prevent exacerbations, pneumonia, and hospitalization in such patients, but the effects are limited to a certain extent by less than ideal immunization rates and antigenic shifts that decrease the effectiveness of the vaccine. exacerbations that occur as a result of an infl uenza virus infection should be treated with inhaled bronchodilators, systemic corticosteroids, and antibiotics aimed at suspected bacterial superinfections and low-flow oxygen when appropriate. other nonspecifi c measures such as suffi cient fl uid intake, bed-rest, antipyretic drugs, and/or cool mist humidifi ers are recommended as they are in otherwise healthy adults. four drugs are currently available for the prophylaxis or treatment of influenza infections: amantadines (amantadine and rimantadine) and n-inhibitors (zanamivir and oseltamivir). the amantadines inhibit viral uncoating inside host cells. they are effective against influenza a only, and the effects are limited because of the emergence of resistant strains. also, they have several toxic side-effects that further reduce their usefulness (jefferson et al ) . n-inhibitors are effective against all nsubtypes and therefore, other than amantadines, they can be used against all strains of influenza. they act by preventing the release of virions from infected host cells. generally it is recommended not to use n-inhibitors routinely for seasonal influenza and use these drugs only with associated public-health measures in a pandemic situation (moscona ) . furthermore, both drugs have no significant effect on asymptomatic influenza. neuraminidase-inhibitors have been tested in various scenarios, but no studies specifi cally performed in copd patients are currently available. published prophylaxis and treatment trials suggest that both zanamivir and oseltamivir are effective in preventing and treating the symptoms and complications of infl uenza infection but that they do not prevent the infection in itself and will not prevent voidance of viruses from the nose. the literature regarding the effects of n-inhibitors for preventing and treating infl uenza in healthy adults has recently been reviewed by jefferson and colleagues ( ) . this excellent review summarizes the result of randomized controlled trials testing n-inhibitors in controlled clinical prophylaxis, post-exposure prophylaxis, and treatment trials. they conclude that oseltamivir in a daily oral dose of mg and of inhaled zanamivir mg daily have no effect in prophylaxis of infl uenza-like illness compared with placebo. whether higher doses are more effective is uncertain. the effi cacy of oseltamivir compared with placebo, orally administered in a dose of mg daily, against symptomatic infl uenza is %. in a dose of mg daily, the effi cacy is % (jefferson et al ) . these authors argue against the use of these drugs in routine seasonal infl uenza control. in general n-inhibitors have low effectiveness, high effi cacy, and appear well-tolerated. the possibility of emerging resistance has been put forward. with oseltamivir, resistance has been reported to be around . % (zambon and hayden ; monto et al ) . in households, the transmission of seasonal infl uenza has been shown to be interrupted (welliver et al ) . neuraminidase inhibitors are recommended for the treatment of at-risk patients who present with infl uenza-like illness and who can start within hours of the onset of symptoms. ideally treatment is started earlier, preferably within hours after the onset of symptoms (aoki et al ) . currently, no controlled studies on the effectiveness and the safety of n-inhibitors specifi cally for copd patients or patients with other underlying respiratory disease are available. from observational studies it is concluded that n-inhibitors can be used in addition to infl uenza vaccination in patients with disorders of the respiratory system including copd, who are at high-risk of developing infl uenza related complications (gorse et al ; williamson and pegram ) . under these conditions they can affect respiratory complications such as pneumonia or bronchitis. at present no robust data are available to support the use of n-inhibitors in avian infl uenza (jefferson et al ) . oseltamivir has been used in an uncontrolled setting but data infl uenza in copd regarding the effectiveness does not allow for reaching a fi rm conclusion (leneva et al ) . unlike the older antiviral drugs, amantadine and rimantadine, n-inhibitors rarely cause central nervous system adverse effects, yet these drugs may have side-effects. zanamivir has been shown to cause bronchospasm in susceptible patients and should be used with caution in copd-patients (freund et al ) . patients prescribed zanamivir should have fast-acting bronchodilators available. other side effects of zanamivir include diarrhea, whereas oseltamivir has been shown to be able to cause nausea, vomiting, and retching (nicholson et al ) . infl uenza viruses have been shown to be involved in the pathophysiology of copd, both in stable disease and in exacerbations. annual infl uenza vaccinations are recommended for all patients and have been proven effective in all but a few cases. vaccination remains the gold standard for the prevention of infl uenza in at-risk subjects, including patients with chronic diseases such as copd. recommended treatment of infl uenza in copd patients includes the regular nonspecifi c measures that are generally believed to be helpful in all patients. when used early, preferably within hours after the onset of symptoms, the n-inhibitors, zanamivir and oseltamivir, are useful adjuncts to vaccination for the management of patients at risk of developing infl uenza related complications, such as copd patients. n-inhibitors should not be used in routine seasonal infl uenza control, not even in patients with copd. in a serious epidemic or pandemic their use is recommended in conjunction with other public health measures, in copd patients and others alike. early administration of oseltamivir increases the benefi t of infl uenza treatment avian infl uenza a (h n ) infection in humans interactions between infl uenza and bacterial respiratory pathogens: implications for pandemic preparedness randomised, double blind, placebo controlled study of fl uticasone propionate 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during the fi rst three years of their use neuraminidase inhibitors for infl uenza management of infl uenza in patients with asthma or chronic obstructive pulmonary disease global strategy for the diagnosis, management and prevention of chronic obstructive pulmonary disease. nhlbi/who workshop report relation between infl uenza vaccination and out-patient visits, hospitalization, and mortality in elderly persons with chronic lung disease benefi ts of infl uenza vaccination for low-, intermediate-, and high-risk senior citizens effi cacy and safety of oseltamivir in the treatment of acute infl uenza: a randomised controlled trial infl uenza vaccine for patients with chronic obstructive pulmonary disease role of viral infections in asthma and chronic obstructive pulmonary disease respiratory viruses in exacerbations of chronic obstructive pulmonary disease requiring hospitalizations: a case-control study respiratory viruses, symptoms and infl ammatory markers in acute exacerbations and stable chronic obstructive pulmonary disease the impact of infl uenza epidemics on hospitalizations infl uenza role of viruses in exacerbations of chronic obstructive pulmonary disease effectiveness of oseltamivir in preventing infl uenza in household contacts: a randomized controlled trial infl uenza vaccines: position paper respiratory syncytial virus, airway infl ammation and fev decline in patients with chronic obstructive pulmonary disease neuraminidase inhibitors in patients with underlying airways disease infl uenza : diagnosis, management and prophylaxis acute respiratory illness in patients with copd and the effectiveness of infl uenza vaccination global neuraminidase inhibitor susceptibility network. position statement: global neuraminidase inhibitor susceptibility network epidemiology and pathogenesis of infl uenza key: cord- - srslmgk authors: jacobs, m.; van eeckhoutte, h. p.; wijnant, s. r.; janssens, w.; joos, g. f.; brusselle, g. g.; bracke, k. r. title: increased expression of ace , the sars-cov- entry receptor, in alveolar and bronchial epithelium of smokers and copd subjects date: - - journal: nan doi: . / . . . sha: doc_id: cord_uid: srslmgk rationale: smokers and patients with chronic obstructive pulmonary disease (copd) are at increased risk for severe coronavirus disease (covid- ). objectives: we investigated the expression of the severe acute respiratory syndrome coronavirus (sars-cov- ) entry receptor ace and the protease tmprss in lung tissue from never smokers and smokers with and without copd. methods: in a cross-sectional, observational study we measured mrna expression of ace and tmprss by rt-pcr in lung tissue samples from well phenotyped subjects. next, protein levels of ace were visualized by immunohistochemistry on paraffin sections from subjects and quantified in alveolar and bronchial epithelium. finally, primary human bronchial epithelial cells (hbecs) were cultured at air liquid interface and exposed to air or cigarette smoke. results: ace mrna expression was significantly higher in lung tissue from current smokers and subjects with moderate to very severe copd and correlated with physiological parameters of airway obstruction and emphysema. pulmonary expression levels of tmprss were significantly higher in patients with (very) severe copd and correlated significantly with ace expression. importantly, protein levels of ace were elevated in both alveolar and bronchial epithelium of current smokers and subjects with moderate to very severe copd. finally, tmprss mrna expression increased in in vitro cultured hbecs upon acute exposure to cigarette smoke. conclusions: we demonstrate increased expression of ace in lungs of smokers and copd subjects, which might facilitate host cell entry of sars-cov- . these findings help identifying populations at risk for severe covid- . coronavirus disease (covid- ) is a novel emerging respiratory disease caused by the severe acute respiratory syndrome coronavirus (sars-cov- ), and is causing a vast pandemic with huge medical, social, personal and financial impact. the virus first appeared in wuhan, china and rapidly spread across the rest of the world, making covid- the third large-scale pandemic caused by coronaviruses after sars in and middle east respiratory syndrome (mers) in [ , ] . the clinical course of the disease ranges from an asymptomatic course to progressive respiratory failure with need for ventilatory support and even death [ ] . angiotensin-converting enzyme (ace ) was identified as the cell entry receptor used by sars-cov- and sars-cov- [ , ] . ace is a metallopeptidase i and a homologue of the ace-receptor. although both receptors play important roles in the renin-angiotensinaldosterone system (raas), they have profoundly different roles. whereas ace converts angiotensin i (ang i) to angiotensin ii (ang ii), a potent vasoconstrictor, ace converts both ang i and ang ii to ang-( - ) and ang-( - ) respectively, thereby counteracting the effects of ace and ang ii [ , ] . expression of ace was shown in various cells and tissues, including alveolar type ii cells and bronchial epithelial cells, as well as in the oral cavity, oesophagus, heart, kidney, and ileum [ ] . in addition, transmembrane protease, serine (tmprss ) was identified as the host cell protease used by sars-cov- for s protein priming, which is an essential part of the viral entry process [ ] . although sars-cov- can infect any individual, most severe cases are reported in those with comorbidities such as hypertension, diabetes, and chronic obstructive pulmonary disease (copd) [ , [ ] [ ] [ ] . copd is a highly prevalent chronic respiratory disease, characterized by an abnormal inflammatory response to cigarette smoke [ ] . importantly, both smokers and patients with copd are at increased risk for severe complications and a higher mortality upon . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . https://doi.org/ . / . . . doi: medrxiv preprint sars-cov- infection [ , ] . whether this is due to an increased expression of ace in the lungs, and more specifically in the alveolar tissue where pneumonia occurs in severe covid- , needs thorough investigation. a recent paper reported increased ace expression in bronchial brushings and airway epithelia of current smokers and patients with copd, compared to healthy controls [ ] . previous work done by our group, showed upregulation of dipeptidyl peptidase (dpp ), the viral entry receptor for the mers coronavirus, in alveolar tissue of smokers and patients with copd [ ] . we hypothesized that the increased risk for a more severe course of covid- in smokers and patients with copd is due to an increased expression of the sars-cov- entry receptor ace in the lung. therefore, we aimed to investigate the expression of ace , as well as the host cell protease tmprss , in a large number of lung tissue specimens of well phenotyped subjects, including never smokers and smokers with and without airflow limitation. we quantified ace and tmprss mrna expression in the lung, as well as ace protein levels in both alveolar and bronchial epithelium. next, we investigated the independent determinants of pulmonary ace expression by linear regression analysis. finally, we determined mrna expression of ace and tmprss in cigarette smoke-exposed primary human bronchial epithelial cells. . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted june , . methodological details are available in the online data supplement. study design, hypothesis, methods, analyses, and findings are reported according to the strobe checklist for crosssectional studies [ , ] . in this cross-sectional, observational study, we analyzed lung tissue specimens from a total of subjects: lung samples from our large lung tissue biobank at ghent university hospital (collected from lung resections for solitary pulmonary tumors and currently encompassing subjects) and samples from explant lungs from end-stage copd patients collected at uz gasthuisberg leuven, belgium. all lung samples were collected between january and february , before the first reported case of covid- in belgium. a flow-chart illustrating the selection of lung samples for rt-pcr (n= ) and immunohistochemical (n= ) analyses is shown in figure e . based on medical history, smoking history, questionnaires and preoperative spirometry, patients were categorized as never-smokers with normal lung function, smokers without airflow limitation or subjects with copd. subjects were considered exsmokers when they had quitted smoking for more than year. copd severity was defined according to the global initiative for chronic obstructive lung disease (gold) classification. none of the patients were treated with neo-adjuvant chemotherapy. lung tissue of patients diagnosed with solitary pulmonary tumors was obtained at a maximum distance from the pulmonary lesions and without signs of retro-obstructive pneumonia or tumor invasion and collected by a pathologist. written informed consent was obtained from all subjects. this study was approved by the medical ethical committees of the ghent university hospital ( / ; / ; / ) and the university hospital gasthuisberg leuven (s ). . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted june , . primary human bronchial epithelial cells (hbecs) were isolated by enzymatic digestion from lung resection specimens derived from donors ( non-copd and copd gold stage ii or iii) during surgery for lung cancer, as described previously [ ] . after a -day ali culture period, cells were exposed to mainstream cigarette smoke or air, as described previously, and harvested after , or hours [ ] . rna extraction from lung tissue blocks of subjects (including never-smokers, smokers without airflow limitation, patients with copd gold ii and patients with copd gold iii-iv, see table for patient characteristics), as well as from the ali cultured hbecs, was performed with the mirneasy mini kit (qiagen, hilden, germany), between and . next, cdna was prepared with the evoscript universal cdna master kit (roche) in march , followed by rt-pcr analysis for ace , tmprss and reference genes as described previously [ , ] . sections from formalin fixed paraffin embedded lung tissue blocks of subjects (including never-smokers, smokers without copd, subjects with copd gold ii and subjects with copd gold iii-iv, see supplementary table e for patient characteristics) were stained for ace in march and april . after antigen retrieval with citrate buffer (scytek), the slides were incubated with anti-ace antibody (polyclonal rabbit-anti-human, abcam ab ). next, slides were colored with diaminobenzidine (dako, carpinteria, ca, usa) and counterstained with mayer's hematoxylin (sigma-aldrich, st-louis, mo, usa). the isotype control was rabbit igg (r&d systems, ab- -c). . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted june , . . https://doi.org/ . / . . . doi: medrxiv preprint quantitative measurements of the ace -positive signal in alveolar tissue and bronchial epithelium was performed on images of stained paraffin sections as described previously [ ] . a detailed description of the methods can be found in the online supplement. briefly, to quantify the amount of ace -positive signal in alveolar tissue, images of alveolar tissue (not containing airways or blood vessels) were recorded from an average of tissue blocks per patient. the area of brown ace -positive staining was measured and normalized to the total area of alveolar tissue present in each image. additionally, the number of ace -positive cells was manually counted in each image and again normalized to the total area of alveolar tissue. to quantify the amount of ace -positive signal in airway epithelium, images of airways were recorded from an average of tissue blocks per patient. the amount of ace -positive signal was measured only in the airway epithelial layer and normalized to the length of the basement membrane (pbm). the number of airways per patient was between and . statistical analysis was performed with sigma stat software (spss . , chicago, il, usa) and r . . , using student's t-test, kruskal-wallis and mann-whitney u test, fisher's exact test, spearman's rank correlations, and multivariate linear regression analyses. additional details and covariates for the regression analyses are described in the online supplement. characteristics of the study population are presented as median (interquartile range). differences at p-values < . were considered to be significant (*p< . , **p< . and *** p< . ). . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . https://doi.org/ . / . . . doi: medrxiv preprint using real time quantitative pcr, ace mrna levels were determined in lung tissue from subjects. lung tissue from never smokers, smokers without airflow limitation (including current smokers and ex-smokers) and patients with copd gold stage ii (including current smokers and ex-smokers) was derived from lobectomy specimens, whereas tissue from subjects with copd gold stage iii-iv was derived from explant lungs after lung transplantation. demographic and clinical patient characteristics are described in table . ace mrna expression was significantly higher in lung tissue of current smokers without airflow limitation, current smokers with copd gold stage ii, and smokers with copd gold stage iii-iv, compared to never smokers ( figure a ). in addition, ex-smokers without airflow limitation showed significantly lower ace mrna levels, compared to current smokers. tmprss mrna expression was significantly higher in lung tissue of patients with copd gold stage iii-iv, compared to never smokers, smokers without airflow limitation and patients with copd gold stage ii ( figure b) . moreover, there was a significant positive correlation between pulmonary tmrpss mrna expression and ace mrna expression, even after excluding the high tmprss expressing gold stage iii-iv patients ( figure g ). . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . https://doi.org/ . / . . . doi: medrxiv preprint ace protein levels are increased in alveolar tissue and bronchial epithelium of smokers and copd subjects. by immunohistochemical (ihc) staining, ace protein levels were assessed in lung tissue from subjects: never smokers, smokers without copd ( current smokers and exsmokers), patients with copd gold stage ii ( current smokers and ex-smokers) and smokers with copd gold stage iii-iv. patient characteristics are described in supplementary table e . quantification of ace staining in bronchial epithelium revealed numerically higher levels in current smokers without airflow limitation and current smokers with copd gold ii, and significantly higher levels in patients with copd gold iii-iv, compared to never smokers ( figure a-e) . moreover, ace protein levels in bronchial epithelium were significantly higher in patients with copd gold iii-iv, compared to ex-smokers without airflow limitation and ex-smokers with copd gold ii ( figure e ). . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . https://doi.org/ . / . . . doi: medrxiv preprint we investigated whether the increased ace levels in subjects with copd could partially result from cigarette smoking. although the effect size for the association between copd and pulmonary ace mrna expression was affected after adjusting for smoking status in linear regression analyses (unadjusted β . ± . , p = . ; smoke status adjusted β . ± . , p = . ), the association remained statistically significant. secondly, we tested whether the association between copd and pulmonary ace mrna could be confounded by comorbidities or intake of raas-inhibitors (ace-inhibitors or angiotensin receptor blockers (arb)). multivariate linear regression analysis demonstrated that current smoking (β . ± . , p = . ) and copd (β . ± . , p = . ) are both independently associated with increased ace mrna expression in lung tissue, even after adjustment for covariates including age, sex, diabetes, hypertension and use of raas-inhibitors ( figure a ). similar findings were observed for the association between copd and ace protein expression in alveolar tissue ( figure b ) or bronchial epithelium and ( figure e ) . notably, in these models, diabetes mellitus seemed to be significantly associated with increased ace levels in alveolar tissue and bronchial epithelium. ace mrna expression was significantly higher in lung tissue of subjects using oral corticosteroid (ocs), but not in lung tissue of subjects using inhaled corticosteroid (ics) ( figure e ). to test whether increased ace mrna levels in ocs users may be partially due to underlying copd, we performed linear regression analyses. indeed, the significant age-and sex-adjusted association between ocs use and ace mrna expression (β . ± . , p < . ) did not persist after additional adjustment for copd (β . ± . , p = . ). . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . ace and tmprss mrna expression was determined by quantitative rt-pcr in hbecs, cultured at air liquid interface (ali) and exposed to air or cigarette smoke (cs). ace mrna expression was not altered , and hours after cs-exposure ( figure a ). in contrast, after and hours the tmprss mrna expression in cs-exposed hbecs was significantly increased, compared to air exposed cells (figure b ). . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . https://doi.org/ . / . . . doi: medrxiv preprint as healthcare systems around the world are currently under great pressure due to the covid- outbreak, identification of those at high risk is crucial. there is compelling evidence of a more severe course of covid- in smokers and patients with comorbidities such as copd. we clearly demonstrate an increased pulmonary expression of the sars-cov- entry receptor ace in smokers and copd subjects at both mrna and protein level, by rt-pcr and immunohistochemistry respectively. our study in smokers with and without copd confirms our hypothesis that their increased risk for severe covid- may be at least partially attributed to increased ace expression. importantly, we demonstrate higher ace protein levels not only in bronchial epithelium but also in alveolar epithelium of patients with copd, which can [ , ] . importantly, it has been demonstrated in mouse models that transgenic (over)expression of human ace enhances the pathogenicity of sars-cov- and sars-cov- [ , ] . moreover, human ace was essential for viral replication in the lung. the same is true for the presence of host cell proteases such as tmprss and furin, that are essential in the viral entry process [ ] . . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . https://doi.org/ . / . . . doi: medrxiv preprint we measured mrna expression of ace and tmprss in lung tissue samples from never smokers and smokers with and without airflow limitation and demonstrate higher ace mrna levels in current smokers and patients with moderate (gold ii) and severe to very severe copd (gold iii-iv). importantly, ace mrna expression shows an inverse correlation with physiological parameters of airway obstruction and emphysema. linear regression analysis confirms that smoking and copd are associated with increased ace mrna expression, independent of covariables such as age, gender, comorbidities, and medication use. the association between copd and ace mrna seems to be partly driven by smoking as the effect size of the association between copd and ace mrna decreased after adjusting for smoking. the remaining statistically significant association between copd and ace mrna might be explained by other factors such as aggravated pulmonary and systemic inflammation, previous exacerbations or genetic predisposition. interestingly, a recent large meta-analysis of transcriptomic data confirms the increased ace mrna expression in lung tissue of smokers and patients with copd [ ] . tmprss mrna expression is only significantly higher in patients with (very) severe copd. however, there is a significant correlation between tmprss mrna and ace mrna expression levels, even in sensitivity analyses omitting (very) severe copd patients from the analysis. our data suggest that both ace and tmprss are expressed on the same cells, and co-expression might further increase the chance of viral entry. by immunohistochemical (ihc) staining we reveal expression of ace in both bronchial and alveolar epithelial cells, with the latter predominantly in alveolar type ii (atii) pneumocytes. recently been confirmed by both ihc and single cell rna sequencing analyses [ ] [ ] [ ] . similar analyses also confirm the expression of ace in bronchial epithelial cells, including goblet cells [ , ] . . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . https://doi.org/ . / . . . doi: medrxiv preprint by quantification of the ace ihc staining, we demonstrate increased protein levels of ace in both alveolar and bronchial epithelium of current smokers and patients with moderate and (very) severe copd. linear regression analyses suggest that these associations are partly driven by smoking. importantly, we are the first to report quantitative evidence for increased ace protein levels in alveolar epithelium, which is the primary site for pathogenic pulmonary infections and could thus explain why smokers and patients with copd are more prone to develop bilateral pneumonia and/or acute respiratory distress syndrome (ards) in severe covid- . indeed, the preferential expression of ace on alveolar type ii epithelial cells might make these cells more vulnerable to sars-cov- infection and virus-induced cell death. since atii cells produce surfactants which are crucial for preventing alveolar collapse during breathing, sars-cov- induced targeting and lysis of atii cells will alter lung compliance and induce ventilation-perfusion mismatch in severe covid- , leading to hypoxia and respiratory failure [ ] . our findings of increased ace levels in bronchial epithelial cells complement the recent paper of leung et al., who reported increased ace mrna expression in bronchial brushings of smokers and patients with copd [ ] . in vitro cultures of primary hbecs at air liquid interface reveal increased mrna expression of tmprss and hours after a single exposure to cigarette smoke, indicative of an acute effect of smoking on the tmprss levels in the bronchial epithelium. ace expression might be more dependent on chronic cigarette smoke exposure, since no effect on ace mrna expression is observed in these short-term in vitro experiments. inhaled corticosteroids (ics) are essential in the treatment of asthma and a subgroup of copd patients (i.e. with a history of frequent exacerbations). since ics are often regarded as immunosuppressive, there is a general concern on whether or not to continue the use of ics during the covid- pandemic. importantly, our current data shows no association between the ics use and the expression of ace in the lung. we do report significantly increased ace . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . https://doi.org/ . / . . . doi: medrxiv preprint expression in subjects using oral corticosteroids (ocs), albeit based on a low number of subjects using ocs, implicating the need to confirm these preliminary findings in larger studies. by performing linear regression analyses on our data set, we reveal that lifestyle factors and comorbidities that are linked to a more severe course of covid- , such as smoking, copd, and especially diabetes are associated with a higher expression of ace protein in alveolar tissue. however, due to the observational design of this cross-sectional study, we cannot defer any causal relationships from these associations. moreover, our results need to be replicated in larger studies and in subjects of other ethnicities. the main strength of this study is the large number of lung tissue samples from well-phenotyped subjects that are included in the both rt-pcr and ihc analyses. moreover, ihc allowed us to quantify ace protein levels in both bronchial and alveolar epithelium. however, certain limitations should be kept in mind. first, this study consists mainly of lung tissue from lobectomy. since these patients might not be representative for the general population, we cannot exclude selection bias. second, differential information bias may have occurred when questioning smoke status at the time of lobectomy, since copd status was known to the investigator. however, by carefully checking medical records, we ascertained accurateness of the patient characteristics. last, although this study consisted of a relatively large and wellphenotyped cohort, samples size may be insufficient for multivariate linear regression analyses. in conclusion, we report higher ace mrna and protein levels in lung tissue of smokers and subjects with moderate to (very) severe copd. importantly, ace protein levels are not only increased in bronchial but also in alveolar epithelium. in addition, tmprss mrna expression is higher in lung tissue of (very) severe copd subjects and increases in in vitro . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted june , . . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted june , . a pneumonia outbreak associated with a new coronavirus of probable bat origin clinical characteristics of hospitalized patients with novel coronavirus-infected pneumonia in wuhan, china evolution of the novel coronavirus from the ongoing wuhan outbreak and modeling of its spike protein for risk of human transmission comorbidity and its impact on patients with covid- in china: a nationwide analysis clinical course and risk factors for mortality of adult inpatients with covid- in wuhan, china: a retrospective cohort study clinical features of patients infected with new insights into the immunology of chronic obstructive pulmonary disease severity and mortality associated with copd and smoking in patients with covid- : a rapid systematic review and meta-analysis opensafely: factors associated with covid- -related hospital death in the linked electronic health records of million adult nhs patients expression in the small airway epithelia of smokers and copd patients: implications for covid- in lungs of smokers and chronic obstructive pulmonary disease patients strengthening the reporting of observational studies in epidemiology (strobe): explanation and elaboration guidance on statistical reporting to help improve your chances of a favorable statistical review regulation of slpi and elafin release from bronchial epithelial cells by neutrophil defensins aberrant epithelial differentiation by cigarette smoke dysregulates respiratory host defence role of b cell-activating factor in chronic obstructive pulmonary disease microrna profiling reveals a role for microrna- - p in the pathogenesis of chronic obstructive pulmonary disease structure of the sars-cov- spike receptor-binding domain bound to the ace receptor structural basis of receptor recognition by sars-cov- mice transgenic for human angiotensin-converting enzyme provide a model for sars coronavirus infection the pathogenicity of sars-cov- in hace transgenic mice tobacco smoking increases the lung gene expression of ace , the receptor of sars-cov- the functional receptor for sars coronavirus. a first step in understanding sars pathogenesis smoking upregulates angiotensin-converting enzyme- receptor: a potential adhesion site for novel coronavirus sars-cov- (covid- ) sars-cov- entry factors are highly expressed in nasal epithelial cells together with innate immune genes expression in the small airway epithelia of smokers and copd patients: implications for covid- eur respir j .. cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . https://doi.org/ . / . . . doi: medrxiv preprint . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in per (which was not certified by peer review)the copyright holder for this this version posted june , . . https://doi.org/ . / . . . doi: medrxiv preprint . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in per (which was not certified by peer review). cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in per (which was not certified by peer review)the copyright holder for this this version posted june , . . https://doi.org/ . / . . . doi: medrxiv preprint key: cord- -fr uod authors: nan title: saem abstracts, plenary session date: - - journal: acad emerg med doi: . /j. - . . .x sha: doc_id: cord_uid: fr uod nan objectives: we sought to determine if the ocp policy resulted in a meaningful and sustained improvement in ed throughput and output metrics. methods: a prospective pre-post experimental study was conducted using administrative data from community and tertiary centers across the province. the study phases consisted of the months from february to september compared against the same months in . operational data for all centres were collected through the edis tracking systems used in the province. the ocp included main triggers: ed bed occupancy > %, at least % of ed stretchers blocked by patients awaiting inpatient bed or disposition decision, and no stretcher available for high acuity patients. when all criteria were met, selected boarded patients were moved to an inpatient unit (non-traditional care space if no bed available). the primary outcome was ed length of stay (los) for admitted patients. the ed load of boarded patients from - am was reported the editors of academic emergency medicine (aem) are honored to present these abstracts accepted for presentation at the annual meeting of the society for academic emergency medicine (saem), may to in chicago, illinois. these abstracts represent countless hours of labor, exciting intellectual discovery, and unending dedication by our specialty's academicians. we are grateful for their consistent enthusiasm, and are privileged to publish these brief summaries of their research. this year, saem received abstracts for consideration, and accepted . each abstract was independently reviewed by up to six dedicated topic experts blinded to the identity of the authors. final determinations for scientific presentation were made by the saem program scientific subcommittee co-chaired by ali s. raja, md, mba, mph and steven b. bird, md, and the saem program committee, chaired by michael l. hochberg, md. their decisions were based on the final review scores and the time and space available at the annual meeting for oral and poster presentations. there were also innovation in emergency medicine education (ieme) abstracts submitted, of which were accepted. the ieme subcommittee was co-chaired by joanna leuck, md and laurie thibodeau, md. we present these abstracts as they were received, with minimal proofreading and copy editing. any questions related to the content of the abstracts should be directed to the authors. presentation numbers precede the abstract titles; these match the listings for the various oral and poster sessions at the annual meeting in chicago, as well as the abstract numbers (not page numbers) shown in the key word and author indexes at the end of this supplement. all authors attested to institutional review board or animal care and use committee approval at the time of abstract submission, when relevant. abstracts marked as ''late-breakers'' are prospective research projects that were still in the process of data collection at the time of the december abstract deadline, but were deemed by the scientific subcommittee to be of exceptional interest. these projects will be completed by the time of the annual meeting; data shown here may be preliminary or interim. on behalf of the editors of aem, the membership of saem, and the leadership of our specialty, we sincerely thank our research colleagues for these contributions, and their continuing efforts to expand our knowledge base and allow us to better treat our patients. david background: two to ten percent of patients evaluated in the emergency departments (ed) present with altered mental status (ams). the prevalence of non-convulsive seizure (ncs) and other electroencephalographic (eeg) abnormalities in this population is not known. this information is needed to make recommendations regarding the routine use of emergent eeg in ams patients. objectives: to identify the prevalence of ncs and other eeg abnormalities in ed patients with ams. methods: an ongoing prospective study at two academic urban ed. inclusion: patients ‡ years old with ams. exclusion: an easily correctable cause of ams (e.g. hypoglycemia, opioid overdose). a -minute eeg with the standard electrodes was performed on each subject as soon as possible after presentation (usually within hour). outcome: the rate of eeg abnormalities based on blinded review of all eegs by two boardcertified epileptologists. descriptive statistics are used to report eeg findings. frequencies are reported as percentages with % confidence intervals (ci), and inter-rater variability is reported with kappa. results: the interim analysis was performed on consecutive patients (target sample size: ) enrolled from may to october (median age: , range - , % male). eegs for patients were reported uninterpretable by at least one rater ( by both raters). of the remaining , only ( %, %ci - %) were normal according to either rater (n = by both). the most common abnormality was background slowing (n = , %, %ci - %) by either rater (n = by both), indicating underlying encephalopathy. ncs was diagnosed in patients ( %, %ci, - %) by at least one rater (n = by both), including ( %, %ci - %) patients in non-convulsive status epilepticus (ncse). patients ( %, %ci - %) had interictal epileptiform discharges read by at least one rater (n = by both) indicating cortical irritability and an increased risk of spontaneous seizure. inter-rater reliability for eeg interpretations was modest (kappa: . , %ci . - . ). objectives: to define diagnostic sbi and non-bacterial (non-sbi) biosignatures using rna microarrays in febrile infants presenting to emergency departments (eds). methods: we prospectively collected blood for rna microarray analysis in addition to routine screening tests including white blood cell (wbc) counts, urinalyses, cultures of blood, urine, and cerebrospinal fluid, and viral studies in febrile infants days of age in eds . we defined sbi as bacteremia, urinary tract infection (uti), or bacterial meningitis. we used class comparisons (mann-whitney p < . , benjamini for mtc and . fold change filter), modular gene analysis, and k-nn algorithms to define and validate sbi and non-sbi biosignatures in a subset of samples. results: % ( / ) of febrile infants were evaluated for sbi. . % ( / ) had sbi ( ( . %) bac-teremia, ( . %) utis, and ( . %) bacterial meningitis). infants with sbis had higher mean temperatures, and higher wbc, neutrophil, and band counts. we analyzed rna biosignatures on febrile infants: sbis ( meningitis, bacteremia, uti), non-sbis ( influenza, enterovirus, undefined viral infections), and healthy controls. class comparisons identified , differentially expressed genes between sbis and non-sbis. modular analysis revealed overexpression of interferon related genes in non-sbis and inflammation related genes in sbis. genes were differently expressed (p < . ) in each of the three non-sbi groups vs sbi group. unsupervised cluster analysis of these genes correctly clustered % ( / ) of non-sbis and sbis. k-nn algorithm identified discriminatory genes in training set ( non-sbis vs sbis) which classified an independent test ( non-sbis vs sbis) with % accuracy. four misclassified sbis had over-expression of interferon-related genes, suggesting viral-bacterial co-infections, which was confirmed in one patient. background: improving maternal, newborn, and child health (mnch) is a leading priority worldwide. however, limited frontline health care capacity is a major barrier to improving mnch in developing countries. objectives: we sought to develop, implement, and evaluate an evidence-based maternal, newborn, and child survival (mncs) package for frontline health workers (fhws). we hypothesized that fhws could be trained and equipped to manage and refer the leading mnch emergencies. methods: setting -south sudan, which suffers from some of the world's worst mnch indices. assessment/intervention -a multi-modal needs assessment was conducted to develop a best-evidence package comprised of targeted trainings, pictorial checklists, and reusable equipment and commodities ( figure ). program implementation utilized a trainingof-trainers model. evalution - ) pre/post knowledge assessments, ) pre/post objective structured clinical examinations (osces), ) focus group discussions, and ) closed-response questionnaires. results: between nov to oct , local trainers and fhws were trained in of the states in south sudan. knowledge assessments among trainers (n = ) improved significantly from . % (sd . ) to . % (sd . ) (p < . ). mean scores a maternal osce and a newborn osce pre-training, immediately post-training, and upon - month follow-up are shown in the table. closed-response questionnaires with fhws revealed high levels of satisfaction, use, and confidence with mncs materials. participants reported an average of . referrals (range - ) to a higher level of care in the - months since training. furthermore, . % of fhws were more likely to refer patients as a result of the training program. during seven focus group discussions with trained fhws, respondents (n = ) reported high satisfaction with mncs trainings, commodities, and checklists, with few barriers to implementation or use. conclusion: these findings suggest mncs has led to improvements in south sudanese fhws' knowledge, skills, and referral practices with respect to appropriate management of mnch emergencies. no study has compared various lactate measurements to determine the optimal parameter to target. objectives: to compare the association of blood lactate kinetics with survival in patients with septic shock undergoing early quantitative resuscitation. methods: preplanned analysis of a multicenter edbased rct of early sepsis resuscitation targeting three physiological variables: cvp, map, and either central venous oxygen saturation or lactate clearance. inclusion criteria: suspected infection, two or more sirs criteria, and either sbp < mmhg after a fluid bolus or lactate > mmol/l. all patients had an initial lactate measured with repeat at two hours. normalization of lactate was defined a lactate decline to < . mmol/l in a patient with an intial lactate ‡ . . absolute lactate clearance (initial -delayed value), and relative ((absolute clearance)/(initial value)* ) were calculated if the initial lactate was ‡ . . the outcome was in-hospital survival. receiver operating characteristic curves were constructed and areas under the curve (auc) were calculated. difference in proportions of survival between the two groups at different lactate cutoffs were analyzed using % ci and fisher exact tests. results: of included patients, the median initial lactate was . mmol/l (iqr . , . ), and the median absolute and relative lactate clearance were mmol/l (iqr . , . ) and % (iqr , ). an initial lactate > . mmol/l was seen in / ( %), and / ( %) patients normalized their lactate. overall sutures on trunk and extremity lacerations that present in the ed. the use of absorbable sutures in the ed setting confers several advantages: patients do not need to return for suture removal which results in a reduction in ed crowding, ed wait times, missed work or school days, and stressful procedures (suture removal) for children. objectives: the primary objective of this study is to compare the cosmetic outcome of trunk and extremity lacerations repaired using absorbable versus nonabsorbable sutures in children and adults. a secondary objective is to compare complication rates between the two groups. methods: eligible patients with lacerations were randomly allocated to have their wounds repaired with vicryl rapide (absorbable) or prolene (nonabsorbable) sutures. at a day follow-up visit the wounds were evaluated for infection and dehiscence. after months, patients were asked to return to have a photograph of the wound taken. two blinded plastic surgeons using a previously validated mm visual analogue scale (vas) rated the cosmetic outcome of each wound. a vas score of mm or greater was considered to be a clinically significant difference. results: of the patients enrolled, have currently completed the study including in the vicryl rapide group and in the prolene group. there were no significant differences in the age, race, sex, length of wound, number of sutures, or layers of repair in the two groups. the observer's mean vas for the vicryl rapide group was . mm ) and that for the prolene group was . mm ( %ci . - . ), resulting in a mean difference of . mm ( %ci- . to . , p = . ). there were no significant differences in the rates of infection, dehiscence, or keloid formation between the two groups. conclusion: the use of vicryl rapide instead of nonabsorbable sutures for the repair of lacerations on the trunk and extremities should be considered by emergency physicians as it is an alternative that provides a similar cosmetic outcome. objectives: to determine the relationship between infection and time from injury to closure, and the characteristics of lacerations closed before and after hours of injury. methods: over an month period, a prospective multi-center cohort study was conducted at a teaching hospital, trauma center and community hospital. emergency physicians completed a structured data form when treating patients with lacerations. patients were followed to determine whether they had suffered a wound infection requiring treatment and to determine a cosmetic outcome rating. we compared infection rates and clinical characteristics of lacerations with chisquare and t-tests as appropriate. results: there were patients with lacerations; had documented times from injury to closure. the mean times from injury to repair for infected and noninfected wounds were . vs. . hrs (p = . ) with % of lacerations treated within hours and % ( ) treated hours after injury. there were no differences in the infection rates for lacerations closed before ( . %, %ci . - . ) or after ( . %, %ci . - . ) hours and before ( . %, % ci . %- . %) or after ( . %, % ci . %- . %) hours. the patients treated hours after injury tended to be older ( vs. yrs p = . ) and fewer were treated with primary closure ( % vs. % p < . ). comparing wounds or more hours after injury with more recent wounds, there was no effect of location on decision to close. wounds closed after hours did not differ from wounds closed before hours with respect to use of prophylactic antibiotics, type of repair, length of laceration, or cosmetic outcome. conclusion: closing older lacerations, even those greater than hours after injury, does not appear to be associated with any increased risk of infection or adverse outcomes. excellent irrigation and decontamination over the last years may have led to this change in outcome. background: deep burns may result in significant scarring leading to aesthetic disfigurement and functional disability. tgf-b is a growth factor that plays a significant role in wound healing and scar formation. objectives: the current study was designed to test the hypothesis that a novel tgf-b antagonist would reduce scar contracture compared with its vehicle in a porcine partial thickness burn model. methods: ninety-six mid-dermal contact burns were created on the backs and flanks of four anesthetized young swine using a gm aluminum bar preheated to °celsius for seconds. the burns were randomized to treatment with topical tgf-b antagonist at one of three concentrations ( , , and ll) in replicates of in each pig. dressing changes and reapplication of the topical therapy were performed every days for weeks then twice weekly for an additional weeks. burns were photographed and full thickness biopsies were obtained at , , , , and days to determine reepithelialization and scar formation grossly and microscopically. a sample of burns in each group had % power to detect a % difference in percentage scar contracture. results: a total of burns were created in each of the three study groups. burns treated with the high dose tgf-b antagonist healed with less scar contracture than those treated with the low dose and control ( ± %, ± %, and ± %; anova p = . ). additionally, burns treated with the higher, but not the lower dose of tgf-b antagonist healed with significantly fewer full thickness scars than controls ( . % vs. % vs. . % respectively; p < . ). there were no infections and no differences in the percentage wound reepithelialization among all study groups at any of the time points. conclusion: treatment of mid-dermal porcine contact burns with the higher dose tgf-b antagonist reduced scar contracture and rate of deep scars compared with the low dose and controls. background: diabetic ketoacidosis (dka) is a common and lethal complication of diabetes. the american diabetes association recommends treating adult patients with a bolus dose of regular insulin followed by a continuous insulin infusion. the ada also suggests a glucose correction rate of - mg/dl/hr to minimize complications. objectives: compare the effect of bolus dose insulin therapy with insulin infusion to insulin infusion alone on serum glucose, bicarbonate, and ph in the initial treatment of dka. methods: consecutive dka patients were screened in the ed between march ' and june ' . inclusion criteria were: age > years, glucose > mg/dl, serum bicarbonate or ketonemia or ketonuria. exclusion criteria were: congestive heart failure, current hemodialysis, pregnancy, or inability to consent. no patient was enrolled more than once. patients were randomized to receive either regular insulin . units/kg or the same volume of normal saline. patients, medical and research staff were blinded. baseline glucose, electrolytes, and venous blood gases were collected on arrival. bolus insulin or placebo was then administered and all enrolled patients received regular insulin at rate of . unit/kg/hr, as well as fluid and potassium repletion per the research protocol. glucose, electrolytes, and venous blood gases were drawn hourly for hours. data between two groups were compared using unpaired t-test. results: patients were enrolled, with being excluded. patients received bolus insulin; received placebo. no significant differences were noted in initial glucose, ph, bicarbonate, age, or weight between the two groups. after the first hour, glucose levels in the insulin group decreased by mg/dl compared to mg/dl in the placebo group (p = . , % ci . to . ). changes in mean glucose levels, ph, bicarbonate level, and ag were not statistically different between the two groups for the remainder of the hour study period. there was no difference in the incidence of hypoglycemia in the two groups. conclusion: administering a bolus dose of regular insulin decreased mean glucose levels more than placebo, although only for the first hour. there was no difference in the change in ph, serum bicarbonate or anion gap at any interval. this suggests that bolus dose insulin may not add significant benefit in the emergency management of dka. ihca; . return of spontaneous circulation (rsoc). traumatic cardiac arrests were excluded. we recorded baseline demographics, arrest event characteristics, follow-up vitals and laboratory data, and in-hospital mortality. apache ii scores were calculated at the time of rosc, and at hrs, hrs, and hrs. we used simple descriptive statistics to describe the study population. univariate logistic regression was used to predict mortality with apache ii as a continuous predictor variable. discrimination of apache ii scores was assessed using the area under the curve (auc) of the receiver operator characteristic (roc) curve. results: a total of patients were analyzed. the median age was years (iqr: - ) and % were female. apache ii score was a significant predictor of mortality for both ohca and ihca at baseline and at all follow-up time points (all p < . ). discrimination of the score increased over time and achieved very good discrimination after hrs (table, figure) . conclusion: the ability of apache ii score to predict mortality improves over time in the hours following cardiac arrest. these data suggest that after hours, apache ii scoring is a useful severity of illness score in all post-cardiac arrest patients. background: admission hyperglycemia has been described as a mortality risk factor for septic non-diabetics, but the known association of hyperglycemia with hyperlactatemia (a validated mortality risk factor in sepsis) has not previously been accounted for. objectives: to determine whether the association of hyperglycemia with mortality remains significant when adjusted for concurrent hyperlactatemia. methods: this was a post-hoc, nested analysis of a single-center cohort study. providers identified study subjects during their ed encounters; all data were collected from the electronic medical record. patients: nondiabetic adult ed patients with a provider-suspected infection, two or more systemic inflammatory response syndrome criteria, and concurrent lactate and glucose testing in the ed. setting: the ed of an urban teaching hospital; to . analysis: to evaluate the association of hyperglycemia (glucose > mg/dl) with hyperlactatemia (lactate ‡ . mmol/l), a logistic regression model was created; outcome-hyperlactatemia; primary variable of interest-hyperglycemia. a second model was created to determine if concurrent hyperlactatemia affects hyperglycemia's association with mortality; outcome- -day mortality; primary risk variablehyperglycemia with an interaction term for concurrent hyperlactatemia. both models were adjusted for demographics, comorbidities, presenting infectious syndrome, and objective evidence of renal, respiratory, hematologic, or cardiovascular dysfunction. results: ed patients were included; mean age ± years. ( %) subjects were hyperglycemic, ( %) hyperlactatemic, and ( %) died within days of the initial ed visit. after adjustment, hyperglycemia was significantly associated with simultaneous hyperlactatemia (or . , %ci . , . ). hyperglycemia with concurrent hyperlactatemia was associated with increased mortality risk (or . , %ci . , . ) , but hyperglycemia in the absence of simultaneous hyperlactatemia was not (or . , %ci . , . ) . conclusion: in this cohort of septic adult non-diabetic patients, mortality risk did not increase with hyperglycemia unless associated with simultaneous hyperlactatemia. the previously reported association of hyperglycemia with mortality in this population may be due to the association of hyperglycemia with hyperlactatemia. the background: near infrared spectroscopy (sto ) represents a measure of perfusion that provides the treating physician with an assessment of a patient's shock state and response to therapy. it has been shown to correlate with lactate and acid/base status. it is not known if using information from this monitor to guide resuscitation will result in improved patient outcomes. objectives: to compare the resuscitation of patients in shock when the sto monitor is or is not being used to guide resuscitation. methods: this was a prospective study of patients undergoing resuscitation in the ed for shock from any cause. during alternating day periods, physicians were blinded to the data from the monitor followed by days in which physicians were able to see the information from the sto monitor and were instructed to resuscitate patients to a target sto value of . adult patients (age> ) with a shock index (si) of > . (si = heart rate/systolic blood pressure) or a blood pressure < mmhg systolic who underwent resuscitation were enrolled. patients had a sto monitor placed on the thenar eminence of their least-injured hand. data from the sto monitor were recorded continuously and noted every minute along with blood pressure, heart rate, and oxygen saturation. all treatments were recorded. patients' charts were reviewed to determine the diagnosis, icu-free days in the days after enrollment, inpatient los, and -day mortality. data were compared using wilcoxon rank sum and chi-square tests. results: patients were enrolled, during blinded periods and during unblinded periods. the median presenting shock index was . (range . to . ) for the blinded group and . ( . - . ) for the unblinded group (p = . ). the median time in department was minutes (range - ) for the blinded and minutes (range - ) for the unblinded groups (p = . ). the median hospital los was day (range - ) for the blinded group, and days (range - ) in the unblinded group (p = . ). the mean icu-free days was ± for the blinded group and ± for the unblinded group (p = . ). among patients where the physician indicated using the sto monitor data to guide patient care, the icu-free days were . ± for the blinded group and . ± for the blinded group (p = . ). background: inducing therapeutic hypothermia (th) using °c iv fluids in resuscitated cardiac arrest patients has been shown to be feasible and effective. limited research exists assessing the efficiency of this cooling method. objectives: the objective was to determine an efficient infusion method for keeping fluid close to °c upon exiting an iv. it was hypothesized that colder temperatures would be associated with both higher flow rate and insulation of the fluid bag. methods: efficiency was studied by assessing change in fluid temperature ( c) during the infusion, under three laboratory conditions. each condition was performed four times using liter bags of normal saline. fluid was infused into a ml beaker through gtts tubing. flow rate was controlled using a tubing clamp and in-line transducer with a flowmeter, while temperature was continuously monitored in a side port at the terminal end of the iv tubing using a digital thermometer. the three conditions included infusing chilled fluid at a rate of ml/min, which is equivalent to ml/kg/hr for an kg patient, ml/min, and ml/min using a chilled and insulated pressure bag. descriptive statistics and analysis of variance was performed to assess changes in fluid temperature. results: the average fluid temperatures at time were . ( % ci . - . ) ( ml/min), . ( % ci . - . ) ( ml/min), and . ( % ci . - . ) ( ml/min + insulation). there was no significant difference in starting temperature between groups (p = . ). the average fluid temperatures after ml had been infused were . ( % ci . - . ) ( ml/min), . ( % ci . - . ) ( ml/min), and . ( % ci . - . ) ( ml/min + insulation). the higher flow rate groups had significantly lower temperature than the lower flow rate after ml of fluid had been infused (p < . ). the average fluid temperatures after ml had been infused were . ( % ci . - . ) ( ml/min), . ( % ci . - . ) ( ml/min), and . ( % ci . - . ) ( ml/min + insulation). there was a significant difference in temperature between all three groups after ml of fluid had been infused (p < . ). conclusion: in a laboratory setting, the most efficient method of infusing cold fluid appears to be a method that both keeps the bag of fluid insulated and is infused at a faster rate. fluid bolus. patients were categorized by presence of vasoplegic or tissue dysoxic shock. demographics and sequential organ failure assessment (sofa) scores were evaluated between the groups. the primary outcome was in-hospital mortality. data were analyzed using t-tests, chi-squared test, and proportion differences with % confidence intervals as appropriate. results: a total of patients were included: patients with vasoplegic shock and with tissue dysoxic shock. there were no significant differences in age ( vs. years), caucasian race ( % vs. %), or male sex ( % vs. %) between the dysoxic shock and vasoplegic shock groups, respectively. the group with vasoplegic shock had a lower initial sofa score than did the group with tissue dysoxic shock ( . vs. . points, p = . ). the primary outcome of in-hospital mortality occurred in / ( %) of patients with vasoplegic shock compared to / ( %) in the group with tissue dysoxic shock (proportion difference %, % ci - %, p < . ). conclusion: in this analysis of patients with septic shock, we found a significant difference in in-hospital mortality between patients with vasoplegic versus tissue dysoxic septic shock. these findings suggest a need to consider these differences when designing future studies of septic shock therapies. background: the pre-shock population, ed sepsis patients with tissue hypoperfusion (lactate of . - . mm), commonly deteriorates after admission and requires transfer to critical care. objectives: to determine the physiologic parameters and disease severity indices in the ed pre-shock sepsis population that predict clinical deterioration. we hypothesized that neither initial physiologic parameters nor organ function scores will be predictive. methods: design: retrospective analysis of a prospectively maintained registry of sepsis patients with lactate measurements. setting: an urban, academic medical center. participants: the pre-shock population, defined as adult ed sepsis patients with either elevated lactate ( . - . mm) or transient hypotension (any sbp < mmhg) receiving iv antibiotics and admitted to a medical floor. consecutive patients meeting pre-shock criteria were enrolled over a -year period. patients with overt shock in the ed, pregnancy, or acute trauma were excluded. outcome: primary patientcentered outcome of increased organ failure (sequential organ failure assessment [sofa] score increase > point, mechanical ventilation, or vasopressor utilization) within hours of admission or in-hospital mortality. results: we identified pre-shock patients from screened. the primary outcome was met in % of the cohort and % were transferred to the icu from a medical floor. patients meeting the outcome of increased organ failure had a greater shock index ( . vs . , p = . ) and heart rate ( vs , p < . ) with no difference in initial lactate, age, map, or exposure to hypotension (sbp < mmhg). there was no difference in the predisposition, infection, response, and organ dysfunction (piro) score between groups ( . vs . , p = . ). outcome patients had similar initial levels of organ dysfunction but had higher sofa scores at , , and hours, a higher icu transfer rate ( vs %, p < . ), and increased icu and hospital lengths of stay. conclusion: the pre-shock sepsis population has a high incidence of clinical deterioration, progressive organ failure, and icu transfer. physiologic data in the ed were unable to differentiate the pre-shock sepsis patients who developed increased organ failure. this study supports the need for an objective organ failure assessment in the emergency department to supplement clinical decision-making. background: lipopolysaccharide (lps) has long been recognized to initiate the host inflammatory response to infection with gram negative bacteria (gnb). large clinical trials of potentially very expensive therapies continue to have the objective of reducing circulating lps. previous studies have found varying prevalence of lps in blood of patients with severe sepsis. compared with sepsis trials conducted years ago, the frequency of gnb in culture specimens from emergency department (ed) patients enrolled in clinical trials of severe sepsis has decreased. objectives: test the hypothesis that prior to antibiotic administration, circulating lps can be detected in the plasma of fewer than % of ed patients with severe sepsis. methods: secondary analysis of a prospective edbased rct of early quantitative resuscitation for severe sepsis. blood specimens were drawn at the time severe sepsis was recognized, defined as two or more systemic inflammatory criteria and a serum lactate > mm or spb< mmhg after fluid challenge. blood was drawn in edta prior to antibiotic administration or within the first several hours, immediately centrifuged, and plasma frozen at ) °c. plasma lps was quantified using the limulus amebocyte lysate assay (lal) by a technician blinded to all clinical data. results: patients were enrolled with plasma samples available for testing. median age was ± years, % female, with overall mortality of %. forty of patients ( %) had any culture specimen positive for gnb including ( %) with blood cultures positive. only five specimens had detectable lps, including two with a gnb-positive culture specimen, and three were lps-positive without gnb in any culture. prevalence of detectable lps was . % (ci: . %- . %). the frequency of detectable lps in antibiotic-naive plasma is too low to serve as a useful diagnostic test or therapeutic target in ed patients with severe sepsis. the data raise the question of whether post-antibiotic plasma may have a higher frequency of detectable lps. background: egdt is known to reduce mortality in septic patients. there is no evidence to date that delineates the role of using a risk stratification tool, such as the mortality in emergency department sepsis (meds) score, to determine which subgroups of patients may have a greater benefit with egdt. objectives: our objective was to determine if our egdt protocol differentially affects mortality based on the severity of illness using meds score. methods: this study is a retrospective chart review of patients, conducted at an urban tertiary care center, after implementing an egdt protocol on july , (figure) . this study compares in-hospital mortality, length of stay (los) in icu, and los in ed between the control group ( patients from / / - / / ) and the postimplementation group ( patients from / / - / / ), using meds score as a risk stratification tool. inclusion criteria: patients who presented to our ed with a suspected infection, and two or more sirs criteria, a map< mmhg, a sbp< mmol/l. exclusion criteria: age< , death on arrival to ed, dnr or dni, emergent surgical intervention, or those with an acute myocardial infarction or chf exacerbation. a two-sample t-test was used to show that the mean age and number of comorbidities was similar between the control and study groups (p = . and . respectively). mortality was compared and adjusted for meds score using logistic regression. the odds ratios and predicted probabilities of death are generated using the fitted logistic regression model. ed and icu los were compared using mood's median test. results: when controlling for illness severity using meds score, the relative risk (rr) of death with egdt is about half that of the control group (rr = . , % ci [ . - . ], p= . ). also, by applying meds score to risk stratify patients into various groups of illness severity, we found no specific groups where egdt is more efficacious at reducing the predicted probability of death (table ) . without controlling for meds score, there is a trend in reduction of absolute mortality by . % when egdt is used (control = . %, study = . %, p = . ). egdt leads to a . % reduction in the median los in icu (control = hours, study = hours, p = . ), without increasing los in ed (control = hours, study = hours, p = . ). conclusion: egdt is beneficial in patients with severe sepsis or septic shock, regardless of their meds score. background: in patients experiencing acute coronary syndrome (acs), prompt diagnosis is critical in achieving the best health outcome. while ecg analysis is usually sufficient to diagnose acs in cases of st elevation, acs without st elevation is reliably diagnosed through serial testing of cardiac troponin i (ctni). pointof-care testing (poct) for ctni by venipuncture has been proven a more rapid means to diagnosis than central laboratory testing. implementing fingerstick testing for ctni in place of standard venipuncture methods would allow for faster and easier procurement of patients' ctni levels, as well as increase the likelihood of starting a rapid test for ctni in the prehospital setting, which could allow for even earlier diagnosis of acs. objectives: to determine if fingerstick blood samples yield accurate and reliable troponin measurements compared to conventional venous blood draws using the i-stat poc device. methods: this experimental study was performed in the ed of a quaternary care suburban medical center between june-august . fingerstick blood samples were obtained from adult ed patients for whom standard (venipuncture) poc troponin testing was ordered. the time between fingerstick and standard draws was kept as narrow as possible. ctni assays were performed at the bedside using the i-stat (abbott point of care). results: samples from patients were analyzed by both fingerstick and standard ed poct methods (see table) . four resulted in cartridge error. compared to ''gold standard'' ed poct, fingerstick testing has a positive predictive value of %, negative predictive value of %, sensitivity of %, and specificity of %. no significant difference in ctni level was found between the two methods, with a nonparametric intraclass correlation coefficient of . ( % ci . - . , p-value < . ). conclusion: whole blood fingerstick ctni testing using the i-stat device is suitable for rapid evaluation of ctni level in prehospital and ed settings. however, results must be interpreted with caution if they are within a narrow territory of the cutoff for normal vs. elevated levels. additional testing on a larger sample would be beneficial. the practicality and clinical benefit of using fingerstick ctni testing in the ems setting must still be assessed. background: adjudication of diagnosis of acute myocardial infarction (ami) in clinical studies typically occurs at each site of subject enrollment (local) or by experts at an independent site (central). from from - , the troponin (ctn) element of the diagnosis was predicated on the local laboratories, using a mix of the th percentile reference ctn and roc-determined cutpoints. in , the universal definition of ami (ud-ami) defined it by the th percentile reference alone. objectives: to compare the diagnosis rates of ami as determined by local adjudication vs. central adjudication using udami criteria. methods: retrospective analysis of data from the myeloperoxidase in the diagnosis of acute coronary syndromes (acs) study (midas), an -center prospective study with enrollment from / / to / / of patients with suspected acs presenting to the ed < hours after symptom onset and in whom serial ctn and objective cardiac perfusion testing was planned. adjudication of acs was done by single local principal investigators using clinical data and local ctn cutpoints from different ctn assays, and applying the definition. central adjudication was done after completion of the midas primary analysis using the same data and local ctn assay, but by experts at three different institutions, using the udami and the manufacturer's th percentile ctn cutpoint, and not blinded to local adjudications. discrepant dignoses were resolved by consensus. local vs. central ctn cutpoints differed for six assays, with central cutpoints lower in all. statistics were by chi-square and kappa. results: excluding cases deemed indeterminate by central adjudication, cases were successfully adjudicated. local adjudication resulted in ami ( . % of total) and non-ami; central adjudication resulted in ( . %) ami and non-ami. overall, local diagnoses ( %) were either changed from non-ami to ami or ami to non-ami (p < . ). interrater reliability across both methods was found to be kappa = . (p < . ). for acs diagnosis, local adjudication identified acs cases ( %) and non-acs, while central adjudication identified acs ( %) and non-acs. overall, local diagnoses ( %) were either changed from non-acs to acs or acs to non-acs (p < . ). interrater reliability found kappa = . (p < . ). conclusion: central and local adjudication resulted in significantly different rates of ami and acs diagnosis. however, overall agreement of the two methods across these two diagnoses was acceptable. occur four times more often in cocaine users. biomarkers myeloperoxidase (mpo) and c-reactive protein (crp) have potential in the diagnosis of acs. objectives: to evaluate the utility of mpo and crp in the diagnosis of acs in patients presenting to the ed with cocaine-associated chest pain and compare the predictive value to nonusers. we hypothesized that these markers may be more sensitive for acs in nonusers given the underlying pathophysiology of enhanced plaque inflammation. methods: a secondary analysis of a cohort study of enrolled ed patients who received evaluation for acs at an urban, tertiary care hospital. structured data collection at presentation included demographics, chest pain history, lab, and ecg data. subjects included those with self-reported or lab-confirmed cocaine use and chest pain. they were matched to controls based on age, sex, and race. our main outcome was diagnosis of acs at index visit. we determined median mpo and crp values, calculated maximal auc for roc curves, and found cut-points to maximize sensitivity and specificity. data are presented with % ci. results: overall, patients in the cocaine positivegroup and patients in the nonusers group had mpo and crp levels measured. patients had a median age of (iqr, ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) , % black or african american, and % male (p > . between groups). fifteen patients were diagnosed with acs: patients in the cocaine group and in the nonusers group. comparing cocaine users to nonusers, there was no difference in mpo (median [iqr, ] v ng/ml; p = . ) or crp ( [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] v [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] mg/l; p = . ). the auc for mpo was . ( % ci . - . ) v . ( % ci . - . ). the optimal cut-point to maximize sensitivity and specificity was ng/ml which gave a sensitivity of . and specificity of . . using this cutpoint, % v % of acs in cocaine users vs the nonusers would be identified. the auc for crp was . ( % ci . - . ) in cocaine users vs . ( % ci . - . ) in nonusers. the optimal cut point was . mg/l with a sensitivity of . and specificity of . . using this cutpoint, % v % of acs in cocaine users and nonusers would have been identified. conclusion: the diagnostic accuracy of mpo and crp is not different in cocaine users than nonusers and does not appear to have sufficient discriminatory ability in either cohort. results: hrs of moderate pe caused a significant decrease in rv heart function in rats treated with the solvent for bay - : peak systolic pressure (psp) decreased from ± . mmhg, control to ± . , pe, +dp/dt decreased from ± mmhg/sec to ± , -dp/dt decreased from ) ± mmhg/sec to ) ± . treatment of rats with bay - significantly improved all three indices of rv heart function (psp ± . , +dp/dt ± , -dp/dt ) ± ). hrs of severe pe also caused significant rv dysfunction (psp ± , -dp/dt ) ± ) and treatment with bay - produced protection of rv heart function (psp ± , -dp/dt ) ± ) similar to the hr moderate pe model. conclusion: experimental pe produced significant rv dysfunction, which was ameliorated by treatment of the animals with the soluble guanylate cyclase stimulator, bay - . hospital of the university of pennsylvania, philadelphia, pa; cooper university hospital, camden, nj background: patients who present to the ed with symptoms of potential acute coronary syndrome (acs) can be safely discharged home after a negative coronary computerized tomographic angiography (cta). however, the duration of time for which a negative coronary cta can be used to inform decision making when patients have recurrent symptoms is unknown. objectives: we examined patients who received more than one coronary cta for evaluation of acs to determine whether they had disease progression, as defined by crossing the threshold from noncritical (< % maximal stenosis) to potentially critical disease. methods: we performed a structured comprehensive record search of all coronary ctas performed from to at a tertiary care health system. low-tointermediate risk ed patients who received two or more coronary ctas, at least one from an ed evaluation for potential acs, were identified. patients who were revascularized between scans were excluded. we collected demographic data, clinical course, time between scans, and number of ed visits between scans. record review was structured and done by trained abstractors. our main outcome was progression of coronary stenosis between scans, specifically crossing the threshold from noncritical to potentially critical disease. results: overall, patients met study criteria (median age , interquartile range [iqr] ( . - ); % female; % black). the median time between studies was . months (iqr, . patients did not have stenosis in any vessel on either coronary cta, two studies showed increasing stenosis of < %, and the rest showed ''improvement,'' most due to better imaging quality. no patient initially below the % threshold subsequently exceeded it ( %; % ci, - . %). patients also had varying numbers of ed visits (median number of visits , range - ), and numbers of ed visits for potentially cardiac complaints (median , range - ); were re-admitted for potentially cardiac complaints (for example, chest pain or shortness of breath), and received further provocative cardiac testing, all of which had negative results. conclusion: we did not find clinically significant disease progression within a year time frame in patients who had a negative coronary cta, despite a high number of repeat visits. this suggests that prior negative coronary cta may be able to be used to inform decision making within this time period. . - . ) compared to non tro ct patients. there was no significant difference in image quality between tro ct images and those of dedicated ct scans in any studies performing this comparison. similarly, there was no significant difference between tro ct and other diagnostic modalities in regards to length of stay or admission rate. when compared to conventional coronary angiography as the gold standard for evaluation of cad, tro ct had the following pooled diagnostic accuracy estimates: sensitivity . conclusion: tro chest ct is comparable to dedicated pe, coronary, or ad ct in regard to image quality, length of stay, and admission rate and is highly accurate for detecting cad. the utility of tro ct depends on the relative pre-test probabilities of the conditions being assessed and its role is yet to be clearly defined. tro ct, however, involves increased radiation exposure and contrast volume and for this reason clinicians should be selective in its use. background: coronary computed tomographic angiography (ccta) has high sensitivity, specificity, accuracy, and prognostic value for coronary artery disease (cad) and acs. however, how a ccta informs subsequent use of prescription medication is unclear. objectives: to determine if detection of critical or noncritical cad on ccta is associated with initiation of aspirin and statins for patients who presented to the ed with chest pain. we hypothesized that aspirin and statins would be more likely to be prescribed to patients with noncritical disease relative to those without any cad. methods: prospective cohort study of patients who received ccta as part of evaluation of chest pain in the ed or observation unit. patients were contacted and medical records were reviewed to obtain clinical follow-up for up to the year after ccta. the main outcome was new prescription of aspirin or statin. cad severity on ccta was graded as absent, mild ( % to %), moderate ( % to %), or severe ( ‡ %) stenosis. logistic regression was used to assess the association of stenosis severity to new medication prescription; covariates were determined a priori. results: patients who had ccta performed consented to participate in this study or met waiver of consent for record review only (median age, , % female, % black). median follow-up time was days, iqr - days. at baseline, % of the total cohort was already prescribed aspirin and % on statin medication. two hundred seventy nine ( %) patients were found to have stenosis in at least one vessel. in patients with absent, mild, moderate, and severe cad on ccta, aspirin was initiated in %, %, %, and %; statins were initiated in %, %, %, and % of patients. after adjustment for age, race, sex, hypertension, diabetes, cholesterol, tobacco use, and admission to the hospital after ccta, higher grades of cad severity were independently associated with greater post-ccta use of aspirin (or . per grade, % ci . - . , p < . ) and statins (or . , % ci . - . , p < . ). conclusion: greater cad severity on ccta is associated with increased medication prescription for cad. patients with noncritical disease are more likely than patients without any disease to receive aspirin and statins. future studies should examine whether these changes lead to decreased hospitalizations and improved cardiovascular health. background: hess et al. developed a clinical decision rule for patients with acute chest pain consisting of the absence of five predictors: ischemic ecg changes not known to be old, elevated initial or -hour troponin level, known coronary disease, ''typical'' pain, and age over . patients less than required only a single troponin evaluation. objectives: to test the hypothesis that patients less than years old without these criteria are at < % risk for major adverse cardiovascular events (mace) including death, ami, pci, and cabg. methods: we performed a secondary analysis of several combined prospective cohort studies that enrolled ed patients who received an evaluation for acs in an urban ed from to . cocaine users and stemi patients were excluded. structured data collection at presentation included demographics, pain description, history, lab, and ecg data for all studies. hospital course was followed daily. thirty-day follow up was done by telephone. our main outcome was -day mace using objective criteria. the secondary outcome was potential change in ed disposition due to application of the rule. descriptive statistics and % cis were used. results: of visits for potential acs, patients had a mean age of . ± . yrs; % were black and % female. there were patients ( . %) with -day cv events ( dead, ami, pci). sequential removal of patients in order to meet the final rule for patients less than excluded patients based upon: ischemic ecg changes not old (n = , % mace rate), elevated initial troponin level (n = , % mace), known coronary disease (n = , % mace), ''typical'' pain (n = , % mace), and age over (n = , . % mace) leaving patients less than with . % mace [ % ci, . - . %]. of this cohort, % were discharged home from the ed by the treating physician without application of this rule. adding a second negative troponin in patients - years old identified a group of patients with a . % rate of mace [ . - . ] and a % discharge rate. the hess rule appears to identify a cohort of patients at approximately % risk of -day mace, and may enhance discharge of young patients. however, even without application of this rule, the % of young patients at low risk are already being discharged home based upon clinical judgment. background: a clinical decision support system (cdss) incorporates evidence-based medicine into clinical practice, but this technology is underutilized in the ed. a cdss can be integrated directly into an electronic medical record (emr) to improve physician efficiency and ease of use. the christopher study investigators validated a clinical decision rule for patients with suspected pulmonary embolism (pe). the rule stratifies patients using wells' criteria to undergo either d-dimer testing or a ct angiogram (ct). the effect of this decision rule, integrated as a cdss into the emr, on ordering cts has not been studied. objectives: to assess the effect of a mandatory cdss on the ordering of d-dimers and cts for patients with suspected pe. methods: we assessed the number of cts ordered for patients with suspected pe before and after integrating a mandatory cdss in an urban community ed. physicians were educated regarding cdss use prior to implementation. the cdss advised physicians as to whether a negative d-dimer alone excluded pe or if a ct was required based on wells' criteria. the emr required physicians to complete the cdss prior to ordering the ct. however, physicians maintained the ability to order a ct regardless of the cdss recommendation. patients ‡ years of age presenting to the ed with a chief complaint of chest pain, dyspnea, syncope, or palpitations were included in the data analysis. we compared the proportion of d-dimers and cts ordered during the -month periods immediately before and after implementing the cdss. all physicians who worked in the ed during both time periods were included in the analysis. patients with an allergy to intravenous contrast agents, renal insufficiency, or pregnancy were excluded. results were analyzed using a chi-square test. results: a total of , patients were included in the data analysis ( pre-and post-implementation). cts were ordered for patients ( . %) in the pre-implementation group and patients ( . %) in the post-implementation group; p = . . a d-dimer was ordered for patients ( . %) in the pre-implementation group and patients ( . %) in the post-implementation group; p = . . in this single-center study, emr integration of a mandatory cdss for evaluation of pe did not significantly alter ordering patterns of cts and d-dimers. identification of patients with low-risk pulmonary emboli suitable for discharge from the emergency department mike zimmer, keith e. kocher university of michigan, ann arbor, mi background: recent data, including a large, multicenter randomized controlled trial, suggest that a low-risk cohort of patients diagnosed with pulmonary embolism (pe) exists who can be safely discharged from the ed for outpatient treatment. objectives: to determine if there is a similar cohort at our institution who have a low rate of complications from pe suitable for outpatient treatment. methods: this was a retrospective chart review at a single academic tertiary referral center with an annual ed volume of , patients. all adult ed patients who were diagnosed with pe during a -month period from / / through / / were identified. the pulmonary embolism severity index (pesi) score, a previously validated clinical decision rule to risk stratify patients with pe, was calculated. patients with high pesi (> ) were excluded. additional exclusion criteria included patients who were at high risk of complications from initiation of therapeutic anticoagulation and those patients with other clear indications for admission to the hospital. the remaining cohort of patients with low risk pe (pesi £ ) was included in the final analysis. outcomes were measured at and days after pe diagnosis and included death, major bleeding, and objectively confirmed recurrent venous thromboembolism (vte). results: during the study period, total patients were diagnosed with pe. there were ( %) patients categorized as ''low risk'' (pesi £ ), with removed because of various pre-defined exclusion criteria. of the remaining ( %) patients suitable for outpatient treatment, patients ( . %; % ci, . % - . %) had one or more negative outcomes by days. this included ( . %; % ci, % - . %) major bleeding events, ( . %; % ci, % - . %) recurrent vte, and ( . %; % ci, % - . %) deaths. none of the deaths were attributable to pe or anticoagulation. one patient suffered both a recurrent vte and died within days. both patients who died within days were transitioned to hospice care because of worsening metastatic burden. at days, there was bleeding event ( . %; % ci, % - . %), no recurrent vte, and no deaths. the average hospital length of stay for these patients was . days (sd ± . ). conclusion: over % of our patients diagnosed with pe in the ed may have been suitable for outpatient treatment, with % suffering a negative outcome within days and . % suffering a negative outcome within days. in addition, the average hospital length of stay for these patients was . days, which may represent a potential cost savings if these patients had been managed as outpatients. our experience supports previous studies that suggest the safety of outpatient treatment of patients diagnosed with pe in the ed. given the potential savings related to a decreased need for hospitalization, these results have health policy implications and support the feasibility of creating protocols to facilitate this clinical practice change. background: chest x-rays (cxrs) are commonly obtained on ed chest pain patients presenting with suspected acute coronary syndrome (acs). a recently derived clinical decision rule (cdr) determined that patients who have no history of congestive heart failure, have never smoked, and have a normal lung examination do not require a cxr in the ed. objectives: to validate the diagnostic accuracy of the hess cxr cdr for ed chest pain patients with suspected acs. methods: this was a prospective observational study of a convenience sample of chest pain patients over years old with suspected acs who presented to a single urban academic ed. the primary outcome was the ability of the cdr to identify patients with abnormalities on cxr requiring acute ed intervention. data were collected by research associates using the chart and physician interviews. abnormalities on cxr and specific interventions were predetermined, with a positive cxr defined as one with abnormality requiring ed intervention, and a negative cxr defined as either normal or abnormal but not requiring ed intervention. the final radiologist report was used as a reference standard for cxr interpretation. a second radiologist, blinded to the initial radiologist's report, reviewed the cxrs of patients meeting the cdr criteria to calculate inter-observer agreement. patients were followed up by chart review and telephone interview days after presentation. results: between january and august , patients were enrolled, of whom ( %) were excluded and ( . %) did not receive cxrs in the ed. of the remaining patients, ( %) met the cdr. the cdr identified all patients with a positive cxr (sensitivity = %, %ci - %). the cdr identified of the patients with a negative cxr (specificity = %, %ci - %). the positive likelihood ratio was . ( %ci . - . ). inter-observer agreement between radiologists was substantial (kappa = . , %ci . - . ). telephone contact was made with % of patients and all patient charts were reviewed at days. none had any adverse events related to a background: increasing the threshold to define a positive d-dimer in low-risk patients could reduce unnecessary computed tomographic pulmonary angiography (ctpa) for suspected pe. this strategy might increase rates of missed pe and missed pneumonia, the most common non-thromboembolic finding on ctpa that might not otherwise be diagnosed. objectives: measure the effect of doubling the standard d-dimer threshold for ' 'pe unlikely'' revised geneva (rgs) or wells' scores on the exclusion rate, frequency, and size of missed pe and missed pneumonia. methods: prospective enrollment at four academic us hospitals. inclusion criteria required patients to have at least one symptom or sign and one risk factor for pe, and have -channel ctpa completed. pretest probability data were collected in real time and the d-dimer was measured in a central laboratory. criterion standard for pe or pneumonia consisted of cpta interpretation by two independent radiologists combined with necessary treatment plan. subsegmental pe was defined as total vascular obstruction < %. patients were followed for outcome at days. proportions were compared with % cis. results: of patients enrolled, ( %) were pe+ and ( %) had pneumonia. with rgs£ and standard threshold (< ng/ml), d-dimer was negative in / ( %, % ci: - %), and / were pe+ (posterior probability . %, % ci: - . %). with rgs£ and a threshold < ng/ml, d-dimer was negative in / ( %, - %) and / ( . %, . - . %) were pe+, but / missed pes were subsegmental, and none had concomitant dvt. the posterior probability for pneumonia among patients with rgs&# ; and d-dimer< was / ( . %, - %) which compares favorably to the posterior probability of / ( . %, - %) observed with rgs& # ; and d-dimer< ng/ml. of the ( %) patients who also had plain film cxr, radiologists found an infiltrate in only . use of wells£ produced similar results as the rgs&# ; for exclusion rate and posterior probability of both pe and pneumonia. conclusion: doubling the threshold for a positive d-dimer with a pe unlikely pretest probability can significantly reduce ctpa scanning with a slightly increased risk of missed isolated subsegmental pe, and no increase in rate of missed pneumonia. background: the limitations of developing world medical infrastructure require that patients are transferred from health clinics only when the patient care needs exceed the level of care at the clinic and the receiving hospital can provide definitive therapy. to determine what type of definitive care service was sought when patients were transferred from a general outpatient clinic operating monday through friday from : am to : pm in rural haiti to urban hospitals in port-au-prince. methods: design -prospective observational review of all patients for whom transfer to a hospital was requested or for whom a clinic ambulance was requested to an off-site location to assist with patient care. setting -weekday, daytime only clinic in titanyen, haiti. participants/subjects -consecutive series of all patients for whom transfer to another health care facility or for whom an ambulance was requested during the time period of / / - / / and / / - / / . results: between / / - / / and / / - / / patients were identified who needed to be transferred to a higher level of care. sixteen patients ( . %) presented with medical complaints, ( . %) were trauma patients, ( . %) were surgical, and ( . %) were in the obstetric category. within these categories, patients were pediatric and non-trauma patients required blood transfusion. conclusion: while trauma services are often focused on in rural developing world medicine, the need for obstetric care and blood transfusion constituted six ( . %) cases in our sample. these patients raise important public health, planning, and policy questions relating to access to prenatal care and the need to better understand transfusion medicine utilization among rural haitian patients with non-trauma related transfusion needs. the data set is limited by sample size and single location of collection. another limitation of understanding the needs is that many patients may not present to the clinic for their health care needs in certain situations if they have knowledge that the resources to provide definitive care are unavailable. background: the practice of emergency medicine in japan has been unique in that emergency physicians are mostly engaged in critical care and trauma with a multi-specialty model. for the last decade with progress in medicine, an aging population with complicated problems, and institution of postgraduate general clinical training, the us model emergency medicine with single-specialty model has been emerging throughout japan. however, the current status is unknown. objectives: the objective of this study was to investigate the current status of implementation of the us model emergency medicine at emergency medicine training institutions accredited by the japanese association for acute medicine (jaam). methods: the er committee of the jaam, the most prestigious professional organization in japanese emergency medicine, conducted the survey by sending questionnaires to accredited emergency medicine training institutions. results: valid responses obtained from facilities were analyzed. us model em was provided in facilities ( % of facilities), either in full time ( hours a day, seven days a week; facilities) or in part time (less than hours a day; facilities). among these us model facilities, % have a number of beds between - . the annual number of ed visits was less than , in %, and % have ambulance transfers between , - , per year. the number of emergency physicians was less than in % of the facilities. postgraduate general clinical training was offered at us model ed in facilities, and ninety hospitals adopted us model em after , when a -year period of postgraduate general clinical training became mandatory for all medical graduates. sixty-four facilities provided a residency program to be a us model emergency physician, and another institutions were planning to establish it. conclusion: us model em has emerged and become commonplace in japan. the background including advance in medicine, aging population, and mandatory postgraduate general clinical training system are considered to be contributing factors. erkan gunay, ersin aksay, ozge duman atilla, nilay zorbalar, savas sezik tepecik research and training hospital, izmir, turkey background: workplace safety and occupational health problems are increasing issues especially in developing countries as a result of the industrial automatisation and technologic improvements. occupational injuries are preventable but they can occasionally cause morbidity and mortality resulting in work day loss and financial problems. hand injuries are one-third of all traumatic injuries and are the most injured parts after occupational accidents. objectives: we aim to evaluate patients with occupational upper extremity injuries for demographic characteristics, injury types, and work day loss. methods: trauma patients over years old admitted to our emergency department with an occupational upper extremity injury were prospectively evaluated from . . to . . . patients with one or more of digit, hand, forearm, elbow, humerus, and shoulder injuries were included. exclusion criteria were multitrauma, patient refusal to participate, and insufficient data. patients were followed up from the hospital information system and by phone for work day loss and final diagnosis. results: during the study period there were patients with an occupational upper extremity injury. total of ( . %) patients were included. patients were . % male, . % between the age to , and mean age was calculated . ± . years. . % of the patients were from the metal and machinery sector, and primary education was the highest education level for the . % of the patients. most injured parts were fingers with the highest rate for index finger and thumb. crush injury was the most common injury type. . % (n = ) of the patients were discharged after treatment in the emergency department. tendon injuries, open fractures, and high degree burns were the reasons for admission to clinics. mean work day loss was . ± . days and this increases for the patients with laboratory or radiologic studies, consultant evaluation, or admission. the - age group had a significantly lower work day loss average. conclusion: evaluating occupational injury characteristics and risks is essential for identifying preventive measures and actions. with the guidance of this study preventive actions focusing on high-risk sectors and patients may be the key factor for avoiding occupational injuries and creating safer workplace environments in order to reduce financial and public health problems. background: as emergency medicine (em) gains increased recognition and interest in the international arena, a growing number of training programs for emergency health care workers have been implemented in the developing world through international partnerships. objectives: to evaluate the quality and appropriateness of an internationally implemented emergency physician training program in india. methods: physicians participating in an internationally implemented em training program in india were recruited to participate in a program evaluation. a mixed methods design was used including an online anonymous survey and semi-structured focus groups. the survey assessed the research, clinical, and didactic training provided by the program. demographics and information on past and future career paths were also collected. the focus group discussions centered around program successes and challenges. results: fifty of eligible trainees ( %) participated in the survey. of the respondents, the vast majority were indian; % were female, and all were between the ages of and years (mean age years). all but two trainees ( %) intend to practice em as a career. one-third listed a high-income country first for preferred practice location and half listed india first. respondents directly endorsed the program structure and content, and they demonstrated gains in self-rated knowledge and clinical confidence over their years of training. active challenges identified include: ( ) insufficient quantity and inconsistent quality of indian faculty, ( ) administrative barriers to academic priorities, and ( ) persistent threat of brain drain if local opportunities are inadequate. conclusion: implementing an international emergency physician training program with limited existing local capacity is a challenging endeavor. overall, this evaluation supports the appropriateness and quality of this partnership model for em training. one critical challenge is achieving a robust local faculty. early negotiations are recommended to set educational priorities, which includes assuring access to em journals. attrition of graduated trainees to high-income countries due to better compensation or limited in-country opportunities continues to be a threat to long-term local capacity building. background: with an increasing frequency and intensity of manmade and natural disasters, and a corresponding surge in interest in international emergency medicine (iem) and global health (gh), the number of iem and gh fellowships is constantly growing. there are currently iem and gh fellowships, each with a different curriculum. several articles have proposed the establishment of core curriculum elements for fellowship training. to the best of our knowledge, no study has examined whether iem and gh fellows are actually fulfilling these criteria. objectives: this study sought to examine whether current iem and gh fellowships are consistently meeting these core curricula. methods: an electronic survey was administered to current iem and gh fellowship directors, current fellows, and recent graduates of a total of programs. survey respondents stated their amount of exposure to previously published core curriculum components: em system development, humanitarian assistance, disaster response, and public health. a pooled analysis comparing overall responses of fellows to those of program directors was performed using two-sampled t-test. results: response rates were % (n = ) for program directors and % (n = ) for current and recent fellows. programs varied significantly in terms of their emphasis on and exposure to six proposed core curriculum areas: em system development, em education development, humanitarian aid, public health, ems, and disaster management. only % of programs reported having exposure to all four core areas. as many as % of fellows reported knowing their curriculum only somewhat or not at all prior to starting the program. conclusion: many fellows enter iem and gh fellowships without a clear sense of what they will get from their training. as each fellowship program has different areas of curriculum emphasis, we propose not to enforce any single core curriculum. rather, we suggest the development of a mechanism to allow each fellowship program to present its curriculum in a more transparent manner. this will allow prospective applicants to have a better understanding of the various programs' curricula and areas of emphasis. background: advance warning of probable intensive care unit (icu) admissions could allow the bed placement process to start earlier, decreasing ed length of stay and relieving overcrowding conditions. however, physicians and nurses poorly predict a patient's ultimate disposition from the emergency department at triage. a computerized algorithm can use commonly collected data at triage to accurately identify those who likely will need icu admission. objectives: to evaluate an automated computer algorithm at triage to predict icu admission and -day in-hospital mortality. methods: retrospective cohort study at a , visit/ year level i trauma center/tertiary academic teaching hospital. all patients presenting to the ed between / / and / / were included in the study. the primary outcome measure was icu admission from the emergency department. the secondary outcome measure was -day all-cause in-hospital mortality. patients discharged or transferred before days were considered to be alive at days. triage data includes age, sex, acuity (emergency severity index), blood pressure, heart rate, pain scale, respiratory rate, oxygen saturation, temperature, and a nurse's free text assessment. a latent dirichlet allocation algorithm was used to cluster words in triage nurses' free text assessments into topics. the triage assessment for each patient is then represented as a probability distribution over these topics. logistic regression was then used to determine the prediction function. results: a total of , patients were included in the study. . % were admitted to the icu and . % died within days. these patients were then randomly allocated to train (n = , ; %) and test (n = , ; %) data sets. the area under the receiver operating characteristic curve (auc) when predicting icu background: at the saem annual meeting, we presented the derivation of two hospital admission prediction models adding coded chief complaint (ccc) data from a published algorithm (thompson et al. acad emerg med ; : - ) to demographic, ed operational, and acuity (emergency severity index (esi)) data. objectives: we hypothesized that these models would be validated when applied to a separate retrospective cohort, justifying prospective evaluation. methods: we conducted a retrospective, observational validation cohort study of all adult ed visits to a single tertiary care center (census: , /yr) ( / / - / / ). we downloaded from the center's clinical tracking system demographic (age, sex, race), ed operational (time and day of arrival), esi, and chief complaint data on each visit. we applied the derived ccc hospital admission prediction models (all identified ccc categories and ccc categories with significant odds of admission from multivariable logistic regression in the derivation cohort) to the validation cohort to predict odds of admission and compared to prediction models that consisted of demographic, ed operational, and esi data, adding each category to subsequent models in a stepwise manner. model performance is reported by areaunder-the-curve (auc) data and %ci. signs, pain level, triage level, -hour return, number of past visits in the previous year, injury, and one of chief complaint codes (representing % of all visits in the database). outputs for training included ordering of a complete blood count, basic chemistry (electrolytes, blood urea nitrogen, creatinine), cardiac enzymes, liver function panel, urinalysis, electrocardiogram, x-ray, computed tomography, or ultrasound. once trained, it was used on the nhamcs-ed database, and predictions were generated. predictions were compared with documented physician orders. outcomes included the percent of total patients who were correctly pre-ordered, sensitivity (the percent of patients who had an order that were correctly predicted), and the percent over-ordered. waiting time for correctly pre-ordered patients was highlighted, to represent a potential reduction in length of stay achieved by preordering. los for patients overordered was highlighted to see if over-ordering may cause an increase in los for those patients. unit cost of the test was also highlighted, as taken from the medicare fee schedule. physician times. however, during peak ed census times, many patients with completed tests and treatment initiated by triage await discharge by the next assigned physician. objectives: determine if a physician-led discharge disposition (dd) team can reduce the ed length of stay (los) for patients of similar acuity who are ultimately discharged compared to standard physician team assignment. methods: this prospective observational study was performed from / to / at an urban tertiary referral academic hospital with an annual ed volume of , visits. only emergency severity index level patients were evaluated. the dd team was scheduled weekdays from : until : . several ed beds were allocated to this team. the team was comprised of one attending physician and either one nurse and a tech or two nurses. comparisons were made between los for discharged patients originally triaged to the main ed side who were seen by the dd team versus the main side teams. time from triage physician to team physician, team physician to discharge decision time, and patient age were compared by unpaired t-test. differences were studied for number of patients receiving x-rays, ct scan, labs, and medications. results: dd team mean los in hours for discharged patients was shorter at . ( % ci: . - . , n = ) compared to . ( % ci: . - . , n = ) on the main side, p < . . the mean time from triage physician to dd team physician was . hours ( % ci: . - . , n = ) versus to . hours ( % ci: . - . , n = ) to main side physician, p < . . the dd team physician mean time to discharge decision was . hour ( % ci: . - . , n = ) compared to . hours ( % ci: . - . , n = ) for main side physician, p < . . the dd team patients' mean age was . years ( % ci: . - . , n = ) compared to main side patients' mean age of . years ( % ci: . - . , n = .) the dd team patients (n = ) received fewer x-rays ( % vs. %), ct scans ( % vs. %), labs ( % vs. %), and medications ( % vs. %) than main side patients (n = ), p < . for all compared. conclusion: the dd team complements the advanced triage process to further reduce los for patients who do not require extended ed treatment or observation. the dd team was able to work more efficiently because its patients tended to be younger and had fewer lab and imaging tests ordered by the triage physician compared to patients who were later seen on the ed main side. ed objectives: to evaluate the association between ed boarding time and the risk of developing hapu. methods: we conducted a retrospective cohort study using administrative data from an academic medical center with an adult ed with , annual patient visits. all patients admitted into the hospital through the ed / / - / / were included. development of hapu was determined using the standardized, national protocol for cms reporting of hapu. ed boarding time was defined as the time between an order for inpatient admission and transport of the patient out of the ed to an in-patient unit. we used a multivariate logistic regression model with development of a hapu as the outcome variable, ed boarding time as the exposure variable, and the following variables as covariates: age, sex, initial braden score, and admission to an intensive care unit (icu) from the ed. the braden score is a scale used to determine a patient's risk for developing a hapu based on known risk factors. a braden score is calculated for each hospitalized patient at the time of admission. we included braden score as a covariate in our model to determine if ed boarding time was a predictor of hapu independent of braden score. results: of , patients admitted to the hospital through the ed during the study period, developed a hapu during their hospitalization. clinical characteristics are presented in the table. per hour of ed boarding time, the adjusted or of developing a hapu was . ( % ci . - . , p = . ). a median of patients per day were admitted through the ed, accumulating hours of ed boarding time per day, with each hour of boarding time increasing the risk of developing a hapu by %. conclusion: in this single-center, retrospective study, longer ed boarding time was associated with increased risk of developing a hapu. queried ed and inpatient nurses and compared their opinions toward inpatient boarding. it also assessed their preferred boarding location if they were patients. objectives: this study queried ed and inpatient nurses and compared their opinions toward inpatient boarding. methods: a survey was administered to a convenience sample of ed and ward nurses. it was performed in a -bed academic medical center ( , admissions/yr) with a -bed ed ( , visits/yr). nurses were identified as ed or ward and whether they had previously worked in the ed. the nurses were asked if there were any circumstances where admitted patients should be boarded in the ed or inpatient hallways. they were also asked their preferred location if they were admitted as a patient. six clinical scenarios were then presented and their opinions on boarding queried. results: ninety nurses completed the survey; ( %) were current ed nurses (ced), ( %) had previously worked in the ed (ped). for the entire group ( %) believed admitted patients should board in the ed. overall, ( %) were opposed to inpatient boarding, with % of ced versus % of current ward (cw) nurses (p < . ) and % of ped versus % of nurses never having worked in the ed (ned) opposed (p < . ). if admitted as patients themselves, overall ( %) preferred inpatient boarding, with % of ced versus % of cw nurses (p < . ) and % of ped versus % ned nurses (p = . ) preferring inpatient boarding. for the six clinical scenarios, significant differences in opinion regarding inpatient boarding existed in all but two cases: a patient with stable copd but requiring oxygen and an intubated, unstable sepsis patient. conclusion: ward nurses and those who have never worked in the ed are more opposed to inpatient boarding than ed nurses and nurses who have worked previously in the ed. nurses admitted as patients seemed to prefer not being boarded where they work. ed and ward nurses seemed to agree that unstable or potentially unstable patients should remain in the ed. weeks. staff satisfaction was evaluated through pre/ post-shift and study surveys; administrative data (physician initial assessment (pia), length of stay (los), patients leaving without being seen (lwbs) and against medical advice [lama] ) were collected from an electronic, real-time ed information system. data are presented as proportions and medians with interquartile ranges (iqr); bivariable analyses were performed. results: ed physicians and nurses expected the intervention to reduce the los of discharged patients only. pia decreased during the intervention period ( vs minutes; p < . ). no statistically/clinically significant differences were observed in the los; however, there was a significant reduction in the lwbs ( . % to . % p = . ) and lama ( . % to . % p = . ) rates. while there was a reduction of approximately patients seen per physician in the affected ed area, the total number of patients seen on that unit increased by approximately patients/day. overall, compared to days when there was no extra shift, % of emergency physicians stated their workload decreased and % felt their stress level at work decreased. conclusion: while this study didn't demonstrate a reduction in the overall los, it did reduce pia times and the proportion of lwbs/lama patients. while physicians saw fewer patients during the intervention study period, the overall patient volume increased and satisfaction among ed physicians was rated higher. provider-and hospital-level variation in admission rates and -hour return admission rates jameel abualenain , william frohna , robert shesser , ru ding , mark smith , jesse m. pines the george washington university, washington, dc; washington hospital center, washington, dc background: decisions for inpatient versus outpatient management of ed patients are the most important and costliest decision made by emergency physicians, but there is little published on the variation in the decision to admit among providers or whether there is a relationship between a provider's admission rate and the proportion of their patients who return within hours of the initial visit and are subsequently admitted ( h-ra). objectives: we explored the variation in provider-level admission rates and h-ra rates, and the relationship between the two. methods: a retrospective study using data from three eds with the same information system over varying time periods: washington hospital center (whc) ( - ), franklin square hospital center (fshc) , and union memorial hospital (umh) . patients were excluded if left without being seen, left against medical advice, fast-track, psychiatric patients, and aged < years. physicians with < ed encounters or an admission rate < % were excluded. logistic regression was used to assess the relationship between physician-level h-ra and admission rates, adjusting for patient age, sex, race, and hospital. results: , ed encounters were treated by physicians. mean patient age was years sd , % male, and % black. admission rates differed between hospitals (whc = %, umh = %, and fshc = %), as did the h-ra (whc = . %, umh = . %, and fshc = . %). across all hospitals, there was great variation in individual physician admission rates ( . %- . %). the h-ra rates were quite low, but demonstrated a similar magnitude of individual variation ( . %- . %). physicians with the highest admission rate quintile had lower odds of h-ra (or . % ci . - . ) compared to the lowest admission rate quintile, after adjusting for other factors. no intermediate admission rate quintiles ( nd, rd, or th) were significantly different from the lowest admission rate quintile with regard to h-ra. conclusion: there is more than three-fold variation in individual physician admission rates indicating great variation among physicians in hospital admission rates and h-ra. the highest admitters have the lowest h-ra; however, evaluating the causes and consequences of such significant variation needs further exploration, particularly in the context of health reform efforts aimed at reducing costs. background: ed scribes have become an effective means to assist emergency physicians (eps) with clinical documentation and improve physician productivity. scribes have been most often utilized in busy community eds and their utility and functional integration into an academic medical center with resident physicians is unknown. objectives: to evaluate resident perceptions of attending physician teaching and interaction after introduction of scribes at an em residency training program, measured through an online survey. residents in this study were not working with the scribes directly, but were interacting indirectly through attending physician use of scribes during ed shifts. methods: an online ten question survey was administered to residents of a midwest academic emergency medicine residency program (pgy -pgy program, annual residents), months after the introduction of scribes into the ed. scribes were introduced as emr documentation support (epic , epic systems inc.) for attending eps while evaluating primary patients and supervising resident physicians. questions investigated em resident demographics and perceptions of scribes (attending physician interaction and teaching, effect on resident learning, willingness to use scribes in the future), using likert scale responses ( minimal, maximum) and a graduated percentage scale used to quantify relative values, where applicable. data were analyzed using kruskal-wallis and mann-whitney u tests. results: twenty-one of em residents ( %) completed the survey ( % male; % pgy , % pgy , % pgy ). four residents had prior experience with scribes. scribes were felt to have no effect on attending eps direct resident interaction time (mean score . , sd . ), time spent bedside teaching ( . , sd . ), or quality of teaching ( . , sd . ), as well as no effect on residents' overall learning process ( . , sd . ). however, residents felt positive about utilizing scribes at their future occupation site ( . , sd . ). no response differences were noted for prior experience, training level, or sex. conclusion: when scribes are introduced at an em residency training site, residents of all training levels perceive it as a neutral interaction, when measured in terms of perceived time with attending eps and quality of the teaching when scribes are present. the effect of introduction of an electronic medical record on resident productivity in an academic emergency department shawn london, christopher sala university of connecticut school of medicine, farmington, ct background: there are little available data which describe the effect of implementation of an electronic medical record (emr) on provider productivity in the emergency department, and no studies which, to our knowledge, address this issue pertaining to housestaff in particular. objectives: we seek to quantify the changes in provider productivity pre-and post-emr implementation to support our hypothesis that resident clinical productivity based on patients seen per hour will be negatively affected by emr implementation. methods: the academic emergency department at hartford hospital, the principle clinical site in the university of connecticut emergency medicine residency, sees over , patients on an annual basis. this environment is unique in that pre-emr, patient tracking and orders were performed electronically using the sunrise system (eclipsys corp) for over years prior to conversion to the allscripts ed emr in october, for all aspects of ed care. the investigators completed a random sample of days/evening/night/weekend shift productivity to obtain monthly aggregate productivity data (patients seen per hour) by year of training. results: there was an initial . % decrease of in productivity for pgy- residents on average from . patients per hour on average in the three blocks preceding activation of the emr to . patients seen per hour compared in the subsequent three prior blocks. pgy performance returned to baseline in the subsequent three months to . patients per hour. there was no change noted in patients seen per hour of pgy- and pgy- residents. conclusion: while many physicians tend to assume that emrs pose a significant barrier to productivity in the ed, in our academic emergency department, there was no lasting change on resident productivity based on the patients seen per hour metric. the minor decrease which did occur in pgy- residents was transient and was not apparent months after the emr was implemented. our experience suggests that decrease in the rate of patients seen per hour in the resident population should not be considered justification to delay or avoid implementation of an emr in the emergency department. emory university, atlanta, ga; children's healthcare of atlanta, atlanta, ga background: variation in physician practice is widely prevalent and highlights an opportunity for quality improvement and cost containment. monitoring resources used in the management of common pediatric emergency department (ed) conditions has been suggested as an ed quality metric. objectives: to determine if providing ed physicians with severity-adjusted data on resource use and outcomes, relative to their peers, can influence practice patterns. methods: data on resource use by physicians were extracted from electronic medical records at a tertiary pediatric ed for four common conditions in mid-acuity (emergency severity index level ): fever, head injury, respiratory illness, and gastroenteritis. condition-relevant resource use was tracked for lab tests (blood count, chemistry, crp), imaging (chest x-ray, abdominal x-ray, head ct scan, abdominal ct scan), intravenous fluids, parenteral antibiotics, and intravenous ondansetron. outcome measures included admission to hospital and ed length of stay (los); -hr return to ed (rr) was used as a balancing measure. scorecards were constructed using box plots to show physicians their practice patterns relative to peers (the figure shows an example of the scorecard for gatroenteritis for one physician, showing resources use rates for iv fluids and labs). blinded scorecards were distributed quarterly for five quarters using rolling-year averages. a pre/post-intervention analysis was performed with sep , as the intervention date. fisher's exact and wilcoxon rank sum tests were used for analysis. results: we analyzed , patient visits across two hospitals ( , pre-and , post-intervention), comprising . % of the total ed volume during the study period. patients were seen by physicians (mean patients/physician). the table shows overall physician practice in the pre-and post-intervention periods. significant reduction in resource use was seen for abdominal/pelvic ct scans, head ct scan, chest x-rays, iv ondansetron, and admission to hospital. ed los decreased from min to min (p = . ). there was no significant change in -hr return rate during the study period ( . % pre-, . % post-intervention). conclusion: feedback on comprehensive practice patterns including resource use and quality metrics can influence physician practice on commonly used resources in the ed. billboards, via iphone application, twitter, and text messaging. there is a paucity of data describing the accuracy of publically posted ed wait times. objectives: to examine the accuracy of publicly posted wait times of four emergency departments within one hospital system. methods: a prospective analysis of four ed-posted wait times in comparison to the wait times for actual patients. the main hospital system calculated and posted ed wait times every twenty minutes for all four system eds. a consecutive sample of all patients who arrived / over a -week period during july and august was included. an electronic tracking system identified patient arrival date and the actual incurred wait time. data consisted of the arrival time, actual wait time, hospital census, budgeted hospital census, and the posted ed wait time. for each ed the difference was calculated between the publicly posted ed wait time at the time of patient's arrival and the patient's actual ed wait time. the average wait times and average wait time error between the ed sites were compared using a two-tailed student's t-test. the correlation coefficient between the differences in predicted/ actual wait times was also calculated for each ed. results: there were wait times within the four eds included in the analysis. the average wait time (in minutes) at each facility was: . (± . ) for the main ed, . (± . ) for freestanding ed (fed) # , . (± . ) for fed # , and . (± . ) for the small community ed. the average wait time error (in minutes) for each facility was (± . ) for the main ed, (± . ) for fed # , (± . ) for fed # , and (± . ) for the community hospital ed. the results from each ed were statistically significant for both average wait time and average wait time error (p < . ). there was a positive correlation between the average wait time and average wait time error, with r-values of . , . , . , and . for the main ed, fed # , fed # , and the small community hospital ed, respectively. each correlation was statistically significant; however, no correlation was found between the number of beds available (budgeted-actual census) and average wait times. conclusion: publically posted ed wait times are accurate for facilities with less than ed visits per month. they are not accurate for eds with greater than visits per month. reduction of pre-analytic laboratory errors in the emergency department using an incentive-based system benjamin katz, daniel pauze, karen moldveen albany medical center, albany, ny background: over the last decade, there has been an increased effort to reduce medical errors of all kinds. laboratory errors have a significant effect on patient care, yet they are usually avoidable. several studies suggest that up to % of laboratory errors occur during the pre-or post-analytic phase. in other words, errors occur during specimen collection and transport or reporting of results, rather than during laboratory analysis itself. objectives: in an effort to reduce pre-analytic laboratory errors, the ed instituted an incentive-based program for the clerical staff to recognize and prevent specimen labeling errors from reaching the patient. this study sought to demonstrate the benefit of this incentive-based program. methods: this study examined a prospective cohort of ed patients over a three year period in a tertiary care academic ed with annual census of , . as part of a continuing quality improvement process, laboratory specimen labeling errors are screened by clerical staff by reconciling laboratory specimen label with laboratory requisition labels. the number of ''near-misses'' or mismatched specimens captured by each clerk was then blinded to all patient identifiers and was collated by monthly intervals. due to poor performance in , an incentive program was introduced in early by which the clerk who captured the most mismatched specimens would be awarded a $ gift card on a quarterly basis. the total number of missed laboratory errors was then recorded on a monthly basis. investigational data were analyzed using bivariate statistics. background: most studies on operational research have been focused in academic medical centers, which typically have larger volumes of patients and are located in urban metropolitan areas. as cms core measures in begin to compare emergency departments (eds) on treatment time intervals, especially length of stay (los), it is important to explore if any differences exist inherent to patient volume. objectives: the objective of this study is to look at differences in operational metrics based on annual patient census. the hypothesis is that treatment time intervals and operational metrics differ amongst these different categories. methods: the ed benchmarking alliance has collected yearly operational metrics since . as of , there are eds providing data across the united states. eds are stratified by annual volume for comparison in the following categories: < k, - k, - k, and over k. in this study, metrics for eds with < k visits per year were compared to those of different volumes, averaged from - . mean values were compared to < k visits as a reference point for statistical difference using t-tests to compare means with a p-value < . considered significant. results: as seen in the table, a greater percentage of high acuity of patients was seen in higher volume eds than in < k eds. the percentage of patients transferred to another hospital was higher in < k eds. a higher percentage arrived by ems and a higher percentage were admitted in higher volume eds when compared to < k visits. in addition, the median los for both discharged and admitted patients and percentage who left before treatment was complete (lbtc) were higher in the higher volume eds. conclusion: lower volume eds have lower acuity when compared to higher volume eds. lower volume eds have shorter median los and left before treatment complete percentages. as cms core measures require hospitals to report these metrics, it will be important to compare them based on volume and not in aggregate. does the addition of a hands-free communication device improve ed interruption times? amy ernst, steven j. weiss, jeffrey a. reitsema university of new mexico, albuquerque, nm background: ed interruptions occur frequently. recently a hands-free communication device (vocera) was added to a cell phone and a pager in our ed. objectives: the purpose of the present study was to determine whether this addition improved interruption times. our hypothesis was that the device would significantly decrease length of time of interruptions. methods: this study was a prospective cohort study of attending ed physician calls and interruptions in a level i trauma center with em residency. interruptions included phone calls, ekg interpretations, pages to resuscitation, and other miscellaneous interruptions (including nursing issues, laboratory, ems, and radiology). we studied a convenience sampling intended to include mostly evening shifts, the busiest ed times. length of time the interruption lasted was recorded. data were collected for a comparison group pre-vocera. three investigators collected data including seven different addendings' interruptions. data were collected on a form, then entered into an excel file. data collectors' agreement was determined during two additional four hour shifts to calculate a kappa statistic. spss was used for data entry and statistical analysis. descriptive statistics were used for univariate data. chi-square and mann whitney u nonparametric test were used for comparisons. results: of the total interruptions, % were phone calls, % were ekgs to be read, % were pages to resuscitation, and % miscellaneous. there were no significant differences in types of interruptions pre-vs. post-vocera. pre-vocera we collected hours of data with interruptions with a mean . per hour. post-vocera, hours of data were collected with interruptions with a mean . per hour. there was a significant difference in length of time of interruptions with an average of minutes pre-vocera vs. minutes post-vocera (p = . , diff . , % ci . - . ). vocera calls were significantly shorter than non-vocera calls ( vs minutes, p < . ). comparing data collectors for type of interruption during the same -hour shift resulted in a kappa (agreement) of . . conclusion: the addition of a hands-free communication device may improve interruptions by shortening call length. '' talk background: analyses of patient flow through the ed typically focus on metrics such as wait time, total length of stay (los), or boarding time. however, little is known about how much interaction a patient has with clinicians after being placed in a room, or what proportion of the in-room visit is also spent ''waiting,'' rather than directly interacting with care providers. objectives: the objective was to assess the proportion of time, relative to the time in a patient care area, that a patient spends actively interacting with providers during an ed visit. methods: a secondary analysis of audiotaped encounters of patients with one of four diagnoses (ankle sprain, back pain, head injury, laceration) was performed. the setting was an urban, academic ed. ed visits of adult patients were recorded from the time of room placement to discharge. audiotapes were edited to remove all downtime and non-patient-provider conversations. los and door-to-doctor times were abstracted from the medical record. the proportion of time the patient spent in direct conversation with providers (''talk-time'') was calculated as the ratio of the edited audio recording time to the time spent in a patient care area (talk-time = [edited audio time/(los -door-to-doctor)]). multiple linear regression controlling for time spent in patient care area, age, and sex was performed. results: the sample was % male with a mean age of years. median los: minutes (iqr: - ), median door-to-doctor: minutes (iqr: - ), median time spent in patient care area: minutes (iqr: - ). median time spent in direct conversation with providers was minutes (iqr: - ), corresponding to a talk-time percentage of . % (iqr: . - . %). there were no significant differences based on diagnosis. regression analysis showed that those spending a longer time in a patient care area had a lower percentage of talk time (b = ) . , p = . ). conclusion: although limited by sample size, these results indicate that approximately % of a patients' time in a care area is spent not interacting with providers. while some of the time spent waiting is out of the providers' control (e.g. awaiting imaging studies), this significant ''downtime'' represents an opportunity for both process improvement efforts to decrease downtime as well as the development of innovative patient education efforts to make the best use of the remaining downtime. degradation of emergency department operational data quality during electronic health record implementation michael j. ward, craig froehle, christopher j. lindsell university of cincinnati, cincinnati, oh background: process improvement initiatives targeted at operational efficiency frequently use electronic timestamps to estimate task and process durations. errors in timestamps hamper the use of electronic data to improve a system and may result in inappropriate conclusions about performance. despite the fact that the number of electronic health record (ehr) implementations is expected to increase in the u.s., the magnitude of this ehr-induced error is not well established. objectives: to estimate the change in the magnitude of error in ed electronic timestamps before and after a hospital-wide ehr implementation. methods: time-and-motion observations were conducted in a suburban ed, annual census , , after receiving irb approval. observation was conducted weeks pre-and weeks post-ehr implementation. patients were identified on entering the ed and tracked until exiting. times were recorded to the nearest second using a calibrated stopwatch, and are reported in minutes. electronic data were extracted from the patient-tracking system in use pre-implementation, and from the ehr post-implementation. for comparison of means, independent t-tests were used. chi-square and fisher's t-tests were used for proportions, as appropriate. results: there were observations; before and after implementation. the differences between observed times and timestamps were computed and found to be normally distributed. post-implementation, mean physician seen times along with arrival to bed, bed to physician, and physician to disposition intervals occurred before observation. physician seen timestamps were frequently incorrect and did not improve postimplementation. significant discrepancies (ten minutes or greater) from observed values were identified in timestamps involving disposition decision and exit from the ed. calculating service time intervals resulted in every service interval (except arrival to bed) having at least % of the times with significant discrepancies. it is notable that missing values were more frequent post-ehr implementation. conclusion: ehr implementation results in reduced variability of timestamps but reduced accuracy and an increase in missing timestamps. using electronic timestamps for operational efficiency assessment should recognize the magnitude of error, and the compounding of error, when computing service times. background: procedural sedation and analgesia is used in the ed in order to efficiently and humanely perform necessary painful procedures. the opposing physiological effects of ketamine and propofol suggest the potential for synergy, and this has led to interest in their combined use, commonly termed ''ketofol'', to facilitate ed procedural sedation. objectives: to determine if a : mixture of ketamine and propofol (ketofol) for ed procedural sedation results in a % or more absolute reduction in adverse respiratory events compared to propofol alone. methods: participants were randomized to receive either ketofol or propofol in a double-blind fashion according to a weight-based dosing protocol. inclusion criteria were age years or greater, and asa class - status. the primary outcome was the number and proportion of patients experiencing an adverse respiratory event according to pre-defined criteria (the ''quebec criteria''). secondary outcomes were sedation consistency, sedation efficacy, induction time, sedation time, procedure time, and adverse events. results: a total of patients were enrolled, per group. forty-three ( %) patients experienced an adverse respiratory event in the ketofol group compared to ( %) in the propofol group (difference %; % ci ) % to %; p = . ). thirty-eight ( %) patients receiving ketofol and ( %) receiving propofol developed hypoxia, of whom three ( %) ketofol patients and ( %) propofol patient received bag-valve-mask ventilation. sixty-five ( %) patients receiving ketofol and ( %) receiving propofol required repeat medication dosing or lightened to a ramsay sedation score of or less during their procedure (difference %; % ci % to %; p = . ). procedural agitation occurred in patients ( . %) receiving ketofol compared to ( %) receiving propofol (difference . %, % ci % to %). recovery agitation requiring treatment occurred in six patients ( %, % ci . % to . %) receiving ketofol. other secondary outcomes were similar between the groups. patients and staff were highly satisfied with both agents. conclusion: ketofol for ed procedural sedation does not result in a reduced incidence of adverse respiratory events compared to propofol alone. induction time, efficacy, and sedation time were similar; however, sedation depth appeared to be more consistent with ketofol. with propofol and its safety is well established. however, in cms enacted guidelines defining propofol as deep sedation and requiring administration by a physician. common edps practice had been one physician performing both the sedation and procedure. edps has proven safe under this one-physician practice. however, the guidelines mandated separate physicians perform each. objectives: the study hypothesis was that one-physician propofol sedation complication rates are similar to two-physician. methods: before and after, observational study of patients > years of age consenting to edps with propofol. edps completed with one physician were compared to those completed with two (separate physicians performing the sedation and the procedure). all data were prospectively collected. the study was completed at an urban level i trauma center. standard monitoring and procedures for edps were followed with physicians blinded to the objectives of this research. the frequency and incremental dosing of medication was left to the discretion of the treating physicians. the study protocol required an ed nurse trained in data collection to be present to record vital signs and assess for any prospectively defined complications. we used chi-square tests to compare the binary outcomes and asa scores across the time periods, and two-sample t-tests to test for differences in age between the two time periods. results: during the -year study period we enrolled patients: one-physician edps sedations and (- to ) also received bag-valve-mask ( ) [ . to ) ( ) [ . to ] (- to ) two-physician. all patients meeting inclusion criteria were included in the study. total adverse event rates were . % and . %, respectively (p = . ). the most common complications were hypotension and oxygen desaturation, and they respectively showed one-physcian rates of . % and . % and two-physician rates of . % and . % (p = . and . .) the unsuccessful procedure rates were . % vs . % (p = . ). conclusion: this study demonstrated no significant difference in complication rates for propofol edps completed by one physician as compared to two. background: overdose patients are often monitored using pulse oximetry, which may not detect changes in patients on high-flow oxygen. objectives: to determine whether changes in end-tidal carbon dioxide (etco ) detected by capnographic monitoring are associated with clinical interventions due to respiratory depression (crd) in patients undergoing evaluation for a decreased level of consciousness after a presumed drug overdose. methods: this was a prospective, observational study of adult patients undergoing evaluation for a drug overdose in an urban county ed. all patients received supplemental oxygen. patients were continuously monitored by trained research associates. the level of consciousness was recorded using the observer's assessment of alertness/sedation scale (oaa/s). vital signs, pulse oximetry, and oaa/s were monitored and recorded every minutes and at the time of occurrence of any crd. respiratory rate and etco were measured at five second intervals using a capno-stream monitor. crd included an increase in supplemental oxygen, the use of bag-valve-mask ventilations, repositioning to improve ventilation, and physical or verbal stimulus to induce respiration, and were performed at the discretion of the treating physicians and nurses. changes from baseline in etco values and waveforms among patients who did or did have a clinical intervention were compared using wilcoxon rank sum tests. results: patients were enrolled in the study (age , range to , % male, median oaas , range to ). suspected overdoses were due to opioids in , benzodiazepines in , an antipsychotic in , and others in . the median time of evaluation was minutes (range to ). crd occurred in % of patients, including an increase in o in %, repositioning in %, and stimulation to induce respiration in %. % had an o saturation of < % (median , range to ) and % had a loss of etco waveform at some time, all of whom had a crd. the median change in etco from baseline was mmhg, range to . among patients with crd it was mmhg, range to , and among patients with no crd it was mmhg, range to (p = . ). conclusion: the change in etco from baseline was larger in patients who required clinical interventions than in those who did not. in patients on high-flow oxygen, capnographic monitoring may be sensitive to the need for airway support. how reliable are health care providers in reporting changes in etco waveform anas sawas , scott youngquist , troy madsen , matthew ahern , camille broadwater-hollifield , andrew syndergaard , jared phelps , bryson garbett , virgil davis university of utah, salt lake city, ut; midwestern university, glendale, az background: etco changes have been used in procedural sedation analgesia (psa) research to evaluate subclinical respiratory depression associated with sedation regiments. objectives: to evaluate the accuracy of bedside clinician reporting of changes in etco . methods: this was a prospective, randomized, singleblind study conducted in ed setting from june until the present time. this study took place at an academic adult ed of a -bed ( in the ed) and a level i trauma center. subjects were randomized to receive either ketamine-propofol or propofol according to a standardized protocol. loss of etco waveforms for ‡ sec were recorded. following sedation, questionnaires were completed by the sedating physicians. digitally recorded etco waveforms were also reviewed by an independent physician and a trained research assistant (ra). to ensure the reliability of trained research assistants, we compared their analyses with the analyses of an independent physician for the first recordings. the target enrollment was patients in each group (n = total). statistics were calculated using sas statistical software. results: patients were enrolled; ( . %) are males and ( . %) are females. mean age was . ± . years. most participants did not have major risk factors for apnea or for further complications ( . % were asa class or ). etco waveforms were reviewed by ( . %) sedating physicians and ( . %) nurses at the bedside. there were ( . %) etco waveforms recordings, ( . %) were reviewed by an independent physician and ( %) were reviewed by an ra. a kappa test for agreement between independent physicians and ras was conducted on recordings and there were no discordant pairs (kappa = ). compared to sedating physicians, the independent physician was more likely to report etco wave losses (or . , % ci . - . ). compared to sedating physicians, ras were more likely to report etco wave losses (or . , % ci . - . ). conclusion: compared to sedating physicians at the bedside, independent physicians and ras were more likely to note etco waveform losses. an independent review of recorded etco waveform changes will be more reliable for future sedation research. background: comprehensive studies evaluating current practices of ed airway management in japan are lacking. many emergency physicians in japan still experience resistance regarding rapid sequence intubation (rsi). objectives: we sought to describe the success and complication rate of rsi with non-rsi. methods: design and setting: we conducted a multicenter prospective observational study using the jean registry of eds at academic and community hospitals in japan during between and . data fields include ed characteristics, patient and operator demographics, method of airway management, number of attempts, and adverse events. we defined non-rsi as intubation with sedation only, neuromuscular blockade only, and without medication. participants: all patients undergoing emergency intubation in ed were eligible for inclusion. cardiac arrest encounters were excluded from the analysis. primary analysis: we described rsi with non-rsi in terms of success rate on first attempt, within three attempts, and complication rate. we present descriptive data as proportions with % confidence intervals (cis). we report odds ratios (or) with % ci via chi-square testing. results: the database recorded intubations (capture rate %) and met the inclusion criteria. rsi was the initial method chosen in ( %) and non-rsi in ( %). use of rsi varied among institutes from % to %. success cases of rsi on first and within three attempts are intubations ( %, %ci %- %) and intubations ( %, %ci %- %), respectively. the success cases of non-rsi on first and within three attempts are intubations ( %, %ci %- %) and intubations ( %, %ci %- %). success rates of rsi on first and within three attempts are higher than non-rsi (or . , %ci . - . and or . , % ci . - . , respectively). we recorded complications in rsi ( %) and in non-rsi ( %). there is no significant difference of complication rate between rsi and non-rsi (or . , % ci . - . ). conclusion: in this multi-center prospective study in japan, we demonstrated a high degree of variation in use of rsi for ed intubation. additionally we found that success rate of rsi on first and within three attempts were both higher than non-rsi. this study has the limitation of reporting bias and confounding by indication. (originally submitted as a ''late-breaker.'') methods: this was a prospective, randomized, singleblind study conducted in the ed setting from june until the present time. this study took place at an academic adult ed of a -bed ( in the ed) and a level i trauma center. subjects were randomized to receive either ketamine-propofol or propofol according to a standardized protocol. etco waveforms were digitally recorded. etco changes were evaluated by the sedating physicians at the bedside. recorded waveforms were reviewed by an independent physician and a trained research assistant (ra). to ensure the reliability of trained ras, we computed a kappa test for agreement between the analysis of independent physicians and ras for the first recordings. a post-hoc analysis of the association between any loss, the number of losses, and total duration of loss of etco waveform and crp was performed. on review we recorded the absence or presence of loss of etco and the total duration in seconds of all lost etco episodes ‡ seconds. ors were calculated using sas statistical software. results: patients were enrolled; ( . %) are males and are ( . %) females. . % participants were asa class or . waveforms were reviewed by ( . %) sedating physicians. there were ( . %) waveforms recordings, ( . %) were reviewed by an independent physician and ( %) were reviewed by ras, where there were no discordant pairs (kappa = ). there were ( . %) crp events. any loss of etco was associated with a non-significant or of . ( % ci . - . ) for crp. however, the duration of etco loss was significantly associated with crp with an or of . ( % ci . - . ) for each second interval of lost etco . the number of losses was significantly associated with the outcome (or . , % ci . - . ). conclusion: defining subclinical respiratory depression as present or absent may be less useful than quantitative measurements. this suggests that risk is cumulative over periods of loss of etco , and the duration of loss may be a better marker of sedation depth and risk of complications than classification of any loss. background: ed visits present an opportunity to deliver brief interventions (bis) to reduce violence and alcohol misuse among urban adolescents at risk for future injury. previous analyses demonstrated that a brief intervention resulted in reductions in violence and alcohol consequences up to months. objectives: this paper describes findings examining the efficacy of bis on peer violence and alcohol misuse at months. methods: patients ( - yrs) at an ed reporting past year alcohol use and aggression were enrolled in the rct, which included computerized assessment, and randomization to control group or bi delivered by a computer (cbi) or therapist assisted by a computer (tbi). baseline and months included violence (peer aggression, peer victimization, violence related consequences) and alcohol (alcohol misuse, binge drinking, alcohol-related consequences). results: adolescents were screened ( % participation). of those, screened positive for violence and alcohol use and were randomized; % completed -month follow-up. as compared to the control group, the tbi group showed significant reductions in peer aggression (p < . ) and peer victimization (p < . ) at months. bi and control groups did not differ on alcohol-related variables at months. conclusion: evaluation of the saferteens intervention one year following an ed visit provides support for the efficacy of computer-assisted therapist brief intervention for reducing peer violence. violence against ed health care workers: a -month experience terry kowalenko , donna gates , gordon gillespie , paul succop university of michigan, ann arbor, mi; university of cincinnati, cincinnati, oh background: health care (hc) support occupations have an injury rate nearly times that of the general sector due to assaults, with doctors and nurses nearly times greater. studies have shown that the ed is at greatest risk of such events compared to other hc settings. objectives: to describe the incidence of violence in ed hc workers over months. specific aims were to ) identify demographic, occupational, and perpetrator factors related to violent events; ) identify the predictors of acute stress response in victims; and ) identify predictors of loss of productivity after the event. methods: longitudinal, repeated methods design was used to collect monthly survey data from ed hc workers (w) at six hospitals in two states. surveys assessed the number and type of violent events, and feelings of safety and confidence. victims also completed specific violent event surveys. descriptive statistics and a repeated measure linear regression model were used. results: ed hcws completed monthly surveys, and violent events were reported. the average per person violent event rate per months was . . events were physical threats ( . per person in months). events were assaults ( . per person in months). violent event surveys were completed, describing physical threats and assaults with % resulting in injuries. % of the physical threats and % of the assaults were perpetrated by men. comparing occupational groups revealed significant differences between nurses and physicians for all reported events (p = . ), with the greatest difference in physical threats (p = . ). nurses felt less safe than physicians (p = . ). physicians felt more confident than nurses in dealing with the violent patient (p = . ). nurses were more likely to experience acute stress than physicians (p < . ). acute stress significantly reduced productivity in general (p < . ), with a significant negative effect on ''ability to handle/ manage workload'' (p < . ) and ''ability to handle/ manage cognitive demands'' (p < . ). conclusion: ed hcws are frequent victims of violence perpetrated by visitors and patients. this violence results in injuries, acute stress, and loss of productivity. acute stress has negative consequences on the workers' ability to perform their duties. this has serious potential consequences to the victim as well as the care they provide to their patients. a randomized controlled feasibility trial of vacant lot greening to reduce crime and increase perceptions of safety eugenia c. garvin, charles c. branas perelman school of medicine at the university of pennsylvania, philadelphia, pa background: vacant lots, often filled with trash and overgrown vegetation, have been associated with intentional injuries. a recent quasi-experimental study found a significant decrease in gun crimes around vacant lots that had been greened compared with control lots. objectives: to determine the feasibility of a randomized vacant lot greening intervention, and its effect on police-reported crime and perceptions of safety. methods: for this randomized controlled feasibility trial of vacant lot greening, we partnered with the pennsylvania horticulture society (phs) to perform the greening intervention (cleaning the lots, planting grass and trees, and building a wooden fence around the perimeter). we analyzed police crime data and interviewed people living around the study vacant lots (greened and control) about perceptions of safety before and after greening. results: a total of sq ft of randomly selected vacant lot space was successfully greened. we used a master database of , vacant lots to randomly select vacant lot clusters. we viewed each cluster with the phs to determine which were appropriate to send to the city of philadelphia for greening approval. the vacant lot cluster highest on the random list to be approved by the city of philadelphia was designated the intervention site, and the next highest was designated the control site. overall, participants completed baseline interviews, and completed follow-up interviews after months. % of participants were male, % were black or african american, and % had a household income less than $ , . unadjusted difference-in-differences estimates showed a decrease in gun assaults around greened vacant lots compared to control. regression-adjusted estimates showed that people living around greened vacant lots reported feeling safer after greening compared to those who lived around control vacant lots (p < . ). conclusion: conducting a randomized controlled trial of vacant lot greening is feasible. greening may reduce certain gun crimes and make people feel safer. however, larger prospective trials are needed to further investigate this link. screening for violence identifies young adults at risk for return ed visits for injury abigail hankin-wei, brittany meagley, debra houry emory university, atlanta, ga background: homicide is the second leading cause of death among youth ages - . prior studies, in nonhealth care settings, have shown associations between violent injury and risk factors including exposure to community violence, peer behavior, and delinquency. objectives: to assess whether self-reported exposure to violence risk factors can be used to predict future ed visits for injuries. methods: we conducted a prospective cohort study in the ed of a southeastern us level i trauma center. patients aged - presenting for any chief complaint were included unless they were critically ill, incarcerated, or could not read english. recruitment took place over six months, by a trained research assistant (ra). the ra was present in the ed for - days per week, with shifts scheduled such that they included weekends and weekdays, over the hours from am- pm. patients were offered a $ gift card for participation. at the time of initial contact in the ed, patients completed a written questionnaire which included validated measures of the following risk factors: a) aggression, b) perceived likelihood of violence, c) recent violent behavior, d) peer behavior, e) community exposure to violence, and f) positive future outlook. at months following the initial ed visit, the participants' medical records were reviewed to identify any subsequent ed visits for injury-related complaints. data were analyzed with chi-square and logistic regression analyses. results: patients were approached, of whom patients consented. participants' average age was . years, with % female, and % african american. return visits for injuries were significantly associated with hostile/aggressive feelings (rr . , ci . , ) , self-reported perceived likelihood of violence (rr . , ci . , . ) , recent violent behavior (rr . , ci . , . ) , and peer group violence (rr . , ci . , . ) . these findings remained significant when controlling for participant sex. conclusion: a brief survey of risk factors for violence is predictive of return visit to the ed for injury. these findings identify a potentially important tool for primary prevention of violent injuries among young adults visiting the ed for both injury and non-injury complaints. background: sepsis is a commonly encountered disease in ed, with high mortality. while several clinical prediction rules (cpr) including meds, sirs, and curb- exist to facilitate clinicians in early recognition of risk of mortality for sepsis, most are of suboptimal performance. objectives: to derive a novel cpr for mortality of sepsis utilizing clinically available and objective predictors in ed. methods: we retrospectively reviewed all adult septic patients who visited the ed at a tertiary hospital during the year with two sets of blood cultures ordered by physicians. basic demographics, ed vital signs, symptoms and signs, underlying illnesses, laboratory findings, microbiological results, and discharge status were collected. multivariate logistic regressions were used to obtain a novel cpr using predictors with < . p-value tested in univariate analyses. the existing cprs were compared with this novel cpr using auc. results: of included patients, . % died in hospital, % had diabetes, % were older than years of age, % had malignancy, and % had positive blood bacterial culture tests. predisposing factors including history of malignancy, liver disease, immunosuppressed status, chronic kidney disease, congestive heart failure, and older than years of age were found to be associated with mortality (all p < . ). patients who developed mortality tended to have lower body temperature, narrower pulse pressure, higher percentage of red cell distribution width (rdw) and bandemia, higher blood urea nitrogen (bun), ammonia, and c-reactive protein level, and longer prothrombin time and activated partial thromboplastin time (aptt) (all p < . ). the most parsimonious cpr incorporating history of malignancy (or . , % ci . - . ), prolonged aptt ( . , . - . ), presence of bandemia ( . , . - . results: there was poor agreement between the physician's unstructured assessment used in clinical practice and the guidelines put forth by the aha/acc/acep task force. ed physicians were more likely to assess a patient as low risk ( %), while aha guidelines were more likely to classify patients as intermediate ( %) or high ( %) risk. however, when comparing the patient's final acs diagnosis and the relation to the risk assessment value, ed physicians proved better predictors of high-risk patients who in fact had acs, while the aha/acc/acep guidelines proved better at correctly identifying low-risk patients who did not have acs. conclusion: in the ed, physicians are far more efficient at correctly placing patients with underlying acs into a high-risk category, while established criteria may be overly conservative when applied to an acute care population. further research is indicated to look at ed physicians' risk stratification and ensuing patient care to assess for appropriate decision making and ultimate outcomes. compartative conclusion: the amuse score was more specific, but the wells score was more sensitive for acute lower limb dvt in this cohort. there is no significant advantage in using the amuse over the wells score in ed patient with suspected dvt. background: the direct cost of medical care is not accurately reflected in charges or reimbursement. the cost of boarding admitted patients in the ed has been studied in terms of opportunity costs, which are indirect. the actual direct effect on hospital expenses has not been well defined. objectives: we calculate the difference to the hospital in the cost of caring for an admitted patient in the ed and in a non-critical care in-patient unit. methods: time-directed activity-based costing (tdabc) has recently been proposed as a method of determining the actual cost of providing medical services. tdabc was used to calculate the cost per patient bed-hour both in the ed and for an in-patient unit. the costs include nursing, nursing assistants, clerks, attending and resident physicians, supervisory salaries, and equipment maintenance. boarding hours were determined from placement of admission order to transfer to in-patient unit. a convenience sample of consecutive non-critical care admissions was assessed to find the degree of ed physician involvement with boarded patients. results: the overhead cost per patient bed-hour in the ed was $ . . the equivalent cost per bed-hour inpatient was $ . , a differential of $ . . there were , boarding hours for medical-surgical patients in , a differential of $ , , . for the year. for the short-stay unit (no residents), the cost per patient hour was $ . and the boarding hours were , . this resulted in a differential cost of $ , . , a total direct cost to the hospital of $ , , . . review of consecutive admissions showed no orders placed by the ed physician after decision-toadmit. conclusion: concentration of resources in the ed means considerably higher cost per unit of care as compared to an in-patient unit. keeping admitted patients boarding in the ed results in expensive underutilization. this is exclusive of significant opportunity costs of lost revenue from walk-out and diverted patients. this study includes the cost of teaching attendings and residents (ed and in-patient) . in a non-teaching setting, the differential would be less and the cost of boarding would be shared by a fee-for-service ed physician group as well as the hospital. improving identification of frequent emergency department users using a regional health information background: frequent ed users consume a disproportionate amount of health care resources. interventions are being designed to identify such patients and direct them to more appropriate treatment settings. because some frequent users visit more than one ed, a health information exchange (hie) may improve the ability to identify frequent ed users across sites of care. objectives: to demonstrate the extent to which a hie can identify the marginal increase in frequent ed users beyond that which can be detected with data from a single hospital. methods: data from / / to / / from the new york clinical information exchange (nyclix), a hie in new york city that includes ten hospitals, were analyzed to calculate the number of frequent ed users ( ‡ visits in days) at each site and across the hie. results: there were , ( % of total patients) frequent ed users, with , ( %) of frequent users having all their visits at a single ed, while , ( %) frequent users were identified only after counting visits to multiple eds (table ) . site-specific increases varied from % to % (sd . ). frequent ed users accounted for % of patients, but for % of visits, averaging . visits per year, versus . visits per year for all other patients. . % of frequent users visited two or more eds during the study period, compared to . % of all other patients. conclusion: frequent ed users commonly visited multiple nyclix eds during the study period. the use of a hie helped identify many additional frequent users, though the benefits were lower for hospitals not located in the relative vicinity of another nyclix hospital. measures that take a community, rather than a single institution, into account may be more reflective of the care that the patient experiences. indocyanine background: due to their complex nature and high associated morbidity, burn injuries must be handled quickly and efficiently. partial thickness burns are currently treated based upon visual judgment of burn depth by the clinician. however, such judgment is only % accurate and not expeditious. laser doppler imaging (ldi) is far more accurate -nearly % after days. however, it is too cumbersome for routine clinical use. laser assisted indocyanine green angiography (laicga) has been indicated as an alternative for diagnosing the depth of burn injuries, and possesses greater utility for clinical translation. as the preferred outcome of burn healing is aesthetic, it is of interest to determine if wound contracture can be predicted early in the course of a burn by laic-ga. objectives: determine the utility of early burn analysis using laicga in the prediction of -day wound contracture. methods: a prospective animal experiment was performed using six anesthetized pigs, each with standardized wounds. differences in burn depth were created by using a . · . cm aluminum bar at three exposure times and temperatures: degrees c for seconds, degrees c for seconds, and degrees c for seconds. we have shown in prior validation experiments that these burn temperatures and times create distinct burn depths. laicga scanning, using lifecell spy elite, took place at hour, hours, hours, hours, and week post burn. imaging was read by a blinded investigator, and perfusion trends were compared with day post-burn contraction outcomes measured using imagej software. biopsies were taken on day to measure scar tissue depth. results: deep burns were characterized by a blue center indicating poor perfusion while more superficial burns were characterized by a yellow-red center indicating perfusion that was close to that of the normal uninjured adjacent skin (see figure) . a linear relationship between contraction outcome and burn perfusion could be discerned as early as hour post burn, peaking in strength at - hours post-burn. burn intensity could be effectively identified at hours post-burn, although there was no relationship with scar tissue depth. conclusion: pilot data indicate that laicga using lifecell spy has the ability to determine the depth of injury and predict the degree of contraction of deep dermal burns within - days of injury with greater accuracy than clinical scoring. the objectives: we hypothesize that real-time monitoring of an integrated electronic medical records system and the subsequent firing of a ''sepsis alert'' icon on the electronic ed tracking board results in improved mortality for patients who present to the ed with severe sepsis or septic shock. methods: we retrospectively reviewed our hospital's sepsis registry and included all patients diagnosed with severe sepsis or septic shock presenting to an academic community ed with an annual census of , visits and who were admitted to a medical icu or stepdown icu bed between june and october . in may an algorithm was added to our integrated medical records system that identifies patients with two sirs criteria and evidence of endorgan damage or shock on lab data. when these criteria are met, a ''sepsis alert'' icon (prompt) appears next to that patient's name on the ed tracking board. the system also pages an in-house, specially trained icu nurse who can respond on a prn basis and assist in the patient's management. months of intervention data are compared with months of baseline data. statistical analysis was via z-test for proportions. results: for ed patients with severe sepsis, the preand post-alert mortality was of ( %) and of ( %), respectively (p = . ; n = ). in the septic shock group, the pre-and post-alert mortality was of ( %) and of ( %), respectively (p = . ). with ed and inpatient sepsis alerts combined, the severe sepsis subgroup mortality was reduced from % to % (p = . ; n = ). conclusion: real-time ed ehr screening for severe sepsis and septic shock patients did not improve mortality. a positive trend in the severe sepsis subgroup was noted, and the combined inpatient plus ed data suggests statistical significance may be reached as more patients enter the registry. limitations: retrospective study, potential increased data capture post intervention, and no ''gold standard'' to test the sepsis alert sensitivity and specificity. ) . descriptive statistics were calculated. principal component analysis was used to determine questions with continuous response formats that could be aggregated. aggregated outcomes were regressed onto predictor demographic variables using multiple linear regression. results: / physicians completed the survey. physicians had a mean of . ± . years experience in the ed. . % were female. eight physicians ( %) reported never having used the tool, while . % of users estimated having used it more than five times. % of users cited the ''p'' alert on the etb as the most common notification method. most felt the ''p'' alert did not help them identify patients with pneumonia earlier (mean = . ± . ), but found it moderately useful in reminding them to use the tool ( . ± . ). physicians found the tool helpful in making decisions regarding triage, diagnostic studies, and antibiotic selection for outpatients and inpatients ( . ± . , . ± . , . ± . , and . ± . , respectively). they did not feel it negatively affected their ability to perform other tasks ( . ± . ). using multiple linear regression, neither age, sex, years experience, nor tool use frequency significantly predicted responses to questions about triage and antibiotic selection, technical difficulties, or diagnostic ordering. conclusion: ed physicians perceived the tool to be helpful in managing patients with pneumonia without negatively affecting workflow. perceptions appear consistent across demographic variables and experience. objectives: we seek to examine whether use of the salt device can provide reliable tracheal intubation during ongoing cpr. the dynamic model tested the device with human powered cpr (manual) and with an automated chest compression device (physio control lucas ). the hypothesis is that the predictable movement of an automated chest compression device will make tracheal intubation easier than the random movement from manual cpr. methods: the project was an experimental controlled trial and took place in the ed at a tertiary referral center in peoria, illinois. this project was an expansion arm of a similarly structured study using traditional laryngoscopy. emergency medicine residents, attending physicians, paramedics, and other acls-trained staff were eligible for participation. in randomized order, each participant attempted intubation on a mannequin using the salt device with no cpr ongoing, during cpr with a manual compression, and during cpr with an automatic chest compression. participants were timed in their attempt and success was determined after each attempt. results: there were participants in the trial. the success rates in the control group and the automated cpr group were both % ( / ) and the success rate in the manual cpr group was % ( / objectives: our primary hypothesis was that in fasting, asymptomatic subjects, larger fluid boluses would lead to proportional aortic velocity changes. our secondary endpoints were to determine inter-and intra-subject variation in aortic velocity measurements. methods: the authors performed a prospective randomized double-blinded trial using healthy volunteers. we measured the velocity time integral (vti) and maximal velocity (vmax) with an estimated - °pulsed wave doppler interrogation of the left ventricular outflow in the apical- cardiac window. three physicians reviewed optimal sampling gate position, doppler angle and verified the presence of an aortic closure spike. angle correction technology was not used. subjects with no history of cardiac disease or hypertension fasted for hours and were then randomly assigned to receive a normal saline bolus of ml/kg, ml/kg or ml/kg over minutes. aortic velocity profiles were measured before and after each fluid bolus. results: forty-two subjects were enrolled. mean age was ± (range to ) and mean body mass index . ± . (range . to ). mean volume (in ml) for groups receiving ml/kg, ml/kg, and ml/kg were , , and , respectively. mean baseline vmax (in cm/s) of the subjects was . ± . (range to ). mean baseline vti (in cm) was . ± . (range . to . ). pre-and post-fluid mean differences for vmax were ) . (± . ) and for vti . (± . ). aortic velocity changes in groups receiving ml/kg, ml/kg, and ml/kg were not statistically significant (see table) . heart rate changes were not significant. background: clinicians recognize that septic shock is a highly prevalent, high mortality disease state. evidence supports early ed resuscitation, yet care delivery is often inconsistent and incomplete. the objective of this study was to discover latent critical barriers to successful ed resuscitation of septic shock. objectives: clinicians recognize that septic shock is a highly prevalent, high mortality disease state. evidence supports early ed resuscitation, yet care delivery is often inconsistent and incomplete. the objective of this study was to discover latent critical barriers to successful ed resuscitation of septic shock. methods: we conducted five -minute risk-informed in-situ simulations. ed physicians and nurses working in the real clinical environment cared for a standardized patient, introduced into their existing patient workload, with signs and symptoms of septic shock. immediately after case completion clinicians participated in a minute debriefing session. transcripts of these sessions were analyzed using grounded theory, a method of qualitative analysis, to identify critical barrier themes. results: fifteen clinicians participated in the debriefing sessions: four attending physicians, five residents, five nurses, and one nurse practitioner. the most prevalent critical barrier themes were: anchoring bias and difficulty with cognitive framework adaptation as the patient progressed to septic shock (n = ), difficult interactions between the ed and ancillary departments (n = ), difficulties with physician-nurse commu-nication and teamwork (n = ), and delays in placing the central venous catheter due to perceptions surrounding equipment availability and the desire to attend to other competing interests in the ed prior to initiation of the procedure (n = and ). each theme was represented in at least four of the five debriefing sessions. participants reported the in-situ simulations to be a realistic representation of ed sepsis care. conclusion: in-situ simulation and subsequent debriefing provides a method of identifying latent critical areas for improvement in a care process. improvement strategies for ed-based septic shock resuscitation will need to address the difficulties in shock recognition and cognitive framework adaptation, physician and nurse teamwork, and prioritization of team effort. the background: the association between blood glucose level and mortality in critically ill patients is highly debated. several studies have investigated the association between history of diabetes, blood sugar level, and mortality of septic patients; however, no consistent conclusion could be drawn so far. objectives: to investigate the association between diabetes and initial glucose level and in-hospital mortality in patients with suspected sepsis from the ed. methods: we conducted a retrospective cohort study that consisted of all adult septic patients who visited the ed at a tertiary hospital during the year with two sets of blood cultures ordered by physicians. basic demographics, ed vital signs, symptoms and signs, underlying illnesses, laboratory findings, microbiological results, and discharge status were collected. logistic regressions were used to evaluate the association between risk factors, initial blood sugar level, and history of diabetes and mortality, as well as the effect modification between initial blood sugar level and history of diabetes. results: a total of patients with available blood sugar levels were included, of whom % had diabetes, % were older than years of age, and % were male. the mortality was % ( % ci . - . %). patients with a history of diabetes tended to be older, female, and more likely to have chronic kidney disease, lower sepsis severity (meds score), and positive blood culture test results (all p < . ). patients with a history of diabetes tended to have lower in-hospital mortality after ed visits with sepsis, controlling for initial blood sugar level (aor . , % ci . - . , p = . ). initial normal blood sugar seemed to be beneficial compared to lower blood sugar level for in-hospital mortality, controlled history of diabetes, sex, severity of sepsis, and age (aor . , % ci . - . , p = . ). the effect modification of diabetes on blood sugar level and mortality, however, was found to be not statistically significant (p = . ). conclusion: normal initial blood sugar level in ed and history of diabetes might be protective for mortality of septic patients who visited the ed. further investigation is warranted to determine the mechanism for these effects. methods: this irb-approved retrospective chart review included all patients treated with therapeutic hypothermia after cardiac arrest during at an urban, academic teaching hospital. every patient undergoing therapeutic hypothermia is treated by neurocritical care specialists. patients were identified by review of neurocritical care consultation logs. clinical data were dually abstracted by trained clinical study assistants using a standardized data dictionary and case report form. medications reviewed during hypothermia were midazolam, lorazepam, propofol, fentanyl, cisatracurium, and vecuronium. results: there were patients in the cohort. median age was (range - years), % were white, % were male, and % had a history of coronary artery disease. seizures were documented by continuous eeg in / ( %), and / ( %) died during hospitalization. most, / ( %), received fentanyl, / ( %) received benzodiazepine pharmacotherapy, and / ( %) received propofol. paralytics were administered to / ( %) patients, / ( %) with cisatracurium and / ( %) with vecuronium. of note, one patient required pentobarbital for seizure management. conclusion: sedation and neuromuscular blockade are common during management of patients undergoing therapeutic hypothermia after cardiac arrest. patients in this cohort often received analgesia with fentanyl, and sedation with a benzodiazepine or propofol. given the frequent use of sedatives and paralytics in survivors of cardiac arrest undergoing hypothermia, future studies should investigate the potential effect of these drugs on prognostication and survival after cardiac arrest. background: the use of therapeutic hypothermia (th) is a burgeoning treatment modality for post-cardiac arrest patients. objectives: we performed a retrospective chart review of patients who underwent post cardiac arrest th at eight different institutions across the united states. our objective was to assess how th is currently being implemented in emergency departments and assess the feasibility of conducting more extensive th research using multi-institution retrospective data. methods: a total of charts with dates from - were sent for review by participating institutions of the peri-resuscitation consortium. of those reviewed, eight charts were excluded for missing data. two independent reviewers performed the review and the results were subsequently compared and discrepancies resolved by a third reviewer. we assessed patient demographics, initial presenting rhythm, time until th initiation, duration of th, cooling methods and temperature reached, survival to hospital discharge, and neurological status on discharge. results: the majority of cases of th had initial cardiac rhythms of asystole or pulseless electrical activity ( . %), followed by ventricular tachycardia or fibrillation ( . %), and in . % the inciting cardiac rhythm was unknown. time to initiation of th ranged from - minutes with a mean time of min (sd . ). length of th ranged from - minutes with a mean time of minutes (sd ). average minimum temperature achieved was . °c, with a range from . - . °c (sd . °c). of the charts reviewed, ( . %) of the patients survived to hospital discharge and ( . %) were discharged relatively neurologically intact. conclusion: research surrounding cardiac arrest has always been difficult given the time and location span from pre-hospital care to emergency department to intensive care unit. also, as witnessed cardiac arrest events are relatively rare with poor survival outcomes, very large sample sizes are needed to make any meaningful conclusions about th. our varied and inconsistent results show that a multi-center retrospective review is also unlikely to provide useful information. a prospective multi-center trial with a uniform th protocol is needed if we are ever to make any evidence-based conclusions on the utility of th for post-cardiac arrest patients. serum results: mean la was . , sd = . . mean age was . years old, sd = . . a statistically significant positive correlation was found between la and pulse, respiratory rate (rr), wbc, platelets, and los, while a significant negative correlation was seen with temperature and hco -. when two subjects were dropped as possible outliers with la > , it resulted in non-significant temperature correlation, but a significant negative correlation with age and bun was revealed. patients in the higher la group were more likely to be admitted (p = . ) and have longer los. of the discharged patients, there was no difference in mean la level between those who returned (n = , mean la of . , sd = . ) and those who did not (n = , mean la of . , sd = . ), p = . . furthermore, mean la levels for those with sepsis (n = , mean la of . , sd = . ) did not differ from those without sepsis (n = , mean la of . , sd = . ), p = . . conclusion: higher la in pediatric patients presenting to the ed with suspected infection correlated with increased pulse, rr, wbc, platelets, and decreased bun, hco -, and age. la may be predictive of hospitalization, but not of -day return rates or pediatric sepsis screening in the ed. background: mandibular fractures are one of the most frequently seen injuries in the trauma setting. in terms of facial trauma, madibular fractures account for - % of all facial bone fractures. prior studies have demonstrated that the use of a tongue blade to screen these patients to determine whether a mandibular fracture is present may be as sensitive as x-ray. one study showed the sensitivity and specificity of the test to be . % and . %, respectively. in the last ten years, high-resolution computed tomography (hct) has replaced panoramic tomography (pt) as the gold standard for imaging of patients with suspected mandibular fractures. this study determines if the tongue blade test (tbt) remains as sensitive a screening tool when compared to the new gold standard of ct. objectives: the purpose of the study was to determine the sensitivity and specificity of the tbt as compared to the new gold standard of radiologic imaging, hct. the question being asked: is the tbt still useful as a screening tool for patients with suspected mandibular fractures when compared to the new gold standard of hct? methods: design: prospective cohort study. setting: an urban tertiary care level i trauma center. subjects: this study took place from / / to / / in which any person suffering from facial trauma presented. intervention: a tbt was performed by the resident physician and confirmed by the supervising attending physician. ct facial bones were then obtained for the ultimate diagnosis. inter-rater reliability (kappa) was calculated, along with sensitivity, specificity, accuracy, ppv, npv, likelihood ratio (lr) (+), and likelihood ratio (lr) (-) based on a · contingency tables generated. results: over the study period patients were enrolled. inter-rater reliability was kappa = . (se + . ). the table demonstrates the outcomes of both the tbt and ct facial bones for mandibular fracture. the following parameters were then calculated based on the contingency table: sensitivity . (ci . - . ), specificity . (ci . - . ), ppv . (ci . - . ), npv . (ci . - . ), accuracy . , lr(+) . ), lr (-) . (ci . - . ). conclusion: the tbt is still a useful screening tool to rule out mandibular fractures in patients with facial trauma as compared to the current gold standard of hct. background: appendicitis is the most common surgical emergency occurring in children. the diagnosis of pediatric appendicitis is often difficult and computerized tomography (ct) scanning is utilized frequently. ct, although accurate, is expensive, time-consuming, and exposes children to ionizing radiation. radiologists utilize ultrasound for the diagnosis of appendicitis, but it may be less accurate than ct, and may not incorporate emergency physician (ep) clinical impression regarding degree of risk. objectives: the current study compared ep clinical diagnosis of pediatric appendicitis pre-and post-bedside ultrasonography (bus). methods: children - years of age were enrolled if their clinical attending physician planned to obtain a consultative ultrasound, ct scan, or surgical consult specific for appendicitis. most children in the study received narcotic analgesia to facilitate bus. subjects were initially graded for likelihood of appendicitis based on research physician-obtained history and physical using a visual analogue scale (vas). immediately subsequent to initial grading, research physicians performed a bus and recorded a second vas impression of appendicitis likelihood. two outcome measures were combined as the gold standard for statistical analysis. the post-operative pathology report served as the gold standard for subjects who underwent appendectomy, while post -week telephone follow-up was used for subjects who did not undergo surgery. various specific ultrasound measures used for the diagnosis of appendicitis were assessed as well. results: / subjects had pathology-proven appendicitis. one subject was pathology-negative post-appendectomy. of the subjects who did not undergo surgery, none had developed appendicitis at the post -week telephone follow-up. pre-bus sensitivity was % ( - %) while post-bus sensitivity was % ( - %). both pre-and post-bus specificity was % ( - %). pre-bus lr+ was ( - ), while post-bus lr+ was ( - ). pre-and post-bus lr-were . and . , respectively. bus changed the diagnosis for % of subjects ( - %). background: there are very little data on the normal distance between the glenoid rim and the posterior aspect of the humeral head in normal and dislocated shoulders. while shoulder x-rays are commonly used to detect shoulder dislocations, they may be inadequate, exacerbate pain in the acquisition of some views, and lead to delay in treatment, compared to bedside ultrasound evaluation. objectives: our objective was to compare the glenoid rim to humeral head distance in normal shoulders and in anteriorly dislocated shoulders. this is the first study proposing to set normal and abnormal limits. methods: subjects were enrolled in this prospective observation study if they had a chief complaint of shoulder pain or injury, and received a shoulder ultrasound as well as a shoulder x-ray. the sonographers were undergraduate students given ten hours of training to perform the shoulder ultrasound. they were blinded to the x-ray interpretation, which was used as the gold standard. we used a posterior-lateral approach, capturing an image with the glenoid rim, the humeral head, as well as the infraspinatus muscle. two parallel lines were applied to the most posterior aspect of the humeral head and the most posterior aspect of the glenoid rim. a line perpendicular to these lines was applied, and the distance measured. in anterior dislocations, a negative measurement was used to denote the fact that the glenoid rim is now posterior to the most posterior aspect of the humeral head. descriptive analysis was applied to estimate the mean and th to th interquartile range of normal and anteriorly dislocated shoulders. results: eighty subjects were enrolled in this study. there were six shoulder dislocations, however only four were anterior dislocations. the average distance between the posterior glenoid rim and the posterior humeral head in normal shoulders was . mm, with a th to th inter-quartile range of . mm to . mm. the distance in our four cases of anterior dislocation was ) mm, with a th to th interquartile range of ) mm to ) mm. conclusion: the distance between the posterior humeral head to posterior glenoid rim may be mm to mm in patients presenting to the ed with shoulder pain but no dislocation. in contrast, this distance in anterior dislocations was greater than ) mm. shoulder ultrasound may be a useful adjunct to x-ray for diagnosing anterior shoulder dislocations. conclusion: in this retrospective study, the presence of rv strain on focus significantly increases the likelihood of an adverse short term event from pulmonary embolism and its combination with hypotension performs similarly to other prognostic rules. background: burns are expensive and debilitating injuries, compromising both the structural integrity and vascular supply to skin. they exhibit a substantial potential to deteriorate if left untreated. jackson defined three ''zones'' to a burn. while the innermost coagulation zone and the outermost zone of hyperemia display generally predictable healing outcomes, the zone of stasis has been shown to be salvageable via clinical intervention. it has therefore been the focus of most acute therapies for burn injuries. while laser doppler imaging (ldi) -the current gold standard for burn analysis -has been % effective at predicting the need for second degree burn excision, its clinical translation is problematic, and there is little information regarding its ability to analyze the salvage of the stasis zone in acute injury. laser assisted indocyanine green dye angiography (laicga) also shows potential to predict such outcomes with greater clinical utility. objectives: to test the ability of ldi and laicga to predict interspace (zone of stasis) survival in a horizontal burn comb model. methods: a prospective animal experiment was performed using four pigs. each pig had a set of six dorsal burns created using a brass ''comb'' -creating four rectangular · mm full thickness burns separated by · mm interspaces. laicga and ldi scanning took place at hour, hours, hours, and week post burn using novadaq spy and moor ldi respectively. imaging was read by a blinded investigator, and perfusion trends were compared with interspace viability and contraction. burn outcomes were read clinically, evaluated via histopathology, and interspace contraction was measured using image j software. results: laicga data showed significant predictive potential for interspace survival. it was . % predictive at hours post burn, % predictive hours post burn, and % predictive days post burn using a standardized perfusion threshold. ldi imaging failed to predict outcome or contraction trends with any degree of reliability. the pattern of perfusion also appears to be correlated with the presence of significant interspace contraction at days, with an % adherence to a power trendline. ventions, isolation, testing, treatment, and ''other'' category intervention were identified. one intervention involving school closures was associated with a % decrease in pediatric ed visits for respiratory illness. conclusion: most interventions were not tested in isolation, so the effect of individual interventions was difficult to differentiate. interventions associated with statistically significant decreases in ed crowding were school closures, as well as interventions in all categories studied. further study and standardization of intervention input, process, and outcome measures may assist in identifying the most effective methods of mitigating ed crowding and improving surge capacity during an influenza or other respiratory disease outbreak. communication background: the link between extended shift lengths, sleepiness, and occupational injury or illness has been shown, in other health care populations, to be an important and preventable public health concern but heretofore has not been fully described in emergency medical services (ems objectives: to assess the effect of an ed-based computer screening and referral intervention for ipv victims and to determine what characteristics resulted in a positive change in their safety. we hypothesized that women who were experiencing severe ipv and/or were in contemplation or action stages would be more likely to endorse safety behaviors. methods: we conducted the intervention for female ipv victims at three urban eds using a computer kiosk to deliver targeted education about ipv and violence prevention as well as referrals to local resources. all adult english-speaking non-critically ill women triaged to the ed waiting room were eligible to participate. the validated universal violence prevention screening protocol was used for ipv screening. any who disclosed ipv further responded to validated questionnaires for alcohol and drug abuse, depression, and ipv severity. the women were assigned a baseline stage of change (precontemplation, contemplation, action, or maintenance) based on the urica scale for readiness to change behavior surrounding ipv. participants were contacted at week and months to assess a variety of pre-determined actions such as moving out, to prevent ipv during that period. statistical analysis (chi-square testing) was performed to compare participant characteristics to the stage of change and whether or not they took protective action. results: a total of , people were screened and disclosed ipv and participated in the full survey. . % of the ipv victims were in the precontemplative stage of change, and . % were in the contemplation stage. women returned at week of follow-up ( . %), and ( . %) women returned at months of followup. . % of those who returned at week, and % of those who returned at months took protective action against further ipv. there was no association between the various demographic characteristics and whether or not a woman took protective action. conclusion: ed-based kiosk screening and health information delivery is both a feasible and effective method of health information dissemination for women experiencing ipv. stage of change was not associated with actual ipv protective measures. objectives: we present a pilot, head-to-head comparison of x and x effectiveness in stopping a motivated person. the objective is to determine comparative injury prevention effectiveness of the newer cew. methods: four humans had metal cew probe pairs placed. each volunteer had two probe pairs placed (one pair each on the right and left of the abdomen/inguinal region). superior probes were at the costal margin, inches lateral of midline. inferior probes were vertically inferior at predetermined distances of , , , and inches apart. each volunteer was given the goal of slashing a target feet away with a rubber knife during cew exposure. as a means of motivation, they believed the exposure would continue until they reached the goal (in reality, the exposure was terminated once no further progress was made). each volunteer received one exposure from a x and a x cew. the exposure order was randomized with a -minute rest between them. exposures were recorded on a hi-speed, hi-resolution video. videos were reviewed and scored by six physician, kinesiology, and law officer experts using standardized criteria for effectiveness including degree of upper and lower extremity, and total body incapacitation, and degree of goal achievement. reviews were descriptively compared independently for probe spread distances and between devices. results: there were exposures ( pairs) for evaluation and no discernible, descriptive reviewer differences in effectiveness between the x and the x cews when compared. background: the trend towards higher gasoline prices over the past decade in the u.s. has been associated with higher rates of bicycle use for utilitarian trips. this shift towards non-motorized transportation should be encouraged from a physical activity promotion and sustainability perspective. however, gas price induced changes in travel behavior may be associated with higher rates of bicycle-related injury. increased consideration of injury prevention will be a critical component of developing healthy communities that help safely support more active lifestyles. objectives: the purpose of this analysis was to a) describe bicycle-related injuries treated in u.s. emergency departments between and and b) investigate the association between gas prices and both the incidence and severity of adult bicycle injuries. we hypothesized that as gas prices increase, adults are more likely to shift away from driving for utilitarian travel toward more economical non-motorized modes of transportation, resulting in increased risk exposure for bicycle injuries. methods: bicycle injury data for adults ( - years) were obtained from the national electronic injury surveillance system (neiss) database for emergency department visits between - . the relationship between national seasonally adjusted monthly rates of bicycle injuries, obtained by a seasonal decomposition of time series, and average national gasoline prices, reported by the energy information administration, was examined using a linear regression analysis. results: monthly rates of bicycle injuries requiring emergency care among adults increase significantly as gas prices rise (p < . , see figure) . an additional , adult injuries ( % ci - , ) can be predicted to occur each month in the u.s. (> , injuries annually) for each $ rise in average gasoline price. injury severity also increases during periods of high gas prices, with a higher percentage of injuries requiring admission. conclusion: increases in adult bicycle use in response to higher gas prices are accompanied by higher rates of significant bicycle-related injuries. supporting the use of non-motorized transportation will be imperative to address public health concerns such as obesity and climate change; however, resources must also be dedicated to improve bicycle-related injury care and prevention. background: this is a secondary analysis of data collected for a randomized trial of oral steroids in emergency department (ed) musculoskeletal back pain patients. we hypothesized that higher pain scores in the ed would be associated with more days out of work. objectives: to determine the degree to which days out of work for ed back pain patients are correlated with ed pain scores. methods: design: prospective cohort. setting: suburban ed with , annual visits. participants: patients aged - years with moderately severe musculoskeletal back pain from a bending or twisting injury £ days before presentation. exclusion criteria included nonmusculoskeletal etiology, direct trauma, motor deficits, and employer-initiated visits. observations: we captured initial and discharge ed visual analog pain scores (vas) on a - scale. patients were contacted approximately days after discharge and queried about the days out of work. we plotted days out of work versus initial vas, discharge vas, and change in vas and calculated correlation coefficients. using the bonferroni correction because of multiple comparisons, alpha was set at . . results: we analyzed patients for whom complete data were available. the mean age was ± years and % were female. the average initial and discharge ed pain scales were . ± . and . ± . , respectively. on follow-up, % of patients were back to work and % did not lose any days of work. for the plots of the days out of work versus the initial and discharge vas and the change in the vas, the correlation coefficients (r ) were . (p = . ), . (p = . ), and . (p = . ), respectively. conclusion: for ed patients with musculoskeletal back pain, we found no statistically significant correlation between days out of work and ed pain scores. background: conducted electrical weapons (cews) are common law enforcement tools used to subdue and repel violent subjects and, therefore, prevent further injury or violence from occurring in certain situations. the taser x is a new generation of cew that has the capability of firing two cartridges in a ''semi-automatic'' mode, and has a different electrical waveform and different output characteristics than older generation technology. there have been no data presented on the human physiologic effects of this new generation cew. objectives: the objective of this study was to evaluate the human physiologic effects of this new cew. methods: this was a prospective, observational study of human subjects. an instructor shot subjects in the abdomen and upper thigh with one cartridge, and subjects received a -second exposure from the device. measured variables included: vital signs, continuous spirometry, pre-and post-exposure ecg, intra-exposure echocardiography, venous ph, lactate, potassium, ck, and troponin. results: ten subjects completed the study (median age . , median bmi . , % male). there were no important changes in vital signs or in potassium. the median increase in lactate during the exposure was . , range . to . . the median change in ph was ) . , range ) . to . . no subject had a clinically relevant ecg change, evidence of cardiac capture, or positive troponin up to hours after exposure. the median change in creatine kinase (ck) at hours was , range ) to . there was no evidence of impairment of breathing by spirometry. baseline median minute ventilation was . , which increased to . during the exposure (p = . ), and remained elevated at . post-exposure (p = . ). conclusion: we detected a small increase in lactate and decrease in ph during the exposure, and an increase in ck hours after the exposure. the physiologic effects of the x device appear similar to previous reports for ecd devices. use background: public bicycle sharing (bikeshare) programs are becoming increasingly common in the us and around the world. these programs make bicycles easily accessible for hourly rental to the public. there are currently active bikeshare programs in cities in the us, and more than programs are being developed in cities including new york and chicago. despite the importance of helmet use, bikeshare programs do not provide the opportunity to purchase or rent helmets. while the programs encourage helmet use, no helmets are provided at the rental kiosks. objectives: we sought to describe the prevalence of helmet use among adult users of bikeshare programs and users of personal bicycles in two cities with recently introduced bicycle sharing programs (boston, ma and washington, dc). methods: we performed a prospective observational study of bicyclists in boston, ma and washington, dc. trained observers collected data during various times of the day and days of the week. observers recorded the sex of the bicycle operator, type of bicycle, and helmet use. all bicycles that passed a single stationary location in any direction for a period of between and minutes were recorded. data are presented as frequencies of helmet use by sex, type of bicycle (bikeshare or personal), time of the week (weekday or weekend), and city. logistic regression was used to estimate the odds ratio for helmet use controlling for type of bicycle, sex, day of week, and city. results: there were observation periods in two cities at locations. , bicyclists were observed. there were ( . %) bicylists riding bikeshare bicycles. overall helmet use was . %, although helmet use varied significantly with sex, day of use, and type of bicycle (see figure) . bikeshare users were helmeted at a lower rate compared to users of personal bicycles ( . % vs . %). logistic regression, controlling for type of bicycle, sex, day of week, and city demonstrate that bikeshare users had higher odds of riding unhelmeted (or . , % ci . - . ). women had lower odds of riding unhelmeted (or . , . - . ), while weekend riders were more likely to ride unhelmeted (or . , . - . ). conclusion: use of bicycle helmets by users of public bikeshare programs is low. as these programs become more popular and prevalent, efforts to increase helmet use among users should increase. background: abusive head trauma (aht) represents one of the most severe forms of traumatic brain injury (tbi) among abused infants with % mortality. young adult males account for % of the perpetrators. most aht prevention programs are hospital-based and reach a predominantly female audience. there are no published reports of school-based aht prevention programs to date. objectives: . to determine whether a high schoolbased aht educational program will improve students' knowledge of aht and parenting skills. . to evaluate the feasibility and acceptability of a school-based aht prevention program. methods: this program was based on an inexpensive commercially available program developed by the national center on shaken baby syndrome. the program was modified to include a -minute interactive presentation that teaches teenagers about aht, parenting skills, and caring for inconsolable crying infants. the program was administered in three high schools in flint, michigan during spring . student's knowledge was evaluated with a -item written test administered pre-intervention, post-intervention, and two months after program completion. program feasibility and acceptability were evaluated through interviews and surveys with flint area school social workers, parent educators, teachers, and administrators. results: in all, high school students ( % male) participated. of these, ( . %) completed the pretest and post-test with ( %) completing the twomonth follow-up test. the mean pre-intervention, postintervention, and two-month follow-up scores were %, %, and % respectively. from pre-test to posttest, mean score improved %, p < . . this improvement was even more profound in young males, whose mean post-test score improved by %, p < . . of the participating social workers, parent educators, teachers, and administrators, % ranked the program as feasible and acceptable. conclusion: students participating in our program showed an improvement in knowledge of aht and parenting skills which was retained after two months. teachers, social workers, parent educators, and school administrators supported the program. this local pilot program has the potential to be implemented on a larger scale in michigan with the ultimate goal of reducing aht amongst infants. will background: fear of litigation has been shown to affect physician practice patterns, and subsequently influence patient care. the likelihood of medical malpractice litigation has previously been linked with patient and provider characteristics. one common concern is that a patient may exaggerate symptoms in order to obtain monetary payouts; however, this has never been studied. objectives: we hypothesize that patients are willing to exaggerate injuries for cash settlements and that there are predictive patient characteristics including age, sex, income, education level, and previous litigation. methods: this prospective cross-sectional study spanned june to december , in a philadelphian urban tertiary care center. any patient medically stable enough to fill out a survey during study investigator availability was included. two closed-ended paper surveys were administered over the research period. standard descriptive statistics were utilized to report incidence of: patients who desired to file a lawsuit, patients previously having filed lawsuits, and patients willing to exaggerate the truth in a lawsuit for a cash settlement. chi-square analysis was performed to determine the relationship between patient characteristics and willingness to exaggerate injuries for a cash settlement. results: of surveys, were excluded due to incomplete data, leaving for analysis. the mean age was with a standard deviation of , and % were male. the incidence of patients who had the desire to sue at the time of treatment was %. the incidence of patients who had filed a lawsuit in the past was %. of those patients, % had filed multiple lawsuits. fifteen percent [ % ci - %] of all patients were willing to exaggerate injuries for cash settlement. sex and income were found to be statistically significant predictors of willingness to exaggerate symptoms: % of females vs. % of males were willing to exaggerate (p = . ), and % of people with income less than $ , /yr vs. % of those with income over $ , / yr were willing to exaggerate (p = . ). conclusion: patients at a philadelphian urban tertiary center admit to willingness to exaggerate symptoms for a cash settlement. willingness to exaggerate symptoms is associated with female sex and lower income. background: current data suggest that as many as % of patients presenting to the ed with syncope leave the hospital without a defined etiology. prior studies have suggested a prevalence of psychiatric disease as high as % in patients with syncope of unknown etiology. objectives: to determine whether psychiatric disease and substance abuse are associated with an increased incidence of syncope of unknown etiology. methods: prospective, observational, cohort study of consecutive ed patients ‡ presenting with syncope was conducted between / and / . patients were queried in the ed and charts reviewed about a history of psychiatric disease, use of psychiatric medication, substance abuse, and duration. data were analyzed using sas with chi-square and fisher's exact tests. results: we enrolled patients who presented to the ed after syncope, of whom did not have an identifiable etiology for their syncopal event. . % of those without an identifiable etiology were male. ( %) patients had a history of or current psychiatric disease ( % male), and patients ( %) had a history of or current substance abuse ( % male). among males with psychiatric disease, % had an unknown etiology of their syncopal event, compared to % of males without psychiatric disease (p = . ). similarly, among all males with a history of substance abuse, % had an unknown etiology, as compared to % of males without a history of substance abuse (p = . ). a similar trend was not identified in elderly females with psychiatric disease (p = . ) or substance abuse (p = . ). however, syncope of unknown etiology was more common among both men and women under age with a history of substance abuse ( %) compared to those without a history of substance abuse ( %; p = . ). conclusion: our results suggest that psychiatric disease and substance abuse are associated with increased incidence of syncope of unknown etiology. patients evaluated in the ed or even hospitalized with syncope of unknown etiology may benefit from psychiatric screening and possibly detoxification referral. this is particularly true in men. (originally submitted as a ''late-breaker.'') scope background: after discharge from an emergency department (ed), pain management often challenges parents, who significantly under-treat their children's pain. rapid patient turnover and anxiety make education about home pain treatment difficult in the ed. video education standardizes information and circumvents insufficient time and literacy. objectives: to evaluate the effectiveness of a -minute instructional video for parents that targets common misconceptions about home pain management. methods: we conducted a randomized, double-blinded clinical trial of parents of children ages - years who presented with a painful condition, were evaluated, and discharged home in june and july . parents were randomized to a pain management video or an injury prevention control video. primary outcome was the proportion of parents who gave pain medication at home. these data were recorded in a home pain diary and analyzed using a chi-square test. parents' knowledge about pain treatment was tested before, immediately following, and days after intervention. mcnemar's test statistic determined odds that knowledge correlated with the intervention group. results: parents were enrolled: watched the pain education video, and the control video. . % completed follow up, providing information about home pain education use. significantly more parents provided at least one dose of pain medication to their children after watching the educational video: % vs. % (difference %, % ci . %, . %). the odds the parent had correct knowledge about pain treatment significantly improved immediately following the educational video for knowledge about pain scores (p = . ), the effect of pain on function (p < . ), and pain medication misconceptions (p < . ). these significant differences in knowledge remained days after the video intervention. the educational video about home pain treatment viewed by parents significantly increased the proportion of children receiving pain medication at home and significantly improved knowledge about at-home pain management. videos are an efficient tool to provide medical advice to parents that improves outcomes for children. methods: this was a prospective, observational study of consecutive admitted cpu patients in a large-volume academic urban ed. cardiology attendings round on all patients and stress test utilization is driven by their recommendation. eligibility criteria include: age> , aha low/intermediate risk, nondynamic ecgs, and normal initial troponin i. patients > and with a history of cad or co-existing active medical problem were excluded. based on prior studies and our estimated cpu census and demographic distribution, we estimated a sample size of , patients in order to detect a difference in stress utilization of % ( -tailed, a = . , b = . ). we calculated a timi risk prediction score and a diamond & forrester (d&f) cad likelihood score on each patient. t-tests were used for univariate comparisons of demographics, cardiac comorbidities, and risk scores. logistic regression was used to estimate odds ratios (ors) for receiving testing based on race, controlling for insurance and either timi or d&f score. results: over months, , patients were enrolled. mean age was ± , and % ( % ci - ) were female. sixty percent ( % ci - ) were caucasian, % ( % ci - ) african american, and % ( % ci - ) hispanic. mean timi and d&f scores were . ( % ci . - . ) and % ( % ci - ). the overall stress testing rate was % ( % ci - ). after controlling for insurance status and timi or d&f scores, african american patients had significantly decreased odds of stress testing (or timi . ( % ci . - . ), or d&f . ( % ci . - . )). hispanics had significantly decreased odds of stress testing in the model controlling for d&f (or d&f . ( % ci . - . )). conclusion: this study confirms that disparities in the workup of african american patients in the cpu are similar to those found in the general ed and the outpatient setting. further investigation into the specific provider or patient level factors contributing to this bias is necessary. the outcomes for hf and copd were sae . %, . %; death . %, . %. we found univariate associations with sae for these walk test components: too ill to walk (both hf, copd p < . ); highest heart rate ‡ (hf p = . , copd p = . ); lowest sao < % (hf p = . , copd p = . ); borg score ‡ (hf p = . , copd p = . ); walk test duration £ minute (hf p = . . copd p = . ). after adjustment for multiple clinical covariates with logistic regression analyses, we found ''walk test heart rate ‡ '' had an odds ratio of . for hf patients and ''too ill to start the walk test'' had an odds ratio of . for copd patients. conclusion: we found the -minute walk test to be easy to administer in the ed and that maximum heart rate and inability to start the test were highly associated with adverse events in patients with exacerbations of hf and copd, respectively. we suggest that the -minute walk test be routinely incorporated into the assessment of hf and copd patients in order to estimate risk of poor outcomes. the objectives: the objective of this study was to investigate differences in consent rates between patients of different demographic groups who were invited to participate in minimal-risk clinical trials conducted in an academic emergency department. methods: this descriptive study analyzed prospectively collected data of all adult patients who were identified as qualified participants in ongoing minimal risk clinical trials. these trials were selected for this review because they presented minimal factors known to be associated background: increasing rates of patient exposure to computerized tomography (ct) raise questions about appropriateness of utilization, as well as patient awareness of radiation exposure. despite rapid increases in ct utilization and published risks, there is no national standard to employ informed consent prior to radiation exposure from diagnostic ct. use of written informed consent for ct (icct) in our ed has increased patient understanding of the risks, benefits, and alternatives to ct imaging. our team has developed an adjunct video educational module (vem) to further educate ed patients about the ct procedure. objectives: to assess patient knowledge and preferences regarding diagnostic radiation before and after viewing vem. methods: the vem was based on icct currently utilized at our tertiary care ed (census , patients/ year). icct is written at an th grade reading level. this fall, vem/icct materials were presented to a convenience sample of patients in the ed waiting room am- pm, monday-sunday. patients who were < years of age, critically ill, or with language barrier were excluded. to quantify the educational value of the vem, a six-question pretest was administered to assess baseline understanding of ct imaging. the patients then watched the vem via ipad (macintosh) and reviewed the consent form. an eight-question post-test was then completed by each subject. no phi were collected. pre-and post-test results were analyzed using mcnemar's test for individual questions and a paired t-test for the summed score (sas version . ). results: patients consented and completed the survey. the average pre-test score for subjects was poor, % correct. review of vem/icct materials increased patient understanding of medical radiation as evidenced by improved post-test score to %. mean improvement between tests was % (p < . ). % of subjects responded that they found the materials helpful, and that they would like to receive icct. conclusion: the addition of a video educational module improved patient knowledge regarding ct imaging and medical radiation as quantified by pre-and posttesting. patients in our study sample reported that they prefer to receive icct. by educating patients about the risks associated with ct imaging, we increase informed, shared decision making -an essential component of patient-centered care. does objectives: we sought to determine the relationship between patients' pain scores and their rate of consent to ed research. we hypothesized that patients with higher pain scores would be less likely to consent to ed research. methods: retrospective observational cohort study of potential research subjects in an urban academic hospital ed with an average annual census of approximately , visits. subjects were adults older than years with chief complaint of chest pain within the last hours, making them eligible for one of two cardiac biomarker research studies. the studies required only blood draws and did not offer compensation. two reviewers extracted data from research screening logs. patients were grouped according to pain score at triage, pain score at the time of approach, and improvement in pain score (triage score -approach score). the main outcome was consent to research. simple proportions for consent rates by pain score tertiles were calculated. two multivariate logistic regression analyses were performed with consent as outcome and age, race, sex, and triage or approach pain score as predictors. results: overall, potential subjects were approached for consent. patients were % caucasian, % female, and with an average age of years. six patients did not have pain scores recorded at all and did not have scores documented within hours of approach and were excluded from relevant analyses. overall, . % of patients consented. consent rates by tertiles at triage, at time of approach, and by pain score improvement are shown in tables and . after adjusting for age, race, and sex, neither triage (p = . ) nor approach (p = . ) pain scores predicted consent. conclusion: research enrollment is feasible even in ed patients reporting high levels of pain. patients with modest improvements in pain levels may be more likely to consent. future research should investigate which factors influence patients' decisions to participate in ed research. conclusion: in this multicenter study of children hospitalized with bronchiolitis neither specific viruses nor their viral load predicted the need for cpap or intubation, but young age, low birth weight, presence of apnea, severe retractions, and oxygen saturation < % did. we also identified that children requiring cpap or intubation were more likely to have mothers who smoked during pregnancy and a rapid respiratory worsening. mechanistic research in these high-risk children may yield important insights for the management of severe bronchiolitis. brigham & women's hospital, boston, ma background: siblings and children who share a home with a physically abused child are thought to be at high risk for abuse. however, rates of injury in these children are unknown. disagreements between medical and child protective services professionals are common and screening is highly variable. objectives: our objective was to measure the rates of occult abusive injuries detected in contacts of abused children using a common screening protocol. methods: this was a multi-center, observational cohort study of child abuse teams who shared a common screening protocol. data were collected between jan , and april , for all children < years undergoing evaluation for physical abuse and their contacts. for contacts of abused children, the protocol recommended physical examination for all children < years, skeletal survey and physical exam for children < months, and physical exam, skeletal survey, and neuroimaging for children < months old. results: among , children evaluated for abuse, met criteria as ''physically abused'' and these had contacts. for each screening modality, screening was completed as recommended by the protocol in approximately % of cases. of contacts who met criteria for skeletal survey, new injuries were identified in ( . %). none of these fractures had associated findings on physical examination. physical examination identified new injuries in . % of eligible contacts. neuroimaging failed to identify new injuries among eligible contacts less than months old. twins were at significantly increased risk of fracture relative to other nontwin contacts (or . ). conclusion: these results support routine skeletal survey for contacts of physically abused children < months old, regardless of physical examination findings. even for children where no injuries are identified, these results demonstrate that abuse is common among children who share a home with an abused child, and support including contacts in interventions (foster care, safety planning, social support) designed to protect physically abused children. methods: this was a retrospective study evaluating all children presenting to eight paediatric, universityaffiliated eds during one year in - . in each setting, information regarding triage and disposition were prospectively registered by clerks in the ed database. anonymized data were retrieved from the ed computerized database of each participating centre. in the absence of a gold standard for triage, hospitalisation, admission to intensive care unit (icu), length of stay in the ed, and proportion of patients who left without being seen by a physician (lwbs) were used as surrogate markers of severity. the primary outcome measure was the association between triage level (from to ) and hospitalisation. the association between triage level and dichotomous outcomes was evaluated by a chi-square test, while a student's t-test was used to evaluate the association between triage level and length of stay. it was estimated that the evaluation of all children visiting these eds for a one year period would provide a minimum of , patients in each triage level and at least events for outcomes having a proportion of % or more. results: a total of , children visited the eight eds during the study period. pooled data demonstrated hospitalisation proportions of %, %, %, %, and . % for patients triaged at level , , , , and respectively (p < . ). there was also a strong association between triage levels and admission to icu (p < . ), the proportion of children who lwbs (p < . ), and length of stay (p < . ). background: parents frequently leave the emergency department (ed) with incomplete understanding of the diagnosis and plan, but the relationship between comprehension and post-care outcomes has not been well described. objectives: to explore the relationship between comprehension and post-discharge medication safety. methods: we completed a planned secondary analysis of a prospective observational study of the ed discharge process for children aged - months. after discharge, parents completed a structured interview to assess comprehension of the child's condition, the medical team's advice, and the risk of medication error. limited understanding was defined as a score of - from (excellent) to (poor). risk of medication error was defined as a plan to use over-the-counter cough/cold medication and/or an incorrect dose of acetaminophen (measured by direct observation at discharge or reported dose at follow-up call). parents identified as at risk received further instructions from their provider. the primary outcome was persistent risk of medication error assessed at phone interview - days post-discharge. a major barrier to administering analgesics to children is the perceived discomfort of intravenous access. the delivery of intranasal analgesia may be a novel solution to this problem. objectives: we investigated whether the addition of the mucosal atomizer device (mad) as an alternative for fentanyl delivery would improve overall fentanyl administration rates in pediatric patients transported by a large urban ems system. we performed a historical control trial comparing the rate of pediatric fentanyl administration months before and months after the introduction of the mad. study subjects were pediatric trauma patients (age < years) transported by a large urban ems agency. the control group was composed of patients treated in the months before introduction of the mad. the experimental group included patients treated in the months after the addition of the mad. two physicians reviewed each chart and determined whether the patient met predetermined criteria for the administration of pain medication. a third reviewer resolved any discrepancies. fentanyl administration rates were measured and compared between the two groups. we used two-sample t-tests and chi-square tests to analyze our data. results: patients were included in the study: patients in the pre-mad group and in the post-mad group. there were no significant differences in the demographic and clinical characteristics of the two groups. ( . %) patients in the control arm received fentanyl. ( . %) of patients in the experimental arm received fentanyl with % of the patients receiving fentanyl via the intranasal route. the addition of the mad was not associated with a statistically significant increase in analgesic administration. age and mechanism of injury were statistically more predictive of analgesia administration. conclusion: while the addition of the mucosal atomizer device as an alternative delivery method for fentanyl shows a trend towards increased analgesic administration in a prehospital pediatric population, age and mechanism of injury are more predictive in who receives analgesia. further research is necessary to investigate the effect of the mad on pediatric analgesic delivery. methods: this was a prospective study evaluating php-se before (pre) and after (post) a ppp introduction and months later ( -mo). php groups received either ppp review and education or ppp review alone. the ppp included a pain assessment tool. the se tool, developed and piloted by pediatric ems experts, uses a ranked ordinal scale ranging from 'certain i cannot do it' ( ) to 'completely certain i can do it' ( ) for items: pain assessment ( items), medication administration ( ) and dosing ( ) , and reassessment ( ). all items and an averaged composite were evaluated for three age groups (adult, child, toddler). paired sample t-tests compared post-and -mo scores to pre-ppp scores. results: of phps who completed initial surveys, phps completed -mo surveys. ( %) received education and ppp review and ( %) review only. ppp education did not affect php-se (adult p = . , child p = . , toddler p = . ). the largest se increase was in pain assessment. this increase persisted for child and toddler groups at months. the immediate increase in composite se scores for all age groups persisted for the toddler group at months. conclusion: increases in composite and pain assessment php-se occur for all age groups immediately after ppp introduction. the increase in pain assessment se persisted at months for pediatric age groups. composite se increase persisted for the toddler age group alone. background: pediatric medications administered in the prehospital setting are given infrequently and dosage may be prone to error. calculation of dose based on known weight or with use of length-based tapes occurs even less frequently and may present a challenge in terms of proper dosing. objectives: to characterize dosing errors based on weight-based calculations in pediatric patients in two similar emergency medical service (ems) systems. methods: we studied the five most commonly administered medications given to pediatric patients weighing kg or less. drugs studied were morphine, midazolam, epinephrine : , , epinephrine : , and diphenhydramine. cases from the electronic record were studied for a total of months, from january to july . each drug was administered via intravenous, intramuscular, or intranasal routes. drugs that were permitted to be titrated were excluded. an error was defined as greater than % above or below the recommended mg/kg dosage. results: out of , total patients, , were pediatric patients. had documented weights of < kg and patients were given these medications. we excluded patients for weight above the %ile or below the %ile, or if the weight documentation was missing. of the patients and doses, errors were noted in ( %; % ci %, %). midazolam was the most common drug in errors ( of doses or %; % ci %, %), followed by diphenhydramine ( / or %; % ci %, %), epinephrine ( / or %; % ci %, %), and morphine sulfate ( / or %; % ci, %, %). underdosing was noted in of ( %; % ci %, %) of errors, while excessive dosing was noted in of ( %; % ci %, %). conclusion: weight-based dosing errors in pediatric patients are common. while the clinical consequences of drug dosing errors in these patients are unknown, a considerable amount of inaccuracy occurs. strategies beyond provision of reference materials are needed to prevent pediatric medication errors and reduce the potential for adverse outcomes. drivers background: homelessness affects up to . million people a year. the homeless present more frequently to eds, their ed visits are four times more likely to occur within days of a prior ed evaluation, and they are admitted up to five times more frequently than others. we evaluated the effect of a street outreach rapid response team (sorrt) on the health care utilization of a homeless population. a nonmedical outreach staff responds to the ed and intensely case manages the patient: arranges primary care follow-up, social services, temporary housing opportunities, and drug/ alcohol rehabilitation services. objectives: we hypothesized that this program would decrease the ed visits and hospital admissions of this cohort of patients. methods: before and after study at an urban teaching hospital from june, -december, in indianapolis, indiana. upon identification of homeless status, sorrt was immediately notified. eligibility for sorrt enrollment is determined by housing and urban development homeless criteria and the outreach staff attempted to enter all such identified patients into the program. the patients' health care utilization was evaluated in the months prior to program entry as compared to the months after enrollment by prospectively collecting data and a retrospective medical record query for any unreported visits. since the data were highly skewed, we used the nonparametric signed rank test to test for paired differences between periods. results: patients met criteria but two refused participation. the -patient cohort had total ed visits ( pre and post) with a mean of . (sd . ) and median of . (range - ) ed visits in months pre-sorrt as compared to a mean of . (sd . ) and median of . ( - ) in months post-sorrt (p = . ). there were total inpatient admissions pre-intervention and post-intervention, with a mean of . (sd . ) and median of . ( . ) per patient in the pre-intervention period as compared to . (sd . ) and . ( - ) in the post-intervention period (p = . ). in the pre-sorrt period . % had at least one inpatient admission as compared to . % post-sorrt (p = . ). there were no differences in icu days or overall length of stay between the two periods. conclusion: an aggressive case management program beginning immediately with homeless status recognition in the ed has not demonstrated success in decreasing utilization in our population. methods: this was a secondary analysis of a prospective randomized trial that included consenting patients discharged with outpatient antibiotics from an urban county ed with an annual census of , . patients unable to receive text messages or voice-mails were excluded. health literacy was assessed using a validated health literacy assessment, the newest vital sign (nvs). patients were randomized to a discharge instruction modality: ) standard care, typed and verbal medication and case-specific instructions; ) standard care plus text-messaged instructions sent to the patient's cell phone; or ) standard care plus voice-mailed instructions sent to the patient's cell. patients were called at days to determine preference for instruction delivery modality. preference for discharge instruction modality was analyzed using z-tests for proportions. results: patients were included ( % female, median age , range months to years); were excluded. % had an nvs score of - , % - , and % - . among the . % of participants reached at days, % preferred a modality other than written. there was a difference in the proportion of patients who preferred discharge instructions in written plus another modality (see table) . with the exception of written plus another modality, patient preference was similar across all nvs score groups. conclusion: in this sample of urban ed patients, more than one in four patients prefer non-traditional (text message, voice-mail) modalities of discharge instruction delivery to standard care (written) modality alone. additional research is needed to evaluate the effect of instructional modality on accessibility and patient compliance. figure) . conclusion: cumulative saps ii scoring fails to predict mortality in ohca. the risk scores assigned to age, gcs, and hco independently predict mortality and combined are good mortality predictors. these findings suggest that an alternative severity of illness score should be used in post-cardiac arrest patients. future studies should determine optimal risk scores of saps ii variables in a larger cohort of ohca. objectives: to determine the extent to which cpp recovers to pre-pause levels with seconds of cpr after a -second interruption in chest compressions for ecg rhythm analysis. methods: this was a secondary analysis of prospectively collected data from an iacuc-approved protocol. fortytwo yorkshire swine (weighing - kg) were instrumented under anesthesia. vf was electrically induced. after minutes of untreated vf, cpr was initiated and a standard dose of epinephrine (sde) ( . mg/kg) was given. after . minutes of cpr to circulate the vasopressor, compressions were interrupted for seconds to analyze the ecg rhythm. this was immediately followed by seconds of cpr to restore cpp before the first rs was delivered. if the rs failed, cpr resumed and additional vasopressors (sde, and vasopressin . mg/kg) were given and the sequence repeated. the cpp was defined as aortic diastolic pressure minus right atrial diastolic pressure. the cpp values were extracted at three time points: immediately after the . minutes of cpr, following the -second pause, and immediately before defibrillation for the first two rs attempts in each animal. eighty-three sets of measurements were logged from animals. descriptive statistics were used to analyze the data. in most cities, the proportion of patients who achieve prehospital return of spontaneous circulation (rosc) is less than %. the association between time of day and ohca outcomes in the prehospital setting is unknown. objectives: we sought to determine whether rates of prehospital rosc varied by time of day. we hypothesized that night ohcas would exhibit lower rates of rosc. methods: we performed a retrospective review of cardiac arrest data from a large, urban ems system. included were all ohcas occurring in individuals > years of age from / / to / / . excluded were traumatic arrests and cases where resuscitation measures were not performed. day was defined as : am- : pm, while night was : pm- : am. we examined the association between time of day and paramedic-perceived prehospital rosc in unadjusted and adjusted analyses. variables included age, sex, race, presenting rhythm, aed application by a bystander or first responder, defibrillation, and bystander cpr performance. analyses were performed using chisquare tests and logistic regression. objectives: determine whether a smei helps to improve physician compliance with ihi bundle and reduce patient mortality in ed patients with s&s. methods: we conducted a pre-smei retrospective review of four months of ed patients with s&s to determine baseline pre-smei physician compliance and patient mortality. we designed and completed a smei attended by of ed attending physicians and of ed resuscitation residents. finally, we conducted a twenty-month post-smei prospective study of ongoing physician compliance and patient mortality in ed patients with s&s. results: in the four month pre-smei retrospective review, we identified patients with s&s, with a % physician overall compliance and mortality rate of %. the average ed physician smei multiple-choice pre-test score was %, and showed a significant improvement in the post-test score of % (p = . ). additionally, % of ed physicians were able to describe three new clinical pearls learned and % agreed that the smei would improve compliance. in the twenty months of the post-smei prospective study, we identified patients with s&s, with a % physician overall compliance, and mortality rate of %. relative physician compliance improved % (p = . ) and relative patient mortality was reduced by % (p < . ) when comparing pre-and post-smei data. conclusion: our data suggest that a smei improves overall physician compliance with the six hour goals of the ihi bundle and reduces patient mortality in ed patients with s&s. conclusion: using a population-level, longitudinal, and multi-state analysis, the rate of return visits within days is higher than previously reported, with nearly in returning back to the ed. we also provide the first estimation of health care costs for ed revisits. background: the ability of patients to accurately determine their level of urgency is important in planning strategies that divert away from eds. in fact, an understanding of patient self-triage abilities is needed to inform health policies targeting how and where patients access acute care services within the health care system. objectives: to determine the accuracy of a patient's self-assessment of urgency compared against triage nurses. methods: setting: ed patients are assigned a score by trained nurses according to the canadian emergency department triage and acuity scale (ctas). we present a cross-sectional survey of a random patient sample from urban/regional eds conducted during the winters of and . this previously validated questionnaire, based on the british healthcare commission survey, was distributed according to a modified dillman protocol. exclusion criteria consisted of: age - years, left prior to being seen/treated, died during ed visit, no contact information, presented with a privacy-sensitive case. alberta health services provided linked non-survey administrative data. results: , surveys distributed with a response rate of %. patients rated health problems as life-threatening ( %), possibly life-threatening ( %), urgent ( %), somewhat urgent ( %), or not urgent ( %). triage nurses assigned the same patients ctas scores of i (< %), ii ( %), iii ( %), iv ( %) or v ( %). patients self-rated their condition as or points less urgent than the assigned ctas score (< % of the time), points less urgent ( %), point less urgent ( %), exactly as urgent ( %), point more urgent ( %), points more urgent ( %), or or points more urgent ( %, respectively). among ctas i or ii patients, % described their problem as life-threatening/possibly life-threatening, % as urgent (risk of permanent damage), % as urgent (needed to be seen that day), and % as not urgent (wanted to be but did not need to be seen that day). conclusion: the majority of ed patients are generally able to accurately assess the acuity of their problem. encouraging patients with low-urgency conditions to self-triage to lower-acuity sources of care may relieve stress on eds. however, physicians and patients must be aware that a small minority of patients are unable to self-triage safely. when the tourniquet was released, blood spurted from the injured artery as hydrostatic pressure decayed. pressure and flow were recorded in three animals (see table) . the concept was proof-tested in a single fresh frozen human cadaver with perfusion through the femoral artery and hemorrhage from the popliteal artery. the results were qualitatively and quantitatively similar to the swine carcass model. conclusion: a perfused swine carcass can simulate exsanguinating hemorrhage for training purposes and serves as a prototype for a fresh-frozen human cadaver model. additional research and development are required before the model can be widely applied. background: in the pediatric emergency department (ped), clinicians must work together to provide safe and effective care. crisis resource management (crm) principles have been used to improve team performance in high-risk clinical settings, while simulation allows practice and feedback of these behaviors. objectives: to develop a multidisciplinary educational program in a ped using simulation-enhanced teamwork training to standardize communication and behaviors and identify latent safety threats. methods: over months a workgroup of physicians and nurses with experience in team training and simulation developed an educational program for clinical staff of a tertiary ped. goals included: create a didactic curriculum to teach the principles of crm, incorporate principles of crm into simulation-enhanced team training in-situ and center-based exercises, and utilize assessment instruments to evaluate for teamwork, completion of critical actions, and presence of latent safety threats during in-situ sim resuscitations. results: during phase i, clinicians, divided into teams, participated in -minute pre-training assessments of pals-based in-situ simulations. in phase ii, staff participated in a -hour curriculum reviewing key crm concepts, including team training exercises utilizing simulation and expert debriefing. in phase iii, staff participated in post-training minute teamwork and clinical skills assessments in the ped. in all phases, critical action checklists (cac) were tabulated by simulation educators. in-situ simulations were recorded for later review using the assessment tools. after each simulation, educators facilitated discussion of perceptions of teamwork and identification of systems issues and latent hazards. overall, in-situ simulations were conducted capturing % of the physicians and % of the nurses. cac data were collected by an observer and compared to video recordings. over significant systems issues, latent hazards, and knowledge deficits were identified. all components of the program were rated highly by % of the staff. conclusion: a workgroup of pem, simulation, and team training experts developed a multidisciplinary team training program that used in-situ and centerbased simulation and a refined crm curriculum. unique features of this program include its multidisciplinary focus, the development of a variety of assessment tools, and use of in-situ simulation for evaluation of systems issues and latent hazards. this program was tested in a ped and findings will be used to refine care and develop a sustainment program while addressing issues identified. objectives: our hypothesis is that participants trained on high-fidelity mannequins will perform better than participants trained on low-fidelity mannequins on both the acls written exam and in performance of critical actions during megacode testing. the study was performed in the context of an acls initial provider course for new pgy residents at the penn medicine clinical simulation center and involved three training arms: ) low fidelity (low-fi): torso-rhythm generator; ) mid-fidelity (mid-fi): laerdal simmanÒ turned off; and ) high-fidelity (high-fi): laerdal simmanÒ turned on. training in each arm of the study followed standard aha protocol. educational outcomes were evaluated by written scores on the acls written examination and expert rater reviews of acls megacode videos performed by trainees during the course. a sample of subjects were randomized to one of the three training arms: low-fi (n = ), mid-fi (n = ), or high-fi (n = ). results: statistical significance across the groups was determined using analysis-of-variance (anova). the three groups had similar written pre-test scores [low-fi . ( . ), mid-fi . ( . ), and high-fi . ( . )] and written post-test scores [low-fi . ( . ), mid-fi . ( . ), and high-fi . ( . )]. similarly, test improvement was not significantly different. after completion of the course, high-fi subjects were more likely to report they felt comfortable in their simulator environment (p = . ). low-fi subjects were less likely to perceive a benefit in acls training from high-fi technology (p < . ). acls instructors were not rated significantly different by the subjects using the debriefing assessment for simulation in healthcareª (dash) student version except for element , where the high-fi group subjects reported lower scores ( . vs . and . in the other groups, p = . ). objectives: we sought to determine if stress associated with the performance of a complex procedural task can be affected by level of medical training. heart rate variability (hrv) is used as a measure of autonomic balance, and therefore an indicator of the level of stress. methods: twenty-one medical students and emergency medicine residents were enrolled. participants performed airway procedures on an airway management trainer. hrv data were collected using a continuous heart rate variability monitoring system. participant hrv was monitored at baseline, during the unassisted first attempt at endotracheal intubation, during supervised practice, and then during a simulated respiratory failure clinical scenario. standard deviation of beat to beat variability (sdnn), very low frequency (vlf), total power (tp), and low frequency (lf) was analyzed to determine the effect of practice and level of training on the level of stress. a cohen's d test was used to determine differences between study groups. results: sdnn data showed that second-year residents were less stressed during all stages than were fourthyear medical students (avg d = . ). vlf data showed third-year residents exhibited less sympathetic activity than did first-year residents (avg d = ) . ). the opportunity to practice resulted in less stress for all participants. tp data showed that residents had a greater degree of control over their autonomic nervous system (ans) than did medical students (avg d = . ). lf data showed that subjects were more engaged in the task at hand as the level of training increased indicating autonomic balance (avg d = . ). conclusion: our hrv data show that stress associated with the performance of a complex procedural task is reduced by increased training. hrv may provide a quantitative measure of physiologic stress during the learning process and thus serve as a marker of when a subject is adequately trained to perform a particular task. objectives: we seek to examine whether intubation during cpr can be done as efficiently as intubation without ongoing cpr. the hypothesis is that the predictable movement of an automated chest compression device will make intubation easier than the random movement from manual cpr. methods: the project was an experimental controlled trial and took place in the emergency department at a tertiary referral center in peoria, illinois. emergency medicine residents, attendings, paramedics, and other acls trained staff were eligible for participation. in randomized order, each participant attempted intubation on a mannequin with no cpr ongoing, during cpr with a human compressor, and during cpr with an automatic chest compression device (physio control lucas ). participants could use whichever style laryngoscope they felt most comfortable with and they were timed during the three attempts. success was determined after each attempt. results: there were participants in the trial. the success rate in the control group and the automated cpr group were both % ( / ) and the success rate in the manual cpr group was % ( / ). the differences in success rates were not statistically significant (p = . and p = . ). the automated cpr group had the fastest average time ( . sec; p = . ). the mean times for intubation with manual cpr and no cpr were not statistically different ( . sec, . sec; p = . ). conclusion: the success rate of tracheal intubation with ongoing chest compression was the same as the success rate of intubation without cpr. although intubation with automatic chest compression was faster than during other scenarios, all methods were close to the second timeframe recommended by acls. based on these findings, it may not always be necessary to hold cpr to place a definitive airway; however, further studies will be needed. background: after acute myocardial infarction, vascular remodeling in the peri-infarct area is essential to provide adequate perfusion, prevent additional myocyte loss, and aid in the repair process. we have previously shown that endogenous fibroblast growth factor (fgf ) is essential to the recovery of contractile function and limitation of infarct size after cardiac ischemia-reperfusion (ir) injury. the role of fgf in vascular remodeling in this setting is currently unknown. objectives: determine the role of endogenous fgf in vascular remodeling in a clinically relevant, closed-chest model of acute myocardial infarction. methods: mice with a targeted ablation of the fgf gene (fgf knockout) and wild type controls were subjected to a closed-chest model of regional cardiac ir injury. in this model, mice were subjected to minutes of occlusion of the left anterior descending artery followed by reperfusion for either or days. immunofluorescence was performed on multiple histological sections from these hearts to visualize capillaries (endothelium, anti-cd antibody), larger vessels (venules and arterioles, antismooth muscle actin antibody), and nuclei (dapi). digital images were captured, and multiple images from each heart were measured for vessel density and vessel size. results: sham-treated fgf knockout and wild type mice show no differences in capillary or vessel density suggesting no defect in vessel formation in the absence of endogenous fgf . when subjected to closed-chest regional cardiac ir injury, fgf knockout hearts had normal capillary and vessel number and size in the peri-infarct area after day of reperfusion compared to wild type controls. however, after days, fgf knockout hearts showed significantly decreased capillary and vessel number and increased vessel size compared to wild type controls (p < . ). conclusion: these data show the necessity of endogenous fgf in vascular remodeling in the peri-infarct zone in a clinically relevant animal model of acute myocardial infarction. these findings may suggest a potential role for modulation of fgf signaling as a therapeutic intervention to optimize vascular remodeling in the repair process after myocardial infarction. the diagnosis of aortic dissections by ed physicians is rare scott m. alter, barnet eskin, john r. allegra morristown medical center, morristown, nj background: aortic dissection is a rare event. the most common symptom of dissection is chest pain, but chest pain is a frequent emergency department (ed) chief complaint and other diseases that cause chest pain, such as acute coronary syndrome and pulmonary embolism, occur much more frequently. furthermore, % of dissections are without chest pain and % are painless. for all these reasons, diagnosing dissection can be difficult for the ed physician. we wished to quantify the magnitude of this problem in a large ed database. objectives: our goal was to determine the number of patients diagnosed by ed physicians with aortic dissections compared to total ed patients and to the total number of patients with a chest pain diagnosis. methods: design: retrospective cohort. setting: suburban, urban, and rural new york and new jersey eds with annual visits between , and , . participants: consecutive patients seen by ed physicians from january , through december , . observations: we identified aortic dissections using icd- codes and chest pain diagnoses by examining all icd- codes used over the period of the study and selecting those with a non-traumatic chest pain diagnosis. we then calculated the number of total ed patients and chest pain patients for every aortic dissection diagnosed by emergency physicians. we determined % confidence intervals (cis). results: from a database of . million ed visits, we identified ( . %) aortic dissections, or one for every , ( % ci , to , ) visits. the mean age of aortic dissection patients was ± years and % were female. of the total visits there were , ( %) with a chest pain diagnosis. thus there is one aortic dissection diagnosis for every ( % ci to , ) chest pain diagnoses. conclusion: the diagnosis of aortic dissections by ed physicians is rare. an ed physician seeing , to , patients a year would diagnose an aortic dissection approximately once every to years. an aortic dissection would be diagnosed once for approximately every , ed chest pain patients. patients were excluded if they suffered a cardiac arrest, were transferred from another hospital, or if the ccl was activated for an inpatient or from ems in the field. fp ccl activation was defined as ) a patient for whom activation was cancelled in the ed and ruled out for mi or ) a patient who went to catheterization but no culprit vessel was identified and mi was excluded. ecgs for fp patients were classified using standard criteria. demographic data, cardiac biomarkers, and all relevant time intervals were collected according to an on-going quality assurance protocol. results: a total of ccl activations were reviewed, with % male, average age , and % black. there were ( %) true stemis and ( %) fp activations. there were no significant differences between the fp patients who did and did not have catheterization. for those fp patients who had a catheterization ( %), ''door to page'' and ''door to lab'' times were significantly longer than the stemi patients (see table) , but there was substantial overlap. there was no difference in sex or age, but fp patients were more likely to be black (p = . ). a total of fp patients had ecgs available for review; findings included anterior elevation with convex ( %) or concave ( %) elevation, st elevation from prior anterior ( %) or inferior ( %) mi, pericarditis ( %), presumed new lbbb ( %), early repolarization ( %), and other ( %). conclusion: false ccl activation occurred in a minority of patients, most of whom had ecg findings warranting emergent catheterization. the rate of false ccl activation appears acceptable. background: atrial fibrillation (af) is the most common cardiac arrhythmia treated in the ed, leading to high rates of hospitalization and resource utilization. dedicated atrial fibrillation clinics offer the possibility of reducing the admission burden for af patients presenting to the ed. while the referral base for these af clinics is growing, it is unclear to what extent these clinics contribute to reducing the number of ed visits and hospitalizations related to af. objectives: to compare the number of ed visits and hospitalizations among discharged ed patients with a primary diagnosis of af who followed up with an af clinic and those who did not. methods: a retrospective cohort study and medical records review including three major tertiary centres in calgary, canada. a sample of patients was taken representing patients referred to the af clinic from the calgary zone eds and compared to matched control ed patients who were referred to other providers for follow-up. the controls were matched for age and sex. inclusion criteria included patients over years of age, discharged during the index visit, and seen by the af clinic between january , and october , . exclusion criteria included non-residents and patients hospitalized during the index visit. the number of cardiovascular-related ed visits and hospitalizations was measured. all data are categorical, and were compared using chi-square tests. results: patients in the control and af clinic cohorts were similar for all baseline characteristics except for a higher proportion of first episode patients in the intervention arm. in the six months following the index ed visit, study group patients ( . %) visited an ed on occasions, and ( %) were hospitalized on occasions. of the control group, patients ( . %) visited an ed on occasions, and ( %) were hospitalized on occasions. using a chi-square test we found no significant difference in ed visits (p = . ) or hospitalizations (p = . ) between the control and af clinic cohorts. conclusion: based on our results, referral from the ed to an af clinic is not associated with a significant reduction in subsequent cardiovascular related ed visits and hospitalizations. due to the possibility of residual confounding, randomized trials should be performed to evaluate the efficacy of af clinics. reported an income of less than $ , . there were no significant associations between sex, race, marital status, education level, income, insurance status, and subsequent -and- day readmission rates. hla score was not found to be significantly related to readmission rates. the mean hla score was . (sd = . ), equivalent to less than th grade literacy, meaning these patients may not be able to read prescription labels. for each unit increase in hfkt score, the odds of being readmitted within days decreased by . (p < . ) and for - days decreased by . (p < . ). for each unit increase in scbs score, the odds of being readmitted within days decreased by . (p = . ). conclusion: health care literacy in our patient population is not associated with readmission, likely related to the low literacy rate of our study population. better hf knowledge and self-care behaviors are associated with lower readmission rates. greater emphasis should be placed on patient education and self-care behaviors regarding hf as a mechanism to decrease readmission rates. comparison of door to balloon times in patients presenting directly or transferred to a regional heart center with stemi jennifer ehlers, adam v. wurstle, luis gruberg, adam j. singer stony brook university, stony brook, ny background: based on the evidence, a door-to-balloon-time (dtbt) of less than minutes is recommended by the aha/acc for patients with stemi. in many regions, patients with stemi are transferred to a regional heart center for percutaneous coronary intervention (pci). objectives: we compared dtbt for patients presenting directly to a regional heart center with those for patients transferred from other regional hospitals. we hypothesized that dtbt would be significantly longer for transferred patients. methods: study design-retrospective medical record review. setting-academic ed at a regional heart center with an annual census of , that includes a catchment area of hospitals up to miles away. patients-patients with acute stemi identified on ed -lead ecg. measures-demographic and clinical data including time from triage to ecg, from ecg to activation of regional catheterization lab, and from initial triage to pci (dtbt , and door to intravascular balloon deployment (d b). methods: the study was performed in an inner-city academic ed between / / and / / . every patient for whom ed activation of our stemi system occurred was included. all times data from a pre-existing quality assurance database were collected prospectively. patient language was determined retrospectively by chart review. results: there were patients between / / and / / . patients ( %) were deemed too sick or unable to provide history and were excluded, leaving patients for analysis. ( %) spoke english and ( %) did not. in the non-english group, chinese was the most common language, in ( %) background: syncope is a common, potentially highrisk ed presentation. hospitalization for syncope, although common, is rarely of benefit. no populationbased study has examined disparities in regional admission practices for syncope care in the ed. moreover, there are no population-based studies reporting prognostic factors for -and -day readmission of syncope. objectives: ) to identify factors associated with admission as well as prognostic factors for -and -day readmission to these hospitals; ) to evaluate variability in syncope admission practices across different sizes and types of hospitals. methods: design -multi-center retrospective cohort study using ed administrative data from albertan eds. participants/subjects -patients > years of age with syncope (icd : r ) as a primary or secondary diagnosis from to june . readmission was defined as return visits to the ed or admission < days or - days after the index visit (including against medical advice and left without being seen during the index visit). outcomes -factors associated with hospital admission at index presentation, and readmission following ed discharge, adjusted using multivariable logistic regression. results: overall, syncope visits occurred over years. increased age, increased length of stay (los), performance of cxr, transport by ground ambulance, and treatment at a low-volume hospital (non-teaching or non-large urban) were independently associated with index hospitalization. these same factors, as well as hospital admission itself, were associated with -day readmission. additionally, increased age, increased los, performance of a head ct, treatment at a low-volume hospital, hospital admission, and female sex were independently associated with - day readmission. arrival by ground ambulance was associated with a decreased likelihood of both -and - day readmission. conclusion: our data identify variations in practice as well as factors associated with hospitalization and readmission for syncope. the disparity in admission and readmission rates between centers may highlight a gap in quality of care or reflect inappropriate use of resources. further research to compare patient out-comes and quality of patient care among urban and non-urban centers is needed. background: change in dyspnea severity (ds) is a frequently used outcome measure in trials of acute heart failure (ahf). however, there is limited information concerning its validity. objectives: to assess the predictive validity of change in dyspnea severity. methods: this was a secondary analysis of a prospective observational study of a convenience sample of ahf patients presenting with dyspnea to the ed of an academic tertiary referral center with a mixed urban/ suburban catchment area. patients were enrolled weekdays, june through december . patients assessed their ds using a -cm visual analog scale at three times: the start of ed treatment (baseline) as well as at and hours after starting ed treatment. the difference between baseline and hour was the -hour ds change. the difference between baseline and hours was the -hour ds change. two clinical outcome measures were obtained: ) the number of days hospitalized or dead within days of the index visit ( -day outcome), and ) the number of days hospitalized or dead within days of the index visit ( -day outcome). results: data on patients were analyzed. the median -day outcome variable was days with an interquartile range (iqr) of to . the median -day outcome variable was days (iqr to . ). the median -hour ds change was . cm (iqr . to . ). the median -hour ds change was . cm (iqr . to . ). the -day and -day mortality rates were % and % respectively. the spearman rank correlations and % confidence intervals are presented in the table below. conclusion: while the point estimates for the correlations were below . , the % ci for two of the correlations extended above . . these pilot data support change in ds as a valid outcome measure for ahf when measured over hours. a larger prospective study is needed to obtain a more accurate point estimate of the correlations. background: the majority of volume-quality research has focused on surgical outcomes in the inpatient setting; very few studies have examined the effect of emergency department (ed) case volume on patient outcomes. objectives: to determine whether ed case volume of acute heart failure (ahf) is associated with short-term patient outcomes. methods: we analyzed the nationwide emergency department sample (neds) and nationwide inpatient sample (nis), the largest, all-payer, ed and inpatient databases in the us. ed visits for ahf were identified with a principal diagnosis of icd- -cm code .xx. eds were categorized into quartiles by ed case volume of ahf. the outcome measures were early inpatient mortality (within the first days of admission), overall inpatient mortality, and hospital length of stay (los). results: there were an estimated , visits for ahf from approximately , eds in ; % were hospitalized. of these, the overall inpatient mortality rate was . %, and the median hospital los was days. early inpatient mortality was lower in the highest-volume eds, compared with the lowest-volume eds ( . % vs. . %; p < . ). similar patterns were observed for overall inpatient mortality ( . % vs. . %; p < . ). in a multivariable analysis adjusting for patient and hospital characteristics, early inpatient mortality remained lower in patients admitted through the highest-volume eds (adjusted odds ratios [or], . ; % confidence interval [ci], . - . ), as compared with the lowest-volume eds. there was a trend towards lower overall inpatient mortality in the highest-volume eds; however, this was not statistically significant (adjusted or, . ; %ci, . - . ). by contrast, using the nis data including various sources of admissions, a higher case volume of inpatient ahf patients predicted lower overall inpatient mortality (adjusted or, . ; %ci, . - . ). the hospital los in patients admitted through the highest-volume eds was slightly longer (adjusted difference, . day; %ci, . - . ), compared with the lowest-volume eds. conclusion: ed patients who are hospitalized for ahf have an approximately % reduced early inpatient mortality if they were admitted from an ed that handles a large volume of ahf cases. the ''practice-makesperfect'' concept may hold in emergency management of ahf. emergency department disposition and charges for heart failure: regional variability alan b. storrow, cathy a. jenkins, sean p. collins, karen p. miller, candace mcnaughton, naftilan allen, benjamin s. heavrin vanderbilt university, nashville, tn background: high inpatient admission rates for ed patients with acute heart failure are felt partially responsible for the large economic burden of this most costly cardiovascular problem. objectives: we examined regional variability in ed disposition decisions and regional variability in total dollars spent on ed services for admitted patients with primary heart failure. methods: the nationwide emergency department sample (neds) was used to perform a retrospective, cohort analysis of patients with heart failure (icd- code of .x) listed as the primary ed diagnosis. demographics and disposition percentages (with se) were calculated for the overall sample and by region: northeast, south, midwest, and west. to account for the sample design and to obtain national and regional estimates, a weighted analysis was conducted. results: there were , weighted ed visits with heart failure listed as the primary diagnosis. overall, over eighty percent were admitted (see table) . fifty-two percent of these patients were female; mean age was . years (se . ). hospitalization rates were higher in the northeast ( . %) and south ( . %) than in the midwest ( . %) and west ( . %). total monies spent on ed services were highest in the south ($ , , ) followed by the northeast ($ , , ), west ($ , , ) and midwest ($ , , ) . conclusion: this large retrospective ed cohort suggests a very high national admission rate with significant regional variation in both disposition decisions as well as total monies spent on ed services for patients with a primary diagnosis of heart failure. examining these estimates and variations further may provide strategies to reduce the economic burden of heart failure. background: workplace violence in health care settings is a frequent occurrence. gunfire in hospitals is of particular concern. however, information regarding such workplace violence is limited. accordingly, we characterized u.s. hospital-based shootings from - . objectives: to determine extent of hospital-based shootings in the u.s. and involvement of emergency departments. methods: using lexisnexis, google, netscape, pub-med, and sciencedirect, we searched reports for acute care hospital shooting events from january through december , and those with at least one injured victim were analyzed. results: we identified hospital-related shootings ( inside the hospital, on hospital grounds), in states, with victims, of whom were perpetrators. in comparison to external shootings, shootings within the hospital have not increased over time (see figure) . perpetrators were from all age groups, including the elderly. most of the events involved a determined shooter: grudge ( %), suicide ( %), ''euthanizing'' an ill relative ( %), and prisoner escape ( %). ambient societal violence ( %) and mentally unstable patients ( %) were comparatively infrequent. the most common injured was the perpetrator ( %). hospital employees comprised only % of victims; physician ( %) and nurse ( %) victims were relatively infrequent. the emergency department was the most common site ( %), followed by patient rooms ( %) and the parking lot ( %). in % of shootings within hospitals, the weapon was a security officer's gun grabbed by the perpetrator. ''grudge'' motive was the only factor determinative of hospital staff victims (or = . , % ci . - . ). conclusion: although hospital-based shootings are relatively rare, emergency departments are the most likely site. the unpredictable nature of this type of event represents a significant challenge to hospital security and deterrence practices, as most perpetrators proved determined, and many hospital shootings occur outside the building. impact of emergency physician board certification on patient perceptions of ed care quality albert g. sledge iv , carl a. germann , tania d. strout , john southall maine medical center, portland, me; mercy hospital, portland, me background: the hospital value-based purchasing program mandated by the affordable care act is the latest example of how patients' perceptions of care will affect the future practice environment of all physicians. the type of training of medical providers in the emergency department (ed) is one possible factor affecting patient perceptions of care. a unique situation in a maine community ed led to the rapid transition from non-emergency medicine (em) residency trained physicians to all em residency trained and american board of emergency medicine (abem) certified providers. objectives: the purpose of this study was to evaluate the effect of the implementation of an all em-trained, abem-certified physician staff on patient perceptions of the quality of care they received in the ed. methods: we retrospectively evaluated press ganey data from surveys returned by patients receiving treatment in a single, rural ed. survey items addressed patient's perceptions of physician courtesy, time spent listening, concern for patient comfort, and informativeness. additional items evaluated overall perceptions of care and the likelihood that the respondent would recommend the ed to another. data were compared for the three years prior to and following implementation of the all trained, certified staff. we used the independent samples t-test to compare mean responses during the two time periods. bonferroni's correction was applied to adjust for multiple comparisons. results: during the study period, , patients provided surveys for analysis: , during the pre-certification phase and , during the post-certification phase. across all six survey items, mean responses increased following transition to the board-certified staff. these improvements were noted to be statistically significant in each case: courtesy p < . , time listening p < . , concern for comfort p < . , informativeness p < . , overall perception of care p < . , and likelihood to recommend p < . . conclusion: data from this community ed suggest that transition from a non-residency trained, abem certified staff to a fully trained and certified model has important implications for patient's perceptions of the care they receive. we observed significant improvement in rating scores provided by patients across all physicianoriented and general ed measures. background: transfer of care from the ed to the inpatient floor is a critical transition when miscommunication places patients at risk. the optimal form and content of handoff between providers has not been defined. in july , ed-to-floor signout for all admissions to the medicine and cardiology floors was changed at our urban, academic, tertiary care hospital. previously, signout was via an unstructured telephone conversation between ed resident and admitting housestaff. the new signout utilizes a web-based ed patient tracking system and includes: ) a templated description of ed course is completed by the ed resident; ) when a bed is assigned, an automated page is sent to the admitting housestaff; ) ed clinical information, including imaging, labs, medications, and nursing interventions (figure) is reviewed by admitting housestaff; ) if housestaff has specific questions about ed care, a telephone conversation between the ed resident and housestaff occurs; ) if there are no specific questions, it is indicated electronically and the patient is transferred to the floor. objectives: to describe the effects on patient safety (floor-to-icu transfer in hours) and ed throughput (ed length of stay (los) and time from bed assignment to ed departure) resulting from a change to an electronic, discussion-optional handoff system. conclusion: transition to a system in which signout of admitted patients is accomplished by accepting housestaff review of ed clinical information supplemented by verbal discussion when needed resulted in no significant change in rate of floor-to-icu transfer or ed los and reduced time from bed assignment to ed departure. background: emergency physicians may be biased against patients presenting with nonspecific complaints or those requiring more extensive work-ups. this may result in patients being seen less quickly than those with more straightforward presentations, despite equal triage scores or potential for more dangerous conditions. objectives: the goal of our study was to ascertain which patients, if any, were seen more quickly in the ed based on chief complaint. methods: a retrospective report was generated from the emr for all moderate acuity (esi ) adult patients who visited the ed from january through december at a large urban teaching hospital. the most common complaints were: abdominal pain, alcohol intoxication, back pain, chest pain, cough, dyspnea, dizziness, fall, fever, flank pain, headache, infection, pain (nonspecific), psychiatric evaluation, ''sent by md,'' vaginal bleeding, vomiting, and weakness. non-parametric independent sample tests assessed median time to be seen (ttbs) by a physician for each complaint. differences in the ttbs between genders and based on age were also calculated. chi-square testing compared percentages of patients in the ed per hour to assess for differences in the distribution of arrival times. results: we obtained data from , patients. patients with a chief complaint of weakness and dizziness waited the longest with a median time of minutes and patients with flank pain waited the shortest with minutes (p < . ) ( figure ). overall, males waited minutes and females waited minutes (p < . ). stratifying by gender and age, younger females between the ages of - waited significantly longer times when presenting with a chief complaint of abdominal pain (p < . ), chest pain (p < . ), or flank pain (p < . ) as compared to males in the same age group ( figure ). there was no difference in the distribution of arrival times for these complaints. conclusion: while the absolute time differences are not large, there is a significant bias toward seeing young male patients more quickly than women or older males despite the lower likelihood of dangerous conditions. triage systems should perhaps take age and gender better into account. patients might benefit from efforts to educate em physicians on the delays and potential quality issues associated with this bias in an attempt to move toward more egalitarian patient selection. background: detailed analysis of emergency department (ed) event data identified the time from completion of emergency physician evaluation (doc done) to the time patients leave the ed as a significant contributor to ed length of stay (los) and boarding at our institution. process flow mapping identified the time from doc done to the time inpatient beds were ordered (bo) as an interval amendable to specific process improvements. objectives: the purpose of this study was to evaluate the effect of ed holding orders for stable adult . ( . - . ) . ( . - . ) . ( . - . ) . ( . - . ) . ( . - . ) . ( . - . ) inpatient medicine (aim) patients on: a) the time to bo and b) ed los. methods: a prospective, observational design was used to evaluate the study questions. data regarding the time to bo and los outcomes were collected before and after implementation of the ed holding orders program. the intervention targeted stable aim patients being admitted to hospitalist, internal medicine, and family medicine services. ed holding orders were placed following the admission discussion with the accepting service and special attention was paid to proper bed type, completion of the emergent work-up and the expected immediate course of the patient's hospital stay. holding orders were of limited duration and expired hours after arrival to the inpatient unit. results: during the -month study period, patients were eligible for the ed holding orders intervention; ( . %) were cared for using the standard adult medicine order set and ( . %) received the intervention. the median time from doc done to bo was significantly shorter for patients in the ed holding orders group, min (iqr , ) vs. min (iqr , ) for the standard adult medicine group, p < . . similarly, the median ed los was significantly shorter for those in the ed holding orders group, min (iqr , ) vs. min (iqr , ) for the standard adult medicine group, p < . . no lapses in patient care were reported in the intervention group. conclusion: in this cohort of ed patients being admitted to an aim service, placing ed holding orders rather than waiting for a traditional inpatient team evaluation and set of admission orders significantly reduced the time from the completion of the ed workup to placement of a bo. as a result, ed los was also significantly shortened. while overall utilization of the intervention was low, it improved with each month. emergency department interruptions in the age of electronic health records matthew albrecht, john shabosky, jonathan de la cruz southern illinois university school of medicine, springfield, il background: interruptions of clinical care in the emergency department (ed) have been correlated with increased medical errors and decreased patient satisfaction. studies have also shown that most interruptions happen during physician documentation. with the advent of the electronic health record and computerized documentation, ed physicians now spend much of their clinical time in front of computers and are more susceptible to interruptions. voice recognition dictation adjuncts to computerized charting boast increased provider efficiency; however, little is known about how data input of computerized documentation affects physician interruptions. objectives: we present here observational interruptions data comparing two separate ed sites, one that uses computerized charting by conventional techniques and one assisted by voice recognition dictation technology. methods: a prospective observational quality initiative was conducted at two teaching hospital eds located less than mile from each other. one site primarily uses conventional computerized charting while the other uses voice recognition dictation computerized charting. four trained observers followed ed physicians for minutes during shifts. the tasks each ed physician performed were noted and logged in second intervals. tasks listed were selected from a predetermined standardized list presented at observer training. tasks were also noted as either completed or placed in queue after a change in task occurred. a total of minutes were logged. interruptions were noted when a change in task occurred with the previous task being placed in queue. data were then compared between sites. results: ed physicians averaged . interruptions/ hour with conventional computerized charting compared to . interruptions/hour with assisted voice recognition dictation (p = . ). conclusion: computerized charting assisted with voice recognition dictation significantly decreased total per hour interruptions when compared to conventional techniques. charting with voice recognition dictation has the potential to decrease interruptions in the ed allowing for more efficient workflow and improved patient care. background: using robot assistants in health care is an emerging strategy to improve efficiency and quality of care while optimizing the use of human work hours. robot prototypes capable of performing vital signs and assisting with ed triage are under development. however, ed users' attitudes toward robot assistants are not well studied. understanding of these attitudes is essential to design user-friendly robots and to prepare eds for the implementation of robot assistants. objectives: to evaluate the attitudes of ed patients and their accompanying family and friends toward the potential use of robot assistants in the ed. methods: we surveyed a convenience sample of adult ed patients and their accompanying adult family members and friends at a single, university-affiliated ed, / / - / / . the survey consisted of eight items from the negative attitudes towards robots scale (normura et al.) modified to address robot use in the ed. response options included a -point likert scale. a summary score was calculated by summing the responses for all items, with a potential range of (completely negative attitude) to (completely positive attitude). research assistants gave the written surveys to subjects during their ed visit. internal consistency was assessed using cronbach's alpha. bivariate analyses were performed to evaluate the association between the summary score and the following variables: participant type (patient or visitor), sex, race, time of day, and day of week. results: of potential subjects approached, ( %) completed the survey. participants were % patients, % family members or friends, % women, % white, and had a median age of . years (iqr - ). cronbach's alpha was . . the mean summary score was . (sd = . ), indicating subjects were between ''occasionally'' and ''sometimes'' comfortable with the idea of ed robot assistants (see table) . men were more positive toward robot use than women (summary score: . vs . ; p = . ). no differences in the summary score were detected based on participant type, race, time of day, or day of week. conclusion: ed users reported significant apprehension about the potential use of robot assistants in the ed. future research is needed to explore how robot designs and strategies to implement ed robots can help alleviate this apprehension. background: emergency department cardioversion (edc) of recent-onset atrial fibrillation or flutter (af) patients is an increasingly common management approach to this arrhythmia. patients who qualify for edc generally have few co-morbidities and are often discharged directly from the ed. this results in a shift towards a sicker population of patients admitted to the hospital with this diagnosis. objectives: to determine whether hospital charges and length of stay (los) profiles are affected by emergency department discharge of af patients. methods: patients receiving treatment at an urban teaching community hospital with a primary diagnosis of atrial fibrillation or flutter were identified through the hospital's billing data base. information collected on each patient included date of service, patient status, length of stay, and total charges. patient status was categorized as inpatient (admitted to the hospital), observation (transferred from the ed to an inpatient bed but placed in an observation status), or ed (discharged directly from the ed). the hospital billing system automatically defaults to a length of stay of for observation patients. ed patients were assigned a length of stay of . total hospital charges and mean los were determined for two different models: a standard model (sm) in which patients discharged from the ed were excluded from hospital statistics, and an inclusive model (im) in which discharged ed patients were included in the hospital statistics. statistical analysis was through anova. results: a total of patients were evaluated for af over an -month period. of these, ( %) were admitted, ( %) were placed in observation status, and ( %) were discharged from the ed. hospital charges and los in days are summarized in the table. all differences were statistically significant at (p < . ). conclusion: emergency department management can lead to a population of af patients discharged directly from the ed. exclusion of these patients from hospital statistics skews performance profiles effectively punishing institutions for progressive care. background: recent health care reform has placed an emphasis on the electronic health record (ehr). with the advent of the ehr it is common to see ed providers spending more time in front of computers documenting and away from patients. finding strategies to decrease provider interaction with computers and increase time with patients may lead to improved patient outcomes and satisfaction. computerized charting adjuncts, such as voice recognition software, have been marketed as ways to improve provider efficiency and patient contact. objectives: we present here observational data comparing two separate ed sites, one where computerized charting is done by conventional techniques and one that is assisted with voice recognition dictation, and their effects on physican charting and patient contact. methods: a prospective observational quality initiative was conducted at two teaching hospitals located less than mile from each other. one site primarily uses conventional computerized charting while the other uses voice recognition dictation. four trained quality assistants observed ed physicians for minutes during shifts. the tasks each physician performed were noted and logged in second intervals. tasks listed were identified from a predetermined standardized list presented at observer training. a total of minutes were logged. time allocated to charting and that allocated to direct patient care were then compared between sites. results: ed physicians spent . % of their time charting using conventional techniques vs . % using voice recognition dictation (p = . ). time allocated to direct patient care was found to be . % with conventional charting vs . % using dictation (p = ). in total, ed physicians using conventional charting techniques spent / minutes charting. ed physicians using voice recognition dictation spent / minutes dictating and an additional . / minutes reviewing or correcting their dictations. the use of voice recognition assisted dictation rather than conventional techniques did not significantly change the amount of time physicians spent charting or with direct patient care. although voice recognition dictation decreased initial input time of documenting data, a considerable amount of time was required to review and correct these dictations. objectives: for our primary objective, we studied whether emergency department triage temperatures detected fever adequately when compared to a rectal temperature. as secondary objectives, we examined the temperature differences when a rectal temperature was taken within an hour of non-invasive temperature, temperature site (oral, axillary, temporal), and also examined the patients that were initially afebrile but were found to be febrile by rectal temperature. methods: we performed an electronic chart review at our inner city, academic emergency department with an annual census of , patients. we identified all patients over the age of who received a non-invasive triage temperature and a subsequent rectal temperature while in the ed from january through february . specific data elements included many aspects of the patient's medical record (e.g. subject demographics, temperature, and source). we analyzed our data with standard descriptive statistics, t-tests for continuous variables, and pearson chi-square tests for proportions. results: a total of , patients met our inclusion criteria. the mean difference in temperatures between the initial temperature and the rectal temperature was . °f, with . % having higher rectal temperatures ‡ °f, and . % having higher rectal temperatures ‡ °f. the mean temperature difference among the , patients who an initial noninvasive temperature and a rectal temperature within one hour was . °f. the mean difference among patients that received oral, axillary, and temporal temperatures was . °f, . °f, and . °f respectively. approximately one in five patients ( . %) were initially afebrile and found to be febrile by rectal temperature, with an average temperature difference of . °f. these patients had a higher rate of admission, and were more likely to be admitted to the intensive care unit. conclusion: there are significant differences between rectal temperatures and non-invasive triage temperatures in this emergency department cohort. in almost one in five patients, fever was missed by triage temperature. background: pediatric emergency department (ped) overcrowding has become a national crisis, and has resulted in delays in treatment, and patients leaving without being seen. increased wait times have also been associated with decreased patient satisfaction. optimizing ped throughput is one means by which to handle the increased demands for services. various strategies have been proposed to increase efficiency and reduce length of stay (los). objectives: to measure the effect of direct bedding, bedside registration, and patient pooling on ped wait times, length of stay, and patient satisfaction. methods: data were extracted from a computerized ed tracking system in an urban tertiary care ped. comparisons were made between metrics for ( , patients) and the months following process change ( , patients). during , patients were triaged by one or two nurses, registered, and then sent either to a -bed ped or a physically separate -bed fast-track unit, where they were seen by a physician. following process change, patients were brought directly to a bed in the -bed ped, triaged and registered, then seen by a physician. the fast-track unit was only utilized to accommodate patient surges. results: anticipating improved efficiencies, attending physician coverage was decreased by %. after instituting process changes, improvements were noted immediately. although daily patient volume increased by %, median time to be seen by a physician decreased by %. additionally, median los for discharged patients decreased by %, and median time until the decisionto-admit decreased by %. press-ganey satisfaction scores during this time increased by greater than mean score points, which was reported to be a statistically significant increase. conclusion: direct bedding, bedside registration, and patient pooling were simple to implement process changes. these changes resulted in more efficient ped throughput, as evidenced by decreased times to be seen by a physician, los for discharged patients, and time until decision-to-admit. additionally, patient satisfaction scores improved, despite decreased attending physician coverage and a % decrease in room utilization. ) . during period , the ou was managed by the internal medicine department and staffed by primary care physicians and physician assistants. during periods and , the ou was managed and staffed by em physicians. data collected included ou patient volume, length of stay (los) for discharged and admitted patients, admission rates, and -day readmission rates for discharged patients. cost data collected included direct, indirect, and total cost per patient encounter. data were compared using chi-square and anova analysis followed by multiple pairwise comparisons using the bonferroni method of p-value adjustment. results: see table. the ou patient volume and percent of ed volume was greater in period compared to periods and . length of stay, admission rates, -day readmission rates, and costs were greater in period compared to periods and . conclusion: em physicians provide more cost-effective care for patients in this large ou compared to non-em physicians, resulting in shorter los for admitted and discharged patients, greater rates of patients discharged, and less -day readmission rates for discharged patients. this is not affected by an increase in ou volume and shows a trend towards improvement. background: emergency department (ed) crowding continues to be a problem, and new intake models may represent part of the solution. however, little data exist on the sustainability and long-term effects of physician triage and screening on standard ed performance metrics, as most studies are short-term. objectives: we examined the hypothesis that a physician screening program (start) sustainably improves standard ed performance metrics including patient length of stay (los) and patients who left without completing assessment (lwca). we also investigated the number of patients treated and dispositioned by start without using a monitored bed and the median patient door-to-room time. methods: design and setting: this study is a retrospective before-and-after analysis of start in a level i tertiary care urban academic medical center with approximately , annual patient visits. all adult patients from december until november are included, though only a subset was seen in start. start began at our institution in december . observations: our outcome measures were length of stay for ed patients, lwca rates, patients treated and dispositioned by start without using a monitored bed, and door-to-room time. statistics: simple descriptive statistics were used. p-values for los were calculated with wilcoxon test and p-value for lwca was calculated with chi-square. results: table shows median length of stay for ed patients was reduced by minutes/patient (p-value < . ) when comparing the most recent year to the year before start. patients who lwca were reduced from . % to . % (p-value < . ) during the same time period. we also found that in the first half-year of start, % of patients screened in the ed were treated and dispositioned without using a monitored bed and by the end of year , this number had grown to %. median door-to-room time decreased from . minutes to . minutes over the same period of time. conclusion: a start system can provide sustained improvements in ed performance metrics, including a significant reduction in ed los, lwca rate, and doorto-room time. additionally, start can decrease the need for monitored ed beds and thus increase ed capacity. . labs were obtained in %, ct in %, us in %, and consultation in %. % of the cohort was admitted to the hospital. the most commonly utilized source of translation was a layman ( %). a professional translator was used in % and translation service (language line, marty) in %. the examiner was fluent in the patient's language in %. both the patient and examiner were able to maintain basic communication in %. there were patients in the professional/ fluent translation group and patients in the lay translation group. there was no difference in ed los between groups vs min; p = . . there was no difference in the frequency of lab tests, computerized tomography, ultrasound, consultations, or hospital admission. frequencies did not differ by sex or age. conclusion: translation method was not associated with a difference in overall ed los, ancillary test use, or specialist consultation in spanish-speaking patients presenting to the ed for abdominal pain. emergency department patients on warfarin -how often is the visit due to the medication? jim killeen, edward castillo, theodore chan, gary vilke ucsd medical center, san diego, ca background: warfarin has important therapeutic value for many patients, but has been associated with signi-ficant bleeding complications, hypersensitivity reactions, and drug-drug interactions, which can result in patients seeking care in the emergency department (ed). objectives: to determine how often ed patients on warfarin present for care as a result of the medication itself. methods: a multi-center prospective survey study in two academic eds over months. patients who presented to the ed taking warfarin were identified, and ed providers were prospectively queried at the time of disposition regarding whether the visit was the result of a complication or side effect associated with warfarin. data were also collected on patient demographics, chief complaint, triage acuity, vital signs, disposition, ed evaluation time, and length of stay (los). patients identified with a warfarin-related cause for their ed visit were compared with those who were not. statistical analysis was performed using descriptive statistics. results: during the study period, , patients were cared for by ed staff, of whom were identified as taking warfarin as part of their medication regimen. of these, providers identified . % ( patients) who presented with a warfarin-related complication as their primary reason for the ed visit. . % ( ) each hours of daily boarding is associated with a drop of . raw score points in both pg metrics. these seemingly small drops in raw scores translate into major changes in rankings on press ganey national percentile scales (a difference of as much as percentile points). our institution commonly has hundreds of hours of daily boarding. it is possible that patient-level measurements of boarding impact would show stronger correlation with individual satisfaction scores, as opposed to the daily aggregate measures we describe here. our research suggests that reducing the burden of boarding on eds will improve patient satisfaction. background: prolonged emergency department (ed) boarding is a key contributor to ed crowding. the effect of output interventions (moving boarders out of the ed into an intermediate area prior to admission or adding additional capacity to an observation unit) has not been well studied. objectives: we studied the effect of a combined observation-transition (ot) unit, consisting of observation beds and an interim holding area for boarding ed patients, on the length of stay (los) for admitted patients, as well as secondary outcomes such as los for discharged patients, and left without being seen rates. methods: we conducted a retrospective review ( months pre-, months post-design) of an ot unit at an urban teaching ed with , annual visits (study ed). we compared outcomes to a nearby communitybased ed with , annual visits in the same health system (control ed) where no capacity interventions were performed. the ot had beds, full monitoring capacity, and was staffed hours per day. the number of beds allocated to transition and observation patients fluctuated throughout the course of the intervention, based on patient demands. all analyses were conducted at the level of the ed-day. wilcoxon rank-sum and analysis of covariance tests were used for comparisons; continuous variables were summarized with medians. results: in unadjusted analyses, median daily los of admitted patients at the study ed was minutes lower in the months after the ot opened, . to . hours (p < . ). control site daily los for admitted patients increased minutes from . to . hours (p < . ). results were similar after adjusting for other covariates (day of week, ed volume, and triage level). los of discharged patients at study ed decreased by minutes, from . hours to . hours (p < . ), while the control ed saw no significant changes in discharged patient los ( . hours to . hours, p = . ). left without being seen rates did not decrease at either site. conclusion: opening an ot unit was associated with a -minute reduction in average daily ed los for admitted patients and discharged patients in the study ed. given the large expense of opening an ot, future studies should compare capacity-dependent (e.g., ot) vs. capacity-independent (e.g, organizational) interventions to reduce ed crowding. fran balamuth, katie hayes, cynthia mollen, monika goyal children's hospital of philadelphia, philadelphia, pa background: lower abdominal pain and genitourinary problems are common chief complaints in adolescent females presenting to emergency departments. pelvic inflammatory disease (pid) is a potentially severe complication of lower genital tract infections, which involves inflammation of the female upper genital tract secondary to ascending stis. pid has been associated with severe sequelae including infertility, ectopic pregnancy, and chronic pelvic pain. we describe the prevalence and microbial patterns of pid in a cohort of adolescent females presenting to an urban emergency department with abdominal or genitourinary complaints. objectives: to describe the prevalence and microbial patterns of pid in a cohort of adolescent patients presenting to an ed with lower abdominal or genitourinary complaints. methods: this is a secondary analysis of a prospective study of females ages - years presenting to a pediatric ed with lower abdominal or genitourinary complaints. diagnosis of pid was per cdc guidelines. patients underwent chlamydia trachomatis (ct) and neisseria gonorrhea (gc) testing via urine aptima combo assay and trichomonas vaginalis (tv) testing using the vaginal osom trichomonas rapid test. descriptive statistics were performed using stata . . results: the prevalence of pid in this cohort of patients was . % ( % ci . %, . %), . % ( % ci . %, . %) of whom had positive sexually transmitted infection (sti) testing: % ( % ci . %, . %) with ct, . % ( % ci . , . %) with gc, and . % ( % ci . %, . %) with tv. . % ( % ci . , . %) of patients diagnosed with pid received antibiotics consistent with cdc recommendations. patients with lower abdominal pain as their chief complaint were more likely to have pid than patients with genitourinary complaints (or . , % ci . , . ). conclusion: a substantial number of adolescent females presenting to the emergency department with lower abdominal pain were diagnosed with pid, with microbial patterns similar to those previously reported in largely adult, outpatient samples. furthermore, appropriate treatment for pid was observed in the majority of patients diagnosed with pid. impact background: in resource-poor settings, maternal health care facilities are often underutilized, contributing to high maternal mortality. the effect of ultrasound in these settings on patients, health care providers, and communities is poorly understood. objectives: the purpose of this study was to assess the effect of the introduction of maternal ultrasound in a population not previously exposed to this intervention. methods: an ngo-led program trained nurses at four remote clinics outside koutiala, mali, who performed , maternal ultrasound scans over three years. our researchers conducted an independent assessment of this program, which involved log book review, sonographer skill assessment, referral follow-up, semi-structured interviews of clinic staff and patients, and focus groups of community members in surrounding villages. analyses included the effect of ultrasound on clinic function, job satisfaction, community utilization of prenatal care and maternity services, alterations in clinical decision making, sonographer skill, and referral frequency. we used qrs nvivo to organize qualitative findings, code data, and identify emergent themes, and graphpad software (la jolla, ca) and microsoft excel to tabulate quantitative findings results: -findings that triggered changes in clinical practice were noted in . % of ultrasounds, with a . % referral rate to comprehensive maternity care facilities. -skill retention and job satisfaction for ultrasound providers was high. -the number of patients coming for antenatal care increased, after introduction of ultrasound, in an area where the birth rate has been decreasing. -over time, women traveled from farther distances to access ultrasound and participate in antenatal care. -very high acceptance among staff, patients and community members. -ultrasound was perceived as most useful for finding fetal position, sex, due date, and well-being. -improved confidence in diagnosis and treatment plan for all cohorts. -improved compliance with referral recommendations. -no evidence of gender selection motivation for ultrasound use. conclusion: use of maternal ultrasound in rural and resource-limited settings draws women to an initial antenatal care visit, increases referral, and improves job satisfaction among health care workers. methods: a retrospective database analysis was conducted using the electronic medical record from a single, large academic hospital. ed patients who received a billing diagnosis of ''nausea and vomiting of pregnancy'' or ''hyperemesis gravidarum'' between / / and / / were selected. a manual chart review was conducted with demographic and treatment variables collected. statistical significance was determined using multiple regression analysis for a primary outcome of return visit to the emergency department for nausea and vomiting of pregnancy. results: patients were identified. the mean age was . years (sd± . ), mean gravidity . (sd± . ), and mean gestational age . weeks (sd± . ). the average length of ed evaluation was min (sd± ). of the patients, ( . %) had a return ed visit for nausea and vomiting of pregnancy, ( %) were admitted to the hospital, and ( %) were admitted to the ed observation protocol. multiple regression analysis showed that the presence of medical co-morbidity (p = . ), patient gravditity (p = . ), gestational age (p = . ), and admission to the hospital (p = . ) had small but significant effects on the primary outcome (return visits to the emergency department). no other variables were found to be predictive of return visits to the ed including admission to the ed observation unit or factors classically thought to be associated with severe forms of nausea and vomiting in pregnancy including ketonuria, electrolyte abnormalities, or vital sign abnormalities. conclusion: nausea and vomiting in pregnancy has a high rate of return ed visits that can be predicted by young patient age, low patient gravidity, early gestational age, and the presence of other comorbidities. these patients may benefit from obstetric consultation and/or optimization of symptom management after discharge in order to prevent recurrent utilization of the ed. prevalence conclusion: there is a high prevalence of ht in adult sa victims. although our study design and data do not allow us to make any inferences regarding causation, this first report of ht ed prevalence suggests the opportunity to clarify this relationship and the potential opportunity to intervene. background: sexually transmitted infections (sti) are a significant public health problem. because of the risks associated with stis including pid, ectopic pregnancy, and infertility the cdc recommends aggressive treatment with antibiotics in any patient with a suspected sti. objectives: to determine the rates of positive gonorrhea and chlamydia (g/c) screening and rates of empiric antibiotic use among patients of an urban academic ed with > , visits in boston, ma. methods: a retrospective study of all patients who had g/c cultures in the ed over months. chi-square was used in data analysis. sensitivity and specificity were also calculated. results: a positive rate of / ( . %) was seen for gonorrhea and / ( . %) for chlamydia. females had positive rates of / ( . %) and / ( . %) respectively. males had higher rates of / ( . %) (p =< . ) and / ( . %) (p = . ). patients with g/c sent received an alternative diagnosis, the most common being uti ( ), ovarian pathology ( ), vaginal bleeding ( ), and vaginal candidiasis ( ); were excluded. this left without definitive diagnosis. of these, . % ( / ) of females were treated empirically with antibiotics for g/c, and a greater percentage of males ( %, / ) were treated empirically (p < . ). of those empirically treated, / ( . %) had negative cultures. meanwhile / ( . %) who ultimately had positive cultures were not treated with antibiotics during their ed stay. sensitivity of the provider to predict presence of disease based on decision to give empiric antibiotics was . (ci . - . ). specificity was . (ci . - . ). conclusion: most patients screened in our ed for g/c did not have positive cultures and . % of those treated empirically were found not to have g/c. while early treatment is important to prevent complications, there are risks associated with antibiotic use such as allergic reaction, c difficile infection, and development of antibiotic resistance. our results suggest that at our institution we may be over-treating for g/c. furthermore, despite high rates of treatment, % of patients who ultimately had positive cultures did not receive antibiotics during their ed stay. further research into predictive factors or development of a clinical decision rule may be useful to help determine which patients are best treated empirically with antibiotics for presumed g/c. background: air travel may be associated with unmeasured neurophysiological changes in an injured brain that may affect post-concussion recovery. no study has compared the effect of commercial airtravel on concussion injuries despite rather obvious decreased oxygen tension and increased dehydration effect on acute mtbi. objectives: to determine if air travel within - hours of concussion is associated with increased recovery time in professional football and hockey players. methods: prospective cohort study of all active-roster national football league and national hockey league players during the - seasons. internet website review of league sties for injury identification of concussive injury and when player returned to play solely for mtbi. team schedules and flight times were also confirmed to include only players who flew immediately following game (within - hr). multiple injuries were excluded as were players who had injury around all-star break for nhl and scheduled off week in nfl. results: during the - nfl and nhl seasons, ( . %) and ( . %) players experienced a concussion (percent of total players), in the respective leagues. of these, nfl players ( %) and nhl players ( %) flew within hours of the incident injury. the mean distance flown was shorter for nfl ( miles, sd vs. nhl , sd ) miles and all were in a pressurized cabin. the mean number of games missed for nfl and nhl players who traveled by air immediately after concussion was increased by % and % (respectively) than for those who did not travel by air nfl: . (sd . ) vs. . games (sd . ) and nhl: . games (sd . ) vs. . (sd . ); p < . . conclusion: this is an initial report of an increased rate of recovery in terms of more games missed, for professional athletes flying commercial airlines post-mtbi compared to those that do not subject their recently injured brains to pressurized airflight. the obvious changes of decreased oxygen tension with altitude equivalent of , feet, decreased humidity with increased dehydration, and duress of travel accompanying pressurized airline cabins all likely increase the concussion penumbra in acute mtbi. early air travel post concussion should be further evaluated and likely postponed - hr. until initial symptoms subside. background: previous studies have shown better in-hospital stroke time targets for those who arrive by ambulance compared to other modes of transport. however, regional studies report that less than half of stroke patients arrive by ambulance. objectives: our objectives were to describe the proportion of stroke patients who arrive by ambulance nationwide, and to examine regional differences and factors associated with the mode of transport to the emergency department (ed). methods: this is a cross-sectional study of all patients with a primary discharge diagnosis of stroke based on previously validated icd- codes abstracted from the national hospital ambulatory medical care survey for - . we excluded subjects < years of age and those with missing data. the study related survey variables included patient demographics, community characteristics, mode of transport to the hospital, and hospital characteristics. results: patients met inclusion criteria, representing , , patient records nationally. of these, . % arrived by ambulance. after adjustment for potential confounders, patients residing in the west and south had lower odds of arriving by ambulance for stroke when compared to northeast (southern region, or . , % ci . - . , western region, or . , % ci . - . , midwest region, or . , % ci . - . ). compared to the medicare population, privately insured and self insured had lower odds of arriving by ambulance (or for private insurance . , % ci . - . and or for self payers . , % ci . - . ). age, sex, race, urban or rural location of ed, or safety net status were not independently associated with ambulance use. conclusion: patients with stroke arrive by ambulance more frequently in the northeast than in other regions of the us. identifying reasons for this regional difference may be useful in improving ambulance utilization and overall stroke care nationwide. objectives: we sought to determine whether there was a difference in type of stroke presentation based upon race. we further sought to determine whether there is an increase in hemorrhagic strokes among asian patients with limited english proficiency. methods: we performed a retrospective chart review of all stroke patients age and older for year of patients that were diagnosed with cerebral vascular accident (cva) or intracranial hemorrhage (ich). we collected data on patient demographics, and past medical history. we then stratified patients according to race (white, black, latino, asian, and other). we classified strokes as ischemic, intracranial hemorrhage (ich), subarachnoid hemorrhage (sah), subdural hemorrhage (sdh), and other (e.g., bleeding into metatstatic lesions). we used only the index visit. we present the data percentages, medians and interquartile ranges (iqr). we tested the association of the outcome of intracranial hemorrhage against demographic and clinical variables using chi-square and kruskal-wallis tests. we performed a logistic regression model to determine factors related to presentation with an intracranial hemorrhage (ich background: the practice of obtaining laboratory studies and routine ct scan of the brain on every child with a seizure has been called into question in the patient who is alert, interactive, and back to functional baseline. there is still no standard practice for the management of non-febrile seizure patients in the pediatric emergency department (ped). objectives: we sought to determine the proportion of patients in whom clinically significant laboratory studies and ct scans of the brain were obtained in children who presented to the ped with a first or recurrent non-febrile seizure. we hypothesize that the majority of these children do not have clinically significant laboratory or imaging studies. if clinically significant values were found, the history given would warrant further laboratory and imaging assessment despite seizure alone. methods: we performed a retrospective chart review of patients with first-time or recurrent non-febrile seizures at an urban, academic ped between july to june . exclusion criteria included children who presented to the ped with a fever and age less than months. we looked at specific values that included a complete blood count, basic metabolic panel, and liver function tests, and if the child was on antiepileptics along with a level for a known seizure disorder, and ct scan. abnormal laboratory and ct scan findings were classified as clinically significant or not. results: the median age of our study population is years with male to female ratio of . . % of patients had a generalized tonic-clonic seizure. laboratory studies and ct scans were obtained in % and % of patients, respectively. five patients had clinically significant abnormal labs; however, one had esrd, one developed urosepsis, one had eclampsia, and two others had hyponatremia, which was secondary to diluted formula and trileptal toxicity. three children had an abnormal head ct: two had a vp shunt and one had a chromosomal abnormality with developmental delay. conclusion: the majority of the children analyzed did not have clinically significant laboratory or imaging studies in the setting of a first or recurrent non-febrile seizure. of those with clinically significant results, the patient's history suggested a possible etiology for their seizure presentation and further workup was indicated. background: in patients with a negative ct scan for suspected subarachnoid hemorrhage (sah), ct angiography (cta) has emerged as a controversial alternative diagnostic strategy in place of lumbar puncture (lp). objectives: to determine the diagnostic accuracy for sah and aneurysm of lp alone, cta alone, and lp followed by cta if the lp is positive. methods: we developed a decision and bayesian analysis to evaluate ) lp, ) cta, and ) lp followed by cta if the lp is positive. data were obtained from the literature. the model considers probability of sah ( %), aneurysm ( % if sah), sensitivity and specificity of ct ( . % and % overall), of lp (based on rbc and xanthochromia), and of cta, traumatic tap and its influence on sah detection. analyses considered all patients and those presenting at less than hours or greater than hours from symptom onset by varying the sensitivity and specificity of ct and cta. results: using the reported ranges of ct scan sensitivity and the specificity, the revised likelihood of sah following a negative ct ranged from . - . %, and the likelihood of aneurysm ranged from . - . %. following any of the diagnostic strategies, the likelihood of missing sah ranged from - . %. either lp strategy diagnosed . % of sahs versus - % with cta alone because cta only detected sah in the presence of an aneurysm. false positive sah with lp ranged from . - . % due to traumatic taps and with cta ranged from . - . % due to aneurysms without sah. the positive predictive value for sah ranged from . - % with lp and from . - % with cta. for patients presenting within hours of symptom onset, the revised likelihood of sah following a negative ct became . %, and the likelihood of aneurysm ranged from . - . %. following any of the diagnostic strategies, the likelihood of missing sah ranged from . - . %. either lp strategy diagnosed . % of sah versus - % with cta alone. false positive sah with lp was . % and with cta ranged from . - . %. the positive predictive value for sah was . % with lp and from . - % with cta. cta following a positive lp diagnosed . - % of aneurysms. conclusion: lp strategies are more sensitive for detecting sah but less specific than cta because of traumatic taps, leading to lower predictive value positives for sah with lp than with cta. either diagnostic strategy results in a low likelihood of missing sah, particularly within hours of symptom onset. background: recent studies support perfusion imaging as a prognostic tool in ischemic stroke, but little data exist regarding its utility in transient ischemic attack (tia). ct perfusion (ctp), which is more available and less costly to perform than mri, has not been well studied. objectives: to characterize ctp findings in tia patients, and identify imaging predictors of outcome. methods: this retrospective cohort study evaluated tia patients at a single ed over months, who had ctp at initial evaluation. a neurologist blinded to ctp findings collected demographic and clinical data. ctp images were analyzed by a neuroradiologist blinded to clinical information. ctp maps were described as qualitatively normal, increased, or decreased in mean transit time (mtt), cerebral blood volume (cbv), and cerebral blood flow (cbf). quantitative analysis involved measurements of average mtt (seconds), cbv (cc/ g) and cbf (cc/[ g x min]) in standardized regions of interest within each vascular distribution. these were compared with values in the other hemisphere for relative measures of mtt difference, cbv ratio, and cbffratio. mtt difference of ‡ seconds, rcbv as £ . , and rcbf as £ . were defined as abnormal based on prior studies. clinical outcomes including stroke, tia, or hospitalization during follow-up were determined up to one year following the index event. dichotomous variables were compared using fisher's exact test. logistic regression was used to evaluate the association of ctp abnormalities with outcome in tia patients. results: of patients with validated tia, had ctp done. mean age was ± years, % were women, and % were caucasian. mean abcd score was . ± . , and % had an abcd ‡ . prolonged mtt was the most common abnormality ( , %), and ( . %) had decreased cbv in the same distribution. on quantitative analysis, ( %) had a significant abnormality. four patients ( . %) had prolonged mtt and decreased cbv in the same territory, while ( %) had mismatched abnormalities. when tested in a multivariate model, no significant associations between mismatch abnormalities on ctp and new stroke, tia, or hospitalizations were observed. conclusion: ctp abnormalities are common in tia patients. although no association between these abnormalities and clinical outcomes was observed in this small study, this needs to be studied further. objectives: we hypothesized that pre-thrombolytic anti-hypertensive treatment (aht) may prolong door to treatment time (dtt). methods: secondary data analysis of consecutive tpatreated patients at randomly selected michigan community hospitals in the instinct trial. dtt among stroke patients who received pre-thrombolytic aht were compared to those who did not receive pre-thrombolytic aht. we then calculated a propensity score for the probability of receiving pre-thrombolytic aht using a logistic regression model with covariates including demographics, stroke risk factors, antiplatelet or beta blocker as home medication, stroke severity (nihss), onset to door time, admission glucose, pretreatment systolic and diastolic blood pressure, ems usage, and location at time of stroke. a paired t-test was then performed to compare the dtt between the propensity-matched groups. a separate generalized estimating equations (gee) approach was also used to estimate the differences between patients receiving pre-thrombolytic aht and those who did not while accounting for within-hospital clustering. results: a total of patients were included in instinct; however, onset, arrival, or treatment times were not able to be determined in , leaving patients for this analysis. the unmatched cohort consisted of stroke patients who received pre-thrombolytic aht and stroke patients who did not receive aht from - (table) . in the unmatched cohort, patients who received pre-thrombolytic aht had a longer dtt (mean increase minutes; % confidence interval (ci) - minutes) than patients who did not receive pre-thrombolytic aht. after propensity matching (table) , patients who received pre-thrombolytic aht had a longer dtt (mean increase . minutes, % ci . - . ) than patients who did not receive pre-thrombolytic aht. this effect persisted and its magnitude was not altered by accounting for clustering within hospitals. conclusion: pre-thrombolytic aht is associated with modest delays in dtt. this represents a feasible target for physician educational interventions and quality improvement initiatives. further research evaluating optimum hypertension management pre-thrombolytic treatment is warranted. post-pds, % had only pre-pds, and % had both. the most common pds included failure to treat post-treatment hypertension ( , %), antiplatelet agent within hours of treatment ( , %), pre-treatment blood pressure over / ( , %), anticoagulant agent within hours of treatment ( , %), and treatment outside the time window ( , %). symptomatic intracranial hemorrhage (sich) was observed in . % of patients with pds and . % of patients without any pd. in-hospital case fatality was % with and % without a pd. in the fully adjusted model, older age was significantly associated with pre-pds (table) . when post-pds were evaluated with adjustment for pre-pds, age was not associated with pds; however, pre-pds were associated with post-pds. conclusion: older age was associated with increased odds of pre-pds in michigan community hospitals. pre-pds were associated with post-pds. sich and in-hospital case fatality were not associated with pds; however, the low number of such events limited our ability to detect a difference. ct background: mri has become the gold standard for the detection of cerebral ischemia and is a component of multiple imaging enhanced clinical risk prediction rules for the short-term risk of stroke in patients with transient ischemic attack (tia). however, it is not always available in the emergency department (ed) and is often contraindicated. leukoaraiosis (la) is a radiographic term for white matter ischemic changes, and has recently been shown to be independently predictive of disabling stroke. although it is easily detected by both ct and mri, their comparative ability is unknown. objectives: we sought to determine whether leukoaraiosis, when combined with evidence of acute or old infarction as detected by ct, achieved similar sensitivity to mri in patients presenting to the ed with tia. methods: we conducted a retrospective review of consecutive patients diagnosed with tia between june and july that underwent both ct and mri as part of routine care within calendar day of presentation to a single, academic ed. ct and mr images were reviewed by a single emergency physician who was blinded to the mr images at the time of ct interpretation. la was graded using the van sweiten scale (vss), a validated grading scale applicable to both ct and mri. anterior and posterior regions were graded independently from to . results: patients were diagnosed with tia during the study period. of these, had both ct and mri background: helping others is often a rewarding experience but can also come with a ''cost of caring'' also known as compassion fatigue (cf). cf can be defined as the emotional and physical toll suffered by those helping others in distress. it is affected by three major components: compassion satisfaction (cs), burnout (bo), and traumatic experiences (te). previous literature has recognized an increase in bo related to work hours and stress among resident physicians. objectives: to assess the state of cf among residents with regard to differences in specialty training, hours worked, number of overnights, and demands of child care. we aim to measure associations with the three components of cf (cs, bo, and te). methods: we used the previously validated survey, proqol . the survey was sent to the residents after approval from the irb and the program directors. results: a total of responses were received ( % of the surveyed). five were excluded due to incomplete questionnaires. we found that residents who worked more hours per week had significantly higher bo levels (median vs , p = . ) and higher te ( vs , p = . ) than those working less hours. there was no difference in cs ( vs , p = . ). eighteen percent of the residents worked a majority of the night shifts. these residents had higher levels of bo background: emergency department (ed) billing includes both facility and professional fees. an algorithm derived from the medical provider's chart generates the latter fee. many private hospitals encourage appropriate documentation by financially incentivizing providers. academic hospitals sometimes lag in this initiative, possibly resulting in less than optimal charting. past attempts to teach proper documentation using our electronic medical record (emr) were difficult in our urban, academic ed of providers (approximately attending physicians, residents, and physician assistants). objectives: we created a tutorial to teach documentation of ed charts, modified the emr to encourage appropriate documentation, and provided feedback from the coding department. this was combined with an incentive structure shared equally amongst all attendings based on increased collections. we hypothesized this instructional intervention would lead to more appropriate billing, improve chart content, decrease medical liability, and increase educational value of charting process. methods: documentation recommendations, divided into two-month phases of - proposals, were administered to all ed providers by e-mails, lectures, and reminders during sign-out rounds. charts were reviewed by coders who provided individual feedback if specific phase recommendations were not followed. our endpoints included change in total rvu, rvus/ patient, e/m level distribution, and subjective quality of chart improvement. we did not examine effects on procedure codes or facility fees. results: our base average rvu/patient in our ed from / / - / / was . with monthly variability of approximately %. implementation of phase one increased average rvu/patient within two weeks to . ( . % increase from baseline, p < . ). the second aggregate phase implemented weeks later increased average rvu/patient to . ( . % increase from baseline, p < . ). conclusion: using our teaching methods, chart reviews focused on - recommendations at a time, and emr adjustments, we were able to better reflect the complexity of care that we deliver every day in our medical charts. future phases will focus on appropriate documentation for procedures, critical care, fast track, and pediatric patients, as well as examining correlations between increase in rvus with charge capture. identifying mentoring ''best practices'' for medical school faculty julie l. welch, teresita bellido, cherri d. hobgood background: mentoring has been identified as an essential component for career success and satisfaction in academic medicine. many institutions and departments struggle with providing both basic and transformative mentoring for their faculty. objectives: we sought to identify and understand the essential practices of successful mentoring programs. methods: multidisciplinary institutional stakeholders in the school of medicine including tenured professors, deans, and faculty acknowledged as successful mentors were identified and participated in focused interviews between mar-nov . the major area of inquiry involved their experiences with mentoring relationships, practices, and structure within the school, department, or division. focused interview data were transcribed and grounded theory analysis was performed. additional data collected by a institutional mentoring taskforce were examined. key elements and themes were identified and organized for final review. results: results identified the mentoring practices for three categories: ) general themes for all faculty, ) specific practices for faculty groups: basic science researchers, clinician researchers, clinician educators, and ) national examples. additional mentoring strategies that failed were identified. the general themes were quite universal among faculty groups. these included: clarify the best type of mentoring for the mentee, allow the mentee to choose the mentor, establish a panel of mentors with complementary skills, schedule regular meetings, establish a clear mentoring plan with expectations and goals, offer training and resources for both the mentor and mentee at institutional and departmental levels, ensure ongoing mentoring evaluation, create a mechanism to identify and reward mentoring. national practice examples offered critical recommendations to address multi-generational attitudes and faculty diversity in terms of gender, race, and culture. conclusion: mentoring strategies can be identified to serve a diverse faculty in academic medicine. interventions to improve mentoring practices should be targeted at the level of the institution, department, and individual faculty members. it is imperative to adopt results such as these to design effective mentoring programs to enhance the success of emergency medicine faculty seeking robust academic careers. background: women comprise half of the talent pool from which the specialty of emergency medicine draws future leaders, researchers, and educators and yet only % of full professors in us emergency medicine are female. both research and interventions are aimed at reducing the gender gap, however, it will take decades for the benefits to be realized which creates a methodological challenge in assessing system's change. current techniques to measure disparities are insensitive to systems change as they are limited to percentages and trends over time. objectives: to determine if the use of relative rate index (rri) better predicts which stage in the system women are not advancing in the academic pipeline than traditional metrics. methods: rri is a method of analysis that assesses the percent of sub-populations in each stage relative to their representation in the stage directly prior. thus, there is a better notion of the advancement given the availability to advance. rri also standardizes data for ease of interpretation. this study was conducted on the total population of academic professors in all departments at yale school of medicine during the academic year of - . data were obtained from the yale university provost's office. results: n = . there were a total of full, associate, and assistant professors. males comprised %, %, and % respectively. rri for the department of emergency medicine (dem) is . , . , and . , for full, associate, and assistant professors, respectively while the percentages were %, %, and % respectively. conclusion: relying solely on percentages masks improvements to the system. women are most represented at the associate professor level in dem, highlighting the importance of systems change evidence. specifically, twice as many women are promoted to associate professor rank given the number who exists as assistant professors. within years, the dem should have an equal system as the numbers of associate professors have dramatically increased and will be eligible to promote to full professor. additionally, dem has a better record of retaining and promoting women than other yale departments of medicine at both associate and full professor ranks. objectives: we examine the payer mixes of community non-rehabilitation eds in metropolitan areas by region to identify the proportion of academic and nonacademic eds that could be considered safety net eds. we hypothesize that the proportion of safety net academic eds is greater than that for non-academic eds and is increasing over time. methods: this is an ecological study examining us ed visits from through . data were obtained from the nationwide emergency department sample (neds). we grouped each ed visit according to the unique hospital-based ed identifier, thus creating a payer mix for each ed. we define a ''safety net ed'' as any ed where the payer mix satisfied any one of the following three conditions: ) > % of all ed visits are medicaid patients; ) > % of all ed visits are self-pay patients; or ) > % of all ed visits are either medicaid or self-pay patients. neds tags each ed with a hospital-based variable to delineate metropolitan/non-metropolitan locations and academic affiliation. we chose to examine a subpopulation of eds tagged as either academic metropolitan or non-academic metropolitan, because the teaching status of non-metropolitan hospitals was not provided. we then measured the proportion of eds that met safety net criteria by academic status and region. results: we examined , , , , and , weighted metro eds in years - , respectively. table presents safety net proportions. the proportions of academic safety net eds increased across the study period. widespread regional variability in safety net proportions existed across all years. the proportions of safety net eds were highest in the south and lowest in the northeast and midwest. table describes these findings for . conclusion: these data suggest that the proportion of safety-net academic eds may be greater than that of non-academic eds, is increasing over time, and is objectives: to examine the effect of ma health reform implementation on ed and hospital utilization before and after health reform, using an approach that relies on differential changes in insurance rates across different areas of the state in order to make causal inferences as to the effect of health reform on ed visits and hospitalizations. our hypothesis was that health care reform (i.e. reducing rates of uninsurance) would result in increased rates of ed use and hospitalizations. methods: we used a novel difference-in-differences approach, with geographic variation (at the zip code level) in the percentage uninsured as our method of identifying changes resulting from health reform, to determine the specific effect of massachusetts' health care reform on ed utilization and hospitalizations. using administrative data available from the massachusetts division of health care finance and policy acute hospital case mix databases, we compared a one-year period before health reform with an identical period after reform. we fit linear regression models at the area-quarter level to estimate the effect of health reform and the changing uninsurance rate (defined as self-pay only) on ed visits and hospitalizations. results: there were , , ed visits and , hospitalizations pre-reform and , , ed visits and , hospitalizations post-reform. the rate of uninsurance decreased from . % to . % in the ed group and from . % to . % in the hospitalization group. a reduction in the rate of the uninsured was associated with a small but statistically significant increase in ed utilization (p = . ) and no change in hospitalizations (p = . ). conclusion: we find that increasing levels of insurance coverage in massachusetts were associated with small but statistically significant increases in ed visits, but no differences in rates of hospitalizations. these results should aid in planning for anticipated changes that might result from the implementation of health reform nationally. with high levels of co-morbidity when untreated in adolescents. despite broad cdc screening recommendations, many youth do not receive testing when indicated. the pediatric emergency department (ped) is a venue with a high volume of patients potentially in need of sti testing, but assessing risk in the ped is difficult given constraints on time and privacy. we hypothesized that patients visiting a ped would find an audio-enhanced computer-assisted self-interview (acasi) program to establish sti risk easy to use, and would report a preference for the acasi over other methods of disclosing this information. objectives: to assess acceptability, ease of use, and comfort level of an acasi designed to assess adolescents' risk for stis in the ped. methods: we developed a branch-logic questionnaire and acasi system to determine whether patients aged - visiting the ped need sti testing, regardless of chief complaint. we obtained consent from participants and guardians. patients completed the acasi in private on a laptop. they read a one-page computer introduction describing study details and completed the acasi. patients rated use of the acasi upon completion using five-point likert scales. results: eligible patients visited the ped during the study period. we approached ( %) and enrolled and analyzed data for / ( %). the median time to read the introduction and complete the acasi was . minutes (interquartile range . - . minutes). . % of patients rated the acasi ''very easy'' or ''easy'' to use, . % rated the wording as ''very easy'' or ''easy'' to understand, % rated the acasi ''very short'' or ''short'', . % rated the audio as ''very helpful'' or ''helpful,'' . % were ''very comfortable'' or ''comfortable'' with the system confidentiality, and . % said they would prefer a computer interface over in-person interviews or written surveys for collection of this type of information. conclusion: patients rated the computer interface of the acasi as easy and comfortable to use. a median of . minutes was needed to obtain meaningful clinical information. the acasi is a promising approach to enhance the collection of sensitive information in the ped. the participants were randomized to one of three conditions, bi delivered by a computer (cbi), bi delivered by a therapist assisted by a computer (tbi), or control, and completed , , and month follow-up. in addition to content on alcohol misuse and peer violence, adolescents reporting dating violence received a tailored module on dating violence. the main outcome for this analysis was frequency of moderate and severe dating victimization and aggression at the baseline assessment and , , and months post ed visit. results: among eligible adolescents, % (n = ) reported dating violence and were included in these analyses. compared to controls, after controlling for baseline dating victimization, participants in the cbi showed reductions in moderate dating victimization at months (or . ; ci . - . ; p < . , effect size . ) and months (or . ; ci . - . ; p < . , effect size . ); models examining interaction effects were significant for the cbi on moderate dating victimization at and months. significant interaction effects were found for the tbi on moderate dating victimization at and months and severe dating victimization at months. the computer-based intervention shows promise for delivering content that decreases moderate dating victimization over months. the therapist bi is promising for decreasing moderate dating victimization over months and severe dating victimization over months. ed-based bis delivered on a computer addressing multiple risk behaviors could have important public health effects. figure . the -only ordinance was associated with a significant reduction of ar visits. this ordinance was also associated with reduction in underage ar visits, ui student visits, and public intoxication bookings. these data suggest that other cities should consider similar ordinances to prevent unwanted consequences of alcohol. background: prehospital providers perform tracheal intubation in the prehospital environment, and failed attempts are of concern due to the danger of hypoxia and hypotension. some question the appropriateness of intubation in this setting due to the morbidity risk associated with intubation in the field. thus it is important to gain an understanding of the factors that predict the success of prehospital intubation attempts to inform this discussion. objectives: to determine the factors that affect success rates on first attempt of paramedic intubations in a rapid sequence intubation (rsi) capable critical care transport service. methods: we conducted a multivariate logistic analysis on a prospectively collected database of airway management from an air and land critical care transport service that provides scene responses and interfacility transport in the province of ontario. background: motor vehicle collisions (mvcs) are one of the most common types of trauma for which people seek ed care. the vast majority of these patients are discharged home after evaluation. acute psychological distress after trauma causes great suffering and is a known predictor of posttraumatic stress disorder (ptsd) development. however, the incidence and predictors of psychological distress among patients discharged to home from the ed after mvcs have not been reported. objectives: to examine the incidence and predictors of acute psychological distress among individuals seen in the ed after mvcs and discharged to home. methods: we analyzed data from a prospective observational study of adults - years of age presenting to one of eight ed study sites after mvc between / and / . english-speaking patients who were alert and oriented, stable, and without injuries requiring hospital admission were enrolled. patient interview included assessment of patient sociodemographic and psychological characteristics and mvc characteristics. level of psychological distress in the ed was assessed using the -item peritraumatic distress inventory (pdi). pdi scores > are associated with increased risk of ptsd and were used to define substantial psychological distress. descriptive statistics and logistic regression were performed using stata ic . (statacorp lp, college station, texas). results: mvc patients were screened, were eligible, and were enrolled. / ( %) participants had substantial psychological distress. after adjusting for crash severity (severity of vehicle damage, vehicle speed), substantial patient distress was predicted by sociodemographic factors, pre-mvc depressive symptoms, and arriving to the ed on a backboard (table) . conclusion: substantial psychological distress is common among individuals discharged from the ed after mvcs and is predicted by patient characteristics separate from mvc severity. a better under standing of the frequency and predictors of substantial psychological distress is an important first step in identifying these patients and developing effective interventions to reduce severe distress in the aftermath of trauma. such interventions have the potential to reduce both immediate patient suffering and the development of persistent psychological sequelae. figure) the predictive characteristics of pets, pesi, and spesi for -day mortality in emperor, including auc, negative predictive value, sensitivity, and specificity were calculated. results: the of patients ( . %; % ci . %- . %) classified as pets low had -day mortality of . % ( % ci . - . %), versus . % ( % ci . %- . %) in the pets high group, statistically similar to pesi and spesi. pets is significantly more specific for mortality than the spesi ( . % v . %; p < . ), classifying far more patients as low-risk while maintaining a sensitivity of % ( % ci . %- . %), not significantly different from spesi or pesi (p > . ). conclusion: with four variables, pets in this derivation cohort is as sensitive for -day mortality as the more complicated pesi and spesi, with significantly greater specificity than the spesi for mortality, placing % more patients in the low-risk group. external validation is necessary. nicole seleno, jody vogel, michael liao, emily hopkins, richard byyny, ernest moore, craig gravitz, jason haukoos denver health medical center, denver, co background: the sequential organ failure assessment (sofa) score, base excess, and lactate have been shown to be associated with mortality in critically ill trauma patients. the denver emergency department (ed) trauma organ failure (tof) score was recently derived and internally validated to predict multiple organ failure in trauma patients. the relationship between the denver tof score and mortality has not been assessed or compared to other conventional measures of mortality in trauma. objectives: to compare the prognostic accuracies of the denver ed tof score, ed sofa score, and ed base excess and lactate for mortality in a large heterogeneous trauma population. methods: a secondary analysis of data from the denver health trauma registry, a prospectively collected database. consecutive adult trauma patients from through were included in the study. data collected included demographics, injury characteristics, prehospital care characteristics, response to injury characteristics, ed diagnostic evaluation and interventions, and in-hospital mortality. the values of the four clinically relevant measures (denver ed tof score, ed sofa score, ed base excess, and ed lactate) were determined within four hours of patient arrival, and prognostic accuracies for in-hospital mortality for the four measures were evaluated with receiver operating characteristic (roc) curves. multiple imputation was used for missing values. results: of the , patients, the median age was (iqr - ) years, median injury severity score was (iqr - ), and % had blunt mechanisms. thirty-eight percent ( , patients) were admitted to the icu with a median icu length of stay of . (iqr - ) days, and % ( patients) died. in the non-survivors, the median values for the four measures were ed sofa . (iqr . - . ); denver ed tof . (iqr . - . ); ed base excess . (iqr . - . ) meq/l; and ed lactate . (iqr . - . ) mmol/l. the areas under the roc curves for these measures are demonstrated in the figure. conclusion: the denver ed tof score more accurately predicts in-hospital mortality in trauma patients as compared to the ed sofa score, ed base excess, or ed lactate. the denver ed tof score may help identify patients early who are at risk for mortality, allowing for targeted resuscitation and secondary triage to improve outcomes in these critically ill patients. the background: both animal and human studies suggest that early initiation of therapeutic hypothermia (th) and rapid cooling improve outcomes after cardiac arrest. objectives: the objective was to determine if administration of cold iv fluids in a prehospital setting decreased time-to-target-temperature (tt) with secondary analysis of effects on mortality and neurological outcome. methods: patients resuscitated after out-of-hospital cardiac arrest (oohca) who received an in-hospital post cardiac arrest bundle including th were prospectively enrolled into a quality assurance database from november to november . on april , a protocol for intra-arrest prehospital cooling with °c normal saline on patients experiencing oohca was initiated. we retrospectively compared tt for those receiving prehospital cold fluids and those not receiving cold fluids. tt was defined as °c measured via foley thermistor. secondary outcomes included mortality, good neurological outcome defined as cerebral performance category (cpc) score of or at discharge, and effects of pre-rosc cooling. results: there were patients who were included in this analysis with patients receiving prehospital cold iv fluids and who did not. initially, % of patients were in vf/vt and % asystole/pea. patients receiving prehospital cooling did not have a significant improvement in tt ( minutes vs minutes, p = . ). survival to discharge and good neurologic outcome were not associated with prehospital cooling ( % vs %, p = . ) and cpc of or in % vs %, (p = . ). initiating cold fluids prior to rosc showed both a nonsignificant decrease in survival ( % vs %, p = . ) and increase in poor neurologic outcomes ( % vs %, p = . ). % of patients received £ l of cooled ivf prior to hospital arrival. patients receiving prehospital cold ivf had a longer time from arrest to hospital arrival ( vs min, p =< . ) in addition to a prolonged rosc to hospital time ( vs min, p = . ). conclusion: at our urban hospital, patients achieving rosc following oohca did not demonstrate faster tt or outcome improvement with prehospital cooling compared to cooling initiated immediately upon ed arrival. further research is needed to assess the utility of prehospital cooling. assessment background: an estimated % of emergency department (ed) patients years of age and older have delirium, which is associated with short-and long-term risk of morbidity and mortality. early recognition could result in improved outcomes, but the reliability of delirium recognition in the continuum of emergency care is unknown. objectives: we tested whether delirium can be reliably detected during emergency care of elderly patients by measuring the agreement between prehospital providers, ed physicians, and trained research assistants using the confusion assessment method for the icu (cam-icu) to identify the presence of delirium. our hypothesis was that both ed physicians and prehospital providers would have poor ability to detect elements of delirium in an unstructured setting. methods: prehospital providers and ed physicians completed identical questionnaires regarding their clinical encounter with a convenience sample of elderly (age > years) patients who presented via ambulance to two urban, teaching eds over a three-month period. respondents noted the presence or absence of ( ) an acute change in mental status, ( ) inattention, ( ) disorganized thinking, and ( ) altered level of consciousness (using the richmond agitation sedation scale). these four components comprise the operational definition of delirium. a research assistant trained in the cam-icu rated each component for the same patients using a standard procedure. we calculated inter-rater reliability (kappa) between prehospital providers, ed physicians, and research assistants for each component. objectives: this study aimed to assess the association between age and ems use while controlling for potential confounders. we hypothesized that this association use would persist after controlling for confounders. methods: a cross-sectional survey study was conducted at an academic medical center's ed. an interview-based survey was administered and included questions regarding demographic and clinical characteristics, mode of ed arrival, health care use, and the perceived illness severity. age was modeled as an ordinal variable (< , - , and ‡ years). bivariate analyses were used to identify potential confounders and effect measure modifiers and a multivariable logistic regression model was constructed. odds ratios were calculated as measures of effect. results: a total of subjects were enrolled and had usable data for all covariates, ( %) of whom arrived via ems. the median age of the sample was years and % were female. there was a statistically significant linear trend in the proportion of subjects who arrived via ems by age (p < . ). compared to adults aged less than years, the unadjusted odds ratio associating age and ems use was . ( % ci: background: we previously derived a clinical decision rule (cdr) for chest radiography (cxr) in patients with chest pain and possible acute coronary syndrome (acs) consisting of the absence of three predictors: history of congestive heart failure, history of smoking, and abnormalities on lung auscultation. objectives: to prospectively validate and refine a cdr for cxr in an independent patient population. methods: we prospectively enrolled patients over years of age with a primary complaint of chest pain and possible acs from september to january at a tertiary care ed with , annual patient visits. physicians completed standardized data collection forms before ordering chest radiographs and were thus blinded to cxr findings at the time of data collection. two investigators, blinded to the predictor variables, independently classified cxrs as ''normal,'' ''abnormal not requiring intervention,'' and ''abnormal requiring intervention'' (e.g, heart failure, infiltrates) based on review of the radiology report and the medical record. analyses included descriptive statistics, inter-rater reliability assessment (kappa), and recursive partitioning. results: of visits for possible acs, mean age (sd) was . ( . ) and % were female. twenty-four percent had a history of acute myocardial infarction, % congestive heart failure, and % atrial fibrillation. seventy-one ( . %, % ci . - . ) patients had a radiographic abnormality requiring intervention. ing the likelihood of coronary artery disease (cad) could reduce the need for stress testing or coronary imaging. acyl-coa:cholesterol acyltransferase- (acat ) activity has been shown in monkey and murine models to correlate with atherosclerosis. objectives: to determine if a novel cardiac biomarker consisting of plasma cholesteryl ester levels (ce) typically derived from the activity of acat is predictive of cad in a clinical model. methods: a single center prospective observational cohort design enrolled a convenience sample of subjects from a tertiary care center with symptoms of acute coronary syndrome undergoing coronary ct angiography or invasive angiography. plasma samples were analyzed for ce composition with mass spectrometry. the primary endpoint was any cad determined at angiography. multivariable logistic regression analyses were used to estimate the relationship between the sum of the plasma concentrations from cholesteryl palmitoleate ( : ) and cholesteryl oleate ( : ) (defined as acat -ce) and the presence of cad. the added value of acat -ce to the model was analyzed comparing the c-statistics and integrated discrimination improvement (idi). results: the study cohort was comprised of participants enrolled over months with a mean age (± . ) years, % with cad at angiography. the median plasma concentration of acat -ce was lm ( , ) in patients with cad and lm ( , ) in patients without cad (p = . ) (figure) . when considered with age, sex, and the number of conventional cad risk factors, acat -ce were associated with a . % increased odds of having cad per lm increase in concentration. the addition of acat -ce significantly improved the c-statistic ( . vs . , p = . ) and idi ( . , p < . ) compared to the reduced model. in the subgroup of low-risk observation unit patients, the ce model had superior discrimination compared to the diamond forrester classification (idi . , p < . ). conclusion: plasma levels of acat -ce, considered in a clinical model, have strong potential to predict a patient's likelihood of having cad. in turn, this could reduce the need for cardiac imaging after the exclusion of mi. further study of acat -ce as biomarkers in patients with suspected acs is needed. background: outpatient studies have demonstrated a correlation between carotid intima-media thickness (cimt) on ultrasound and coronary artery disease (cad). there are no known published studies that investigate the role of cimt in the ed using cardiac ct or percutaneous cardiac intervention (pci) as a gold standard. objectives: we hypothesized that cimt can predict cardiovascular events and serve as a noninvasive tool in the ed. methods: this was a prospective study of adult patients who presented to the ed and required evaluation for chest pain. the study location was an urban ed with a census of , annual visits and -hour cardiac catheterization. patients who did not have ct or pci or had carotid surgery were excluded from the study. ultrasound cimt measurements of right and left common carotid arteries were taken with a mhz linear transducer (zonare, mountain view, ca). anterior, medial, and posterior views of the near and far wall were obtained ( cimt scores total). images were analyzed by carotid analyzer (mailing imaging application llc, coralville, iowa). patients were classified into two groups based on the results from ct or pci. a subject was classified as having significant cad if there was over % occlusion or multi-vessel disease. results: ninety of patients were included in the study; . % were males. mean age was . ± years. there were ( . %) subjects with significant cad and ( . %) with non-significant cad. the mean of all cimt measurements was significantly higher in the cad group than in the non-cad group ( . ± . vs. . ± . ; p < . ). a logistic regression analysis was carried out with significant cad as the event of interest and the following explanatory variables in the model: objectives: to determine the diagnostic yield of routine testing in-hospital or following ed discharge among patients presenting to an ed following syncope. methods: a prospective, observational, cohort study of consecutive ed patients ‡ years old presenting with syncope was conducted. the four most commonly utilized tests (echocardiography, telemetry, ambulatory electrocardiography monitoring, and cardiac markers) were studied. interobserver agreement as to whether tests results determined the etiology of the syncope was measured using kappa (k) values. results: of patients with syncope, ( %) had echocardiography with ( %) demonstrating a likely etiology of the syncopal event such as critical valvular disease or significantly depressed left ventricular function (k = . ). on hospitalization, ( %) patients were placed on telemetry, ( %) of these had worrisome dysrhythmias (k = . ). ( %) patients had troponin levels drawn of whom ( %) had positive results (k = ); ( %) patients were discharged with monitoring with significant findings in only ( . %) patients (k = . ). overall, ( %, % ci - %) studies were diagnostic. conclusion: although routine testing is prevalent in ed patients with syncope, the diagnostic yield is relatively low. nevertheless, some testing, particularly echocardiography, may yield critical findings in some cases. current efforts to reduce the cost of medical care by eliminating non-diagnostic medical testing and increasing emphasis on practicing evidence-based medicine argue for more discriminate testing when evaluating syncope. (originally submitted as a ''late-breaker.'') unusual fatigue was reported by . % (severe . %) and insomnia by . % (severe . %). these findings have led to risk management recommendations to consider these symptoms as predictive of acute coronary syndromes (acs) among women visiting the ed. objectives: to document the prevalence of these symptoms among all women visiting an ed. to analyze the potential effect of using these symptoms in the ed diagnostic process for acs. methods: a survey on fatigue and insomnia symptoms was administered to a convenience sample of all adult women visiting an urban academic ed (all arrival modes, acuity levels, all complaints). a sensitivity analysis was performed using published data and expert opinion for inputs. results: we approached women, with enrollments. see table. the top box shows prevalences of prodromal symptoms among all adult female ed patients. the bottom box shows outputs from sensitivity analysis on the diagnostic effect of initiating an acs workup for all female ed patients reporting prodromal symptoms. conclusion: prodromal symptoms of acs are highly prevalent among all adult women visiting the ed in this study. this likely limits their utility in ed settings. while screening or admitting women with prodromal symptoms in the ed would probably increase sensitivity, that increase would be accompanied by a dramatic reduction in specificity. such a reduction in specificity would translate to admitting, observing, or working up somewhere between % and % of all women visiting the ed, which is prohibitive in terms of personal costs, risks of hospitalization, and financial costs. while these symptoms may or may not have utility in other settings such as primary care, their prevalence, and the implied lack of specificity for acs suggest they will not be clinically useful in the ed. length methods: we examined a cohort of low-risk chest pain patients evaluated in an ed-based ou using prospective and retrospective ou registry data elements. cox proportional hazard modeling was performed to assess the effect of testing modality (stress testing vs. ccta) on the los in the cdu. as ccta is not available on weekends, only subjects presenting on weekdays were included. cox models were stratified on time of patient presentation to the ed, based on four hour blocks beginning at midnight. the primary independent variable was first test modality, either stress imaging (exercise echo, dobutamine echo, stress mri) or ccta. age, sex, and race were included as covariates. the proportional hazards assumption was tested using scaled schoenfield residuals, and the models were graphically examined for outliers and overly influential covariate patterns. test selection was a time varying covariate in the am strata, and therefore the interaction with ln (los) was included as a correction term. after correction for multiple comparisons, an alpha of . was held to be significant. results: over the study period, subjects (of , in the registry) presented on non-weekend days. the median los was . hours (iqr . - . hours), % were white, and % were female. the table shows the number of subjects in each time strata, the number tested, and the number undergoing stress testing vs. ccta. after adjusting all models for age, race, and sex, the hazard ratio (hr) for los is as shown. only those patients presenting between am and noon noted a significant improvement in los with ccta use (p < . ). objectives: determine the validity of a managementfocused em osce as a measure of clinical skills by determining the correlation between osce scores and faculty assessment of student performance in the ed. methods: medical students in a fourth year em clerkship were enrolled in the study. on the final day of the clerkship students participated in a five-station em osce. student performance on the osce was evaluated using a task-based evaluation system with - critical management tasks per case. task performance was evaluated using a three-point system: performed correctly/timely ( ), performed incorrectly/late ( ), or not performed ( ). descriptive anchors were used for performance criteria. communication skills were also graded on a three-point scale. student performance in the ed was based on traditional faculty assessment using our core-competency evaluation instrument. a pearson correlation coefficient was calculated for the relationship between osce score and ed performance score. case item analysis included determination of difficulty and discrimination. the acgme also requires that trainees are evaluated on these ccs during their residency. trainee evaluation in the ccs are frequently on a subjective rating scale. one of the recognized problems with a subjective scale is the rating stringency of the rater, commonly known as the hawk-dove effect. this has been seen in standardized clinical exam scoring. recent data have shown that score variance can be related to evaluator performance with a negative correlation. higher-scoring physicians were more likely to be a stringent or hawk type rater on the same evaluation. it is unclear if this pattern also occurs in the subjective ratings that are commonly used in assessments of the ccs. objectives: comparison of attending physician scores on the acgme ccs with attending ratings of residents for a negative correlation or hawk-dove effect. methods: residents are routinely evaluated on the ccs with a - numerical rating scale as part of their training. the evaluation database was retrospectively reviewed. residents anonymously scored attending physicians on the ccs with a cross-sectional survey that utilized the same rating scale, anchors, and prompts as the resident evaluations. average scores for and by each attending were calculated and a pearson correlation calculated by core competency and overall. results: in this irb-approved study, a total of attending physicians were scored on the ccs with evaluations by residents. attendings evaluated residents with a total of , evaluations completed over a -year period. attending mode score was ranging from to ; resident scores had a mode of with a range of to . there was no correlation between the rated performance of the attendings overall or in each ccs and the scores they gave (p = . - . ). conclusion: hawk-dove effects can be seen in some scoring systems and has the potential to affect trainee evaluation on the acgme core competencies. however, a negative correlation to support a hawk-dove scoring pattern was not found in em resident evaluations by attending physicians. this study is limited by being a single center study and utilizing grouped data to preserve resident anonymity. background: all acgme-accredited residency programs are required to provide competency-based education and evaluation. graduating residents must demonstrate competency in six key areas. multiple studies have outlined strategies for evaluating competency, but data regarding residents' self-assessments of these competencies as they progress through training and beyond is scarce. objectives: using data from longitudinal surveys by the american board of emergency medicine, the primary objective of this study was to evaluate if resident self-assessments of performance in required competencies improve over the course of graduate medical training and in the years following. additionally, resident self-assessment of competency in academic medicine was also analyzed. methods: this is a secondary data analysis of data gathered from two rounds of the abem longitudinal study of emergency medicine residents ( - and - ) and three rounds of the abem longitudinal study of emergency physicians ( , , ). in both surveys, physicians were asked to rate a list of items in response to the question, ''what is your current level of competence in each of the following aspects of work in em?'' the rated items were grouped according to the acgme required competencies of patient care, medical knowledge, practice-based learning and improvement, interpersonal and communication skills, and system-based practice. an additional category for academic medicine was also added. results: rankings improved in all categories during residency training. rankings in three of the six categories improved from the weak end of the scale to the strong end of the scale. there is a consistent decline in rankings one year after graduation from residency. the greatest drop is in medical knowledge. mean self-ranking in academic medicine competency is uniformly the lowest ranked category for each year. conclusion: while self-assessment is of uncertain value as an objective assessment, these increasing rankings suggest that emergency medicine residency programs are successful at improving residents' confidence in the required areas. residents do not feel as confident about academic medicine as they do about the acgme required competencies. the uniform decline in rankings the first year after residency is an area worthy of further inquiry. screening medical student rotators from outside institutions improves overall rotation performance shaneen doctor, troy madsen, susan stroud, megan l. fix university of utah, salt lake city, ut background: emergency medicine is a rapidly growing field. many student rotations are limited in their ability to accommodate all students and must limit the number of students they allow per rotation. we hypothesize that pre-screening visiting student rotators will improve overall student performance. objectives: to assess the effect of applicant screening on overall rotation grade and mean end of shift card scores. methods: we initiated a medical student screening process for all visiting students applying to our -week elective em rotation starting in . this consisted of reviewing board scores and requiring a letter of intent. students from our home institution were not screened. all end-of-shift evaluation cards and final rotation grades (honors, high pass, pass, fail) from to were analyzed. we identified two cohorts: home students (control) and visiting students. we compared pre-intervention ( ) ( ) ( ) ( ) ( ) and postintervention ( - ) scores and grades. end of shift performance scores are recorded using a fivepoint scale that assesses indicators such as fund of knowledge, judgment, and follow-through to disposition. mean ranks were compared and p-values were calculated using the armitage test of trend and confirmed using t-tests. results: we identified visiting students ( pre, post) and home students ( pre, post). ( . %) visiting students achieved honors pre-intervention while ( . %) achieved honors post-intervention (p = . ). no significant difference was seen in home student grades: ( . %) received honors pre- and ( . %) received honors post- conclusion: we found that implementation of a screening process for visiting medical students improved overall rotation scores and grades as compared to home students who did not receive screening. screening rotating students may improve the overall quality of applicants and thereby the residency program. background: there are many descriptions in the literature of computer-assisted instruction in medical education, but few studies that compare them to traditional teaching methods. objectives: we sought to compare the suturing skills and confidence of students receiving video preparation before a suturing workshop versus a traditional instructional lecture. methods: first and second year medical students were randomized into two groups. the control group was given a lecture followed by minutes of suturing time. the video group was provided with an online suturing video at home, no lecture, and given minutes of suturing time during the workshop. both groups were asked to rate their confidence before and after the workshop, and their belief in the workshop's effectiveness. each student was also videotaped suturing a pig's foot after the workshop and graded on a previously validated -point suturing checklist. videos were scored. results: there was no significant difference between the test scores of the lecture group (m = . , sd = . , n = ) and the video group (m = . , sd = . , n = ) using the two-sample independent ttest for equal variances (t( ) = ) . , p = . ). there was a statistically significant difference in the proportion of students scoring correctly for only one point: ''curvature of needle followed'': / in the lecture group and / in the video group (chi = . , df = , p = . ). students in the video group were found to be . times more likely to have a neutral or favorable feeling of suturing confidence before the workshop (p = . , ci . - . ) using a proportional odds model. no association was detected between group assignment and level of suturing confidence after the workshop (p = . ). there was also no association detected between group assignment and opinion of the suturing workshop (p = . ) using a logistic regression odds model. among those students who indicated a lack of confidence before training, there was no detected association (p = . ) between group assignment and having an improved confidence using a logistic regression odds model. conclusion: students in the video group and students in the control group achieved similar levels of suturing skill and confidence, and equal belief in the workshop's effectiveness. this study suggests that video instruction could be a reasonable substitute for lectures in procedural education. background: accurate interpretation of the ecg in the emergency department is not only clinically important but also critical to assess medical knowledge competency. with limitations to expansion of formal didactics, educational technology offers an innovative approach to improve the quality of medical education. objectives: the aim of this study was to assess an online multimedia-based ecg training module evaluating st elevation myocardial infarction (stemi) identification among medical students. methods: a convenience sample of fifty-two medical students on their em rotations at an academic medical center with an em residency program was evaluated in a before-after fashion during a -month period. one cardiologist and two ed attending physicians independently validated a standardized exam of ten ecgs: four were normal ecgs, three were classic stemis, and three were subtle stemis. the gold standard for diagnosis was confirmed acute coronary thrombus during cardiac catheterization. after evaluating the ecgs, students completed a pre-intervention test wherein they were asked to identify patients who required emergent cardiac catheterization based on the presence or absence of st segment elevation on ecg. students then completed an online interactive multimedia module containing minutes of stemi training based on american heart association/american college of cardiology guidelines on stemi. medical students were asked to complete a post-test of the ecgs after watching online multimedia. objectives: our objective was to quantify the number of pre-verbal pediatric head cts performed at our community hospital that could have been avoided by utilizing the pecarn criteria. methods: we conducted a standardized chart review of all children under the age of who presented to our community hospital and received a head ct between jan st, and dec st, . following recommended guidelines for conducting a chart review, we: ) utilized four blinded chart reviewers, ) provided specific training, ) created a standardized data extraction tool, and ) held periodic meetings to evaluate coding discrepancies. our primary outcome measure was the number of patients who were pecarn negative and received a head ct at our institution. our secondary outcome was to reevaluate the sensitivity and specificity of the pecarn criteria to detect citbi in our cohort. data were analyzed using descriptive statistics and % confidence intervals were calculated around proportions using the modified wald method. results: a total of patients under the age of received a head ct at our institution during the study period. patients were excluded from the final analysis because their head cts were not for trauma. the prevalence of a citbi in our cohort was . % ( % ci . %- . %) ( (dti) measures disruption of axonal integrity on the basis of anisotropic diffusion properties. findings on dti may relate to the injury, as well as the severity of postconcussion syndrome (pcs) following mtbi. objectives: to examine acute anisotropic diffusion properties based on dti in youth with mtbi relative to orthopedic controls and to examine associations between white matter (wm) integrity and pcs symptoms. methods: interim analysis of a prospective casecontrol cohort involving youth ages - years with mtbi and orthopedic controls requiring extremity radiographs. data collected in ed included demographics, clinical information, and pcs symptoms measured by the postconcussion symptom scale. within hours of injury, symptoms were re-assessed and a -direction, diffusion weighted, spin-echo imaging scan was performed on a t philips scanner. dti images were analyzed using tract-based spatial statistics. fractional anisotropy (fa), mean diffusivity (md), axial diffusivity (ad), and radial diffusivity were measured. results: there were no group demographic differences between mtbi cases and controls. presenting symptoms within the mtbi group included gcs = %, loss of consciousness %, amnesia %, post-traumatic seizure %, headache %, vomiting %, dizziness %, and confusion %. pcs symptoms were greater in mtbi cases than in the controls at ed visit ( . ± . vs. . ± . , p < . ) and at the time of scan ( . ± . vs. . ± . , p < . ). the mtbi group displayed decreased fa in cerebellum and increased md and ad in the cerebral wm relative to controls (uncorrected p < . ). increased fa in cerebral wm was also observed in mtbi patients but the group difference was not significant. pcs symptoms at the time of the scan were positively correlated with fa and inversely correlated with rd in extensive cerebral wm areas (p < . , uncorrected). in addition, pcs symptoms in mtbi patients were also found to be inversely correlated with md, ad, and rd in cerebellum (p < . ). conclusion: dti detected axonal damage in youth with mtbi which correlated with pcs symptoms. dti performed acutely after injury may augment detection of injury and help prediction of those with worse outcomes. background: sports-related concussion among professional, collegiate, and more recently high school athletes has received much attention from the media and medical community. to our knowledge, there is a paucity of research in regard to sports-related concussion in younger athletes. objectives: the aim of this study was to evaluate parental knowledge of concussion in young children who participate in recreational tackle football. methods: parents/legal guardians of children aged - years enrolled in recreational tackle football were asked to complete an anonymous questionnaire based on the cdc's heads up: concussion in youth sports quiz. parents were asked about their level of agreement in regard to statements that represent definition, symptoms, and treatment of concussion. results: a total of out of parents voluntarily completed the questionnaire ( % response rate). parent and child demographics are listed in table . ninety four percent of parents believed their child had never suffered a concussion. however, when asked to agree or disagree with statements addressing various aspects of concussion, only % (n = ) could correctly identify all seven statements. most did not identify that a concussion is considered a mild traumatic brain injury and can be achieved from something other than a direct blow to the head. race, sex, and zip code had no significant association with correctly answering statements. education ( . ; p < . ) and number of years the child played ( . ; p < . ) had a small effect. fifty-three percent of parents reported someone had discussed the definition of concussion with them and % the symptoms of concussion. see table for source of information to parents. no parent was able to classify all symptoms listed as correctly related or not related to concussion. however, identification of correct concussion definitions correlated with identification of correct symptoms ( . ; p < . ). conclusion: while most parents had received some education regarding concussion from a health care provider, important misconceptions remain among parents of young athletes regarding the definition, symptoms, and treatment of concussion. this study highlights the need for health care providers to increase educational efforts among parents of young athletes in regard to concussion. figure ). / ( %) of patients with baseline liver dysfunction were (oh)d deficient and / ( %) of deaths were patients who had insufficient levels of (oh)d. there was an inverse association between (oh)d level and tnf-a (p = . ; figure ) and il- (p = . ). background: fever is common in the emergency department (ed), and % of those diagnosed with severe sepsis present with fever. despite data suggesting that fever plays an important role in immunity, human data conflict on the effect of antipyretics on clinical outcomes in critically ill adults. objectives: to determine the effect of ed antipyretic administration on -day in-hospital mortality in patients with severe sepsis. methods: single-center, retrospective observational cohort study of febrile severe sepsis patients presenting to an urban academic , -visit ed between june and june . all ed patients meeting the following criteria were included: age ‡ , temperature ‡ . °c, suspected infection, and either systolic blood pressure £ mmhg after a ml/kg fluid bolus or lactate of ‡ . patients were excluded for a history of cirrhosis or acetaminophen allergy. antipyretics were defined as acetaminophen, ibuprofen, or ketorolac. results: one hundred-thirty five ( . %) patients were treated with an antipyretic medication ( . % acetaminophen). intubated patients were less likely to receive antipyretic therapy ( . % vs. . %, p < . ), but the groups were otherwise well matched. patients requiring ed intubation (n = ) had much higher in-hospital mortality ( . % vs. . %, p < . ). patients given an antipyretic in the ed had lower mortality ( . % vs. . %, p < . ). when multivariable logistic regression was used to account for apache-ii, intubation status, and fever magnitude, antipyretic therapy was not associated with mortality (adjusted or . , . - . , p = . ). conclusion: although patients treated with antipyretic therapy had lower -day in-hospital mortality, antipyretic therapy was not independently associated with mortality in multivariable regression analysis. these findings are hypothesis-generating for future clinical trials, as the role of fever control has been largely unexplored in severe sepsis (grant ul rr , nih-ncrr). , and caval index ) . ± . (ci ) . , ) . ) and all were statistically significant. the groups receiving ml/kg and ml/kg had statistically significant changes in caval index; however the ml/kg group had no significant change in mean ivc diameter. one-way anova differences between the means of all groups were not statistically different. conclusion: overall, there were statistically significant differences in mean ivc-us measurements before and after fluid loading, but not between groups. fasting asymptomatic subjects had a wide inter-subject variation in both baseline ivc-us measurements and fluid-related changes. the wide differences within our ml/kg group may limit conclusions regarding proportionality. there were significant differences in performance on ed measures by ownership (p < . ) and region (p = . ). scores on ed process measures were highest at for-profit hospitals ( % above average) and hospitals in the south ( % above average), and lowest at public hospitals ( % below average) and hospitals in the northeast ( % below average). conclusion: there was considerable variation in performance on the ed measures included in the vbp program by hospital ownership and region. ed directors may come under increasing pressure to improve scores in order to reduce potential financial losses under the program. our data provide early information on the types of hospitals with the greatest opportunity for improvement. methods: design/setting -an independent agency mandated by the government collected and analyzed ed patient experience data using a comprehensive, validated multidimensional instrument and a random periodic sampling methodology of all ed patients. a prospective pre-post experimental study design was employed in the eight community and tertiary care hospitals most affected by crowding. two . month study periods were evaluated (pre: / - / / ; post: / / - / / ). outcomes -the primary outcome was patient perception of wait times and crowding reported as a composite mean score ( - ) from six survey items with higher scores representing better ratings. the overall rating of care by ed patients (composite score) and other dimensions of care were collected as secondary outcomes. all outcomes were compared using chi-square and two-tailed student's t-tests. results: a total of surveys were completed in both the pre-ocp and post-ocp study periods representing a response rate of %. we compared in-patient mortality from ami for patients who lived in a community with either . miles or miles of a closure but did not need to travel farther to the nearest ed with those who did not. we used patient-level data from the california office of statewide health and planning development (oshpd) database patient discharge data, and locations of patient residence and hospitals were geo-coded to determine any changes in distance to the nearest ed. we applied a generalized linear mixed effects model framework to estimate a patient's likelihood to die in the hospital of ami as a function of being affected by a neighborhood closure event. results background: fragmentation of care has been recognized as a problem in the us health care system. however, little is known about ed utilization after hospitalization, a potential marker of poor outpatient care coordination after discharge, particularly for common inpatient-based procedures. objectives: to determine the frequency and variability in ed visits after common inpatient procedures, how often they result in readmission, and related payments. methods: using national medicare data for - , we examined ed visits within days of hospital discharge after six common inpatient procedures: percutaneous coronary intervention, coronary artery bypass grafting (cabg), elective abdominal aortic aneurysm repair, back surgery, hip fracture repair, and colectomy. we categorized hospitals into risk-adjusted quintiles based on the frequency of ed visits after the index hospitalization. we report visits by primary diagnosis icd- codes and rates of readmission. we also assessed payments related to these ed visits. results: overall, the highest quintile of hospitals had -day ed visit rates that ranged from a low of . % with an associated . % readmission rate (back surgery) to a high of . % with an associated . % readmission rate (cabg). the most variability was more than -fold and found among patients undergoing colectomy in which the worst-performing hospitals saw . % of their patients experienced an ed visit within days while the best-performing hospitals saw . %. average total payments for the -day window from initial discharge across all surgical cohorts varied from $ , for patients discharged without subsequent ed visit; $ , for those experiencing an ed visit(s); $ , for those readmitted through the ed; and $ , for those readmitted from another source. if all patients who did not require readmission also did not incur an ed visit within the -day window, this would represent a potential cost savings of $ million. conclusion: among elderly medicare recipients there was significant variability between hospitals for -day ed visits after six common inpatient procedures. the ed visit may be a marker of poor care coordination in the immediate discharge period. this presents an opportunity to improve post-procedure outpatient care coordination which may save costs related to preventable ed visits and subsequent readmissions. objectives: we sought to assess the effect of pharmacist medication review on ed patient care, in particular time from physician order to medication administration for the patient (order-to-med time). methods: we conducted a multi-center, before-after study in two eds (urban academic teaching hospital and suburban community hospital, combined census of , ) after implementation of the electronic prospective pharmacy review system (prs). the system allowed a pharmacist to review all ed medication orders electronically at the time of physician order and either approve or alter the order. we studied a -month time period before implementation of the system (pre-prs, / / - / / ) and after implementation (post-prs, / / - / / ). we collected data on all ed medication orders including dose, route, class, pharmacist review action, time of physician order, and time of medication administration. differences in order-to-medication between the pre-and post-prs study periods were compared using a results: ed metrics that were significantly associated with lbtcs varied across ed patient-volume categories (table) . for eds seeing less than k patients annually, the percentage of ems arrivals admitted to the hospital and ed square footage were both weakly associated with lbtcs (p = . ). for eds seeing at least k- k patients, median ed length of stay (los), percent of patients admitted to hospital through the ed, percent of ems arrivals admitted to hospital, and percent of pediatric patients were all positively associated, while percent of patients admitted to the hospital was negatively associated with lbtcs. for eds seeing k- k, median los and percent of x-rays performed were positively associated, while percent of ekgs performed was negatively associated with lbtcs. for eds seeing k- k, percent of patients admitted to the hospital through the ed was negatively associated and percent of ekgs performed was positively associated with lbtcs. for eds with volume greater than k, none of the selected variables were associated with lbtc. conclusion: ed factors that help explain high lbtc rates differ depending on the size of an ed. interventions attempting to improve lbtc rates by modifying ed structure or process will need to consider baseline ed volume as a potential moderating influence. objectives: our study sought to compare bacterial growth of samples taken from surfaces after use of a common approved quat compound and a virtually non-toxic, commercially available solution containing elemental silver ( . %), hydrogen peroxide ( %), and peroxyacetic acid ( %) (shp) in a working ed. we hypothesized that, based on controlled laboratory data available, shp compound would be more effective on surfaces in an active urban ed. methods: we cleaned and then sampled three types of surfaces in the ed (suture cart, wooden railing, and the floor) during midday hours one minute after application of tap water, quat, and shp and then again at hours without additional cleaning. conventional environmental surface surveillance rodac media plates were used for growth assessment. images of bacterial growth were quantified at and hours. standard cleaning procedures by hospital staff were maintained per usual. results: shp was superior to control and quat one minute after application on all three surfaces. quat and water had x and x more bacterial growth than the surface cleaned with shp, respectively. hours later, the shp area produced fewer colonies sampled from the wooden railing: x more bacteria for quat, and x for water when compared to shp. h cultures from the cart and floor had confluent growth and could not be quantified. conclusion: shp outperforms quat in sterilizing surfaces after one minute application. shp may be a superior agent as a non-toxic, non-corrosive, and effective agent for surfaces in the demanding ed setting. further studies should examine sporidical and virucidal properties in a similar environment. objectives: evaluate the effect on patient satisfaction of increasing waiting room times and physician evaluation times. methods: emergency department flow metrics were collected on a daily basis as well as average daily patient satisfaction scores. the data were from july through february , in a , census urban hospital. the data were divided into equal intervals. the arrival to room time was divided by minute intervals up to minutes with the last group being greater than minutes. the physician evaluation times were divided into minute intervals, up to , the last group greater than with days in the group. data were analyzed using means and standard deviations, and well as anova for comparison between groups. results: the overall satisfaction score for the outpatient emergency visit was higher when the patient was in a room within minutes of arrival ( . , std deviation . ), analysis of variation between the groups had a p = . , for the means of each interval (see table ). the total satisfaction with the visit as well as satisfaction with the provider dropped when the evaluation extended over minutes, but was not statistically significant on anova analysis (see table for means). conclusion: once a patient's time in the waiting room extends beyond minutes, you have lost a significant opportunity for patient satisfaction; once they have been in the waiting room for over minutes, you are also much more likely to receive a poor score. physician evaluation time scores are much more consistent but as longer evaluation times occurred beyond total of minutes we started to see a trend downward in the satisfaction score. results: in all three eds, pain medication rates (both in ed and rx) varied significantly by clinical factors including location of pain, discharge diagnosis, pain level, and acuity. we observed little to no variation in pain medication rates by patient factors such as age, sex, race, insurance, or prior ed visits. the table displays key pain management practices by site and provider. after adjusting for patient and clinical characteristics, significant differences in pain medication rates remained by provider and site (see figure) . conclusion: within this health system, the approach to pain management by both providers and sites is not standardized. investigation of the potential effect of this variability on patient outcomes is warranted. results: all measures showed significant differences, p < . . average pts/h decreased post-cpoe and did not recover post transitional period, . ± . vs . ± . , p < . . rvu/h also decreased post-cpoe and did not recover post transitional period, . ± . vs . ± . and . ± . , p < . . charges/h also decreased after cpoe implementation and did not recover after system optimization. there was a sustained significant decrease in charges/h of . % ± . % post cpoe and . % ± . % post optimization, p < . . sub-group analysis for each provider group was also evaluated and showed variability for different providers. conclusion: there was a significant decrease in all productivity metrics four months after the implementation of cpoe. the system did undergo optimization initiated by providers with customization for ease and speed of use. however, productivity measurements did not recover after these changes were implemented. these data show that with the implementation of a cpoe system there is a decrease in productivity that continues even after a transition period and system customization. background: procedural competency is a key component of emergency medicine residency training. residents are required to log procedures to document quantity of procedures and identify potential weaknesses in their training. as emergency medicine evolves, it is likely that the type and number of procedures change over time. also, exposure to certain rare procedures in residency is not guaranteed. objectives: we seek to delineate trends in type and volume of core em procedures over a decade of emergency medicine residents graduating from an accredited four-year training program. methods: deidentified procedure logs from - were analyzed to assess trends in type and quantity of procedures. procedure logs were self-reported by individual residents on a continuous basis during training onto a computer program. average numbers of procedures per resident in each graduating class were noted. statistical analysis was performed using spss and includes a simple linear regression to evaluate for significant changes in number of procedures over time and an independent samples two-tailed t-test of procedures performed before and after the required resident duty hours change. results: a total of procedure logs were analyzed and the frequency of different procedures was evaluated. a significant increase was seen in one procedure, the venous cutdown. significant decreases were seen in procedures including key procedures such as central venous catheters, tube thoracostomy, and procedural sedation. the frequency of five high-stakes/ resuscitative procedures, including thoracotomy and cricothyroidotomy, remained steady but very low (< per resident over years). of the remaining procedures, showed a trend toward decreased frequency, while only increased. conclusion: over the past years, em residents in our program have recorded significantly fewer opportunities to perform most procedures. certain procedures in our emergency medicine training program have remained stable but uncommon over the course of nearly a decade. to ensure competency in uncommon procedures, innovative ways to expose residents to these potentially life saving skills must be considered. these may include practice on high-fidelity simulators, increased exposure to procedures on patients during residency (possibly on off-service rotations), or practice in cadaver and animal labs. objectives: to study the effectiveness of a unique educational intervention using didactic and hands-on training in usgpiv. we hypothesized that senior medical students would improve performance and confidence with usgpiv after the simulation training. methods: fourth year medical students were enrolled in an experimental, prospective, before and after study conducted at a university medical school simulation center. baseline skills in participant's usgpiv on simulation vascular phantoms were graded by ultrasound expert faculty using standardized checklists. the primary outcome was time to cannulation, and secondary outcomes were ability to successfully cannulate, number of needle attempts, and needle-tip visualization. subjects then observed a -minute presentation on correct performance of usgpiv followed by a -minute hands-on practical session using the vascular simulators with a : to : ultrasound instructor to student ratio. an expert blinded to the participant's initial performance graded post-educational intervention usgpiv ability. pre-and post-intervention surveys were obtained to evaluate usgpiv confidence, previous experience with ultrasound, peripheral iv access, usg-piv, and satisfaction with the educational format. objectives: this study examines the grade distribution of resident evaluations when the identity of the evaluator was anonymous as compared to when the identity of the evaluator was known to the resident. we hypothesize that there will be no change in the grades assigned to residents. methods: we retrospectively reviewed all faculty evaluations of residents and grades assigned from july , through november , . prior to july , the identity of the faculty evaluators was anonymous, while after this date, the identity of the faculty evaluators was made known to the residents. throughout this time period, residents were graded on a five-point scale. each resident evaluation included grades in the six acgme core competencies as well as in select other abilities. specific abilities evaluated varied over the dates analyzed. evaluations of residents were assigned to two groups, based on whether the evaluator was anonymous or made known to the resident. grades were compared between the two groups. results: a total of , grades were assigned in the anonymous group, with an average grade of . ( ci . , . ). a total of , grades were assigned in the known group with an average grade of . ( ci . , . ). specific attention was paid to assignment of unsatisfactory grades ( or on the five-point scale). the anonymous group assigned grades in this category, comprising . % of all grades assigned. the known group assigned grades in this category, comprising . % of all grades assigned. unsatisfactory grades were assigned by the anonymous group . % ( ci . , . ) more often. additionally, . % ( ci . , . ) fewer exceptional grades ( or on the five-point scale) were assigned by the anonymous group. conclusion: the average grade assigned was closer to average ( on a five-point scale) when the identity of the evaluator was made known to the residents. additionally, fewer unsatisfactory and exceptional grades were assigned in this group. this decrease of both unsatisfactory and exceptional grades may make it more difficult for program directors to effectively identify struggling and strong residents respectively. testing to improve knowledge retention from traditional didactic presentations: a pilot study david saloum, amish aghera, brian gillett maimonides medical center, brooklyn, ny background: the acgme requires an average of at least hours of planned educational experiences each week for em residents, which traditionally consists of formal lecture based instruction. however, retention by adult learners is limited when presented material in a lecture format. more effective methods such as small group sessions, simulation, and other active learning modalities are time-and resource-intensive and therefore not practical as a primary method of instruction. thus, the traditional lecture format remains heavily relied upon. efficient strategies to improve the effectiveness of lectures are needed. testing utilized as a learning tool to force immediate recall of lecture material is an example of such a strategy. objectives: to evaluate the effect of immediate postlecture short answer quizzes on em residents' retention of lecture content. methods: in this prospective randomized controlled study, em residents from a community based -year training program were randomized into two groups. block randomization provided a similar distribution of postgraduate year training levels and performance on both us-mle and in-training examinations between the two groups. each group received two identical -minute lectures on ecg interpretation and aortic disease. one group of residents completed a five-question short answer quiz immediately following each lecture (n = ), while the other group received the lectures without subsequent quizzes (n = ). the quizzes were not scored or reviewed with the residents. two weeks later, retention was assessed by testing both groups with a -question multiple choice test (mct) derived in equal part from each lecture. mean and median test results were then compared between groups. statistical significance was determined using a paired t-test of median test scores from each group. results: residents who received immediate post-lecture quizzes demonstrated significantly higher mct scores (mean = %, median %, n = ) compared to those receiving lectures alone (mean = %, median = %, n = ); p = . . conclusion: short answer testing immediately after a traditional didactic lecture improves knowledge retention at a -week interval. limitations of the study are that it is a single center study and long term retention was not assessed. background: the task of educating the next generation of physicians is steadily becoming more difficult with the inherent obstacles that exist for faculty educators and the work hour restrictions that students must adhere to. the obstacles make developing curricula that not only cover important topics but also do so in a fashion that helps support and reinforce the clinical experiences very difficult. several areas of medical education are using more asynchronous techniques and self-directed online educational modules to overcome these obstacles. objectives: the aim of this study was to demonstrate that educational information pertaining to core pediatric emergency medicine topics could be as effectively disseminated to medical students via self-directed online educational modules as it could through traditional didactic lectures. methods: this was a prospective study conducted from august , through december , . students participating in the emergency medicine rotation at carolinas medical center were enrolled and received education in a total of eight core concepts. the students were divided into two groups which changed on a monthly basis. group was taught four concepts via self-directed online modules and four traditional didactic lectures. group was taught the same core concepts, but in opposite fashion to group . each student was given a pre-test, post-test, and survey at the conclusion of the rotation. results: a total of students participated in the study. students, regardless of which group assigned, performed similarly on the pre-test, with no statistical difference among scores. when looking at the summative total scores between online and traditional didactic lectures, there was a trend towards significance for more improvement among those taught online. the student's assessment of the online modules showed that the majority either felt neutral or preferred the online method. the majority thought the depth and length of the modules were perfect. most students thought having access to the online modules was valuable and all but one stated that they would use them again. conclusion: this study demonstrates that self-directed, online educational modules are able to convey important concepts in emergency medicine similar to traditional didactics. it is an effective learning technique that offers several advantages to both the educator and student. background: critical access hospitals (cah) provide crucial emergency care to rural populations that would otherwise be without ready access to health care. data show that many cah do not meet standard adult quality metrics. adults treated at cah often have inferior outcomes to comparable patients cared for at other community-based emergency departments (eds). similar data do not exist for pediatric patients. objectives: as part of a pilot project to improve pediatric emergency care at cah, we sought to determine whether these institutions stock the equipment and medications necessary to treat any ill or injured child who presents to the ed. methods: five north carolina cah volunteered to participate in an intensive educational program targeting pediatric emergency care. at the initial site visit to each hospital, an investigator, in conjunction with the ed nurse manager, completed a -item checklist of commonly required ed equipment and medications based on the acep ''guidelines for care of children in the emergency department''. the list was categorized into monitoring and respiratory equipment, vascular access supplies, fracture and trauma management devices, and specialized kits. if available, adult and pediatric sizes were listed. only hospitals stocking appropriate pediatric sizes of an item were counted as having that item. the pharmaceutical supply list included antibiotics, antidotes, antiemetics, antiepileptics, intubation and respiratory medications, iv fluids, and miscellaneous drugs not otherwise categorized. results: overall, the hospitals reported having % of the items listed (range - %). the two greatest deficiencies were fracture devices (range - %), with no hospital stocking infant-sized cervical collars, and antidotes, with no hospital stocking pralidoxime, / hospitals stocking fomepizole, and / hospitals stocking pyridoxine and methylene blue. only one of the five institutions had access to prostaglandin e. the hospitals stated cost and rarity of use as the reason for not stocking these medications. conclusion: the ability of cah to care for pediatric patients does not appear to be hampered by a lack of equipment. ready access to infrequently used, but potentially lifesaving, medications is a concern. tertiary care centers preparing to accept these patients should be aware of these potential limitations as transport decisions are made. background: while incision and drainage (i&d) alone has been the mainstay of management of uncomplicated abscesses for decades, some advocate for adjunct antibiotic use, arguing that available trials are underpowered and that antibiotics reduce treatment failures and recurrence. objectives: to investigate the role of antibiotics in addition to i&d in reducing treatment failure as compared to management with i&d alone. methods: we performed a search using medline, embase, web of knowledge, and google scholar databases (with a medical librarian) to include trials and observational studies analyzing the effect of antibiotics in human subjects with skin and soft-tissue abscesses. two investigators independently reviewed all the records. we performed three overlapping meta-analy-ses: . only randomized trials comparing antibiotics to placebo on improvement of the abscess during standard follow-up. . trials and observational studies comparing appropriate antibiotics to placebo, no antibiotics, or inappropriate antibiotics (as gauged by wound culture) on improvement during standard follow-up. . only trials, but broadened outcome to include recurrence or new lesions during a longer follow-up period as treatment failure. we report pooled risk ratios (rr) using a fixed-effects model for our point estimates with shore-adjusted % confidence intervals (ci). results: we screened , records, of which studies fit inclusion criteria, of which were meta-analyzed ( trials, observational studies) because they reported results that could be pooled. of the studies, enrolled subjects from the ed, from a soft-tissue infection clinic, and from a general hospital without definition of enrollment site. five studies enrolled primarily adults, pediatrics, and without specification of ages. after pooling results for all randomized trials only, the rr = . ( % ci: . - . ). exposure being ''appropriate'' antibiotics (using trials and observational studies) resulted in a pooled rr = . ( % ci: . - . ). when we broadened our treatment failure criteria to include recurrence or new lesions at longer lengths of follow-up (trials only), we noted a rr = . ( % ci: . - . ). conclusion: based on available literature pooled for this analysis, there is no evidence to suggest any benefit from antibiotics in addition to i&d in the treatment of skin and soft tissue abscesses. (originally submitted as a ''late-breaker.'') primary objectives: to compare wound healing and recurrence rates after primary vs. secondary closure of drained abscesses. we hypothesized the percentage of drained ed abscesses that would be completely healed at days would be higher after primary closure. methods: this randomized clinical trial was undertaken in two academic emergency departments. immunocompetent adult patients with simple, localized cutaneous abscesses were randomly assigned to i & d followed by primary or secondary closure. randomization was balanced by center, with an allocation sequence based on a block size of four, generated by a computer random number generator. the primary outcome was percentage of healed wounds seven days after drainage. a sample of patients had % power to detect an absolute difference of % in healing rates assuming a baseline rate of %. all analyses were by intention to treat. results: twenty-seven patients were allocated to primary and to secondary closure, of whom and , respectively, were followed to study completion. healing rates at seven days were similar between the primary and secondary closure groups ( we compared consecutive patients each scanned on the or slice ccta in - . measures and outcomes-data were prospectively collected using standardized data collection forms required prior to performing ccta. the main outcomes were cumulative radiation doses and volumes of intravenous contrast. data analysis-groups compared with t-, mann whitney u, and chi-square tests. results: the mean age of patients imaged with the and scanners were (sd ) vs. ( ) (p = . ). male:female ratios were also similar ( : vs. : respectively, p = . ). both mean (p < . ) and median (p = . ) effective radiation dose were significantly lower with the ( . and msv) vs. the -slice scanner ( . and msv) respectively. prospective gating was successful in % of the scans and only in % of the scans (p < . ). mean iv contrast volumes were also lower for the vs. the -slice scanner ( ± vs. ± ml; p < . ). the % non-diagnostic scans was similarly low in both scanners ( % each). there were no differences in use of beta-blockers or nitrates. conclusion: when compared with the -slice scanner, the -slice scanner reduces the effective radiation doses and iv contrast volumes in ed patients with cp undergoing ccta. need for beta-blockers and nitrates was similar and both scanners achieved excellent diagnostic image quality. background: a few studies have demonstrated that bedside ultrasound measurement of inferior vena cava to aorta (ivc-to-ao) ratio is associated with the level of dehydration in pediatric patients and a proposed cutoff of . has been suggested, below which a patient is considered dehydrated. objectives: we sought to externally validate the ability of ivc-to-ao ratio to discriminate dehydration and the proposed cutoff of . in an urban pediatric emergency department (ed). methods: this was a prospective observational study at an urban pediatric ed. we included patients aged to months with clinical suspicion of dehydration by the ed physician and an equal number of control patients with no clinical suspicion of dehydration. we excluded children who were hemodynamically unstable, had chronic malnutrition or failure to thrive, open abdominal wounds, or were unable to provide patient or parental consent. a validated clinical dehydration score (cds) (range to ) was used to measure initial dehydration status. an experienced sonographer blinded to the cds and not involved in the patient's care measured the ivc-to-ao ratio on the patient prior to any hydration. cds was collapsed into a binary outcome of no dehydration or any level of dehydration ( or higher). the ability of ivc-to-ao ratio to discriminate dehydration was assessed using area under the receiver operating characteristic curve (auc) and the sensitivity and specificity of ivc-to-ao ratio was calculated for three cutoffs ( . , . , . ). calculation of auc was repeated after adjusting for age and sex. results: patients were enrolled, ( %) of whom had a cds of or higher. median age was (interquartile range - ) months, and ( %) were female. the ivcto-ao ratio showed an unadjusted auc of . ( % ci . - . ) and adjusted auc of . ( % ci . - . ). for a cutoff of . sensitivity was % ( % ci %- %) and specificity % ( % ci %- %); for a cutoff of . sensitivity was % ( % ci %- %) and specificity % ( % ci %- %); for a cutoff of . sensitivity was % ( % ci %- %) and specificity % ( % ci %- %). conclusion: the ability of the ivc-to-ao ratio to discriminate dehydration in young pediatric ed patients was modest and the cutoff of . was neither sensitive nor specific. background: while early cardiac computed tomographic angiography (ccta) could be more effective to manage emergency department (ed) patients with acute chest pain and intermediate (> %) risk of acute coronary syndrome (acs) than current management strategies, it also could result in increased testing, cost, and radiation exposure. objectives: the purpose of the study was to determine whether incorporation of ccta early in the ed evaluation process leads to more efficient management and earlier discharge than usual care in patients with acute chest pain at intermediate risk for acs. methods: randomized comparative effectiveness trial enrolling patients between - years of age without known cad, presenting to the ed with chest pain but without ischemic ecg changes or elevated initial troponin and require further risk stratification for decision making, at nine us sites. patients are being randomized to either ccta as the first diagnostic test or to usual care, which could include no testing or functional testing such as exercise ecg, stress spect, and stress echo following serial biomarkers. test results were provided to physicians but management in neither arm was driven by a study protocol. data on time, diagnostic testing, and cost of index hospitalization, and the following days are being collected. the primary endpoint is length of hospital stay (los). the trial is powered to allow for detection of a difference in los of . hours between competing strategies with % power assuming that % of projected los values are true. secondary endpoints are cumulative radiation exposure, and cost of competing strategies. tertiary endpoints are institutional, caregiver, and patient characteristics associated with primary and secondary outcomes. rate of missed acs within days is the safety endpoint. results: as of november st, , of patients have been enrolled (mean age: ± , . % female, acs rate . %). the anticipated completion of the last patient visit is / / and the database will be locked in early march . we will present the results of the primary, secondary, and some tertiary endpoints for the entire cohort. conclusion: romicat ii will provide rigorous data on whether incorporation of ccta early in the ed evaluation process leads to more efficient management and triage than usual care in patients with acute chest pain at intermediate risk for acs. (originally submitted as a ''late-breaker.'') meta background: many studies have documented higher rates of advanced radiography utilization across u.s. emergency departments (eds) in recent years, with an associated decrease in diagnostic yield (positive tests / total tests). provider-to-provider variability in diagnostic yield has not been well studied, nor have the factors that may explain these differences in clinical practice. objectives: we assessed the physician-level predictors of diagnostic yield using advanced radiography to diagnose pulmonary embolus (pe) in the ed, including demographics and d-dimer ordering rates. methods: we conducted a retrospective chart review of all ed patients who had a ct chest or v/q scan ordered to rule out pe from / to / in four hospitals in the medstar health system. attending physicians were included in the study if they had ordered or more scans over the study period. the result of each ct and vq scan was recorded as positive, negative, or indeterminate, and the identity of the ordering physician was also recorded. data on provider sex, residency type (em or other), and year of residency completion were collected. each provider's positive diagnostic yield was calculated, and logistic regression analysis was done to assess correlation between positive scans and provider characteristics. results: during the study period, , scans ( , cts and , v/qs) were ordered by providers. the physicians were an average of . years from residency, % were female, and % were em-trained. diagnostic yield varied significantly among physicians (p < . ), and ranged from % to %. the median diagnostic yield was . % (iqr . %- . %). the use of d-dimer by provider also varied significantly from % to % (p < . ). the odds of a positive test were significantly lower among providers less than years out of residency graduation (or . , ci . - . ) after controlling for provider sex, type of residency training, d-dimer use, and total number of scans ordered. conclusion: we found significant provider variability in diagnostic yield for pe and use of d-dimer in this study population, with % of providers having diagnostic yield less than or equal to . %. providers who were more recently graduated from residency appear to have a lower diagnostic yield, suggesting a more conservative approach in this group. background: the literature reports that anticoagulation increases the risk of mortality in patients presenting to emergency departments (ed) with head trauma (ht). it has been suggested that such patients should be treated in a protocolized fashion, including ct within minutes, and anticipatory preparation of ffp before ct results are available. there are significant logistical and financial implications associated with implementation of such a protocol. objectives: our primary objective was to determine the effect of anticoagulant therapy on the risk of intracranial hemorrhage (ich) in elderly patients presenting to our urban community hospital following bunt head injury. methods: this was a retrospective chart review study of ht patients > years of age presenting to our ed over a -month period. charts reviewed were identified using our electronic medical record via chief complaints and icd- codes and cross referencing with written ct logs. research assistants underwent review of at least % of their contributing data to validate reliability. we collected information regarding use of warfarin, clopidogrel, and aspirin and ct findings of ich. using univariate logistic regression, we calculated odds ratios (or) for ich with % ci. results: we identified elderly ht patients. the mean age of our population was , ( . %) admitted to using anticoagulant therapy, and % were on antiplatelet drugs. ( . %) of the cohort had icb, patients required neurosurgical intervention, and had transfusion of blood products. of the non-anticoagulated patients, ( . %) were found to have ich, half of those ( ) , and mir- ) were measured using real-time quantitative pcr from serum drawn at enrollment. il- , il- , and tnf-a were measured using a bio-plex suspension system. baseline characteristics, il- , il- , tnf-a and micrornas were compared using one way anova or fisher exact test, as appropriate. correlations between mirnas and sofa scores, il- , il- , and tnf-a were determined using spearman's rank. a logistic regression model was constructed using in-hospital mortality as the dependent variable and mirnas as the independent variables of interest. bonferroni adjustments were made for multiple comparisons. results: of patients, were controls, had sepsis, and had septic shock. we found no difference in serum mir- a or mir- between cohorts, and found no association between these micrornas and either inflammatory markers or sofa score. mir- demonstrated a significant correlation with sofa score (q = . , p = . ), il- (q = . , p = . ), but not il- or tnf-a (p = . , p = . ). logistic regression demonstrated mir- to be associated with mortality, even after adjusting for sofa score (p = . ). conclusion: mir- a or mir- failed to demonstrate any diagnostic or prognostic ability in this cohort. mir- was associated with inflammation, increasing severity of illness, and mortality, and may represent a novel prognostic marker for diagnosis and prognosis of sepsis. objectives: to examine the association between emergency physician recognition of sirs and sepsis and subsequent treatment of septic patients. methods: a retrospective cohort study of all-age patient medical records with positive blood cultures drawn in the emergency department from / - / at a level i trauma center. patient parameters were reviewed including vital signs, mental status, imaging, and laboratory data. criteria for sirs, sepsis, severe sepsis, and septic shock were applied according to established guidelines for pediatrics and adults. these data were compared to physician differential diagnosis documentation. the mann-whitney test was used to compare time to antibiotic administration and total volume of fluid resuscitation between two groups of patients: those with recognized sepsis and those with unrecognized sepsis. results: sirs criteria were present in / reviewed cases. sepsis criteria were identified in / cases and considered in the differential diagnosis in / septic patients. severe sepsis was present in / cases and septic shock was present in / cases. the sepsis -hour resuscitation bundle was completed in the emergency department in cases of severe sepsis or septic shock. patients who met sepsis criteria and were recognized by the ed physician had a median time to antibiotics of minutes (iqr: - ) and a median ivf of ml (iqr: - ). the patients who met sepsis criteria but went unrecognized in the documentation had a median time to antibiotics of minutes (iqr: - ) and median volume of fluid resuscitation of ml (iqr: . median time to antibiotics and median volume of fluid resuscitation differed significantly between recognized and unrecognized septic patients (p = . and p = . , respectively). conclusion: emergency physicians correctly identify and treat infection in most cases, but frequently do not document sirs and sepsis. lack of documentation of sepsis in the differential diagnosis is associated with increased time to antibiotic delivery and a smaller total volume of fluid administration, which may explain poor sepsis bundle compliance in the emergency department. background: severe sepsis is a common clinical syndrome with substantial human and financial impact. in the first consensus definition of sepsis was published. subsequent epidemiologic estimates were collected using administrative data, but ongoing discrepancies in the definition of severe sepsis led to large differences in estimates. objectives: we seek to describe the variations in incidence and mortality of severe sepsis in the us using four methods of database abstraction. methods: using a nationally representative sample, four previously published methods (angus, martin, dombrovskiy, wang) were used to gather cases of severe sepsis over a -year period ( ) ( ) ( ) ( ) ( ) ( ) . in addition, the use of new icd- sepsis codes was compared to previous methods. our main outcome measure was annual national incidence and in-hospital mortality of severe sepsis. results: the average annual incidence varied by as much as . fold depending on method used and ranged from , ( / , population) to , , ( , / , ) using the methods of dombrovskiy and wang, respectively. average annual increase in the incidence of severe sepsis was similar ( . - . %) across all methods. total mortality mirrored the increase in incidence over the -year period ( background: radiation exposure from medical imaging has been the subject of many major journal articles, as well as the topic of mainstream media. some estimate that one-third of all ct scans are not medically justified. it is important for practitioners ordering these scans to be knowledgeable of currently discussed risks. objectives: to compare the knowledge, opinions, and practice patterns of three groups of providers in regards to cts in the ed. methods: an anonymous electronic survey was sent to all residents, physician assistants, and attending physicians in emergency medicine (em), surgery, and internal medicine (im) at a single academic tertiary care referral level i trauma center with an annual ed volume of over , visits. the survey was pilot tested and validated. all data were analyzed using the pearson's chi-square test. results: there was a response rate of % ( / ). data from surgery respondents were excluded due to a low response rate. in comparison to im, em respondents correctly equated one abdominal ct to between and chest x-rays, reported receiving formal training regarding the risks of radiation from cts, believe that excessive medical imaging is associated with an increased lifetime risk of cancer, and routinely discuss the risks of ct imaging with stable patients more often (see table ). particular patient factors influence whether radiation risks are discussed with patients by % in each specialty (see table ). before ordering an abdominal ct in a stable patient, im providers routinely review the patient's medical imaging history less often than em providers surveyed. overall, % of respondents felt that ordering an abdominal ct in a stable ed patient is a clinical decision that should be discussed with the patient, but should not require consent. conclusion: compared with im, em practitioners report greater awareness of the risks of radiation from cts and discuss risks with patients more often. they also review patients' imaging history more often and take this, as well as patients' age, into account when ordering cts. these results indicate a need for improved education for both em and im providers in regards to the risks of radiation from ct imaging. background: in nebraska, % of emergency departments have annual visits less than , , and the predominance are in rural settings. general practitioners working in rural emergency departments have reported low confidence in several emergency medicine skills. current staffing patterns include using midlevels as the primary provider with non-emergency medicine trained physicians as back-up. lightly-embalmed cadaver labs are used for resident's procedural training. objectives: to describe the effect of a lightlyembalmed cadaver workshop on physician assistants' (pa) reported level of confidence in selected emergency medicine procedures. methods: an emergency medicine procedure lab was offered at the nebraska association of physician assistants annual conference. each lab consisted of a -hour hands-on session teaching endotracheal intubation techniques, tube thoracostomy, intraosseous access, and arthrocentesis of the knee, shoulder, ankle, and wrist to pas. irb-approved surveys were distributed pre-lab and a post-lab survey was distributed after lab completion. baseline demographic experience was collected. pre-and post-lab procedural confidence was rated on a six-point likert scale ( - ) with representing no confidence. the wilcoxon signed-rank test was use to calculate p values. results: pas participated in the course. all completed a pre-and post-lab assessment. no pa had done any one procedure more than times in their career. pre-lab modes of confidence level were £ for each procedure. post-lab modes were > for each procedure except arthrocentesis of the ankle and wrist. however, post lab assessments of procedural confidence significantly improved for all procedures with p values < . . conclusion: midlevel providers' level of confidence improved for emergent procedures after completion of a procedure lab using lightly-embalmed cadavers. a mobile cadaver lab would be beneficial to train rural providers with minimal experience. background: use of automated external defibrillators (aed) improves survival in out-of-hospital cardiopulmonary arrest (ohca). since , the american heart association has recommended that individuals one year of age or older who sustain ohca have an aed applied. little is known about how often this occurs and what factors are associated with aed use in the pediatric population. objectives: our objective was to describe aed use in the pediatric population and to assess predictors of aed use when compared to adult patients. methods: we conducted a secondary analysis of prospectively collected data from u.s. cities that participate in the cardiac arrest registry to enhance survival (cares). patients were included if they had a documented resuscitation attempt from october , through december , and were ‡ year old. patients were considered pediatric if they were less than years old. aed use included application by laypersons and first responders. hierarchical multivariable logistic regression analysis was used to estimate the associations between age and aed use. results: there were , ohcas included in this analysis, of which ( . %) occurred in pediatric patients. overall aed use in the final sample was , , with , ( . %) total survivors. aeds were applied less often in pediatric patients ( . %, % ci: . %- . % vs . %, % ci: . %- . %). within the pediatric population, only . % of patients with a shockable rhythm had an aed used. in all pediatric patients, regardless of presenting rhythm, aed use demonstrated a statistically significant increase in return of spontaneous circulation (aed used . %, % ci: . - . vs aed not used . %, % ci: . - . , p < . ), although there was no significant increase in survival to hospital discharge (aed used . %; aed not used . %; p = . ). in the adjusted model, pediatric age was independently associated with failure to use an aed (or . , % ci: . - . ) as was female sex (or . , % ci: . - . ). patients who had a public arrest (or . , % ci: . - . ) or one that was witnessed by a bystander (or . . %: ci . - . ) were also predictive of aed use. conclusion: pediatric patients who experience ohca are less likely to have an aed used. continued education of first responders and the lay public to increase aed use in this population is necessary. does implementation of a therapeutic hypothermia protocol improve survival and neurologic outcomes in all comatose survivors of sudden cardiac arrest? ken will, michael nelson, abishek vedavalli, renaud gueret, john bailitz cook county (stroger), chicago, il background: the american heart association (aha) currently recommends therapeutic hypothermia (th) for out of hospital comatose survivors of sudden cardiac arrest (cssca) with an initial rhythm of ventricular fibrillation (vf). based on currently limited data, the aha further recommends that physicians consider th for cssca, from both the out and inpatient settings, with an initial non-vf rhythm. objectives: investigate whether a th protocol improves both survival and neurologic outcomes for cssca, for out and inpatients, with any initial rhythm, in comparison to outcomes previously reported in literature prior to th. methods: we conducted a prospective observational study of cssca between august and may whose care included th. the study enrolled eligible consecutive cssca survivors, from both out and inpatient settings with any initial arrest rhythm. primary endpoints included survival to hospital discharge and neurologic outcomes, stratified by sca location, and by initial arrest rhythm. results: overall, of eligible patients, ( %, % ci - %) survived to discharge, ( %, % ci - %) with at least a good neurologic outcome. twelve were out and were inpatients. among the outpatients, ( %, % ci - %) survived to discharge, ( %, % ci - %) with at least a good neurologic outcome. among the inpatients, ( %, % ci - ) survived to discharge, ( %, % ci - %) with at least a good neurologic outcome. by initial rhythm, patients had an initial rhythm of vf/t and non-vf/t. among the patients with an initial rhythm of vf/t, ( %, ci - %) survived to discharge, all with at least a good outcome, including out and inpatients. among the patients with an initial rhythm of non-vf/t, ( %, ci - %) survived to discharge, ( %, ci - %) with at least a good neurologic outcome, including out and inpatients. conclusion: our preliminary data initially suggest that local implementation of a th protocol improves survival and neurologic outcomes for cssca, for out and inpatients, with any initial rhythm, in comparison to outcomes previously reported in literature prior to th. subsequent research will include comparison to local historical controls, additional data from other regional th centers, as well as comparison of different cooling methods. protocolized background: therapeutic hypothermia (th) has been shown to improve the neurologic recovery of cardiac arrest patients who experience return of spontaneous circulation (rosc). it remains unclear as to how earlier cooling and treatment optimization influence outcomes. objectives: to evaluate the effects of a protocolized use of early sedation and paralysis on cooling optimization and clinical outcomes in survivors of cardiac arrest. methods: a -year ( - ), pre-post intervention study of patients with rosc after cardiac arrest treated with th was performed. those patients treated with a standardized order set which lacked a uniform sedation and paralytic order were included in the pre-intervention group, and those with a standardized order set which included a uniform sedation and paralytic order were included in the post-intervention group. patient demographics, initial and discharge glasgow coma scale (gcs) scores, resuscitation details, cooling time variables, severity of illness as measured by the apache ii score, discharge disposition, functional status, and days to death were collected and analyzed using student's t-tests, man-whitney u tests, and the log-rank test. results: patients treated with th after rosc were included, with patients in the pre-intervention group and in the post-intervention group. the average time to goal temperature ( °c) was minutes (pre-intervention) and minutes (post-intervention) (p = . ). a -hour time target was achieved in . % of the patients (post-intervention) compared to . % in the pre-group (p = . ). twenty-eight day mortality was similar between groups ( . % and . %) though hospital length of stay ( days pre-and days post-intervention) and discharge gcs ( preand -post-intervention) differed between cohorts. more post-intervention patients were discharged to home ( . %) compared to . % in the pre-intervention group. conclusion: protocolized use of sedation and paralysis improved time to goal temperature achievement. these improved th time targets were associated with improved neuroprotection, gcs recovery, and disposition outcome. standardized sedation and paralysis appears to be a useful adjunct in induced th. background: ct is increasingly used to assess children with signs and symptoms of acute appendicitis (aa) though concerns regarding long-term risk of exposure to ionizing radiation have generated interest in methods to identify children at low risk. objectives: we sought to derive a clinical decision rule (cdr) of a minimum set of commonly used signs and symptoms from prior studies to predict which children with acute abdominal pain have a low likelihood of aa and compared it to physician clinical impression (pci). methods: we prospectively analyzed subjects aged to years in u.s. emergency departments with abdominal pain plus signs and symptoms suspicious for aa within the prior hours. subjects were assessed by study staff unaware of their diagnosis for clinical attributes drawn from published appendicitis scoring systems and physicians responsible for physical examination estimated the probability of aa based on pci prior to their medical disposition. based on medical record entry rate, frequently used cdr attributes were evaluated using recursive partitioning and logistic regression to select the best minimum set capable of discriminating subjects with and without aa. subjects were followed to determine whether imaging was used and use was tabulated by both pci and the cdr to assess their ability to identify patients who did or did not benefit based on diagnosis. results: this cohort had a . % prevalence ( / subjects) of aa. we derived a cdr based on the absence of two out of three of the following attributes: abdominal tenderness, pain migration, and rigidity/ guarding had a sensitivity of . % ( % ci: . - . ), specificity of . % ( % ci: . - . ), npv of . % ( % ci: . - . ), and negative likelihood ratio of . ( % ci: . - . ). the pci set at aa < % pre-test probability had a sensitivity of . % ( % ci: . - . ), specificity of . % ( % ci: . - . ), npv of . % ( % ci: . - . ), and negative likelihood ratio of . ( % ci: . - . ). the methods each classified % of the patients as low risk for aa. our cdr identified . % ( / ) of low risk subjects who received ct but being aa (-), could have been spared ct, while the pci identified . % ( / ). conclusion: compared to physician clinical impression, our clinical decision rule can identify more children at low risk for appendicitis who could be managed more conservatively with careful observation and avoidance of ct. negative background: abdominal pain is the most common complaint in the ed and appendicitis is the most common indication for emergency surgery. a clinical decision rule (cdr) identifying abdominal pain patients at a low risk for appendicitis could lead to a significant reduction in ct scans and could have a significant public health impact. the alvarado score is one of the most widely applied cdrs for suspected appendicitis, and a low modified alvarado score (less than ) is sometimes used to rule out acute appendicitis. the modified alvarado score has not been prospectively validated in ed patients with suspected appendicitis. objectives: we sought to prospectively evaluate the negative predictive value of a low modified alvarado score (mas) in ed patients with suspected appendicitis. we hypothesized that a low mas (less than ) would have a sufficiently high npv (> %) to rule out acute appendicitis. methods: we enrolled patients greater than or equal to years old who were suspected of having appendicitis (listed as one of the top three diagnosis by the treating physician before ancillary testing) as part of a prospective cohort study in two urban academic eds from august to april . elements of the mas and the final diagnosis were recorded on a standard data form for each subject. the sensitivity, specificity, negative predictive value (npv), and positive predictive value (ppv) were calculated with % ci for a low mas and final diagnosis of appendicitis. background: evaluating children for appendicitis is difficult and strategies have been sought to improve the precision of the diagnosis. computed tomography is now widely used but remains controversial due to the large dose of ionizing radiation and risk of subsequent radiation-induced malignancy. objectives: we sought to identify a biomarker panel for use in ruling out pediatric acute appendicitis as a means of reducing exposure to ionizing radiation. methods: we prospectively enrolled subjects aged to years presenting in u.s. emergency departments with abdominal pain and other signs and symptoms suspicious for acute appendicitis within the prior hours. subjects were assessed by study staff unaware of their diagnosis for clinical attributes drawn from appendicitis scoring systems and blood samples were analyzed for cbc differential and candidate proteins. based on discharge diagnosis or post-surgical pathology, the cohort exhibited a . % prevalence ( / subjects) of appendicitis. clinical attributes and biomarker values were evaluated using principal component, recursive partitioning, and logistic regression to select the combination that best discriminated between those subjects with and without disease. mathematical combination of three inflammation-related markers in a panel comprised of myeloid-related protein / complex (mrp), c-reactive protein (crp), and white blood cell count (wbc) provided optimal discrimination. results: this panel exhibited a sensitivity of % ( % ci, - %), a specificity of % ( % ci, - %), and a negative predictive value of % ( % ci, - %) in this cohort. the observed performance was then verified by testing the panel against a pediatric subset drawn from an independent cohort of all ages enrolled in an earlier study. in this cohort, the panel exhibited a sensitivity of % ( % ci, - %), a specificity of % ( % ci, - %), and a negative predictive value of % ( % ci, - %). conclusion: appyscore is highly predictive of the absence of acute appendicitis in these two cohorts. if these results are confirmed by a prospective evaluation currently underway, the appyscore panel may be useful to classify pediatric patients presenting to the emergency department with signs and symptoms suggestive of, or consistent with, acute appendicitis and thereby sparing many patients ionizing radiation. background: there are no current studies on the tracking of emergency department (ed) patient dispersal when a major ed closes. this study demonstrates a novel way to track where patients sought emergency care following the closure of saint vincent's catholic medical center (svcmc) in manhattan by using de-identified data from a health information exchange, the new york clinical information exchange (nyclix). nyclix matches patients who have visited multiple sites using their demographic information. on april , , svcmc officially stopped providing emergency and outpatient services. we report the patterns in which patients from svcmc visited other sites within nyclix. objectives: we hypothesize that patients often seek emergency care based on geography when a hospital closes. methods: a retrospective pre-and post-closure analysis was performed of svcmc patients visiting other hospital sites. the pre-closure study dates were january , -march , . the post closure study dates were may , -july , . a svcmc patient was defined as a patient with any svcmc encounter prior to its closure. using de-identified aggregate count data, we calculated the average number of visits per week by svcmc patients at each site (hospital a-h). we ran a paired t-test to compare the pre-and post-closure averages by site. the following specifications were used to write the database queries: of patients who had one or more prior visits to svcmc for each day within the study return the following: a. eid: a unique and meaningless proprietary id generated within the nyclix master patient index (mpi). b. age: thru the age of . persons over were listed as '' + '' c. ethnicity/race d. type of visit: emergency e. location of visit: specific nyclix site. results: nearby hospitals within miles saw the highest number of increased ed visits after svcmc closed. this increase was seen until about miles. hospitals > miles away did not see any significant changes in ed visits. see table. conclusion: when a hospital and its ed close down, patients seem to seek emergency care at the nearest hospital based on geography. other factors may include the patient's primary doctor, availabilities of outpatient specialty clinics, insurance contracts, or preference of ambulance transports. this study is limited by the inclusion of data from only the eight hospitals participating in nyclix at the time of the svcmc closure. upstream methods: data were collected on all ed ems arrivals from the metro calgary (population . million) area to its three urban adult hospitals. the study phases consisted of the months from february to october (pre-ocp) compared against the same months in (post-ocp). data from the ems operational database and the regional emergency department information system (redis) database were linked. the primary analysis examined the change in ems offload delay defined as the time from ems triage arrival until patient transfer to an ed bed. a secondary analysis evaluated variability in ems offload delay between receiving eds. conclusion: implementation of a regional overcapacity protocol to reduce ed crowding was associated with an important reduction in ems offload delay, suggesting that policies that target hospital processes have bearing on ems operations. variability in offload delay improvements is likely due to site-specific issues, and the gains in efficiency correlate inversely with acuity. methods: a pre-post intervention study was conducted in the ed of an adult university teaching hospital in montreal (annual visits = ). the raz unit (intervention), created to offload the acu of the main ed, started operating in january, . using a split flow management strategy, patients were directed to the raz unit based on patient acuity level (ctas code and certain code ), likelihood to be discharged within hours, and not requiring an ed bed for continued care. data were collected weekdays from : to : for months (september -december ) (pre-raz) and for . months (february -march ) (post-raz). in the acu of the main ed, research assistants observed and recorded cubicle access time, and nurse and physician assessment times. databases were used to extract socio-demographics, ambulance arrival, triage code, chief complaint, triage and registration time, length of stay, and ed occupancy. background: telephone follow-up after discharge from the ed is useful for treatment and quality assurance purposes. ed follow-up studies frequently do not achieve high (i.e. ‡ %) completion rates. objectives: to determine the influence of different factors on the telephone follow-up rate of ed patients. we hypothesized that with a rigorous follow-up system we could achieve a high follow-up rate in a socioeconomically diverse study population. methods: research assistants (ras) prospectively enrolled adult ed patients discharged with a medication prescription between november , and september , from one of three eds affiliated with one health care system: (a) academic level i trauma center, (b) community teaching affiliate, and (c) community hospital. patients unable to provide informed consent, non-english speaking, or previously enrolled were excluded. ras interviewed subjects prior to ed discharge and conducted a telephone follow-up interview week later. follow-up procedures were standardized (e.g. number of calls per day, times to place calls, obtaining alternative numbers) and each subject's follow-up status was monitored and updated daily through a shared, web-based data system. subjects who completed follow-up were mailed a $ gift card. we examined the influence of patient (age, sex, race, insurance, income, marital status, usual major activity, education, literacy level, health status), clinical (acuity, discharge diagnosis, ed length of stay, site), and procedural factors (number and type of phone numbers received from subjects, offering two gift cards for difficult to reach subjects) on the odds of successful followup using multivariate logistic regression. results: of the , enrolled, % were white, % were covered by medicaid or uninsured, and % reported an annual household income of <$ , . % completed telephone follow-up with % completing on the first attempt. the table displays the factors associated with successful follow-up. in addition to patient demographics and lower acuity, obtaining a cell phone or multiple phone numbers as well as offering two gift cards to a small number of subjects increased the odds of successful follow-up. conclusion: with a rigorous follow-up system and a small monetary incentive, a high telephone follow-up rate is achievable one week after an ed visit. methods: an interrupted time-series design was used to evaluate the study question. data regarding adherence with the following pneumonia core measures were collected pre-and post-implementation of the enhanced decision-support tool: blood cultures prior to antibiotic, antibiotic within hours of arrival, appropriate antibiotic selection, and mean time to antibiotic administration. prescribing clinicians were educated on the use of the decision-support tool at departmental meetings and via direct feedback on their cases. results: during the -month study period, complete data were collected for patients diagnosed with cap: in the pre-implementation phase and post-implementation. the mean time to antibiotic administration decreased by approximately one minute from the pre-to post-implementation phase, a change that was not statistically significant (p = . ). the proportion of patients receiving blood cultures prior to antibiotics improved significantly (p < . ) as did the proportion of patients receiving antibiotics within hours of ed arrival (p = . ). a significant improvement in appropriate antibiotic selection was noted with % of patients experiencing appropriate selection in the post-phase, p = . . use of the available support tool increased throughout the study period, v = . , df = , p < . . all improvements were maintained months following the study intervention. conclusion: in this academic ed, introduction of an enhanced electronic clinical decision support tool significantly improved adherence to cms pneumonia core measures. the proportion of patients receiving blood cultures prior to antibiotics, antibiotics within hours, and appropriate antibiotics all improved significantly after the introduction of an enhanced electronic clinical decision support tool. background: emergency medicine (em) residency graduates need to pass both the written qualifying exam and oral certification exam as the final benchmark to achieve board certification. the purpose of this project is to obtain information about the exam preparation habits of recent em graduates to allow current residents to make informed decisions about their individual preparation for the abem written qualifying and oral certification exams. objectives: the study sought to determine the amount of residency and individual preparation, to determine the extent of the use of various board review products, and to elicit evaluations of the various board review products used for the abem qualifying and certification exams. methods: design: an online survey instrument was used to ask respondents questions about residency preparation and individual preparation habits, as well as the types of board review products used in preparing for the em boards. participants: as greater than % of all em graduates are emra members, an online survey was sent to all emra members who have graduated for the past three years. observations: descriptive statistics of types of preparation, types of resources, time, and quantitative and qualitative ratings for the various board preparation products were obtained from respondents. results: a total of respondents spent an average of . weeks and hours per week preparing for the written qualifying exam and spent an average of weeks and . hours per week preparing for the oral certification exam. in preparing for the written qualification exam, % used a preparation textbook with % using more than one textbook and % using a board preparation course. in preparing for the oral qualifying exam, % used a preparation textbook while % used a preparation course. sixty-seven percent of respondents reported that their residency programs had a formalized written qualifying exam preparation curriculum of which % was centered on the annual in-training exam. eight-five percent of residency programs had a formalized oral certification exam preparation. respondents reported spending on average $ preparing for the qualifying exam and $ for the certification exam. conclusion: em residents spend significant amounts of time and money and make use of a wide range of residency and commercially available resources in preparing for the abem qualifying and certification exams. background: communication and professionalism skills are essential for em residents but are not wellmeasured by selection processes. the multiple mini-interview (mmi) uses multiple, short structured contacts to measure these skills. it predicts medical school success better than the interview and application. its acceptability and utility in em residency selection is unknown. objectives: we theorized that the mmi would provide novel information and be acceptable to participants. methods: interns from three programs in the first month of training completed an eight-station mmi developed to focus on em topics. pre-and post-surveys assessed reactions using five-point scales. mmi scores were compared to application data. results: em grades correlated with mmi performance (f( . ) = : , p < . ) with honors students having higher mmi summary scores. higher third year clerkship grades trended to higher mmi performance means, although not significantly. mmi performance did not correlate with a match desirability rating and did not predict other individual components of the application including usmle step or usmle step . participants preferred a traditional interview (mean difference = . , p < . ). a mixed format was preferred over a pure mmi (mean difference = . , p < . ). preference for a mixed format was similar to a traditional interview. mmi performance did not significantly correlate with preference for the mmi; however, there was a trend for higher performance to associate with higher preference (r = . , t( ) = . , n.s.) performance was not associated with preference for a mix of interview methods (r = . , t( ) = . , n.s.). conclusion: while the mmi alone was viewed less favorably than a traditional interview, participants were receptive to a mixed methods interview. the mmi appears to measure skills important in successful completion of an em clerkship and thus likely em residency. future work will determine whether mmi performance correlates with clinical performance during residency. background: the annual american board of emergency medicine (abem) in-training exam is a tool to assess resident progress and knowledge. when the new york-presbyterian (nyp) em residency program started in , the exam was not emphasized and resident performance was lower than expected. a course was implemented to improve residency-wide scores despite previous em literature failing to exhibit improvements with residency-sponsored in-training exam interventions. objectives: to evaluate the effect of a comprehensive, multi-faceted course on residency-wide in-training exam performance. methods: the nyp em residency program, associated with cornell and columbia medical schools, has a year format with - residents per year. an intensive -week in-training exam preparation program was instituted outside of the required weekly residency conferences. the program included lectures, pre-tests, high-yield study sheets, and remediation programs. lectures were interactive, utilizing an audience response system, and consisted of core lectures ( - . hours) and three review sessions. residents with previous in-training exam difficulty were counseled on designing their own study programs. the effect on intraining exam scores was measured by comparing each resident's score to the national mean for their postgraduate year (pgy). scores before and after course implementation were evaluated by repeat measures regression modeling. overall residency performance was evaluated by comparing residency average to the national average each year and by tracking abem national written examination pass rates. results: resident performance improved following course implementation. following the course's introduction, the odds of a resident beating the national mean increased by . ( % ci . - . ) and the percentage of residents exceeding the national mean for their pgy year increased by % ( % ci %- %). following course introduction, the overall residency mean score has outperformed the national exam mean annually and the first-time abem written exam board pass rate has been %. conclusion: a multi-faceted in-training exam program centered around a -week course markedly improved overall residency performance on the in-training exam. limitations: this was a before and after evaluation as randomizing residents to receive the course was not logistically or ethically feasible. . years of practice. among the nonresidency trained, non-boarded em physicians, the percentage of individuals with board actions against them was significantly higher ( . % vs. . %, % ci for difference of . % = . to . %), but the incidence of actions was not significant ( . vs. . events/ years of practice, % ci for difference of . / = ) / to + / ), but the power to detect a difference was %. conclusion: in this study population, em-trained physicians had significantly fewer total state medical board disciplinary actions against them than non-em trained physicians, but when adjusted for years of practice (incidence), the difference was not significantly different at the % confidence level. the study was limited by low power to detect a difference in incidence. objectives: we chose pain documentation as a long term project for quality improvement in our ems system. our objectives were to enhance the quality of pain assessment, to reduce patient suffering and pain through improved pain management, to improve pain assessment documentation, to improve capture of initial and repeat pain scales, and to improve the rate of pain medication. this study addressed the aim of improving pain assessment documentation. methods: this was a quasi-experiment looking at paramedic documentation of the pqrst mnemonic and pain scales. our intervention consisted of mandatory training on the importance and necessity of pain assessment and treatment. in addition to classroom training, we used rapid cycle individual feedback and public posting of pain documentation rates (with unique ids) for individual feedback. the categories of chief complaint studied were abdominal pain, blunt injury, burn, chest pain, headache, non-traumatic body pain, and penetrating injury. we compared the pain documentation rates in the months prior to intervention, the months of intervention, and months post intervention. using repeated-measures anova, we compared rates of paramedic documentation over time. results: our ems system transported patients during the study period, of whom were for painful conditions in the defined chief complaint categories. there were paramedics studied, of whom had complete data. documentation increased from of painful cases ( . %) in qtr to of painful cases ( . %) in qtr . the trend toward increased rates of pain documentation over the three quarters was strongly significant (p < . ). paramedics were significantly more likely to document pain scales and pqrst assessments over the course of the study with the highest rates of documentation compliance in the final -month period. conclusion: a focused intervention of education and individual feedback through classroom training, one on one training, and public posting improves paramedic documentation rates of perceived patient pain. background: emergency medical services (ems) systems are vital in the identification, assessment, and treatment of trauma, stroke, myocardial infarction, and sepsis and improving early recognition, resuscitation, and transport to adequate medical facilities. ems personnel provide similar first-line care for patients with syncope, performing critical actions such as initial assessment and treatment as well as gathering key details of the event. objectives: to characterize emergency department patients with syncope receiving initial care by ems and their role as initial providers. methods: we prospectively enrolled patients over years of age who presented with syncope or near syncope to a tertiary care ed with , annual patient visits from june to june . we compared patient age, sex, comorbidities, and -day cardiopulmonary adverse outcomes (defined as myocardial infarction, pulmonary embolism, significant cardiac arrhythmia, and major cardiovascular procedure) between ems and non-ems patients. descriptive statistics, two-sided ttests, and chi-square testing were used as appropriate. results: of the patients enrolled, ( . %) arrived by ambulance. the most common complaint in patients transported by ems was fainting ( . %) or dizziness ( . %); syncope was reported in ( . %). compared to non-ems patients, those who arrived by ambulance were older (mean age (sd) . ( . ), vs. . ( . ) years, p = . ). there were no differences in the proportion of patients with hypertension ( . % vs . %, p = . ), coronary artery disease ( . % vs . %, p = . ), diabetes mellitus ( . % vs . %, p = . ), or congestive heart failure ( . % vs . %, p = . ). sixtynine ( . %) patients experienced a cardiopulmonary event within days. twenty-eight ( . %) patients who arrived by ambulance and ( . %) non-ems patients had a subsequent cardiopulmonary adverse event (rr . , %ci . - . ) within days. the table tabulates interventions provided by ems prior to ed arrival. conclusion: ems providers care for more than one third of ed syncope patients and often perform key interventions. ems systems offer opportunities for advancing diagnosis, treatment, and risk stratification in syncope patients. background: abdominal pain is the most common reason for visiting an emergency department (ed), and abdominopelvic computed tomography (apct) use has increased dramatically over the past decade. despite this, there has been no significant change in rates of admission or diagnosis of surgical conditions. objectives: to assess whether an electronic accountability tool affects apct ordering in ed patients with abdominal or flank pain. we hypothesized that implementation of an accountability tool would decrease apct ordering in these patients. methods: before and after study design using an electronic medical record at an urban academic ed from jul-nov , with the electronic accountability tool implemented in oct for any apct order. inclusion criteria: age >= years, non-pregnant, and chief complaint or triage pain location of abdominal or flank pain. starting oct th , , resident attempts to order apct triggered an electronic accountability tool which only allowed the order to proceed if approved by the ed attending physician. the attending was prompted to enter the primary and secondary diagnoses indicating apct, agreement with need for ct and, if no agreement, who was requesting this ct (admitting or consulting physician), and their pretest probability ( - ) of the primary diagnosis. patients were placed into two groups: those who presented prior to (pre) and after (post) the deployment of the accountability tool. background: there has been a paradigm shift in the diagnostic work-up for suspected appendicitis. edbased staged protocols call for the use of ultrasound prior to ct scanning because of its lack of radiation, and the morbidity related to contrast. a barrier to implementation is the lack of / availability of ultrasound. objectives: to evaluate the impact of the implementation of ed performed appendix ultrasounds (apus) on ct utilization in the staged workup for appendicitis in the emergency department. methods: we performed a quasi-experimental, before/ after study. we compared data from the first months of , before the availability of ed performed apus, with the same interval in after introduction of ed apus. we excluded patients who had appendectomies for reasons other than appendicitis or had been diagnosed prior to arrival. no patient identifiers were included in the analysis and the study was approved by the hospital irb. we report the following descriptive statistics (percentages, sensitivities, and absolute utilization changes conclusion: implementation of an ed apus in the staging work up of appendicitis was associated with a significant reduction in overall ct utilization in the ed. objectives: this study aims to evaluate ed patients' knowledge of radiation exposure from ct and mri scans as well as the long-term risk of developing cancer. we hypothesize that ed patients will have a poor understanding of the risks, and will not know the difference between ct and mri. methods: design -this was a cross-sectional survey study of adult, english-speaking patients at two eds from / / - / / . setting -one location was a tertiary care center with an annual ed census of , patient visits and the other was a community hospital with annual ed census of , patient visits. obser-vations -the survey consisted of six questions evaluating patients' understanding of radiation exposure from ct and mri as well as long-term consequences of radiation exposure. patients were then asked their age, sex, race, highest level of education, annual household income, and whether they considered themselves health care professionals. results: there were participants in this study, (of , total) from the academic center and (of , total) from the community hospital during the study period. overall, only % ( % ci - %) of participants understood the radiation risks associated with ct scanning. % ( % ci - %) of patients believed that an abdominal ct had the same or less radiation as a chest x-ray. % ( % ci - %) believed that there was an increased risk of developing cancer from repeated abdominal cts. only % ( % ci - %) of patients knew that mri scans had less radiation than ct. % ( % ci - %) either didn't know or believed that repeated mris were associated with an increased risk of developing cancer. higher educational level, household income, and identification as a health care professional all were associated with correct responses, but even within these groups, a majority gave incorrect responses. conclusion: in general, ed patients do not understand the radiation risks associated with advanced imaging modalities. we need to educate these patients so that they can make informed decisions about their own health care. background: homelessness has been associated with many poor health outcomes and frequent ed utilization. it has been shown that frequent use of the ed in any given year is not a strong predictor of subsequent use. identifying a group of patients who are chronic high users of the ed could help guide intervention. objectives: the purpose of this study is to identify if homelessness is associated with chronic ed utilization. methods: a retrospective chart review was accomplished looking at the records of the most frequently seen patients in the ed for each year from - at a large, urban academic hospital with an annual volume of , . patients' visit dates, chief complaints, dispositions, and housing status were reviewed. homelessness was defined by self-report at registration. patients were categorized according to their ed utilization with those seen > times in at least three of the five years of the study identified as chronic high utilizers; and those who visited the ed > times in at least three of the five years of the study were identified as chronic ultra-high utilizers. descriptive statistics with confidence intervals were calculated, and comparisons were made using non-parametric tests. results: during the -year study period, , unique patients were seen, of whom . % patients were homeless. patients were identified as frequent users. there were patients who presented on the top utilizer lists from multiple years. ( %, %ci - ) patients were identified as homeless. patients were seen > times in at least three of the years and ( %, - ) were homeless. patients were seen > times in at least three of the years and ( %, - ) were homeless. our facility has a % admission rate; however, non homeless chronic ultra-high utilizers had admission rates of % and homeless chronic ultra-high utilizers were admitted %. conclusion: chronic ultra-high utilizers of our ed are disproportionately homeless and present with lower severity of illness. these patients may prove to be a cost-effective group to house or otherwise involve with aggressive case management. the debate over homeless housing programs and case management solutions can be sharpened by better defining the groups who would most benefit and who represent the greatest potential saving for the health system. background: the prevalence of obese patients presenting to our emergency department (ed) is %: obese patients present in disproportionate number compared to the general population (us rate = %). in spite of this, there is a disconnect in patients' perceptions of weight and health: many patients underestimate their weight and report a key barrier to weight loss is patient-provider communications; such discussions have proven to be highly effective in smoking, drug, and alcohol cessation, an important initial step toward promoting wellness. information about patient provider communication is essential for designing and implementing emergency department (ed) based interventions to help increase patient awareness about weightrelated medical issues and provide counseling for weight reduction. objectives: we assessed patients' perceptions about obesity as disease and patient communication with their providers through two questions: do you believe your present weight is damaging to your health? has a doctor or other health professional every told you that you are overweight? methods: a descriptive cross-sectional study was performed in an academic tertiary care ed. a randomized sample of patients (every fifth) presenting to the ed (n = ) was enrolled. pregnant patients, patients who were medically unstable, cognitively impaired, or who were unable or unwilling to provide informed consent were excluded. percentages of ''yes'' and ''no'' are reported for each question based on patient bmi, ethnicity, sex, and the number of comorbid conditions. regression analysis was used to determine differences in responses between subgroups. results: among overweight/obese, white/black patients, . % do not feel their weight is damaging to their health and . % reported they have not been told by a doctor they are overweight. of individuals who have been told by a doctor they were overweight, . % still believe their present weight is not damaging to their health. of individuals who have not been told by a doctor they were overweight, . % believe their present weight is damaging to their health. differences in race and age were not found. p values < . for all results. conclusion: our data point toward a disconnect regarding patients' perceptions of health and weight. timely education about the burden of obesity may lead to a decrease in its overall prevalence. (originally submitted as a ''late-breaker.'') objectives: to examine the attitudes and expectations of patients admitted for inpatient care following an emergency department visit. methods: a descriptive study was done by surveying a voluntary sample of adult patients (n = ) admitted to the hospital from the emergency department in one urban teaching hospital in the midwest. a short, ninequestion survey was developed to assess patient attitudes and expectations towards hiv testing, consent, and requirements. analyses consisted of descriptive statistics, correlations, and chi-square analyses. results: the majority of patients report that hiv testing should be a routine part of health care screening ( . %) and that the hospital should routinely test admitted patients for hiv ( . %). despite these overall positive attitudes towards hiv testing, the data also suggest that patients have strong attitudes towards consent requirements with % acknowledging that hiv testing requires special consent and % reporting that separate consent should be required. the data also showed a statistically significant difference in the proportion of patients who believed that hiv testing is a part of routine health care screening by race (v = . , df = , p = . ). conclusion: patients attitudes and expectations towards routine hiv testing are consistent with the cdc recommendations. emergency departments are an ideal setting to initiate hiv testing and the findings suggest that patients expect hospital policies outline procedures for obtaining consent and screening all patients who are admitted to the hospital from the ed. results: the analysis revealed a ''hot spot'', a cluster of counties ( . %) with high ca rates adjacent to counties with high ca rates, located across the southeastern us (p < . ). within these counties, the average ca rate was % higher than the national average. a ''cool spot'', a cluster of counties ( . %) with low rates, was located across the midwest (p < . ). in this cool spot the average ca rate was % lower than the national average. figures and show us adjusted rates and spatial autocorrelation of ca deaths, respectively. conclusion: we identify geographic disparities in ca mortality and describe the cardiac arrest belt in the southeastern us. a limitation of this analysis was the use of icd- codes to identify cardiac arrest deaths; however, no other national data exist. an improved understanding of the drivers of this variability is essential to targeted prevention and treatment strategies, especially given the recent emphasis on development of cardiac resuscitation centers and cardiac arrest systems of care. an understanding of the relation between population density, cardiac arrest count, and cardiac arrest rate will be essential to the design of an optimized cardiac arrest system. we defined ed utilization during the past months as non-users ( visits), infrequent users ( - visits), frequent users ( - visits), and super-frequent users ( ‡ visits). we compared demographic data, socioeconomic status, health conditions, and access to care between these ed utilization groups. results: overall, super-frequent use was reported by . % of u.s. adults, frequent use by %, and infrequent ed use by %. higher ed utilization was associated with increased self-reported fair to poor health ( % for super-frequent, % for frequent, % for infrequent, % for non-ed users). frequent ed users were also more likely to be impoverished, with % of superfrequent, % of frequent, % of infrequent, and % of non-ed users reporting a poverty-income ratio < . adults with higher ed utilization were more likely to report the ed as the place they usually go when sick ( % for super-frequent, % for frequent, % for infrequent, . % for non-ed users). they also reported greater outpatient resource utilization, with % of super-frequent, % of frequent, % of infrequent, and % of non-ed users reporting ‡ outpatient visits/year. frequent ed users were also more likely than non-ed users to be covered by medicaid ( % for super-frequent, % for frequent, % for infrequent, % for non-ed users). conclusion: frequent ed users were a vulnerable population with lower socioeconomic status, poor overall health, and high outpatient resource utilization. interventions designed to divert frequent users from the ed should also focus on chronic disease management and access to outpatient services, rather than focusing solely on limiting ed utilization. objectives: we explored factors associated with specialty provider willingness to provide urgent appointments to children insured by medicaid/chip. methods: as part of a mixed method study of child access to specialty care by insurance status, we conducted semi-structured qualitative interviews with a purposive sample of specialists and primary care physicians (pcps) in cook county, il. interviews were conducted from april to september , until theme saturation was reached. resultant transcripts and notes were entered into atlas.ti and analyzed using an iterative coding process to identify patterns of responses in the data, ensure reliability, examine discrepancies, and achieve consensus through content analysis. results: themes that emerged indicate that pcps face considerable barriers getting publicly insured patients into specialty care and use the ed to facilitate this process. ''if i send them to the emergency room, i'm bypassing a number of problems. i'm fully aware that i'm crowding the emergency room.'' specialty physicians reported that decisions to refuse or limit the number of patients with medicaid/chip are due to economic strain or direct pressure from their institutions ''in the last budget revision, we were [told], 'you are losing money, so you need to improve your patient mix'''. in specialty practices with limited medicaid/chip appointment slots, factors associated with appointment success included: high acuity or complexity, personal request from or an informal economic relationship with the pcp, geography, and patient hardship. ''if it's a really desperate situation and they can't find anybody else, i will make an exception''. specialists also acknowledged that ''patients who can't get an appointment go to the er and then i am obligated to see them if they're in the system.'' conclusion: these exploratory findings suggest that a critical linkage exists between hospital eds and affiliated specialty clinics. as health systems restructure, there is an opportunity for eds to play a more explicit role in improving care coordination and access to specialty care. albert amini, erynne a. faucett, john m. watt, richard amini, john c. sakles, asad e. patanwala university of arizona, tucson, az background: trauma patients commonly receive etomidate and rocuronium for rapid sequence intubation (rsi) in the ed. due to the long duration of action of rocuronium and short duration of action of etomidate, these patients require prompt initiation of sedatives after rsi. this prevents the potential of patient awareness under pharmacological paralysis, which could be a terrifying experience. objectives: the purpose of this study was to evaluate the effect of the presence of a pharmacist during traumatic resuscitations in the ed on the initiation of sedatives and analgesics after rsi. we hypothesized that pharmacists would decrease the time to provision of sedation and analgesia. methods: this was an observational, retrospective cohort study conducted in a tertiary, academic ed that is a level i trauma center. consecutive adult trauma patients who received rocuronium in the ed for rsi were included during two time periods: / / to / / (pre-phase -no pharmacy services in the ed) and / / to / / (post-phase -pharmacy services in the ed). since the pharmacist could not respond to all traumas in the post-phase, this was further categorized based on whether the pharmacist was present or absent at the trauma resuscitation. data collected included patient demographics, baseline injury data, and medications used. the median time from rsi to initiation of sedatives and analgesics was compared between the pre-phase group (group ), post-phase pharmacist absent group (group ), and post-phase pharmacist present group (group ) using the kruskal-wallis test. results: a total of patients were included in the study (group = , group = , and group = ). median age was , . , and . years in groups , , and , respectively (p = . ). there were no other differences between groups with regard to demographics, mechanism of injury, presence of traumatic brain injury, glasgow coma scale score, vital signs, ed length of stay, or mortality. median time between rsi and post-intubation sedative use was , , and minutes in groups , and , respectively (p < . ). median time between rsi and post-intubation analgesia use was , , and minutes in groups , , and , respectively (p < . ). the presence of a pharmacist during trauma resuscitations decreases time to provision of sedation and analgesia after rsi. background: outpatient antibiotics are frequently prescribed from the ed, and limited health literacy may affect compliance with recommended treatments. objectives: among patients stratified by health literacy level, multimodality discharge instructions will improve compliance with outpatient antibiotic therapy and follow-up recommendations. methods: this was a prospective randomized trial that included consenting patients discharged with outpatient antibiotics from an urban county ed with an annual census of , . patients unable to receive text messages or voicemails were excluded. health literacy was assessed using a validated health literacy assessment, the newest vital sign (nvs). patients were randomized to a discharge instruction modality: ) usual care, typed and verbal medication and case-specific instructions; ) usual care plus text messaged instructions sent to the patient's cell phone; or ) usual care plus voicemailed instructions sent to the patient's cell phone. antibiotic pick-up was verified with the patient's pharmacy at hours. patients were called at days to determine antibiotic compliance. z-tests were used to compare -hour antibiotic pickup and patient-reported compliance across instructional modality and nvs score groups. results: patients were included ( % female, median age , range months to years); were excluded. % had an nvs score of - , % - , and % - . the proportion of prescriptions filled at hours varied significantly across nvs score groups; self-reported medication compliance at days revealed no difference across different instructional modalities nor nvs scores (table ) . conclusion: in this sample of urban ed patients, hour prescription pickup varied significantly by validated health literacy score, but not by instruction delivery modality. in this sample, patients with lower health literacy are at risk of not filling their outpatient antibiotics in a timely fashion. has been developed, validated, and utilized to study the processes of care involved in successful care transitions from inpatient to outpatient settings, but has not been utilized in the ed. objectives: we hypothesized that the ctm- could be successfully implemented in the ed without differential item difficulty by age, sex, education, or race; and would be associated with measures of quality of care and likelihood of following physician recommendations. methods: a descriptive study design based on exit surveys was used to measure ctm- scores and likelihood of following treatment recommendations. surveys were administered to a daily cross-sectional sample of all patients leaving the ed between a- a by research assistants in an urban academic ed setting for weeks in november . we report means and standard deviations, and analysis of variance to identify differences in ctm- scores for those who planned and did not plan to follow ed recommendations. results: surveys were completed; patients were ± years old, % black, % female, % with at least some college education, and % were admitted. average ctm- score was . ± . (range - ). scores were not associated with sex (p = . ), race (p = . ), or education level (p = . ). lower ctm scores were associated with increasing age (p = . ), patient perceptions that the ed team was less likely to use words that they understood, listen carefully to them, inspire their confidence and trust, or encourage them to ask questions (all p < . ). those who reported they were ''very likely'' to follow ed treatment had an average score of ± , while those who were ''unlikely'' or ''very unlikely'' to follow ed treatment plans had an average score ± (p = . ). conclusion: the ctm- performs well in the ed and exhibited only differential item difficulty by age; there was no significant difference by race, sex, or education level. furthermore, it is highly associated with likelihood of following physician recommendations. future studies will focus on ctm- scores ability to discriminate between patients who did or did not experience a subsequent ed visit or rehospitalization. age and race were found to be significant predictors of the race pathway. regression of the data by race revealed blacks (or . : ci . - . ; p < . ), hispanics (or . : ci . - . ; p = . ), and asians (or . : ci . - . ; p = . ), were more likely to enter the race cohort than were whites; however, much of this discrepancy is accounted for by age. the mean age of minority patients was years, while white patients were older at years (p = . ). conclusion: in a diverse demographic population we found that racial minorities were presenting at younger ages for chest pain and were more likely to receive cardiac testing at bedside than their white counterparts; and hence, were selected to a lower level of care (nonmonitored unit background: expanding insurance coverage is designed to improve access to primary care and reduce use of emergency services. whether expanding coverage achieves this is of paramount importance as the united states prepares for the affordable care act. objectives: we examined ed and outpatient department use after the state children's health insurance program (schip) coverage expansion, focusing on adolescents (a major target group for schip) versus young adults (not targeted). we hypothesized that coverage would increase use of outpatient services and emergency department services would decrease. methods: using the national ambulatory medical care survey and the national hospital ambulatory medical care survey, we analyzed years - as baseline and then compared use patterns in - after schip launch. primary outcomes were populationadjusted annual visits to ed versus non-emergency outpatient settings. interrupted time-series were performed on use rates to ed and outpatient departments between adolescents ( - years old) and young adults ( - years old) in the pre-schip and schip periods. outpatient-to-ed ratios were calculated and compared across time periods. results: the mean number of outpatient adolescent visits increased by visits per persons ( % ci, - ), while there was no statistically significant increase in young adult outpatient visits across time periods. there was no statistically significant change in the mean number of adolescent ed visits across time periods, while young adult ed use increased by visits per persons ( % ci, - ). the adolescent outpatient-to-ed ratio increased by . ( % ci, . - . ), while the young adults ratio decreased by . across time periods ( % ci, ) . to ) . ). conclusion: since schip, adolescent non-ed outpatient visits increased while ed visits remained unchanged. in comparison to young adults, expanding insurance coverage to adolescents improved access to health care services and suggests a shift to non-ed settings. as an observational study we are unable to control for secular trends during this time period. also as an ecological study we are unable to examine individual variation. expanding insurance through the affordable care act of will likely increase use of outpatient services but may not decrease emergency department volumes. background: cancer patients are receiving a greater proportion of their care on an outpatient basis. the effect of this change in oncology care patterns on ed utilization is poorly understood. objectives: to examine the characteristics of ed utilization by adult cancer patients. methods: between july and march , all new adult cancer patients referred to a tertiary care cancer centre were recruited into a study examining psychological distress. these patients were followed prospectively until september . the collected data were linked to administrative data from three tertiary care eds. variables evaluated in this study included basic we have previously shown that reducing non-value-added activities through the application of the lean process improvement methodology improves patient satisfaction, physician productivity and emergency department length of stay. objectives: in this investigation, we tested the hypothesis that non-value-added activities reduce physician job satisfaction. methods: to test this hypothesis, we conducted timemotion studies on attending emergency physicians working in an academic setting and categorized their activities into value-added (time in room with patient, time discussing cases and educating medical learners, time in room with patient and learner), necessary non-valueadded activities (charting, sign out, looking up labs), and unnecessary non-value-added activities (looking for things, looking for people, on the phone). the physicians were then surveyed using a -point likert scale to determine their relative satisfaction with each of the individual tasks ( worst part of day, best part of day). results: physicians spent % of their shift performing value-added work, % of their shift performing necessary non-value-added activities, and % of their shift performing unnecessary non-value-added activities (waste). weighted physician satisfaction (satisfaction x [percent time spent performing the activity / percent time engaged in activity category]) was highest when the physician was performing value-added work ( . ) compared to performing either necessary non-valueadded work ( . ) or waste ( . ). conclusion: the attending physicians we studied spent the majority of their time performing non-value-added activities, which were associated with lower satisfaction. application of process improvement techniques such as lean, which focus on reducing non-value-added work, may improve emergency physician job satisfaction. background: rocuronium and succinylcholine are the most commonly used paralytics for rapid sequence intubation (rsi) in the ed. after rsi, patients need sustained sedation while they are mechanically ventilated. however, the longer duration of action of rocuronium may influence subsequent sedation dosing, while the patient is therapeutically paralyzed. objectives: we hypothesized that patients who receive rocuronium would be more likely to receive lower doses of post-rsi sedation compared to patients who receive succinylcholine. methods: this was an observational, retrospective cohort study conducted in a tertiary, academic ed. consecutive adult patients, who received rsi using etomidate for induction of sedation between / / to / / , were included. patients were then categorized based on whether they received rocuronium or succinylcholine for paralysis. the dosing of post-rsi sedative infusions was compared at , , , and minutes after initiation between the two groups using the wilcoxon rank-sum test. results: a total of patients were included in the final analysis (rocuronium = , succinylcholine = ). mean age was and years in the rocuronium and succinylcholine groups, respectively (p = . ). there were no other baseline differences between groups with regard to demographics, reason for intubation, stroke, traumatic brain injury, glasgow coma scale score, pain scores, or vital signs. in the overall cohort, . % (n = ) of patients were given a sedative infusion or bolus in the ed. most patients were initiated on propofol (n = ) or midazolam (n = ) infusions. median propofol infusion rates at , , , and minutes were , , . , and mcg/kg/min in the rocuronium group and , , , and mcg/kg/ min in succinylcholine group, respectively. the difference was statistically significant at (p < . ) and (p = . ) minutes. median midazolam infusion rates at , , , and minutes were , , , and mg/hour in the rocuronium group and , , , and . mg/hour in succinylcholine group, respectively. the difference was statistically significant at (p = . ) and (p = . ) minutes. conclusion: patients who receive rocuronium are more likely to receive lower doses of sedative infusions post-rsi due to sustained therapeutic paralysis. this may put them at risk for being awake under paralysis. what is the impact of the implementation of an there was a difference in presenting pain (p < . ), stress (p < . ), and anxiety (p < . ) among patients that received an opioid in the ed. there was a difference in presenting pain (p < . ) for patients discharged with an opioid prescription, but not for stress (p = . ) or anxiety (p = . ). conclusion: patient-reported pain, stress, and anxiety are higher among patients who received an opiate in the ed than in those who did not, but only pain is higher among patients who received a discharge prescription for an opioid. methods: this was a prospective, randomized crossover study on the use of gvl and dl by incoming pediatric interns prior to advanced life support training. at the start of the study, the interns received a didactic session and expert modeling of the use of both devices for intubation. two scenarios were used: ( ) normal intubation with a standard airway and ( ) difficult intubation with tongue edema and pharyngeal swelling. interns then intubated laerdal simbaby in each scenario with both gvl and dl for a total of four randomized intubation scenarios. primary outcomes included time to successful intubation and the rate of successful intubation. the interns also rated their satisfaction with the devices using a visual analog scale ( - ) and chose their preferred device for their next intubation. results: interns were included in this study. in the normal airway scenario, there were no differences in the mean time for intubation with gvl or dl ( . ± . vs . ± . seconds, p = ns) or the number of interns who performed successful intubation ( vs , p = ns). in the difficult airway scenario, the interns took longer to intubate with gvl than dl ( . ± . vs . ± . seconds, p = . ), but there were no differences in the number of successful intubations ( vs , p = ns). interns rated their satisfaction higher for gvl than dl ( . ± . vs . ± . , p = . ) and gvl was chosen as the preferred device for their next intubation by a majority of the interns ( / , %). conclusion: for novice clinicians, gvl does not improve the time to intubation or intubation success objectives: to determine the time to intubation, the number of attempts, and the occurrence of hypoxia, in patients intubated with a c-mac device versus those intubated using a standard laryngoscope. methods: randomized controlled trial using exception from informed consent that included patients undergoing endotracheal intubation with a standard laryngoscope at an urban level i trauma center. eligible patients were randomized to undergo intubation using the c-mac or standard laryngoscopy. standard laryngoscopy was performed using a c-mac device laryngoscope with the video output obstructed to ensure equivalent laryngoscope blades in the two groups. data were collected by a trained research assistant at the patient's bedside and video review by the investigators. the number of attempts made, the initial and lowest oxygen saturation (spo ), and the total time until the intubation was successful was recorded. hypoxia was defined as an oxygen saturation < %. data were compared with wilcoxon rank sum and chi-square tests. results: thirty-eight patients were enrolled, ( % male, median age , range to , median spo %, range to ) in the standard laryngoscopy group and ( % male, median age , range to , median spo . %, range to ) in the c-mac group. the median number of attempts for standard laryngoscopy was , range to , and for c-mac was , range to (p = . ). the median time to intubation for the standard laryngoscopy group was seconds (range to ) and for the c-mac group was seconds (range to )(p = . ). hypoxia was detected in / ( %) in the standard laryngoscopy group and / ( %) in the c-mac group (p = . ). the median decrease in oxygen saturation during the attempt was . % (range % to %) for the standard laryngoscopy group and . % (range % to %) for the c-mac group. conclusion: we did not detect a difference in number of attempts, the occurrence of hypoxia, or the diagnosis of aspiration pneumonia between standard laryngoscopy and the c-mac. the time to successful intubation was shorter for patients intubated with the c-mac. the c-mac device appears to be superior to standard laryngoscopy for emergent endotracheal intubation. (originally submitted as a ''late-breaker.'') the background: aspiration pneumonia is a complication of endotracheal intubation that may be related to the difficulty of the airway procedure. objectives: to determine the association of the device used, the time to intubation, the number of attempts to intubate, and the occurrence of hypoxia with the subsequent development of aspiration pneumonia. methods: this was a prospective observational study of patients undergoing endotracheal intubation by emergency physicians at an urban level i trauma center conducted from / / until / / . the device used on the initial attempt to intubate was at the discretion of the treating physician. data were collected by a trained research assistant at the patient's bedside. the device used, the number of attempts made to intubate, the lowest oxygen saturation during the attempt, and the total time until intubation was successfully accomplished were recorded. patient's medical records were reviewed for the subsequent diagnosis of aspiration pneumonia. hypoxia was defined as an oxygen saturation < %. data were analyzed using multinomial logistic regression and odds ratios (or). results: patients were enrolled; ( %) subsequently developed aspiration pneumonia. were intubated with a standard laryngoscope (sl), using the c-mac, with an intubating laryngeal mask, and with nasotracheal intubation (ni) (or . , % ci = . - . ). comparison of individual devices versus sl did not show an association by device type. the median number of attempts for patients with aspiration pneumonia was , range to , and for those without was , range to (or . , %ci = . - . ). the median time to intubation for patients who developed aspiration pneumonia was seconds (range to ) and for those who did not was seconds (range to )(or . , %ci = . - . ). hypoxia during intubation was detected in / ( %) in the aspiration pneumonia group and / ( %) in the no aspiration pneumonia group (or . , % ci = . - . ). conclusion: there was not an association between the device used, the number of attempts, the time to intubation, or the occurrence of hypoxia during the intubation, and the subsequent occurrence of aspiration pneumonia. background: japanese census data estimate that million, or nearly % of the overall population, will be over age by the year . similar trends are apparent throughout the developed world. although increased patient age affects airway management, comprehensive information in emergency airway management for the elderly is lacking. objectives: we sought to characterize emergency department (ed) airway management for the elderly in japan including success rate, and major adverse events using a large multi-center registry. methods: design and setting: we conducted a multicenter prospective observational study using the japanese emergency airway network (jean) registry of eds at academic and community hospitals in japan between and inclusive. data fields included ed characteristics, patient and operator demographics, methods of airway management, number of attempts, success rate, and adverse events. participants: patient inclusion criteria were all adult patients who underwent emergent tracheal intubation in the ed. primary analysis: patients were divided to into two groups defined as follows: to years old and over years old. we describe primary success rates and major adverse events using simple descriptive statistics. categorical data are reported as proportions and % confidence intervals (cis). results: the database recorded patients (capture rate %) and met the inclusion criteria. of patients, patients were to years old ( %) and were over years old ( %). the older group had a significantly higher success rate at first attempt intubation ( / ; . %, % ci . - . %) compared with the younger group ( / ; . %, % ci . - . %). the older group had similar major adverse event rates ( / ; . %, % ci . - . %) compared with the younger group ( / ; . %, % ci . - . %). (see table ) background: the degree to which a patient's report of pain is associated with changes in blood pressure, heart rate, and respiratory rate is not known. objectives: to determine to what degree a standardized painful stimulus effects a change in systolic blood pressure (sbp), diastolic blood pressure (dbp), heart rate (hr), or respiratory rate (rr), and compare changes in vital signs between patients based on pain severity. methods: prospective observational study of healthy human volunteers. subjects had their sbp, dbp, hr, and rr measured prior to pain exposure, immediately after, and minutes after. pain exposure consisted of subjects placing their hand in a bath of degree water for seconds. the bath was divided into two sections; the larger half was the reservoir of cooled water monitored to be degrees, the other half filled from constant overflow over the divider. water drained from this section into the cooling unit and was then pumped up into the base of the reservoir through a diffusion grid. subjects completed a mm visual analog scale (vas) representing their perceived pain during the exposure and graded their pain as minimal, moderate or severe. data were compared using % confidence intervals. results: subjects were enrolled, mean pain vas mm, range to , reported mild pain, moderate pain, and severe pain. the percent change from baseline in vital signs during the exposure and minutes after are presented in the table. conclusion: there was a wide variety in reported pain among subjects exposed to a standard painful stimulus. there was a larger change in heart rate during the exposure among subjects who described a standardized painful exposure as moderate than in those who described it as severe. the small observed changes in blood pressure and respiratory rate seen during the exposure did not differ by pain report or persist after minutes. background: vital signs are often used to validate intensity of pain. however, few studies have looked at the capacity of vital signs to estimate pain intensity, particularly in patients with a diagnosis that a majority of physicians would agree produce significant pain in the ed. objectives: to determine the association between pain intensity and vital signs in consecutive ed patients and in a sub-group of patients with diagnosis known to cause significant pain. methods: we performed a post-hoc analysis of prospectively acquired data in a cohort study done in an urban teaching hospital with computerized triage and nurses records. we included all consecutive ed adult patients ( ‡ years old), who had any level of pain intensity measured during triage, from march to november . the primary outcome was the mean heart rate, systolic and diastolic blood pressure for every pain intensity level from to on a verbal numerical scale. our secondary outcomes where the same but limited to patients with the following diagnosis: fracture, dislocation, and renal colic. we performed descriptive statistics, one-way and two-way anovas when appropriate. results: during our study period, , patients ‡ years old where triaged with a pain intensity of at least / and had a diagnosis known to cause significant pain. . % of patients were female, with a mean pain intensity of . / , mean age of . years (± . ), and . % were ‡ years old. there was a statistically significant difference (p < . ) in mean heart rate, systolic and diastolic blood pressure for each level of pain intensity, ex: difference between / and / for mean heart rate was . beats per minutes, for systolic pressure was . mmhg and for diastolic . mmhg. results are similar for painful diagnosis: difference for mean heart rate was . beats per minutes, for systolic pressure was . mmhg and diastolic . mmhg. however, these differences are not clinically significant. conclusion: although our study is a post hoc analysis, pain intensity, heart rate, systolic and diastolic pressures during triage are usually reliable data and a prospective study would likely produce the same result. these vital signs cannot be used to estimate or validate pain intensity in the emergency department. % had a positive urine drug screen. logistic multivariate regressions analyses revealed the following factors to be significantly associated with the risk of having an abnormal head ct: association with seizure (p = . ); length of time of loss of consciousness, ranging from none to - min to > min (p = . ); alteration of consciousness (p = . ); post-traumatic amnesia (p = . ); alcohol intake prior to injury (p = , ); and initial ed gcs (p = . ). conclusion: in an emergency department cohort of patients with traumatic brain injury, symptoms including loss of or alteration in consciousness, seizure, post traumatic amnesia, and alcohol intake appear to be significantly associated with abnormal findings on head ct. these clinical findings on presentation may be useful in helping triage head injury patients in a busy emergency department, and can further define the need for urgent or emergent imaging in patients without clearly apparent injuries. background: the etiology of neurogenic shock is classically attributed to diminished peripheral vascular resistance (pvr) secondary to loss of sympathetic outflow to the peripheral vasculature. however, the sympathetic nervous system also controls other key elements of the cardiovascular system such as the heart and capacitance vessels and disruptions in their function could complicate the hemodynamic presentation. objectives: we sought to systematically examine the hemodynamic profiles of a series of trauma patients with neurogenic shock. methods: consecutive trauma patients with documented spinal cord injury complicated by clinical shock were enrolled. hemodynamic data including systolic and diastolic blood pressure, heart rate (hr), impedance-derived cardiac output, pre-ejection period (pep), left ventricular ejection time (lvet), and calculated systemic pvr were collected in the ed. data were normalized for body surface area and a validated integrated computer model of human physiology (guyton model) was used to analyze and categorize the hemodynamic profiles based on etiology of the hypotension using a systems analysis. correlation between markers of sympathetic outflow (hr, pep, lvet) and shock etiology category was examined. results: of patients with traumatic neurogenic shock, the etiology of shock was decrease in pvr in ( %; % ci to %), loss of vascular capacitance in ( %; to %), and mixed peripheral resistance and capacitance responsible in ( %; to %). the markers of sympathetic outflow had no correlation to any of the elements in the patients' hemodynamic profiles. conclusion: neurogenic shock is often considered to have a specific well-characterized pathophysiology. results from this study suggest that neurogenic shock can have multiple mechanistic etiologies and represents a spectrum of hemodynamic profiles. this understanding is important for the treatment decisions made in the management of these patients. -year ( - ) , pre-post intervention study of trauma patients requiring massive blood transfusion was performed. we divided the population into two cohorts: a pre-protocol group (pre) which included trauma patients receiving mbt not aided by a protocol, and a post-protocol group (post) who underwent mbt via the mbtp. patient demographics, hour blood component totals, timing of blood component delivery, trauma injury severity score (iss), initial glasgow coma scale (gcs) score, trauma mechanism, and patient mortality data were collected and analyzed using fisher's exact tests, student's t-tests, and mann-whitney u tests. results: fifty-two patients were included for study. median times to delivery of first products were reduced for prbcs ( minutes), ffp ( minutes), and platelets ( minutes) between the pre and post cohorts. median time to delivery of any subsequent blood product was significantly reduced ( minutes) in the post cohort (p = . ). the median number of blood products delivered was increased by . units for prbcs, units for ffp, . units for platelets, and unit for cryoprecipitate after implementation of mbtp. the percentage of patients receiving higher blood product ratios (> : ) was reduced between the pre and post cohorts for prbc to ffp ( % reduction) and prbc to platelet ratio groups ( % reduction). despite improved transfusion timing and ratios, we found no significant difference in mortality (p = . ) between pre and post cohorts when we adjusted for injury severity. conclusion: protocolized delivery of massive blood transfusion might reduce time to product availability and delivery, though it is unclear how this affects patient mortality in all us trauma centers. background: burns are common injuries that can result in significant scarring leading to poor function and disfigurement. unlike mechanical injuries, burns often progress both in depth and size over the first few days after injury, possibly due to inflammation and oxidative stress. a major gap in the field of burns is the lack of an effective therapy that reduces burn injury progression. objectives: since mesenchymal stem cells (msc) have been shown to improve healing in several injury models, we hypothesized that species-specific msc would reduce injury progression in a rat comb burn model. methods: using a gm brass comb preheated to degrees celsius, we created four rectangular burns, separated by three unburned interspaces on both sides of the backs of male sprague-dawley rats ( g). the interspaces represented the ischemic zones surround-ing the central necrotic core. left untreated, most of these interspaces become necrotic. in an attempt to reduce burn injury progression, rats were randomized to tail vein injections of ml rat-specific msc cells/ml (n = ) or normal saline (n = ) minutes after injury. tracking of the stem cells was attempted by injecting several rats with quantum dot-labeled msc. results: by four days post-injury, all of the interspaces in the control rats ( / , %) became necrotic while in the experimental group, / ( %) of the interspaces became necrotic (fisher's exact test; p < . ). at days, the percentage of the unburned interspaces that became necrotic in the msc treated group was significantly less than in the control group ( % vs. %, p < . ). we were unable to identify any quantum dot labeled msc in the injured skin. no adverse reactions or wound infections were noted in rats injected with msc. conclusion: intravenous injection of rat msc reduced burn injury progression in a rat comb burn model. although basic demographics of bicyclists in accidents have been described, there is a paucity of data describing the street surface involved in accidents, and whether designated bicycle roadways offer protection. this lack of information limits informed attempts to change infrastructure in a way that will decrease morbidity and/or mortality of cyclists. objectives: to identify road surface types involved in pedal cyclist injuries and determine the relationship between injury severity and the use of designated bicycle roadways (dbr) versus non-designated roadways (ndr). we hypothesized that more severe injuries would happen at intersections regardless of dbr versus ndr. methods: this retrospective cohort study reviewed the trauma database from a level i trauma center in tucson, az. we identified all bicyclists in the database injured in accidents involving a motor vehicle from january , , through december , . the patients were then linked to a local government database that documents location (latitude/longitude) and direction of travel of the cyclist. seventy-eight total incidents were identified and categorized as occurring on a dbr versus ndr and occurring at an intersection versus not at an intersection. results: only one patient who arrived at the trauma center died. fifty-one of the accidents ( %) occurred on dbrs; % of accidents occurring on dbrs took place in intersections. conversely, % of accidents on ndrs occurred outside of intersections. the odds of an injury occurring at an intersection versus not at an intersection were . times higher ( % ci: . - . ) for dbrs compared to ndrs. the odds of a trauma being severe (admitted) versus not severe (discharged home) were . times higher ( % ci: . - . ) when a collision occurred not at an intersection versus at an intersection. conclusion: contrary to our hypothesis, in this study group severe injuries were more likely outside of an intersection. however, intersections on dbrs were identified as problematic as cyclists on a dbr were more likely to be injured in an intersection. future city planning could target improved cyclist safety in intersections. background: minor thoracic injury (mti) is frequent and a significant proportion will still have moderate to severe pain at days. there is a lack of risk factors to orient specific treatment at ed discharge. objectives: to determine risk factors of having pain ( ‡ / , on a numerical intensity pain score from to ) at days in a population of minor thoracic injury patients discharged from the ed. methods: a prospective multi-center cohort study was conducted in four canadian eds, from november to january . all consecutive patients, years and older, with mti (with or without rib fracture), a normal chest x-ray, and discharged from the ed were eligible. a standardized clinical and radiological evaluation was done at and weeks. standardized phone interviews were done at and days. pain evaluation occurred at five time points (ed visit, and weeks, and days). using a pain trajectory model (sas), we planned to identify groups with different pain evolution at days. the final model was based on the importance of difference in pain evolution, confidence intervals, and number of patients in each group. to judge the adequacy of the final model, we examined whether the posteriori probabilities (i.e., a participant's probability of belonging to a certain trajectory group) averaged at least % for each trajectory group. then using logistic multinomial regression and the low risk group of having pain as the control group, we identified significant predictors of patients in the moderate and high risk groups having pain at days. results: in our cohort of , patients, , had an evaluation at days. we identified three groups at low ( %), moderate ( . %), and high risk ( . %) of having pain ‡ / at days. using risk factor identified by univariate analysis, we created a model to identify patients at risk containing the following predictors: age ‡ years old, women, current smoker, two or more rib fractures, complaint of dyspnea, and saturation < % at initial visit. posteriori probabilities for low, moderate, and high risk were %, %, and %. conclusion: to our knowledge, this is the first study to identify potential risk factor for having pain at days after minor thoracic injury. these risk factors should be validated in a prospective study to guide specific treatment plan. the use of ultrasound to evaluate traumatic optic neuropathy benjamin burt, lisa montgomery, cynthia garza meissner, sanja plavsic-kupesic, nadah zafar ttuhsc -paul l foster school of medicine, el paso, tx background: whenever head trauma occurs, there is the possibility for a patient to have an optic nerve injury. the current method to evaluate optical nerve swelling is to look for proptosis. however, by the time proptosis presents, significant damage has already occurred. therefore, there is a need to establish a method to evaluate nerve injury prior to the development of proptosis. objectives: fundamental to understanding the pathophysiology of optic nerve injury and repair is an understanding of the optic nerve's temporal response to trauma including blood flow changes and vascular reactivity. the aim of our study was to assess the dependability and reproducibility of ultrasound techniques to sequence optic nerve healing and monitor the vascular response of the ophthalmic artery following an optic nerve crush. methods: the rat's orbit was imaged prior to and following a direct injury to the optic nerve, at hours and at days. d, d, and color doppler techniques were used to detect blood flow and the course of the ophthalmic artery and vein, to evaluate the course and diameter of the optic nerve, and to assess the extent of optic nerve trauma and swelling. the parameters used to evaluate healing over time were pulsatility and resistance indices of the ophthalmic artery. results: we have established baseline ultrasound measurements of the optic nerve diameter, normal resistance and pulsatility indices of the ophthalmic artery, and morphological assessment of the optic nerve in a rat model. longitudinal assessment of d and d ultrasound parameters were used to evaluate vascular response of the ophthalmic artery to optic nerve crush injury. we have developed a rat model system to study traumatic optic nerve injury. the main advantages of ultrasound are low cost, non-invasiveness, lack of ionizing radiation, and the potential to perform longitudinal studies. our preliminary data indicate that d and d color doppler ultrasound may be used for the evaluation of ophthalmic artery and total orbital perfusion following trauma. once baseline ultrasound and doppler measurements are defined there is the opportunity to translate the rat model to evaluate patients with head trauma who are at risk for optic nerve swelling and to assess the usefulness of treatment interventions. background: alcoholism is a chronic disease that affects an estimated . million american adults. a common presentation to the emergency department (ed) is a trauma patient with altered sensorium who is presumed to be alcohol intoxicated by the physicians based on their olfactory sense. often ed physicians may leave patients suspected of alcohol intoxication aside until the effects wear off, potentially missing major trauma as the source of confusion or disorientation. this practice often results in delays in diagnosing acute potentially life-threatening injuries in the patients with presumed alcohol intoxication. objectives: this study will determine the accuracy of physicians' olfactory sense for diagnosing alcohol intoxication. methods: patients suspected of major trauma in the ed underwent an evaluation by the examining physician for the odor of alcohol as well as other signs of intoxication. each patient had determination of blood alcohol level. alcohol intoxication was defined as a serum ethanol level ‡ mg/dl. data were reported as means with % confidence intervals ( % ci) or proportions with inter-quartile ranges (iqr %- %). results: one hundred and fifty one patients ( % males) were enrolled in the study, median age years (iqr - ). the median score for glasgow coma scale was . the level of training of examining physician was a median of pgy (iqr pgy -attending). prevalence of alcohol intoxication was % ( % ci: % to %). operating characteristics: physician assessment of alcohol intoxication, sensitivity % ( % ci: % to %), specificity % ( % ci: % to %), positive likelihood ratio . ( % ci: . to . ), negative likelihood ratio . ( % ci: . to . ), and accuracy % ( % ci: % to %). patients who were falsely suspected of being intoxicated were . % ( % ci: % to %). conclusion: although the physicians had a high degree of accuracy in identifying patients with alcohol intoxication based on their olfactory sense, they still falsely overestimated intoxication in a significant number of non-intoxicated trauma patients. the background: optimal methods for education and assessment in emergency and critical care ultrasound training for residents are not known. methods of assessment often rely on surrogate endpoints which do not assess the ability of the learner to perform the imaging and integrate the imaging into diagnostic and therapeutic decisions. we designed an educational strategy that combines asynchronous learning to teach imaging skills and interpretation with a standardized assessment tool using a novel ultrasound simulator to assess the learner's ability to acquire and interpret images in the setting of a standardized patient scenario. objectives: to assess the ability of emergency medicine and surgical residents to integrate and apply information and skills acquired in an asynchronous learning environment in order to identify pathology and prioritize relevant diagnoses using an advanced cardiac ultrasound simulator. methods: em r residents and r surgical residents completed an online focused training program in cardiac ultrasonography (iccu elearning, https:// www.caeiccu.com/lms). this consisted of approximately hours of intensive training in cardiac ultrasound. residents were then given cases with a patient scenario that lacked significant details that would suggest a specific diagnosis. the resident was then given a list of possible diagnoses and asked to rank the top five diagnoses in order of most likely to least likely. each resident (blinded to the pathology displayed by the simulator) then imaged using an ultrasound simulator. after imaging, the residents were given the same list of potential diagnoses, and asked to rank them again from - . results: overall, residents ranked the correct diagnosis in the top five significantly more times post-ultrasound than pre-ultrasound. additionally, the residents made the correct diagnosis significantly more times postultrasound than pre-ultrasound. similar patterns occur for congestive heart failure, pericardial effusion with tamponade, and pleural effusion. there was no significant difference pre-and post-ultrasound for pulmonary embolism and anterior infarction. conclusion: an asynchronous online learning program significantly improves the ability of emergency medicine and surgical residents to correctly prioritize the correct diagnosis after imaging with a standardized pathology imaging simulator. mark favot, jacob manteuffel, david amponsah henry ford hospital, detroit, mi background: em clerkships are often the only opportunity medical students have to spend a significant amount of time caring for patients in the ed. it is imperative that students gain exposure to as many of the various fields within em as possible during this time. if the exposure of medical students to ultrasound is left to the discretion of the supervising physicians, we feel that many students would complete an em clerkship with limited skills and knowledge in ultrasound. the majority of medical students receive no formal training in ultrasound during medical school and we believe that the em clerkship is an excellent opportunity to fill this educational gap. objectives: evaluate the usefulness and effectiveness of a focused ultrasound curriculum for medical students in an em clerkship at a large, urban, academic medical center. methods: prospective cohort study of fourth year medical students doing an em clerkship. as part of the clerkship requirements, the students have a portion of the curriculum dedicated to the fast exam and ultrasound-guided vascular access. at the end of the month they take a written test, and month later they are given a survey via e-mail regarding their ultrasound experience. em residents also completed the test to serve as a comparison group. all data analysis was done using sas . . scores were integers ranging between and . descriptive statistics are given as count, mean, standard deviation, median, minimum, and maximum for each group. due to non-gaussian nature of the data and small group sizes, a wilcoxon two-sample test was used to compare the distributions of scores between the groups. results: in the table, the distribution of scores was compared between the residents (controls) and the students (subjects). the mean and median scores of the student group were higher than those of the resident group. the difference in scores between the two groups was statistically significant (p = . ). conclusion: our data reveal that after completing an em clerkship with time devoted to learning ultrasound for the fast exam and vascular access, fourth year medical students are able to perform better than em residents on a written test. what remains to be determined is if their skills in image acquisition and in performance of ultrasound-guided vascular access procedures also exceed those of em residents. results: there were respondents (total response rate . %). compared to non-em students, students pursuing em ( students, . %) were more drawn to their specialty for work hour control (p < . ) and shorter residency length (p < . ). em students were less likely than non-em students to be drawn to their chosen specialty for future academic opportunities (p < . ). em students formed their mentorships by referral significantly more than non-em students (p < . ), though there was no statistical difference in quality of existing mentorships amongst students. of the students not currently and never formerly interested in em, the most common response ( . %) for why they did not choose em was the lack of a strong mentor in the field. conclusion: the results confirmed previous findings of lifestyle factors drawing students to em. future academic opportunities were less likely to draw students to em than students pursuing other specialties. lack of mentorship in the field was the most common reason given for why students did not consider em. given the lack of direct em exposure until late in the curriculum of most medical schools, mentorship may be particularly important for em and future study should focus on this area. background: misdiagnosis is a major public health problem. dizziness leads to million visits annually in the us, including . million to the emergency department (ed). despite extensive ed workups, diagnostic accuracy remains poor, with at least % of strokes missed in those presenting with dizziness. ed physicians need and want support, particularly in the best method for diagnosis. strong evidence now indicates the bedside oculomotor exam is the best method of differentiating central from peripheral causes of dizziness. objectives: after a vertigo day that includes instruction in head impulse testing, emergency medicine residents will feel comfortable discharging a patient with signs of vestibular neuritis and a positive head impulse test without ordering a ct scan. methods: post graduate year - emergency medicine residents participated in a four hour vertigo day. we developed a mixed cognitive and systems intervention with three components: an online game that began and ended the day, a didactic taught by dr. newman-toker, and a series of small group exercises. the small group sessions included the following: a question and answer session with the lecturer; vertigo special tests (cerebellar assessment, dix hall-pike, epley maneuver); a head impulse hands-on tutorial using a mannequin; and a video lecture on other tests useful in vertigo evaluation (nystagmus, test of skew, vestibulocular reflex, ataxia). results: thirty emergency medicine residents were studied. before and after the intervention the residents were given a survey in which one question asked ''in a patient with acute vestibular syndrome and a history and exam compatible with vestibular neuritis, i would be willing to discharge the patient without neuroimaging based on an abnormal head impulse test result that i elicited''. resident answers were based on a sevenpoint likert scale from strongly agree to strongly disagree. twenty-five residents completed both surveys. of the seven residents who changed their responses pre to post,a significant proportion ( %) changed their answer from disagree/neutral to agree after a hour vertigo day (mcnemar's test, p value = . ). conclusion: in this single-center study, teaching headimpulse testing as part of a vertigo day increases resident comfort with discharging a patient with vestibular neuritis without a ct scan. background: previous studies have been inconsistent in determining the effect of increased ed census on resident workload and productivity. we examined resident workload and productivity after the closure of a large urban ed near our facility, which resulted in a rapid % increase in our census. objectives: we hypothesized that the closure of a nearby hospital closure with a resulting influx of ed patients to our facility would not change resident productivity. methods: this computer-assisted retrospective study compared new patient workups per hour and patient load before and after the closure of a large nearby hospital. specifically, new patient workups per hour and the pm patient census per resident were examined for a one-year period in the calendar year prior to the closing and also for one year after the closing. we did not include the four month period surrounding the closure in order to determine the long-term overall effect. background: emergency medicine residents use simulation for training due to multiple factors including the acuity of certain situations they are faced with, and the rarity of others. current training on highfidelity mannequin simulators is often critiqued by residents over the physical exam findings present, specifically the auscultatory findings. this detracts from the realism of the training, and may also lead a resident down a different diagnostic or therapeutic pathway. wireless remote programmed stethoscopes represent a new tool for simulation education which allows any sound to be wirelessly transmitted to a stethoscope receiver. objectives: our goal was to determine if a wireless remote programmed stethoscope was a useful adjunct in simulation-based cases using a high-fidelity mannequin. our hypothesis was that this would represent a useful adjunct in simulation education of emergency medicine residents. methods: starting june , pgy - emergency medicine residents were assessed in two simulation-based cases using pre-determined scoring anchors. an experimental randomized crossover design was used in which each resident performed a simulation case with and without a remote programmed stethoscope on a highfidelity mannequin. scoring anchors and surveys were used to collect data with differences of means calculated. results: fourteen residents participated in the study. residents noted most realistic physical exam findings associated with the case with the adjunct in / ( %) and that their preference was for the use of the adjunct in / ( %). based off of a five-point likert scale, with being the most realistic, the adjunct-associated case averaged . as compared to . without (difference of means . , p = . ). average scores of residents with the adjunct were . / with the use of the adjunct and . / without (difference of means . , p = . ). average total times were : with the adjunct as compared to : without. conclusion: a wireless remote programmed stethoscope is a useful adjunct in simulation training of emergency medicine residents. residents noted physical exam findings to be more realistic, preferred its use, and had approached significant improvement of scores when using the adjunct. background: prior studies predict an ongoing shortage of emergency physicians to staff the nation's eds, especially in rural areas. to address this, em organizations have discussed broadening access to acgme or aoa accredited em residency programs to physicians who previously trained in another specialty and focusing on physicians already practicing in rural areas. objectives: to investigate whether em program directors (pds) from allopathic and osteopathic residency programs would be willing to accept applicants previously trained in other specialties and whether this willingness is modified by applicants' current practice in rural areas. methods: a five-question web-based survey was sent to u.s. em pds asking questions about their policies on accepting residents with past training and from rural practices. questions included whether a pd would accept a resident with prior training in other specialties, how many years from this training would the applicant be still a competitive candidate and if a physician was practicing in a rural region would the likelihood of acceptance to the program be improved. different characteristics of the residency programs were recorded including length of program, years in existence, size, type, and location of program. we compared responses by program characteristics using chi-square test. results: of the ( %) pds responding to date, a large majority ( %) reported they do accept applicants with previous residency training, although directors of osteopathic programs were less likely to accept these applicants ( % vs % for allopathic; p < . ). overall, % of pds reported no limit on the length of time from prior training to when they are accepted at an em program. % reported it is very or possibly realistic they would accept a candidate who had completed training and was board certified in another specialty. a majority of all respondents ( %) felt a physician practicing in a rural setting might be viewed as a more favorable candidate, even if the resident would only be in the program for years after receiving training credit. directors of newer programs (< years of existence) were more likely to view these candidates favorably than older programs ( % vs %; p = . ). conclusion: there appear to be many em residency programs that would at least review the application and consider accepting a candidate who trained in another specialty. a qualitative assessment of emergency medicine self-reported strengths todd guth university of colorado, aurora, co background: self-reflection has been touted as a useful way to assess the acgme core competencies. objectives: the purpose of this study is to gain insight into resident physician professional development through analysis of self-perceived strengths. a secondary purpose is to discover potential topics for selfreflective narrative essays relating to the acgme core competencies. methods: design: a small qualitative study was performed to explore the self-reported strengths of emergency medicine (em) residents in a single four-year residency. participants: all residents regardless of year of training were also asked to report their selfperceived strengths. observations: residents were asked: ''what do you feel are your greatest strengths as a resident? provide a quick description.'' the author and another reviewer identified themes from within each year of residency with abraham maslow's conscious competence conceptual framework in mind. occurrences of each theme were counted by the reviewers and organized according to frequency. once the top ten themes for each year of residency were identified and exemplar quotes identified, the two reviewers identified trends. inter-rater agreements were calculated. results: representing unconscious incompetency, the first trend was the reported presence of ''enthusiasm and a positive attitude'' from residents early in their training that decreases further along in training. additionally, a ''willingness and motivation to improve and learn'' was reported as a strength throughout all the years of training but most frequently reported in the first two years of residency. entering into conscious incompetence, the second trend identified was ''recognition of limitations and openness to constructive feedback'' that was mentioned frequently in the second and third years of residency. demonstrating conscious competence, the third trend identified was the increase in identification of the strengths of ''educational leadership, teamwork skills and communication, and departmental patient flow and efficiency'' in the later years of residency. conclusion: self-reported strengths has helped to identify both themes within each year of residency and trends among the years of residency that can serve as areas to explore in self-reflective narratives relating to the acgme core competencies. training. pofu can also be used to assess the acgme core competency of practice-based learning. the exact form or frequency of pofu assessment among various em residencies, however, is not currently known. objectives: we aimed to survey em residencies across the country to determine how they fulfill the pofu requirement and whether certain program structure variables were associated with different pofu systems. we hypothesized that implementation of pofu systems among em residencies would be highly variable. methods: in this irb-approved study, all program directors of acgme allopathic em residencies were invited to complete a -question survey on their current approaches to pofu. respondents were asked to describe their current pofu system's characteristics and rate its ease of use, effectiveness, and efficiency. data were collected using surveymonkey(tm) and reported using descriptive statistics. results: of residencies surveyed, ( %) submitted complete data. . % were completed by program directors and over three-fourths ( . %) of em residencies require monthly completion of pofus. the mean total pofus required per year was ( % ci - ), with a median of and a range of - . almost / ( %) of residencies use an electronic pofu system. most ( %) -year em residencies use an electronic pofu system, compared with half ( %) of -year residencies (difference %, p = . , % ci . %- . %). seven commercially available electronic programs are used by % of the residencies, while % use a customized product. most respondents ( %) rated their pofu system as easy to use, but less than half ( %) felt it was an effective learning tool or an efficient one ( %). onethird ( %) would use a different pofu system if available, and almost half ( %) would be interested in using a multi-residency pofu system. conclusion: em residency programs use many different strategies to fulfill the rrc requirement for pofu. the number of required pofus and the method of documentation vary considerably. about two-thirds of respondents use an electronic pofu system. less than half feel that pofu logs are an effective or efficient learning tool. background: certification of procedural competency is requisite to graduate medical education. however, little is known regarding which platforms are best suited for competency assessment. simulators offer several advantages as an assessment modality, but evidence is lacking regarding their use in this domain. furthermore, perception of an assessment environment has important influence on the quality of learning outcomes, and procedural skill assessment is ideally conducted on a platform accepted by the learner. objectives: to ascertain if a simulator performs as well as an unembalmed cadaver with regard to residents' perception of their ability to demonstrate procedural competency during ultrasound (us) guided internal jugular vein (ij) catheterization. methods: in this cross-sectional study at an urban community hospital during july of , residents in their second or third year of training from a -year em residency program performed us guided catheterizations of the ij on both an unembalmed cadaver and a simulator manufactured by blue phantom. after the procedure, residents completed an anonymous survey ascertaining how adequately each platform permitted their demonstration of proficiency on predefined procedural steps. answers were provided on a likert scale of to , with being poor and being excellent. p values < . were considered educationally significant. results: the median overall rating of the simulator (s) to serve as an assessment platform was similar to that of the cadaver (c) with scores of . and . respectively, p = . . median ratings for permitting the demonstration of specific procedural steps were as follows: conclusion: senior em residents positively rate the blue phantom simulator as an assessment platform and similarly to that of a cadaver with regard to permitting their demonstration of procedural competency for us guided ij catheterization, but did prefer the cadaver to a greater degree when identifying and guiding the needle into the ij. methods: in fall , wcmc and wcmc-q students taking the course completed a question pre-and post-test. wcmc-q students also completed a postcourse single-station objective structured clinical examination (osce) that evaluated their ability to identify and perform eight actions critical for a first responder in an emergency situation (table ) . results: on both campuses, mean post-test scores were significantly higher than mean pre-test scores (p £ . ). on the pre-test, mean wcmc student scores were significantly higher than for wcmc-q students (p = . ); however, no difference was found in mean post-test scores (p = . ). there was no association between the scores on the osce (mean = . , sd = . ) and the post-test (p = . ) even after adjusting for a possible evaluators' effect (table ) . clinical skills course was effective in enhancing student knowledge in both qatar and new york as evidenced by the significant improvement in scores from the pre-to post-tests. the course was able to bring wcmc-q student scores and presumably knowledge up to the same level as wcmc students. students performed well on the osce, suggesting that the course was able to teach them the critical actions required of a first responder. the lack of association between the post-test and osce scores suggests that student knowledge does not independently predict ability to learn and demonstrate critical actions required of a first responder. future studies will evaluate whether the course affects the students' clinical practice. assess breathing assess circulation call ems call ems and assess abcs prior to other interventions immobilize localize and control bleeding splint fractured extremity and skills specific to wilderness medicine by incorporating simulated medical scenarios into a day-long adventure race. this event has gained acceptance nationally in wilderness medical circles as an excellent way to appreciate the challenges of wilderness medicine, however its effectiveness as a teaching tool has not yet been verified. objectives: the objective of this study was to determine if improvement in simulated clinical and didactic performance can be demonstrated by teams participating in a typical medwar event. methods: we developed a complex clinical scenario and written exam to test the basic tenets that are reinforced through the medwar curriculum. teams were administered the test and scored on a standardized scenario immediately before and after the midwest medwar race. teams were not given feedback on their pre-race performance. scenario performance was based on the number of critical actions correctly performed in the appropriate time frame. data from the scenario and written exams were analyzed using a standard paired difference t-test. results: a total of teams participated in both the pre-and post-event scenarios. the teams' pre-race scenario performance was . % (sd = . , n = ) of critical actions met compared to a post-race performance of . % (sd = . , n = ). the mean improvement was . % (sd = . , n = , % ci . , . ) with a significant paired two-tailed t-test (p £ . ). a total of individual subjects took the written pre-and posttests. the written scores averaged pre-race . % (sd = . , n = ) and post-race . % (sd = . , n = ). the mean improvement was . % (sd = . , n = , ci ) . , . ), with a significant paired twotailed t-test (p £ . ). conclusion: medwar participants demonstrated a significant improvement in both written exam scores and the management of a simulated complex wilderness medical scenario. this strongly suggests that medwar is an effective teaching platform for both wilderness medicine knowledge and skills. palliative methods: ed residents and faculty of an urban, tertiary care, level i trauma center were asked to complete an anonymous survey ( / - / ). participants ranked statements on a five-point likert scale ( = strongly disagree- = strongly agree). statements covered four main domains of barriers related to: ) education/training, ) communication, ) ed environment; ) personal beliefs. respondents were also asked if they would call pc consult for ed clinical scenarios (based on established triggers). results: / ( %) eligible participants completed the survey ( residents, faculty), average age was years, % ( / ) male, and % ( / ) caucasian. respondents identified two major barriers to ed-pc provision: lack of hour availability of pc team (mean score . ) and lack of access to complete medical records ( . ). listed domain barriers included: communication-related issues (mean . ) like access to family or primary providers, ed environment ( . ) for example chaotic setting with time-constraints, education/training ( . ) related to pain/pc, and personal beliefs regarding end-of-life ( . ). all respondents agreed that they would call pc consult for a 'hospice patient in respiratory distress', and a majority ( %) would consult pc for 'massive intracranial hemorrhage, traumatic arrest, and metastatic cancer'. however, traditional in-patient triggers like frequent re-admits for organ failure issues (dementia, congestive heart failure, and obstructive pulmonary disease exacerbations) were infrequently ( %) chosen for pc consult. conclusion: to enhance pc provision in the ed setting, two main ed physician perceived barriers will likely need to be addressed: lack of access to medical records and lack of - availability of pc team. ed physicians may not use the same criteria to initiate pc consults as compared to the traditionally established inpatient pc consult trigger models. percent of charts with an mse by ait prior to resident evaluation (a measure of reduced diagnostic uncertainty and decision-making), ( ) ed volume. results: there were no educationally significant differences in productivity or acuity between the pre-ait and post-ait groups. mse was recorded in the chart prior to resident evaluation in . % of cases. ed volume rose by . % between periods. conclusion: ait did not affect productivity or acuity of patients seen by em s. while some volume was directed away from residents by ait (patients treated-andreleased by ait only), overall volume increased and made up the difference. this is similar to previously reported rankings that program directors gave to the same criteria. although medical students agreed with program directors on the importance of most aspects of the nrmp application areas of discordance included higher medical student ranking for extracurricular activities and a lower relative ranking for aoa status than program directors. this can have implications for medical student mentoring and advising in the future. background: emergency care of older adults requires specialized knowledge of their unique physiology, atypical presentations, and care transitions. older adults often require distinctive assessment, treatment and disposition. emergency medicine (em) residents should develop expertise and efficiency in geriatric care. older adults represent over % of most emergency department (ed) volumes. yet many em residencies lack curricula or assessment tools for competent geriatric care. the geriatric emergency medicine competencies (gemc) are high-impact geriatric topics developed to help residencies meet this demand. objectives: to examine the effect of a brief gemc educational intervention on em resident knowledge. methods: a validated -question didactic test was administered at six em residencies before and after a gemc focused lecture delivered summer and fall of . scores were analyzed as individual questions and in defined topic domains using a paired student's t-test. results: a total of exams were included. the testing of didactic knowledge before and after the gemc educational intervention had high internal reliability ( . %). the intervention significantly improved scores in all domains (table ) . graded increase in geriatric knowledge occurred by pgy year with the greatest improvement seen at the pgy level (table ) . conclusion: even a brief gemc intervention had a significant effect on em resident knowledge of critical geriatric topics. a formal gemc curriculum should be considered in training em residents for the demands of an ageing population. the overall procedure experience of this incoming class was limited. most r s had never received formal education in time management, conflict of interest management, or safe patient trade-off. the majority lacked confidence in their acute and chronic pain management skills. these entry level residents lacked foundational skill levels in many knowledge areas and procedures important to the practice of em. ideally medical school curricular offerings should address these gaps; in the interim, residency curricula should incorporate some or all of these components essential to physician practice and patient safety. background: the american heart association and international liaison committee on resuscitation recommend patients with return of spontaneous circulation following cardiac arrest undergo post-resuscitation therapeutic hypothermia. in post-cardiac arrest patients presenting with a rhythm of vf/vt, therapeutic hypothermia has been shown to reduce neurologic sequelae and decrease overall mortality. objectives: to explore clinical practice regarding the use of therapeutic hypothermia and compare survival outcomes in post-cardiac arrest patients. a secondary outcome was to assess whether the initial presenting cardiac arrest rhythm (ventricular fibrillation/ventricular tachycardia (vf/vt) versus pulseless electrical activity (pea) or asystole) was associated with differences in outcomes. methods: a retrospective medical record review was conducted for all adult ( ‡ years) post-cardiac arrest patients admitted to the icu of an academic tertiary care centre (annual ed census , ) from - . data were extracted using a standardized data collection tool by trained research personnel. results: patients were enrolled. mean (sd) age was ( ) and . % were male. of ( . %) patients treated with hypothermia, ( . %) presented with an initial rhythm of vf/vt and ( . %) presented with pea or asystole. nine ( . %) patients with vf/vt were treated with therapeutic hypothermia and discharged from hospital compared to ( . %) patients with pea or asystole (d . %; % ci: . %, . %). of patients not treated with hypothermia, ( . %) presented with vf/vt, ( . %) presented with pea or asystole, and ( . %) initial rhythms were unknown. fifteen ( . %) patients with vf/vt, not treated with hypothermia, were discharged from hospital compared to ( . %) patients with pea or asystole (d . %; % ci: . %, . %). regardless of initial presenting rhythm or initiation of therapeutic hypothermia, ( . %) discharged patients had good neurological function as assessed by the cerebral performance category (cpc score - ). conclusion: although recommended, post-cardiac arrest therapeutic hypothermia was not routinely used. patients with vf/vt and treated with hypothermia had better outcomes than those with pea or asystole. further research is needed to assess whether cooling patients with presenting rhtyhms of pea or asystole is warranted. racial background: chronic obstructive pulmonary disease (copd) is a major public health problem in many countries.the course of the disease is characterised by episodes, known as acute exacerbations (ae), when symptoms of cough, sputum production, and breathlessness become much worse. the standard prehospital management of patients suffering from an aecopd includes oxygen therapy, nebulised bronchodilators, and corticosteroids. high flow oxygen is used routinely in prehospital areas for breathless patients with copd. there is little high quality evidence on the benefits or potential dangers in this setting but audits have shown increased mortality, acidosis, and hypercarbia in patients with aecopd treated with high flow oxygen. objectives: to compare standard high flow oxygen treatment with titrated oxygen treatment for patients with an aecopd in the prehospital setting. methods: cluster randomized controlled parallel group trial comparing high flow oxygen treatment with titrated oxygen treatment in the prehospital setting. in an intention to treat analysis (n = ), the risk of death was significantly lower in the titrated oxygen arm compared with the high flow oxygen arm for all patients and for the subgroup of patients with confirmed copd (n = ). overall mortality was % ( deaths) in the high flow oxygen arm compared with % ( deaths) in the titrated oxygen arm; mortality in the subgroup with confirmed copd was % ( deaths) in the high flow arm compared with % ( deaths) in the titrated oxygen arm. titrated oxygen treatment reduced mortality compared with high flow oxygen by % for all patients (p = . ) and by % for the patients with confirmed chronic obstructive pulmonary disease (p = . ). patients with copd who received titrated oxygen according to the protocol were significantly less likely to have respiratory acidosis or hypercapnia than were patients who received high flow oxygen. conclusion: titrated oxygen treatment significantly reduced mortality, hypercapnia, and respiratory acidosis compared with high flow oxygen in aecopd. these results provide strong evidence to recommend the routine use of titrated oxygen treatment in patients with breathlessness and a history or clinical likelihood of copd in the prehospital setting. (originally submitted as a ''late-breaker.'') trial registration australian new zealand clinical trials register actrn . background: toxic particulates and gases found in ambulance exhaust are associated with acute and chronic health risks. the presence of such materials in areas proximate to ed ambulance parking bays, where emergency services' vehicles are often left running, is potentially of significant concern to ed patients and staff. objectives: investigators aimed to determine whether the presence of ambulances correlated with ambient particulate matter concentrations and toxic gas levels at the study site ed. methods: the ambulance exhaust toxicity in healthcare-related exposure and risk [aether] program conducted a prospective observational study at an academic urban ed / level i trauma center. environmental ambient gas was sampled over a continuous five-week period from september to october . two sampling locations in the public triage area (public patient dropoff area without ambulances) and three sampling locations in the ambulance triage area were randomized for -hour monitoring windows with a temporal resolution of minutes to obtain days of non-contiguous data for each location. concentrations of particulate matter less than . microns in aerodynamic size (pm . ), oxygen, hydrogen sulfide (h s), and carbon monoxide (co) as well as lower explosive limit for methane (lel) were monitored with professionally calibrated devices. ambulance traffic was recorded through offline review of / security video footage of the site's ambulance bays. results: , measurements at the public triage nurse desk space revealed pm . concentrations with a mean of . ± . lg/m (median . lg/m ; maximum , . lg/m ). , ambulance triage nurse desk space pm . concentrations recorded a mean of . ± . lg/m (p < . , unpaired t test; median . lg/m ; maximum . lg/m ). oxygen levels remained steady throughout the study period; co, h s, and lel were not detected. ambulance activity levels had the highest correlations with pm . concentrations at the ambulance triage foyer (r = . ) and desk area (r = . ) where patients wait and ed staff work - hr shifts. conclusion: ed spaces proximate to ambulance parking bays had higher levels of pm . than areas without ambulance traffic. concentrations of ambient particulate matter in acute care environments may pose a significant health threat to patients and staff. an ems ''pit crew'' model improves ekg and stemi recognition times in simulated prehospital chest pain patients sara y. baker , salvatore silvestri , christopher d. vu , george a. ralls , christopher l. hunter , zack weagraff , linda papa orlando regional medical center, orlando, fl; florida state university college of medicine, orlando, fl background: prehospital teams must minimize time to ekg acquisition and stemi recognition to reduce overall time from first medical contact to reperfusion. auto-racing ''pit crews'' model rapid task completion by pre-assigning roles to team members. objectives: we compared time-to-completion of key tasks during chest pain evaluation in ems teams with and without pre-assigned roles. we hypothesized that ems teams using the ''pit crew'' model would improve time to recognition and treatment of stemi patients. methods: a randomized, controlled trial of paramedic students was conducted over months at orlando medical institute, a state-approved paramedic training center. we compared a standard ems chest pain management algorithm (control) with a pre-assigned tasks (''pit crew'') algorithm (intervention) in the evaluation of simulated chest pain patients. students were randomized into groups of three; intervention and control groups did not interact after randomization. all students reviewed basic prehospital chest pain management and either the standard or pre-assigned tasks algorithm. groups encountered three simulated patients. laerdal simmanÒ software was used track completion of tasks: taking vital signs, iv access, ekg acquisition and interpretation, asa administration, hospital stemi notification, and total time on scene. results: we conducted simulated-patient encounters ( control / intervention encounters). mean time-to-completion of each task was compared in the control and intervention groups respectively. time to obtain vital signs was : vs. : min (p = . ); time to asa administration was : vs : min (p < . ); time to ekg acquisition was : vs : min (p < . ); time to ekg interpretation was : vs : min (p < . ); time to iv access was : vs : min (p = . ); time to stemi notification was : vs : min (p < . ); and time to scene completion was : vs : min (p < . ). conclusion: paramedic student teams with pre-assigned roles (the ''pit crew'' model) were faster to obtain vital signs, administer asa, acquire and interpret the ekg, stemi notification, and overall time on scene during simulated patient encounters. further study with experienced ems teams in actual patient encounters is necessary to confirm the relevance of these findings. background: use of automated external defibrillators (aed) has remained low in the u.s. understanding the effect of neighborhoods on the probability of having an aed used in the setting of a public arrest may provide important insights for future placement of aeds. objectives: to determine associations between the racial and income composition of neighborhoods (as defined by u.s. census tracts), individual arrest characteristics, and whether bystanders or first responders initiate aed use. methods: cohort study using surveillance data prospectively submitted by emergency medical services systems and hospitals from u.s. sites to the cardiac arrest registry to enhance survival between october , and december , . neighborhoods were defined as high-income vs. low-income based on the median household income being above or below $ , and as white or black if > % of the census tract was of one race. neighborhoods without a predominant racial composition were defined as integrated. arrests that occurred within a public location (excluding medical facilities and airports) were eligible for inclusion. hierarchical multi-level modeling, using stata v . , was used to determine the association between individual and census tract characteristics on whether an aed was used. results: of , eligible cases, an aed was used in arrests ( . %) by a first responder (n = , , . %) or bystander (n = , . %). patients whose arrest was witnessed (odds ratio [or] . ; % confidence interval [ci] . - . ) were more likely to have an aed used (table) . when compared to high-income white neighborhoods, arrest victims in low-income black neighborhoods were least likely to have an aed used (or . ; % ci . - . ). arrest victims in lowincome white (or . ; % ci . - . ) and lowincome integrated (or . ; % ci . - . ) were also less likely to have an aed used. conclusion: arrest victims in black and low-income neighborhoods are least likely to have an aed used by a layperson or first responder. future research is needed to better understand the reasons for low rates of aed use for cardiac arrests in these neighborhoods. the impact of an educational intervention on the pre-shock pause interval among patients experiencing an out-of-hospital cardiac arrest jonathan studnek , eric hawkins , steven vandeventer carolinas medical center, charlotte, nc; mecklenburg ems agency, charlotte, nc background: pre-shock pause duration has been associated with survival to hospital discharge (std) among patients experiencing out-of-hospital cardiac arrest (oohca) resuscitation. recent research has demonstrated that for every -second increase in this interval there is an % decrease in std. objectives: determine if a decrease in the pre-shock pause interval for patients experiencing oohca could be realized after implementation of an educational intervention. methods: this was a retrospective analysis of data obtained from a single als urban ems system from / / to / / and / / to / / . in august , an educational intervention was designed and delivered to approximately paramedics emphasizing the importance of reducing the time off chest during cpr. specifically, the time period just prior to defibrillation was emphasized by having rescuers count every th compression and pre-charge the defibrillator on the th compression. in order to determine if this change resulted in process improvement, months of data were assessed before and months after the educational intervention. pre-shock pause was the outcome variable and was defined as the time period after compressions ceased until a shock was delivered. this interval was measured by a cpr feedback device connected to the defibrillator. inclusion criteria were adult patients who required at least one defibrillation and had the cpr feedback device connected during the defibrillation attempt. analysis was descriptive utilizing means and % ci as well as wilcoxon rank sum test to assess difference between the two time periods. results: in the pre-intervention period there were patients who received defibrillations compared to patients receiving defibrillations in the post-intervention phase. the mean duration of the pre-shock pause pre-intervention was seconds ( % ci - ) while the post-intervention duration was seconds ( % ci - ). the difference in pre-shock pause duration was statistically significant with p < . . conclusion: these data indicate that after a simple educational intervention emphasizing decreasing time off chest prior to defibrillation the pre-shock pause duration decreased. future research must describe the sustainability of this intervention as well as the effects this process measure may have on outcomes such as survival to hospital discharge. background: the broselow tape (bt) has been used as a tool for estimating medication dosing in the emergency setting. the obesity trend has demonstrated a tendency towards insufficient pediatric weight estimations from the bt, and thus potential under-dosing of resuscitation medications. objectives: this study compared drug dosing based on the bt with dosing from a novel electronic tool (et) that accounts for provider estimation of body habitus. methods: data were obtained from a prospective convenience sample of children ages to years arriving to a pediatric emergency department. a clinician performed an assessment of body habitus (average/underweight, overweight, or obese), blinded to the patient's actual weight and parental weight estimate. parental estimate of weight and measured length and weight were collected. epinephrine dosing was calculated from the measured weight, the bt measurement, as well as from a smart-phone tool based on the measured length and clinician's estimate of body habitus, and a modified tool (mt) incorporating the parent estimate of habitus. the wilcoxson rank-sum test was used to compare median percent differences in dosing. results: one hundred children (mean age years) were analyzed; % were overweight or obese. clinicians correctly identified children as overweight/obese % of time (ci . - . ). adding parent estimate of weight improved this to a sensitivity of % (ci . - . ). the median difference between the weight-based epinephrine dose and bt dose was %. for the et the median difference from the weight-based dose was % (p = . compared to the bt), and for the mt was . % (p < . compared to the bt). when a clinically significant difference was defined as ± % of the actual dose, bt was within that range % of the time, et was within range % of the time (p = . ), and mt was within range % of the time ( background: in most out-of-hospital cardiac arrest (ohca) events, a call to - - is the first action by bystanders. accurate diagnosis of cardiac arrest by the call taker depends on the caller's verbal description. if cardiac arrest is not suspected, then no telephone cpr instructions will be given. objectives: we measured the effect of a change in the ems call taker question sequence on the accuracy of diagnosis of cardiac arrest by - - call takers. methods: we retrospectively reviewed the cardiac arrest registry to enhance survival (cares) dataset for january , through june , from a city, population , , with a longstanding telephone cpr program (apco). we included ohca cases of any age who were in arrest prior to the arrival of ems and for whom resuscitation was attempted. in early , - - call takers were taught to follow a revised telephone script that emphasized focused questions, assertive control of the caller, and provision of hands-only cpr instructions. the medical director personally explained the reasons for the changes, emphasizing the importance of assertive control of the caller and the comparative safety of chest compressions in patients not in cardiac arrest. beginning in , call recordings were reviewed regularly with feedback to the call taker by the - - center leadership. the main outcome measure was sensitivity of the - - call taker in diagnosing cardiac arrest. bystander cpr was reported by ems crews attending the event. we compared with and using the v test and odds ratios (or). results: there were ohca cases in , cases in , and in the first half of ( / , population). the mean age was ± years, and % of the events were witnessed. before the revision, % of ohca cases were identified by - - dispatchers; and after the revised questioning sequence, % were identified (or . , % ci . - . ). the false positive rate changed little (from /month to /month). the mean time to question callers was unchanged ( vs seconds). bystander cpr was performed in . % of events in , . % in , and . % of events in (p < . ). conclusion: emphasis on scripted assessment improved sensitivity without loss of specificity in identifying ohca. with repeated feedback, it translated to an increase in victims receiving bystander cpr. in an out-of hospital cardiac arrest population confirmed by autopsy salvatore silvestri, christopher hunter, george ralls, linda papa orlando regional medical center, orlando, fl background: quantitative end-tidal carbon dioxide (etco ) measurements (capnography) have consistently been shown to be more sensitive than qualitative (colorimetric) ones, and the reliability of capnography for assessing airway placement in low perfusion states has sometimes been questioned in the literature. objectives: this study examined the rate of capnographic waveform presence of an intubated out-of-hospital cardiac arrest cohort and its correlation to endotracheal tube location confirmed by autopsy. our hypothesis is that capnography is % accurate in determining endotracheal tube location, even in low perfusion states. methods: this cross-sectional study reviewed a detailed prehospital cardiac arrest database that regularly records information using the utstein style. in addition, the ems department quality manager routinely logs the presence of an alveolar (four-phase) capnographic waveform in this database. the study population included all cardiac arrest patients from january , through december , managed by a single ems agency in orange county, florida. patients were included if they had endotracheal intubation performed, had capnographic measurement obtained, failed to regain return of spontaneous circulation (rosc), and had an autopsy performed. the main outcome was the correlation of the presence of an alveolar waveform and the location of the ett at autopsy. results: during the study period, cardiac arrests were recorded. of these, had an advanced airway placed (ett or laryngeal tube airway), and no rosc. of the advanced airway cases, were managed with an ett. autopsies were performed on of these patients and resulted in our study cohort. the location of the ett at autopsy was recorded on all of these cases. capnographic waveforms were recorded in the field in all of these study patients, and % of the tubes were located within the trachea at autopsy. the sensitivity of capnography in determining proper endotracheal tube location was % in this study. conclusion: in our study, the presence of a capnographic waveform was % reliable in confirming proper placement of endotracheal tubes placed in outof-hospital patients with poor perfusion states. results: over variables were presented to the ems medical directors responding ( % survey population captured). among the myriad of responses, ( %) initiate cardiopulmonary resuscitation (cpr) at compressions to ventilations consistent with il-cor/aha guidelines. seven ( %) initiate continuous chest compressions from the start of cpr with no pause and interposed ventilations. nine ( %) begin chest compressions only during the first - minutes, with either passive oxygenation by oxygen mask (six; %) or no oxygen (three; %). airway management following non-invasive oxygenation and ventilation by primary endotracheal intubation occurs in systems ( %), while six ( %) use supraglottic devices. fourteen ( %) allow paramedics to decide between endotracheal and supraglottic device placement. thirty systems ( %) utilize continuous waveform capnography. the initial approach to non-ems witnessed ventricular fibrillation is chest compression prior to first defibrillation in systems ( %). eighteen systems ( %) escalate defibrillation energy settings, with four systems ( %) utilizing dual sequential defibrillation. twenty ( %) initiate therapeutic hypothermia in the field. conclusion: wide variability in ca care standards exists in america's largest urban ems systems in mid- , with many current practices promoting more continuity in chest compressions than specified in the ilcor/aha guidelines. endotracheal intubation, a past mainstay of ca airway management, is deemphasized in many systems. immediate defibrillation of non-ems witnessed ventricular fibrillation is uncommon. objectives: determine the out-of-hospital cardiac arrest survival in this area of puerto rico using the utstein method. methods: prospective observational cohort study of adult patients presenting with an out-of-hospital cardiac arrest to the upr hospital ed. study endpoints will be survival and neurologically intact survival at hospital discharge, months, and months. results: a total of consecutive cardiac arrest events were analyzed for a period of years. one-hundred fifteen events met criteria for primary cardiac etiology ( . %). the average age for this group was . years. there were female ( . %) and male ( . %) participants. the average time to start cpr was . minutes. transportation to the ed was . % by ems and . % by private vehicle. a total of events were witnessed ( . %). the survival rate to hospital admission was . %. the overall cardiac arrest survival was . % and overall neurologically intact survival was . %. neurologically intact survival at and months was . %. the rate of bystander cpr in our population was . % with a survival rate of . %. conclusion: survival from out-of-hospital cardiac arrest in the area served by the upr hospital is low but comparable to other cities in the us as reported by the cdc cardiac arrest registry to enhance survival (cares). this low survival rate might be due to low bystander cpr rate and prolonged time to start cpr. background: hyperventilation has been directly correlated with increased mortality for out-of-hospital cpr. ems providers may hyperventilate patients at levels above national bls guidelines. real-time feedback devices, such as ventilation timers, have been shown to improve cpr ventilation rates towards bls standards. it remains unclear if the combination of a ventilation timer and pre-simulation instruction would influence overall ventilation rates and potentially reduce undesired hyperventilation. objectives: this study measured ventilation rates of standard cpr (and pre-instruction on effects of hyperventilation) compared to cpr with the use of a commercial ventilation timer (and pre-instruction on effects of hyperventilation). we propose that use of a ventilation timer, measuring and displaying to ems providers real-time ventilations delivered, will have no difference in ventilation rates when comparing these groups. methods: this prospective study placed ems providers into four groups: two controls measuring ventilation rates before ( a) and after instruction ( b) on the deleterious effects of hyperventilation, and a concurrent intervention pair with before ( a) and after instruction ( b), with the second pair measuring ventilation rates with a ventilation timer that provides immediate feedback on respirations given. ventilation rates were measured for a -second period after one minute of simulated cpr using mannequins. the control set without instruction ( a, n = ) averaged . breaths ( % ci = . - . ) and with instruction ( b, n = ) averaged . breaths ( % ci = . - . ). the intervention set without instruction ( a, n = ) averaged . breaths ( % ci = . - . ) and with instruction ( b, n = ) averaged . breaths ( % ci = . - . ). there was a significant improvement (p = . ) in ventilation rates with use of a ventilation timer (control group versus intervention group regardless of pre-instruction). there was no statistically significant difference between groups with respect to instruction alone (p = . ). conclusion: the use of a ventilation timer significantly reduced overall ventilation rates, providing care closer to bls guidelines. the addition of pre-simulation instruction added no significant benefit to reducing hyperventilation. background: in , the american heart association (aha) recommended a compression rate of (roc) / min and a depth of compressions (doc) at least inches for effective cpr. as an educational tool for lay rescuers, the aha as adopted the catch phrase ''push hard, push fast''. objectives: in this irb-exempt study, we sought to determine if persons without formal cpr training could perform non-ventilated cpr as well as those who have been trained in the past or those currently certified. methods: a convenience sample of patrons of the new york state fair was asked to perform minutes of hands-only cpr on a prestan pp-am- m adult cpr manikin. these devices provide visual indicators of acceptable rate and depth of compressions. each subject was video recorded on a dell latitude laptop computer with a logitech quick cam using logitech quick cam . . for windows software. results: a total of volunteers ( male, female) aged - years participated: were never certified (nc) in cpr, were previously certified (pc), and were currently certified (cc). there was no difference in age across the groups. the cc group had a higher proportion of females (chi-square = . , p < . ). cc volunteers sustained roc and doc for an average of . seconds as compared to an average of . seconds (pc) and . seconds (nc) respectively. (f = . , p < . ). the cc maintained roc of closer to / min (mean . /min) when compared to the pc (mean . /min) and nc (mean . /min) groups (f = . , p < . ). a higher proportion of volunteers of the cc group were able to perform adequate doc (chi-square = . , p < . ), and hand placement (chisquare = . , p < . ) when compared to the other two groups. conclusion: compared to the target roc and doc, none of the groups did well and only subjects met target roc/doc. increased out-of-hospital cardiac arrest survivability due to lay rescuer intervention is only assured if cpr is effectively administered. the effect and benefit of maintaining formal cpr training and certification is clear. background: more than , out-of-hospital cardiac arrests (ohcas) occur annually in the united states (us). automated external defibrillators (aeds) are life-saving devices in public locations that can significantly improve survival. an estimated million aeds have been sold in the us; however, little is known about whether locations of aeds match oh-cas. these data could help determine optimal placement of future aeds and targeted cpr/aed training to improve survival. objectives: we hypothesized that the majority (> %) of aeds are not located in close proximity ( feet) to the occurrence of cardiac arrests in a major metropolitan city. methods: this was a retrospective review of prospectively collected cardiac arrest data from philadelphia ems from january , until december , . included were ohcas of presumed cardiac etiology in individuals years of age or older. excluded were oh-cas of presumed traumatic etiology, cases where resuscitation was terminated at the scene, and those dead on arrival. aed locations in philadelphia were obtained from myheartmap, a database of installed and wallmounted aeds in pennsylvania. we used gis mapping software to visualize where ohcas occurred relative to where aeds were located and to determine the radius of ohcas to aeds. arrests within a , , and foot radius of aeds were identified using the attribute location selection option in arcgis. the lengths of radii were estimated based on the average time it would take for a person to walk to and from an aed ( feet minutes; feet minutes; feet minutes). results: we mapped , ohcas and , aeds in philadelphia county. ohcas occurred in males ( %; / ) and the mean age was . years. ventricular fibrillation occurred in % ( / ). aeds were primarily located in schools/universities ( %), office buildings ( %), and residential buildings ( %). aeds were not identified within feet in % ( , ) of ohcas, within feet of % ( , ) of ohcas, and within feet in % ( , ) of ohcas. the figure (large black circles) illustrates aed/ohca within feet on the left and feet on the right. conclusion: aeds were rarely close to the locations of ohcas, which may be a contributor to low cardiac arrest survival rates. innovative models to match aed availability with ohcas should be explored. (originally submitted as a ''late-breaker.'') potential background: early and frequent epinephrine administration is advocated by acls; however, epinephrine research has been conducted primarily with standard cpr (std). active compression-decompression cpr with an impedance threshold device (acd-cpr + itd) has become the standard of care for out of hospital cardiac arrest in our area. the hemodynamic effects of iv epinephrine under this technique are not known. objectives: to determine the hemodynamic effects of iv epinephrine in a swine model undergoing acd-cpr+itd. methods: six female swine ( ± kg) were anesthetized, intubated, and mechanically ventilated. intracranial, thoracic aorta, and right atrial pressures were recorded via indwelling catheters. carotid blood flow (cbf) was recorded via doppler. etc , sp , and ekg were monitored. ventricular fibrillation was induced and went untreated for minutes. three minutes each of standard cpr (std), std-cpr+itd, and acd-cpr+itd was preformed. at minute of the resuscitation, lg/kg of iv epinephrine was administered and acd-cpr+itd was continued for minute. statistical analysis was performed with a paired t-test. results: aortic pressure and calculated cerebral and carotid perfusion pressures increased from std < std+itd < acd-cpr+itd (p £ . ). epinepherine administered during acd-cpr+itd signficantly increased mean aortic ( ± vs ± , p = . ), cerebral ( ± vs ± , p = . ), and coronary perfusion pressures ( ± vs ± , p = . ); however, mean cbf and etco decreased (respectively ± vs ± . , p = . ; ± vs ± , p = . ). conclusion: the administration of epinepherine during acd-cpr+itd signficantly increased markers of macrocirculation, while significantly decreasing etco , a proxy for organ perfusion. while the calculated cerebral perfusion pressures increased, the directly measured cbf decreased. this calls into question the ability of calculated perfusion pressures to accurately reflect blood flow and oxygen delivery to end organs. hypoxia background: during cardiac arrest most patients are placed on % oxygen with assisted ventilations. after return of spontaneous circulation (rosc), % oxygen is typically continued for an extended time. animal data suggest that immediate post-arrest titration of oxygen by pulse oximetry produces better neurocognitive/ histologic outcomes. recent human data suggest that arterial hyperoxia is associated with worse outcomes. objectives: to assess the relationship between hypoxia, normoxia, and hyperoxia post-arrest and outcomes in post-cardiac arrest patients treated with therapeutic hypothermia. methods: we conducted a retrospective chart review of post-arrest patients admitted to an academic medical center between january, and december, who had arterial blood gases (abg) drawn after rosc. demographic variables were analyzed using anova and chi-square tests as appropriate. unadjusted logistic regression analyses were performed to assess the relationship between hypoxia (pao < mmhg), normoxia ( - mmhg), hyperoxia (> mmhg), and mortality. results: on first abg ( patients), ( . %) were hypoxic, ( . %) normoxic, and ( . %) hyperoxic. the average age of the cohort was . years (no difference for hypoxic, normoxic, and hyperoxic patients). overall mortality was . % ( / ). there were no significant differences between initial heart rate, systolic blood pressure, sex, race, or pre-arrest functional status. in-hospital mortality was significantly higher when the first abg demonstrated hypoxia ( . %; / ) than for normoxia ( . %; / ) or hyperoxia ( %; / ). in unadjusted logistic regression analysis of first pao values, hyperoxia was not associated with increased mortality (or . ; % ci . - . ) but hypoxia was associated with increased mortality (or . ; % ci . - . ). conclusion: hypoxia but not hyperoxia on first abg was associated with mortality in a cohort of post-arrest patients. background: there are over , deaths due to cardiac arrest per year in the us. the aha recommends monitoring the quality of cpr primarily through the use of end tidal co (etco ). the level of etco is significantly dependant on minute ventilation and altered by pressor and bicarbonate use. cerebral oximetry (cereox) uses near infrared spectroscopy to non-invasively measure oxygen saturation of the frontal lobes of the brain. cereox has been correlated with cerebral blood flow and jugular vein bulb saturations. objectives: the objective of this study is to compare the simultaneous measurement of etco and cereox to investigate which monitoring method provides the best measure of cpr quality as defined by return of spontaneous circulation (rosc). methods: a prospective cohort of a convenient sample of patients using out-of-hospital and ed cardiac arrest from two large eds. patients were monitored simultaneously by etco and cereox during cpr. patient demographics and arrest data were collected using the utstein criteria. all patients were monitored throughout the resuscitation efforts. rosc was defined as a palpable pulse and a measurable blood pressure for a minimum of thirty minutes. results: twenty two patients were enrolled with complete data sets; % of the subjects had rosc. average down time of rosc subjects was minutes (sd ± . ) and minutes (sd ± . ) for subjects without rosc. the inability to obtain a value of either for etco or cereox was % and % specific with an % and % npv respectively for predicting lack of rosc. obtaining a value of either for etco or cereox was % and % sensitive, respectively in identifying rosc. subjects with rosc had sustained values above for . mins on cereox and . mins on etco prior to rosc. the increase in values over a three minute period prior to rosc was . on cereox and . on etco . conclusion: the inability to obtain a value of on either the etco or cereox strongly predicted lack of rosc. cereox provides a larger magnitude and closer temporal increase prior to rosc than etco . attaining a value of on cereox was more predictive of rosc than etco . an discrepancies due to communicating information to multiple listeners in a short amount of time. this creates a communication barrier not always apparent to practitioners. we examine the perceptions of ems and ed personnel on the transfer of care and its correlation to missing patient data. objectives: evaluate provider perception of information transfer by ems and ed personnel and compare this to an external observer's objective assessment. methods: this is a retrospective quality improvement program at an academic level i trauma center. transfers of medical and trauma patients from ems to ed personnel were attended by trained external observers, research associates (ra). ra recorded the data communicated: name, age, past medical history (pmh), allergies, medications, events, active problems, vital signs (vs), level of consciousness (loc), iv access, and treatments given. then, ems and ed staff rated their perception of transfer on a - rating scale. results: ra evaluated patient transfers ( medical and trauma). transfer time did not differ, . minutes for medical ( % ci: . - . ), . minutes for trauma patients ( % ci: . - . )(p = . ). missing data between the two groups also did not differ, except loc and treatment were missed more in medical transfers, while pmh was missed more in the trauma transfers. comparing the transfers with all vs present ( %, / ) and all vs missing ( %, / ), with all vs missing, there was no difference in perception of transfer for ems ( . / vs present vs . / vs absent) or ed staff ( . / vs present, . / vs absent). when all vital signs were missing, ra rated . % of transfers as poor, whereas when all vs were present . % of transfers were considered good. conclusion: ems and ed staff felt transfers of care were professional, teams were attentive, and had similar amounts of interruptions for both medical and trauma cases. their perception of transfer of care was similar even when key information was missing, although external observers rated a significant amount of transfers poorly. thus, ems and ed staffs were not able to evaluate their own performance in a transfer of care and external observers were found to be better evaluators of transfers of care. swati singh, john brown, prasanthi ramanujam ucsf, san francisco, ca background: ems transports a large number of psychiatric emergencies to emergency departments (ed) across the us. research on paramedic education related to behavioral emergencies is sparse, but based on expert opinion we know that gaps in paramedic knowledge and training exist. in our system, paramedics triage patients to medical, detoxification, and purely psychiatric destinations, so a paramedic's understanding of these emergencies directly affects the flow of patients in our eds. objectives: our objectives were to understand the gaps in current training and develop a targeted curriculum for field providers with a long term goal of appropriately recognizing and triaging subjects to the ed. methods: data were collected using a survey that was distributed during a paramedic association meeting in october . subjects were excluded if they did not complete the survey. survey questions addressed demographics of paramedics, frequency of various psychiatric emergencies and their confidence in managing these emergencies. data were collated, analyzed, and presented as descriptive statistics. results: forty-nine surveys were distributed with a response rate of % (n = / ). of the respondents, % (n = ) were male and % (n = ) had at least five years experience. mood, thought, and cognitive disorders were the most frequently encountered presentations and % (n = ) of respondents came across psychiatric emergencies multiple times a week. many respondents did not feel confident managing agitated delirium (n = , %), acute psychosis (n = , %), and intimate partner or elder abuse (n = , %). a third to a half of the respondents felt they have little or no training in chemical sedation (n = , %), verbal de-escalation (n = , %), and triaging patients (n = , %). conclusion: we identified a need for a revised curriculum on management of psychiatric emergencies. future steps will focus on development of a curriculum and change in knowledge after implementation of this curriculum. background: prehospital endotracheal intubation has long been a cornerstone of resuscitative efforts for critically ill or injured patients. paramedic airway management training will need to be modified due to the acc/aha guidelines to ensure maintenance of competency in overall management of airway emergencies. how best to modify the training of paramedics requires an understanding of current experience. objectives: the purpose of this report is to characterize the airway management expertise of experienced and non-experienced paramedics in a single ems system. methods: we retrospectively reviewed all prehospital intubations from an urban/suburban ambulance service (professional ambulance, inc.) over a five-year period (january , to december , ). characteristics of airway management by paramedics with - years of experience (group ) were compared to those with greater than years of experience (group ). airway management was guided by massachusetts statewide treatment protocols governing direct laryngoscopy and all adjunctive approaches. attempts are characterized by laryngoscope blade passing the lips. difficult and failed airways were managed with extraglottic devices (egd) or needle cricothyroidotomy. we reviewed patient characteristics, intubation methods, rescue techniques, and adverse events. results: patients required airway management: ( %) were performed by group and ( %) were performed by group . group was both faster to intubate ( . vs . attempts, p = . ) and less likely to use a rescue device ( . % vs . %, p = . ). both are equally likely to go directly to a rescue device ( % vs %, p = . ). all patients were successfully oxygenated and ventilated with either an endotracheal tube or egd. no surgical airways were performed and no patients died as a result of a failed airway. conclusion: while intubation success rates of paramedics with less than and greater than five years of experience are similar, less experienced paramedics use fewer attempts and are less likely to use a rescue device. both recognize difficult airways and go directly to rescue devices equally. this highlights difficulties faced maintaining competence. education requirements must be evaluated and redesigned to allow paramedics to maintain competence and emphasize airway management according to the latest resuscitation guidelines. how well do ems - - protocols predict ed utilization for pediatric patients? stephanie j. fessler , harold k. simon , daniel a. hirsh , michael colman emory university, atlanta, ga; grady health systems, atlanta, ga background: the use of emergency medical services (ems) for low-acuity pediatric problems has been well documented. however, it is unclear how accurately general ems dispatch protocols predict the subsequent ed utilization for these patients. objectives: to determine the ed resource utilization rate of pediatric patients categorized as low acuity by - - dispatch protocols and then subsequently transferred to a children's hospital. methods: all transports for pediatric patients from the scene by a large urban general ems provider that were prioritized as low acuity by initial - - dispatch protocols were identified. protocols were based on the national academy of medical priority dispatch system, v . starting on jan , , consecutive cases of patients transported to three pediatric emergency departments (ped) of a large tertiary care pediatric health care system were reviewed. demographics, ped visit characteristics, resource utilization, and disposition were recorded. those patients who received meds other than po antipyretics, had labs other than a strep test, a radiology study, a procedure, or were not discharged home were categorized into the significant ed resource utilization group. results: % of the patients were african american and either had public insurance or self-pay ( %, % respectively). the median age was months ( d- yr). % were female. none of these low-acuity patients were upgraded by ems operators en route. upon arrival to the ped, % of transported patients were classified into the significant utilization group. six of the total patients were admitted, including a y/o requiring emergent intubation, an m/o old with a broken cvl, a y/o with sickle cell pain crisis, and a y/o with altered mental status. the remainder of the significant resource utilization group consisted of children needing procedures, anti-emetics, narcotic pain control, labs, and xrays. conclusion: in this general ems - - system, dispatch protocols for pediatric patients classified as low priority did poorly in predicting subsequent ed utilization with % requiring significant resources. further, ems operators did not recognize a critical child who needed emergent intervention. opportunity exists to refine general ems - - protocols for children in order to more accurately define an ems priority status that better correlates with ultimate needs and resource utilization. the objectives: determine if there is an association between a patient's impression of the overall quality of care and his or her satisfaction with provided pain management. it was hypothesized that satisfaction with pain management would be significantly associated with a patient's impression of the overall quality of care. methods: this was a retrospective review of patient satisfaction survey data initially collected by an urban als ems agency from / / to / / . participants were randomly selected from all patients transported proportional to their paramedic defined acuity; categorized as low, medium, or high with a goal of interviews per month. the proportions of patients sampled from each acuity level were % low, % medium, and % high. patients were excluded if there was no telephone number recorded in the prehospital patient record or they were pronounced dead on scene. all satisfaction questions used a five-point likert scale with ratings from excellent to poor that were dichotomized for analysis as excellent or other. the outcome variable of interest was the patient's perception of the overall quality of care. the main independent variable had patients rate the staff who treated them at the scene on their helping to control or reduce their pain. demographic variables were assessed for potential confounding. results: there were , patients with complete data for the outcome and main independent variable with . % male respondents and an average age of . (sd = . ). overall quality of care was rated excellent by . % of patients while . % rated their pain management as excellent. of patients who rated their pain management as excellent, . % rated overall quality of care as excellent while only . % of patients rated overall quality excellent if pain management was not excellent. when controlling for potential confounding variables, those patients who perceived their pain management to be excellent were . ( % ci . - . ) times more likely to rate their overall quality of care as excellent compared to those with non-excellent perceived pain management. conclusion: patients' perceptions of the overall quality of care were significantly associated with their perceptions of pain management. objectives: the purpose of this study is to determine whether ground-based paramedics could be taught and retain the skills necessary to successfully perform a cricothyrotomy. methods: this retrospective study was performed in a suburban county with a population of , and , ems calls per year. participants were groundbased paramedics in a local ems system who were taught wire-guided cricothyrotomy as part of a standardized paramedic educational update program. as part of the educational program, paramedics were taught wire-guided cricothyrotomy on a simulation model previously developed to train emergency medicine residents. after viewing an instructional video, the participants were allowed to practice using a step checklist. not all of these steps were automatic failures. each paramedic was individually supervised performing a cricothyrotomy on the simulator until successful; a minimum of five simulations was required. retention was assessed using the same -step checklist during annual skills testing, after a minimum of weeks to a maximum of months posttraining. results: a total of paramedics completed both the initial training and reassessment during the time period studied. during the initial training phase, % ( of ) of the paramedics were successful in performing all steps of the wire-guided cricothyrotomy. during the retention phase . % ( of ) retained the skills necessary to successfully perform the wire-guided cricothyrotomy. of the -step checklist, most steps were performed successfully by all the paramedics or missed by only of the paramedics. step # , which involved removing the needle prior to advancing the airway device over the guidewire, was missed by . % ( of ) of the participants. step # was not an automatic failure since most participants immediately self-corrected and completed the procedure successfully. conclusion: paramedics can be taught and can retain the skills necessary to successfully perform a wireguided cricothyrotomy on a simulator. future research is necessary to determine if paramedics can successfully transfer these skills to real patients. helicopter emergency medical services in background: netcare is one of the largest private providers of emergency air medical care in south africa. each hems (helicopter emergency medical service) crew is manned by a physician-paramedic team and is dispatched based on specific medical criteria, time to definitive care, and need for physician expertise. objectives: to describe the characteristics of net-care air medical evacuations in gauteng province and to analyze the role of physicians in patient care and effect on call times. methods: all patients transported by a netcare helicopter over a one year period from january -december were enrolled in the study. injury classifications, demographics, procedures, scene and flight times were collected retrospectively from run sheets. data were described by medians and interquartile intervals. results: a total of patients were transported on flights originating from the netcare gauteng helicopter base. ninety-two percent were traumarelated, with % resulting from motor vehicle accidents. physician expertise was listed % of the time as the indication for air medical response. a total of advanced procedures were performed by physicians on patients, including paralytic-assisted intubations, chest tube placement, and cardiac pacing. the median total call time was minutes with minutes spent on scene, compared with and minutes when advanced procedures were performed by hems (p < . ). conclusion: trauma accounts for an overwhelming majority of patients requiring emergency air medical transportation. advanced medical procedures were performed by physicians in nearly a quarter of the patients. there were significant differences in call times when advanced procedures were performed by hems. objectives: we sought to evaluate the level of awareness and adoption of the off-line protocol guidelines by utah ems agencies. methods: we surveyed all ems agencies in utah months after protocol guideline release. medical directors, ems captains, or training coordinators completed a short phone survey regarding their knowledge of the emsc protocol guidelines, and whether their agency had adopted them. in particular, participants were asked about the pain protocol guideline and their management of pediatric pain. results: of the agencies, participated in the survey ( %). of those participating, agencies ( %) were excluded from the analysis: ( %) who only treat adults and ( %) who do not participate in electronic data entry. of the remaining agencies ( %), ( %) were familiar with the utah emsc protocol guidelines; agencies ( %) have either partially or fully adopted the protocol guidelines. agencies ( %) were familiar with the pain treatment protocol guideline; ( %) had adopted it; ( %) planned to either partially or fully adopt the protocol. overall, agencies ( %) had offline protocols allowing the administration of narcotics to children. of those, ( %) had intranasal fentanyl as an available medication and delivery route. of the agencies with offline protocols for pain, ( %) reported familiarity with the emsc pain protocol guideline. conclusion: the creation and dissemination of statewide emsc protocol guidelines results in widespread awareness ( %) and to date % of agencies have adopted them. future investigation into factors associated with protocol adoption should be explored. background: intranasal (in) naloxone is safe and effective for the treatment of opioid overdose. while it has been extensively studied in the out-of-hospital environment in the hands of paramedics and lay people, we are unaware of any studies evaluating the safety and efficacy of in naloxone administration by bls providers. in recent years in naloxone has been added to the bls armamentarium; however, most services/states require an als unit be dispatched and attempt an intercept if in naloxone is administered by the bls providers. objectives: the purpose of this study is to evaluate the safety and effectiveness of bls-administered in naloxone in an urban environment. methods: retrospective cohort review as part of the ongoing qa process of all patients who had in naloxone administration by bls providers. the study was part of a special projects waiver by massachusetts oems from february through november in a busy urban tiered ems system in the metro-boston area. exclusion criteria: cardiac arrest. demographic information was collected, as well as vital signs, number of naloxone doses by bls, patient response to bls naloxone administration (clinical improvement in mental status and/or respiratory status), als intercept. descriptive statistics and confidence intervals are reported using microsoft excel and spss . . results: fifty-six cases of bls-administered in naloxone were identified, and were excluded as cardiac arrests. the included cases had a mean age of . years ± . (range - ), and % (ci - ) were male. of the included cases, % (ci - ) of patients responded to bls administration of naloxone. of the responders, % (ci - ) required two doses. there were protocol violations representing % (ci . - . ) of the total administrations, however in % of these protocol violations the patients had a positive response to the administration of in naloxone. seven of the protocol violations were patients who required a second mg dose of naloxone. eleven cases did not have an als intercept; only of these patients did not respond to bls administration of naloxone. there were no identified adverse events. conclusion: bls providers safely and successfuly administered in naloxone achieving a response rate consistent with studies of als providers' administration of in naloxone. given the success rate of bls providers, it may be feasible for bls to manage responders without the aid of an als intercept. background: an estimated % of patients arriving by ambulance to the ed are in moderate to severe pain. however, the management of pain in the prehospital setting has been shown to be inadequate, and untreated pain may have negative consequences for patients. objectives: to determine if focused education on pediatric pain management and implementation of a pain management protocol improved the prehospital assessment and treatment of pain in adult patients. specifically, this study aimed to determine if documentation of pain scores and administration of morphine by ems personnel improved. methods: this was a retrospective before and after study conducted by reviewing a county-wide prehospital patient care database. the study population included all adult patients transported by ems between february and february with a working assessment of trauma or burn. ems patient care records were searched for documentation of pain scores and morphine administration years before and years after an intensive pediatric focused pain management education program and implementation of a pain management protocol. frequencies and % cis were determined for all patients meeting the inclusion criteria in the before and after time period and chisquare was used to compare frequencies between time periods. a secondary analysis was conducted using only subjects documented as meeting the protocol's treatment guidelines. results: , ( %) of , adult patients transported by ems during the study period met the inclusion criteria: , in the before and , in the after period. subject demographics were similar between the two periods. documentation of pain score did not change between the time periods ( background: there is a presumption that ambulance response times affect patient outcome. we sought to determine if shorter response times really make a difference in hospital outcomes. objectives: to determine if ambulance response time makes a difference in the outcomes of patients transported for two major trauma (motor vehicle crash injuries, penetrating trauma) and two major medical (difficulty breathing and chest pain complaints) emergencies. methods: this study was conducted in a metropolitan ems system serving a population total of , including urban and rural areas. cases were included if the private ems service was the first medical provider on scene, the case was priority , and the patient was years and older. a -month time period was used for the data evaluation. four diagnoses were examined: motor vehicle crash injuries, penetrating trauma, difficulty breathing, and chest pain complaints. ambulance response times were assessed for each of the four different complaints. the patients' initial vital signs were assessed and the number of vital signs out of range was recorded. a sampling of all cases which went to the single major trauma center was selected for evaluation of hospital outcome. using this hospital sample, number of vital signs out of range were assessed as a surrogate marker indicating severity of hospital outcome. correlation coefficients were used to evaluate interactions between independent and outcome variables. results: of the cases we reviewed over the month period, we found that the ems service responded significantly faster to trauma complaints at . minutes (n = ) than medical complaints at . minutes (n = ) . in the hospital sample of cases, number of vital signs out of range were positively correlated with hospital days (r = . ), admits (r = . ), icu admits (r = . ), and deaths (r = . ), but not response times (r = (-) . ). in the entire sample, there was no correlation between vital signs out of range and response times for any diagnosis (see figure) . conclusion: conclusions: based on our hospital sample which showed that number of vital signs out of range was a surrogate marker of worse hospital outcomes, we find that hospital outcomes are not related to initial response times. adverse effects following prehospital use of ketamine by paramedics eric ardeel baylor college of medicine, houston, tx background: ketamine is widely used across specialties as a dissociative agent to achieve sedation and analgesia. emergency medical services (ems) use ketamine to facilitate intubation and pain control, as well as to sedate acutely agitated patients. published studies of ems ketamine practice and effects are scarce. objectives: describe the incidence of adverse effects occurring after ketamine administration by paramedics treating under a single prehospital protocol. methods: a retrospective analysis was conducted of consecutive patients receiving prehospital ketamine from paramedics in the suburban/rural ems system of montgomery county hospital district, texas between august , and october , . ketamine administration indications were: need for rapid control of violent/agitated patients requiring treatment and transport; sedation and analgesia after trauma; facilitation of intubation and mechanical ventilation. ketamine administration contraindications were: equivalent ends achieved by less invasive means; hypertensive crisis; angina; signs of significantly elevated intracranial pressure; anticipated inability to support or control airway. all patients were included, regardless of indication for ketamine administration. data were abstracted from electronic patient care records and available continuous physiologic monitoring data, and analyzed for the presence of adverse effects as defined a priori in ''clinical practice guidelines for emergency department ketamine dissociative sedation: update.'' results: no patients were identified as experiencing adverse effects as defined by the referenced literature. ketamine was utilized most often for patients with the following nemsis provider's primary impression: ( %) altered level of consciousness, ( %) behavioral/psychiatric, ( %) traumatic injury. overall, combativeness was associated with ( %) patients. the mean age was years (range - years) and ( %) were male. the mean ketamine dose was mg (range - mg) and twenty-four ( %) patients received multiple administrations. conclusion: in this patient population, our data indicate that prehospital ketamine use by ems paramedics, across all indications for administration, was safe. further study of ketamine's utility in ems is warranted. an background: rigorous evaluation of the effect of implementing nationally vetted evidence-based guidelines (ebgs) has been notoriously difficult in ems. specifically, human subjects issues and the health insurance portability and accountability act (hipaa) present major challenges to linking ems data with distal outcomes. objectives: to develop a model that addresses the human subjects and hipaa issues involved with evaluating the effect of implementing the traumatic brain injury (tbi) ebgs in a statewide ems system. methods: the excellence in prehospital injury care (epic) project is an nih-funded evaluation of the effect of implementing the ems tbi guidelines throughout arizona (ninds- r ns - a ). to accomplish this, a partnership was developed between the arizona department of health services (adhs), the university of arizona, and more than ems agencies that serve approximately % of the state's population. results: ebg implementation: implementation follows all routine regulatory processes for making changes in ems protocols. in arizona, the entire project must be carried out under the authority of the adhs director. evaluation: a before-after system design is used (randomization is not acceptable). hipaa: as an adhsapproved public health initiative, epic is exempt from hipaa, allowing sharing of protected health information between participating entities. for epic, the state attorney general provided official verification of hi-paa exemption, thus allowing direct linkage of ems and hospital data. irb: once epic was officially deemed a public health initiative, the university irb process was engaged. as an officially sanctioned public health project, epic was determined to not be human subjects research. this allows the project to implement and evaluate the effect of this initiative without requiring individual informed consent. conclusion: by utilizing an ems-public health-university partnership, the ethical and regulatory challenges related to evaluating implementation of new ebgs can be successfully overcome. the integration of the department of health, the attorney general, and the university irb can properly protect citizens while permitting efficient implementation and rigorous evaluation of the effect of ebgs. this novel approach may be useful as a model for evaluation of implementing ems ebgs in other states and large counties. ( . %- . % by age) were transported to non-trauma centers. the most common reasons cited by ems for hospital selection were: patient preference ( . %), closest facility ( . %), and specialty center ( . %). patient preference increased with age (p for trend . ) and paralleled under-triage ( figure ). iss ‡ patients transported to non-trauma hospitals by patient request had lower unadjusted mortality ( . %, %ci . - . ) than similar patients transported to trauma centers ( . %, %ci . - . ) or transported for other reasons ( . %, %ci . - . ) (figure ) . under-triage appears to be influenced by patient preference and age. self-selection for transport to non-trauma centers may result in under-triaged patients with inherently better prognosis than triagepositive patients. background: only % of all out-of-hospital cardiac arrest (ohca) patients receive bystander cpr (cardiopulmonary resuscitation). the neighborhood in which an ohca occurs has significant influence on the likelihood of receiving bystander cpr. objectives: to utilize geographic information systems to identify ''high-risk'' neighborhoods, defined as census tracts with high incidence of ohca and low cpr prevalence. methods: design: secondary analysis of the cardiac arrest registry to enhance survival (cares) dataset for denver county, colorado. population: all consecutive adults (> years old) with ohca due to cardiac etiology from january , through december , . data analysis: analyses were conducted in arc-gis. three spatial statistical methods were used: local morans i (lmi), getis-ord gi*(gi*), and spatial empirical bayes (seb) adjusted rates. census tracts with high incidence of ohca, as identified by all three spatial statistical methods, were then overlain with low bystander cpr census tracts, which were identified in at least two out of three statistical methods (lmi, gi*, or the lowest quartile of bystander cpr prevalence). overlapping census tracts identified with both high ohca incidence and low cpr prevalence were designated as ''highrisk''. results: a total of arrests in census tracts occurred during the study period, with arrests included in final sample. events were excluded if they were unable to be geocoded (n = ), outside denver county (n = ), or occurred in a jail (n = ), hospital/ physician's office (n = ), or nursing home (n = ). for high ohca incidence: lmi identified census tracts, gi* identified census tracts, and the seb method identified census tracts. twenty-five census tracts were identified by all three methods. for low bystander cpr prevalence: lmi identified census tracts, gi* identified census tracts, and census tracts were identified as being in the lowest quartile of cpr prevalence. twenty-four census tracts were identified by two of the three methods. two census tracts were identified as high-risk having both high ohca incidence and low cpr prevalence (figure) . high-risk census tract demographics as compared to denver county are shown in the table. conclusion: the two high-risk census tracts, comprised of minority and low-income populations, appear to be possible sites for targeted community-based cpr interventions. objectives: we sought to assess the accuracy and correlation of geographic information system (gis) derived transport time compared to actual ems transport time in ohca patients. methods: prospective, observational cohort analysis of ohca patients in vancouver, b.c., one of the sites of the resuscitation outcomes consortium (roc). a random sample from all of the ohca cases from / through / was selected for analysis from one site of the roc epistry. using gis, ems transport time was derived from reported latitude/longitude coordinates of the ohca event to the actual receiving hospital. this was calculated via the actual network distance using arcgis. this gis-derived time was then compared to the actual ems transport time (in minutes) using the wilcoxon signed rank test. scatter plot analysis of actual vs. gis times were created to evaluate the relationship between actual and calculated time. a linear regression model predicting actual ems transport time from the derived gis-time was also developed in order to examine the potential relationship between the two variables. differences in the relationship were also investigated based on time of the day to reflect varying traffic conditions. results: cases were randomly selected for analysis. the median actual transport time was significantly longer than the median gis derived transport time ( . minutes vs. . minutes). scatter plot analysis did not reveal any significant correlation between actual and gis-based time. additionally, there was poor approximation of gis-based time and actual ems time (r = . ) with no evidence of a significant linear relationship between the two. the poorest correlation of time was observed during the morning hours ( : - : ; r = . ) while the strongest correlation was during the overnight hours ( : - : ; r = . ). conclusion: gis derived time does not appear to correlate well with actual ems transport time of ohca patients. efforts should be made to accurately obtain actual ems transport times for ohca patients. objectives: we first sought to describe the incidence of ohca presenting to the ed. we then sought to determine the association between hospital characteristics and survival to hospital admission. methods: we identified patients with diagnoses of cardiac arrest or ventricular fibrillation (icd- . or . ) in the nationwide emergency department sample, a nationally representative estimate of all ed admissions in the us. eds reporting ‡ patient with ohca were included. our primary outcome was survival to hospital admission. we examined variability in hospital survival rate and also classified hospitals into high or low performers based on median survival rate. we used this dichotomous hospital level outcome to examine factors associated with survival to admission including hospital and patient demographics, ed volume, cardiac arrest volume, and cardiac catheterization availability. all unadjusted and adjusted analyses were performed using weighted statistics and logistic regressions. results: of the hospitals, ( . %) were included. in total, , cases of cardiac arrest were identified, representing an estimated , cases nationally. overall ed ohca survival to hospital admission was . % (iqr . %, . %) in adjusted analyses, increased survival to admission was seen in hospitals with teaching status (or . , % ci . - . , p < . ), annual ed visits ‡ , (or . , % ci . - . , p < . ), and pci capability (or . , % ci . - . , p = . ). in separate adjusted analyses including teaching status and pci capabilities, hospitals with > annual cardiac arrest cases (or . , % ci . - . , p < . ) were also shown to have improved survival (figure) . conclusion: ed volume, cardiac arrest volume, and pci capability were associated with improved survival to hospital admission in patients presenting to the ed after ohca. an improved understanding of the contribution of ed care to ohca survival may be useful in guiding the regionalization of cardiac arrest care. background: prior investigations have demonstrated regional differences in out-of-hospital cardiac arrest (ohca) outcomes, but none have evaluated survival variability by hospital within a single major us city. objectives: we hypothesized that -day survival from ohca would vary considerably among one city's receiving hospitals. methods: we performed a retrospective review of prospectively collected cardiac arrest data from a large, urban ems system. our population included all ohcas with a recorded social security number (which we used to determine -day survival through the social security death index) that were transported to a hospital between / / and / / . we excluded traumatic arrests, pediatric arrests, and hospitals receiving less than ohcas with social security numbers over the three-year study period. we examined the associa-tion between receiving hospital and -day survival. additional variables examined included: level i trauma center status, teaching hospital status, ohca volume, and whether post-arrest therapeutic hypothermia (th) protocols were in place in . statistics were performed using chi-square tests and logistic regression. results: our study population comprised arrest cases delivered to unique hospitals with an overall -day survival of . %. mean age was . (sd . ) years. males comprised . % of the cohort; . % of victims were black. thirty-day survival varied significantly among the hospitals, ranging from . % to . % (chi-square . , p = . ). ohcas delivered to level i trauma centers were significantly more likely to survive ( . % vs. . %, p = . ), as were those delivered to hospitals known to offer post-arrest th ( . % vs. . %, p = . ). hospital teaching status and ohca volume were not associated with survival. conclusion: there was significant variability in ohca survival by hospital. patients were significantly more likely to survive if transported to a level i trauma center or hospital with post-arrest th protocols, suggesting a potential role for regionalization of ohca care. limiting our population to ohcas with recorded social security numbers reduced our power and may have introduced selection bias. further work will include survival data on the complete set of ohcas transported to hospitals during the three-year study period. background: traumatic brain injury is a leading cause of death and disability. previous studies suggest that prehospital intubation in patients with tbi may be associated with mortality. limited data exist comparing prehospital (ph) nasotracheal (nt), prehospital orotracheal (ot), and ed ot intubation and mortality following tbi. objectives: to estimate the associations between ph nt, ph ot, and ed ot intubation and in-hospital mortality in patients with moderate to severe tbi, with hypotheses that ph nt and ph ot intubation would be associated with increased mortality when compared to ed ot or no intubation. methods: an analysis using the denver health trauma registry, a prospectively collected database. consecutive adult trauma patients from - with moderate to severe tbi defined as head abbreviated injury scale (ais) scores of - . structured chart abstraction by blinded physicians was used to collect demographics, injury and prehospital care characteristics, intubation status and timing, in-hospital mortality and survival time, and neurologic function at discharge. poor neurologic function was defined as cerebral performance category score of - . multivariable logistic regression and survival analyses were performed, using multiple imputation for missing data. results: of the , patients, the median age was (iqr - ) years. the median ph gcs was (iqr - ), median injury severity score was (iqr - ), and median head ais was (iqr - ). ph nt occurred in . %, ph ot in . %, and ed ot in . %, while mortality occurred in . %. the -, -, and -hour survival analyses are outlined in the table. survival curves for ph nt, ph ot, and ed ot are demonstrated in the figure (p < . ) . conclusion: prehospital intubation in patients with moderate to severe tbi is associated with increased mortality. contrary to our initial hypothesis, there was also a significant association between ed intubation and mortality. these associations persisted despite survival time, and while adjusting for injury severity. background: sbdp is a breakdown product of the cytoskeletal protein alpha-ii-spectrin found in neurons and has been detected in severe tbi. objectives: this study examined whether early serum levels of sbdp could distinguish: ) mild tbi from three control groups; ) those with and without traumatic intracranial lesions on ct (+ct vs -ct); and ) those having a neurosurgical intervention (+nsg vs -nsg) in mild and moderate tbi (mmtbi). methods: this prospective cohort study enrolled adult patients presenting to two level i trauma centers following mmtbi with blunt head trauma with loss of consciousness, amnesia, or disorientation and a gcs - . control groups included uninjured controls and trauma controls presenting to the ed with orthopedic injuries or an mvc without tbi. mild tbi was defined as gcs and moderate tbi as having a gcs < . blood samples were obtained in all patients within hours of injury and measured by elisa for sbdp (ng/ml). the main outcomes were: ) the ability of sbdp to distinguish mild tbi from three control groups; ) to distinguish +ct from -ct and; ) to distinguish +nsg from -nsg. data were expressed as means with %ci, and performance was tested by roc curves (auc and %ci). results: there were patients enrolled: tbi patients ( gcs , gcs - ), trauma controls ( mvc controls and orthopedic controls), and uninjured controls. the mean age of tbi patients was years (range - ) with % males. fourteen ( %) had a +ct and % had +nsg. mean serum sbdp levels were . ( %ci . - . ) in normal controls, . ( . - . ) in orthopedic controls, . ( . - . ) in mvc controls, . ( . - . ) in mild tbi with gcs , and . ( . - . ) in tbi with gcs - (p < . ). the auc for distinguishing mild tbi from both controls was . ( %ci . - . ). mean sbdp levels in patients with -ct versus +ct were . ( . - . ) and . ( . - . ) respectively (p < . ) with auc = . ( %ci . - . ). mean sbdp levels in patients with -nsg versus +nsg were . ( . - . ) and . ( . - . ) respectively (p < . ) with auc = . ( %ci . - . ). conclusion: serum sbdp levels were detectable in serum acutely after injury and were associated with measures of injury severity including ct lesions and neurosurgical intervention. further study is required to validate these findings before clinical application. utility of platelet background: pre-injury use of anti-platelet agents (e.g., clopidogrel and aspirin) is a risk factor for increased morbidity and mortality in patients with traumatic intracranial hemorrhage (tich). some investigators have recommended platelet transfusion to reverse the anti-platelet effects in tich. objectives: this evidence-based medicine review examines the evidence regarding the effect of platelet transfusion in emergency department (ed) patients with pre-injury anti-platelet use and tich on patientoriented outcomes. methods: the medline, embase, cochrane library, and other databases were searched. studies were selected for inclusion if they compared platelet transfusion to no platelet transfusion in the treatment of adult ed patients with pre-injury anti-platelet use and tich, and reported rates of mortality, neurocognitive function, or adverse effects as outcomes. we assessed the quality of the included studies using ''grading of recommendations assessment, development and evaluation'' (grade) criteria. categorical data are presented as percentages with % confidence interval (ci). relative risks (rr) are reported when clinically significant. results: five retrospective, registry-based studies were identified, which enrolled patients cumulatively. based on standard criteria, three studies were of ''low'' quality evidence and two studies had ''very low'' qualities. one study reported higher in-hospital mortality in patients with platelet transfusion (ohm et al), another showed a lower mortality rate in patients receiving platelet transfusion (wong et al). three studies did not show any statistical difference in comparing mortality rates between the groups (table) . no studies reported intermediate-or long-term neurocognitive outcomes or adverse events. conclusion: five retrospective registry studies with suboptimal methodologies provide inadequate evidence to support the routine use of platelet transfusion in adult ed patients with pre-injury anti-platelet use and tich. abnormal levels of end-tidal carbon dioxide (etco ) are associated with severity of injury in mild and moderate traumatic brain injury (mmtbi) linda papa , artur pawlowicz , carolina braga , suzanne peterson , salvatore silvestri orlando regional medical center, orlando, fl; university of central florida, orlando, fl background: capnography is a fast, non-invasive technique that is easily administered and accurately measures exhaled etco concentration. etco levels respond to changes in ventilation, perfusion, and metabolic state, all of which may be altered following tbi. objectives: this study examined the relationship between etco levels and severity of tbi as measured by clinical indicators including glasgow coma scale (gcs) score, computerized tomography (ct) findings, requirement of neurosurgical intervention, and levels of a serum biomarkers of glial damage. methods: this prospective cohort study enrolled adult patients presenting to a level i trauma center following a mmtbi defined by blunt head trauma followed by loss of consciousness, amnesia, or disorientation and a gcs - . etco measurements were recorded from the prehospital and emergency department records and compared to indicators of tbi severity. results: of the patients enrolled, ( %) had a normal etco level and ( %) had an abnormal etco level. the mean age of enrolled patients was (range - ) and ( %) were male. mechanisms of injury included motor vehicle collision in ( %), motor cycle collision in ( %), fall in ( %), bicycle/ pedestrian struck in ( %), and other in ( %). eight ( %) patients had a gcs - and ( %) had a gcs - . of the ( %) patients with intracranial lesions on ct, ( %) had an abnormal etco level (p = . ). of the ( %) patients who required a neurosurgical intervention, % had an abnormal etco level (p = . ). levels of a biomarker indicative of astrogliosis were significantly higher in those with abnormal etco compared to those with a normal etco (p = . ). conclusion: abnormal levels of etco were significantly associated with clinical measures of brain injury severity. further research with a larger sample of mmtbi patients will be required to better understand and validate these findings. background: acetaminophen (apap) poisoning is the most frequent cause of acute hepatic failure in the us. toxicity requires bioactivation of apap to toxic metabolites, primarily via cyp e . children are less susceptible to apap toxicity; one current theory is that children's conjugative pathway (sulfonation) is more active. liquid apap preparations contain propylene glycol (pg), a common excipient that inhibits apap bioactivation and reduces hepatocellular injury in vitro and in rodents. cyp e inhibition may decrease toxicity in children, who tend to ingest liquid apap preparations, and suggests a potential novel therapy. objectives: to compare phase i (toxic) and phase ii (conjugative) metabolism of liquid versus solid prepara-tions of apap. we hypothesize that ingestion of a liquid apap preparation results in decreased production of toxic metabolites relative to a solid preparation, likely due to the presence of pg in the liquid preparations. methods: design-pharmacokinetic cross-over study. setting-university hospital clinical research center. subjects-adults ages - taking no chronic medications. interventions-subjects were randomized to receive a mg/kg dose of a commercially available solid or liquid apap preparation. after a washout period of greater than week, subjects received the same dose of apap in the alternate preparation. apap, apap-glucuronide and apap-sulfate (phase metabolites), apap-cysteinate and apap-mercapturate (phase metabolites) were analyzed via lc/ms in plasma over hours. peak concentrations and measured auc were compared using paired-sample t-tests. plasma pg levels were measured. results: fifteen subjects completed the protocol. peak concentrations and aucs of the cyp e derived toxic metabolites were significantly lower following ingestion of the liquid preparation (table, figure) . the glucuronide and sulfate metabolites were not different. pg was present following ingestion of liquid but not solid preparations. conclusion: ingestion of liquid relative to solid preparations in therapeutic doses results in decreased plasma levels of toxic apap metabolites. this may be due to inhibition of cyp e by pg, and may explain the decreased susceptibility in children. a less hepatotoxic formulation of apap can potentially be developed if co-formulated with a cyp e inhibitor. background: pressure immobilization bandages have been shown to delay mortality for up to hours after coral snake envenomation, providing an inexpensive and effective treatment when antivenin is not readily available. however, long-term efficacy has not been established. objectives: determine if pressure immobilization bandages, consisting of an ace wrap and splint, can delay morbidity and mortality from coral snake envenomation, even in the absence of antivenin therapy. methods: institutional animal care and use committee approval was obtained. this was a randomized, observational pilot study using a porcine model. ten pigs ( . kg to . kg) were sedated and intubated for hours. pigs were injected subcutaneously in the left distal foreleg with mg of lyophilized m. fulvius venom resuspended in water, to a depth of mm. pigs were randomly assigned to either a control group (no compression bandage and splint) or a treatment group (compression bandage and splint) approximately minute after envenomation. pigs were monitored daily for days for signs of respiratory depression, decreased oxygen saturations, and paresis/paralysis. in case of respiratory depression, pigs were euthanized and time to death recorded. chi-square was used to compare rates of survival up to days and a kaplan-meier survival curve constructed. results: average survival time of control animals was ± minutes compared to , ± , minutes for treated animals. significantly more pigs in the treatment group survived to hours than in the control group (p = . ). two of the treatment pigs survived to the endpoint of days, but showed necrosis of the distal lower extremity. conclusion: long-term survival after coral snake envenomation is possible in the absence of antivenin with the use of pressure immobilization bandages. the applied pressure of the bandage is critical to allowing survival without secondary consequences (i.e. necrosis) of envenomation. future studies should be designed to accurately monitor the pressures applied. background: patients exposed to organophosphate (op) compounds demonstrate a central apnea. the kölliker-fuse nuclei (kf) are cholinergic nuclei in the brainstem involved in central respiratory control. objectives: we hypothesize that exposure of the kf is both necessary and sufficient for op-induced central apnea. methods: anesthetized and spontaneously breathing wistar rats (n = ) were exposed to a lethal dose of dichlorvos using three experimental models. experiment (n = ) involved systemic op poisoning using subcutaneous (sq) dichlorvos ( mg/kg or x ld ). experiment (n = ) involved isolated poisoning of the kf using stereotactic microinjections of dichlorvos ( micrograms in microliters) into the kf. experiment (n = ) involved systemic op poisoning with isolated protection of the kf using sq dichlorvos ( mg/kg) and stereotactic microinjections of organophosphatase a (opda), an enzyme that degrades dichlorvos. respiratory and cardiovascular parameters were recorded continuously. histological verification of injection site was performed using kmno injections. animals were followed post-poisoning for hour or death. betweengroup comparisons were performed using a repeated measured anova or student's t-test where appropriate. results: animals poisoned with sq dichlorvos demonstrated respiratory depression starting . min post exposure, progressing to apnea . min post exposure. there was no difference in respiratory depression between animals with sq dichlorvos and those with dichlorvos microinjected into the kf. despite differences in amount of dichlorvos ( mg/kg vs . mg/kg) and method of exposure (sq vs cns microinjection), min following dichlorvos both groups (sq vs microinjection respectively) demonstrated a similar percent decrease in respiratory rate ( . vs . , p = . ), minute ventilation ( background: patients sustaining rattlesnake envenomation often develop thrombocytopenia, the etiology of which is not clear. laboratory studies have demonstrated that venom from several species, including the mojave rattlesnake (crotalus scutulatus scutulatus), can inhibit platelet aggregation. in humans, administration of crotaline fab antivenom (av) has been shown to result in transient improvement of platelet levels; however, it is not known whether platelet aggregation also improves after av administration. objectives: to determine the effect of c. scutulatus venom on platelet aggregation in vitro in the presence and absence of crotaline fab antivenom. methods: blood was obtained from four healthy male adult volunteers not currently using aspirin, nsaids, or other platelet-inhibiting agents. c. scutulatus venom from a single snake with known type b (hemorrhagic) activity was obtained from the national natural toxins research center. measurement of platelet aggregation by an aggregometer was performed using five standard concentrations of epinephrine (a known platelet aggregator) on platelet-rich plasma over time, and a mean area under the curve (auc) was calculated. five different sample groups were measured: ) blood alone; ) blood + c. scutulatus venom ( . mg/ml); ) blood + crotaline fab av ( mg/ml); ) blood + venom + av ( mg/ ml); ) blood + venom + av ( mg/ml). standard errors of the mean (sem) were calculated for each group. results: antivenom administration by itself did not significantly affect platelet aggregation compared to baseline ( . ± . %, p = . ). administration of venom decreased platelet aggregation ( . ± . %, p < . ). concentrated av administration in the presence of venom normalized platelet aggregation ( . ± . %) and in the presence of diluted av significantly increased aggregation ( . ± . %); p < . for both groups when compared to the venom-only group. to control for the effects of the venom and av, each was run independently in platelet-rich plasma without epinephrine; neither was found to significantly alter platelet aggregation. conclusion: crotaline fab av improved platelet aggregation in an in vitro model of platelet dysfunction induced by venom from c. scutulatus. the mechanism of action remains unclear but may involve inhibition of venom binding to platelets or a direct action of the antivenom on platelets. background: routine use of both breathalyzers and hand sanitizers is common across emergency depart-ments. the most common hand sanitizer on the market, purell, contains % ethyl alcohol and a lesser amount of isopropyl alcohol. previous investigations have documented that risk is low to the health care worker who applies frequent hand sanitizers to themselves. however, it is unknown whether this alcohol mixture causes false readings on a breathalyzer machine being used to determine alcohol levels on others. objectives: to determine the effect on the measurement of breathalyzer readings in individuals who have not consumed alcohol after hand sanitizer is applied to the experimenter holding a breathalyzer machine. methods: after obtaining informed consent, a breathalyzer reading was obtained in participants who had not consumed any alcohol in the last hours. three different experiments were performed with different participants in each. in experiment , two pumps of hand sanitizer were applied to the experimenter. without allowing the sanitizer to dry, the experimenter then measured the breathalyzer reading of the participant. in experiment , one pump of sanitizer was applied to the experimenter. measurements of the participant were taken without allowing the sanitizer to dry. in experiment , one pump of sanitizer was placed on the experimenter and rubbed until dry according to the manufacturer's recommendations. readings were recorded and analyzed using paired t-tests. results: the initial breathalyzer reading for all participants was . after two pumps of hand sanitizer were applied without drying (experiment ), breathalyzers ranged from . to . , with a mean above the legalintoxication limit of . (t( ) = ) . , p < . ). after one pump of hand sanitizer was applied without drying (experiment ), breathalyzers ranged from . to . , with a mean of . (t( ) = ) . , p < . ). after one pump of hand sanitizer was applied according to manufacturer's directions (experiment ), breathalyzers ranged from . to . with a mean of . (t( ) = ) . , p < . ). conclusion: use of hand sanitizer according to the manufacturer's recommendations results in a small but significant increase in breathalyzer readings. however, the improper and overuse of common hand sanitizer elevates routine breathalyzer readings, and can mimic intoxication in individuals who have not consumed alcohol. stephanie carreiro, jared blum, francesca beaudoin, gregory jay, jason hack objectives: the primary aim of this study is to determine if pretreatment with ile affects the hemodynamic response to epinephrine in a rat model. hemodynamic response was measured by a change in heart rate (hr) and mean arterial pressure (map). we hypothesized that ile would limit the rise in map and hr that typically follow epinephrine administration. methods: twenty male sprague dawley rats (approximately - weeks of age) were sedated with isoflurane and pretreated with a ml/kg bolus of ile or normal saline, followed by a mcg/kg dose of epinephrine intravenously. intra-arterial blood pressure and hr were monitored continuously until both returned to baseline (biopaq). a multifactorial analysis of variance (manova) was performed to assess the difference in map and hr between the two groups. standardized t-tests were then used to compare the peak change in map, time to peak map, and time to return to baseline map in the two groups. results: overall, a significant difference was found between the two groups in map (p = . ) but not in hr (p = . ). there was a significant difference (p = . ) in time to peak map in the ile group ( sec, % ci - ) versus the saline group ( sec, % ci - ) and a significant difference (p = . ) in time to return to baseline map in ile group ( sec, % ci - ) versus the saline group ( sec, % ci - ). there was no significant difference (p = . ) in the peak change in map of the ile group ( . , mmhg, % ci - ) versus the saline group ( . mmhg, % ci - ). conclusion: our data show that in this rat model ile pretreatment leads to a significant difference in map response to epinephrine, but no difference in hr response. ile delayed the peak effect and prolonged the duration of effect on map but did not alter the peak increase in map. this suggests that the use of ile may delay the time to peak effect of epinephrine if the drugs are administered concomitantly to the same patient. further research is needed to explore the mechanism of this interaction. rasch analysis of the agitation severity scale when used with emergency department acute psychiatry patients tania d. strout, michael r. baumann maine medical center, portland, me background: agitation is a frequently observed and problematic phenomenon in mental health patients being treated in the emergency setting. the agitation severity scale (agss), a reliable and valid instrument, was developed using classical test theory to measure agitation in acute psychiatry patients. objectives: the aim of this study was to analyze the agss according to the rasch measurement model and use the results to determine whether improvements to the instrument could be made. methods: this prospective, observational study was irb-approved. adult ed patients with psychiatric chief complaints and dsm-iv-tr diagnoses were observed using the agss. the rasch rating scale model was employed to evaluate the items comprising the agss using winsteps statistical software. unidimensionality, item fit, response category performance, person and item separation reliability, and hierarchical ordering of items were all examined. a principle components analysis (pca) of the rasch residuals was also performed. results: variable maps revealed that all of the agss items were used to some degree and that the items were ordered in a way that makes clinical sense. several duplicative items, indicating the same degree of agitation, were identified. item ( . ) and person ( . ) separation statistics were adequate, indicating appropriate spread of items and subjects along the agitation continuum and providing support for the instrument's reliability. keymaps indicated that the agss items are functioning as intended. analysis of fit demonstrated no extreme misfitting items. pca of the rasch residuals revealed a small amount of residual variance, but provided support for the agss as being unidimensional, measuring the single construct of agitation. the results of this rasch analysis support the agss as a psychometrically robust instrument for use with acute psychiatry patients in the emergency setting. several duplicative items were identified that may be eliminated and re-evaluated in future research; this would result in a shorter, more clinically useful scale. in addition, a gap in items for patients with lower levels of agitation was identified. generation of additional items intended to measure low levels of agitation could improve clinician's ability to differentiate between these patients. background: attempted suicide is one of the strongest clinical predictors of subsequent suicide and occurs up to times more frequently than completed suicide. as a result, suicide prevention has become a central focus of mental health policy. in order to improve current treatment and intervention strategies for those presenting with suicide attempt and self-injury in the emergency department (ed), it is necessary to have a better understanding of the types of patients who present to the ed with these complaints. objectives: to describe the epidemiology of ed visits for attempted suicide and self-inflicted injury over a year period. methods: data were obtained from the national hospital ambulatory medical care survey (nhamcs). all visits for attempted suicide and self-inflicted injury (e -e ) during - were included. trend analyses were conducted using stata's nptrend (a nonparametric test for trends that is an extension of the wilcoxon rank-sum test) and regression analyses. a two-tailed p < . was considered statistically significant. results: over the -year period, there were an average of , annual ed visits for attempted suicide and self-inflicted injury ( . [ % confidence interval (ci) . - . ] visits per , us population). the overall mean patient age was years, with visits most common among ages - ( . ; %ci . - . ). the average annual number of ed visits for suicide attempt and self-inflicted injury more than doubled from , in - to , in - . during the same timeframe, ed visits for these injuries per , us population almost doubled for males ( . to . ), females ( . to . ), whites ( . to . ), and blacks ( . to . ). no temporal differences were found for method of injury or ed disposition; there was, however, a significant decrease in visits determined by the physician to be urgent/emergent from % in to % in . conclusion: ed visit volume for attempted suicide and self-inflicted injury has increased over the past two decades in all major demographic groups. awareness of these longitudinal trends may assist efforts to increase research on suicide prevention. in addition, this information may be used to inform current suicide and self-injury related ed interventions and treatment programs. benjamin l. bregman, janice c. blanchard, alyssa levin-scherz george washington university, washington, dc background: the emergency department (ed) has increasingly become a health care access point for individuals with mental health needs. recent studies have found that rates of major depression disorder (mdd) diagnosed in eds are far above the national average. we conducted a study assessing whether individuals with frequent ed visits had higher rates of mdd than those with fewer ed visits in order to help guide screening and treatment of depressed individuals encountered in the ed. objectives: this study evaluated potential risk factors associated with mdd. we hypothesized that patients who are frequent ed visitors will have higher rates of mdd. methods: this was a single center, prospective, crosssectional study. we used a convenience sample of noncritically ill, english speaking adult patients presenting with non-psychiatric complaints to an urban academic ed over months in . we oversampled patients presenting with ‡ visits over the previous days. subjects were surveyed about their demographic and other health and health care characteristics and were screened with the phq , a nine-item questionnaire that is a validated, reliable predictor of mdd. we conducted bivariate (chi-square) and multivariate analysis controlling for demographic characteristics using sta-ta v. . . our principal dependent variable of interest was a positive depression screen (phq score ‡ ). our principal independent variable of interest was ‡ visits over the previous days. results: our response rate was . % with a final sample size of . of our total sample, ( . %) had three or greater visits within the prior days. one hundred ( %) frequent visitors had a positive phq mdd screen as compared to ( . %) of subjects with fewer than three visits (p < . ). in our multivariate analysis, the odds for having three or more visits for subjects who had a positive depression screen was . ( . , . ). of subjects with three or more visits with a positive depression screen, only ( %) were actively being treated for mdd at the time of their visit. conclusion: our study found a high prevalence of untreated depression among frequent users of the ed. eds should consider routinely screening patients who are frequent consumers for mdd. in addition, further studies should evaluate the effect of early treatment and follow up for mdd on overall utilization of ed services. access to psychiatric care among patients with depression presenting to the emergency department janice c. blanchard, benjamin l. bregman, dana rosenfarb, qasem al jabr, eun kim george washington university, washington, dc background: literature suggests that there is a high rate of major depressive disorder (mdd) in emergency department (ed) users. however, access to outpatient mental health services is often limited due to lack of providers. as a result, many persons with mdd who are not in active treatment may be more likely to utilize the ed as compared to those who are currently undergoing outpatient treatment. objectives: our study evaluated utilization rates and demographic characteristics associated with patients with a prior diagnosis of mdd not in active treatment. we hypothesized that patients who present to the ed with untreated mdd will have more frequent ed visits. methods: this was a single center, prospective, crosssectional study. we used a convenience sample of noncritically ill, english speaking adult patients presenting with non-psychiatric complaints to an urban academic ed over months in . subjects were surveyed about their demographic and other health and health care characteristics and were screened with the phq , a nine-item questionnaire that is a validated, reliable predictor of mdd. we conducted bivariate (chi-square) and multivariate analysis controlling for demographic characteristics using stata v. . . our principal dependent variable of interest was a positive depression screen (phq ‡ ). our analysis focused on the subset of patients with a prior diagnosis of mdd with a positive screen for mdd during their ed visit. results: our response rate was . % with a final sample size of . ( . %) patients screened positive for mdd with a phq score ‡ . of the patients with a positive depression screen, . % reported a prior history of treatment for mdd (n = ). of these patients, only . % were currently actively receiving treatment. hispanics who screened positive for depression with a history of mdd were less likely to actively be undergoing treatment as compared to non-hispanics ( . % versus . %, p = . ). patients with incomes less than $ , were more likely to actively be receiving treatment as opposed to higher incomes ( . % versus . % p = . ). conclusion: patients presenting to our ed with untreated mdd are more likely to be hispanic and less likely to be low income. the emergency department may offer opportunities to provide antidepressant treatment for patients who screen positive for depression but who are not currently receiving treatment. evaluation of a two-question screening tool (phq- ) for detecting depression in emergency department patients jeffrey p. smith, benjamin bregman, janice blanchard, nasser hashim, mary pat mckay george washington university, washington, dc background: the literature suggests there is a high rate of undiagnosed depression in ed patients and that early intervention can reduce overall morbidity and health care costs. there are several well validated screening tools for depression including the nine-item patient health questionnaire (phq- ). a tool using a two-question subset, the phq- , has been shown to be an easily administered, reasonably sensitive screening tool for depression in primary care settings. objectives: to determine the sensitivity and specificity of the phq- in detecting major depressive disorders (mdd) among adult ed patients presenting to an urban teaching hospital. we hypothesize that the phq- is a rapid, effective screening tool for depression in a general ed population. methods: cross sectional survey of a convenience sample of adult, non-critically ill, english speaking patients with medical and not psychiatric complaints presenting to the ed between am and pm weekdays. patients were screened for mdd with the phq- . we used spss v . to analyze the specificity, sensitivity, positive predictive value (ppv), negative predictive value (npv), and kappa of phq- scores of and (out of possible total score of ) compared to a validated cut-off score of or higher of points on the phq- . the two questions on the phq- are: ''over the last two weeks, how often have you had little interest in doing things? how often have you felt down, depressed or hopeless?'' responses are scored from - based on ''never'',''several days'', ''more than half'', ''nearly every day''. results: subjects of approached agreed to participate ( . % response rate), and ( . %) completed the phq- . the phq- identified ( . %) subjects with mdd. table outlines the percent of subjects who were positive and the sensitivity, specificity, positive, and negative predictive values and kappa for each cut-off on the phq- . conclusion: the phq- is a sensitive and specific screening tool for mdd in the ed setting. moreover, the phq- is closely correlated with the phq- , especially if a score of or greater is used. given the simplicity and ease of using a two-item questionnaire and the high rates of undiagnosed depression in the ed, including this brief, self-administered screening tool to ed patients may allow for early awareness of possible mdd and appropriate evaluation and referral. patients. however, much of this self-harm behavior is not discovered clinically and very little is known about the prevalence and predictors of current ed screening practices. attention to this issue is increasing due to the joint commission's patient safety goal , which focuses on identification of suicide risk in patients. objectives: to describe the prevalence and predictors of screening for self-harm and of presence of current self-harm in eds. methods: data were obtained from the nimh-funded emergency department safety assessment and followup evaluation (ed-safe). eight u.s. eds reviewed charts in real time for - hours a week between / and / . all patients presenting during enrollment shifts were characterized as to whether a selfharm screening had been performed by ed clinicians. a subset of patients with a positive screening was asked about the presence of self-harm ideation, attempts, or both by trained research staff. we used multivariable logistic regression to identify predictors of screening and of current self-harm. data were clustered by site. in each model we examined day and time of presentation, age < years, sex, race, and ethnicity. results: of the , patients presenting during research shift, , ( %) were screened for self-harm. screening rates varied among sites and ranged from % to %, with one outlier at %. of those screened, , ( %) had current self-harm. among those with selfharm approached by study personnel (n = , ), ( %) had thoughts of self-harm (suicidal or non-suicidal), ( %) had thoughts of suicide, ( %) had self-harm behavior, and ( %) had suicide attempt(s) over the preceding week. predictors of being screened were: age < years, male sex, weekend presentation, and night shift presentation (table) . among those screened, predictors of current self-harm were: age < years, white race, and night shift presentation. conclusion: screening for self-harm is uncommon in ed settings, though practices vary dramatically by site. patients presenting at night and on weekends are more likely to be screened, as are those under age and males. current self-harm is more common among those presenting on night shift, those under age , and whites. results: there were out-of-hospital records reviewed, and hospital discharge data were available in non-cardiac arrest patients. of the patients, ( . %) patients survived to hospital discharge and ( . %) died during hospitalization. the mean age of those transported was years (sd ), ( %) were male, ( %) were trauma-related, and ( %) were admitted to the icu. average systolic blood pressure (sbp), pulse (p), respiratory rate (rr), oxygen saturation (o sat), and end-tidal carbon dioxide (etco ) were sbp = (sd ), p = (sd ), rr = (sd ), o sat = % (sd ), and etco = (sd conclusion: of all the initial vital signs recorded in the out-of-hospital setting, etco was the most predictive of mortality. these findings suggest that pre-hospital etco is a useful clinical tool for determining severity of illness and appropriate triage. background: the prehospital use of continuous positive airway pressure (cpap) ventilation is a relatively new management for acute cardiogenic pulmonary edema (acpe) and there is little high quality evidence on the benefits or potential dangers in this setting. objectives: the aim of this study was to determine whether patients in severe respiratory distress treated with cpap in the prehospital setting have a lower mortality than those treated with usual care. methods: randomized, controlled trial comparing usual care versus cpap (whisperflowÒ) in a prehospital setting, for adults experiencing severe respiratory distress, with falling respiratory efforts, due to a presumed acpe. patients were randomised to receive either usual care, including conventional medications (nitrates, furosemide, and oxygen) plus bag-valve-mask ventilation, versus conventional medications plus cpap. the primary outcome was prehospital or in-hospital mortality. secondary outcomes were need for tracheal intubation, length of hospital stay, change in vital signs, and arterial blood gas results. we calculated relative risk with % cis. results: fifty patients were enrolled with mean age ae (sd ae ), male ae %, mortality ae %. the risk of death was significantly reduced in the cpap arm with mortality ae % ( deaths) in the usual care arm compared to ae % ( death) in the cpap arm (rr, ae ; % ci ae to ae ; p = ae ). patients who received cpap were significantly less likely to have respiratory acidosis (mean difference in ph ae ; % ci ae to ae ; p = ae ; n = ) than patients receiving usual care. the length of hospital stay was significantly less in the patients who received cpap (mean difference ae days; % ci ) ae to ae , p = ae ). conclusion: we found that cpap significantly reduced mortality, respiratory acidosis, and length of hospital stay for patients in severe respiratory distress caused by acpe. this study shows the use of cpap for acpe improves patient outcomes in the prehospital setting. (originally submitted as a ''late-breaker.'') trial reg. anzctr actrn ; funding fisher and paykal suppliers of the whisperflowÒ cpap device. background: because emergency service utilization continues to climb, validated methods to safely identify and triage low-acuity patients to either alternate care destinations or a complaint-appropriate level of ems response is of keen interest to ems systems and potentially payers. though the literature generally supports the medical priority dispatch system (mpds) as a tool to predict low-acuity patients by various standards, correlation with initial patient physiologic data and patient age is novel. objectives: to determine whether the six mpds priority determinants for protocol (sick person) can be used to predict initial ems patient acuity assessment or severity of an aggregate physiologic score. our longterm goal is to determine whether mpds priority can be used to predict patient acuity and potentially send only a first responder to do an in-person assessment to confirm this acuity, while reserving als transport resources for higher acuity patients. methods: calls dispatched through the wichita-sedgwick county - - center between july , and october , using mpds protocol (sick person) were linked to the ems patient care record for all patients and older. the six mpds priority determinants were evaluated for correlation with initial ems acuity code, initial vital signs, rapid acute physiology score (raps), or patient age. the ems acuity code scores patients from low to severe acuity, based on initial ems assessment. results: there were calls dispatched using protocol for those years of age and older during the period, representing approximately % of all ems calls. there is a significant difference in the first encounter vital signs among different mpds priority levels. based on the logistic regression model, the mpds priority code alone had a sensitivity of % and specificity of % for identifying low-acuity patients with ems acuity score as the standard. the area under the curve (auc) for roc is . for mpds priority codes alone, while addition of age increases this value to . . if we use the raps score as the standard to the mpds priority code, auc is . . if we include both mpds and age in the model, the auc is . . conclusion: in our system, mpds priority codes on protocol (sick person) alone, or with age or raps score, are not useful either as predictors of patient acuity on ems arrival or to reconfigure system response or patient destination protocols. alternate ambulance destination program c. nee-kofi mould-millman , tim mcmahan , michael colman , leon h. haley , arthur h. yancey emory university, atlanta, ga; grady ems, atlanta, ga background: low-acuity patients calling - - are known to utilize a large proportion of ems and ed resources. the national association of ems physicians and acep jointly support ems alternate destination programs (adps) in which low-acuity patients are allocated alternative resources non-emergently. analysis of one year's adp data from our ems system revealed that only . % of eligible patients were transported to alternate destinations (ambulatory clinics). reasons for this low success rate need investigation. objectives: to survey emts and discover the most frequent reasons given by them for transportation of eligible patients to eds instead of to clinics. methods: this study was conducted within a large, urban, hospital-based ems system. upon conducting an adp for months, a paper-based survey was created and pre-tested. all medics with any adp-eligible patient contact were included. emts were asked about personal, patient, and system related factors contributing to ed transport during the last months of the adp. qualitative data were coded, collated, and descriptively reported. results: sixty-three respondents ( emt-intermediates and emt-paramedics) completed the survey, representing % of eligible emts. thirty-one emts ( %) responded that they did not attempt to recruit eligible patients into the adp in the last program months. of those emts, ( %) attributed their motive to multiple, prior, failed recruitment attempts. the emts who actively recruited adp patients were asked reasons given by patients for clinic transport refusals: ( %) cited that patients reported no prior experience of care at the participating clinics, and ( %) reported patients had a strong preference for care in an ed. regarding system-related factors contributing to non-clinic transport, of the emts ( %) reported that clinic-consenting patients were denied clinic visits, mostly because of non-availability of same-day clinic appointments. conclusion: respondents indicated that poor emt enrollment of eligible patients, lack of available clinic time slots, and patient preference for ed care were among the most frequent reasons contributing to the low success rate of the adp. this information can be used to enhance the success of this, and potentially other adp programs, through modifications to adp operations and improved patient education. the effect of a standardized offline pain treatment protocol in the prehospital setting on pediatric pain treatment brent kaziny , maija holsti , nanette dudley , peter taillac , hsin-yi weng , kathleen adelgais university of utah, school of medicine, salt lake city, ut; university of colorado, school of medicine, aurora, co background: pain is often under treated in children. barriers include need for iv access, fear of delayed transport, and possible complications. protocols to treat pain in the prehospital setting improve rates of pain treatment in adults. the utah ems for children (emsc) program developed offline pediatric protocol guidelines for ems providers, including one protocol that allows intranasal analgesia delivery to children in the prehospital setting. objectives: to compare the proportion of pediatric patients receiving analgesia for orthopedic injury by prehospital providers before and after implementation of an offline pediatric pain treatment protocol. methods: we conducted a retrospective study of patients entered into the utah prehospital on-line active reporting information system (polaris, a database of statewide ems cases) both before and after initiation of the pain protocol. patients were included if they were age - years, with a gcs of - , an isolated extremity injury, and were transported by an ems agency that had adopted the protocol. pain treatment was compared for years before and months after protocol implementation with a wash-out period of months for agency training. the difference in treatment proportions between the two groups was analyzed and % cis were calculated. results: during the two study periods, patients met inclusion criteria. patient demographics are outlined in the table. / ( . %) patients were treated for pain before compared to / ( . %) patients treated after the pain protocol was implemented; a difference of . % ( % ci: . %- . %). patients were more likely to receive pain medication if they had a pain score documented (or: . ; % ci: . - . ) and if they were treated after the implementation of a pain protocol (or: . ; % ci: . - . ). factors not associated with the treatment of pain include age, sex, and mechanism of injury. conclusion: the creation and adoption of statewide emsc pediatric offline protocol guideline for pain management is associated with a significant increase in use of analgesia for pediatric patients in the prehospital setting. background: evidence-based guidelines are needed to determine the appropriate use of air medical transport, as few criteria currently used predict the need for air transport to a trauma center. we previously developed a clinical decision rule (cdr) to predict mortality in injured, helicopter-transported patients. objectives: this study is a prospective validation of the cdr in a new population. methods: a prospective, observational cohort analysis of injured patients ( ‡ y.o.) transported by helicopter from the scene to one of two level i trauma centers. variables analyzed included patient demographics, diagnoses, and clinical outcomes (in-hospital mortality, emergent surgery w/in hrs, blood transfusion w/in hrs, icu admit greater than hrs, combined outcome of all). prehospital variables were prospectively obtained from air medical providers at the time of transport and included past medical history, mechanism of injury, and clinical factors. descriptive statistics compared those with and without the outcomes of interest. the previous cdr (age ‡ , gcs £ , sbp < , flail chest) was prospectively applied to the new population to determine its accuracy and discriminatory ability. results: patients were transported from october -august . the majority of patients were male ( %), white ( %), with an injury occurring in a rural location ( %). most injuries were blunt ( %) with a median iss of . overall mortality was %. the most common reasons for air transport were: mvc with high risk mechanism ( %), gcs £ ( %), loc > minutes ( %), and mvc > mph ( %). of these, only gcs £ was significantly associated with any of the clinical outcomes. when applying the cdr, the model had a sensitivity of % ( . %- %), a specificity of . % ( . %- . %), a npv of % ( . %- %), and a ppv of . % ( . %- . %) for mortality. the area under the curve for this model was . , suggesting excellent discriminatory ability. conclusion: the air transport decision rule in this study performed with high sensitivity and acceptable specificity in this validation cohort. further external validation in other systems and with ground transported patients are needed in order to improve decision making for the use of helicopter transport of injured patients. background: acute non-variceal upper gastrointestinal (gi) bleeding is a common indication for hospital admission. to appropriately risk-stratify such patients, endoscopy is recommended within hours. given the possibility to safely manage patients as outpatients after endoscopy, risk stratification as part of an emergency department (ed) observation unit (ou) protocol is proposed. objectives: our objective was to determine the ability of an ou upper gi bleeding protocol to identify a lowrisk population, and to expeditiously obtain endoscopy and disposition patients. we also identified rates of outcomes including changes in hemoglobin, abnormal endoscopy findings, admission, and revisits. background: acute uncomplicated pyelonephritis (pyelo) requires no imaging but a ct flank pain protocol (ctfpp) may be ordered to determine if patients with pyelo and flank pain also have an obstructing stone. the prevalence of kidney stone and the characteristics predictive of kidney stone in pyelo patients is unknown. objectives: to determine elements on presentation that predict ureteral stone, as well as prevalence of stone and interventions in patients undergoing ct for pyelo. methods: retrospective study of patients at an academic ed who received a ctfpp scan between / and / . ctfpps were identified and randomly selected for review. pyelo was defined as: positive urine dip for infection and > wbc/hpf on formal urinalysis in addition to flank pain/cva tenderness, chills, fever, nausea, or vomiting. patients were excluded for age < y.o., renal disease, pregnancy, urological anomaly, or recent trauma. clinical data ( elements) were gathered blinded to ct findings; ct results were abstracted separately and blinded to clinical elements. ct findings of hydronephrosis and hyrdroureter (hydro) were used as a proxy for hydro that could be determined by ultrasound prior to ct. patients were categorized into three groups: ureteral stone, no significant findings, and intervention or follow-up required. classification and regression tree analysis was used to determine which variables could identify ureteral stone in this population of pyelo patients. results: out of the patients, ( . %) met criteria for pyelo; subjects had a mean age of ± . and % (n = ) were female. ct revealed ( %, % ci = . - . ) symptomatic stones, and ( %, % ci = . - . ) exams with no significant findings. two patients needed intervention/ follow-up ( %, % ci = . - . ), one for perinephric hemorrhage and the other for pancreatitis. hydro was predictive for ureteral stone with an or = . ( % ci = . - , p < . ). eleven ( %) ureteral stone patients were admitted and ( %) of them had procedures. of these patients, % had ct signs of obstruction, ( %) had hydronephrosis, and ( %) had hydroureter. conclusion: hydronephrosis was predictive of ureteral stone and in-house procedures. prospective study is needed to determine whether ct scan is warranted in patients with pyelonephritis but without hydronephrosis or hydroureter. curative objectives: the specific aim of this analysis was to describe characteristics of patients presenting to the emergency department (ed) at their index diagnosis, and to determine whether emergency presentation precludes treatment with curative intent. methods: we performed a retrospective cohort analysis on a prospectively maintained institutional tumor registry to identify patients diagnosed with crc from - . emrs were reviewed to identify which patients presented to the ed with acute symptoms of crc as the initial sign of their illness. the primary outcome variable was treatment plan (curative vs. palliative). secondary outcome variables included demographics, tumor type and location. descriptive statistics were conducted for major variables. chi-squre and fisher's exact tests were used to detect the association between categorical variables. two-sample t-test was used to identify the association between continuous and categorical variables. results: between jan and dec , patients were identified at our institution with crc. ( %) were male and ( %) were female, with mean age . ; sd: . . thirty-three patients ( . %) initially presented to the ed, of whom ( . %) received palliation. of patients who initially presented elsewhere, ( . %) received palliation. acute ed presentation with crc symptoms did not preclude treatment with curative intent (p = . ). patients who presented emergently were more likely to be female ( % vs male %; p = . ) and older ( vs. ; p = . ). there was no statistically significant relationship between age, sex, tumor location, or type and treatment approach. conclusion: patients with crc may present to the ed with acute symptoms, which ultimately leads to the diagnosis. emergent presentation of crc does not preclude patients from receiving therapy with curative intent. cannabinoid (or . , , and white blood cell (wbc) count ‡ , /mm (or . , % ci . - . ). conclusion: age ‡ years is not associated with need for admission from an ed observation unit. older adults can successfully be cared for in these units. initial temperature, respiratory rate, and pulse were not predictive of admission, but extremely elevated blood pressure was predictive. other relevant predictor variables included comorbidities and elevated wbc count. advanced age should not be a disqualifying criterion for disposition to an ed observation unit. older adult fallers in the emergency department luna ragsdale, cathleen colon-emeric duke university, durham, nc background: approximately / of community-dwelling older adults experience a fall each year, and . million are treated in u.s. emergency departments (ed) annually. the ed offers a potential location for identification of high-risk individuals and initiation of fall-prevention services that may decrease both fall rates and resource utilization. objectives: the goal of this study was to: ) validate an approach to identifying older adults presenting with falls to the ed using administrative data; and ) characterize the older adult who falls and presents to the ed and determine the rate of repeat ed visits, both fall-related and all visits, after an index fall-related visit. methods: we identified all older adults presenting to either of the two hospitals serving durham county residents during a six month period. manual chart review was completed for all encounters with icd codes that may be fall-related. charts were reviewed months prior and months post index visit. descriptive statistics were used to describe the cohort. results: a total of older adults were evaluated in the ed during this time period; ( . %) had an icd code for a potentially fall-related injury. of these, record review identified ( %) with a fall from standing height or less. of the fallers, . % of the patients were discharged, % were admitted, and % were admitted under observation. of those who fell, . % had an ed visit within the previous year. approximately / ( . %) of these were fall related. over half ( . %) of the patients who fell returned to the ed within one year of their index visit. a large proportion ( . %) of the return visits was fall-related. follow-up with a primary care provider or specialist was recommended in % of the patients who were discharged. overall mortality rate for fallers over the year following the index visit was %. conclusion: greater than fifty percent of fallers will return to the ed after an index fall, with a large proportion of the visits related to a fall. a large number of these fallers are discharged home with less than fifty percent having recommended follow-up. the ed represents an important location to identify high-risk older adults to prevent subsequent injuries and resource utilization. objectives: we studied whether falls from a standing position resulted in an increased risk for intracranial or cervical injury verses falling from a seated or lying position. methods: this is a prospective observational study of patients over the age of who presented with a chief complaint of fall to a tertiary care teaching facility. patients were eligible for the study if they were over age , were considered to be at baseline mental status, and were not triaged to the trauma bay. at presentation, a questionnaire was filled out by the treating physician regarding mechanism and position of fall, with responses chosen from a closed list of possibilities. radiographic imaging was obtained at the discretion of the treating physician. charts of enrolled patients were subsequently reviewed to determine imaging results, repeat studies done, or recurrent visits. all patients were called in follow-up at days to assess for delayed complications related to the fall. data were entered into a standardized collection sheet by trained abstractors. data were analyzed with fisher's exact test and descriptive statistics. this study was reviewed and approved by the institutional review board. results: two-hundred sixty two patients were enrolled during the study period. one-hundred ninety eight of these had fallen from standing and fell from either sitting or lying positions. the mean age for patients was (sd . ) for those who fell from standing and (sd . ) for those who fell from sitting or lying. there were patients with injuries who fell from standing: three with subdural hematomas, one with a cerebral contusion, one with an osteophyte fracture at c , and one with an occipital condyle fracture with a chip fracture of c . there were patients with injuries who fell from a seated or lying position: one with a traumatic subarachnoid hemorrhage and one with a type ii dens fracture. the overall rate of traumatic intracranial or cervical injury in elders who fell was %. no patients required surgical intervention. there was no difference in rate of injury between elders who fell from standing versus those who fell from sitting or lying (p = ). (table) . conclusion: both instruments identify the majority of patients as high-risk which will not be helpful in allocating scarce resources. neither the isar nor the trst can distinguish geriatric ed patients at high or low risk for or -month adverse outcomes. these prognostic instruments are not more accurate in dementia or lower literacy subsets. future instruments will need to incorporate different domains related to short-term adverse outcomes. background: for older adults, both inpatient and outpatient care involves not only the patient and physician, but often a family member or informal caregiver. they can assist in medical decision making and in performing the patient's activities of daily living. to date, multiple outpatient studies have examined the positive roles family members play during the physician visit. however, there is very limited information on the involvement of the caregiver in the ed and their relationship with the health outcomes of the patient. objectives: to assess whether the presence of a caregiver influences the overall satisfaction, disposition, and outpatient follow-up of elderly patients. we performed a three-step inquiry of patients over years old who arrived to the upenn ed. patients and care partners were initially given a questionnaire to understand basic demographic data. at the end of the ed stay, patients were given a satisfaction survey and followed through days to assess time to disposition, whether the patient was admitted or discharged, outpatient follow-up, and ed revisit rates. chi-square and t-tests were used to examine the strength of differences in the elderly patients' sociodemographics, self-rated health, receiving aid with their instrumental activities of daily living, and number of health problems by accompaniment status. multivariate regression models were constructed to examine whether the presence or absence of caregivers affected satisfaction, disposition, and follow-up. results: overall satisfaction was higher among patients who had caregivers ( . points), among patients who felt they were respected by their physician ( . points), and had lower lengths of stay ( hours). patients with caregivers were also more likely to be discharged home (or . ) and to follow-up with their regular physician (or . ). there was no evidence to suggest caregivers affected the overall rates of revisits back to an ed. conclusion: for older adults, medical care involves not only the patient and physician, but often a family member or an informal care companion. these results demonstrate the positive influence of caregivers on the patients they accompany, and emergency physicians should define ways to engage these caregivers during their ed stay. this will also allow caregivers to participate when needed and can help to facilitate transitions across care settings. background: shared decision making has been shown to improve patient satisfaction and clinical outcomes for chronic disease management. given the presence of individual variations in the effectiveness and side effects of commonly used analgesics in older adults, shared decision making might also improve clinical outcomes in this setting. objectives: we sought to characterize shared decision making regarding the selection of an outpatient analgesic for older ed patients with acute musculoskeletal pain and to examine associations with outcomes. methods: we conducted a prospective observational study with consecutive enrollment of patients age or older discharged from the ed following evaluation for moderate or severe musculoskeletal pain. two essential components of shared decision making, ) information provided to the patient and ) patient participation in the decision, were assessed via patient interview at one week using four-level likert scales. results: of eligible patients, were reached by phone and completed the survey. only % ( / ) of patients reported receiving 'a lot' of information about the analgesic, and only % ( / ) reported participating 'a lot' in the selection of the analgesic. there were trends towards white patients (p = . ) and patients with higher educational attainment (p = . ) reporting more participation in the decision. after adjusting for sex, race, education, and initial pain severity, patients who reported receiving 'a lot' of information were more likely to report optimal satisfaction with the analgesic than those receiving less information ( % vs. %, p < . ). after the same adjustments, patients who reported participating 'a lot' in the decision were also more likely to report optimal satisfaction with the analgesic ( % vs. %, p < . ) and greater reductions in pain scores (mean reduction in pain . vs. . , p < . ) at one week than those who participated less. background: quality of life (qol) measurements have become increasingly important in outcomes-based research and cost-utility analyses. dementia is a prevalent, often unrecognized, geriatric syndrome that may limit the accuracy of patient self-report in a subset of patients. the relationship between caregiver and geriatric patient qol in the emergency department (ed) is not well understood. objectives: to qualify the relationship between caregiver and geriatric patient qol ratings in ed patients with and without cognitive dysfunction. methods: this was a prospective, consecutive patient, cross-sectional study over two months at one urban academic medical center. trained research assistants screened for cognitive dysfunction using the short blessed test and evaluated health impairment using the quality of life-alzheimer's disease (qol-ad) test. when available in the ed, caregivers were asked to independently complete the qol-ad. consenting subjects were non-critically ill, english-speaking, community-dwelling adults over years of age. responses were compared using wilcoxon signed ranks test to assess the relationships between patient and caregiver scores from the qol-ad stratified by normal or abnormal cognitive screening results. significance was defined by p < . . results: patient qol ratings were obtained from patient-caregiver pairs. patients were % female, % african-american, with a mean age of -years, and % had abnormal cognitive screening tests. compared with caregivers, cognitively normal patients had no significant qol assessment differences except for questions of energy level and overall mood. on the other hand, cognitively impaired patients differed significantly on questions of energy level and ability to perform household chores with a trend towards significant differences for living setting (p = . ) and financial situation (p = . ). in each category, the differences reflected a caregiver underestimation of quality compared with the patient's self-rating. conclusion: discrepancies between qol domains and total scores for patients with cognitive dysfunction and their caregivers highlights the importance of identifying cognitive dysfunction in ed-based outcomes research and cost-utility analyses. further research is needed to quantify the clinical importance of the patient-and caregiver-assessed quality of life. background: age is often a predictor for increased morbidity and mortality. however, it is unclear whether old age is a predictor of adverse outcome in syncope. objectives: to determine whether old age is an independent predictor of adverse outcome in patients presenting to the emergency department following a syncopal episode. methods: a prospective observational study was conducted from june to july enrolling consecutive adult ed patients (> years) presenting with syncope. syncope was defined as an episode of transient loss of consciousness. adverse outcome or critical intervention were defined as gastrointestinal bleeding or other hemorrhage, myocardial infarction/percutaneous coronary intervention, dysrhythmia, alteration in antidysrhythmics, pacemaker/defibrillator placement, sepsis, stroke, death, pulmonary embolus, or carotid stenosis. outcomes were identified by chart review and -day follow-up phone calls. results: of patients who met inclusion criteria, an adverse event occurred in % of patients. overall, % of patients with risk factors had adverse outcomes compared to . % of patients with no risk factors. in particular, / ( %; % ci - %) of patients < with risk factors had adverse outcomes, while / ( %; % ci - %) of the elderly with risk factors had adverse outcomes. in contrast, among young people / ( %; % ci . - . %) of patients without risk factors had adverse outcomes while / ( . %; % ci . - %) of patients ‡ without risk factors had adverse outcomes. conclusion: although the elderly are at greater risk for adverse outcomes in syncope, age ‡ or older alone does not appear to be a predictor of adverse outcome following a syncopal event. based on these data, it should be safe to discharge home from the ed patients with syncope, but without risk factors, regardless of age. (originally submitted as a ''late-breaker.'') antibiotics background: adherence to national guidelines for hiv and syphilis screening in eds is not routine. in our ed, hiv and syphilis screening rates among patients tested for gonorrhea and chlamydia (gc/ct) have been reported to be % and %, respectively. objectives: to determine the effect of a sexually transmitted infection (sti) laboratory order set on hiv and syphilis screening among ed patients tested for gc/ct. we hypothesized that a sti order set would increase screening rates by at least %. methods: a -month, quasi-experimental study in an urban ed comparing hiv and syphilis screening rates of gc/ct-tested patients before (control phase) and after the implementation of a sti laboratory order set (intervention phase). the order set linked blood-based rapid hiv and syphilis screening with gc/ct testing. consecutive patients completing gc/ct testing were included. the primary outcome was the absolute difference in hiv and syphilis screening rates among gc/ ct-tested patients between phases. we estimated that subjects per phase were needed to provide % power (p-value of £ . ) to detect an absolute difference in screening rates of %, assuming a baseline hiv screening rate of %. results: the ed census was , . characteristics of patients tested for gc/ct were similar between phases: the mean age was years (sd = ) and most were female ( %), black ( %), hispanic ( %), and unmarried ( % services have recommended the use of immunization programs against influenza disease within hospitals since the s. the emergency department (ed) being the ''safety net'' for most non-insured people is an ideal setting to intervene and provide primary prevention from influenza. objectives: the purpose of this study is to assess whether a pharmacist-based influenza immunization program is feasible in the ed, and successful in increasing the percentage of adult patients receiving the influenza vaccine. methods: implementation of pharmacist-based immunization program was developed in coordination with ed physicians and nursing staff in . the nursing staff, using an embedded electronic questionnaire within their triage activity, screened patients for eligibility for the influenza vaccine. the pharmacist using an electronic alert system within the electronic medical record identified patients who we deemed eligible and if agreed the pharmacist vaccinated the patient. patients who refused to be vaccinated were surveyed to ascertain their perception concerning immunization offered by a pharmacist in the ed. feasibility and safety data for vaccinating patient in the ed were recorded. results: patients were approached and enrolled into the study. of the , % agreed to receive the influenza vaccine from a pharmacist in the ed. the median screening time was minutes and median vaccination time was minutes for a total of minutes from screening time to vaccination time. % were willing to receive the influenza vaccine from a pharmacist, and % were willing to receive the vaccine in the ed. the main reason given for refusing to receive the influenza vaccine was ''patient does not feel at risk of getting the disease''; only . % stated they were vaccinated recently. conclusion: a pharmacist-based influenza immunization program is feasible in the ed, and has the potential to successfully increase the percentage of adult patients receiving the vaccine. . ± . , p < . ). ed visits by hiv-infected patients also had longer lengths of ed stay ( ± . minutes vs. . ± . minutes, p < . ) and were more likely to be admitted ( % vs. %, p < . ), than their non-hiv infected counterparts. conclusion: although ed visits by hiv-infected individuals in the u.s. are relatively infrequent, they occur at rates higher than the general population, and consume significantly more ed resources than the general population. the background: the influence of wound age on the risk of infection in simple lacerations repaired in the emergency department (ed) has not been well studied. it has traditionally been taught that there is a ''golden period'' beyond which lacerations are at higher risk of infection and therefore should not be closed primarily. the proposed cutoff for this golden period has been highly variable ( - hours in surgical textbooks). objectives: to answer the following research question: are wounds closed via primary repair after the golden period at increased risk for infection? methods: we searched medline, embase, and other databases as well as bibliographies of relevant articles. we included studies that enrolled ed patients with lacerations repaired by primary closure. exclusion: . intentional delayed primary repair or secondary closure, . wounds requiring intra-operative repair, skin graft, drains, or extensive debridement, and . grossly contaminated or infected at presentation. we compared the outcome of wound infection in two groups of early versus delayed presentations (based on the cut-offs selected by the original articles). we used ''grading of recommendations assessment, development and evaluation'' (grade) criteria to assess the quality of the included trials. frequencies are presented as percentages with % confidence intervals. relative risk (rr) of infection is reported when clinically significant. results: studies were identified. four trials enrolling patients in aggregate met our inclusion/exclusion criteria. two studies used a -hour cut-off and the other two used a -hour cut-off for defining delayed wounds. the overall quality of evidence was low. the infection rate in the wounds that presented with delay ranged from . % to %. one study with the smallest sample size (morgan et al), which only enrolled lacerations to the hand and forearm, showed higher rates of infection in patients with delayed wounds (table). the infection rates in delayed wound groups in the remaining three studies were not significantly different from the early wounds. conclusion: the evidence does not support the existence of a golden period, nor does it support the role of wound age on infection rate in simple lacerations. background: although clinical studies in children have shown that temperature elevation is an independent and significant predictor of bacteremia in children, the relationship in adults is largely unknown or equivocal. objectives: review the incidence of positive blood cultures on critically ill adult septic patients presenting to an emergency department (ed) and determine the association of initial temperature with bacteremia. methods: july to july retrospective chart review on all patients admitted from the ed to an urban community hospital with sepsis and subsequently expiring within days of admission. fever was defined as a temperature ‡ °c. sirs criteria were defined as: ) temperature ‡ °c or £ °c, ) heart rate ‡ beats/ minute, ) respiratory rate ‡ or mechanical ventilation, ) wbc ‡ , /mm or < , or bands ‡ %. objectives: we examined the utility of limited genetic sequencing of bacterial isolates using multilocus sequence typing (mlst) to discriminate between known pathogenic blood culture isolates of s. epidermidis and isolates recovered from skin. methods: ten blood culture isolates from patients meeting the centers for disease control and prevention (cdc) criteria for clinically significant s. epidermidis bacteremia and ten isolates from the skin of healthy volunteers were studied. mlst was performed by sequencing bp regions of seven genes (arc, aroe, gtr, muts, pyr, tpia, and yqil) . genetic variability at these sites was compared to an international database (www.sepidermidis.mlst.net) and each strain was then categorized into a genotype on the basis of known genetic variation. the ability of the gene sequences to correctly classify strains was quantified using the support vector machine function in the statistical package r. , bootstrap resamples were performed to generate confidence bounds around the accuracy estimates. results: between-strain variability was considerable, with yqil being most variable ( alleles) and tpia being least ( allele). the muts gene, responsible for dna repair in s. epidermidis, showed almost complete separation between pathogenic and commensal strains. when the seven genes were used in a joint model, they correctly predicted bacterial strain type with % accuracy (iqr , %). conclusion: multilocus sequence typing shows excellent early promise as a means of distinguishing contaminant versus truly pathogenic isolates of s. epidermidis from clinical samples. near-term future goals will involve developing more rapid means of sequencing and enrolling a larger cohort to verify assay performance. conference are presented by influenza scenario in table and background: antiviral medications are recommended for patients with influenza who are hospitalized or at high risk for complications. however, timely diagnosis of influenza in the ed remains challenging. influenza rapid antigen tests have short turn-around times, making them potentially useful in the ed setting, but their sensitivities may be too low to assist with treatment decisions. objectives: to evaluate the test characteristics of the binaxnow influenza a&b rapid antigen test (rat) in ed patients. methods: we prospectively enrolled a systematic sample of patients of all ages presenting to two eds with acute respiratory symptoms or fever during three consecutive influenza seasons ( ) ( ) ( ) ( ) . research personnel collected nasal and throat swabs, which were combined and tested for influenza with rt-pcr using cdc-provided primers and probes. ed clinicians independently decided whether to obtain a rat during clinical care. rats were performed in the clinical laboratory using the binaxnow influenza a&b test on nasal swabs collected by ed staff. the study cohort included subjects who underwent both a research pcr and clinical rat. rat test characteristics were evaluated using pcr as the criterion standard with stratified sub-analyses for age group and influenza subtype (pandemic h n (ph n ), non-pandemic influenza a, influenza b). results: subjects were enrolled; subjects were pcr positive for influenza ( ph n , non-pandemic influenza a, and influenza b). for all age groups, rat sensitivities were low and specificities were high ( hiv infection with cd < ; and among nursing home residents, inability to independently perform activities of daily living. sources for bacterial cultures included blood, sputum (adults only), bronchoalveolar lavage (bal), tracheal aspirate, and pleural fluid. only sputum specimens with a bartlett score ‡ + were considered adequate for culturing. results: among children enrolled, ( %) had s. aureus cultured from ‡ specimen, including with methicillin-resistant s. aureus (mrsa) and with methicillin-susceptible s. aureus (mssa). specimens positive for s. aureus included pleural fluid, blood, tracheal aspirates, and bal. two children with s. aureus had evidence of co-infection: influenza a, and streptococcus pneumoniae. among adults enrolled, ( %) grew s. aureus from ‡ specimen, including with mrsa and with mssa. specimens positive for s. aureus included blood, sputum, and bal. five adults with s. aureus had evidence of co-infections: coronavirus, respiratory syncytial virus, s. pneumoniae, and pseudomonas aeruginosa. presenting clinical characteristics and outcomes of subjects with staphylococcal cap are summarized in tables - . conclusion: these preliminary findings suggest s. aureus is an uncommon cause of cap. although the small number of staphylococcal cases limits conclusions that can be drawn, in our analysis staphylococcal cap appears to be associated with co-infections, pleural effusions, and severe disease. future work will focus on continued enrollment and developing clinical prediction models to aid in diagnosing staphylococcal cap in the ed. background: emergency care has been a neglected public health challenge in sub-saharan africa. the goal of global emergency care collaborative (gecc) is to develop a sustainable model for emergency care delivery in low-resource settings. gecc is developing a training program for emergency care practitioners (ecps). objectives: to analyze the first patient visits at karoli lwanga ''nyakibale'' hospital ed in rural uganda to determine the knowledge and skills needed in training ecps. methods: a descriptive cross-sectional analysis of the first consecutive patient visits in the ed's patient care log was reviewed by an unblinded abstractor. data on demographics, procedures, laboratory testing, bedside ultrasounds (us) performed, radiographs (xrs) ordered, and diagnoses were collated. all authors discussed uncertainties and formed a consensus. descriptive statistics were performed. results: of the first patient visits, procedures were performed in ( . %) patients, including ( . %) who had ivs placed, ( . %) who received wound care, and ( . %) who received sutures. complex procedures, such as procedural sedations, lumbar punctures, orthopedic reductions, nerve blocks, and tube thoracostomies, occurred in ( . %) patients. laboratory testing, xrs, and uss were performed in ,( . %), ( . %), and ( %) patients, respectively. infectious diseases were diagnosed in ( . %) patients; ( . %) with malaria and ( . %) with pneumonia. traumatic injuries were present in ( %) patients; ( . %) needing wound care and ( . %) with fractures. gastrointestinal and neurological diagnoses affected ( . %) and ( . %) patients, respectively. conclusion: ecps providing emergency care in sub-saharan africa will be required to treat a wide variety of patient complaints and effectively use laboratory testing, xrs, and uss. this demands training in a broad range of clinical, diagnostic, and procedural skills, specifically in infectious disease and trauma, the two most prevalent conditions seen in this rural sub-saharan africa ed. assessment of point-of-care ultrasound in tanzania background: current chinese ems is faced with many challenges due to a lack of systematic planning, national standards in training, and standardized protocols for prehospital patient evaluation and management. objectives: to estimate the frequency with which prehospital care providers perform critical actions for selected chief complaints in a county-level ems system in hunan province, china. methods: in collaboration with xiangya hospital (xyh), central south university in hunan, china, we collected data pertaining to prehospital evaluation of patients on ems dispatches from a '' - - '' call center over a -month period. this call center services an area of just under km with a total population of . million. each ems team consists of a driver, a nurse, and a physician. this was a cross-sectional study where a single trained observer accompanied ems teams on transports of patients with a chief complaint of chest pain, dyspnea, trauma, or altered mental status. in this convenience sample, data were collected daily between am and pm. critical actions were pre-determined by a panel of emergency medicine faculty from xyh and the university of maryland school of medicine. simple statistical analysis was performed to determine the frequency of critical actions performed by ems providers. results: during the study period, patients were transported, of whom met the inclusion criteria. ( . %) evaluations were observed directly for critical actions. the table shows the frequency of critical actions performed by chief complaint. none of the patients with chest pain received an ecg even though the equipment was available. rapid glucose was checked in only . % of patients presenting with altered mental status. a lung exam was performed in . % of patients with dyspnea, and the respiratory rate was measured in . %. among patients transported for trauma, blood pressure, and heart rate were only measured in % and . %, respectively. conclusion: in this observation study of prehospital patient assessments in a county-level ems system, critical actions were performed infrequently for the chief complaints of interest. performance frequencies for critical actions ranged from to . %, depending on the chief complaint. standardized prehospital patient care protocols should be established in china and further training is needed to optimize patient assessment. trends little is known about the comparative effectiveness of noninvasive ventilation (niv) versus invasive mechanical ventilation (imv) in chronic obstructive pulmonary disease (copd) patients with acute respiratory failure. objectives: to characterize the use of niv and imv in copd patients presenting to the emergency department (ed) with acute respiratory failure and to compare the effectiveness of niv vs. imv. methods: we analyzed the - nationwide emergency department sample (neds), the largest, all-payer, us ed and inpatient database. ed visits for copd with acute respiratory failure were identified with a combination of copd exacerbation and respiratory failure icd- -cm codes. patients were divided into three treatment groups: niv use, imv use, and combined use of niv and imv. the outcome measures were inpatient mortality, hospital length of stay (los), hospital charges, and complications. propensity score analysis was performed using patient and hospital characteristics and selected interaction terms. results: there were an estimated , visits annually for copd exacerbation and respiratory failure from approximately , eds. ninety-six percent were admitted to the hospital. of these, niv use increased slightly from % in to % in (p = . ), while imv use decreased from % in to % in (p < . ); the combined use remained stable ( %). inpatient mortality decreased from % in to % in (p < . ). niv use varied widely between hospitals, ranging from % to % with median of %. in a propensity score analysis, niv use (compared to imv) significantly reduced inpatient mortality (risk ratio . ; % confidence interval [ci] . - . ), shortened hospital los (difference ) days; %ci ) to ) ), and reduced hospital charges ; ) . niv use was associated with a lower rate of iatrogenic pneumothorax compared with imv use ( . % vs. . %, p < . ). an instrumental analysis confirmed the benefits of niv use, with a % reduction in inpatient mortality in the niv-preferring hospitals. conclusion: niv use is increasing in us hospitals for copd with acute respiratory failure; however, its adoption remains low and varies widely between hospitals. niv appears to be more effective and safer than imv in the real-world setting. background: dyspnea is a common ed complaint with a broad differential diagnosis and disease-specific treatment. bronchospasm alters capnographic waveforms, but the effect of other causes of dyspnea on waveform morphology is unclear. objectives: we evaluated the utility of capnographic waveforms in distinguishing dyspnea caused by reactive airway disease (rad) from non-rad in adult ed patients. methods: this was a prospective, observational, pilot study of a convenience sample of adult patients presenting to the ed with dyspnea. waveforms, demographics, past medical history, and visit data were collected. waveforms were independently interpreted by two blinded reviewers. when the interpreters disagreed, the waveform was re-reviewed by both reviewers and an agreement was reached. treating physician diagnosis was considered the criterion standard. descriptive statistics were used to characterize the study population. diagnostic test characteristics and inter-rater reliability are given. results: fifty subjects were enrolled. median age was years (range - ), % were female, % were caucasian. / ( %) had a history of asthma or chronic obstructive pulmonary disease. rad was diagnosed by the treating physician in / ( %) and / ( %) had received treatment for dyspnea prior to waveform acquisition. the interpreters agreed on waveform analysis in / ( %) cases (kappa = . ). test characteristics for presence of acute rad, including %ci, were: overall accuracy % ( . %- . %), sensitivity % ( . %- . %), specificity % ( . %- . %), positive predictive value % ( . %- . %), negative predictive value % ( . %- . %), positive likelihood ratio . ( . - . ) , negative likelihood ratio . ( . - . ). conclusion: inter-rater agreement is high for capnographic waveform interpretation, and shows promise for helping to distinguish between dyspnea caused by rad and dyspnea from other causes in the ed. treatments received prior to waveform acquisition may affect agreement between waveform interpretation and physician diagnosis, affecting the observed test characteristics. asthma background: asthma and chronic obstructive pulmonary disease (copd) patients who present to the emergency department (ed) usually lack adequate ambulatory disease control. while evidence-based care in the ed is now well defined, there is limited inform-ation regarding the pharmacologic or non-pharmacologic needs of these patients at discharge. objectives: this study evaluated patients' needs with regard to the ambulatory management of their respiratory conditions after ed treatment and discharge. methods: over months, adult patients with acute asthma or copd, presenting to a tertiary care alberta hospital ed and discharged after being treated for exacerbations, were enrolled. using results from standardized in-person questionnaires, charts were reviewed by respiratory researchers to identify care gaps. results: overall, asthmatic and copd patients were enrolled. more patients with asthma required education on spacer devices ( % vs %). few asthma ( %) and no copd patients had written action plans; asthma patients were more likely to need adherence counseling ( % vs %) for preventer medications. more patients with asthma required influenza vaccination ( % vs %; p = . ); pneumococcal immunization was low ( %) in copd patients. only % of asthmatics reported ever being referred to an asthma education program and % of the copd patients reported ever being referred to pulmonary rehabilitation. at ed presentation, % of the asthmatics required the addition of inhaled corticosteroids (ics) and % required the addition of ics/long acting beta-agonist (ics/laba) combination agents. on the other hand, % of copd patients required the addition of long-acting anticholinergics while most ( %) were receiving preventer medications. finally, % of copd and % of asthma patients who smoked required smoking cessation counseling. conclusion: overall, we identified various care gaps for patients presenting to the ed with asthma and copd. there is an urgent need for high-quality research on interventions to reduce these gaps. methods: this is an interim, sub-analysis of an interventional, double-blinded study performed in an academic urban-based adult ed. subjects with acute exacerbation of asthma with fev < % predicted within minutes following initiation of ''standard care'' (including a minimum of mg nebulized albuterol, . mg nebulized ipratropium, and mg corticosteroid) who consented to be in a trial were included. all treatment was administered by emergency physicians unaware of the study objectives. patients were randomly assigned to treatment with placebo or an intravenous beta agonist. all subjects had fev and ds obtained at baseline, , , and hours after treatment. fev was measured using a bedside nspire spirometer, and ds was calculated using a modified borg dyspnea score. results: thirty-eight patients were included for analysis. spearman's rho test (rho) was used to measure correlations between fev and ds at , , and hours post study entry and subsequent hospitalization. rho is negative for fev (higher fev correlates to lower rate of hospitalization) and positive for ds (higher ds correlates to higher rate of hospitalization). at each time point, ds were more highly correlated to hospitalization than were fev (see table) . conclusion: dyspnea score at , , and hours were significantly correlated with hospital admission, whereas fev was not. in this set of subjects with moderate to severe asthma exacerbations, a standardized subjective tool was superior to fev for predicting subsequent hospitalization. methods: this is an interim, subgroup analysis of a prospective, interventional, double-blind study performed in an academic urban ed. subjects who were consented for this trial presented with acute asthma exacerbations with fev £ % predicted within minutes following initiation of ''standard care'' (includes a minimum of . mg nebulized albuterol, . mg nebulized ipratropium, and mg of a corticosteroid). ed physicians who were unaware of the study objectives administered all treatments. subjects were randomized in a : ratio to either placebo or investigational intravenous beta agonist arms. blood was obtained at and . hours after the start of the hour long infusion. blood was centrifuged and serum stored at ) °c, and then shipped on dry ice for albuterol and lactate measurements at a central lab. the treatment lactate and d lactate were correlated with hr serum albuterol concentrations and hospital admission using partial pearson correlations to adjust for ds. results: subjects were enrolled to date, with complete data. the mean baseline serum lactate level was . mg/dl (sd ± . ). this increased to . mg/ dl (sd ± . ) at . hrs. the mean hr ds was . (sd ± . ). the correlations between treatment lactate, d lactate, hr serum albuterol concentrations (r, s and total) and admission to hospital are shown (see table) . both treatment and d lactate were highly conrrelated with total serum albuterol, r albuterol, and s albuterol. there was no correlation between treatment lactate or d lactate and hospital admission. conclusion: lactate and d lactate concentrations correlate with albuterol concentrations in patients presenting had asthma. fifty one percent were < years old and % were female. we found a decline of % ( % ci: %- %, p < . ; r = . , p < . ) in the overall yearly asthma visits to total ed visits from to . when we analyzed sex and age groups separately, we found no statistically significant changes for females or for males < years old (r £ . , p ‡ . ). for females and males > years old, yearly asthma visits to total ed visits from to decreased % ( % ci: %- %, p < . ; r = . , p < . ) and % ( % ci: %- %, p < . ; r = . , p < . ), respectively. conclusion: we found an overall decrease in yearly asthma visits to total ed visits from to . we speculate that this decrease is due to greater corticosteroid use despite the increasing prevalence of asthma. it is unclear why this decrease was seen in adults and not in children and why it was greater for adult females than males. objectives: our objectives were to describe the use of a unique data collection system that leveraged emr technology and to compare its data entry error rate to traditional paper data collection. methods: this is a retrospective review of data collection methods during the first months of a multicenter study of ed, anti-coagulated, head injury patients. on-shift ed physicians at five centers enrolled eligible patients and prospectively completed a data form. enrolling ed physicians had the option of completing a one-page paper data form or an electronic ''dotphrase'' (dp) data form. our hospital system uses an epicÒbased emr. a feature of this system is the ability to use dps to assist in medical information entry. a dp is a preset template that may be inserted into the emr when the physician types a period followed by a code phrase (in this case ''.ichstudy''). once the study dp was inserted at the bottom of the electronic ed note, it prompted enrolling physicians to answer study questions. investigators then extracted data directly from the emr. our primary outcomes of interest were the prevalence of dp data form use and rates of data entry errors. results: from / through / , patients were enrolled. dp data forms were used in ( . %; % ci . , . %) cases and paper data forms in ( . %; % ci . , . %). the prevalence of dp data form use at the respective study centers was %, %, %, %, and %. sixty-six ( . %; % ci . , . %) of physicians enrolling patients used dp data entry at least once. using multivariate analysis, we found no significant association between physician age, sex, or tenure and dp use. data entry errors were more likely on paper forms ( / , . %; % ci . , . %) than dp data forms ( / , . %; % ci . , . %), difference in error rates . % ( % ci . , . %, p < . ). conclusion: dp data collection is a feasible means of study data collection. dp data forms maintain all study data within the secure emr environment obviating the need to maintain and collect paper data forms. this innovation was embraced by many of our emergency physicians. we found lower data entry error rates with dp data forms compared to paper forms. background: inadequate randomization, allocation concealment, and blinding can inflate effect sizes in both human and animal studies. these methodological limitations might in part explain some of the discrepancy between promising results in animal models and non-significant results in human trials. whereas blinding is not always possible, in clinical or animal studies, true randomization with allocation concealment is always possible, and may be as important in minimizing bias. objectives: to determine the frequency with which published emergency medicine (em) animal research studies report randomization, specific randomization methods, allocation concealment, and blinding of interventions and measurements, and to estimate whether these have changed over time. methods: all em animal research publications from / through / in ann emerg med and acad emerg med were reviewed by two trained investigators for a statement regarding randomization, and specific descriptions of randomization methods, allocation concealment, blinding of intervention, and blinding of measurements, when possible. raw initial agreement was calculated and differences were settled by consensus. the first (period = - ) and second (period = - ) -year periods were compared with % confidence intervals. results: of em animal research studies, were appropriate for review because they involved intervention in at least two groups. blinding of interventions and measurements were not considered possible in % and %, respectively. significant differences between period and were absent, although there was a trend towards less blinding of interventions and more blinding of measurements. raw agreement was %. conclusion: although randomization is mentioned in the majority of studies, allocation concealment and blinding remain underutilized in em animal research. we did not compare outcomes between blinded and non-blinded, randomized and non-randomized studies, because of small sample size. this review fails to demonstrate significant improvement over time in these methodological limitations in em animal research publications. journals might consider requiring authors to explicitly describe their randomization, allocation, and blinding methods. background: cluster randomized trials (crts) are increasingly utilized to evaluate quality improvement interventions aimed at health care providers. in trials testing ed interventions, migration of eps between hospitals is an important concern, as contamination may affect both internal and external validity. objectives: we hypothesized geographically isolating emergency departments would prevent migratory contamination in a crt designed to increase ed delivery of tpa in stroke (the instinct trial). methods: instinct was a prospective, cluster-randomized, controlled trial. twenty-four michigan community hospitals were randomly selected in matched pairs for study. following selection of a single hospital, all hospitals within miles were excluded from the sample pool. individual emergency physicians staffing each site were identified at baseline ( ) and months later. contamination was defined at the cluster level, with substantial contamination defined a priori as > % of eps affected. non-adherence, total crossover (contamination + non-adherence), migration distance and characteristics were determined. results: emergency physicians were identified at all sites. overall, ( . %) changed study sites. one moved between control sites, leaving ( . %) total crossovers. of these, ( . %) moved from intervention to control (contamination) and ( . %) moved from control to intervention (non-adherence). contamination was observed in of sites, with % and % contamination of the total site ep workforce at follow-up, respectively. two of crossovers occurred between hospitals within the same health system. average migration distance was miles for all eps in the study and miles for eps moving from intervention to control sites. conclusion: the mobile nature of emergency physicians should be considered in the design of quality improvement crts. use of a -mile exclusion zone in hospital selection for this crt was associated with very low levels of substantial cluster contamination ( of ) and total crossover. assignment of hospitals from a single health system to a single study group and/or an exclusion zone of miles would have further reduced crossovers. increased reporting of contamination in cluster randomized controlled trials is encouraged to clarify thresholds and facilitate crt design. objectives: an extension of the lr, the average absolute likelihood ratio (aalr), was developed to assess the average change in the odds of disease that can be expected from a test, or series of tests, and an example of its use to diagnose wide qrs complex tachycardia (wct) is provided. methods: results from two retrospective multicenter case series were used to assess the utility of qrs duration and axis to assess for ventricular tachycardia (vt) in patients with undifferentiated regular sustained wct. serial patients with heart rate (hr) > beats per minute and qrs duration > milliseconds (msec) were included. the final tachydysrhythmia diagnosis was determined by a number of methods independent of the ecg. the aalr is defined as: aalr = /n total [r (n i *lr i ) (for lr > ) + r (n k /lr k ) (for lr < )], where lr i and lr k are the interval lrs, and n i and n k are the number of patients with test results within the corresponding intervals. roc curves were constructed, and interval lrs and aalrs were calculated for the qrs duration and axis tests individually, and when applied together. confidence intervals were bootstrapped with , replications using the r boot package. results: patients were included: with supraventricular tachycardia (svt) and with vt. optimal qrs intervals (msec) for distinguishing vt from svt were: qrs £ , < qrs < , and qrs ‡ . qrs axis results were dichotomized to upward right axis ( - degrees) or not () to degrees). results are listed in the table. conclusion: application of the qrs interval and axis tests together for patients with wide qrs complex tachycardia changes the odds of ventricular tachycardia, on average, by a factor of . ( % ci . to . ), and this is mildly improved over the qrs duration test alone. both a strength and weakness of the aalr is its dependence on the pretest probability of disease. the aalr may be helpful for clinicians and researchers to evaluate and compare diagnostic testing approaches, particularly when strategies with serial non-independent tests are considered. consultation for adults with metastatic solid tumors at an urban, academic ed located within a tertiary care referral center. field notes were grouped into barrier categories and then quantified when possible. patient demographics for those who did and did not enroll were extracted from the medical record and quantified. patients who did not meet inclusion criteria for the study (e.g., cognitive impairment) were excluded from the analysis. results: attempts were made to enroll eligible patients in the study, and were successfully enrolled ( % enrollment rate). barriers to enrollment were deduced from the field notes and placed into the following categories from most to least common: patient refusal ( ); diagnostic uncertainty regarding cancer stage ( ); severity of symptoms preclude participation ( ); patient unaware of illness or stage ( ); and family refusal ( ). conclusion: patients, families, and diagnostic uncertainty are barriers to enrolling ed patients with advanced illness in clinical trials. it is unclear whether these barriers are generalizable to other study sites and disease processes other than cancer. objectives: the purpose of this study was to evaluate the use of a high-fidelity mannequin bedside simulation scenario followed by a debriefing session as a tool to improve medical student knowledge of palliative care techniques. methods: third year medical students participating in a -week simulation curriculum during a surgery/ emergency medicine/anesthesia clerkship were eligible for the study. all students were administered a pretest to evaluate their baseline knowledge of palliative care and randomized to a control or intervention group. during week or , students in the intervention group participated in and observed two end-of-life scenarios. following the scenarios, a faculty debriefer trained in palliative care addressed critical actions in each scenario. during week , all students received a posttest to evaluate for improvement in knowledge. the pre-test and post-test consisted of questions addressing prognostication, symptom control, and the medicare hospice benefit. students were de-identified and pre-and post-tests were graded by a blinded scorer. results: from jan-dec , students were included in the study and were excluded due to incomplete data. the mean score on the pre-test for the intervention group was . , and for the control group was . (p = . the results indicate that educators identify the most important scenarios as protocol-based simulations. respondents also suggested that scenarios of very common emergency department presentations bear a great deal of importance. emergency medicine educators assign priority to simulations involving professionalism and communication. finally, many respondents noted that they use simulation to teach the presentation and management of rare or less frequent, but important disease processes. the identification of these scenarios would suggest that educators find simulation useful for filling in ''gaps'' in resident education. background: prescription drug misuse is a growing problem among adolescent and young adult populations. objectives: to determine factors associated with past year prescription drug misuse defined as using prescription sedatives, stimulants, or opioids to get high, taking them when they were prescribed to someone else or taking more than was prescribed among patients seeking care in an academic ed. methods: adolescents and young adults ( - ) presenting for ed care at a large, academic teaching hospital were approached to complete a computerized screening questionnaire regarding demographics, prescription drug misuse, illicit drug use, alcohol use, and violence in the past months. logistic regression was used to predict past year prescription drug misuse. results: over the study time period, there were participants ( % response rate) of whom ( . %) endorsed past year prescription drug misuse. specifically, rates of past year misuse for opioids was . %, sedatives was . %, and stimulants was . %. significant overlap exists among classes with over % misusing more than one class of medications. in the multivariate analysis significant predictors of past year prescription drug misuse included female gender (or conclusion: approximately one in seven adolescents or young adults seeking ed care have misused prescription drugs in the past year. while opioids are the most common drug misused, significant overlap exists among this population. given the correlation of prescription drug misuse with the use and misuse of other substances (i.e. alcohol, cough medicine, marijuana) more research is needed to further understand these relationships and inform interventions. additionally, future research should focus on understanding the differences in demographics and risk factors associated with misuse of each separate class of prescription drugs. prospective objectives: this study aims to examine the association of depression with high ed utilization in patients with non-specific abdominal pain. methods: this single-center, prospective, cross-sectional study was conducted in an urban academic ed located in washington, dc as part of a larger study to evaluate the interaction between depression and frequency of ed visits and chronic pain. as part of this study, we screened patients using the phq- , a nineitem questionnaire that is a validated, reliable predictor of major depressive disorder. we analyzed the subset of respondents with a non-specific abdominal pain diagnosis (icd- code of .xx). our principal outcome of interest was the rate of a positive depression screen in patients with non-specific abdominal pain. we analyzed the prevalence of a positive depression screen among this group and also conducted a chi-square analysis to compare high ed use among abdominal pain patients with a positive depression screen versus those without a positive depression screen. we defined high ed utilization as > visits in a -day period prior to the enrollment visit. background: numerous studies have found high rates of co-morbid mental illness and chronic pain in emergent care settings. one psychiatric diagnosis frequently associated with chronic pain is major depressive disorder (mdd). objectives: we conducted a study to characterize the relationship between mdd and chronic pain in the emergency department (ed) population. we hypothesized that patients who present to the ed with selfreported chronic pain will have higher rates of mdd. methods: this was a single-center, prospective, crosssectional study. we used a convenience sample of noncritically ill, english speaking adult patients presenting with non-psychiatric complaints to an urban academic ed over months in . we oversampled patients presenting with pain-related complaints (musculoskeletal pain or headache). subjects were surveyed about their demographic and other health and health care characteristics and were screened with the phq , a nine-item questionnaire that is a validated, reliable predictor of mdd. we conducted bivariate (chi-square) and multivariate analysis controlling for demographic characteristics (race, income, sex, age) using stata v. . . our principal dependent variable of interest was a positive depression screen (phq score ‡ ). our principal independent variable of interest was the presence of self-reported chronic pain (greater than months). results: of patients enrolled, did not meet all inclusion criteria. had two or more assessments for comparison. their average age was (range - ), % were male, and % were in police custody. % used methadone alone; % heroin alone; % oxycodone alone; and the rest used multiple opioids. the average dose of im methadone was . mg (range - mg); all but patients received mg. the mean cows score before receiving im methadone was . (range - ), compared to . (range - ) minutes after methadone (p < . ; mean difference = ) . ; % ci = ) . to ) . ). the mean wss before and after methadone was ) . (range ) to ) ) and ) . (range ) to ), respectively (p < . ; % ci = ) . to ) . ). the mean physician-assessed wss was significantly lower than the patient's own assessment by . (p < . ). adverse events included an asthmatic patient with bronchospasm whose oxygen saturation decreased from % to % after receiving methadone, a patient whose oxygen saturation decreased from % to %, and two patients whose amss decreased from ) to ) (indicating moderate sedation). background: as the us population ages, the coexistence of copd and acute coronary syndrome (acs) is expected to be more frequent. very few studies have examined the effect of copd on outcomes in acs patients, and, to our knowledge, there has been no report on biomarkers that possibly mediate between copd and long-term acs patient outcomes. objectives: to determine the effect of copd on longterm outcomes in patients presenting to the emergency department (ed) with acs and to identify prognostic inflammatory biomarkers. methods: we performed a prospective cohort study enrolling acs patients from a single large tertiary center. hospitalized patients aged years or older with acs were interviewed and their blood samples were obtained. seven inflammatory biomarkers were measured, including interleukin- (il- ), c-reactive protein (crp), tumor necrosis factor-alpha (tnf-alpha), vascular cell adhesion molecule (vcam), e-selectin, lipoprotein-a (lp-a), and monocyte chemoattractant protein- (mcp- ). the diagnoses of acs and copd were verified by medical record review. annual telephone follow-up was conducted to assess health status and major adverse cardiovascular events (mace) outcomes, a composite endpoint including myocardial infarction, revascularization procedure, stroke, and death. background: aortic dissection (ad) is an uncommon life-threatening condition requiring prompt diagnosis and management. thirty-eight percent of cases are missed upon initial evaluation. the cornerstone of accurate diagnosis hinges on maintaining a high index of clinical suspicion for the various patterns of presentation. quality documentation that reflects consideration for ad in the history, exam, and radiographic interpretation is essential for both securing the diagnosis and for protecting the clinician in missed cases. objectives: we sought to evaluate the quality of documentation in patients presenting to the emergency department with subsequently diagnosed acute ad. methods: irb-approved, structured, retrospective review of consecutive patients with newly diagnosed non-traumatic ad from to . inclusion criteria: new ad diagnosis via ed. exclusion criteria: ad diagnosed at another facility; chronic, traumatic, or iatrogenic ad. trained/monitored abstractors used a standardized data tool to review ed and hospital medical records. descriptive statistics were calculated as appropriate. inter-rater reliability was measured. our primary performance measure was the prevalence of a composite of all three key historical elements ( . any back pain, . neurologic symptoms including syncope, and . sudden onset of pain.) in the attending emergency physician's documentation. secondary outcomes included documentation of: ad risk factors, pain quality, back pain at multiple locations, presence/absence of pulse symmetry, mediastinal widening on chest radiograph, and migratory nature of the pain. results: / met our inclusion/exclusion criteria. the mean age was . years; % were male, ( . %) were stanford a. ( %) presented with a chief complaint of chest pain. primary outcome measure: / ( . %; %ci = . , . ) documented the presence/ absence of all three key historical elements. [back pain = / ; . % ( . , . ); neuro symptoms = / ; % ( . , . ); sudden onset = / ; . % ( . , . ).] limitations: small number of confirmed ad cases. conclusion: in our cohort, emergency physician documentation of key historical, physical exam, and radiographic clues of ad is suboptimal. although our ed miss rate is lower than that which has been reported by previous authors, there is an opportunity to improve documentation of these pivotal elements at our institution. objectives: this study assessed the opinions of iem and gh fellowship program directors, in addition to recent and current fellows regarding streamlining the application process and timeline in an attempt to implement change and improve this process for program directors and fellows alike. methods: a total of current iem and gh fellowship programs were found through an internet search. an electronic survey was administered to current iem and gh fellowship directors, current fellows, and recent graduates of these programs. results: response rates were % (n = ) for program directors and % (n = ) for current and recent fellows. the great majority of current and recent fellows ( %) and program directors ( %) support transitioning to a common application service. similarly, % of current and recent fellows and % of program directors support instituting a uniform deadline date for applications. however, only % of recent/current fellows and % of program directors would support a formalized match process like nrmp. conclusion: the majority of fellows and program directors support streamlining the application for all iem and gh fellowship programs. this could improve the application process for both fellows and program directors, and ensure the best fit for the candidates and for the fellowship programs. in order to establish effective emergency care in rural sub-saharan africa, the unique practice demographics and patient dispositions must be understood. objectives: the objectives of this study are to determine the demographics of the first patients seen at nyakibale hospital's ed and assess the feasibility of treating patients in a rural district hospital ed in sub-saharan africa. methods: a descriptive cross-sectional analysis of the first consecutive patient visits in the ed's patient care log was reviewed by an unblinded abstractor. data collected included age, sex, condition upon discharge, and disposition. all authors discussed uncertainties and formed a consensus. descriptive statistics were performed. results: of the first patient visits, ( . %) occurred when the outpatient clinic was open. there were ( %) male visits. the average age was . years (sd ± . ). pediatric visits accounted for ( . %) patients, and ( . %) visits were for children under five years old. only one patient expired in the ed, and ( . %) were in good condition after treatment, as subjectively defined by the ed physicians. one person was transferred to another hospital. after treatment, ( %) patients were discharged home. of those admitted to an inpatient ward, ( . %) patients were admitted to medical wards, ( . %) to pediatrics, and ( %) to surgical. only six ( . %) patients went directly to the operating theatre. conclusion: this consecutive sample of patient visits from a novel rural district hospital ed in sub-saharan africa included a broad demographic range. after treatment, most patients were judged to be in ''good condition'', and over one third of patients could be discharged after ed management. this sample suggests that it is possible to treat patients in an ed in rural sub-saharan africa, even in cases where surgical backup and transfers to higher level of care are limited or unavailable. background: communication failures in clinical handoffs have been identified as a major preventable cause of patient harm. in italy, advanced prehospital care is provided predominantly by physicians who work on ambulances in teams with either nurses or basic rescuers. the hand-offs from prehospital physicians to hospital emergency physicians (eps) is especially susceptible to error with serious consequences. there are no studies in italy evaluating the communication at this transition in patient care. studying this, however, requires a tool that measures the quality of this communication. objectives: the purpose of this study is to develop and validate a tool for the evaluation of communication during the clinical handoff from prehospital to emergency physicians in critically ill patients. methods: several previously validated tools for evaluating communication in hand-offs were identified through a literature search. these were reviewed by a focus group consisting of eps, nurses, and rescuers, who then adapted and translated the australian isbar (identification, situation, background, assessment, recommendation), the tool most relevant to local practice. the italian isbar tool consists of the following elements: patient and provider identification; patient's chief complaint; patient's past medical history, medications, and allergies; prehospital clinical assessment (primary survey, illness severity, vital signs, diagnosis); treatment initiated and anticipated treatment plan. we conducted and video-taped the hand-offs of care from the prehospital physicians to the eps in pediatric critical care simulations. four physician raters were trained in the italian isbar tool and used it to independently assess communication in each simulation. to assess agreement we calculated the proportion of agreement among raters for each isbar question, fleiss' kappas for each simulation, as well as mean agreement and mean kappas with standard deviations. results: there was % agreement among the four physicians on % of the items. the mean level of agreement was % (sd . ). the overall mean kappa was . (sd . ). conclusion: the standardized tool resulted in good agreement by physician raters. this validated tool may be helpful in studying and improving hand-offs in the prehospital to emergency department setting. objectives: we hypothesized that residents who were provided with vps prior to hfs would perform more thoroughly and efficiently than residents who had not been exposed to the online simulation. methods: we randomized a group of residents from an academic, pgy - emergency medicine program to complete an online vps case, either prior to (vps group, n = residents) or after (n = ) their hfs case. the vps group had access to the online case (which reviewed asthma management) days prior to the hfs session. all residents individually participated in their regularly scheduled hfs and were blinded to the content of the case -a patient in moderate asthma exacerbation. the authors developed a dichotomous checklist consisting of items recorded as done/not done along with time completed. a two sample proportion test was used to evaluate differences in the individual items completed between groups. a wilcoxon rank sum test was used to determine the differences in overall and subcategory performance between the two groups. median time to completion was analyzed using the log-rank test. results: the vps group had better overall checklist performance than the control group (p-value . ). in addition, the vps group was more thorough in obtaining an hpi (p-value . ). specific actions (related to asthma management) were performed better by the vps group: inquiring about last/prior ed visits ( . ), total number of hospitalizations in the prior year ( . ), prior intubations ( . ), and obtaining peak flow measurements ( . ). overall there was no difference in time to event completion between the two groups. conclusion: we found that when hfs is primed with educational modalities such as vps there was an improvement in performance by trainees. however, the improved completeness of the vps group may have served as a barrier to efficiency, inhibiting our ability to identify a statistical significant efficiency overall. vps may aid in priming the learners and maximize the efficiency of training using high-fidelity simulations. training using an animal model helped develop residents' skills and confidence in performing ptv. retention was found to be good at months post-training. this study underscores the need for hands-on training in rare but critical procedures in emergency medicine. methods: in this cross-sectional study at an urban community hospital, residents in their second or third year of training from a -year em residency program performed us-guided catheterizations of the ij on a simulator manufactured by blue phantom. two board-certified em physicians observed for the completion of pre-defined procedural steps using a checklist and rated the residents' overall performance of the procedure. overall performance ratings were provided on a likert scale of to , with being poor and being excellent. residents were given credit for performing a procedural step if at least one rater marked its completion. agreement between raters was calculated using intraclass correlation coefficients for domain and summary scores. the same protocol was then repeated on an unembalmed cadaver using two different board-certified em physician raters. criterion validity of the residents' proficiency on the simulator was evaluated by comparing their median overall performance rating on the simulator to that on the cadaver and by comparing the proportion of residents completing each procedural step between modalities with descriptive statistics. results: em residents' overall performance rating on the simulator was . ( % ci: . to . ) and on the cadaver was . ( % ci: . to . ). the results for each procedural step are summarized in the attached figure. inter-rater agreement was high for assessments on both the simulator and cadaver with overall kappa scores of . and . respectively. background: the environment in the emergency department (ed) is chaotic. physicians must learn how to multi-task effectively and manage interruptions. noise becomes an inherent byproduct of this environment. previous studies in the surgical and anesthesiology literature examined the effect of noise levels and cognitive interruptions on resident performance during simulated procedures; however, the effect of noise distraction on resident performance during an ed procedure has not yet been studied. objectives: our aim was to prospectively determine the effects of various levels of noise distraction on the time to successful intubation of a high-fidelity simulator. methods: a total of emergency medicine, emergency medicine/internal medicine, and emergency medicine/family medicine residents were studied in a background noise environments of less than decibels (noise level ), - decibels (noise level ), and of greater than decibels (noise level ). noise levels were standardized by a dosimeter (ex tech instruments, heavy duty ). each resident was randomized to the order in which he or she was exposed to the various noise levels and had a total of minutes to complete each of the intubation attempts, which were performed in succession. time, in seconds, to successful intubation was measured in each of these scenarios with the start time defined as the time the resident picked up the storz c-mac video laryngoscope blade and the finish time defined as the time the tube passed through the vocal cords as visualized by an observer on the storz c-mac video screen. analytic methods included analysis of variance, student's t-test, and pearson's chi-square. results: no significant differences were found between time to intubation and noise level nor did the order of noise level exposure affect the time to intubation (see table) . there were no significant differences in success rate between the three noise levels (p = . ). a significant difference in time to intubation was found between the residents' second and third intubation attempts with decreased time to intubation for the third attempt (p = . ). conclusion: noise level did not have an effect on time to intubation or intubation success rate. time to intubation decreased between the second and third intubations regardless of noise level. background: growing use of the emergency department (ed) is cited as a cause of rising health care costs and a target of health care reform. eds provide approximately one quarter of all acute care outpatient visits in the us. eds are a diagnostic center and a portal for rapid inpatient admission. the changing role of eds in hospital admissions has not been described. objectives: to compare if admission through the ed has increased compared to direct hospital admission. we hypothesized that the use of the ed as the admitting portal increased for all frequently admitted conditions. methods: we analyzed the nationwide inpatient sample (nis), the largest us all-payer inpatient care database, from - . nis contains data from approximately million hospital stays each year, and is weighted to produce national estimates. we used an interactive, webbased data tool (hcupnet) to query the nis. clinical classification software (ccs) was used to group discharge diagnoses into clinically meaningful categories. we calculated the number of annual admissions and proportion admitted from the ed for the most frequently admitted conditions. we excluded ccs codes that are rarely admitted through the ed (< %) as well as obstet- background: the optimal dose of opioids for patients in acute pain is not well defined, although . mg/kg of iv morphine is commonly recommended. patient-controlled analgesia (pca) provides an opportunity to assess the adequacy of this recommendation as use of the pca pump is a behavioral indication of insufficient analgesia. objectives: to assess the need for additional analgesia following a . mg/kg dose of iv morphine by measuring additional self-dosing via a pca pump. methods: a three-arm randomized controlled trial was performed in an urban ed with , annual adult visits. a convenience sample of ed patients ages to with abdominal pain of < days duration requiring iv opioids was enrolled between / and / . all patients received an initial dose of . mg/kg iv morphine. patients in the pca arms could request additional doses of mg or . mg iv morphine by pressing a button attached to the pump with a -minute lock-out period. for this analysis, data from both pca arms were combined. software on the pump recorded times when the patient pressed the button (activation) and when he/she received a dose of morphine (successful activation). results: patients were enrolled in the pca arms. median baseline nrs pain score was . mean amount of supplementary morphine self-administered over the hour study period subsequent to the loading dose was . mg and . mg for the and . mg pca groups respectively. patients activated the pump at least once ( %, % ci: to %). figure shows the frequency distribution of the number of times the pump was activated. of those who activated the pump, the median number of activations per person was (iqr: to ). there were activations of the pump. % of activations were successful (followed by administration of morphine), while % were unsuccessful as they occurred during the -minute lock-out periods. % of the activations occurred in the first minutes, % in the second minutes, % in the third minutes, and % in the last minutes after the initial loading dose. conclusion: almost all patients requested supplementary doses of pca morphine, half of whom activated the pump five times or more over a course of hours. this frequency of pca activations suggests that the commonly recommended dose of . mg/kg morphine may constitute initial oligoanalgesia in most patients. marie-pier desjardins, benoit bailey, fanny alie-cusson, serge gouin, jocelyn gravel chu sainte-justine, montreal, qc, canada background: administration of corticosteroid at triage has been suggested to decrease the time to corticosteroid administration in the ed. objectives: to compare the time between arrival and corticosteroid administration in patients treated with an asthma pathway (ap) or with standard management (sm) in a pediatric ed. methods: chart review of children aged to years diagnosed with asthma, bronchospasm, or reactive airways disease seen in the ed of a tertiary care pediatric hospital. for a one year period, % of all visits were randomly selected for review. from these, we reviewed patients who were eligible to be treated with the ap ( ‡ months with previous history of asthma and no other pulmonary condition) and who had received at least one inhaled bronchodilator treatment. charts were evaluated by a data abstractor blinded to the study hypothesis using a standardized datasheet. various variables were evaluated such as age, respiratory rate and saturation at triage, type of physician who saw patient first, treatment prior to visit, in ed, and at discharge, time between arrival and corticosteroid administration, and length of stay (los background: return visits comprise . % of pediatric emergency department (ped) visits, at a cost of >$ million/year nationally. these visits are typically triaged with higher acuity and admission rates and raise concern for lapses in quality of care and patient education during the first visit. objectives: the aim of this qualitative study was to describe parents' reasons for return visits to the ped. methods: we prospectively recruited a convenience sample of parents of patients under the age of years who returned to the ped within hours of their previous visit. we excluded patients who were instructed to return, had previously left without being seen, arrived without a parent, were wards of the state, or did not speak english. after obtaining consent, the principal investigator (ce) conducted confidential, in-person, tape-recorded interviews with parents during ped return visits. parents answered open-ended questions and closed-ended questions using a five-point likert scale. responses to open-ended questions were analyzed using thematic analysis techniques. the scaled responses were grouped into three categories of agree, disagree, or neutral. results: from the closed-ended responses, % of parents agreed that their children were getting sicker, and % agreed that their children were not getting better. % agreed that they were unsure how to treat the illness, however only % agreed they did not feel figure : frequency distribution of number of pca activations comfortable taking care of the illness. only % agreed that the medical condition and/or the instructions were not clearly explained in the first visit. some common themes from the open-ended questions included worsening or lack of improvement of symptoms. many parents reported having unanswered questions about the cause of the illness and hoped to find out the cause during the return visit. conclusion: most parents brought their children back to the ped because they believed the symptoms had worsened or were not improving. although a large proportion of parents believed that the medical condition was clearly explained at the first visit, many parents still had unanswered questions about the cause of their child's illness. while worsening symptoms seemed to drive most return visits, it is possible that some visits related to failure to improve might be prevented during the first ped visit through a more detailed discussion of disease prognosis and expected time to recover. pediatric background: experience indicates that it is difficult to effectively quell many parents' anxiety toward pediatric fevers, making this a common emergency department (ed) complaint. the question remains as to whether athome treatment has any effect on the course of emergency department treatment or length of stay in this population. objectives: to determine whether anti-pyretic treatment prior to arrival in the emergency department affects the evaluation or emergency department length of stay of febrile pediatric patients. methods: a convenience sample of children, ages - years, who presented to a tertiary care ed with chief complaint of fever were enrolled. parents were asked to participate in an eight-question survey. questions related to demographic information, pre-treatment of the fever, contact with primary care providers prior to ed arrival, and immunization status. upon admission or discharge, investigators recorded information regarding length of stay, laboratory tests and imaging ordered, and medications given. results: eighty-one patients were enrolled in the study. seventy-six percent of the patients were pre-treated with some form of anti-pyretic by the caregiver prior to ed arrival. there was no significant effect of pre-treatment on whether laboratory tests or medications were ordered in the ed or whether the patient was admitted or discharged. the length of ed stay was found to be significantly shorter among those who received anti-pyretics prior to arrival ( ± vs. ± minutes; p = . ). conclusion: among febrile children, those who receive anti-pyretics prior to their ed visit had statistically significant shorter length of stays. this also supports implementation of triage or nursing protocols to administer an anti-pyretic as soon as possible in the hope of decreasing ed throughput times. background: during the past two decades, the prevalence of overweight (bmi percentile > ) in children has more than doubled, reaching epidemic proportions both nationally and globally. the public health burden is enormous given the increased risk of adult obesity as well as the adverse consequences on cardiovascular, metabolic, and psychological health. despite the overwhelming prevalence, the effect of obesity on emergency care has received little attention. objectives: the goal of this study is to determine the relation of weight on reported emergency department visits in children from a nationally representative sample. methods: weight (as reported by parents) and height along with frequency of and reason for emergency department (ed) use in the last months were obtained from children aged - y (n = , ) in the cross-sectional, telephone-administered, national survey of children's health (nsch). bmi percentiles were calculated using sex-specific bmi for age growth charts from the cdc ( ). children were categorized as: underweight (bmi percentile£ ), normal weight (> to < ), at-risk for overweight ( to < ), and overweight ( ‡ ). prevalence of ed use was estimated and compared across bmi percentile categories using chisquare analysis and multivariable logistic regression. taylor-series expansion was used for variance estimation of the complex survey design. results: the prevalence of at least one ed use in the past months increased with increasing bmi percentiles (figure , p < . ). additionally, overweight children were more likely to have more than one visit. overweight children were also less likely to report an injury, poisoning, or accident as the reason for ed visit compared to other bmi categories ( , , , % in overweight, at-risk, normal, and underweight respectively, p < . ). conclusion: as rates of childhood obesity continue to grow in the u.s., we can expect greater demands on the ed. this will likely translate into an increased emphasis on the care of chronic conditions rather than injuries and accidents in the pediatric ed setting. results: mean pediatric satisfaction score was . (sd . ) compared with . ( . ) for adult patients (p < . ); monthly sample sizes ranged from - and from - for the two populations, respectively. both populations showed an increase in satisfaction after opening of the ped-ed. for both populations there was no significant trend in patient satisfaction from the beginning of the study period to the opening of the ped-ed, but after the opening the models of the populations differed. the pediatric satisfaction model was an interrupted two-slope model, with an immediate jump of . points in november and an increase of . points per month thereafter. in contrast, adult satisfaction scores did not show a jump but increased linearly (two slope model) after / at a rate of . per month. prior to the opening of the ped-ed, mean monthly pediatric and adult satisfaction scores were . ( . ) and . ( . ), respectively (difference . % ci . - . , p = . ). after the opening the mean scores were . ( . ) and . ( . ), respectively (difference . , % ci . - . , p < . ). conclusion: opening of a dedicated ped-ed was associated with a significant increase in patient satisfaction scores both for children and adults. patient satisfaction for children, as compared to adults, was higher before and after opening a ped-ed. the background: there are racial disparities in outcomes among injured children. in particular, black race appears to be an independent predictor of mortality. objectives: to evaluate disparities among ed visits for unintentional injuries among children ages - . methods: five years of data ( ) ( ) ( ) ( ) ( ) from the national hospital ambulatory cares survey were combined. inclusion criteria were defined as unintentional injury visits (e-code . to . or . to . ) and age - years. visit rates per population (defined by the us census) were calculated by race and age group. weighted multivariate logistic regression analysis was performed to describe associations between race and specific outcome variables and related covariates. primary statistical analyses were performed using sas version . . . results: , , of , , weighted ed visits met our inclusion criteria ( . %). per persons, black children had . times as many ed visits for unintentional injuries as whites (table) . there were no racial differences in the sex ratio ( . boy visits: girl), proportion of visits by age, ed disposition, immediacy with which they needed to be seen, whether or not they were evaluated by an attending physician, metropolitan vs. rural hospital, admission length of stay, mode of transportation for ed arrival, number of procedures, diagnostic services, or ed medications. background: sudden cardiac arrests in schools are infrequent, but emotionally charged events. little data exist that describes aed use in these events. objectives: the purpose of our study was to ) describe characteristics and outcomes of school cardiac arrests (ca), and ) assess the feasibility of conducting bystander interviews to describe the events surrounding school ca. methods: we performed a telephone survey of bystanders to ca occurring in k- schools in communities participating in the cardiac arrest registry to enhance survival (cares) database. the study period was from / - / and continued in one community through . utstein style data and outcomes were collected from the cares database. a structured telephone interview of a bystander or administrative personnel was conducted for each ca. a descriptive summary was used to assess for the presence of an aed, provision of bystander cpr (bcpr), and information regarding aed deployment, training, and use and perceived barriers to aed use. descriptive data are reported. results: during the study period there were , ca identified at cares communities, of which were identified as educational institutions. of these, ( . %) events were at k- schools with ( . %) being high schools. of the arrests, a minority were children ( ( . %) < age ), most ( , . %) were witnessed, a majority ( , . %) received bcpr, and ( . %) were initially in ventricular fibrillation (vf). most arrests / ( %) occurred during the school day ( a- p). overall, ( . %) survived to hospital discharge. interviews were completed for of ( . %) k- events. eighteen schools had an aed on site. most schools ( . %) with aeds reported that they had a training program and personnel identified for its use. an aed was applied in of patients, and of these were in vf and survived to hospital discharge. multiple reasons for aed non-use (n = ) were identified. conclusion: cardiac arrests in schools are rare events; most patients are adults and received bcpr. aed use was infrequent, even when available, but resulted in excellent ( / ) survival. further work is needed to understand aed non-use. post-event interviews are feasible and provide useful information regarding cardiac arrest care. physician background: gastroenteritis is a common childhood disease accounting for - million annual pediatric emergency visits. current literature supports the use of anti-emetics reporting improved oral re-hydration, cessation of vomiting, and reduced need for iv re-hydration. however, there remains concern that using these agents may mask alternative diagnoses. objectives: to assess outcomes associated with use of a discharge action plan using ed-dispensed ondansetron at home in the treatment of gastroenteritis. methods: a prospective, controlled, observational trial of patients presenting to an urban pediatric emergency department (census , ) over a -month period for acute gastroenteritis. fifty patients received ondansetron in the ed. twenty-nine patients were enrolled in the pediatric emergency department discharge action plan (ped-dap) where ondansetron for home use was dispensed by the treating clinician. twenty-one patients were controls. control patients did not receive home ondansetron. ped-dap patients were given instructions to administer the ondansetron for ongoing symptoms any time hours post ed discharge. all patients were followed by phone at - days to assess for the following: time of emesis resolution, alternative diagnoses, unscheduled visits, and adverse events. results: all patients were followed by phone. / ped-dap patients received home ondansetron. / patients had resolution of emesis in the ed. / had resolution of their emesis between time of discharge and hours. / of ped-dap patients reported emesis after hours from ed discharge. five patients reported an unscheduled visit. all five return visits returned to the ed ( / returned for emesis, / for diarrhea). / controls reported resolution of symptoms within the ed. / of controls had resolution between time of discharge and hours. / of the control patients had resolution with between and hours post discharge. / had an unscheduled appointment with the pmd at hours post-discharge for ongoing fever and nausea. in follow-up there were no alternative diagnoses identified. the effect of the ped-dap on resolution of emesis between discharge and hours appears to be statistically significant (p value < . ). conclusion: ondansetron given in schedule with a discharge action plan appears to provide a modest benefit in resolution of symptoms relative to a control population. objectives: to determine the repeatability coefficient of a mm vas in children aged to years in different circumstances: assessments done either at or minute interval, when asked to recall their score or to reproduce it. methods: a prospective cohort study was conducted using a convenience sample of patients aged to years presenting to a pediatric ed. patients were asked to indicate, on a mm paper vas, how much they liked a variety of food with four different sets of three questions: (set ) questions at minute interval with no specific instruction other than how to complete the vas and no access to previous scores, (set ) same format as set except for questions at minute interval, (set ) same as set except patients were asked to remember their answers, and (set ) same as set except patients were shown their previous answers. for each set, the repeatability coefficient of the vas was determined according to the bland-altman method for measuring agreement using repeated measures: . x Ö x s w where s w is the within-subject standard deviation by anova. the sample size required to estimate s w to % of the fraction value as recommended was patients if we obtained three measurements for each patient. results: a total of patients aged . ± . years were enrolled. the repeatability coefficient for the questions asked at minute intervals was mm, and mm when asked at minute interval. when asked to remember their previous answers or to reproduce them, the repeatability coefficient for the questions was mm and mm, respectively. conclusion: the condition of the assessments (variation in intervals or patients asked to remember or to reproduce their previous answers) influence the testretest reliability of the vas. depending on circumstances, the theoretical test-retest reliability in children aged to years varies from to mm on a mm paper vas. background: skull radiographs are a useful tool in the evaluation of pediatric head trauma patients. however, there is no consensus on the ideal number of views that should be obtained as part of a standard skull series in the evaluation of pediatric head trauma patients. objectives: to compare the sensitivity and specificity of a two-and four-film x-ray series in the diagnosis of skull fracture in children, when interpreted by pediatric emergency medicine physicians. methods: a prospective, crossover experimental study was performed in a tertiary care pediatric hospital. the skull radiographs of children were reviewed. these were composed of the most recent cases of skull fracture for which a four-film radiography series was available at the primary setting and controls, matched for age. two modules, containing a random sequence of two-and four-film series of each child, were constructed in order to have all children evaluated twice (once with two films and once with four films). board-certified or -eligible pediatric emergency physicians evaluated both modules two to four weeks apart. the interpretation of the four-film series by a radiologist, or when available, the findings on ct scan, served as the gold standard. accuracy of interpretation was evaluated for each patient. the sensitivity and specificity of the two-film versus the four-film skull xray series, in the identification of fracture, were compared. this was a non-inferiority cross-over study evaluating the null hypothesis that a series with two views would have a sensitivity (specificity) that is inferior by no more than . compared to a series with four views. a total of controls and cases were needed to establish non-inferiority of the two-film series versus the four-film series, with a power of % and a significance level of %. results: ten pediatric emergency physicians participated in the study. for each radiological series, the proportion of accurate interpretation varied between . to . . the four-film series was found to be more sensitive in the detection of skull fracture than a two-film series (difference: . , %ci . to . ). however, there was no difference in the specificity (difference: . , %ci ) . to . ). conclusion: for children sustaining a head trauma, a four-film skull radiography series is more sensitive than a two-film series, when interpreted by pediatric emergency physicians. the objectives: we developed a free online video-based instrument to identify knowledge and clinical reasoning deficits of medical students and residents for pediatric respiratory emergencies. we hypothesized that it would be a feasible and valid method of differentiating educational needs of different levels of learners. methods: this was an observational study of a free, web-based needs assessment instrument that was tested on third and fourth year medical students (ms - ) and pediatric and emergency medicine residents (r - ). the instrument uses youtube video triggers of children in respiratory distress. a series of cased-based questions then prompts learners to distinguish between upper and lower airway obstruction, classify disease severity, and manage uncomplicated croup and bronchiolitis. face validity of the instrument was established by piloting and revision among a group of experienced educators and small groups of targeted learners. final scores were compared across groups using t-tests to determine the ability of the instrument to differentiate between different levels of learners (concurrent validity). cronbach's alpha was calculated as a measure of internal consistency. results: response rates were % among medical students and % among residents. the instrument was able to differentiate between junior (ms , ms , and r ) and senior (r , r ) learners for both overall mean score ( % vs. %, p < . ) and mean video portion score ( vs. %, p = . ). table compares results of several management questions between junior and senior learners. cronbach's alpha for the test questions was . . conclusion: this free online video-based needs assessment instrument is feasible to implement and able to identify knowledge gaps in trainees' recognition and management of pediatric respiratory emergencies. it demonstrates a significant performance difference between the junior and senior learners, preliminary evidence of concurrent validity, and identifies target groups of trainees for educational interventions. future revisions will aim to improve internal consistency. results: the survey response rate was % ( / ). among responding programs, ( %) reside within a children's hospital (vs. general ed); ( %) are designated level i pediatric trauma centers. forty-three ( %) programs accept - pem fellows per year; ( %) provided at least some eus training to fellows, and ( %) offer a formal eus rotation. on average this training has existed for ± years and the mean duration of eus rotations is ± weeks. twenty-eight ( %) programs with eus rotations provide fellow training in both a general ed and a pediatric ed. there were no hospital or program level factors associated with having a structured training program for pem fellows. conclusion: as of , the majority of pem fellowship programs provide eus training to their fellows, with a structured rotation being offered by most of these programs. background: ed visits are an opportunity for clinicians to identify children with poor asthma control and intervene. children with asthma who use eds are more likely than other children to have poor control, not be using controller medications, and have less access to traditional sources of primary care. one significant barrier to ed-based interventions is recognizing which children have uncontrolled asthma. objectives: to determine whether the pacci, a item parent-administered questionnaire, can help ed clinicians better recognize patients with the most uncontrolled asthma and differentiate between intermittent and persistent asthma. methods: this was a randomized controlled trial performed at an urban pediatric ed. parents were asked to answer questions about their child's asthma including drug adherence and history of exacerbations, as well as answer demographic questions. using a convenience sample of children - years presenting with an asthma exacerbation, attending physicians in the study were asked to complete an assessment of asthma control. physicians were randomized to receive a completed pacci (intervention) or not (control group). using an intent-to-treat approach, clinicians' ability to accurately identify ) four categories of control used by the national heart, lung, and blood institute (nhlbi) asthma guidelines, ) intermittent vs. persistent level asthma, and ) controlled / mildly uncontrolled vs. moderate/severely uncontrolled asthma were compared for both groups using chi-square analysis. results: between january and august , patients were enrolled. there were no statistically significant differences between the intervention and control groups for child's sex, age, race and parents' education. conclusion: the pacci improves ed clinicians' ability to categorize children's asthma control according to nhlbi guidelines, and the ability to determine when a child's control has been worsening. ed clinicians may use the pacci to identify those children in greatest need for intervention, to guide prescription of controller medications, and communicate with primary care providers about those children failing to meet the goals of asthma therapy. figure) . fewer than half of physicians reported the parent of a -year-old being discharged from their ed following an mvc-related visit would receive either child passenger safety information or referrals (table) . conclusion: emergency physician report of child passenger safety resource availability is associated with trauma center designation. even when resources are available, referrals from the ed are infrequent. efforts to increase referrals to community child passenger safety resources must extend to the community ed settings where the majority of children receive injury care. background: pediatric subspecialists are often difficult to access following ed care especially for patients living far from providers. telemedicine (tm) can potentially eliminate barriers to access related to distance, and cost. objectives: to evaluate the overall resource savings and access that a tm program brings to patients and families. methods: this study took place at a large, tertiary care regional pediatric health care system. data were collected from / - / . metrics included travel distance saved (round trip between tm presenting sites and the location of the receiving sites), time savings, direct cost savings (based on $ . /mile) and potential work and school days saved. indirect costs were calculated as travel hrs saved/encounter (based on an average speed of miles/hr). demographics and services provided were included. results: tm consults were completed by separate pediatric subspecialty services. most patients were school aged ( % >/= yrs old objectives: to analyze test characteristics of the pathway and its effects on ed length of stay, imaging rates, and admission rate before versus after implementation. methods: children ages - presenting to one academic pediatric ed with suspicion for appendicitis from october -august were prospectively enrolled to a pathway using previously validated lowand high-risk scoring systems. the attending physician recorded his or her suspicion of appendicitis and then used one of two scoring systems incorporating history, physical exam, and cbc. low-risk patients were to be discharged or observed in the ed. high-risk patients were to be admitted to pediatric surgery. those meeting neither low-nor high-risk criteria were evaluated in the ed by pediatric surgery, with imaging at their discretion. chart review and telephone follow-up were conducted two weeks after the visit. charts of a random sample of patients with diagnoses of acute appendicitis or chief complaint of abdominal pain and undergoing a workup for appendicitis in the eight months before and after institution of the pathway were retrospectively reviewed by one or two trained abstractors. results: appendicitis was diagnosed in of patients prospectively enrolled to the pathway ( %). mean age was . years. of those with appendicitis, were not low-risk (sensitivity . %, specificity . %). the high-risk criteria had a sensitivity of . % and specificity of . %. a priori attending physician assessment of low risk had a sensitivity of % and specificity of . %. a priori assessment of high risk had a sensitivity of . % and specificity of . %. we reviewed visits prior to the pathway and after. mean ed length of stay was similar ( minutes before versus after). ct was used in . % of visits before and . % after (p = . ). use of ultrasound increased ( . % before versus . % after, p < . ). admission rates were not significantly different ( . % before versus . % after, p = . ). conclusion: the low-risk criteria had good sensitivity in ruling out appendicitis and can be used to guide physician judgment. institution of this pathway was not associated with significant changes in length of stay, utilization of ct, or admission rate in an academic pediatric ed. computer-delivered alcohol and driver safety behavior screening and intervention program initiated during an emergency department visit mary k. murphy , lucia l. smith , anton palma , david w. lounsbury , polly e. bijur , paul chambers yale university, new haven, ct; albert einstein college of medicine, bronx, ny background: alcohol use is involved in percent of all fatal motor vehicle crashes and recent estimates show that at least , people were injured due to distracted driving last year. patients who visit the emergency department (ed) are not routinely screened for driver safety behavior; however, large numbers of patients are treated in the ed every day creating an opportunity for screening and intervention on important public health behaviors. objectives: to evaluate patient acceptance and response to a computer-based traffic safety educational intervention during an ed visit and one month follow-up. methods: design. pre /post educational intervention. setting. large urban academic ed serving over , patients annually. participants. medically stable adult ed patients. intervention. patients completed a self-administered, computer-based program that queried patients on alcohol use and risky driving behaviors (texting, talking, and other forms of distracted driving). the computer provided patients with educational information on the dangers of these behaviors and collected data on patient satisfaction with the program. staff called patients one month post ed visit for a repeat query. results: patients participated; average age ( - ), % hispanic, % male. % of patients reported the program was easy to use and were comfortable receiving this education via computer during their ed visit. self-reported driver safety behaviors pre, post intervention (% change): driving while talking on the phone %, % () %, p = . ), aggressive driving %, % () %, p = . ), texting while driving %, % () %, p = . ), driving while drowsy %, % () %, p = . ), drinking in excess of nih safe drinking guidelines %,% () %, p = . ), drinking and driving %, % () %, p = . ). conclusion: we found a high prevalence of selfreported risky driving behaviors in our ed population. at month follow-up, patients reported a significant decrease in these behaviors. overall patients were very satisfied receiving educational information about these behaviors via computer during their ed visit. this study indicates that a low-intensity, computer-based educational intervention during an ed visit may be a useful approach to educate patients about safe driving behaviors and promote behavior change. prevalence of depression among emergency department visitors with chronic illness janice c. blanchard, benjamin l. bregman, jeffrey smith, mohammad salimian, qasem al jabr george washington university, washington, dc background: persons with chronic illnesses have been shown to have higher rates of depression than the general population. the effect of depression on frequent emergency department (ed) use among this population has not been studied. objectives: this study evaluated the prevalence of major depressive disorder (mdd) among persons presenting with depression to the george washington university ed. we hypothesized that patients with chronic illnesses would be more likely to have mdd than those without. methods: this was a single center, prospective, crosssectional study. we used a convenience sample of noncritically ill, english-speaking adult patients presenting with non-psychiatric complaints to an urban academic ed over months in . subjects were screened with the phq , a nine-item questionnaire that is a validated, reliable predictor of mdd. we also queried respondents about demographic characteristics as well as the presence of at least one chronic disease (heart disease, hypertension, asthma, diabetes, hiv, cancer, kidney disease, or cerebrovascular disease). we evaluated the association between mdd and chronic illnesses with both bivariate analysis and multivariate logistic regression controlling for demographic characteristics (age, race, sex, income, and insurance coverage). results: our response rate was . % with a final sample size of . of our total sample, ( . %) had at least one of the chronic illnesses defined above. of this group, ( . %) screened positive for mdd as compared to ( . %) of the group without chronic illnesses (p < . ). in multivariate analysis, persons with chronic illnesses had an odds ratio for a positive depression screen of . ( . , . ) as compared to persons without illness. among the subset of persons with chronic illnesses (n = ), . % had ‡ visits in the prior days as compared to . % of persons with chronic illnesses without mdd (p = . ). conclusion: our study found a high prevalence of untreated mdd among persons with chronic illnesses who present to the ed. depression is associated with more frequent emergency department use among this population. initial blood alcohol level aids ciwa in predicting admission for alcohol withdrawal craig hullett, douglas rappaport, mary teeple, daniel butler, arthur sanders university of arizona, tucson, az background: assessment of alcohol withdrawal symptoms is difficult in the emergency department. the clinical institute withdrawal assessment (ciwa) is commonly used, but other factors may also be important predictors of withdrawal symptom severity. objectives: the purpose of this study is to determine whether ciwa score at presentation to triage was predictive of later admission to the hospital. methods: a retrospective study of patients presenting to an acute alcohol and drug detoxification hospital was performed from july through january . patients were excluded if other drug withdrawal was present in addition to alcohol. initial assessment included age, sex, vital signs, and blood alcohol level (bal) in addition to hourly ciwa score. admission is indicated for a ciwa score of or higher. data were analyzed by selecting all patients not immediately admitted at initial presentation. logistic regression using wald's criteria for stepwise inclusion was used to determine the utility of the initially gathered ciwa, bal, longest sobriety, liver cirrhosis, and vital signs in predicting subsequent admission. results: there were patients who fit the inclusion criteria, with admitted for treatment at initial intake and another admitted during the following hours. logistic regression indicated that presenting bal was a strong predictor (p = . ) of admission for treatment after initial presentation, as was presenting ciwa (p = . ). thus, presenting bal provided a substantial addition above initial ciwa in predicting later admission. no other variables added significantly to the prediction of later admission. to determine the interaction between presenting bal and ciwa scores, we ran a repeated measures analysis of the first five ciwa scores (from presentation to hours later), using bal split into low (bal < . ) and high (bal > . ) groups (see figure) . their interaction was significant, f ( , ) = . , p < . , g = . . those presenting with higher initial bal had suppressed ciwa scores that rose precipitously as the alcohol cleared. those with low presenting bal showed a decline in ciwa over time conclusion: initial assessment using the common assessment tool ciwa is aided significantly by bal assessment. patients with higher presenting bal are at higher risk for progression to serious alcohol withdrawal symptom. objectives: to describe patient and visitor characteristics and perspectives on the role of visitors in the ed and determine the effect of visitors on ed and hospital outcome measures. methods: this cross-sectional study was done in an , -visit urban ed, and data were attempted to be collected from all patients over a consecutive -hour period from august to , . trained data collectors were assigned to the ed continuously for the study period. patients assigned to a rapid care section of the ed ( %) were excluded. a visitor was defined as a person other than a health care provider (hcp) or hospital staff present in a patient's room at any time. patient perspectives on visitors were assessed in the following domains: transportation, emotional support, physical care, communication, and advocating for the patient. ed and hospital outcome measures pertaining to ed length of stay (los) and charges, hospital admission rate, hospital los and charges were obtained from patient medical records and hospital billing. data analyses included frequencies, student's t-tests for continuous variables, and chi-square tests of association for categorical variables. all tests for significance were two-sided. objectives: to examine the effect of sunday alcohol availability on ethanol-related visits and alcohol withdrawal visits to the ed. methods: study design was a retrospective beforeafter study using electronically archived hospital data at an urban, safety net hospital. all adult non-prisoner ed visits from / / to / / were analyzed. an ethanol-related ed visit was defined by icd- codes related to alcohol ( .x, .x, . , . ). an alcohol withdrawal visit was defined by icd- codes of delirium tremens ( . ), alcohol psychosis with hallucination ( . ), and ethanol withdrawal ( . ). we generated a ratio of ethanol-related ed visits to total ed visits (ethanol/total) and ratio of alcohol withdrawal ed visits to total ed visits (withdrawal/total). a day was redefined as am to am. the ratios were averaged within the four seasons to account for seasonal variations. data from summer were dropped as it spanned the law change. we stratified data into sunday and non-sunday days prior to analysis to isolate the effects of the law change. we used multivariable linear regression to estimate the association of the ratio with the law change while adjusting for time and the seasons. each ratio was modeled separately. the interaction between time and the law change was assessed using p < . . results: during the study there were a total of , ed visits including , ( % of total) ethanol-related visits and , ( % of total) alcohol withdrawal visits. unadjusted ratios in seasonal blocks are plotted in the figure with associated % ci and best fit regression line for before and after law change, respectively. after adjusting for time and season in the multivariable linear regression, we found no significant association of either ethanol/total or withdrawal/total with the law change. this remained true for both sunday and non-sunday data. all interactions assessed were not significant. conclusion: the change in colorado law to allow the sale of full-strength alcoholic beverages on sundays did not significantly affect ethanol-related or alcohol withdrawal ed visits. background: olanzapine is a second-generation antipsychotic (sga) with actions at the serotonin/histamine receptors. post-marketing reports and a case report have documented dangerous lowering of blood pressure when this antipsychotic is paired with benzodiazepines, but a recent small study found no bigger decreases in blood pressure compared to another antipsychotic like haloperidol. decreases in oxygen saturations, however, were larger when olanzapine was combined with benzodiazepines in alcohol-intoxicated patients. it is unclear whether these vital sign changes are associated with the intramuscular (im) route only. objectives: the assessment of vital signs following administration of either oral (po) or im olanzapine, either with or without benzodiazepines (benzos) and with or without concurrent alcohol intoxication. methods: this is a structured retrospective chart review of all patients who received olanzapine in an academic medical center ed from - who had vital signs documented both before medication administration and within four hours afterwards. vital signs were calculated as pre-dose minus lowest post-dose vital sign within hours, and were analyzed in an anova with route (im/po), benzo use (+/)), and alcohol use (+/)) as factors. significance level was set to < . . results: there were patients who received olanzapine over the study period. a total of patients ( po, im) met inclusion criteria. systolic blood pressures decreased across all groups as patients reduced their agitation. neither the route of administration, concurrent use of benzos, nor the use of alcohol were associated with significant changes in systolic bp (p = ns for all comparisons; see figure ). decreases in oxygen saturations, however, were significantly larger for alcoholintoxicated patients who subsequently received im olanzapine + benzos compared to other groups (route: p < . ; alcohol: p < . ; route x alcohol: p < . ; route x benzos x alcohol: p < . ; see figure ). conclusion: alcohol and benzos are not associated with significant decreases in blood pressure after po olanzapine, but im olanzapine + benzos is associated with potentially significant oxygen desaturations in patients who are intoxicated. intoxicated patients may have differential effects with the use of im sgas such as olanzapine when combined with benzos, and should be studied separately in drug trials. patients with a psychiatric diagnosis rasha buhumaid, jessica riley, janice blanchard george washington university, washington, dc background: literature suggests that frequent emergency department (ed) use is common among persons with a mental health diagnosis. few studies have documented risk factors associated with increased utilization among this population. objectives: to understand demographic characteristics of frequent users of the emergency department and describe characteristics associated with their visits. it was hypothesized that frequent visitors would have a higher rate of medical comorbidities than infrequent visitors. methods: this was a retrospective study of patients presenting to an urban, academic emergency department in . a cohort of all patients with a mental health-related final icd- coded diagnosis (axis i or axis ii) was extracted from the electronic medical record. using a standard abstraction form, a medical chart review collected information about medical comorbidities, substance abuse, race, age, sex, and insurance coverage, as well as diagnosis, disposition, and time of each visit. results: our sample consisted of frequent users ( ‡ visits in a day period) and infrequent users (£ visits in a day period). frequent users were more likely to be male ( % vs. . % p = . ), black ( % vs. % p < . ), and had a higher average number of comorbid conditions ( . , %ci . , . ) as compared to infrequent users ( . , %ci . , . ). a higher percentage of visits in the infrequent user group occurred during the day ( % vs. . % p < . ) while a higher number of visits in the frequent users occurred after midnight ( . % vs. . % p = . ). visits in the frequent user group were less likely to be for a psychiatric complaint ( . % vs. . %) and less likely to result in a psychiatric admission ( . % versus . %) as compared to the infrequent user group (p < . ). conclusion: our data indicate that among patients with psychiatric diagnoses, those who make frequent ed visits have a higher rate of comorbid conditions than infrequent visitors. despite their increased use of the ed, frequent visitors have a significantly lower psychiatric admission rate. many of the visits by frequent users are for non-psychiatric complaints and may reflect poor access to outpatient medical and mental health services. emergency departments should consider interventions to help address social and medical issues among mental health patients who frequently use ed services. background: the world health organization estimates that one million people die annually by suicide. in the u.s., suicide is the fourth leading cause of death between the ages of and . many of these patients are seen in ed, while outpatient visits for depression are also high. no recent analysis has compared these groups in the recent years. objectives: to determine if there is a relationship between the incidence of suicidal and depressed patients presenting to emergency departments and the incidence of depressed patients presenting to outpatient clinics from - . the secondary objective is to analyze trends in suicidal patients in the ed. methods: we used nhamcs (national hospital ambulatory medical care survey) and namcs (national ambulatory medical care survey), national surveys completed by the centers for disease control, which provide a sampling of emergency department and outpatient visits respectively. for both groups, we used mental-health-related icd- -cm, e codes and reasons for visit. we compared suicidal and depressed patients who presented to the ed, to those who presented to outpatient clinics. our subgroup analyses included age, sex, race/ethnicity, method of payment, regional variation, and urban verses rural distribution. results: ed visits for depression ( . %) and suicide attempts ( . %) remained stable over the years, with no significant linear trend. however, office visits for depression significantly decreased from . % of visits in to . % of visits in . non-latino whites had a higher percentage of ed visits for depression ( . %) and suicide attempt ( . %) (p < . ), and a higher percentage of office visits for depression than all other groups. among patients age - years, ed visits for suicide attempt significantly increased from . % in to . % in . homeless patients had a higher percent of ed visits for depression ( . %) and suicide attempt ( background: for potentially high-risk ed patients with psychiatric complaints, efficient ed throughput is key to delivering high-quality care and minimizing time spent in an unsecured waiting room. objectives: we hypothesized that adding a physician in triage would improve ed throughput for psychiatric patients. we evaluated the relationship between the presence of an ed triage physician and waiting room (wr) time, time to first physician order, time to ed bed assignment, and time spent in an ed bed. methods: the study was conducted from / - / at an academic ed with annual visits and a dedicated on-site emergency psychiatric unit. we performed a pre/post retrospective observational cohort study using administrative data, including weekend visits from noon- pm, months pre and post addition of weekend triage physicians. after adjusting for patient age, sex, insurance status, emergency severity index score, mode of arrival, ed occupancy rate, wr count, boarding count, and average wr los, multiple linear regression evaluated the relationship between the presence of a triage physician and four ed throughput outcomes: time spent in the wr, time to first order, time spent in an ed bed, and the total ed los. results: visits met inclusion criteria, in the months before and in the months after physicians were assigned to triage on weekends. table reports demographic data; multivariate analysis results are found in table . the presence of a triage physician was associated with an ( % ci . - . ) minute increase in wr time and no associated change in time to first order, time spent in an ed bed, or in the overall ed los. conclusion: use of triage physicians has been reported to decrease the time patients spend in an ed bed and improve ed throughput. however, for patients with psychiatric complaints, our analysis revealed a slight increase in wr time without evident change in the time to first order, time spent in an ed bed, or total ed los. improvements in ed throughput for psychiatric patients will likely require system-level changes, such as reducing ed boarding and improving lab efficiency to speed the process of medical clearance and reduce time spent in the unsecured wr. these findings may not be generalizable to eds without a dedicated ed psychiatric unit with full-time social workers to assist with disposition. initial assessment included ciwa scoring, repeated hourly, as well as other variables (see table ). treatment and admission to the inpatient hospital was indicated for a ciwa score of or higher. statistical analysis was performed utilizing repeated measures general linear modeling for ciwa scores and anova for all other variables. results: there were patients who fit the inclusion criteria, with admitted for treatment at initial intake and another admitted during the following hours. the table below compares the three most prevalent ethnic populations seen at our hospital. native americans presented at a significantly younger age (p < . ) than the other two ethnicities. initial ciwa scores taken on admission were significantly lower in the native american group than the other two groups (p < . ) and at hour a difference existed but failed to reach significance. repeated measures analysis indicate that ciwa scores progressed in a u-shaped curvilinear fashion (see figure ) conclusion: initial assessment utilizing ciwa scores appears to be affected by ethnicity. care must be taken when assessing and making decisions on a single initial ciwa score. further research is needed in this area as our numbers are small and differences might be seen in subsequent scoring. in addition, our study consists of primarily male patients and does not include african-american patients. background: age is a risk factor for adverse outcomes in trauma, yet evidence supporting the use of specific age cut-points to identify seriously injured patients for field triage is limited. objectives: to evaluate under-triage by age, empirically examine the association between age and serious injury for field triage, and assess the potential effect of mandatory age criteria. methods: this was a retrospective cohort study of injured children and adults transported by ems agencies to hospitals in regions of the western u.s. from - . hospital records were probabilistically linked to ems records using trauma registries, emergency department data, and state discharge databases. serious injury was defined as an injury severity score (iss) ‡ (the primary outcome). we assessed under-triage (triage-negative patients with iss ‡ ) by age decile, different mandatory age criteria, and used multivariable logistic regression models to test the association (linear and non-linear) between age and iss ‡ , adjusted for important confounders. results: , injured patients were evaluated and transported by ems over the -year period. under-triage increased markedly for patients over years, reaching % for those over years ( figure ). mandatory age triage criteria decreased under-triage, while substantially increasing over-triage: one iss ‡ patient identified for every additional patients triaged to major trauma centers. among patients not identified by other criteria, age had a strong non-linear association with iss ‡ (p < . ); the probability of serious injury steadily increased after years, becoming more notable after years ( figure ). conclusion: under-triage in trauma increases in patients over years, which may be reduced with mandatory age criteria at the expense of system efficiency. among patients not identified by other criteria, serious injury steadily increased after years, though there was no age at which risk abruptly increased. background: although limited resuscitation with hemoglobin-based oxygen carriers (hbocs) improves survival in several polytrauma models, including those of traumatic brain injury (tbi) with uncontrolled hemorrhage (uh) via liver injury, their use remains controversial. objectives: we examine the effect of hboc resuscitation in a swine polytrauma model with uh by aortic tear +/) tbi. we hypothesize that limited resuscitation with hboc would offer no survival benefit and would have similar effects in a model of uh via aortic tear +/) tbi. methods: anesthetized swine subjected to uh inflicted via aortic tear +/) fluid percussion tbi underwent equivalent limited resuscitation with hboc, lr, or hboc+nitroglycerin (ntg) (vasoattenuated hboc) and were observed for hours. comparisons were between tbi and no-tbi groups with adjustment for resuscitation fluid type using two-way anova with interaction and tukey kramer adjustment for individual comparisons. results: there was no independent effect of tbi on survival time after adjustment for fluid type (anova, tbi term p = . ) and there was no interaction between tbi and resuscitation fluid type (anova interaction term p = . ). there was a significant independent effect of fluid type on survival time (anova p = . background: intracranial hemorrhage (ich) after a head trauma is a problem frequently encountered in the ed. an elevated inr is recognized as a risk of bleeding. however, in a patient with an inr in normal range, a level associated with a lower risk of ich is not known. objectives: the aim of this study was to identify an inr threshold that could predict a decreased risk of an ich after a head trauma in patients with a normal inr. it is hypothesized that there is a threshold at which the likelihood of bleeding decreases significantly. methods: we did a study using data from a registry of patients with mild to severe head trauma (n = ) evaluated in a level i trauma center in canada between march and february . all the patients with a documented scan interpreted by a radiologist and a normal inr, defined as a value less then . , were included. we determined the correlation between inr value binned by . and the proportion of patients with an ich. threshold was defined by consensus as an abrupt change of more than % in the percentage of patients with ich. univariate frequency distribution was tested with pearson's chisquare test. logistic regression analysis was then used to study the effects of inr on ich with the following confounding factors: age, sex, and intake of warfarin, clopidogrel, or aspirin. results are presented with % confidence intervals. results: patients met the inclusion criteria. the mean age was . years ± . and % were men. patients ( . %) had an ich on brain scan. we found a significantly lower risk of ich at a threshold of inr less than . (p < . , univariate or = . , %ci . - . ) and a strong correlation between the risk of bleeding for every increase of the inr (r = . ). in fact, after adjustment for confounding variables, every . inr increase was associated with an increased risk of having an ich (or . ; % ci . - . ). conclusion: we were able to demonstrate an inr threshold under which the probability of ich was significantly lower. we also found a strong association between the risk of bleeding and the increase in inr within a normal range, suggesting that clinicians should not be falsely reassured by a normal inr. our results are limited by the fact that this is a retrospective study and a small proportion of traumatic brain injured patients in our database had no scan or inr at their ed visit. a prospective cohort study would be needed to confirm our results. background: increasingly, patients with tbi are being seen and managed in the emergency neurology setting. knowing which early signs are associated with prognosis can be helpful in directing the acute management. objectives: to determine whether any factors early in the course of head trauma are associated with shortterm outcomes including inpatient admission, in-hospital mortality, and return to the hospital within days. methods: this irb-approved study is a retrospective review of patients head injury presenting to our tertiary care academic medical center during a -month period. the dataset was created using redcap, a data management solution hosted by our medical school's center for translational science institute. results: the median age of the cohort (n = ) was , iqr = - yrs, with % being male. % had a gcs of - (mild tbi), % - (moderate tbi), and % gcs < (severe tbi). % of patients were admitted to the hospital. the median length of hospital stay was days, with an iqr of - days. of those admitted, % had an icu stay as well. the median icu los was also days, with an iqr of - days. twenty nine ( %) patients died during their hospital stay. lower gcs was predictive of inpatient admission (p = . ) as well as icu days (p < . ). significant predictors of re-admission to the hospital within days included hypotension (p = . ) upon initial presentation. the prehospital and ed gcs scores were not statistically significant. significant predictors of in-hospital death in a model controlling for age included bradycardia (p = . ), hyperglycemia (p = . ), and lower gcs (p = . ). the incidence of bradycardia (hr < ) was . %. conclusion: early hypotension, hyperglycemia, and bradycardia along with lower initial gcs are associated with significantly higher likelihood of hospital admission, including icu admission, as well as intrahospital death and re-admission. background: over , people per day require treatment for ankle sprains, resulting in lost workdays and training for athletes. platelet rich plasma (prp) is an autologous concentration of platelets which, when injected into the site of injury, is thought to improve healing by promoting inflammation through growth factor and cytokine release. studies to date have shown mixed results, with few randomized or placebo-controlled trials. the lower extremity functional scale (lefs) is a previously validated objective measure of lower extremity function. objectives: is prp helpful in acute ankle sprains in the the emergency department? methods: prospective, randomized, double-blinded, placebo-controlled trial. patients with severe ankle sprains and negative x-rays were randomized to trial or placebo. severe was defined as marked swelling and ecchymosis and inability to bear weight. both groups had cc of blood drawn. trial group blood was centrifuged with a magellan autologous platelet separator (arteriocyte, cleveland) to yield - cc of prp. prp along with . cc of % lidocaine and . cc of . % bupivicaine was injected at the point of maximum tenderness by a blinded physician under ultrasound guidance. control group blood was discarded and participants were injected in a similar fashion substituting sterile . % saline for prp. both groups had visual analog scale (vas) pain scores and lefs on days , , , and . all participants had a posterior splint and were made non weight bearing for days after which they were reexamined, had their splint removed, and were asked to bear weight as tolerated. participants were instructed not to use nsaids during the trial. results: patients were screened and were enrolled. four withdrew before prp injection was complete. eighteen were randomized to prp and to placebo. see tables for results. vas and lefs are presented as means with sd in parentheses. demographics were not statistically different between groups. conclusion: in this small study, prp did not appear to offer benefit in either pain control or healing. both groups had improvement in their pain and functionality and did not differ significantly during the study period. limitations include small study size and large number of participant refusals. methods: a structured chart review of all icd- radius fracture coded charts spanning march , to july , was conducted. specific variable data were collected and categorized as follows: age, moi, body mass index, and fracture location. the charts were reviewed by two medical students, with % of the charts reviewed by both students to confirm inter-rater reliability. frequencies and inter-quartile ranges were determined. comparisons were made with fisher's exact test and multiple logistic regression. results: charts met inclusion criteria. charts were excluded due to one of the following reasons: no fracture or no x-ray ( ), isolated ulnar fracture ( ), or undocumented or penetrating moi ( ). of the analyzed patients (n = ), distal radius fractures were most common ( %), followed by proximal ( %) and midshaft ( %). chart reviewers were found to be reliable (j = ). age and moi were significantly associated with fracture location (see table) . ages - and bike accidents were more strongly associated with proximal radius fractures (odds ratio: [ - ] and [ - ], respectively). conclusion: patients presenting to our inner city ed with a radius fracture are more likely to have a distal fracture. adults - and bike accidents had a significantly higher incidence of proximal fractures than other ages or mois. background: trauma centers use guidelines to determine the need for a trauma surgeon in the ed on patient arrival. a decision rule from loma linda university that includes penetrating injury and tachycardia was developed to predict which pediatric trauma patients require emergent intervention, and thus are most likely to benefit from surgical presence in the ed. objectives: our goal was to validate the loma linda rule (llr) in a heterogeneous pediatric trauma population and to compare it to the american college of surgeons' major resuscitation criteria (mrc). we hypothesized that the llr would be more sensitive than the mrc for identifying the need for emergent operative or procedural intervention. methods: we performed a secondary analysis of prospectively collected trauma registry data from two urban level i pediatric trauma centers with a combined annual census of approximately , visits. consecutive patients < years old with blunt or penetrating trauma from through were included. patient demographics, injury severity scores (iss), times of ed arrival and surgical intervention, and all variables of both rules were obtained. the outcome (emergent operative intervention within hour of ed arrival or ed cricothyroidotomy or thoracotomy) was confirmed by trained, blinded abstractors. sensitivities, specificities, and % confidence intervals (cis) were calculated for both rules. results: , patients were included with a median age of . years and a median iss of . emergent intervention was required in patients ( . %). the llr had a sensitivity ranging from . %- . % ( % ci: . %- . %) and specificity ranging from . %- . % ( % ci: . %- . %) between both institutions. the mrc had a sensitivity ranging from . %- . % ( % ci: . %- . %) and specificity ranging from . %- . % ( % ci: . %- . %) between institutions. conclusion: emergent intervention is rare in pediatric trauma patients. the mrc was more sensitive for predicting the need for emergent intervention than the llr. neither set of criteria was sufficiently accurate to recommend their routine use for pediatric trauma patients. droperidol for sedation of acute behavioural disturbance leonie a. calver , colin page , michael downes , betty chan , geoffrey k. isbister calvary mater newcastle and university of newcastle, newcastle, australia; princess alexandra hospital, brisbane, australia; calvary mater newcastle, newcastle, australia; prince of wales hospital, sydney, australia background: acute behavioural disturbance (abd) is a common occurrence in the emergency department (ed) and is a risk to staff and patients. there remains little consensus on the most effective drug for sedation of violent and aggressive patients. prior to the food and drug administration's black box warning, droperidol was commonly used and was considered safe and effective. objectives: this study aimed to investigate the effectiveness of parenteral droperidol for sedation of abd. methods: as part of a prospective observational study, a standardised protocol using droperidol for the seda-acute and delayed behavioral deficits were demonstrated in this rat model of co toxicity, which parallels the neurocognitive deficit pattern observed in humans (see figure) . similar to prior studies, pathologic analysis of brain tissue demonstrated the highest percentage of necrotic cells in the cortex, pyramidal cells, and cerebellum. the collected data are summarized in the table. we have developed an animal model of severe co toxicity evidenced by behavioral deficits and neuronal necrosis. future efforts will compare neurologic outcomes in severely co poisoned rats treated with hypothermia and % inspired o versus hbo to normothermic controls treated with % inspired o . increasing in popularity, attracting more than , annual participants worldwide. prior studies have consistently documented renal function impairment, but only after race completion. the incidence of renal injury during these multi-day ultramarathons is currently unknown. this is the first prospective cohort study to evaluate the incidence of acute kidney injury (aki) in runners during a multi-day ultramarathon foot race. objectives: to assess the effect of inter-stage recovery versus cumulative damage on resulting renal function during a multi-day ultramarathon. methods: demographic and biochemical data gathered via phlebotomy and analyzed by istatÒ (abbott, nj) were collected at the start and finish of day ( miles), ( miles), and ( miles) during racing the planet'sÒ -mile, -day self-supported desert ultramarathons. pre-established rifle criteria using creatinine (cr) and glomerular filtration rate (gfr) defined aki as ''no injury'' (cr < . x normal, decrease of gfr < %), ''risk'' (cr . x normal, decrease of gfr by - %), and ''injury'' (cr x normal, decrease of gfr by - %). results: thirty racers ( % male) with a mean (+/) sd) age of + /- years were studied during the sahara (n = , . %), gobi (n = , %), and namibia (n = , . %) events. the average decrease in gfr from day start to day finish was + /- (p < . , % ci . - . ); day start to day finish was . + /- . (p < . , % ci . - . ); and day start to day finish was . ± . (p < . , % ci . - ). runners categorized as risk and injury for aki after stage was . % and %; after stage was % and %, and after stage was . % and . % conclusion: the majority of participants developed significant levels of renal impairment despite recovery intervals. given the changes in renal function, potentially harmful non-steroidal anti-inflammatory drugs should be minimized to prevent exacerbating acute kidney injury. background: more than % of the elderly abuse prescription drugs, and emergency medicine providers frequently struggle to identify features of opioid addiction in this population. the prescription drug use questionnaire (pduqp) is a validated, -item, patient-administered tool developed to help health care providers better identify problematic opioid use, or dependence, in patients who receive opioids for the treatment of chronic pain. objectives: to identify the prevalence of prescription drug misuse features in elderly ed patients. methods: this cross-sectional, observational study was conducted between / and / in the ed of an urban, university-affiliated community hospi-tal that serves a large geriatric population. all patients aged to inclusive were eligible, and were recruited on a convenience basis. exclusion criteria included known dementia, and critical illness. outcomes of interest included self-reported history of prior prescription opioid use, substance abuse history, aberrant medication-taking behaviors, and pduqp results. results: one hundred patients were approached for participation. two were excluded for inability to read english, three were receiving analgesia for metastatic cancer, had never taken a prescription opioid, and seven refused to participate beyond pre-screening. sixty patients completed the study (see table ). of those, . % reported four or more visits within months; chronic pain was reported by . %; debilitating pain by . %; prior pain management referral by . %; and storing opioids for future use by %. seventeen patients reported current prescription opioid use, and were administered the pduqp (see figure) . in this population, . % thought their pain was not adequately being treated; . % reported having to increase the amount of pain medication they were taking over the prior months; . % saved up future pain medication; . % had doctors refuse to give them pain medication for fear that the patient would abuse the prescription opioids; and . % reported having a previous drug or alcohol problem. conclusion: screening instruments, such as the pduqp, facilitate identification of geriatric patients with features of opioid misuse. a high proportion of patients in this study save opioids for further use. interventions for safe medication disposal may decrease access to opioids and subsequent morbidity. age extremes, male sex, and several chronic health conditions were associated with increased odds of heat stroke, hospital admission, and death in the ed by a factor of - . chronic hematologic disease (e.g. anemia) was associated with a - fold increase in adjusted odds of each of these outcomes. conclusion: hri imposes a substantial public health burden, and a wider range of chronic conditions confer susceptibility than previously thought. males, older adults, and patients with chronic conditions, particularly anemia, are likely to have more severe hri, be admitted, or die in the ed. background: carbon monoxide (co) poisoning is a remarkable cause of death worldwide. co, produced by the incomplete combustion of hydrocarbons, has many toxic effects on especially the heart and brain. co binds strongly to cytochrome oxidase, hemoglobin, and myoglobin causing hypoxia of organs and issues. co converts hemoglobin to carboxyhemoglobin and makes transport of oxygen through the body impossible and causes severe hypoxia. objectives: the aim of this study is to investigate the levels of s b and neuron specific enolase (nse) measured both during admittance and at the sixth hour of hyperbaric and normobaric oxygen therapy carried out on patients with a diagnosis of co poisoning. methods: the study is designed as a prospective observational laboratory study. forty patients were enrolled in the study: underwent normobaric oxygen therapy (nbot) and the other underwent hyperbaric oxygen therapy (hbot). levels of s b and nse were measured both during admittance and at the sixth hour of admittance of all patients. demographic data, clinical characteristics, and outcome measures were recorded. all data were statistically analyzed. results: in both treatment groups, mean levels of nse after therapy were significantly lower than admittance levels. although levels of nse measured before and hours after treatment in hbot group were high, the difference between groups was not statistically significant (p > . ). in both treatment groups, mean levels of s b after therapy were significantly lower than admittance levels; likewise nse. although levels of s b measured before and hours after treatment in hbot group were high, the difference between groups was not statistically significant (p > . ). additionally, while levels of s b measured after treatment in the hbot group were lower compared to the nbot group, the difference between groups was also not statistically significant (p > . ). conclusion: levels of s b and nse as evidence for brain injury elevation in case of co poisoining and decrease by therapy according to our study as well as previous studies. decrease in levels of s b is more significant. according to our results, s b and nse may be useful markers in case of co poisoning; however, we did not meet any data providing more value in determining hbot indications and determining levels of cohb in the management of patients with a diagnosis of co poisoining. neurons objectives: this study was conducted to determine if neurons in the dmh, and its neighbor the paraventricular hypothalamus (pvn), were likewise involved in mdma-mediated neuroendocrine responses, and if serotonin a receptors ( -ht a) play a role in this regional response. methods: in both experiments, male sprague dawley rats (n = - /group) were implanted with bilateral cannulas targeting specific regions of the brain, i.v. catheters for drug delivery, and i.a. catheters for blood withdrawal. experiments were conducted in raturn cages, which allow blood withdrawal and drug administration in free moving animals while recording their locomotion. in the first experiment, rats were microinjected into the dmh, the pvn, or a region between, with the gabaa agonist muscimol ( pmol/ nl/side) or pbs ( nl) and min later were injected with either mdma ( . mg/kg i.v.) or an equal volume of saline. blood was withdrawn prior to microinjections and minutes after mdma for ria measurement of plasma acth. locomotion was recorded throughout the experiment. in a separate experiment of identical design, either the -ht a antagonist way (way, nmol/ nl/side) or saline was microinjected followed by i.v. injection of mdma or saline. in both experiments, increases in acth and distance traveled were compared between groups using an anova analysis. results: when compared to controls, microinjections of muscimol into the dmh, pvn, or the area in between attenuated plasma increases in acth and locomotion evoked by mdma. when microinjected into the dmh or pvn, way had no effect on acth, but when injected into the region of the dmh it significantly increased locomotion. background: poor hand-offs between physicians when admitting patients have been shown to be a major source of medical errors. objectives: we propose that training in a standardized admissions protocol by emergency medicine (em) to internal medicine (im) residents would improve the quality of and quantity of communication of vital patient information. methods: em and im residents at a large academic center developed an evidence-based admission handover protocol termed the ' ps' (table ) . em and im residents received ' ps' protocol training. im residents recorded prospectively how well each of the seven ps were communicated during each admission pre-and post-intervention. im residents also assessed the overall quality of the handover using a likert scale. the primary outcome was the change in the number of 'ps' conveyed by the em resident to the accepting im resident. data were collected for six weeks before and then for six weeks starting two weeks after the educational intervention. results: there were observations recorded in the preintervention (control) group and observations in the post-intervention group. for each of the seven 'ps' the percentage of observation where all of the information was communicated is shown in table . the communication of 'ps' increased following the intervention. this rise was statistically significant for patient information and pending tests. in the control group the mean of total communicated ps was and in the intervention group, the mean increased to (p < . ). the quality of the handover communication had a mean rating of . in the control group and . in the intervention group (p < . ). conclusion: this educational intervention in a cohort of em and im residents improved the quality and quantity of vital information communicated during patient handovers. the intervention was statistically significant for patient information transfer and tests pending. the results are limited by study size. based on our preliminary data, an agreed-upon handover protocol with training improved the amount and quality of communication during patients' hospital admission on simple items that were likely had been taken for granted as routinely transmitted. we recruited a convenience sample of residents and students rotating in the pediatric emergency department. a two-sided form had the same seven clinical decisions on each side: whether to perform blood, urine, spinal fluid tests, imaging, iv fluids, antibiotics, or a consult. the rating choices were: definitely not, probably not, probably would, and definitely would. trainees rated each decision after seeing a patient, but before presenting to the preceptor, who, after evaluating the patient, rated the same seven decisions on the second side of the form. the preceptor also indicated the most relevant decision (mrd) for that patient. we examined the validity of the technique using hypothesis testing; we posited that residents would have a higher degree of concordance with the preceptor than would medical students. this was tested using dichotomized analyses (accuracy, kappa) and roc curves with the preceptor decision as the gold standard. results: thirty-one students completed forms (median forms; iqr , ) and residents completed ( ; iqr , ). preceptors included attending physicians and fellows ( ; iqr , ). students were concordant with preceptors in % (k = . ) of mrd while residents agreed in . % (p = . ), k = . . roc analysis revealed significant differences between students and residents in the auc for the mrd ( . vs . ; p = . ). conclusion: this measure of trainee-preceptor concordance requires further research but may eventually allow for assessment of trainee clinical decision-making. it also has the pedagogical advantage of promoting independent trainee decision-making. background: basic life support (bls) and advanced cardiac life support (acls) are integral parts of emergency cardiac care. this training is usually reserved in most institutions for residents and faculty. the argument can be made to introduce bls and acls training earlier in the medical student curriculum to enhance acquisition of these skills. objectives: the goal of the survey was to characterize the perceptions and needs of graduating medical students in regards to bls and acls training. methods: this was a survey-based study of graduating fourth year medical students at a u.s. medical school. the students were surveyed before voluntarily participating in a student-led acls course in march of their final year. the surveys were distributed before starting the training course. both bls and acls training, comfort levels, and perceptions were assessed in the survey. results: of the students in the graduating class, participated in the training class with ( %) completing the survey. % of students entered medical school without any prior training and % started clinics without training. . % of students reported witnessing an average of . in-hospital cardiac arrests during training (range of - ). overall, students rated their preparedness . (sd . ) for adult resuscitations on a - likert scale with being the unprepared. % and % of students believe that bls and acls should be included in the medical student curriculum respectively with a preference for teaching before starting clerkships. % of students avoided participating in resuscitations due to lack of training. of those, % said they would have participated had they been trained. conclusion: to our knowledge, this is one of the first studies to address the perceptions and needs for bls and acls training in u.s. medical schools. students feel that bls and acls training is needed in their curriculum and would possibly enhance perceived comfort levels and willingness to participate in resuscitations. background: professionalism is one of six core competency requirements of the acgme, yet defining and teaching its principles remains a challenge. the ''social contract'' between physician and community is clearly central to professionalism so determining the patient's understanding of the physician's role in the relationship is important. because specialization has created more narrowly focused and often quite different interactions in different medical environments, the patient concept of professionalism in different settings may vary as well. objectives: we hoped to determine if patients have different conceptions of professionalism when considering physicians in different clinical environments. methods: patients were surveyed in the waiting room of an emergency department, an outpatient internal medicine clinic, and a pre-operative/anesthesia clinic. the survey contained examples of attributes, derived from the american board of internal medicine's eight characteristics of professionalism. participants were asked to rate, on a -point scale, the importance that a physician possess each attribute. an anova analysis was used to compare the sites for each question. results: of who took the survey, were in the emergency department, were in the medicine clinic, and were in the pre-operative clinic. females comprised % of the study group and the average age was with a range from to . there was a significant difference on the attribute of ''providing a portion of work for those who cannot pay;'' this was rated higher in the emergency department (p = . ). there was near-significance (p = . ) on the attribute of ''being able to make difficult decisions under pressure,'' which was rated higher in the pre-op clinic. there was no difference for any of the other questions. the top four professional attributes at each clinical site were the same -''honesty,'' ''excellence in communication and listening,'' ''taking full responsibility for mistakes,'' and ''technical competence/ skill;'' the bottom two were ''being an active leader in the community'' and ''patient concerns should come before a doctor's family commitments.'' conclusion: very few differences between clinical sites were found when surveying patient perception of the important elements of medical professionalism. this may suggests a core set of values desired by patients for physicians across specialties. emergency medicine faculty knowledge of and confidence in giving feedback on the acgme core competencies todd guth, jeff druck, jason hoppe, britney anderson university of colorado, aurora, co background: the acgme mandates that residency programs assess residents based upon six core competencies. although the core competencies have been in place for a number of years, many faculty are not familiar with the intricacies of the competencies and have difficulty giving competency-specific feedback to residents. objectives: the purpose of the study is to determine the extent to which emergency medicine (em) faculty can identify the acgme core competencies correctly and to determine faculty confidence with giving general feedback and core competency focused feedback to em residents. methods: design and participants: at a single department of em, a survey of twenty-eight faculty members, their knowledge of the acgme core competencies, and their confidence in providing feedback to residents was conducted. confidence levels in giving feedback were scored on a likert scale from to . observations: descriptive statistics of faculty confidence in giving feedback, identification of professional areas of interest, and identification of the acgme core competencies were determined. mann-whitney u tests were used to make comparisons between groups of faculty given the small sample size of the respondents. results: there was a % response rate of the faculty members surveyed. eight faculty members identified themselves as primarily focused on education. although those faculty members identifying themselves as focused on education scored higher than non-education focused faculty for all type of feedback (general feedback, constructive feedback, negative feedback), there was only a statistical difference in confidence levels . versus . (p < . ) for acgme core competency specific feedback when compared to noneducation focused faculty. while education focused faculty correctly identified all six of acgme core competencies % of the time, not one of the non-education focused faculty identified all six of the core competencies correctly. non-education focused faculty only correctly identified three or more competencies % of the time. conclusion: if residency programs are to assess residents using the six acgme core competencies, additional faculty development specific to the core competencies will be needed to train all faculty on the core competencies and on how to give core competency specific feedback to em residents. there is no clear consensus as to the most effective tool to measure resident competency in emergency ultrasound. objectives: to determine the relationship between the number of scans and scores on image recognition, image acquisition, and cognitive skills as measured by an objective structured clinical exam (osce) and written exam. secondarily, to determine whether image acquisition, image recognition, and cognitive knowledge require separate evaluation methodologies. methods: this was a prospective observational study in an urban level i ed with a -year acgme-accredited residency program. all residents underwent an ultrasound introductory course and a one-month ultrasound rotation during their first and second years. each resident received a written exam and osce to assess psychomotor and cognitive skills. the osce had two components: ( ) recognition of images, and ( ) acquisition of images. a registered diagnostic medical sonographer (rdms)-certified physician observed each bedside examination. a pre-existing residency ultrasound database was used to collect data about number of scans. pearson correlation coefficients were calculated for number of scans, written exam score, image recognition, and image acquisition scores on the osce. results: twenty-nine residents were enrolled from march to february who performed an average of scans (range - ). there was no significant correlation between number of scans and written exam scores. an analysis of the number of scans and the ocse found a moderate correlation with image acquisition (r = . , p = . ) and image recognition (r = . , p = < . )). pearson correlation analysis between the image acquisition score and image recognition score found that there was no correlation (r = . , p = . ). there was a moderate correlation with image acquisition scores to written scores (r = . , p = . ) and image recognition scores to written scores (r = . , p = . ). conclusion: the number of scans does not correlate with written tests but has a moderate correlation with image acquisition and image recognition. this suggests that resident education should include cognitive instruction in addition to scan numbers. we conclude that multiple methods are necessary to examine resident ultrasound competency. background: although emergency physicians must often make rapid decisions that incorporate their interpretation of an ecg, there is no evidence-based description of ecg interpretation competencies for emergency medicine (em) trainees. the first step in defining these competencies is to develop a prioritized list of ecg findings relevant to em contexts. objectives: the purpose of this study was to categorize the importance of various ecg diagnoses and/or findings for the em trainee. methods: we developed an extensive list of potentially important ecg diagnoses identified through a detailed review of the cardiology and em literature. we then conducted a three-round delphi expert opinion-soliciting process where participants used a five-point likert scale to rate the importance of each diagnosis for em trainees. consensus was defined as a minimum of percent agreement on any particular diagnosis at the second round or later. in the absence of consensus, stability was defined as a shift of percent or less after successive rounds. results: twenty-two em experts participated in the delphi process, sixteen ( %) of whom completed the process. of those, fifteen were experts from eleven different em training programs across canada and one was a recognized expert in em electrocardiography. overall, diagnoses reached consensus, achieved stability, and one diagnosis achieved neither consensus nor stability. out of potentially important ecg diagnoses, ( %) were considered ''must know'' diagnoses, ( %) ''should know'' diagnoses, and ( %) ''nice to know'' diagnoses. conclusion: we have categorized ecg diagnoses within an em training context, knowledge of which may allow clinical em teachers to establish educational priorities. this categorization will also facilitate the development of an educational framework to establish em trainee competency in ecg interpretation. ''rolling refreshers background: cardiac arrest survival rates are low despite advances in cardiopulmonary resuscitation. high quality cpr has been shown to impart greater cardiac arrest survival; however, retention of basic cpr skills by health care providers has been shown to be poor. objectives: to evaluate practitioner acceptance of an in-service cpr skills refresher program, and to assess for operator response to real-time feedback during refreshers. methods: we prospectively evaluated a ''rolling refresher'' in-service program at an academic medical center. this program is a proctored cpr practice session using a mannequin and cpr-sensing defibrillator that provides real-time cpr quality feedback. subjects were basic life support-trained providers who were engaged in clinical care at the time of enrollment. subjects were asked to perform two minutes of chest compressions (ccs) using the feedback system. ccs could be terminated when the subject had completed approximately seconds of compressions with < corrective prompts. a survey was then completed by to obtain feedback regarding the perceived efficacy of this training model. cpr quality was then evaluated using custom analysis software to determine the percent of cc adequacy in -second intervals. results: enrollment included subjects from the emergency department and critical care units ( nurses, physicians, students and allied health professionals). all participants completed a survey and cpr performance data logs were obtained. positive impressions of the in-service program were registered by % ( / ) and % ( / ) reported a self-perceived improvement in skills confidence. eighty-three percent ( / ) of respondents felt comfortable performing this refresher during a clinical shift. thirtynine percent ( / ) of episodes exhibited adequate cc performance with approximately seconds of cc. of the remaining episodes, . ± . % of cc were adequate in the first seconds with . ± . % of cc adequate during the last second interval (p = . ). of these individuals, improved or had no change in their cpr skills, and individuals skills declined during cc performance (p = . ). conclusion: implementation of a bedside cpr skill refresher program is feasible and is well received by hospital staff. real time cpr feedback improved upon cpr skill performance during the in-service session. teaching emergency medicine skills: is a self-directed, independent, online curriculum the way of the future? tighe crombie, jason r. frank, stephen noseworthy, richard gerein, a. curtis lee university of ottawa, ottawa, on, canada background: procedural competence is critical to emergency medicine, but the ideal instructional method to acquire these skills is not clear. previous studies have demonstrated that online tutorials have the potential to be as effective as didactic sessions at teaching specific procedural skills. objectives: we studied whether a novel online curriculum teaching pediatric intraosseus (io) line insertion to novice learners is as effective as a traditional classroom curriculum in imparting procedural competence. methods: we conducted a randomized controlled educational trial of two methods of teaching io skills. preclinical medical students with no past io experience completed a written test and were randomized to either an online or classroom curriculum. the online group (og) were given password-protected access to a website and instructed to spend minutes with the material while the didactic group (dg) attended a lecture of similar duration. participants then attended a -minute unsupervised manikin practice session on a separate day without any further instruction. a videotaped objective structured clinical examination (osce) and post-course written test were completed immediately following this practice session. finally, participants were crossed over into the alternate curriculum and were asked to complete a satisfaction survey that compared the two curricula. results were compared with a paired t-test for written scores and an independent t-test for osce scores. results: sixteen students completed the study. pre-course test scores of the two groups were not significantly different prior to accessing their respective curricula (mean scores of % for og and % for dg, respectively; p > . ). post-course written scores were also not significantly different (both with means of %; p > . ); however, for the post-treatment osce scores, the og group scored significantly higher than the dg group (mean scores of . % and . %; t( ) = . , p < . .) conclusion: this novel online curriculum was superior to a traditional didactic approach to teaching pediatric io line insertion. novice learners assigned to a selfdirected online curriculum were able to perform an emergency procedural skill to a high level of performance. em educators should consider adopting online teaching of procedural skills. background: applicants to em residency programs obtain information largely from the internet. curricular information is available from a program's website (pw) or the saem residency directory (sd). we hypothesize that there is variation between these key sources. objectives: to identify discrepancies between each pw and sd. to describe components of pgy - em residency programs' curricula as advertised on the internet. methods: pgy - residencies were identified through the sd. data were abstracted from individual sd and pw pages identifying pre-determined elements of interest regarding rotations in icu, pediatrics, inpatient (medicine, pediatrics, general surgery), electives, orthopedics, toxicology, and anesthesia. agreement between the sd and pw was calculated using a cohen's unweighted kappa calculation. curricula posted on pws were considered the gold standard for the programs' current curricula. results: a total of pgy - programs were identified through the sd and confirmed on the pw. ninetyone of programs ( %) had complete curricular information on both sites. only these programs were included in the kappa analysis for sd and pw comparisons. of programs with complete listings, of programs ( %) had at least one discrepancy. the agreement of information between pw and sd revealed a kappa value of . ( % ci . - . ). analysis of pw revealed that pgy - programs have an average of . (range, - ), . (range, - ), . (range, - ), and . (range, - ) blocks of icu, pediatrics, elective, and inpatient, respectively. common but not rrc-mandated rotations in orthopedics, toxicology, and anesthesiology are present in , , and percent of programs, respectively. conclusion: publicly accessible curricular information through the sd and pw for pgy - em programs only has fair agreement (using commonly accepted kappa value guides). applicants may be confused by the variability of data and draw inaccurate conclusions about program curricula. from the gravid uterus and improves cardiac output; however, this theory has never been proven. objectives: we set out to determine the difference in inferior vena cava (ivc) filling when third trimester patients were placed in supine, llt, and right lateral tilt (rlt) positions using ivc ultrasound. methods: healthy pregnant women in their third trimester presenting to the labor and delivery suite were enrolled. patients were placed in three different positions (supine, rlt, and llt) and ivc maximum (max) and minimum (min) measurements were obtained using the intercostal window in short axis approximately two centimeters below the entry of the hepatic veins. ivc collapse index (ci) was calculated for each measurement using the formula (max-min)/max. in addition, blood pressure, heart rate, and fetal heart rate were monitored. patients stayed in each position for at least minutes prior to taking measurements. we compared ivc measurements using a one-way analysis of variance for repeated measures. results: twenty patients were enrolled. the average age was years (sd . ) with a mean estimated gestational age of . weeks (sd . ). there were no significant differences seen in ivc filling in each of the positions (see table ). in addition, there were no differences in hemodynamic parameters between positions.ten ( %) patients had the largest ivc measurement in the llt position, ( %) patients in the rlt position, and ( %) in the supine position. conclusion: there were no significant differences in ivc filling between patient positions. for some third trimester patients llt may not be the optimal position for ivc filling. background: although the acgme and rrc require competency assessment in ed bedside ultrasound (us), there are no standardized assessment tools for us training in em. objectives: using published us guidelines, we developed four observed structured competency evalua-tions (osce) for four common em us exams: fast, aortic, cardiac, and pelvic. inter-rater reliability was calculated for overall performance and for the individual components of each osce. methods: this prospective observational study derived four osces that evaluated overall study competency, image quality for each required view, technical factors (probe placement, orientation, angle, gain, and depth), and identification of key anatomic structures. em residents with varying levels of training completed an osce under direct observation of two em-trained us experts. each expert was blinded to the other's assessment. overall study competency and image quality of each required views were rated on a five-point scale ( poor, -fair, -adequate, -good, -excellent), with explicit definitions for each rating. each study had technical factors (correct/incorrect) and anatomic structures (identified/not identified) assessed as binary variables. data were analyzed using cohen's and weighted k, descriptive statistics, and % ci. results: a total of us exams were observed, including fast, cardiac, aorta, and pelvic. total assessments included ratings of overall study competency, ratings of required view image quality, ratings of technical factors, and ratings of anatomic structures. inter-rater assessment of overall study competency showed excellent agreement, raw agreement . ( . , . ), weighted k . ( . , . ). ratings of required view image quality showed excellent agreement: raw agreement . ( . , . ), weighted k . ( . , . ). inter-rater assessment of technical factors showed substantial agreement: raw agreement . ( . , . ), cohen's k . ( . , . ). ratings of identification of anatomic structures showed substantial agreement: raw agreement . ( . , . ), cohen's k . ( . , . ). conclusion: inter-rater reliability is substantial to excellent using the derived ultrasound osces to rate em resident competency in fast, aortic, cardiac, and pelvic ultrasound. validation of this tool is ongoing. a objectives: the objective of this study was to identify which transducer orientation, longitudinal or transverse, is the best method of imaging the axillary vein with ultrasound, as defined by successful placement in the vein with one needle stick, no redirections, and no complications. methods: emergency medicine resident and attending physicians at an academic medical center were asked to cannulate the axillary vein in a torso phantom model. the participants were randomized to start with either the longitudinal or transverse approach and completed both sequentially, after viewing a teaching presentation. participants completed pre-and post-attempt questionnaires. measurements of each attempt were taken regarding time to completion, success, skin punctures, needle redirections, and complications. we compared proportions using a normal binomial approximation and continuous data using the t-distribution, as appropriate. a sample size of was chosen based on the following assumptions: power, . ; significance, . ; effect size, % versus %. results: fifty-seven operators with a median experience of prior ultrasounds ( to iqr) participated. first-attempt success frequency was / ( . ) for the longitudinal method and / ( . ) for the transverse method (difference . , % ci . - . ); this difference was similar regardless of operator experience. the longitudinal method had fewer redirections (mean difference . , % ci . - . ) and skin punctures (mean difference . , % ci ) to . ). arterial puncture occurred in / longitudinal attempts and / transverse attempts, with no pleural punctures in either group. among successful attempts, the time spent was seconds less for longitudinal method ( % ci - ). though % of participants had more experience with the transverse method prior to the training session, % indicated after the session that they preferred the longitudinal method. methods: a prospective single-center study was conducted to assess the compressibility of the basilic vein with ultrasound. healthy study participants were recruited. the compressibility was assessed at baseline, and then further assessed with one proximal tourniquet, two tourniquets (one distal and one proximal), and a proximal blood pressure cuff inflated to mmhg. compressibility was defined as the vessel's resistance to collapse to external pressure and rated as completely compressible, moderately compressible, or mildly compressible after mild pressure was applied with the ultrasound probe. results: one-hundred patients were recruited into the study. ninety-eight subjects were found to have a completely compressible basilic vein at baseline. when one tourniquet and two tourniquets were applied and participants, respectively, continued to have completely compressible veins. a fisher's exact test comparing one versus two tourniquets revealed no difference between these two techniques (p = . ). only two participants continued to have completely compressible veins following application of the blood pressure cuff. the compressibility of this group was found to be statistically significant by fisher's exact test compared to both tourniquet groups (p < . ). furthermore, participants with the blood pressure cuff applied were found to have moderately compressible veins and participants were found to have mildly compressible veins. conclusion: tourniquets and blood pressure cuffs can both decrease the compressibility of peripheral veins. while there was no difference identified between using one and two tourniquets, utilization of a blood pressure cuff was significantly more effective to decrease compressibility. the findings of this study may be utilized in the emergency department when attempting to obtain peripheral venous access, specifically supporting the use of blood pressure cuffs to decrease compressibility. background: electroencephalography (eeg) is an underused test that can provide valuable information in the evaluation of emergency department (ed) patients with altered mental status (ams). in ams patients with nonconvulsive seizure (ncs), eeg is necessary to make the diagnosis and to initiate proper treatment. yet, most cases of ncs are diagnosed > h after ed presentation. obstacles to routine use of eeg in the ed include space limitations, absence of / availability of eeg technologists and interpreters, and the electrically hostile ed environment. a novel miniature portable wireless device (microeeg) is designed to overcome these obstacles. objectives: to examine the diagnostic utility of micro-eeg in identifying eeg abnormalities in ed patients with ams. methods: an ongoing prospective study conducted at two academic urban eds. inclusion: patients ‡ years old with ams. exclusion: an easily correctable cause of ams (e.g. hypoglycemia, opioid overdose). three -minute eegs were obtained in random order from each subject beginning within one hour of presentation: ) a standard eeg, ) a microeeg obtained simultaneously with conventional cup electrodes using a signal splitter, and ) a microeeg using an electrocap. outcome: operative characteristics of micro-eeg in identifying any eeg abnormality. all eegs were interpreted in a blinded fashion by two board-certified epileptologists. within each reader-patient pairing, the accuracy of eegs and were each assessed relative to eeg . sensitivity, specificity, and likelihood ratios (lr) are reported for microeeg by standard electrodes and electrocap (eegs and ). inter-rater variability for eeg interpretations is reported with kappa. results: the interim analysis was performed on consecutive patients (target sample size: ) enrolled from may to october (median age: , range: - , % male). overall, % ( % confidence interval [ci], - %) of interpretations were abnormal (based on eeg ). kappa values representing the agreement of neurologists in interpretation of eeg - were . ( . - . ), . ( . - . ), and . ( . - . ), respectively. conclusion: the diagnostic accuracy and concordance of microeeg are comparable to those of standard eeg but the unique ed-friendly characteristics of the device could help overcome the existing barriers for more frequent use of eeg in the ed. (originally submitted as a ''late-breaker.'') a background: patients who use an ed for acute migraine are characterized by higher migraine disability scores, lower socio-economic status, and are unlikely to have used a migraine-specific medication prior to ed presentation. objectives: to determine if a comprehensive migraine intervention, delivered just prior to ed discharge, could improve migraine impact scores one month after the ed visit. methods: this was a randomized controlled trial of a comprehensive migraine intervention versus typical care among patients who presented to an ed for management of acute migraine. at the time of discharge, for patients randomized to comprehensive care, we reinforced their diagnosis, shared a migraine education presentation from the national library of medicine, provided them with six tablets of sumatriptan mg and tablets of naproxen mg, and if they wished, provided them with an expedited free appointment to our institution's headache clinic. patients randomized to typical care received the care their attending emergency physician felt was appropriate. the primary outcome was a between-group comparison of the hit score, a validated headache assessment instrument, one month after ed discharge. secondary outcomes included an assessment of satisfaction with headache care and frequency of use of migraine-specific medication within that one month period. the outcome assessor was blinded to assignment. results: over a month period, migraine patients were enrolled. one month follow-up was successfully obtained in % of patients. baseline characteristics were comparable. one month hit scores in the two groups were nearly identical ( vs , %ci for difference of : ) , ), as was dissatisfaction with overall headache care ( % versus %, %ci for difference of %: ) , %). not surprisingly, patients randomized to the comprehensive intervention were more likely to be using triptans or migraine-preventive therapy ( % versus %, %ci for difference of %: , %) one month later. conclusion: a comprehensive migraine intervention, when compared to typical care, did not improve hit scores one month after ed discharge. future work is needed to define a migraine intervention that is practical and useful in an ed. background: lumbar puncture (lp) is the standard of care for excluding non-traumatic subarachnoid hemorrhage (sah), and is usually performed following head ct (hct). however, in the setting of a non-diagnostic hct, lp demonstrates a low overall diagnostic yield for sah (< % positive rate). objectives: to describe a series of ed patients diagnosed with sah by lp following a non-diagnostic hct, and, when compared to a set of matched controls, determine if clinical variables can reliably identify these ''ct-negative/lp-positive'' patients. methods: retrospective case-control chart review of ed patients in an integrated health system between the years - (estimated - million visits among eds). patients with a final diagnosis of non-traumatic sah were screened for case inclusion, defined as an initial hct without sah by final radiologist interpretation and a lp with > red blood cells/mm , along with either ) xanthochromic cerebrospinal fluid, ) angiographic evidence of cerebral aneurysm or arteriovenous malformation, or ) head imaging showing sah within hours following lp. control patients were randomly selected among ed patients diagnosed with headache following a negative sah evaluation with hct and lp. controls were matched to cases by year and presenting ed in a : ratio. stepwise logistic regression and classification and regression tree analysis (cart) were employed to identify predictive variables. inter-rater reliability (kappa) was determined by independent chart review. results: fifty-five cases were identified. all cases were hunt-hess grade or . demographics are shown in table . thirty-four cases ( %) had angiographic evidence of sah. five variables were identified that positively predicted sah following a normal hct with % sensitivity ( % ci, - %) and % specificity ( % ci, - %): age > years, neck pain or stiffness, onset of headache with exertion, vomiting with headache, or loss of consciousness at headache onset. kappa values for selected variables ranged from . - . ( % sample). the c-statistic (auc) and hosmer-lemeshow test p-value for the logistic regression model are . and . , respectively (table ) . conclusion: several clinical variables can help safely limit the amount of invasive testing for sah following a non-diagnostic hct. prospective validation of this model is needed prior to practice implementation. background: post-thrombolysis intracerebral hemorrhage (ich) is associated with poor outcomes. previous investigations have attempted to determine the relationship between pre-existing anti-platelet (ap) use and the safety of intravenous thrombolysis, but have been limited by low event rates thus decreasing the precision of estimates. objectives: our objective was to determine whether pre-existing ap therapy increases the risk of ich following thrombolysis. methods: consecutive cases of ed-treated thrombolysis patients were identified using multiple methods, including active and passive surveillance. retrospective data were collected from four hospitals from - , and distinct hospitals from - as part of a cluster randomized trial. the same chart abstraction tool was used during both time periods and data were subjected to numerous quality control checks. hemorrhages were classified using a pre-specified methodology: ich was defined as presence of hemorrhage in radiographic interpretations of follow up imaging (primary outcome). symptomatic ich (secondary outcome) was defined as radiographic ich with associated clinical worsening. a multivariable logistic regression model was constructed to adjust for clinical factors previously identified to be related to postthrombolysis ich. as there were fewer sich events, the multivariable model was constructed similarly, except that variables divided into quartiles in the primary analysis were dichotomized at the median. results: there were patients included, with % having documented pre-existing ap treatment. the mean age was years, the cohort was % male, and the median nihss was . the unadjusted proportion of patients with any ich was . % without ap and . % with ap (difference . %, % ci ) . % to . %); for sich this was . % without ap and % with ap (difference . %, %ci ) to . %). no significant association between pre-existing ap treatment with radiographic or symptomatic ich was observed (table) . conclusion: we did not find that ap treatment was associated with post-thrombolysis ich or sich in this cohort of community treated patients. pre-existing tobacco use, younger age, and lower severity were associated with lower odds of sich. an association between ap therapy and sich may still exist -further research with larger sample sizes is warranted in order to detect smaller effect sizes. background: post-cardiac arrest therapeutic hypothermia (th) improves survival and neurologic outcome after cardiac arrest, but the parameters required for optimal neuroprotection remain uncertain. our laboratory recently reported that -hour th was superior to -hour th in protecting hippocampal ca pyramidal neurons after asphyxial cardiac arrest in rats. cerebellar purkinje cells are also highly sensitive to ischemic injury caused by cardiac arrest, but the effect of th on this neuron population has not been previously studied. objectives: we examined the effect of post-cardiac arrest th onset time and duration on purkinje neuron survival in cerebella collected during our previous study. methods: adult male long evans rats were subjected to -minute asphyxial cardiac arrest followed by cpr. rats that achieved return of spontaneous circulation (rosc) were block randomized to normothermia ( . deg c) or th ( . deg c) initiated , , , or hours after rosc and maintained for or hours (n = per group). sham injured rats underwent anesthesia and instrumentation only. seven days post-cardiac arrest or sham injury, rats were euthanized and brain tissue was processed for histology. surviving purkinje cells with normal morphology were quantified in the primary fissure in nissl stained sagittal sections of the cerebellar vermis. purkinje cell density was calculated for each rat, and group means were compared by anova with bonferroni analysis. results: purkinje cell density averaged (+/) sd) . ( . ) cells/mm in sham-injured rats. neuronal survival in normothermic post-cardiac arrest rats was significantly reduced compared to sham ( . % ( . %)). overall, th resulted in significant neuroprotection compared to normothermia ( . % ( . %) of sham). purkinje cell density with -hour duration th was . % ( . %) of sham and -hour duration th was . % ( . %), both significantly improved from sham (p = . between durations). th initiated , , , and hours post-rosc provided similar benefit: . % ( . %), . % ( . %), . % ( . %), and . % ( . %) of sham, respectively. conclusion: overall, these results indicate that postcardiac arrest th protects cerebellar purkinje cells with a broad therapeutic window. our results underscore the importance of considering multiple brain regions when optimizing the neuroprotective effect of post-cardiac arrest th. the effect of compressor-administered defibrillation on peri-shock pauses in a simulated cardiac arrest scenario joshua glick, evan leibner, thomas terndrup penn state hershey medical center, hershey, pa background: longer pauses in chest compressions during cardiac arrest are associated with a decreased probability of successful defibrillation and patient survival. having multiple personnel share the tasks of performing chest compressions and shock delivery can lead to communication complications that may prolong time spent off the chest. objectives: the purpose of this study was to determine whether compressor-administered defibrillation led to a decrease in pre-shock and peri-shock pauses as compared to bystander-administered defibrillation in a simulated in-hospital cardiac arrest scenario. we hypothesized that combining the responsibilities of shock delivery and chest-compression performance may lower no-flow periods. methods: this was a randomized, controlled study measuring pauses in chest compressions for defibrillation in a simulated cardiac arrest. medical students and ed personnel with current cpr certification were surveyed for participation between july and october . participants were randomized to either a control (facilitator-administered shock) or variable (participantadministered shock) group. all participants completed one minute of chest compressions on a mannequin in a shockable rhythm prior to initiation of prompt and safe defibrillation. pauses for defibrillation were measured and compared in both study groups. results: out of total enrollments, the data from defibrillations were analyzed. subject-initiated defibrillation resulted in a significantly lower pre-shock handsoff time ( . s; % ci: . - . ) compared to facilitator-initiated defibrillation ( . s; % ci: . - . ). furthermore, subject-initiated defibrillation resulted in a significantly lower peri-shock hands-off time ( . s; % ci: . - . ) compared to facilitator-initiated defibrillation ( . s; % ci: . - . ). conclusion: assigning the responsibility for shock delivery to the provider performing compressions encourages continuous compressions throughout the charging period and decreases total time spent off the chest. this modification may also decrease the risk of accidental shock and improve patient survival. however, as this was a simulation-based study, clinical implementation is necessary to further evaluate these potential benefits. objectives: to determine the sensitivity and specificity of peripheral venous oxygen (po ) to predict abnormal central venous oxygen saturation in septic shock patients in the ed. methods: secondary analysis of an ed-based randomized controlled trial of early sepsis resuscitation targeting three physiological variables: cvp, map, and either scvo or lactate clearance. inclusion criteria: suspected infection, two or more sirs criteria, and either systolic blood pressure < mmhg after a fluid bolus or lactate > mm. peripheral venous po was measured prior to enrollment as part of routine care, and scvo was measured as part of the protocol. we analyzed for agreement between venous po and scvo using spearman's rank. sensitivity and specificity to predict an abnormal scvo (< %) were calculated for each incremental value of po . results: a total of were analyzed. median po was mmhg (iqr , ). median initial scvo was % (iqr , ). thirty-nine patients ( %) had an initial scvo < %. spearman's rank demonstrated fair correlation between initial po and scvo (q = . ). a cutoff of venous po < was % sensitive and % specific for detecting an initial scvo < %. twenty-seven patients ( %) demonstrated an initial po of > . conclusion: in ed septic shock patients, venous po demonstrated only fair correlation with scvo , though a cutoff value of was sensitive for predicting an abnormal scvo . twenty percent of patients demonstrated an initial value above the cutoff, potentially representing a group in whom scvo measurement could be avoided. future studies aiming to decrease central line utilization could consider the use of peripheral o measurements in these patients. sessions. ninety-two percent were rns, median clinical experience was - years, and % were from an intensive care unit. provider confidence increased significantly with a single session despite the highly experienced sample (figure ). there was a trend for further increased confidence with an additional session and the increased confidence was maintained for at least - months given the normal sensitivity analysis. conclusion: high fidelity simulation significantly increases provider confidence even among experienced providers. this study was limited by its small sample size and recent changes in acls guidelines. background: recent data suggest alarming delays and deviations in major components of pediatric resuscitation during simulated scenarios by pediatric housestaff. objectives: to identify the most common errors of pediatric residents during multiple simulated pediatric resuscitation scenarios. methods: a retrospective observational study conducted in an academic tertiary care hospital. pediatric residents (pgy and pgy ) were videotaped performing a series of five pediatric resuscitation scenarios using a high-fidelity simulator (simbaby, laerdal): pulseless non-shockable arrest, pulseless shockable arrest, dysrhythmia, respiratory arrest, and shock. the primary outcome was the presence of significant errors prospectively defined using a validated scoring instrument designed to assess sequence, timing, and quality of specific actions during resuscitations based on the aha pals guidelines. residents' clinical performances were measured by a single video reviewer. the primary analysis was the proportion of errors for each critical task for each scenario. we estimated that the evaluation of each resident would provide a confidence interval less than . for the proportion of errors. results: twenty-four of residents completed the study. across all scenarios, pulse check was delayed by more than seconds in % ( %ci: %- %). for non-shockable arrest, cpr was started more than seconds after recognizing arrest in % ( %ci - %) and inappropriate defibrillation was performed in % ( %ci - %). for shockable arrest, participants failed to identify the rhythm in % ( %ci - %), cpr was not performed in % ( %ci - %), while defibrillation was delayed by more than seconds in % ( %ci - %) and not performed in one case. for shock, participants failed to ask for a dextrose check in % ( %ci - %), and it was delayed by more than seconds for all others. conclusion: the most common error across all scenarios was delay in pulse check. delays in starting cpr and inappropriate defibrillation were common errors in non-shockable arrests, while failure to identify rhythm, cpr omission, and delaying defibrillation were noted for shockable arrests. for shock, omission of rapid dextrose check was the most common error, while delaying the test when ordered was also significant. future training in pediatric resuscitation should target these errors. background: many scoring instruments have been described to measure clinical performance during resuscitation; however, the validity of these tools has yet to be proven in pediatric resuscitation. objectives: to determine the external validity of published scoring instruments to evaluate clinical performance during simulated pediatric resuscitations using pals algorithms and to determine if inter-rater reliability could be assessed. methods: this was a prospective quasi-experimental design performed in a simulation lab of a pediatric tertiary care facility. participants were residents from a single pediatric program distinct from where the instrument was originally developed. a total of pgy s and pgy s were videotaped during five simulated pediatric resuscitation scenarios. pediatric emergency physicians rated resident performances before and after a pals course using standardized scoring. each video recording was viewed and scored by two raters blinded to one another. a priori, it was determined that, for the scoring instrument to be valid, participants should improve their scores after participating in the pals course. differences in means between pre-pals and post-pals and pgy and pgy were compared using an anova test. to investigate differences in the scores of the two groups over the five scenarios, a two-factor anova was used. reliability was assessed by calculating an interclass correlation coefficient for each scenario. results: following the pals course, scores improved by . % ( . to . ), . % ( . to . ), . % () . to . ), . % ( . to ), and . % () . to . ) for the pulseless non-shockable arrest, pulseless shockable arrest, dysrhythmia, respiratory, and shock scenarios respectively. there were no differences in scores between pgy s and pgy s before and after the pals course. there was an excellent reliability for each scoring instrument with iccs varying between . and . . conclusion: the scoring instrument was able to demonstrate significant improvements in scores following a pals course for pgy and pgy pediatric residents for the pulseless non-shockable arrest, pulseless shockable, and respiratory arrest scenarios only. however, it was unable to discriminate between pgy s and pgy s both before and after the pals course for any scenarios. the scoring instrument showed excellent inter-reliability for all scenarios. a background: medical simulation is a common and frequently studied component of emergency medicine (em) residency curricula. its utility in the context of em medical student clerkships is not well defined. objectives: the objective was to measure the effect of simulation instruction on medical students' em clerkship oral exam performance. we hypothesized that students randomized to the simulation group would score higher. we predicted that simulation instruction would promote better clinical reasoning skills and knowledge expression. methods: this was a randomized observational study conducted from / to / . participants were fourth year medical students in their em clerkship. students were randomly assigned on their first day to one of two groups. the study group received simulation instruction in place of one of the lectures, while the control group was assigned to the standard curriculum. the standard clerkship curriculum includes lectures, case studies, procedure labs, and clinical shifts without simulation. at the end of the clerkship, all students participated in written and oral exams. graders were not blinded to group allocation. grades were assigned based on a pre-defined set of criteria. the final course composite score was computed based on clinical evaluations and the results of both written and oral exams. oral exam scores between the groups were compared using a two-sample t-test. we used the spearman rank correlation to measure the association between group assignment and the overall course grade. the study was approved by our institutional irb. results: sixty-one students participated in the study and were randomly assigned to one of two groups. twenty-nine ( . %) were assigned to simulation and the remaining ( . %) students were assigned to the standard curriculum. students assigned to the simulation group scored . % ( % ci . - . %) higher on the oral exam than the non-simulation group. additionally, simulation was associated with a higher final course grade (p < . ). limitations of this pilot study include lack of blinding and interexaminer variability. conclusion: simulation training as part of an em clerkship is associated with higher oral exam scores and higher overall course grade compared to the standard curriculum. the results from this pilot study are encouraging and support a larger, more rigorous study. initial approaches to common complaints are taught using a standard curriculum of lecture and small group case-based discussion. we added a simulation exercise to the traditional altered mental status (ams) curriculum with the hypothesis that this would positively affect student knowledge, attitudes, and level of clinical confidence caring for patients with ams. methods: ams simulation sessions were conducted in june and ; student participation was voluntary. the simulation exercises included two ams cases using a full-body simulator and a faculty debriefing after each case. both students who did and did not participate in the simulations completed a written post-test and a survey related to confidence in their approach to ams. results: students completed the post-test and survey. ( %) attended the simulation session. ( %) attended all three sessions. ( %) participated in the lecture and small group. ( %) did not attend any session. post-test scores were higher in students who attended the simulations versus those who did not: (iqr, - ) vs. (iqr, - ); p < . . students who attended the simulations felt more confident about assessing an ams patient ( % vs. %; p = . ), articulating a differential diagnosis ( % vs. %; p = . ), and knowing initial diagnostic tests ( % vs. %; p = . ) and initial interventions ( % vs. %; p = . ) for an ams patient. students who attended the simulations were more likely to rate the overall ams curriculum as useful ( % vs. %; p < . ). conclusion: addition of a simulation session to a standard ams curriculum had a positive effect on student performance on a knowledge-based exam and increased confidence in clinical approach. the study's major limitations were that student participation in the simulation exercise was voluntary and that effect on applied skills was not measured. future research will determine whether simulation is effective for other chief complaints and if it improves actual clinical performance. background: the acgme has defined six core competencies for residents including ''professionalism'' and ''interpersonal and communication skills.'' integral to these two competencies is empathy. prior studies suggest that self-reported empathy declines during medical training; no reported study has yet integrated simulation into the evaluation of empathy in medical training. objectives: to determine if there is a relation between level of training and empathy in patient interactions as rated during simulation. methods: this is a prospective observational study at a tertiary care center comparing participants at four different levels of training: first (ms ) and third year (ms ) medical students, incoming em interns (pgy ), and em senior residents (pgy / ). trainees participated in two simulation scenarios (ectopic pregnancy and status asthmaticus) in which they were responsible for clinical management (cm) and patient interactions (pi). this was the first simulation exposure during an established simulation curriculum for ms , ms , and pgy . two independent raters reviewed videotaped simulation scenarios using checklists of critical actions for clinical management (cm: - points) and patient interactions (pi: - points). inter-rater reliability was assessed by intra-class correlation coefficients (iccs objectives: we explored attitudes and beliefs about the handoff, using qualitative methods, from a diverse group of stakeholders within the ems community. we also characterized perceptions of barriers to high-quality handoffs and identified strategies for optimizing this process. methods: we conducted seven focus groups at three separate gatherings of ems professionals (one local, two national) in / . snowball sampling was used to recruit participants with diverse professional, experiential, geographic, and demographic characteristics. focus groups, lasting - minutes, were moderated by investigators trained in qualitative methods, using an interview guide to elicit conversation. recordings of each group were transcribed. three reviewers analyzed the text in a multi-stage iterative process to code the data, describe the main categories, and identify unifying themes. results: participants included emts, paramedics, physicians, and nurses. clinical experience ranged from months to years. recurrent thematic domains when discussing attitudes and beliefs were: perceptions of respect and competence, professionalism, teamwork, value assigned to the process, and professional duty. modifiers of these domains were: hierarchy, skill/training level, severity/type of patient illness, and system/ regulatory factors. strategies to improving barriers to the handoff included: fostering familiarity and personal connections between ems and ed staff, encouraging two-way conversations, feedback, and direct interactions between ems providers and ed physicians, and optimizing ways for ems providers to share subjective impressions (beyond standardized data elements) with hospital-based care teams. conclusion: ems professionals assign high value to the ed handoff. variations in patient acuity, familiarity with other handoff participants, and perceptions of respect and professionalism appear to influence the perceived quality of this transition. regulatory strategies to standardize the contents of the handoff may not alone overcome barriers to this process. miology, public health) then developed an approach to assign ems records to one of symptom-based illness categories (gastrointestinal illness, respiratory, etc). ems encounter records were characterized into these illness categories using a novel text analytic program. event alerts were identified across the state and local regions in illness categories using either change detection from baseline with (cusum) analysis (three standard deviations) and a novel text-proportion (tap) analysis approach (sas institute, cary, nc). results: . million ems encounter records over a year period were analyzed. the initial analysis focused upon gastrointestinal illness (gi) given the potential relationship of gi distress to infectious outbreaks, food contamination and intentional poisonings (ricin). after accounting for seasonality, a significant gi event was detected in feb (see red circle on graph). this event coincided with a confirmed norovirus outbreak. the use of cusum approach (yellow circle on graph) detected the alert event on jan , . the novel tap approach on a regional basis detected the alert on dec , . conclusion: ems has the advantage of being an early point of contact with patients and providing information on the location of insult or injury. surveillance based on ems information system data can detect emergent outbreaks of illness of interest to public health. a novel text proportion analytic technique shows promise as an early event detection method. assessing chronic stress in the emergency medical services elizabeth a. donnelly , jill chonody university of windsor, windsor, on, canada; university of south australia, adelaide, australia background: attention has been paid to the effect of critical incident stress in the emergency medical services (ems); however, less attention has been given to the effect of chronic stress (e.g., conflict with administration or colleagues, risk of injury, fatigue, interference in non-work activities) in ems. a number of extant instruments assess for workplace stress; however, none address the idiosyncratic aspects of work in ems. objectives: the purpose of this study was to validate an instrument, adapted from mccreary and thompson ( ) , that assesses levels of both organizational and operational work-related chronic stress in ems personnel. methods: to validate this instrument, a cross-sectional, observational web-based survey was used. the instrument was distributed to a systematic probability sample of emts and paramedics (n = , ). the survey also included the perceived stress scale (cohen, ) to assess for convergent construct validity. results: the survey attained a . % usable response rate (n = ); respondent characteristics were consistent across demographic characteristics with other studies of emts and paramedics. the sample was split in order to allow for exploratory and confirmatory fac-tor analyses (n = /n = ). in the exploratory factor analysis, principal axis factoring with an oblique rotation revealed a two-factor, -item solution (kmo = . , v = . , df = , p £. ). confirmatory factor analysis suggested a more parsimonious, two-factor, -item solution (v = . , df = , p £ . , rmsea = . , cfi = . , tli = . , srmr = . ). the factors demonstrated good internal reliability (operational stress a = . , organizational stress a = . ). both factors were significantly correlated (p £ . ) with the hypothesized convergent validity measure. conclusion: theory and empirical research indicate that exposure to chronic workplace stress may play an important part in the development of psychological distress, including burnout, depression, and posttraumatic stress disorder (ptsd). workplace stress and stress reactions may potentially interfere with job performance. as no extant measure assesses for chronic workplace stress in ems, the validation of this chronic stress measure enhances the tools ems leaders and researchers have in assessing the health and well-being of ems providers. effect of naltrexone background: survivors of sarin and other organophosphate poisoning can develop delayed encephalopathy that is not prevented by standard antidotal therapy with atropine and pralidoxime. a rat model of poisoning with the sarin analogue diisoprophylfluorophosphate (dfp) demonstrated impairment of spatial memory despite antidotal therapy with atropine and pralidoxime. additional antidotes are needed after acute poisonings that will prevent the development of encephalopathy. objectives: to determine the efficacy of naltrexone in preventing delayed encephalopathy after poisoning with the sarin analogue dfp in a rat model. the hypothesis is that naltrexone would improve performance on spatial memory after acute dfp poisoning. the sarin analogue dfp was used because it has similar toxicity to sarin while being less dangerous to handle. methods: a randomized controlled experiment at a university animal research laboratory of the effects of naltrexone on spatial memory after dfp poisoning was conducted. long evans rats weighing - grams were randomized to dfp group (n = , rats received a single intraperitoneal (ip) injection of dfp mg/kg) or dfp+naltrexone group (n = , rats received a single ip injection of dfp ( mg/kg) followed by naltrexone mg/kg/day). after injection, rats were monitored for signs and symptoms of cholinesterase toxicity. if toxicity developed, antidotal therapy was initiated with atro-background: one of the primary goals of management of patients presenting with known or suspected acetaminophen (apap) ingestion is to identify the risk for apap-induced hepatotoxicity. current practice is to measure apap level at a minimum of hours post ingestion and plot this value on the rumack-matthew nomogram. one retrospective study of apap levels drawn less than hours post-ingestion found a level less than mcg/ml to be sufficient to exclude toxic ingestion. objectives: the aim of this study was to prospectively determine the negative predictive value (npv) for toxicity of an apap level of less than mcg/ml obtained less than hours post-ingestion. methods: this was a multicenter prospective cohort study of patients presenting to one of five tertiary care hospitals that are part of the toxicology investigator's consortium (toxic). eligible patients presented to the emergency department less than hours after known or suspected ingestion and had the initial apap level obtained at greater than but less than hours post ingestion. a second apap level was obtained at hours or more post-ingestion and plotted on the rumack-matthew nomogram to determine risk of toxicity. the outcome of interest was the npv of an initial apap level less than mcg/ml. a power analysis based on an alpha = . and power of . yielded the requirement of subjects. results: data were collected on patients over a month period from may to nov . patients excluded from npv analysis consisted of: initial apap level greater than mcg/ml ( ), negligible apap level on both the initial and confirmatory apap level ( ), initial apap level drawn less than one hour after ingestion ( ), or an unknown time of ingestion ( ). ninety-three patients met the eligibility criteria. two patients ( . %) with an initial apap level less than mcg/ml ( mcg/ml at min, mcg/ml at min) were determined to be at risk for toxicity based on oh s saem annual meeting abstracts implementation of an emergency department sign-out checklist improves patient hand-offs at change of shift nicole m ma computer-assisted self-interviews improve testing for chlamydia and gonorrhea in the pediatric emergency department is the australian triage system a better indicator of psychiatric patients' needs for intervention than the ena emergency severity index triage system? patients were given an initial dose of mg droperidol intramuscularly followed by an additional dose of mg after min if required. inclusion criteria were patients requiring physical restraint and parenteral sedation. the primary outcome was the time to sedation. secondary outcomes were the proportion of patients requiring additional sedation within the first hour, over-sedation measured as - on the sedation assessment tool, and respiratory compromise measured as oxygen saturation < %. results: droperidol was administered to patients and of these had sedation scores documented. presentations included % with alcohol intoxication. dose ranged from . mg to mg, median mg (interquartile range conclusion: droperidol is effective for rapid sedation for abd and rarely causes over-sedation serum creatinine (scr) is widely used to predict risk; however, gfr is a better assessment of kidney function. objectives: to compare the ability of gfr and scr to predict the development of cin among ed patients receiving cects. we hypothesized that gfr would be the best available predictor of cin. methods: this was a retrospective chart review of ed patients ‡ years old who had a chest or abdomen/pelvis cect between / / and / / . baseline and follow-up scr levels were recorded. patients with initial scr > . mg/dl were excluded, as per hospital radiology department protocol. cin was defined as a scr increase of either %, . mg/dl, or a gfr decrease of % within hours of contrast exposure. gfr was calculated using the ckd epi and mdrd formulae, and analyzed in original units and categorized form (< , ‡ ) with each additional unit decrease in ckd epi, subjects were % more likely to develop cin (or = . ) (p < . ). additionally, subjects with ckd epi < were . (or) times more likely to have cin than subjects with ckd epi ‡ in original units, ckd epi (p < . ) and mdrd (p < . ) both had a significantly higher auc than scr. conclusion: age, as an independent variable, is the best predictor of cin, when compared with scr and gfr. due to a small number of cases with cin, the confidence intervals associated with the odds ratios are wide. future research should focus on patient risk stratification and establishing ed interventions to prevent cin. a rat model of carbon monoxide induced neurotoxicity heather ellsworth non-traumatic subarachnoid hemorrhage diagnosed by lumbar puncture following non-diagnostic head ct: a retrospective case-control study and decision a dass score of > has been previously defined as an indicator of increased stress levels. multivariable logistic regression was utilized to identify demographic and work-life characteristics significantly associated with stress. results: . % of individuals responded to the survey ( , / , ) and prevalence of stress was estimated at . %. the following work-life characteristics were associated with stress: certification level, work experience, and service type. the odds of stress in paramedics was % higher when compared to emt-basics (or = . , % ci = . - . ). when compared to £ years of experience - . ) were more likely to be stressed. ems professionals working in county (or = ci = . - . ) and private services (or = ) were more likely than those working in fire-based services to be stressed. the following demographic characteristics were associated with stress: general health and smoking status finally, former smokers (or = . , % ci = . - . ) and current smokers (or = . , % ci = . - . ) were more likely to be stressed than non-smokers literature suggests this is within the range of stress among nurses, and lower than physicians. while the current study was able to identify demographic and work-life characteristics associated with stress, the long-term effects are largely unknown methods: design: prospective randomized controlled trial. subjects: female sus scrofa swine weighing - kg were infused with amitriptyline . mg/kg/minute until the map fell to % of baseline values. subjects were then randomized to experimental group (ife ml/kg followed by an infusion of . ml/kg/minute) or control group (sb meq/kg plus equal volume of normal saline). interventions: we measured continuous heart rate (hr), sbp, map, cardiac output (co), systemic vascular resistance (svr), and venous oxygen saturation (svo ). laboratory values monitored included ph, pco , bicarbonate, lactate, and amitriptyline levels. descriptive statistics including means, standard deviations, standard errors of measurement, and confidence limits were calculated. results: of swine, seven each were allocated to ife and sb groups. there was no difference at baseline for each group regarding hr, sbp, map, co, svr, or svo . ife and sb groups required similar mean amounts of tca to reach hypotension one ife and two sb pigs survived. conclusion: in this interim data analysis of amitriptyline-induced hypotensive swine, we found no difference in mitigating hypotension between ife and sb lipid rescue : a survey of poison center medical directors regarding intravenous fat emulsion therapy michael r. christian , erin m. pallasch cook county hospital (stroger), chicago, il reliability of non-toxic acetaminophen concentrations obtained less than hours after ingestion evaluating age in the field triage of injured background: hiv screening in eds is advocated to achieve the goal of comprehensive population screening. yet, hiv testing in the ed is sometimes thwarted by a patient's condition (e.g. intoxication) or environmental factors (e.g. other care activities). whether it is possible to test these patients at a later time is unknown. objectives: we aimed to determine if ed patients who were initially unable to receive an hiv testing offer might be tested in the ed at a later time. we hypothesized that factors preventing testing are transient and that there are subsequent opportunities to repeat testing offers. methods: we reviewed medical records for patients presenting to an urban, academic ed who were approached consecutively to offer hiv testing during randomly selected periods from january to january . patients for whom the initial attempted offer could not be completed were reviewed in detail with standardized abstraction forms, duplicate abstraction, and third-party discrepancy adjudication. primary outcomes included repeat hiv testing offers during that ed visit, and whether a testing offer might eventually have been possible either during the initial visit or at a later visit within months. outcomes are described as proportions with confidence intervals. results: of patients approached, initial testing offers could not be completed for ( %). these were % male, % white, and had a median age of ( - ). a repeat offer of testing during the initial visit would have been possible for / ( %), and / ( %) were actually offered testing on repeat approach. of the for whom a testing offer would not have been possible on the initial visit, ( %) had at least one additional visit within months, and / ( %) could have been offered testing on at least one visit. overall, a repeat testing offer would have been possible for / ( %, % ci - %). conclusion: factors preventing an initial offer of hiv testing in the ed are generally transient. opportunities for repeat approach during initial or later ed encounters suggest that, given sufficient resources, the ed could succeed in comprehensively screening the population presenting for care. ed screening personnel who are initially unable to offer testing should repeat their attempt. hiv adopt an ''opt-out'' rapid hiv screening model in order to identify hiv infected patients. previous studies nationwide have shown acceptance rates for hiv screening of - % in emergency departments. however, it is unknown how acceptance rates will vary in a culturally and ethnically diverse urban emergency department.objectives: to determine the characteristics of patients who accept or refuse ''opt-out'' hiv screening in an urban emergency department.methods: a self-administered, anonymous survey is administered to ed patients who are to years of age. the questionnaire is administered in english, russian, mandarin, and spanish. questions include demographic characteristics, hiv risk factors, perception of hiv risk, and acceptance of rapid hiv screening in the emergency department. results: to date patients responded to our survey. of the , ( . %) did not accept an hiv test (group ) in their current ed visit and ( . %) accepted an hiv test (group ). the major two reasons given for opting out (i.e., group ) was ''i do not feel that i am at risk'' ( . %) and ''i have been tested for hiv before'' ( . %). there was no difference between the groups in regards to sex (p = . ), age (p = . ), religious affiliation (p = . ), marital status (p = . ), language spoken at home (p = . ), and whether they had been hiv tested before ( . % in group and . % in group ; p = . ). however, there was a statistically significant difference with regards to educational level and income. more patients in group ( . %) and . % in group had less than a college level education (p < . ). similarly, more patients in group ( . %) and only . % in group had an annual household income of £$ , (p < . ). conclusion: in a culturally and ethnically diverse urban emergency department, patients with a lower socioeconomic status and educational level tend to opt out of hiv screening test offered in the ed. no significant difference in acceptance of ed hiv testing was found to date based on primary language spoken at home or religious affiliation background: antimicrobial resistance is a problem that affects all emergency departments. objectives: our goal was to examine all urinary pathogens and their resistance patterns from urine cultures collected in the emergency department (ed).methods: this study was performed at an urban/suburban community-teaching hospital with an annual volume of , visits. using electronic records, all cases of urine cultures received in were reviewed for data including type of bacteria, antibiotic resistance, and health care exposure (hcx). hcx was defined as no prior hospitalization within the previous six months, hospitalization within the previous three months, hospitalization within the previous six months, nursing home resident (nh), and presence of an indwelling urinary catheter (uc). an investigator abstracted all data with a second re-abstracting a random % for kappa statistics between . and . . group background: approximately - % of patients treated with epinephrine for anaphylaxis receive a second dose but the risk factors associated with repeat epinephrine use remain poorly defined. objectives: to determine whether obesity is a risk factor for requiring + epinephrine doses for patients who present to the emergency department (ed) with anaphylaxis due to food allergy or stinging insect hypersensitivity. methods: we performed a retrospective chart review at four tertiary care hospitals that care for adults and children in new england between the following time periods: massachusetts general hospital ( / / - / / ), brigham and women's hospital ( / / - / / ), children's hospital boston ( / / - / / ), hasbro children's hospital ( / / - / / ). we reviewed the medical records of all patients presenting to the ed for food allergy or stinging insect hypersensitivity using icd cm codes. we focused on anthropomorphic data and number of epinephrine treatments given before and during the ed visit. among children, calculated bmis were classified according to cdc growth indicators as underweight, healthy, overweight, or obese. all patients who presented on or after their th birthday were considered adults.background: transitions of care are ubiquitous in the emergency department (ed) and inevitably introduce the opportunity for errors. despite recommendations in the literature, few emergency medicine (em) residency programs provide formal training or standard process for patient hand-offs. checklists have been shown to be effective quality improvement measures in inpatient settings and may be a feasible method to improve ed hand-offs. objectives: to determine if the use of a sign-out checklist improves the accuracy and efficiency of resident sign-out in the ed as measured by reduced omission of key information, communication behaviors, and time to sign-out each patient. methods: a prospective study of first-and second-year em and non-em residents rotating in the ed at an urban academic medical center with an annual ed volume of , . trained clinical research assistants observed resident sign-out during shift change over a two-week period and completed a -point binary observable behavior data collection tool to indicate whether or not key components of sign-out occurred. time to sign out each patient was recorded. we then created and implemented a computerized sign-out checklist consisting of key elements that should be addressed during transitions of care, and instructed residents to use this during hand-offs. a two-week post-intervention observation phase was conducted using the same data collection tool. proportions, means, and non-parametric comparison tests were calculated using stata. results: one hundred fifteen sign-outs were observed prior to checklist implementation and after; one sign-out was excluded for incompleteness. significant improvements were seen in four of the measured signout components: inclusion of history of present illness increased by % (p < . ), likely diagnosis increased by % (p = . ), disposition status increased by % (p < . ), and patient/care team awareness of plan increased by % (p < . ). (figure ) time data for sign-outs pre-implementation and post-implementation were available. seven sign-outs were excluded for incompleteness or spurious values. mean length of sign out was s ( % ci to ) and . s ( % ci to ) per patient. conclusion: implementation of a checklist improved the transfer of information but did not affect the overall length of time for the sign-out. the objectives: to determine risk factors associated with adult patients presenting to the ed with cellulitis who fail initial antibiotic therapy and require a change of antibiotics or admission to hospital. methods: this was a prospective cohort study of patients ‡ years presenting with cellulitis to one of two tertiary care eds (combined annual census , ). patients were excluded if they had been treated with antibiotics for the cellulitis prior to presenting to the ed, if they were admitted to hospital, or had an abscess only. trained research personnel administered a questionnaire at the initial ed visit with telephone follow-up weeks later. patient characteristics were summarized using descriptive statistics and % confidence intervals (cis) were estimated using standard equations. backwards stepwise multivariable logistic regression models determined predictor variables independently associated with treatment failure (failed initial antibiotic therapy and required a change of antibiotics or admission to hospital). results: patients were enrolled, were excluded, and were lost to follow-up. the mean (sd) age was . ( . ) and . % were male. ( . %) patients were given antibiotics in the ed. ( . %) were given oral, ( . %) were given iv, and ( . %) patients were given both oral and iv antibiotics. ( . %) patients had a treatment failure. fever (temp > °c) at triage (or: . , % ci: . , . ), leg ulcers (or: . , % ci: . , . ), edema or lymphedema (or: . , % ci: . , . ), and prior cellulitis in the same area (or: . , % ci: . , . ) were independently associated with treatment failure. conclusion: this analysis found four risk factors associated with treatment failure in patients presenting to the ed with cellulitis. these risk factors should be considered when initiating empiric outpatient antibiotic therapy for patients with uncomplicated cellulitis. use background: children presenting for care to a pediatric emergency department (ped) commonly require intravenous catheter (iv) placement. prior studies report that the average number of sticks to successfully place an iv in children is . . successfully placing an iv requires identification of appropriate venous access targets. the veinviewer visionÒ (vvv) assists with iv placement by projecting a map of subcutaneous veins on the surface of the skin using near infrared light. objectives: to compare the effectiveness of the vvv versus standard approaches: sight (s) and sight plus palpation (s+p) for identifying peripheral veins for intravenous catheter placement in children treated in a ped. methods: experienced pediatric emergency nurses and physicians identified peripheral venous access targets appropriate for intravenous cannulation of a cross-sectional convenience sample of english speaking children aged - years presenting for treatment of sub-critical injury or illness whose parents provided consent. the clinicians marked the veins with different colored washable marker and counted them on the dorsum of the hand and in the antecubital fossa using the three approaches: s, s+p, and vvv. a trained research assistant photographed each site for independent counting after each marking and recorded demographics and bmi. counts were validated using independent photographic analyses. data were entered into sas . and analyzed using paired t-tests. results: patients completed the study. clinicians were able to identify significantly more veins on the dorsum of the hand using vvv than s alone or s+p, . (p < . , ci . - . ) and . (p < . , ci . - . ), respectively, as well as significantly more veins in the antecubital fossa using vvv than s alone or s+p, . (p < . , ci . - . ) and . (p < . , ci . - . ), respectively. the differences in numbers of veins identified remained significant at p < . level across all ages, races, and bmis of children and across clinicians and validating independent photographic analyses. conclusion: experienced emergency nurses and physicians were able to identify significantly more venous access targets appropriate for intravenous cannulation in the dorsum of the hand and antecubital fossa of children presenting for treatment in a ped using vvv than the standard approaches of sight or sight plus palpation. an background: mental health emergencies have increased over the past two decades, and contribute to the ongoing rise in u.s. ed visit volumes. although data are limited, there is a general perception that the availability of in-person psychiatric consultation in the ed and of inpatient psychiatric beds is inadequate. objectives: to examine the availability of in-person psychiatry consultation in a heterogeneous sample of u.s. eds, and typical delays in transfer of ed patients to an inpatient psychiatric bed. methods: during - , we mailed a survey to all ed directors in a convenience sample of nine us states (ar, co, ga, hi, ma, mn, or, vt, and wy). all sites were asked: ''are psychiatric consults available in-person to the ed?'' (yes/no), with affirmative respondents asked about the typical delay. sites also were asked about typical ed boarding time between a request for patient transfer and actual patient departure from the ed to an inpatient psychiatric bed. ed characteristics included rural/urban location, visit volume (visits/hour), admission rate, ed staffing, and the proportion of patients without insurance. data analysis used chi-square tests and multivariable logistic regression. results: surveys were collected from ( %) of the eds, with > % response rate in every state. overall, only % responded that psychiatric consults were available in-person to the ed. in multivariable logistic regression, ed characteristics independently associated with lack of in-person psychiatric consultation were: location within specific states (eg, ar, ga), rural location, lower visit volume, and lower admission rate. among the subset of eds with psychiatric consults available, % reported a typical wait time of at least hour. overall, % of eds reported that the typical time from request to actual patient transfer to an inpatient psychiatric bed was > hours, and % reported a maximum time in past year of > day (median days, iqr - ). in a multivariable model, location in ma and higher visit volume were associated with greater odds of a maximum wait time of > day. conclusion: among surveyed eds in nine states, only % have in-person psychiatric consultants available. moreover, approximately half of eds report boarding times of > h from request for transfer to actual departure to an inpatient psychiatric bed.background: many emergency departments (ed) in the united states use a five tiered triage protocol that has a limited evaluation of psychiatric patients. the australian triage scale (ats), a psychiatric triage system, has been used throughout australia and new zealand since the early s. objectives: the objective of the study is to compare the current triage system, emergency nurses association (ena) esi -tier, to the ats for the evaluation of the psychiatric patients presenting to the ed. methods: a convenience sample of patients, years of age and older, presenting with psychiatric complaints at triage were given the ena triage assessment by the triage nurse. a second triage assessment, performed by a research fellow, included all observed and reported elements using the ats protocol, a self-assessment survey and an agitation assessment using the richmond agitation sedation scale (rass). the study was performed at an inner city level i trauma center with , visits per year. the ed was a catchment facility for the police department for psychiatric patients in the area. patients were excluded if they were unstable, unable to communicate, or had a non-psychiatric complaint. results were analyzed in spss v . the analysis of data used frequencies, descriptive and anova. results: a total of patients were enrolled in the study: % were african american, % caucasian, % hispanic, % asian, and % indian; % of subjects enrolled were male. the patients' level of agitation using rass showed % were alert and calm, % were restless and anxious, % were agitated, and % combative, violent, or dangerous to self. the only significant correlation found was among the ats and several self assessment questions: ''i feel agitated on a to scale'' (p = . ) and ''i feel violent on a to scale'' (p = . ). there were no significant correlations found among the ena triage, rass scores, and throughput times. conclusion: the ats test was more sensitive to the patient declaring that he or she was agitated or felt violent. this shows that this system might be a more useful system in determining the severity of need of psychiatric patients presenting to the ed. variations background: hemoglobin-based oxygen carriers (hbocs) have been evaluated for small-volume resuscitation of hemorrhagic shock due to their oxygen carrying capability, but have found limited utility due to vasoactive side-effects from nitric oxide (no) scavenging. objectives: to define an optimal hboc dosing strategy and evaluate the effect of an added no donor, we use a prehospital swine polytrauma model to compare the effect of low-vs. moderate-volume hboc resuscitation with and without nitroglycerin (ntg) co-infusion as an no donor. we hypothesize that survival time will improve with moderate resuscitation and that an no donor will add additional benefit. methods: survival time was compared in groups (n = ) of anesthetized swine subjected to simultaneous traumatic brain injury and uncontrolled hemorrhagic shock by aortic tear. animals received one of three different resuscitation fluids: lactated ringers (lr), hboc, or vasoattenuated hboc with ntg co-infusion. for comparison, these fluids were given in a severely limited fashion (sl) as one bolus every minutes up to four total, or a moderately limited fashion (ml) as one bolus every minutes up to seven total, to maintain mean arterial pressure ‡ mmhg. comparison of resuscitation regimen and fluid type on survival time was made using two-way anova with interaction and tukey kramer adjustment for individual comparisons. results: there was a significant interaction between fluid regimen and resuscitation fluid type (anova, p = . ) indicating that the response to sl or ml resuscitation was fluid type-dependent. within the lr and hboc+ntg groups, survival time (mean, %ci) was longer for sl, . min ( injuries are common and result from many different mechanisms of injury (moi). knowing common fracture locations may help in diagnosis and treatment, especially in patients presenting with distracting injuries that may mask the pain of a radius fracture.objectives: we set out to determine the incidence of radius fracture locations among patients presenting to an urban emergency department (ed).background: carbon monoxide (co) is the leading cause of poisoning morbidity and mortality in the united states. standard treatment includes supplemental oxygen and supportive care. the utility of hyperbaric oxygen (hbo) therapy has been challenged by a recent cochrane review. hypothermia may mitigate delayed neurotoxic effects after co poisoning as it is effective in cardiac arrest patients with similar neuropathology. objectives: to develop a rat model of acute and delayed severe co toxicity as measured by behavioral deficits and cell necrosis in post-sacrifice brain tissue.methods: a total of rats were used for model development; variable concentrations of co and exposure times were compared to achieve severe toxicity. for the protocol, six senescent long evans rats were exposed to , ppm of co for minutes then , ppm for minutes, followed by three successive dives at , ppm with an endpoint of apnea or seizure; there was a brief interlude between dives for recovery. a modified katz assessment tool was used to assess behavior at baseline and hours, day, and , , , , , and weeks post-exposure. following this, the brains were transcardially fixed with formalin, and lm sagittal slices were embedded in paraffin and stained with hematoxylin and eosin. a pathologist quantified the percentage of necrotic cells in the cortex, hippocampus (pyramidal cells), caudoputamen, cerebellum (purkinje cells), dentate gyrus, and thalamus of each brain to the nearest % from randomly selected high power fields ( x background: there remains controversy about the cardiotoxic effects of droperidol, and in particular the risk of qt prolongation and torsades des pointes (tdp).objectives: this study aimed to investigate the cardiac and haemodynamic effects of high-dose parenteral droperidol for sedation of acute behavioural disturbance (abd) in the emergency department (ed). methods: a standardised intramuscular (im) protocol for the sedation of ed patients with abd was instituted as part of a prospective observational safety study in four regional and metropolitan eds. patients with abd were given an initial dose of mg droperidol followed by an additional dose of mg after min if required. inclusion criteria were patients requiring physical restraint and parenteral sedation. the primary outcome was the proportion of patients who have a prolonged qt interval on ecg. the qt interval was plotted against the heart rate (hr) on the qt nomogram to determine if the qt was abnormal. secondary outcomes were frequency of hypotension and cardiac arrhythmias. results: ecgs were available from of patients with abd given droperidol. the median dose was mg (iqr - mg; range: to mg). the median age was years (rnge: to ) and were males ( %). a total of four ( %) qt-hr pairs were above the ''at-risk'' line on the qt nomogram. transient hypotension occurred in ( %), and no arrhythmias were detected.conclusion: droperidol appears to be safe when used for rapid sedation in the dose range of to mg. it rarely causes hypotension or qt prolongation. blood background: soldiers and law enforcement agents are repeatedly exposed to blast events in the course of carrying out their duties during training and combat operations. little data exist on the effect of this exposure on the physiological function of the human body. both military and law enforcement dynamic entry personnel, ''breachers'', began expressing sensitivity to the risk of injury as a result of multiple blast exposures. breachers apply explosives as a means of gaining access to barricaded or hardened structures. these specialists can be exposed to as many as a dozen lead-encased charges per day during training exercises.objectives: this observational study was performed by the breacher injury consortium to determine the effect of short-term exposure to blasts by breachers on whole blood lead levels (blls) and zinc protoporphyrin levels (zppls). methods: two -week basic breaching training classes were conducted by the united states marine corps' weapons training battalion dynamic entry school. each class included students and up to three instructors, with six non-breaching marines serving as a control group. to evaluate for lead exposure, venous blood samples were acquired from study participants on the weekend prior and following training in the first training class, whereas the second training class had an additional level performed mid-training. blls and zppls were measured in a whole-blood sample using the furnace atomic absorption method and hematofuorimeter method, respectively. results: analysis of these blast injury data indicated students demonstrated significantly increased blls post-explosion (mean = mcg/dl, sd . , p < . ) compared to pre-training (mean = mcg/dl, sd . ) and control subjects (mean = mcg/dl, sd . , p < . ). instructors also demonstrated significantly increased blls post explosion (mean = mcg/dl, sd . , p < . ) compared to pre-training (mean = mcg/ dl, sd . ) and control subjects (mean = mcg/dl, sd . , p < . ). student and instructor zppls were not significantly different in post-training compared to pretraining or control groups. conclusion: the observation from this study that breachers are at risk of mild increases in blls support the need for further investigation into the role of lead following repeated blast exposure with munitions encased in lead. direct observation of the background: notification of a patient's death to family members represents a challenging and stressful task for emergency physicians. complex communication skills such as those required for breaking bad news (bbn) are conventionally taught with small-group and other interactive learning formats. we developed a de novo multi-media web-based learning (wbl) module of curriculum content for a standardized patient interaction (spi) for senior medical students during their emergency medicine rotation.objectives: we proposed that use of an asynchronous wbl module would result in students' skill acquisition for breaking bad news. methods: we tracked module utilization and performance on the spi to determine whether students accessed the materials and if they were able to demonstrate proficiency in its application. performance on the spi was assessed utilizing a bbn-specific content instrument developed from the griev_ing mnemonic as well as a previously validated instrument for assessing communication skills.results: three hundred seventy-two students were enrolled in the bbn curriculum. there was a % completion rate of the wbl module despite students being given the option to utilize review articles alone for preparation. students interacted with the activities within the module as evidenced by a mean number of mouse clicks of . (sd . ). overall spi scores were . %, (sd . ) with content checklist scores of . % (sd . ) and interpersonal communication scores . % (sd . ). five students had failing content scores (< %) on the spi and had a mean number of clicks of . (sd . ), which is not significantly lower than those passing (p = . ). students in the first year of wbl deployment completed self-confidence assessments which showed significant increases in confidence ( . tobackground: pelvis ultrasonography (us) is a useful bedside tool for the evaluation of women with suspected pelvic pathology. while pelvic us is often performed by the radiology department, it often lacks clinical correlation and takes more time than bedside us in the ed. this was a prospective observational study comparing the ed length of stay (los) of patients receiving ed us versus those receiving radiology us. objectives: the primary objective was to measure the difference in ed los. the secondary objectives were to ) assess the role of pregnancy status, ob/gyn consult in the ed, and disposition, in influencing the ed los; and ) to assess the safety of ed us by looking at patient return to the ed within weeks and whether that led to an alternative diagnosis.methods: subjects were women over years old presenting with a gi or gu complaint, and who received either an ed or radiology us. a t-test was used for the primary objective, and linear regression to test the secondary objective. odds ratios were performed to assess for interaction between these factors and type of ultrasound. subgroup analyses were performed if significant interaction was detected. results: forty-eight patients received an ed us and patients received a radiology us. subjects receiving an ed us spent minutes less in the ed (p < . ). in multivariate analysis, even when controlling for pregnancy status, ob/gyn consult, and disposition, patients who received an ed us had a los reduction of minutes (p < . ). in odds ratio analysis, patients who were pregnant were times more likely to have received an ed us (p < . ). patients who received an ob/gyn consult in the ed were five times more likely to receive a radiology us (p < . ). there was no association between type of us and disposition. in subgroup analyses, pregnant and non-pregnant patients who received an ed us still had a los reduction of minutes (p < . ) and minutes (p < . ), respectively. sample sizes were inadequate for subgroup analysis for subjects who had ob/gyn consults. in patients who did not receive an ob/gyn consult, those who received an ed us had a los reduction of minutes (p < . ). finally, % of subjects returned within two weeks, but none led to an alternative diagnosis. conclusion: even when controlling for disposition, ob/gyn consultation, and pregnancy status, patients who received an ed us had a statistically and clinically significant reduction in their ed los. in addition, ed us is safe and accurate. background: although early surface cooling of burns reduces pain and depth of injury, there are concerns that cooling of large burns may result in hypothermia and worse outcomes. in contrast, controlled mild hypothermia improves outcomes after cardiac arrest and traumatic burn injury. objectives: the authors hypothesized that controlled mild hypothermia would prolong survival in a fluidresuscitated rat model of large scald burns. methods: forty sprague-dawley rats ( - g) were anesthetized with mg/kg intramuscular ketamine and mg/kg xylazine, with supplemental inhalational isoflurane as needed. a single full-thickness scald burn covering % of the total body surface area was created per rat using a mason-walker template placed in boiling water ( deg c) for a period of seconds. the rats were randomized to hypothermia (n = ) and nonhypothermia (n = ). core body temperature was continuously monitored with a rectal temperature probe. hypothermia was induced through intraperitoneal injection of cooled ( deg c) saline. the core temperature was reduced by deg c and maintained for a period of hours, applying an ice or heat pack when necessary. the rats were then rewarmed back to baseline temperature. in the control group, room temperature saline was injected into the intraperitoneal cavity and core temperature was maintained using a heating pad as needed. the rats were monitored until death or for a period of days, whichever was greater. the primary outcome was death. the difference in survival was determined using a kaplan-meier analysis or log rank test. results: the mean core temperatures were . deg c for the hypothermic group and . deg c for the normothermic group. the mean survival times were hours for the hypothermic group ( % confidence interval [ci] = to ) and hours for the normothermic group ( % ci = to ). the seven-day survival rates in the hypothermic and non-hypothermic groups were % and %. these differences were not significant, p = . for both comparisons. conclusion: induction of brief mild hypothermia increases but does not significantly prolong survival in a resuscitated rat model of large scald burns. serum objectives: we sought to determine levels of serum mtdna in ed patients with sepsis compared to controls and the association between mtdna and both inflammation and severity of illness among patients with sepsis. methods: prospective observational study of patients presenting to one of three large, urban, tertiary care eds. inclusion criteria: ) septic shock: suspected infection, two or more systemic inflammatory response (sirs) criteria, and systolic blood pressure (sbp) < mmhg despite a fluid bolus; ) sepsis: suspected infection, two or more sirs criteria, and sbp > mmhg; and ) control: ed patients without suspected infection, no sirs criteria, and sbp > mmhg. three mtdnas (cox-iii, cytochrome b, and nadh) were measured using real-time quantitative pcr from serum drawn at enrollment. il- and il- were measured using a bio-plex suspension array system. baseline characteristics, il- , il- , and mtdnas were compared using one way anova or fisher exact test, as appropriate. correlations between mtdnas and il- /il- were determined using spearman's rank. linear regression models were constructed using sofa score as the dependent variable, and each mtdna as the variable of interest in an independent model. a bonferroni adjustment was made for multiple comparisons.results: of patients, were controls, had sepsis, and had septic shock. we found no significant difference in any serum mtdnas among the cohorts (p = . to . ). all mtdnas showed a small but significant negative correlation with il- and il- (q = ) . to ) . ). among patients with sepsis or septic shock (n = ), we found a small but significant negative association between mtdna and sofa score, most clearly with cytochrome b (p = . ). conclusion: we found no difference in serum mtdnas between patients with sepsis, septic shock, and controls. serum mtdnas were negatively associated with inflammation and severity of illness, suggesting that as opposed to trauma, serum mtdna does not significantly contribute to the pathophysiology of the sepsis syndromes. methods: we consecutively enrolled ed patients ‡ years of age who met anaphylaxis diagnostic criteria from april to july at a tertiary center with , annual visits. we collected data on antihypertensive medications, suspected causes, signs and symptoms, ed management, and disposition. markers of severe anaphylaxis were defined as ) intubation, ) hospitalization (icu or floor), and ) signs and symptoms involving ‡ organ systems. antihypertensive medications evaluated included beta-blockers, angiotensin converting enzyme (ace) inhibitors, and calcium channel blockers (ccb). we conducted univariate and multivariate analyses to measure the association between antihypertensive medications and markers of severe anaphylaxis. because previous studies demonstrated an association between age and the suspected cause of the reaction with anaphylaxis severity, we adjusted for these known confounders in multivariate analyses. we report associations as odds ratios (ors) and corresponding % cis with p-values. results: among patients with anaphylaxis, median age (iqr) was ( - ) and ( . %) were female. eight ( . %) patients were intubated, ( %) required hospitalization, and ( %) had ‡ system involvement. forty-nine ( %) were on beta-blockers, ( %) on ace inhibitors, and ( . %) on ccb. in univariate analysis, ace inhibitors were associated with intubation and ‡ system involvement and ccb were associated with hospital admission. in multivariate analysis, after adjusting for age and suspected cause, ace inhibitors remained associated with hospital admission and beta-blockers remained associated with both hospital admission and ‡ system involvement. conclusion: in ed patients, beta-blocker and ace inhibitor use may predict increased anaphylaxis severity independent of age and suspected cause of the anaphylactic reaction. background: advanced cardiac life support (acls) resuscitation requires rapid assessment and intervention. some skills like patient assessment, quality cpr, defibrillation, and medication administration require provider confidence to be performed quickly and correctly. it is unclear, however, whether high-fidelity simulation can improve confidence with a multidisciplinary group of providers with high levels of clinical experience. objectives: the purpose of the study was to test the hypothesis that providers undergoing high-fidelity simulation of cardiopulmonary arrest scenarios will express greater confidence. methods: this was a prospective cohort study conducted at an urban level i trauma center from january to october with a convenience sample of registered (rn) and license practical nurses, nurse practitioners, resident physicians, and physician assistants who agreed to participate in / high-fidelity simulation (laerdal g) sessions of cardiopulmonary arrest scenarios about months apart. demographics were recorded. providers completed a validated preand post-test five-point likert scale confidence measurement tool before and after each session that ranged from not at all confident ( ) to very confident ( ) in recognizing signs and symptoms of, appropriately intervening in, and evaluating intervention effectiveness in cardiac and respiratory arrests. descriptive statistics, paired t-tests, and anova were used for data analysis. sensitivity testing evaluated subjects who completed their second session at months rather than months. results: sixty-five subjects completed consent, completed one session, and completed at least two background: prehospital studies have focused on the effect of health care provider gender on patient satisfaction. we know of no study that has assessed patient satisfication with patient and prehospital provider gender. some studies have shown higher patient satisfaction rates when cared for by a female health care provider.objectives: to determine the effect of ems provider gender on patient satisfaction with prehospital care. methods: a convenience sampling of all adult patients brought in to our ed, an urban level i trauma center by ambulance. a trained research associate (ra) stationed at triage conducted a survey using press ganey ems patient satisfaction questions. there were thirteen questions evaluating prehospital provider skills such as driving, courtesy, listening, medical care, and communication. each skill was assigned a point value between one and five; the higher the value the better the skill was performed. the patient's ambulance care report was copied for additional data extraction.results: a total of surveys were done. average patient age was , and % were female. scores for all questions totaled (mean . ± . ). prehospital providers pairings were: male-male (n = ), male-female (n = ), and female-female (n = ). there were no statistically significant differences in scores between our pairings (mean scores for male:male . , male:female . , and female:female . ; p = . ). we found nonstatistical differences in satisfaction scores based on the gender of the emt in the back of the ambulance: males had a mean score of . and females had a mean score of . (p = . ). we examined gender concordance by comparing gender of the patient to the gender of the prehospital provider and found that male-male had a mean score of . , female-female . , and when the patient and prehospital provider gender did not match, . (p = . ). conclusion: we found no effect of gender difference on patient satisfaction with prehospital care. we also found that overall, patients are very satisfied with their prehospital care. objectives: we set out to determine the sensitivity and specificity of eps in determining the presence of recently ingested tablets or tablet fragments.methods: this was a prospective volunteer study at an academic emergency department. healthy volunteers were enrolled and kept npo for hours prior to tablet ingestion. over minutes subjects ingested ml of water and tablets. ultrasounds video clips were performed prior to any tablet ingestion, after drinking ml of water, after tablets, after tablets, after tablets, and minutes after the final tablet ingestion yielding six clips per volunteer. all video clips were randomized and shown to three eps who were fellowship-trained in emergency ultrasound. eps recorded the presence or absence of tablets.results: ten volunteers underwent the pill ingestion protocol and sixty clips were collected. results for all cases and each rater are reported in the table. overall there was moderate agreement between raters (kappa = . ). sub-group analysis of , , or pills did not show any significant improvement in sensitivity and specificity.conclusion: ultrasound has moderate specificity but poor sensitivity for identification of tablet ingestion. these results imply that point-of-care ultrasound has limited utility in diagnosing large tablet ingestion. background: intravenous fat emulsion (ife) therapy is a novel treatment that has been used to reverse the acute toxicity of some xenobiotics with varied success. us poison control centers (pcc) are recommending this therapy for clinical use, but data regarding these recommendations are lacking.objectives: to determine how us pcc have incorporated ife as a treatment strategy for poisoning. methods: a closed-format multiple-choice survey instrument was developed, piloted, revised, and then sent electronically to every medical director of an accredited us pcc using surveymonkey in march ; addresses were obtained from the aapcc listserv, participation was voluntary and remained anonymous; three reminder invitations were sent during the study period. data were analyzed using descriptive statistics.results: forty-five of ( %) pcc medical directors completed the survey. all respondents felt that ife therapy played a role in the acute overdose setting. thirty ( %) pcc have a protocol for ife therapy: ( %) recommend an initial bolus of . ml/kg of a % lipid emulsion, ( %) pcc recommend an infusion of lipids, and / pcc recommend an initial infusion rate of . ml/kg of a % lipid emulsion. thirty-three ( %) felt that ife had no clinically significant side effects at a bolus dose of . ml/kg ( % emulsion). forty-four directors ( %) felt that the ''lipid sink'' mechanism contributed to the clinical effects of ife therapy, but ( %) felt that there was a yet undiscovered mechanism that likely contributed as well. in a scenario with cardiac arrest due to a single xenobiotic, directors stated that their center would always or often recommend ife after overdose of bupivicaine ( ; %), verapamil ( ; %), amitriptyline ( ; %), or an unknown xenobiotic ( ; %). in a scenario with significant hemodynamic instability due to a single xenobiotic, directors stated that their pcc would always or often recommend ife after overdose of bupivicaine ( ; %), verapamil ( ; %), amitriptyline ( ; %), or an unknown xenobiotic ( ; %).conclusion: ife therapy is being recommended by us pcc. protocols and dosing regimens are nearly uniform. most directors feel that ife is safe but are more likely to recommend ife in patients with cardiac arrest than in patients with severe hemodynamic compromise. further research is warranted. levels drawn at hours or more ( mcg/ml at hours, mcg ⁄ ml at hours, respectively). npv for toxic ingestion of an initial apap level less than mcg/ml was . % ( % ci . - . %).conclusion: an apap level of less than mcg/ml drawn less than hours after ingestion had a high npv for excluding toxic ingestion. however, the authors would not recommend reliance on levels obtained under hours to exclude toxicity as the potential for up to . % false negative results is considered unacceptable. background: genetic variations in the mu-opioid receptor gene (oprm ) mediate individual differences in response to pain and addiction.objectives: to study whether the common a g (rs ) mu-opioid receptor single nucleotide polymorphism (snp) or the alternative splicing snp of oprm (rs ) was associated with overdose severity, we assessed allele frequencies of each including associations with clinical severity in patients presenting to the emergency department (ed) with acute drug overdose. methods: in an observational cohort study at an urban teaching hospital, we evaluated consecutive adult ed patients presenting with suspected acute drug overdose over a -month period for whom discarded blood samples were available for analysis. specimens were linked with clinical variables (demographics, urine toxicology screens, clinical outcomes) then de-identified prior to genetic snp analysis. in-hospital severe outcomes were defined as either respiratory arrest (ra, defined by mechanical ventilation) or cardiac arrest (ca, defined by loss of pulse). blinded taqman genotyping (applied biosystems) of the snps were performed after standard dna purification (qiagen) and whole genome amplification (qiagen repli-g). the plink . genetic association analysis program was used to verify snp data quality, test for departure from hardy-weinberg equilibrium, and test individual snps for statistical association. results: we evaluated patients ( % female, mean age . ) who overall suffered ras and cas (of whom died). urine toxicology was positive in %, of which there were positives for benzodiazepines, cocaine, opiates, methadone, and barbiturates. all genotypes examined conformed to hardy-weinberg equilibrium. the g allele was associated with . fold increased odds of ca/ra (or . , p < . ). the rs mutant allele was not associated with ca/ ra. conclusion: these data suggest that the g mutant allele of the oprm gene is associated with worse clinical severity in patients with acute drug overdose. the findings add to the growing body of evidence linking the a g snp with clinical outcome and raise the question as to whether the a g snp may be a potential target for personalized medical prescribing practices with regard to behavioral/physiologic overdose vulnerability. key: cord- -o hr mox authors: nan title: proceedings of réanimation , the french intensive care society international congress date: - - journal: ann intensive care doi: . /s - - - sha: doc_id: cord_uid: o hr mox nan rationale: expiratory muscles has recently been stated as the «neglected component» in mechanically ventilated patient. several authors stated these muscles importance in cough capacity, contractile efficiency of the diaphragm or reduction of hyperinflation. however, few studies reported potential factors leading to expiratory muscle weakness and its importance on weaning success or survival after mechanical ventilation. patients and methods: this study is a secondary analysis of our previously described cohort of patients ventilated for at least h assessed for respiratory muscles function. maximal expiratory pressure (mep) measurement was carried out during spontaneous breathing trial using a manometer with an unidirectional valve. mep diagnostic accuracy to predict icu-aw (icu acquired weakness), weaning success and sursvival within days were assessed using expiratory muscle strength as absolute values (cmh o), as %predicted values and as %lower limit of normal. results: due to the paucity of data reporting threshold value for expiratory muscle weakness, we considered our median value ( cmh o (iqr )) as the threshold value for expiratory muscle weakness group (mep ≤ cmh o) and normal expiratory muscle group (mep > cmh o). patients with low mep received more catecholamines (p = . ) and a higher duration of mechanical ventilation (p = . ). inversely, higher body mass index was associated with higher mep. patients with low mep presented more icu-aw compared to normal mep patients ( % vs. %; p = . ). no other outcomes were different between groups. mep was statistically able to predict icu-aw but area under (auc) receiving operating curves showed weak predictive ability (auc: . ( % ic . - . ; p < . ) for a threshold value ≤ cmh o. expiratory muscle weakness was unable to predict critical outcomes when adjusting mep to the %predicted or lower limit of normal. discussion: possible explanation is that contrary to inspiratory muscle weakness, cough inefficacy after weaning from mechanical ventilation could be managed with cough supplementation techniques (i.e. mechanical in-exsufflation). conclusion: in our cohort, mep was not associated with mechanical ventilation weaning or death. despite our results, different clinical techniques for quantifying expiratory muscle weakness may provide more beneficial results. compliance with ethics regulations: yes rationale: venoarterial extracorporeal membrane oxygenation (va-ecmo) is used to support tissue perfusion during extracorporeal cardiopulmonary resuscitation (e-cpr). shock, resuscitation and the extracorporeal circuit may trigger a capillary leakage and a vasoplegic shock. currently, in these situations, high doses of norepinephrine (ne) are required. because high ne doses may have significant cardiovascular side effects, alternative options to support arterial blood pressure are needed. in recent years, several approaches to decrease the administration of high ne doses have been tested, one of them is the administration of vasopressin (avp). randomized trials have shown that avp infusion increases arterial pressure and systemic vascular resistance, decreases catecholamine requirements in patients with or at high risk of vasoplegic syndrome and attenuates vascular dysfunction. currently, no data are available for the study of the effects of avp in shock state in post refractory cardiac arrest. patients and methods: pigs were randomized into two groups, in order to receive avp or ne. a refractory cardiac arrest of ischemic origin was surgically created and va-ecmo was started after a min period of cardio-pulmonary resuscitation. then, resuscitation lasted h in each randomization group. the evolution of the consequences of the shock was evaluated by lactatemia and microcirculation (sdf and nirs) at baseline hour, h (when ecmo starts), h and h . renal and hepatic functions were assessed. results: experimental conditions were met for animals (avp, n = ; ne, n = ). the groups were comparable on the shock impact and its severity. no significant differences were found between populations for ecmo flow and map. there was a significant difference on fluid volume resuscitation amount ( [ . - . ] ml in the ne group versus ml in the avp group, p < . ) (fig. ). no significant difference between the ne and avp groups for lactate clearance between h and h ( . [− . to . ]% vs . [ . - . ]%, p = . ). we did not find any significant for sublingual microcirculation indices and nirs values. renal and liver function evolution were similar in the two groups during the protocol. conclusion: avp administration in refractory cardiac arrest resuscitated by va-ecmo when compared to ne is associated with less fluid volume for similar global and regional hemodynamic effects. compliance with ethics regulations: yes. patients and methods: a single-center prospective study. patients younger than months with severe bronchiolitis and supported by niv or hfnc were included. niv/hfnc was discontinued according to the local practices and no protocol existed. exceptt the principal investigator, the attending team was blinded to the study. weaning failure was defined as the need to reinstate niv/hfnc in the h after discontinuation. ethical approval was not necessary for this study in accordance with the french data protection autority methodology reference number mr- . results: a total of patients (median age days, ( %) males) were included. respectively, ( %) and patients ( %) were supported by niv and hfnc at admission (fig. ) . regarding the mode of niv, a bilevel mode was used in patients ( %) (fig. ). in patients supported by hfnc, the ventilatory support was discontinued progressively by decreasing air flow in patients ( %) while it was stopped abruptly in ( %). in patients supported by niv, the respiratory support was stopped abruptly in ( %) of them while hfnc was used as a weaning method for ( %) patients. a total of ( %) patients experienced a weaning failure. patients supported by niv/ hfnc who experienced a prompt weaning had a lower pediatric intensive care unit (picu) length of stay as compared to patients in whom hfnc was used as a weaning method ( ± h versus ± h, p = . ). however, the hospital length of stay was similar according to the weaning method ( ± days versus ± days for prompt and progressive methods respectively, p = . ). the duration of the weaning process did not differ according to the bed-availability in picu. in patients with severe bronchiolitis, a prompt weaning from niv/hfnc was associated with a lower length of stay in picu. however, the hospital length of stay was similar according to the weaning method. we suggest that a prompt weaning should be preferred in order to reduce the risk of picu related complications. compliance with ethics regulations: yes. information and incitation to open a twitter account and to follow critical care journal feeds) or group (control group). ict were interrogated on their recent medical literature knowledge at and month on trials published in pre-selected journals. results: during the study period, on the french ict contacted, agree to participate: were already on twitter, were randomized to twitter incitation and to control group. at month, there were who answered electronic questionnaire. self-declaration of article knowledge was not different between groups (p = . ). knowledge of primary outcome of each trial was not significantly better in groups (p = . ). in per-protocol analysis of ict on twitter or not, knowledge of article and primary outcome were also not significantly different (respectively p = . and p = . ). short incitation to open a twitter account and follow major medical journals with specific focus on cardiac arrest did not improve knowledge of medical literature by intensive care trainees at month. further trials are needed to better imply intensive care trainees in scientific medical literature. compliance with ethics regulations: yes. - . ] ; p = . ) as independently associated with in-hospital mortality ( fig. ). discussion: triple therapy is the recommended first-line treatment of caps. however, herein, it was not significantly associated with better survival in critically ill, thrombotic aps patients. for the subgroup of "definite/probable caps" patients, double and triple regimens were associated with survival. but the bivariable analyses including the day- saps ii showed that survival was linked to in-icu anticoagulation and corticosteroids-not ivig or plasmapheresis. our findings indicate that corticosteroids should probably be added to in-icu anticoagulation to treat "definite/probable caps". frequent fever and elevated c-reactive protein in all thrombotic aps patients suggest a marked inflammatory state that could explain corticosteroid efficacy. neither plasmapheresis nor ivig impacted the prognosis of "definite/ probable caps", but that finding could be explained by a lack of power compared to caps registry data. conclusion: in-icu anticoagulation was the only aps-specific treatment independently associated with survival for all patients. doublebut not triple-therapy was independently associated with better survival of "definite/probable caps" patients. in these patients, double therapy should be used as first-line therapy while the role of triple therapy requires further evaluation. compliance with ethics regulations: yes. motor deficiency ( %) ( %) ( %) . cognitive impairment ( %) ( %) ( %) . intra-individual relationships between Δpdi and tfdi for mechanically ventilated (mv) patients (a) and healthy subjects (c). relationships between Δpdi and tfdi when breathing cycles were averaged for all participants during each condition for mv patients (b) and healthy subjects (d). − %: initial settings minus % inspiratory help, + %: initial settings plus % more inspiratory help, pep : zero positive end-expiratory pressure, sbt: spontaneous breathing trial. healthy subjects performed spontaneousbreathing (sb) and ventilation against inspiratory threshold at , , , and % of maximal inspiratorypressure (mip) groups. airway closure occurrence increased with bmi ( %, % and %, p = . ). when present, airway opening pressure was . cmh o ( . - . ) and similar between the groups. with increasing bmi, total peep increased from . to . cmh o between groups (p = . ). all values of esophageal pressure increased with bmi. endexpiratory esophageal pressure was strongly correlated with bmi (rho = . , p < . ), as illustrated in fig. . consequently end-expiratory transpulmonary pressure decreased from − . to − . cm h o with increasing bmi (p = . ). the ratio of eelv to predicted functional residual capacity was negatively correlated with end-expiratory pressure (rho = − . , p = . ), but not with bmi. driving pressure and elastance of the respiratory system, chest wall and lung were similar across all ranges of bmi. likewise, eelv was similar between groups. conclusion: in ards, increasing bmi is associated with increased occurrence of airway closure and increased values of esophageal pressure. conversely, chest wall elastance is not influenced by bmi, as well as lung elastance. including bmi in interpreting respiratory mechanics in ards patients can provide additional information for the clinical management. compliance with ethics regulations: yes. rationale: low tidal volume is the cornerstone of protective ventilation inthe initial phase of ards ( ) . whether such low tidal volume can still be achieved when the patient is allowed to breathe spontaneously under pressure support ventilation (psv) is unknown. in moderate-tosevere ards patients receiving neuromuscular blockade, we assessed the tidal volume and its potential association with the outcome during the "transition period" following neuromuscular blockade. patients and methods: retrospective observational study in two university intensive care units. patients fulfilling moderate-to-severe ards criteria less than h after intubation and receiving neuromuscular blockers were included upon entry in the "transition period". we defined the "transition period" as the h following neuromuscular blockers cessation. ventilatory and hemodynamic parameters were recorded every h during the "transition period". primary outcome was the association between mean tidal volume under pressure support ventilation (psv) during the "transition period" and the -day mortality after adjustment for confounding factors. data are reported as median [ st- rd quartile] or number (percentage). results: one hundred nine patients were included, with a pao /fio ratio of mmhg at intubation and mmhg at inclusion and a sofa score at [ . - ] . patients had been ventilated days [ - . ] before inclusion. during the "transition period", patients ( . %) were switched to psv. the median duration of psv was h . the mean tidal volume under psv was significantly lower in survivors than in non survivors at day ( . ml/kg [ . - . ] vs. . ml/kg [ . - . ] respectively, p = . ). by multivariate analysis (cox proportional hazards regression model), mean tidal volume during psv remained independently associated with the -day mortality after adjusting for sofa score and immunosuppression. patients with a mean tidal volume above ml/kg under psv during the "transition period" had a lower cumulative probability of survival at day as compared with others (log rank test, p = . ) (fig. ) . conclusion: in patients with moderate-to-severe ards, a higher tidal volume under psv within the h following neuromuscular blockers cessation is independently associated with the -day mortality.compliance with ethics regulations: yes. kaplan-meier estimate of the cumulative probability of survival according to the mean tidal volume (vt)-lower of higher than ml/ kg-under pressure support ventilation (psv) during the "transition period" transfusion is associated with adverse events, and equipoise remains on the optimal transfusion strategy in oncologic patients in surgical setting. patients and methods: this is a retrospective, single center study. all adults admitted to the intensive care unit (icu) after oncologic surgery from january to december were eligible. the following types of surgery for cancer or metastasis resection with a high risk of bleeding were eligible: thoracic, abdominal, neurosurgery, gynecologic, urologic, otorhinolaryngology or spinal surgery. the primary outcome was a composite outcome including post-operative complications (respiratory, cardiac, renal, thromboembolic, infectious and/or hemorrhagic) and/or hospital mortality. results: of the patients included, patients ( . %) had anemia (based on the who definition: hemoglobin level - . g/dl for female; hemoglobin level - . g/dl for male), patients ( %) had moderate anemia (hemoglobin level: - . g/dl) and patients ( . %) severe anemia (hemoglobin level < g/dl). fifty-six patients ( . %) received at least one rbc transfusion during their hospital stay. patients exposed to moderate and severe anemia required more often renal replacement therapy (rrt) for acute kidney injury (aki) ( . % vs. . %; p = . ), had more surgery-related infections ( . % vs. . %; p = . ). patients who received rbc had more often aki with rrt ( . % vs. . %; p < . ), thromboembolic events ( . % vs. . %; p = . ), sepsis ( . % vs. . %; p = . ), pneumonia ( . % vs. . %; p = . ), surgical site infections ( . % vs. . ; p < . ) and second surgery for infection ( % vs. . %; p = . ). the multivariate analysis found an association between moderate and severe anemia (moderate anemia: or . [ . - . ] ; severe anemia: or . [ . - . ]; p = . ) and severe post-operative complications (fig. a) . there was also an association between rbc transfusion and severe post-operative complications ]; p < . ) (fig. b) . conclusion: anemia was frequent in oncologic surgical patients. anemia, including moderate anemia, was independently associated to patient outcomes; however, rbc transfusion also negatively impacts on patients' prognosis. our study highlights the need for further research to identify the optimal hemoglobin threshold for rbc transfusion in surgical oncologic patients. compliance with ethics regulations: yes. rationale: right ventricular (rv) failure is a common complication in moderate to severe acute respiratory distress syndrome (ards). rv failure is exacerbated by hypercapnic acidosis and overdistension induced by mechanical ventilation. veno-venous extracorporeal co removal (ecco r) might allow ultraprotective mechanical ventilation strategy with a low tidal volume (vt) and plateau pressure (pplat). this study investigated if ecco r therapy could have beneficial effects on rv function. patients and methods: this prospective monocentric pilot study was conducted in a french icu from january to march . patients with moderate to severe ards with pao /fio ratio between to mmhg were enrolled. ventilation parameters, arterial blood gases, echocardiographic parameters performed by transthoracic echocardiography (tte), low-flow ecco r system operational characteristics, outcomes and adverse events were collected during the protocol. primary end point was evolution of rv echocardiographic parameters with ultraprotective ventilation strategy at ml/kg pbw during the -h following the start of ecco r. results: eighteen patients were included. efficacy of ecco r allowed an ultraprotective strategy in all patients. we observed a significant improvement of rv systolic function parameters assessed by tte (fig. ). tricuspid annular plane systolic excursion (tapse) increased significantly under ultraprotective ventilation compared to baseline (from . to . mm; p < . ). systolic excursion velocity (s') also increased after -day protocol (from . m/s to . m/s; p < . ). a significant improvement of aortic velocity time integral (vtiao) under ultraprotective ventilation settings was observed. there were no significant differences in the values of systolic pulmonary arterial pressure (spap). when patients were separated in two groups according to baseline paco level above or under mmhg, we showed the deleterious effect of hypercapnia on rv function, and observed in both groups a beneficial impact of an ultraprotective ventilation strategy on tapse. no severe adverse events directly related to ecco r were observed in our small cohort. conclusion: the low-flow ecco r allows ultraprotective ventilation strategy and improve rv function in moderate to severe ards patients. similarly to prone positioning, ecco r could become a strategy that enables to reconcile lung protective approach with rv protective approach in ards patients. large-scale clinical studies, including patients with severe rv dysfunction, will be required to confirm these results and to assess the overall benefits, in particular the best timing of beginning ecco r in ards patients. compliance with ethics regulations: yes. rationale: bronchoalveolar lavage (bal) is usually deemed to allow the diagnosis of a large array of pulmonary diseases and is usually considered as well tolerated in intensive care unit (icu) patients. however, recent data suggest that the diagnostic yield of bal could be rather low ( ) , and may question its innocuity ( ) . the present study aimed at assessing the benefit-to-risk balance of bal in icu patients. patients and methods: the study was approved by the appropriate ethics committee and registered with clinicaltrials.gov (nct ). in icus, from april to october , we prospectively collected adverse events (ae) during or within h after bal and assessed the bal input for decision-making in consecutive adult patients. aes were categorized in grades of increasing severity. the occurrence of a clinical ae at least of grade , i.e. sufficiently severe to need therapeutic action (s), including modification (s) in respiratory support, defined poor bal tolerance. the bal input for decision-making was declared satisfactory if it allowed to interrupt or initiate one or several treatments. results: we included bal in patients (age yrs ; female gender: [ . %]; simplified acute physiology score ii: ; immunosuppression [ . %], chronic pulmonary disease [ / ( . %)]). bal was performed either in non-intubated patients receiving standard o therapy (n = [ . %]), or noninvasive ventilation (n = [ . %]), or high-flow nasal cannula o therapy ( [ . %]), or in patients under invasive mechanical ventilation (n = [ . %]). a total of aes were observed in ( . %) patients. sixty-seven ( . %) patients reached the grade of ae or higher. the main predictor of poor bal tolerance identified by logistic regression was the association of a bal performed by a non-experienced physician (non-pulmonologist, or intensivist with less than years in the specialty or less than bal performed) in non-intubated patients (or: . [ % confidence interval . - . ] ; p < . ). ordinal regression also showed that when bal was performed by a non-experienced physician in a non-intubated patient, this was associated with an increased risk of ae of any grade (or: . [ . - . ]). a satisfactory bal input for decision-making was observed in ( . %) cases and was not predictable using logistic regression. conclusion: adverse events related to bal in icu patients are frequent, and sometimes serious. our findings call for an extreme caution when envisaging a bal in icu patients and for a mandatory accompaniment of the less experienced physicians. compliance with ethics regulations: yes. meningitis is a rare complication of critically ill patients with severe pneumococcal community-acquired pneumonia paul jaubert, julien charpentier, jean-daniel chiche, frédéric pene, alain cariou, guillaume savary, marine paul, jean-paul mira, mathieu jozwiak cochin, paris, france; mignot, versailles, france correspondence: paul jaubert (paul.jaubert@gmail.com) ann. intensive care , (suppl ): rationale: severe pneumococcal community-acquired pneumonia (pcap) is a frequent infection requiring intensive care unit (icu) admission. pneumococcal meningitis associated with pcap has been reported and could worsen the prognosis of patients. however, this complication is difficult to predict and lumbar puncture is not systematically performed, regardless the severity of pcap. thus, we investigated the characteristics of patients with pcap associated with pneumococcal meningitis. patients and methods: we retrospectively included all patients admitted for pcap in our icu between (inception of our electronic medical sheet) and the end of . community-acquired pneumonia was defined according to the criteria of the american thoracic society. we excluded all patients admitted in icu with initial suspicion of meningitis. variables regarding epidemiology, clinical and microbiological characteristics, management and prognosis of these patients were collected and analyzed. results: among the patients admitted for pcap ( ± years old, saps ii ± , % of men), % of the patients required mechanical ventilation and % vasopressors infusion. the icu mortality was %. s. pneumoniae was documented by a positive antigen test in % of the patient and/or by a positive sputum smear, tracheal aspirate or distal protected airway specimen in % of the patients, and/or by pleural aspirate in % of the patients and/or by positive blood culture in % (n = ) of the patients. a lumbar puncture was performed in % (n = ) of the patients with bacteriemia and in % (n = ) of the patients without bacteriemia, with a median delay of h [interquartile range: after the onset of antibiotherapy. alllumbar punctures (n = ) were performed for neurological signs: % of coma, % of confusion and % of seizures. when a lumbar puncture was performed, meningitis was diagnosed in % (n = ) of the patients with bacteriemia and in % (n = ) of the patients without bacteriemia (p < . ). the icu mortality ( % vs. %, respectively), age ( ± vs. ± years old, respectively), saps ii ( ± vs. ± , respectively) or icu length of stay ( ± vs. ± days, respectively) were not different between patients with and without meningitis (each p = ns). conclusion: meningitis is a rare complication of pcap and is more frequent in patients with bacteriemia. suprisingly, meningitis is not associated with higher icu mortality. further analyses are ongoing to identify independent risk factors of meningitis in patients with pcap. compliance with ethics regulations: yes. rationale: shock is the clinical expression of a circulatory failure that results in inadequate cellular oxygen utilization. whereas the host response to septic shock has been extensively described, knowledge of the pathogenesis of non-septic shocks remains limited. we aimed to characterize the systemic host response in shock related to non-septic conditions (nssh) as compared with septic shock (ssh). patients and methods: we performed a prospective study in two intensive care units (icus) in patients admitted for ssh (n = ) or nssh (n = ). immune responses were determined upon icu admission by measuring plasma biomarkers reflecting host response pathways implicated in the pathogenesis of critical illness (in ssh and nssh patients), and by applying genome-wide blood mrna expression profiling (in ssh and nssh patients). results: compared with nssh, patients with ssh had more chronic comorbidities, greater disease severity (apache iv score vs. , p < . ) and worse outcomes resulting in higher mortality rates up to one year after icu admission ( . % vs. . %, p < . ). plasma biomarker analysis revealed severely disturbed host responses in both ssh and nssh patients. however, ssh patients displayed more prominent inflammatory responses, endothelial cell activation, loss of vascular integrity and a more pro-coagulant state relative to nssh patients. blood leukocyte genomic responses were more than % common between ssh and nssh patients relative to health (fig. a) , comprising overexpression of innate pro-and anti-inflammatory pathways, and underexpression of lymphocyte and antigen-presentation gene sets. direct comparison of ssh to nssh patients matched for severity (fig. b) showed overexpression of genes involved in mitochondrial dysfunction and specific metabolic pathways, and underexpression of lymphocyte, nf-κb and cytokine pathways. conclusion: patients with ssh and nssh present with largely similar host response aberrations at icu admission; however, patients with septic shock show more dysregulated inflammatory and vascular host responses, as well as specific leukocyte transcriptome alterations consistent with greatermetabolic reprogrammingand more severe immune suppression. compliance with ethics regulations: yes. rationale: aki is associated with short and long term mortality and morbidity. although recovery has been demonstrated to be associated with outcome of critically ill patients, interpretation of available data is limited by time dependent nature of recovery and by competing risks. our objective was to describe renal recovery, pattern of recovery according to adqi definitions and risk factor of this later. monocenter retrospective cohort study. adult patients admitted in our icu from july to december were included. aki was defined according to kdigo criteria and recovery according to adqi definition. incidence of recovery at each time point was depicted using competing risk survival analysis. risk of transition between aki and no-aki was assessed by a semi-markov model. last, a trajectoire analysis was performed to depict most frequent recovery patterns. results are reported as n (%) or median (iqr). results: patients were included with a median age of ( - ). median sofa score at admission was [ ] [ ] [ ] [ ] [ ] [ ] . at icu admission, patients ( . %) had an aki stage , patients ( . %) an aki stage and patients ( . %) an aki stage . according to adqi criteria, aki was defined as rapidly reversed in patients ( . % of aki patients), persistent aki in patients ( . %) and as acute kidney disease (akd) in patients ( . %), remaining patients couldn't be classified (n = ). risk of recovery was of % per day until day then % per day (fig. a) . fine and gray model, taking into account death as competing risk, identified risk factors negatively associated with renal recovery, namely sofa score (shr = . per point; % ic = [ . - . ]), preexisting hypertension (shr = . ; % ic = [ . - . ]) and aki severity (stage vs. stage shr = . ; % ic = [ . - . ]). risk of de novo aki was maximal during the first days and ranged from to % per day. trajectoire model identified clusters of patients ( fig. b) , closely associated with patients' outcome: a) low patients' severity and no or mild aki (n = ; hospital mortality: %); b) moderate to severe aki but little associated organ dysfunction (n = , hospital mortality: . %); c) severe aki and multiple organ failure (n = ; hospital mortality: . %). conclusion: this study, assessing aki recovery patterns, is the first to our knowledge using adqi definition. despite the high rate of early recovery and of rapidly reversed aki, up to % of aki patients had not recovered at day and could therefore be classified has having akd. compliance with ethics regulations: yes. rationale: sepsis is the most frequent cause of acute kidney injury (aki). the "acute disease quality initiative workgroup" recently proposed new definitions for aki, classifying it as transient or persistent. we aimed to determine the incidence, attributable mortality and host response characteristics of transient and persistent aki in patients with sepsis. patients and methods: we performed a prospective observational study comprising consecutive admissions for sepsis in intensive care units (icus) in the netherlands, stratified according to the presence and evolution of aki. attributable mortality fraction (excess risk for dying with persistent aki relative to transient aki) was determined using a logistic regression model adjusting for confounding variables. in a subset of sepsis patients, plasma biomarkers indicative of major pathways involved in sepsis pathogenesis were measured. in a second subset of patients, whole-genome blood-leukocyte transcriptomes were analyzed. results: sepsis patients were included. aki occurred in . % (n = ), of which . % (n = ) was transient and . % (n = ) persistent. patients with persistent aki had higher disease severity scores on admission than patients with transient aki or without aki and more frequently had severe (injury of failure) rifle aki-stages on admission (n = , . %) than transient aki patients (n = , . %, p < . ). persistent aki, but not transient aki, was associated with increased mortality by day- (adjusted or . , % ci . - . ; p = . ) ( figure) and up to -year (adjusted or . , % ci . - . ;p = . ). the attributable mortality of persistent relative to transient aki by day- was . % ( % ci . - . %). persistent aki was associated with enhanced and sustained inflammatory and procoagulant responses during the first days, and a more severe loss of vascular integrity compared with transient aki. baseline blood gene expression showed minimal differences with respect to the presence or evolution of aki. conclusion: persistent aki is associated with higher sepsis severity, sustained inflammatory and procoagulant responses, and loss of vascular integrity as compared with transient aki, and independently contributes to sepsis mortality. compliance with ethics regulations: yes. rationale: to address the paucity of data on the epidemiology of patients admitted to intensive care units (icus) with in-hospital cardiac arrest (ihca), we examined key features, mortality and trends in mortality in a large cohort of patients admitted in french icus over the past years. patients and methods: from to database of the collège des utilisateurs de bases de données en réanimation (cub-réa), we determined temporal trends in the characteristics of ihca, patients' outcomes and predictors of icu mortality. results: of the icu admissions, ( . %) were cardiac arrests and were ihca ( . %). during the study period, the age of ihca patients increased by . years (p = . ) and patients presented more comorbidities (chronic heart disease, chronic kidney disease and cancer). patients were also more critically ill over the period as reflected by the increase of saps-ii by . % (p < . ). paradoxically, in-hospital management became lighter through the time with reduced respiratory support (p < . ), renal support (p < . ) and use of vasoactive drugs (p < . ). crude in-icu mortality decreased from % to . % over the past eighteen years (p < . ), fig. rationale: in surgery, prophylaxis antibiotic aims at preventing the occurrence of post-operative infections. for adults, it is currently recommended to only use prophylactic antibiotic therapy during the time of the intervention. but in pediatric cardiac surgery, there is no consensus around the optimal duration of use of antibiotic prophylaxis. the protocol was modified in in the icu and its time reduced to h. we aimed to determine whether h of post-sternotomy antibiotic prophylaxis was not less effective than h treatment to help prevent care-associated infections. patients and methods: after agreement of the ethics committee of our institution, we performed a retrospective non inferiority study, with an inferiority margin to %. the primary objective is to compare the incidence of care-related infections between a second-generation cephalosporin (c g) antibiotic prophylaxis during h and a -h protocols. the secondary objectives are to determine the infection's incidence, to identify the risk factors for nosocomial infections and to compare the incidence of multidrug-resistant infections. results: between january and july , children underwent cardiac surgeries with sternal opening. received h of c g antibiotic prophylaxis and received h of c g treatment. five previously infected children have been excluded. both groups were demographically and surgically similar. the median age was months (range a few hours of life to . years old) and the median weight was . kg. in the intent-to-treat analysis, incidence of care-related infections is at . % in the c g- h group and . % in the c g- h group. a multivariate analysis shows that the shorter -h time antibiotic prophylaxis is not inferior regarding infection prevention compared to h of antibiotic prophylaxis, p = . . as in the per protocole analysis, the c g- h group rate was . % and . % for the g g- h group. conclusion: it demonstrates that shortening the antibiotic prophylaxis treatment time to h does not affect or increase the rate of infections after a pediatric sternotomy surgery compared to -h protocole. prophylaxis in pediatric cardiac surgery should be short-lived. a multicenter prospective study would allow a consensus and confirm this decision. compliance with ethics regulations: yes. rationale: the use of "big data" is getting increasingly popular in the medical field, especially in intensive care where large amounts of data are continuously generated. however, big data can be misleading when essential clinical data are missing. the adequate adjustment for potential confounding factors (e.g., severity of respiratory distress) should be the key procedure in the big data analyses; however, it is challenging to capture the clinical severity within large electronic databases. bronchiolitis is one main reason for admission to pediatric intensive care unit (picu). the modified wood's clinical asthma score (mwcas) is widely used to assess the severity of bronchiolitis. the objective of the study is to build an automated mwcas (a-mwcas) to continuously assess the severity of respiratory distress in critically ill children. this retrospective study included all infants < years old with a clinical diagnosis of bronchiolitis, ventilated with non-invasive neurally adjusted ventilatory assist, in a canadian picu, between october and june . we developed an algorithm, using python . , which was directly connected to the electronic medical record. the components of the score were collected using structured query language (sql) queries and processed to derive the a-mwcas. for validation, the a-mwcas score was compared to the mwcas manually computed by a clinical expert (m-mwcas) . results: sixty-four infants were included in the study, for which of a-mwcas and m-mwcas were generated respectively. the cohen's kappa coefficient was applied to estimate the agreement between the two scores which was . ( % confidence interval) ( table ) which corresponds to . % of complete agreement. . % of the a-mwcas scores were within ± . of the m-mwcas. the kappa coefficient for the each score component were: . for the oxygen saturation, . for the expiratory wheezing, . for the inspiratory breath sounds, . for the use of accessories muscles and . for the mental status, respectively. discussion: the largest discrepancy was observed in the mental status, which clinical evaluation is relatively subjective and varies among care team members (doctor, nurse, respiratory therapist…). the automated score likely decreases this variability by consistently using the same source (respiratory therapist), but its validity should be confirmed in a prospective study. the a-mwcas provides a valid estimation of the mwcas that is fast and robust. after external prospective validation, it may help to add some clinical sense within large electronic databases, with improved assessment of the respiratory distress. compliance with ethics regulations: yes. rationale: in paediatric intensive care units (picu), survival rates have dramatically improved. this has been accompanied by increased morbidity, including psychological morbidity. these new impairments, that can affect the survivors and their families have been conceptualized under the frame of post-intensive care syndrome (pics) and picsfamily. the aim of this study was to explore the experience of critically ill children parent's during the stay in picu, and its impact on the family. patients and methods: we planned a prospective, single centre study for months. we collected qualitative written data from parents whose child had been admitted to the picu for the first time, for at least two nights. results: fifty-seven questionnaires were analysed from thirty-seven admissions. picu admissions were mostly unplanned. among parents % experienced very painful memories during admission and % have feared for their child's life. during the stay, noise has bothered % of parents, and many have described difficulties to rest at night. % had the sensation that their child was suffering, mostly from pain, tiredness, anxiety or fear. during picu stay, % of parents had to stop working, and siblings schooling was impacted in % of cases, % of parents considered themselves to be useful for their child and % have participated to nursing care. more than % were satisfied about information given and communication, % appreciated empathy and support from care givers. parents received support from family, friends, and also from other parents of hospitalized children. parents expressed relief ( %) and serenity ( %) to leave picu, % of them were in demand to meet picu staff again after discharge. conclusion: picu parent's experience is tough, and the impact on family is clear. these are known risks factors for pics. on a very positive note, parents seemed to be satisfied by family-centred care, and were able to preserve their parental role. however, there is still room for improvement of practices. compliance with ethics regulations: yes. the gut has been suspected to be involved in multiple organs dysfunction syndrome (mods) in the intensive care unit (icu). studies suggested a link between gastrointestinal dysfunction (gid) and outcomes. but these studies included very few patients and most of them were retrospective. patients and methods: this study is a secondary analysis of data from a previous study that included patients from french icus. gid is defined as the association of vomiting and constipation or diarrhea during the first week after icu admission. patients included were treated with vasopressors and mechanical ventilation. the first goal was to determine if gid is a risk factor of -day mortality in this population. secondary goals were to assess the impact of gid on nosocomial infections. results: among included patients, ( . %) had gid. by day- , ( %) of the patients with gid and ( %) of the patients without gid had died (odds ratio . [ . - . ]; p = . ). multivariable regression model did not show any association between gastrointestinal dysfunction and increased risk of -day mortality in patients (odds ratio . [ . - . ], p = . ). gastrointestinal dysfunction was strongly associated with other secondary outcomes ( table ). patients with gid had longer ventilation duration, icu length of stay and hospital length of stay. they also had more nosocomial infections, in particularly ventilator-associated pneumonia. this association still existed in a multivariable regression model for prediction of nosocomial infection including the same variables than the previous model (odds ratio . [ . - . ], p = . ). no association with day- mortality was observed. conclusion: gastrointestinal dysfunction was not a risk factor of day- mortality but was associated with an increased risk of nosocomial infection and an increased length of stay. this study is observational and no causality link can be done. however, our data suggest further studies on strategies aimed to limit gid. compliance with ethics regulations: yes. rationale: acute cholangitis (ac), a bacterial infection related to an obstruction of the biliary tree, may be responsible for life-threatening organ failure. however, little is known about the outcome and the predictive factors of mortality of critically ill patients admitted in icu for acute cholangitis. we aimed to describe characteristics of patients admitted in icu for ac and to analyze predictive factors of in-hospital mortality including the time to biliary drainage procedure. patients and methods: retrospective study of all cases of acute cholangitis admitted in french icus ( tertiary hospitals and non-ter- [ . ; . ] µg/l. % of patients (n = ) have positive blood culture, mostly gram negative bacilli ( %) and % producing extended spectrum beta lactamase enterobacteriaecae. at icu admission, persisting obstruction was frequent ( %) and therapeutic endoscopic retrograde cholangiopancreatography was performed in % of them. in a multivariable analysis, at icu admission, several factors were significantly associated with in-hospital mortality: sofa score (or = . [ % ic . ; . ] by point, p = . ), arterial lactate (or = . [ . ; . ] by mmol/l, p < . ), total serum bilirubin (or = . [ . ; . ] by umol/l, p < . ), obstruction nonrelated to gallstones (p < . ) and ac complications (liver abcess and/or pancreatitis) (or = . [ . ; . ] p = . ). in addition, time > h between icu admission and biliary drainage was associated to in-hospital mortality (adjusted or = . [ . ; . ] p = . ). conclusion: acute cholangitis is responsible for high mortality in icu. organ failure severity, causes and local complications of cholangitis are predictive factors of mortality as well as delayed biliary drainage. compliance with ethics regulations: yes. the united kingdom) were included (n = ). predictors of one-year mortality were retrospectively screened and tested on a single center training cohort. a predictive score was developed and tested on an independent multicenter cohort. results: four independent pre-transplantation risk factors were associated with one-year mortality after transplantation in the training cohort: age ≥ years (or = . , % ci = . - . , p = . ), pre-transplantation arterial lactate level ≥ mml/l (or = . , % ci = . - . , p = . ), mechanical ventilation with pao / fio ≤ mmhg (or = . , % ci = . - . , p = . ) and pretransplantation leukocyte count ≤ g/l (or = . , % ci = . - . , p = . ). a simplified version of the model was derived by assigning point to each risk factor: the transplantation for aclf- model (tam) score. a cut-off at points distinguished a high-risk group (score > ) from a low-risk group (score ≤ ) with one-year survival of . % vs. . % respectively (p < . ). the model and its simplified version were validated on the independent multicenter cohort. there was a significant difference between the high-risk and low-risk group with one-year survival of % vs. . % respectively (p < . ). conclusion: liver transplantation can be an effective treatment for critically ill cirrhotic patients with hepatic and extra hepatic organ failure provided patients are carefully selected and that they are transplanted at the optimal time in the intensive care. the tam score can help stratify post-transplantation survival and assist clinicians in the transplantation decision-making process at the bedside of aclf- patients. compliance with ethics regulations: yes. rationale: trans-thoracic echocardiography (tte) is commonly used in the initial management of patients with shock in icu. there is little published evidence for any mortality benefit. we compared the effect of echocardiography protocol versus standard care for survival and clinical outcomes. patients and methods: this randomized controlled trial included selected shocked patients (systolic blood pressure < mm hg and signs of organ hypoperfusion) randomized to early tte plus standard care versus standard care without tte. the primary outcome measure was survivalto days. secondary outcome measures included initial treatment and vasopressor weaning. results: consecutive subjects with circulatory shock (low systolic arterial blood pressure (sap) and signs of organ hypoperfusion) at the time of icu admission are included in the study. in the tte group: fluid prescription during the first h was significantly lower rationale: both the negative prognostic value and reversibility of left ventricular (lv) diastolic dysfunction in septic patients remain debated. the excess of mortality in septic shock patients with hyperdynamic profile has only been reported by small-size studies. accordingly, the primary objective of the prodiasys study was to assess the impact of lv diastolic dysfunction (and its severity) and of lv hyperkinesia echocardiographically identified during the initial phase of septic shock on -day survival. the secondary objective was to assess the potential link between lv diastolic dysfunction, cumulative water balance (on day ), and outcome. patients and methods: this was a multicenter, prospective, observational, cohort study. patients older than years hospitalized in icu for septic shock (sepsis- definition) were eligible. exclusion criteria were administration of inotropes, severe left valvular disease, constrictive pericarditis and moribund patients. in each patient, echocardiography was first performed within h after the diagnosis of septic shock and then daily until day , after vasopressor discontinuation, at icu discharge and on day or at hospital discharge, whichever occurred first. vital and biological parameters usually monitored for septic shock management were collected at each echocardiographic assessment. vital status was collected on day . associations between lv diastolic dysfunction or lv hyperkinesia and day- mortality were analyzed using a chi test. adjusted analyses were performed using logistic regression models, including variables known to be linked with the prognosis of septic shock (e.g., severity scores, delay of antibiotherapy). the relationship between the grade (i to iii) of lv diastolic dysfunction and -day survival were analyzed using a logistic regression model. the relationship between the presence of lv diastolic dysfunction and cumulated water balance on day were analyzed using a linear regression model adjusted on the body weight on admission. the relationship between the grade of lv diastolic dysfunction and cumulated water balance on day were analyzed using a linear regression model. diaphragm dysfunction and weaning induced pulmonary edema are two frequent causes of weaning failure but their coexistence and interaction have been poorly investigated. we hypothesized that diaphragm dysfunction may not induce a sufficient decrease in intra-thoracic pressure to increase venous return and generate a weaning induced pulmonary edema. we therefore investigated whether weaning induced pulmonary edema and diaphragm dysfunction are or not associated and evaluated the effect of diaphragm dysfunction on cardiac function and lung aeration during a spontaneous breathing trial (sbt). patients and methods: patients with readiness to wean criteria who had failed a first sbt were eligible. before and after a second sbt, diaphragm function was assessed by measuring the change in tracheal pressure induced by a bilateral phrenic nerve stimulation (ptr, stim), cardiac function (cardiac output, systolic pulmonary arterial pressure) was evaluated with echocardiography and lung aeration was estimated from the lung ultrasound score (lus). plasma protein concentration and hemoglobin were also sampled before and after the sbt. diaphragm dysfunction was defined by ptr, stim < − cmh o and weaning induced pulmonary edema was diagnosed in case of sbt failure associated with ) increase in plasma protein concentration or hemoglobin > % during the spontaneous breathing trial and/or ) early (e) over late peak diastolic velocity ratio > . or e over peak diastolic velocity ratio > . . results: fifty-three patients were included and / ( %) failed the sbt. diaphragm dysfunction was present in / ( %) of patients with weaning induced pulmonary edema, in / ( %) patients with sbt success and in / ( %) patients with other causes of sbt failure (p < . ). during the sbt, diaphragm dysfunction induced a significant increase in systolic pulmonary arterial pressure but no change in cardiac output. patients with diaphragm dysfunction had a higher lus as compared to their counterparts ( ± vs. ± , respectively, p < . ). conclusion: diaphragm dysfunction induces a loss of lung recruitment and a significant increase in systolic pulmonary arterial pressure during the sbt. coexistence of diaphragm dysfunction and weaning induced pulmonary edema is common in case of sbt failure but weaning induced pulmonary edema appears more likely to be involved than diaphragm dysfunction. compliance with ethics regulations: yes. rationale: diaphragmatic weakness in the intensive care unit (icu) is associated with poor outcome. prolonged mechanical ventilation is associated either with a decrease (atrophy) or an increase (supposed injury) in diaphragmatic thickness, both associated with prolonged weaning. shear wave elastography is a non-invasive technique that measures diaphragm shear modulus (sm), a surrogate of its mechanical properties. the aim of this study was to describe the diaphragm shear modulus during the icu stay and to describe its relation with diaphragm thickness. patients and methods: this prospective and monocentric study included all consecutive critically ill patients. ultrasound examination of the diaphragm (aixplorer; supersonic-imagine, aix-en-provence, france) was obtained by two investigatorsevery other day until icu discharge. demographics, diaphragm thickness, sm and outcomes were collected. a mixed model regression was used to study the relation between sm and diaphragm thickness. results: we enrolled patients from december st to june st, being invasively mechanically ventilated during the stay. diaphragm ultrasound evaluation was feasible in / ( %) patients. the duration of mechanical ventilation during the icu stay was [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] days with [ ] [ ] [ ] [ ] [ ] days spent on controlled mechanical ventilation. sm was . ± . kpa and diaphragm end-expiratory thickness was . ± . cm upon icu admission. increase and decrease ≥ % during icu stay occured in and percent of the patients respectively for diaphragmatic thickness, and in and percent of the patients respectively for diaphragmatic sm. diaphragm thickness over time was inversely correlated with diaphragm sm and with time spent under mechanical ventilation (table) . diaphragm sm over time was correlated with time spent under pressure support ventilation or under spontaneous breathing (compared to controlled ventilation) and with time spent under deep sedation. diaphragm sm was inversely correlated with age, sepsis, exposition to steroids (table) . no association was found between diaphragm sm and outcomes. discussion: our results are in line with the myotrauma concept, suggesting alteration in diaphragm mechanical properties associated with increased diaphragm thickness in critically ill patients. we hypothesize that this observation most likely reflects muscle injury and tissue infiltration with edema and inflammatory cells. conclusion: shear wave ultrasound elastography suggests that in critically ill patients, the increase in diaphragmatic mass is associated with an alteration in diaphragm mechanical properties as measured by sm. compliance with ethics regulations: yes. rationale: diaphragm dysfunction and intensive care unit (icu) acquired weakness (icu-aw) are associated with poor outcomes in the icu but their long term impact on prognosis and health-related quality of life (hrqol) is poorly established. this study sought to determine whether diaphragm dysfunction is associated with negative long-term outcomes and whether the coexistence of diaphragm dysfunction and icu-aw has a particular impact on two-year survival and hrqol. patients and methods: we used a previous cohort study conducted in our institution to follow up mechanically ventilated patients in whom diaphragm and limb muscle functions were investigated at the time of liberation from mechanical ventilation. diaphragm dysfunction was defined by tracheal pressure generated by phrenic nerve stimulation < cmh o and icu-acquired weakness was defined by medical research council (mrc) score < . hrqol was evaluated with the sf- questionnaire. results: sixty-nine of the patients enrolled in the original study were included in the survival analysis and were interviewed. overall two-year survival was % ( / ): % ( / ) in patients with diaphragm dysfunction, % ( / ) in patients without diaphragm dysfunction, % ( / ) in patients with icu-acquired weakness and % ( / ) in patients without icu-acquired weakness. patients with concomitant diaphragm dysfunction and icu-acquired weakness had a poorer outcome with a -year survival rate of % ( / ) compared to patients without diaphragm function and icu-acquired weakness ( % ( / ) (p < . )). hrqol was not influenced by the presence of icu-acquired weakness, diaphragm dysfunction or their coexistence. conclusion: icu-acquired weakness but not diaphragm dysfunction has a strong negative impact on two-year survival of critically ill patients. the presence of diaphragm dysfunction appears more likely to be a determinant of early prognosis and does not appear to have a significant impact on long-term survival. compliance with ethics regulations: yes. rationale: influenza can lead to severe condition with acute respiratory failure and acute respiratory distress syndrome due to a massive pulmonary inflammatory in response to the viral invasion. lung bacteriobiota has been described to be associated with pulmonary inflammation in chronic respiratory diseases such as chronic obstructive pulmonary disease or cystic fibrosis. lung mycobiota has been poorly investigated despite the well-known role for fungi in numerous respiratory diseases. the aim of our study was to assess the prognostic value of lung bacteriobiota and mycobiota among critically ill influenza patients. patients and methods: we prospectively included influenza patients admitted to icu. sputum were stored a - °c. bacterial and fungal dna were extracted thanks to qiaamp ® powerfecal ® pro dna kit. s rrna gene v -v regions and its regions were amplified by pcr and sequenced on illumina miseq ® . taxonomic assignation was obtained by dada pipeline and microbiota analysis were performed according to day- mortality by the mean of phyloseq package on r . . software. results: thirty-nine patients were admitted to icu for influenza with sputa available and finally dna samples available after extraction. bacteriobiota alpha diversity was significantly lower among non-survivors than survivors when expressed by the mean of shannon index, simpson index or evenness (respectively p = . , p = . , p = . ). area under the curve to predict day- mortality was . , ci [ . ; . ] for shannon index, . ci [ . ; . ] for simpson index and . ci [ . ; . ] for evenness. β-diversity analysis also demonstrated significant differences between survivors and non-survivors (adjusted permutational multivariate anova, p = . ). nonsurvivors had a higher abundance of staphylococcus, haemophilus, streptococcus and moraxella. none of the fungal alpha-diversity index nor beta-diversity were significantively different between survivors and non-survivors. non-survivors had a higher proportion of candida albicans and malassezia but not of aspergillus. conclusion: the lung bacteriobiota profile, but not the mycobiota one, of critically ill influenza patients is associated with day- mortality and may be used to identify subjects with a poor prognosis at the time of admission. compliance with ethics regulations: yes. that takes into account the interaction between multiple cellular pathways. the pathway profiles between moderate and severe influenza were then compared to delineate the biological mechanisms underpinning the progression from moderate to severe influenza. results: patients ( severe and moderate influenza patients) and healthy control subjects were included in the study. severe influenza was associated with upregulation in several neutrophilrelated pathways, including pathways involved in neutrophil differentiation, migration, degranulation and neutrophil extracellular trap (net) formation. the degree of upregulation in neutrophil-related pathways was significantly higher in severely infected patients compared to moderately infected patients. severe influenza was also associated with downregulation in immune response pathways, including pathways involved in antigen presentation, cd + t-cell co-stimulation, cd + t cell and natural killer (nk) cells effector functions. apoptosis pathways were also downregulated in severe influenza patients compared to moderate and healthy controls. conclusion: these findings showed that there are changes in gene expression profile that may highlight distinct pathogenic mechanisms associated with progression from moderate to severe influenza infection. compliance with ethics regulations: yes. rationale: herpesviridae reactivation among non-immunocompromised critically ill patients is associated with impaired prognosis, especially during acute respiratory distress syndrome (ards). however, few is known about herpes simplex virus (hsv) and cytomegalovirus (cmv) reactivation occurring in patients with severe ards under venovenous extracorporeal membrane oxygenation (ecmo). we tried to determine the frequency of herpesviridae reactivation and its impact on patients'prognosis during ecmo for severe ards. patients and methods: we conducted an observational, retrospective study in a medical icu (ards and ecmo referee center) between and . patients with a severe ards requiring a venovenous ecmo for days or more were included. hsv and/or cmv reactivation occurring after ecmo insertion was screened for these patients. patients with immunosuppression, antiviral therapy against hsv and/ or cmv prior to inclusion, or hsv/cmv reactivation known at the time of ecmo insertion were excluded. hsv reactivation was defined by a positive qualitative throat sample (virocult ® ) pcr or positive bronchoalveolar lavage (bal) pcr. cmv reactivation was defined by a positive quantitative blood or bal pcr. results: during a five-year period, non-immunocompromised patients with a severe ards necessitating a veno-venous ecmo were included. sixty-seven ( %) experienced hsv and/or cmv reactivation during ecmo course ( viral co-infection, hsv alone and cmv alone). hsv reactivation occurred earlier than cmv after the beginning of mv ( ( - ) vs. ( - ) days; p < . ) and after ecmo implementation ( ( - ) vs. ( - ) days; p < . ). in univariate analysis, hsv/cmv reactivation was associated with a longer duration of mechanical ventilation ( ( - . ) vs. . ( - ) days; p < . ), a longer duration of . ) vs. ( - ) days;p < . ), and a prolonged vs. ( - ) days; p < . ) and hospital stay ( ( - . ) vs. ( - ) days; p < . ). however, in multivariate analysis, viral reactivation remained associated with prolonged mv only. when comparing patients having cmv (alone or combined with hsv) vs. hsv reactivation alone, cmv positive patients had a longer mechanical ventilation duration and fewer ventilator-free days at day- and a longer icu and hospital length of stay. conclusion: herpesviridae reactivation is frequent among patients with sevre ards under veno-venous ecmo and is associated with a longer duration of mechanical ventilation. cmv seems to have a proper negative role on pulmonary fiunction as compared to hsv alone. hsv and cmv deserve to be researched in severe ards patients under ecmo. compliance with ethics regulations: yes. charlotte vandueren , benjamin zuber , eve garrigues , antoine gros , nicolas epaillard , guillaume voiriot , yacine tandjaoui rationale: respiratory syncytial virus (rsv) is a common cause of pediatric bronchiolitis and influenza-like illness in adults. its involvement in severe infections in adults remains unclear. the captif study aimed at comparing characteristics and prognosis of icu patients infected with rsv and influenza, assuming that, based on the limited evidence, the mortality of rsv infection would be lower than the influenza related one. patients and methods: multicenter franco-belgian retrospective study. adults admitted to icus between /nov/ and / apr/ with respiratory rsv infection were included and matched : to influenza patients on center and icu admission date. patients' characteristics, clinical presentation, and outcome were compared between groups using univariate and multivariable analyses. results: we report here the results for the first cases among included patients. mean age was . ( . ) years and saps- score was ( ), not different between groups. compared to influenza patients, rsv patients more frequently had chronic respiratory failure ( % vs %, p < . ) or immune suppression ( vs %, p = . ). frequencies of cardiac, renal and hepatic chronic diseases were similar. almost all patients had respiratory symptoms (> %), extrarespiratory symptoms were more frequent in influenza patients ( vs %, = . ). rsv patients more frequently had bronchospasm ( vs %, p = . ). clinical presentation such as ards ( %), shock ( %) and pulmonary coinfection ( %) were similar, however sofa score was higher in rsv patients ( . ( . ) vs . ( ), p = . ). the p/f ratio was around mmhg in both groups, paco was higher in rsv patients ( vs mmhg, < . ). respiratory assistance at diagnosis tended to differ (p = . ), rsv patients receiving more non invasive ventilation ( vs %) and less high flow oxygen therapy ( vs %) but invasive ventilation was required similarly ( vs %). during icu stay, ards was more frequent in rsv patients ( vs %, p = . ), accordingly prone position ( . vs . %) and ecmo ( . vs . %) were more frequently needed. length of mechanical ventilation ( days ( - ) ) and icu los ( days ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ) were not different. icu mortality was similar in rsv and influenza patients ( . % and . %), the multivariate analysis did not find an association between type of virus and mortality. conclusion: rsv infection is frequent in adult icu patients. it presents more frequently than influenza as an acute on chronic respiratory failure with bronchospasm. despite difference in case mix and clinical presentation, vrs severity and burden appear similar to influenza justifying effort to prevent and treat it. compliance with ethics regulations: yes. rationale: mortality in acute stroke patients requiring mechanical ventilation ranges from to % at year. studies evaluating indicators of outcome in these patients have limitations, including singlecenter, retrospective designs and no adjustment for withholding/ withdrawal of life-sustaining treatments (wlst). our objective was to identify factors associated with -year survival in acute stroke patients requiring mechanical ventilation. patients and methods: retrospective analysis of a prospective multicenter database between and . icu stroke patients entered in the database and requiring mechanical ventilation within h were included. were excluded patients with stroke of traumatic origin, subdural hematoma or venous cerebral thrombosis. factors associated with -year survival were identified using a cox model stratified on inclusion center, adjusted on wflst occurring during the first h. data are presented as median [q -q ] or percentages. cox model results are presented as hazard ratios (hr) and % confidence intervals (ci). results: we identified patients from icus, aged [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] years and % males. on admission, the glasgow coma score (gcs) was [ ] [ ] [ ] [ ] [ ] [ ] and the saps score was . types of strokes were ischemic ( %), hemorrhagic ( %) and subarachnoid hemorrhage (sah) ( %). ischemic stroke patients received thrombolysis or thromboaspiration in / ( %) cases, and hemorrhagic stroke/ sah patients received neurosurgery or embolization in / ( %) cases. reasons for endotracheal intubation were coma ( %), acute respiratory failure ( %), seizures ( %), cardiac arrest ( %) and elective procedure ( %). sixty-five ( %) patients received a decision of wflst in the first h. one-year survival year was %. variables independently associated with -year survival were stroke type (ischemic as reference, hemorrhagic hr . (fig. ) . inclusion period ( inclusion period ( - inclusion period ( / inclusion period ( - inclusion period ( / inclusion period ( - or having a stroke unit on site was not associated with -year survival. conclusion: in acute stroke patients requiring mechanical ventilation, the reason for intubation and the opportunity to receive a specific stroke therapy are independently associated with long-term survival. these variables should be integrated in the decision process regarding initiation of mv in acute stroke patients. compliance with ethics regulations: yes. rationale: international guidelines recommend targeted temperature management (ttm) between ° and °c for out-of-hospital cardiac arrest (ca) patients. however, it is unknown if this treatment is effective whatever the severity of the insult. we aimed to examine the association between ttm and long-term neurological outcome according to the risk evaluated at time of admission in intensive care unit (icu) using a dedicated and validated score. patients and methods: we used data prospectively collected in the sudden death expert center (sdec) registry (great paris area, france) between may and december and in the resuscitation outcome consortium-continuous chest compression (roc-ccc) between june and may . we used a modified version of the cardiac arrest hospital prognosis (mcahp) score to assess the risk of poor outcome at icu admission in each of datasets. we finally studied the association between ttm use and long-term neurological prognosis according to mcahp score at icu admission divided into tertiles of severity in each of the datasets. results: there were patients analyzed in the french dataset and in the north-american dataset. the mcahp identified categories: low risk (score < points, % of unfavourable outcome), medium risk ( ≤ score < , % of unfavourable outcome) and high-risk group (score > , % of unfavourable outcome). according to the mcahp score at icu admission, ttm was associated with a better long-term neurological prognosis in patients with low risk (aor = . [ . - . rationale: acute ischaemic stroke is associated with a high risk of mortality, morbidity and healthcare-related costs. over the last decades new treatments, such as thrombolysis and thrombectomy, have been introduced. because of their further improvement, complications have been decreasing. this also led to extending indications for treatment to patients who were previously not eligible. the impact of this evolution on long-term outcome and cost-effectiveness has mainly been assessed in clinical trials and simulation studies. patients and methods: this single-centre retrospective study included patients treated for stroke between january and february . functional outcome at days was assessed by the modified rankin scale (mrs). cost data were retrieved from individual invoices of patients. undiscounted total healthcare costs were calculated for the index hospital stay, capped at days. contribution of cost categories to total costs was analysed. mrs at days was used as a proxy for utilities to define quality-adjusted life years (qalys). multivariate analysis was done for gender, age, charlson comorbidity index, pre-stroke mrs, stroke severity (nihss) and treatment modality (thrombectomy, thrombolysis, thrombectomy + thrombolysis, no intervention). incremental cost-effectiveness ratios (icers), associated to each treatment modality, were calculated. results: no intervention was done in patients ( . %). patients ( . %) required thrombolysis, ( . %) thrombectomy and ( . %) the combination. total costs were mean , eur ) . hospitalisation costs (mean , eur, iqr - , ) represented % of total costs, compared with drug costs ( eur, iqr - ), procedural costs ( eur, iqr - ), honoraria ( eur, iqr - ), lab ( eur, iqr - ) and imaging ( eur, iqr - ). mean total costs differed between treatment modalities: , (iqr - , ) eur for no intervention, , ) eur for thrombolysis, , (iqr , ) eur for thrombectomy and , (iqr , ) eur for the combination (p < . ). drivers for total costs were treatment modality (p < . ) and nihss-stroke severity (p < . ). utility scores were . rationale: emergency endotracheal intubation (eti) in the intensive care unit (icu) often concerns hypoxemic patients with hemodynamic instability. a cardiovascular collapse (cvc) after eti is a life-threatening complication. french guidelines suggested systematic fluid loading prior to eti. our study aimed to predict cvc after eti, while using echocardiography, and to evaluate the impact of fluid loading. patients and methods: a prospective study of consecutive intubations was performed from june to november in three icus. patients were selected if mean blood pressure measurements ≥ mmhg before eti. cvc was defined as mean blood pressure < mmhg within min following eti. four echocardiographic examinations were performed: - min before and - min after eti (or when a cvc occurred); -after passive leg raising; - h following eti. patients were classified as fluid responders when the left ventricular outflow tract velocity-time integral increased by at least % compared with baseline. results: echocardiographic examinations were performed. cvc occurred in / procedures ( %). in cvc group, mean dose of diprivan, used for fast sequence induction, was higher ( . ± mg/kg vs . ± . mg/kg, p = . ). in the cvc group, fluid responsiveness was considered in % patients and left ventricular (lv) systolic dysfunction %. lv diastolic dysfunction did not concern any patient in the cvc group. systolic blood pressure (sbp) < mmhg was the sole independent risk factor for cvc occurrence in multivariate analysis: or . ci % . - . , p = . . fluid responsiveness independent risk factors for cvc patients was sbp < mmhg (or . , ci % . rationale: the autonomic nervous system is highly adaptable and allows the organism to maintain its balance when experiencing stress. heart rate variability (hrv) is a mean to evaluate cardiac effects of autonomic nervous system activity and a relation between hrv and outcome has been proposed in various types of patients. we attempted to evaluate the best determinants of such variation in survival prediction using a physiological data-warehousing program (reastoc clinicaltrials identifier nct ). patients and methods: physiological tracings were recorded at hz from the standard monitoring system (intelliview philips mp ) using the synapse software (ltsi inserm umr ), for a h period, during the h following icu admission. all measurements were recorded while patients were laying in bed, with the head at ° and without any medical intervention. physiological data were associated with metadata collection by a dedicated research assistant. hrv was derived using kubios hrv, in either temporal ( (sdnn), (rmssd) and triangular index (ti)), frequency ( (lf), (hf)), non-linear domains (poincaré plotting) and entropy. results: consecutive patients were recorded between may and april . a lower lf/hf (< . ) and sd /sd (< . ) ratios on admission were associated with a higher icu mortality. multivariate analysis enabled to develop a mortality predictive model (bicus) associating spo /fio and hrv parameters (lf/hf and shannon entropy) with an auc = . (p < . ) for a bicus value > (fig. ) . conclusion: hrv measured on admission enables to predict prognosis in the icu, independently of the admission diagnosis, treatment and mv requirements. bicus may help predict prognosis on a real time basis, using parameters derived from standard routine monitoring. compliance with ethics regulations: yes. rationale: stroke, in the context of type diabetes (t d) is associated with a worse outcome than in non-diabetic conditions, reflected by an increased ischemic volume and more intracerebral hemorrhage. an unbalanced diet is one of major risk for developing t d. we aimed at creating a reproducible mouse model of stroke in impaired glucose tolerance condition induced by high fat diet. patients and methods: adult c bl mice ( male and female) were fed for months with either high fat diet (hfd, % lipids, % proteins, % carbohydrates) or a normal diet (nd, . % lipids, . % proteins, . % carbohydrates) . we used a model of middle cerebral artery occlusion (mcao) by a monofilament for min. oral glucose tolerance test and insulin tolerance test were used for evaluating the pre-diabetic state. mice were euthanized h after reperfusion. systemic inflammation, cerebral infarct volume and hemorrhagic transformation were determined. results: hfd was associated with an increased glycaemia following the oral glucose tolerance test. plasma leptinlevels in stroke conditions were significantly higher in hfd vs nd group. the hfd group presented a significant increase of infarct volume (hfd: . ± . mm vs nd: . ± . mm p = . ) and hemorrhagic transformation (hfd: . ± . vs nd: . ± . p = . ) (fig. ) compared to nd group. discussion: in humans, one of the mechanisms leading to insulin resistance is low-grade inflammation. hfd increases gut permeability, which leads microbiota dysbiosis, thereby promoting metabolic endotoxaemia and a low-grade inflammation state. experimental mouse models available for diabetes studies use leptin receptor deficient mice which develop t d or destruction of pancreatic beta cells by streptozotocine injection (t d). studies using diet-induced insulin resistance models generally feed the mice for weeks or more. however, metabolic disorders could appear earlier such as increase inflammatory markers. in our model, a short exposition to hfd ( weeks) leads to an increase of the pro-inflammatory markers as plasma leptin and a more severe stroke status (infarct and hemorrhagic transformation). conclusion: two months of hfd in adult mice altered hyperglycemia control. this metabolic disorder was associated with significantly higher leptin production, increased infarct volume and hemorrhagic complications than in normal-fed mice. this new model is particularly relevant to study stroke under pre-diabetic conditions induced by hfd. compliance with ethics regulations: yes. eight weeks of hfd increase ischemic volume and hemorrhagic transformation. (a)-infarct volume (v) h after reperfusion, all value are mean ± sem, hfd: v = . ± . mm , n = , nd: v = . ± . mm , n = , *p = . (b)-hemorrhage transformation (ht) score h after mcao. all value are mean ± sem hfd: ht score = . ± . , n = , nd: ht score = . +/+ . , n = *p = . rationale: cardiac arrest (ca), as massive ischemia reperfusion (ir), is an universal health issue. medication taken at the time of the ca could have prognosis consequences. no medication has proven its benefit on ca prognosis. pharmacological pre-or postconditioning aims to reduce ir injury but with disappointing results. metformin (met) is a worldwide-prescribed antidiabetic drug, and several clinical reports plead for a potential protective effect in various settings of sterile and non sterile inflammation, including ir. our hypothesis is that met act as a preconditioning drug against ca-induced ir. patients and methods: retrospective single academic medical center survival study (french west indies) on resuscitated ca in icu (institutional ethical committee approval). data were extracted from medical charts, pmsi, and laboratory dbsynergy ™ software. anonymized data were entered on a excel ™ and transferred to ibm ® -spss ® software (v . . . ) for analysis. univariate study (chi- , fisher exact tests, student-t test, mann-whitney u-test if required) was followed by a multivariate model (odd ratio or and % ic: kaplan-meier estimator and non parametric logrank test-mantel cox model). assuming an overall in-hospital mortality for ca in icu of % with an expected mortality decrease of % by met, the number of patients to be included is . results: the inclusion period was to , with included patients ( diabetic patients among whom took met). the d mortality was % in met+ patients (n = ) versus % in nomet patients (n = ), p < . . comparing alive (n = ) versus deceased (n = ) at d in univariate then multivariate analysis, asystole on the first ekg, number of iterative cardiac arrest,sofa, no-flow, lactate, low-flow and sapsii appear as independent criteria associated with d mortality.conversely, met intake showed up as a protective criterion (or . , ci . - . ). the survival curve, including strata of low-flow duration at the cut-off min, is reported on the fig. . among diabetic patients (n = ), the mortality of patients in the met+ (n = ) was % versus % in the nomet (n = ), p = . . conclusion: in diabetic patients suffering of massive ir related to resuscitated ca, a current treatment by met is associated with a better survival. these results support a protective effect of met and are important to initiate prospective evaluations, because of millions diabetic people around the world and the potential benefit of met. the potential benefit in non diabetic patients and in sterile as well as non sterile inflammation should be addressed. compliance with ethics regulations: yes. rationale: during systemic inflammation, the accumulation of misfolded proteins in the endoplasmic reticulum (er) induces er stress (ers). in animal models, the inhibition of ers reduces inflammatory response and organ failure. cardiopulmonary bypass (cpb) induces a significant systemic inflammatory response but ers expression has never been described in cardiac surgery patients. our objective was to describe the variations of the glucose related protein of kda (grp ), the final effector of the ers, during cpb. patients and methods: we conducted a prospective monocenter study including patients undergoing cardiac surgery with cpb. two samples (paxgene ® tube + edta tube) were taken at three times: before cpb, h after the end of cpb (h -cpb) and h after (h -cpb). after rna isolation and reverse transcription, we performed a quantitative polymerase chain reaction to evaluate the expression of gene encoding for grp and determined the plasma level of grp using enzyme-linked immunosorbent assay. our main objective was to study the variation of grp between pre-cpb and h -cpb samples. our secondary objectives were to evaluate the association of ers with morbi-mortality: organ failure at h (catecholamines and/or invasive ventilation and/or acute renal failure), troponinemia and pao /fio ratio (lung damage control). fig. ). we found an inverse correlation between grp plasma level and troponinemia at h (r = − . ; % ci[− . ; − . ]; p = . ) and a correlation between the pao /fio ratio and grp plasma level at h (r = . ; % ci[ . ; . ]; p = . ). we showed a significant relationship between the variation in plasma concentration of grp and post-operative organ failure after cpb. further studies are needed to better understand the molecular mechanisms of ers in acute inflammatory organ failure in humans. compliance with ethics regulations: yes. patients and methods: in a retrospective monocentric study ( / - / ) conducted in cardio-vascular surgical intensive care unit (icu) in henri mondor teaching hospital, all consecutive adult patients who underwent peripheral va-ecmo were included, with exclusion of those dying in the first h. diagnosis of acute mesenteric ischemia was performed using digestive endoscopy, abdominal ct-scan or fist-line laparotomy. significative results in the univariate analysis were analyzed in a multivariate analysis using logistic regression. results: va-ecmo were implanted. median age was ( - ) years and median . va-ecmo was implanted after a cardiotomy in % of the cases and for a medical reason in % of the cases including % of refractory cardiac arrest. patients characteristics are reported in the table. acute mesenteric ischemia was suspected in patients, with a delay of ( - ) days after ecmo implantation. digestive endoscopy was performed in patients, ctscan in five patients and first-line laparotomy in three patients. acute mesenteric ischemia was confirmed in patients, i.e. an incidence of %. laparotomy was performed in six of the patients, two having a stage i colitis ischemitis with stable conditions and being considered too severe to undergo futile surgery. overall mortality was %. all the patients with acute mesenteric ischemia died in the icu. independent risk factors of developing acute mesenteric ischemia were renal replacement therapy , p = . )) and onset of a second shock state within the first days of icu stay (or . ( % ic . - . , p = . )). conversely, early enteral nutrition was negatively associated with acute mesenteric ischemia (or . ( % ic . - . ), p . ). conclusion: acute mesenteric ischemia is a relatively frequent condition among patients under va-ecmo for cardiogenic shock. its extremely poor prognosis requires low threshold of suspicion. compliance with ethics regulations: yes. ( ). it allows the computation of trans-pulmonary pressure ( ) and can be used to set positive end-expiratory pressure (peep) ( . ) . prone position(pp) can reduce mortality in patients with acute respiratory distress syndrome (ards), but peep selection in pp is controversial. in human ards end-expiratory pes at zero flow (peept,es) was not different between supine (sp) and pp at same peep ( ). as no study measured ppl in sp and pp in ards we aimed at comparing peept,es and end-expiratory ppl at zero flow (peept,ppl) in this condition. our hypothesis was that peept,es was close to dorsal peept,ppl (peept,ppldorsal) in sp and to ventral peept,ppl (peept,pplventral) in pp. in eight female pigs of kgs intubated, sedated, paralyzed and mechanically ventilated, ards was induced by repeated saline lavage until pao /fio < mmhg under fio and peep cmh o. pes was measured by nutrivent catheter. ppl was measured by custom-made pouch sensors inserted surgically into the right anterior and posterior sixth intercostal space. ppl sensors were filled with air. after ards induction animals were randomly assigned to sp or pp. in each position, a recruitment manoeuver was performed and peep decreased from to cmh o by steps of cmh o lasting min each, then the animals were crossed over into the alternate position where the same procedure was done. at the end of each step nonstressed volume and correct position (baydur maneuver) were determined for pes and ppl sensors, then a -s end-expiratory occlusion was performed and pes and ppl recorded. linear mixed model was used to compare the value of pes and ppl at each peep and position. results: box-and-whisker plots of pes and ppl in sp and pp are shown in fig. . there is marked dorsal-to-ventral gradient in ppl at each peep in sp, which is reverted in pp at peep and only. there was no interaction between pressures and peep or position. with increasing peep pes increased significantly from peep in sp and pp. peept,pplventral was significantly lower than peept,es in sp but not in pp. (medtronic) , carescape (ge)) were set in pressure support cmh o, peep cmh o, fio % and equipped with the same double limb ventilator circuit (intersurgical) without any humidification device. asl bench model was set with inspiratory/expiratory resistance (r) and compliance (c) combinations: r / -c , r / -c and r / -c mimicking normal, ards and copd conditions, respectively ( ) . inspiratory effort generated by asl consisted of consecutive breaths obtained from the esophageal pressure in a real patient at the time of a spontaneous breathing trial. for each icu ventilator and rc combination, two steps were performed: in the first, atc was not activated and ventilator attached to asl without ett (atc-ett-); in the second, atc was set on at % compensation for an ett mm id and such an ett (shiley hi contour, covidien) joined icu ventilator to asl (atc+ ett+). the null hypothesis is that vtatc+ ett+ minus vtatc-ett-is . primary end point was the breath by breath paired difference betwen atc+ ett+ and atc-ett-. it was tested to zero for each ventilator in each rc condition. results: median vt was ml. table displays mean (± sd) difference in vt (ml) between atc+ ett+ and atc-ett-: a negative value means that atc under delivers and a positive value that atc over delivers vt for a given patient's inspiratory effort and rc. in four ventilators (c , s , elisa and ) atc almost systematically under delivered vt. in several instances under compensation was greater than % median vt. by contrast atc performed better with the other three ventilators (evita xl, v and carescape ). conclusion: atc tended to under deliver vt. furthermore, there were marked differences between icu ventilators the clinician should be aware of when using the atc option. compliance with ethics regulations: na. rationale: during the last decades, identification of factors associated with ventilation-induced lung injury has led to improved survival in patients with ards. the mechanical power of ventilation is the total energy transmitted from the ventilator to the respiratory system per unit of time and comprises three different components: elastic related to peep, elastic related to tidal volume and resistive. this integrative variable has been recently proposed as an useful predictor of ventilationinduced lung injury and death among ventilated patients. our goal was to determine the respective impact of the total mechanical power and its three components on the outcome of patients with ards. patients and methods: we performed a post hoc analysis of a randomized, controlled study of patients with ards with a pao /fio ratio < . themechanical power at inclusion and averaged on the first days after inclusion (total and its three different components) was computed according to the following equation: powerrs (j/ min) = . respiratory rate tidal volume [peep ( ) + ½ driving pressure ( ) + (peak pressure-plateau pressure) ( )], where the ( ), ( ) and ( ) parts correspond respectively to the elastic related to peep, elastic related to tidal volume and resistive components. the association between each of these four types of mechanical power evaluated during the first days after inclusion and mortality at d was assessed one after the other through multiple logistic regression, allowing control for potential confounding variables at inclusion (age, igs score without age, group of randomization, pao /fio , arterial ph). results: data from patients were analyzed, among which ( . %) died before d . there was no difference concerning the mechanical power at inclusion between survivors and non survivors (either total or its three components). among the four different types of mechanical power tested during the first days after inclusion, the elastic component related to tidal volume was the only one that was independently associated with mortality at d (or . ; % ci . - . ; p = . ) (figure) . conclusion: our study shows that only the elastic component of the mechanical power related to tidal volume independently predicted mortality at d among patients with ards, whereas the total mechanical power, its elastic component related to peep and its resistive component did not. further studies are needed to better define how the mechanical power of ventilation could be useful to synthetize the risk of ventilation-induced lung injury. compliance with ethics regulations: yes. probability of death at d as a factor of mean value (on d -d ) of the elastic component related to tidal volume of the mechanical power. to examine the effect of early-stage mechanical ventilation (mv) on diaphragmatic contractility. in the nd step, if a diaphragmatic dysfunction was detected, we assessed its influence on the weaning from ventilator. patients and methods: we measured prospectively the ultrasounddiaphragmatic thickening fraction (dtf) between groups: a study group versus a control group (n = for each). the study group included all adult patients receiving mv, in whom, the dtf was measured within a minimum of h and a maximum of days of mv. for the control group, were enrolled after their approval for participation, adult volunteers in spontaneous ventilation (sv). patients with factors affecting the diaphragmatic contractility (neuromuscular disease, severe obesity, and neuromuscular blockers…) were excluded. the ultrasound measurements were obtained at the zone of apposition of the right hemithorax. teleinspiratory and telexpiratory diameters (tid/ ted) were taken on the medio-axillary lines: posterior, median and anterior. the dtf was calculated as following: dtf = (tid-ted/ted) x . at the st step, the dtfs were compared and at the nd step: the relationship between dtf and weaning was analysed. results: our groups were comparable in corpulence and co morbidities. the sv group was younger ( vs. years, p < . ) with a predominant female composition. the diaphragmatic exploration concluded that in the mv group, the mean tid tended to be higher but without significant difference ( . + versus . + mm, p = . ), the mean ted was significantly higher ( . + versus . + . mm, p = . ) and dtf was significantly lower ( . + . % versus + . %, p = . ). the ventilation mode had no effect on dtf ( . + % for control volume vs. . + % for psv mode, p = . ). fourteen among ventilated patients had a successful weaning with a mean duration of days. a negative correlation was found close to significance between dtf and weaning duration (rho = − . and p = . ). a dtf value > % wasassociated with weaning success (or = , % ci = [ . - . ] and p = . ) with sensitivity = . %, specificity = %, ppv = % and npv = %. conclusion: the diaphragmatic contractile function was altered from the first days of mv. weaning duration seemed to be negatively correlated with dtf, and a dtf at the first days of mv greater than % was predictive of weaning success. compliance with ethics regulations: yes. rationale: mechanical ventilation is a life-saving treatment that is however associated with lung injury and/or diaphragm dysfunction. the optimal ventilator settings to provide lung protective ventilation while maintaining safe diaphragm activity are difficult to determine. a noninvasive and bedside evaluation of the diaphragm activity could be helpful in this context. the present study investigated whether changes in diaphragm shear modulus (i.e. stiffness, Δsmdi) assessed by ultrasound shear wave elastography (swe) may be used as a surrogate of changes in transdiaphragmatic pressure (Δpdi) in mechanically ventilated patients. patients and methods: patients had to be ventilated for at least h without contraindications for the placement of an oeso-gastric catheter. pdi was monitored continuously and smdi was measured at the zone of apposition of the right hemi-diaphragm, at hz sampling rate. measurements were performed twice under initial ventilator settings and at the end of a weaning trial. pearson correlation coefficients (r) were computed to determine within-individual correlations between pdi and smdi and changes in pdi and in smdi occurring between initial ventilator settings and the end of the sbt were compared by a paired test. results: twenty-five patients were enrolled and displayed a significant correlation between Δsmdi and Δpdi (mean r = . , range = . - . , all p < . ) (fig. a ). compared to their counterparts, patients with significant within correlations had a lower respiratory rate ( . ± . vs . ± . breath/min. respectively; p < . ) and a significant increase in Δsmdi ( . ± . kpa vs . ± . kpa. p < . ) between initial ventilator settings and the sbt. patients without Δsmdi-Δpdi correlation only displayed an increase in Δpdi ( . ± . vs . ± . cmh o, p < . ) at the end of the sbt with no concomitant significant increase in Δsmdi ( . ± . kpa vs . ± . kpa, p > . ). (fig. b) . conclusion: smdi obtained by swe appears as a promising technique to assess diaphragm activity in mechanically ventilated patients but technological improvements are necessary to increase swe sampling rate before enabling its generalization in the icu. compliance with ethics regulations: yes. rationale: end-inspiratory (eip) and end-expiratory (eep) pauses are commonly used during volume assist control ventilation to assess plateau pressure and total positive end-expiratory pressure (peeptot). they can also be used during assisted ventilation (av) for muscle pressure assessment. it requires ventilators able to perform eip during av. plateau pressure (pplat) usually increases in av during eip due to "hidden" inspiratory effort. pressure muscular index (pmi) is equal to pplat minus the sum of peeptot (measured during an eep) and set pressure support (ps); it theoretically reflects patient's effort without esophageal pressure (pes) monitoring. pes is the gold standard method to assess inspiratory muscle pressure (pmus, difference of pes drop at neural end-inspiration and correction factor for chest wall elastance and tidal volume). we aimed to illustrate the feasibility of measuring pmi using a standard icu ventilator at the bedside and study the correlation between pmus and pmi. patients and methods: measurements were recorded in icu patients. pes was measured using an nasogastric probe (equipped with an esophageal balloon) inserted for advanced monitoring (severe acute respiratory distress syndrome-ards) or for a study protocol (difficult weaning after copd exacerbation). recorded eip, eep and pes were used for post hoc analyses. results reported as ranges and median [iqr] . correlation between pmus and pmi tested with spearman correlation test. results: out of eip and eep duos could be analyzed ( -esophageal spasm/ -calibration error). ventilator mode was pressure support ventilation (ps - cmh o). cmh o, pmus = . [ . - . ] cmh o, pmi = . [ . - . ]. for all recordings, spearman r coefficient between pmus and pmi was . (p = . ). conclusion: muscular effort can be assessed in av using eip and eep using icu ventilators. however, recordings can be influenced by expiratory muscles contraction. patient's ability to follow directions during the maneuvers is an important factor to obtain reliable values. there seem to be a correlation in our small sample between muscular pressure assessed without and with pes. compliance with ethics regulations: yes. rationale: severe pneumonia can culminate in acute respiratory distress syndrome (ards). an uncontrolled inflammatory response is a key feature favoring transition towards ards. however, the underlying mechanisms remain poorly understood. in this context, the contribution of "innate t cells" (itc) -a family of non-peptide reactive t cells comprising nkt cells, mucosal associated invariant t (mait) cells and γδt cells-has never been explored. itc have emerged as key players in orchestration of the host response during infections and inflammation processes. for these reasons, these cells are already seen as potential therapeutic targets in other medical fields (especially oncology). here, we hypothesized that a tight regulation of their functions could be paramount to control the inflammatory response and to prevent ards development. patients and methods: to explore this, we combined a murinemodel of influenza a virus (iav) infection mimicking ardssymptoms and a clinical study recruiting patients admitted in icu for severe pneumonia. using flow-cytometry approaches, we investigated ( ) the abundance and dynamics of itc in various compartments, ( ) their pattern of activation/regulation markers (respectively cd and pd- ) and ( ) their cytokine production. results: during experimental iav pneumonia, itc were transiently recruited into the airways. unlike γδt and nkt, mait cells phenotype was largely changed, displaying a progressive cd overexpression and increased il- a production. during the resolution phase, up to % of pulmonary maits expressed pd- (versus < % in controls), which can suggest emergence of regulatory functions. last, using gene-targeted mice, we suggested that mait cells confer a protective effect during pneumonia. in the ongoing clinical study, the proportion of circulating mait cells in patients was markedly decreased compared to controls ( . ± . % versus . ± . % of t cells), but not for nkt or γδt cells. notably, some patients with severe ards presented detectable levels of maits in their respiratory fluids. in addition, circulating mait cells in patients overexpressed cd and pd- ( . % and % respectively), but with a reduced proportion able to produce il- and ifnγ, compared to healthy controls. lastly, proportion of activated (cd +) mait cells significantly decreased with clinical improvement. conclusion: this translational approach combining in vivo animal experiments and clinical samples with ex vivo experiments indicates a preferential modulation in mait cells functions during severe pneumonia. these data justify an in-depth analysis of mait cells activation mechanisms and functions in this context, in order to further explore a potential use as a disease-progression marker and -in a long term perspective-as a potential therapeutic target. compliance with ethics regulations: yes. representative flow-cytometry dot-plots of mait cells labelling using fluorophore-conjugated mr tetramers loaded with -op-ru from lungs of an infected mouse (a) and blood sample of a patient with pneumonia (b). c: frequency of mait cells, proportion of cd and pd- + mait cells in bronchoalveolar lavage during experimental murine pneumonia. d: blood frequency of mait cells in patients with pneumonia compared with healthy controls (as % of total t cells) rationale: immune paralysis following hyperinflammatory states increases the risk of secondary infections and death. reversing t-cells exhaustion using recombinant il or immune checkpoints inhibitors may improve the prognosis of patients with sepsis admitted to the icu. however, there is an unmet need to better characterize the state of t-cells exhaustion in these patients, its reproducibility and its correlation with the outcomes before implementing immunotherapy in the therapeutic armamentarium against sepsis. patients and methods: prospective observational cohort study performed in two tertiary-care icus in a university hospital. peripheral blood mononuclear cells were collected at day in adult patients with sepsis admitted to the icu. the level of cd + and cd + t-cells exhaustion was quantified using multi-color flux cytometry targeting the following exhaustion markers: pd- , b and cd . cd + regulatory t-cells (cd + cd + cd hi cd lo cells) were also assessed. results: the patients included in the study could be split in five clusters according to their dominant pattern of exhaustion markers on cd + t-cell (i.e. no markers, pd- +, b +, b + cd + and b + pd- +) and independently of their underlying morbidities. no patients harbored a fully exhausted triple-positive pattern. by multivariate analysis, saps gravity score at day (p = . ), a dominant b and/or pd- cd + pattern (p = . ) and lung sepsis (p = . ) where associated with the risk of death at day , whereas hemoglobin level was associated with survival (p = . ). no cd + or cd + exhaustion pattern independently predicted the risk of secondary infections. neither the level of cd + regulatory t-cells nor the dominant cd + exhaustion pattern was associated with the outcomes. rationale: there is growing use of multiplex polymerase chain reaction (mpcr) for respiratory virus testing in patients with communityacquired pneumonia (cap). data on one-year outcomes in patients with severe cap of bacterial, viral and unidentified etiology are scarce. patients and methods: a single-center retrospective study was performed in intensive care unit (icu) patients with known one-year survival status who had undergone respiratory virus testing for cap by mpcr. one year after icu admission, mortality rates and functional status were compared in patients with cap of bacterial, viral or unidentified etiology. results: there were ( . %) patients in the bacterial group, ( . %) in the viral group and ( . %) with unidentified etiology. one-year mortality was . % (n = / ), % (n = / ) and . % (n = / ), respectively (p = . ). in multivariate analysis, one-year mortality was higher in the bacterial group than in the viral group (hr . , % ic . - . , p = . ), had a trend to be higher in the bacterial group compared to the unidentified etiology group (hr . , % ic . - . , p = . ) and was not different between the viral and unidentified etiology groups (hr . , % ic . - . , p = . ). severe dyspnea (mmrc score = or death), major adverse respiratory events (new homecare ventilatory support or death) and severe autonomy deficiencies (adl katz score ≤ ordeath) were observed in / ( . %), / ( . %) and / ( . %) patients, respectively, with no difference between groups. conclusion: cap of bacterial origin was associated with a poorer prognosis than viral or unidentified etiology. impaired functional status was observed in a substantial proportion at one-year, irrespective of the causative microorganisms involved. compliance with ethics regulations: yes. interest of unyvero multiplex pcr (curetis) for bal rapid microbiologic and antibiotic susceptibility documentations in immunocompromised patients under antibiotic therapy jean-luc baudel , jacques tankovic , redouane dahoumane , salah gallah , laurent benzerara , jean-remy lavillegrand , razach abdallah , geoffroy hariri , naike bige , hafid ait-oufella , nicolas veziris , eric maury , bertrand guidet rationale: our aim was to evaluate the interest of the unyvero rapid ( . h) multiplex pcr assay (performed on bronchoalveolar lavage [bal] samples) for the management of immunocompromised patients already treated with antibiotics and diagnosed with pneumonia (according to clinical and radiological findings). we thus performed an observational study that compared the results (and the length of time to obtain them) of routine microbiological evaluation and unyvero assay. patients and methods: from july to january and from april to august , we examined bal samples from immunocompromised patients (coming from hematology, oncology, hepatology, gastroenterology, internal medicine, and neurology units) diagnosed with pneumonia (based on clinical and radiological findings), and already receiving antibiotic treatment. the following data were collected: age, gender, saps score, lung ct scan ( %) or x-ray ( %) results, duration and content of prior antibiotic therapy, direct examination, culture, antibiogram and unyvero results, secondary confirmation of pneumonia or not, possible changes in antibiotic therapy that could have been made after obtention of unyvero results. informed consent was obtained from all patients. results: bal samples were analyzed in immunocompromised patients (m/f ratio . , saps . ± . ) mostly with hematologic ( %) or oncologic ( %) diseases. the patients received either corticosteroids ( %), or chemotherapy ( %), or immunotherapy ( %). % of the patients were under mechanical ventilation, % under optiflow. % presented a shock, % had aplasia or neutropenia, % were allografted, % were autografted. the duration of prior antibiotic therapy at the time of bal were . ± . days. direct examination was positive in . % of the cases, culture (both above and under the classical threshold of cfu/ml) in %, unyvero in . %. a retrospective analysis of all the cases confirmed the initial diagnosis of pneumonia in only % of the cases. compared to culture, the sensitivity of unyvero was %, its specificity %. unyvero could permit to rapidly deescalate antibiotic therapy in % of the cases and to rapidly stop it in %. the unyvero assay on bal samples is useful in this specific population for rapid obtention of microbiological results and also for confirmation of the negativity of cultures and thus permits a better management of antibiotic therapy, leading to a reduction of antibiotic resistance selection pressure in the icu. compliance with ethics regulations: yes. do not underestimate rsv pneumonia among critically ill patients erwan begot , suzanne champion , charline sazio , benjamin clouzeau , alexandre boyer , hoang-nam bui , marie-edith lafon , camille ciccone , julia dina , didier gruson , renaud prével chu bordeaux, medical intensive care unit, bordeaux, france; chu bordeaux, virology laboratory, bordeaux, france; national reference center for measles mumps and rubella, chu de caen, caen, france correspondence: erwan begot (erwan.begot@chu-bordeaux.fr) ann. intensive care , (suppl ):f- rationale: respiratory syncitial virus (rsv) is a well-known cause of respiratory failure among neonates but its pathogenicity in adults is now emerging as a potential cause of viral pneumonia. data are limited with conflicting results regarding rsv pneumonia severity in adults. data are lacking about critically ill rsv patients' characteristics and outcomes. the aim of this study is to compare rsv patients' characteristics, care and outcomes to influenza patients' ones. patients and methods: patients diagnosed with rsv and influenza pneumonia admitted to our medical icu were included. data were retrospectively recorded. quantitative data are expressed by median and interquartile range and compared by use of mann-whitney test. qualitative data are expressed by number and percentages and compared by use of fischer exact t-test. rsv strains were prospectively collected. results: eighteen critically ill patients with rsv pneumonia and with influenza pneumonia were included. rsv and influenza patients had the same characteristics at admission except for age (respectively yo [ ; ] and acute respiratory distress syndrome rates (respectively / ( %) vs / ( %), p = . ). they received similar treatment as suggested by oro-tracheal intubation rates (respectively / ( %) vs / ( %), p: . ) and antibiotics prescription (respectively / ( %) vs / ( %), p: . ). rsv and influenza patients also had the same rates of bacterial co-infections ( / ( %) vs ( %), p: . ). invasive aspergillosis remained a rare event but also occurred among rsv patients ( / ( %) vs / ( %), p: . ). acute coronary syndromes were as frequent in both groups (respectively / ( %) vs / ( %), p = . ). day- mortality was similar between rsv and influenza patients (respectively / ( %) rationale: respiratory distress from seawater drowning is commonly considered multifactorial. etiologies are debatable and include heart failure, infection and acute respiratory distress syndrome (ards). documented bacterial infections seems mostly related to the site of drowning. data in this regard are scarce with prospective studies lacking. the objective of our study was to describe prospectively the characteristics and determinants of respiratory distress from seawater drowning. patients and methods: all patients admitted for seawater drowning to seven intensive care units (icu) on the french riviera in the summers of and were prospectively included. recorded data included clinical features on examination, personal history, chest x-rays, echocardiography and biological results obtained within the first h. a paired student's t-test was used to study statistical differences between quantitative variables on admission and during early evaluation (i.e. first h). results: forty-eight patients were admitted to seven centers of which ( %) were diagnosed as having ards, ( %) early pneumonia and ( %) acute cardiogenic pulmonary edema. twenty-one ( %) respiratory samples were collected but bacterial culture was positive in only cases. multidrug-resistant bacteria were not observed, and amoxicillin-clavulanate as first-line treatment was effective in all cases. echocardiography performed in ( %) patients was normal and unable to identify specific patient profiles. the median clinical pulmonary infection score (cpis) on admission was (iqr, - ) and decreased rapidly and significantly (p < . ) within h to (iqr, - ) (fig. ) . conclusion: data from this multicenter cohort suggest that respiratory distress following seawater drowning can mimic bacterial pneumonia during the first h with subsequent rapid clinical improvement in patients admitted to the icu. probabilistic antibacterial therapy should therefore be limited to the most severe patients. isolate ards is often the only etiology found and is resolutive within h. this prospective cohort is the largest of its kind and gives a better insight into the limited impact of cardiogenic and infectious processes on sea drowning-related respiratory distress. compliance with ethics regulations: yes. rationale: patients treated with "extracorporeal membrane oxygenation" (ecmo) are at a higher risk of developing nosocomial infections and they are consequently often treated with beta-lactams. french guidelines recommend obtaining beta-lactam trough concentrations above four times the minimal inhibitory concentration (mic) of the causative bacteria. the ecmo device may alter the pharmacokinetics of these medications, which may result in underexposure to beta-lactam antibiotics. patients and methods: this observational, prospective, multicenter, case-control study was performed in the intensive care units of two tertiary care hospitals in france. ecmo patients with sepsis treated with piperacillin-tazobactam were enrolled. control patients were matched according to sofa score and creatinine clearance. the pharmacokinetics of piperacillin was described based on a population pharmacokinetic model, allowing to calculate the time spent above × the mic breakpoint for pseudomonas aeruginosa susceptibility after the first dose and at steady state between two piperacillin infusions. results: forty-two patients were included. the median age was years [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] , the sofa score was [ ] [ ] [ ] [ ] [ ] [ ] , and median creatinine clearance was ml/min . there was no significant difference in the time above x mic in patients treated with ecmo and controls during the first administration (p = . ) and at steady state (p = . ). there was no significant difference between the trough at steady state (p = . ), with / patients ( %) exhibiting concentrations of piperacillin lower than x mic. ecmo support was not associated with a steady state trough concentration below x mic (or = . [ . - . ], p = . ). the only variable independently associated with this risk was a creatinine clearance ≥ ml/min, (or = . [ . - . ], p = . ). conclusion: ecmo support has no significant impact on piperacillin exposure. intensive care unit patients with sepsis are, however, frequently underexposed with piperacillin, which suggest that therapeutic drug monitoring should be strongly recommended for severe infections. impact of a visual support dedicated to prognosis of patients on symptoms of stress of family members rationale: family members commonly have inaccurate expectations of patient's prognosis. adding to classic oral information a visual support, depicting day by day the evolution of the condition of the patient, improves the concordance in prognosis estimate between physicians and family members. the objective of this study was to evaluate the impact of this support on symptoms of anxiety/depression of family members. patients and methods: we conducted a bi-center prospective beforeafter study. all consecutive patients admitted in the two icus were eligible. in the before period ( months), family members received classic oral information. in the after period ( months) , in addition to classic oral information, the visual support ( fig. ) was available for family members in the patient's room from the day of admission until discharge from the icu. at day and from admission, symptoms of anxiety/depression of referent family member were evaluated by hospital anxiety and depression scale (hads). results: patients and their referent family members were included ( in period before and after). characteristics of patients of the two groups were similar regarding age, reason for admission, saps ii at admission and sofa score at day . also characteristics of referent family members were comparable in terms of age, sex ratio, type of relationship with the patient and number of visits since admission. at day , total had score was [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] in the group before without the support and [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] in the group after with the support (p = . ). the prevalence of symptoms of anxiety (had-a score > ) and depression (had-d score > ) was similar in the two groups (respectively . % and . % in the group before, and . % and . % in the group after (ns)). at day , total had score was in the group before [ - ] and [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] in the group after (p = . ). by multivariate analysis the following factors were significantly associated with total had score > at day : age of patient ]), number of visits of referent ) and previous or current treatment of referent for anxiety or depression . ]). conclusion: in this study, the use of a visual support dedicated to prognosis of patients did not modify the level of stress of family members. compliance with ethics regulations: yes. rationale: the use of sedation and opioids at the end of life is a topic of considerable ethical debate. incidence of discomfort during the end-of-life of icu patients and impact of sedation on discomfort are poorly known. patients and methods: post-hoc analysis of an observational prospective multicenter study comparing terminal weaning vs. immediate extubation for end-of-life in icu patients, aimed at assessing the incidence of discomfort events according to levels of sedation. discomforts including gasps, significant bronchial obstruction or high behavioral pain scale score, were prospectively assessed by nurses from mechanical ventilation withdrawal until death. level of sedation was assessed using the richmond agitation sedation scale (rass). results: among the patients included in the original study, ( %) experienced discomfort after mechanical ventilation withdrawal. patients with discomfort received lower doses of midazolam and equivalent morphine, and less frequently had deep sedation (rass - ) than patients without discomfort ( % vs %, p < . ). after multivariate logistic regression, immediate extubation was the only factor associated with discomfort whereas deep sedation and administrations of vasoactive drugs were two factors independently associated with no discomfort. death occurred less rapidly in patient with discomfort than in those without discomfort ( . h [ . - . ] vs . [ . - . ], p < . ) (figure) . long-term evaluation of psychological disorders in family members of dead patients did not differ between those with discomfort and the others. discussion: despite the theoretically expected anticipatory titrated doses of opioids and benzodiazepines to alleviate any discomfort after withdrawal of mechanical ventilation, half of the patients did not receive sedation or opiate when the decision to withdraw mechanical ventilation was taken. a major point that could interfere with the continuous deep sedation practice until death is the fear of potentially hastening death, and there is much controversy regarding its proper use in end-of-life care. conclusion: discomfort was frequent during end-of-life of icu patients and was mainly associated with terminal extubation and less profound sedation. compliance with ethics regulations: yes. rationale: bereavement in intensive care unit (icu) is associated with psychiatric disorders on relatives called post-intensive care syndrome family (pics-f). no isolated intervention (such as condolence letter) has shown a positive effect on these disorders, despite a well acceptance by relatives. we thought that a more integrated bereavement program should be considered. the goal of this study is to evaluate a combined psychologist-physician post-death meeting (pdm) in a bereavement program to evaluate needs and adhesion of relatives, and the effect on symptoms of anxiety and depression. patients and methods: monocentric, prospective study focused on relatives of patient admitted > h and deceased in icu. during patient's stay, relatives' presence was allowed on a h-basis and they could meet a clinician psychologist. formal meeting between relatives and the staff was realized at patient's admission and after important decision-making treatment. two weeks after patient's death, the psychologist called relatives to offer emotional support and to invite to a pdm. pdm occurs weeks after patient's death with the psychologist and the physician in charge of the patient. the objectives of the meeting were to provide emotional support, to answer medical question, and to detect symptoms of anxiety and/or depression with the hospital anxiety and depression scale (hads). we hypothesized that pmd would be able to alleviate pics-f at months. we aimed to enroll families to detect a % lowering of hads. results: the rate of pdm acceptance was lower than expected. after inclusions, only relatives accepted the pdm, whereas the phone call was well perceived ( %). main association with acceptance of pmd was a short duration of icu stay ( . days [ - . ] vs . days [ . - . ] p = . ) and icu admission for acute respiratory failure ( . % vs . %, p = . ) ( table ) . we found no relation between the number of in icu meeting (psychologist of medical staff) and pmd acceptance. for relatives who accept pmd we found a high proportion of symptoms of anxiety and depression ( % and %) with a hads at . [ - . ] (median, iqr). no evaluation was performed at months. conclusion: post death contact appears well perceived by relatives but pmd quite useless. this result may be explained by the inclusion of only late death (> h) where psychologist and medical staff had the opportunity to support relatives. further study should focus on early death (< h). compliance with ethics regulations: yes. rationale: pediatric intensivists frequently question themselves on the issue of limitation or termination of life-sustaining treatments (llst) carried out on children. such a decision comes under the claeys-leonetti law which forbids doctors from applying unreasonable treatment however, every so often, parents oppose themselves to a collegial llst decision that the medical and paramedical team had taken. such cases can even end up in court. in order to sort out this problem, this study focused on the factors that underlie the disagreement and the solution brought forward by pediatricians whenever parents demand to persue treatments although considered as unreasonable obstinacy. patients and methods: we carried out a qualitative study involving three multipurpose pediatric critical care unit. all pediatricians operating within these units were contacted. those who volonteered were met individually for a semi-directed interview. every interview was recorded and entitled to a complete hand-written retranscription. the interviews were analysed following the phenomenological interpretive analysis method and were subject to dual listing. results: pediatricians out of took part in the study. / claimed they would increase treatments or carry out cardiopulmonary resuscitation acts if asked to do so by parents, even if this went against the initial collegial decision. / claimed they would persue treatments although not beyond the current level. / said they would oppose themselves to parents concerning blood transfusion for comfort reasons. several key factors were identified as leading a doctor to the non-application of a llst decision: the certainty regarding the child's death on a short or mid-term basis ( / ), the litigiousness risk ( / ), the apprehension of mediatic pressure ( / ), the fear of a violent reaction from parents ( / ), other self-interest positions within the medical team ( / ), empathy towards parents ( / ), the uncertainty concerning the neurological prognosis ( / ), the lapse of time needed to fully accept the application in force of a decision ( / ). pediatricians out of admitted their own-suffering when confronted to the situation. conclusion: this study points out that pediatricians tend to follow parents' position when confronted to parental opposition. in such situations, pediatricians go against their own decision in order to safeguard the parental alliance even if it leads to unreasonable obstinacy, thus conflicting with medical deontological code obligations. compliance with ethics regulations: yes. rationale: end-of-life management strategies are clearly a worldwide issue of major importance that intensivists have to deal with on a daily basis. advance directives may be the solution sought to guide physicians to take such difficult decisions. yet, health care directives are not legislated in tunisia. the objective of this project was to draw a general descriptive overview to assess patients' wishes in tunisia. patients and methods: data were collected from a -item-questionnaire based on the french intensive care society's form for advance directives which was filled by people of general population in tunisia, including doctors and paramedics, from may to mid-september . all people included were or older and well informed of the form's utility. results: a total of participants were included. the mean age was . ± . years with extremes of and and a sex ratio of . . fourty-one ( . %) were either doctors or nurses and ( %) did suffer from a severe medical condition. among all the participants, ( . %) thought that end-of-life decisions were up to the doctor. for the rest, they willingly chose to be hospitalized in an icu, to undergo cardiopulmonary rescuscitation and to have ventilation support with orotracheal intubation or tracheostomy respectively in ( . %), ( . %) and ( . %) of the cases. only ( . %) refused temporary dialysis. when asked about sequelae they can live with, participants accepted hemiplegia in . % and paraplegia in . % of the cases. on the contrary, ( . %) refused to live in permanent coma and ( . %) disagreed to undergo tracheostomy and ventilation for life. moreover, ( . %) found that serious un aesthetic sequelae was a fatal consequence they could not survive. as well, only ( . %) consented to live with deep intellectual deficiency. regarding palliative care, ( . %) participants wished to be profoundly sedated until death, ( . %) prefered to die home over ( . %) in hospital. sixtytwo ( . %) desired to see a representative of their religion. furthermore, ( %) were for organ donnation. gender, being a health care professional and age under versus equal or over were not significant in dependent factors (p > . ). conclusion: it is our duty ashealth care professionals to spread advance directives awareness and education. nevertheless, the law should keep the pace with ethics evolution. compliance with ethics regulations: yes. rationale: adapted organ support techniques are needed to enhance reliability of preclinical animal experiments in the intensive care setting (guillon, annals of intensive care- ). a few renal replacement therapy (rrt) models have already been developed in rats, mostly hemodialysis in chronic kidney disease models or hemofiltration techniques in sepsis experiments. mounting evidence from clinical (gaudry, nejm- ) and histopathological studies suggest that rrt for acute kidney injury (aki) could impair renal recovery by acting as a 'second hit' leading to a maladaptive repair of tubular epithelium. we aimed to study this hypothesis in a hemodialysis model in rats with septic aki. patients and methods: on day , sprague-dawley rats were injected with lipopolysaccharide or placebo (nacl . %) intraperitoneally. on day , anesthetized rats underwent femoral artery catheterization for hemodynamic parameters monitoring. at the same time, one femoral vein and one carotid artery were catheterized for arterio-venous sterile extracorporeal circulation with or without passing through a miniature sterile polyester sulfone hemodialyzer ( cm surface, kda pores, microkros ® ) filled with dialyzate liquid in the outer compartment (table ) . vessels were ligated after the procedure and rats allowed to awaken. on day , rats were sacrificed. results: all rats injected with lipopolysaccharides o :b mg/kg survived at day . anesthesia was much challenging: ketamine + xylazine and tiletamine-zolazepam + xylazine required induction and maintenance intraperitoneal injections. these medications induced important hemodynamic parameters fluctuations and high mortality. isoflurane gas inhalation enabled better stability, less hypothermia and quick awakening. adequate temperature was controlled with a heating pad during the procedure and an incubator after. supine position was maintained. the whole circuit was anticoagulated with ml of heparinized saline ui/ml, since clots occurred in the absence of anticoagulation and bleeding when higher dosing was used. circuit (< . ml including dialyzer) was filled with saline solution before initiation, and total restitution of blood at the end of the experiment prevented any blood transfusion requirement. hematocrit was determined at beginning ( %) and end of experiment ( %). a peristaltic pump provided a blood flow rate of . ml/min, (higher rate was not tolerated) for h. of note, rats who underwent sham procedure (vessels ligature only) survived and did not display aki. circulation of a counterflow dialysate in the dialyzer is planned but has not been performed yet. conclusion: this hemodialysis system for rats is feasible at a reasonable price and might help research involving rrt in either ckd or aki. compliance with ethics regulations: yes. there were no significant relationship between rri and past medical history or severity score. we observed a significant negative correlation between rri and diastolic arterial pressure (p = . ) and heart rate (p = . ) as it could be expected by rri formula. an increased rri was associated with higher potassium (p = . ) and higher creatinine levels (p = . ). although not significant, we found a higher rate of subsequent rrt in the high rri group ( % vs %, p = . ). over the first days, fluid balance was significantly different between groups ( ml vs - ml respectively for low and high rri group, p = . ). since standard of care were similar, this suggests different fluid volume status between the two groups. in the low rri group, the cause of aki could predominantly be prerenal since positive fluid balance was not explained by more severe aki with refractory oliguria as shown by the low rrt rate. nevertheless, we did not observed any relationship between rri and the evolution of serum urea or creatinine levels, nor with the presumed aetiology of aki. conclusion: when focussing on the first rri measurement once stage aki was reached, rri ≤ . seems to be in favour of prerenal and transient renal dysfunction even if this is not supported by creatinine serum evolution. compliance with ethics regulations: yes. rationale: critically ill patients are at higher risk of bleeding but also dialysis filter clotting (inflammatory state). intermittent hemodialysis with calcium-free citrate-containing ( . mmol/l) dialysate (cafcit-ihd) recently emerged as a new safe and simple alternative to continuous renal replacement therapy allowing heparin-free extended dialysis sessions (> h). in this study, we aimed to answer to two issues still unresolved: (i) can citrate contained in the dialysate accumulate and lead to citrate intoxication in patients with liver disorders, and (ii) can citrate be avoided using citrate-and calcium-free dialysate (ccf-ihd)? patients and methods: monocentric retrospective study. among the sessions performed with cafcit-ihd, the ihd sessions ( critically ill patients) with citrate measurement available before and after the dialysis filter were reviewed. estimation of the liver clearance was performed using the picco lemon ® system (pulsion). in addition, sessions performed using ccf-ihd were reviewed. results: all the patients had liver disorders (post-liver transplantation period n = ; cirrhosis with child > a ). among the eighteen cafcit-ihd patients, fifteen ( %) and six ( %) received mechanical ventilation or vasopressive drugs, respectively. the median time of the dialysis session was h [ ] [ ] [ ] [ ] , with hourly ultrafiltration rate of ml (one premature termination not related to dysfunctional catheter). in all patients, ionized calcium (ica) decreased below . mmol/l after the filter, whereas post-filter calcium reinjection according to ionic dialysance led to a stable pre-filter (i.e. patient) ica. median citrate concentrations were all below . mmol/l after the filter (minimal concentration to obtain anticoagulation mmol/l) and all except one below the normal value (< µmol/l) before the filter. during all the sessions, ionized to total calcium ratio was below . and the strong ionized gap decreased. when available (n = ), no correlation could be identified between serum citrate concentration and liver clearance. last, in ccf-ihd sessions performed in critically ill patients, no premature termination occurred (median time of the sessions h) and post-filter ica also decreased below . mmol/l. no citrate accumulation could be identified in critically ill patients (even with liver disorders) and receiving extended dialysis sessions ( h or more) using calcium-free citrate containing-ihd. interestingly, we demonstrated that citrate is not required to obtain optimal regional anticoagulation (i.e. post-filter ica < . mmol/l), and a citrate-and calcium-free dialysate could be a safe alternative. compliance with ethics regulations: yes. rationale: ventilator induced diaphragmatic dysfunction is highly prevalent in adult critical care and associated with worse outcomes. specificities in pediatric respiratory physiology suggest that critically ill children may be at high risk of developing this complication, but no study has described the evolution of diaphragmatic function in critically ill children undergoing mechanical ventilation. this study aims to validate a method to quantify diaphragmatic function in mechanically ventilated children. in this prospective single-center observational study, children between week and years old intubated for elective ent surgery and without pre-existing neuromuscular disease or recent muscle paralysis were recruited. immediately after intubation, diaphragmatic function was evaluated using brief airway occlusion maneuvers during which airway pressure at the endotracheal tube (paw) and electrical activity of the diaphragm (eadi) were simultaneously measured for consecutive spontaneous breaths, while the endotracheal tube was occluded with a specific valve. occlusion maneuvers were repeated times. in order to account for central respiratory drive and sedation use, we recorded the neuromechanical efficiency ratio (nme, paw/eadi), in addition to the maximal inspiratory force (mif). in order to determine the optimal measure of nme during an occlusion, the variability over the three occlusion maneuvers of different variables (first breath, last breath, breath with maximal paw deflection, breath with maximal nme value, and median nme value) was assessed using coefficients of variation and repeatability coefficients. results: patients had a median age of . years (interquartile range . - . ), a median weight of kg ( - ), and were male ( %). the median evolution of paw, eadi, and nme ratio over the occluded breaths are represented on fig. . nme values corresponding to the last breath and the breath with maximal paw deflection were the least variable, with median coefficient of variation of % and % and repeatability coefficients of . and . , respectively. conclusion: brief airway occlusions can be used to assess diaphragmatic function in intubated children through both mif and nme ratio, and the latter should ideally be computed on the last breath or the breath with the largest pressure deflection to improve repeatability and decrease variation. compliance with ethics regulations: yes. epidemiology is poorly understood due to the rare use of validated diagnostic tools. the main objective of the study was to determine, by systematically calculating the wat- score, the incidence of ws in our surgical picu. the secondary objective was to analyze the risk factors, consequences and management modalities of ws. patients and methods: following institutional review board approval, we conducted a prospective monocentric study between july and january . all consecutive mechanically ventilated children admitted in our surgical picu with sedation/analgesia by continuous intra-venous (iv) benzodiazepines (bzd) and/or opioids for at least h were included. as soon as sedation was decreased and during h following their total discontinuation, wat- score was assessed twice a day. ws was defined by a wat- score > . the search for risk factors and consequences associated with ws was performed by univariate analysis (mann-whitney and chi test). ethical standards were satisfied and the lack of opposition from patients and their parents was systematically checked. results: the incidence of ws was % among the patients of our cohort including % of children admitted postoperatively and % after severe traumatic brain injury (tbi). significant results are reported in table . our results show that even for sedation time less than days, children could develop ws ( / patients). on the other hand, age, severity (pelod score), number of previous surgeries and severe tbi were not associated with ws. our study also demonstrated that cessation of sedation and prevention of ws was not uniform in our unit. the high incidence of withdrawal syndrome in our study, even in children sedated for less than days, and its consequences require thinking about prevention. we suggest a systematic monitoring of the occurrence of this adverse event using a validated score, from days of continuous iv sedation/analgesia. compliance with ethics regulations: yes. rationale: severe traumatic brain injury (tbi) is a major healthcare problem. amplitude and duration of intracranial hypertension is highly associated with patient outcome. the intracranial pressure (icp) is therefore one key parameter to monitor in the acute phase. when icp is monitored with an external ventricular drain, the pressure recorded by the monitor does not always correspond to the real icp, depending on the status (open/closed) of the -way tap. misleading values could therefore be sent to the patient medical record. our hypothesis is that a machine-learning algorithm will be able to identify automatically and in real time the reliable and non-reliable values of the icp signal. we retrospectively studied pediatric patients having an external ventricular drain between july and july , in a single pediatric intensive care unit. the icp signals were extracted from a high-frequency database ( hz) and pre-processed adequately. to train the algorithms, an annotated database was manually created with two classes: reliable icp vs. non-reliable icp (drain system opened to allow cerebrospinal fluid removal). eleven signal characteristics were compared between the two classes (mann-whitney test), and significantly differing variables were tested in the algorithms. we compared the performance of two machine-learning algorithms: the k-nearest neighbors (knn) and the support vector machine (svm). using -fold cross-validation method, % of the data was used to train the algorithms and % was used for testing. the best classifier was further validated by simulating a real-time icp analysis, using a s sliding-window approach with % overlap. the study was approved by the localresearch ethics committee. results: sixteen patients were included in the study. the training database created from patients, contained segments (of s duration) per class and per patient. eight signal variables were identified and kept to define the segments. the knn algorithm, with k = , led to the best performance, with a mean of % (mean ± sd: % ± . %). the knn was then visually validated on icp signals from the remaining two patients ( figure) . by simulating a real-time icp extraction, our algorithm was able to efficiently identify the reliable icp segments, and to display a mean value only for valid segments. university hospital picu (paris). all consecutive children ( month- years) admitted for acute encephalitis were included and diagnosis was confirmed using the consensus conference criteria's. data regarding clinical, biological and radiological presentations were collected as well as data on the therapeutics used and outcomes at discharge and at the last medical consultation. results: patients were included with a mean age of . years (range . to years old). infectious causes were identified in % (n = ), autoimmune causes in % (n = ) and acute demyelinating encephalomyelitis in % (n = ) of cases. etiology remained undetermined in % of cases (n = ). the most common pathogens were, in order of frequency, influenzae virus, mycoplasma pneumoniae and epstein-bar virus. the main clinical features were fever ( % n = ); epileptic seizures ( % n = ) and coma ( % n = ). regarding therapeutics, % of patients required mechanical ventilation and % of patients required hemodynamic support. % received corticosteroids, % intravenous immunoglobulins and % plasmatic exchanges. the use of these specific treatments was heterogeneous, especially in infectious and undetermined encephalitis, where respectively % and % received boluses of corticoids. the mean length of stay in picu was . days (range - days). the mortality rate was % and the overall rate of sequelae at discharge was % and % at distance, with % considered as severe (gose-ped score > ). the use of mechanical ventilation and young age at diagnosis were risk factors associated with poor prognosis at discharge. the etiology of acute encephalitis remains indeterminate in more than % cases with a clear predominance of infectious causes when an etiology is found. this is a severe pathology responsible for significant mortality and morbidity requiring long-term follow-up. compliance with ethics regulations: yes. rationale: preserving neurological outcome of children under extracorporeal membrane oxygenation (ecmo) remains challenging. acute brain injury (abi) is a frequent complication of ecmo that could be prevented by continuous neuromonitoring. cerebral near infrared spectroscopy (nirs) is routinely used for detecting cerebral complications of cardiac surgery. in adults and infants under prolonged ecmo, cerebral hypoxia is associated with poor neurological outcome. the aim of this study was to assess the value of an impaired cerebral oxygenation on mortality and occurrence of an abi in children under ecmo. patients and methods: children under years old were included in this observational retrospective monocentric study if they needed veno-venous (v-v) or veno-arterial (v-a) ecmo for respiratory and/ or circulatory failure and had concomittant nirs monitoring. cerebral desaturation was defined as a rsco value under % or under % from the baseline; cerebral hyperoxia was defined as a rsco value above %. proportion of time in cerebral desaturation and hyperoxia were recorded. neurological lesions were identified on imaging (mri or scan) by blinded radiologist and classified as major or minor. abi was defined as any hemorragic or ischemic lesion on cerebral imaging, including brain death. results: patients were included. ecmo duration was [ ; ] days. the mortality rate was ( . %), and the proportion of abi was ( %) including brain deaths, ( . %) major lesions, and ( . %) minor lesions. mean rsco was ± % in the right hemisphere, and ± % in the left hemisphere. there was no significant difference in cerebral hypoxia between survivors and non survivors, and between patients with and without an abi. cerebral hyperoxia was associated with a better survival (p = . in the right hemisphere, and p = . in the left hemisphere). in v-v ecmo and at the right conclusion: in our study, cerebral hypoxia was not associated with poor neurological outcome, but cerebral hyperoxia seems to be protective especially in v-v ecmo. this is the first study assessing the value of cerebral oxymetry in all age ranges pediatric ecmo. in this population, multimodal monitoring might be better than nirs alone to predict neurological impairment. further prospective studies are needed to assess first the feasibility, then the impact of such a monitoring. compliance with ethics regulations: yes. cerebral autoregulation impairment is associated with acute neurological events during pediatric extracorporeal membrane rationale: children supported by extracorporeal membrane oxygenation (ecmo) present a high risk of adverse neurological complications. as some animal studies have shown, cerebral autoregulation (ca) impairment after exposure to ecmo, may be a key factor. our main objective was to investigate the feasibility of ca continuous monitoring during ecmo treatment. the second objective was to analyze the relationship between ca impairment and neurological outcome. patients and methods: an observational prospective study including children treated by ecmo in centers was conducted. a correlation coefficient between the variations of regional cerebral oxygen saturation (rsco ) and the variations of mean arterial blood pressure(map) was calculated as an index of ca (cerebral oxygenation reactivity index, cox) during ecmo. a cox > . was considered as indicative for dysautoregulation. cox values were averaged inside mmhg-map bins, allowing determining optimal map (mapopt) and lower (lla) and upper (ula) limits of autoregulation in -h periods. neurological outcome was assessed by the onset of an acute neurologic event (ane) defined by occurrence of hemorrhagic or ischemic stroke and/ or clinical or electrical seizure and/or brain death during the ecmo treatment. rationale: myocardial ischemia reperfusion (ir) injury is the leading cause of perioperative morbi-mortality. protective effect of pharmacologic preconditioning such as anesthetic preconditioning (apc) with sevoflurane (sev) has been widely demonstrated in animal and human models. apc seems to protect myocardial cells from apoptosis, a programmed process of cell death tightly controlled by bcl- family proteins. however, the involved mechanisms in apc have yet to be characterized. we hypothesized that apc protects against myocardial apoptotic cell death by regulating bcl- anti-apoptotic members. to study the sev-induced apc mechanisms against myocardial ir, we used a validated in vitro model reproducing ir injury. rat cardiomyoblast cells h c were cultivated in . % o hypoxia in the presence of ischemia-mimicking medium. after min of ischemia, the reperfusion injuries are induced by replacing the culture medium with a krebs-henseleit normoxic medium for min. apc was performed by adding sev directly into the culture medium at an initial concentration of mm, prior to ischemia, for min. we then used another preconditioning agent, metformin (met), to explore the same signaling pathways. apoptotic cell death was measured by caspase activity assay and western blotting (expression of cleaved caspase ) under ir and apc conditions. results: our model faithfully reproduced the protective effect of apc which results in a significant decreased apoptosis under ir ( % reduction of the caspase enzymatic activity, correlated with a decrease of caspase cleavage). we showed that sev induces overexpression of the anti-apoptotic protein bcl-xl, which is responsible for the protective effect of apc. furthermore, these observations were confirmed in vivo in mouse heart lysates. we demonstrated that bcl-xl overexpression was due to the activation of the protein kinase akt. interestingly, we were able to show that preconditioning with met reproduces the protective effect of sev by inducing an akt-dependent bcl-xl overexpression. indeed, sev and met, which are both complex inhibitors of mitochondrial respiratory chain, seem to share a common reactive oxygenated species-dependent protective mechanism responsible for bcl-xl protein regulation. rationale: despite early endovascular treatment with successful recanalization, % of acute ischemic stroke (ais) patients experience a poor functional outcome after a large vessel occlusion. sepsis is frequent at the acute phase of stroke and is associated with poorer short and long term outcomes. we aimed to investigate the cerebral consequences of sepsis after recanalized ais and explore possible mechanisms involved. patients and methods: male c bl mice were randomly assigned to a x factorial plan to one of the following groups: ) a -minute middle cerebral artery (t-mcao) transient occlusion under inhaled general anesthesia, followed min after recanalization by intraperitoneal (i.p.) sepsis (lps, µg/g diluted in µl of nacl . %), (tmcao/ lps group); ) t-mcao followed by i.p. placebo ( µl of nacl . %) (tmcao/placebo group); ) sham operation (cervicotomy without carotid catheterization) followed by i.p. lps. (sham/lps group); ) sham operation followed by i.p. placebo, (sham/placebo group). in all groups, animals received subcutaneous fluid resuscitation ( µl nacl . %) immediately after the procedure and h later. twenty-four hours after recanalization, animals were scored for sepsis features and neurological deficit (on the modified neurological severity scale), (mnss) before sacrifice. the primary outcome measurement was a composite of death and hemorrhagic transformation at h. secondary outcome measurements included neurological deficit, sepsis features, neutrophil activation reflected by plasmatic myeloperoxydase (mpo) levels, stroke volume, and microglial activation in brain parenchyma (infarct core, perilesional area, controlateral hemisphere). results: t-mcao/lps animals had higher mnss ( . fold, p = . ) and sepsis ( fold, p = . ) scores at h with increased plasma mpo levels at h ( . fold, p < . ) and h ( . fold, p < . ), as well as, lower temperature ( . °c reduction, p = . ) and glycemia ( . g/l reduction, p = . ) as compared to tmcao/placebo animals. t-mcao/lps animals had a higher risk of unfavorable outcome at h ( -group comparison: p = . ; x analysis: t-mcao/lps, / − %vs. t-mcao/placebo / - %-, p < . ), whereas stroke volumes were not significantly different between groups. detailed results are presented in table . compared to t-mcao/placebo group, t-mcao/ lps animals had . fold increase (p = . ) in the mean number of microglial cells in the hemisphere controlateral to t-mcao, whereas no significant difference was observed in infarct core or peri-infarct parenchyma. conclusion: early sepsis after experimental ais worsens outcome and neurological deficit, without impacting stroke volume. early sepsisinduced systemic activation of neutrophils and increased microglial activation in the hemisphere contralateral to ischemia may have an important role on neurological outcomes observed in this setting. compliance with ethics regulations: yes. rationale: extracellular vesicles (evs) regulate diverse cellular and biological processes via facilitating intercellular cross-talk. several studies have suggested an association between lung injury and the generation of evs derived from platelets, neutrophils, monocytes, lymphocytes, red blood cells, endothelial cells, and epithelial cells. every year more than , patients require cardiac surgery with cardiopulmonary bypass (cpb). this cpb allows a substitution of the heart pump function and an oxygenation of the blood permitting a stop of the mechanical ventilation (mv). stopping mv during cpb is responsible for lung damage, leading to postoperative systemic inflammation while maintaining mv with positive expiratory pressure (peep) diminished the occurrence of atelectasis and the postoperative inflammatory response. in addition, this surgery is marked by immune dysfunction, leading to real immunosuppression of patients in postoperative care. a link between pulmonary injury and postoperative immunosuppression has been established, however, the mechanisms underlying this association are not fully known and evs may have a role in this post-operative immunosuppression. the purpose of this study is to investigate whether lung injury induced during cardiac surgery with cpb lead to the emergence of evs. the effect of mv during cpb on the production of these evs has also been studied. patients and methods: patients were prospectively divided into two groups: without mv during cpb and dead space mv with positive end-expiratory pressure during cpb. pao (arterial oxygen tension)/ fio (inspired oxygen fraction) ratio, biological markers of lung injury (cxcl , ccl , tnf-α, il- β, il- , rage, il- ) and blood cell count were collected before, h and days after surgery. the quantification of plasma evs was performed using turnable resistive pulse sensing and characterization of evs was performed using flow cytometry before, h and days after surgery. rationale: the benefit of prone positioning (pp) during moderate to severe acute respiratory distress syndrome (ards) may be related to its impact on the inflammatory response to ventilator-induced lung injuries. [ c]-pk is a positron emission tomography (pet) radiotracer that allows the non-invasive quantification of macrophages. we aimed to evaluate the effects of pp on [ c]-pk lung uptake in animals with experimental ards. patients and methods: experimental ards (by hydrochloric acid) was induced in pigs in supine position (sp), to obtain a pao / fio < mmhg. animals were under general anesthesia, neuromuscular blockade, and ventilated with a ml kg − tidal volume, and cmh o of positive end-expiratory pressure (peep). immediately after experimental ards, animals were randomized to be prone positioned, or to remain in sp. pet and computerized tomography (ct) were acquired h after randomization (h ). [ c]-pk uptake was measured on the whole lungs, and by dividing the lungs into regions or slices-of-interest (soi) along the ventro-dorsal axis, and was quantified by the standardized uptake value (suv), corrected for lung tissue density. results: pp was performed in animals, and sp in . after ards induction, pao /fio was [iqr, [ . - . ] in sp animals (p = . ). in pp animals, [ c]-pk suv was significantly lower in ventral soi, compared to sp, and significantly increased in dorsal soi ( fig. , *: p < . between groups in a given soi). in univariate analysis, [ c]-pk regional suv was positively associated with regional ct-measured peep-related increase in gas volume, and negatively with peep-related lung recruitment, but not with regional tidal volume. conclusion: during experimental ards, pp redistributed lung macrophage recruitment estimated by [ c]-pk uptake from ventral lung regions to dorsal regions, without affecting global macrophage influx. the intensity of macrophage recruitment was associated with peep-related lung inflation. compliance with ethics regulations: yes. rationale: acute respiratory distress syndrome (ards) is a pleiomorphic disease characterized by a severe respiratory failure associated with an increased mortality. nowadays, predicting clinical outcome of patients suffering from ards remains difficult. therefore, identifying new biomarkers to predict patient outcome, to evaluate response to therapy and to identify new potential pathways of interest are highly needed. exosomes are extracellular vesicles involved in cell-cell communication by transferring micrornas (mirnas) from donor to recipient cells. thus, exosomal mirnas can significantly affect biological pathways within recipient cells resulting in alterations of cellular function and the development of a pathological state. as biomarkers are highly needed in the particular field of ards, we realized a monocentric and prospective study to identify a new potential biomarker of interest. therefore, a prospective plasma sampling at the diagnosis of moderate to severe ards according to the definition of "berlin" has been performed. we analysed mirna content of exosomes from plasma ards patients compared to healthy subjects (hs) in order to identify new potential predictive biomarkers in ards. during one-year period, patients hospitalized in the icu of chu sart tilman suffering from infectious moderate-to-severe ards have been included. the ethical committee review boards of the hospital approved the research protocol (b , ref: / ), and informed consents were obtained. exosomes were isolated from plasma samples of ards patients and hs with standard ultracentrifugation protocol. exosomal mirna content was analyzed using small rna sequencing method, and diseases/biological processes associated to altered mirs were determined by bioinformatic analysis. results: for the first time, exosomal mirna expression modifications were studied in patients with moderate-to-severe infectious ards. we identified a new signature statistically significant composed of three up-regulated mirnas (mir- , mir- a and mir- ) and one downregulated (mir-let- b). conclusion: we identified potential biomarkers for ards from plasma exosomes. our findings may thus lead to predict ards outcome but also a better understanding about the roles of these mirs in the pathogenesis of ards and thus open new avenues for therapeutic approaches. in particular, exploit and develop the pro-fibrotic pathway induced by down-expression of mir-let- b. but also confirm in the future the current interest about mir- in its ability to restore pulmonary integrity after trauma. compliance with ethics regulations: yes. rationale: diabetic ketoacidosis (dka) is a life-threatening emergency. microvascular hyporeactivity was reported in these patients and was completely reversibly when ph was corrected with treatment: aggressive rehydration, electrolyte replacement and insulin therapy ( ) . red blood cell (rbc), a component of the microcirculation, showed alterations oftheir shape in diabetic patients ( ) but no data were available concerning the time course of the rbc deformability during treatment for dka. we aimed to assess the rbc deformability during dka treatment in icu patients. patients and methods: after approval by the ethics committee, rbcs deformability was assessed, in all icu patients admitted for dka and without infection, by ektacytometry technique (laser-assisted optical rotational red cell analyzer-lorrca): at icu admission, + h, + h and at the end of the icu stay ( - h). elongation index (ei) was defined as (l − w)/(l + w), where l is the length and w is the width. at °c, ei values were determined in the function of shear stress (ss) in a range of . - pa, based upon the laser diffraction pattern changes. a higher ei indicates greater rbc deformation. rbc deformability from patients with dka was compared at icu admission to healthy volunteers (v) and to diabetic patients followed in consultation (d). we also studied the evolution of deformability during treatment. results: icu dka patients compared to d and v were studied. as expected, glycemia and glycated hemoglobin were significantly higher in dka compared to d (respectively: glycemia: ( - ) vs ( - ) mg/dl and . % ( . - . ) vs . ( . - . ); all p < . ). dka patients received ( - ) ml of fluids and . ui/ kg bw ( . - . ) of insulin during their first h of icu stay. rbcs deformability from dka patients was significantly more altered at icu admission compared to others groups ( fig. ) and these alterations persists despite treatment. no correlations were observed between these alterations and quantity of fluids or insulin received, glycemia, glycated hemoglobin, ph, natremia, age or length of diabetes history. conclusion: in contrast of reversible microvascular hyporeactivity, rbc deformability from dka patients was already altered at icu admission and remains altered despite treatment. these alterations could contribute to the blood flow abnormalities observed in these patients. compliance with ethics regulations: yes. rationale: sepsis remains the first cause of acute circulatory failure in the emergency department (ed). standardized fluid resuscitation may not be adapted in certain patients, especially those with early sepsisinduced cardiac dysfunction in whom excessive fluid administration could be deleterious. information on early hemodynamic profile of septic patients in the ed are scarce. accordingly, we aimed at describing hemodynamic profiles encountered in septic patients assessed shortly after their ed admission using focused echocardiography. patients and methods: we prospectively enrolled adult patients with sepsis (qsofa score ≥ ) from january to july in the ed (nct ). focused echocardiography were performed by emergency physicians previously trained to ecmu level. each patient was evaluated according to a standardized protocol based on a limited number of simple binary clinical questions. investigators interpreted on-line the echocardiographic examination, determined the hemodynamic profile based on simple yet robust criteria (hypovolemia, left ventricular [lv] or right ventricular [rv] failure, vasoplegia with hyperdynamic state, tamponade, severe mitral or aortic regurgitation, or apparently normal profile), and recorded any substantial change in planned therapeutic management (surviving sepsis campaign ). data were digitally stored and validated off-line by an expert in critical care echocardiography. results: focused echocardiography were performed in patients (mean age: ± years; men: %; source of infection: pulmonary %, urinary %, abdominal %) after a median fluid loading of ml (iqr: - ml). according to sepsis- definition, patients had sepsis and sustained septic shock. mean sofa score was . ± . (hemodynamic failure %, respiratory failure %, renal failure %), mean lactate reached . ± . mmol/l, icu admission involved % of patients and overall -day mortality reached %. hemodynamic profile was hypovolemia in patients ( %), vasoplegia in patients ( %), cardiac failure in patients ( %) (lv failure: n = ; rv failure: n = ) and without relevant hemodynamic abnormality in patients ( %). ongoing therapy was altered based on early echocardiographic assessment in % of cases. mortality rate was not significantly different between groups (p = . ). conclusion: although hypovolemia was predominantly identified in patients presenting to the ed with sepsis during hemodynamic assessment, early ventricular dysfunction involved one-quarter of patients. these results suggest that early focused echocardiographic assessment promises to help the front-line physician tailoring the therapeutic management of septic patients in ed, especially regarding fluid resuscitation. compliance with ethics regulations: yes. right ventricular failure in septic shock characterization, incidence and impact on fluid-responsiveness guillaume geri , amélie prigent , xavier repessé , marine goudelin , gwenael prat , bruno evrard , cyril charron , philippe vignon , antoine vieillard-baron ambroise paré hospital, boulogne-billancourt, france; ambroise paré hospital, medical icu, aphp, boulogne-billancourt, france; chu limoges, limoges, france; chu brest, brest, france correspondence: guillaume geri (guillaume.geri@aphp.fr) ann. intensive care , (suppl ):f- rationale: right ventricular (rv) failure was defined by rv dilatation with systemic congestion. tricuspid annular plane systolic excursion (tapse) could be of limited value. we report the incidence of rv failure in patients with septic shock, its potential impact on the response to fluids, as well as tapse values. patients and methods: ancillary study of the hemopred prospective multicenter study including patients under mechanical ventilation with circulatory failure. with septic shock were analyzed. patients were classified in groups based on central venous pressure (cvp) and rv size (rv/lv end-diastolic area, eda). in group , patients had no rv dilatation (rv/lveda < . ). in group , patients had rv dilatation (rv/ lveda ≥ . ) with a cvp < mmhg (no venous congestion). rv failure was defined in group by rv dilatation and a cvp ≥ mmhg. passive leg raising (plr) was performed. results: % of patients were in group , % in group and % in group . in group and , rv/lv eda was higher than in group , . [ . ; . ] versus . [ . ; . ]. cvp was [ ; . ] mmhg in group . a correlation between rv size and cvp was only observed in group . higher rv size was associated with a lower response to plr (figure) . a large overlap of tapse values was observed between the groups. . % of patients with rv failure had an abnormal tapse. conclusion: rv failure is frequent in septic shock and alters fluid responsiveness. tapse was not accurate enough to diagnose rv failure. compliance with ethics regulations: yes. rationale: weaning-induced pulmonary oedema (wipo) is a leading cause of weaning failure in high-risk patients (heart failure, copd, obesity). we hypothesized that hypervolemia associated with positive fluid balance facilitates wipo in high-risk patients. patients and methods: in this prospective, observational, singlecenter study, patients with copd and/or heart failure with reduced ejection fraction (< %) were studied. exclusion criteria were nonsinus rhythm, severe mitral valve disease and inability to obtain adequate echocardiographic views. echocardiography was performed immediately before and during spontaneous breathing trial (sbt, -min t-tube). patients who failed sbt were treated according to echocardiographic results before undergoing a second sbt. fluid balance and body weight were collected at each sbt. shows interesting performance to predict fluid responsiveness in spontaneously breathing patients. nevertheless, measurement sites of inferior vena cava (ivc) diameters remain controversial for that purpose. the aim of the study was to test the accuracy of different measurement sites of civc to predict fluid responsiveness in spontaneously breathingpatients. this study is a post hoc analysis of two prospective cohorts. we included spontaneously breathing patients without mechanical ventilation presenting with sepsis-related acute circulatory failure and considered for volume expansion (ve). we assessed hemodynamic status at baseline and after a fluid challenge (fc) induced by a min-infusion of ml-gelatin %. the ivc diameters were measured off-line with ultrasonography using the bi-dimensional mode on a subcostal long-axis view. the civc was calculated as [ (expiratory-inspiratory)/expiratory] diameters during standardized (civc-st) and unstandardized breathing (civc-ns) conditions. breathing standardization consisted of a deep inspiration with concomitant control of buccal pressures and passive exhalation. patients were referred to be responders to fc (i.e. fluid responsive) when the stroke volume increased by ≥ %. results: among the patients included in the study, ( %) were responders to fc. the accuracy of civc-st and civc-ns before fc to predict fluid responsiveness differed significantly by measurement sites (interaction p value < . and < . , respectively). measuring ivc diameters cm from the junction of the ivc and the right atrium provided the best accuracy to predict fluid responsiveness ( fig. ). at cm caudal to the right atrium, civc-st was significantly better than civcns to predict fluid responsiveness: area under roc curve . ( % ci . - . ) versus . ( % ci . - . ), p < . . at cm, a civcst ≥ % and a civc-ns ≥ % predicted fluid responsiveness with sensitivity of % and %, and specificity of % and %, respectively. conclusion: accuracy of civc to predict fluid responsiveness in spontaneously breathing patients depends on both measurement sites of ivc diameters and breathing conditions. measuring ivc diameters during a standardized inspiration maneuver at cm caudal to the right atrium is the most relevant mean to optimize civc performance to guide ve. compliance with ethics regulations: yes. rationale: intermittent hemodialysis (ihd) is increasingly used in patients admitted to intensive care unit (icu) with acute kidney injury (aki) requiring renal replacement therapy (rrt). however, this technique is associated with nearly % of episodes of perdialytic hemodynamic instability (hi), a common cause of increased morbidity and mortality. at the same time, trans-thoracic echocardiography (tte) has become widely used in intensive care units and is now one of the hemodynamic monitoring methods used daily in the icu setting. patients and methods: search for one or more pre-dialysis tte criteria predictive of perdialytic hi, defined by a systolic blood pressure (sbp) lesser than mmhg or a suddain decrease in sbp of more than mmhg. prospective, observational study of standard care in a medical icu. collection of demographic, clinical and pre-dialysis echocardiographic data from included patients. results: twenty-five patients with a total of sessions of ihd between november and november were included in the study. tte was performed for each patient before each ihd session. hi occurred in hemodialysis sessions. in univariate analysis, the existence of prior heart disease ( % vs %, p = . ), a greater diameter of the left atrium ( . vs . cm, p = . ), a lower cardiac output ( . vs . l/min, p = . ), a right dysfunction assessed by lowered tapse and s-wave ( vs mm, p < . and . vs . cm/s, p = . , respectively) and an increase in paps ( vs mmhg, p = . ) were significantly associated with the occurrence of perdialytic hi (fig. rationale: several transthoracic echocardiography (tte) parameters of left (lv) and right ventricular (rv) systolic function are available. we compared the ability of these different parameters to track changes in lv or rv systolic function and to detect lv or rv systolic dysfunction in critically-ill patients. in patients ( mechanically ventilated and with atrial fibrillation), tte examinations were performed before and after i) infusion of -ml of saline (n = ), ii) changes in norepinephrine (n = ), iii) or in dobutamine (n = ) dosage. for the lv systolic function, we compared the mitral annular plane systolic excursion (mapse), the systolic (s') peak velocity of the lateral mitral annulus and the global longitudinal strain (glslv) to the lv ejection fraction (lvef), considered as the gold standard. for the rv systolic function, we compared the tricuspid annular plane systolic excursion (tapse), the systolic peak (s) velocity of the tricuspid annulus and the global longitudinal strain (glsrv) to the rv fractional area change (fac), considered as the gold standard. results: after pooling all values, lvef ( ± % at baseline) was better correlated to glslv (r = . ) than to mapse (r = . ) and s' wave (r = . ) (each p < . ). the concordance rate between changes (in %) in lvef and in the other parameters of lv systolic function was % for glslv, % for mapse and % for s' wave. both mapse and s' wave could not reliably detect moderate ( % ≤ lvef ≤ %) or severe (lvef < %) lv dysfunction. conversely, a glslv > − % predicted moderate lv dysfunction with a sensitivity of % ( % ic: - %) and a specificity of % ( % ic: - %) and a glslv > − . % predicted severe lv dysfunction with a sensitivity of % ( % ic: - %) and a specificity of % ( % ic: - %). after pooling all values, fac ( ± % at baseline) was better correlated to glsrv (r = . ) than to tapse (r = . ) and s wave (r = . ) (each p < . ). the concordance rate between changes (in %) in fac and in the other parameters of rv systolic function was % for glsrv, % for tapse and % for s wave.both tapse and s wave could detect rv dysfunction (fac ≤ %) with moderate reliability only. conversely, a glsrv > − % detected rv dysfunction with a sensitivity of % ( % ic: - %) and a specificity of % ( % ic: - %). in critically-ill patients, glslv and glsrv seem to be the best tte parameters of lv and rv systolic function. enrolments are still ongoing, which may allow further analysis. compliance with ethics regulations: yes. rationale: passive leg raising (plr), pulse pressure variation (ppv), and the -second end-expiratory occlusion test (eexpo) are frequently used to assess preload responsiveness. however, there are conditions in which they are not valid or feasible, which may preclude their applicability in the daily clinical practice. the aim of this study was to estimate the prevalence of such conditions in critically ill patients with acute circulatory failure. between january and april , all patients of a -bed medical icu were daily screened and those with acute circulatory failure, defined by norepinephrine infusion or fluid therapy > l during the previous h, were included. in each of them, we screened the criteria of validity/feasibility of ppv, plr and eexpo. results: eighty-four patients ( % with septic shock, % with cardiogenic shock, % with hypovolemic shock, % with non-septic vasoplegic shock) were enrolled in the study. among them, norepinephrine infusion was ongoing at the time of enrolment in % of the patients whilst % were under mechanical ventilation, and % with acute respiratory distress syndrome. plr was not applicable in % of cases. this was mainly due to venous compression stocking ( % of cases), intra-abdominal hypertension ( % of cases), and either an absence of cardiac output monitoring or impossibility to perform echocardiography ( % of cases). among the intubated patients, ppv was applicable in % of cases, including cases with high ppv under conditions generating false negatives (low tidal volume or lung compliance) or low ppv values under conditions generating false positives (spontaneous breathing, cardiac arrythmias). however, ppv was not interpretable in % of cases. this was mainly due to low tidal volume ventilation ( % of cases), spontaneous breathing activity ( % of cases), while the remaining non-interpretable cases ( %) had more than one reason. in the intubated patients, eexpo was not applicable in % of cases. this was due to impossibility for patients to sustain a -s hold of mechanical ventilation in % of cases, and either an absence of cardiac output monitoring or the impossibility to perform echocardiography in % of cases. plr and eexpo were both valid and feasible in % of the patients, and the three tests were all feasible in only % of patients. rationale: comorbid association between chronic respiratory diseases and sleep apnea syndrome (sas) revealed frequent with systematic search in icu following icu stay. this association carries prognosis impact depending whether specific treatment is implemented or not. nosas and stop bang scores are proposed for screening of sas in general population. the aim of the present study is to report the prevalence of sas in icu patients admitted for hypercapnic respiratory failure and compare association of nosas and stop bang score with sas severity. the study was conducted between january and september . patients consecutively admitted in the icu for hypercapnic respiratory failure had calculation of a no sas and stop bang scores at admission. in survivors nocturnal polygraphic records was performed to weeks following icu discharge. the association between the number of apnea-hypopnea episodes, bmi, and clinical variables suggestive of sas, was tested by poisson regression model. results: during the study-period, patients (mean age: ± years, ph . ± . , paco ± ) were admitted for hypercapnic respiratory failure. non invasive ventilation was used in % and death occurred in six patients. polygraphic records were performed in ( lost to follow-up) mean apnea-hypopnea index was ± with a minimum of and a maximum of . poisson logistic regression showed that no sas (p = . ) but not stop bang (p = . ) was associated with the level of apnea-hypopnea index. rationale: patients with severe acute exacerbations of chronic obstructive pulmonary disease (copd) may benefit from high-flow nasal oxygen regarding its physiological effects and good tolerance. bronchodilator vibrating mesh nebulization through high-flow nasal oxygen circuit has been described to induce similar effect to standard facial mask jet nebulization in stable copd patients. we aim to evaluate whether vibrating mesh nebulization of salbutamol through highflow nasal oxygen circuit is efficient in unstable patients with copd. patients and methods: we conducted a monocenter non-randomized physiological prospective cross-over study, between january and september , including icu patients with severe acute exacerbation of copd and respiratory acidosis treated by salbutamol nebulization. spirometry and airway resistances records were performed after a -h wash-out period without bronchodilator, before and after vibrating mesh nebulization of mg salbutamol through high-flow nasal oxygen circuit. the primary endpoint was forced expiratory volume in s after salbutamol nebulization. secondary endpoints included other spirometry parameters, clinical parameters, dyspnea assessed by a borg scale. results: fourteen consecutive patients were included, forced expiratory volume in s increased significantly after salbutamol nebulization through high-flow nasal oxygen ( ± ml, p = . ), as well as forced vital capacity ( ml ± , p = . ). airway resistances were not significantly changed after nebulization (− . ± . , p = . ) as well as peak expiratory flow (+ ml ± , p = . ). no difference was observed on borg scale (p = . ) and respiratory rate (p = . ) after salbutamol nebulization, while heart rate increased significantly (p = . ). discussion: salbutamol nebulization using vibrating mesh nebuliser placed on high-flow nasal oxygen circuit induces a significant but moderate bronchodilation in patients with severe acute exacerbation of copd. moreover, improvement of forced vital capacity after salbutamol nebulization suggests a reduction of dynamic hyperinflation. conclusion: salbutamol vibrating mesh nebulization through highflow nasal oxygen circuit increases significantly forced expiratory volume in s. compliance with ethics regulations: yes. t-piece versus sub-therapeutic pressure support for weaning from invasive mechanical ventilation in patients with chronic obstructive pulmonary disease: a comparative prospective study amira jamoussi, fatma jarraya, samia ayed, takoua merhabene, jalila ben khelil, mohamed besbes abderrahmen mami hospital, tunis, tunisia correspondence: amira jamoussi (dr.amira.jamoussi@gmail.com) ann. intensive care , (suppl ):f- rationale: the best weaning strategy for patients with chronic obstructive pulmonary disease (copd) remains unknown. the spontaneous breathing trial (sbt) represents a crucial step of weaning, but the choice between the t-piece (sv-tube) or the sub-therapeutic setting of the level of pressure support without positive expiratory pressure (psv) is still a matter of debate. we aimed to compare the success of extubation between two groups of copd patients according to the sbt type (vs-tube vs psv). patients and methods: it was a prospective and comparative study, from april to march , at the abderrahmen mami hospital's intensive care unit (icu). copd patients who underwent invasive mechanical ventilation (mv) for at least h and met the criteria for weaning were included and randomized to sv-tube or psv. a multivariate analysis was performed to determine the association between the sbt modality and the success of extubation (no re-intubation during the h following extubation). results: during the two years' study, patients were included. the mean age was ± years, the sex-ratio was . . weaning process was simple in patients ( %), difficult in patients ( %) and prolonged in patients ( %). fifteen and patients were respectively randomized to the sv-tube and psv groups. the mean duration of mv before randomization was comparable between the groups (sv-tube . ± . days vs psv . ± . days, p = . ). mean weaning time (days) was . [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] for the sv-tube group and . [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] for the psv group. the mean total mv duration (days) was higher in the sv-tube group than in the psv group ( . vs . , p = . ). the number of re-intubated patients within h following extubation was higher in the psv group ( / vs / , p = . ) as well as the overall reintubation rate ( . % vs %, p = . ). in multivariate analysis, the sbt's trial was independently associated to the success of extubation (or = . , ic [ . - . ], p = . ) in favor of sv-tube' modality. the median length of stay in intensive care was days [ ; ]. the mortality was higher in the psv group ( / vs / , p = . ). extubation failure was a factor associated with mortality (or = . , ci [ . , . ], p = . ). conclusion: ventilation weaning was easy in % of intubated copd patients. sv-tube as sbt modality was associated to success of extubation in patients with copd. mortality in intensive care was significantly higher in re-intubated patients. compliance with ethics regulations: yes. rationale: non-invasive ventilation has become the mainstay in hypercapnic respiratory failure. delaying intubation and invasive ventilation is associated with a worse outcome in these patients. although a predictive score of niv failure has been validated for hypoxemic respiratory failure no such score exists in hypercapnic respiratory failure. the aim of our study is to compare the performance of two scores in the predictive niv failure hypercapnic respiratory failure. patients and methods: consecutive patients admitted between january and july for hypercapnic respiratory failure, were included. hacor score and rox score were calculated in each patient at admission. in patients ventilated non-invasively, the outcome (niv success or failure) was noted. the area under curve (auc) and operative characteristics were computed for both scores. results: during the study-period, out of patients admitted for hypercapnic respiratory failure received niv as the primary ventilatory mode. these patients were mainly men ( / ), had a mean age of . ± years and had the following pulmonary disease: copd exacerbation . %, obesity-hypoventilation syndrome . %, bronchiectasis . %, and other diseases: . %. niv failure occurred in patients ( . %) and icu mortality in . %. mean hacor score and rox score were . ± . and . ± , respectively. the auc under roc was higher for hacor than rox ( . and . respectively) ( fig. ). the hacor score (cut-off ) had a sensitivity of . and specificity of . . conclusion: hacor score seems more accurate in predicting niv failure in hypercapnic respiratory failure. further prospective validation is needed. compliance with ethics regulations: na. rationale: published data on outcomes in respiratory weaning centers are limited and seem to depend on the organisation of healthcare systems and patient case-mix. the weaning center of our university hospital (post intensive care rehabilitation unit) admits for weaning and rehabilitation patients from medical and surgical intensive care units without severe neurological pathologies. the aim of this study was to describe patient's characteristics and outcome (weaning outcomes and survival) and to compare in subgroups according to the initial medical, surgical or cardiac surgical context. patients and methods: we conducted a monocentric retrospective observational study between / / and / / . «successful outcome» was defined by the association of survival and weaning from invasive ventilation. factors associated with evolution were investigated by uni-and multivariate analysis. survival after discharge was analysed according to the initial context and according to the type of ventilation at discharge. results: among patients included, ( . %) had a successful outcome with high use of non-invasive ventilation (niv) ( %). respiratory history (p = . ), female gender (p < . ), igs score at admission to the srpr (p = . ) and non-cardiac surgical setting (p < . ) were associated with an adverse course. the -month survival rate was % in discharged patients. the outcome was not different in the tree subgroups. niv rate at discharge was high in the subgroup of cardiac surgery patients. a multidisciplinary and personalised approach by a specialized weaning unit can provide a successful service model for patients who require liberation from prolonged invasive mechanical ventilation. compliance with ethics regulations: yes. rationale: high-dose insulin euglycemic therapy (hiet) is recommended as first line therapy for calcium channel blockers (ccbs) poisoning because of its inotropic effect. our first objective was to study its hemodynamic impact. we performed a retrospective cohort study of all consecutive patients admitted for ccbs poisoning treated with hiet, in one icu at the university hospital of lille between january and july . the hemodynamic impact was studied through mean arterial pressure (map), vasoactive-inotropic score (vis) and map/vis ratio during the h following hiet initiation. metabolic parameters were also collected. results: patients admitted for ccbs poisoning. patients treated with hiet in icu ( patients without circulatory shock, patients with shock after hiet and patients with shock at baseline before hiet). among shocked patients at baseline (n = ), no hemodynamic improvement was found except an increased map/vis ratio at h (p < . ). on the contrary, an initial worsening of vis ( [ rationale: ketamine is used in the induction and maintenance of general anesthesia. recently, there were concerns regarding its liver toxicity. we conducted a study to investigate the link between ketamine use and liver dysfunction (ld) in intensive care unit (icu) patients. patients and methods: data were extracted from the [anonymized] study, a randomized controlled trial designed to evaluate the effect of cisatracurium on -day mortality rate in moderate and severe acute respiratory distress syndrome (ards) patients. the main endpoint was the occurrence of a ld defined as a total serum bilirubin superior or equal to micromol/l. a matched case-control cohort was created: cases, receiving at least day of continuous ketamine infusion, were paired for with controls according to treatment with cisatracurium, hepatic and cardiovascular sofa sub-score, total serum bilirubin level at the time of inclusion, age, sex, ards from septic origin, shock anytime after inclusion. an analysis was also made on the whole cohort comparing the patients receiving at least day of continuous ketamine infusion to all patients who did not fulfill this criterion. results: cases were identified and matched to controls. in the ketamine group, the median ketamine duration was ( - ) days, and median total cumulative dose . ( . - . ) g. the occurrence of ld was higher in the ketamine group than in the matched control group ( . % versus . %, p = . , fig. ). the hazard ratio (hr) for ld in the ketamine group was . ( % ci . - . , p = . ). there was an increased risk of ld of . % per day of exposure to ketamine (hr . , % ci . - . p = . ) and of . % per gram of ketamine infused (hr . , % ci . - . , p = . ), with a risk starting to be statistically significant after days and gr. in multivariate analysis on the whole cohort, ketamine exposure (hr . , % ci . - . , p = . ), cumulative dose in gram (hr: . , % ic: . - . , p = . ) and ketamine exposure in days (hr: . , % ic: . - . , p < . ) remained independent risk factors for ld occurrence. conclusion: ketamine use in critically ill patients treated for ards is associated to a higher risk of liver dysfunction, assessed by total serum bilirubin. this risk is dose-dependent and increases with duration of treatment. the prescription of high doses or prolonged treatment with ketamine should probably be avoided in critically ill patients. compliance with ethics regulations: yes. rationale: ciguatera is one of the most common cases of marine poisoning associated with fish consumption in the world. the incidence of this intoxication is largely unreported. in martinique, the incidence of this intoxication seems constantly increasing. during the last years, numerous cases of large collective poisonings have been reported in martinique, especially during summer. the spectrum of clinical manifestations is large including gastrointestinal, neurological andcardiovascular symptoms. ciguatoxin, the toxin responsible for ciguatera fish poisoning is considered as a sodium channel agonist with cholinergic and adrenergic activity. it is rarely fatal and management of poisoned patients is essentially based on supportive care. the objective of this study was to describe the clinical characteristics and complications of ciguatera poisoning in martinique, focusing on the cardiovascular ones. observational, retrospective, single-center study covering six-year period from october to september , including all patients admitted to the emergency department of the university hospital of martinique (chu), and all patients who were declared to the regional health agency (ars) for ciguatera intoxication. results: one hundred and forty-nine patients ( ) who were ciguatera-affected were included. the incidence rate found was to be . cases per . patient-years in martinique over the period. about % of patients had gastrointestinal symptoms such as nausea, vomiting, diarrhea, or abdominal pain; % neurological disorders and % cardiovascular symptoms including, bradycardia, hypotension and interventricular block. ingestion of carangue fish was related to a major risk of chronic signs. conclusion: the incidence of ciguatera in martinique is increasing, with . cases/ . patient-years. the clinical presentation is defined mainly by digestive signs, followed by peripheral neurological disorders and cardiovascular symptoms. ciguatera fish poisoning in martinique presents similar clinical presentation to that of the other caribbean islands. there is no specific treatment. acute ciguatera poisoning is responsible for significant cardiovascular complications. physicians should be aware of the potential cardiovascular risk of ciguatera poisoning. compliance with ethics regulations: yes. rationale: pesticides have represented the most incriminated products in severe acute poisonings, in the developing countries, due to the availability of these products. organophosphate poisoning accounts for million poisonings/year worldwide. organophosphate (op) pesticides are used mainly as insecticides in agriculture. the moroccan anti-poison and pharmacovigilance centrer shows that op poisoning are responsible for % of all poisonings combined. the aim of our study: epidemiological, clinical, management and prognostic factors. patients and methods: a retrospective study was conducted on patients with op poisoning admitted to our nine-bed medical intensive care unit between january and december . inclusion criteria were: all patients over years of age and the exlusion criteria were: pesticide poisoning other than op, alcohol poisoning, drug poisoning, scorpionic poisoning and snake bites. statistical analysis was performed with spss software. results: forty patients were admitted for acute op poisoning. in morocco, organophosphores are available over-the-counter in several forms: rodentocides, malathion, cockroach trap, baygon insecticide ( fig. ). the average age was years with a female prévalence of . %. the intoxications were mostly intentional ( %). the symptomatology was determined by the three syndromes: central syndrome in %, muscarinic syndrome in %, nicotinic syndrome in %. rhythm disorders in %, and cardiovascular collapse in %. the symptomatic treatment was applied to all patients, antidotic treatment was administered in % of patients. the average length of hospitalization was days. conclusion: acute op poisoning is a real public health problem. its associated symptomatic treatment (respiratory and neurological resuscitation) and antidotic treatment. the mortality remains high in our context, therefore, we must attach great importance to the prevention. compliance with ethics regulations: yes. ( ). over an -month period, health officials in guadeloupe and martinique reported more than . such cases. assault of these brown algae represents not only an environmental and economic disaster, but also a threat for human health. after h on seashore, large amounts of toxic gas are produced by matter decomposition, including hydrogen sulfide (h s) and ammoniac (nh ). the acute effects on humans after exposure to high concentrations of h s are well described and of increasing severity with concentration, leading to potentially fatal hypoxic pulmonary, neurological and cardiovascular injuries (table ) ; however, the association of long-term exposure to sargassum and health events is unknown. although less documented, long term exposures may result in conjunctiva and upper airways irritation, headaches, vestibular syndrome, memory loss, and modification of learning abilities. in the absence of any available antidote, management of h s intoxication relies on supportive care and prevention using individual protection. the objective of this study was to evaluate the clinical characteristics and consequences of long-term exposure to sargassum among the local population. we conducted a prospective observational cohort study including all patients admitted to the emergency department at the university hospital of martinique from march to december due to exposure to sargassum. patients were managed according to the protocol established by the research group on sargassum in martinique. we assessed the patients exposure to sargassum and air pollutants using monitor located near of the patient's residence. demographics and clinical data (including cardiovascular, neurological and respiratory events) were collected. data are presented as mean ± sd or %.comparisons were performed using univariate analysis. results: in months, patients were included (age: ± years, m/ w, past history: hypertension (n = ), diabetes (n = ), asthma ( ). patients arrived with referral letter from their general practitioner ( %) and presented headaches ( %), developed gastrointestinal disturbances ( %), dizziness ( %), skin lesions ( %), cough ( %) and conjunctivitis ( %). not all patients were clinically symptomatic. in the patients presented in june ( %), symptoms more frequently occurred in the workplace or at home (p < . ). initial lung function tests were normal ( %). three patients were admitted in intensive care unit. conclusion: our study indicates that the magnitude of health effects following long-term exposure to sargassum may be larger than previously recognized. efforts to limit long-term exposure are mandatory. compliance with ethics regulations: yes. rationale: liver consequences of out-of-hospital cardiac arrest (ohca) have been poorly studied. the aim of this study was to describe the characteristics of ohca-induced acute liver dysfunction and its association with outcomes. we analyzed all consecutive ohca patients admitted to two academic centers between and . patients treated with vitamin k antagonist were not included. acute hepatocellular insufficiency (ahi), liver failure (lf) and hypoxic hepatitis (hh) were defined as a prothrombin (pt) ratio < %, a hepatic sofa sub-score > and an increase in transaminases > times the normal values, respectively. indocyanine green (icg) clearance was used as the reference measure of liver function in a subset of patients. multivariate logistic regression was used to identify potential risk factors for day mortality. rationale: neuron-specific-enolase (nse) is commonly used as a biomarker reflecting the extent of brain injury in different settings. in post-cardiac arrest patients, previous clinical studies reported that an increase in nse was predictive of a poor outcome but did not specifically focused on neurological outcome. in this prospective study, we aimed to determine the nse performance for prediction of severe brain damage in post-cardiac arrest patients. patients and methods: all consecutive patients admitted in our icu after cardiac arrest between january and february that were still comatose at h and had at least one measurement of serum nse were included. blood samples for nse measurement were serially collected at (h ) and h (h ) after cardiac arrest and serum nse levels were measured within h. we used the following criteria for the definition of severe brain damage (primary endpoint): cerebral performance categories (cpc) or level at discharge, brain death or withdrawal of life-sustaining treatments (wlst) based on neurological status. we also assessed the predictive value of serum nse using allcause mortality as a secondary endpoint. results: during the study period, patients were available for the analysis. they were mostly male ( . %), with an age of . years. among these patients, ( . %) had a good neurologic outcome (cpc - ) and patients were classified as having a severe brain damage ( wlst based on neurological status, brain deaths and survivors with . in univariate analysis, patients with severe brain damage less frequently received bystander cpr, had longer duration of no-flow, less initial shockable rhythm, more post-resuscitation shock and higher nse values: mean at h were . versus . ; and . versus . at h (p < . ). nse levels at h and h were strong predictors of severe brain damage (auc of . and . respectively, figure ) and also predicted all-cause mortality (auc of . and . respectively). to predict severe brain damage with % specificity, best nse cutoff values at h and h were . and . µg/l, with a sensitivity of . and . % respectively. conclusion: a high serum nse measured at h and h after cardiac arrest accurately predicted severe brain damage with a high specificity. our results support the use of nse for neuroprognostication after cardiac arrest, in combination with other predictors. compliance with ethics regulations: yes. rationale: the psychological care of patients, their relatives and of healthcare workers is a major issue in the intensive care unit (icu). psychologists may provide emotional support during trying times. the intervention of a psychologist may alleviate long term mental health issues such as post-traumatic stress disorder. the main objective of our study was to describe the availability of psychologists in french-speaking icus. patients and methods: internet survey conducted between march and may using surveymonkey (san mateo, usa). survey consisting of questions sent to subscribers of the srlf mailing list via mailchimp software (atlanta, usa). frequencies and percentages were determined for categorical variables and median and interquartile range for continuous variables. the icus with or without psychologist were compared using nonparametric fisher exact test. stata used (lakeway drive, te, usa). results: responses were obtained from unique icus in france (n = ), belgium (n = ), switzerland (n = ), algeria (n = ), morocco (n = ) and tunisia (n = ). ( %) icus were part of public hospitals, ( %) of private facilities. ( %) icus cared for adult patients, ( %) for children. the median number of beds was [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . ( %) icus were open to visitors / , ( %), to visitors > h/day and ( %) to visitors < h/day. psychological consults were established in ( %) wards ( icus did not answer). pediatric icus employed more psychologists than adult icus (p = . ). comparison of icus based on the presence or not of a psychologist appears in table . in icus where a consulting psychologist is available, their effective availability is . [ . - ] full time equivalent. consults are delivered to: patients ( %), families ( %) or healthcare workers ( %). out of the icus without a psychological consult, responders from ( . %) icus believe that a psychological consult is undesirable. out of the icus without psychological consult, ( %) responders cannot obtain a psychological consult, whatever the circumstances, ( %) can require an outside psychological consult when needed, while ( %) can require assistance from a psychologist working in another unit (several answers possible for each respondent). conclusion: psychologists consult in only half of adult icus but in almost all pediatric icus. % of icus are unable to provide a psychological consult. psychological consults are delivered in similar proportions to patients, their family and to a lesser extent to healthcare workers. responders from . % icus without an established psychological consult believe that the availability of a psychologist is undesirable. compliance with ethics regulations: na. rationale: comfort of patients in intensive care unit (icu) is now a real concern for the healthcare teams. perceived patient discomfort assessment is a daily practice for our staff. the primary objective of our study was to assess whether the overall discomfort score reported by patients hospitalized in a separate intermediate care unit differs from that reported by patients hospitalized in icu. a tailored multicomponent program consisting of assessment of icu-related self-perceived discomforts with a -item questionnaire, immediate and monthly feedback to healthcare teams and site-specific tailored interventions, was applied in our department, located in a general hospital, and comprising a -bed icu and a separate -bed intermediate care unit rationale: the transition period surrounding the discharge from icu to hospital ward is a critical period in the course of the patient. handoff of complex patients is at high risk for communication failures between providers, inaccurate cares and icu readmission. a transition program including a post icu follow-up has been proposed to improve handoff quality. post icu consults by icu team represent, also, an opportunity for improving feedback on the quality of icu cares. the goal of the present study is to assess the feasibility and the impact of a systematic early post-icu consult (epicuc) program on handoff quality in a bed mixed icu. patients and methods: before the development of the epicuc program, standardized handoffs were already applied including identified day and hour of discharge and both verbally communicate and written medical and nurse information for receiving team. from st march to th october , all patients who were discharged to the ward of our hospital were candidates for epicuc. epicuc were performed by icu staff (at least one icu physician) within the days following discharge. the epicuc consisted of a face-to-face discussion with the receiver team to assess the accuracy, completeness and understanding of passing information and of a patient visit. a standardized form was used for collecting data. the impact of epicuc on handoff quality was assessed by the number of communication failures and the number of patients in whom epicuc resulted in a management change. personal feeling of epicuc providers on its usefulness was assessed by a - rating scale. results: among the candidates for epicuc, were dead and already discharged alive from hospital at epicuc time. epicuc were performed in patients ( %) within ± days after icu discharge. epicuc ( %) were performed by both, nurse and icu physician. ( %) patients and receiver teams ( %) were available at epi-cuc time. epicuc duration was ± min. a communication failure was identified in epicuc ( %), either a rectification of passing information (n = ; %) and/or a change in patient management (n = ; %). the usefulness of the epicuc was rated at ± and ± by icu physicians and nurses, respectively. conclusion: the time spent for epicuc appears reasonable. epi-cuc identified a communication failure in one-third of handoffs and allowed care readjustment in one quarter of patients. factors associated with handoff failures will be presented during the congress. compliance with ethics regulations: yes. rationale: surviving a critical illness is a challenging condition for patients and relatives. the psychological aspects are directly affected by physical status and performance. patients can feel depressed or anxious facing difficulties during recovery time. the aim of this study was to correlate patients' perceptions of his health status and his clinical performance measured after icu discharge. patients and methods: this is a prospective pilot study of an icu follow-up clinic conducted in a single center from january to july . this clinic is multidisciplinary and includes two visits at and months after icu discharge. patients with more than days of icu los were eligible. all patients at and -m visit were evaluated with sf- , mwt, mrc and time-up-and-go test. we conducted an analysis comparing clinical performance data and qualitative data between and months after icu discharge. the investigation included patients who had at least days of icu length of stay. patients attended the consult at -m and patients attended the consult both times. the median age (iqr) was ( - ) and % were men. %, % and % of patients had medical, scheduled surgical and emergency surgical admission causes respectively, with median (iqr) saps iii score ( - ). %, % and % of patients had sepsis, delirium and mechanical ventilation as a support. the physical status was progressively increased overtime likewise the physical capacity assessed by sf- score with p-value . between and -m. however, no significant difference between the subjective dimension of sf- , which analyses the perception of the patient about his physical capacity, assessed at -m and at -m was demonstrated (p . ). in this pilot-phase of following a cohort of critically ill patients, the natural physical improvement does not seem to change the patient's perception of their performances. this paradigm rouses a different perspective that should take into account when setting up rehabilitation programs. compliance with ethics regulations: yes. post-traumatic stress disorder after discharge from an acute medical unit basma lahmer , naoufel madani , , jihane belayachi , , redouane abouqal rationale: post-traumatic stress disorder (ptsd) occurs after exposure to a traumatic event and comprises of symptoms of repeated re-experiencing of the said event, avoidance of reminders, emotional numbing and persistent hyperarousal. in individuals exposed to "medical stress", various studies found evidence of ptsd occurring after the onset, diagnosis, or treatment of physical illness. our study aims to determine ptsd's risk factors in patients of an acute medical unit (amu) after their discharge. patients and methods: it was a prospective, analytical study conducted over a period of months at an acute medical unit. we collected sociodemographic and clinical data, patients' medical history, and evaluated the symptoms of anxiety and depression during their stay using the hospital anxiety and depression scale (hads). the prevalence of severe ptsd symptoms was assessed with the impact of events scale-revised (ies-r) at weeks and months using a cutoff of . associations between ptsd as evaluated by ies-r at months and patients' characteristics, including hads scores at admission were investigated using unadjusted linear regression, for univariate and multivariate regression analysis. statistical analyses were carried out using spss for windows (spss, inc., chicago, il, usa). we included patients in our study with a mean age of . ± . . in our population, . % of patients scored higher than a ies-r cutoff at weeks compared to . % at months. the mean hads-anxiety score is . ± and that of the hads-depression score is . ± . . on one hand, higher hads-anxiety score during the stay in the amu was linked to higher ies-r scores at months β: rationale: objective of critical care includes restoration of functional capacities. prompt identification of muscle acquired weakness (icu-aw) is crucial to target efficient rehabilitation. in published literature, data of quadriceps strength (qs) cannot be compared because of insufficient standardization of measurement protocols. we recently validated a highly standardized protocol of qs measurement. in order to build basic and comparable knowledge and to identify the weakest patients, this study aimed to describe qs of critically ill (ci) patients during their short-term evolution, and to compare them to surgical (s) and healthy (h) subjects. patients and methods: this observational study included ci patients who spent at least days in icu, patients scheduled for elective colorectal surgery (s) and young healthy volunteers (h). maximal isometric qs was assessed using a handheld dynamometer (microfet ® ) and expressed in newton/kg (n/kg). dominant leg was tested in supine position using a highly standardized procedure. ci and s patients were tested at t (as soon as collaborative in icu) and month after discharge (m rationale: the post intensive care syndrome (pics) gathers various disabilities, associated with a substantial healthcare use. however, patients' comorbidities and active medical conditions prior to intensive care unit (icu) admission may partly drive healthcare use after icu discharge. to delineate the relative contribution of critical illness and pics per se to post-critical illness increased healthcare use, as opposed to pre-existing comorbidities, we conducted a population-based evaluation of patients' healthcare use trajectories. patients and methods: using discharge databases in a . -million-people region in france, we retrieved, over three years, all adult patients admitted in icu for septic shock or acute respiratory distress syndrome (ards), intubated at least days and discharged alive from hospital. healthcare use (days spent in healthcare facilities) was analyzed two years before and two years after icu admission. healthcare trajectories were next explored at individual level: patients were assembled according to their individual pre-icu healthcare use trajectory by clusterization with the k-means method. results: eight-hundred and eighty-two ( ) patients were included. median duration of mechanical ventilation was days (interquartile ranges [iqr] ; ), mean saps was , and median hospital length of stay was days (iqr ; ). prior to icu admission, we observed, at the scale of the whole study population, a progressive increase in healthcare use. however, clusterization of individual according to pre-icu healthcare trajectories identified patients with elevated and increasing healthcare use (n = ), and two main groups with low (n = ) or no (n = ) pre-icu healthcare use. patients with high healthcare use had significantly more comorbidities than those with low healthcare use. in icu, however, saps , duration of mechanical ventilation and length of stay were not different across the groups. interestingly, analysis of post-icu healthcare trajectories for each group revealed that patients with low or no pre-icu healthcare (which represented % of the population) switched to a persistent and elevated healthcare use during the two years post-icu. conclusion: for % of ards/septic shock survivors, critical illness appears to have a pivotal role in healthcare trajectories, with a switch from a low and stable healthcare use prior to icu, to a sustained higher healthcare recourse two-years after icu discharge. this underpins the hypothesis of long-term critical illness and pics-related quantifiable consequences in healthcare use, measurable at a population level. compliance with ethics regulations: yes. ( ) to describe the pre-hospital grading protocol developed by the northern french alps emergency network (trenau) for children, ( ) to evaluate its quality to detect the most severe trauma patients and ( ) to assess the accuracy of this procedure to perform an adequate triage. patients and methods: our regional trauma system included hospitals categorized as level i, ii or iii pediatric trauma centers. eachpatient was graded a, b or c by an emergency physician, according to the seriousness of their injuries at presentation on scene. the triage was performed according to this grading and the categorization of centers. this study is a registry analysis of an -year period ( to ). results: a total of children (mean age years, % were boys) with severe trauma were included in the cohort. fifty-seven, % and % of patients were admitted to a level i, ii and iii, respectively. road accident was the main mechanism of injury ( % of patients). thirtysix percent of patients had a severe trauma, defined as an injury severity score (iss) higher than . one quarter of patients had at least severe lesions and one-third of patients had a trauma brain injury. the pre-hospital gradation was closely related with injury severity score (iss) and intra-hospital mortality rate. the triage protocol had a sensitivity of % and a specificity of % to predict adequate admission of patients with iss more than . using a specific trauma score (including occurrence of death, an admission in intensive care unit and the need for urgent surgery), sensitivity and specificity reached and %, respectively. fourty-six percent of patients were not graded at the scene (non-graded group). undertriage rate was significantly reduced in the graded group compared with the non-graded group, ( % versus %), without significant modification of the overtriage rate ( % versus %). overall, mortality at discharge from hospital was %, but % in grade a patients. conclusion: implementation of a regional pediatric trauma system with a specific pre-hospital triage procedure was effective in detecting severe pediatric trauma patients and in lowering the rate of prehospital undertriage. compliance with ethics regulations: yes. rationale: critically ill children suffer from pathophysiological changes, leading to large between-subject variability in drug clearance. since piperacillin is eliminated mainly via the kidney, changes in renal function go along with a modified elimination, and possible subtherapeutic or toxic drug concentrations. we aimed to determine the most accurate glomerular filtration rate (gfr) estimation formula for assessing piperacillin clearance in critically-ill children. patients and methods: all children hospitalized in pediatric intensive care unit and receiving piperacillin were included. piperacillin was quantified by high performance liquid chromatography. pharmacokinetics were described using the non-linear mixed effect modeling software monolix. in the initial pharmacokinetics model, gfr was estimated according to the schwartz formula. in the study, gfr was estimated with additional formulas, developed with plasma creatinine and/or cystatin c. biases, precisions, spearman's rank correlation coefficient and normalized prediction distribution error (npde) were used to assess the models. results: we included children with a median (range) postnatal age of . ( . - ) years, body weight of . ( . - ) kg and estimated gfr according to the schwartz formula of . ( - ) ml min- . . m . piperacillin concentrations were best predicted with the model using the creatinine clearance. the correlations were most accurate: r = . between the population-predicted and the observed concentrations, r = . and r = . for the npde versus population-predicted concentrations and time, respectively. concerning the individual predicted concentrations, bias and precision were respectively − . mg l − and . mg l − . gfr estimations based on serum creatinine were higher than those based on cystatin c (p = . ). conclusion: in summary, the -h creatinine clearance is the best predictor of piperacillin clearance and this could be investigated for drugs with renal elimination. as a whole, literature and our findings strongly suggest using creatinine clearance to also estimate gfr in critically ill children. the gap between the gfr estimations is large depending on the formulas, with higher estimations with equations based on serum creatinine. compliance with ethics regulations: yes. rationale: acute pancreatitis (ap) incidence have increased dramatically over the past years. new guidelines in were recently published in order to standardize the definition and management of ap. the aim of this study is to describe the management of children that were diagnosed with ap from the pediatric intensive care unit (picu) in two french hospitals. patients and methods: this retrospective cohort study included children aged under years old, who were admitted to the picu of robert-debré hospital and trousseau from to with a discharge diagnosis of ap. data collected included management, severity and outcomes. we have also obtained data on clinical, biological and radiological presentation. results: sixty patients were included, the median age was years ( - ) and % had a co-morbidity mainly hematologic ( / ). most of the ap were moderate ( %) or severe ( %). hemodynamic failure was the main reason for picu admission requiring a median fluid resuscitation ml/kg complemented by a median intravenous fluid therapy of ml/kg/h ( - ) during the first h. twenty patients ( %) required mechanical ventilation. fasting has been instituted in patients ( %) for a median of days ( - ), whereas patients ( %) received parenteral nutrition, only patients ( %) received enteral nutrition. antibiotic therapy was given to patients ( %) including % for curative therapy. the median length of stay in picu was days ( ) ( ) ( ) ( ) ( ) . the mortality rate was %. conclusion: this is the first french study which precisely described the management of patients with ap in picu. it highlighted the differences withthe new international guidelines. this study could improve the management of pa in picu and open research perspectives. compliance with ethics regulations: yes. rationale: apheresis and therapeutic plasma exchange (tpe) for children diseases has been poorly investigated in mostly small-uncontrolled studies. the purpose of this study is to describe indications and safety of tpe in children. patients and methods: in this single center and retrospective study, we included patients who underwent tpe with an age < years old in the pediatric center of necker-enfants-malades hospital from january to december . data were retrospectively collected in an electronic case report form via a web-based data collection system. results: patients with a median age of . years [range . ; . ] were selected. they achieved a total number of procedures. indications were antibody-mediated rejection (n = ; %) or desensitization therapy (n = ; %) for solid organ or hematopoietic transplantations; microangiopathy (n = ; %); renal diseases (n = ; %) and pediatric inflammatory diseases (n = ; %); or hyperviscosity syndrome (n = ; %). each patient had an average of procedures for the first session [range ; ] with a median volume of ml [range ; ml] corresponding to a median (rang) total plasma volume (tpv) equivalent of . l/m [ . - . ]. within days since the beginning of sessions, patients ( %) present a total of adverse events (aes) potentially related to tpe. there was a median (range) of aes/patients [ - ]. there was no association between aes and diseases, severity of patients, venous access, plasma substitute and body weight. few of aes (n = for patients) were potentially life-threatening and concerned mostly critically ill children. allergic reactions represented only aes for patients (grade i n = ; grade ii n = ; grade iii n = ). at the months endpoint, ( %) patients died and ( %) patients had severe persistent disease. no death had been related to the tpe process. we describe one of the largest retrospective pediatric cohort updated to the last international recommendations. tpe in children is performed for specific and potentially refractory disease. it is feasible without a major risk of life threatening adverse events. compliance with ethics regulations: yes. yacine benhocine university hospital nedir mohamed, tizi-ouzou, algeria correspondence: yacine benhocine (yacine @yahoo.fr) ann. intensive care , (suppl ):f- rationale: although analysis of literature data shows that implantable chamber catheters (iccs) are less at risk of infectious complications than other central venous catheters, these complications can be serious, which may differ from ongoing treatments such as chemotherapy, and may lead to the removal of the implanted device. the literature on preventing these infections is quite disparate, as practices. purpose: to evaluate the incidence of infections, to identify responsible germs and to measure the impact of preventive measures. patients and methods: prospective, descriptive, mono-centric study, from january to january . all patients under the age of who have benefited from an implantable chamber catheter, whose insertion procedure is as follows: local anesthesia, surgical asepsis (polyvidone iodine) in an operating room, double disinfection, no antibiotic prophylaxis, routes used: subclavian ( %), internal jugular ( %) by anatomic registration. the main criteria of judgment are: the incidence of local and general infections, their time of onset, responsible microorganisms. statistical analysis used the statistical package for the social sciences software. results: patients were included, the average incidence density of early infection is . / day-catheters. the time of onset of infection is essentially between the nd and rd week post-exposure, of which % is general infection. ablation involved % of infected catheters. the causative organisms are mainly gram-positive cocci ( . %), gram-negative bacilli are less involved ( . %), with a significant number of candida infections ( %). discussion: higher incidence of data from the literature. to remedy this requires the implementation of additional hygiene measures: antiseptic showers preoperatively, chlorhexidine??, and practice changes: echo guidance, antibiotic prophylaxis or locks? second generation catheters? our practices are disparate especially since the recommendations specifically concerning the prevention of infectious risk associated with internationally published iccs are rare. conclusion: at the end of this work, our perspectives are to: update the procedure, highlight risk factors on which it is possible to act, the adhesion of the different staff to the protocols. compliance with ethics regulations: yes. rationale: the sepsis and septic shock pediatric guidelines advise to treat patients using care bundles. in the first hour, the «resuscitation bundle» contains an appropriate fluid resuscitation, a broad-spectrum antibiotics administration after blood cultures, and initiation of inotrope if needed. the objectives were to evaluate the resuscitation bundle compliance in a cohort of septic children with cardiovascular dysfunction, and to analyze the effect on severity and outcome in pediatric intensive care unit (picu). patients and methods: retrospective analysis of the diabact iii study. this study analyzed the care course of children with severe community-acquired bacterial infection, hospitalized in picus in france's west departments, between august and january . children with severe sepsis and cardiovascular dysfunction were retrospectively included. results: we included children of whom ( . %) had compliant bundled care. the severity scores at picu's admission were similar between groups (p = . for the prism score and . for the pelod ). there was the same proportion of fluid-refractory shock (p = . ), mechanical ventilation (p = . ), neurological dysfunction (p = . ) and cardiac arrest (p = . ). in the «resuscitation bundle compliant» group, . % died versus . % in the other group (p = . ). we highlighted a severity bias: the sickest patients were more likely to receive compliant bundled care. conclusion: in our cohort, the resuscitation bundle's compliance was low. we did not show some effect on morbidity nor mortality. however, this study helps understand the factors associated with resuscitation bundle's compliance. rationale: nosocomial infections with extended-spectrum β-lactamase (esbl) producing gram-negative bacilli (gnb) are an important cause of hospital morbidity and mortality. the objective of this study was to determine the incidence and risk factors of nosocomial esbl-producing gnb infections in a paediatric intensive care unit (picu). patients and methods: a prospective surveillance study was performed from january through march in a picu. all patients hospitalized for more than h were included. centers for disease control and prevention criteria were applied for the diagnosis of nosocomial infection. results: during the study period, patients (median age: ± days) were included. the average length of stay was ± days with a total of , days of hospitalization. newborns accounted for . % of patients. sixty-two per cent of patients were colonized with multi drug resistant gram-negative rods, on admission or during their stay in the picu. one hundred and nineteen bacterial infectious episodes were registered ( . / patient days). one hundred infectious episodes were caused by a gnb and ( . %) by esbls producing gnb with an incidence of . / patient days (bloodstream infections: episodes, ventilator acquired pneumonia: episodes). esbls producing gnb infection had a specific incidence of . per catheter-days, and . per mechanical ventilation-days. fifty-nine percent of patients infected with esbls producing gnb had a prior digestive colonization with a multidrug-resistant gnb. forty-one episodes ( %) occurred in patients with central venous catheters. klebsiella pneumoniae was the most frequently isolated bacteria ( . %). mortality in the esbls producing gnb group was high ( . %). associated factors of nosocomial esbls producing gnb infection were mechanical vrntilation (p < . ), central venous catheterization (p < . ) and colonization with multiple drug-resistant gram-negative bacteria (p < . ). conclusion: nosocomial esbl-producing gnb infection had an incidence of . per patient days in our unit and seems to increase the mortality rate. factors associated with this infection were identified. marie lemerle , aline schmidt , valérie thepot-seegers , achille kouatchet , valérie moal , mélina raimbault , corentin orvain , jean-francois augusto , julien demiselle chu angers, médecine intensive réanimation, angers, france; chu angers, maladie du sang, angers, france; chu angers-ico, angers, france; chu angers, pharmacie, angers, france; chu angers, labora-toire de biochimie, angers, france; chu angers, néphrologie dialyse transplantation, angers, france correspondence: marie lemerle (marielemerle@yahoo.fr) ann. intensive care , (suppl ):f- rationale: acute kidney injury (aki) is associated with high morbidity and mortality in the setting of tumor lysis syndrome (tls). thus, strategies aimed at preventing aki occurrence represent a major goal to improve prognosis of patients with tls. the role of hyperphosphatemia as a risk factor of tls has been poorly analyzed. the aim of this study was to study the association between hyperphosphatemia and aki, and to determine whether a cut-off value of phosphatemia or phosphatemia's variation was associated with aki development during tls. patients and methods: in this retrospective and monocentric study, we included all patients with tls and whithout aki at admission, admitted to hematology, nephrology and intensive care units of the university hospital of angers between / / and / / . results: one hundred and thirty tls episodes were identified in patients. aki developed during episodes of tls ( %). hospital mortality was much higher in aki patients ( . % versus . %, p = . ). phosphate maximal values ( . ± . versus . ± . ) and ldh maximal values ( . ± . versus . ± . ) were higher in tls with aki, before aki occurrence (p = . and p = . , respectively). we found no association between the other biological parameters of tls and aki (serum calcium, uric acid and potassium). after adjustment for cofounders, there was a strong association between a rise in phosphate level of . mmol/l (hr . ic % [ . - . ], p < . ), exposure to platinum salts (hr . ic % [ . - . ], p = . ) and increasing maximal ldh value (hr per ui/l increase . ic % [ . - . ], p = . ) with aki. conclusion: this study highlights the utmost importance of serum phosphate in the setting of tls: phosphate is an early relevant biomarker for the risk of aki development. further studies are needed to assess whether aggressive prophylactic treatment to control serum phosphate concentration, such as renal replacement therapy before aki onset, constitutes a valuable approach. compliance with ethics regulations: yes. retrospective cohort of patients admitted to the medical icu of university affiliated hospital after carts treatment between august and august . results: of the patients treated by carts in the haematology department, ( %) were subsequently admitted to icu. median age was [ . - . ] years, and ( . %) were female. carts were indicated for r/r lymphoma. the median time between carts injection and icu admission was [ . - . ] days. all patients had cytokine release syndrome (crs), and ( . %) developed car-related encephalopathy syndrome (cres). median sofa score and saps were [ - . ] and [ . - . ], respectively. four ( . %) patients had hypotension treated by fluid bolus (n = ) or vasopressors (n = ), and ( . %) had acuterespiratory failure requiring oxygen therapy (n = ) or mechanical ventilation (n = ). six ( . %) patients had neurological symptoms (impaired consciousness n = , confusion n = , transient aphasia n = ), of whom one developed refractory convulsive status epilepticus afterwards. all patients received broad spectrum antibiotics, of whom ( . %) had documented infections. six ( . %) patients received interleukin- inhibitor (single dose n = , multiple doses n = ), and ( . %) received intravenous dexamethasone. one patient died in the icu from septic shock. median icu and hospital length of stays were [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] and [ . - . ] days, respectively. two ( . %) patients died from relapsing malignancy before hospital discharge. three months after icu admission, four ( . %) patients were alive in complete remission. conclusion: more than % of patients treated with carts required icu admission for the management of a crs or a cres. early icu admission, close collaboration between haematologists and intensivists, and prompt administration of appropriate therapy (il- inhibitor and/or dexamethasone) and supportive care resulted in a good prognosis. compliance with ethics regulations: yes. rationale: tisagenlecleucel (ctl ) is a chimeric antigen receptor t cell therapy that reprograms autologous t cells to target cd + leukemia cells, approved in the us since august and in the eu since august for children and young adult (< years old) with relapsed/refractory b-cell acute lymphoblastic leukemia (b-all). this study reports the experience of picu management of ctl toxicity in patients treated in robert-debré university hospitals. patients and methods: all patients (age < years old) treated by tisagenlecleucel infusions between march , and september , , included in sponsored-clinical trials or treated within the french compassionate program or with the commercial product, were retrospectively analyzed. results: twenty-four patients were infused and patients ( %) were managed in picu for stays. ( stays: n = and stays: n = ). median age at picu admission was . years old [ . ; . ] with a median delay after car-t cells infusions of days [ . ; ] . the median length of stay in picu was days [ . ; ] with a max at days. cytokine release syndrome (crs) was the main indication of picu hospitalization ( . %, n = ) with grade (n = ) and grade (n = ) according to american society for transplantation and cellular therapy (astct) consensus grading system and treated by corticosteroid (n = . ) and tocilizumab (n = , only one infusion). norepinephrine was the only vasopressor used. the median vaso-inotrope score (vis) for grade was [ . ; . ] with a maximum at . neurologic toxicity was observed in patients with a grade (status epilepticus) and grade (focal edema on neuroimaging with depressed level of consciousness) according to immune effector cell-associated neurotoxicity syndrome (icans) grading system from astct consensus. the status epilepticus was managed with anti-epileptic drugs without mechanical ventilation. the focal edema was related to hhv and toxoplasmosis encephalitis. evolution was positive with foscavir and ganciclovir and days of mechanical ventilation. one patient was hospitalized for septic shock secondary to gram-negative central line bloodstream infection in aplasia, with a vis score at . evolution was favorable with antibiotics and central line removal. no death in picu from severe tisagenlecleucel toxicity was observed since the beginning of the car-t cells program. conclusion: toxicity profile of tisagenlecleucel required frequent and early picu hospitalization after infusions for severe crs and icans management. compliance with ethics regulations: yes. rationale: car-t cell (chimeric antigen receptor t) therapy is a promising treatment in refractory acute lymphoid leukemia (all) and diffuse large b cell lymphoma (dlbcl). the main complication consists in a cytokine release syndrome (crs) leading to an inflammatory state that can be very severe with life-threatening organ failure. neurological toxicity is also reported. we aim to describe car-t cells-related complications in icu patients. patients and methods: this is a single-center prospective study conducted between july and august . all the patients who have received car-t cells and who required icu admission were included. crs grading was defined according to the most recent classification of the asbmt and neurological toxicity was assessed with the cartox scale. each admission is considered independent and therefore corresponds to one patient. results: admissions, representing patients ( men and women), were considered. the median age was years . twothirds of the patients have been diagnosed with dlbcl (n = , %) and one-third with all (n = , %), months [ - ] ago. they had received lines [ ] [ ] of chemotherapy and had a high tumor burden ( % of lymphomas classified stage iv). the majority of the patients was admitted because of hemodynamic failure (n = , %) or respiratory failure (n = , %), days [ ] [ ] [ ] [ ] [ ] after car-t cells infusion. sofa at admission was [ ] [ ] [ ] [ ] [ ] . all the patients presented at least one complication ( figure) , the most common being crs (n = , %) with a median grade of [ ] [ ] . neurological toxicity was reported in ( %) patients (worst grade at [ ] [ ] [ ] ). documented bacterial infection involved % of the patients and consisted in catheter-related infections for half of the cases. in the icu patients were managed with fluid resuscitation (n = , %) during the first day, vasopressors (n = , %) and broad spectrum antibiotics ( %). a single patient required mechanical ventilation and two patients underwent dialysis. tocilizumab (anti-il receptor) was given to patients ( % of crs) in a median time of . h [ . - . ] after icu admission. patients ( %) received corticosteroids. the median icu length of stay was . days [ ] [ ] [ ] [ ] . patients ( %) died in the icu and hospital mortality was %. the -fluorouracil ( -fu)-induced hyperammonemic encephalopathy is a rare but serious -fu adverse drug reaction, which could require the admission of patients in intensive care unit (icu). given the paucity of data regarding this -fu adverse drug reaction, we performed a retrospective national survey from the french pharmacovigilance database to better characterize -fu-induced hyperammonemic encephalopathy and its management. patients and methods: since the inception of the french pharmacovigilance database, we identified all patients that experienced -fu-induced encephalopathy. variables regarding epidemiology, characteristics, management and prognosis of these patients were collected and analyzed. results: from from to years-old, % of women) were included. overall mortality was % (n = ) and % (n = ) of patients were admitted in icu. the -fu-induced hyperammonemic encephalopathy started [ ] [ ] [ ] [ ] days after the onset of -fu infusion. the most common neurological disorders were consciousness impairment, confusion and seizures. abnormalities in ct scan, mri, electroencephalogram and lumbar puncture were found in %, %, % and % of the whole population respectively, similar in icu and non-icu patients. ammonemia was dosed in % of the whole population and in % of icu patients. hyperammonemia tended to be higher in icu than in non-icu patients ( [ - ] vs. [ - ] µmol/l, respectively, p = ns) and in patients with the lowest glasgow outcome scale, but was not different between survivors and non-survivors. among icu patients, % required mechanical ventilation and % anti-epileptic drugs administration. besides -fu discontinuation, lactulose intake, renal replacement therapy or ammonium chelators were used to decrease hyperammonemia in %, % and % of patients respectively. a complete neurological recovery was observed in up to % of icu and non-icu patients within a delay of [ - ] days. a dihydropyrimidine deshydrogenase (dpd) deficiency was found in % of tested patients. a -fu rechallenge was considered in % (n = ) of patients with complete neurological recovery, including a patient with a partial dpd deficiency, within a delay of [ - ] days after recovery. a -fu-induced hyperammonemic encephalopathy relapse was observed in % of patients with -fu rechallenge. no relapse was observed when -fu rechallenge was performed with a decreased -fu dosage. conclusion: we report the first national survey and the largest cohort of patients with -fu-induced hyperammonemic encephalopathy so far. this serious -fu adverse drug reaction must be known by intensivists, since more than half of patients are admitted in icu and specific treatments are available. compliance with ethics regulations: yes. immune related adverse events: a retrospective look into the future of oncology in the intensive care unit adrien joseph , annabelle stoclin , antoine vieillard-baron , guillaume geri , jean-marie michot rationale: immune checkpoint inhibitors (ici) represent a paradigmatic shift in oncology. with their new position as a mainstay in cancer treatment, new toxicities called immune related adverse events (iraes) have emerged. patients and methods: retrospective study including patients admitted in the icu within days after treatment with an ici in french hospitals. patients were classified into groups according to the reason for admission: irae, intercurrent adverse event (intae) or event related to tumor progression (tumprog). results: patients were admitted during the course of an ici treatment, including irae, intae and tumprog, with a significant increase between (n = ) and (n = patients, p for trend < . ). irae included pneumonitis, colitis, diabetes complications, hypophysitis, nephritis, myocarditis and cardiac disorders, hepatitis or allergic reaction and meningitis. the immune related nature of the complication was known before admission in only ( %) cases. mean age was (± ) years and % had a performance status of - . primary tumors were melanomas ( , %), non-small cell lung cancers ( , %) , urothelial carcinomas ( , %) and hodgkin lymphomas ( , %) . ici at the time of admission included anti-ctla ( , %), anti-pd /pdl ( , %) and anti-ctla /anti-pd combination in ( %) patients. mean duration of stay in the icu was . (± ) days. three patients required vasopressor therapy alone, with mechanical ventilation and one with extracorporeal membrane oxygenation. three patients required non-invasive ventilation and renal replacement therapy alone. six required only endocrine or electrolytic equilibration and others did not receive any form of organ support. icu mortality was %. compared with other admissions, anti-ctla or anti-ctla /anti-pd combination treatments were associated with irae diagnosis (or = . [ . - . ] , p = . for anti-ctla and . [ . - . ] for anti-ctla /anti-pd , p = . ) and so was the diagnosis of melanoma ( . [ . - . ] , p = . ). there was no difference in terms of icu and post-icu survival between irae (median post-icu survival months [ -na]), intae ( . [ . -na]) and ). six patients admitted for an irae were rechallenged with the same ici after icu discharge and achieved complete response. conclusion: we conducted the first study describing patients admitted in the icu for iraes. their specific and heterogeneous profile, along with the expected increase in the number of admissions, underlines the need for an in-depth knowledge for icu physicians in order to take part in the multidisciplinary care required by these patients. compliance with ethics regulations: yes. rationale: patients with advanced-stage non-small-cell lung cancer have high mortality rates in the intensive care unit (icu). in this context, acute respiratory failure due to cancer involvement is the worst situation. in the last two decades, targeted therapies have changed the prognostic of patients with lung cancer outside the icu. unlike cytotoxic chemotherapy, the fast efficacy of targeted therapies led some intensivists to use them as rescue therapy for icu patients. we sought to investigate the outcomes of patients with lung cancer involvement responsible for acute respiratory failure and who received tyrosine kinase inhibitor during icu stay. patients and methods: we performed a national multicentric retrospective study with the participation of the grrroh (groupe de recherche en réanimation respiratoire en onco-hématologie). all patients with non-small-cell lung cancer admitted to the icu for acute respiratory failure between and were included in the study if a tyrosine kinase inhibitor was initiated during icu stay. cases were identified using hospital-pharmacies records. we collected demographic and clinical data in icu charts. vital status was assessed at the time of study completion (august ). the primary outcome was overall survival days after icu admission. results: twenty-nine patients (age: ± years old) admitted to a total of icus throughout france were included. seventeen patients ( %) were nonsmoker. the most frequent histological type was adenocarcinoma (n = , %) and a majority had metastatic cancer (n = , %). epithelial growth factor receptor mutation was the most common oncologic driver identified (n = , %). during the icu stay, ( %) patients required invasive mechanical ventilation, ( %) catecholamine infusion, ( %) renal replacement therapy and one ( %) extracorporeal membrane oxygenation. in addition to tyrosine kinase inhibitor, ( %) patients received steroids (beyond . mg/kg/day) and ( %) cytotoxic chemotherapy during icu stay. seventeen patients ( %) were discharged alive from icu and ( %) were still alive after days (see kaplan-meier curve figure) . moreover, patients ( %) were alive one year after icu discharge. conclusion: despite a small sample size this study showed that, in the context of lung cancer involvement responsible for acute respiratory failure, the use of tyrosine kinase inhibitor should not be refrained in patients with severe condition in icu. compliance with ethics regulations: yes. rationale: acute respiratory failure is the leading reason for intensive care unit (icu) admission in immunocompromised patients and the need for invasive mechanical ventilation has become a major clinical end-point in randomized controlled trials (rct). however, data are lacking on whether intubation is an objective criteria that is used unbiasedly across centers. this study explores how this outcome varies across icus. patients and methods: hierarchical models and permutation procedures for testing multiple random effects were applied on both data from observational cohort (the trial-oh study: patients, icus) and randomized controlled trial (the high trial: patients, icus) to characterize icu variation in intubation risk across centers. results: the crude intubation rate varied across icus from % to % in the observational cohort and from to % in the rct. this center effect on the mean icu intubation rate was statistically significant, even after adjustment on individual patient characteristics (observational cohort: p-value = . , median or . [ . - . ]; rct: p-value: . , median or . [ . - . ]). two icu-level characteristics were associated with intubation risk (the annual rate of intubation procedure per center and the time from respiratory symptoms to icu admission) and could partly explain this center effect. in the rct that controlled for the use of high-flow oxygen therapy, we did not find significant variation in the effect of oxygenation strategy on intubation risk across centers, despite a significant variation in the need for invasive mechanical ventilation. conclusion: invasive mechanical ventilation has become an important endpoint in immunocompromised patients with acute respiratory failure. however, we found significant variation in intubation risk across icu in both an observational cohort and a randomized controlled trial. our results highlight the need to take into account center effect in analysis because it could be an important confounder. reasons for heterogeneity are various (case-mix differences, center practices). this gives opportunities to future improvement in care management and study design. compliance with ethics regulations: yes. rationale: influenza virus (iv) infection is a major cause of ards that has been the focus of attention since the pandemic h n (h n pdm ) iv. although iv-mediated damage of the airway has beenextensively studied emphasizing specificity compared to other causes of ards, the impact of iv infection on the prognosis of ards patients, compared to the other causes of ards, has been few assessed. patients and methods: systematic detection of iv in times of epidemic using rt-pcr in respiratory specimen is routine practice in our icu along with prospective data collection of patients admitted to our icu for ards with pao /fio ratio ≤ mmhg. all patients received lung-protective ventilation, the sequential organ failure assessment (sofa) score was calculated on the first days of mechanical ventilation. the primary endpoint compared the -day survival from the diagnosis of ards between patients with and without iv infection. results: from october, to may, , patients (pts) [median saps ii score = ( - ); age years ( - ); pao / fio ≤ mmhg, n = ( %)] were admitted to our icu for ards with pao /fio ratio ≤ mm/hg, including pts ( %) with iv infection (h n pdm iv a, n = ; h n a virus, n = ; b virus, n = ; associated bacteria, n = ). other main causes of ards were bacterial pneumonia without iv ( %), aspiration ( %), non-pulmonary sepsis ( %). ( %) received prone positioning, and ( %) extra-corporeal membrane oxygenation. the overall mortality rate at day- for the entire population was % ( pts ( %) with iv infection versus pts ( %) without iv infection, p = . ). kaplan-meier survival curves showed that survival was significantly higher in patients with iv infection than in those without iv infection. iv infection remained independently associated with a better prognosis at day- when entered as dichotomous variable (iv infection, yes/no) (adjusted hazard ratio (hr) = . , % ci . - . , p = . ) and when iv infection only was distinguished from other causes of ards including mixed infection iv plus bacteria (adjusted hr = . , % ci . - . , p = . ). of note, within the first days of mechanical ventilation, non-pulmonary sofa scores were significantly lower in iv patients although similar pulmonary sofa scores. conclusion: our results suggest that patients with iv related ards have less severe non-pulmonary organ dysfunctions than those with ards from other and a lower mortality at day- despite similar ards severity. compliance with ethics regulations: yes. rationale: acute respiratory distress syndrome (ards) remains frequent in intensive care unit (icu) with % to % mortality. according to joint theater trauma system, ards occurs among % of war casualties: direct lung trauma, blast lesions, burn, massive transfusion and systemic inflammatory response syndrome lead to ards development. however, there is no data reporting ards among french evacuated casualties from forward environment. our study's aim is to describe ards incidence and its severity concerning medical evacuations from war theater. patients and methods: this is an observational retrospective multicentric study analyzing all evacuated patient from war theater and admitted in icu. all patients developing ards according to berlin definition have been included. study has been approved by local ethic committee. primary study endpoint was ards developing. second study endpoints were ards severity, duration of invasive ventilation, ards treatments, icu length of stay and mortality. results: patients have been admitted in icu between and . have been excluded. a total of patients have been analyzed. % (n = ) were military aged ( - ) years. % (n = ) developed ards. we found % (n = ) war casualties, % (n = ) trauma not related to war and % (n = ) medical patients. among severe trauma, median iss was ( - ), ais thorax ( ) ( ) ( ) , and % benefited from surgery on forward environment and % (n = ) received massive transfusion. % (n = ) suffered from mild ards, % (n = ) moderate ards and % (n = ) severe ards. evacuation time was ( - ) h. at admission in icu, pao /fio ratio was ( - ) (fig. ). all patients were intubated. ards treatments used were curarization ( %, n = ), prone position ( %, n = ), inhaled nitric oxide (noi) ( %, n = ), almitrine ( %, n = ) and extracorporeal life support (ecls) ( %, n = ). invasive ventilation duration was ( - ) days, length of stay ( - ) days, and -month mortality % (n = ). conclusion: according to our study, ards among french evacuated patients from war theaters remains frequent: it occurs on % among icu admitted patients. % suffer from severe ards with % global mortality. those datas are consistent with us studies. also, we wonder if we must adapt our treatment capacities on forward environment for the most severe patients. in us army, a specialized team (acute lung rescue team) is trained to care the most hypoxemic war casualties with more treatment options as noi, ecls. compliance with ethics regulations: yes. rationale : we recently reported that septic shock patients with pneumonia exhibit a high risk of icu-acquired pneumonia, suggesting that a primary pulmonary insult may drive profound alterations in lung defence towards secondary infections ( ) . given their importance in lung immune surveillance, alveolar macrophages (am) are likely to play a pivotal role in this setting. the objective of this experimental study is to address the impact of primary pulmonary or non-pulmonary infectious insults on lung immunity. patients and methods: we established relevant double-hit experimental models that mimic common clinical situations. c bl/ j mice were first subjected either to polymicrobial peritonitis induced by caecal ligation and puncture (clp), or to bacterial pneumonia induced by intra-tracheal instillation of staphylococcus aureus or escherichia coli. respective control mice were subjected to sham laparotomy or intratracheal instillation of phosphate-buffered saline. seven days later, mice that survived the primary insult were subjected to intra-tracheal instillation of pseudomonas aeruginosa (pao strain). we assessed survival and pulmonary bacterial clearance of post-septic animals subjected to p. aeruginosa pneumonia, as well as the distribution and functional changes in alveolar macrophages. results: when compared to sham-operated mice, post-clp animals exhibited increased susceptibility to secondary p. aeruginosa pneumonia as demonstrated by defective lung bacterial clearance and increased mortality rate ( % vs. %, p < . ). in contrast, all postpneumonia mice survived and even exhibited improved bacterial clearance as compared to their control counterparts. when addressing whole-lung immune cell distribution at the time of second hit (day ), amounts of am were decreased in post-clp mice while preserved or even increased in post-pneumonia mice. antigen-presenting functions of am appeared similar in all conditions. percentages of apoptotic (annexinv + ) and necrotic ( -aad + ) am were comparable at day and day after the first hit. interestingly, both ly c high and ly c low monocytes were sustainably increased in the lungs of post-clp mice, while only transiently expanded following pneumonia, suggesting that differences in am counts could be related to modulated turnover from precursor monocytes. conclusion: using clinically relevant double-hit experimental models, a primary pulmonary infection conferred resistance to secondary bacterial pneumonia. ongoing investigations are aimed at addressing the antibacterial am functions, as well as the turnover-driving mechanisms.compliance with ethics regulations: yes. rationale: little is known on the role of exit-site signs in predicting intravascular catheter infections. the current study aimed to describe the association between local signs at the exit-site and catheter-related bloodstream infection (crbsi), which factors substantially influenced local signs and which clinical conditions may predict crb-sis if inflammation at insertion site is present. patients and methods: we used individual data from multicenter randomized-controlled trials in intensive care units (icus) that evaluated various prevention strategies regarding colonization and crbsi in central venous and arterial catheters. we used univariate and multivariate logistic regression stratifying by center in order to identify variables associated with redness, pain, non-purulent discharge, purulent discharge and ≥ local sign and subsequently evaluate the association between crbsi and local signs. moreover, weevaluated the role of thedifferent local signs for developing crbsi in subgroups of clinically relevant conditions. results: a total of patients, , catheters ( , catheterdays) and crbsi ( . %) from icus withdescribed local signs were included. redness, pain, non-purulent discharge, purulent discharge and ≥ local signs at removal were observed in ( . %), ( . %), ( . %), ( . %) and ( . %) episodes, respectively. the sensitivity of ≥ local sign for crbsi was by . %, whereas the highest specificities were observed for pain ( . %) and purulent discharge ( . %). positive predictive value (ppv) was low for redness ( %), pain ( %), non-purulent discharge ( %) and ≥ local sign ( %), but increased for purulent discharge ( . %). negative predictive values were high for all local signs. after adjusting on confounders, crbsi was associated with redness, non-purulent discharge, purulent discharge and ≥ local sign (fig. ). conditions independently associated with ≥ local sign were age ≤ years old (or . , % ci . - . , p < . ), sofa score (sofa < or . , % ci . - . , p < . ), non-immunosuppression (or . , % ci . - . , p < . ), catheter maintenance > days (or . , % ci . - . , p < . ) and insertion site (or for subclavian site . , % ci . - . , p < . ). however, the presence of ≥ local sign was more predictive for crbsi in the first days of catheter maintenance (or . , % ci . - . vs. > catheter-days or . , % ci . - . , p heterogeneity = . ). conclusion: this post hoc analysis showed that local signs were related to crbsis in the icu. local signs were independently associated with specific patient's and catheter's conditions. in the first days of catheter maintenance, local signs were predictive for crbsi. compliance with ethics regulations: yes. rationale: pneumococcal meningitis (pm) is the leading cause of bacterial meningitis in adult patients requiring icu admission and is associated with a high case fatality rate (cfr), ranging from to more than % ( ) ( ) ( ) . patients with pm may develop sepsis or septic shock that may impact management and outcomes. we aim to describe the epidemiology and outcomes of pm associated with sepsis in adult patients in france. we analysed the occurrence of pm with sepsis from to in adult patients, using the national french hospital database pmsi (programme de médicalisation des systèmes d'information). for all analyses, only the first hospital admission was considered. cases were identified using a combination of a diagnosis code for pm plus a diagnosis code for sepsis (either a code for organ failure or a procedure code for organ support). data recorded included comorbidities ( ), characteristics of the hospital stay, severity of the patients including major intracranial complications and characteristics of the infection. costs and endpoints were determined at the end of all the hospital stays related to the first admission for pm with sepsis. standardized incidence, hospital mortality, and cfr were estimated. temporal trends were assessed using cochran armitage tests of trends and linear trend analyses. results: a total of pm with sepsis aged ≥ years were hospitalized in france during - . the incidence of pm decreased from . to . per m inhabitants (p < . ) (fig. ) . most of them came from home ( %), were admitted in an academic institution ( %) and benefited from icu ( %). their median age was [ ; ] years. twothird of them had at least one comorbidity. the initial neurological presentations included coma ( %), focal signs ( %), seizures ( %) and brain stem involvements ( %). the saps ii score was [ ; ] points. the main neurological complications were cerebrovascular complications ( %), cerebral abscess ( %) and hydrocephaly ( %). pm was associated with pneumococcal septicaemia or pneumococcal pneumonia in % and % of cases respectively. the length of icu and hospital stays were [ ; ] and [ ; ] days respectively and only icu length of stay decreased over time (p < . ). the prognosis was poor since only . % of the patients were discharged to home. indeed, . % of them died and % were transferred to rehabilitation units. no temporal trends could be observed for these outcomes. the average hospital costs per case were , € [ . ; . ] . conclusion: pm with sepsis in adult in france remained a real burden associated with a high mortality rate, and disability. compliance with ethics regulations: na. rationale: mucormycosis is an emerging fungal infection, especially in patients with hematological malignancies. although this infection may lead to multi organ failure, no study has been dedicated to critically ill patients with hematological malignancy. the primary objective was to assess outcome in this setting. the secondary objective was to assess prognostic factors. patients and methods: this retrospective cohort study was performed in icus. critically ill adult patients with hematological malignancies and mucormycosis were included between and . mucormycosiswas classified as "probable"or "proven" regarding eortc criteria. variables are reported as median [iqr] or number (%). adjusted analysis was performed using cox model. results: twenty-six patients were included with a median age of years [iqr, . acute leukemia was the most frequent underlying disease (n = , %). nine patients ( %) were allogeneic stem cell transplantation (sct) recipients. nineteen patients ( %) had neutropenia and patients ( %) had received steroids. the main reason for admission was acute respiratory failure (n = , %) followed by shock (n = , %). the median sofa score at admission was [iqr, - ] points. only patients ( %) had received prior anti-fungal prophylaxis effective against mucorales. mucormycosis was "proven" in patients and "probable" in patients. diagnosis was made by histopathologic examination in patients, direct microscopy or culture in , and polymerase chain reaction in . rhizopus and mucor were the most frequent documented species. seven patients ( %) had concurrent aspergillus infection. mucormycosis was diagnosed day [− to + ] after icu admission. ten patients ( %) had pulmonary involvement whereas five patients ( %) had rhino-cerebral involvement. infection was disseminated in eight patients ( %). twenty-two patients ( %) were treated with liposomal amphotericin b. twelve patients ( %) received antifungal combination including posaconazole in . eight patients ( %) underwent curative surgery. multiple organ failure was frequent, patients ( %) requiring invasive mechanical ventilation (imv), ( %) vasopressors, and ( %) renal replacement therapy. icu and hospital mortality rates were % and %, respectively. only two patients were alive at day . three variables were associated with mortality in a cox model including allogeneic sct . ]; figure), sofa score (hr . [ % ic . - . ]) and dual therapy (hr . [ % ic . - . ]) (fig. ) . conclusion: mucormycosis is associated with a high mortality rate in patients with hematological malignancies, especially in allogeneic sct recipients. futility of icu management in these patients is to be considered and strategies aiming to improve these patients' outcome are urgently needed. compliance with ethics regulations: yes. rationale: sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection. several mediators, alone or in combination, were proposed to characterize individual response, but none was proven to have good external validity. the aim of this work was to establish whether some combinations are linked to clinical phenotypes in patients with presumed sepsis, using the data collected in the captain multicenter cohort which methods and first results were previously published (parlato, icm ). patients and methods: patients were prospectively included at the time of sepsis criteria, ( %) of whom with a secondary confirmed infection. community acquired pneumonia was causal in % of infections. saps score = points [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] , age = years , male sex = %. patients were followed for more than days, in whom usual icu clinical and biological parameters were collected, as well as plasma biomarkers and leucocyte associated rnas. patients were clinically classified according to their acute severity (sofa score, serum lactate), confirmed initial infection, outcome (secondary infection occurrence, icu survival). non-supervised principal component analysis of the maximal values of biomarkers assessed on first days of sepsis, and varimax rotation technique of the selected components using sas software. results: patients, med sofa day = pts, med serum lactates day = . meq/l, bacterial infection = ( %), enterobacteriaceae infection = ( %), vap and/or bacteremia after day = ( %), alive at icu d/c = ( %). five components explain % of the variance of the biomarkers. the first component ( % of the variance) was not linked to the clinical predetermined phenotypes. the second component ( % of the variance) was principally made of hla-dr rna, cd rna and cx cr rna, and linked to a lower initial severity (r = − . , p = . ), a less frequent confirmation of initial infection (p = . ), a lower occurrence of pneumonia or bacteremia (p = . ) or death (p = . ). conclusion: in our cohort, using non supervised analysis, we could separate a biomarker association linked to lower initial severity, lower rate of a bacterial cause to sepsis, and better outcome. the markers found are among those which are regularly considered as describers of the peripheral alteration of the immune system observed during sepsis (pachot, ccm ; friggeri, cc ; peronnet icm ) . compliance with ethics regulations: yes. ( ) compared a standard of care to a procalcitonin (pct) oriented use of antimicrobials for sepsis in icus. serial blood samples were biobanked in / icus ( / patients enrolled for pro-adrenomedullin (proadm) and pct concentrations). patients and methods: the aim of the study was to evaluate the respective impact of serial pct and proadm measurements in predicting relapse or superinfection and death on day *. relapse was defined as the growth of one or more of the initial causative bacterial strains (i.e., same genus, species) from a second sample taken from the same infection site at h or more after stopping of antibiotics, combined with clinical signs or symptoms of infection. superinfection was defined as the isolation from the same or another site of one or more pathogens different from that identified during the first infectious episode, together with clinical signs or symptoms of infection [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] points at amission, medical admission: ( %), immunocompromised: ( %), on mechanical ventilation ( %), pct and proadm at inclusion were [ . - . ] ng/ml and . [ . - . ] nm/l respectively. ( %) patients developed a first episode of recurrence or supereinfection after a median delay of days [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] and ( %) died before d . the hr maximization process proposed an optimal cut point of ng/ml for pct and nm/l for pro adm to predict d death. in the multivariate cox model, both pct and proadm were associated with death but not with relapse or superinfection (table ) . conclusion: conclusion: both serial measurements of pct and proadm are independent predictors of death in patients treated for sepsis in icu. our study confirmed the use of nm/l as a good prognosis cut point for proadm. . compliance with ethics regulations: yes. rationale: the performance of serum ( - )-β-d-glucan (bdg) and its evolution to predict the occurrence of invasive fungal infection (ifi) in a high risk non immunocompromized population remains to be determined ( ). in a post hoc analysis of the empiricus randomized clinical trial ( ), we aimed to assess the prognostic value of repeated measures of bdg on the occurrence of invasive fungal infections. patients and methods: non-neutropenic, non-transplanted, critically ill patients with icu-acquired sepsis, multiple candida colonization, multiple organ failure, exposed to broad-spectrum antibacterial agents, and enrolled between july and february in french icus were included. bdg were collected in icu at day , , , and after inclusion. a value time of more than pg/ ml, pg/ml and an increase by more than % from the previous measurement (threshold of measurement error) were assessed at baseline and overtime. for that purpose, we conducted cause specific hazard models with death as a competing risk. we also planned subgroup analyses on the placebo and the micafungin groups. cumulative risk (cumrisk) of ifi at day were derived from models. [ . ; . ] ). neither a bdg > pg/ml, nor an increase by % of bdg over time were associated with the occurrence of ifi. similar results were found in the placebo subgroup. conclusion: among high risk patients, a first measurement of bdg over pg/ml was highly associated with the occurrence of ifi. neither a cut-off of pg/ml, nor repeated measurements of bdg over time seemed to be useful to predict the occurrence of ifi. the cumulative risk of ifi in the placebo group if bdg > pg/ml is . % questioning about the potential interest of empirical therapy in this subgroup. compliance with ethics regulations: yes. rationale: since the sepsis- conference, the distinction between sepsis and septic shock is based on blood lactate value. septic shock may be encountered in the pre-hospital setting. in order to reduce the mortality, the precocity of treatments implementation has been emphasized, particularly early antibiotic administration. prior antibiotic administration, and blood culture drawing must be performed. the aim of this survey was to clarify the capabilities of french prehospital emergency service (pems) to measure blood lactate and to draw blood culture prior to hospital admission for septic shock. patients and methods: we performed an electronic survey of auto-questions addressed to the deputy chair of the french pems in . results: sixty pems ( %) participated in the survey. twenty-five percent are able to measure blood lactate and % are able to draw blood culture in the prehospital setting. ninety-five percent declared lactate measurement is helpful in assessing severity. ninety percent claimed that the lactate value influences the hospital facility, emergency department vs. intensive care unit. twenty-eight percent believe that the impossibility to draw blood culture precludes prehospital antibiotic administration. sixty-three percent estimate that a protocol for septic shock management would be beneficial. conclusion: few french pems are able to measure lactate and draw blood culture in the prehospital setting. the impact of blood lactate measurement and blood culture drawing by pems on septic shock outcome requires further studies. compliance with ethics regulations: yes. rationale: head injury is a common cause of morbidity and mortality in the first four decades of life, accounting for approximately , annual hospital admissions in the united kingdom. the majority of patients recover without intervention, however some may develop a long-term disability or even die. the early detection of pathology is therefore absolutely critical in determining patients' prognosis, helping to provide appropriate timely management. the national institute for health and care excellence (nice) adult head injury guidelines, recommend that head injuries with specific risk factors should have a ct scan within h of risk factors being identified. furthermore the provisional report should be made available within h of the scan. this audit assessed the compliance of staff to the nice adult head injury guidelines. patients and methods: the previous adult ct head scans, requested due to head injury, from the emergency department (ed) at london north west healthcare nhs trust were analysed for compliance to the nice guidelines. the standards measured were: ( ) time from request of scan to completion of scan should be within h; ( ) time from completion of scan to publication of provisional report should be within h. the locally agreed target for both standards was %. results: on review of the ct scans, ( %) were completed within h of request. from the scans ( %) not completed within the hour, were due to porter unavailability, due to an uncooperative patient and the remaining reasons were not clear from documentation. following completion of the scan, scans ( %) were provisionally reported within h. conclusion: this study highlighted a good compliance by hospital staff in ensuring patients with head injuries are managed appropriately, following detection of risk factors indicating a ct head scan. having said that, the locally agreed targets were just short of being met. one factor resulting in delayed scans was porter availability. an intervention recently introduced is the use of the "e-portering" application, which will endeavour to save time for referrers requesting porters and allow patient tracking. it is also worth educating porters, via email bulletins, on the importance of priority scans, such as ct head following injury. furthermore, the findings of the audit were relayed to the radiology department to help improve reporting times and to the ed to re-emphasize prompt requesting of ct head scans when clinically indicated. compliance with ethics regulations: yes. rationale: continuous insufflation of oxygen (cio) performed with specific endotracheal tube during cardiopulmonary resuscitation (cpr) is as effective as intermittent ventilation on endotracheal tube. experimental data suggest that cio improves the efficacy of external cardiac massage and reduces gastric dilatation. as endotracheal intubation is a cause of cpr interruption and requires skilled staff, a specific device has been developed to perform cio without intubation. this device has been implemented progressively in our fire department since . we evaluated this practice. patients and methods: longitudinal study comparing the patients with out-of-hospital cardiac arrest managed by our fire department with cio or bag-valve ventilation between january and april . patients who received mechanical chest compression were excluded. the main outcome was hospital survival. secondary outcomes were the return of spontaneous circulation (rosc) and cpr quality. univariate and multivariate analysis was performed in the whole cohort and in the sub-groups of patient with shockable and non-shockable rhythms to take into account factors associated with survival (shockable rhythm, witness, age). results: among the patients included, have been ventilated with cio and with valve-bag. the mortality was similar in the two groups (cio: . % valve-bag: . % p . ). mortality and rosc were not associated with cio in the multivariate analysis (odds ratio or . %-confidence interval ci [ . - . ] and . [ . - . ], respectively). cpr quality was better with cio than with valve-bag regarding cpr fraction (ratio of duration of chest compressions on total duration of cpr, versus % p < . ) and adequacy to the guidelines of the rhythm and depth of chest compressions ( % vs % p < . and % vs % p < . , respectively). in both subgroups of patients, cpr quality was still better with cio than with valve-bag. in the subgroup of patients with shockable rhythm, univariate analysis showed a lower mortality among the patients with cio than among the patients with valve-bag ( . % vs . % p < . ) but this difference was not confirmed by the multivariate analysis (or . ci [ . - . ], p . ). conclusion: cio without intubation is associated with an improvement of cpr quality but neither with mortality nor return of spontaneous circulation in case of out-of-hospital cardiac arrest. compliance with ethics regulations: yes. rationale: cardiovascular accidents are a leading cause of death. a cardiopulmonary resuscitation (cpr) of quality has well shown that can reduce the mortality; despite this, survival rate has not changed significantly during last years. the aim of this study is to test a new wearable glove to provide lay people with instructions during out-ofhospital cpr. patients and methods: we performed a blinded, controlled trial on an electronic mannequin ambuman to test the performance of adult volunteers, non-healthcare professionals performing a simulated cpr both, without and with glove, following the glove instructions. the group without glove, also called "no-glove" is intended as control group. each compression performed on the electronic mannequin ambuman was recorded by a connected laptop computer, drawing a depth frequency curve over the time. primary outcome was to compare the accuracy of the two simulated cpr sessions in terms of depth and frequency of chest compressions performed by the same lay volunteers. secondary outcome was to compare the decay of performance and percentage of time in which the candidate performed accurate cpr. finally, the participants were asked if the glove was useful for cpr maneuvers. the difference between the two groups in regard to change in chest compression depth over time due to fatigue, defined as decay were also analyzed. results: chest compressions were included: in control group, in glove group (table ) . mean depth of compression in the control group was . mm versus . mm in the glove-group (p = . ). compressions with an appropriate depth were not statistically different ( . % vs . %, p = . ). mean frequency of compressions in the group with glove was . rpm vs . rpm in the control group (p < . ). the percentage of compression cycles with an appropriate rate (> rpm) was . % in the group with the glove versus % in the control group, with an observed difference of . % between the two groups, which was statistically significant (p < . ,ci = %). a mean reduction over time of compressions depth of . mm (sd . ) was observed in the control group versus a mean reduction of . mm in the group wearing the glove (sd . ), but this mean difference in the decay of compressions delivery was not statistically significant (f-ratio = . , ss = . , df = , ms = . , p = . ). conclusion: the visual and acoustic feedbacks provided by the device were useful in dictating the correct rhythm for non-healthcare professionals, translating in a significantly more accurate cpr. compliance with ethics regulations: yes. rationale: neuroprognostication after cardiac arrest (ca) is a crucial issue and current guidelines recommend delayed multimodal approach. we aimed to describe reasons for death in a prospective cohort of ca patients and evaluate the diagnostic accuracy of early combined neurological prognostication tools such as automated pupillometry (ap), continuous amplitude electroencephalography (aeeg) and cardiac arrest hospital prognosis (cahp) score performed h after return of spontaneous circulation (rosc). we set up a monocentric prospective cohort of adult ca patients admitted in icu after sustained rosc and collected data according to utstein style recommendations. reasons for death were described under recently proposed classification: withdrawal of life-sustaining therapies (wlst) for neurological reasons, wlst due to comorbidities, refractory shock or recurrence of sudden ca or respiratory failure. for patients who kept abnormal neurologic state after rosc with glasgow coma scale < , we analysed accuracy of early neuroprognostication tools (ap, aeeg and cahp score) to predict poor neurological outcome, i.e. cerebral performance category (cpc) > at hospital discharge. results: patients were admitted after sustained rosc from ca during the period ( . . to . . ). in-hospital mortality was %. neurological wlst was the first reason for death ( %). exhaustive early neuroprognostication with ap, aeeg and cahp score was available for patients. among them, poor neurological outcome at hospital discharge (cpc > ) was observed for patients ( % (fig. ) . this strategy would falsely misclassificate % of patients in a good neurologic outcome category. other survivors ( %) should then be investigated with further classical delayed neuroprognostication tools. compliance with ethics regulations: yes. rationale: management delay is one of the determining factors in the assessment of emergency department quality of care. asking for a specialized advice seems to increase the time of delay. our study aimed at measuring the delays in obtaining specialized advice and identify their major causes. patients and methods: we conducted a prospective study over the period of month. we included all adult patients presenting to the emergency department who required specialized advice. data of all patients was collected. waiting times and influencing factors were studied. results: a total of patients were included. the main reason for calling for a specialized advice was to ask for a department transfer in % of cases. the time of the day when specialized advice was solicited (n (%)): in the morning ( ); in the afternoon ( ); in the evening ( ). the main solicited specialties were (n (%)): visceral surgery ( ), trauma medicine ( ), cardiology ( ), urology ( ), and pulmonology ( ). the average waiting time between calling for and getting the specialized advice was ± min. seventy-five percent of the specialized advice was obtained within h. the causes of the delay were (n (%)): physician busy in the operating room ( ), unreachable physician ( ), physician in the outpatient clinics ( ). the impact of the waiting time was (n (%)): conflict ( ), worsening patient state ( ). the average time between calling for the specialized advice and reaching a management decision was ± min. conclusion: the increasing length of stay of patients in the ed is strongly correlated to the delay in obtaining specialized advice. the implementation of a strategy to reduce the waiting time is necessary to avoid overcrowding the emergency departments and provide optimal care. compliance with ethics regulations: yes. rationale: hypnoanalgesia has been used since few years to reduce icu-patients physical and psychological discomfort during invasive procedures. however, feasibility of overall well-being management of intubated patients with hypnosis has not been described. patients and methods: we report here the hypnotic accompaniment of a -year old patient without significant medical history hospitalized in our icu for a severe gbs during months. the gbs was diagnosed by electrophysiological study and immunologic markers. patient had nearly complete paralysis of all extremities, but no facial or bulbar muscles. he received mechanical ventilation during days, including weaning time. tracheotomy was performed at day . sedative drugs were stopped days after intubation. hypnosis sessions were startedvery early after intubation by one of our trained intensivist. eight hypnotic sessions of hypnoanalgesia or hypnotherapy were performed after approval of the patient and his parents. time distribution is reported in fig. . first and second sessions were performed in order to induce relaxation and reduce anxiety. following sessions were dedicated to: ) decrease pain intensity (initially neuropathic, then induced by physiotherapy), ) attenuate the negative perception of paralysis, ) reduce the discomfort of tracheotomy ) promote the belief in healing ) facilitate swallowing exercises. furthermore the patient was quickly trained to use self-hypnosis in order to dissociate him from pain, anxiety and icu pollutions. results: feasibility of hypnosis was judged satisfactory by the operating physician, despite mechanical ventilation. after extubation, final debriefing with the patient indicates that the most efficient sessions were those focused on anxiety disorders (using the suggestion of a safe place) and suggestions of mobility (using a mangas metaphor). the patient reported very positive perception of hypnosis use. he explained that self-hypnosis was effective to reduce many discomfort. he used it frequently (generally twice a day) for a puff of anxiety or before enoxaparin injection. our observation suggests that hypnosis seems feasible in icu-awake patients and may be an interesting way to improve their icu lived experience in combination with validated measures. further investigations are needed to evaluate its effects on post-traumaticstress disorder. compliance with ethics regulations: yes. rationale: there is little medical reference for hypnosis in the intensive care field. closed specialties such as anesthesia, emergency medicine can help and refer to hypnosis for certain technical procedures. objective: to propose landmarks for a successful implementation of hypnosis by intensivists within the intensive care unit. patients and methods: this monocentric prospective observational study was performed from february to june in the -bed medical icu of brest university hospital. collected data were: characteristics of patients and hypnosis sessions performed, demographic data, physiological parameters (heart and respiratory rates) and objective and subjective evaluation of hypnosis sessions quality. results: patients were included (mean age . ± years, saps ii . ± points). hypnosis sessions were performed, of which / under mechanical ventilation. patterns of hypnosis sessions were: anxiety/comfort ( %), during a technical procedure ( %): toe, cvc placement, thoracic drainage, upper digestive or bronchial endoscopy), initiation of noninvasive ventilation or before intubation. most of time, the hypnotic trance was permitted by formal hypnosis techniques with travel and nature themes suggestion. efficacy was qualitatively assessed and rated as "total effectiveness" for % of sessions. qualitative evaluation by hypnotherapist, technical operator and observers was respectively . ± . , . ± . and ± / . heart rate decreased from ± to ± bpm and respiratory rate/min decreased from ± to . ± rpm during sessions. discussion: after a meeting, the healthcare team carried out a brainstorming to propose hypnosis in our unit. several difficulties were observed to explain implementation failures such as: finding competent patient, respiratory assistance, difficult communication, noisy environment, many nursing care, unexpected emergencies, etc.…). this experience allowed writing a vademecum to perform hypnosis in intensive care. our aims are to get more trained caregivers and to integrate hypnosis during our postresuscitation consultation, especially for post-traumatic stress. conclusion: hypnotic tools can facilitate technical procedures and improve patients' and caregivers' quality of life within the icu. compliance with ethics regulations: yes. effect of a musical intervention during central venous catheterization in an intensive care unit: the music cat prospective randomized pilot study sophie jacquier, brice sauvage, gregoire muller, thierry boulain, mai-anh nay chr, orléans, france correspondence: sophie jacquier (sophie.jacquier@chr-orleans.fr) ann. intensive care , (suppl ):f- rationale: evaluate the effect of a musical intervention on patient anxiety during a central venous access or a dialysis catheter implantation in an intensive care unit. patients and methods: the music cat study was a prospective, single-centre, controlled, open-label, two-arm randomized trial, conducted from february to february . central venous catheterization with musical intervention was compared to standard care, i.e., the usual procedure of central venous catheterization without listening to music. eligible patients had to be able to hear, understand explanations and consent. randomisation was stratified according to ventilation type (mechanical ventilation or not) and catheter site (superior vena cava or femoral vein). the music care ® (paris, france) application was used to make the patients listen to music through headphones. each patient chose his/her musical topic on a digital tablet, just before the catheterization. the primary outcome was the change in anxiety visual analogic scale (vas) between the beginning and the end of the catheterization procedure (t -tf anxiety vas). secondary outcomes included the patient's pain vas at the end of the procedure (tf pain vas). results: patients were included in the standard care group versus in the musical intervention group. main reasons for admission were the need of central catheter for chemotherapy ( , %), and sepsis and/or shock in both groups ( , %). catheters were inserted in the internal jugular vein in most cases ( , %) and about one-third were tunnelled in both groups. there was no between-group difference regarding median t -tf anxiety vas: [iqr:− to ] in the standard care group versus − [− to ] in the music intervention group (p = . ) (fig. ) , with no significant interaction between the variables of stratification or the operator experience and the intervention. the median tf pain vas was not statistically different between groups: [ to . ] in standard care group and [ to ] in music intervention group (p = . ), with no significant interaction between the variables of stratification or the operator experience and the intervention. conclusion: in this first randomized pilot study of musical intervention for central venous catheterization in awake patients in the intensive care unit, the musical intervention did not reduce patients' anxiety as compared to usual care. as the study may have been underpowered, larger size trials are needed. compliance with ethics regulations: yes. rationale: sleep is markedly altered in icu-patients under mechanical ventilation and may be due to noise, light, patient-care activities, patient-ventilator asynchronies, or the result of acute brain dysfunction induced by sedative drugs. to our knowledge, sleep has never been studied at icu admission before any sedation. our study aimed at assessing sleep quality of non-intubated sedation-free patients admitted to icu for acute respiratory failure. patients and methods: observational study performed in a single centre of a teaching hospital. patients admitted to icu for acute respiratory failure (respiratory rate ≥ breaths/min and pao / fio < mm hg under high-flow nasal oxygen) could be enrolled. patients with hypercapnia, central nervous disease, intubated early after admission and those with a do-not-intubate order were excluded. sleep was evaluated by complete polysomnography (psg) that started in the afternoon following admission and was continuously performed until the next morning. results: over a -year period patients were screened and patients were included. among them, patients were excluded for the following reasons: patient was intubated shortly after psg initiation, psg was lost, and eeg recordings ( %) were stopped before midnight (electrodes turned off or loss of signal). therefore, patients in whom psg was complete during the nocturnal period were retained in the analysis ( rationale: convulsive status epilepticus (cse) is a common neurological emergency associated with high mortality and morbidity rates. there are strong experimental data suggesting a potential impact of secondary brain insults (sbi) on outcome after cse. however, there is no clinical proof to support this hypothesis. our objective was to evaluate the association between sbi (mean arterial blood pressure, arterial partial pressure of carbon dioxide, arterial partial pressure of oxygen, temperature, natremia, and glycemia) at day and neurological outcomes days after cse. patients and methods: this was a post hoc analysis of the hyber-natus multicenter open-label clinical trial randomized critically ill patients with cse requiring mechanical ventilation to either therapeutic hypothermia ( - °c for h) plus standard care or standard care alone. patients still alive at day after inclusion were enrolled from march to january in french medico-surgical icus. the primary outcome was favourable outcome days after cse defined as a glasgow outcome scale score of . results: median age was of years . a previous history of epilepsy was noted in ( %) patients. most episodes ( / , %) occurred out-of-hospital, and ( %) were witnessed from their onset. cse was refractory in ( %) patients and total seizure duration was min ( - ). a favorable -day outcome occurred in ( %) patients. maximal glycemia value and hyperglycemia > . mmol/l at day were the only sbi variables associated with outcome in univariate analysis. by multivariate analysis, age > years (or, . ; % ic, . - . ; p = . ), refractory cse (or, . ; % ic, . - . ; p = . ), and primary brain insult (or, . ; % ic, . - . ; p = . ) were associated with an increased risk of poor outcome, and a bystander-witnessed onset of cse (or, . ; % ic, . - . ; p = . ) was associated with a decreased risk of poor outcome. conclusion: in our population, secondary brain insults were not associated with outcome in critically ill patients with convulsive status epilepticus; whereas age, bystander-witnessed onset of status epilepticus, refractory status epilepticus and primary brain insult were identified as strong predictors of -day functional impairment. further studies are warranted to confirm our findings. compliance with ethics regulations: yes. rationale: acute stroke (as) is a leading cause of morbidity and mortality worldwide. however, data on the prognosis andfunctional outcome of patients with as requiring icu management is limited. our purpose was to identify factors associated with good outcome (defined by a modified rankin score (mrs) of - ) months after icu admission. patients and methods: retrospective cohort of patients admitted to the medical icu of a university-affiliated hospital between january and december and coded for acute stroke using the icd- criteria. patients with traumatic stroke and isolated subarachnoid hemorrhage were excluded. results: we identified patients. median age was [ . - ] years and ( . %) were males. main reasons for icu admission were coma ( %), hemodynamic instability ( . %), acute respiratory failure ( %), and cardiac arrest ( . %). glasgow coma score at icu admission was [ ] [ ] [ ] [ ] [ ] [ ] [ ] and points. types of stroke were hemorrhagic in ( . %) patients and ischemic in ( . %). mechanical ventilation was required in patients ( . %). seizures occurred in . % of the patients and convulsive status epilepticus in . %. pneumonia was diagnosed in ( . %) patients (aspiration pneumonia n = , ventilator associated pneumonia n = ). thrombolysis or thromboaspiration were performed in ( %) patients with ischemic stroke. surgical evacuation of expanding hematoma was performed in ( . %) patients, ( . %) had craniectomy, and ( . %) had external shunt for hydrocephalus. icu and hospital mortality were . % and %, respectively. six months after icu admission, ( . %) patients had a good outcome (mrs - ), ( . %) had significant disability (mrs - ), and ( . %) were deceased (lost follow-up n = , . %). on multivariable analysis, age (or . per year ( . - . ), p = . ), saps (or . per point ( . - . ), p = . ), and hemorrhagic stroke (or . ( . - . ), p = . ) reduced the likelihood of good outcome (mrs - ) months after icu admission. conclusion: in our study, prognosis of acute stroke requiring icu admission was poor and a good functional outcome occurred in less than % of the patients at months. age, severity at icu admission, and type of stroke predicted outcome. compliance with ethics regulations: yes. rationale: in intensive care units, severe spontaneous hemorrhagic brain injuries have a poor prognosis for mortality and functional outcomes. affected patients face particular ethical issues regarding the difficulty of anticipating their eventual recovery. in this context, prognostic scores can help clinicians in patients/relatives counseling and therapeutic decisions. the previous reviews pointed out many prognostic tools for intracranial hemorrhage and subarachnoid hemorrhage but did not focus on injuries explicitly severe nor assessed the methodological limitations of the models. our systematic review aimed to assess methodologically prognostic tools for functional outcomes in severe spontaneous haemorrhagic brain, with particular attention to their clinical utilities. patients and methods: following prisma recommendations, we queried medline, embase, web of science, and the cochrane by february , . we included multivariate prognostic models explicitly developed or validated on adults with severe intracranial or subarachnoid haemorrhage. we evaluated the articles following the charms recommendations (checklist for critical appraisal and data extraction for systematic reviews of prediction modelling studies) and the tri-pod statements (transparent reporting of a multivariable prediction model for individual prognosis. results: our review confirmed the multiple publications of prognostic scores, as we found articles aiming to develop or validate prognostic tools. relying on guidelines, we discarded articles due to the lack of prognostic capacities, validation, or predictor selection. articles developed and validated a prognostic tool and externally validated existing models (fig. ) . no score was of good methodological quality in intracranial hemorrhage. we highlighted two prognostic scores in subarachnoid hemorrhages: the sahit predicting unfavorable outcome or mortality at months and the fresh predicting unfavorable outcome at months. conclusion: although prognostic studies on haemorrhagic brain injuries abound in the literature, they generally lack of methodological robustness or show incomplete reporting. with the numerous published scores, we believe that it is time to stop developing new scores. ongoing validation, recalibration, and impact studies would keep improving existing good tools. the use of "patient-centered" approaches could also enhance them, and be more appropriate to inform patients and families about their long-term potential recovery. these considerations should drive future research in the modern era of neurocritical care prognosis. compliance with ethics regulations: na. rationale: respiratory pattern analysis by a visual examination is an important part of clinical assessment but is dependent on caregiver expertise and is subjective. furthermore, there is no easy medical device used in picu to measure tidal volume (vt) and minute ventilation (mv) in spontaneous breathing patients. the clinical research unit in critical care of chusj and ets have developed a non-invasive computerized d video analyzing system (retract system) to detect and perform a video analysis of respiratory status in children. the aim of this study is to test the reliability of the retract system to monitor respiratory distress in critically ill children. the retract system is detailed in reference . in summary, cameras reproduce in d the thorax and abdomen of a subject. the respiratory status (respiratory rate (rr), tidal volume (vt), minute ventilation (mv)) assessed by the retract system was compared on a bench test (high-fidelity mannequin) and in critically ill children, to the ventilator measurements and clinician expert evaluation (gold standard). bland-altman plots were used for comparison. results: we observed a significant agreement, on mannequin, between retract system and gold standard method in estimating vt, rr and mv, i.e. % of the paired differences were within the limits of agreement in bland-altman plots, as illustrated in fig. . in critically ill children (n = ), the correlation between the pairs of measures was also high (r > . , p < . ) and thecoefficient of determination with a high fit ( . < r < . , p < . ). for good correlation, the retract system needed to have a visual access to thorax and abdomen in a quiet subject. the retract system measurements of vt, rr and mv for respiratory distress monitoring in patients seems reliable. more testing are required to validate this method in usual practice and to develop the retractions signs video analysis. compliance with ethics regulations: yes. rationale: severe bronchiolitis requires hospitalization in paediatric intensive care unit (picu). non-invasive ventilation (niv) has been demonstrated to treat them since twenty years, its use is well defined but there is no consensus for the weaning. this study evaluated the application of a nurse-driven niv weaning protocol in hospitalized infants with severe bronchiolitis and verified its safety. this was a retrospective monocentric study in a picu of robert debré hospital-paris, france. in the epidemic period of bronchiolitis between and , all patients under one year old with severe bronchiolitis and requiring niv were included. two groups were compared: one group using the nurse-driven niv weaning protocol and one group without using this protocol. occurrences of complications, duration of ventilatory support and length of stay (los) in picu and total los were compared. results: patients were included in the study, in the no-protocol group, and in the protocol group. the nurse-driven protocol was using at the rate of % (n = / in the protocol group (p = . ). picu los were . days [ ] [ ] [ ] in the no-protocol group versus days [ - . ] in the protocol group (p = . ), hospital los was days [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] in the no-protocol group versus days [ ] [ ] [ ] [ ] [ ] [ ] in the protocol group (p = . ) (fig. ) . the use of this first nurse-driven niv weaning protocol was feasible and simple with a very good application rate. its utilization was safe. the occurrence of complications did not increase by the use of this protocol. it would allow an optimal niv weaning without prolonging the ventilatory support duration nor picu los or hospital los. the professional practices appeared to be coordinated and the nurses appeared to be more autonomous. compliance with ethics regulations: yes. no-protocol and protocol groups comparison: cpap duration ( ), ventilatory support duration ( ), picu los ( ), hospital los ( ) rationale: first-line management of severe acute bronchiolitis in infants is mainly based on non-invasive ventilation (niv) and high-flow nasal cannula (hfnc) therapy. however, pediatric data regarding weaning from niv/hfnc are lacking. this study aims to identify the weaning practices from niv/hfnc in children with severe bronchiolitis. the weaniv-survey is a cross-sectional survey. a questionnaire was sent to french-speaking physicians with key roles in pediatric intensive care units. results: a total of % ( / ) of french university hospital were represented in the study. only % of pediatric centers used a protocol for weaning from niv/hfnc and nurses were considered as key-actors of the weaning process for half of participants. continuous positive airway pressure (cpap) was the mode of ventilation mainly used as the first-line therapy in clinical practice. the main criteriaconsidered toinitiate weaning process were: noor slight respiratory distress, a fio < %, a respiratory rate < /min and no significant apnea. three strategies to discontinue niv/hfnc were identified: /gradual decrease of ventilatory parameters (pressure or flow), /abrupt discontinuation and /gradual increase in off-ventilation time. abrupt weaning strategy was the most commonly used, no matter the mode of ventilation. a significant level of respiratory distress, the presence of apneas, an increase in oxygen requirement, and a respiratory rate > / min were identified as weaning failure criteria by most pediatric intensive care physicians. conclusion: in most centers, the weaning process does not follow any protocol. abrupt weaning seems to be commonly used as weaning strategy in children with severe bronchiolitis supported by niv/hfnc. based on the study findings, we suggest that criteria for weaning initiation and for weaning failure must be defined and weaning protocols generated. compliance with ethics regulations: yes. complications secondary to prone positioning occured for patients ( . %). conclusion: this first study, which evaluate prone positioning efficacy in severe p-ards shows evidence that prone positioning improves oxygenation parameters and survival rate. these results highlight the necessity to develop a multicentric prospective randomized study to confirm these conclusions. compliance with ethics regulations: yes. ( vs ) and vasoactive-inotropic score (vis) ( vs ) were significantly higher in the non-survivor group. cannulation was veno-venous ( %) or veno-arterial ( %) and patients ( %) were finally not initiated on ecmo. we observed an increase of patients cannulated in our picu over time (fig. ). there was no significant difference in mortality between patients transported on ecmo after cannulation in our picu and those who were transported to be cannulated in a referral ecmo center. the median time between the decision and the cannulation was . h and the median time taken in charge by picu transport team was approximately h. these periods were not significantly different between cannulation on site or in an ecmo center and between survivors and not-survivors. conclusion: in our study, multiple organ dysfunction, particularly hematologic and acuterenal failures, seems to be a risk factor of mortality. the delay between decision and management is similar whatever the cannulation site. specific ecmo mobile team and picu transport team seem to be essential, fast and trained to transfer these patients. it would be interesting to compare our cohort with children requiring ecmo already hospitalized in a referral ecmo center. compliance with ethics regulations: yes. rationale: life expectancy in patients with metastatic breast cancer (mbc) has substantially improved over the last decade. life threatening complications result from advanced diseases, infection and treatment-related toxicity. only few studies have assessed outcomes in this setting. we performed a hospital-wide study to investigate how icu resources are needed in patients with mbc. patients and methods: all patients with mbc managed at our hospital between and were retrospectively included. the primary outcome was overall survival (os). factors associated with icu mortality were identified using a multivariable cox proportional hazard model with sensitivity analysis. results are expressed as median [interquartile ranges] unless stated otherwise. results: among the patients managed at our hospital, ( %, including male) were admitted to the icu ( [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] patients per year). age was [ - ] years. patients were receiving their nd [ st- rd] line of treatment and had [ ] [ ] metastatic sites. sofa score at admission was [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . main reason for icu admission was sepsis (n = , %), acute respiratory failure (n = , %), coma (n = , %) and metabolic disorder (n = , %). invasive mechanical ventilation was required for patients ( %) and renal replacement therapy for ( %). sixteen ( %) patients died in icu. following icu discharge, median os was . months ( % ci [ . - . ]) and / ( . %) patients died within months. an antineoplastic treatment was resumed for / ( %) patients alive after icu discharge. factors independently associated with mortality were performance status ≥ (hr . , % ic [ . - . ] ) and sofa score at day (hr . per point, % ic [ . - . ] ). after sensitivity analysis, the number of treatment lines at icu admission was not associated with mortality. conclusion: icu admission is required in the course of the mbc disease for % of the patients. determinants of short term outcomes rely on performance status and disease severity but not on the characteristics of the underlying disease. ongoing analyses will assess whether icu survivors reach life expectancy of patients never admitted to the icu. compliance with ethics regulations: yes. hubert gheerbrant , jean-françois timsit , nicolas terzi , stephane ruckly , mathieu laramas , matteo giaj levra , emmanuelle jacquet , loic falque , denis moro-sibilot , anne-claire toffart chu grenoble alpes, grenoble, france; aphp, paris, france; outcom-erea, bobigny, france correspondence: hubert gheerbrant (hgheerbrant@chu-grenoble.fr) ann. intensive care , (suppl ):p- rationale: the prognosis of critically ill cancer patients admitted in intensive care unit (icu), remains an issue. our objective was to assess the factors associated with -and -month survival of icu cancer survivors. patients and methods: based on the french outcomerea ™ database, we included solid cancer patients discharged alive, between december and november , from the medical icu of the university hospital in grenoble, france. patient characteristics and outcome at and months following icu discharge were extracted from available database. results: of the cancer patients with unscheduled admissions, ( %) were discharged alive from icu. the main primary cancer sites were digestive ( %) and thoracic ( %). the -and -month mortality rates were % and %, respectively. factors independently associated with -month mortality included ecog performance status (ecog-ps) of [ ] [ ] . . - . ). interestingly, cancer chemotherapy prior to icu admission was independently associated with lower -month mortality (or, . ; % ic: . - . ). among patients with an ecog-ps - at admission, % (n = ) and % (n = ) displayed an ecog-ps - at and months, respectively. at months, ( %) patients received anticancer treatment, ( %) were given exclusive palliative care. discussion: factors associated with -month mortality are almost the same as those known to be associated with icu mortality. we highlighted that most patients recovered an ecog-ps of - at and months, in particular those with a good ecog-ps at icu admission, and could benefit from an anticancer treatment following icu discharge. conclusion: these results should be taken into account when deciding upon icu admission. it is of paramount importance to have an evaluation of both patient's general condition and anticancer treatment opportunities following icu discharge. compliance with ethics regulations: yes. rationale: the decision to urgently initiate medical anti-cancer treatment in cancer patients admitted to intensive care unit for cancerrelated organ failure is an issue. we currently lack criteria to select patients who may benefit from the treatment initiation. the purpose of our exploratory study was therefore to evaluate the characteristics of patients whose medical anti-cancer treatment is initiated in icu and to identify prognostic factors for in-hospital mortality. in these patients. patients and methods: we analyzed retrospectively, over a period of years ( / / to / / ), cancer patients over -year old admitted to our icu bordet and in whose anti-cancer medicaltreatment was initiated during in-icu stay. to identify prognostic factors for in-hospital mortality, we carried out a multivariate analysis of the factors influencing this mortality, considered as a binary. we also analyzed the long term survival of patients alive after their hospital stay (from the day of going out of hospital). results: overall, patients were included, men ( %) and women ( %), with a median age of years ( - ). of these, patients ( %) had a solid tumor and ( %) had a hematological tumor. in-icu mortality is % ( % ci - %) and in-hospital mortality % ( % ci - %). the prognostic factors for in-hospital mortality were age (mean vs in those who survived), the sofa score (median vs ), the saps ii score (mean vs ), the charlson score (mean vs. . ), the number of organ failure (mean . vs . ) and the presence of a therapeutic limitation (ntbr stated within h: % vs %). survival at year of patients who survived the hospital stay was % and median survival time was estimated to be . year ( % ci . - . ). in patients with a solid tumor, -year survival was % and % in those with a hematological tumor (p < . ). conclusion: we observed, in selected cancer patients admitted to the icu for a cancer-related complication, that the initiation of an anti-cancer medical treatment is feasible and can lead to interesting results, particularly in patients with a hematological tumor. compliance with ethics regulations: yes. rationale: considerable progress in the management of onco-hematology (oh) malignancies led to an increase in the number of patients proposed for intensive care unit (icu) admission. several guidelines offer decision models for icu transfer of these patients. we aimed to describe prognosis, adequacy of icu admission and denial in oncohematology patients. we included all oh patients proposed for icu admission in a tunisian medical icu, between january and july . from an admission proposal registry, were collected patient underlying condition, functional status, malignancy and predicted prognosis, acute critical illness and its reversibility, adequacy of icu rationale: cancer patients frequently need intensive care support for a life-threatening condition due to the underlying neoplasm or an adverse therapy-related event. however, there are poor data on their characteristics and outcomes in the intensive care setting. the aim of the present study was to describe clinical characteristics and to identify factors associated with in-icu mortality in critically ill cancer patients. patients and methods: it is a retrospective study conducted in the medical icu of farhat hached teaching hospital between january and december . all cancer patients with complete records were included. baseline characteristics, clinical parameters, severity of illness, primary tumor location and outcomes were collected. univariate and multivariate regression analyses were carried out to identify factors independently associated to poor prognosis. rationale: prognostic impact of underlying malignancy seems limited in most studies assessing outcome of critically ill cancer patients [ ] . however, only limited number of characteristics, namely disease progression status and preexisting stem cell transplantation, were usually assessed [ ] . primary objective of this study was to assess influence of hematological malignancy aggressiveness on hospital outcome. secondary objective was to assess influence hematological malignancy aggressiveness on type of infection. patients and methods: post-hoc analysis of prospective multicenter cohort performed in hospitals in france and belgium and including critically ill adults with underlying hematological malignancy admitted in icu from jan to may . a cox model was used to adjust for confounding variables then a propensity score matching on characteristics associated with underlying malignancy aggressiveness was performed. results: of the included patients, ( . %) had low grade malignancy (lg), the most frequent being myeloma (n = ), chronic lymphocytic leukemia (n = ), and myelodysplasia (n = ). patients with lg malignancy were older, underwent more frequently autologous stem cell transplantation (sct) and had less frequently altered performans status. they had more severe organ failure at icu admission (sofa score [ ] [ ] [ ] [ ] [ ] [ ] vs. [ ] [ ] [ ] [ ] [ ] [ ] , p = . ). before adjustment, mortality was % (n = ) and . % (n = ) respectively in patients with and without lg malignancy (p = . ). after adjustment for confounder using a cox model, a higher mortality was associated with nonlow grade malignancy (or . ; % ic . - . ). a propensity score then allowed a : matching upon variable associated with malignancy aggressiveness. after matching unadjusted mortality was % (n = ) in patients with lg malignancy and . % (n = ) in patients with high grade malignancy (p = . ) (figure) . in the matched cohort and after adjustment for confounder, high grade malignancies were associated with lower mortality (or . ; % ic . - . ). risk of fungal infection was unchanged by underlying malignancy before adjustment ( % vs. . % of patients with and without lg malignancy; p = . ) or after adjustment (hr . ; % ic . - . ). conclusion: despite anti-cancer advances, aggressiveness of hematological malignancies is associated with overall icu outcome. lowgrade malignancies displaying a better prognosis than non-low grade. aggressiveness of the underlying malignancy is not associated with risk of fungal infection. compliance with ethics regulations: yes. rationale: guillain-barré syndrome is the most common cause of acute flaccid paralysis and is associated with pulmonary embolism due to the mobility limitation. the aim of this study is to describe the incidence, the severity of pulmonory embolism in patients admitted to an intensive care unit (icu) for guillain-barre syndrome (gbs). patients and methods: twenty-eight adults patients with confirmed diagnosis of gbs were admitted to the icu in our university hospital center over a -year period and they were all included. prevalence, risk factors and course of vte were analyzed in icu patients with various forms and severity of gbs. results: during the study period, adult gbs patients were included. five ( . %) developped pulmonary embolism. the mean age was . ± . years and the sex ratio was . . the comparaison betewen the groups with and without pe showed that factors associated with the development of this complication were: respiratory failure requiring mecanical ventilation (p = . ), infectious complications (p < . ), blood pressure lability (p = . ), the delay of icu admission (p = . ), the delay to treatment initiation (p = . ), the sofa score (p = . ) and the presence of quadriplegia (p = . ). conclusion: pulmonary embolism is a frequent complication in patients with gbs. factors associated with this complication were: respiratory failure requiring mecanical ventilation, infectious complications, the delay of icu admission, the delay to treatment initiation, a high sofa score and the presence of quadriplegia. preventive measures in this category of patients have to be improved. rationale: acute respiratory distress syndrome (ards) is a life-threatening pathology associated with very high morbidity and mortality ( - %) in intensive care units (icu) and with even higher mortality among the severly burned patients worldwide ( à %). the aim of our study was to describe in tunisia burn patients with ards and to identify prognosis factors. patients and methods: we conducted a descriptive retrospective study between - - to - - , in burns icu, in ben arous, in tunisia. all burns who presented an ards, according to the berlin definition, during their stay in the icu, were included. when clinical or gasometric data was uncomplete, these patients were excluded. results: during the study period, patients were admitted to our burn unit including ventilated patients. fifty patients presented an ards: fifteen patients were excluded for lack of information, and patients were retained. the sex ratio was . . patients had a mean age of ± years, an average burned area of % ± %, an average unit of burn skin score (ubs score) of ± and an average sequential organ failure assessment score (sofa score) of . none of the patients had a history of cardiovascular or pulmonary diseases. the average time of onset of ards was ± days. ards was mild in case, moderate in and severe in . the etiology of ards was pulmonary in cases ( %) and extra-pulmonary in ( %). the pulmonary ards had as cause pneumonia isolated in patients, an isolated pulmonary burn in patients and a combination of pneumonia and lung burns in patients. extra-pulmonary ards were all due to sepsis and mainly to bacteremia. septic shock was associated with ards in patients ( %). the treatment was a conventional treatment based on protective ventilation, curarization and prone positioning in addition to the etiological treatment. the average length of stay in icu was days and mortality was % in these patients. conclusion: mortality from ards in burns in tunisia, is important especially in those with pulmonary burns as well as those with sepsis. the introduction of new treatments, such as extracorporeal membrane oxygenation, remains essential to improve the prognosis of burn patients. compliance with ethics regulations: yes. rationale: aspiration pneumonia (ap) is common in intensive care unit (icu). the incidence of ap among adults hospitalized with pneumonia ranges between and . %. usually one or more risk factors are identified to be involved in ap. the aim of this study was to determine the risk factors and predictors of mortality on patients with ap. patients and methods: we retrospectively included patients aged more than years and who were hospitalized in our icu for ap. patients were excluded if they had history of tuberculosis, if they have bronchiectasis or metastatic brain tumor. results: a total of patients were included. history of diabetes, hypertension, epilepsy and ischemic stroke were found respectively in . %, . %, . %, and . % of cases. the reason of icu admission were coma ( %), acute respiratory failure ( %), poisoning ( %) and cardiac arrest ( %). the incidence of acute respiratory distress syndrome (ards) was %. the most common organism isolated was staphylococcus aureus ( cases). risk factors for ap were epilepsy ( %), swallowing disorders ( %), ischemic stroke ( %), copd ( %) and degenerative neurological disease ( %). the mortality rate was . %. the median duration of mechanical ventilation was days [iqr - ]. in multivariate logistic regression analysis; saps ii score (or = . , % ic [ . - . ], p = . ) and ards (or = . , % ic [ . - . ], p = . ) were independently associated with mortality. conclusion: risk factors for aspiration pneumonia were epilepsy, swallowing disorders and ischemic stroke. ards and saps ii score were independent predictive factors of mortality. compliance with ethics regulations: yes. undetermined. the aim of this study was to evaluate the impact of hyperoxia on morbidity and mortality. patients and methods: this was a prospective study performed in the icu of abderrahmen mami hospital during a -month period. all patients admitted in icu during the study-period were included. those who didn't need oxygen therapy or in end of life stage were excluded. arterial blood gases were analyzed daily and each day with at least one value of oxygen arterial saturation (sao ) > % was considered as a day with hyperoxia. for each patient included, the number of times and days spent in hyperoxia was recorded as well as complications during the icu stay and the outcome. results: during the study-period, patients were included but only were eligible. mean age was ± years. acute on chronic respiratory failure was the most frequent reason of admission ( %). non-invasive ventilation was required for % of patients and invasive mechanical ventilation was necessary in % of cases. overall mortality was %. hyperoxia was observed in % of cases, with an average of ± times during the icu stay and ± days. a statistically significant association was observed between a long duration of hyperoxia and the occurrence of ventilator acquired pneumonia (p < - ), ventilator acquired bronchitis (p = . ), acute respiratory distress syndrome (p < - ), atelectasis (p < - ), septic shock (p < - ), rythm disorders (p = . ), reintubation (p < - ) and tracheostomy (p = . ). on multivariate analysis, independent factors of mortality were: simplified acute physiology score ii, cardiac failure, need for invasive mechanical ventilation and septic shock. hyperoxia was not independently associated with mortality. conclusion: hyperoxia is frequent in icu. it is significantly associated with icu complications but not independently associated with mortality. compliance with ethics regulations: yes. experience of the practice of prone position in patientswith acute respiratory distress syndrome in intensive care (chu oran) nabil ghomari, soumia benbernou, djebli houria faculté de medecine d'oran, oran, algeria correspondence: nabil ghomari (nabilghomari@hotmail.fr) ann. intensive care , (suppl ):p- rationale: mechanical ventilation (mv) in the prone position (pp) and low tidal volume have become recommendations with a high level of scientific evidence in recent years. the pp has been practiced for years in the chu oran emergency resuscitation service. we wanted to report the service experience in the practice of pp in patients with ards. patients and methods: retrospective study performed in patients with severe hypoxia ards with spo < % under fio > % or pao /fio < during the period march to december . results: patients received ventilation in pp. ards was secondary to thoracic trauma in % of patients, septic shock in % and aspiration pneumonitis in %. analysis of the success factors and improvement of oxygenation found that lobar ards, the delay < h and a duration of pp ≥ h were statistically significant. conclusion: the pp must be integrated into the arsenal of care of the patients in ards especially in our country where we do not have all the therapeutic options. compliance with ethics regulations: yes. julien goutay, nicolas cousin, thibault duburcq, erika parmentier-decrucq chu de lille, pôle de réanimation, hôpital salengro, lille, france correspondence: julien goutay (julien.goutay@gmail.com) ann. intensive care , (suppl ):p- rationale: in veno-venous extracorporeal membrane oxygenation (vv-ecmo) therapy, blood flow is the main determinant of arterial oxygenation and should be - ml/kg/min in adults. this flow rate is determined by several factors including the size of the inflow cannula. the impact on clinical outcomes of arterial cannula's size in veno-arterial ecmo (va-ecmo) has already been studied, and showed no difference for survival to discharge, weaning success rate and initial flow rate between a small cannula group and a larger one. our first objective was to describe the impact of inlet cannula size on the assistance flow rate in patients treated with vv-ecmo. secondary objectives were to analyze its impact on ecmo weaning, mechanical ventilation characteristics and mortality. patients and methods: we retrospectively reviewed all cases of respiratory failure treated with vv-ecmo admitted in the medical intensive care unit (icu) of lille's teaching hospital from january st, through march st, . inlet cannula size was collected and divided into two groups: the "small cannula" group had inlet cannula less than or equal to fr, while "large cannula" were larger than fr. primary endpoint was the initial flow rate according to the inlet cannula size, and its changes during the first h of assistance. secondary endpoints were the analysis of predictive factors associated with the choice of a larger inlet cannula, and the impact of its size on clinical outcomes such as successful ecmo weaning. results: patients treated with vv-ecmo were admitted in our hospital. eleven ( %) were cannulated with a large inlet device. mean initial ecmo flow rate was statistically higher in the "large cannula" group than in the "small cannula" one: . l/min (± . ) versus . (± . ) respectively, p < . . the difference was also significant during the first h of assistance. we found no difference between the two groups on clinical outcomes such as ecmo weaning time. in univariate analysis, weight was heavier in the "large cannula" group [ (± ) kg] than "small cannula" [ (± )], p < . . conclusion: ecmo initial flow rate was higher in a "large inlet cannula" group (internal diameter more than fr) compared with a "small cannula" group. we found no correlation with cannula-related haemorrhagic or thrombotic complications. inlet cannula size did not influence ecmo weaning, and duration time, but this may be a lack of statistical power. further prospective studies should confirm this results. compliance with ethics regulations: yes. rationale: burn patients are at risk of multidrug-resistant (mdr) bacterial infections with high mortality rate. therefore, monitoring the emergence of mdr pathogens in these vulnerable patients is important. this study aimed to assess digestive colonization with carbapenemase-producing gram-negative bacilli (cp-gnb) in patients admitted to the burn intensive care unit. patients and methods: our study was prospective and conducted over a one-year period (january to december ). every admitted patient was subjected to the screening. a double swab set was used to collect rectal swab specimens. one swab was used for mdr screening by disk diffusion method on selective media; the other for multiplex real-time pcr (cepheid's genexpert ® ) allowing detection of the most common carbapenemase-encoding genes (ceg) (blaoxa- , blakpc, blandm, blavim and blaimp). results: among the studied patients, ( . %) were detected positive at admission for cp-gnb by the genexpert ® carba-r assay. eleven patients, initially not colonized, acquired positive faecal carriage subsequently during their hospital stay. forty-two colonized patients ( . %) developed cp-gnb infection during their hospitalization. the ceg blandm quantitatively dominated by far with detections; either alone ( cases) or associated with other ceg ( cases). the second most frequent gene was blaoxa- . it was detected alone eight times and in association with other ceg times. forty-three patients carried blavim gene, usually in association with other ceg ( %). however, only one patient carried blakpc gene. the parallel screening by classical microbiology methods (disk diffusion on selective media) detected the presence of cp-gnb in all molecular positive samples. conclusion: our study describes the characterization of carbapenemase in burn patients and highlights their alarming spread. this emphasizes the importance of an active surveillance program by early detection of cp-gnb carriers and an isolation policy to limit the mdr infections expansion. compliance with ethics regulations: yes. rationale: invasive fungal infections are increasingly observed in the icus especially in burn units. inthe absence of simple and accessible techniques for early microbiological diagnosis, the use of antifungal treatment is increasing. little is known about the extent of the problem of antifungal prescription in burn icus. we aimed to evaluate the antifungal prescription in major burn patients. patients and methods: during the study period ( - ), all prescriptions of antifungals were analysed. analysis concerned demographics, clinical circumstances, as well as the basis of antifungal prescribing (targeted vs. empiric). among the patients admitted in this period, patients were treated with antifungals (sex ratio: . ; mean age: ± years, with low associated comorbidity). the tbsa was . % [ . - . ], ubs was [ . [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . most of the patients ( . %) were transferred from another hospital structure within ± h. antifungal treatment was started at the average of the seventh day post wound injury, more often on an empiric basis. sofa score at the beginning of the treatment was ± . . lymphopenia was present in % and thrombopenia was present in %. index of colonisation was positif only in cases. the average candida score was . ± . . microbiological results were tardily collected, within weeks, in %. fungal urine infections were found in cases. candidemia and catheter-related infections were considered only in cases. the risk factors of fungal infection as described in literature were found in most of the patients including mechanical ventilation ( . %), length period of stay ( days [ . - . ]), central venous line ( %), severe sepsis or septic shock ( %), large-spectrum antibiotherapy for more than days ( %). conclusion: the management of antifungal infections in major burn patients is still challenging. antifungal prescription is based on clinical presumption. the empirical prescription reflects the lack of efficient laboratory support and late microbiological results prompting physicians to rely on clinical informations. the management of fungal infections is based on the improvement of mycological investigations. compliance with ethics regulations: na. rationale: invasive candidiasis is a widespread and alarming infection in intensive care units (icu) patients. its diagnosis is often difficult because of the lack of specificity of clinical signs and the low sensitivity of blood cultures. while the candida albicans species remain the most common cause of bloodstream infections, non-albicans are emerging. these infections are serious, associated with high mortality rate and requiring early diagnosis and appropriate treatment. in tunisia, few data are available. we aimed to determine the epidemiological profile of a series of candidemia in icu, the risk factors associated with the occurrence of candidemia and to describe the modalities of the mycological diagnosis of candidemia and their etiological profile. patients and methods: a retrospective longitudinal descriptive study conducted in the parasitology-mycology laboratory with the collaboration of the medical icu of la rabta hospital-tunis over a -year period from january , to december , . all hospitalized icu patients with at least one candida-positive blood culture were included. results: forty-three patients among hospitalized patients during the study period had at least one candidemia infection. the main risk factors for development of candidemia infection include invasive procedures, a prior use of antibiotics and parenteral nutrition. c. albicans was the most common species, detected in . % of patients. nonalbicans candida species were prominent ( . %), represented by c parapsilosis, followed by c. tropicalis and c. krusei then c. glabrata and finally c. lusitaniae. all the isolates tested were sensitive to the common antifungal agents. the mortality rate of our patients was high ( . %), and the detection of the albicans species in blood cultures was the only prognostic factor identified (or = . [ . - . ], p = . ). conclusion: candidemia in the medical icu patients is common and is associated with high mortality rate. despite the progress of biological tools, the diagnosis is difficult and needs to take into account the risk factors of the patients as well as scores based on clinical and microbiological parameters. a better identification of risk patients may help to early initiate empirical antifungal treatment. compliance with ethics regulations: yes. necrotizing soft-tissue infections in the intensive care unit: a retrospective hospital-based study kais regaieg, sabrine nakaa, arnaud mailloux, madjid boukari, johana cohen, dany goldgran-toledano groupe hospitalier intercommunal le raincy-montfermeil, montfermeil, france correspondence: kais regaieg (kais.regaieg@gmail.com) ann. intensive care , (suppl ):p- rationale: the objective of our study is to describe the epidemiological and clinical characteristics of necrotizing soft-tissue infections (nsti) and to improve therapeutic management. we conducted a retrospective observational study that included patients admitted in the intensive care unit (icu) of general hospital between september and aout with a primary or secondary diagnosis of nsti. we collected demographic and clinical data, cultured pathogens, lengths of stay, and in-icu mortality. results: during the study period, a total of patients admitted to the icu were diagnosed with nsti ( . % of the total number of patients). the mean of age was years. the sex ratio (m/w) was . . ten patients ( %) were directly admitted to the icu, others were transferred from medical or surgical wards. the mean of saps ii was . ( . ). the main indication to admission in icu was shock ( %). the most common comorbidity was diabetes ( %). the other co-morbidities associated with nsti were cardiovascular diseases ( %), obesity ( %) and carelessness ( %). the sites most commonly affected were extremities in patients ( %) and abdomen/ano-genital in patients ( %). in icu, a total of patients ( %) were mechanically ventilated [ (median duration: . days ( . )], patients ( %) were given vasopressors, and patients ( %) underwent renal-remplacement. all patients underwent one or more chirurgical intervention. patients ( %) underwent radical necrosectomy. in cases, an amputation was necessary. polymicrobian infection was seen in patients ( %). in patients ( %), we used vacuum assited closure therapy, which in patients was followed by definitive reconstruction by split skin grafts. the mortality in icu was %. the mean stay in icu was days . the mean duration of hospitalization of the patients who survived was days ( - ). on the basis of a univariate analysis, higher saps ii score and lactate levels were associated with increased mortality (p < . ). conclusion: ntsi is rare in icu but it's a life-threatening and disabling disease with a high mortality requiring a multidisciplinary management. early diagnosis and adequate treatment are necessary to improve clinical outcome and must be known by everyone. more studies are needed to estimate the interest and delay of new strategies such as negative pressure therapy. compliance with ethics regulations: yes. rationale: nosocomial infections remain a major cause of mortality and morbidity in burn patients. providing information about the main causative bacterial agents and determination of their susceptibility to antibiotics may improve empiric therapy and early detection of emerging antimicrobial resistance. the aim of our study was to investigate the species distribution and antibiotic susceptibility of isolated strains from a burn intensive care unit (icu). patients and methods: this study was performed retrospectively on all bacteriological samples taken from the burn icu at the trauma and burn center in tunisia during a seven year period (from january to december ). all isolated microorganisms were identified on the basis of standard microbiological techniques. antibiotic susceptibility testing was carried out by the agar disk diffusion method, and susceptibility results were interpreted using clinical breakpoints according to ca-sfm guidelines. minimum inhibitory concentration of colistin was determined using the e-test ® method (biomérieux), then using the eucast broth micro-dilution method (umic, biocentric ® ) since may . results: during the study period, the most frequent identified species were pseudomonas aeruginosa ( . %), staphylococcus aureus ( %), klebsiella pneumoniae ( . %) and acinetobacter baumannii ( %). these strains have been mainly isolated from blood cultures ( %) and skin samples ( . %). pseudomonas aeruginosa resistance to ceftazidime increased from . % in to . % in and resistance to imipenem and ciprofloxacin was . % and . %, respectively. four strains were resistant to colistin. rationale: community-acquired peritonitis is a heterogeneous condition characterized by peritoneum inflammation in response to a bacteria injury. the aim of our study is to describe the epidemiological, clinical, bacteriological, etiological, therapeutic characteristics of community peritonitis, and to evaluate the prognostic factors. patients and methods: this is a retrospective descriptive and analytical study spanning three years (between january and december ) involving cases of community peritonitis, hospitalized in the surgical emergency resuscitation department p ibn rochd casablanca university hospital. our study included adult patients with community-acquired peritonitis who underwent medical and surgical management. the studied parameters are the demographic data, the clinical and paraclinical signs, the care taken and the evolution of the patients. the study showed that the mean age was . ± . years, with a sex ratio of . . patients medical history included tobacco ( . %), extra-abdominal signs [hemodynamic failure ( %), renal failure (n = , %), hematological disorders (n = , %) and respiratory disorders (n = , %)]. therapeutic management was based on perioperative resuscitation, treatment of organ failure, probabilistic antibiotic therapy and median laparotomy surgery. the main etiologies of community peritonitis were: digestive perforation ( . %), purulent effusion ( %), intestinal necrosis ( . %), cholecystitis ( . %). intraoperative bacteriological specimens yielded the following bacteriological profile: predominance of ngb ( . %) dominated by e. coli ( . %) followed by klebsiella pneumoniae and enterobacter cloacae ( . %) the mean hospital stay was . ± . days. the mortality rate was . %. conclusion: improvement in the prognosis of community-acquired peritonitis can only be achieved by constant assessment of very early diagnosis and initiation of appropriate resuscitation and antibiotic therapy associated with a complete surgery carefully codified according to guidelines. compliance with ethics regulations: yes. rationale: klebsiella pneumoniae carbapenemase (kpc)-producing bacteria are a group of emerging highly drug-resistant gram-negative bacilli causing infections associated with significant morbidity and mortality. the aim of our study is to point out the incidence of bloodstream infections (bsi) caused by kpc in icu patients, its clinical presentation and course. patients and methods: we conducted a retrospective descriptive study. all patients hospitalized in the icu of our hospital who developed bsi caused by kpc from january , to december , were included. results: during the study period, patients were included. the mean age was . ± . years ranging from to years. sex ratio (m/f) was . trauma was the major cause of hospitalization in cases ( %). the most common past medical diseases were arterial hypertension in patients ( %). length of hospital stay prior to icu admission was ± . days. at infection onset, mean saps ii was ± . , mean sofa was . ± . and mean apache ii was . ± . . during icu hospitalization, all patients required invasive mechanical ventilation during . ± . days, had a central venous catheter (cvc) and an indwelling urinary catheter in place, patients ( . %) had tracheotomy, ( %) underwent surgery, ( %) presented acute kidney failure and ( %) needed hemodialysis. before the isolation of kpc, all patients presented infections. antibiotics prescript were: colistin in patients ( %), carbapenems in patients ( %), amoxicillin/clavulanic acid in patients ( %), cephalosporins in patients ( %), fluoroquinolones in patients ( %), tigecycline in patients ( %), aminosids in patients ( %), rifampicin in patients ( %), fosfomycin in patients ( %), glycopeptides in patients ( %). the delay for kpc-bsi onset was . ± . days. the most common infection sources responsible of kpc-bsi were: cvc in patients ( %) and pneumonia in patients ( %). kpc infection was responsible of septic shock in patients ( %). resistance rates were: gentamycin ( %), amikacin ( %), colistin ( %), fosfomycin ( %) and tigecycline ( %). antibiotics used to treat kpc bloodstream infection were resumed in table . the mean length of icu stay was . ± . days. out of the included patients, patients died (the mortality rate was %). death was related to kpc infection in patients. conclusion: the high prevalence of kpc-bsi in icu patients dictates the importance of implementation of infection control measures and strict antibiotic policies. compliance with ethics regulations: not applicable. we identified episodes of nosocomial infections in patients, representing a cumulative incidence rate of . per exposed patients. the incidence density was . infections per days of hospitalization. the prevalence of pneumonia was . %, followed by urinary tract infections . %, central venous catheterization infections . %, bacteriemia . %, meningitis . % and surgical site infections . %. the incidence rate of intubation-related pneumonia was . / day of exposure. the incidence rate of bladder-related urinary tract infection was . / day of exposure. the incidence rate of positive culture of the central venous catheter was . / day of exposure. the incidence rate of bacteremia related to stay was . / day of exposure. the mortality rate was . % with a significant difference between infected and uninfected patients (p = . ). microorganisms were gram negative bacteria in % of cases. conclusion: epidemiological surveillance of healthcare-associated infections is needed to establish prevention plans. compliance with ethics regulations: not applicable. in the prehospital setting, early identification of septic shock (ss) with high risk of mortality is essential to guide hospital orientation (emergency department (ed) or intensive care unit (icu)) prior to early treatment initiation. in this context, the severity assessment is most of the time restricted to clinical tools. in this study, we describe the association between prehospital shock index (si) and mortality at day of patients with ss initially cared for in the prehospital setting by a mobile intensive care unit (micu in this study, we reported an association between prehospital si and mortality of patients with prehospital ss. a si > . is a simple tool to assess severity and to optimize prehospital triage between ed and icu of patients with ss initially cared for in the prehospital setting by a micu. the association of si with biomarkers may be helpful to improve the screening for ss and decision making of ss in the prehospital setting. compliance with ethics regulations: yes. the failure rate and complications were comparable between the groups, but the ultrasound-guided internal jugular catheter appears to be faster to insert and requires fewer punctures, so it could be an alternative to the femoral one in emergency situations. rationale: neuromyelitis optica (nmo) is a rare but severe disease. the prognosis of treated nmo attacks remains unclear. we evaluated our practice, the early evolution and the prognosis of nmo patients. patients and methods: an observational study was performed on patients with nmo attacks presenting with visual or medullar symptoms admitted for plasma exchange (pe) therapy from january to august . treatment efficiency was defined as a negative shift of the visual or motor disability score (edss). nonparametric mann-whitney and fisher exact tests were used for statistical analysis as required. results: twenty-four patients had pe sessions. characteristics of the cohort are described in table . ( . %) died from complications of nmo attacks. treatment had an effect in ( . %) patients. the shift in the ambulatory and visual edss was respectively − . + . and − . + . . the non-survivor patients had all aqp antibodies (p < . ). residual edss was higher in the non-survivor group ( . + . vs . + . , p < . ). pulse steroids were administered in ( %) patient in the non-survivor group vs ( %) patients in the survivor group (p < . ). twelve ( %) patients previously given pulse steroid therapy responded to pe. discussion: we assessed the handling of nmo attacks and identified our flaws. we concluded that pulse steroid therapy should not be withheld or replaced by lower dosage. we also need to find a way to make attacks identified by physicians earlier to shorten the delay between its onset and patient's admission in a specialized care unit. we observed that the mean improvement is modest during the early phase of our treatment. but a modest improvement in the edss can have a great impact in the patient's quality of life and even survival. conclusion: nmo attacks remain a threatening disease despite aggressive treatment. shortening the delay of treatment and ensure adequate pulse steroid therapy coupled to pe could be a way to improve the prognosis. compliance with ethics regulations: yes. rationale: acute kidney injury in trauma patients is a problem that has been little studied in the intensive care unit (icu). its occurrence has been shown to be associated with high morbidity and mortality. we aim to determine the outcome of icu trauma patients with acute kidney injury (aki), including the incidence of death in the icu, of nonreversible renal impairment and icu complications. patients and methods: this is a prospective study, conducted in the department of emergencies and icu, including trauma patients with a minimum icu stay of days. renal failure was defined based on the new kdigo classification. predictors of mortality and poor outcome were identified using univariate and then multivariate analysis. results: one hundred and fifty patients were admitted during the study period for the management of post-traumatic injuries, among which patients were included. the incidence of aki in the studied population was % ( cases) with ( %) diagnosed with stage one, ten ( %) with stage two and ten ( %) with stage three. the overall mortality of patients with post-traumatic aki was . % ( patients) with a mean icu lengh of stay (los) at ± days and of days on ventilator at ± . eight patients ( . %) needed renal replacement therapy and thirty-four had non-reversible renal impairement ( %). during icu stay, eight patients ( %) were diagnosed with pulmonary embolism. on univariate analysis, the following variables were associated to mortality in patients with post-tramatic aki including; age, hemodynamic instability on the day of diagnosis and bilirubin levels on the day of aki diagnosis. besides, according to our analysis, the use of renal replacement therapy and the non-reversibility of renal impairment during icu stay were also associated to icu mortality. among these factors, the non-reversibility of renal impairment in the icu was a predictor of mortality on multivariate analysis (p = . , or = , . in this cohort, the following variables were predictive of non-reversible renal impairment during icu stay; including age (with a best cut-off of years old), medical history of hypertension, higher iss and diuretics' administration. on multivariate analysis, the age (p = . , or = . , ci . - . ) and use of diuretics (p = . , or = , ci . - ) were associated to non-reversible aki in the icu. conclusion: our study confirms that post-traumatic aki in the icu is associated to high morbidity and mortality. the identification of outcome predictors could be valuable to guide the management of aki. compliance with ethics regulations: yes. rationale: the occurrence of acute kidney injury (aki) in trauma patients is a problem that has been little studied to date. its presence has been shown to be associated with an increased risk of morbidity and mortality in affected individuals. to determine the incidence of post-traumatic aki and identify its predictive risk factors that could be eventually prevented. patients and methods: this is a -month long prospective cohortstudy, conducted in the department of emergencies and intensive care unit (icu) of a university hospital, including trauma patients with a minimum icu stay of days. renal failure was defined based on the new kdigo classification. predictors of aki were identified using univariate and then multivariate analysis. results: one hundred thirty patients were admitted during the study period for the management of post-traumatic injuries, among which patients were included. the incidence of aki in the studied population was % ( cases) with ( %) diagnosed with stage one, ten ( %) with stage two and ten ( %) with stage three. on univariate analysis, older age and medical history of diabetes or hypertension were predictors of aki. injury assessment found traumatic brain injury (ais > ), glasgow (gcs) on admission, and the diagnosis of fat embolism to be associated to post-traumatic aki. moreover, hemodynamic instability on admission and during icu stay, shock-index on admission, the amount of fluid administered the use of vasoactive drugs, sepsis, hyperbilirubinemia, p/f ratio and acute respiratory distress syndrome (ards) were also associated to post-traumatic aki. among these factors, ards (p = . , or = , ci - ), fat embolism (p = . , or = , ci . ) without preload-dependence, and were unclassified. multivariate analysis (using variables collected prior to hypotension) identified the following variables as risk factors for the occurrence of hypotension associated with preload-dependence: preload-dependence before hypotension (odds ratio = . , p < . ), fluid removal rate by crrt (or = . per increase in sd, p < . ), and lactate levels (or = . per increase in sd, p < . ). in this single center study, preload dependence-associated hypotension was slightly more frequent than hypotension without preload dependence in icu patients undergoing crrt. testing for preload dependence to adjust fluid removal could help prevent hypotension incidence during crrt. rationale: few studies report the relation between functionnal brain alterations during and after icu stay and abnormalities of cbf displayed on tcd. using vti as hemodynamic parameter is unusual for evaluation of cbf. the purpose of this preliminary study was to compare the values of vti of healthy controls (c) versus icu (p) with usual parameters (i.e. diastolic (vd) and mean velocities (vm), resistance (ir) and pulsatility index (ip)). rationale: accurate diagnosis of the level of consciousness is a challenge and different states such as coma, vegetative state (vs) or minimally conscious state (mcs) are often confused while they convey meaningful prognostic information. this distinction rely on the coma recovery scale-revised (crs-r) gold-standard. however, this clinical scale is imperfect since unresponsive patients can exhibit genuine signs of consciousness using advance neuroimaging techniques. expanding the range of behaviors indexing consciousness at bedside is thus of decisive importance. patients and methods: we designed and proposed a new clinical sign of mcs, the habituation to auditory startle reflex (asr), based on the blink response to repeated sounds: either inhibition of the automatic asr response (extinguishable) or nohabituation (inextinguishable response). we prospectively tested this new sing in patients suffering from disorders of consciousness after severe brain injury and first compared its diagnostic performances with the current gold-standard (crs-r) using standard discrimination metrics (auc, sensitivity, specificity, likelihood ratios) and their % confidence interval. we then investigated the correlates of this new sign on two validated neuroimaging diagnostic procedures (multivariate eeg-based classification of the state of consciousness and fdg-pet metabolic index of the best preserved hemisphere) using an anova with the state of consciousness and the asr response as independent variable. rationale: although continuous electroencephalography (ceeg) is commonly recommended in neurocritical care patients, implementation of this monitoring in routine is facing the need for a specific training of professionals. we evaluated the effectiveness of a training program for the basic interpretation of ceeg to critical care staffs in a prospective multicentre study. patients and methods: after completion of a pre-test, participants (physicians and nurses) recruited in french intensive care units (icu) received a face-to-face eeg learning course, followed by additional e-learning sessions at day- (post-course), day- , day- and day- , based on training tests followed by illustrated and commented answers. each test was designed in order to evaluate knowledge and skills through correct recognition of predefined eeg sequences covering the most common normal and abnormal patterns. the primary objective was to achieve a success rate of more than % of correct answers at day- in at least % of participants. results: among participants, ( . %) completed the full training program and of these ( . %) full-training participants achieved at least % of correct answers at day- . paired comparisons between scores obtained at each evaluation demonstrated a statistically significant increase over time. at day , rates of correct answers were greater than % for all predefined usual eeg sequences, excepted for the recognition of periodic and burst-suppression patterns and reactivity, which were identified in only . % ( % ci . - . ) and . % ( . - . ) and . ( . - . ) tests, respectively. discussion: this multicentric prospective study, which evaluated a training program for the basics of electroencephalography offered to critical care teams, provides interesting information about the training process and its impact on learners according to their different characteristics. we believe that participants reflect the heterogeneity of the various use of ceeg in the critical care setting. participants came from university and non-university icus, and whereas some of them used to monitor patients with ceeg, others were in an implementation process when the last monitored neurocritical care patients with intermittent eeg. in accordance with previous studies, we focused to the entire medical and nursing icu staffs. conclusion: a -months training program aiming to teach the basic interpretation of continuous eeg in the intensive care units was associated with a significant attrition in participation over time. however, participants who received the full training program were capable to accurately recognize the vast majority of eeg patterns that are encountered in critically ill patients. compliance with ethics regulations: yes. mourad goulmane oran hospital and university center, oran, algeria correspondence: mourad goulmane (goulmane.mourad@univ-oran . dz) ann. intensive care , (suppl ):p- rationale: cerebral venous thrombosis (cvt) is a rare but very serious disease with various clinical and etiological aspects. unlike ischemic arterial accidents, epidemiological studies are limited. the aim of our work was to study the clinical, etiological and evolutionary features of cvt in the algerian population from a sample of patients. patients and methods: this is a retrospective observational study conducted in the neurology department of the chu d'oran between january and december . in a clinical context suggestive of cvt, the diagnosis of certainty was provided by brain mri coupled with mra. all subjects benefited from a complete etiological assessment. the anticoagulant treatment was based on the low molecular weight heparin relayed by the anti-vitamin k. the duration of the follow-up was months. results: the mean age was . ± . years, the sex ratio was ( f/ h), the onset was subacute in % of cases. the main early signs were headache ( . %), visual disturbances ( %), epileptic seizures ( . %) and motor deficit ( . %). thrombosis predominated in the upper sagittal sinus and lateral sinuses; parenchymal lesions were associated in / of the cases. gynecologic obstetric causes were by far the most frequent. the evolution was favorable in . % of the cases. discussion: cvt is characterized by its clinical polymorphism, its predominance in young women, and its most often favorable evolution. the causes are multiple and often intricate requiring the realization of a systematic etiological assessment even if the cause seems obvious. the treatment of choice remains early anticoagulation, based on heparinotherapy even in case of hemorrhagic softening. the characteristics of cvt in the algerian population are distinguished by a high frequency of gynecological obstetric causes. awareness campaigns for women of childbearing age are useful. compliance with ethics regulations: not applicable. rationale: the ct-dragon score was developed to predict longterm functional outcome after acute stroke in the anterior circulation treated by thrombolysis. its implementation in clinical practice is hampered by the plethora of variables included. in addition, the score has not been validated in important subgroups such as stroke patients undergoing thrombectomy. given these limitations, the current study was designed to evaluate the use of a simplified score based on machine learning, as a possible alternative. this single-centre retrospective study included patients treated for stroke, in the anterior and posterior cerebral circulation, between - and - . at days, favourable (modified rankin scale (mrs): - ) and miserable outcome (mrs: - ) were predicted by ct-dragon. machine learning selected the aim was to describe the adherence rates to gold guidelines in critically ill copd patients and to identify predictors of low adherence. patients and methods: a prospective cohort study conducted from december to april in a -bed medical intensive care unit of farhat hached hospital. all adult patients admitted for aecopd during the period of the study were included. demographic and clinical data were recorded. adherence to gold was evaluated. univariate and multivariate regression analyses were carried out to identify factors independently associated to non-adherence to gold guidelines. results: seventy-seven patients were recruited. patients' characteristics were : mean age, . ± years; male ( . %); median duration of the disease, [ - ] years; mmrc scale ≥ , ( . %); health insurance coverage rate, ( %); pulmonologist follow up, ( , %); frequent exacerbator (≥ exacerbations in the last year), ( . %); median exacerbations episodes, [ ] [ ] [ ] . long-term oxygen use and home mechanical ventilation were respectively used in ( . %) and ( . %). eight ( . %), ( . %) and ( . %) belonged to copd groups b, c and d, respectively. pharmacological treatment included: saba-ics combination, ( . %), laba-ics, ( . %), laba-lama, ( . %) and lama-laba-ics, ( . %). overall adherence to gold guidelines treatment recommendations for the different stages of copd was ( . %). two patients ( . %) were over treated and ( . %) were undertreated. inappropriate treatment rate was ( %) in gold b, ( . %) in gold c and ( . %) in gold d. univariate analysis identified two factors associated with non-adherence to gold : the absence of pulmonologist follow-up ( % vs. . %; p = . ) and the low income ( . % vs. . %; p = . ). in multivariate analysis only the lack of pulmonologist follow-up was identified as an independent risk factor associated with gold guidelines discrepancies (or, ; % ci [ . - . ]; p = . ). there is a lack of adherence to gold guideline treatment recommendations in tunisian copd patients. this may lead to severe exacerbations. discrepancies were due to the poor access of severe copd patients to an appropriate pulmonologist follow-up. compliance with ethics regulations: yes. the operating theaters concerned were: the otolaryngology block, ophthalmology, vascular and thoracic surgery, and gynecological surgery. all patients over years of age were enrolled using the clinical parameters of difficult intubation (arne score > ), which will benefit from orotracheal intubation. the main judgment criteria were: first-pass success rate, intubation time, which is defined as the time between inserting the slide into the patient's mouth and obtaining the capnography curve, the cormack-lehane score and the pogo score (percentage of opening of the glottis). statistical analysis used spss software. results: a total of patients were included. no cases of failure with this device were observed, the duration of intubation was on average . s (only cases required more than min). the cormack-lehane score and involved patients ( . %), and the pogo score greater than % involved patients ( . %). one case required the features of the simplified score. discrimination, calibration and misclassification of both models were tested. results: % had proximal anterior stroke, % proximal posterior stroke and % lacunar infarcts in either circulation. in % no thrombus was objectivated. % of patients were treated with thrombectomy, % received thrombolysis and % underwent both thrombolysis and thrombectomy. % only received anti-platelet therapy. the area under the receiver-operating-characteristic curve (auc-roc) for ct-dragon was . ( % ci . - . ) for favourable and . ( % ci . - . ) for miserable outcome. r ofct-dragon was . and . for favourable (lack of fit, p = . ) and miserable (lack of fit, p = . ) outcome respectively. misclassification rate was % for favourable and % for miserable outcome with ct-dragon. selection of predictors from the ct-dragon was done by logistic regression, bootstrap forest and decision tree analysis. nih stroke scale, pre-stroke mrs and age were identified as the strongest contributors to favourable and miserable outcome, and included in the simplified score. auc-roc was . ( ci% . - . ) and . ( ci% . - . ) for the prediction of favourable and miserable outcome respectively. r was . and . for the prediction of favourable (lack of fit p = . ) and miserable (lack of fit p = . ) outcome respectively. misclassification rate was % for favourable and % for miserable outcome with the simplified score. the simplified score had better discriminative power than ct-dragon for both outcomes (both p < . ). the ct-dragon score revealed acceptable discrimination in our cohort of both anterior and posterior circulation strokes, receiving a variety of treatment modalities. the simplified score had a better discrimination, while maintaining comparable and good specificity and misclassification rate for miserable outcome. the simplified score needs further validation in a prospective, multi-centre study. compliance with ethics regulations: yes. rationale: the gold report represents a major revision to gold strategy guidelines. it brings new recommendations regarding diagnosis, severity assessment, and both pharmacologic and non-pharmacologic treatment of copd. however, adherence to evidence-based therapeutic guidelines is often poor in low-income developing countries and represents a significant barrier to optimal management. the setting up of an lma-fastrach (desaturation). a case of glottic edema has been noted. discussion: this study shows a very high success rate with this technique ( . % in the first trial and . % in the second trial), in the context of a predictable difficult intubation. the video-airtraq allows a very good visualization of laryngeal structures, a shortening of the duration of intubation, and is rarely responsible for immediate or secondary complications. all the data in the literature go in the same direction. conclusion: at the end of this work, our perspectives are to update the difficult intubation procedure, integrating the video-airtraq into our algorithm, as well as into our difficult intubation trolley. to take into consideration the cost of this device to eventually generalize it to all our structures. compliance with ethics regulations: yes. ) and beds of continuous monitoring. the activity of the cp is organized in a medical visit in the morning and in conducting projects in the afternoon. the activity is presented using a -years balance sheet results: the activity of pharmaceutical interventions (pi) or answers to requests from teams is shown in table . the solicitations doubled the second year. the cp is involved in the conduct of internal or polar projects (set up of cooperative sedation, nutrition…), the good use of health products (relay iv/po, infusion, crushed tablets and compatibility with gastric probe, drug incompatibilities, proton pump inhibitors…), the efficiency of the drug circuit (link with the pharmacy, reflection on the improvement of the circuit, regular meetings with nurses), medico-economic analysis of health products spending and the formalization of actions by protocolisation. he is also very involved in clinical research: patient screening, clinical study setup: blipic study (beta-lactam's dosing in pneumonia in icu in patients treated by continuous renal replacement therapy; clinicaltrials nct ) or in candiarea project (invasive infections to candida and preemptive treatment guided by biomarkers; in progress). a satisfaction survey submitted at months to nurses ( answers/ ) or to doctors/ residents ( / ) reported cp competence in the accompaniment of teams (> %) [in medico-economical, contribution of knowledge, vigilance reflex…], relevance of information transmitted (> %) [administration of drugs, dosage adjustments, …] and his relationship adapted to the units (> %) [communication, availability] . the development of clinical pharmacy in icu involves mastery of the specificities of icu by the cp, requiring a learning period and relationships adapted to clinical situations and teams. many health products projects specific to critical care are coordinated by the cp and made possible by medical and paramedical involvement. the cp appears as a vector of good use both in medical (reasoned prescription) and paramedical (good practices) with increasing solicitation of teams since his arrival. this reception has been facilitated by an innovative approach of clinical pharmacy deployment in our icu on an impulse of the clinical pole compliance with ethics regulations: yes. predicting models such as the news has been developed in the emergency department, but it has only been fewly evaluated in the icu. heart rate variability (hrv) reflects the autonomic nervous system response in various pathological situations and may vary according to patients' physiological status. the rox index, which reflects the acute respiratory failure severity, seems to be a good predictor of high-flow nasal canula failure. the aim of this study was to evaluate the potential value of news, hrv and irox (inversed rox) as poor outcome predictors, using artificial intelligence and machine learning. a retrospective analysis of a prospective datawarehousing project (reastoc clinicaltrials identifier nct ) on icu patients who did not require invasive ventilation. physiological parameters were collected on admission, within a -h delay. news, hrv (in time, frequency, and non-linear domains), and irox were computed and integrated into the prediction model. analysis was performed using medcalc and matlab machine-learning work-package. results: one hundred and twelve patients were included. patients who died in the icu (n = ) had highest news as compared with icu survivors ( . [ . - . ] vs. . [ . - . ] respectively; p = . ). the irox was higher ( . [ . - . ] vs. . [ . - . ], p = . ) and most hrv parameters also depicted higher values for icu survivors. considering a composite icu prognostic outcome parameter (mortality and/or need for any form of respiratory assistance and/or an icu los > median los), there was also a difference for news, hrv and irox (p < . ). the best value to predict icu mortality for news was (auc = . , p = . ), irox > . (auc = . , p = . ) and hrv (shannon entropy) > . (auc = . , p = . ). the best model to predict the need fo respiratory assistance combines irox and hrv (sd /sd ; auc = . , p = . ). adding shannon entropy on this model predicts either the need for respiratory assistance and icu survival (respectively auc . , p = . and auc . , p = . ). in icu spontaneously breathing patients, news, irox and hrv are different in between survivors and patients who died. the best model to predict the need for respiratory assistance combines irox and hrv (sd /sd ). compliance with ethics regulations: yes. rationale: sepsis is known for its important mortality in critically ill patients. the last guidelines defined sepsis as life threatening organ dysfunction. it rejected the concept of systemic inflammatory response syndrome (sirs) associated to suspected or confirmed infection, and considered the concept of dysregulated response to infection. actual guidelines recommend the quick sequential organ failure assessment score (qsofa) to identify patients with sepsis especially when outside intensive care unit. thus, outcomes have mainly to judge the value of sirs in the sepsis- era. the purpose of our study was to compare whereas qsofa score or the sirs criterion are superior to predict in-hospital mortality, shock and mechanical ventilation use in sepsis. our study includes patients in whom the sepsis- definition is met. therefore, this inclusion was retrospectively performed throughout emergency department (ed) admission cases for clinically suspected infection. we collected patients admitted to ed for sepsis. mean age was years ± with bornes of and . men were % of the patients. death occurs in . % of patients, sepstic shock in % and the use of mechanical ventilation in . %. qsofa ≥ has a significant association with in-hospital mortality (p < . ) but not sirs ≥ ( . ). neither qsofa ≥ nor sirs ≥ has association with the use of mechanical ventilation (p = . vs. p = ). whereas, both have a significant association for prediction of septic shock. the absolute sensitivity and negative predictive value in our study can be explained by the small size of our sample. this needs confirmation with literature data about the fact that sirs criterion are superior in term of sensitivity and npv than qsofa to predict septic shock. despite the weak odds ratio (or) of sirs before that of qsofa and the poor specificity and positive predictive value (ppv), we can conclude that sirs according to its sensitivity and npv, seems to persist useful in the sepsis- era as a reliable prognostic tool in the ed. this may need more large studies for confirmation. conclusion: despite sirs has no significant association with mortality in sepsis, it has largely higher sensitivity and superior npv to predict septic shock than qsofa in ed. compliance with ethics regulations: yes. our study aimed to determine the predictive factors of mortality in our patients. retrospective study over years in the intensive care unit of the hospital august. all patients with septic shock were included. a p value < . was considered significant. results: patients were collected. the age ranged from to years old. the average duration of hospitalization in pre-intensive care was days. the reasons for admission: (febrile respiratory distress: % of cases, polytrauma: % and % for sepsis), the most frequent infections: pulmonary ( %) and blood ( %). % received prior antibiotic therapy and % were immunocompromised. the overall mortality was %. the analytical study of the data shows that the age, the length of stay before admission in intensive care and that in intensive care, fever, hypothermia, slimming, hypotension, collapse, failures (respiratory, hematological, renal, hepatic and neurological) and the use of catecholamines are correlated with mortality, whereas sex, chest pain, tachycardia or bradycardia and mottling are not predictive of mortality. conclusion: despite improved techniques for the diagnosis and treatment of patients with septic shock, mortality remains high, especially in the presence of certain risk factors, hence the value of prevention in immunocompromised patients and the reduction in their length of stay in a hospital setting. compliance with ethics regulations: yes. conclusion: p. mirabilis is among the leading bacteria responsible for nosocomial infections in icu. they are emerging highly drug resistant pathogens whose incidence is rapidly increasing in icu. so that, it early identification with in vitro testing is of paramount importance to the success of infectioncontrol efforts. compliance with ethics regulations: not applicable. rationale: influenza is a potential lethal disease causing dozens of thousands excess deaths per year both in europe and in the united states. besides hygiene procedures, vaccination is a cornerstone of influenza prevention and guidelines recommend for vaccination among health workers (hw), especially if they are in close contact with frail people. despite these recommendations, the vaccination coverage is low among health workers both in europe and in the us. the relevance of a mandatory vaccination for health workers is currently a hot topic but data are scarce regarding intensive care unit health workers' opinion. patients and methods: health workers from medical, surgical and polyvalent icus received a link to the electronic record of the survey. results: among the icus, icu health workers (hw) (medical: and paramedical: ) were questioned. three hundred and forty-one icu ( %) answered, ( %) medical health workers (mhw) and ( %) paramedical health workers (phw) (p < . ). among mhw / ( %) were vaccinated vs only / ( %) phw (p < . ). discrepancies exist between medical and paramedical icu health workers' opinions and beliefs about vaccination for influenza and its acceptance. medical health workers were more prone to consider influenza as a potentially lethal disease occurring not only among frail people but also in healthy people, to consider the vaccine efficient and safe. to agree with "vaccination for influenza is mostly related with gain for pharmaceutical industry" (or: [ . - ] ) and to disagree with "the risk of guillain-barré syndrome is higher after an episode of influenza than after vaccination for influenza" (or: . [ . - ] ) were independently associated to the disagreement with a mandatory vaccination for icu hw. conclusion: vaccination for influenza should be strongly recommended as a tool of individual protection for icu health workers as for general population. as confidence in vaccine efficacy and concerns about vaccine side-effects impact the vaccination rate, objective information should be provided to icu health workers about the efficacy and the side effects of vaccination for influenza. compliance with ethics regulations: yes. rationale: intra-abdominal infections are a major cause of morbidity and mortality. sfar recommendations on this topic were published in february . the purpose of this work was to evaluate whether our antibiotic therapy was adequate for these recommendations and whether they were adapted to our unit. the secondary objectives were to look for different risk factors for mortality, to evaluate the impact of inappropriate antibiotic therapy, to evaluate the relevance of carbapenem prescription. this is a single-center retrospective observational study of secondary peritonitis in the tourcoing intensive care unit. for each peritonitis, the epidemiological data and the co-morbidities of the patients were collected. bacteriology and anti-infectious therapies were described to determine the rates of adaptation of our antibiotic therapy and that recommended by sfar. the adequacy of our treatments to the recommendations was also quantifiable. the description of the stay, the occurrence of a death was specified. results: peritonitis were included. the rate of adaptation of the sfar antibiotic therapy was %. the rate of adaptation of our antibiotic therapy was % and its adequacy rate of %. the main differences in prescriptions concerned over-prescription of antifungals, molecule against gram positive bacillus and a sub-prescription of aminoglycosides and beta-lactams, in particular carbapenems. the different mortality risk factors found were sofa score > (or . % ci . - . ), the charlson score > (or . % ci . - . ), the hollow organ perforation (or . % ci . - . ). a comparison of the appropriate or not antibiotic groups did not reveal a significant difference in mortality, number of surgical revision and length of stay. in % of nosocomial peritonitis, antibiotic therapy with carbapenem was recommended. after recovery of microbiological data, it was only necessary for . % of cases. conclusion: our work showed a low rate of compliance with sfar recommendations. these recommendations are applicable to our service by providing a particular reflection for fungal infections. our study does not show a correlation between mortality and inadequate antibiotic therapy, surgery remaining the major treatment. compliance with ethics regulations:yes. rationale: acinetobacter baumannii is a gram-negative opportunistic bacteria that has gained several drug resistance mechanisms over the last decades. analysis of a. baumanii's resistance profile helps to establish a prompt control and a prevention program. the aim of this study was to evaluate the epidemiology and antimicrobial resistance of a. baumannii isolates in a trauma and burn center in tunisia. patients and methods: retrospectively, we studied all strains of acinetobacter baumannii isolated over a -year period (from january to december ). conventional methods were used for identification. antimicrobial susceptibility testing was performed with the disk diffusion method, and susceptibility results were interpreted using clinical breakpoints according to ca-sfm guidelines. data were analyzed using the sir-system. minimum inhibitory concentration (mic) of colistin was determined using the e-test ® method (biomérieux), then using the eucast broth micro-dilution method (umic, biocentric ® ) since may . results: during the study period, non-repetitive strains of acinetobacter baumannii were isolated representing . % of all isolates, % of gram-negative bacilli (gnb) and . % of non-fermenting gnb. in our center, infections due to a. baumannii were endemic with epidemic peaks. a. baumannii was mainly isolated from burn intensive care unit ( %) and anesthesiology department ( . %). the most frequent sites of isolation were blood cultures ( . %), catheters ( %), respiratory specimens ( . %) and skin samples ( % sampling duration is also reduced, improving workflow. evaluators consider that bronchosampler rationalizes the cumbersome sampling process and that the closed system design reduces the risk of losing sample or sample contamination. the set-up, the suction capacity, the sampling quality and quantity have all been evaluated better or far better than that usually observed with usual sampling techniques and devices. finally, ( %) of users prefer bronchosampler to commonly used method. conclusion: this satisfaction survey shows that with its simple but revolutionary design, bronchosampler brings a real effective benefit in sampling procedure enabling the clinician to perform it alone, and ( %) of the survey evaluators consider that bronchosampler should replace their current practice. compliance with ethics regulations: yes. rationale: the possibility of having a sensitive, specific and prognostic biological marker for bacterial infections is a considerable challenge. a step was taken with the discovery of pracalcitonin. patients and methods: this is a prospective observational cohort study of patients in the medical resuscitation department of the university hospital of casablanca during the -month period, including patients in whom the pct was dosed. the data collected allowed us to form two groups according to the pct value: pct+ group with pct > ng/ml and pct− group with pct < ng/ml. the statistical analysis of these different data was carried out using epi info software version . . . results: % of our patients had a bacterial infection and % did not have one. we also distinguished community infections ( % of i+ patients) and nosocomial infections ( % of i+ patients). we found that the highest rates of pct were in nosocomial infections and the lowest pct rates were found in community-acquired infections. then, in each type of organ involvement we tried to vary the pct thresholds to . - and ng/ml in order to find the best threshold for which pct allowed to diagnose bacterial infection, justifying our choice of departure. we concluded that the best pct cut-off value in general was ng/ml, because it gave us the best sensitivity/specificity ratio ( % and % respectively) with a positive predictive value of % and a negative predictive value of %. the link between pct and bacterial infection was moderate (yule q-factor at . ). by analyzing the different therapeutic aspects, we showed that % of our patients had been treated with atb before the pct assay and that the broadest spectrum antibiotics available to our service were used in patients with pct levels the highest. finally, concerning the evolution, the higher the rate of pct, the higher the death rate, especially since % of patients with pct > ng/ml died. conclusion: procalcitonin is considered to be one of the best markers of systemic bacterial infection. indeed, its elevation is earlier than that of crp and its specificity is better compared to il- and il- . the rate of procalcitonin remains low in the presence of viral infection. procalcitonin is also a prognostic marker, its elevation is correlated with the severity of the infection, and its decrease is a good indicator of the effectiveness of antibiotic therapy. compliance with ethics regulations: not applicable. rationale: due to induction immunosuppression infection is the most common cause of mortality within the first year after lung transplantation (ltx). the management of perioperative antibiotic therapy is a major issue, but little is known about worldwide practices. we sent by email a survey to ltx centers around the world dealing with daily clinical vignettes concerning perioperative antibiotic therapy. we considered perioperative period as the period of the transplant surgery (per operative) and the postsurgery time before any infection occurrence (postoperative). after general questions on local practices, we asked each center for colonization definition and their diagnostic methods for microbial screening in recipients and donors. the clinical cases were related to specific issues concerning the management of antibiotic therapy in different clinical situations, including no prior colonization, prior colonization with sensitive or multi-drug resistant (mdr) microorganisms including prior colonization with mdr bacteria not sensitive to beta-lactams. the invitation and a weekly reminder were sent to lung transplant specialists for a single consensus answer per center between june and september . we received a total of responses from countries, mostly from western europe (n = ) and the usa (n = ), (fig. ) . systematic screening for bronchial colonization before ltx was mostly performed with sputum samples ( %), regardless of the underlying lung disease. definition of colonization was very heterogeneous and the delay between the last bacterial isolation in pre-transplant and the ltx to consider if the therapy should target these bacteria varied between week and more than year. in recipients without colonization, antibiotics with activity against gram-negative bacteria resistant strains (piperacillin/tazobactam, cefepime, ceftazidime, carbapenems) were reported in % of the centers, and antibiotics with activity against methicillin-resistant staphylococcus aureus (mainly vancomycin) were reported in % of the centers. for these recipients, the duration of antibiotics reported was days ( %) or less ( %) or stopped when cultures of donor and recipients were reported negatives ( %). in recipients with pre-transplant colonization, antibiotics were adapted to the susceptibility of the most resistant strain isolated in pre-transplant samples and given for at least days ( %). conclusion: practices vary widely around the world, but resistant bacterial strains are mostly targeted even if no colonization occurs. the antibiotic duration reported was longer for colonized recipients. compliance with ethics regulations: not applicable. the vancomycin was therefore considered as justified or not and appropriate or not. occurrence of nephrotoxicity and supratherapeutic exposure in this study group was compared to critically ill children control group. results: thirty one children receiving vancomycin lines of treatment whose ( %) observed a risk of acute kidney injury (aki) (n = ) and an aki (n = ) during the vancomycin treatment period were included. there was a trend to inversed relationship between plasmatic concentrations of vancomycin and estimated creatinine clearance (r = . ). seven patients observed a nephrotoxicity related to vancomycin, they had a higher plasmatic concentration of vancomycin (p = . ). seven patients ( %) had a supratherapeutic exposure to vancomycin. nephrotoxicity and supratherapeutic exposure were higher in children with or combined liver-kidney transplantation than in comparative critically ill children group. we found blood stream infection due to the central catheter and blood stream infections probably due to the central catheter. one hundred thirtyfive bacteria were identified of which ( %) were staphylococcus coagulase negative. nineteen ( %) lines of vancomycin were appropriate and ( %) were justified. conclusion: vancomycin could have been avoided in one third of children with liver or combined liver-kidney transplantation during the early phase of postoperative stage. vancomycin is associated with a risk of both nephrotoxicity and supratherapeuric exposure. vancomycin should be used with caution, appropriate indications and dosing in this vulnerable population. compliance with ethics regulations: yes. rationale: early bacterial infection is a major and severe complication occurring within the first month after pediatric liver transplantation (lt). the rise of antimicrobial resistance, especially extended-spectrum beta lactamase producing enterobacteriaceae (esbl-pe), is henceforth a concern for these patients. this study aimed to assess the epidemiology of early bacterial infections, including those caused by multidrugresistant (mdr) pathogens, and to identify the risk factors for infection. rationale: the number of cancer patients admitted to emergencies is clearly increasing and digestive oncology is the leading cause of consultation. the aim of this work is to identify the epidemiological factors, the therapeutic modalities as well as the predictive factors of mortality and to compare them with the data of the literature. patients and methods: patients admitted to visceral emergencies for an urgent syndrome revealing or complicating a primary or secondary digestive cancer, and who required immediatemedical and/or surgical intervention and who had stayed at the surgical resuscitation level in our hospital center for a duration of years. several data were entered on excel and analyzed using the spss version software.-epidemiological, concerning age and sex; -clinics including risk factors, history, general condition of the patient and clinical examination data; -para-clinical, interesting biological assessments, and morphological examinations-medical and surgical therapeutics; -postoperative follow-up-treatment results. the three most frequent sites were rated in order of increasing frequency: colo-rectum ( %), pancreas ( %), and stomach ( %). the age group most found was age over years with % of cases, % of patients had under years. this series includes men and women with a sex ratio of , . the installation method was mostly gradual with % of cases. our patients have consulted for urgent clinical presentations mainly occlusive syndrome noted in % of patients. abdominal ct was the first examination performed, followed by abdominal ultrasonography in % and %, respectively. the therapeutic management was medico-surgical. the surgery done in % of patients, % for palliative indication: % were operated for an ostomy discharge, % for a digestive bypass, % for a palliative resection and % for a stoma feeding. postoperative outcomes were % morbidity and % mortality. the main cause of death was septic shock in % of cases, thanks to multivariate statistical analysis three factors were deduced significantly related to mortality: the asa score: p = . ; or = . ; ic: [ . ; . icu and hospital mortality rates were % (n = ) and . % (n = ), respectively. ten patients were alive months after with a median rankin score at [ - ]. more than half of the patients without stupor had a favorable neurological outcome (fig. ) . in univariate analysis, mechanical ventilation and stupor were correlated with mortality, whereas dic and apl were not. by multivariate analysis stupor was the only factor significantly associated with a higher mortality (hr: . [ . - . ] ). conclusion: intracranial hemorrhage is associated with a high mortality rate in al patients, stupor at the onset of intracranial bleeding being independently associated with poor outcome. up to one third of patients will nevertheless survive and experience a favorable neurological outcome. compliance with ethics regulations: yes. neurological outcome assessing by modified rankin scale according to stupor or coma at intracranial hemorrhage diagnosis (blank reflect missing data) rationale: sinusoidal obstruction syndrome (sos, previously known as veno-occlusive disease) is a complication of high dose chemotherapy, frequently occurring during bone marrow transplantation (bmt). severe sos is associated with a high mortality rate, related to multi-organ failure (mof). defibrotide being the only available option for prevention and treatment. prognosis of patients with sos requiring intensive care unit (icu) admission remains unknown. the primary objective was to assess the outcome of these patients. secondary objective was to assess risk factors associated with hospital mortality. patients and methods: retrospective study conducted between january and july in french icus. critically ill adult patients with sos (according to ebmt classification) who received defibrotide were included. results are reported as median [iqr] or number (%). adjusted analysis was performed using cox model. results: seventy-one patients were included with a median age of years . underlying hematologic diseases were acute myeloid leukemia ( %), lymphoma ( %),myelodysplasia/myeloproliferative neoplasm ( %) or acute lymphoid leukemia ( %). sos occurred during myeloablative allogeneic bmt ( %), reduced conditioning allogeneic bmt ( %), autologous bmt ( %) or chemotherapy ( %, including gemtuzumab ozogamycin in patients). median sofa score at icu admission was ]. ebmt prognostic score was often "very severe" ( %). main reasons for icu admission were respiratory failure (n = ), acute renal injury (n = ), shock (n = ), liver failure (n = ), coma (n = ) and monitoring (n = ). median bilirubin level at icu admission was µmol/l [iqr - ] and platelets count g/l . mechanical ventilation (mv), vasopressors, and renal replacement therapy (rrt) were required in % (n = ), % (n = ) and % (n = ) of patients, respectively. sixteen patients receiving defibrotide experienced bleeding events. icu and hospital mortality rates were % and % respectively, mainly related to organ dysfunction. in univariate analysis, delayed defibrotide initiation, bilirubin level, organ supports, sofa, and ebmt scores were associated with hospital mortality. cox model identified older age (hr . , % ci . - . ), mv (hr . , % ci . - . ), rrt (hr . , % ci . - . ), as associated with mortality. prophylactic defibrotide was correlated with a better outcome (hr . , % ci . - . ). similar results were observed after adjustment for center effect. conclusion: when organ support is required, icu management is associated with high mortality. organ support (namely rrt and mv) and older age were associated with poor outcome. prophylactic defibrotide was associated with survival either due to selection process or to efficacy in this setting. additional studies are needed to confirm these results. compliance with ethics regulations: yes. rationale: prognosis of critically ill immunocompromised patients (ciip) has improved over time. neutropenia is common and is found in one third of these patients. prognostic impact of neutropenia remains controversial and little data focus on ciip admitted in a context of acute respiratory failure (arf). primary objective was to assess prognostic impact of neutropenia on outcome of these patients. secondary objective was to assess etiology of arf according to neutropenia. patients and methods: retrospective analysis of prospective multicenter multinational dataset. adults immunocompromized patients with arf were included. adjusted analyses included ( ) a hierarchical model with center as random effect; ( ) propensity score (ps) matched cohort; and ( ) adjusted analysis in the matched cohort. results: overall, patients were included in this study. median age was [iqr - ] and patients ( . %) were of female gender. median sofa score was [ ] [ ] [ ] [ ] [ ] [ ] [ ] and ps was [ ] [ ] [ ] [ ] . main immune defect were hematological malignancy in patients ( %), solid tumor in ( %), systemic disease in ( . %), and other immunosuppressive drugs in ( %). neutropenia at admission was observed in patients ( %). initial oxygenation strategy was oxygen in patients ( %), high flow nasal oxygen in ( %), non-invasive ventilation in ( %) and invasive mechanical ventilation in ( %). before adjustment, hospital mortality was significantly higher in neutropenic patients ( % vs. % in non-neutropenic patients; p = . ). after adjustment for confounder in a mixed model, neutropenia was no longer associated with outcome (or . , % ci . - . ). after ps matching, neutropenic and non-neutropenic patients were compared. hospital mortality was similar in both groups ( % vs. % respectively; p = . ). after adjustment for variables associated with mortality, neutropenia was not associated with hospital mortality (or . , % ci . - . ). arf etiologies were distributed similarly in both neutropenic and non-neutropenic patients (fig. ) , main etiologies being bacterial pneumonia ( % vs. %), invasive fungal infection ( % vs. %), pneumocystis jiroveci pneumonia ( % vs. . %), and undetermined etiology ( % vs. %) (p = . ). conclusion: neutropenia at icu admission is not associated with hospital mortality in this cohort of ciip admitted for arf. surprisingly, arf etiology did not differ despite the multiplicity of observed immune defects. compliance with ethics regulations: yes. rationale: hepatic dysfunction (hd) is commonly observed in patients with hematologic malignancies and associated with an increased mortality in allogeneic hematopoietic stem cell transplantation patients. we aimed to assess incidence, risk factors and prognostic impact of hd in a large multicenter cohort study of critically ill patients with hematologic malignancies. patients and methods: this research was a post hoc analysis of a franco-belgian multicenter prospective study assessing the prognosis of patients with hematologic malignancies admitted to intensive care unit (icu) between january and may . hd was defined as serum total bilirubin ≥ µmol/l at icu admission. for patients with hd, a review of medical hospital records was performed by an expert panel to assess management of hd by attending physicians. results: among the patients with hematologic malignancies admitted to icu, were included in the study, mainly patients with non-hodgkin lymphoma ( . %) or acute myeloid leukemia ( . %). hd at icu admission occurred in patients ( . %). factors independently associated with hd were the use of cyclosporine (or = . , % ci . - . , p < . ) and antimicrobial treatment (or = . , % ci . - . , p = . ) before icu admission, abdominal symptoms at icu admission (or = . , % ci . - . , p < . ), ascites (or = . , % ci . - . , p = . ), hepatic charlson comorbidity (or = . , % ci . - . , p = . ), increased creatinine at icu admission (or = . , % ci - . , p = . ), neutropenia (or = . , % ci . - . , p = . ) and myeloma (or = . , % ci . - . , p = . ). hospital mortality was . % and . % in patients with hd and patients with no hd respectively (p < . ). hd appeared as an independent factor of hospital mortality after adjustment with other organ failure (oradj = . , % ci . - . , p = . ). factors independently associated with hospital mortality among patients with hd at icu admission are reported in table . etiologic diagnoses for hd by physicians were undetermined for patients ( . %) including ( . %) for whom the existence of hd has not even been mentioned in the medical record. investigations were performed in % and only % of patients received a specific treatment for hd. conclusion: hd at icu admission is common, underestimated, poorly investigated, and impairs outcome in critically ill patients with hematologic malignancies. hd should be considered and managed as other organ dysfunctions. it raises the importance of an early severity assessment of hd and a development of diagnosis strategies to get therapeutic options, in close collaboration between hematologists and intensivists. compliance with ethics regulations: yes. rationale: acute respiratory failure (arf) is the main cause for admission to the icu for patients with hematological malignancies (hm). viral pneumonia is poorly described in this population. respiratory viruses pcr is a rapid and sensitive diagnostic tool. thoracic ct allows to guide the diagnosis but is also poorly described. the primary objective was to describe ct features suggesting viral pathogenicity. secondaryobjectives were to assess risk factors associated with the use of invasive mechanical ventilation (imv) and icu mortality. rationale: high-dose methotrexate (hd-mtx) is commonly used in the treatment of solid tumours and hematological malignancies. severe toxicities are frequent, leading to organ dysfunction, multiple organ failure and death. outcome of these patients when critical illness occurs is poorly studied. this study aims to describe mtx-induced toxicities and to assess outcome in critically ill patients. in this retrospective study conducted in the icu of one university hospital between january and december , all the patients who were given hd-mtx (single dose greater than mg/m ) in the icu were included. results are presented as median [interquartile range] and number (percent). results: patients ( men and women) aged years [ - ], were included. b-cell lymphoma had been diagnosed in patients (burkitt, n = ; diffuse large b cell lymphoma with cns (central nervous system) involvement, n = ; primary cns lymphoma, n = ) and t-cell lymphoma in two patients. patients were mainly admitted for coma (n = ; %) or acute kidney injury (n = ; %). mtx was administered at a median dose of . g [ - ] . fourteen patients had concomitant medication interacting with mtx. median mtx clearance was days [ ] [ ] . frequent mtx-related complication were mucositis (n = , %), diarrhea (n = , %) or hepatic failure (n = , %). during icu stay, patients experienced acute kidney injury (kdigo stage . [ ] [ ] ). two patients received carboxypeptidase and three underwent dialysis. overall, patients ( %) required mechanical ventilation, ( %) vasopressors. hospital mortality was % (n = ). cox model identified mtx concentration h after administration higher than . µmol/l as associated with hospital mortality (hr . , % ci . - . ) (fig. ) . conclusion: to our knowledge this is the first study assessing characteristics and outcome of critically ill patients receiving hd-mtx. mtx concentration at h was associated with hospital mortality. despite underlying malignancy, icu support of these patients was associated with a meaningful survival. compliance with ethics regulations: yes. rationale: high-dose methotrexate ( g/m ; hdmtx) is the cornerstone of chemotherapy in acute lymphoblastic leukemia (all) and several high-grade non-hodgkin lymphoma (hnhl). despite standardized prevention, acute kidney injury (aki) and other life-threatening complications still occur. given the cost of glucarpidase, an enzyme that metabolizes mtx in few minutes, and the complexity of hematological patients admitted to the icu, a better comprehensive view of the factors that predict hdmtx toxicity, as well as the role of glucarpidase as rescue therapy in patients with organ failure, is mandatory. patients and methods: retrospective monocenter study including all the adult patients referred for all or hnhl in a french university hospital, and who received hdmtx. aki was defined according to the kdigo classification. univariate analysis (fischer exact or mann-withney tests) followed by multivariate analysis (stepwise logistic regression) were used to identify before hdmtx the clinical and biological predictive factors of aki. outcomes following glucarpidase were also addressed. results: from dec- to sept- , patients received hdmtx (median dose g/m ; all n = , hnhl n = ), totalizing hdmtx pulses. sixty-nine patients ( . %) developed aki after a median time of days (stage n = , stage n = , stage n = including one requiring dialysis in the first week). by multivariate analysis, only age, body mass index and a diagnosis of all were significantly and independently associated with the risk to develop aki. mtx exposure (maximal serum concentration at h - ) was also associated with aki (auc . , p < . ). glucarpidase was used in patients ( %) that differed by a higher age and bmi, and a lower basal egfr. glucarpidase was followed by a rapid renal improvement but serum creatinine did not return to baseline ( vs. micromol/l). thirty patients with aki or delayed mtx elimination did not receive glucarpidase but none required renal replacement therapy and egfr was only slightly but not significantly reduced at the end of follow-up. extra-renal adverse-events (rbc and platelets transfusions, neutropenia, hepatitis, severe diarrhea, mucitis) were more frequent in patients that developed aki. eighteen patients were admitted to the icu, including and that required mechanical ventilation or vasopressor drugs, respectively. conclusion: few actionable factors predict the development of aki after hdmtx, suggesting additional genetic factors. aki was reversed by glucarpidase but progression toward ckd was the rule. further studies will have to identify patients that will actually beneficiate from glucarpidase. compliance with ethics regulations: yes. khaoula ben ismail, sana khedher, ameni khaled, nassereddine foudhaili, mohamed salem usi digestif-service de gastroenterologie-eps charles nicolles.tunis-tunisie., tunisia, tunisia correspondence: khaoula ben ismail (khaoula @hotmail.fr) ann. intensive care , (suppl ):p- rationale: infection is common and accounts for major morbidity and mortality in cirrhosis. patients with cirrhosis are immunocompromised and have increased susceptibility to develop spontaneous bacterial infections, hospital-acquired infections, and a variety of infections from uncommon pathogens. we aimed to evaluate the impact of infection on hepatic encephalopathy. patients and methods: this is a prospective study, conducted over a period of years from january to december . consecutive patients with approved decompensated cirrhosis admitted to our department are included. all clinical and biological data were collected from the medical records. univariate and multivariate analysis were used to identify the impact of infection on hepatic encephalopathy. results: a total of patients diagnosed with decompensated cirrhosis were enrolled in this study. mean of age was years ( - ). sex ratio was . . hcv ( %) was the main etiology of cirrhosis. the reasons of hospitalization were: oedema with ascitic syndrome ( % of cases), digestive bleeding ( % of cases), fever ( % of cases), and encephalopathy ( % of cases). patients with infection seemed to have a high incidence of hepatic encephalopathy with % versus % when the patients are none infections. the results also showed that in those with hepatic encephalopathy, an effective antibiotic treatment accelerates significantly wakefulness under h with a rate of % vs. % (p < . ) . in addition, the infection does not influence mortality or length of stay compared to other complications such as digestive bleeding. conclusion: we found that infection caused more episodic hepatic encephalopathy than other complication and an effective antibiotherapy accelerate wakefulness. compliance with ethics regulations: yes. rationale: hepatic encephalopathy (he) is a common cause of hospitalization in patients with cirrhosis. pharmacologic treatment for acute (overt) he has remained the same for decades. to compare polyethylene glycol electrolyte solution (peg) and lactulose treatments in patients with cirrhosis admitted to the hospital for he. we hypothesized that rapid catharsis of the gut using peg may resolve he more effectively than lactulose. patients and methods: this is a prospective study, conducted over a period of years. from janury to december , we have been interested in cirrhotic patients with hepatic encephalopathy. all clinical and biological data were collected from the medical records. univariate and multivariate analysis were used to identify the difference beteween peg and lactulose in the treatement of hepatic encephalopathy. results: a total of patients diagnosed with decompation of cirrhosis were enrolled in this study. mean of age was years ( - ). sex ratio was . . hcv ( %) was the main etiology of cirrhosis. the hospitalization reasons were: edematous-ascitic syndrome in %, gastro-intestinal bleeding %, fever in %, and encephalopathy was present in % of cases. a total of patients were randomized to each treatment arm. baseline clinical features at admission were similar in the groups. twelve of patients in the standard therapy arm ( %) had an improvement of or more in hesa score, thus meeting the primary outcome measure, compared with of evaluated patients receiving peg ( %) (p < . ). the mean ± sd hesa score at h for patients receiving standard therapy changed from . ± . to . ± . compared with a change from . ± . to . ± . for the peg-treated groups (p = . ). the median time for he resolution was days for standard therapy and day for peg (p = . ). adverse events were uncommon, and none wasdefinitely study related. conclusion: we found that peg led to more rapid he resolution than standard therapy, suggesting that peg may be superior to standard lactulose therapy in patients with cirrhosis hospitalized for acute he. compliance with ethics regulations: yes. acute pancreatitis and pregnancy janati adnane, lina berrada obstetric intensive care unit, casablanca, morocco correspondence: janati adnane (adnanejanati@gmail.com) ann. intensive care , (suppl ):p- rationale: the association of acute pancreatitis and pregnancy is rare but not negligible, it often cause a diagnostic problem given the gravidal context that can lead to serious repercussions. the objective of our study is to assess the particularities in the diagnosis, management and prognosis of acute pancreatitis during pregnancy patients and methods: this is a retrospective study about cases of acute pancreatitis occurred during pregnancy over a -year period ( - ) at the obstetric intensive care unit of the meriem maternity hospital in the chu ibn rochd casablanca. a retrospective analysis of the medical files of these patients was carried out, considering epidemiological and etiological criteria, the treatments administered and maternal/fetal fate. we found cases during this period, with an incidence of / . the average age of onset was years, % of cases occurred in the rd trimester. epigastric pain and vomiting were the common symptomatology. ultrasound showed biliary lithiasis in % of cases with increased pancreas size in % of cases. maternal mortality was zero. uncomplicated benign forms are the most common ( %). severe hypokalemia was found in % of patients. neonatal morbidity was marked by six premature deliveries. among them, a newborn died at day- of life discussion: the association of acute pancreatitis and pregnancy is rare, more frequent during the rd trimester, it mainly affects the young woman. lithiasic biliary pathology remains by far the most frequent etiology. the diagnosis is clinical most often represented by epigastralgia with vomiting and biological via lipasemia and amylasemia dosage. uncomplicated benign forms are the most common. hydroelectrolytic disorders are often found. abdominal ultrasound allows the etiological diagnosis. the treatment is above all symptomatic whose objective is the digestive rest, the correction of the hydroelectrolyte disorders but first of all relieve the pain. conclusion: acute pancreatitis is a rare event in pregnant women, but can have a maternal and fetal prognosis. it must be systematically evoked in front of the acute abdominal pains of the pregnant woman because the confirmation of the diagnosis is easy and the maternal results depend mainly on therapeutic management. prematurity remains the predominant factor in neonatal morbidity. compliance with ethics regulations: not applicable. rationale: aclf is a clinical concept defined in patients with chronic liver disease who presented organ failure(s) secondary to an acute decompensated event. liver transplantation in this indication showed good results in selected patients. the aim of this prospective study was to evaluate the outcome and the factors associated with a favorable selection to liver transplantation in this population. patients and methods: all consecutive patients admitted to the icu with cirrhosis and aclf, were recruited. patient with age < years or with fulminant hepatitis were excluded. results: between july and february , cirrhotic patients were admitted to icu. mean age was . ± . years ( . % male). cirrhosis was due to alcohol in . % of the patients. aclf grading at admission was: . % aclf (n = ), . % aclf (n = ), . % aclf (n = ), and . % aclf (n = ). of the patients, . % (n = ) were considered to be eligible for a transplant project and were assessed for liver transplantation. the main reasons were alcohol abuse ( . %, n = ), death within days after admission ( . %, n = ) and rapid improvement of the liver disease. of the eligible patients, % were transplanted with a mean time between admission to icu and liver transplantation of . ± . days. twelve patients died on the waiting list ( % of the listed patients), mainly of septic shock. among those who were assessed for liver transplantation but not listed (n = ), . % died before the listing (n = ) and . % were not listed because of severe comorbidities (n = ). the global mortality rate was . % (n = ). the and days rate mortality were respectively . % and . %. the overall -month patient survival was respectively % and % in the transplant and non-transplant group (p < . ) for the entire cohort. among eligible patients, factors associated with the absence of liver transplantation, in the multivariate analyses, were mechanical ventilation (hr . , % ci rationale: body composition is known to be a prognostic factor in cirrhotic patients. however, the link between this and the prognosis of patients in intensive care unit (icu) is unknown. the computed tomography offer accurate estimations of muscle mass by analysing a cross-section usually going through the third lumbar vertebrae. this retrospective study aimed to assess the feasibility of body composition (bc) analysis in cirrhotic patients with septic shock, using computed tomography (ct) and evaluate the impact of bc (muscle mass, subcutaneous and visceral fat) on outcome. patients and methods: this retrospective study included cirrhotic patients with septic shock hospitalized in icu who underwent an abdomino pelvic ct scan within h of admission. we collected the surface areas of muscle mass and adipose tissue on the ct scans. we compared bc data with mortality and with the number of organ failures. the average age was years . the average child and meld scores were respectively . [ - ] and . . the prevalence of sarcopenia was %. it was not associated with a higher mortality rate at day (p = . ) or with a higher number of organ failures at day (p = . ). we observed a higher subcutaneous adiposity index in patients who died at day (p = . ) and in patients with renal insufficiency at admission (p = . ). there was a trend (p = . ) towards more visceral fat in patients who died in icu. the assessment by ct of body composition reveal evaluation of bc using ct is feasible and reproducible and may constitute a promising tool to evaluate in cirrhosis critically ill patients. visceral fat mass seems associated with poor outcome in cirrhotic patients with septic shock compliance with ethics regulations: yes. rachid jabi, mohammed bouziane chu mohammed vi, oujda, morocco correspondence: rachid jabi (jabirachid@gmail.com) ann. intensive care , (suppl ):p- rationale: the infection of the necrosis constitutes a pejorative element in the management of the necrotico-haemorrhagic pancreatitis, in the absence of the drainage the mortality approaches %. the morbidity and mortality of surgery can be avoided with minimally invasive treatments. purpose: to compare the morbidity and mortality of the two groups of post-ercp pancreatitis and the other etiologies. patients and methods: a retrospective study over years between and and a comparison between pancreatitis secondary to post-ercp and other etiologies of pancreatitis. a p value of . is considered significant. the surgical treatment used in cases of superinfection post ercp against seven cases of other etiologies of pancreatitis. high mortality in post-ercp pancreatic arm % vs. % (p = . ). high morbidity in the operated group % vs. % (p = . ) represented mainly digestive haemorrhages. duration of stay was significantly longer in the operated group vs. days (p = . ). thrombocytopenia and beta-lactamase-producing enterobacteria have further complicated management in the post-ercp infected pancreatitis arm. the antibiotic resistance of infected pancreatitis in post-ercp patients is . % for ciprofloxacin, . % for imipenem and % for amikacin. conclusion: pancreatitis the most common adverse effect of ercp with significant morbidity and mortality. the collaboration between the intensive care unit gastroenterologist and the surgeon improves management since the risk factors are mainly related to the patient and can not be modified. compliance with ethics regulations: yes. gautier nitel, aghiles hamroun, anne bignon, gilles lebuffe chru lille, lille, france correspondence: gautier nitel (gautier.nitel@gmail.com) ann. intensive care , (suppl ):p- rationale: liver transplantation (lt) has been recently experiencing an expansion of its indications, allowing patients with potentially more co-morbidities to access to transplantation. in our era of graft shortage, we should focus on the identification of the best lt candidates. the aim of our work is to study the determinants of early morbidity and mortality after lt from three angles: occurrence of a major cardiovascular event (mace) or acute renal failure (kdigo stage - aki) in the first days postoperative, and death in the year following lt. retrospective study investigating the occurrence of mace or aki (kdigo - ) within days post-operative and mortality at year after lt, including patients who received a first lt between january and december in our center. analysis of risk factors by a multivariate step-by-step analysis. statistical significance for p < . . data presented in odds ratio (or) rationale: infectious complications are frequently reported in critically ill patients supported by veno-arterial extracorporeal membrane oxygenation (va-ecmo) for refractory cardiogenic shock, but their diagnosis is challenging. no study has specifically studied bloodstream infection (bsi) in this population and some recommendations suggest performing systematic blood culture (bc). in our unit, systematic bc are daily sampled. we investigated the interest of systematic bc to detect bsi under va-ecmo. patients and methods: in a retrospective analysis ( - ), and after exclusion of patients dying within h, all adult patients from cardio-vascular intensive care unit supported by va-ecmo were included. systematic daily and "on demand" bc (at the physician's discretion) performed from va-ecmo implantation to days after withdrawal were analyzed. bsi was defined as at least one bc positive to a pathogen (except for contaminants bsi which required at least two positive bc with the same bacteria in h). multivariable logistic regression was performed to identify risk factors for positivity of systematic bc. rationale: fungal infections are constantly increasing in hospitals. indeed, the increase in these infections and especially candida yeast infections is almost parallel to the increase in the widespread use of a wide range of implanted medical devices such as catheters. for this reason, we have been investigating, isolating and identifying candida yeast colonizing vascular catheters and studying the epidemiological and clinical characteristics of patients with colonized catheters. patients and methods: it is a prospective, transversal study conducted at the intensive care and neurosurgery services of the sétif university hospital, evaluating the fungal colonization of vascular catheters. these are collected from hospitalized patients for a period of months. a culture of the distal end of the catheter is performed directly after its ablation. the results obtained showed that among the samples taken, six are colonized by the yeasts, the incidence is %. six yeast of candida spp were isolated, % of them were candida albicans species, . % candida parapsilosis and . % were candida glabrata. conclusion: it appears that colonization of catheters occurs most frequently in patients with the following characteristics: extreme ages of life, male sex, antibiotic therapy and length of hospitalization or prolonged catheterization. compliance with ethics regulations: yes. rationale: the threat of emergent extensively drug-resistant bacteria (exdr) dissemination worldwide is real. it has become a global public health issue. in fact, glycopeptides-resistant enterococcus faecium (gre) and carbapenemase-producing enterobacteriaceae (cpe) are the lead microorganisms in the high resistant bacteria category. the aim of our study was to characterize the molecular mechanisms and to determinate the antimicrobial susceptibility profiles of gre and cpe isolated from burn patients. patients and methods: prospectively, we studied all cpe and gre strains isolated from burn patients between january and december . all isolated microorganisms were identified on the basis of conventional microbiological techniques. antibiotic susceptibility testing was carried out by the agar disc diffusion method, and susceptibility results were interpreted using clinical breakpoints according to ca-sfm guidelines. molecular characterization was performed by multiplex real-time pcr (cepheid, genexpert ® ) allowing detection of the most prevalent carbapenemase encoding genes (blavim, blandm, blaimp, (blaoxa- and blakpc) as well as the genes vana and vanb of gre. results: during the study period, exdr were isolated from burn patients. the most frequent sites of isolation were blood cultures ( %) and skin samples ( . %). cpe represented . % of isolated exdr ( strains). among them, the most frequently identified species was klebsiella pneumoniae ( . %) followed by enterobacter cloacae ( %). twenty-four cpe ( . %) expressed the blandm gene. the blaoxa- gene was found in strains ( . %) and ten strains ( . %) carried both genes. of the cpe, . % revealed ertapenem mic > mg/l whereas most strains were susceptible to imipinem and meropenem with . % and . % of susceptibility, respectively. the antibiotics showing the highest resistance rates were cefotaxime ( . %), piperacillin-tazobactam ( . %), ciprofloxacin ( . %) and amikacin ( . %). the most active agents were colistin and fosfomycin with . % of resistance for each. seven strains of gre were isolated ( . % of exdr). all of them expressed the vana gene, with vancomycin mic > mg/l. however, teicoplanin mics ranged from to mg/l. all gre strains were beta-lactam resistant and highly resistant to aminosides. linezolid and tigecycline were the only active antibiotics. the dissemination of these extensively drug-resistant bacteria must be contained by implementation of strict isolation methods and better hygienic procedures in order to limit their economical and health consequences. compliance with ethics regulations: yes. rationale: stenotrophomonas maltophilia has emerged as an important pathogen that induces nosocomial infections. it is a non-fermentative, gram-negative bacillus that causes severe infectious diseases, particularly bacteremia in the hospital setting. morbidity and mortality due to stenotrophomonas maltophilia seems to be high, particularly in critically ill patient. the aim of this study was to describe the clinical features, management and outcome of patients with stenotrophomonas maltophilia infections. patients and methods: this was a retrospective analysis of prospectively collected data of patients hospitalized in intensive care unit (icu) between january and december . collected data were: age, gender, comorbidities, severity scores on admission, prior infections, use of antibiotics, use of invasive devices (urinary tract catheter, or mechanical ventilation), microbiological data, and antimicrobial therapy and outcome. results: during the study period, patients with stenotrophomonas maltophilia infection were included, with a mean age of ± years. the simplified acute physiology score ii and acute physiology and chronic health evaluation ii on admission were respectively ± and ± . bacteremia caused by stenotrophomonas maltophilia was observed in patients ( %) and ventilator acquired pneumonia in two patients ( %). twenty four episodes were classified as primary bacteraemia and only one as secondary bacteraemia due to urinary infection. four patients ( %) developed septic shock. mean sofa on the day of stenotrophomonas maltophilia infection was ± . prior antibiotic use was observed in % including an antipseudomonal agent in % of cases. infection due to stenotrophomonas maltophilia was considered in cases. empiric antibiotic therapy was administered to patients ( %) and had included an appropriate agent in only five cases ( %). after adapting antibiotics, monotherapy was the choice for six ( %) patients while a combination of two antibiotics was indicated in the others ( %). the most used antibiotic was the colistin in episodes ( %). intensive care mortality was %. univariate comparison between dead and survivors showed a significant difference in prior nosocomial infection and respiratory comorbidities. no independent risk factor of mortality was found in multivariate analysis. rationale: thrombocytopenia is a frequent disorder in critically ill patients, and several studies have reported its correlation with poor prognosis. considering the major role of platelets in hemostasis, a significant drop in platelet count is an alarming sign in septic patients. the aim of this study was to show the relationship between thrombocytopenia and platelet level changes and mortality in septic patients. patients with criteria for septic shock (based on the third international consensus definitions for sepsis and septic shock) at admission or at any time during hospitalization were included in a prospective study conducted for a period of months (january -august , ) in a medical surgical intensive care unit. patients hospitalized for less than h were excluded. thrombocytopenia was defined as a platelet count less than . /mm , and recovery was defined as returning to levels more than . /mm after presenting thrombocytopenia. we assessed the platelet count during the hospitalization and its outcomes. we included patients. the mean ± sd age was . ± . years. sex ratio was . . thrombocytopenia during sepsis (group ) was found in patients ( %) with a mortality rate at %. the mortality rate among patients not showing thrombocytopenia (group ) was significantly lower % (p = . ). the receiver operating characteristic showed that in (group ), a drop in the platelet count (from admission to septic shock day) more than % was associated with poor outcome (sensibility = %, specificity = %, auc = . ). among the (group ), % showed recovered platelet counts. the mortality was significantly higher in the patients with uncovered thrombocytopenia ( % vs. %, p = . ). conclusion: thrombocytopenia was shown to be an indicatorof poor prognosis in our study. in addition, drops of > % and failure to recover the platelet counts were further determinants of unfavorable outcomes. compliance with ethics regulations: yes. mehdi gaddas , sarra dhraief , karim mechri , imen jami , amenallah messaadi , lamia thabet rationale: pseudomonas aeruginosa is known as an opportunistic pathogen frequently causing serious infections. multidrug resistance in this bacterium is increasing worldwide and poses a major problem in the treatment of infections due to this microorganism. analysis of resistance profile to antibiotics of p. aeruginosa helps to establish a prompt control and prevention program. the aim of this study was to evaluate epidemiological profile and antimicrobial resistance of p. aeruginosa isolates in a trauma and burn center. patients and methods: retrospectively, we studied all p. aeruginosa isolates over a -year period (from january to december ). conventional methods were used for identification. antimicrobial susceptibility testing was performed with disk diffusion method and susceptibility results were interpreted using clinical breakpoints according to ca-sfm guidelines. data were analyzed using the sirsystem. minimum inhibitory concentration of colistin was determined using the e-test ® method (biomérieux), then using the eucast broth micro-dilution method (umic, biocentric ® ) since may . results: during study period, non-repetitive strains of p. aeruginosa were isolated, representing % of all isolates. in our center, infections due to p. aeruginosa were endemic with epidemic peaks. p. aeruginosa was mainly isolated from burn intensive care unit ( . %) and anesthesiology department ( . %). the most frequent sites of isolation were skin samples ( . %), blood cultures ( . %), catheters ( . %) and urines ( . %). the survey of antibiotic susceptibility showed high percentage of resistance to the different antibiotics: . % of strains were resistant to ceftazidime, % to ticarcillin, . % to pipercaillin-tazobactam, % to imipenem, . % to ciprofloxacin and % to gentamicin. resistance to colistin was rare. it concerned only four strains, isolated from burn patients. the survey of antibiotic susceptibility evolution have shown a global increase of resistance to commonly prescribed antibiotics between and : from % to . % to imipenem, from . to . % to ticarcillin-clavulanate, from . % to % to ceftazidime and from . to % to gentamicin. whereas ciprofloxacin resistance rate have decreased from . to %. antibiotic resistant strains were mainly isolated from burn intensive care unit, with % of resistance to imipenem and . % to ceftazidime. the dissemination of multidrug-resistant strains of p. aeruginosa in our center must be contained by the implementation of strict isolation methods and better hygienic procedures. compliance with ethics regulations: yes. acinetobacter baumanii: therapeutic impasse sabah benhamza, mohamed lazraq, abdelhak bensaid, youssef miloudi, najib el harrar réanimation de l'hôpital du août, casablanca, morocco correspondence: sabah benhamza (benhamzasabah @gmail.com) ann. intensive care , (suppl ):p- rationale: acinetobacter baumanii (ab) is frequently responsible for nosocomial infection in the intensive care units, and its resistance to antibiotics continues to increase. the objective of our study is to determine the epidemiological profile and antibiotic sensitivity of isolated bacteria in the intensive care unit august , in order to optimize the probabilistic antibiotherapy of bacteremia in intensive care. patients and methods: this is a retrospective study performed in the intensive care unit of the hospital august , , spread over a period of years from january to january . results: the incidence of ab infection in our department was . % for all patients admitted to intensive care. the average age was years ± , male predominance (sex ratio . ). the average time to onset of infection was days. during the study period, ab strains were isolated, % of which were pulmonary, % blood, and % urinary. resistance to c g reached % in , % in and % in . for imipenem resistance was % in , % in , % in . for amikacin, resistance was % in , % in , and % in . for fluoroquinolones resistance was % in , % in and % in . cotrimoxazole resistance was around % in the last years conclusion: the resistance of ab to antibiotics has reached very alarming levels, especially for carbapenems. this requires resuscitators to change their antibiotic prescription behavior and to invest in the prevention of nosocomial infections. compliance with ethics regulations: yes. this is a prospective observational study conducted at the ed during the period of year. data of all patients admitted with suspected infection of any cause were collected. poor outcomes were defined as death and transfer to an icu within h. results: during the study period, a total of patients with a mean age of ± were included. % were male. within h of management in the ed, % of patients were transferred to the icu and % died. independent predictors of icu-transfer and death included low systolic blood pressure, fever and tachycardia. a prediction model containing these independent predictors had a good predictive accuracy with an area under the curve of . ( % ci . - . ). sensitivity was %, specificity %, positive predictive value % and negative predictive value %. conclusion: assessing readily available clinical variables at arrival to the ed can aid in predicting poor outcomes. [ ] [ ] [ ] [ ] [ ] [ ] . the most common co-morbidities were chronic respiratory failure (crf, n = ) and hypertension (n = ). respiratory distress (n = ) and coma (n = ) were the major indications for iv. us diaphragmatic exploration was performed at a median delay of iv at days [ ] [ ] [ ] [ ] [ ] [ ] . % of patients received sedation and . % received neuromuscular blockers. the ventilator mode was control volume in patients via endotracheal tube (n = ) and tracheostomy cannula (n = ). no major incident was detected during the turning of patients. both tid and ted decreased from the sp to the pp (fig. ) : tid (mm) ( in sp vs. . in pp, p = . ), ted (mm) ( . in sp vs. in pp, p = . ). the observed dtf was lower in the pp but without significance ( . vs. . %, p = . ). no difference was showed when the comparison between sp-dtf and pp-dtf was adjusted on the ventilator mode, obesity, neuromuscular blockers and crf. the positioning in pp in ventilated patients reduces both tele-inspiratory and tele-expiratory diameters of the diaphragm but not altered its contractile function. compliance with ethics regulations: yes. significance was considered at p < . . results: results are presented in the table below. discussion: nebuliser type influences the efficiency of aerosol delivery, with the vmn delivering a significantly higher % aerosol dose than the jn at the two circuit positions (p = . on inspiratory limb; p = . at the dry side of humidifier). in agreement with previous reports using bias flow, for both nebulisers, the location within the circuit has a significant effect, with the nebuliser on the dry side of the humidifier delivering more aerosol than on the inspiratory limb (p = . for vmn; p = . for jn). conclusion: for a mechanically ventilated adult tracheotomy patient, the type of nebuliser and the location of the nebuliser within the circuit influences aerosol delivery. rationale: automatic tube compensation (atc) is a mode available in most icu ventilators. it compensates for the resistive pressure into endotracheal tube/tracheostomy canula by continuously providing a pressure assistance based on internal diameter of a new endotracheal tube/tracheostomy tube. its use in icu is unclear. we designed a survey to further explore this. patients and methods: the survey was endorsed by the acute respiratory failure section and the clinicaltrials group of the european society of intensive care medicine (esicm). the pool was sent out via an email on june to the esicm members worldwide. the following closed questions were: country, years in icu, kind of icu, kind of hospitals, kind of respirators, atc use (never, always or in some patients), reasons to or not to use atc, ventilatory mode in which atc was used. the database was frozen on august st after two reminders. we used the gross national income per capita (usd) provided by the world bank to transform the respondent's country into a geographical-economical variable with levels: high-europe, high-noneurope and middle ( ) . atc use was coded as yes or no. the primary end-point was atc rate of use and the hypothesis was that less than % of the respondents do use it. variables were expressed as counts. groups were compared by chi square test. a logistic regression analysis was performed to explore the contributing factors to atc use. we received responses without any doublons, of which six were empty, from countries. four-hundred and nine respondents used atc always or in some patients ( % atc rate of use). this rate was not different between economical-geographical regions, icu, hospitals and years in icu. for those respondents who did not use atc the reasons were: atc mode not available in icu ventilators ( . %), atc not helpful mode ( . %), atc not known ( . %) and atc provides too much pressure assistance ( . %). for those respondents who used atc the reasons were: helpful in weaning ( . %), set by default ( . %) and physiological benefit ( . %). they used atc during spontaneous breathing trial ( . %), with any assisted mode ( . %) and with specific modes ( . %). we found no risk factor for atc use in the logistic regression model (fig. ) . the atc rate of use was unexpectedly high in this survey. this may result from respondents selection bias or from an a priori underestimation of its use. compliance with ethics regulations: yes. rationale: during pressure support ventilation (psv), adjusting the level of assistance mainly aims at maintaining the patient's respiratory effort within a normal range. however, respiratory effort measurement is impeded in clinical routine by the need of esophageal pressure recording. in this study, we evaluated the accuracy of assessing the respiratory effort from the flow and airway pressure signals using several machine learning algorithms based on the equation of motion of the respiratory system. patients and methods: using the asl simulator (ingmar medical) connected to a pb ventilator (medtronic) set in psv, we simulated a massive number of different respiratory cycles. each simulated cycle represented a unique combination of compliance and resistance of the respiratory system, duration and intensity of the muscle pressure (pmus), positive end-expiratory pressure (peep) and pressure support levels. using least squares regression methods, the flow waveform was fitted according to the equation of motion of the respiratory system to determine the compliance and resistance of the respiratory system, and the pmus. the hypothesis used (alone or in combination) to constrain the system were: linearity of pmus at the onset of the inspiratory effort, nullity of pmus at the end of insufflation, and nullity of pmus during expiration. thus, nine methods were built and tested. calculated and actual peak pmus values were compared using the bland-altman method. the nine methods of pmus assessment were evaluated using different simulated cycles. by limiting the analysis to selected cycles with a predefined applicability criterion (intrinsic peep less than cmh o), a limited inspiratory effort (peak pmus less than cmh o) and a high quality of fitting (r > . ), the method using the three hypothesis together to constrain the system was characterized by a bias of . cmh o and limits of agreement of - . and . cmh o. however, when widening the analysis to all the simulated conditions, no method allowed an accurate estimation of the peak pmus : the best one exhibited a bias of - . cmh o and limits of agreement of − . and . cmh o. conclusion: among the nine machine learning methods tested, some provided an accurate estimate of the respiratory effort in selected cycles but none allowed such accuracy across all simulated conditions. this incites to assess automated methods using a more complex physiological and physical model. compliance with ethics regulations: not applicable. rationale: there is a growing interest in esophageal pressure monitoring in mechanically ventilated patients. esophageal pressure can be measured with a specific nasogastric catheter equipped with esophageal balloon and connected to a pressure transducer. it is used as a surrogate for pleural pressure and may be considered as a corner stone in advanced care of ventilated patients to better assess lung and chest wall mechanics and easily detect patient-ventilator asynchronies. however, this promising technique is still seldom used in clinical practice. trained icu nurses may perform oesophageal pressure measurements which may help facilitate its implementation in the usual patient care. this study aimed at assessing whether a specific educational program to train nurses to perform esophageal pressure monitoring allowed reliable measurements. this was a prospective monocenter study performed in an academic icu. written informed consent was obtained from the nurses before inclusion in the study. the specific educational program consisted of a -min online theoretical course, a -h group theoretical teaching and a -min simulation training on a mannequin. then each participating nurse performed three esophageal pressure measurements (using nutrivent ® catheters and an icu monitor connected to arterial line pressure transducers system) on three different mechanically ventilated paralysed patients under supervision. a knowledge assessment was performed with a short written mcq test. the skill evaluation was by two trained experts. concretely the trained nurses performed an esophageal pressure measurement without assistance. their ability to control the esophageal balloon position by an occlusion test, to measure the inspiratory and expiratory airway and transpulmonary pressures and to calculate of respiratory system, lung and chest wall compliances was assessed at the bedside using a standardized evaluation form. we present here the preliminary results of the first nine included nurses. the written knowledge assessment was considered as rationale: several modalities of ventilatory support have been proposed to gradually withdraw patients from mechanical ventilation. we conducted this study to compare t-piece and pressure support ventilation (psv) ( cmh and peep ) in the process of weaning of mechanical ventilation in burns. patients and methods: it was a prospective randomized trial in burn icu in tunisia during months. mechanically ventilated patients who met standard weaning criteria were included [ ] . patients were randomized into two groups: group under t-piece and group under psv. duration of the test: - min. the tolerance of the vs test should be judged on clinical criteria. stopping the test if occurred: agitation, tachypnea > cycles/ min, tachycardia > / min, spo < %. successful withdrawal was defined as the ability to maintain spontaneous respiration for h after extubation. results: thirty patients were included, randomized into two groups. the mean age was ± years with a ratio sex of . the average tbsa was ± %. the cause of mechanical ventilation was essentially a face neck burned ( %). the following table shows the weaning outcome of both modalities. eighty percent of succeeded extubation for both groups (n = / ). the cause of failure of extubation was secretion retention and clutter in majority of cases followed by neurological and cardiac distress. the duration of mechanical ventilation does not influence the outcome of the weaning test (p < . ), with a mean of duration of ± days. conclusion: our study did not show any difference between the two weaning modalities in the matter of outcome of extubation. the choice of weaning test of mechanical ventilation is to be judged by the clinician according of the state of his patient. compliance with ethics regulations: not applicable. rationale: when expiratory tidal flow does not go up after increasing expiratory driving pressure expiratory flow limitation (efl) occurs. it is thought that efl heralds airway closure (ac). we investigated the role of chest wall elastance (ecw) in both efl and ac in acute respiratory distress syndrome (ards) patients. our hypothesis was that the lower the ecw to lung elastance (el) ratio the higher the likelihood of efl and ac. patients and methods: twenty-five moderate to severe ards patients were prospectively included in two centers. mechanical ventilation was delivered in volume-controlled mode with tidal volume ml/kg predicted body weight at positive end-expiratory pressure cmh o in semi-recumbent position. airway (paw) and esophageal (pes) pressures and flow were continuously recorded during min by a data logger (biopac ). then, end-expiratory and end-inspiratory occlusions were performed for s, then respiratory system was slowly inflated at constant flow. finally, patient was allowed to breathe out freely to atmosphere by using a three-way stop lock by-passing expiratory valve. ac and airway opening pressure (aop) were determined according to chen et al. ( ) . efl was assessed by the atmospheric method ( ) . dynamic elastance of chest wall (edyn,cw) and lung (edyn,l) were obtained from least square linear regression method over consecutive breaths. static elastance (est,cw and est,l) were determined by classic formulas and also by taking into account aop (est,cw_aop and est,l_aop, respectively). the performance of ecw/el ratio to predict efl and ac was assessed by the area under receiver operating characteristic (aucroc) curve. results: efl was observed in patients ( %) and ac in ( %). median aop was . cmh o ( % ci . - . ) . aucrocs for ecw/el ratios to detect efl and ac are shown in table . edyn,cw/edyn,l ratio was better to detect efl than est,cw/est,l ratio with edyn,cw/edyn,l ≤ . % sensitivity and % specificity. correction for aop made the performance of est,cw/est,l ratio as good as that of the edyn ratio. ac was poorly predicted by edyn and est ratios but its prediction greatly improved with aop correction. however, with the est,cw/ est,l_aop the critical ratio was . (sensitivity %, specificity %) and . (sensitivity and specificity %) for predicting efl and ac, respectively. conclusion: efl and ac are frequent in ards at peep cmh o. edyn,cw/edyn,l ratio lower than best predicted efl occurrence. once ac is taken into account est,cw/est,l ratio greater than accurately predicts ac. efl and ac are two distinct phenomena. compliance with ethics regulations: yes. rationale: anesthesia outside the operatingroom (aoor) in a pediatric environment was giving increasingly increasing indications and a lot of progress because of its interest in carrying out diagnostic and/or therapeutic explorations: % of the acts of anesthesia are performed outside the operating room. the objective of our study is: to clarify the importance and the frequency of the practice of the ahbo, to define its particularities, as well as an evaluation of the ratio: benefit/risk in order to reduce the morbidity and mortality. patients and methods: we report in this study the experience of the service of the resuscitation mother-child on the gestures of aoor. this is a prospective observational study, spread over a period of months: from / / to / / , dealing with acts performed for endoscopic digestive and bronchial procedures, cures in dermatology and radiotherapy, and medical imaging (ct and mri). results: of the procedures performed: were performed for ct, for mri, for arteriography and for endoscopic digestive procedures, for bronchoscopies, for radiotherapy treatments, for laser treatments in dermatology. anesthesia techniques use intravenous induction in % of cases using: hypnotics (propofol, midazolam, ketamine), morphine (remifentanyl, fentanyl), inhalation induction in % of cases (sevoflurane, halothane) and curare for cases of bronchoscopy (rocuronium). this anesthesia was marked by the occurrence of accidents in order of frequency: cardiac in % of cases (tachycardia, hypotension and rhythm disorders), and then respiratory in % of cases. the most serious accidents were admitted in reality and are represented by cases, of which required an intubation (bronchoscopy), a case of cardiorespiratory arrest recovered, cases of severe hypoxia associated with bradycardia and which required the ventilation with the mask (radiotherapy), and cases of bronchospasm requiring the deepening of the anesthesia (absence of tci). a good knowledge of the patient and the intervention, and difficulties specific to each specialty is necessary, as well as a preanesthetic consultation. the aoor must obey the same safety rules as in the operating theater and that in terms of: equipment, monitoring (integrate the capnograph to respiratory monitoring whenever deep sedation and when the continuous control of vas is difficult), anesthetic technique (tcbi) and post-procedure wakefulness management that must meet the same requirements as the sspi, especially for prolonged sedation. compliance with ethics regulations: yes. umbilical vein catheterization through wharton's jelly: a possibility for a fast and safe way to deliver treatments in the delivery room? suzanne borrhomée hôpital rené dubos, france correspondence: suzanne borrhomée (suzanne.borrhomee@gmail. com) ann. intensive care , (suppl ):p- rationale: a fast and safe venous access can be a critical issue in the delivery room during neonatal cardiopulmonary resuscitation, or before endotracheal intubation. here, we describe a new method to inject drugs using the umbilical vein, directly punctured through wharton's jelly. this method was performed in newborns between november and may . umbilical vein was identified and punctured easily and a reflux was obtained in all patients. the first step was antisepsis, and then the umbilical vein was punctured. the puncture was made approximately to cm above the navel. after checking for blood reflux, the nurse injected the treatment. the cannula was left in the vein during the injection and removed as soon as the intervention was over (intubation was performed, or the heart rate had increased). results: here, we report ten cases of emergency injection in the delivery room using this method: -four cases of cardiopulmonary resuscitation using this method to deliver epinephrine. cardiac massage was performed on all patients.-six cases of intubations in the delivery room using this method to administer the premedication. in all patients, the umbilical vein was identified easily. the equipment was the one usually used for venous injection in our unit and was manipulated and handled with ease. venous access was obtained in a matter of seconds, and blood reflux was observed in all patients. the treatments were efficient in all but two patients, which was imputable to the method in one patient. discussion: although this method has been known in our nicu for several years, there has been no publication regarding this method in neonates. inserting an umbilical vein catheter in the delivery room has been validated for resuscitation but this technique is lengthy and requires some sterility conditions that makes it even longer, and thus non-fitting for an emergency tracheal intubation. our method is fast and can be performed easily with no specific training. the whole manipulation procedure, from the beginning of the puncture to the end of the flush-out takes to s. we only identified few specific risks related to this method, mostly infectious, and the risk of drug diffusion. we describe a new route for administration of drugs in the delivery room that was successfully used in nine neonates. umbilical vein needle catheterization is not only safe and efficient, but is also fast and easy to perform without any special training. compliance with ethics regulations: yes. rationale: liver transplantation (lt) is the only option for children with end stage liver disease. recent advances in surgical procedure and immunosuppression have permitted a better patient and long term graft survival. however, acute cellular rejection remains a frequent complication occuring in to % of the cases according to different studies. it is more likely to occur during the first weeks post lt. many predictive factors of acute rejection have been described in litterature and results differ from one study to another. pediatric studies regarding this topic are few. the aim of this work is to study acute cellular rejection prevalence in the days following lt and to determine predictive factors. rationale: sedation practices for pediatric magnetic resonance imaging (mri) are highly heterogenous. the main challenge is to keep children immobile while being alone in a traumatizing environment for a long time. clinicians have to ensure hemodynamic and respiratory stability in this isolated environment while minimizing sedation neurologic adverse effects. in this series, we report the potential usefulness, feasibility, efficacy and safety of dexmedetomidine sedation for pediatric mri. patients and methods: a single center retrospective review of six children sedated with dexmedetomidine for mri in an emergency context. all children were hospitalized in the pediatric intensive care unit of a university hospital at the time of mri. results: data on six patients aged months to years is reported. five patients received dexmedetomidine by intravenous route (bolus of - µg/kg over min, followed by a continuous infusion of µg/ kg/h). one child received dexmedetomidine by intranasal route ( µg/ kg with atomization device). one child experienced bradycardia that did not require any intervention. very few movements were recorded during the mris for which images were rated as good quality. conclusion: dexmedetomidine seems a promisingly useful sedation agent for pediatric mri, thanks to its efficient sedative properties and good tolerability without respiratory compromise. compliance with ethics regulations: yes. rationale: computational models, or virtual patients, could be used to teach cardiorespiratory physiology and ventilation, determine optimal ventilation management as well as forecast the effect of various ventilatory support strategies. currently, there is no virtual patient specifically designed for modelling children cardiorespiratory system. thus, our research team has developed a cardiorespiratory simulator for children called "simulresp©". according to summers et al., the quality of a physiologic model is evaluated by three specific criteria: qualitatively, which relates to the model's ability to provide directionally appropriate predictions; quantitatively in steady states and in dynamics, which is the ability of the model to provide accurate predictions in steady state situations as well as dynamic transitions. the purpose of this study was to evaluate the quality ofsimulresp© according to these criteria. this study consisted in a prospective evaluation of the simulresp©'s predictions with simulated healthy subjects. the tests were performed with patients from to years old ( , , , , , years), with different characteristics; gender (m, f) and weight ( th, th and th percentile). blood gas values (ph, pco , po and spo ) were simulated for several virtual healthy patients with different characteristics. this study was conducted for both spontaneously breathing and mechanically ventilated patients. simulresp©'s quality and reliability were evaluated in terms of accuracy, robustness, repeatability and reproducibility. results: simulresp©'s validation procedures are ongoing. we intend simulresp© to be accurate when simulating healthy spontaneously breathing patients. but we hypothezised that simulresp© would not be able to simulate accurate blood gas values of mechanically ventilated patients conclusion: simulresp© is a promising computational model that will serve to perform calibration and validation procedures of clinical decision support systems and help clinican to determine optimal respiratory support strategies at bedside. further calibration procedures are yet required. compliance with ethics regulations: yes. the isthmic surgical tracheostomy, which was performed in the operating room by otolaryngologist under general anesthesia. the cutaneous incision was transversal in all cases.the choice of the cannula was adapted to the age, and the decanulation was carried out according to the evolution of the underlying disease. complications associated with tracheotomy are diverse, and common complications are such as careassociated pneumonia ( . %), tracheostomy tube obstruction ( . %), accidental decannulation ( . %), pneumothorax ( . %) and cases of tracheal stenosis ( . %). the mortality rate amounted to . %, where in most cases was due to the poor prognosis of the underlying diseases. the main factors of evolution are the patient's previous condition, cranial trauma, guillain-barré syndrome, tracheostomy time, prolonged tracheal intubation and the presence of complications. conclusion: regardless of the indication, the tracheotomy is an act of survival whose usefulness and effectiveness are certain. rationale: aspiration pneumonia (ap) is a frequently suspected complication of drug overdose requiring mechanical ventilation (mv) and admission to intensive care unit (icu). in the absence of reliable biomarkers for distinguishing between aspiration pneumonia and aspiration pneumonitis, antibiotic therapy is frequently prescribed. latest studies suggest that a care protocol could better select patients requiring antibiotic therapy. the objective was to determine the impact of a care protocol on the antibiotic prescription among patient admitted to icu for toxic coma with mv. we conducted a prospective observational cohort study in four icu. we included all patients admitted for toxic coma with mv. in the university-affiliated icu, a care protocol was applied. in the three others icu, physicians declared that they did not follow formalized conduct within the service and did as usual. results: we included patients in care protocol group and in control group. the mean saps ii was . (± . ) with a mean glasgow coma scale score at . (± . ) before intubation. within the total population, patients ( %) had a pulmonary bacteriologic sample (pbs), mostly because purulent tracheobronchial aspirate and new infiltrates on the chest x-ray (respectively . % and . % of the population with a bacteriological sample). among the patients with a bacteriological sample, ( %) were culture positive. the incidence of probabilistic antibiotherapy did not differ between the care protocol group (n = ) and the control group (n = ) . there was no difference for the incidence of pbs ( in each group). the others secondary outcomes did not differ either (table ) . conclusion: our study does not show that a care protocol allows a reduction of antibiotic prescription among patient admitted to icu for toxic coma with mv. our incidence of antibiotic prescription is lower than the previous studies. the absence of difference can be explain by two reasons: some of the physicians of the control group had been trained in the university-affiliated icu in the last years and may follow a management approach similar to that of the control group; despite our precautions, the existence of the study could have modify the practices in the control group. compliance with ethics regulations: yes. rationale: pancreatic surgery is associated with high morbidity, mostly due to infectious complications, so that many centers introduce post-operative antibiotics for all patients. such systematic prescriptions are not consensual and often rely on local practices. the aims of the study were to describe the occurrence of surgical site infection (ssi) and the antibiotic (atb) prescription after pancreatic surgery, and to determine the risk factors of post-operative surgical site infection, in order to better define the clinical indications for the prescription of antibiotics after major pancreatic surgery. patients and methods: all patients undergoing a scheduled major pancreatic surgery from january to november were included in the study. patients were classified in four groups according to the occurrence of a surgical site infection and to the post-operative antibiotic prescription as follows (ssi+/atb+; ssi-/atb+; ssi+/atb-, ssi-/ atb-). in addition, risk factors (fever and pre-operative biliary prosthesis) associated with the occurrence of a surgical site infection and with the antibiotic prescription, were analyzed using a logistic regression model. results: data from patients ( pancreaticoduodenectomies and splenopancreatectomies) were analyzed and classified as presented in the table. thirty patients ( . %) experienced a surgical site infection and ( . %) received post-operative antibiotics. we did not find any difference on post-operative antibiotic prescriptions ( . % versus . %, p = . ) between patients who developed a surgical site infection and those who did not. amongst the patients who were not prescribed antibiotics post-operatively, ( . %) did not develop a surgical site infection while ( . %) did. in-icu mortality did not differ between infected and non-infected patients ( versus %, p = . ). post-operative fever was different between ssi+ and ssi-( . versus . %, p < . ), while the prevalence of pre-operative biliary prosthesis was similar ( . versus . %, p = . ). amongst patients who did not develop a surgical site infection, antibiotic prescription was not associated with fever (p = ), but associated with a higher prevalence of preoperative biliary prosthesis ( . versus . %, p = . ). conclusion: non-systematic antibiotic prescription after major pancreatic surgery allowed to appropriately spare antibiotics in ( %) patients at the cost of under prescription in ( . %) patients. these results suggest that systematic post-operative antibiotic prescription could be excessive. fever appears to be a relevant clinical sign for individual-based prescription, whereas the presence of a biliary prosthesis does not. compliance with ethics regulations: yes. ( , ) . however, there is little evidence to support those recommendations ( ) . we aimed to describe care paths of pm with sepsis in french hospitals and to assess outcomes depending on their hospital trajectory. we conducted a retrospective analysis of the french medico administrative (pmsi) database of consecutive patients with pm and sepsis admitted to french hospitals, between and . only the first hospital admission was considered. cases were identified using a combination of a diagnosis code for pm plus a diagnosis code for organ failure or a procedure code for organ support. hospital trajectories were determined from the first admission to death or discharge, taking into account all potential transfers. costs and endpoints were determined at the end of patients' trajectories. five groups of patients were defined, according to care pathways: direct icu admission ( sticu); secondary icu admission, after initial admission to another unit including wards (ward ndicu) rationale: new-onset atrial fibrillation (af) is a common complication in patients with sepsis and is associated with increased mortality and morbidity rates. this condition results from a complex chain of events in response to infection, involving immunologic, humoral and cellular process and sympathetic overactivity. landiolol, the new injectable beta-blocker, with high beta selectivity and minimal impact on arterial blood pressure, may have beneficial effects in such a context. in this study, we aimed to investigate whether landiolol decrease the newonset of atrial fibrillation in a mice model of endotoxin-induced sepsis. patients and methods: thirty c bl/ male mice were randomly allocated to the following groups: sham (administration of µl of isotonic saline intraperitoneally-ip), septic (administration of µl of isotonic saline with mg/kg of lipopolysaccharide-lps-of e. coli o :b ip) and septic + landiolol (administration of isotonic saline with mg/kg of lps and, two hours later mg/kg of landiolol ip). four hours later, an attempt of af occurrence was triggered by a transesophageal electric pacing at fixed rate (as previously reported) in all mice previously anesthetized by isoflurane %. ekg was continuously recorded. results: ten mice per group (mean weight: ± g) have been included and analyzed. among the sham group the mean heart rate was at bpm versus bpm in the septic group. among the septic + landiolol group the mean heart rate was at bpm (p < , ). after transesophageal stimulation, none mice in the sham group had af, seven mice ( %) in the septic group had an af, and mice ( %) in the septic + landiolol group had an af. landiolol decreased the incidence of new-onset, sepsis-induced atrial fibrillation in mice (p = . ). conclusion: landiolol seems to have a protective effect against sepsis-induced af in mice. however, the mechanisms, including sympathetic activation and inflammasome pathways, should be investigated before drawn definitive conclusion regarding to efficiency of landiolol to prevent new-onset af during sepsis. compliance with ethics regulations: yes. - mg/l at or h, proportion of patients with a vancomycin serum concentration < mg/l, previously associated with resistance emergence and assessment of mortality and test of cure. results: a serum vancomycin concentration between - mg/l was reported in out of included patients ( %). a serum vancomycin concentration < ml/l and > mg/l were reported in patients ( %) and patients ( %), respectively. vancomycin serum concentrations during follow-up are shown in fig. . in multivariate regression analysis, a longer time between admission and initiation of vancomycin was the only parameter associated with a serum vancomycin out of this target, while acute kidney injury (aki) was associated with a lower incidence of subtherapeutic concentration. acute kidney injury rate was significantly higher in patients with a serum vancomycin concentration > mg/l. discussion: an adequate therapeutic target of serum vancomycin concentration was reached in % patients with nearly % < mg/l, which was similar to previous studies. aki and rrt requirement were higher in patients with serum vancomycin concentration > mg/l, whereas it is hardly to know whether it is a cause or a consequence. conclusion: these findings highlight the importance of a larger loading dose, vancomycin monitoring and measured creatinin clearance to improve vancomycin dosing protocol. compliance with ethics regulations: yes. rationale: suicide is a global phenomenon and one of the leading causes of death in the world. tunisia ranks second in the suicide rate in the maghreb, with . cases of suicide per , inhabitants. the aim of this study was to reconstruct the state of suicidal subjects before the act in order to identify their psychiatric profile. patients and methods: a -year prospective observational singlecenter ( -bed intensive care unit) study including all patients hospitalized for suicide attempt (sa). psychiatric evaluation of patients and contact with their families were done before intensive care unit discharge. results: seventy-one patients were enrolled with female predominance (sex ratio . ). mean age was ± years. familial or personal history of mental illness were found in ( %) and cases ( %) respectively. personal mental disorders were depression ( %), bipolar disorder ( %), schizophrenia ( %) and border line personality disorder ( %). twenty-five per cent had prior sa. sixty-three per cent were single, % married and % divorced. the common methods of suicide included drug ( %), chloralose ( %) and pesticide ( %) poisoning. mean igs ii and apache ii scores were ± and ± respectively. on admission, % of all patients were in coma, % had shock and % developed aspiration pneumonia. mechanically ventilation was done in % of all cases with mean duration of days. the mean length of stay in intensive care unit was days. mortality rate was %. psychiatric evaluation and contact with families deduced that the main precipitating factors for suicide were traumatic events. in fact: relationship problems (familial, marital or breakups), school failure and mourning were found in %, % and % of all cases respectively. reactional sa accounted for %. rationale: poisoning is a worldwide problem, associated with high morbidity and moratlity. in tunisia, the rate of fatal poisoning has been increasing in the last years, with emergence of new toxic substances. regardless of the toxic, fatal poisining is considered as a non natural death, that requires medico-legal investigation, to assess whether it is suicidial, crimnal or accidental death. this study aimes to determine the epidemiological characteristics of the cases of fatal poisoning in south, to identify the toxics used in oder to deduce the preventive measures. patients and methods: we conducted a retrospective study of all cases of fatal poisoning recorded in the forensic department of habib bourguiba university hospital in sfax, tunisia, over a -years period ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) . results: during the study period, cases of fatal poisoning were autopsied. the number of victims recorded per year varied between and cases with an average of cases per year. the average age was years with extrems ranging from months to years. nearly half ( . %) were younger than years. a male predominance was noted with a sex-ratio of . . the majority of victims were single, loweducated and from rural origin. personal antecedent of psychiatric pathology was found in . % of cases. psychotic disorders (schizophrenia) and depression were the most common pathologies. in our study we noticed that death occured every weekday without significant difference between days. however, the frequency of fatal poisoning was slightly higher in cold seassons ( . %). in . % of cases, victims were found dead at home. accidental fatal poisoning was the most common ( %). no criminal cases have been observed. we noted a male predominance in accidental forms and a female predominance in suicidal forms. carbon monoxide poisoning was the most common ( cases) followed by the organophosphorus poisoning which was noted in cases. conclusion: decreasing the mortality rate from poison ingestion requires increasing public awareness about poisons and improving emergency service equipment and health personnel training. compliance with ethics regulations: yes. severe acute poisoning by organophosphate pesticides: report of cases at the oran hospital and university center mourad goulmane hospital and university center of oran, oran, algeria correspondence: mourad goulmane (goulmane.mourad@univ-oran . dz) ann.intensive care , (suppl ):p- rationale: organophosphate pesticides are synthetic organic pesticides widely used in agriculture mainly as an insecticide, nemacid or acaricide. these are the agricultural products, the most incriminated in poisoning in our context. the objective of this work was to determine the clinical, paraclinical, and progressive characteristics of this poisoning in a resuscitation environment. patients and methods: retrospective study of cases admitted to intensive care (january -december ). inclusion criteria were clinical, para-clinical, therapeutic and progressive. results: cases were identified: women and men, mean age = . ± years. the suicide attempt was the main reason for the intoxication ( cases). the glasgow coma score averaged ± . the central syndrome was present in % of our patients, followed by muscarinic syndrome % and nicotinic syndrome in % of cases. therapeutic management consisted of mechanical ventilation in % of cases, the use of vasoactive drugs in % of cases and the administration of antidotal treatment in % of cases. the overall mortality was . %. conclusion: organophosphate pesticides intoxication is a real health problem in algeria. it is a serious condition dominated by the respiratory and neurological distress that causes most deaths. it concerns in our context especially young women who ingest the product for the purpose of autolysis. the diagnosis is based on the clinical and dosage of cholinesterase activity in the plasma. treatment combines symptomatic measures that rely primarily on respiratory and neurological resuscitation to antidotal treatment. the clinical course in this type of intoxication is generally favorable under treatment with regression of signs in a few days. mortality is high in our context, so it should be considered a diagnostic and therapeutic emergency. the commercial availability of these products is worrisome, justifying the use of a broad prevention program to inform the public and authorities of the danger of organophosphate pesticides compliance with ethics regulations: not applicable. . the clinical examination revealed that five patients met the criteria for serious intoxication with the following signs: coma in four patients requiring the use of mechanical ventilation, seizures (n = ), rhabdomyolysis (n = ), shock (n = ), toxic takotsubo (n = ) and hepatocellular failure (n = ) leading to patient's death. the use of mechanical ventilation was necessary in patients. the analysis of the severity factors did not show a statistically significant association between severity, age (p = . ), sex (p = ) and chronic consumption of psychoactive substances (p = . ). on the other hand, we did not find a statistically significant association between serious intoxication, the number of tablets ingested (p = . ), the apacheii score (p = . ) and the average length of stay (p = . ). conclusion: ecstasy acute poisoning is becoming more common in our country and can potentially be very serious regardless of age, sex, medical history or number of tablets ingested. on the other hand, the concentration of nmda could be the only factor to be taken into consideration upon admission. compliance with ethics regulations: yes. quarter of early trauma-related mortality, in some series. early identification of poor outcome predictors could be valuable to guide the most appropriate care. we aim to determine factors associated to mortality in patients with severe non-penetrating chest trauma admitted to the icu. patients and methods: this is a prospective cohort study, including all patients with isolated severe blunt chest trauma (abbreviated injury scale ais > ) admitted to the intensive care unit of a university hospital, over a one-year period. the primary objective was to analyse risk factors associated to death and poor outcome using univariate and multivariate analysis. results: one hundred-thirty patients were admitted to the icu for blunt chest trauma among them were diagnosed with severe isolated chest trauma and were included. the mean age was at ± , mean iss at ± and mean tts at ± . twenty-eight ( %) patients were diagnosed with acute respiratory distress syndrome, ( %) with post-traumatic acute kidney injury and fourteen ( %) with post-traumatic pulmonary embolism. the mean length of icu stay (los) was at ± days and mean number of days on ventilator was at ± days. thirty-two ( %) patients underwent elective tracheostomy for prolonged intubation. thirty-seven patients ( %) developed infections, among them thirty ( %) were diagnosed with pulmonary infection and seven ( %) with non-thoracic infections. overall mortality had an incidence of . % ( patients rationale: early hyperglycaemia in traumatic brain injury (tbi) is a part of the stress response. it is an important indicator of severity and a reliable predictor of prognosis. we aimed to describe the epidemiological, clinical and paraclinical characteristics and to assess the prognostic impact of this hyperglycaemia on the tbi. we conducted a retrospective study in the intensive care unit (icu) of our hospital between and . were included all patients with tbi and blood glucose > mmol/l at the first h post-trauma. results: during the study period, patients were hospitalized in our icu with tbi. early hyperglycemia (> mmol / l) was found in patients ( . %). in univariate analysis, glycaemia > . mmol/l (= mg/dl) at admission was significantly associated with mortality (p = . ). we observed that glycaemia > . mmol/l at h , > . mmol/l at h , > . mmol/l at h and > . mmol/l at h was significantly associated with mortality (p = . ; p < . ; p = . and p = . , respectively). the risk factors significantly associated with mortality were age > years (p < . ), saps ii > (p < . ), initial shock (p < . ), glasgow coma scale (gcs) < / (p < . ), coma period > days (p = . ). the ct scan lesions statistically associated with mortality were: subdural hematoma (p < . ), cerebral oedema (p < . ), intra cerebral haemorrhage (p = . ), cortical contusion (p = . ), contusion of cerebral trunk (p = . ), contusion of the corpus callosum (p = . ), thalamus contusion (p = . ). in multivariate analysis, independent risk factors statistically associated with mortality were age > years old (or = . ic [ . - . ]; (p = . )), glycaemia > . mmol/l at admission (or = . ic [ . - . ]; (p = . )),gcs < / (or = . ic [ . - . ]; p < . ), intracerebral hematoma (or = . ic [ . - . ]; p = . ). we recommend a mandatory control of the blood glucose levels during a tbi with a target between . and . mmol/l in the acute phase. compliance with ethics regulations: not applicable. the fat embolism syndrome (fes) is a set of clinical, biological and radiological signs resulting in the obstruction of microcirculation by micro-droplets of insoluble fats.the clinical signs of the fes are not very specific, the diagnosis is difficult and the risk of misunderstanding this syndrome is very real.the fes appears after a trauma, often few days later. however, it sometimes occurs without previous trauma; and it is particularly difficult to recognize in these cases. the aim of this work is to define the epidemiological profile, the clinical and para-clinical features of this syndrome and its therapeutic management. rationale: sedative and analgesic treatment administered to critically ill patients with mechanical ventilation need to beregularly assessed to ovoid complications of oversedation mainly in elderly patients. our objective is to evaluate our sedation practice in the elderlyin our unit patients and methods: it was a prospective observational study, including elderly patients over years of age without acute brain injury requiring sedation more than h of hospitalization in the intensive care unit of our university hospital between april and december . thirty patients were included. the aged was . years, the sex ratio was . . respiratory distress was the most common reason for hospitalization %. the most accepted diagnoses were the decompensation of copd in % of cases and septic shock in % of cases. the saps ii averaged ± points, sofa averaged ± . points. renal failure was found in patients ( %), hepatic impairment was noted in patients ( %), hypoproteinemia was marked in patients ( %). midazolam was used in % of patients. it was in combination with fentanyl in % of cases and remifentanyl in % of cases. the median ramsay score . ± . on the first day of sedation and . ± . on the second day of sedation. the median rass scale was − . ± . on the first day of sedation and − . ± . on the second day of sedation. the median bps scale . ± . on the first day of sedation and . ± . on the second day of sedation. the mean wake up time was ± , days. neuromyopathy of resuscitation was suspected in seven patients ( %), withdrawal syndrome was observed in two patients ( %) and acute cognitive dysfunction in two patients ( %). the median duration of sedation was . days ± . days, the median duration of mechanical ventilation was . ± . days, the median length of stay was . ± . days. ventilator-associated pneumonia was diagnosis among % of patients. the mortality in intensive care was %. conclusion: sedation analgesia in the elderly person should be adapted according to age, ideal weight and renal and hepatic function by decreasing the initial doses. it should be evaluated by the recommended scores by setting a sedation objective according to the pathology. compliance with ethics regulations: not applicable. rationale: more than original articles are newly indexed in pub-med every day. journal club (jc) is one way to cope with this abyssal amount of medical information. we aimed at ( ) describing journals and articles analyzed during our jc sessions ( ), reporting the proportion of published articles being analyzed during jc sessions and ( ) assessing the clinical impact on our daily practices for each journal. patients and methods: a retrospective analysis of prospectively collected data over a -year period from to in a universityaffiliated icu. jc sessions were scheduled weekly and participants were free to choose and expose orally an article recently published in any medical journal (general, icu or non-icu specialized). clinical impact of a journal was retrospectively and independently assessed by two attending intensivists (dc, hm) and was defined by the ratio of articles considered as having a direct impact on our daily practices over the number of articles of the same journal read during the same period. results: from august to august , jc sessions were held and articles-mostly original (n = / ; %)-from journals were analyzed, accounting for . % of the articles ( . % of the original articles) referenced in pubmed during the same period. median number of articles exposed per session was [ ] [ ] [ ] [ ] . median number of doctors attending each session was [ ] [ ] [ ] (attendings: [ ] [ ] , fellows: [ ] [ ] , residents: [ ] [ ] ). general, icu and non-icu specialized journals accounted for %, % and % of the exposed articles, respectively. most of the reported articles dealt with intensive care (n = , %) especially infectious diseases (n = / ; %), hemodynamics (n = / ; %) or icu-organization (n = / ; %). compared to general and non-icu specialized journals, the proportion of read-over-published articles was higher for icu-specialized journals ( . % vs. . % vs. . %, respectively; p < . ). among original articles, only ( . %) [interventional (n = / ; %); observational (n = / ; %) studies] were considered as having a clinical impact on our daily practices. compared to icu and non-icu specialized journals, general journals had a higher clinical impact ( . % vs. . % vs. . %, respectively; p = . ). data regarding the most read general, icu and non-icu specialized journals are detailed in table . in a french university-affiliated icu with regular jc sessions, the proportion of read-over-published articles and the clinical impact of medical journals appear minor. in the ocean of medical literature, general medical journals appear more worth reading by intensivists than icu-specialized journals. compliance with ethics regulations: yes. rationale: the world's population is aging and the and over's age group is growing fast (+ . % per year). this aging population is impacting intensive care units with exponential rates of elderly patients ( . % in , % in ) , associated with significant mortality (from % to %). the evolution and the prognostic factors of these elderly patients in intensive care are therefore a public health issue for optimal management. patients and methods: we included all patients aged and over who were operated and admitted to surgical resuscitation in our center, with a duration of stay greater than h, from april to july . the data collected were: general characteristics of this population, mortality in intensive care, at day and at months and the prognostic factors guiding their evolution in intensive care and at months. results: of the patients included in our study, mortality was . % in intensive care, . % at day and . % at months. the prognostic factors in the intensive care unit were the average dose of noradrenaline at day (threshold at . mg/h), the sofa score at day (threshold at points) and the igs score (threshold at points). the prognostic factors at months were ventilatory autonomy on day (spontaneous ventilation, non-invasive ventilation, invasive ventilation), the reason for admission to intensive care (acute respiratory distress or septic shock) and the fragility score (clinical failure scale with a threshold at ). conclusion: the mortality of patients aged and over is influenced by prognostic factors easily obtained daily at patient's bed. these prognostic factors could be an aid for the resuscitation teams to evaluate the relevance of the care undertaken in elderly or even very elderly patients admitted in an acute situation. compliance with ethics regulations: not applicable. assessing patient safety culture perception in the intensive care unit in tunisia oussama jaoued, chaoueh sabrina, sik ali habiba, wael chemli, gharbi rim, fekih hassen mohamed, elatrous souheil hôpital taher sfar, mahdia, tunisia correspondence: oussama jaoued (oussamajaoued@gmail.com) ann. intensive care , (suppl ):p- rationale: in tunisia health care system, patient safety has become a priority of quality assessment. the aim of our study was to describe the safety culture perception of the intensive care unit staff. patients and methods: the safety attitude questionnaire (saq-icu) was distributed to all intensive care unit staff by email. the questionnaire explores safety culture domains: "team work", "safety climate", "job satisfaction", "stress recognition", "perception of the hospital and intensive care unit management" and "work condition". results: eighty participants responded to the questionnaire, % of them were women. participants were doctors in . %. the coordination between physicians and nurses was very good only in %. thirtynine participants thought that the workload was high and % like their work. medical errors are handled appropriately in % of cases and it was difficult to discuss errors in % of cases. the hospital is a good place to work in % of participants, % of participants were less effective at work when there were tired. the hospital did a good effort of training new personal in % of cases. the number of medical staff was lower than expected in % of cases. half of participants would feel safe being treated as patients in their respective units. all domains explored by saq-icu could be improved according to attendants. conclusion: safety culture perception among intensive care unit staff had several deficiencies, mainly the working conditions, the ignorance of medical error reporting procedures and the lack of communication. rationale: the simplified acute physiology score ii (saps ii) is an icu scoring system used to predict the mortality risk in patients presenting at the icu. however the majority of critically ill patients present initially at the ed and their transfer to the icu may be delayed for hours. therefore, the ability to accurately assess mortality risk at ed may have a great impact. the purpose of this study was to evaluate the performance of saps ii in predicting early and late mortality in ed patients. patients and methods: this prospective study was conducted at the ed during a -month period. data for adult ed patients were evaluated. saps ii score was used to predict early and late mortality rates at -h and -day respectively. discrimination was evaluated by calculating the area under the receiver operating characteristic curve (auroc). results: during the study period patients were enrolled. the mean age was ± years, % of the patients were men. the mean saps ii was . the early mortality rate was % and late mortality rate was %. saps ii was efficient in predicting early mortality, with an auroc of . ( % ci . - . ). however, it demonstrated no value in predicting late mortality with an auroc of . ( % ci . - . ) conclusion: in this study, saps ii score was accurate in predicting early mortality, however this tool appears less suitable for predicting late mortality. compliance with ethics regulations: yes. oussama jaoued, chaoueh sabrina, sik ali habiba, yosri ben ali, fekih hassen mohamed, elatrous souheil hôpital taher sfar, mahdia, tunisia correspondence: oussama jaoued (oussamajaoued@gmail.com) ann. intensive care , (suppl ):p- rationale: the aging of the population increased the number of hospitalizations in icu. the aim of our study was to determine the impact of hospitalization of patients over the age of on morbi-mortality and consumption of care (omega score). patients and methods: this is a retrospective study carried out in the icu in the hospital of taher sfar in mahdia over a period of years. all patients hospitalized in the icu were included in this study. two groups of patients were individualized: g : patients over years old, g : patients under years old. results: during the study period, patients ( < years old and ≥ years old) with a mean age ± years and with a mean sapsii ± were included. the common reason for hospitalization was acute respiratory failure in % of cases. comparing the two groups, the severity score sapsii was higher among patients older than years ( ± vs ± , p < . ). the use of mechanical ventilation was more common in the first group ( % vs. %, p < . ). the incidence of nosocomial infections was similar in both groups ( % in the group g and % in group g , p = . ) and the use of renal replacement therapy was also similar in tow groups ( % in the g group and % in the g group, p = . ). the duration of mechanical ventilation and length of stay were similar between the two groups. workload evaluated by the omega score was higher in the first group ( rationale: icu outcome depends on quality of pre-icu care. we aimed to assess the chain of care of deteriorating ward patients (dwp), through evaluation of preadmission severity and delays before admission, and association with outcome. patients and methods: retrospective observational study in a single center ( beds general hospital) for year-may th of to . all adult patients admitted in the icu from the wards were included, except for scheduled surgery, or unexpected event in the operative theater. preadmission severity was assessed through levels of national early warning score (news ): group with news inferior to , group with news between and , and group with news superior to . these scores were established from vital signs during the h before icu admission. patterns of patients, including sofa and saps , knaus index, charlson comorbidity score, cause of admission and technics used in the icu, length of stay in the icu and in the hospital, limitations of life-supporting care, and mortality at and days after icu stay. satistical analysis was performed through chi and fisher tests on qualitative parameters, and with kruskal-wallis, student and mann-whitney tests for quantitave data. results: sixty-eight patients were studied: in group , in group and in group . most patients (all except ) had not respiratory rate monitoring before icu admission. icu mortality was associated with rising preadmission severity (group : . %; group : . %; group : . %). base patterns (charlson comorbidity score, knaus index) did not differ between the groups, and . % of patients presented with sepsis. main causes of admission were respiratory ( . %), hemodynamic ( %) or neurologic ( . %) failures. all patients admitted after cardiac arrest resuscitation ( patients) belonged to group . acute severity scores (sofa and saps ) followed preadmission severity. limitation or withdrawing of life support in the icu was higher in group ( . %) than in groups ( %) and ( . %) . median delay between first news equal or superior to and icu admission was h, and h between news equal or superior to . diffrences in delays were not associated with outcome. discussion: our study outlines weaknesses in the chain of care of dwp. emphasis should be put on respiratory rate monitoring and better assessment of severity. rationale: access to critical care is controversial in older patients for reasons: lack of available icu-beds and speculation on induced costs. in contrast, admission of young patients aged or under is infrequently questioned even though they develop catastrophic multiple-organ failure requiring full care. in addition, emotive reaction triggered in staff by these patients often represents a heavy psychological burden when icu-stay is < h. information on the epidemiology, clinical information and induced costs regarding such patients is lacking. patients and methods: this study retrospectively assessed the records of patients aged or under, and admitted from january to august . cost-related expenses charged to care-payers were obtained from our medical information department. data (number, percentages or medians) were reported and discussed by comparison with those of nonagenarians during the same period. results: of , icu-admissions, were aged or under ( %), of whom ( . %) died within the icu, with ( %) dying within h of admission despite full intensive care. the latter represent our study population ( . % of the screened population). the median age was . years , male gender was prevalent ( %). half the patients (n = , %) were referred from the emergency department, ( . %) from hematology, from oncology ( . %), from medical intermediate care units ( . %), and one from digestive surgery ( . %). the first diagnosis at admission was septic shock (n = , . %), followed by post-anoxic encephalopathy (n = , . %), coma (n = , . %), acute respiratory failure (n = , . %) and cardiogenic shock (n = , . %). sapsii was . all patients were ventilated and infused norepinephrine. two patients underwent ecmo, and others mars. mean (± sem) retribution per stay was , ± €, and mean retribution per "day of stay" €. discussion: full care of these icu-patients, with early mortality has a financial impact similar to that of nonagenarians at , ± , €; the cost per "day of stay" is therefore on average % higher than that of nonagerians (mean length of stay: . days), and, in our experience, % higher than that of average patients. conclusion: icu-patients aged or under represent a small percentage of admissions and display half our overall mortality: one third of them die within h of admission with a not insignificant financial impact for cost-payers. septic shock is the first cause of referral, followed by unexpected cardiac arrest. compliance with ethics regulations: yes. rationale: severity scores in patients with sepsis are useful for triaging and predicting mortality. mortality in emergency department sepsis (meds) score is validated in patients with sepsis in the emergency department. curb- is validated in patients with communityacquired pneumonia but not in sepsis. curb- is a simple bedside tool that has many common elements with new sepsis identification score-q sofa. the study aimed to assess the accuracy of curb- score in predicting icu admittance and mortality compared to meds score. patients and methods: this prospective study was conducted at the ed during a -month period. we enrolled all adult patients with sepsis admitted to the ed. meds and the curb- scores were calculated at admission. patients were studied using curb- score and their icu admission and in-hospital mortality were ascertained. results: a total of patients were enrolled. the mean age was ± years. % of the patients were men. % of patients had a curb- score ≥ points with a mean meds score of %. among these patients, % were admitted to icu and % died. the curb- score,was efficient in predicting both icu admittance and in-hospital mortality with an auroc of . ( % ci . - . ) and . ( % ci . - . ), respectively. conclusion: a higher curb- score was correlated with higher rates of icu admittance and mortality in patients with sepsis due to any cause. compliance with ethics regulations: yes. abderrahim achouri, hadil mhadhbi, khedija zaouche, hamida maghraoui, radhia boubaker, kamel majed university hospital center rabta of tunis, tunis, tunisia correspondence: abderrahim achouri (achouryabderrahim@gmail. com) ann. intensive care , (suppl ):p- rationale: sepsis is a major cause of mortality. in other hand, preexistent chronic diseases seem to worsen outcomes among critically ill patients. the acknowledgement of this fact may motivate studies in this type of situations in order to improve survival in sepsis. on that purpose, our study tried to check the impact of chronic pre-existent illnesses on outcomes in this type of emergency patients. patients and methods: we have included patients in whom the sepsis- definition was met throughout emergency department admission cases for infection. in this study, considered outcomes were in-hospital mortality, shock occurence and the use of mechanical ventilation. results: we collected patients admitted to ed for sepsis. mean age was years ± with bornes of and . men were % of the patients. cormorbidities were: insulin dependent diabetes mellitus in . % of patients, non insulin dependent diabetes mellitus in . %, chronic obstructive lung disease in . %, chronic renal failure in . % with % in chronic replacement therapy from total patients, coronary artery disease in . %, with stent in . % and . % with aortic coronary graft from total patients, arterial hypertension in %, chronic heart failure in . %, atrial fibrillation in . %,. death occurs in . % of total patients, septic shock in % and the use of mechanical ventilation in . %. we did not find any association between comorbidity and the use of mechanical ventilation, but association with in-hospital mortality was found in pre-existent coronary artery disease (p = . ) and in patients with coronary artery stent (p = . ). odds ratio (or) was respectively . ( % ic = [ . - . ]) and . ( % ic = [ . - . ] ). we found significant association between chronic heart failure and shock (p = . ) with or = . ( % ic = [ . - . ] ). discussion: the small size of our sample may enlimit the contibution of other comorbidities on outcomes in sepsis such chronic renal failure, especially with renal replacement therapy and diabetes mellitus. whereas, we can conclude that cardiac diseases have the most important impact on outcomes in sepsis. outcomes in sepsis can be affected by comorbidities, especially cardiac diseases. therefore, that needs large studies to check it. compliance with ethics regulations: yes. micafungin population pk analysis in critically ill patients receiving continuous veno-venous hemofiltration or continuous veno-venous hemodiafiltration nicolas garbez , litaty mbatchi , steven c. wallis , laurent muller , jeffrey lipman , jason a. roberts , jean-yves lefrant , claire roger chu nîmes, nîmes, france; university of queensland, brisbane, australia correspondence: nicolas garbez (nicolas.garbez@umontpellier.fr) ann. intensive care , (suppl ):p- rationale: to compare the population pharmacokinetics (pk) of micafungin in critically ill patients receiving continuous veno-venous hemofiltration (cvvh, ml/kg/h) to those receiving equidoses of hemodiafiltration (cvvhdf, ml/kg/h + ml/kg/h). critically ill patients in septic shock undergoing continuous renal replacement therapy (crrt) and receiving mg micafungin once daily were eligible for inclusion. total micafungin plasma concentrations were analyzed using pmetrics ® . probability of target attainment (pta) was calculated from monte carlo simulations using -hour area under curve/minimum inhibitory concentration (auc - /mic) cut-offs (c. parapsilosis), (all candida species) and (c. non parapsilosis). daily dosing regimens of , and mg were simulated for the first days of treatment. results: eight patients were included in the study. micafungin concentrations were best described by a two-compartmental pk model. no covariate, including crrt modality (cvvh and cvvhdf), was retained in the final model, confirmed by internal validation. the mean parameter estimates (standarddeviation) were . ( . ) l/h for clearance, . ( . ) l for the volume of the central compartment, . ( . ) /h and . ( . ) /h for rate constants. the standard mg daily dosing was unable to reach % of pta for all candida species except c. albicans on the second day of therapy (fig. ) . conclusion: there was no difference in micafungin pk between equidoses of cvvh and cvvhdf. a dose escalation to mg is suggested to achieve the pk/pd target of candida species with mics exceeding . mg/l in this population. these "off-label" dosing regimens should be further investigated in clinical trials knowing the favourable toxicity profile and the post-antifungal effect of micafungin in order to ensure efficacy and to prevent the emergence of resistance due to an inadequate initial antifungal dosing regimen. compliance with ethics regulations: yes. rationale: sepsis is an important cause of morbidity and mortality in hospitalized patients. recognizing and responding to patients who experience clinical deterioration remains challenging in daily practice. our purpose was to assess the ability of the quick sequential organ failure assessment (qsofa) score to identify, among patients reviewed by an intensivist, those at risk of adverse outcomes. patients and methods: retrospective cohort of patients with suspected infection reviewed by an intensivist in a university-affiliated hospital between january and june . outcomes of interest were hospital mortality and a combined criterion of hospital mortality or icu stay of days or more. results: during the study period, patients were reviewed by an intensivist, of whom ( . %) had suspected infection according to the sepsis- criteria. at the time of review, ( . %) patients with suspected infection were qsofa positive (≥ ) and ( . %) were qsofa negative ( - ). following the review, ( . %) patients were admitted to the icu, among whom ( . %) had a prolonged stay (≥ days). in-hospital mortality was . %, and . % of the patients met the combined criterion of in-hospital mortality or prolonged icu stay. qsofa positive patients required more frequently mechanical ventilation ( . % vs. . %, p = . ) and vasopressor support ( . % vs. . %, p < . ) than qsofa negative patients. moreover, qsofa positive patients had higher hospital mortality than qsofa negative patients ( . % vs. . %, p = . ). for the prediction of in-hospital mortality, a positive qsofa had a predictive positive value (ppv) of %, and a negative predictive value (npv) of %. for the prediction of in-hospital mortality or prolonged icu stay, a positive qsofa had a ppv of % and a npv of %. conclusion: hospitalized patients with suspected infection for whom a review by an intensivist was requested, are at high risk of hospital mortality. although the accuracy of qsofa for identifying patients at risk of adverse outcomes is limited, its integration in a multimodal risk assessment approach may help distinguish the subset of patients who will benefit from an escalation of care. compliance with ethicsregulations: yes. rationale: according to the sepsis- consensus, sepsis is identified as an increase of at least points in the sepsis-related organ failure assessment (sofa) score in patients who presented infection. the quick sofa or qsofa is considered as a predictive tool of sepsis and mortality when it is equal to points or more. systemic inflammatory response syndrome (sirs) criteria are of limited utility because of their low sensitivity. hyperlactatemia, as known is a determinant of tissue hypoperfusion. our objective was to evaluate the prognostic value of sofa > , sirs > , qsofa > and lactate level > mmol/l in infected patients. nine-month prospective cohort study. patients aged years or older who had a proven or suspected infection were included. sofa score, sris criteria, sofa q and lactate levels were determined within the first h of infection. the primary endpoint was hospital mortality at days. the predictive power of the studied parameters was determined using using the area under the receiver operating characteristic curve (auroc). results: a cohort of cases was studied with mean age at . years. bacterial pneumonia was the most common infection site ( %). in the first h of onset of infection the medians [iqr - ] of the sofa, sris, and sofa scores and lactate levels were respectively [ ] [ ] [ ] [ ] [ ] [ ] [ ] , [ ] [ ] , [ - ] and . [ . - . ] . the progression to severe septic status was observed in patients ( %) and norepinephrine was introduced in cases. median length of stay was days [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] and mortality was %. overall, the accuracy in predicting mortality of the studied parameters was poor. an increase of sofa score by at least points had greater accuracy with auroc = . [ . - . ], sensitivity = % and specificity = %. conclusion: in infected patients, the sofa score had greater prognostic accuracy than the sirs criteria, the qsofa score or the lactate level. these results suggest that sirs, qsofa, and high lactate level may be useful in screening for sepsis, but this utility is limited in predicting mortality. compliance with ethics regulations: yes. rationale: quick sequential organ failure assessement (qsofa) has been validated for patients with presumed sepsis and others in general emergency department (ed) population. however, it has not been validated in specific subgroups of patients with a high mortality. the aim of this study is to evaluate the ability of qscore to predict prognosis in patients with decompensated liver cirrhosis. patients and methods: this is a retrospective study, conducted over a period of years from january to december . consecutive patients with decompensated cirrhosis, admitted in our department are included. data of all patients were collected and the qsofa score was calculated at admission. the main study endpoints were length of stay, complications and in-hospital mortality. results: a total of patients diagnosed with decompensated cirrhosis were enrolled. mean of age was years ( - ). sex ratio was . . hcv ( %) was the main etiology of cirrhosis. the reasons of hospitalization were: oedema with ascitic syndrome in % of cases, digestive haemorrhage ( % of cases), fevers ( % of cases), and hepatic encephalopathy was present in % of cases. the mean duration of stay was days ± . in-hospital mortality rate was % and mean score qsofa was . .the qsofa score was significantly correlated with length of stay (p = . ) and complications(p = . ) but not with in-hospital mortality (p = . ). conclusion: the qsofa score was not useful for predicting in hospital mortality in patients with decompensated liver cirrhosis but it was significantly correlated to the length of stay and complications. compliance with ethics regulations: yes. angioedema associated with thrombolysis for ischemic stroke: analysis of a case-control study clara vigneron , aldéric lécluse , thomas ronzière , sonia alamowitch , olivier fain , nicolas javaud médecine interne, centre de référence associé sur les angioedèmes à kinines (créak), hôpital saint-antoine, aphp, paris, france; neurologie, chu angers, angers, france; neurologie, chu pontchaillou, rennes, france; neurologie, hôpital saint-antoine, aphp, paris, france; urgences, centre de référence associé sur les angioedèmes à kinines (créak), hôpital louis mourier, aphp, colombes, france correspondence: clara vigneron (claravigneron@hotmail.fr) ann. intensive care , (suppl ):p- rationale: bradykinin-mediated angioedema is a complication associated with thrombolysis for acute ischemic stroke. risk factors are unknow and management is discussed. the aim of this study was to clarify risk factors associated with bradykinin-mediated angioedema after thrombolysis for acute ischemic stroke. patients and methods: in a case-control study conducted at a french reference center for bradykinin angioedema, patients with thrombolysis for acute ischemic stroke and a diagnosis of bradykinin-mediated angioedema, were compared to controls treated with thrombolysis treatment without angioedema. two matched control subjects were analyzed for each case. results: thrombolysis-related angioedema were matched to control subjects. the sites of attacks following thrombolysis for ischemic stroke mainly included tongue ( / , %) and lips ( / , %). the upper airways were involved in ( %) cases. three patients required mechanical ventilation. patients with bradykinin-mediated angioedema were more frequently women ( ( %) vs. ( %); p = . ), had higher frequency of prior ischemic stroke ( ( %) vs ( %); p = . ), hypertension ( ( %) vs. ( %); p = . ), were more frequently treated with angiotensinconverting enzyme inhibitor ( ( %) vs. ( %); p < . ) and were more frequently hospitalized in intensive care unit ( ( %) vs. ( %); p = . ). in multivariate analysis, factors associated with thrombolysisrelated angioedema were female sex (odds ratio [or], . ; % confident interval [ci], . - . ; p = . ) and treatment with angiotensin-converting enzyme inhibitors ([or], . ; % [ci], . - . ; p < . ). discussion: because of theretrospective case-control design and the lack of the total number of thrombolysis for ischemic stroke, the incidence of this complication could not be evaluated in our study. previous studies reported an incidence of . to . % of angioedema in patients treated with a thrombolytic therapy for acute ischemic stroke. our case-control study permits for the first time to analyse more cases to evaluate associated risk factors of this rare complication. conclusion: this case-control study points out angiotensin-converting enzyme inhibitors and female sex as risk factors of bradykininangioedema associated with thrombolysis for ischemic stroke. compliance with ethics regulations: yes. rationale: patients with inflammatory bowel disease (ibd), frequently treated by immunosuppressive drugs, are more susceptible to be admitted to the intensive care unit (icu). however, outcome and predictive factors of mortality are little known. therefore, we aimed to assess the outcome and prognostic factors for critically ill ibd patients. patients and methods: we retrospectively studied data of consecutive ibd (i.e. crohn's disease and ulcerative colitis) patients admitted in icus between and . in-icu and one-year mortalities were estimated and predictive factors of in-icu mortality were identified by univariate and multivariate analysis. results: seventy-six patients (male: %, median age: . [ . - . ] years, charlson index: [ . - . ]) entered the study. ibd type was largely represented by crohn's disease ( . %) and its localization was mostly extensive: l ( . % of crohn's disease) or e ( % of ulcerative colitis) according to the montreal classification. twenty-seven patients ( . %) were treated with corticosteroids and ( %) with immunosuppressive therapy (azathioprine: . % and anti-tnfα: %). reasons for admission were shock/sepsis ( . %) and acute respiratory failure ( . %). icu diagnoses were infection ( %), ibd flare-up ( . %) or both ( . %), and pulmonary embolism ( . %). at admission, sofa score was [ . - . ] and . fifty-three patients ( . %) required mechanical ventilation, ( . %) vasoactive drugs, and ( . %) renal replacement therapy. twenty-three patients underwent emergency surgery ( . %) and six urgent endoscopic treatment ( . %). in-icu and one-year mortality rate were . % and . %, respectively. prognostic factors of in-icu mortality were sofa score (hr . , % ci [ . - . ], p < . ) and azathioprine treatment before icu admission (hr . , % ci [ . - . ], p < . ) (fig. ) . previous immunosuppressive treatment with anti-tnf did not alter the prognosis and even the type of ibd. conclusion: our study showed that more than % of ibd critically ill patients were discharged alive from the icu and a majority of them survived after one-year ( . %). we also found that sofa score and previous azathioprine immunosuppressive treatment worsened icu outcome. higher severity of the acute event affected short-term prognosis and should be taken into account for best icu triage and management. intensivists should pay particular attention to patients treated by azathioprine. compliance with ethics regulations: yes. fig. outcome of ibd patients admitted to the icu according to precious treatment with azathioprine status all aps patients with any new thrombotic manifestation(s) admitted to icus. results: one hundred and thirty-four patients (male/female ratio: . ; mean age at admission: . ± . years), who experienced caps episodes, required icu admission. the numbers of definite, probable or no-caps episodes (fig. ) , respectively, were: ( . %), ( . %) and ( . %). no histopathological proof of microvascular thrombosis was the most frequent reason for not being classified as definite caps. overall, / ( . %) episodes were fatal, with comparable rates for definite/probable caps and no caps ( % vs. . % respectively, p = . ). the kaplan-meier curve of estimated probability of survival showed no between-group survival difference (log-rank test p = . ). discussion: our results suggest that the caps criteria do not sufficiently encompass all the parameters responsible for thrombotic aps patients' disease severity in the icu. the absence of items referring to organ dysfunction/failure in the caps criteria probably limited their ability to predict mortality. albeit useful for the retrospective classification and comparison of patients, the caps criteria may be too stringent and not yet ready-to-use for the management of icu patients. for physicians outside expert aps centres, the absence of caps criteria could be misleading and lead to rejection of the diagnosis for near-caps patients, thereby preventing them from receiving the appropriate aggressive treatment they indeed require. we think that, when confronted with a critically-ill thrombotic aps patient, caps criteria should be interpreted with caution and should not be the only elements taken into account to decide the intensity of the therapeutic management. rationale: % of resuscitation patients develop anemia during their stay, it can worsen the prognosis, prolong the length of stay and lead to transfusions that can be the cause of complications. the objective of our work is to specify the incidence of anemia in our unit, its etiologies and its therapeutic management. patients and methods: we conducted a descriptive and analytical retrospective study within the surgical emergency resuscitation department of ibn rochd university hospital of casablanca, over a period of years from to . we included all anemic patients. statistical analysis was performed with spss statistics . p < . was considered significant. results: we included patients with an estimated incidence of %, the average age was years, the sex ratio h / f was . . % of admissions were for traumatic pathology and % postoperative digestive surgery. % had hypotension at admission and the mean temperature was . % .the onset of anemia and its depth were related to length of stay with . % of patients who were anemic beyond the th day of hospitalization with a hemoglobin level that became < . g / dl beyond the th day. % of the patients had a normochromic normocytic anemia becoming microcytic with the lengthening of the duration of stay. ferritinemia dosed in % of patients and was normal. % of our patients had exclusive parenteral nutrition while % had an enteral / parenteral combination. % were transfused in red blood cells (rbc) and % of patients were transfused more than once. % received between and rbc units. in patients who received transfusion episodes costing euros, the transfusion was inappropriate. the total cost of the transfusion was estimated at around , euros. % were supplemented with oral iron with an increase in hemoglobin in % of them. % of the patients came out of the intensive care unit with a hemoglobin level < g/dl/l. the mortality rate of our patients was % with as predictive factors in multivariate analysis, hyperthermia, coagulopathy, the transfusion appears as a factor of good prognosis. the prevention of blood spoliation and the fight against inflammation and nosocomial infection remain the pillars of the management of anemia in intensive care but in view of our results and the protective role of transfusion it would be interesting to see again the transfusion thresholds in our context. compliance with ethics regulations: yes. (fig. ). discussion: we described a series of patients with severe acute viral myopericarditises associated with anti-rnapol autoantibodies, an association that has never been reported previously. the fortuitous association of these autoantibodies with acute myopericarditis is highly unlikely. acute myocarditis is a very rare disease with a reported incidence of / , inhabitants. anti-rnapol -antibody detection is also very rare: . % positive tests (including the patients in this series) out of samples during a -year period in our immunology laboratory. this % proportion of patients with proven influenza-virus infections suggest that such severe infections could trigger anti-rnapol autoantibody production. however, influenza is a common disease and anti-rnapol autoantibodies are very rare. furthermore, no anti-rnapol autoantibodies were detected in the patients with severe influenza-related ards. last, anti-rnapol autoantibodies remained detectable several months after the viral infection had been cured. conclusion: this previously unknown association between severe acute viral myopericarditis and anti-rnapol autoantibodies is probably not fortuitous. anti-rnapol antibody detection in acute myopericarditis patients could imply individual susceptibility to severe viral infection. further studies are needed to investigate the pathophysiological mechanisms involved in this entity and potential specific therapeutic strategies. fig. relative frequencies of digestive manifestations in critically ill tma patients rationale: arrhythmia-induced cardiomyopathy has been recognized for several decades, but most severe forms, i.e. cardiogenic shock and refractory cardiogenic shock requiring mechanical circulatory support, were rarely described in adults. in this retrospective study, we described patients admitted in our tertiary care center for non-ischemic acute cardiac dysfunction (or worsening of previously known cardiac dysfunction) and recent onset supraventricular arrhythmia who developed cardiogenic shock requiring veno-arterial ecmo (va-ecmo). results: in a years period, patients had va-ecmo for acute non ischemic cardiac dysfunction and recent onset supraventricular arrhythmia (table ). fourteen ( %) patients had known nonischemic cardiomyopathy and ( %) known paroxystic atrial fibrillation. cardiogenic shock was the first manifestation of the disease in patients. atrial fibrillation was the main cause of arrythmia ( % of cases). at ecmo implantation, sofa score was [ - ], inotropic score , lvef % [ - ] and lactate level was [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] mmol/l. twelve patients had sustained successful reduction after amiodarone and/or electric shock, all were weaned from ecmo and survived without transplantation nor long term assist device. among the patients with failure of reduction, underwent an atrio-ventricular ablation while on ecmo and had atrial tachycardia ablation; all were weaned from ecmo and survived. among the remaining patients without reduction and without ablation procedure, only the patients who were bridged to heart transplantation or left ventricular assist device survived. in univariate analysis, factors associated with unfavorable outcome were previously known heart disease, heart rate, renal replacement therapy, nt-probnp level, failure of rhythm reduction after amiodarone load and/or electric shock. among the patients who recovered and survived ( with successful reduction and with successful ablation), lvef increased from [ - ]% before ecmo implantation to [ - ]% at long term follow-up. discussion: this is the largest cohort of arrhythmia induced cardiomyopathies on va-ecmo and the first description of atrio-ventricular node ablation with favorable outcome in this setting. conclusion: arrhythmia induced cardiomyopathy is probably underrecognized and should be considered in any patient with nonischemic acute cardiac dysfunction and recent onset supraventricular arrhythmia. recovery is possible in the most severely ill patients on va-ecmo, even with severe left ventricular dilation. aggressive rate control by av-node ablation may be warranted in case of failure of reduction, and may allow recovery and favorable outcome. compliance with ethics regulations: yes. rationale: diagnosis of sepsis is a major challenge in intensive care units and is associated with a high morbidity and mortality. sepsis identification is even more difficult in patients with extracorporeal membrane oxygenation (ecmo) because of many confounding factors. the primary objective was to study the ability of c-reactive protein (crp) and procalcitonin (pct) values measured at ecmo support initiation (day ) to predict the occurrence of early sepsis in patients undergoing venoarterial ecmo (va-ecmo) or venovenous ecmo (vv-ecmo). the secondary objectives were to study the association between these biomarkers and mortality rate during ecmo support and in-hospital mortality rate. furthermore, we investigated the relationship between early sepsis and mortality. patients and methods: we performed a retrospective, monocentric study in the cardiovascular intensive care unit of the university hospitals of lille, france. between november , and december , , we included patients over years old, who underwent an ecmo support for a medical or surgical indication, and for whom biomarkers (crp and pct) levels were available for at least the first days of admission. biomarkers and blood cultures were daily assessed for the first ecmo support days. early sepsis was defined by sepsis diagnosis in the first days after circulatory assistance initiation. in-hospital mortality rate was censored at days. after univariate analysis, a cox multivariate regression model was used to assess if the association between biomarkers levels and early sepsis or mortality rate was independent. a kaplan-meier survival plot was used to describe the association between early sepsis and mortality. results: among patients included, underwent va-ecmo and underwent vv-ecmo. an early sepsis diagnosis was made in . % of va-ecmo patients and in % of vv-ecmo patients. pct and crp levels on day were significantly associated with early sepsis diagnosis (fig. rationale: fluids are one of the most prescribed drug in intensive care, particularly among patient with circulatory failure. yet, very little is known about their pharmacodynamic properties and this topic has been left largely unexplored. several factors may impact the haemodynamic efficacy of fluids among which the infusion rate. the aim of this study was to investigate the influence of the rate of fluid administration on the fluid pharmacodynamics, in particular by studying mean systemic pressure (pms). we conducted a prospective observational study in patients with septic shock to compare two volume expansion strategies. a fluid bolus, ml of normal saline were administered and several haemodynamic variables were recorded continuously: cardiac output (co), arterial pressure (ap), mean systemic pressure (pms, estimated from ci, pvc and map). infusion rate was left at the discretion of the attending physician. a "slow" and a "fast" groups were determined based on the median of the infusion duration. fluids effect was measured by the area under the curve (auc), maximal effect (emax) and time to maximal effect (tmax) for each haemodynamic variable. the effects of fluid on psm disappeared in one hour on average. compared to patients of the "slow" group, those of the "fast" group had a shorter tmax and a higher emax for pms (p = . and . respectively). the auc for pms was identical between group, while in case of similar effect of infusion rates, it should be larger in the "slow" group. regarding co, tmax was also shorter in the "fast" than in the "slow" group (p = . ). the decreasing slope from maximal effect was comparable between groups, for pms as for co. the effect of a ml fluid bolus with normal saline in septic shock patients vanished within one hour. a faster infusion rate increased the maximal and total effect of the fluid bolus and shortened the delay to reach the maximal effect. rationale: significant hypotension following spinal anesthesia is a common issue in everyday clinical practice. toavoid this potentially harming situation, an empirical fluid administration is usually performed before the procedure. inferior vena cava (ivc) ultrasound has been demonstrated effective in guiding fluid therapy in critical care patients. the purpose of this study was to evaluate the ivc ultrasound guided volemic status optimization in order to decrease post-spinal hypotension rate. patients and methods: in this prospective, controlled, randomised study, consecutive patients were recruited and patients were randomly assigned to a control group, consisting of pre-anesthesia empirical fluid administration (itt), an ivc ultrasound group in which fluid management was based on an ivc ultrasound evaluation, and a passive leg raising test (plrt) group in which volume optimization was performed following the above mentioned test. primary outcome was the hypotension rate reduction after spinal anaesthesia following fluid optimization therapy between the groups. secondary outcomes were the total fluid amount administered, the total vasoactive drug amount used and the time needed to realize the whole anaesthetic procedure in all three groups. results: % reduction in hypotension rate ( % ci - %, p = . ) was observed between the echocardiography group and the control group, and there was a reduction of hypotension rate by % (ci % - %, p = . ) between the echocardiography group and the plrt group. the total fluid amount administered was significantly greater in the ultrasound group than in the control group ( ml; sd ml, versus ml; sd ml, p = . ). the total amine consumption was % in control group, % in ivc group and % in plrt group. an increased of total study time was observed for the echocardiography group min (sd min) in comparison with the control group min (sd min) and ptlr group min (sd min), (p < . ). the study showed a faint but positive trend toward the use of ivc-ultrasound to identify patients in spontaneous breathing needing fluid optimization before spinal anesthesia compliance with ethics regulations: yes. rationale: we performed a systematic review and a meta-analysis of studies investigating the ability of the end-expiratory occlusion (eexpo) test to predict preload responsiveness, through the changes in cardiac output (co) or its surrogates, in adult patients. this meta-analysis was prospectively registered on prospero (crd- ). we screened pubmed, embase and cochrane database to identify all original articles published between and evaluating the ability of the eexpo test to predict a significant increase in co or surrogate, compared to the one induced by a subsequent volume expansion or by passive leg raising (plr). the meta-analysis determined the pooled area under the receiver operating characteristics curve (auroc) of eexpo testinduced changes in co to detect preload responsiveness, as well as pooled sensitivity and specificity and the best diagnostic threshold. subgroup analysis and sensitivity analysis were planned to investigate potential sources of heterogeneity. results: thirteen studies ( patients) were identified and included in the analysis. nine studies were performed in the intensive care unit and four in the operating room. preload responsiveness was defined according to co changes induced by fluid administration in studies (fluid-induced increase in co ≥ % or ≥ %) and according to co changes induced by plr in one study. the duration of the respiratory hold ranged between and s. for the eexpo test-induced changes in co, the pooled sensitivity and specificity were [ - ]% and [ - ]%, respectively, while the pooled auroc curve was . ± . (fig. ) . the corresponding best diagnostic threshold was . ± . %. when changes in co were monitored through pulse contour analysis compared to other methods the accuracy of the test was significantly higher ( ( ). continuing (decrease to % of peak level) or modification (decrease < %) of antibiotic therapy was guided by a serum pct assay from the third day of treatmentand every h until antibiotic was stopped. this last was stopped when pct levels had decreased of % from the initial value. results: a total of patients had been diagnosed as sepsis (n = , %) and septic shoc (n = , %). mean age was years ± . an average ubs and absi score of % and . the average length of stay in icu was days. patients were assigned into two groups: group a (favorable evolution, n = ); group b (unfavorable evolution, n = ). the therapeutic attitude according to the kinetics of the pct are presented in the table . we found a significant difference between patients with unfavorable evolution compared to those with a favorable evolution (in whom we stopped antibiotics) (p < . ), in terms of hemodynamic state, pct concentration and renal clearance. pctguided antibiotic treatment has been proven to significantly reduce length of antibiotic therapy in our patients. the average duration of antibiotic was . ± days. conclusion: pct measurement may help with the decision to initiate antibiotic therapy in low risk acuity of infection and allows more judicious antibiotic use by reducing antibiotic exposure. compliance with ethics regulations: not applicable. rationale: reducing the risk of severe hypoxemia during endotracheal-intubation (eti) is a major concern in intensive care unit but little attention was paid to co variations during this period. we conducted a prospective observational study to describe transcutaneous co (ptcco ) throughout intubation in patients who received preoxygenation with standardoxygen therapy (sot), non-invasive ventilation (niv), or high flow nasal cannula oxygen therapy (hfncot). patients and methods: patients over years undergoing eti in icu were continuously monitored for ptcco during intubation and the following h under mechanical ventilation (mv). haemodynamics and respiratory parameters were also recorded as well as arterial partial pressure of co (paco ) to evaluate reliability of the transcutaneous measure. results: two hundred and two patients were included in the study. we found a strong correlation between ptcco recorded at preoxygenation and the last paco available before intubation (r = . , p < . ). in % of patients ptcco values recorded at initiation of mv were out of - mmhg ranges. ptcco recorded at eti, at initiation of mv, min and h of mv were significantly higher than ptcco during preoxygenation (p < . by anova). variations of ptcco were significantly different according to the preoxygenation method (p < . for interaction in anova). lastly, a decrease in ptcco higher than mmhg within half an hour after the beginning of mv was independently associated with postintubation hypotension (pih) (odds ratio = . , % confident interval . - . , p = . ). conclusion: ptcco is a valuable tool to record paco variation in patients requiring invasive mechanical ventilation and could be useful to prevent pih. compliance with ethics regulations: yes. rationale: intubation in intensive care unit (icu) is a critical procedure which leads to serious adverse event in to % of cases. several recent trials were conducted to help physicians to choose medications, devices and modality of intubation. especially, videolaryngoscope (vl) led to several publications in the last few years, with increasing tools marketed and spread use (difficult airway management, routineintubation). we designed an online survey to take a picture of intubation process and devices availability in france. toolbox. it was positioned as a first line laryngoscope for every intubation in critically ill patients to reinforce the vl skill training. present study was performed using prospectively collected data from a continuous quality improvement database about airway management in a -beds french teaching hospital medical icu. all consecutive intubation procedure performed with vl from september to june were included. "first attempt success" group and "first attempt failure" group were compared by univariate and multivariate analysis in order to analyze the first attempt intubation success rate according to the level of operators' expertise, identify factors associated with first pass intubation failure and describe the intubation related complications. results: we enrolled consecutive endotracheal intubations. overall first attempt success rate was ( %). comorbidities, junior operator, the presence of cardiac arrest and coma were associated with a lower first attempt success rate. the first attempt success rate was less than % in novice operators ( - previous experiences with vl, independently of airway expertise with direct laryngoscopies) and % in expert operators (greater than previous experiences with vl) (fig. rationale: tracheostomy in intensive care unit (icu) has many advantages. but only patient comfort and shorter icu and hospital stay were demonstrated. the timing of this procedure is still debated. the aim of this study was to determine the impact of early tracheostomy on prognosis. we performed a retrospective study in a medical icu ( beds unit) from january to november . the technique of tracheostomy was exclusively surgical in the operating room made by the surgeon. the primary endpoint was mortality in icu. the secondary outcomes were post-tracheostomy incidence of ventilator acquired pneumonia, duration of mechanical ventilation and length of stay in icu. these criteria were assessed in relation to timing of the tracheostomy defined as early when performed before day of mechanical ventilation. results: forty-two patients were enrolled during the study period. mean age of patients was ± years. median length of stay in icu was of days. mortality rate was of %. comparing the two groups, early vs late tracheostomy, no difference was found with respect to mortality ( % vs. %, p = . ), vap occurrence ( % vs. %, p = . ), post-tracheostomy duration of mechanical ventilation ( ± d vs. ± d, p = . ), or length of stay in icu ( ± d vs. ± d, p = . ). in multivariate analysis, the only factor independently related to mortality was the sofa score patient on tracheostomy day with p = . and or = . (ci % [ . - . ] ). conclusion: tracheostomy in the intensive care unit remains a justified alternative despite the discordant data in the literature. in our study, the delay of the procedure didn't interfere with the evolution. however, the patient severity as attested by sofa score at the day of tracheostomy, was the only independent prognostic factor. those results should be confirmed by other large prospective studies. compliance with ethics regulations: not applicable. sabah benhamza, mohamed lazraq, youssef miloudi, abdelhak bensaid, najib el harrar réanimation de l'hôpital du août, casablanca, morocco correspondence: sabah benhamza (benhamzasabah @gmail.com) ann. intensive care , (suppl ):p- rationale: many unknowns remain as to the place of tracheostomy in intensive care. reluctance to perform a tracheotomy is numerous, especially when pre-exists chronic respiratory failure, but some data suggest benefits. we report in this work our experience in tracheotomy in the intensive care unit of the august hospital, casablanca. patients and methods: this is a retrospective descreptive study over years (january to january ) including all patients that have been tracheostomized in the intensive care unit of the august hospital . results: during the study period, patients were tracheostomized with a prevalence of . % in years, the predominance was male (sex ratio . ). the average age was ± years old. the indication for tracheostomy was prolonged ventilation in % of cases, extubation failure in % of cases, and intubation failure in % of cases. tracheostomy was performed on average on the th day of intubation. all patients were tracheostomized in the operating room by ent surgeons. the main complications attributable to tracheotomy were hemorrhage of the tracheostomy orifice in patients ( %) immediately resumed, cases of subcutaneous emphysema ( %), case of pneumothorax ( %), cases of orifice infection ( %). no patient died of a tracheostomy related cause. the tracheotomy in intensive care is still a subject of debate especially concerning the time of its realization. however it seems to reduce the duration of mechanical ventilation, facilitates the care and also the ventilatory weaning. compliance with ethics regulations: yes. rationale: hfnco is a frequently used device providing heated and humidified high flow oxygen with several advantages: decreased work of breathing, decreased dead space, increased end expiratory lung volume (eelv), more stable fio . the increase in eelv is relying of the positive expiratory effect generated by the device. the level of generated pep seems however to largely depend on whether the mouth is open or not. this study was aimed to assess the impact of mouth opening on eelv increase induced by hfnco using electric impedance tomography. patients and methods: the following hfnco trial was proposed to healthy subjects who used hfnco on a regular basis for patients care. oxygen flow was set successively during min periods at , and l/min (optiflowtm; fisher & paykel healthcare, auckland, nz). these three conditions were tested in semi recumbent and supine position chosen at random. measurement started in supine position with no flow (baseline) and each period was separated from the following by a wash out period on min during which the subject could breath normally with no supplemental oxygen. electric impedance tomography (pulmovista ® , dräger medical gmbh, lündbeck, germany) was performed applying a electrodes belt placed between the th and th intercostal space, including a reference electrode located on the abdomen. as no spirometer was used, the data of eelv computed on the eit device were expressed as percentage of variation of the value measured in supine or semi recumbent position with no flow. demographic data were expressed as median and extreme values. comparisons were performed using u mann whitney test. [ . - . ] accepted to participate to the study. when subjects received hfnco with open mouth (whatever position) no modification of eelv was observed (table ) . conversely, a significant increase in eelv was noted with closed mouth, whatever position. in the semi recumbent position the increase in eelv was even more important with l/min. conclusion: electrical impedance tomography illustrates the impact of mouth closure on eelv increase among healthy subjects receiving hfnco. compliance with ethics regulations: yes. rationale: in stable copd patients, nasal high flow oxygen (nhf) use can be associated with reduction in respiratory rate (rr) and minute ventilation (mv). in thesepatients, paco remains stable or decreases under nhf. this suggests a possible dead space reduction related to a washout effect of nhf. the aim of this study was to assess the physiological effects of nhf in hypercapnic patients with acute copd exacerbation. patients and methods: crossover study in hypercapnic patients suffering from acute copd exacerbation and treated with intermittent non-invasive ventilation (niv). nhf l/min or standard oxygenotherapy (stand o ) were randomly administered during h between niv treatments. rr, tidal volumes (vt), mv and corrected mv (cormv = mv x paco / ) variations were recorded during the last min of each study period using a respiratory inductive plethysmography vest. blood gas analysis was performed at the end of each oxygen administration period. visual analogic dyspnea score (vas) quoted from to was assessed by the patient after and min. results given as median [iqr] . wilcoxon tests were used to compare data between stand o and nhf. results: twelve patients were included and data could be recorded in ( (fig. ). dyspnea scores were not different between the modalities. conclusion: in case of acute copd exacerbation, using nhf between niv treatments was associated with paco and rr decrease. mv concomitantly decreased suggesting a deadspace volume reduction related to a washout effect of nhf. corrected mv decreased in all the patients except one. these results suggest that nhf could be used to deliver oxygen between niv treatments to copd patients suffering from acute exacerbation and could contribute reducing paco . compliance with ethics regulations: yes. rationale: the role of atypical micro-organisms in acute exacerbation of chronic obstructive pulmonary disease (copd) that require mechanical ventilation is poorly none. the aim of this study was to determine the role of atypical pathogens in severe acute exacerbation of copd. patients and methods: in this prospective study we included all patients admitted for acute exacerbation of copd requiring mechanical ventilation. atypical pathogens (chlamydophila pneumoniae and mycoplasma pneumoniae) were searched by serological diagnosis and by culture of sputum samples. in this study we included patients aged ± years. sixty-eight percent of sputum culture were considered significant. six cultures were positive with different microorganisms. neither chlamydophila pneumoniae nor mycoplasma pneumoniae were found. the prevalence of chlamydophila pneumoniae was . % (positive igg serum). the demographic characteristics was similar between patients with and without positive culture. the rate of noninvasive ventilation (niv) failure was % in positive serology group versus % in negative serology group (p = . ). the mortality was similar in both groups. in multivariate logistic regression analysis only positive serology (or = . ; % ic [ . - . ], p = . ) was an independent factor of niv failure. conclusion: a positive serology of chlamydophila pneumoniae was a predictive factor of niv failure without an impact on the morbidity and mortality of copd patient treated with mechanical ventilation. compliance with ethics regulations: yes. rationale: emergency departments (ed) receive a growing up number of patients with acute exacerbation of chronic obstructive pulmonary disease (copd) .non-invasive ventilation (niv) could be a good alternative to achieve a respiratory support, avoiding as much as possible the complications of invasive ventilation. the study aimed to assess the clinical outcomes of using niv in acute exacerbation of copd at ed and to identify whether clinical variables present at admission are predictive of niv failure. we conducted a prospective study conducted at the ed over a period of one year. data of all patients admitted for acute exacerbation of copd for all causes and requiring non-invasive ventilation were collected. niv failure was defined as need for endotracheal intubation or death. results: during the study period, a total of patients with a mean age of years (± ) were included. acute exacerbation of copd was due to bronchitis in %, to pneumonia in % of cases. % of patients had no apparent etiology of acute exacerbation of copd. bilevel positive airway pressure was performed on all patients, during a mean period of h (± ). clinical niv success was observed in patients ( %). the predictors of niv failure were advanced age, tachycardia, and hypercapnia. conclusion: the efficiency of niv in the management of acute exacerbations of copd at ed is well documented. this is further supported by our study which showed a clinical success in % of patients with acute exacerbation of copd. compliance with ethics regulations: yes. rationale: non invasive ventilation (niv) is often performed in elderly patients with acute respiratory failure (arf) at emergency department (ed). this technique may be subject to many difficulties, due to the presence of frequent co-morbidities. the aim of this study was to identify the predictive factors of niv failure in elderly patients with arf at ed. patients and methods: this was a retrospective study conducted at ed on year and months including patients aged more than years and who required the use of niv for an arf. all data were collected and analyzed using the spss software. patients were divided into two groups: niv failure and niv success. niv failure was defined by inhospital mortality, requirement of intubation or hospitalization at intensive care unit. results: during the study period, a total of elderly patients that required niv for arf were included. median age was years (min = , max = ) and sex ratio was . . the median charlson index was (min = , max = ). the etiological diagnoses of arf were acute decompensation of chronic obstructive pulmonary disease ( %), acute heart failure ( %), pneumonia ( %) and pulmonary embolism ( %). the arf was hypercapnic in % of cases and nonhypercapnic in %. niv failure concerned %. predictive factors of niv failure were clinical signs of right heart dysfunction (p < . ), c reactive protein (p = . ), initial ph (p = . ) and kidney dysfunction (p < . ). conclusion: in our study, niv failure in elderly patients with arf at ed was influenced by clinical signs of right heart dysfunction, c reactive protein, initial ph and kidney dysfunction. these clinical and biological factors could be useful to identify the most critical elderly patients and to better guide therapeutic decisions. compliance with ethics regulations: yes. rationale: the interest of ecco r in the management of very severe acute asthma exacerbations is still unclear. since it could help to control respiratory acidosis and /or to limit dynamic hyperinflation, its clinical benefits are uncertain, even in mechanically ventilated patients. the rexecor observatory is a prospective ecco r cohort in the great paris area. tencases of severe asthma treated by ecco r were retrospectively reviewed. mainly, arterial blood gases (abg), duration of ecco r and imv were collected and in-icu mortality were assessed. data are reported as median (iqr). results: ten patients ( men, age: (ic: - ) years, bmi: . (ic: . - . ) kg/m , fev- : . (ic: . - . ) l, ( (ic: - ) %), saps : . (ic: . - . ) points) were included. one patient suffered from cardiac arrest before admission and one had pneumothorax at icu admission. nine patients were under imv (started on the day of admission for ). before ecco r, patients received systemic corticosteroids, paralyzing agents, epinephrine and salbutamol. two patients suffered from pneumonia. ecco r was started (ic: - . ) days after intubation. venous vascular access was achieved via the right internal jugular route in patients and via the femoral route in . the hemolung device was used in patients, the ila activve in and the prismalung in . abg before and after day of ecco r are reported in table . duration of ecco r was (ic: . - ) days and patients were weaned from imv under ecco r. for the remaining patients, duration of imv after ecco r was (ic: - . ) days. icu stay was . (ic: - . ) days. the only one niv patient was not intubated. ecco r as stopped in patients because of complications (one hemolysis, one internal bleeding and one membrane clotting). one patient died in icu after limitation of life-sustaining therapy decision. we report a preferential use of ecco r in imv patients, contrasting with a marginal use in only one niv patient to prevent intubation. the mortality rate was low, in line with previous case series of severe acute asthma with ecmo or ecco r support. more studies are needed ( ) to better delineate the pathophysiological benefits of ecco r in asthma patients and ( ) to confirm strong clinical benefits. compliance with ethics regulations: not applicable. rationale: acute exacerbations of chronic obstructive pulmonary disease (aecopd) are the most important events characterizing respiratory illness progression. their management often needs noninvasive or invasive ventilation (iv). data of literature confirm that the mortality of aecopd requiring iv is high but are discordant about prognostic factors. the aim of our study was to describe the epidemiologic and clinical features of patients admitted for aecopd requiring iv, the treatment and the evolution in intensive care unit in order to deduce the independent factors of mortality. patients and methods: a -year retrospective analytic observational single-center study including patients hospitalized for aecopd requiring iv. results: fifty-eight patients were enrolled. mean age was ± years with sex-ratio of . . eighty one percent were smokers and % were classified gold stage . history of intensive care hospitalization and prior iv were found in % and % of all cases respectively. mean apache ii score was ± . the predominant precipitating factor for aecopd was respiratory tract infection ( % of all cases). twenty two percent of all patients presented septic shock. iv was initiated on admission in % of all cases and after noninvasive ventilation failure in % of all cases. forty-eight per cent of all patients developed septic shock as evolutionary complication. mortality rate was %. in univariate analysis: male gender (p = . ), duration of respiratory disease progression (p = . ), annual exacerbations frequency (p < − ), gold stage (p = . ), prior iv (p < − ), duration of symptoms before hospitalization (p = . ), apache ii score (p = . ), ph (p = . ), shock on admission (p = . ) and septic shock as evolutionary complication (p = . ) were predictors of mortality in our study. besides; shock on admission (p = . ) and as evolutionary complication (p = . ) were the two independent prognostic factors in multivariate analysis. conclusion: vital and functional prognosis of aecopd requiring iv depends on the severity of the underlying respiratory illness, the severity of the exacerbation and the quality of an early management. this emphasizes the importance of controlling modifiable risk factors including smoking cessation, basic treatment improvement and early appropriate treatment of these exacerbations. compliance with ethics regulations: yes. medical background, biological parameters, death-rate and outcome of patients have been compared. results: in total, patients have been included in the "hlh" population. death-rate in intensive care unit was % in the "hlh" group compared to % in the "not hlh" group (p = . ). we used more extrarenal cleansing in the "hlh" group ( % vs. %, p < . ), the duration of assisted ventilation was longer ( . days vs. . days, p < . ), as well as the duration of extrarenal cleansing ( . days vs. . days, p < . ) and those of amines ( . days vs. . days, p = . ). the average time of hospitalization was significantly longer in the "hlh" group ( . days vs. . days, p < . ). the secondary hlh to sepsis in intensive care unit, not well known and understudied, seems to have a different profile and a more serious outcome but no change in death-ratehas been found considering the pairing with the sofa. further studies are needed to plan a better therapeutic strategy within this population. compliance with ethics regulations: not applicable. serum and peritoneal exudate concentrations after high doses of ß-lactams in critically ill patients with severe intra-abdominal infections: an observational prospective study lisa leon, philippe guerci, elise pape, nathalie thilly, amandine luc, adeline germain, anne-lise butin-druoton, marie-reine losser, julien birckener, julien scala bertola, emmanuel novy chru nancy, vandoeuvre les nancy, france correspondence: lisa leon (lisaleon @gmail.com) ann. intensive care , (suppl ):p- rationale: critically ill patients with severe intra-abdominal infections (iais) requiring urgent surgery may undergo several pharmacokinetic alterations that can lead to ß-lactam under dosage. the aim of this study is to measure serum and peritoneal exudate concentrations of ß-lactams after high doses and optimal administration schemes. patients and methods: this observational prospective study included critically ill patients with suspicion of iai who required surgery and a ß-lactam antibiotic as empirical therapy. serum and peritoneal exudate concentrations were measured during surgery and after a h steady-state period. the pharmacokinetic/pharmacodynamic (pk/ pd) target was to obtain ß-lactam concentrations of % ƒt> x mic (minimum inhibitory concentration) based on a worst-case scenario (highest ecoff value) before bacterial documentation (a priori) and redefined on the mic of the isolated bacteria (a posteriori). results: forty-eight patients were included with a median [iqr] age of [ - ] and a saps ii score of . septic shock occurred in % of cases. the main diagnosis was secondary nosocomial peritonitis. piperacillin/tazobactam was the most administered ß-lactam antibiotic ( %). prior to bacterial documentation, patients ( . %) achieved the a priori pk/pd target. iai was documented in patients ( %). enterobacteriaceae were the most isolated bacteria. based on the mic (n = ) of isolated bacteria, % of the patients achieved the pk/pd target ( % ƒt> xmic). in the fig. we presented serum ß-lactams pk/pd target attainment and observed total concentrations of piperacillin-tazobactam at each timepoint in serum and peritoneal exudate. in critically ill patients with severe iais, high doses of ß-lactams ensured % ƒt> xmic in % of critically ill patients with severe iais within the first h. a personalized ß-lactam therapeutic scheme with a pk/pd target based on local ecology should be warranted. compliance with ethics regulations: yes. rationale: intensive care unit acquired bloodstream infections (icu-bsi) are frequent, and associated with high morbidity and mortality rates. the objective of our study was to describe the epidemiology and the prognosis of icu-bsi in our icu (cayenne general hospital). secondary objectives were to search for factors associated to icu-bsi caused by esbl-pe, and those associated with mortality at days. patients and methods: we retrospectively studied icu-bsi in the medical-surgical intensive care unit of the cayenne general hospital, during months (january to june ). we assessed survival at days from the diagnosis of icu-bsi. results: icu-bsi was diagnosed in . % of admissions giving a density incidence of . icu-bsi/ days. the median delay to the first rationale: necrotizing soft tissue infections (nsti) are a heterogenous group of severe infections. among them, group a streptococcal (gas) infection represent a subgroup that could benefit from specific therapies targeting the toxinic pathway, such as intravenous immunoglobulins or clindamycin. nevertheless, previous trials evaluating these treatments suffered from a low rate of gas infection among the study population. early identification of patients at high risk of gas infection would allow for assessing targeted treatment strategies. patients and methods: we conducted a secondary analysis of a previously published cohort of patients admitted to our tertiary center for surgically proven nsti between and . admission characteristics and microbiological documentation based on surgical samples, blood cultures or subcutaneous puncture were recorded. we compared patients with a documented gas infection to all other patients regarding admission characteristics. a generalized linear regression model was used to identify admission characteristics associated with a subsequent documentation of gas infection. results: among patients, ( %) had a gas infection, which was monomicrobial in ( %) cases. admission characteristics associated with gas infections by univariate analysis were nsaid treatment before admission ( ( . %) for gas infections vs ( . %) for others, p = . ) and leukocytosis as a continuous variable ( , /mm [ , - , ] vs. , [ - , ], p = . ). those inversely correlated with gas infections were immunodeficiency ( ( %) vs. ( . %), p = . ), and an abdominoperineal topography ( ( . %) vs. ( . %), p > . ). after multivariate analysis only immunodeficiency (or = . [ . - . ], p = . ) and an abdominoperineal infection (or = . [ . - . ], p = . ) remained associated with the absence of gas infection. using these criteria allowed for identifying subgroups of patients with increased likelihood of gas infections: from % overall (n = ) to % for non-abdominoperineal infections (n = ), % for patients without immunodeficiency (n = ) and % for both non abdominoperineal infections in patients without immunodeficiency (n = ). a sensitivity analysis for monomicrobial gas infections yielded similar results with the addition of younger age and non-nosocomial infections as predictors. conclusion: upon admission, the absence of immunodeficiency and of an abdominoperineal infection in nsti patients were covariables associated with gas infection. compliance with ethics regulations: yes. rationale: sickle-cell disease is the most common genetic disorder in the world. a complication of this disease is the acute chest syndrome (acs) which is associated with a high risk of death. respiratory tract infections are often mixed up and the introduction of betalactam antibiotics is recommended. glomerular hyperfiltration is common and responsible of a high risk of underdosing. this study compares cefotaxim continuous infusion to intermittent bolus in adult patients with acs. patients and methods: this observational retrospective monocentric study included acs admitted in intensive care unit and treated by cefotaxim with at least one plasmatic dosing between may and august . results: thirty patients received bolus administration while the others received continuous infusion. we observed patients ( %) and patients ( %) with a cefotaxim trough level ≥ mg/l in the bolus and continuous group, respectively (p < . ). the median residual concentration was mg/l [ - ] and . mg/l [ . - . ] in the bolus and continuous group, respectively (p < . ). there was no toxic effect induced by overdosing of cefotaxim. conclusion: compared to intermittent bolus infusion, continuous cefotaxim administration maximizes the pharmacokinetics parameters by obtaining a plasmatic concentration times above the minimal inhibitory concentration of usual germs associated with acs. continuous infusion of time-dependant antibiotics seems to decrease the risk of underdosing in patients with sickle cell disease. compliance with ethics regulations: not applicable. (n = , %), followed by esophageal varices rupture (n = , %), ulcer bleeding (n = , %) and diverticular hemorrhage (n = , %). infectious diseases were diagnosed in three patients ( %), including one clostridium colitis, one erosive gastritis with helicobacter pylori and one esophageal candidiasis. conclusion: gib is associated with a high mortality rate in immunocompromised patients, especially in patients with hematological malignancies. specific malignant lesions were the main etiology and may be difficult to treat. comparison with critically ill non-immunocompromised patients with gib will help physicians to provide specific therapeutic strategies in this population. compliance with ethics regulations: yes. risk factors for delayed defecation and impact on outcome in critically ill patients: a multicenter prospective non-interventional study benoît painvin ,* , arnaud gacouin , antoine roquilly , claire dahyot-fizelier , sigsimond lasocki , chloe rousseau , denis frasca , philippe seguin anesthésie-réanimation/chu rennes, rennes, france; réanimation médicale/chu rennes, rennes, france; réanimation chirurgicale/ chu nantes, nantes, france; réanimation chirurgicale/chu poitiers, poitiers, france; anesthésie-réanimation/chu angers, angers, france; centre investigation clinique/chu rennes, rennes, france; anesthésie-réanimation/chu poitiers, poitiers, france; réanimation chirurgicale/chu rennes, rennes, france correspondence: benoît painvin (painvinbe@gmail.com) ann. intensive care , (suppl ):p- rationale: delayed defecation is very common in intensive care units (icu) and it increases length of mechanical ventilation (mv), icu length of stay (los) and possibly mortality. the objective of this prospective multicenter study was to determine risks factors for constipation in icu and to evaluate their impact on mortality. patients and methods: it was a prospective multicenter non-interventional trial performed in university icus in france from january to october . all patients ≥ years old who had an expected los of days and mechanically ventilated for at least days were eligible. defecation was defined as the time of the first stool passage. results: patients were included in the analysis. a stool passage was observed in % of the patients during their icu stay with a mean delay of ± days. in multivariate analysis, risk factors for delayed passage of stool were non-invasive ventilation use and time spent under invasive ventilation whereas alcoholism, laxative treatment (before and after icu admission) and nutrition ≤ h favoured passage of stool (table ) . no relations between constipation and mortality were found. conclusion: we highlighted new and important independent factors for constipation in critically ill patients leading to a better prevention of this phenomenon.. compliance with ethics regulations: yes. rationale: community peritonitis is a frequent medical-surgical emergency of the adult, acquired by the patient in a non-hospital setting. careful multidisciplinary care is essential, involving surgeons, anesthetists, microbiologists and radiologists. the objective of our study is to determine the bacteriological aspects of intra-abdominal sepsis, to describe their sensitivity profiles and to propose treatment regimens for the management of community peritonitis. we conducted a descriptive retrospective study spanning a period of two years from january to january involving cases of community abdominal sepsis operated in the operating room of surgical emergencies of our hospital. we included in our study adult patients admitted for suspected or confirmed abdominal sepsis who had undergone bacteriological examinations on the abdominal collections. samples taken are sent directly to the bacteriology laboratory for bacteriological analysis of the results. the studies showed the mean age is . years old, with a sex ratio of . . we found positive results mainly of peritoneal origin with a percentage of . % peritonitis, dominate by intestinal peritonitis . % followed by the appendicular origin . % then peritonitis by perforation of ulcer. the most incriminated organism in intraabdominal sepsis is e. coli with a percentage of . % of the total germs found, followed by streptococcus spp . %, enterococci . %, non-fermenting bgn composed mainly of pseudomonas aeruginosa . %, staphylococci . % and acinetobacter baumanii . %. note also the presence of bacteroides fragilis is %. e. coli had a very low sensitivity profile for amoxicillin/clavulanic acid ( . %), unlike ceftriaxone, gentamicin, amikacin and ertapenem, which had a sensitivity of . %, respectively. . %, %, . %. conclusion: knowledge of the bacterial ecology of intraabdominal sepsis is important in the choice of probabilistic antibiotherapy, pending bacteriological findings. no data are yet available about nutritional management and risk of malnutrition in tunisian medical intensive care units (icu). the purpose of this study was to describe nutritional management in medical intensive care patients and to evaluate the risk of malnutrition. patients and methods: we conducted a prospective observational cross-sectional study in medical icus all around the tunisian country on the th september . all participant units received a questionary form about routine nutritional management and data of all patients hospitalized in icu on the study day. collected data were: demographic characteristics, reason for admission, severity scores and subjective evaluation of nutritional status on admission, type and volume of nutritional support on the study day and the day before, nutritional status, nutric score and biological data on the study day, reasons for nutritional interruption and other supports prescribed. results: thirteen icu all around tunisia participated to the study. no icu had a nutrition team and only one had a written nutrition protocol. four icus evaluated systematically the nutritional status on admission. all icus were aware and practiced early enteral nutrition in patients unable to maintain oral intake with a systematic supplementation of oligoelements and minerals. neither target energy nor protein intake were calculated. on the study day, patients were hospitalized with an occupation rate of %. mean age was ± years. mean body mass index was ± and % of patients were judged well nourished. enteral nutrition support was prescribed on admission in % of cases with a mean caloric intake of ± kcal/day. the mean caloric target on the study day was ± kcal/day with a mean caloric intake of ± kcal/day and a mean caloric gap of ± kcal/day. the mean nutric score and body mass index on the study day were ± and ± respectively. twenty patients were judged malnourished by the nutric score and twenty two by clinical evaluation. a good correlation was found between nutric score and clinical evaluation of nutritional status (k = . ). conclusion: tunisian icus don't have nutrition team or nutritional written protocol. early enteral feeding and supplementation is common. a good correlation exists between nutric score and clinical nutrition status evaluation. compliance with ethics regulations: yes. rationale: whether more intensive glycemic control (gc) is beneficial or harmful forcritically ill patient has been debated over the last decades. gc has been shown hard to achieve safely and effectively in intensive care. the associated increased hypoglycemia and glycemic variability is associated with worsened outcomes. however, modelbased risk-based dosing approach have recently shown potential benefits, improving significantly gc safety and performances. the stochastic targeted (star) gc framework is a model-based controller using a unique risk-based dosing approach. star identifies modelbased patient-specific insulin sensitivity and assesses its potential variability over the next hours. these predictions are used to assess hypoglycemic risks associated with a specific insulin and/or nutrition intervention to reach a specific target band. this study analyzes preliminary clinical trial results of star in a belgian icu compared to the local standard protocol (sp). the mean age in our series was . years with a male predominance (sex ratio = . ). the main revealing symptoms were epigastralgia, weight loss and vomiting. subtotal gastrectomy was performed in . % of cases and total gastrectomy in . % of cases. curative resection could only be performed in . % of cases. operative mortality was . % and morbidity was . %. the main factor influencing operative mortality was age greater than years. in univariate analysis the main prognostic factors; tumor size, degree of parietal invasion, presence of ganglionic invasion, presence of more than ganglia invaded, presence of metastases, locally advanced tumor, tumor stage and curative nature of resection. patient-related factors such as age associated blemishes and biological factors have a significant influence on the patient's prognosis. the prognosis of gastrectomies, although it has improved overall, remains mediocre. the only way to improve the prognosis remains the early diagnosis with an effective surgical management and the introduction of an adapted resuscitation. compliance with ethics regulations: yes. efficacy of multiple second line agents in refractory status epilepticus in a pediatric intensive care unit lea savary, claire le reun chu tours, tours, france correspondence: lea savary (lea.savary@hotmail.com) ann. intensive care , (suppl ):p- rationale: convulsive status epilepticus (cse) is the most common neurological emergency in children. refractory status epilepticus (rse) occurs whenseizures are not controlled with first-and secondline agents. in adults, rse requires pharmacological induced coma. in pediatric patients, association of second line treatment is often used to avoid general anesthesia although there is currently no data on the efficacy of this association. we performed a monocentric retrospective study to assess the efficacy of multiple second line agents in pediatric rse. all children admitted to clocheville hospital (tours) between january and december with a diagnosis of rse were included. our population was divided into two groups: need of general anesthesia (midazolam+) or not (midazolam-). results: children were included ( in group midazolam+, in group midazolam−) during the study period. among the patients with multiple second line agents, % did not need general anesthesia (n = ). in group midazolam+, cse was % longer in patients treated with multiple second line agents ( rationale: drowning is an acute respiratory failure resulting from immersion or submersion in a liquid. patients and methods: we report cases of drowning collated in the pediatric reanimation department during a period from to . the aim of our retrospective study was to analyze and compare the different epidemiological, clinical, parcalinical, therapeutic and evolutionary of drowning in our study. results: our study contains boys and girls, with a sex ratio (m/f) of , in an age between months and years. for cases studied, no one was classified stage i, . % classified stage ii, % stage iii, and . % stage iv. all cases collected by ou service were victim of accidental drowning, . % were secondary to the lack of parental supervision. among cases, had respiratory complications, cases of hydroelectrolytic disorders, case with infectious complications, cases of neurological and cases of cardiac or hypothermic complication. in our study, cases recovered well and cases died. the survival of the drowned person depends on the speed and efficiency of the intervention, which in thefirst place is prehospital, thus ensuring the first actions at the scene of the accident, which will have repercussions on the hospital care. this has an equal share in the improvement of the victim's prognosis. compliance with ethics regulations: not applicable. epidemiology of severe pediatric trauma following winter sport accidents in the northern french alps emilien maisonneuve , nadia roumeliotis , pierre bouzat , guillaume mortamet chu grenoble, grenoble, france; chu sainte-justine, montréal, canada correspondence: emilien maisonneuve (emilienmaisonneuve@orange. fr) ann. intensive care , (suppl ):p- rationale: this study describes the epidemiology of severe injuries related to winter sports (skiing, snowboarding and sledding) in children, and assesses potential preventive actions. we did a single-center retrospective study in our pediatric intensive care unit in the french alps. we include all patients less than years old, admitted to the intensive care unit following a skiing, snowboarding or sledding accident from to . results: we included patients (mean age . years and % were male); of which ( %), ( %) and ( %) had skiing, snowboarding and sledding accidents, respectively. the average iss (injury severity score) was . the major lesions were head (n = patients, %) and intra-abdominal (n = patients, %) injuries. compared to skiing and snowboarding, sledding accidents affected younger children ( vs. years, p < . ); most of whom did not wear a helmet ( % vs. %, p < . ). severity scores were similar amongst winter sports (iss = for skiing, for snowboarding and for sledding accident, p = . ). rationale: best strategies for the management of severe pediatric traumatic brain injury (tbi) are still not clearly established and wide variations among professional practices have been reported in the literature. unfortunately, these variations in practice have an impact on the patient's outcome. the objectives of this work were to assess the adequacy of professional practices to the guidelines for the management of severe head injury and to assess the level of agreement of respondents in the absence of guideline. patients and methods: a practice survey was conducted in frenchspeaking hospitals in canada, belgium, switzerland and france from april st to june th, . the survey was conducted as a progressive clinical case with questions based on guidelines and the literature from to . the questions related to the assessment and management of tbi during the acute and intensive care phase. results: seventy-eight questionnaires were included. the adherence to guidelines was good, with items out of obtaining an adherence rate of more than % regardless of the annual number of tbi managed by the centre. there was strong agreement among clinicians on the intracranial pressure (pic) (> %) and cerebral perfusion pressure (> %) thresholds used according to age. guidelines for indication of pic monitoring were almost perfectly followed in the case of glasgow score < and abnormal brain ct scan (n = , %). on the other hand, the natremia and glycemia thresholds and the role of transcranial doppler were not consistent. strong adherence to recent recommendations was achieved: seizure prophylaxis with levitracetam (n = / , %) and capnia threshold (n = , %). assessment of o pressure in brain tissue (n = , %) and autoregulation (n = ; %) was not a common practice. conclusion: overall, practices for the management of tbi appear to be standardised. variations persist in areas where there is a lack of literature and guidelines in paediatrics, so clinicians seem to refer to adult guidelines. compliance with ethics regulations: yes. choubeila guetteche chu constantine, constantine, algeria correspondence: choubeila guetteche (cguetteche@gmail.com) ann. intensive care , (suppl ):p- rationale: ingesting a coin cell is a common household accident in children, which can have serious consequences. the goal is to determine prognostic factors to improve management and reduce complications. patients and methods: we conducted a retrospective study including children under admitted in pediatric intensive care between january and may for ingestion of button cells, with epidemiological, clinical and paraclinical data collection. results: twenty-six children boys ( %), and girls ( %) were included, with an average age of months ( - ), increased incidence in recent years. clinical signs indicative were dysphasia with hyper-sialorrhea in cases, cervical pain in one case, respiratory distress in one case, the cell was located in the upper third of the esophagus in cases, third average in cases, third inferior in cases, the mean time before extraction was h. complications: cases of mediastinitis, cases of oesotracheal fistula, a case of perforation. conclusion: the young age of the child, the diameter of the battery, and especially the time of care are risk factors for the occurrence of complications, the prevention passes through the education of the general public and creation of channel of taking into account fast charge. compliance with ethics regulations: not applicable. yacine benhocine university hospital center nedir mohamed, tizi-ouzou, algeria correspondence: yacine benhocine (yacine @yahoo.fr) ann. intensive care , (suppl ):p- rationale: inhalation of foreign bodies is a common and serious accident in children, especially between and years old. at this age, children use their mouth to explore their environment. asphyxia is the immediate risk and respiratory sequelae may appear secondarily. the severity of this incident has been considerably reduced due to the progress of the instrumentation and anesthesia which condition the smooth running of the therapeutic act. aim: to evaluate the anesthetic modalities of the extraction of the foreign bodies of the airways in children, in order to optimize our care with a maximum of security. a prospective, mono-centric, descriptive study from january to november of patients treated for inhalation of foreign bodies in the airways. study population wasdefined by: age, sex, hospitalization context, physical and radiological examination data, anestheticmanagement. results: the average age of the patients was . months, the male predominated ( %), and the hospitalization context was polymorphic. general anesthesia was necessary in all cases, sevoflurane mainly for narcosis; the combination of an opioid in . % of cases and a curare in . %. spontaneous ventilation is desirable, but % was manually broken down intermittently between extraction attempts. cases of desaturation, bronchospasm, bradycardia, and pneumothorax have been reported. . % had a good evolution. discussion: the results of the epidemiological data are consistent with those of the literature. the penetration syndrome is very revealing. the chest x-ray is the key examination, the diagnosis is often based on indirect signs. in case of asphyxia by foreign body enclosed above or between the vocal cords, laryngoscopy and oxygenation is the first step to perform. in other cases, a rigid bronchoscopy is performed under general anesthesia; inhalation induction with sevoflurane is the technique of choice for many experienced authors. controlled ventilation is used in the majority of cases because spontaneous ventilation is not often not possible. the heterogeneity of anesthetic practices accounts for the multiplicity of clinical situations. conclusion: the inhalation of a foreign body is a diagnostic and therapeutic emergency. extraction of the foreign body takes place under general anesthesia, which is difficult and at risk. compliance with ethics regulations: yes. non-invasive neurally adjusted ventilatory assist (nava) in infants with bronchiolitis: a retrospective cohort study alex lepage-farrell, sally al omar, atsushi kawaguchi, sandrine essouri, philippe jouvet, guillaume emeriaud chu sainte justine, université de montréal, montréal, canada correspondence: alex lepage-farrell (alex.lepage-farrell@umontreal.ca) ann. intensive care , (suppl ):p- rationale: bronchiolitis is one main reason for admission to pediatric intensive care unit. most infants are successfully managed with nasal cpap or high-flow nasal cannula, but about a third of these patients are not sufficiently supported and require an alternative support. non-invasive neurally adjusted ventilatory assist (niv-nava) improves patient-ventilator interactions and could therefore improve the effectiveness of non-invasive support. our hypothesis is that niv-nava is feasible in infants with bronchiolitis and that it reduces the respiratory effort. patients and methods: we retrospectively studied all patients under years of age with a clinical diagnosis of bronchiolitis ventilated with niv-nava in our pediatric intensive care unit, between october and june . patients characteristics, respiratory and physiologic parameters, including diaphragmatic electrical activity (edi) were extracted from an electronic medical database (data collected every s). respiratory effort was estimated using the modified wood clinical score for asthma (mwcas) and the inspiratory peak edi, and -h periods before and after niv-nava initiation were compared (wilcoxon rank test). the study was approved by the local research ethics committee. results: during the study period, patients were admitted with bronchiolitis; infants ( boys) with a median ( th- th percentile) age of ( - ) days were treated with niv-nava after a failure of other non-invasive support methods, and all were included. twentyfive subjects ( %) had at least one comorbidity. the interfaces used were predominantly face masks ( %). the maximum ventilatory settings were nava level of . ( . - . ), peep of ( - ) cmh o, fio of % ( - ) and maximal pressure of ( - ) cmh o. total duration of non-invasive ventilation was ( - ) hours, including ( - ) hours in niv-nava. as detailed in the table , mwcas significantly decreased after niv-nava initiation, from . ( . - . ) to . ( . - . ), p < . . a decrease in inspiratory peak edi was also observed, which was particularly clinically relevant in infants with high baseline edi (> mcv). capillary blood ph and pco also significantly improved after niv-nava introduction. six patients ( %) needed escalation to endotracheal intubation. conclusion: this study confirms the feasibility of niv-nava in infants with bronchiolitis after failure of first line non-invasive support, with a low failure rate. niv-nava initiation was followed by a decrease in respiratory effort and an improvement in blood gases. this observational study supports the needs for prospective interventional trial. compliance with ethics regulations: yes. rationale: the use of blood transfusion is frequent in pediatric intensive care units and has increased significantly since . considered as therapeutic, it requires an assessment of the benefit / risk balance before making the transfusion decision. the aim of our study is to describe the transfusion practices in the pediatric resuscitation department of the ehs canastel, algeria. patients and methods: a retrospective observational study over a -month period from january of any blood transfusion performed in hospitalized patients, in the pediatric intensive care unit. we studied : the age, the sex, the history of blood transfusion, the indication of transfusion, the haemodynamic and respiratory parameters, the transfusional accidents, the length of stay in intensive care, the evolution after a blood transfusion. results: these included transfusion patients out of hospitalizations during the -month period, mean age was months.all patients had no transfusion history, % of patients had their anemia admission and % developed it during their stay. the reason for hospitalization was respiratory distress in %, convulsive condition in %, polytrauma in %, and head trauma in %. the indication of the transfusion was placed on a hb inferior or equal to g / dl in % of cases, in % on an hb superior to g / dl in addition to the clinical criteria of intolerance to anemia; in % of the cases no clinical or biological criteria found, the nature of the blood products was of the red cell in % of the cases and of the plasma concentrate in / of the cases and pfc in %. % received a+, % of a-, % of b+, % of o+ and % of o-. % of the patients had a transfusion-like reaction at min after the start of the transfusion; % of the patients were under artificial ventilation and % were under hemodynamic support, % under diuretic.the average length of stay was days; the favorable outcome was % of the patients after the transfusion with an increase in the hb level beginning, % of the patients had complications of their pathology and the death in % of the cases. conclusion: current transfusion practices in children often do not reflect the implementation of our current knowledge of the need for transfusion. hence the need to review the protocols and practice other transfusion alternatives to avoid complications and improve the quality of care. compliance with ethics regulations: not applicable. rationale: bacterial multi drug resistance is medical actuality nowadays, because of its morbidity and mortality especially in intensive care, it constitutes a real problem in our hospitals. we conducted a retrospective descriptive study, to identify bacterial drug resistance profile of patients with cross infections in the department of intensive care in august hospital. this study included patients hospitalized between st january and st december . the data was collected from medical records of this unit as from the register of the bacteriology service of ibn rochd university hospital. results: patients were hospitalized in the resuscitation service, of which had nosocomial infection, an incidence of . %. the mean age of the patients was years with male predominance (sex ratio . ), the average stay in intensive care was days. the site of infection was pulmonary in % of cases, blood in % of cases, urinary in % of cases, central catheter in %, neuro-meningeal in . % of cases. the germs isolated were: acinetobacter baumanii in . % of cases, pseudomonas aeroginosa in . % of cases, klebsiella pneumonia in . % of cases, enterococcus feacalis in . % of cases, e.coli in . % of cases and staphylococcus aureus in % of cases. acinteobacter baumanii showed resistance rates of up to % for the impenem and % for amikacin. regarding pseudomonas, it was resistant to impenem in % of cases and in % of cases to amikacin. compared to klebsiella, resistance to imipenem was % and % for amikacin. the mortality rate of infected patients was % conclusion: in the light of this work, we found that important emergence of multidrug resistance bacteria in intensive care unit is related to not only the immunocompomised state of patients but also to daily bad practices of health professionals such as the misuse of antibiotics. compliance with ethics regulations: yes. overnight culture of escherichia coli, klebsiella pneumoniae, staphylococcus aureus and pseudomonas aeruginosa, was also sequenced. results: twenty-four samples and the pc were analyzed. amplicon sequence analyses found similar results with the two primer pairs in % of cases. cultured pathogen was found in % ( / ) for human primer pair and in % ( / ) for earth primer pair. for each eta, ngs revealed bacteria unknown as pathogen globally identified as oropharyngeal flora in conventional microbiology (table ) . alpha diversity decreased for all vap patients overtime, average shannon . ( ; . ) versus ( . ; . ), and was higher in upper respiratory tract (os) versus lower respiratory tract (eta): average shannon . ( . ; . ) vs. . ( . ; . ) (ns). conclusion: this pilot study highlights the impact of s rdna amplification procedures (especially oligonucleotide sequences) used on the results in microbiome research. concordance between ngs and bacterial culture, as well as similar evolution of the alpha diversity than previously described ( ), enables us to validate our methodology using the "gut primers" pair f- r. these findings allow furthers major studies on the pulmonary microbiome of icu ventilated patients including comparison according to the occurrence of a vap or not. compliance with ethics regulations: yes. rationale: in the field of intensive care only few studies have explored bacterial microbiota whereas virome remained hardly considered. it appears essential to describe both evolution in mechanically-ventilated patients to improve the pathophysiological understanding of ventilator-associated pneumonia (vap) development. to date no study had been simultaneously conducted on lower respiratory tract with a single nucleic acid extraction before metagenomics analysis of bacterial microbiota and virome. we conducted a preliminary study to validate our methodology based on a common automated extraction of nucleic acids. patients and methods: twelve mechanically ventilated patients were selected: five who developped (vap) and seven controls (c) who did not. endotracheal aspirate (eta) were collected between intubation and day (or dvap for vap patients). conventional bacterial microbiology and multiplex respiratory viruses pcr were also performed. total nucleic acids were extracted using nuclisens easymag extractor. for the bacterial microbiota, region v of the s rrna genes was amplified. for the virome, the nextera dna xt kit (illumina) and rna seq trio kit (nugen) protocols were used to prepare viral dna and rna libraries. libraries underwent paired-end sequencing on the illumina miseq (bacteria) or nextseq- (virus) platform. after bioinformatics analysis we compared the performance of metagenomics analysis with conventional bacterial culture and other common viral detection methods. results: for culturable bacteria, concordance between conventional microbiology and sequencing was found in % ( / table . our preliminary results confirm the feasability of exploring both bacterial microbiota and virome on the same sample using a common extraction method. data from metagenomics were highly concordant with conventionnal detection methods for known pathogenic viruses and bacteria in lower tract respiratory sample and enables identification of other microorganisms. this is the first step for a large cohort study that aims to compare evolution of global lung microbiome in patients at risk of vap and assess how bacteria and virus interplay. compliance with ethics regulations: yes. references . clancy department of medical and toxicological critical care, lariboisière hospital one microorganism was isolated in . % and two in . % of cases. the main isolated microorganism were enterobacteriaceae in . % of patients. they were esbl-producers in . % of cases. initial antibiotic therapy was appropriate in . % of cases. factors independently associated with esbl-pe as the causative microorganism of icu-bsi were esbl-pe carriage prior to icu-bsi the sensitivity of esbl-pe carriage to predict esbl-pe as the causative microorganism of icu-bsi was . %, and specificity was . %. mortality at days was . % in the general population in multivariable analysis, there was no parameter which was independently associated to mortality at day from the occurrence of icu-bsi. conclusion: icu-bsi complicates . % of admission to icu and was associated with % in-hospital mortality assessing and applying individualized treatment for group a streptococcal necrotizing soft-tissue infection is possible service de réanimation médicale intensive care decompressive craniectomy in traumatic brain injury: about cases karama bouchaala sex ratio of . . the mean (sd) length of stay in icu was . ± . days. the mean glasgow coma score (gcs) (sd) was . ± . and gcs ≤ in . %. sofa score > was found in patients ( . %) and sapsii score ≥ in patients ( . %). the cerebral ctscan at admission showed acute subdural hematoma (asdh) in ( . %), cerebral oedema ( . %) and cerebral contusions ( %) teaching: fresenius medical care; patent or product inventor: gml czech republic banydeen rishika: no conflict of interest baptiste amandine: no conflict of interest baptiste olivier: no conflict of interest barbar saber davide: no disclosure barbier françois: no disclosure barbierlouise: trainings, teaching: ethicon, astellas; invitation to national or international congresses: sandoz, astellas barnerias christine: no disclosure baron aurore: no disclosure baron elodie: no conflict of interest barr att -due andreas: no disclosure barrau stephanie: no disclosure barraud damien: no disclosure barraud helene: no disclosure barrois brigitte: no conflict of interest baruchel andré: no disclosure bastide marie anaïs: no conflict of interest baudel jean-luc: no conflict of interest baudin florent: invitation to national or international congresses: dr baudin has received speaking fees from maquet critical care (epnv teaching: drager; invitation to national or international congresses: msd; hill rom beganton frankie: no conflict of interest begot erwan: no disclosure beinse guillaume: research support/scientific studies: association pour la recherche contre le cancer ion and fresenius kabi bensaid abdelhak: no disclosure bensardi fatimazahra: no disclosure benyamina mourad: no disclosure benzerara laurent: patent or product inventor: aphp benzerdjeb nazim: research support/scientific studies: amarape, icap; consultancy, expert: alphasights, msd; trainings, teaching: msd beqiri erta: no disclosure bÉranger agathe: no conflict of interest berard emilie: no conflict of interest berdai adnane: no disclosure berger patrick: no disclosure bernal william: no disclosure bernardin gilles: no disclosure berrada lina: no conflict of interest berthaud romain: no conflict of interest berthet guillaume: no conflict of interest berti enora: no conflict of interest bertoli sarah: no disclosure bertrand pierre-marie no conflict of interest besbes lamia: no disclosure besbes mohamed: no conflict of interest besch camille: invitation to national or international congresses: abbvie no conflict of interest boisseau chloé: no disclosure boissel nicolas: no disclosure boissier florence: no conflict of interest boivin alexandra: no conflict of interest bonacorsi stéphane: no conflict of interest bongiovanni filippo: no conflict of interest bonnardel eline: no conflict of interest bonnefoy-cudraz eric: no disclosure bonnet sixtine: no conflict of interest bonnevie tristan: research support/scientific studies invitation to national or international congresses: fresenius kabi and fresenius medi-calcare bucur petru: no disclosure buetti niccolo: research support/scientific studies: swiss national science foundation research grant and bangerter rhyner foundation supporting my postdoc bui hoang-nam: no disclosure burelli gabrielle: no conflict of interest burgel pierre-régis: no disclosure burghi g: no conflict of interest bustarret olivier: no conflict of interest butin-druoton anne-lise: invitation to national or international congresses expert: astra-zeneca; invitation to national or international congresses expert: hamilton medical; invitation to national or international congresses: hamilton medical chemli wael: no conflict of interest chenouard alexis: no conflict of interest cherkab rachid: no conflict of interest chevret sylvie: no disclosure chhun stephanie: no conflict of interest chiche jean-daniel: no disclosure chicoisneau maxence: no conflict of interest chlilek abdelaziz: no disclosure chocron richard: consultancy, expert: aspen chommeloux juliette: no conflict of interest chomton maryline: no conflict of interest chosidow olivier: no disclosure chouchana laurent expert: biotest; invitation to national or international congresses: sanofi research support/scientific studies: fresenius medical care; consultancy, expert: fresenius medical care; invitation to national or international congresses: xenios novalung, heilbronn, germany dachraoui fahmi: no disclosure dahoumane redouane: no conflict of interest dahyot-fizelier claire: no disclosure daix thomas: no conflict of interest daly foued: no conflict of interest damonti lauro: no conflict of interest dantan etienne: no conflict of interest darmon michaël: research support/scientific studies: msd no disclosure das vincent: no disclosure daubin cedric: no conflict of interest daubin delphine: no conflict of interest daudon michel: no disclosure daufresne pierre: no conflict of interest dauger stéphane: no conflict of interest daviet florence: invitation to national or international congresses: sandosz de courson hugues: no conflict of interest de jong audrey: trainings, teaching: baxter, medtronic; invitation to national or international congresses teaching: cardiosleep delhaes laurence: no disclosure delignette marie-charlotte: no conflict of interest dellamonica jean: trainings, teaching: medtronic; invitation to national or international congresses: msd, general electrics delpierre clément: no conflict of interest delville marianne: no conflict of interest demailly zoé: research support/scientific studies: srlf demarest elsa: no disclosure demaret pierre: no conflict of interest demiselle julien: no conflict of interest demondion pierre: no conflict of interest demoule alexandre: research support/scientific studies: drager, philips; consultancy, expert: baxter, respinor, lungpacer; trainings, teaching: fisher & paykel, hamilton, baxter; invitation to national or international congresses: fisher & paykel denis manon: no conflict ofinterest depeyre fanny: invitation to national or international congresses: pfizer deplante yvon: no conflict of interest dequin pierre-françois: research support/scientific studies: medimmune combioxin ferring pharmaceuticals a/s asahi kasei pharma america corporation derauglaudre lucie: no conflict of interest derbel karim: no disclosure derkaoui ali: no disclosure dervin krystel: no conflict of interest desaive thomas: no conflict of interest desguerre isabelle: research support/scientific studies: ptc inc, avexis; consultancy, expert: avexis, ptc inc, biogene; trainings, teaching: roche, ptc inc, avexis; invitation to national or international congresses: sarepta, biogen, avexis, biomarin desnos cyrielle: no conflict of interest desroys du roure françois: no conflict of interest detollenaere charles: no conflict of interest devaquet jérôme: invitation to national or international congresses expert: lungpacer; invitation to national or international congresses: lungpacer dreyfuss didier: research support/scientific studies: grant from french ministry of health drouot xavier: no disclosure du cheyron damien: no conflict of interest dubÉ bruno-pierre: consultancy, expert: novartis, gsk dubert marie: no conflict of interest dubost baptiste: no conflict of interest dubost jean-louis: no conflict of interest duburcq thibault: no conflict of interest duchemann boris: consultancy, expert: bms, msd, roche; invitation to national or international congresses no conflict of interest frÉrou aurélien: no conflict of interest fritz caroline: no disclosure fromentin mélanie: research support/scientific studies: msd; invitation to national or international congresses: msd frouin antoine: no conflict of interest frugier alexandre: no disclosure gaboriau louise: no conflict of interest gaci rostane: invitation to national or international congresses: bard gacouin arnaud: no disclosure gaddas mehdi: no conflict of interest gaillard arnaud: trainings, teaching: zoll medical gaimard sophie: no conflict of interest gainnier marc: no conflict of interest galbois arnaud: no conflict of interest galerneau louis-marie: invitation to national or international congresses: agir À domicile galicier lionel: consultancy, expert: novartis, eusapharma; trainings, teaching: baxalta, pfizer; invitation to national or international congresses no conflict of interest ichaÏ philippe: no conflict of interest imen sioud: no conflict of interest ioos vincent: no disclosure iserin franck: no disclosure issa nahema: no conflict of interest jaber samir: consultancy, expert: drager, fisher-paykel; medtronic; baxter xenios fresenius; invitation to national or international congresses: drager no conflict of interest jacq gwenaëlle: no conflict of interest jacquet emmanuelle: research support/scientific studies: unicancer (esme and storm studies invitation to national or international congresses: pfizer université laval-qc-ca labbe vincent: no disclosure labro laura: no disclosure lacaille florence: no conflict of interest lacampagne alain: no disclosure lacan claire: no conflict of interest lacherade jean-claude: no conflict of interest ladjemi maha-zohra: no conflict of interest lafon charles: no conflict of interest lafon marie-edith: no disclosure lafon thomas: no conflict of interest lagache laurie: invitation to national or international congresses advertising documents: philips; trainings, teaching: novartis, gsk, astra zeneca, boeringher; invitation to national or international congresses: chiesi, astra zeneca, sos oxygene, novartis, boeringher lamoth frédéric: consultancy, expert: gilead, msd, basilea; invitation to national or international congresses: msd expert: norgine; trainings, teaching: fujifilm, boston scientific lebreton guillaume: no disclosure lebrun-vignes benedicte: research support/ scientific studies: novartis; consultancy, expert: ansm lebuffe gilles: no disclosure leclerc maxime: no conflictof interest lÉcluse aldéric: research support/scientific studies: pgrx avc study; consultancy, expert: bms-pfizer, boerhinger ingelheim, bayer; invitation to national or international congresses: bms-pfizer, boerhinger ingelheim ledoux didier: no disclosure lefebvre francois: no conflict of interest macloughlin ronan: research support/scientific studies: aerogen ltd no conflict of interest mari arnaud: no conflict of interest marie damien: no conflict of interest marijon eloi: no disclosure mariotte eric: consultancy, expert: sanofi-aventis marjanovic nicolas: no disclosure marjanovic zora: no disclosure maroni arielle: no conflict of interest marot benoit: no conflict of interest marque sophie: no conflict of interest marti teaching: zambon, chiesi; invitation to national or international congresses no conflict of interest matusik elodie: no conflict of interest mauchien benedicte: no conflict of interest maury eric: research support/scientific studies: doran international, drager; trainings, teaching: vygon maxime virginie: no conflict of interest mayaux julien: invitation to national or international congresses stock shareholder: tanderev; patent or product inventor: tanderev mercat alain: research support/scientific studies: fisher-paykel, general electric; consultancy, expert: faron pharmaceuticals no disclosure merhabene takoua: no conflict of interest merle jean-claude: no disclosure mesotten dieter: no conflict of interest messaadi amenallah: no conflict of interest messika jonathan: invitation to national or international congresses: cslbehring; fisher&paykel metaxa victoria: no disclosure metogo mbengono junette arlette: no conflict of interest meunier anne: no conflict of interest meurice jean-claude: no disclosure meybeck agnes: consultancy, expert: janssen, gilead; 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consultancy, expert: msd, gilead, pfizer; invitation to national or international congresses: gilead, pfizer nesseler nicolas: no conflict of interest neviere remi: no disclosure nguyen alexandre: no disclosure nguyen khoa thao: no conflict of interest nicolau-travers marie-laure: no disclosure niÉrat marie cécile: no conflict of interest nieszkowska ania: no disclosure nigeon olivier: no conflict of interest nitel gautier: no conflict of interest nodea elena madalina: no conflict of interest noel marine: no conflict of interest nogier marie-béatrice: no disclosure noorah zaid: no disclosure nouira wiem: no conflict of interest noumeir rita: stock shareholder: softmedical noury norbert: no conflict of interest novy emmanuel: research support/scientific studies: msd; invitation to national or international congresses: pfizer expert: air liquide medical system ollivier veronique: no conflict of interest onimus thierry: no conflict of interest oppenheimer anne: invitation to national or international congresses: gedeon richter orkisz maciej: no conflict of interest orliaguet gilles: research support/scientific studies research support/scientific studies: oxynov; patent or product inventor: oxynov patrier juliette: no conflict of interest paugam catherine: no disclosure paul marine: no conflict of interest paul-bellon rachel: no disclosure paulo nicolas: no conflict of interest pavot arthur: invitation to national or international congresses: fresenius medical care france pehlivan jonathan: no conflict of interest peigne vincent: invitation to national or international congresses: air liquide pÉju edwige: no conflict of interest pene frédéric: consultancy, expert: alexion pÉpin-lehalleur adrien: invitation to national or international congresses: chiesi pere morgane: no conflict of interest pereira bruno: no disclosure perez didier: no disclosure perez pierre: no disclosure perez yonatan: no conflict of interest perier françois: no disclosure perin nicolas: no conflict of interest biomerieux robin emmanuel: no conflict of interest robin nicolas: no disclosure robineau olivier: no disclosure roch antoine: no disclosure roche anne: no conflict of interest roger claire: consultancy, expert: pfizer, fre-senius medical care; 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consultancy, expert: fresenius medical care france; invitation to national or international congresses: xenios novalung, heilbronn no conflict of interest sirault bruno: no disclosure sirodot michel: no disclosure slama michel: no disclosure slim amine: no disclosure smielewski peter: no disclosure soares marcio: stock shareholder: epimed solutions teaching: gilead; invitation to national or international congresses: pfizer spagnoletti marco: no conflict of interest steckelmacher claire: no disclosure stockx luc: research support/scientific studies: phenox, medtronic; consultancy no conflict of interest voiriot guillaume: research support/scientific studies: biomérieux, sos oxygène, janssen; consultancy, expert: biomérieux; invitation to national or international congresses: biomérieux von kietzell matthias: invitation to national or international congresses expert: aguettant; invitation to national or international congresses: vifor yacoubi wejden: no conflict of interest yager hélène: no conflict of interest yahya yosra: no conflict of interest yakini khalid: no disclosure yakouben karima: no disclosure yonis hodane: invitation to national or international congresses: lvl medical et pfizer younan romy: no conflict of interest youssoufa atika: no disclosure zacharia mahi: no disclosure zafrani lara: research support/scientific studies: jazz pharmaceuticals zambon olivier: no disclosure zaouak nadia: no conflict of interest zaouche khedija: no conflict of interest zarrougui wafa: no conflict of interest ze minkande jacqueline: no disclosure zeghdoud dalila: no disclosure zerbib yoann: no conflict of interest zerhouni amel: no conflict of interest zerhouni amine: no conflict of interest zerimech farid: no conflict of interest zerouali khalid: no disclosure zheng yi: no conflict of interest zimmerli stefan: research support/scientific studies: msd, pfizer, gilead; consultancy, expert: msd, pfizer; trainings, teaching: gilead; invitation to national or international congresses springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations farhat hached hospital, sousse, tunisia; yassminet regional hospital, ben arous, tunisia; habib bougatfa regional hospital, bizerte, tunisia; larabta hospital, tunis, tunisia; carthagene private hospital, tunis, tunisia; regional hospital of zaghouan, zaghouan, tunisia; regional hospital of tozeur, tozeur, tunisia; habib thameur hospital, tunis, tunisia correspondence: samia ayed (samia.ayed@yahoo.fr) ann. intensive care , (suppl ):p- geoffroy hariri, kyann hodjat-panah, laurene blum, jean-rémi lavillegrand, idriss razach, naike bige, jean-luc baudel, bertrand guidet, eric maury, hafid ait-oufella médecine intensive-réanimation, hôpital saint-antoine, paris, france correspondence: geoffroy hariri (geoffroyhariri@hotmail.com) ann. intensive care , (suppl ):p- rationale: hemolytic anemia (ha) is a common condition in intensive care unit but its diagnosis remains challenging. free hemoglobin (and heme) degradation leads to co release that can bind to hemoglobin to form carboxyhemoglobin (hbco). we hypothesized that hbco concentration could be used as a reliable diagnosis tool for ha. patients and methods: we performed a monocentric retrospective study in a -bed intensive care unit at st antoine hospital, paris, between and . all patients hospitalized for ha with arterial hbco dosage at admission were included. arterial hbco was measured in routine in our department with an il system ph/ blood gas analyzer. demographic and biological data were collected. a group control of patients with non-hemolytic anemia (hb < g/ dl) (nha) was also included. finally, we analyzed patients outcome according to hbco changes during icu stay. results: between and , patients with ha were included. nha patients were included in the control group. patients with ha were younger than patients with nha ( [ ; ] vs. [ ; ] years old, p = . ) but admission sofa was not different between groups ( [ ; ] , vs. [ ; ] , p = ns). among patients with ha, % had thrombotic microangiopathy, % had autoimmune hemolytic anemia and % had sickle cell disease. at icu admission, ha patients had higher hbco level than patients with nha ( . [ . ; . ] vs. . [ . ; . ] %; p < . ). hbco was a reliable biomarker of hemolysis (auc . ( . ; . ) p < . ). an hbco level threshold at . % identify hemolysis with a sensitivity ( - ) % and a specificity ( - ) %. in ha group, hbco was negatively correlated to hb level (r = . ; p < . ). in ha patients, changes of hbco level during icu management were associated with outcome, decreasing in survivors ( . [ ; . ] vs. . [ . ; . ] ; p = . ) but not in non-survivors ( . [ . ; . ] vs. . [ . ; . ] %; p = . ). conclusion: carboxyhemoglobin is a reliable diagnosis and prognosis biomarker for hemolytic anemia in icu compliance with ethics regulations: yes. rationale: thrombocytopenia is the most commonly hemostatic disorder encountered in intensive care, present in to % of patients. the mortality associated with this thrombocytopenia, the numerous pathological contexts associated with resuscitation and the lack of a recommended management strategy led to the establishment of these guidelines. the aim of our study was to determine the incidence, causes and risk factors associated with the occurrence of thrombocytopenia, as well as the impact of thrombocytopenia on the mortality and length of stay in the icu ibn medical resuscitation unit. rochd de casablanca, over a period of months. patients and methods: this was a prospective study, carried out in the medical resuscitation department of ibn rochd university hospital in casablanca over a period of months. there were two groups: ''sick'' group with thrombocytopenia with a platelets count < , / mm , and a ''control'' group without thrombocytopenia. patients with previous platelet disorders, hematologic malignancies, and patients undergoing chemotherapy were excluded. of the patients included, episodes of thrombocytopenia were identified, anoverall incidence of . %. sepsis was incriminated times ( . %), followed by ards in patients ( . %), massive filling in patients ( . %), disseminated intravascular coagulation in patients ( . %), and massive transfusion in patients ( . %). the drug origin was incriminated in patients ( . %). it was due to quinolones and imipenem. the mortality rate was deaths ( . %) which was inversely proportional to the lowest platelet count in the thrombocytopenia group, compared to deaths ( %) in the control group. the mean duration of stay in the thrombocytopenia group was ± days with extremes ranging from to days. conclusion: thrombocytopenia was a common abnormality in the intensive care system, it occured in many pathological situations and was a factor of morbidity and excess mortality. the most common etiology in this study was sepsis. the diagnostic and therapeutic approach depended on the particular clinical context in which thrombocytopenia occurs. its onset may constitute a hematological emergency, particularly when there is a major mucocutaneous and / or visceral hemorrhagic syndrome, which necessitates a rapid etiological diagnosis, and the establishment of an effective treatment, both symptomatic and specific. compliance with ethics regulations: not applicable. marc pineton de chambrun , romaric larcher , frédéric pene , laurent argaud , alexandre demoule , rémi coudroy , elie azoulay , yacine tandjaoui-lambiotte , stanislas faguer , alain combes , charles-edouard luyt , zahir amoura sorbonne université, aphp, hôpital la pitié-salpêtrière, institut de cardiométabolisme et nutrition (ican), service de médecine intensive-réanimation, paris, paris, france; rationale: catastrophic antiphospholipid syndrome (caps), the most severe manifestation of antiphospholipid syndrome (aps), is characterised by simultaneous thromboses in multiple organs. diagnosing caps can be challenging but its early recognition and management is crucial for a favourable outcome. this study was undertaken to evaluate the frequencies, distributions and ability to predict mortality of "definite/probable" or "no-caps" categories of thrombotic aps patients requiring admission to the intensive care unit (icu rationale: septic acute kidney injury (s-aki) is a frequent complication in critically ill patients and is associated with high morbidity and mortality. it is well known that chronic kidney disease increases the risk of pulmonary embolism (pe), but few studies have investigated the relationship between acute kidney injury (aki) and pe occurrence in septic patients. the aim of this study is to determine whether patients with aki are at increased risk of developing pe. patients and methods: were included, in a prospective study conducted over months (january -june , ) in a medical surgical intensive care unit, all the patients older than years with septic shock at admission or during hospitalization. two groups were compared: patients with kidney injury (aki+ group) and patients without kidney injury (aki− group). we studied the occurrence of pe in these two groups. results: we included patients. the mean (sd) age was . ( ± ) years. sex ratio was . . thirty one ( . %) patients developed pe. the occurrence of pe was significantly higher in (aki + group) [ patients ( %) vs. patients ( %); p = . ]. the incidence of pe according to kidney injury severity was patients ( %) kdigo i, patients ( %) kdigo ii, patients ( %) kdigo iii. in the aki+ group, pe was significantly associated with increased sofa score at admission ( points vs. points; p = . ), lower platelets count ( , vs. , ; p = . ), higher lacatatemia at septic shock day [ . vs. . mmol/l; p = . ] and higher c reactive protein level [ mg/l vs. mg/l; p = . ]. in a multivariate analysis the pe risk factors in (aki+ group) were thrombopenia (odds ratio = . ; ci [ . - . ], p = . ) and c-reactive protein value (odds ratio = . ; ci[ . - . ], p = . ). discussion: the increased risk for pe with aki may be due to endothelial involvement, vascular injury and the related changes found in procoagulant proteins (increased levels of fibrinogen, factor vii, factor viii, von willebrand factor, and plasminogen activator inhibitor- ). in our study, lower platelet and higher c reactive protein level were found in patients with pe, suggesting the participation of disseminated intravascular coagulation. these factors may contribute to increase pe risk. conclusion: the risk of pe is higher in septic patients with aki than in those with normal kidney function. therefore, because of paucity of evidence, larger studies are needed to understand pe pathway in septic aki and to establish efficient prophylaxis protocols. compliance with ethics regulations: yes. and of these patients ( . %) required intensive care. the lasted were males ( %) and a majority ( %) were younger than years of age. in intensive care patients, only ( . %) had nosocomial infection, majority were community acquired infections ( . %) with ( %) pneumoniae, ( . %) profound abscess, pyelonephritis ( . %), ( %) meningitidis. patients( %) required mechanical ventilation for days ( % ci - ), length of stay in icu was days ( % ci - ) and mortality rate was %. conclusion: hmkp infections lead young patients in intensive care unit in one third of case with a majority of pneumoniae requiring mechanical ventilation and with a high rate of mortality. furthers studies are needed to investigate the role of this particular strain in severity. compliance with ethics regulations: yes. rationale: infections secondary to snakebite occur in a number of patients, and are potentially life-threatening. bothrops lanceolatus bites in martinique average thirty cases per year and may result in severe thrombotic and infectious complications. we aimed to investigate the infectious complications related to bothrops lanceolatus bite. patients and methods: a retrospective single-center observational study over seven years ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) was carried out, including all patients admitted to the hospital due to bothrops lanceolatus bite. clinical and biological data were reported using the dx care, x-plore et cyberlab softwares of the emergency medicine and analyzed. one hundred and seventy snake-bitten patients ( males and females) were included. thirty-nine patients ( %) presented grade or envenoming. twenty patients ( %) developed wound infections. the isolated bacteria were aeromonas hydrophila ( cases), morganella morganii ( cases), group a streptococuss, and group b streptococcus (one case each). patients were treated empirically with third-generation cephalosporin (or amoxicillin/clavulanate), aminoglycoside and metronidazole combinations. outcome was favorable. the main factor significantly associated with the occurrence of infection following snakebite was the severity of envenoming (p < . ). our findings clearly point towards the frequent onset of infectious complications in b. lanceolatusbitten patients presenting with grade and envenoming. conclusion: infectious bite-related complications of bothrops lanceolatus account for approximately % of the cases, with a strong predominance for grade iii and iv. thus, based on the bacteria identified in the wounds; we suggest that empiric antibiotic therapy including third-generation cephalosporin should be administered to those patients on hospital admission. compliance with ethics regulations: yes. rationale: endocrine abnormalities have been reported with varying frequencies, following traumatic brain injury (tbi). few studies have examined the clinical features and outcomes of isolated acute thyrotropic hormone deficiencies after tbi. theaim of the study was to evaluate the early changes in thyrotropic hormone levels after traumatic brain injury (tbi) and to evaluate whether hormone changes are related to outcome patients and methods: we conducted a months long prospective cohort, including all patients admitted to a university hospital icu with moderate to severe traumatic brain injury (tbi), defined as a glasgow coma scale below twelve (gcs < ). blood samples for basal hormone values of thyroid-stimulating hormone (tsh) and free thyroxine (ft ) were obtained on days , , and . tsh serum concentrations were considered normal at > . mu/l; ft at > pmol/l. a thyrotropic insufficiency was defined as low ft and low tsh plasma levels. all patients were screened with a brain mri. patients were also monitored for neurological deterioration, including cognitive decline, convulsive seizures, increase in cerebral edema and brain herniation that were simultaneous to the diagnosis. results: during our study period's, trauma patients were admitted to our icu and met the inclusion criteria. on admission, our patients had a mean age at . ± , a mean injury severity score (iss) at ± , a mean abbreviated injury severity (ais) of the head at . ± . and a mean gcs at ± . of the patients a thyrotropic insufficiency was diagnosed in patients ( %) during the first days. the median delay to thyrotropic insufficiency diagnosis was days. in three of ( %), the thyrotropic insufficiency was nonrecovering during the patient's icu stay and was transient for the rest. none of the patients with acute thyrotropic insufficiency had direct hypothalamic or pituitary lesions on the brain mri. factors associated to the occurrence of acute thyrotropic insufficiency were: the ais of the head ( . ± . vs. ± . , p = . ), cerebral contusions ( % vs. %, p = . ), subarachnoid haemorrhage ( % vs. %, p = . ) and subdural haematoma ( % vs. %, p = . ). thyrotropic insufficiency was associated to neurological deterioration (p = . ) on the day of diagnosis but did not affect icu mortality ( % vs. %, p = . ). in this study, low pituitary-thyrotropic axis hormone levels were found in the acute phase of tbi and were associated to neurological deterioration but with no perceived effect on icu mortality. compliance with ethics regulations: yes. rationale: acute diabetes insipidus following head injury and its effect on patients outcome have not been sufficiently evaluated in large prospective studies. the aim of this study was to determine the incidence of acute cdi, delay of onset predictive factors and its impact on tbi patients. we conducted a prospective cohort, including all patients admitted to icu with moderate to severe tbi, defined as a glasgow coma scale (gcs) below twelve. for each tbi patient plasma sodium was measured daily, and if abnormally high, urine specific gravity and osmolality were measured. cdi was diagnosed using the seckl and dunger criteria. acute cdi was defined as cdi diagnosed in the first week following injury. all patients were screened with a brain mri. results: during our study's period, trauma patients were admitted to our icu, presented with moderate to severe tbi and were included. on admission, our patients had a mean age at . ± , a mean injury severity score (iss) at ± , a mean abbreviated injury severity (ais) of the head at . ± . and a mean gcs at ± . twenty-three percents ( patients) of the patients developed hypernatremia and % ( patients) were diagnosed with acute cdi. in of ( %), the cdi was nonrecovering. the median delay to develop transient cdi was h and for non-recoviring cdi was h (p = . ). none of the patients with acute cdi had direct hypothalamic or pituitary lesions. factors associated to the occurrence of acute cdi were: younger age ( ± vs ± , p = . ), neuro-surgery ( % vs. %, p < . ), hemorrhagic shock ( % vs. %), p < . ), cerebral edema ( % vs. %), p < . ), and fractures to the base of the skull ( % vs. %, p = . ). patients who developed cdi had a significantly higher mortality than those who did not ( of ( %) vs. of ( %), p < . ). there were no difference in terms of mortality between non-recovering and transient cdi ( % vs. %, p = . ), similarly the onset of cdi did not affect mortality ( h vs. h, p = . ). patients with acute cdi had poor glasgow outcome scale ( ± . vs. . ± . , p < . ) and longer icu los ( ± vs. ± , p = . ). conclusion: acute cdi is associated with higher mortality and poor outcome. therefore it is essential to diagnose and treat it promptly and correctly. compliance with ethics regulations: yes. acute glucocorticoid deficiency following traumatic brain injury mariem dlela, rania ammar zayani, abir bouattour, najeh baccouche, mounir bouaziz habib bourguiba hospital, sfax, tunisia correspondence: mariem dlela (mariem @gmail.com) ann. intensive care , (suppl ):p- rationale: published data demonstrates that long-term hypopituitarism could be common after traumatic brain injury (tbi).however, few studies focused on radiological, clinical, and repetitive endocrine assessment in the acute phase. the aim of the study was to evaluate the early changes in the adrenal axis following (tbi) and to evaluate whether hormone changes affect patient's outcome. we conducted a prospective study, including all patients admitted to a university hospital icu with moderate to severe traumatic brain injury (tbi), defined as a glasgow coma scale below twelve (gcs < ). each patient underwent sequential measurement of plasma cortisol (pc) on days , , and after tbi. we defined adrenal insufficiency as pc less than ng/ml. patients who received glucocorticosteroid therapy were excluded. outcome was measured by incidence of death, and glasgow outcome scale (gos) on day thirty. souhila sadat, dalila zeghdoud, dalila bougdal, kamel guenane ehs salim zemirli, alger, algeria correspondence: souhila sadat (sadatsouhila@hotmail.fr) ann. intensive care , (suppl ):p- rationale: the renewed interest in the pathophysiology of severe traumatic brain injury (tcg), allowed the understanding of the pathophysiological mechanisms leading to neuronal death.the non-invasive, easy, patient-based technical dtc allows evaluation of cerebral blood flow. purpose of the study: to determine the contribution of transcranial doppler (dtp) in the prevention of post-traumatic ischemia. patients and methods: a monocentric, observational, prospective study over a period of years, including tcg in the monitoring of cerebral blood flow (dsc) was provided by the dtc. we collected the following data: age, gender, lesion mechanism, lesion association, glasgow score at admission, time to perform the initial scan, time to perform the initial doppler, various abnormalities found at the initial dtp, the analysis of the level of map according to each situation of cerebral blood flow, the proposed therapies, the time to obtain a correct dtc. ( %), the statistical analysis showed no difference between the delay in setting up a hypohemia and the presence of a correct cerebral blood flow (p = . ), the statistical analysis of the map in the dtc group hypohemia compared to the correct dtc group objectified the absence significant difference between the two groups. the realization of dtp allowed therapeutic prioritization, the introduction of norepinephrine was in % of cases, osmotherapy in % of cases, optimization of sedation in . % of cases, the introduction of penthotal in . % of cases and the completion of decompressive in . % of cases. statistical analysis of mortality showed a significant difference in mortality (p = . ) in the hypohemic dtc group compared with the correct doppler . conclusion: ttc is an essential monitoring tool of cerebral hemodynamics, which may in prove the neurologic outiome of tcg. compliance with ethics regulations: yes. rationale: hyponatremia is a frequent electrolyte disturbance in hospitalized patients. it is particularly common in brain-injured patients with significantly elevated morbidity and mortality. the aim was to study the prevalence of hyponatremia in the acute phase of post-traumatic cerebral aggression, its degree of severity, its predictive factors as well as its prognostic impact in the population of post-traumatic brain injury. patients and methods: this is a retrospective study, carried out over a period of years about all traumatized head patients who developed hyponatremia during the first h of their stay. the descriptive part treated all patients who developed hyponatremia by detailing its different stages of severity.the analytical part treated the patients who developed a hypo-osmolar hyponatremia with a threshold of mmol/l retained to define the severity. during the study period, the incidence of hyponatremia in head trauma patients was . %. the occurrence of hyponatremia was associated only with the occurrence of early seizures (p = . ).severe hyponatraemia was associated with paroxysmal occurrence (p = . ), mass effect (p = . ), and hemostasis disorders. the multivariate study revealed that severe hyponatremia was associated with the glasgow score (p < . ) and pupillary changes (p = . ). on the other hand, it is the initial variation in serum sodium that was associated with both the severity of the initial neurological examination; glasgow (p < . ), saps (p = . ), pts (p = . ) and prism scores (p = . ), haemodynamic instability (p = . ) and neurovegetative disorders (p = . ). lesional features have also been found.regarding the prognosis, the occurrence of initial hyponatremia had a protective effect: a more favorable gos score p = . and a lower mortality (p = . ). a poor neurologic prognosis as well as a high mortality were associated with the most severe hyponatraemia and particularly with the initial variation of the sodium level (p = . ;). the mortality was . %. it was also particularly related to the initial change in sodium levels (p < . , . ). we concluded that there is no association between post traumatic early hyponatremia and the severity of the initial clinical presentation. however, the depth of hyponatremia and especially the initial change in sodium levels have been associated with more severe clinical pictures and a more limited prognosis. compliance with ethics regulations: yes. rationale: post-traumatic epilepsy (pte) is one of the complications described in the aftermath of headtrauma. its incidence is variable in the literature because of its clinical polymorphism. objectives of the study was to analyze the epidemiological profile (clinico-biological, radiological, therapeutic and evolutionary) of the patients having presented pte and to determine the risk factors for this pathology by comparing them with the rest of the traumatized brain patients. patients and methods: our study was retrospective. it was conducted in the intensive care unit (icu) of our university hospital between and . were included in our study all patients admitted to the service with brain injury and a glycaemia above mmol/l during the first h post-trauma. results: the incidence of pte was . %. ( among ) the average age was . ± . years. the sex ratio was . . the average of gcs was . ± . . three ( . %) patients had initial motor impairment. seizures were observed in ( . %) patients during the first h of hospitalization. the mean delay of occurrence of pte was ± . months. pte was diagnosed before the end of the first post-traumatic year in patients ( % of cases). the most commonly observed brain lesions were cortical brain contusions ( rationale: electrolytic disorders are common in neuro-resuscitation, especially dysnatremias and dyskalemias. hyponatremias are the most frequent, including the main etiologies: the syndrome of inappropriate secretion of antidiuretic hormone (siadh) and the "cerebral salt wasting" syndrome (csw). diabetes insipude of central origin secondary to a lack of dha secretion is the second most common disorder. patients and methods: it is a prospective study, analysing all the brains injured admitted to the a intensive care unit of chu hassan in fez, morocco. study spread over a -month period from / / to / / . the objective of the study is to detect the most frequent hydro-electrolytic disorders and to evaluate the therapeutic effectiveness of the service protocols. results: all these brains injured have caused he disorders over a period of time varying between d and d : * cases of hyponatremia ( %)/ cases of hypernatremia ( %), * cases of hypokaliemia ( %)/ cases of hyperkaliemia ( %), * cases of hyperchloremia, or %/ cases of hypochloremia ( %). * cases of diabetes insipidus, or . %. * cases without he disorder ( . %). the treatment for these disorders was: *for hypona; it reached mmol/l, initially corrected by a -hour water restriction, followed by an increase in the basic ration and furosemide boluses according to the ecv, even sodium loads for a single case of salt loss syndrome, while the main etiology remains the siadh. *for hyperna, it has reached mmol/l, evaluated by the extracellular volume, corrected by enteral tap water after calculation of the hydric deficit. if hperna is associated with polyuria greater than cc/kg/h; we speak of: *insipude diabetes, with polyuria up to cc/kg/h, compensated with potassium-containing solutions and blood ionogram monitored every h. desmopressin was used in titration, by bolus of . µg, with a diuresis objective between and . ml/kg/h. *for hypokalemia, up to . g/dl, observed mainly in the acute phase of brain aggression, corrected by increase in br for a k between . and g/l, and by potassium loads if k below . g/l. the evolution: deaths or . % ( cases of uncorrected diabetes insipidus), the restriction of disorders were corrected. conclusion: a knowledge of the hydroelectrolytic disorders encountered in this context is essential, as well as the implementation of a diagnostic and therapeutic protocol, which will reduce the time required to correct these disorders. compliance with ethics regulations: yes. . ] u/h). however, workload was increased under star ( vs. measurements per day), as expected from measurement interval difference between star ( -hourly) and the sp ( -hourly). conclusion: this unique patient-specific risk-based dosing approach gc framework was successful in controlling all patients safely and effectively. these preliminary results are encouraging and show gc can be achieved safely and effectively at lower target bands. in turns, these improved gc outcomes could improve patient outcomes. compliance with ethics regulations: yes. rationale: although its incidence has declined in recent years, gastric cancer remains common worldwide and is the leading cause of gastrectomy. his treatment is mainly surgical, but his prognosis remains poor. many studies on survival and prognostic factors have been carried out in foreign series. patients and methods: this is a retrospective study covering a period of three years from january to december interesting patients who had a gastrectomy and hospitalized in emergency resuscitation department surgical uhc ibnou rochd from casablanca. the statistical analysis of the different clinical, paraclinical and therapeutic data was carried out thanks to an exploitation sheet. rationale: gram-negative bloodstream infections (gnbsi) require timely appropriate antimicrobial therapy in intensive care units (icu) patients. conventional techniques usually take - h for antimicrobial susceptibility testing (ast). innovative approaches (accelerate pheno ™ system) provide pathogen identification in ~ h and ast including minimal inhibitory concentrations (mics) in ~ h. we report, in icu patients with gnbsi, results of implementation of the accelerate pheno ™ in our laboratory. we prospectively screened all gnbsi episodes reported in adult icu patients between september and september . to allow integration into the laboratory workflow, the accelerate pheno ™ was run on blood bottles positive before am (day ), in parallel with routine procedures: maldi-tof identification after short incubation on solid media (day ), β lacta (bio-rad ® ) test (day ) and disk diffusion method for ast (day+ ). for each episode, antimicrobial regimen was reassessed by a multidisciplinary team of bacteriologists, infectious diseases and icu physicians by the end of day . we measured: (i) concordance of accelerate pheno ™ results with conventional techniques, (ii) number of antibiotic adaptations on day and (iii) number of patients within the therapeutic range (free fraction over x mic and below concentration at risk of adverse events), based on real-time measurement of beta-lactams concentrations. results: of patients reported with gnbsi over the study period, were included. mean age was of ± . years, / were males. main sources of gnbsi were pulmonary (n = ) and digestive (n = ). bacterial identification of the accelerate pheno ™ was concordant with standard techniques in ( %): enterobacteriacae (n = ), pseudomonas aeruginosa (n = ). overall categorical agreement for ast was of % ( errors including very major errors). by the end of day , the antibiotic regimen was de-escalated in ( %) patients, which was appropriate in ( %). in cases, de-escalation was possible, but not fulfilled by icu physicians. twenty patients had beta-lactams concentrations measurements: were in the therapeutic range, below and over. conclusion: accelerate pheno ™ provided rapid and accurate results for most microorganisms isolated in blood cultures of icu patients with gnbsi. however, in a laboratory with routine maldi-tof early identification and β lacta test performed on day , the impact on early adaptation of the antibiotic regimen was evident in around patient over . compliance with ethics regulations: not applicable. jean-luc baudel , jacques tankovic , redouane dahoumane , jean-remy lavillegrand , razach abdallah , geoffroy hariri , naike bige , hafid ait-oufella , nicolas veziris , eric maury , bertrand guidet service bactériologie, hôpital saint-antoine, paris, france; service réanimation médicale, hôpital saint-antoine, paris, france correspondence: jean-luc baudel (jean-luc.baudel@aphp.fr) ann. intensive care , (suppl ):p- rationale: evaluation of the accurateness of the accelerate phenotest bc kit for rapid analysis ( . h for microorganism identification and additional hours for antibiotic susceptibility testing) of positive blood cultures from icu and hematology patients. patients and methods: from february to august , we included patients from the icu and hematology units with positive blood cultures. the following informations were collected : gender, age, duration of prior antibiotherapy, source of the infection, results obtained by conventional microbiological methods and by phenotest (data obtained and time to obtention of results). informed consent was obtained from all patients. results: blood cultures were analyzed in patients (m/f ratio . , age . ±, from the icu and from hematology). % of the patients were receiving antibiotics at the time of blood culture collection (mean duration : . days). the source of infection was unknown in % of cases, urinary in %, catheter-related in %, ascites in %, pneumonia in %. in cases ( %), there was a perfect match between phenotest and conventional results (identification and antibiotic susceptibility testing). in cases ( %), the bacterium responsible was not present in the phenotest panel. in cases ( %), phenotest identification was correct, but some discrepancies were observed regarding antibiogram. in cases ( %) phenotest identification was again correct but no antibiogram was available. in cases ( %), where two bacteria were present, phenotest could not identify one of them. in cases, phenotest did not provide bacterial identification because too few bacteria were present in the blood culture bottle. conclusion: the phenotest panel covered % of the bacteria implicated in this study. when the bacterium responsible was present in the panel, the results given by the phenotest correlated in % of cases with those of conventional methods. some rare discrepancies were observed regarding antibiotic susceptibility testing that have to be analyzed further. in the remaining % of cases, where too few bacteria or two different bacteria were present in the blood culture bottle, technical limitations did not permit to correctly identify microorganism(s) present or to obtain an antibiogram. compliance with ethics regulations: yes. mélanie fromentin, antoine bridier-nahmias, constance vuillard, jean-damien ricard, damien roux inserm umr iame infection antimicrobials modelling evolution, paris, france correspondence: mélanie fromentin (mel.fromentin@wanadoo.fr) ann. intensive care , (suppl ):p- rationale: studying human lower respiratory tract microbiota by using ngs (new generation sequencing) method is complex because of many unexpected biases due to dna extraction and amplification procedures. lung microbiota evolution under mechanical ventilation evolution may be highly informative to evaluate the actual risk of vap (ventilator-associated pneumonia) development. before starting a large study on the lung microbiome of ventilated icu patients, a methodological study was mandatory. patients and methods: five control and three vap patients were selected. endotrachealaspirate (eta) and oropharyngeal swab (os) were collected at icu admission for control patients and, days before and on the day of vap diagnosis for vap patients. after automated extraction of total dna, hypervariable region v of the s rdna genes was amplified with two different pairs of primers f- r: oligonucleotides from the earth microbiome project (earth primer pair) and from the gut microbiome project (gut primer pair), followed by sequencing on illumina miseq plateform. after bioinformatics analysis with mothur ® software, we compared the performance of ngs alongsideconventional bacterial culture. differences in alpha diversity (microbial diversity in a sample), expressed as the shannon index, across respiratory tract site (upper or lower) and across time (before and at vap time) has been investigated. a positive control (pc), rationale: colistin is used as a last-line treatment to combat multidrug-resistant (mdr) gram-negative bacilli (gnb). worryingly, colistin resistance in klebsiella pneumoniae, pseudomonas aeruginosa and acinetobacter baumannii is increasingly reported worldwide. we hereby report the prevalence of colistin resistance among gnb isolated from burn patients in tunisia. the study was carried out on strains of gnb isolated from microbiological samples of burn patients hospitalized in the intensive care unit between october and december . identification was performed by conventional methods. antimicrobial susceptibility was tested by disk diffusion method and the results were interpreted according to ca-sfm guidelines. minimum inhibitory concentration (mic) of colistin was determined using the eucast broth micro-dilution method (umic, biocentric ® ) results: pseudomonas aeruginosa was the most frequently isolated bacteria ( strains), followed by acinetobacter baumannii ( strains) and klebsiella pneumoniae ( strains). the most common sites of isolation were blood cultures ( %), catheters ( %) and skin samples ( %). most of p. aeruginosa isolates were multidrug-resistant with high levels of resistance to imipenem ( . %), ceftazidime ( %) and ciprofloxacin ( . %). however, all of them were susceptible to colistin. in fact, mics of colistin against all p.aeruginosa isolates were less than or equal to . mg/l. a. baumannii strains had high resistance rates to beta-lactams : % to ceftazidime and % to imipenem. only one strain was resistant to colistin with a mic equal to mg/l. all k. pneumoniae isolates were resistant to extended-spectrum cephalosporins. one third of these strains were resistant to imipenem and more than half ( . %) were resistant to amikacin. two strains were resistant to colistin with high mics (> mg/l). both were carbapenemase-producers, carrying oxa- and ndm carbapenemase encoding genes. conclusion: these data suggest that colistin-resistant or pan-drug resistant gnb clinical isolates are still relatively rare. however, they have important global public health implications because of the therapeutic problems they present, especially for vulnerable populations such as severely burned patients. hence the need to test colistin regularly in the laboratory and to set up a monitoring program for mdr pathogens. compliance with ethics regulations: yes. rationale: descending necrotizing mediastinitis (dnm) are medicosurgical emergencies whose forecast is closely related to the precocity of the therapeutic assumption. the purpose of our work is to profile these patients as well as the therapeutic and evolutionary aspects. patients and methods: retrospective study over years in the intensive care unit of the hospital august. all patients with dnm on cervicofacial cellulitis were included. results: cases were collected, % of cellulitis, incidence of . patients / year. average age , sex ratio of . . smoking, chronic alcoholism and diabetes are the most common antecedents. the favoring factors were: (poor dental conditions: % of cases, non steroidien anti-inflammatory drugs: %, diabetes: %). in % of cases the front door was dental. average time taken to take care of days. c-reactive protein and procalcitonin were positive in all patients. in % the chest x-ray was normal. all patients received tri-antibiotic therapy. intubation were difficult in all patients, we used nasofibroscope in % of cases and a rescue tracheotomy in one patient. only one patient had a cervico-thoracic surgical approach; for all the others she was cervical alone. streptococcus was the most isolated germ. the complications were (septic shock: %, ards: %). the average hospital stay was days with a mortality rate of %. conclusion: dnms are poorly prognostic. the best treatment remains prevention by better management of dental abscesses and tonsillar phlegmons. rationale: the initial, empirical antibiotic therapy of ventilator-associated pneumonia (vap) is often based on timing of its occurrence in relation to the onset of mechanical ventilation. this is due to reported differences between causal pathogens associated with early-onset (e-vap < - days of mechanical ventilation) compared to late-onset vap (l-vap ≥ - days of mv). e-vap is most often reported to be due to antibiotic-sensitive pathogens while l-vap is frequently attributed to antibiotic-resistant pathogens. however, there is emerging evidence that the isolated microorganisms may be similar regardless of onset time. the aim of our study was to compare the clinical outcomes of critically ill patients developing e-vap and l-vap and to compare the causative pathogens of the two groups. patients and methods: all the patients with the diagnosis of vap admitted between january and december were retrospectively included. vap was suspected on the basis of clinical and chest x-ray findings. the identification of the causative organisms was performed with endotracheal aspirate (eta) cultures. results: ninety patients developed vap. e-vap was observed in patients ( , %), whereas patients ( , %) developed l-vap. among patients with early-onset vap, % received antibiotics prior to the development of pneumonia, compared to % with late-onset vap (p = . ). otherwise, no differences (sociodemographic factors, antecedents, severity score, length of stay, length of mv) between the two groups were observed. the most common pathogens associated with e-vap were enterobacter species ( . %), pseudomonas aeruginosa ( . %) and oxacillin-resistant staphylococcus aureus (orsa , %). enterobacter species ( . %), acinetobacter baumannii ( . %) and pseudomonas aeruginosa ( %) were the most common pathogens associated with l-vap. no difference was noted in the contribution of multidrug resistant bacteria mdr ( % vs. %). hospital mortality was significantly greater for patients with l-vap caused by mdr ( %) compared to patients with e-vap ( %) (p = . ). conclusion: this classification is no longer helpful for empirical antibiotic therapy, since both early-onset and late-onset vap were caused by mdr bacteria. this justifies the need of intensive care unit-specific knowledge of causal agents associated with vap to reduce the rate of administration of inadequate antimicrobial therapy. compliance with ethicsregulations: yes. key: cord- -ak pq authors: nan title: th european congress of intensive care medicine athens - greece, october – , abstracts date: journal: intensive care med doi: . /bf sha: doc_id: cord_uid: ak pq nan objectives: evaluate the levels of tnf, il- and pai-i in different moments of the ards and the possible relationships among them. methods: septic patients with ards were studied. also significant differences for: tnf, pai-i and il- in septic patients and both evaluations of ards with control gropup; pai- between septics and nd evaluation in ards, and between the ist and nd evaluation in ards; il- between septics and both evaluations in ards; and il-~ in both evaluations in ards patients in relation to mortality. conclusions: i) elevations of tnf, pai-i and il- , with clinical signs, are suggestive of infection; ) the persistent and progressive elevation of pai-i with any clinical criteria may suggest evolution to ards; ) due to its own kynetics, il- takes part later in the acute phase, its levels being related to the magnitude of the injury in the tissues. objectives: the influence of long-term volume therapy with different solutions on plasma levels of circulating adhesion molecules was studied. methods: according to a randomized sequence, patients with sepsis secondary to major surgery exclusively received either hydroxyethylstarch solution ( % hes, mean molecular weight (mw) , daltons, degree of substitution (ds) . ) or human albumin % (ha) for volume therapy for days. plasma levels of circulating (soluble) adhesion molecules (endothelial leukocyte adhesion melecule- [selam -i] , intercellular adhesion molecule- [sicam -i] , vascular cell adhesion molecule- [svcam -i] , and p-selectin ) were serially measured on the day of admission to the intensive care unit (='baseline ' value) and during the next days. results: selam-i, sicam-i, and svcam-i plasma levels were markedly higher than normal at baseline in both groups. in the hes-patients, selam-j decreased to normal range, whereas it further increased in the ha-group (from • to • during the study period, sicam-i and svcam-i plasma levels remained unchanged in the hes-patients, but further increased in the ha-group (from • to , • sgmp- increased significatly only in the ha-group ( • to • only pao /fio was significantly correlated to plasma levels of adhesion molecules. conclusions: sepsis is associated with markedly elevated plasma levels of adhesion molecules indicating endothelial activation or damage. by long-term volume therapy with hes, these levels remained unchanged or even decreased, whereas volume therapy with human albumin did not have any beneficial effects on soluble adhesion. central venous catheters are frequently used in the care of the critically ill patient. the incidence of catheter related sepsis varies in the literature. we investigated the occurrence of contamination and sepsis compared to results of the epic study as part of quality assesment in our intensive care unit. from january until august all removed central venous catheters were examined for microbiological culture. the patients who showed signs of sepsis were also registered. the results of the contaminated catheters and septic patients were compared with results from the epic study. during the month period , patients were hospitalized on our intensive care unit. central venous catheters were examined for microbiological culture. specimens appeared to be possitive ( %). patients showed clinical signs of sepsis. the incidence of sepsis due to contaminated central venous catheters was / ( %). the incidence of sepsis due to the presence of all central venous lines was / ( %). the microorganisms responsible for the sepsis syndrom were : stapylococcus aureus (n= ), escherichia colt (n= ), others (n= ). in the epic study the percentage for sepsis on the icu was . % for the netherlands and . % for europe. despite a high number of positive culture from removed intravascular lines, a low percentage of sepsis was seen compared to results of the epic study. we recommend routine bacteriological culture of all removed central venous lines and recommend to look at colonization and sepsis due to intravascular lines as a measure of quality control in the intensive care unit. objectives: prognostic assessment of simplified acute physiology score (saps) in granulocytopenie patients with septic shock (ss). methods: the medical records of admissions to an intensive care unit (icu) of granuloeytopenic patients with ss are reviewed. fiftytwo patients had haematological malignancies. seven patients had aplastie anaemia. patients were categorised as survivors (discharged from icl and non-survivors (died in the icu). saps index was calculated for patients daily during their stay in icu. all patients were severe granulocytopenic (total white cell count less than , ] ] ). results: five patients ( , %) were discharged from icu. fifty-four patients died in icu. non-survivors had saps on admission higher than survivors ( . + . and . + . , respectively, p< , , mann-whitney u test). no patient with a saps greater than survived. mortality among the patients with saps from to was , %o. the evolution of ss was rapid. the mean stay in icu among non-survivors was only hours. an analysis of the saps index on admission of non-survivors showed an inverse correlation with the duration of their stay in icu (r=- , , p= . ). all survivors recovered from granulocytopenia. they had normal white cell counts at the time of discharge from icu. there was inverse correlation in survivors between saps and white cell counts, when these parameters were evaluated daily. however, the saps index alone cannot be considered to be on individual predictor factor of mortality. patients who had failure of the malignancy to respond to chemotherapy and who had persistent granuloeytopenia died in icu despite saps index on admission and recovery from ss. conclusion: saps index greater than , failure of the malignancy to respond to chemotherapy and persistent leueopenia all point to a poor outcome of granulocytopenie patients with ss. introduction: antipyretics sometimes are used for fever control in febrile neutropenic patients with hematological malignancies(hm). we observed a dramatic fall of blood pressure(bp) and development of septic shock(ss) in some of the patients who received antipyretics. aim: to clarify can antipyretics provoke ss in neutropenic patients with infection. methods: retrospective review of medicat records of neutropenic(wbc < , / )patients with hm, admitted to the intensive care unit for ss, was performed. there was selected group of patients receiving antipyretics shortly before a fall of bp. results: there was a definite causal relationship between receiving antipyretics and fall of bp in from patients. all patients had fever due to infection and had normal level of bp before receiving antipyretics. hypotension developed within minutes up to , hours after administration of antipyretics. three patients received , g of metamisol and one , g ofparacetamol per os. in all cases we observed dramatic diaphoresis and the temperature fall to subnormal level ( . + . ~ accompanied'by hypotension. but in - hours the fever was coming back without blood pressure elevation. the fluid replacement was controlled by central venous or wedge pressures. there were required + ml colloid and cristalloid solutions for volume loading. in spite of fluid administration the hypotension persisted and all patients required inotropic therapy. only one patient survived and is alive now. conclusion: it seems to us that our data offer to state that antipyretics administration can initiate ss in febrile neutropeuic patients with infection. objectives: to assess the agreement between cardiac output (co) measured by odm t and by other methods used in icu patients. methods: we prospectively studied adu t patients requiring hemodynamic monitoring with a pulmonary artery catheter. an esophageal doppler monitor provided measurements of co (odm), stroke volume and flow time (ft) used as an indirect evaluation of patient's volume status. patient hemodynamic status was evaluated by a modified fast response pulmonary artery catheter (baxter health care corporation, santa ana, ca), allowing co measurements by thermodilution "d) and an evaluation of right ventricular ejection fraction and end diastolic volume (rvef and rv-edv). in the last six patients co was measured by transthoracic echocardiography (echo) and oxygen consumption was measured by a deltatrack ii metabolic monitor (datex) allowing co calculation according to the fick formula (fick). the agreement between methods measuring co and their reproducibility, were evaluated by bland and altman analysis. results: agreement between co measurements is expressed as bias (d) and % limits of agreement (l of a = d_+ sd . td-fick - . - . to . fick-echo . - . to . there was no correlation between ft and rv-edv. conclusions: although co measurements by odmil had the best reproducibility, the limits of agreement between the four methods tested were unacceptable for clinical purposes. further investigation is required in order to improve the accuracy of co measurement in the icu. phd, a. paltzev, v.bajbikov, b.dobryakov d.sc., a.ostanin phd, o.leplifia phd, h.chernykh phd munieip. hosp. n l, n ; inst. of clin. immunol., novosibirsk, russia objectivies: efficiency of native cytokines used in the treatment of patients with severe surgical infections has been studied. methods: for two years patients were treated with cytokine mixture (ssp) obtained by arterio-venous perfusion of swine spleen and contained the following cytokines: il- , il- , il- , tnfa, ifny, gm-csf. results: ssp intravenous infusions were shown to accompany with mortality decrease from . % to . % in patients with abscessed pneumonia and lung abscesses and from % to % if disease course was complicated with sepsis. in patients with purulent peritonitis and sepsis efficiency of ssp was decreased due to endotoxieosis. thus, we used adoptive immunotherapy with mnc activated in vitro with ssp or recombinant il- . intravenous infusions of such cells resulted in transformation of a pathologic process from destructive into productive one. moreover, clinical manifestations of sepsis were controlled in % and mortality was decreased from % to %. conclusions: the use of eytokines themselves as well as cytokine-treated lymphoeytes permits to control the disease and leads to the mortnlity decrease owing to stimulation of host defence mechanisms. background: although red blood cell transfusions (rbct) are used to increase oxygen availability in septic patients, several lines of evidence suggest that rbct may actually worsen tissue hypoxia. thus, rbct may negatively influence outcome of septic patients. objectives: to determine the association of ) rbct ; ) number of units transfused; and ) mean age of the units transfused on the first day of transfusion with mortality of critically ill septic patients. methods: we prospectively identified patients who met strict criteria for sepsis syndrome (ss) seen in the icu of st. paul's hospital from to and excluded patients who died in the first days after the onset of sepsis. we recorded clinical characteristics, multiple system organ failure score, and apache ii at onset of sepsis. then, we retrospectively recorded the total number and age of rbc units transfused during the first days after onset of sepsis. overall -day mortality was %. results: the main results are shown in the table. the mortality of patients who received rbct was nearly double the mortality of those who did not receive rbct even after adjusting for severity of illness using apache ii. objectives: gastric mucosal acidosis is frequently observed in patients with sepsis. the aim of this study was to determine whether volume infusion using pentaspan| decreases abnormal gastric mucosal pco (pico ) in patients who have sepsis syndrome (ss) who have already been resuscitated using clinical endpoints. methods: we prospectively identified patients who met strict criteria for ss, had a pulmonary artery catheter and a gastric tonometer in place, and pico > mmhg. pentaspan| ( ml) was infused in rain. measurements of hemodynamics, hemoglobin, arterial lactate, blood gas analysis, and pico were performed before and repeated miff and hr after pentaspun| infusion. we calculated the pico -arterial pco' difference (pico -paco ) and phi (using henderson-hasselbach equation). anova was used to assess statistical significance. results: all patients werereceiving adrenergie drugs. map was : : mmhg and lactate . : : . mmol/l. pentaspan| increased ci by % (p< . ) but did not change pico ( and increase m oxygen o* wery were simimny achieved in both groups. nevertheless, epinephrine was associated with a lactic acidosis and increased laetate/pyruvatemia ratio (l/p) that evoke a dysoxia rather than a metabolic effect. an higher gastric mucosal pco in the ep group compared to nor-rob suggests the hypothesis of an anaerobic production of co in favor of a splanchnic hypoxia. in both group, arterial ketone body ratio that reflects hepatic mitochondrial redox state, compared to a control group without shock was decreased but increased between and hours after restoration of arterial pressure. the association norepinephrine-dobutamine seems to be better for splanehnic circulation than epinephrine and should be used for dopamine resistant septic shock. moreover, the increase in arterial pressure with nor-dob improved gastric mueosal ph and hepatic mitochondrial redox state and argue to reconsider arterial pressure as a significant goal for resuscitation in septic shock. conclusion: significantly higher malondialdehyde and ghitathione levels and glutathione-peroxidase activity in group ns at the end of icu stay were related to mortality these findings indicate an increased generation of free oxygen radicals together with increased anfioxidant activity in this group and sapport the employment of antioxidant interventions in critically ill patients. oblecfives: to determine the role of nitric oxide (no) in the mechanism of septic shock induced by isolated limb perfuslen with recombinant tnfcr methods: we have measured tnfr~ and metebo~ites of no in patients with signs ot septic shock following treatment with isolated limb perfusion for nonresectable soft tissue tumors and melanomas of a limb. perfuslen was carried out with melphalan (burroughs wellcome) and recombinant tnfcr (boehringer). tnfc~ was determined by specific radiometric assay (medgenix diagnostics), nitrate and nitrite were measured with a modification of the guess reaction ~. results: results are shown in the table. conclusions: during isolated limb pedusion with recombinant tnf~ very high levels of tnfcr were measured in arterial blood in patients. they all showed signs of severe sepsis syndrome with shock from vasodilafion, probably due to leak of recombinant tnft~ from the peduslen circuit to the systemic circulation. tnfc~-induced vasodilation was not accompanied by a rise in serum no-metsbolites. our findings do not confirm the widely accepted theory, mainly based on animal experiments, that genera• of no is the key pathogenefic mechanism in septic vasodilafion , nor that tnfrt invariably induces forreafion of no. the precise mechanism of shock in these patients remains to be elucidated. references: . moshage h, kok b, huizenga jr, jansen plm nitrite and nitrate determinaiions in plasma: a critical evaluation. clin chem : / . . moncada s, higgs a. the l-argioine-nitrio oxide pathway. n engl j med ; : - ec is a commonly used for prolonged, stable animal anesthesia. noting that the hypotension after iv lps was attenuated by ec, we hypothesized ec also protects against lps toxicity. sprague-dawley rats received ip saline (s), thiobutabarbita mg/kg (tb), or varied doses of ec, followed hours later by bolus mg/kg iv lps. -day survival is shown below: group: s tb ec( . gmikgi ec( .sgm/kg) ec(i. gm/kg) alive (n) t ~ total (n) s s "signiflcant;y different from all other groups, p< . s / rats given lps followed hours later by ec ( . gm/kg) also died. additional rats were treated with s (n= ) or gm/kg ec (n= ) followed by mg/kg lps, then sacrificed at hours. blood glucose (bg, mg/dl),.hematocrit (hct), leukocyte count (wsc/mm~ platelet count (pltxl ~/mm ), bicarbonate (hco, mg/dl), gross bowel hemorrhage (bh, - scale) and lung myeioperoxidase activity (mpo, ~vmirvgm wet lung) are shown below ( we conclude that ec reduces the lethality and multiple organ toxit;~ty of lps. its diverse effects suggest asite of activity upstream from the cytokine cascade. these results are important for studies of lps which may use ec anesthesia and may have potential in the therapy of septic shock. [zo = hz impedance (z; {dyn.sec.cm " }); zl = first harmonic z; zc = characteristic z; z ph. = t'trst harmonic phase angle {radians}; f, #, * at least p < . between fio . and . , fio . and fio . &no - . _+ . - . _+ . # - . + . m - . + . * - . + . * - . + . * - . _+ . * in hyperoxia, compared to dogs at the same q, minipigs had a higher ppa ( + rnmhg versus + mmhg; p < . ). hypoxia increased (ppa-ppao) at all levels of q by an average of mmi-ig in minipigs and mmhg in dogs. inhaled no inhibited hypoxia-induced (ppao-ppa)/q changes in both species. conclusions: we conclude ~ that the minipig is an animal model of elevated pulmonary vascular resistance and impedance, and ~ that hypoxia-induced alterations in pvz spectrum are due to changes of resistance in small arteries. objectives: ) to determine the toxicity of ng-monomethyi-larginine (nma) administered by intravenous bolus to patients with refractory septic shock. ) to investigate the biologic activity of nitric oxide synthase inhibitors in septic shock. methods: from august to january , thirteen patients with vasopressor refractory septic shock received nma intravenously in escalating doses from to mg/kg. results: no hepatic, renal, gastrointestinal, or hematologic toxicity was observed at doses of nma as high as mg/kg. significant biological activity was observed at all dose levels consisting of increased blood pressure (systolic blood pressure from . mm hg + . to . _+ . s.e.m., p= . , systemic vascular resistance ( + to + dyne.sec/ cm s, p=. ), and a decrease in vasopressor requirements. the magnitude and duration of these effect were dose dependent. decreased cardiac output ( . _+ . to . _+ . i/min p=. ) and increased pulmonary artery pressure ( . _+ . to . _+ . mm hg; p=. ) were also observed. no significant effects on heart rate, pulmonary capillary wedge pressure, or central venous pressure were observed. four of patients survived for more than days, patients died of cancer complications (all patients had maintained blood pressure for h on nma) and patients died of complication attributable to septic shock (mods, ards, dic, refractory hypotension), and patient was unevaluable. conclusions: no adverse clinical effects have been observed in patients receiving bolus doses of nma as high as mg/kg. the increased pulmonary artery pressures observed in septic shock patients is further augmented by nma and may limit the dose which can be administered by intravenous bolus. other schedules of drug dosing may attenuate this effect. glucose-insulin-potassium (gik) solutions have been shown to improve cardiac contractility and increase oxygen availability in experimental and clinical settings of septic shock. several mechanisms have been proposed to explain these effects including a direct improvemeut of the energy balance by glucose, a direct influence of insulin on cardiac performance or an increase in intravascular volume due to the hyperosmolarity of the solution. to explore the role of hyperosmolapity, we compared the effects of gik to those of a isoosmolar hypertonic saliue solutiou in endotoxin shock in dogs. methods : the study included mongrel dogs ( • pentobarbitalanesthetized aud mechanically ventilated with air. thirty minutes after the intravenotls administration of mg/kg of e. coli endotoxin, the dogs were randomized to receive a ml/kg infusion in rain of a hypertonic ( mosm]l) solution iucludiug either a mixture of glucose % with u insulin and meq kcl/l (glk-group ) or hydroxyethyl starch . % in naci . % (hes-group ). in each dog, a . % saline infi~sion was continued to maintain the puhnonary arlery occluded pressure at baseline level. hemodynamic, blood gas aualysis and laboratory data were collecled at baseline and miu, rain, rain, and nunutes later.. results : eudotoxin administration was followed by a fall in mean arterial pressure (map) aud cardiac index (ci) and a rise in blood lactate levels. resuscitation with either gik or hes hypertoaic solutions resulted in similm increases in map, ci, oxygen delivery and left ventricular stroke index (table ) . we conclude that during resuscitation from endotoxic shock the use of gik solutions is not superior to hypertouic hes solutions. the higher blood lactate levels observed in the dogs receiving gik can be attributed to the glucose metabolism. , for group , for group ) were drawn and immediately analysed at ~ using the abl radiometer for po , pco and ph, and the osm radiometer for hbo %, hbco% and methb%. psost (i.e. the ps at ph= . , pco = mmhg and temperature at ~ c) was calculated automatically by the instruments on mixed venous blood, as was the ps "in vivo" (i.e. the ps at the patient's value of ph, pcoz and temperature), using siggaard-andersen's algorithm. the data were compared by the one-way anova test and by the t-test for paired and unpaired samples. results: the mean resulting values (in mmhg) with the statistical differences are shown in table i. in addition, the time series analysis shows the mean ps~st values as statistically below the psin vivo" in the septic patients while the opposite is shown for the cardiac patients. no differences in the time analysis are demonstrated for the second group. a possible clinical significance may be drawn from these different behaviours. objectives:toxemia degree and humoral immunity condition have been studied in patients aged from to with progressive course of sepsis and polyorganic insufficience. methods: such toxemia and humoral immunity findings as lencositlcindex of toxication (lii), level of oligopeptides of the middle molecular mass registered at the wave length of nm(mmi) & nm (mm ), distribution index (id), immunoglobulins a,m,g, concentration of circulating immunocomplexes (cici & cic ) and also some clinical and biochemical findings on the , , day after the operation serve as criteria for treatment effect. results: it was founded that in intensive therapy and detoxication, level of lii is successively decreased from . ~ . to . +. on the -th day after the operation. true decrease of the level mm from . ~. to . +. un & optimal density and increase of distribution index from . to . are argued. conclusions: in studlng the dynamics of the immunoglobulin's spectrum and the true increase of immunoglobulin g level from . +. g/i to i . +. g/i on the -th day after the operation simultaneously with the decrease of cic from . ~ to . ~ . (p . ) were founded. some stages of the investigation true increase of lymphocytes from . + . % to . + . % was noted and it appeared to be a favourable prognosis finding for disease outcome. high correlation dependence between bacillus-and segmentonuclear neutrophils and immunoglobullns g & m (r=. -. in p<. ) was discovered and it also showed positive dynamics of the course of the disease. a year old male patient was admitted to the icu with severe paraquat poisoning. treatment consisted of gastic lavage and oral administration of fullers earth. because of very high plasma levels hemodialysis together with charcoal hemoperfusion was started within one hour after admission. this treatment was further continued by continuous veno-venous hemofiltration in order to remove the circulating paraquat and also circulating cytokines. nevertheless patient s condition worsened necessitating artificial. ventilation and hemodynamic support. patient died hours after admission of acute multiple organ failure due to paraquat poisoning. serum levels of paraquat were determined by colorimetric method (table) . levels of interleukin (il ) and (il ), tumor necrosis factor (tnf-alpha), interleukin i receptor antagonist (il ra) were determined both in plasma and ultrafiltrate ( q~!ectives : evaluate in critically ill patients the effects of tow-dose dopamine on gastric mucosal blood flow (gmbf) using laser-doppler flowmetry, a continuous non invasive method of assessing microcirculation. methods : patients requiring both mechanical ventilation and pulmonary artery catheterization for multiple trauma (n= ), ards (n= ) and pancreatitis (n=l) were included. in each patient, the laser-doppler (ld) probe was inserted through a naso-gastric tube. the ld signal is proportional to the number of red blood cells moving in the measuring volume and the mean velocity of these cells. when the ld signal was satisfactory, an aspiration was created into a catheter which was fixed in parallel to the ld probe, to maintain the tip of the probe against the gastric wall at the site of measurement. data (systemic hemodynamic parameters and gmbf) were obtained at the end of a rain resting period (baseline), then min after dopamine ( mcg/kg/min) infusion, and finally rain after the end of dopamine infusion (recovery gmbf _+ (perfusion units) gmbf ~a% vs baseline) * p < . vs "baseline" and "recovery". conclusions : ) despite a slight increase in co (+ %), the dramatical increase in gmbf (+ %) with dopamine, strongly suggests a selective vasodilator effect of low-dose dopamine on gasaic mucosal perfusion. ) laser-doppler flowmetry appears a promising method to assess gastric microcircalation in critically ill patients. increasing evidence suggests that the activation of inos is the final common pathway for vasodilation in human sepsis associated with endotoxic shock. activation of the cellular immune system induces the excessive release of the pteridines neopterin (n) and , -dihydroneopterin (nh ) by human macrophages/monocytes. besides the well established diagnostic value of pteridines in several inflammatory diseases, it is speculated that these substances per se exhibit biochemical functions. thus we hypothesize that pteridines can modulate inos gene expression in vascular smooth muscle cells (vsmc) in vilro. cdtured rat aortic vsmc from female wistar kyoto rats were incubated with n ( pm), nh ( ilm), lipopolysaccharide (lps, ~g/ml), and interferone-~/(ifn-~/, u/ml) for h, respectively, inos gene expression was measured by competitive reverse transcription polymerase chain reaction. the results are summarized in the table. the present study demonstxates a neopterin induced increase in inos mrna expression at the transcriptional level in vsmc. while coincuhation of cells with n + lps resulted in an additive effect on inos gene expression, n + ifn- seem to have a more than additive effect nh did not alter inos mrna synthesis, but it suppresses the lps as well as the ifn-yinduced augmentation of inos gene expression. we speculate that this pteridine-mediated modulation of inos gene expression is involved in the regulation of the vascular tone in endotoxic septic shock. the relationship of sepsis and coagulation abnormalities is well known, mainly in severe sepsis and septic shock. still farther, the extreme expression of hemostasis abnormalities (disseminated intravascular coagulation) in sepsis, has been extensively described. we studied the changes in several coagulation and fibrinolysis markers in septic patients, trying to correlate them with the evolution of the sepsis phenomenon, with an emphasis in its early stages, where therapeutic intervention might be more drastic. in patients, with sepsis, with severe sepsis and with septic shock, as well as in healthy volunteers (control group) we measured : platelet (ptl), coagulation markers [fxii, fvii, fviii, fvw, fibrinogen (fibr) we conclude that all parts of the coagulation system are gradually changed during the evolution of sepsis phenomenon , even in the earliest stage of sepsis. the expression of an inducible nitric oxide (no) synthase (inos) plays a major role in the pathophysiology of septic shock (ss). inhibition of inos could therefore be of therapeutic value. however, such an inhibition has been shown to be detrimental, increasing tissue anoxia (and end-organ damage), possibly through the simultaneous blockade of constitutive nos (cnos). thus, selective inhibition of inos might be more suitable. we evaluated the effects of l-canavanine (can), a more potent inhibitor of inos than cnos, in an animal model of ss. method: in anesthetized rats, catheters were placed in the femoral vein and artery. rats were given an iv bolus of lipopolysaccharide (lps, mg/kg), at baseline (to). after h (t ), rats received at random an infusion of either can ( mg/kg/h; can group, n=l ) or an equivalent volume of . % naci ( cc/kg/h; nac group, n= ), giyen over h (t -t ). a third group (sham group, n= ) received . % nac in place of lps, and then was treated like the nac group. mean blood pressure (mbp), blood lactate and nitrates (no ) were measured each h. glucose, creatinine and asat were also measured in rats (n= in each group). the can _+ * + "t . + . "~ . +_ . "t + " + " *p< . can vs naci ?p< . vs sham can suppressed the hypotension, reduced the hypoglycemia and hyperlactatemia, and attenuated the biological signs of renal and hepatic dysfunction induced by endotoxemia. these effects were associated with a lesser elevation of blood no , confirming a partial inhibition of inos. conclusion: l-canavanine attenuates the hemodynamic and metabolic consequences of endotoxemia in the rat. these effects may be related to a partial inhibition of inos. they contrast with the deleterious effects described with non selective inhibitors of nos. l-canavanine could become a new tool for the treatment of septic shock. rocalc tonin :marker of sepsis, ii~flammaiiur% t~ boifi .cheval*~ jf.timsit*, m.assicot**, b.misset*,/.carlet*, c.bohuon** saint joseph heap, paris**biochemistry institut g roussy, villejuif, ce bi~)l~i~ttectives_: high serum levels of procalcitoaln (proct) have been shown to be ~ss-ocinted with bacterial infection. however, few data exist about the ability of proct to differenciate septic shock and shock from other origin in which an activation of intlmmamtory mediators has been also demonstrated. methods: thirteen patients with bacterial septic shock (ss), patients with non septic shock (nss), patients with bacterial infection without shock ( nf) and icu patients without shock and without infection (control) were compared for proct levels at dayl, , , , . patients were classified blindly and independently fi'om proct results. twelve patients were excluded because any classification was impossible due to mixed pathology. proct was measured with ebemoluminescenee (brahms diagnostica-berlin). results: dayl, proct levels are significantly different between the four groups. dayl proct levels are correlated with saps (p= . ), infection ( . +_ vs _+ ,p= . ), shock ( _+ vs +.- ,p= . ), death at day ( _+ vs _+ ,p= . ). when shock and infection are introduced in multifactor &nov& only infection remains correlated with day proct levels ( = . ) in patients with shock, dayl proct levels are correlated with saps, infection and death at day , but not with arterial lactate levels (p= . ), white blood calls (p= . ) or fever (p= . ). proct levels remain higher i~i septic shock patients at day , and ( figure) . i c edpsion: procalcitonin levels in the first three days of shock are differen[" between septic and non septic shock patients. in patients with diseases known to induce acute an inflammatory process, procaldtonin seems to be a marker o~ infection. obiectives-to evaluate the effect of endotoxic shock on the distribution of blood flow between the mucosal and the muscular layer of the intestinal wall. methods: in fasted pigs, mean aortic pressure (map, mm hg), cardiac output (co, ml/min-kg),superior mesenteric artery flow (q sma, ml/min.kg), and phi, where measured before (control) and after i.v. endotoxin ( gg/kg). the blood flow to the mucosal and the muscular layer was measured in regions (proximal jejunum (pj), mid-small intestine (mi) and terminal ileum (ti)) by colored microspheres, using adjacent samples in each region. the muscular layer was separated from the mucosa by blunt dissection, and the flow determined independently in each layer. results: endotoxin with fluid resuscitation induced the expected decrease in map ( . _+ . vs . -+ . , p< . ), and phi ( . !-_ . vs . _+ . , p< . ), with a constant co ( _+ vs _+ , p= . ) and qst, aa ( . _+ . vs . _+ . , p= . ). the results of regional pertusion are presented in the table. (flow in ml/rain g of tissue; mean _+ sem ; * p< . vs control by two-way anova) conclusions-these data indicate that the mucosal flow increased during septic shock. they suggest that a decrease in phi may be due to hypoper~usion of the muscular layer or to metabolic alterations within the mucosa, despite a % increase in flow. acute increase in wbc count (from a mean of lo.oo mm a to o /mm~), between the rd and the th day of therapy. there was a decline of the wbc count to an average of about . mm a after decreasing the daily dose of the medication to mcg there was no increase in tile absolute number of the eosinophils during the whole course of the medication. there was a slight decrease in the c complement between . to . g/i. normal values . to . g/i there was no change in c values. conclusions : an early increase in wbc count was observed ( rd day) without subsequent increase in the number of immature types from bone marrow, probably due to the mobilization of wbc from the periphery and this increase was dose dependent. there was a slight decrease in c fraction of complement, probably due to the consumption of this fraction in the process of opsonization. no adverse effects of the medication were observed, during the treatment with the above dose. these data sugest that cm csf may be a useful complement to tile main antimlcrobial treat,nent ~ of septic [cu patients. objectives: as part of a large multicentric, placebo-controlled, randomized clinical trial investigating the effects of interleukin- receptor antagonist (ii-lra) in the treatment of severe sepsis and septic shock, this substudy evaluated in dem.il the acute hemodynamic effects of ii-lra in patients who were invasively monitored. methods: in a total of evaluable patients in whom vasoactive support was little altered, hemodynamic measurements were performed at baseline (twice), and i hour, h, h, h, h, and h after the administration of mg/kg (n= ) or mg/kg (n= ) of i - ra or the corresponding placebo (n = ). / patients ( %) were treated with adrenergie agents and / ( %) with mechanical ventilation. data were analyzed by a kruskal-wallis test. results: during the study, there was no significant difference with time or between groups in arterial pressure, cardiac filling pressures, cardiac index or left ventricular stroke work (figure). burmester, "~ man and h. djonlagic medical university (internal medicine, "cardiology, *'microbiology) and "**southern city hospital, lfibeck, germany obiectives: evaluation of the incidence of bacteremia and sepsis in patients with nontyphoidal salmonella (s.) infections, specification of risk factors, need of icu treatment, clinical course, and mortality in the group of the patients who developed septic complications. methods: data of all patients with microbiologically proven s. infections hospitalized in the medical university of lobeck and in the southern city hospital of l beck from to . results: within the observation period s. was isolated from the stool cultures of patients. in patients (g m, f, median age yrs) s. could be detected in blood cultures ( s. enteritidis, s. typhimurium). in addition, in of these patients s. was also isolated from other specimens (urine, liquor, and tissue fluids derived from abscess punctures). in all patients with positive blood cultures the clinical course of s, infection was complicated: ? patients developed mof (acute renal failure, ards, hemodynamic instability, dic) and required icu treatment for at least up to days, of the patients died. the predisposing disorders in the patients with s. bacteremia were (n=): aids ( ), immunosuppressive drugs ( ), chronic alcoholism ( ), malignancies ( ), none ( ). septic complications in patients with nontyphoidal s, infections are relatively rare (in this study < % of all hospitalized patients with microbiologically proven salmonellosis) but severe (mortality of approx. %). patients at risk for a complicated clinical course are predominantly those with predisposing disorders but occasionally also patients without evidence for an underlying disease. age (yr) + + death (n) duration of shock (h) + + noradrenaline (rag/h) , _+ + temperature (~ , + , + pvr (dynxsecxcm - ) + + co (ljmin) , _+ , , + , lactate (mmol/l) + , , + interleukin- (pg/ml) _+ + interleukin- (pg/ml) , _+ , , + , tnf-alpha (pg/ml) , + , + neopterin (nmol/l) , + , + crp (rag/l) _+ +_ pro-ct (ng/ml) , + , , + there was no positive correlation between serum lactate levels, degree of shock, hypoxemia and pro-ct positivity. pts with septic shock of bacterial origin entirely developed hyperprocalcitoninemia, whereas pts with cardiogenic shock, who expired within h did not. however, in late cardiogenic shock (> h) all pts developed fever of unknown origin and consecutive hyperprocalcitoninemia. these data suggest bacterial inflammation and/or mucosal translocation of bacterial products in pts with prolonged cardiogenic shock. the use of a loading dose of quinine ( . mg/kg base in h) is recommended in previously untreated patients (pts) with sfm, particularly in multi-drug resistance areas. this protocol is difficult to validate, since the viability of microorganisms is not assessed routinely in parasitology laboratories. objectives: to examine the evolution of parasite viability during the early phase of therapy of sfm. methods: from / to / , pts with sfm (who ) treated with iv quinine for less than h were included prospectively. blood samples were collected at o, , , , , and h viability was assessed by culturing parasitized red blood cells in the presence of h-hypoxanthine, and radioactivity was determined at h by scintillation counting. viability was expressed as the percentage of radioactivity compared to the initial sample. plasma quinine was determined by liquid chromatography. tile ratio plasma quinine (pmol/ )xlo /icso for quinine (nmo]/]) was called the parasiticida/ index. results: pts were included, • saps . -+ . . the initial parasitemia was t. + . %. complications of malaria were coma ( pts), shock ( pts), renal failure ( pts) and acute lung injury ( pts). all strains were sensitive to quinine (icso -- nmol/ ). in pts who were not given a loading dose, parasite viability increased by and %, with concomitantly low quinine levels ( and #mow] at h); pt died. in pts that received a loading dose (serum quinine at h = . -- . ~mol/]) a marked decrease of parasite viability (by +_ % at h) was shown. viability was inversely correlated with plasma quinine (r=. , p-.o ) and parasiticidal index (r=. , p-.o ). conclusions: even with fully sensitive strains, the use of a loading dose of quinine seems warranted in severe falciparum malaria in order to reach rapidly adequate plasma quinine ]evels, necessary to inhibit significantly parasite viability. l nkka, e ruokonell j takala. critical care research program, department of intensive care, kuopio univ hospital, finland objective: to determine the incidence of positive blood cultures, their microbial subgroups and to evaluate the outcome of icu patients with different bacleremias. material and methods: we analysed all positive blood cultures in consecutive admission to a university hospital icu in - and the icu and hospital survival of the bacteremia patients. during these years patients had positive blood cultures that were considered as clinically relevant, excluding colonizations or contanfinations. results: patients with positive blood cultures had an icu survival of . % (vs. , % in all icu patients) and six month survival of . % (vs. . % in all icu patients). the most common bacteria were enterobacteriaceae ( , %), staphylococcus aureus ( , %) , coagulase negative staphylococci ( . %), pseudomonas ( . %) and slieptococci ( . %). obiectives: to evaluate prognostic factors and mortality in consecutive patients (pts) with hiv infection and septic shock. methods: from - to - , records of consecutivepts with septic shock (crit care med , : - ) admitted to the icu were reviewed retrospectively. results: among pts with septic shock admitted during the study period, had hiv infection- of whom had aids-(gr. i) and were hiv-negative (gr. ill. ten gr. ii pts ( %) were irnmunosuppressed because of neoplastic or immune dlsease. mechanica] ventilation was required in % gr. i and % gr. ii pts in gr . i pts ( %) a multivariate analysis demonstrated that hiv infection and sap i were independently predictive of death in pts with septic shock. ~onclusions: evidence of increased mortality, number of organ failures and higher severity scores (saps i does not take into account immunosuppression) is demonstrated in hi v-positive pts, infection with hiv appears to be an independent prognostic factor in pts with septic shock. the frequency of opportunistic infections (often responsible for delayed diagnosis and treatment) may contribute to the poor prognosis in this population. obiectives: to determine interleukin (il)-i levels in plasma of patients with sepsis and septic shock. to analyze the relationship between plasma il- and the proinflammatory mediators, tumor necrosis factor-aifa (tnf) and il- , the underlying severity of the disease and the evolution of patients with sepsis. methods: we studied critically ill patients ( men, women; - years old) in three diferents groups. group i: patients without evidence of infection, group i : patients with sepsis and with septic shock (group iii). we measured plasma il-lo, tnf and il- levels in the first hours of diagnosis. severity of illness was estimated with the acute physiology and chronic health evaluation (apache ii) scoring sytem. results: plasma levels of il- were higher in group iii (median, pg/ml; range, - pg/ml) than in group ii (median, pg/ml; range, - pg/ml; p <. ) and group i (median, pg/ml; range, - pg/ml; p <. ). median il- concentrations did not differ among patients who survived (median pg/ml; range, - pg/ml) and those who died during the overall follow-up period ( days) (median, ; range, - pg/ml); but patients who died in short-term (< hours) with catecholamine-refractory hypotension showed the highest concentrations of il-io (median, pg/ml; range, - pg/ml). in patients with bacteriemia ( %), levels of il- were higher (median, pg/ml; range, - pg/ml) than in those with negative blood culture (median, , pg/ml; range - . pg/ml; p< . ). there was a good correlation between plasma il-io concentration and levels of tnf (r= . ; p < . ) and il- (r= . ; p < . ). the correlation between levels of il- and the apache ii score was significant only in the septic shock group (r= . ; p <. ). conclusions: in septic shock, il-io and proinflammatory citokines are released in high concentrations. the significant correlation observed in patients with septic shock between il- levels and apache ii, short-term death and bacteriemia can possibly be explained by the massive inflammatory response in septic shock with fulminant course. intensive care department -calmette hospital - lille -france. in septic shock, inadequate splanchnic blood flow may play a prominent role in the pathogenesis of multiple organ failure. measurement of gastric phi has been propose to evaluate tissue oxygenation in splanchnic organs. objectives: to compare gastric phi values with hepatic icg clearance, an index of liver blood flow and function ; to determine if one of these two methods could be proposed to assess the entire splanctmic peffusion in septic shock. methods : patients (age : • years ; saps ii : • were prospectively investigated (septic shock : bone criteria). following parameters were collected during hours : systemic hemodynamic parameters (swan ganz catheter a h -ref computer -baxter lab.), calculated systemic oxygen transport (do ), oxygen consumption (vo ) by indirect calorimetry (deltatrac datex lab.), gastric intramucosal pco (pco ss) and phi (trip -ngs catheter -tonometrics lab.) and plasma disappearance rate of icg (pdr dye) (femoral artery fiberoptic/thermistor catheter , cold z computer -pulsian medizintechnik, germany). correlations were performed using a linear regression. elevated in all days with the highest value in second and third days of treatment. nonsurvivors had higher values of these parameters than survivors but differences did not reach statistical significance. another trend of changes were observed in selectin p (gmp- ) concentration. in all patients concentrations measured were elevated but in survivors after not significant decrease this parameter in second day another one had simmilar values. in patients who died we noted significant decrease in third day (p < . ) whereafter prominent increase, significant after seventh day, in comparison to third day value and value in survivors group. icam- concentrations in all patients reached high levels and in nonsurvivors after four day of treatment significant increase in comparison to survivors we found. conclusions: multiple trauma complicated with sepsis induce rapid elevation of concentrations of il- , il- and increased expressior of adhession molecules (selectin e, p, icam- ) measure of icam- and selectin p concentration determine lung injury severity and prognosis as to health and life. (clp) .pathophysiology of cip is unclear, but changes in regional bloodflow may be a ~ignificant factor. nerve blood flow (nbf)is reduced in rat models of hemorrhagic shock (g),but no information is available in sepsis. we studied the comparative effect of acute endotoxemic shock {etx)& h on perfusion of rat sciatic nerve. methods: male sprague-dawley rats were anesthetized with pentobarbital (ip), instrumented with a tracheostomy, carotid arterial & venous catheters and mechanically ventilated (fi = . ). the left sciatic nerve was surgically exposed. monitored variables included: a) mean arterial pressure (map,mmhg) ,b) nbf (ml/ o g/min) by laser doppler flow meter,c) nerve internal arterial diameter (id ~ m) by video image shearing and splitting method. after stable baseline measurements were obtained, acute hypotension was induced by randomly assigning the rats to etx ( . b , difco) in saline at mg/kg or h. both interventions produced % reduction in map within min., which recovered to baseline values spontaneously in etx group, & by reinfusion of heparinized withdrawn blood in m. data were analyzed by linear regression, two-way repeated measures analysis of variance followed by bonferroni-t method. experimental stages were:( )baseline, ( ) mid-point of map reduction; ( ) nadir of hypotension, ( )midpoint of map recovery, & ( ) after stable recovery of map. both etx & h induced shock result in similar reduction in nbf consistent with lack of autoregulation in peripheral nerve vessels independent of etiology. since cip is primarily associated with sepsis, it is not likely that acute reduction in nbf alone causes cip. direct & indirect neurotoxic effects of mediators of sepsis need to be evaluated. .':_.~::::o o:oc ., objectives : evaluate the relationship between il- , a cytokine which inhibits tnf, production and protects mice from endotoxin toxicity, and the other proinflammatory cylokines, tnf~, il and ils in severe sepsis and septic shock. methods : twenty-eight icu patients ( m, f, mean age + y) were studied as soon as they developped a severe sepsis (n = ) or a septic shock episode (n= ) as defined by a conference consensus in ( ). tnf~, il , il s and il- plasma levels were measured by immuno-radiometrie assays from medgenix (fleurus, belgium). lc mean and range. results : the comparisons between cytokine levels in severe sepsis versus septic shock were made using the logarithm of the value in order to normalize the distribution of data, and student test. il- plasma levels were higher in patients with septic shock than in patients in severe sepsis. there was a significant correlation (p < . ) between il- and tnf a (r= . ), il- and il~ (r = . ) and il- and il s (r = . ) as well as between il- and apache n score (r= . ). patients who died (n = ) had il- levels higher than patients who survived but this difference was not statistically significant ( pg/ml vs . pg/ml; p> . ). conclusions : during severe sepsis and sepsis shock, il- seems at least to follow the same evolution (increase in plasmatic level) with the severity of sepsis as the other cytokines. reference : ( ) crit care med ; : - . objectives: to evaluate the effects of steroids on hemodynamics and mortality in septic patients with konwn levels of cortisol concentration. methods: retrospectively we analyzed data ofpatients with documented septic shock who received steroids after assessment of adrenal function. in all patients hemodynamic parameters as well as the necessary vasoactive medication were assessed, before and hours after corticosteroid medication. immediately before administration of corticosteroids adrenal function was evaluated with cortisol levels before and after synthetic corticotropin ( . mg). finally we studied mortality. we defined a positive respons on corticosteroids as an elevation of map of at least mmhg and/or a decrease in the necessary vasoactive medication of at least % within hours. adrenal insufficiency was defined as a cortisol level after stimulation of less than nmol/l. results: of patients were found to respond to steroid medication, did not. mean cortisol levels before and after corticotropin were • and • nmol/l in the responder group (rg) and • and • nmol/l in the non responder group (nrg). in the rg out of ( %) were found to have an adrenal insufficiency, in the nrg out of ( %). in the rg -weeks mortality was . % (l out of ), the overall mortality % ( out of ). mortality in the nrg was % ( out of ) (p < . ) and % ( out of ) (p < . ) respectively. conclusions: in patients in septic shock there is a beneficial effect of steroids in case of adrenal insufficiency, but also in a subgroup with normal adrenal f{unction. obiectives: intercellular adhesion is a critical step in the accumulation of leukocytes. postischemic cardiac lymph has the capacity to stimulate icam-i. in the coronary microcirculation neutrophils can be trapped and in many cases obstruct capillaries, previously we found that troponin t (s-tnt) a marker for myocardial iechemia, was increased in septic patients. the aim of the study was to follow slcam- and s-tnt levels continuously starting at the beginning of sepsis. methods: patients were ingluded in this institutionally approved study after relatives had given their informed consent. all patients were included within hrs following the beginning of sepsis. blood was drawn every hrs in the first ;~ hrs, after hrs, followed once per day for days. s-tnt, icam- , elam (elisa's, boehringer mannheim inc, r&d systems ltd.) arterial and venous blood gases were determined, an ecg and a complete hemedynamir measurement including cardiac output were obtained. all patients received adequate volume and catecholamine therapy (norepinephrine, dopamine, dobutamine; median (range) . ( . - . ), . ( . - ), . ( . - . ) pg/kg/min, respectively). statistical analysis: wileoxon signed rank-sum test. . ( . - . ) . patients had s-tnt levels > . pg/l. of these died, whereas only of patients died with s-tnt values < . pg/l (p= . ). all patients that died had elevated sjcam- levels ( ilg/l:cut-off ) whereas in the survivor group only % had elevated icam- levels (p= , ). conclusions: increased slcam- and s-tnt levels were found during early sepsis in the majority of patients, a high sicam- and s-tnt value was associated with a higher mortality. the research of the noninvasive haemodynamic monitoring accelerated recently all over the world. the aim of our study was to test whether the changes of the haemodynamk parameters measured by impedance cardiography (icg) were corresponded to clinical changes in septic patients. investigations were performed on critically ill postoperative septic patients (their multiple organ failure score was - /with icg monitor. in cases the investigation~ were performed in septic shock. the measured parameters were: heart rate (hr), mean arterial pressure (map), cardiac output (co), peripherial resistance (svr),preejection period (pep), and ventricular ejection time (vet). these parameters were measured during - hours in every minutes, depending on the patients cl~tnical condition. results: at the septic patients the hr and the co ]~reased. in septic shock the co was significantly higher the svr lower than in the septic group. in the hr there was no difference between the two groups. in septic shock noradrenalin influenced more effectively the measured parameters than dobutamin. conclusion: the trend of the measured icg parameters correlated with the clinical changes of septic patient's state. the noninvasive haemodynamic monitoring by impedance cardiography helps the planning and leading the adequate intensive therapy of these critically ill septic patients. to evaluate the development of sirs, sepsis and septic shock in hospitalized patients with fever, a prospective study was performed on patients using previously defined criteria. methods: normotensive patients with fever (temperature > . ~ axillary), admitted to the department of internal medicine were evaluated for the existence of sirs during the first three days of the study and sepsis at inclusion. during a follow-up period of days the patients were daily evaluated for the development of sepsis or septic shock. results: most patients ( %) had or developed sirs within the first three days, patients ( %) did not. sepsis was present in % at inclusion. in patients with sirs, % did not progress to sepsis or septic shock, % progressed to sepsis (mean interval . • . days), and patient (< %) directly progressed from sirs to septic shock. in patients with sepsis, % progressed to septic shock (mean interval . • . days). sepsis was preceded by sirs in %. septic shock was preceded by sepsis in % and by sirs in %. conclusions: % of patients with fever in an internal medicine department develop sirs, or sepsis. furthermore, progression from sirs to sepsis or septic shock is poorly predicted by fever or sirs. nevertheless, all patients with septic shock were preceded bysirs or sepsis. taken together, this may indicate a severity hierarchy of the syndromes. however, fever, sirs and sepsis are relatively poor indicators of development of septic shock. this supports further research on additional predictors of septic shock. b. m.manuylov, v.b.skobelsky (moscow) in recent years sodium hypochlorite (sh) has been successfully used to eliminate pyo-septic complications. moreover, the mechanism of the sh effect on the immune system has not been sufficiently studied. the aim of the present investigation was to study the mechanism of sh effect in inflammatory pulmonary diseases. patients with double pneumonia were subjected to the evaluation. sh in the concentration of mg/l in the volume of - m / hours was administered by drop infusion into the central vein. to evaluate one of the defence systems the leukocytes activity by the chemoluminescence technique was studied. in all the patients baseline secondary immunodeficiency which was indicated by the decrease in the luminescence level was established. even hour after the sh administration the leukocytes activation exp-ressed by the enhancement of their chemoluminescence . - times was observed. this supports the available findings that accumulation and liberation of the oxygen active forms (ol'oh, ' , h ) are accompanied by the increased phagocytosis, i,e. the signs of "the oxydation explosion" testify to the favourable sh effect on the course of inflammation processes. the use of sh permitted to decrease the percentage of lethality in double pneumonia by % in the intensive care unit over the year. at the same time, excessive activation of free radical oxygen may be a damaging factor. therefore, precise individual control over the choice of concentration, dosage and the preparation administration rate is required. prospective, double-blind, placebo-controlled, trial of atiii substitution in sepsis r. a. balk objective: pilot study to evaluate the efficacy and safety of atiii substimtion therapy in patients with sepsis. efficacy assessed using change in mortality or organ failure/dysfunction. adult patients meeting a definition of sepsis and cared for in a tertiary care academic medical center in chicago were identified and prospectively randomied to receive either atiii (kybernin p) or placebo in a double-blind treatment protocol. all other therapy and patient management were under the direction of the patient's attending physician. all patient's were followed for days and the organ dysfunction/failure were scored using published scoring systems (jordan et al crit. care med. , goris et al arch. surg. , kuaus et al ann. surg. colldusions:wha~ we met the shomaeker objectiv% the mortality and the pro~os[s were i~ttc*. those criteria were obtained with file tradititmal t~ctor likr doht~mme, hut c.~vh ~,as ca in~aertam measure. they ac~s smxergically in the optimizatic~l of the fell vmtrictdar work index, tad fimdameatally cavh seox~s to have an impo.aat role in the better respiratory ev-altmtioa, leaving yet the possibility to coltrol the flui& r althou~l eomproved it's not aec~pt~xl file importmlce h* the diminution, of the sepsis modiat~lrs llke fnt and il- with h~wmotiltrafi(al, stopphlg the evolution to nmltiorganic failure mid de~easethe mortality. with ours clhlicals results, we could saythat cavii in multiol~atlie disfut~oa septic patieats, se~r~ to be an c xilna] supoa or troatmeat maesure. of anaesthesia and intensive therapy, medical university of prcs, p~csf hungary. objectives: since some biological effects of bacterial endotoxin require an interaction between the lps molecule and a serum factor(s), we hypothesized that lps-induced no production and cgmp accumulation in vascular smooth muscle cells (vsmc), a mechanism ~thought to underlie cardiovascular collapse associated with septic shock, is modulated by serum factor(s). methods: cultured vsmc from rat aorta were challenged with e. coli lps for - hours either in the presence or absence of fetal calf serum (fbs), and no production was monitored by radioimmunoassay determination of cgmp content of hci extracts. results: in the absence of serum, o ng/ml lps was required to increase cgmp levels, whereas the presence of % fbs shifted the lps concentration curve i times to the left. similarly to fbs, human serum also potentiated lps-induced cgmp accumulation. in contrast to lps, serum had no effect on cgmp accumulation elicited by sodium nitroprusside, a no releasing agent, suggesting that the sensitivity of vsmc to generate cgmp in response to exogenous no is not modulated by serum. heat inactivation (> ~ min) but not removal of small molecules (< , d) from the serum by dialysis, reduced the potentiation of cgmp accumulation by serum. time course studied indicated that serum is required within the first min of lps exposure to increase cgmp levels. to investigate whether the effect of serum is specific for lps, we treated the cells with increasing concentration of interleukin -~ (il-i). % fbs shifted the il-iinduced cgmp responses five times to the left. conclusions: our study suggests that lower concentrations of e. cell lps and il-i require a heat labile macromolecule in the serum in order to elicit no production. this factor is present in the human serum and it may play a potentially important role during no synthesis induction in vsmc. objective: to evaluate the factors of acquisition and the outcome of methicillin resistant staphylococcus aureus (mrsa) bacteremia in an intensive care unit (icu). methods: all patients in which bacterermia due to staphylococcus aureus developed > hours following admission to our icu, during a year period ( january through january ) were reviewed. patients (pts) were included, mean age , y (sd , ), saps , (sd , ), mac cabe ( and ) %, mortality directly due to sepsis %. pts had mrsa bacteremia and methicillin susceptible staph. aureus (mssa) . both groups were compared using the chi square (with correction of yates), fisher's exact, student's t or wilcoxon test. results: there was no statistically significant difference between mrssa and mssa regarding at age ( , + , vs , + , ) , saps ( , + , vs , + , ), use of vancomycin ( % vs %), mechanical ventilation ( % vs %), number of days (d) before the drawing of the first positive blood culture (median d, range - d vs median d, range - d). more mrsa than mssa pts had previous use of nonsteroidal anti-inflammatory drugs (nsaid) ( % vs % p< , ), central venous catheter infection due to staph.aureus ( , % vs % p< , ), but previous use of antibiotics was not significantly different ( , % vs %). the outcome of the bacteremic pts was not statistically different: saps at the first day of bacteremia ( , +_. , vs , + , ), severe sepsis and septic shock ( % vs %), persistence of the bacteremia ( % vs %), mortality directly due to bacteremia ( % vs %). conclusion: previous use of nsaid, infection of venous central catheter are more frequently associated with mrsa bacteremia. thus, similar to others studies (hershow infect control hosp epidemio ; : - ) , these results do not indicate that mrsa is associated with increased virulence. objectives: to closer definition of mosf formation mechanismes in nosocomial sepsis (ns) the complex clinicobiochemical, microbiological, immunological, functional exaroination of cases with ns had been done. methods: examination of cellular and humoral immunity, nonspecific immunologic reactivity, systemic and hepatic circulation, microbiological examination of blood,electro-and echocardiography, sonography and computer tomography of chest and abdomen organs were obligatory. autopsy findings of dead cases had been analized. results: in cases ( , %) opportunistic pathogen microscopic flora ( staphylococcus anreus,staphylococcus epidermidis, staphylococcus saprophyticus) had been found out in blood inoculations. in cases ( %) side by side with destructive process in lungs the bacterial endo-and myocarditis with blood circulation failure had been determined.in cases ( %) simultanious lesion of three organs (heart,lungs,liver) had been found. morphologic examinations of dead cases ( %) internal revealed involvement of them in mosf-syndrome.hyperplasia of adenohypophysis;sclerosis of adrenal glands cortical layer;perivascular brain oedema,paralysis of brain capillaries and plasmorrhagia, cerebral thrombosis and cerebral abscess,necrobiosis of epithelium tubules of the kidney,pletora of hepar, fatty and granular degeneration of hepatocytes had been found.atrophy of white pulp and hyperplasia of red pulp, supress of lymphoid tissue, plethora and formation of infarctious had been found in spleen. mentioned changes in spleen were indispensable in ns. conclusion: in ns spleen can not secure it functions to support and appropriate detoxication potencial of organism,elimination of microbes,toxines,antoallergenes. insolvency of immunological link of antimicrobic defence is the starting mechanism of mosf developmentin ns. %neviere, jl. chagnon, b. vallet, d. mathieu, n lebleu, f. wattel ] ept of intensive care, hop calmette, lille, france ~everal studies have described tiypoperfusion of intestine during sepsis. owever, it is unknow whether the mesenteric blood flow is associated with nucosal hypoperfusion. additionally, the effects of resuscitation on the ntestinal microcirculation remain controversial. bjectives : to describe the effects of endotoxin in a porcine model during ~hock and resuscitation. ~ethods : ten pigs ( kg) were anesthetized and instrumented for "neasurement of cardiovascular variables. gastric and gut oxygenation vere assessed by intra-mucosal ph and microvascular laser doppler lowmetry. after baseline data collection, a minute intravenous infusion )f escherichia colt (serotype h , sigma, st. louis, mo) was begun ~t a rate of pg/kg. an infusion of either saline at . ml/kg/min (group ; n= ) or saline and dobutamine at a rate of pg/kg/min (group ii; n= ) vas begun mn after the end of the endotoxin infusion. tesults : to td t ~ fl w fluid ioadin,q alone sfyras d, k perreas, e douzinas, k spanou, m pitaridis and c roussos critical care dpt, evangelismos hosp., athens univ, school of medicine. obiectives: much controversy exists concerning the beneficial effects of cvvh on sepsis. we studied the effects of cvvh application on septic patients with reference to the following parameters: i) survival rate ii) cytokines' removal and iii) timing of cwh onset. methods: patients with sepsis (criteria according to accp/sccm, ) underwent cvvh as soon as they developed renal failure or dysfunction (urinary output< ml/ h, cr> . mg/dl and bun> mgd'dl ). specimens were collected: blood samples before cvvh and therafter both blood and ultrafiltrate (uf) samples on , and hours. cytokines tnfa, i - and ii- were measured by the immunoassay method in all specimens (uf and plasma -p) and sieving coefficient ([uf]/[p]) and h solute mass transfer of tnf and i - were calculated (v h x [uf] ). the apache ii score before cvvh onset, the duration of icu stay and the timing of cwh application related to the sepsis onset in days (ta) were recorded.with respect the mortality two groups were formed, i.e. group a (survivors) and group b (non-survivors) . the morbidity period in days of those septic patients who died in the past year and were not subjected to cwh (group c) was compared to that of group b. results: group a included pts and group b pts with mean+sd age ( _+ vs _+ , ns) and apache scores( _+ vs -+ . , ns). the mean ta-+ sd was . + vs -+ , p< . . the mean_+se morbidity period of group b vs group c was _+ vs _+ . p< . . the mean values of cytokines are presented in the following figures. the sieving coefficient for tnf was . and for i - was . . the solute mass tranfer was -fold the actual plasma content at a given time. . o conclusions: i) early application of cvvh seems to favourably affect the outcome of septic patients, ii) cytokine plasma levels do not decrease although cytokine removal is substantial, iii) it seems that cwh application in sepsis of any stage helps to buy time for further treatment. the most commonly monitored variables in shock stages idclude : arterial pressure, heart rate, central venous pressure, pulmonary artery wedge pressure and cardiac index. with vigorous therapy it is possible to bring these values back into the normal range in both survivors and nonsurvivors. therapeutic goal in septic shock stages is to maximize the values of cardiac index, delivery (do ) and consumption (c ). objectives: the main purpose of this article is to determine the relationship betwee~ delivery an consumption as a sign of hypoxia. fifteen patitents with septic shock were treated with intention to maximize the value of ci,d and v . we compared the levels of these parameters between the survivors and nonsurvivors and found no significant differences after hours. high levels of do and v may not guarantee against tissue hypoxia in early stage of septic shock. zjar~iic, dj janjic, lj. gvozdenovic, a.komareevic. t.petrovic, &marjanovic, institute of surgery, novi sad, yugoslavia objectives: evaluation and mutual comparison of clinical signs, laboratory data and microbiological monitoring in the patients with burn sepsis. method: retrospective analysis of the recorded data of all burn patients treated in our department between january and december . specially attentions were given to data considering wound infection, positive haemocultures, positive urinocultures and characteristics of septic state. results: out of patient there were ( , ~) adults and ( , ( ~) children. almost two thirds of the patients ( - , ~) were males. the predominantly cause ( , ~) of children's burns was scalding b~y hot liquids and flame burns ~ , ~) in adult patients. the most frequdntly species isolated from surface swat~ were pseudomonas aeruginosa ( " in adult patients) and staphyloccocus epidermidis ( , % in children). in only five patients ( , ~ the haenmcultures were positive -pseudomonas aeruginosa was isolated in three and staphyloccocus aureus in two patients. urine infection was diagnosed in , % of all patients. the treatment protocol included use of imipenem and polyvalent pseudomonas vaccine again~ pseudomonas aeruginosa and vancomycin and aminoglycosides against staphylococcus aureus. total mortality rate in this group of burned patients was , ~, but the mortality rate caused of sepsis was low (i %) . conclusions: early detection of any signs of wound infection and symptoms of septic state is a foundation for prevention and treatment of burn sepsis. the burn sepsis could be reliable detected by continuously monitoring the patient's status and by systematic microbacteriological monitoring of the burned patients. hyperdynamic vasoplegic septic shock p.f. laterre, p. goffette, j. roeseler, j.p, fauville, a. poncelet, p. lonneux, m.s. l~eynaert. dept. of intensive care, st. luc univ. hospital, brussels, belgium. splanchnic ischemia is described as a common feature of septic shock and could determine the development of msof. therapy such as noradrenaline (na) aiming at improving blood pressure is expected to worsen splanchnic ischemia by its vasoconstrictive effect and subsequent reduction in intestinal blood flow. ob[ective: evaluate the effect of na on splanchnic blood flow. material and method : in a patient admitted for variceal bleeding, ards and sepsis with positive blood culture, a fiberoptie catheter was positionned in the portal vein after recanalisation of its portosystemic stent shunt. blood pressure (bp-mmhg) , ci, svr, do (vigilance ~ baxter), v (indirect colorimetry), arterial, mixed venous and portal vein blood gases, phi were determined before (to) and during (t ) na infusion ( , to , hcg/kg/min.) . changes in splanchnic flow were assessed by changes in portal oxygen saturation (sp ) and arterio-portal oxygen saturation gradient (sao, -spoe laterre, ,lp. pedgrim, th. dugernier, v. delrue, ph. hantson, p. mahieu, m.s. reynaert. dept. of intensive care, st. luc univ. hospital, brussels, belgium. aim of the study : prospective determination of plasma levels of in patients with ss and their correlation with the type of microorganism and outcome. material and methods : in patients (pts) with ss and severe sepsis, plasma levels of tnfti, ill-b, il and il were determined every hours for days and on day after fulfilling the criteria of ss and severe sepsis. results : in pts, sepsis was caused by a gram (-) microorganism, in pts by a gram (+) and in pts no microorganism was identified. there were survivors ( %) (s) and non-survivors ( %) (ns) . cytokines profiles and levels were not different between gram (+) and gram (-) sepsis. ill-b levels were seldom elevated whatever the group studied. tnfot and il- were significantly higher in ns than in s ( objective: to evaluate the effects on the nitric oxide synthase inhibitor l-n~ hcl ( c ) on myocardial performance in human septic shock. method: septic shock was defined as severe sepsis with either persistent hypotension (mean arterial pressure; map< mmhg) or the requirement for a noradrenaline (na) infusion >_ .i ]tg/kg/min with a map _< mmhg. cardiovascular support was limited to na _+ dobutamine (db), c was administered for up to h at a fixed dose-rate of either , . , , or mg/kg/h iv. during c infusion, na was to be reduced and if possible withdrawn, whilst maintaining map above mmhg and the cardiac index (ci) as clinically appropriate. assessments were made at baseline (t = ); at i h from the start of treatment (t = ); and at the end of treatment (t = ) with c . conclusions: c can restore systemic vascular tone in patients with septic shock enabling na therapy to be reduced and/or removed. the ci tends to fall whilst lv performance is sustained over time. c is a novel vasoacfive agent for the treatment of septic shock, which is undergoing further clinical evaluation. laterre, f. thys, e. danse, j.p. pelgrim, e. florence, z roeseler, m.s. r eynaert. dept, of intensive care, st. luc univ, hospital, brussels, belgium. therapy aiming at improving blood pressure and cardiac index in septic shock (ss) might have deleterious effects on regional blood flow. objectives : compare the influence of volume loading (vl), dobutamine (dobu) and noradrenaline (na) on sushepatic oxygen saturation (shoe) and svoe-sho, gradient in treated ss. material and methods : in patients with ss, ci (thermodilution) , doe, svo,. sho,, svoe-sho e gradient and lactate (l) were determined before (to) and after (t ); vl, dobu and na. results: in patients with treated ss, tests were performed (vl n= ; dobu n= ; na n= method: septic shock was defined as severe sepsis with either persistent hypotension (mean arterial pressure; map< mmhg) or the requirement for a noradrenaline (na) infusion ~> . ~g/kg/min with a map _< mmhg. cardiovascular support was limited to na + dobutamine (db), c was administered for up to h at a fixed dose-rate of either i, . , , or mg/kg/h iv. during c infusion, na was to be reduced and if possible withdrawn, whilst maintaining map above mmhg and the cardiac index (ci) as clinically appropriate. assessments were made at baseline (t = ); at h from the start of treatment (t = ); and at the end of treatment (t - ) with c . conclusions: c is a novel vasoactive agent that can sustain map in patients with septic shock, enabling na support to he reduced and/or removed. there is a tendency for the ci to fall during treatment, which may be reflex in response to the increase in systemic vascular tone. c is a promising new therapy for septic shock, which will now be evaluated in a randomised, placebo-controlled safety and efficacy study. k. guntupalli objective: to evaluate the acute effects of the nitric oxide synthase inhibitor l-n~ hc ( c ) on selected indices of organ function in patients with septic shock. method: septic shock was defined as severe sepsis with either persistent hypotension (mean arterial pressure; map < mmhg) or the requirement for a noradrenaline (na) infusion --> . [xg/kg/ min with a map _< mmirlg. cardiovascular support was limited to na + dobutamine. c was given for up to h at a fixed dose-rate of either , . , , or mg/kg/h iv. during c infusion, na was to be reduced and if possible withdrawn, whilst maintaining map above mmhg and the cardiac index (ci) as clinically appropriate. indices of organ function were assessed at baseline (t = ); at the end of treatment (t = ); and h after treatment (t = ) with c . results. -median values (* assessment made at h or when c discontinued). conclusions: there was no appareut dose-dependent adverse effect on these indices of organ function either during or after exposure to c . the plmelet count tended to fall whilst creadnine appeared to increase over time in all dose cohorts. this novel and promising therapy for septic shock will now be evaluated in a randomised, placebo-controlled safety and efficacy sludy. pharmacokinetics of c in patients with septic shock preliminary results z. hussein, b. jordan, c. fook-sheung, k. guntupalli objective: to evaluate the pharmacokinetics of the nitric oxide synthase inhibitor l-n~ hc ( cg ) given by continuous infusion for h in patients with septic shock. method: septic shock was defined as severe sepsis with either persistent hypotension (mean arterial pressure; map < mmhg) or the requirement for a noradrenaline (na) infusion --> . ~tg/kg/min with a map _< mmhg. cardiovascular support was limited to na • dobutamine. c was administered for up to h at a fixed dose-rate of either , . , , or mg/kg/h iv. plasma was collected from each patient over a h period and analysed for c . pharmacokinetic parameters were derived from plasma concentration-time profiles using non-compartmental pharmacokinetic analysis. results: the (cm~ -maximum plasma concentration; auc -area under curve; cl -plasma clearance; v,, s -steady state volume of distribution; t'/ -plasma elimination halflife). conclusion: the pharmacokinetics of c in patients with septic shock are dose-independent at infusion rates up to . mg/kg/h. at higher rates, clearance of c decreases without any marked change in volume of distribution. c metabolism may be partially saturable at dose-rates above . mg/kg/h. obiectives: investigate the effect of the no synthase inhibitor, l-nt-methylarginine hc ( c ) on the haemodynamics and survival rate in a conscious mouse model of endotoxin shock. methods: female cd- mice ( - g) were instrumented under gaseous anaesthesia (isofluorane, %) and connected to a swivel tether system for continuous monitoring of blood pressure and drug administration. results: after h recovery, endotoxin administration (e. col• :b , - . mgkg - i.v.) elevated the plasma concentration of nitrite/nitrate (nox) and caused a progressive fall in mean arterial pressure (map) from + to + mmhg (n= , p< . ) at h, with a survival rate at h, h and h of %, % and % respectively. c administered as a h continuous infusion ( mgkg-th -t i.v., n= ), h after endotoxin, inhibited the elevation of plasma nox and attenuated the fall in map from + to + mmhg (n= ) at h, with an improved survival rate at h, h and h of %, % and % respectively. conclusions: this study suggests that overproduction of no is involved in the hypotension and mortality characteristic of septic shock. inhibition of no synthase using c represents a novel and promising treatment for septic shock. cultures of e.coli ( , %) and candida( , %) were olso received from autopsy material of children;p.aeruginosa,unspored anaerobes,proteus sp.,s.aureus,b.pneumonia were found in the few cases. in adults the spectrum of bacterioflora was mo~ re limited speaking about the number of species and cultures. in generalized forms of bacterial pyo-septic pathology a wider specific spectrum of causative agents was revealed usua fly with associations. e.coli and k.pneumonia played the leading role in children as well as in adults. in general,k.pneumonia ( , %cultures) and common e.coli( , %)prevailed according to the date of microbiological investigations of authopsy material in pyo-septfc pathology in . objectives: .in spite of all clinical exertion sepsis is still the reason for high clinica! lethality. this study is characterizing the group of patients which survived a septi~ shock. methods: during a period of months all surgical patients on icu were registrated prospectively, more than parameters for each of them were documented'daily in a paradox file. results (see table ): of patients fulfilled the criterion of a septic shock (r. bone, ) , of them died at the lth day, while the surviving group of patients stayed almost days at icu. obiectives: to compare the effects of and % pentastarch solutions to a human albumin solution on oxygen delivery (do ) in septic patients. methods: this stud}, included septic patients with fever (t > ~ tachycardia flqr > /rain), tachypnea (rr > /min) or mechanical ventilation, leukocytosis (wbc> /mm ) or leukopcnla (wbc< ()/mm ) and a clinical source of infection, who required a fluid challenge. in each patient the pulmonary arterial occlusion pressure (paop) was < mmhg. patients were randomized to receive ml of % albunun (n:i ), hydroxyethyl starch (hes -mw /d.s. . ) % (n: ) or t % (n=i ); patients were also treated with adrenergic agents. results cardiac index (c ) increased significantly only in % lies (table) hemoglobin (hb) decreased significantly at min in the same group. there was not significant change in oxygen delivery ( do ). baseline ci alb . :: . (l'min/m ) hes % . = . hes % . polyneuropathy of the critically ill (pci ) is a well recognized complication, acquired in the course of severe illness. we undertook a prospective study, to estimate the severity, extension and time of onset of pci in a selected group of patient with established septic shock ( bone's criteria ). all patients received inotropic circulatory support and were mechanically ventilated. none received relaxants or aminoglycosides. pci was diagnose<by clinical investigation and by emg, and repeated weekly ( axonal degeneration ). after days ( day = onset of septic shock ) in % of the patients pci was demonstrable. after days % of the patients had pci. there was a strong correlation between pci and other mof and between pci and encephalopathy ( eeg ). we conclude that i. pci is a common complication after septic shock. . pci develops early in the course of illness ( % after days ). . pci can be considered as a part of mof, suggesting a common pathogenesis. objectives: we addressed two questions: ) can serial measurements of vapco and avph also reflect the onset of tissue hypoxia during endotoxemia? ) are whole body changes in vapco and avph associated with parallel changes in regional circulation? methods: in anesthetized, mechanically ventilated dogs exhaled gases were sampled for determination of oxygen consumption (vo ). a catheter was positioned into the pericardial cavity to induce cardiac tamponade. ultrasonic flow probes were placed around superior mesenteric, left renal and left femoral arteries, and the corresponding veins were cannulated. group l served as control (n= ), group (n-- ) received mg/kg of endotoxin. thirty min later, tamponade was induced to gradually reduce do . results: systemic do crit was higher ( . _+ . vs . + . ml/kg.min, p < . ) and critical oxygen extraction ratio (o ererit) was lower ( . +_ . vs . +_ . %, p< . ) in the endotoxie than in the control group. meslenteric and femoral do crit were higher in the endotoxic than in the control group ( . _+ . vs . _+ . mlll g tissue.min and . _+ . vs . _+ . ml/min, respectively, both p< . ). regional o ercrit were lower in we endotoxic than in the control group (mesenteric: . _+ . vs .i_+ . %, renal: . + . vs . -+ . % and femorah . -+ . vs . _+ . %, all p< . ). vapco and avph followed a similar pattern in both groups, increasing slightly before do crit was reached, but dramatically wh,en do fell below do crit. in the presence like in the absence of endotoxin, systemic and regional do crit calculated from vo , from vapco , or from avph were similar; do crit was also significantly higher in the mesenteric and the femoral beds of the endotoxic than the control dogs. systemic and regional do crit could be calculated from the blood lactate levels only in the control group. conclusions: during an acute reduction in blood flow i) vapco and avph can reflect hypoxic threshold in the presence like in the absence of endotoxemia. ) alterations in organ oxygen extraction capabilities induced by endotoxin can be reflected by regional changes in vapco and avph. objectives: enhanced nitric oxide (no) release has been incriminated in the vasodilation and myocardial depression characterizing septic shock, but the administration of no blockers has yielded equivocal results. the present study explored the systemic and regional effects of a no donor linsidomine (sin-i) during endotoxic shock. methods: anesthetized dogs received endotoxin ( mg/kg iv), followed min later by a saline infusion to keep cardiac filling pressures constant. oxygen uptake (vo ) was derived from the expired gas analysis. regional blood flow was measured by an ultrasonic flowmeter (transonic). results: the control endotoxie group (n= ) maintained low arterial pressure and systemic vascular resistance. the dogs receiving a continuous infusion of , , ~ug/kg.min of sin- starting min following initial fluid resuscitation (each dose for h), had a higher cardiac index ( . -+ . vs . _+ . l/min.kg, p< . ) and lower systemic and pulmonary vascular resistance than the control group ( -+ vs -+ and -+ vs -+ dyne.sec/cm , respectively, both p< . ). arterial pressure and pulmonary artery pressure were not influenced. sin- significantly increased the mesenteric blood flow from -+ to + % of baseline levels and renal blood flow from -+ to -+ % (both p< . ) but did not influence femoral blood flow. the relative blood flow was increased in the mesenteric bed (at all doses), and reduced in the femoral bed (at highest dose). systemic oxygen delivery, vo , oxygen extraction and blood lactate levels had similar course in the two groups. conclusions: in fluid-resuscitated endotoxic shock dogs, the no donor sin- increased cardiac index without deleterious effects on arterial pressure, and increased splanchnic blood fl w. objectives: sepsis syndrome is associated with the release of a variety of inflammatory mediators, such as interleukins, tumor necrosis factor and platelet-activating factor (paf). administration of paf, a naturally occuring phospolipid, to laboratory animals has been demonstrated to resullt in pathological changes that closely resemble those found in sepsis. in addition, paf antagonists of various origins have been demonstrated to attenuate cardiovascular collaps and to protect against lethality in endotoxemia. in the present study the efficacy and safety of the paf-antagonist tcv- g was investigated in sepsis syndrome patients. in addition, the putative inflammatory parameters tumor necrosis factor (tnf), interleukin il) - il- , and soluble (s) e-selectin were measured in both tcv- and placebo treated patients. metho.~a randomized, double-biind, multi-center study was undertaken to compare the safety and efficacy of intravenously administered tcv versus placebo (takeda chemical industries ltd., osaka, japan). tcv- was used as add-on to conventional therapy in the treatment of patients with severe sepsis and septic shock ( . mg/kg body weight intravenously over hrs, twice a day for one week). day mortality was registered, as well as vital signs, laboratory parameters, hemodynamic parameters, apache ii score and mof score. plasma samples for the determination of inflammatory parameters were collected twice a day for one week. the study was approved by each institutional review board and written informed consent was obtained for each patient. results: a total of patients were included in the study. one patient had to be excluded as a result of protocol violation of the remaining patients patients were randomised to receive tcv- and to be treated with placebo. there were no significant differences between the treatment group with respect to age. gender, and apache i~ score on admission. however, admission levels of il- and il- , considered to reflect severity of disease, tended to be higher in tcv treated patients: . . vs . ng/ml for il- (p. ) and . vs . ng/ml for il- (p. ) in tcv- and placebo treated patients, respectively. a remarkable difference in survival, however not significant, was observed at day i.e. the end of tcv treatment (mortality: out of in the tcv group and out of patients in the placebo group). the inc;dence ui ~-,~verse events, 'n both treatment groups were comparable. plasma il- and plasma il- levels tended to decrease more rapidly in tcv treated patients compared to controls (p=. and p=. , for il- and /l- respectively) conclusions: tcv- is safe as add-on treatment in sepsis syndrome patients. the data presented indicate that tcv- may enhance survival of sepsis syndrome which will be assessed in a phase ill study. objective: oxidation of lipids by free oxygen radicals playes an important role in sepsis. an important source of oxygen radicals is the respiratory burst of phagocytic leukocytes, especially~ polymorphonuclear leukocytes. clinically the hallmark of sepsis is the capillary leak, which is mediated in part by oxyradicals. the adult respiratory distress syndrom (ands} represents the most studied capillary leak phenomenon in sepsis. methods: in ii patients (df,~m, aged - y.) with verified septicemia had been included in this study. beginning from day oxidisable lipidautoantibodies (club), ~opterin and crp were determined in the patients serum and compared against the apache ii score during the days - . patients, f and m died @u= ring their stay at the icu, of them in less than h~urs: after admission. at the begin surviving patients showed olab values between - %, non-survivors between - %, com= pared to neopterin values of - m~ol/l in survivors and - ~mol/l in non-survivors. apache ii score didn t show any difference. during the following days olab sbowed an in= crease in survivors, while in non-survivors olab stayed equal or showed a decrease. no difference between both groups was found in neopterin, crp and apache ii score. as result we conclude, tbat lipidperoxidation playes an important role during septicemia. olab as a marker of this process are predictive for the outcome of patients. obiectives : to evaluate the influence of cardiopulmonary bypass ongastrointestinal transit. meth~xls; gastrocoecal transit time (gtt) in consecutive children on day after uncomplicated open heart surgery was compared to gtt in children after closed heart thoracic surgery and to healthy controls. gtt was measured by hydrogen breath testing, using lactulose (o, g/kg in a % aequous solution) as nonabsorbable marker. exspiratory hydrogen content was measured using a electrochemical system (stimotron). patients in both groups had continuous infusion of morphine and midazolam and were comparable in respect to catecholamine dose. children with a history of toddler's diarrhoea and children with elevated central venous pressure were excluded. results: gastrocoecal transit was delayed in all patients after cpb, no transit was achieved within minutes in / . after closed heart surgery gtt was delayed (+- ) min vs. (+- ) compared to controls, but transit was achieved in all aptients within rain. mean dopamine dose was , mcg/kgmin after cpb and , meg after closed heart surgery.. conclusions: after uncomplicated cpb gastmcoecal transit is extremely delayed. the degree of delay is not explained neither by the use of analgetic and sedative drugs neither by the use of catecholamines. factors directly related to cpb (e.g. low flow perfusion, hypothe,mia) may be responsible. these findings are of limited clinical relevance in ancomplicated cases. in critically ill patients delayed enteral feeding may contribute to infectious complications. studies of therapentic measures to accelerate gastrointestinal transit therefore are warranted. neonatal ecmo -czech experience. nekvasil r., penkova z, vasek l., plier p., bobula a novotna e., pavlicek v., hnilicka m. nicu and ecmo center brno and dept. pediatric surge ', children's hospital brno, czech republic. introduction. in spite of the fact that neonatal ecmo has been gradually considered a standard method of solving uncontrollable respiratol t failure in newborns in most countries of the western europe, the introduction of this sophisticated method in countries of the former communist block meets a lot of problem. material methods. in the course of two years, only newborns, b.w. - g, were reffered to neonatal ecmo because of uncontrollable respiratow failure. at the admission the average values of oxygenation index were + , and aado , -+ , kpa. results. newborns ( %) died shortly alter" admission or during transport without possibity to further is newborns ( , %) were treated using high-frequency ventilation (hfo or hfjv), one for conspicuous airway resistance paradoxically with low-frequency ippb. all ventilated newborns survived. ecmo was applied in newborns ( , %) and of them survived the mortality rate of group mentioned was %. conclusion. the fact that in the czech republic ( mil. population with natality rate of about . newborns/year) only small part of patients was reffered to neonatal ecmo has a number of causes. the most important are: unacquaintance of prognostic and indication criteria at forwarding workplaces and the aversion of neonatologist to all new.therapeutic interventions. last but not least, a negative role is also played by current change of health service systems when, under the influence of health-service insurance companies a newborn in serious condition given only a standard intensive care in primary and secondary nicu is literally "the golden calf", and therefore these workplaces either do not send him or send him too iate ~o an ecmo center. stndy aim: urfactant, which is being applied into the lungs for treatment of respiratory distress syndrome, can reach the circulatory blood system by absorption. it refinances local fimctiun of macrophages and lymphocytes and increases the accumulation of nentrophils into the hmgs this eunld influence the local acute phase reactiml in the hmgs after surfactant application. "ilia aim of the stud), was to investigate the influence of oatural and artificial surfactaat onto the acute phase reaction and the blood elottiog system. material :and methods: a) measurement of tnf-a, - , ltb and thromboxane b release in whole blood: each of . ml hepariaised blood of healthy adult volunteers was iucubated lbr hears with eillier ill ug/ml lps, mg/ml b&,ine smfactant (alveulhct/themae), rag/nil artificial surfactant (exosurf/wellcome), og lps + i mg/ml bovine surfactant or i ug lps + i mghal artificial sorfactant, tleparinised bhx-,d without additions was used for controls. ' e concentration of e)lokines and eicosanoids ".van measured semiquantilatively by eijsa or eia (dimmva/hamburg) after ceatrifagalion, b) measurement of platelet aggregation: each of . ml haparinised hltxxl of healthy adult vohmteers was inculmled lbr hours with eilher aghnl i,ps, i mg/ml bovine surfactant (alveafact/thomae), i mg/ml artificial snrlhctant (exosurf/wellcotne), it} ug lps + i mghnl bovine snrfactant or ug lps + i mg/ml artificial surfaetant, tlepminised blood withont additions was nsed for controls. platelet aggregation in whole blood was measured by impedance in the aggregometer (g~nstaedt). c) measurement of the dotting activity: citrated bleed of healthy adult w~lunlccrs was mixed with difl'ereul couccalrations of imvine or artificial snrfactant fad then prolhrombiu tiaras and imrlial thrmnlx~plaslia filues were ineasnrcd. for measurement of the prokoagulatioo acfivily the reagent in the qnick test was replaced by surfaclant. results: dependmlt on the dose both surfactants stimulated the release of - but not or tnf-a io wlmle blood. "illere was no suppression of the lps-indaeed eytokine-release. both surfaclants did not directly influence the extrinsic blood coagulation system, while both activated the inniasie activity dependant on the dose. platelat aggregatiun was slightly stimulated by bovine snrfactunt and strongly inhibited by by artificial surthctant. in comhinafion with . ~ both factors showed no difft.'renca to lps ahme.'fhe reltu.tse of eiconasnid~." was stimolated more by artificial surfactant then by bovine surfilctant with regard to the cyehmxygelmse (thromboxsne b ) and the lipooxygenase (lencotrieae b ) pathways. conclusion: we cooclude: ) i:lovine as well as artificial surfaelant stimulate the cellular inmnn]e response. ) bovine as well as artificial surfnctant activate the intrinsic ctmgnlation cascade. ) bovine surlilctant stimulates platelet aggregation, artificial sar-fijctant inhibits platelet aggregation.. introduction: although the use of modem noninvasive methods like measurement of tope , tcpco or san leeds to an carly infonnation about pathologic alterations of the gas exdmage of ventilated patients, these methods cannot replace invasive bloodgas analysis. a new noninvasive method to monitor the capillary gas exchange is the reflection spectrophotometry. to record reflection spectra with a ldgh sensitivity on the surface of tissue we eonstnmted a special mierolightgnide photospectronmter (empito). this spectrometer enables the investigation of local helerogenities of llbo and lb content, capillary flow rate and oxygen uptake rate. aim of the study: ) to compare the sousitivity and specifity ofthe empilo with other non-invasive method~ of monitoring the gas exchange in neonatal intensive care patients. ) to investigate the possibility of obtainiug infonnations about the local nptake and the venous as well as arterial satnration. patients and methods:we investigaled non-selected patients of oar pediatric intensive care unit. for coulinnons monitoring we conslracted a special sappert to fix file end nf the microlightguide+ during the investigation tope , tcpco and san were measured by standard methods. "fo investigate the local tisslm oxygen uptake we recorded spectres within minutes by moving the lightgnide over an described area of the skin of the patient. 'lhe reselting i(gx) l ibo vahms were sorted by a software package. on the assumption that the low values correspond to the tibo value of the veaons ends of the capillaries and the high values to those of the arterial ends we ) it is possible to gel infonnations about the local o -uptake and arterial saturation ia the peripheral tissue by photoslg'ctroscopy. ) in combination with noninvasive pl i-measorement it seems possible to reduce withdrawal of blood for invasivn bhmd gas analysis. objectives:improve ventilation,tissue oxygenation and acid base balance among extremly low birth weightand premature infants. methods: fourteen cases were s~udied,their gestational age ranged from( - )ws.continnous positive air way pressure was applied to six cases at peep level from ( - )cm h o through nasal pronge,(group i),the other cases were managed as routine,(group ii).blood gases, tcpo ,tcco ,resp.rate,depth and pattern were monitored for assessment of tissue oxygenation and ventilation, results: our rasults showed that early application of cpap improve ventilation among ( . %)of cases,while ( . %)of cases need imv.the cases of group ii need imv among ( %)of the studied cases during the second or the third day of life. conclusions:-this preliminary study showed the import-............ ance of early application of cpap before the onset of respiratory distress syndrom to improve spontaneous ve ventilation,tissue oxygenation and to gecrease the risk of intubation. comparative assessment of pediatric intensive care; a national multicenfre siudy. reinoud j.b.j. gemkc, gouke j. bonsel , the dutch picasso (pediatric intensive care assessment of outcome) study group. twilbelmina children's hospital and utrecht university, utrecht department of clinical epidemiology, academic medical center, : amsterdam, the netherlands the performance of all ( ) pediatric intensive care units (icus) in the netherlands ( tertairy and non-tertiary) was analyzed in an open prospective muiticenter study. effectiveness of care was defined as the ratio of observed to prism-score derived expected mortality aenee, standardized mortality rate). efficiency was determined by objective criteria (mortality risk > % or administration of at least icu-dependent therapy)'. consecutive admissions aged < years old were included. overall, observed and expected mortality were in good agreement (p > . ). between hospitals, crude mortality showed wide variations (mean . %, range - %). however, in each center, observed and expected mortality were similar (mean ratio . , range . - . ). in tertiary care centres, severity of illness corrected mortality in high-risk patients was less than in non-tertiary care centres; paradoxically, in low-risk patients the opposite was found. probably the large proportion of low-risk tertiary care patients suffering from severe, incurable chronic disease, explains the higher mortality in this group. this indicates that simultaneous assessment of circumstances of dying and of long term morbidity in similar future studies is imperative. the average proportion of efficient icu days was %, however large variations between units were found (range: - %). in conclusion differences in mortality rates among pediatric icus were explained by differences in severity of illness. high efficiency rates in combination with adequate effectiveness, found in several centres suggest that admission and discharge decisions might be improved by a better selection of high risk patients requiring icu-dependent therapies, especially in less efficient centres. objectives: previously published studies showed that serum lactate levels correlated with outcome of severe ill adult, 'we hypothesized that critically ill newborns are often incurred hypopeffusion manifested by elevated lactate levels. these initial blood lactate levels should be related to nicu outcome. design: prospective study with ethical comfnittee approval. setting: the -bed neonatal intensive care unit of a university hospital material and method: a total of consecutive outbem newborns admitted to nlod from , . to ., . were enrolled to the study. babies who died or were discharged from the unit within hours of treatment were excluded from the study, mean birth weight was g (+/- r), mean gestatational age was weeks (+/- . wks), mean age at the admission was h (+/- hi. multiple (~_ j organ system failure occurred jn . % of babies at the admission./~tertal lactates were measure/at the admission, among - hour and - hour of n[c'lj therapy. outcome was defined as a mortality and length of nicu stay. results" survival rate was . %, mean length of nicu stay for survivors was . days (+/- . day). we found high lactate levels at the admission in . % babies (~ . % with levels above . retool/i). the mean arterial lactate concentrations for nonsurvivors were signiftcahtly higher than for survivors durin~ consecutive da~ as follows: objectives: the purpose of our research was to analyze the frequency of bronchial asthma (b.a.) exacerbations in pregnant women and health status of infants. methods: the research was based on the epidemiological investigation and prolonged observation of pregnant women with b.a. during the gestation period. remission of b.a. before the pregnancy in excess of years was recorded in patients ( . %), patients ( . %) reported a - year remission and patients ( . %) had a remission lasting less than months before they became pregnant. results: seven patients ( . %) developed medium attacks in the second half of pregnancy, four patients ( . %) experienced light attacks of b.a. asthma attacks were most frequently caused by acute respiratory diseases and stress factors. in two cases with grave manifestation of b.a., the pregnancy ended in abortion within the first - weeks due to the frequent and heavy choking attacks. to fight b.a. attacks, five patients used adrenomimetics (salbutamol, becotid) in sprays, six women were administered theophyllinum and salbutamol in the form of tablets during - weeks. a significant portion of pregnant women with b.a. ( %) exhibited frequent complications during pregnancy (toxemia, late gestosis, threat of miscarriage). our findings prove that babies born from women with b.a. of domestic and pollen origin had a low body weight ( - gr), functional immaturity and chronic antenatal and intranatal hypoxia twice as often as the infants born from healthy women without allergic background. conclusions: preventive treatment of women with b.a. prior to pregnancy is required to maintain a stable remission of the disease, which is a key to having healthy children delivered by mothers suffering from b.a. introduction. intracerebral hemorrhage (ich) is a common event in human prematudty, affecting about % of newborns weighing below g who are born before weeks of gestation, however, little is known about the pathogenesis of ich with exception of the prematurity of the brain itself, (birth) trauma, and asphyxia. the postischemic production of oxygen free radicals (ofr) dudng reoxygenation as a cause of brain damage has been demonstrated in animal research. since almost all preventive antioxidant activity of plasma is associated with ceruloplasmin and transferdn we investigated the association of such iron-oxidizing resp. iron-binding proteins and ich. we could demonstrate significantly reduced levels of both, iron-oxidizing and iron-binding proteins, in premature asphyxiated newboms pdor to development of ich. an increase of suparoxide after hypoxia in the presence of iron ions facilitates the formation ofthe highly reactive hydroxyl radicals. our data support the theory that ich may be caused by ofr, which can damage any sensitive tissue including growing endothelial cells. the estimation of transferrin-saturation and measurement of ceruleplesmin levels might help to identify an infant at dsk before the onset of ich. with the new medos | hia-vad | cardiac assist system the missing tool in the armamentarium of cardiac surgeons is available in two pediatric sizes: i -ml and -ml pump volume. the right sided pumps are % smaller for biventricular use. between february and may we implanted this assist system in children. the indications and demographics are indicated in the following table (left ventricular assist device-lvad, right vad-rvad univentricular vad-uvad, post cardiotomy cardiac failure-pcf, dilated cardiomyopathy-cmr bland white garland syndrome-bwg, tetralogy of fallot-tof, hypoplastic left heart syndrome-hlhs). objectives: evaluate tile effeci'of inhaled nitric oxide (no) as puhnona] t vasodilating agent ill tile posloperalivc period after correclion of congenital heart defects in infant. patient n.l: kg, lnonlhs, down syndrome undenvcnl rep~fir of atrioventricular septal defect (avsd). after surgery the puhnonary arlcry pressure (pap) slowly rose to tile syslemic dcspilc tnaximal eonvcnlional fllerapy (fentanyl mcg/kg/h, hypocapnia of mmhg and metabolic alcalinization). no was delivered into tile inspiratory branch of!be breathing circuit at ppm, and the gas aoalyser for no and no (polylron dmger) were situated at the espiratory branch, a rapid dccrcasc of pap io i/ of systemic was obtained with a dramalic improvement. no was continued at ppm for six days and the baby was exlnbated if! days after surgery and discharged from the icu days after. patient n. : . kg, monlhs, onderwen! repair of avsd. the day after surgery the systemic oxygen salnralion was % wilh a pap at % of systemic. two hours of c wenlional therapy failed o improve ihc patient and no administration was slarled at ppm. so dramatically incrcased to %, but the pap dropped only to % of syslemic. nevertheless ihe clinical conditions improved and the no administration could be reduced at ppm in the following days. she was extubaled days after surgery and discharged from the icu days after. patient n. : kg, 'ears. underwen| hearl tral~splantalion for congenital heart disease with moderate hypoplasia of pulmonary arlcrics. at the end of cardiopulmonary bypass the transpnlnlonary al~erio-venoas gradient yeas higher than mnfflg and we speculaled !hat w'ls due to a degree of puhnonary vasocostrictiont. the nsnal dose of no was otilised, however no significant modilicalion of pulmonary pressure or systemic oxygen saluralion was noled, and after h no was discontinned. tile palienl was carried io the icu with maximal inotropic support, extubated after d;b's and disclmrged from the icu after days. in all patient no major adverse effect relaled to no admilfistration ",','as holed. conclusion: in our experience no ms a pulmonary vasodilaling agent is effective and easily adjustable to tile palienls requiemenls, however its use remains limited ill those palienl ill whoin tile alnonll! of fixed inlllllojliify vascular resistance is predominanl. we report the use of ecmo support in two unusual cases of severe tracheal disruption in which it had become impossible to achieve adequate ventilation. case : severe tracheal laceration due to aspiration of a share forelan bodv: a previously healthy month old toddler was referred for ecmo following aspiration of a porcelain foreign body (with razor sharp edges) which had become embedded in the right mainstem bronchus with massive extrusion of air. this was removed on veno-arteda[ ecmo support, as the patient was unventilatable prior to bronchoscopy due to ongoing airieak. ecmg was continued after bronchoscopy to permit airway healing without the presence of an endotracheal tube. unfortunately, an extensive pulmonary haemorrhage on day of ecmo necessited re-exploration of the airway. this revealed a posterior tracheal tear from the cricoid to the middle of the right lower lobe. following repair the patient was left on ecmo support together with high frequency oscillation ventilation (hfov), the latter being used to minimise potential aideak and maximise alveoli recruitment. ecmo was weaned after days ( hours) -the patient was extubated weeks later. case : tracheal wound dehiscence due to seosls -tracheal transelant on ecmo: a month old infant with a c[inically significant congenital long segment tracheal stenosis and left pulmonary artery sling underwent resection of the stenosis, followed by primary reanastomosis. this was complicated, days later, by severe mediastinitis and complete dehiscence of the anastomosis. an autologous pericardial patch was used to repair this, however, the tracheal wound again dehisced days later making mechanical ventilation impossible. in view of ongoing sepsis and a severely disrupted trachea ecmo was the only possible form of support. following resolution of the local sepsis ( days) a definitive procedure in the form of a tracheal homograft (transplant) was undertaken on ecmo. the patient was managed on ecmo and hfov for a further days, the hfov being used to optimize rapid lung inflation. unfortunately this patient died months after weaning from ecmo due to complete disintegration of the homograft, which was not deemed reparable. conclusions: ) ecmo can be used in the acute management of oxygenation when there is major airway disruption making mechanical ventilation impossible. ) hfov was a useful adjunct in aiding recruitment of lung volume on ecmo in these two patients. backoreund: persistent pulmonary hypertension of the newborn (pphn) consists of a heterogenous group of diseases ranging from transient reversibte pulmonary hypertension to fixed primary malformations of the lung (primary pulmonary dyspfasia-ppd). inhaled nitric oxide (ino), a selective pulmonary vasodilator, has been proposed as a treatment for severe pphn. obiective and methods: ino was administered to near term neonates with severe persistent pphn, oxygenation index > and echocardiogrephic evidence of pulmonary hypertension, in order to further determine the clinical role of ino in the treatment of pphn. the response to ino was also analysed retrospectively to examine whether this could be of diagnostic value in differentiating at an early stage patients with reversible from fixed causes of pphn results: twenty one of the patients studied responded to the initial trial of no ( ppm x minutes), as defined by a greater than percent improvement in pad as well as a fall in the el to < . these patients were continued on ino therapy, with patterns of response emerging: pattern babies (n= ) continued to show a sustained response to ino and were successfully weaned from it within days -all survived. pattern babies (n= ) failed to sustain their response to ino over hours, as definded by a rise in the el > . six survived, five with ecmo. pattern babies (n= ) had a sustained dependence on ino for - weeks. all three died and lung histology revealed severe primary pulmonary dysplasia (ppd). patients with ppd (pattern ) not only required ino for longer periods of time than did the sustained responders (pattern ), but also required significantly higher doses of ino we report on the air transport of paediatric intensive care patients. these transports fall into three categories: ) retrieval of critically ill neonates and paediatdc patients referred for either ecmo or inhaled nitric oxide (ino) (n = ). one patient was transferred on ind. mean transfer time . hours (se + . hrs). ) long distance international transport using chartered aircraft (n = ). the indications for these transfers included both urgent retrievals for cardiac surgery and semi-elective transfer of stable patients back to their referring unit following treatment in tertiary centres. mean transfer time . hours (se + . hrs) ) long distance international transport using commercial aircraft (n = ). indications for transfer were either semi-elective retrieval for tertiary treatment or the return of stable chronically ventilated patients to their referring hospitals. mean transfer time hours (se _+ .fhrs, longest hrs). the transport team consisted of a paediatric intensive care doctor of at least registrar grade and a registered sick chidrens nurse with intensive care experience. the administrative components of the transfer (ambulances, airlines, customs) were managed in collaboration with companies specializing in air ambulance transfers. outcome: all the patients were safely transported to their destination without mortality or morbidity. complications durino transfer ir~lv~; ) patient complications -semielective endotracheal tube change and central access needed in the only patient brought to the commercial aircraft by the referring hospital (all others retrieved directly from referral hospital), seizure in patient with known encephalopathy, severe cyanotic spells in patient with fallots tetralogy who was retrieved for urgent surgery for this indication ) mechanical compfications -ventilator failure, incubator battery failure, oxygen regulator failure -all occurred with equipment sent from referral hospital, this was unfamiliar and unchecked by our transport team -it was not the decision of the transfer team to use this equipment on this single occassion. ) administrative complications -confiscation of incubator battery by airport security police, excessive delay by custom officials ( hours) in the airport. the incidence of such problems were felt to be low and unpredictable. in conclusion: mechanically ventilated paediatric patients can be safely transported on both chartered and commercial airlines. these transports are best accomplished by trained intensive care medical and nursing staff with the backing of an air ambulance organization competent in arranging the necessary administrative details. it is essential to use your own equipment and to retrieve the patient _directly from the referrin(] hospital to minimise ootential complications. our experience with anaesthesia for paediatric electromyography _w_._pla_ti_k_a_n_o_v, r.eousseff, k.pavlova, d.marinova dpts. of anaesthesiology and int. care and clinika] neurophysiology, med. university, pleven, bulgaria ~)_b_j#~ti_v~. to t~st a " heavv sedation " regimen of anaest-es~a for the purpose of paediatric electromyography d#s~gil~ non-randomized,non-blinded human trial in the seting of an uriiversity hospetal. _m_a_t_eri_a_is_a_nd_ m_e_th_od_s_. children,asa i-if,median age years,range - who undervent eleetrcmyography required anaesthesia. they recieved low-dose ketamine + i~iazepam or midazolam via musculary route( children,age - yrs,ketamine , mg/kg, diazepam - mg total dose ) or per os ( children,ketamine - mg/kg,diazepam , mg/kg or midazclam , - , mg/kg ) _resu_l_t_s. - minutes after medication a state of heavy sedation with weak spontaneos and stimuli-provoked movements was achieved in all children, that lasted - minutes and allowed adequate needle emg and nerve conduction investigation. children recieved additional , - , vol.% halothane during the placement of the needle. non -invasive blood pressure , breath and heart sounds and hb sad by pulse oxymetry were monitored.none of the older children disclosed memories of pain when asked after they regained adequate verbal contact.no complicationes were observed. antenatal maternal steroids reduce the risk of periventricular-intraventricular hemorrhage in very premature neonates treated with natural surfactants. i.apostolidou, c.papagaroufalis, g.touloumi, m.xanthou, n.kalpoyannis a' and b" neonatal icu "ag. sophia" children" s hosp. athens, greece. dept of hygiene and epidemiology, athens university, greece. obiectives: the aim of the study was to evaluate the association of periventricular-intraventricular hemorrhage (p-ivh) in surfactanl treated premature neonates with pre-and postnatal variables. methods: the population of the study was neonates admitted during the years to , with gestational age _< weeks and severe respiratory distress syndrome (rds) (mechanical ventilation and arterialalveolar oxygen tension ratio (ajapo ) < . ), who received rescue therapy of at least two doses of natural surfactants (alveofact or curosurf) and examined with ultrasound and/or autopsy for the presence of p-ivh (papile's classification). the examined factors in each neonate were the following: gestational age, birth weight, sex, multiple pregnancy, antenatal maternal steroids (complete and incomplete course of betamethasone), a/apo before the administration of the st dose of surfeclant, delivery, apgar score at min, type of surfactant, pneumothorax and patent ductus arteriosus. the statistical methods used were x and one-way analyses of variance followed by logistic regression medels, results: the incidence ot p-ivh was . %. three factors were found to have an independent relation to p-ivh (final logistic regression model): gestalional age, a/apo before surfactant administration, and antenatal administration of maternal steroids (complete and incomplete courses). for every weeks of lower gestational age the neonates had an almost doubled associated risk of p-ivh (or: . , % c : . , . ). for every . on average decrease of a/apo before surfactant administration the risk of p-ivh in the neonates was . times higher ( % ci: . , . ). the neonates whose mothers received antenatally steroids had only one tenth of the risk of p-ivh of the neonates whose mothers had not (or: . , % ci: . , . ). conclusions: our results suggest that the antenatal administration of maternal steroids, even less than hours before delivery, reduce the risk of pqvh in very premature neonates treated with natural surfactants, whereas the small gestational age and the lung immaturity still remain the main risk factors tor the development of p-ivh. we analysed retrospectively the management of ( boys, girls) accidental ingestions of foreign bodies in children (mean age : . years, range : months- years). no child had ingested more than foreign object. the majority of the ingested foreign bodies were : coins (n : ), toy parts (n : ), jewellery (n : ), batteries (n : ), "sharp" materials such as needles and pins (n : ), "large" amounts of food (n : ). impaction of food occurs more frequently in children after oesophageal reconstruction in cases of oesophageal atresia. although according to literature "coca-cola" is reported to be effective, this was not seen in our experience. / patients had minor transient symptoms at the moment of ingestion, such as retrosternal pain. only children experienced severe manifestations (cyanosis, dysphagia). in these children, endoscopy revealed oesophageal and gastric erosions. children were seen at the emergency ward within a few hours after the accident ( mean : hours, range min. - hours). chest and/or abdominal x-ray was performed as first-line investigation ( / objects were radio-opaque), and revealed an (unexpected) oeeophageal impaction in children. in / the foreign body was in the stomach. batteries, sharp objects and objects trapped in the oesophagus were removed, either by endoscopy or by magnet-extraction whenever possible. the outcome of the patients was excellent. no complications were observed. extraction is recommended in symptomatic patients, and whenever the foreign body is trapped in the oesophagus, or if the foreign object is "sharp" or a battery. objectives: two strategies were used for management of malignant diphtheria in children aged from . to years. methods: protocol n consisted of intravenous administration of diphtheria antitoxic serum, prednisolone ( mg/kg bw/day), plasmapheresis and supportive care. protocol n included the use of antitoxic serum against the background of high-dose dexasone ( - mg/kg bw/day), hemocarioperfusion and a preventive use (before the clinical manifestation of myocardial damage) of inotropic medications, inhibitors of angiotensin-converting enzyme and pentoxyphylline. each of protocols included the monitoring of serum toxin (diphtherin) levels. results: the group of patients treated according to the protocol n consisted of children with malignant diphtheria, of them with severe malignant diphtheria (grade and ). all patients exhibited the circulation of toxin during at least three days after the start of treatment. all patients with severe grade of disease demonstrated heavy cardiovascular disturbances associated with malignant diphtheria. of the children in the group died seven. the children of the second group were treated according to the protocol n . out of total of patients of this group. patients had severe malignant diphtheria. in all children a significant reduction in serum toxin level was revealed after hemocarboperfusion. in all but one case the satisfactory control of cardiovascular function on was achieved. of children admitted to the trial survived, one child with malignant diphtheria of grade and congenital filbroelastosys of the left ventriculum died. the severity of neurological complications was similar in each of groups. conclusions: the use of hemocarboperfusion, high-dose dexasone and early prevention of heart failure as a adjunct to the standart treatment has been shown to be of benefit in the management of malignant diphtheria. t. schaible, i. reiss, j. m er, l. gortner med. university of lqbeck, children's hospital, kahlhorststr. - , l~beck, germany surfactant therapy seems a promising approach for the treatment of the biochemical and biophysical abnormalities of the pulmonary surfactant system in severe ards. patients and methods: over a months period non-neonatal pediatric ards patients (age - months) in a "pre-ecmo"-situation (oi over h) were treated with bovine surfactant (alveofact| the underlying conditions-of ards were pneumonia ( ), sepsis ( ), immunosuppression ( ), near drowning ( ), neurogenous ards ( ). a total of - mg/kg b.w. was applied in several fractions. before surfactant therapy, we first tried different ventilation (best peep-finding, inversed i/e-ratio, hfo-ventilation) while monitoring the pulmonary mechanics. for hemodynamic stabilisation both norepinephrine and epoprostenol were used to optimize pulmonary perfusion for max. hrs. if there was no improvement of the oi by at least , further treatment with surfactant was initiated. in addition to surfactant all patients received a treatment with dexamethasone of mg/kg in doses. patients with no benefit (oi remained unchanged or increased within the max. - hrs) were taken on ecmo. results: nine patients improved within hours after surfactant therapy: the oi decreased from a level of (mean, range - ) before our treatment to a level of (mean, range - ) thereafter. in patients we were able to continue the positive effects of our treatment and they could be weaned of the respirator within - days. the other patients got worse despite respiratory improvement, they suffered of multiorgan failure of more than organ systems. the last patient did not benefit from surfactant, he had to be put on ecmo, but died because of a complication (hemopericard)after days. the autopsy of the ecmo-patient showed a pulmonary fibrosis, but the other death were not due to pulmonary failure. conclusion: a different sequential ards treatment integrating surfactant therapy can reduce the number of patients requiring ecmo. but ecmo as a therapeutic tool should be available in centers involved in ards treatment. l.blindl, t.p.le, h.weinzheimer, centre for paediatrics, university of bonn, germany selective reduction of elevated pulmonary vascular resistance by inhaled prostacycliu (pgi) has been reported in adults with acute lung injury, neonates with persistent pulmonary hypertension and in one infant with idiopathic pulmonary hypertension. we report on the effect of aerosolized prostacyclin in two children with secondary pulmonary hypertension. patient : in a boy with down's syndrome an avsd had been surgically corrected at month of age. at , yr of age a catheter examination revealed a pulmonary vascular resistance of % of systemic vascular resistance in room air and at an fin of . . prostacyclin ( . mcg/ml) was administered with a jet nebulizer at an fin of . . pvr declined to . systemic vascular resistance and returned to baseline after stopping pgi-inhalation. subsequent intravenous infusion ( ng/kg rain) had to be stopped after minutes because of systemic arterial hypotension. patient : a month old male infant with bronchopulmonary dysplasia developed suprasystemic right ventricular pressure inspire of therapy with oxygen and nifedipin. while he was spontaneously breathing % oxygen via face mask pao was mmhg, arterial ph was . . systolic arterial pressure was mmhg, a rv-ra gradient of mmhg was measured by cw-doppler. while fio was maintained aerosolized prostacyclin was administered over minutes. rv-ra gradient was mmhg, systemic blood pressure mmhg, pao mmhg. two hours later nitric oxide ( ppm) was inhaled at an fio of ( , . rv-ra gradient declined from to mmhg, systemic systolic blood pressure remained stable at mlnhg. discussion: sporadic experience shows that aerosolized prostacyclin selectively reduces elevated pulmonary vascular resistance in some patients. in patient the poor response to inhaled pgi compared to inhaled nitric oxide may be explained by the fact that the action of pgi is not independent from endothelial function, limiting it's effect in severe vascular disease. during the last two years ( - ), infants weighing less than gr. admitted to our referral unit. thirty four of them ( %) survived, ( % of infants weighing - g and % of infants weighing - gr survived) for the years - - the survival of these infants was % and for the years - - , % (p< . ). we analyzed the perinatal and neonatal factors influencing the outcome of these infants. the comparison among neonatal survivors ( ) to neonatal deaths ( ) shows: gestational age: . w ( ) to . w ( ) (s). birth weight: . g ( ) to . ( ) (s). apgar score: , ( ) to . ( ) (ns). presentation and mode of delivery: breech presentation is associated with higher incidence of neonatal deaths. i.v.h. (at the age of weeks): no one of the survival infants had evidence of i.v.h. respiratory problems: intubation, at the admittance of the infants . ",,( ) to % ( ) (s) use of surfactant: % ( ) to % ( ). bpd observed in % of the babies and only one was dependent on oxygen at home. antenatal betamethasone was given in % of the mothers. in conclusion: ) a great improvement in the survival rate observed in these infants the last years in our unit. ) factors with positive effect are increasing gestational age and birth weight, the absence of i.v.h. and the use of surfactant. the breech presentation and the severe respiratory problems increase the incidence of death. animal experiments demonstrated, that brain temperature determines the amount of neuronal damage caused by hypoxia and that mild hypothermia may have a protective effect. until now there is no method described and evaluated to measure brain temperature in neonatal intensive care units. we non-invasively measured brain temperature analogues, nasopharyngeal (tnasoph) and zero-heat-flux temperature (zht) at the temple whereby under zero heat flux surface temperature represents deep head and thus brain temperature. the aim of our study was to investigate the practicability of the method, the relationship of the two brain temperature analogues to rectal temperature (trect) and their dependence on insulation, thermal environment, body activity and time course. we investigated healthy preterms less then weeks postnatal age (gestational age +_ . wks; x + sd, weight +_ g) in an incubator. tnasoph was measured by a thermistor within a feeding tube, advanced to the nasopharynx, zht temple by a thermistor and a heat flux transducers both covered by an insulating pad, and trect thermal environment was characterised by operant temperature (tair . . + twall . ). body activity was video taped. measurements were performed during the following interventions: i/ insulation increased by turning the temple with sensors onto the mattress ( rain). ii) insulation increased by a cap ( min), iii) min after its removal, iiii) increased operant temperature by . + . ~ ( min). results: seven children with ea had a gasless abdomen, the endoscopic procedure excluded ( ) or diagnosticated an upper pouch fistula ( ). in patients who suspected "h" fistula ( ) broncoscopy has strong advocated method to make diagnosis and established cervical approach. from july newborns with ea and lower pouch tef received a selective transtracheal incannulation. we were not able to proceed just in case with congenital subglottie stenosis. in these patients we provided gastric drainage by radiopaque and flexible - french catheter. the knowledge of the precise anatomic position of tef consent to adjust the tip of the endotracheal tube in order to achieve best ventilation. the presence of the catheter through the fistula helps the surgeon to identify, it quickly. no complications were correlated to the procedure and no babies had early pneumonia. alimentary continuity was achieved in all patients ( primary anastomosis, resections of tef, oesophagocoloplasty and died with gastrooesofagostomy). the late mortality . % ( ) was only directly related to the severity of associated malformations. conclusion: the advantages of this technical approach are unquestionable for the anaesthesiologist and the surgeon. in our experienc e the procedure improves perioperative management of babies and appears to be safe. relation between cytokines, prethrombotic markers and endotelial injury markers in children with septic shock objectives: to establish the relationship between cytokines (tnf, il- , il- ) prethrombotic markers (d.d., pcam) and endothelial injury markers (tm, uwf) in pediatric patients with sepsis and bacteriemia without shock, and patients with septic shock. design and methods: prospective study, children ( months- years) were admitted in our picu in with the following diagnosis: bacteriemia ( ) sepsis ( ) and septic shock ( ) according to jacob's r f criteria. measurements: il- , il- , tnf, tm, vnf, d.d. pcam and routine laboratory data on admision, , , hours and on discharge. the prism (pediatric risk of mortality score) was also recorded. results and conclusions: two patients in the septic shock group died. significant differences were found between non-shock and septic shock patients in relation to tm, dd, pcam, il- , il- and tne high levels of tnf and il- are closely associated with the severity of septic shock with purpura in children. low levels of pcam on admission were associated with severe shock. who underwent open hea~nt surgery, hypervotaemia with or without oliguria was the most frequent reason to start pd ( %). in patients pd lasted less then one week and there were no complications; in patients it lasted - days (one child had a peritonitis). instillation of dialysis fluid into the peritoneal cavity was associated with a significant increase in central venous pressure. there were no significant changes in cardiac output or arterial oxygeu saturation. in all patients pd dhnjnished fluid overload or improved the metabolic status. patients ( %) survived the postoperative course and all had complete reintegration of renal function. conclusion: pd is a useful method to treat the fluid overload and acute renal failure in paediatric patients following open heart surgery with file effects of little importance on the cardiovascular fimction. obieetives: with the marketing of computerised systems for lung function testing in newborns, there has been an increasing interest in clinical approaches. percentile curves of pulmonary parameters permit an appropriate and clinically useful interpretation. however, the manual evaluation of the results using different curves is an impractical technique. therefoi'e a computer programme was developed. methods: the percentiles ( %, %, ~ %, %) of the most important pulmonary parameters were determined non-parametrically in weight-classes. for the calculation we have taken results of our own as well as other laboratories using a meta-analysis of reference studies. in all, individual data of - healthy newborns ageing between - days were collated. using these percentiles, for every parameter in relation to the body-weight the cumulative distribution was calculated approximately using piecewise linear and exponential functions. as shown in the figure the results of computing are represented numerically as well as graphically and can be included in the patient report. conelusions: clinic~d experiences with the programme have shown that representation of all measured parameters on standardised % scales allows an easy interpretation at first sight and improves the detection of pathologic patterns in the parameters. ")supported by bmft, fp "risikoneugeborene" prism (pediatric risk of mortality) score is a well known, already validated scoring system that quantifies severity of illness based on routinely clinical and laboratory variables measuring physiological instability. once computed the score by summing up the weights corresponding to the most abnormal value recorded during the first hours, the overall risk of mortality can be predicted by using the coefficients estimated by a logistic regression where prism score is the main independent variable. (pollack mm et al, -pediatric risk of mortality (prism) score. crit. care med. ; : - . to assess the applicability and validity of prism in the italian setting we launched out a prospective data collection in a sample of pediatric icus. measures of calibration (goodness of fit statistics) and discrimination (receiver operating characteristics and area under the roc curve) are planned to be adopted in the cohort of patients recruited during year period. as the validation study started on july , data collection is still on going and validation analyses will be carried out on july . up to now centers recruited cases. at present, characteristics of the sample recruited are the following: most of the patients were male ( %); the mean age is years with % of patiens having less than days; more than half were medical cases ( %) admitted from emergency room or from hospital floor ( %); % cases were admitted with an organ failure while % to be intensively monitored. icu-mortality was l %. the paper will present final results of calibration and discrimination analyses that will be carried out in the whole sample and across subgroups known to differ in terms of clinical relevance and prognosis. if calibration and discrimination assessment will produce not satisfactoty findings, a customization of the current coefficients will be made allowing a formal comparision of previous and new parameters. jf riera-faneao, m wells, j lipman. baragwanath intensive care unit, university of the witwatarsrand, south africa. [background the prism score is designed to assess the likelihood of death in ipaediatdc icu patients, using only acute physiological disturbances, age and [operative status to predict mortality. there is no evaluation of chronic health status, [including malnutrition. this may significantly affect its ability to accurately predict outcome in a population where malnutdtion is common. aim to determine the influence of nutritional insufficiency, as indicated by a low weight-for-age on outcome prediction by prism. patients & methods we analysed prism, weight and demographic data co ected prospectively from consecutive paediatdc icu admissions over a year pedod. a proportional weight (pwt) was calculated as a percentage from the th centile of the who weight-for-age growth charts. the pwt was compared for survivors and nonsurvivors, and mortality compared for pwt categodes nho wellcome classification). multivariate statistical techniques were used to identity associations with non-survival and to develop a modified logistic regression equation including a measure of i nutdtional status. receiver operating characteristic (roc) analysis was performed including and excluding patients with low pwt for the odginal and modified equations. results non-survivors had a lower weight than survivors ( . kg and . kg medians p = ) a lower pwt ( % and % medians p = . " . the incidence of malnutdtion , in our icu population was %. the mortality of manoudshed patients was' significantly increased (p = . ), with a good correlation with the degree of malnutrition. the accuracy of prism was significantly improved when malnourished patients were excluded from the analysis (roc value increased from . to . ). ! logistic regression and discriminant analysis identified a significant association between prism, pwt and outcome; age and operative status were not significantly related to mortality. the use of a modified equation including the raw prism score, pwt category and age can significantly improve the discriminatory power (az dm/elopmental sample . , az validation sample . ). the modified formula is: legit = - . + . *prism score - . *age + . *weight category, where the probability of mortality is exp(iog/t)/ + exp(iogio. discussion although we can improve the prediction of mortality by a modified or recelibrated formula, this still does not compare with the reference prism population. the need for validation of the score itself, in the association with outcome of the acute physiological variables themselves, is thus apparent. we conclude that while the odginal prism formula can be improved significantly, a modification of the basic variables in this and other third wodd populations may be essential. a high incidence of malnutrition is an independent risk factor of mortality, and an important cause of the poor discriminatory performance of prism. in order to improve the accuracy of prism, nutritional status should be taken into account. objectives: to assess the value of inhaled no to differentiate between pulmonary vascular constriction or fixed anatomical obstruction. methods: we assessed the response to ppm inhaled no in patients( m, f, median age . months, range day to years) with signs of increased pulmonary vascular resistance, there were pre and postoperative patients. patients were divided into responders(+) or non-responders(-). a positive response was defined as a % reduction in pulmonary arterial pressure and pulmonary vascular resistance(pvr) or in the presence of a left to right shunt, a fall in pvr accompanied by increasing pulmonary blood flow. left atrioventricular valve atresia + mustard pat: pulmonary atresia vsd: ventricular septal defect asd: atrial septal defect pda: patent ductus arteriosus tapvc: total anomalous pulmonary venous connection the responders( / ) were characterised by left to right shunts or pulmonary venous hypertension( / ). patient# was weaned from ecmo with inhaled no. patient# , without congenital heart disease, underwent a lung biopsy which confirmed reversible pulmonary vascular changes. patient# had a pulmonary hypertensive crisis which responded to no. all non-responders( / ) had evidence of anatomic obstruction to pulmonary blood flow (# , , )or a low pvr(# ) on subsequent cardiac catheterisation. in patient # , lung biopsy confirmed severe obliterative vascular disease. conclusions: inhaled no appears to be an effective pulmonary vasodilator. a failed response may be evidence of either irreversible pulmonary vascular disease or a residual anatomical obstruction which may be surgically remediable in the postoperative cardiac patient. therefore, inhalation of no may be a useful diagnostic test to differentiate between fixed anatomical obstruction and reversible vasoconstriction. results: during these years, the incidence of sdra was . % of the total of admissions. the most common etiology was meningococcic septic shock. since , there is a decrease of its incidence. (from % to %) and an increase of pneumonia and immtmodeficiencies. mean age of our patients was , years ( % males, % females), total mortality by sdra was % and there is an increase up to % since mean time of stay of the dead was , days and , days those who survived. although during the late years we offer in the picu a better attendance quality to the patients with sdra and the mean stay is longer, both for those who die and for those who survive, mortality of patients with sdra have increased. the incidence of sdra secondary to the septic shock of a meningococcic etiology have decreased. on the contrary, the sdra secondary to infections by opportunistic germs in patients with congenital inmmunodeficiencies or acquired immuodeficiencies have a tendency to increase. in our series, this change of aetiology is the responsible for the increase in mortality. hospital infantil unlversitario "virgen de roclo". sevilla. espalqa aims:to assess the incidence, etiology, clinical course, sequelae and mortality of the patients admitted to a paedfiatic intensive care unit with the diagnosis of severe traumatism. material and method: cases of severe traumatism in children admitted to our icu in the period from january to june were reviewed. age of patient ranged from months to years, % were males. in our series, % of cases suffered traumatism due to a traffic collision and % had a fall from a considerable height. only in one case was traumatism due to violence to the child. we assessed the first assistance received in % of cases: where was it performed, interval of time since the accident, and steps taken. these data were also studied in relation to the latter evolution. results: % of our patients suffered cranioencephalic traumadsm (ct); in % it was an isolated picture and in % of cases was associated to other lesions. there was participation of thoracic and/or abdominal organs in % of cases. % of cases presented important maxillofacial involvement. only one case presented serious cervical medullar lesion. mortality in our series was . %. in . % important sequelae remained. all of these patients presented tepas on admission equal or lower than . % of those with traumatises had slight sequelae. . % of the total evolve towards healing. a polytraumatized child is a patient that benefits considerably of it admission in a paedriatic !cu. the rapidity in receiving first aid and its quality are essential to avoid sequelae and to make mortality decrease. after unilateral lungtransplantation % of the patients develop a lung failure with decrease of perfusion and increase of pulmonary blood pressure in the transplantated lung. the improvement of perfusion is an importent task in the postoperative period. case report: a year old girl with idiopathic pulmonary fibrosis received a left sided single lung transplantation. during the early postoperative period occured a higtter demand of oxygen and an increasment of the pulmonary vascular resistence in the left lung. the pulmonary ventilation and perfusion scintigraphy indicated in comparison with the right lung a reduced perfusion of only % in spite of a ventilation of % of the transplanted lung. to improve the perfusion of the transplant we administrated per inhalation prostacyclin in a maximal dose of ng/kg/min. the arterial blood pressure decreased but the perfusion continued nearly at the same level. during the following administration of ppm no in the respiratory air we achieved a significant reduction of the respiration pressure f~m to nun h and of the pulmonary arterial pressure. the perfusion in the transplanted lung increased to ca/of the total pulmonary perfusion. after days of administration with no we were able to withdraw the axtifical respiration without any following complications. conclusions: the perfusion of transplanted lungs is a major proble_r~ in the postoperative period. this case demonstrated the advantage of no towards the inhalativ application of prostacyclin. no showed a significant improvement of perfusion in the transplanted lung of a year old girl. results: a total of children with ards were treated with bovine surfactant (alveofact| cases were evalable. the median age was . years (range weeks to , years). in six cases ards was associated with pneumonia, in two cases with lung hemorrhage; in one case isolated ards followed hemihepatectomy. the first surfactant application was performed with a median latency of clays (range - days) after first symptoms of ards witha median doseof mg/ kg (range - mg/kg). in patients doses of surfactant were applied. during the hour before therapy, the median pao / fio -ratio was - . within min. after application of exogenous surfactant the pao / fio -ratio increased to with successive decrease over a period of hours to . accordingly, an increase in pao and oxygen saturation and (less significant) a decrease in ventilation parameters could be observed. analysis of broncho-alveolar lavage before surfactant application in children receiving repeated doses revealed in most examined cases either clear surfactant deficiency or pathological function. of treated patients survived ( of the , respectively). of the surfactant doses were applied in the surviving patients.conclusions: the application of exogenous surfactant in children with ards caused a significant increase in oxygenation, which declined over a period of - hours. the effect often could repeatedly reproduced, in one case after applications. the increase in oxygenation often allowed the reduction of fio and/or the inspiratory pressure. no side effects were observed after exogenous surfactant application.in many cases the application of surfactant wag too late after first symptoms of disease (median latency days). ards mostly due to pneumonia seemed to respond to surfactant therapy less well or not at all. permanent junctional reciprocating tachycardia (pjrt) is the most common incesant supraventricular tachycardia (svt) in children. it is usually drug resistant and its onset in early life has been associated with dilated eardiomyopathy. we report our clinical experience with patients detected antenatally and another diagnosed at months of age. method.diagnosis: negative p waves were detected in leads ii,iii and f, p'r > rp" and there was not warm-up at tachycardia onset.clinical records, ekg,x-rays, echo and holter were reviewed. ep studies were undertaken only with therapeutic purposes. results. in a year period patients under y of age fullfilled diagnostic criteria; were detected prenatally ( - weeks) and one was diagnosed at age mo. the fetuses had intermitent svt during gestation. all of them had pjrt in the first month of life at rates between and bpm. they were admitted to the icu but did not develop signs of heart failure. they were controlled with digoxine (d); d and quinidine; d and propafenone in to days. one was in sinus rhytm until age y; he then showed persistent pjrt over % of the day on repeated holters and underwent successful radiofrecuency catheter ablation (rfca).the other two patients showed initially a lowering of tachycardia rate followed by sinus rhytm for over % of the day (follow-up ran and y). the mo. old infant was admitted to the icu in severe cardiac failure. echocardiogram showed marked systolic dysfunction (shortening fraction %) treatment with digoxine, amiodarone and propafenone were unsuccessful despite lowering heart rate to ; rfca was performed at m. of age with restoration of sinus rhytm and rapid recovery of contractility. all patients were given atp at admission with transient ( to see) recovery of sinus rhytm. ff,s clinical course of pjrt is variable. atp is useful only as a diagnostic tool. initial treatment with digoxine + amiodarone or propafenone is adviced. rfca is a very useful therapeutic modality and can also be performed in young infants twelve patients ( %) died. these were meningitis, head injury, sub-arachnoid bleeds, status epileptieus, leukaemie, drowning, and multiple trauma. calculated from the a admission day p edialric risk of mortality score (prism), the probability of death (p) ranged from - %. of the deaths, i were predicted by prism analysis except for the leukaemie patient (p i%) who died from haematological complications following chemotherapy. two children predicted to die (p % & %) survived. the median length of stay was days (range - days). patlents( %) received ventilatn~ support and patienta( %) were transferred to specialist units ( neurosciences, liver, cardiac, bums). this data supports the view that many paediatric patients are being adequately treated in a dgh icu. meningitis and other neurological illness caused the majority of deaths and respiratory problems caused most admissions. most deaths ( of ) occurred within a few hours of admission. ectopic junctional tachycardia (ejt) is one of the most dangerous arrhythmias in the postoperative setting of congenital heart defects since it does not respond to antiarrhythmics or defibrilation. the object of this presentation is to report on two patients who presented f_jt in the early postoperative period and developed intense congestive heart failure which could be controlled after treatment with moderate topical hypothermia. two patients, m and y, diagnosed of atdoventficular septal defect and tetralogy of fallot developed intense heart failure in the early postoperative period. taehyeardia rate was and bpm. medical drug therapy included weaning from vasoactive drugs, iv digitalization and iv amiodarone treatment. there was not response. they were both surfaced cooled by placing plastic bags filled with cold water over the patient's chest and abdomen. temperature was monitored to obtain a central temperature of ~ there was a gradual decrease in heart rate in the following hours ( - bpm) paralel to the degree of surface cooling and clinical course estabilized.both recovered normal sinus rhytm in to hours. there were not significant arrhytmias after the procedure and postop, was uneventful. conclusions. moderate hypothermia is a very useful manuever for the treatment of drug resistant ejt. since it lacks side effects of other antiarrthymics we beleave it should be the treatment of choice for the treatment of ejt in the postoperative patient. present understanding of the pathogenesis of sepsis, based on the theory of systemic inflammatory reaction, has risen new interest in the more invasive methods of treatment, like plasmapheresis, leucapheresis and exchange transfusion (et). obiectives: evaluate the effect of et in the treatment of neonatal sepsis. material and methods: from september to december , a prospective study was carried out, where the severest cases of bacteriologically proven neonatal sepsis (n= ) were treated with et. in total newborns were treated for culture positive sepsis in the intensive care unit during this study period. diagnosis of sepsis was based on the clinical criteria of suspected neonatal sepsis, used by mc harris et al., laboratory data and positive blood culture. newborns with severe congenital malformations were excluded. et was carried out with fresh (less than hours old) adsol-conserved erythrocytes, from which buffy coat had been removed, and same donors plasma, using a slow continuous two-site technique. the mean volume of et was . ml/kg. the effect of et was assessed as a change in the score for acute neonatal physiology (snap), general treatment results were compared with a historical control group of newborns, treated for culture-positive sepsis in the same icu during the first eight months in . students ttest and chi-square test were used in statistical analysis of the data. results: with the use of el a significant decrease in mortality was achieved: death of cases during the study period, compared to deaths among the controls (p< . ). no baby, receiving et, died. the incidence of severe complications did not differ in the two groups. the snap-score showed quick improvement by the first post-transfusion day (p<o. ) and the effect persisted during the five following days. conclusions: we conclude, that the use of et in the treatment of critical cases may help to lower the mortality of neonatal sepsis. it provides a quick improvement in the clinical condition of septic neonates. the granulocyte-colony stimulating factor (g-csf) is largely employed in granulocytopenic patients. experimental studies have' demonstrated the effectiveness and safety of the therapeutic use, nevertheless the human employ is reported almost exclusively in neoplastic patients submitted to chemotherapy and in patients with fungal or pseudomona~ spp infections. the authors report the data concerning three non granulocytopenic children: in the first, o girl years old, affected by pseudomomm aerug/n~a pyeionephritis, the antibiotic therapy was not tolerated in consequence of renal and hepatic failure. the second patient, an infant months old, has been treated with salbactam-ampiciilin, ceftriaxone and chioramphenicol because of haemepldlw iafluem~ meningitis; a late neurological aggravation required the antibiotic therapy recommencement the last, a years old insulin dependent diabetic boy, was affected by cared/do spp systemic infection; the antifungnl therapy w~ not practicable in consequence of renal and hepatic involvement in all the g-csf was administred subcutaneously at the'dose of $ u for days. a significant increase of granulocytes was ever noted already after the second administration until hours after the last dose. clinical signs, fever and biochemical values are promptly influenced positively and all patients are restored to health. no side affects were noted. the granulocyte colony stimulating factor, at indicated doses, can prove of great help in critical patients, in who the antibiotic or antifangal therapies can result toxye or cannot be tolerated. the ~reptococcas p~, among the gram pmltlve~ represents the main causative organism of bacterial meningitis in children, with the majority of deaths occurring within hours of admission, the third generation cepohlosporim were indicated as antibiotic of first choice, and some literature reports have demonstrated no significant dlffereuces in dinical course of patients treated with ce~rlaxoae and of those treated with ampieibin and chlornmphenicol. the authors report the ease of on infant, male, months old, submitted to a neurosurgical interventiol after days the infant became febrile and lethargic and a bacterial meningitis by ~trepmcecctz ~ was diagnosed, in spite of he was given the eoftriaxone therapy.. an amelioration was found only when a systemic treatment with vaucomyein was added. after days an intrathecal administration of vancomyein m~day was started: the norbmlization of the spinal fluid profile was uoted two days later and the infant receve~d progressively. the follow-up after eight months doem't evidentiate motosensorini sequelae-the individuation' of ~cscc~ pmmmsm/ae strains heta-loctam antibiotics resistant requires alternative therapeutic regimens: the k~terity quead vitam and quoad valetudinem of these infections justifies an intrathecal therapy, especially failing o prompt answer to the systemic treatment objectives: to evaluate the incidence of the burnout (bo) of the staff in a picu in a university hospital. the bo is a syndrome charactedzed by many factors like emotional stress, lack of personality and reduced work ability. this syndrome represents a kind of abnormal response in the working habitat, above all, where psychological and personal characters are mostly involved. the symptoms of bo are represented by demoralisation, demotivation, incapability, boredom, isolation up to organic disturbances, like migraine, insomnia, dizziness and gastrointestinal disturbances. the major incidence of this syndrome was found in the hospital staff, especially among the nurses, working in an atmospher of high emotional dsk, just like in an intensive care unit. methods: from january ' till april ' , all the staff of the picu of the a. gemelli hospital of rome, underwent a test to evaluate the bo. the test used was taken from the book "bumout: from tedium to personal growth", by pines and aronson. twenty seven people were studied ( females, males)i out of which doctors, residents and nurses. it was considered sign!ficant as mild bo, a score between - and as severe, the score of bo >. . results: subjects ( %) resulted positive for bo, out of which were females ( %) and were males ( %). the subjects with mild bo were / : was a doctor, residents and nurses. the subjects with severe bo were / , out of which resident and nurses. conclusion: the results obtained show that bo is a condition well represented in the staff of our picu. the category most at dsk seem to be the nurses ( subjects), as well as residents ( subjects), as in literature, which shows a major incidence of the syndrome in younger subjects and having a limited partecipation of functional decision. the results obtained obliged us to start a programme of serial controls so that the subjects most exposed can have a necessary psychological support to react adequately to this condition. the term systemic inflammatory response syndrome (sirs) was adopted by the consensus conference to denote a type of systemic response to severe infection or otherinsults in critically ill patients. when sirs occurs from infection it is called sepsis. sepsis occurs more frequently in persons with perexisting illness or severe trauma. there has been tremendous advances in prophylaxis, diagnosis, and treatment of sepsis. a comprehensive model of the disease progression from sirs to mods should be developed giving priority to severity of illness scoring system and other predictive methods. some recommendations for future clinical trials include: trials should not start with humans. before proceeding to human trials, animal studies should indicate an acceptable risk/benefit ratio. appropriate patient populations must be defined and treatment protocols should be standardized. full and rapid reporting of all results should be mandatory and a central repository of published and unpublished study results could be helpful. accrual at each center should be of sufficient size, and should include the number of patients accrued, mortality rates, and patient characteristics. pivotal trial should be preceded by sufficient pilot or phase ii studies. correct drug dosage and usage should be delineated in pilot studies. large, multicenter, trials should be used to enhance the unversality of trial results. analyses should be planned a priori. definitions for the target population should be explicit, reproducible, and include illness severity scores. outcomes should be relevant reproducible and include both measures of benefit and harm. mods and its reversal should be considered as an endpoint. quality of life should also be considered as an endpoint. the estimators of overall treatment effects should be controlled for base-line prognostic factors and subgroup anaiysis should only be used for hypothesis generation and not to modify the conclusoin of the trial. economic analysis should be included as part of clinical design. evaluatin of source control should be a critical component of any study. standardized clinical mediator assays should be pursued. placebo patients in clinical trials should be studied for a better understanding of the pathogenesis and epidemiology of sirs, evidence based medicine should be used to evaluate the validity of clinical. introduction: use of inhaled nitric oxide (no) as a modulator for optimizing ventilation-perfusion or lowering pulmonary artery pressure is becoming increasingly common. no is a free radical but little toxicological research has been published. clearance of nebulized mtc-dtpa is known to be, a sensitive indicator for early function impaimaent of the alveolocapillary barrier. we investigated whether exposure to no increased clearance of ~tc-dtpa from the lung. methods: three groups of white sealand rabbits (bw . kg) were anesthetized, tracheotomized and paralyzed. groups were ventilated for six hours at pressure regulated volume control, set to deliver ml/kg with a frequency of /rain, i/e ratio = : and peep = cm hzo using a modified servo ventilator (siemens, solna, sweden) with computerized no delivery system. gas mixture per group was either / or / [no (ppm) / fioz]. after six hours of ventilation in these groups and immediately after anesthesia in group (control), ~tc-dtpa was nebulized into the inspiratory line of the breathing circuit and administered as a fine aerosol. gamma counting was measured for minutes, monoexponential curves were fitted to the data and the clearance half-time (t was calculated. the t~/ mean • sd of the different groups were: t~a (mean -sd) h"e,i witl~ arf : di.ff:erent kinds, aged .q-ore mon't.hes to [ gears o : (bodi weight .~rom ., to kg), is presen .... "ed ( i,,~u::trl:e i:ibstraclive d:lse~se... ~ .ards'- ; :~,;,,arf o~ ::entral genes:i s .- , ,~ :inc lud ing men ingeenceph it :is- ~ reye ' s ~yrtdro~e-..#~,bri~:ln pes~.re~nimatior~ disease.." ). int:lrl~]. pa-. "iiulle'i,~s ariel regymes o+ l;mv,l;i"t"v were cle'l'.ermllled by ba- 'i~ier was. about . tuber,, dopamin tiara-:. t.io; was ~.".,,'.r:~r~led. cmv,cppv d~.!"~tion raniled -~rom f to dayns.,~ < .-:in , "t -irl lo;and> davs'-in 'l~atierr~{s i'i"ai s:ltiol~ o ; patterers to imv, simv modee was per.r:)rmed, ~herl pif:' decrease.d to - ml~ar, fi ~ecreased to , . lind less with a = /,,. i:lesq.lts:{ in pat:i.ents e{ group :l, who were tre,~d.ed w&th f'f'v, teoph :i. : . l:i.r~ (is- .mg/kg/day), g lucecdr t icostei~oids ( .... :~;mg/kg/day), when r exceeded in , -.];, times normal va i tea the e aqes/,'!:l"oln ~j,, ite :i.~;::.!;, ~ml"lrj), it was possible 't'(' ce 'e~ e aad]t:..~rom ! . '.' i', to !..'; , - , mml-lg in ~}.. :~.[~ houi,!; ~d'l(:i to ru:}l",g'd!~l:i. e i::h,:~e,'~c['el';i.stil obieetives : this chapter will describe what is knovca of the psychlogical responses of infant and children to hospiuiisation and attendant procedures. the factors which may modify these responses will he discussed and important considemtiorts will be outlined for optimal anaesthetic management and postoperative period of infants and children which will minimised the rise of emotional upset. methods : in this paper the autors will discttssed the probl of: . health children (asa i, ii) facing single uncomplicated surgical elective procedures . various abnormal situations including neurotic children, children facing repeted operations, chronically ill, buaaes and tsaumatically impired ones . unfortunate young patient facing and often expoclting fatal outcome from le "ul'ukaemia, tumors, cystic fibroses or otheq" disease. : management of each child must vary greatly, ifi general the phases of emotional conditioning include home and preadmissiun preparation, admitiun preoperated and operative care and postoperative period. the authors would be happy if the child passes all stages without any trauma which could be prolonged in the future life. introduction ino is used to selectively reduce pulmonary vascular resistan(~e. we applied ino in the postoperative intensive care of patients with pulmonary hypertension and the risk of right ventricular failure after surgical correction of a congenital cardiac defect. methods - ppm no were added to the ventilatory gas mixture using a specially designed equipment (messer-griesheim, germany/austria). indications for application included pulmonary artery pressure > % systemic pressure, critically depressed right, ventricular function or an oxygenation index > . assessment of n oefficiacy consisted of on-off-on measurements according to the clinical stability of the patient including hemodynamic parameters, pulmonary gas exchange, continuous monitoring of ventitatory function and transesophageal echocardiography of the right heart. results in situations ( patients, age days- , years), ino was applied - h postoperatively. oxygenation was improved in situations from _+ to + mmhg pc ; pulmonary pressure was reduced in situations from -* % to _+ % of systemic pressure. in situations, no reduction of pulmonary pressure was present, but measurement of cardiac output or echocardiographic analysis indicated an improvement of right ventricular function (right ventricular stroke volume + -* %, cardiac output + -* %). in situations (immediately postoperativ with suprasystemic pulmonary artery pressures [n= ], multi-organ-failure [n= ]), no response to ino could be determined. conclusions for a special group of patients, the selective reduction of pulmonary vascular resistance by ino has become an important part of postoperative therapy. using this selective afterload reduction, postoperatively depressed right ventricular function can be improved. this effect of ino seems to be the most important one in the postoperative period. thus, ino appears justified to be appfleo when impaired right ventdcular function could be improved even when pulmonary artery pressure is not raised or remains unchanged. obiectives : premature infant are exposed to danger of apaea due to anaesthesia during their tirst months of life. it is yet unknown whether prematurity is corelated to any other kind of reslgratory disorder due to anaesthesia within the tirst year of life. methods : we theretbre researched retrospectively for respiratory disorders in all infants under months of life belonging to asa group . they all had been anaesthetised in . in our clinic for the following surgical reasons: ingvinal haemia, umbilical haemia, hydrocelae testis and phymosis. results : in cases we tbund: lafingospasm during induction in anaesthesia ( , %), bronchospasm during induction in anaesthesia ( , %), impaired intubation ( , ~ postanaesthetic laringospasm ( , %), supposed aspiration ( , %),postanaesthetic inspiratory stridor ( , %), postinductional inngoedema ( , %), death after months in consequative of infection pneumonie ( , %), none of these disorders was correlated the prematurity, infants suffered of post anaesthetic apnea, of them had premature medical history. concludions : prematurity does not enhance the risk of respiratory disorders due to anaesthesia within the first year of life, except the danger of postanaesthetic almea needs spetial cosideration. it could be demonstrated that aepgi lowers pulmonary vascular resistance and indirectly improves cardiac function. this effect seemed to be selective, and was comparable to ino in the doses we have examined. therefore, aepgi could represent a clinically useful alternate to inc. however, further research is necessary to work up the benefits of either therapeutic strategy. objectives: heat and moisture exchange filtem (hme) are used as artificial noses for intubated patients to prevent tracheo-bronchial or pulmonary damage resulting from dry and cold inspired gases. furthermore they are used for the prevention of bacterial contamination of the anesthetic apparatus by the patient's exspired air. so they are considered as a time-and money-saving device in anesthesia. filters are mounted directly on the tracheal tube, where they collect a large fraction of the heat and moisture of the exspired air, adding this to the subsequent inspired breath. the effective performance depends on the water-and bacteria-retention capacity of the filter. this study evaluates the efficiency of four different filters under clinical conditions. methods: four different types of filters ( dar hygrobac, gibeck humidvent, medisize hygrevent and pall bb ) were investigated dudng mechanical ventilation over a pedod of hours. minipigs with hemorrhagic shock were intubated and ventilated for days in an animal intensive care unit (icu). after hours of mechanical ventilation the filter was randomly replaced maintaining the individual ventilatory conditions. the weight of the filter was determined before use and after removal after hours. the airway pressure was monitored online to record changes during use. tracheal secretions and both sides of the filter were microbiolologically tested to see whether bacteria of the animal's respiratory system could be found on the patient's side of the filter or if they even would have penetrated the barrier. results and discussion: over a pedod of hours of types of filters showed an increase in weight of + % and airway pressure. bactedal celonisation ccured in nearly all fillers ( of ) on the patient's side, whereas only three of four types of filters showed identical bacterial colonisation on both sides. the only filter that did not show bacterial penetration, increase in weight or airway pressure was the pall-hme, a condensation humidifier without hygroscopic salts for moisture retention. with respect to our data one should use a condensation humidifier if airway conditions should remain stable dudng mechanical ventilation and desinfection of the anesthetic apparatus should be avoided after each patient. aim: to assess the clinical uses of, and experiences with, the hayek oscillator. this is a non-invasive device capable ef delivering not only continuous negative pressure (cnp) but also external oscillatory ventilation around a negative baseline (eov-nb) using an external cuirass. this type of ventilation avoids the need for intubation and intermittent positive pressure ventilation (ippv) and facilitates weaning in ventilator dependent patients. patients and methods: patients in respiratory failure, age range weeks to years in a total of patient episodes were treated using either cnp or eov-nb mode. duration of treatment varied from hours to days. indications for use ef the device were: ) to facilitate weaning from ippv ) prevent reintubation of patients following unsuccessful extubation, and ) avoid intubation and ippv altogether using the hayek oscillator as the on[y means of respiratory support. results: there was an increase in pao :fio ratio after cnp and eov-nb (p < . , and p= . respectively, wilcoxon signed rank test). patients who were in respiratory failure with hypercapnia showed a statistically significant reduction in paco both with eov-nb and cnp (p= . and p= . respectively) but the magnitude of change was individually greater in the patients who were treated with eov-nb. all patients, however, showed a fall in respiratory rate (p< . ) after the application of the cuirass in cnp mode. there was no physiological deterioration related to the application of external extrathoracic negative pressure in either cnp or eov-nb modes. conclusion: the improvement in pao :fio , the fall in paco and respiratory rate were indicators of an improvement in ventilation. the proposed mechanisms include improvement in frc, recruitment of additional alveolar units, and improvement in secretion clearance resulting in reduction in the work of breathing. meek to ~ month of the lifo,the bemodyuanicfacls were defined uitb the help of tetropolar reography method!. the excretion of !he catbocholauines fcfi] mith the urine gas detertend by taylor ll,laoorsy ~ iacg/dayl. hsaltl in the hypercuagulation stage of bic we deflorteeed the acliuutiun of the tbrubio and plasiin syaet~ mitb the increase of the inhihitnrs, in this case we registered in full uahe dot this process coabined uitb the dayl~ excreliou with lho urine epinopbr ne e], nor~pinopbr no tel and dophanine io], lbat shod the inlensificatiou of the s~nthosis prnoe-s~es and the release of ea in blood fron hissue deport the actffat on of the svnpathadrenui systen ]sfisl assisted to furl the b?perd~nanical rosins of the eircuidion and increase the ,icrocirculatinn, the klinicai sings of the insufissieutly of the circulalion have not defined,that has been associated the conpensatury character uf the ehan~es of ~ and heludy~enic status, t~e uun~u|p-lion ceugulupatby bus been donoustraled in the hypocougulatien stage ~bat man xauifosted b the exhaust of lhe confulalion nod oessel-platel heuostasis, the consuxptton of cnnpononts tbronbln ,plnstin, kallek~eiu-kinln s~slots and the forniration eat in fell canoe clot uas accoqaued bs docrea,e of fl,nfl,o, the products of the xotabolisx of c~ and the activation of xonoaninoxydasu. the decrease of the extoll'on g and the exhaust deport co indicahd about t!e ]ou fund/anal reserve of ~fl~. it was one of the lain reason of ~bo heiod~uanic disbroed iheat insnfissient]~] and the uicrncireulaflion lintestinal codeme with the low effectife periferal flow] and nul[iplay organ failure,the distrued deport of sos mitb throubocytupenin no; be one of the nechanisn the dislrood of uessej-plalol heioshasis, the correlation bolueeo changes of boiostosis c~ and circulation ore reguired aduinistration nedidns, thai reslore the love s of c~ in the blood, prevent uulliplay organ failure and hetorrnge in children with sepsis, ~b~ectives: multi-measured correlative analysis of the most number of non-invasive indices of the cardiorespiratory system function was made to determine the structure of their interrelation and the ways of their adequate and effective correction. hethods: spiremetry, capno~raphy, oxygenography, indirect fick method at recurrent respiration, plethysmography, integral rheography -in all indices were used. the received data were processed on a computer by a standard package of statistical bmdp programs. results: women with ~h-gestosis (i group) and somatically healthy pregnant women (ii group) were studied. cluster analysis has shown that the rate of the mean correlation connection between ventilation indices was % in the ist group and % in the iind group; gaseous metabolism - % and %, respectively; central hemodynamics was ~ in both groups. conclusion: cluster interpretation allowed to suggest that an increase of the rate of the mean correlation connection between the indices was characteristic of effective adaptation as the system was multi-component and well-regulated. on the contrary, the increase of the rate of strong correlation connection between the indices reveals the rigidity of the system and the tensity of adaptation mschaniams, i.e. the proximity to decompensation. it follows from this that in cases of eph-gestgsis, the reliability of regulating ventilation and gaseous metabolism decreases. seve/e hypoxemia in non intubated patients represents a major contraindicafion to fiberoptic bronehoscopy (fob) and bronehoalveolar levage (bal), but these procedures are often required for a correct diagnosis of the causative agent of pneumonia. aim of this investigation was to veaify the safety and efficacy of bronehoseopic procedures during pressure support ventilation administered through facial mask (fm-psv). five intensive care patients, all immunoeompromised, ( males and females; mean age . • were enrolled in the study. all patients presented criteria for pneumonia with pao /fio ratio ~ and were responders to fm-psv. fob and bal were performed afte~ topical anesthesia with fm-psv ( ps = em h ; peep = emh ; trigger = -lemh ) continuously admires" tered ( ' before fob fio = . ; during fob, fio = and for ' alter fob, fio = . ). pao /fio ratio as well as saturation (sat) did not show signifteative changes during the procodure (fig.l) . no complication was observed and hemodynamic conditions were stable for all patients. cmv, pnenmoeystiis ( ), legionella and mycobaetermm tuberculosis were identified from bal allowmg a prompt and targeted therapy. we concluded that mask psv can represent an excellea~ technique to pexform fob and bal in severely hypoxemic patients without deterioration of gas exchanges and avoiding endotraoheal intubation. intensive care unit, hospital general of albacete, albacet~ spain. objective: to analyze the current incidence and epidemiology of total parenteral nutrition (tpn) among critically ill patients placed on mechanical ventilation. design: prospective observational study. setting: medical intensive care unit in a tertiary hospital. patients: a total of consecutive l'ritically ill patients with non-coronary related disease needing mechanical ventilation admitted in our icu during a months period. measurements: data of sex, age, diagnosis, and outcome were recorded. severity of illness and therapeutic effort in the first hours were measured using acute physiology score and chronic health evaluation (apache ii) and therapeutic intervention scoring system (ties). r~ults: mechanically ventilated patients, male and female, were studied. only ten patients needed tpn and their main diagnoses were: five cases of multiple organ failure secondary to pneumonia ( ), ards ( ) and septic shock ( ); two eases of acute panereatitis; and one mesenteric throngmsis, one status epilepticas, and one ,prolonged cholinergic crisis b~ suicidal organophnsphate insecticide subcutaneous injection. no statistically significant differences between both tpn and non-tpn groups were found: objectives: evaluate the efficacy of prone position in ards and determine its importance in the therapeutic algorithm. methods: consecutive patients with severe ards (murray-score > , ; pao / fit < mmhg; male, female, mean age years) were conventionally ventilated (pcv, peep - mbar, i:e=i:i, ppeak < mbar). if after hours pulmonary function did not improve patients were placed in prone position. change from prone to supine position was done every hours. beside ultimate survival, parameters investigated were aado , pao /fio , and venous admixture (qs/qt). results: during the first hours in prone position of patients showed a significant decrease in qs/qt ( . % vs. . %) and aado ( vs. mmhg), and an increase in pao /fio ( vs. mmttg). changes were most pronounced in patients with high qs/qt, and in patients with an onset of ards less than hours before first application of prone position. after an average of position changes ( to ) of patients could be weaned from the ventilator. patient could leave tile hospital. i the later course letality was primarily determined by additional organ failures and by the severity of the underlying disease. negative side effects were minor, including slight cardio-vascular depression and increase in p~co , and never posed a limitation to continuation of prone position. especially in patients with septic shock skin lesions in exposed areas could not always be prevented, prone position could easily be combined with all ventilation modes and with all intensive care interventions. also immediately after major surgery and in patients with open packing prone position was possible. conclusions: in this investigation prone position proved to be an efficient and safe method in the treatment of severe ards. patients with a pronounced ventilation/ perfusion mismatch and patients in the early stages of ards appear to profit most from prone position. though the immediate effect on oxygenation is striking, still more the % of all patients die from multi organ failure and underlying diseases. a proposed therapeutic algorithm for ards is as follows: if under conservative ventilation (pcv, peep < mbar, ppeak < mbar) pulmonary function does not improve within - hours prone position should be applied. when after - position changes no lasting effect can be achieved further ventilation modes (e.g. pc-irv, aprv, no, etc.) should be used in addition to prone position. standard intensive care principles, such as fluid restriction and optimization of circulation, apply also to patients in prone position. objectives: nitric oxide reacts with superoxide to form peroxynitrite, an extremely reactive and toxic species. we quantified the presence nitrotyrosine, the stable product of the interaction ' of peroxynitrite with tyrosine residues in the lungs of pediatric patients that died with respiratory distress syndrome (rds). methods: paraffin embedded lung sections, obtained at autopsy, were incubated with a polyclonal antibody raised against nitretyrosine, followed by a secondary fluorescent antibody. alveolar structure-associated fluorescence was quantified using existing methods. results: tissue sections from patients who died with rds exhibited significant specific immunostaining which was uniformly distributed across the blood-gas barrier. in contrast only background levels of fluorescence were seen in the lungs of patients who died from non-pulmonary causes. intense staining was also seen in the lungs of rats that breathed % for h, a condition known to result in rds-type illness; no immunostaining was observed in air-breathing rats. conclusions: significant levels of peroxynitrite may be formed in the lungs of patients with acute lung injury. peroxynitrite may be contributing to the pathology of rds by damaging key components of the alveolar epithelium including the pulmonary surfactant system. mechanical ventilation time was prolonged ,g • days in patients with ardsvs , _+ l, days in control . mean staylcuwas lg _+ ,g days in the ards group vs , • , days in control group postoperative mortality rate was % in ards patients vs , % in those without respiratory failure. -ards incidence in liver transplantation is low ( , % in our sene) but it causes high mortality ( %) page, gas ventilation of the perfluorocarbon-f'dled lung, supports gas exchange and circulation in small animals (< kg) with lung disease. we hypothesized that large animals could be supported by page without adverse effects on bemodynamics. we first elucidated the determinants of gas exchange in normal sheep, and applied them to a model of adult respkatory distress syndrome (ards). methods: using the ventilator settings determined to be optimal in our pilot study (fio of . , peep of cm h , imv of bpm, it of %, and tv of ml/kg), sheep weighing . ~ . ) kg had lung injury induced by instilling ml/kg of . n hc into the trachea. ten minutes after injury, sheep with pao < ton" were randomized to continue gas ventilation (control, n= ) or to institute page (n= ). page was instituted by instilling . l of unoxygenated pefflubron into the trachea and resuming gas ventilation at the previous settings. abg's were drawn at baseline, minutes after injury, minutes after injury, and then every minutes for hours. objectives: inhaled nitric oxide (no) can improve oxygenation and decrease mean pulmonary artery pressure (papm) in hypoxemic patients with ards. in severe hypoxemic copd patients, it is not known whether inhaled no can exert a similar effect on hemodynamics and gas exchange. therefore, we investigated die response of inhaled no in hypoxemic copd patients and the results compared with those obtained in a group of ards patients. methods: ten copd patients (age _+ y;fev~ . _+ . l) and ards patients (age _+ ; lis . _+ . ) mechanically ventilated were studied. hemodynamic parameters were measured using a swan ganz catheter. arterial and mixed venous blood gas determinations, sao , svo , hb and methb were measured (abl ,osm ). mean intratracheal concentrations of no and no were continuously monitored using a chemiluminescence analyzer (nox ) . during the study the ventilatory pattern and fioz were kept constant. the protocol was for ards group: basalt, no loppm, basal~; copd group: basalz, no lo ppm, no ppm, no ppm and basal . after a steady state of rain hemodynamic and gas exchange measurements were performed. a positive noresponse was defined as a % increment in pao . results: papm was similar in both groups and decreased significantly after no (ards, basal . _+ . mmhg, no . + . mmhg, p < . ) (copd, basal . _+ . mmhg, no- . _+ . nrmhg, p< . ). all other hemodynamic variables remained unchanged after no. basal oxygenation was higher in copd group (paojfio _+ mmhg) vs ards group (paojfio _+ mmhg)(p< . ). after no- , pao increased ( _+ mmhg to _+ mmhg, p< . ) and qs/qt decreased ( + % to _+ %, p< . ) only in ards group. in both groups, significant correlations between basal papm and inhaled no-induced decrease in papm were found. inhaled no-induced increase in pao /fio was not correlated with basal paoflfio . no responders were / ( %) in ards group and / ( %) in copd group (p< . ). conclusions. in hypoxemic ards and copd patients, inhaled no decreased mean pulmonary artery pressure. however, oxygenation only ameliorated in ards group because die number of responders to inhaled no were higher in ards group and this effect seems not to be related to the basal hypoxemia. these results might be explained by the v/q abnormalities present in copd patients. grant fis / . objectives: it has been recently reported that expired con slope as a function of time is modulated by total respiratory system resistance (rrs) in critically ill patients (chest ; : - ) . in this study, we analyze the relative contribution of disease (dis), endotracheal tube resistance (rtube), airway resistance (rmin), additional resistance (~rrs), autopeep (peepi) and dylmmic/static elastance (ed/es) to the co elimination in different clinical conditions. methods: we have studied adult patients ( controls, acute respiratory failure, severe ards and copd) mechalfically ventilated (servo and c, siemens) without peep. we recorded tracheal pressure, airflow and capnograms. signals were analogic to digital converted for posterior data analysis. objectives: alveolar ejection volume (van) can be defined as the fraction of tidal volume (vt) with minimal dead space (vd) contamination. according to the classical paradigm: limvd_~ [vco /vt] =facoz, vco vs vt relationship tends asyntotically to a constant slope when approaches end-tidal volume. we have defined van as the volume that defines this relationship until a limit of % variation. methods: six subjects with normal respiratory mechanics were studied during anesthesia for minor surgery. two subjects, otherwise normals but having high values of total resistance and dynamic compliance, were also studied. capnograms were recorded in steady-state at levels of vt ( . , . and . l) and four levels of peep ( , , and cmh objectives: patients with ards presented lung abnormalities which originate an increase in airway resistance (rmin), in additional resistance (~rrs) and in static elastance (ers). application of peep further increases ~rrs. capnographic indexes reflect lung ventilation]per fusion inhomogeneities. in these conditions, the effects of peep on lung mechanics could be better understood by simultaneous measurement of capnographic indexes. methods: we studied groups of subjects. n: normal subjects scheduled for minor surgery; arf: critically ill patients with mild acute respiratory failure; ards: patients with early ards (< h). we recorded tracheal pressure, airflow and capnograms. signals were analogic to digital converted for posterior data analysis. respiratory system mechanics was assessed by constant end-inspiratory and end-expiratory occlusions technique. at equal tidal volmne ( . l) a peep level of , , and cmh was applied in all patients. we calculated ers (cmh /l), rmin, c~rrs (cmh /l/s) and autopeep. capnographic indexes were alveolar ejection volume (vae)/vt ratio and expired co slope beyond vae (sipco in contrast to synthetic surfactant natural suffactants (alveofact| are able to inhibit pmn-activation. after incubation of activated neutrophils with surfactant, l-selectin expression is decreased. these effects depends on which preparation is used. we conclude, that natural surfactant (aveofact| can perhaps influence early recruitment (,,rolling") of pmn in patients with respiratory failure like ards. with ards hormann cb, baum m, putensen c, knapp r, lingnau w, putz g . clinic for anesthesia and general lntensiv care medicine, university of lnnsbruck, anichstrabe , innsbruck objectives: in thoracic ct scans of patients with severe ards atelectasis and pleural effusion can be found in the dependent lung regions. by rotating these patients from left lateral position to right lateral position a redistribution of the ct densities, a recruitment of atelectasis and therefore an improvement of gasexchange is possible within a few days ( , ). the objective of this study was to find out the mechanism of alveolar recruitment during lateral positioning by ct scanning in left and right lateral position. methodes: after approvel by the local institutional reviewboard we investigated ventilated patients with severe ards (entry criterias: murray score > , ) in the ct scann of the university hospital. after a stabilisation period of minutes in supine position a thoracic ct scan slice cm above diaphragm was taken. then two different positions of the patients were studied in a randomized order: a) degree of left lateral position, b) degree of right lateral position. each lateral position was held for minutes. at the end of each of these periods a thoracic ct scan slice cm above diaphragm was taken. quantitative analysis of ct scan data was based on the frequency distribution of the ct numbers. to quantify the alveolar recruitment during lateral positioning by means of ct scan we defined compartments within the lungs: a) normaly inflated lung, b) poorly inflated lung, c) noninflated lung ( = atelectases) ( ). results: independant of the side of lateral positioning (l) in the non-dependent upper lung a significant increase of the normaly inflated compartment (s: %; l: %) as well as a significant decrease of the noninflated compartment (s: %, l: %) was observed in comparison to supine position (s). in the dependant lower lung the normaly inflated compartment decreased significantly (s: %, l: %) whereas the noninflated compartment increased significantly (s: %, l: %). throughout the whole studyperiode we did not observe any significant change regarding gasexchange and hemodynamic parameters. conclusions: in lateral position the non-dependent upper lung is decompressed. therefore a significant recruitment of atelectases is observed in the upper lung within minutes. on the other hand the dependent lung is compressed by the weight of the upper lung and the mediastinum. a great amount of the alveoli of the dependant lung collapse in this short time intervall. therefore the net effect of recruitment of one positioning maneuver is very small. when positioning patients one should be aware, that the patient is kept in each lateral position long enough to clean up the atelectases in the non-dependant lung and short enough to compress less lung tissue in the dependant lung. objective: to analyze effects of low-dose no inhalation ia patients with severe aeut~ respiratory distress syndrome (ards) over five days. methods: we prospectively studied patients ( men, woman) with severe ards admitted to our icu between may and may who required no inhalation with a dose of ppm for at least days. entry criteria for no injaalafioa were murray score >i . aud pat/fie < nun hg with peep >~ em i~o for at least hours. all patients were sedated, intubated and mechanicauy vantil~ed with volume assist-control ventilation, and had indwelling arterial catheters (pulmonary artery, and radial or femoral artery) to measure cardiac output (by thermodilufion) and relevant intravaseular pressures, and to calculate derived parameters. no was administered between y piece of the ventilator and endotraeheal tube and flow was adjusted to obtain ppm no in the inhaled gas. the no, no and no x concentrations were continuously measured at the distal end of the endouacheal tube by the chemiluminiscence method (nox , see-seres, france). metahemoglobinemia levels were mesured daily. no inhalation was manteined if paojfio ~ improved at least % and was stopped when the change in pao /fio ~ was below % or when the patient presented a paojf > mm hg a~er minutes without no inhalation. every day we made an on-off test to determine if no inhalation improved pao /fio ~. statistics: analysis of vmiance. data: mean + standard deviation. results: the mean age was . +_ . years and mean lung injury score was . • . . mortality was % ( / ), metahemoglobinemia . • . %, and no concentrations zero. paojf~o always improved significantly al~er ppm no inhalation (see :~ conclusions: reintubation in salf-extubated patients strongly depends on the type of meehamcal venfilatory support: the probability of needing a reintabation ff ese occurs during fult vontilatory support is higher than ff ese occurs during weaning. these data suggest that some patients may remain under weaning from mechanical ventilation for unnecessarily prolonged periods of time. objective: the aim of this study was to evaluate the acute effects on gas exehonge and hemodynamics due to positional changes from supine (sp) to prone (pp) in patients with severe acute respiratory distress syndrome (ards). methods: nine intubated, sedated, paralyzed and mechanically ventilated patients with severe ards were prospectively studied. all had a murray score > . , and a pao /f~o < with peep ~ cm h for at least h. all patients had indwelling arterial catheters in the pulmonary artery as well as in the radial or femoral artery in order to measure cardiac output (by thermodilution) mad relevont pressures, and to withdraw blood samples. arterial blood gases and hemodynamie parameters were measured first in sp, and then in pp after minutes of stabilization. vontilatoly parameters remaing unchanged during all the study. statistical analysis was done by the non parametric wdeoxon test. data are expressed as mean ~= sd. results: there were men and women with a mean age of . years ( - ) and mortality was % ( / ). main results are shown below: objective: to describe and compare a new method for obtaining p-v loops (p-vcv) by using a two-way collins valve (twv) with thosu obtained by the supersyringe method (p-vss). methodology: we prospectively studied patients who had an aeute lung injury and were intubated, sedated and paralyzed, and mechanieany ventilated. we performed the p-vev loops and p-vss loops in random order, and the static inflation pressure was limited to emh with both methods. pressure (p) was measured at the airway opening by means of a differential p transducer, and volume was obtained from flow (measured with a pneumotacograph) integration. the p-vse method has already been described (h~trf a,et al.bepr ; : - ) . the p-vev method consists in the following: the inlet of a twv is connected to the ventilator's y-piece, and both outlets are couneeted to the endotraeheal tube by means of an additional y-piece; one of this outlets has a one-way rudolph valve in order to allow inspiration but not expiration during the inflation maneuver. changing the twv tap position allows basal ventilation or progressiveinflation of the respiratory system. this maneuver is as follows: during an end-expiratory occlusion, the ventilatory settings are adjusted to deliver a ml v r with a respiratory rate of /min and i/e ratio : ; at the same time the twv tap is ehonged in order to divert flow through the one-way valve. inflation then begins alter releasing the expiratory oonlusion. pressure and flow signals were digitized and acquired by a computer for subsequent data analysis. we analyzed the following parameters: inflation compllonee ( objective: to analyze the variables which eventually may differentiate ards patients who do and do not respond to low doses of inhaled no. we prospectively studied patients ( men, woman) with severe ards admitted to our icu between may and may who were treated with no ( ppm). the onta'y criteria for no inhalation were murray score >/ . and paojfo z < mm fig and peep >/ cm i~o for at least hours. all patients were sedated, intubated and mechanically ventilated with volume assist-control ventilation. tidal volume was between and ml&g, with constant inspiratory flow, respiratory rate was - /rain, and i/e ratio between : to : . all patients had indwelling arterial catheters (pulmonary artery, and radial or femoral artery) in order to measure cardiac output (by thermodiintion) and relevant intravascular pressures, and to calculate derived parameters. no was administered between y piece of the ventilator and ondotracheal tube, and flow was adjusted to obi~a ppm no in the inhaled gas. the no, no and no x concentrations were continuously measured at the distal end of the endotracheal tube by the chemilumiinscenee method (nox , see-seres, france). metahemogtobinemia levels were measured daily. we considered a response to no inhalation when an improvement in paoz/fo above % was observed after the inhalation of ppm no (group r) . when the cha~age in paojfi z was below % it was considered a lack of response (group non-r small airways functional abnormalities have been recognized as a common feature of lung pathology. however peripheral airways contribute relatively little (~ %) resistance to flow and there disturbances can not be adequately estimated by conventional measurements of respiratory mechanics. the purpose of the study was to evaluate the relationship between raw and small airways conductance following weaning from ventilator methods. patients (age: - years; males) with no serious complications al~er mitral or multiple valves replacements and with more than hrs on mechanical ventilation have been enrolled in this study. the modified flow interrupter technique (ptg "gould" with fleish head # ; differential pressure transducer pm- -tc "statham" w amplifier "kistler ") and flow-volume recording of forced expiration (fleish head # ) have been applied before surgery and following operation on mechanical ventilation (my), after extubation (t:xtijb), on ( nay) and ( day) days. airways specific conductance (sg aw) has been calculated as a mean of - consequent measurements in each patient at each stage. the sac was estimated by max expiratory flow at and % of vc on - f-v curves (mef .~ , mef ) all the data were statistically analyzed with t-test introduction : noninvasive ventilation (niv) reduces the need for endotracheal intubation, the length of stay in icu and the mortality rate in acute exacerbation of copd. however, some patients failed to be ventilated with niv. .objectives...; to further delineate patients who failed to be ventilated with niv and to obtain predicted factors of failure. patients : a cohort of patients ( • years) presenting with acute exacerbation of copd (fevi: • ml, paco : • , ph: . • . ) and nonmvasively ventilated (pressure support through a full-face mask) between april and may twenty-seven ( %) were successfully ventilated with niv (discharged alive without the need for endotracheal intubation) while ( %) failed, requiring endotracheal intubation. .methods : patients successfully ventilated and those who failed were compared according to respiratory and nonrespiratory variables univariate analysis (wilcoxon rank-sum test and fisher-exact test) was performed to select variables included in a multivariate analysis by stepwise logistic regression. results : underlying disease assessed by the simplified acute physiologic score ( • vs • , p = . ), creatinine serum concentration ( • vs • gm/l, p = . ), blood urea nitrogen (bun : • vs mm/l, p = . ), age ( • vs • , p = . ) were higher and encephalopathy ( vs %, p = . ) more frequent in patients who failed. multivariate analysis showed that encephalopathic patients (or (odd ratio) = , p = . ) older than years (or = , p = . ) and presenting with bun >_ mmyl (or = , p = . ) failed to be ventilated with niv. variables related to the respiratory" status (i.e. paco , pao , fev ) were unable to predict tile failure of niv. conclusion : copd patients older than years, presenting with acute exacerbation, encephalopathy and bun > ram/l, should be carefully monitored because of high probability of failure with niv. methods:from february to december we studied pa_ timnts, males and females(mean age +/- ); of the se had emphysema,lo chronic bronchitis, dilatative car diomyopatia,with tracheostomy and emphysema.mean pac at admission in icu was +/- mmhg,while when weaningbegan, +/- .mean autopeep was cmh ( - ).all patients were ventilated in crpv as long as four hours to calculate st tic and dynamic cmpliance and autopeep.then the ventila tion was continued with psv+cpap(peep cmh objectives: analysis of the incidence of neurogenic pulmonary edema (npe) in a population of headtrauma patients with acute respiratory failure (arf). npe can occur after a central nervous system insult. differential diagnosis: cardiogenic pulmonary edema and other forms of non eardiogenic pulmonary edema. true incidence and pathophysiohigy remain poorly defined, however the role of catecholamines seems undeniable. early onset npe (within h after trauma) is characterised by hypoxemia, transient pulmonary hypertension and bilateral central fluffy infiltrates on chestx-ray. characteristics of cardiogenic edema or pneumonia are absent. late onset npe, (beyond hours after trauma), is more insidious. the clinical and radiographic picture has to clear within to hours. ( ) methods: all headtrauma patients admitted from january to december , in a nearotrauma icu setting were retrospectively analyzed for arf with as sole criterinm a pao -fio ratio < . results: neurotrauma patients were admitted during . patients ( %) presented with severe head injury (gcs< ), patients ( . %) with moderate (gcs - ) and patients ( . %) with minor head injury (gcs - ). overall mortulity was . % early (within h. after trauma) and delayed onset respiratory incidents were distinguished, counting for ( . %), respectively patients ( . %), patients ( . %) had early and late respiratory complications. early respiratory insufficiency was caused in patients ( . %) by aspiration, in patients ( . %) by lung contusion, in patient ( . %) by fat embolism and in patients ( %) by npe. in the late onset group patients ( . %) presented with pneumonia, ( . %) with fat embolism and ( . %) with npe. the npe group, patients, presented as follows: patients ( . %) developed early npe, and ( . %) delayed onset npe. patients ( %) died within the first days after admission, showing high mortality. gcs was less than in patients ( . %), indicating severity of head injuries. conclusions: high incidence of arf with various etiology ( , ~ was found in this population. in about % of all admitted hcadtrauma patients ( , % of arf) npe was causing attetial hypoxemia. occurrence of npe seems to be related to the severity of the brain injury and thus to outcome. these data call for extreme vigilance in respect of the insidious occurrence of npe. were included if recovering from respiratory failure and if in the opinion of the primary physician were ready for extubation. patients were excluded if undergoing compassionate withdrawal of support or had tracheostomies. the attending physicians were blinded to the measurements. included patients were placed on pressure support (ps) of em h with demand-flow continuous positive airway pressure (cpap) cm h . after a minimum of minutes on the above sehiogs: gastric intramucosai pc'o , abg, and a p . were measured. the padents were then disconnected from the ventilator for a period of one minute and the patients" respiratory rate and minute ventilation were measured using a wrights respirometer to calculate the frequency to tidal volume ratio (f/vt). patients were then extubated. extubafion failure was defined as the inability to maintain spontaneous ventilation for hours for any reason. results: twenty patients met criteria and were studied over one month period in october . six of the twenty patients ( %) failed weaning. the mean and standard deviation is outlined in failure . +/- . . +/- . . +/- . . +/- . comparison between roc areas shows phi and p . to each show a statistically significant difference from an area of . (p<o. ). the area at which the test has no discriminative value. this is not the case for either the integrative index or the f/vt ratio. the differences between areas for each curve is not statistically significant. the area's for each roc curve is shown in table #' . results. of the newborns referred to us for ecmo-therapy developed barotrauma, of the required ecmo and one of the three other patients who did not recieve ecmo-therapy died. to determine the correlation between the risk factor barotrauma and the severity of the pulmonary situation, we determined the oxygenation index of each patient referred to us for ecmo-therapy . the table demonstrates , d- giessen, frg. inhalation of nitric oxide (no) and aerosulizatiun of prostaglandin (pg) i: have been suggested to achieve selective pulmonary vasodilation and improvement of arterial oxygenation in patients with acute respiratory distress syndrome (ards). we directly compared these two modes of transbronchial vasodilator therapy in ards patients mechanically ventilated for - h (mean murray lung injury score [ ] . + . ). patients were randomized to receive either first no and then pgi (n= ), or vice versa (n= ), with an intermediate baseline period. each drug was titrated individually to find the lowest effective dose for maximum improvement of arterial oxygenation. gas exchange variables, including data from the multiple inert gas elimination technique (miget), and hemodymmaics under application of no/pgi were compared to pro-and past-challenge values. no (mean dose . + . ppm) increased the mean oxygenation index (pao /fio ) from + to + mmi-ig (p < . ) and reduced the shunt-flow from . + . to . : . % (p < . ). aernselized pgi (mean dose . + . " ng/kg rain) augmented pao /fio from + to + mmhg (p < . ), and decreased shunt from . + . to . + . % (p < . ). the miget analysis showed predominant redistribution of blood-flow from shunt areas to regions with normal ventilation-perfusion ratios in response to both agents. in patients, both no and pgi caused an increase in pao /fio by at least rnmhg. two further patients displayed a corresponding improvement of arterial oxygenation in response to either no or pgiz. the mean pulmonary artery pressure decreased from . : . to . : . mmhg in response to no, and from . : . to . : . mmhg (p < . ) in response to pgi . cardiac output, systemic arterial pressure, and right and left heart filling pressures were not affected by either agent. we r that individually titrated doses of inhaled no and aerosolized pgi~ effect selective pulmonary vasodilation and redistribute blood-flow from shunt-areas to weu-ventilated regions with nearly identical efficacy profiles. obieetives: the use of extraeorporeal bypass systems for oxygenation and co -removal is performed in patients with acute respiratory distress syndrome (ards) to reduce mortality and to improve restitution of pulmonary functions. high-dose heparin -commonly used in such patients to prevent thrombotic complications -might cause incurable bleadings as a major risk. this lead to the development of heparinized bypass systems; results of animal and first clinical studies proposed that such systems might run with low-dose heparin or even without any systemic anticoagulation. methods: since , patients with severe ards were treated with extracorporeal lung assist (ela) using heparin-coated systems (type maxima, medtronic, carmeda coating) in our icu. they received a moderate systemic heparinization. standard clotting assays (act, aptt, tt, ptt, at-ill, fbg, fsp) as well as special tests (tat, r~-tg, pf , pal-l, d-dimers, protein c, cl-inhibitor) were performed. results: covalent heparin-eoating of the ela-systems combined with lowdose heparinization could not prevent major changes in coagulation: ) in mean, platelets dropped from /nl to /nl within h after onset of ela. ) tat levels were already elevated before ela start ( ug/]) and demonstrated an additional peak h after onset of ela (up to ug/[). ) in parallel, there was a transient peak of pai-i levels (from to au/ml} h after onset of ela. ) in mean, fibrinogen levels dropped from to mg/ ml within h after onset of ela. ) in mean, cl-inhibitor levels dropped significantly from % to % after onset of ela and reached the initial levels within h. ) after membrane change, there were significant changes for c -inhibitor, fibrin-d-dimers and tt. ) global clotting tests such as aptt, ptt and tt were within normal range. conclusions: patients with severe ards develop a prethrombotic state already before they get connected to the ela bypass system. after onset of ela, they experience additional involvement of procoagulant, anticoagulant, fibrinolytic, and complement systems. in parallel to laboratory findings, clinical data suggest that the use of heparin-coated systems with accompanying systemic low-dose heparinization does not avoid thrombembolic and hemorrhagic complications in tong-term ela patients. thus, at the present, higher dosed individually adjusted heparin treatment has to be recommended. thereby, standard clotting monitoring is not sufficient. objective: poor muscle performance contributes to prolonged dependence on mechanical ventilation. longitudinal data on muscle function in icu patients is scarce. we evaluated changes in inspiratory and peripheral muscle performance during prolonged intensive care in patients with acute respiratory failure. methods: patients requiring intensive care for more than one week were studied. maximum inspiratory pressure (pimax) was measured twice a week for a maximum of three weeks. handgrip power (dynamometer) and subjective fatigue (keldet score) were obtained in survivors only. one measurement was done on the date of extubation. pimax pressure was obtained by occluding the airway for seconds or at least five inspiratory breath attempts. obiectives -measurement of peep-induced changes in lung volume helps to assess respiratory mechanics in acute lung injury (ali). we evaluated the accuracy and stability of a new respiratory inductive plethysmograph (rip), in the measurement of peep induced changes in end-expiratory lung volume (eelv) and tidal volume (vt) against volume reference, pneumotachograph (pnt), methods -two hours periods of basal ventilation and stepwise increases and reductions of peep ( - - - - cm h ) were recorded in patients with all. in addition, the new rip device (respitrace plus tm) was compared to an older rip (respigraph tm, nims, fl, usa) to determine its thermal stability using cold and warm devices and a ventilated lung model. results -the difference between the new rip and pnt in the measurement of vt was - _+ mi (x _+ se) or a - . _+ . % error. increasing peep from to cm h induced a + ml change in eelv. a difference of + ml ( . % of max. eelv change) (ns) was found between rip and pnt eelv readings. during controlled ventilation with constant settings the mean change in eelv was _+ ml/ min (fig.i) . validation of calibration showed a mean error of -+ . % after rain. the new rip had a higher drift when cold (cold + ml/ min vs warm _+ ml/ min), whereas the old rip was thermally stable (cold - + ml/ rain vs warm i + ml/ min). trauma icu, hospital traumatologia y rehabilitacidn. vall d'rebron. barcelona. spain. recent data suggest that the proportion of patients with relevant discrepancies between two jugular bulb (jb) oxygen saturation (sjo ) values is higher than suspected. objectives: determine the incidence, the significance and the pro nosis value of those differences,if they exist,in severe head injured-patients. material and methods: severe head-injured patients, coma glasgow scale (gcs) , with diffuse brain injury according to marshall criteria in the first ct scan, icp recorded, with an interval from accident-double jb monitoring < than hours, were studied. data from bilateral sjo were obtained simultaneously, every hours. discrepancies were considered significant, when differences in sjo were > %. no chan es in treatment protocol (hyperventilation, man• etc) were carried out due to this study. results: men and women were studied, aged • yrs. at arrival at hospital, gcs were < in and ) in to. the incidence of high icp() mmhg) were sz at the entry. the mean therapy index level required to control lop was ~l all patients required vasopressor therapy to maintain upp over ds mmhg. in patients a s.s f swan-ganz fiberoptic catheter was used to obtain a continuous recording of sjo . in the others , sj were intermittently controhed.the mean time of monitoring were d. • days. ten patients died within this period. a total of . blood samples were analized. at arrival, sjo discrepancies were found in patients, b %. at hours, the incidence were lower, / , . %. at th day, were h/ , z and at day , when the catheters were retired, ii[ , z showed discrepancies. the ct showed new injuries in g z of patients with differences > ~ in sd values throughout treatment period. none of those were considered for neurosurgical treatment. no correlation was found between iop and sjo values and sjo differences. conclusions: the incidence of discrepancies between sjo was higher than expected in severe head-injured patients. these situation could reflect disturbances between demands. when differences are known, and those lend to change, the ct scan, nearly always, will show new injuries. platelet-activating factor (paf) is an inflamatory mediator implicated in the pathogenesis of bronchial asthma and acute respiratory distress syndrome (ards). its inhalation in healthy subjects produces transient bronchoconstriction and mild ventilation-perfusion mismatch, together with peripheral leukopenia as a result of intrapulmonary neutrophil (pmn) sequestration. likewise our group has shown in healthy subjects and asthmatic patients that aaibutamol (s) inhibits both pulmonary and systemic effects of paf, suggesting that s may inhibit paf-induced venoconstriction in pulmonary microoirculation. the aim of the present study was to investigate if s inhalation decreases pmn by lung sequestration induced by paf. we studied healthy, non-atop• nonsmoking subjects ( m/ f, + yr), which were pre-treated with s ( ,ug) or placebo, with a randomized, double-blind, crossover, design, before paf ( ,ug) inhalation. we measured the respiratory system resistance (rrs) by forced oscillation, arterial btood gases and both total white cell and pmn count every min over a min. period. simultaneously, we recorded continuously the lung dynamics of inm-neutrophil and tc m-erythrocytes activity, with a gammacamara. after placebo, paf inhalation decreased white cells (from to x /l), and pmn(from to _+ x /l), and increased aapo (from . _+ . to . + . mmhg, p<o. ) and rrs(from . . to . . cmh .s.i q ) (p < . each). the fall in total white cell count correlated with the intrapulmonary pmn retention (r = . , p < . ). by contrast, after s, paf did not induce any change in white ceil count (from to + x /i), pmn count (from to x /i), aapo (from . to . + . mmhg), and rrs (from . . to . . cmh .s.i ). compared with placebo, after s there was a lower ~lln-pmn lung activity ( . . vs . . cts/mci/pixel, p<o. ), lower intrapulmonary pmn retention ( . . vs . . %, p=o, ), and a faster washout ( . . vs . . s ~, p= , ). our results indicate that s inhibits paf-induced intrapulmonary pmn sequestration, being consistent with the hypothesis that s may offset the venoconstriction of pulmonary microcirculadon caused by this mediator. supported inpiratory muscle fatigue with failure of force generation as def'med by a tensiontime index (tti)> . - . has been shown to occur in normal volunteers and in stable copd patients with a specific imposed breathing pattern. its role, however, in hypercapnic respiratory failure is less certain. we studied failed weaning trials in copd patients in which breathing pattern, tension-time index (tti) of inspimtory muscles, dynamic peepi, dynamic lung elastance, lung resistance, and arterial paco and ph were measured at the beginning and end of a t-piece weaning trial. in addition, the change in esophageal pressure during a mueller maneuver (apes max) was measured. a weaning trail has been prospectively defined to have failed if one of the following criteria was met: a rise in pco > mmhg from baseline accompanied by a fall in ph< . ; a respiratory frequency (f) > /min; excessive accessory inspiratory muscle recruitment; and a marked increase in dyspnea. values are expressed as mean • se. weaning failure was characterized by a more rapid, shallow breathing pattern, worsened mechanics, hypercapnia and respiratory acidemia despite an unchanged tri and pes max. we conclude that in this setting hypercapnic respiratory failure is not a consequence of inspiratory muscle fatigue. rather the adopted breathing strategy and resultant hypercapnia may represent an adaptation to forestall the onset of muscle fatigue. concerning the investigated elf-par~eters, no stadstically signhqcant differences were detected between the pgi and the control group. histopathologlcal changes occured in both groups and consisted in rare focal flaaaning f tracheal epithelium with loss of cilia and slight inflammatory cell infiltration, as well as slight swelling of alveolar typo pneumoeytes. sections of generation , and from bronchial tree were free of pathological changes. conclusion: alter h inhalation of p~ji no signs of respiratory-lract tissue damage caused by the aerosol could be detected. the minor pathological findings in the trachea are most likely due to mechanical irritation by bronchoscopy, changes of the alveolar epithelium are known for long-term mechanical ventilation . objectives: the aim of this study was to evaluate of efficiacy of ganglion stetlate blockade in patients with respiratory failure. methods: two groups of patients were investigated: group i (n = ) trauma patients with acute lung injury (ali), group if (n = ) patients with asthmatic status. in all cases continuous mandatory ventilation (cmv) was used with bennett ae. in both groups bilateral ganglion stellate blockade with antero-lateral approach was performed, using . % marcain. the following parameters were analysed: pao , sao , paco~, pip and c~t~t. results: in trauma patients with aij after bilateral ganglion stellate blockade short -lived and slight improvement of pao and sao , decrease of pacoz and pir and increase of static compliance of respiratory system were found. in second group bilateral ganglion stellate blockade interrupted the asthmatic status and significant statistical improvement of parameters of oxygenation, ventilation and respiratory system mechanics were observed. conclusions: we suggest that the bilateral ganglion stellate blockade is a very useful method in treatment of patients with obstructive respiratory insufficiency. the aim of the study was to analyse whether there exists serum and urine electrolyte disorder in patients(pts.) with acute respiratory insufficiency(ari). the study included t pts. with ari (pao : , @ , kpa. paco : , i- , kpa, ph: ~: , , hco : , :~ , mmol/ , sao : , ~- , %) who were hospitally treated due to pneumonia( pts.),emboly of the pulmonary artery( pts.) and severe attack of bronchial asthma ( pts). among tham there were ( , %) males and ( , %) females, average age , ~: , years, otherwise previously healthy. electrolyte concentracions were measured at the onset of the disease in serum and urine collected during hours (sodium-na,potassium-k, chlorine-c , calcium-ca,magnesium-mgand phosphorus-p). the measured serum and urine electrolyte concentrations were compared with respective referent values (rv). by serum electrolyte analysis, the following average velues were obtained: na:l o, the object of our investigation was a group of pts with massive pneumonias, males ( . %), females ( . %),mean age yrs.thirteen ( %) of them were smokers, ( %) nonsmokers. only pt ( . %) had pre-existing chronic respiratory disease, and ( . %) were admitted for the first lime,with no previous respiratory anamnesis. diagnose was based on anamnestic data of productive cough in pts( . %),physicaly ~onchial breathing in i~s ( . %),white cell count onder x /l in pts( . %). radiographicly, bilateral massive homogeneous shadows were found in pts ( . %), onilateral in pts( . %),pleural effusion in pts ( . %). abnormal renal function was found in pts ( . %). sputum culture was positive in pts ( %): slr.pneumoniae, str.pyogenes, pse'udomonas aerug, in , , cases respectively. all patients had remarcable hypoxernia (pao range from , to , kpa) without hypercalmea. all patients needed oxygenotherapy together with antibiotics and other .symptomatic therapy. nineteen pts had anaelioration of general condition and normalization of blood gas analyses, while pts with the lowest hypoxcmia died.in conclusion, massive pneumonias are frequently followed by respiratory insufficiency which is one of the markers of pneumonia severity. as existing hypoxemia complicates the course of the disease,prolonges the recovery, makes therapy more complexe and may be cause of death , frequent blood gas measurement is recomanded. we studied the effects of bosentan (bos), an eta and etb receptor antagonist, to examine if endogenous et mediates pulmonary hypertension in anesthetized and ventilated dogs with acute lung injury due to oleic acid (oa). the gradient between pulmonary artery pressure (ppa) and occluded ppa (ppao), and gas exchange (evaluated by arterial blood gases and sf intrapulmonary shunt) were measured at controlled flow. in dogs (treatment), data were collected at baseline, during long injury (obtained rain after intravenous administration of oa . ml/kg), and again after bos ( mg/kg intravenously). in dogs (pretreatment), data were obtained at baseline, after bos and then after oa. in treated dogs, oa increased (ppa-ppao, mmhg, table, means + sem, * p < . vs base) and deteriorated gas exchange. after oa, bos did not affect pulmonary vascular tone nor gas exchange. in pretreated dogs, bos had no effect on baseline pulmonary vascular tone but prevented the increase in (ppa-ppao) after oa. the deterioration in gas exchange after oa was not influenced by bos pretreatment. objectives: the alveolar tension is measured by the application of the alveolar air equation in which the arterial pco is used or by the simplified form of this equation in which the respiratory exchange ratio is taken at the value of . . the purpose of this study was to estimate the effective alveolar tension (pao eff) during spontaneous breathing with a new bedside technique which is simple non-invasive in normal subjects and patients with chronic bronchitis-emphysema. we also compared these values with the ideal alveolar po (pao (i)), measured from the alveolar air equation in which paco was substituted by the effective alveolar pco (paco eff) and with the alveolar po measured from the simplified alveolar air equation (pa ). this study is complemantary to previous work for the estimation of paco eff. methods: the subjects breathed quietly through the equipment assembly (mouthpiece monitoring ring, fleisch transducer head) connected to a pneumotachograph and a fast response and co analyzer. the method is a computerised calculation of the effective alveolar po quite similar to that of paco eff, obtained from the simultaneously recorded at the mouth expiratory flow, and co concentration versus time curves. results: the results showed a mean difference (pao eff-pa (i)) of - . kpa in normal subjects and - , in patients. the mean of the difference (pao eff-paq ) and (pad (i]-pao z) was much greater than . in all subjects. the limits of agreement for the difference (paozeff-pa (i))were - . to . kpa in normal subjects and - . to . in patients, while those for the differences (pao eff-pad ) and (pao (i)-pad ) were very large ( > - . to > . ) in all subjects. conclusions: the effective alveolar po is very close to the ideal one in normal subjects, tn patients pao eff may excessively deviate from pa (i) due to the observed significant difference between the alveolar/tidal volume ratio for o and that for co . the alveolar po measured from the simplified alveolar air equation (pao ) differed substantially from pao eff and pad (i) in all subjects. the essential role of glucoprotein hormone erythropoietin is to control red cell production. hypoxemia, reduced blood -carrying capacity and increased affinity of hemoglobin for are the primary stimuli for erythropoietin production. both anemia and hypoxemia induce rapidly erythropoietin secretion. kidney erythropoietin rna levels correlate inversely with hematocrit and directly with plasma erythropoietin level. similarly, hypoxemia increases kidney erythropoietin rna and plasma erythropoietin. the effect of hyperoxemia (pa >lo mmhg) on erythropoietin secretion isn't very well understood. the purpose of this study was first to evaluate the erythropoietin secretion in patients with acute respiratory failure and second to determine the effect of hyperoxemia on erythropoietin secretion in patients with and without anemia. sixteen patients with acute or acute on chronic respiratory failure needed mechanical ventilation were included in this study. these patient were divided in two groups. the patient who developed anemia were included in group i and the patients without anemia in group i . erythropoietin was estimated in venous blood in three stages. the first sample was taken during hypoxemia, the second during hyperoxemia and third during normoxemia. all the patients had high erythropoietin level during the hypoxemia period (mean value • mu/ml). during hyperoxemia etythropoietin levels were reduced in both groups ( mean value . + . mu/ml in group i, . • mu/ml in group ii). in normoxemia stage, erythropoietin increased again in anemic patients, and decreased more in the patients of group i . we conclude that hyperroxemia inhibit erythropoietin secretion in spite of anemia and tow arterial oxygen content. hyperoxemia may be a factor of the insisted anemia in with oxygen treated icu patients. the purpose of this study was to determine the relationship between clinical features of acute lung injury (all) and parameters like total proteins, total and individual phospholipids, the presence of paf, and acetylhydrolase activity in bal of mechanically ventillated patients. acetylhydrolase catalyses the cleavage of acetyl-group from the second position of the glycerylether backbone of paf, leading to its inactivation. mechanically ventillated patients were divided to three groups. group i includes patients without all; group ii, comprisespatients with moderate degree all, ( . <g-i < . ); and group iii comprises patients with severe ards (all score > . ). broncoalveolar lavage (bal) was obtained after infusion of normal saline at ~ to intubated patients and cooled immediately. cells were removed after mild centrifugation ( x g, min, oc). aliquots from the supernatant were used for total protein, phospholipid and paf analysis and determination. acetylhydrolase activity was assessed after incubation of bal with h-paf labelled on the acetyl group. released label was measured by liquid scintillation counter in the supernatant after trichloroacetic acid precipitation of the non-reacted substrate. kinetic characteristics of the enzymes were also studied. total phospholipids appear reduced in bal of patients with all, while total proteins increase. these factors appear to correlate with the severity of all. paf was not present in bal samples pretreatad with equal volume of % acetic acid to denaturate acetylhydrolase. detection limit for paf under our experimental conditions: pg paf/ml bal. instead, acetylhydrolase activity was detected in amounts increasing with the total protein content. background: intubated patients without lung injury or impaired breathing control normally display an inspiratory peak flow of below l/s. the aim of our study was to investigate the inspiratory peak flow generated by patients with acute respiratory insufficiency (ari). we had to take into account that both an inspiratory pressure support (ips) and the resistance of the endotracheal tube considerably influence the flow pattern generated by the patient. patients and methods: to investigate the non-influenced flow pattern we developed a new ventilatory mode which automatically compensates for the flow-dependent resistance of the endotracheal tube (automatic tube compensation, atc). furthermore, the mode maintains a constant tracheal pressure in inspiration and expiratio n . consequently, the measured flow pattern exactly corresponds to the flow pattern generated by the patient except that the ventilator modified for this mode (evita, driiger liibeck, germany) was not able to deliver a gas flow of more than l]s. we have investigated patients with ari arising from different reasons. results: the inspiratory peak flow measured in the atc-mode was . l/s _+ . l/s. the maximal deliverable flow of l/s was obtained in of patients. the figure shows the flow pattern under atc and ips in [~s] oi:) one of these patients. conclusions: patients with ari display a highly increased inspiratory peak flow. ventilators used for spontaneous breathing should therefore be able to deliver a gas flow of more than l/s. an overproduction of no and reactive oxygen species (ros) has been demonstratred in septic shock. ros and nitric oxide (.no) are free radicals which are known to react together leading to peroxynitrite anions that can decompose to form nitrogen dioxide (no ) and hydroxyl radical (oh~ thus, no has been reported to have a dual effect on lipid peroxidation (prooxydant via the peroxinitrite or antioxidant via the chelation of ros). in the present study we have investigated in different models the in vitro and in vivo action of no on lipid peroxidation. copper-induced ldl oxidation was used as an in vitro model of lipid peroxidation. ldl ( ~g apob/ml) was incubated with cu + ( , ~tm) in presence or absence of no donor (sodium nitroprussiate or glutathione-no) from to ~m. oxidation of ldl was monitored continuously with conjugated diene formation ( nm) and hydroxy nonenal accumulation (hne). exogenous no prevents in a dose dependent maner the progress of copperinduced oxidation. ischaemia-reperfusion injury (i/r), characterized by an overproduction of ros, is used as an in vivo model. anaesthetized rats were submitted to hour renal isehaemia following by hours of reperfusion. sham operated rats (sop) were used as control. lipid peroxidation was evaluated by measuring the hne accumulated in rat kidneys in presence or absence of l-arginine or d-arginine infusion. l-arginine, but not darginine, enhances hne accumulation in i/r but not in sop (< . nmol/g tissue in sop versus . nmol/g tissue in i/r), showing that in this experimental conditions, no produced from l-arginine, enhances the toxicity of ros. this study shows that the pro-or antioxydant effects of no are different in vivo and in vitro and could be driven by environemental conditions such as ph, relative concentration of no and ros, ferryl species...these conditions are impaired in circulatory shock. methods:" the diagnostic and therapeutic approach was standardized so that data collected over a -year period were comparable. a progressive deterioration of clinical conditions and/or pulmonary gas exchanges was considered as indication for my. variables potentially predicting the need for hv were derived from clinical and arterial gas data, extrapulmonary diseases, use of drugs, chest x-ray and ecg abnormalities. results: rv, performed with external and/or internal ventilators, was necessary in patients ( %). at the hospital admission, pac was higher and ph was lower in patients requiring rv ( pneumomediastinum, pneumothorax, ateleetasis and myocardial infarction are rarely seen in bronchial asthma. these complications occur as a result of the severe asthma.the aim of our retrospective study was to analyse the complications seen in acute asthma attacks. during the years through , patients were admitted to hospital in acute asthma episode. there were ( , %) pts with complications; mean age of yrs; females ( %). clinical history, ecg and chest radiogr~hs were analysed. the mean duration of bronchial asthma was yrs (range from months to yrs), all patients were atopics. there were four ex-smokem and one smoker. the worsening of asthma symptoms begun two days before the admission (range from to days). on ecg all patients had tschycardia. rightward shift of the qrs axis and st-t changes indicative of right ventrieutur strain were found in three pts. these were the transient fmdings that improved after curing the acute asthma attack. non-q myocardial infarction oeeured in one patlent and resulted from the hypoxaemia of asthma. hyperinfl~ion was the usual finding on the chest radiograpk pneumomediastinum and subcutaneous emphysema were apparent in five pts and required no additional treatment unilateral pneumothoraccs were present in two pts and needed eontimous intrapleural drainage; one of these patienst died in eardiorespiratory insufficiency. ateleetasis of right upper lobe was present in one patient. it oceured due to inspissated secretions and needed no additional treatment all these patients, except one who died, improved on lreaanent with oxygcr~ steroids, beta-two agonists, theophylline and antibiotics. in conclusion, complications occur in acute asthma episodes as a result of the severe asthma mediastir,*l emphysema and atelectasis are not serious complications. pneumothorax and myocardial infarction are very serious life-treatening complications and always have to i:m considered in taati~ts with sev~ asthma. acute bronchial asthmatic episodes represent one of the most common respiratory mnergendes, its maximmum expression "status asthmatiens" is one entity of low incidence, still it is a risk to the physical integrity of the patient. during a total of patients with diagnosis of status asthmabcas were hospitalized. out of these palients six had a near-fatsl asthma and they were subjected to a complex examination. near-fatal asthma was defined as either respiratory arrest or acute asttuua with paco greater than , kpa and/or an altered state of consciousness. mean age was , -d: , yrs, four male and two female sex. at presentation two patients suffered from coma, others were confused. they exh'bited severe dystmoes, diffieul~ speaking, used accessory muscles of respiration, increased whee~tg while two cases had silent chest on auscultation. cyanosis indicated a very severe asthma attack in all six patients. mean respiratory rate was ~ /min and puts rate .d: bts/imn. arterial blood gases revealed a pao of , ~ , kpa, paco of , • kpa and ph of , -+- , . area-careful evaluation they received conventional therapy (immediately continuous oxygen, impelled nebulization with high doses of betatwo agonists and ipmtropium bromide, intmvanous st~oids and theophylline). in two eases signs and symptoms of deteriorating airflow and respiratory muscle fatigue determined the need for mechanical ventilation. out of six near-fatal attacks aggressive lrealanent was suscessfull in four patients and fatal in two eases. one patient admittcxl in coma died in severe hypoxae~a upon one hour and one mechanicaly ventilated died from cardiac arrhythmia. life-threatening attacks in asthmatics in our group developed gradual worsening despite neatment which r symptoms in most other patients. one patient had "brittle asthma", other long-standing acute episodes ireated with systemic steroids. conclusions: idantitiechon of fatality prone subjects may lead to fttrther muetion of seveze episodes. respiratory affest and coma upon admission, severe dyspnoca with silent chest on ausouhation, oyanusis and use of accessory muscles of respiration constitute the basic cfinieal picture. hypoxasmia must be immediately eon'ected.the patients and physicians should be able to assess the severity of asthma, a major factor in near-fatal and fatal asthma attacks. objectives :our purpose was to asses if the evolution of patients with a adult respiratory distress syndrome (ards) ,shows any relation to the pulmonary or systemic origin of the disease and whether or not there were differences in the frequency of the syndrome in both groups. methods : randomized prospective study in multidisciplinary icu. one hundred and sixteen patients with a high risk developing ards were distributed into two groups. one was named systemic origin group(so) and the other pulmonary origth group (po).ai patients only showed one cause (pulmonary or systemic) with potential risk of ards.the patient's hemodynamic and respiratory status was evaluated every hours the first day and every hours the second and third day. at the end of hours the patients were diagnosed as ards or non-ards. measurements and main results : of the total patients, were finally included in the so group and in the po group.patients in so group and po group had comparable ages (p<. ).peep in both groups was comparable (=. ) at the mmnent of admission to the study. there were no statistically significant differences for cardiac index and systemic vascular resistances. the pulmonary vascular resistances (pvr) showed significant differences at h.(p<. ) and h. (p<. ).the oxygen comsumption (vo) in patients of the so group showed statistically significant differences at h. (p<. ) with respect to initial values.fifteen cases of ards ( . %) in the so group and twenty five cases ( . %) in the po group were identified. the time of onset of ards was _+ hours in the so group and + b hours in the po group.the final outcome was very similar th both groups : mortality of % in the so group versus % in the pc group. conclusions : the pathogenesis of ards depends on whether the lesion is originated at or outside the lung. the po group showed a sborter thne of onset of ards, a faster and more severe increase of pulmonary shunt and a higher percentage of patients developing ards compared with patients of the so group.the so group showed a higher and faster increase in puhnonary resitances tbat po group and a decrease th oxygen comsumption earlier and more severe than in the po group. these data thus seem to show that there could be two mechanisms involved in the genesis of ards depending on the cause. the fact that the ards genesis is shorter in the cases of pulmonary etiology with faster impairment of pulmonary shunt, and a slower increase in pulmonary resistances in this pulmonary group, would indicate that the underlying mechanisms responsible for the hypoxemia are different to those which thitiate the increase in pulmonary resistances. finally, the exclusive inapairinent of oxygen consumption, which appears earlier than the onset of ards in the systemic origth group, could show the generalized character of the process in this group. perfusion of prostacyclin (pgi ) to treat pulmonary hypertension in adult respiratory distress syndrome (ards) worse pulmonary gas exchange due to a marked impairement of ventilation/perfusion mismatch. recently has been shown that if prostacyclin is given by aerosol instead of intravenous the net effect is an improvement of arterial oxigenation due to a redistribution of blood flow to well ventilated areas. objectives: to asses the effects of inhaled proatacyclin on pulmonary haemodynamics and gas exchange in patients with severe ards. methods : two patients with severe ards (murray score > ) recived inhaled pgi at - ng.kg.min " using an ultrasonic nebulizer. haemodynamic measurements, arterial and mixed venous blood gas analysis were performed before and after rain of pgi inhalation. results: short-terro p~i inhalation improved pulmonary g-~ e-'~hange in both patients. arterial oxygen partial pressure (pao ) increased from to mmhg in patient and from to in patient , the ratio pao to the fraction of inspired oxygen increased from to (patient ) and from to (patient ). venous admixture decreased from % to % and from % to % in patient and respectively. mean pulmonary artery pressure decreased slightly from to mmhg in patient and from to mmhg in patient . no effects on systemic haemodynamics were observed in any patient. conclusions: pgi inhalation improves gas exchange and produces selective pulmonary vaaodilation, thus can be an alternative therapy for the treatment of pulmonary hypertension and hypexemia in patients with severe respiratory falllure. methods: we treated ards-patients (age yr ( - ) mean, range) during - . the lowest pao /fio -ratio was ( - ), the worst murray score . ( . - . ), icu-stay ( - ) days and hospital mortality %. the costs of intensive care were calculated according to intensivity of patient care as assessed by tiss-scoring (therapeutic intervention scoring system). the more intensive the care, the higher are the costs. costs per year of life saved (=life-year" in us $) were compaired by other medical treatments ( - ). it is assumed that the mean expected length of remaining life in ards-survivors after intensive care is years. treatment life-year ($) ' bone marrow transplantation (acute leukemia) lowering cholesterol using iovastatin treating hypertension using nifedipine heart transplantation intensive care of ards-patients conclusions: intensive care of patients with severe ards is highly more cost-effective as compared with many other routinely used medical treatment strategies, the usually good recovery and the reasonable quality of life in survivors justifies investments to care of these patients ( ). there is a close correlation between these two methods of measuring evlw. however there is an underestimation of . % in this kind of pulmonary edema ( oleie acid induced ) with the double dilution method. although the size of the sample is small, in normal lungs there appear not to be this underestimation. the effect of peep on evlw has been studied with contradictory results, probably as a consequence oft differences in methods of measuring evlw, variations in the type and severity of lung injury, and different timings of peep application. objective= ) to analyse the effect of different levels of peep ( , and omh ) on evlw during hpe; ) to establish whether increases in intrathoracic pressure due to high peep levels can obstruct lymphatic drainage. material and methodet hpe was provoked in groups of dogs by inflating a foley catheter in left auricular to a pressure of - r~uhg. peep levels of , i or m~hg were applied. resultst objective: to assess the effect on extravascular lung water (evlw) of the application of peep and the reduction of vt in an oleic acid pulmonary edema model in pigs, using three ventila~ary strategies. material and methods: twelve adolescent pigs (weighing over kg) were randomly divided in three gmups immediately alter infusing via a central vein . ml/kg of oleic acid to produce a permeability pulmonary edema. the ventilatory parameters for each group were as follows: group i (n= ) : vt: - ml/kg; zeep. group :(n= ) : vt: - ml/kg; peep: cm h . group :(n= ) : vt: - ml/kg; peep: emil . (resulting in permissive hypereapnla) after a four-hour period of ventilation the animals were killed and the lungs excised to calculate gravimetrically the extravascular lung water using a standardized procedure ( hemoglobin content method ). ill evlw (ml/kg) group obiective: in the postoperative period, maintenance of adeguate arterial oxygen tension is a major problem in morbidly obese patients probably because of a large reduction in functional residual capacity (frc). the aim of this study was to evaluate the effects of peep on respiratory mechamcs and gas exchange in this kind of patients. methods: in nine postoperative mechanically ventilated morbidly obese patients (bmi> kg/m ) we partitioned the total respiratory system mechanics into its lung ( ) and chest wall (w) components using the airway occlusion technique associated with the esophageal balloon, during constant flow inflation (jap ; : ) . at three different levels of peep ( , , cmh ) we measured: compliance (cst), airway (rim) and "additional" (dr) resistance, frc and gas exchange. obiectives. to describe the use of prone position in our icu we analyzed the clinical records of all patients admitted in - , selecting adult patients with arf defined as: intubation and pao /fio < mmhg plus an fio > . or peep> cm i . results. patients met the arf criteria: of them ( . %) underwent prone positioning (p+). prone position use began in the early phase of arf ( . • days from the beginning, range - , median ). out of p+ pts were treated with controlled ventilation (cppv or pcv), while were on assisted ventilation (simv+ps) and on spontaneous breathing (cpap). only pts were awake when turned prone, while pts required adjuncts of sedation to tolerate the change of position. the duration of prone positioning was variable (average lenght . • h, range . - h). only minor side effects were observed (eyelids and facial edema, chest and facial pressure bruises). we consider responders (r+) those patients presenting at least . mmhg increase in pao /fio : / patients ( . %.) were responders when first pruned. the pao /fio changes induced by prone position are reported in the figure. pao /fio increased when patients were pruned (*p< . ) and remained higher than baseline values when returning supine(*p< . ). paco remained unchanged. prone positioning was used at least twice in / ( conclusions. this retrospective analysis confirms that prone positioning improves oxtgenation in the majorib' of arf patients. altough we have no available criteria to discriminate in advance r+ from r-pts, we now routinely consider the use of prone position in the treatment of severe arf. palo a, otivei m*, galbusera c, veronesi r, sala gallini g, zanierato m, iotti g, braschi a.servizio anest. e rianim. i, *laboratorio biotecnologie e tecnologie biomediche irccs s. matteo, pavia, italy inhaled no can improve arterial oxygenation and reduce pulmonary hypertension in ards patients; little information is, however, available about the dose-response curves. methods seven ards patients (lis . +. ) submitted to mechanical ventilation randomly received inhaled no doses in increasing or decreasing sequence: . , , , , , and ppm. reference measurements were obtained before and after the entire period of no inhalation. hemodynamic parameters and blood gases were measured after min in each condition. cmv was administered under sedation and paralysis, with constant ventilation, peep (lol-_ cmh ) and fit (. +. ). the changes in vt and fit due to the no ( ppm in n ) injection in the ventilator external circuit were compensated for. results . the dose of . ppm, ineffective on papm, significantly improved oxygenation. the increase of pat and the decrease of q'va/q' and papm were nearly maximal at - ppm. no deterioration of arterial oxygenation was observed at no doses as high as ppm. co exchange was not influenced by no inhalation. systemic hemodynamic variables did not change throughout the study. these results suggest that a concentration around ppm is adequate for obtaining maximum effects on hypoxemia and pulmonary hypertension in patients with ards. low-dose inhaled nitric oxide (no) induces redistribution of pulmonary perfusion in patients with severe ards and causes improvement of oxygenation [ ] . however, addition of exogenous lowdose no in the inspiratory gas mixture might be only a replacement of missing atmospheric no ( - ppb) in hospital central-supplied medical air. [ ] we have realised nitric oxide measurements in ten healthy volunteers, ( smokers and non-smokers) breathing with a mouthpiece and occluded nostrils through a ventilator circuit, with separation of inhaled and exhaled gases by a valve. no concentration was measured with a double-chamber chemiluminometer (environnement sa, france) and with charcoal/silicate purified compressed air. there was no nitric oxide detectable in the inspirat ry limb of the ventilator. unfiltered central supply medical air contained : - ppb of no and - ppb of no , whereas central supplied oxygen was no/no free. samples were taken after equilibration periods of minutes, with increasing fit levels of . , . and . for subsequent minutes periods; paired values were recorded every s. the mean no value was . ppb (sd . ) and n o significant differences were found for different fit levels both in smokers and non-smokers. these data suggest that the no concentration of pulmonary origin in the exhaled air of' healthy volunteers is probably lower than that reported by other authors [ ] and that, previously reported, differences between smokers and non-smokers are not always striking [ ] . we suggest the use of activated charcoal/silicate filters for clinical trials in order to achieve standard conditions. [ objective: to compare efficacy and safety of two doses of salbutamol. methods: sixteen adults who had severe acute a~hma were randomly assigned to receive either rag (n= ) or rag (n= ) of nebulized sulbutamol. both groups were similar with respect to age, duration of a~hma, duration of attack before arrival at the hospital and severity of a~hma according to baseline measurements (table) . evaluation was performed , , and rain after the start of nebulization. results: compared with mg regimen, mg regimen resulted in the same improvement in peak-flow and fischl index (figure). the changes in heart rate, respiratory rate and pace did not differ significantly between both groups. the incidence of side effects, which included tremor, palpitations, cardiac arrythmlas and other symptoms, was not sj~ificanfly different in the two populations. conclusion:the results of this study suggest that nebulization of ng of salbutamol is not more effective than rag in the initial treatment of acute severe asthma in adult patients. the prognostic factors of neutropenic patients admitted to the icu remain poorly known. the aim of this study was to determine the respective weight of underlying malignancy and organ system failures on the outcome of these patients. patients and methods: the charts of neutropenic patients (wbc < /mm and/or pmn < /ram ), admitted to the icu between and , were retrospectively reviewed. the characteristics of the neoplastic disease (h~emopathy or solid tumor, tumoral evolution, duration of cancer disease and of neutropenia), the mac cabe's score, the organ system (respiratory, hemodynamic, renal, neurologic, hepatic) failures and the severity scores (saps, saps ii ,osf) were registred within the st day in the icu. when discharged from the icu, the patients were classified as alive or dead. results: fifty-seven patients ( . %) had a h~ematologic malignancy, and ( . %) a solid tumor. fifty-nine of the patients died ( . %); the mortality rate did not differ between both groups ( . and % respectively, p = . ). with univariate analysis, none of the tumoral features is linked to the prognosis; only the respiratory (p < - ) and cardiovascular (p < - ) failures, and the number of organ system failures (p < - ) are associated to the risk of death. the saps (p < - ) and saps ii scores (p < - ) were higher in patients who died. with multivariate analysis (logistic regression), only the respiratory failure is correlated to the risk of death (p = - ); neither the features of the underlying malignancy (p > . ), nor the duration of neutropenia before admission in icu (p = . ), nor the severity scores figs ii: p = . ) are linked to the outcome. conclusions: the tumoral characteristics do not modify the prognosis after admission to the icu. they should not influence the decision to admit or refuse a cancer patient in the icu. respiratory failure at icu admission has the predominent weight on the risk of death in the icu. patients with respiratory acidosis due to asthma occasionally require levels of mechanical ventilation that place them at risk for barotrauma. a few case reports have described the use of an extra-corporeal membrane oxygenator(ecmo) circuit as an alternative means of co removal. generally, this has been used for short periods of time (< h) without serious complications and with low blood flows through the extra-corporeal circuit. we report a case of refractory asthma who could not tolerate even small-volume breaths from a mechanical ventilator due to severe bilateral airleak. ecmo therapy was initiated at the referring hospital prior to helicoptor transport. high blood flows were used ( % of the patient's cardiac output), sufficient to achieve both co removal and oxygenation. satisfactory gas-exchanged was accomplished (pco = - mmhg) with nearly total lung rest for a prolonged period ( h). however, the long ecmo duration was associated with two severe complica-ti ns: ) bilateral hemothoraces due to anticoagu!ation in the extra-corporeal circuit, and ) prolonged weakness as a result of neuromuscular blockade for six days. the patient was discharged from the hospital in good condition. we present the respiratory and hemodynamic features of this case aw well as the potential complications of ecmo therapy in asthma. objectives: parameters derived from tidal expiratory flow ~e) and volume (vt) can be used to detect airflow obstruction in copd patients who might be unable to perform forced spirometry (e.g., icu). however, indices such as ave/v t and at/re are highly variable (thorax, : ; ) . methods: we investigated whether the standardized for v m effective time (teff~) of a tidal breath, which is derived by asimple mathematical procedure (teff,= j'vdt/vt ), is a more reproducible and sensitive detector of airways obstruction, we studied nine normal subjects ( male, -+ yr) and copd patients ( male, -+ yr) in the seated position, with a noseclip on. they breathed quietly, through a pneumotashograph to measure flow (v). volume was obtained by numerical integration of thellow signal. each subject had an initial - min trial run, in order to become accustomed to the apparatus and procedure. when regular breathing had been achieved, all breaths over a min time interval were recorded. the mean value of six consecutive breaths (ers criteria) for each subject was used for analysis under the condition that within session variation of tidal volume (vt) was < %. lung function tests were: in normals (mean-sd), fevl%pred = • fevl/fvc%= -+ % , and in copd patients, fev~%pred= __. and fevi/fvc%= --. %. results: values are shown as mean-..+-sd in the following a su~ve~ os literature sources p~oves that t~aditlona], i.e. medicinal medication and physiothe~apeutic methods os t~eatment often p~ove to be insufficientl~ effective both currently and in the ~emote future. the goal of this study was to investigate the efficacy os t~eatment of b~onchial asti~ma patients by means os speleo-and artificial sp~ay therapy. speleotherapy t~eatment was conducted in the conditions os mic~oclimate os salt mine in solotvino hospital. a~tis sp~ay the-~apy was conducted by means os a self-made device. ou~ method is based on the p~inci-~ le os using the majo~ facto~ of speleo-he~apy -highly dispe~sed sp~ay s sodium chloride. the obtained ~esults ~e~e analyzed in five g~adations. at the end os the speleothe~apy improvement and considerable improvement was observed in , ~ os patients; inconsiderable improvement -in , ~ os patients. having evaluated the e~s os t~eatment using a~tis sp~ay therapy the indices a~e , h and , ~ ~espectively. remote ~esults of t~eatment a~e an important index os t~eatment, the ~esult os ~hich ~e~e studied by means s a ~uestionnaive-method. patients ~ho had been t~eated by speleothe~apy mo~e f~eguently ~e-po~ted a ~elapse in disease ust afte~ the course o~ t~eatment ( , h). ho~eve~, in a ]ate~ phase the ~emission ~ould last ]on-~e~ (s months in , ~ os patients, till one yea~ in ~ ~). in , ~ os patients who passed the co~se os a~tificial sp~ay therapy a ~elapse was ~egiste~ed immediately as the co~se os t~eatment. then thei~ condition stabilized ~hile in , ~ os patients a period os ~emission lasted s ha]s a yea~. , ~ of patients dida't ~epo~t a ~elapse of the disease du~in~ one yea~. evangelismos hospital, critical care department, athens, greece method#: mechanically ventilated patients ( copd, ards, other pulmonary diseases) were studied in two phases: ) during the acute phase of respiratory failure; ) during recovery - days later. we measured mip and monitored the pattern of breathing while the patients were breathing spontaneously through the respirator (pressure support mode with - cmh ) until either the point they were unable to sustain spontaneous breathing (sb) any longer (phase ) or for two hours when they could sustain sb indefinitely (phase ). subsequently the patients were sedated, paralyzed and mechanically ventilated. then we simulated the pattern of sb at the end of the sb trial by manipulating the variables of the ventilator and assessed respiratory mechanics b y the end-inspiratory and end-expiratory occlusion technique. . during recovery, a combination of reduced inspiratory load and increased venfilatory capability makes a patient previously unable to sustain sb to breathe spontaneously. . inspiratory load is reduced during recovery, mainly because both intrinsic peep and breathing frequency are diminished. obiectives: although elevated concentrations of a few cytokines have been shown to be present in the bronchoalveolar lavage (bal) fluid (balf) of patients with the adult (acute) respiratory distress syndrome (ards), the pethogenesis of ards is largely unknown. leukemia inhibitory factor (lif), a growth factor recently recognised as a polyfunctional cytokine integrated in cytokine networks was measured in unconcentrated balf of patients from different patient groups. methods: lif was measured in balf by means of a specific and sensitive elisa (detection limit pg/ml)in balf (lavage of x ml in the right middle lobe). results: lif was not detected in the balf of healthy control patients and in only one ( pg/ml) out of patients at risk for ards (after cadiopulmonary bypass surgery) who underwent bal h after the end of the extracorporeal circulation. high and detectable levels were found in the unconcentrated balf of out of patients with full-blown ards ( + , mean + sem, range - pg/ml). there was a good correlation between the level of lif in the balf and a number of markers of inflammation: neutrophils/ml (r: . , p= . ), albumin ( r: . , p= . ) and protein level (r: . , p= . ). conclusions:the biological role of lif in these balfs is not readily explained by its currently known actions and it is unkwon whether lif contributes to or is a response to local tissue damage. our results indicate that this cytokine with lots of interesting _functions is a pert of the inflammatory cytokine cascade in ards. background and obiective : we recently demonstrated that cisapride -a new prokinetic drug -enhanced enteral feeding in a heter genoas group of ventilated icu patients by significantly accelerating their gastric clearance (crit care meal, ; : - ) . it remains unknown, however, whether certain subgroups of patients might benefit more from adding cisapfide to their enteral nutrition regimen than others. patients with chronic obstructive pulmonary disease (copd) might represent such a subgroup since their illness and its specific treatment put them at risk for gastric emptying disorders. design and setting : prospective, consecutive sample study in an adult medical intensive care unit in a university hospital. patients : mechanically ventilated and hemodynamically stable copd patients. interventions : gastric emptying was evaluated by bedside scintigraphy and expressed as the time at which % of a tcg~-labelled test meal was eliminated from the stomach (t / ). baseline data (do) were recorded after enteral nutrition reached to ml daily. scintigraphic measurements were repeated days after cisapride ( ml orally, q.i.d) had been added to this regimen (d ). patients were considered cisapride responders when gastric clearance improved by more than % from baseline. results : normal values for the test meal and for scintigraphic acquisitions obtained in the supine position were found to be + min. in healthy volunteers (crit care med, ; : - ) . five patients responded to cisapride (t / : + rain vs. + min at do and d , respectively) and five did not (t / : + min vs. _+ rain at do and d , respectively). in contrast with non-responders, all five responders had clinically significant maldigestion at baseline (excessive (> ml) gastric residues, vomiting (> times/day and abdominal distension) which disappeared in of them after the administration of cisapride. conclusion : copd patients who tolerate enteral nutrition well have basal gastric emptying times which are comparable with those of healthy volunteers and are not influenced by cisapride. however, cisapride treatment provides both scintigraphic and clinical improvement in those copd patients who exhibit clinically obvious gastric emptying disorders. cernv v., dostal p., zivny p., zabka l. dept. of anesth. and critical care, charles university, faculty hospital, i-irade~ kralove , czech republic objective: the aim of the study was to evaluate the effect of early entera nutrition started within hours of injury on the incidence of multiple orgar failure (mof) in trauma patients requiring vantilatory support. methods: after institutional approval patients were enrolled in the study enteral feeding was begun within hours of injury in trauma patients (en group) admitted to icu. nasuenteric tube was placed as soon as possible after admission into the distal duodenum under endoscopy. additional parenteral nutrition was used to meet patients energy and protein requirements. the control group (pn) consisted of patients fed during this period paretuerally. severity score apache ii, trauma score, cumulative balance of nitrogen (g), incidence of mof (three and more organs) and length of ventilatury support (days) were calculated. values are expressed as mean + sd. results: tab introduction : parenteral nutrition (pn) is an important aspect in the optimal treatment of patients on gastroenterology or intensive care. the aim of this bi-center study in patients has been to assess tolerence and efficacy of a new protein-lipid mixture for pn from a simple preparation. patients and m~hods : patients were selected in two hospitals (tenon and saint-lazare, paris) and were divided into two groups : group a (gastroenterology~ l short bowel syndrome) and group b (intensive care, surgical patients). all patients likely to require pig for a period of days (group a) or days (group b) were studied. the pn regimens administered were the following : combination with g of mct/lct fat emulsion end , g of nitrogen, in liter end glucose requirements were met by imfizsion of l liter of glucose - % via a "y " connection. lipid thus provided % of the non introgen calories. total daily calorie intake was to ] kced. this study monitored, before and at the end of infusions, the sennn albumin (alb), preaiburtun (prealb), triglycendes (tg), cholesterol (cs), and the serum ammotransferases (sgot and sgpt) end alkaline phosphatase (alp) activities. statistical significances were calculated using the wilcoxon-tost. introduction: many cu patients present a catabolic illness in response to inflammation and infection, characterized by a rapid loss in skeletal-muscle mass despite optimal nutritional support. growth hormone (gh) is responsible for a rise of lipolysis, enhancing the energetic balance, and of protein synthesis. recombinant human gh (rhgh) is nowaday available for clinical use, but its cost is very high. therefore, rhgh should only be prescribed to icu patients when its efficacy can reasonably be anticipated (ie. when the patients are catabolic or stressed, but in order to avoid overprescription for unstressed patients and for those who are overly catabolic). hence, we, as others, recently demonstrated that rhgh had no favorable effect in highly stressed icu patients. objective: to detect on a clinical basis, low (ls), mild (ms) and severe stress (ss) states in icu patients and validate this clinical judgement by objective metabolic mesurements, in order to select early those icu patients potentially able to benefit from rhgh therapy. methods: consecutive icu patients were prospectively stratified as ls, ms and ss by two experienced icu senior consultants (temperature; agitation; heart rate; arterial blood pressure; presence of an infection; respiratory rate; exogenous catecholamines). anabolic (insulin, igf- , gh) and catabolic (cortisol, ghicagon) hormones, and nitrogen balance were determined for each patient within hours after admission in the icu. metabolic and clinical data were then compared. the clinical stress states determined by icu physicians correlate with an objective metabolic assessment. therefore, the patients who will more likely benefit from adjuvant rhgh therapy can be detected simply and early. a prospective study on rhgh therapy in ms icu patients is in progress. berger mm md , chiolero r md , pannatier a phd , berger l , cayeux c , voirol p , hurni m md . surgical icu, pharmacy, and cardiac surgery, chu vaudois, ch-iotl lausanne, switzerland objective. nutrition of the compromised cardiac surgical patient is challenging. numerous factors influence the gastrointestinal (gi) absorption function, among which gut perfusion, which depends largely on the systemic hemodynamic status. patients in hemodynamic failure are prone to organ failure, and may benefit from an early jejunal feeding. the study was designed to assess the absorption function after cardiac surgery in patients with adequate and altered hemodynamic status, using paracetamol as tracer of gi absorption. methods. after cardiac surgery, patients, aged _+ years (mean_+sd) were assigned to groups (anaesthesia: fentanyl gg/kg + midazolam): group (n= ): reference group, with normal hemodynamic status, easy recovery. group ('n= ): patients in low output syndrome, cardiac index < . i/m on day (d ) after surgery, requiring prolonged intensive care, mechanical ventilation + nutritional support. paracetamol g, was given intragastrically on d + d : plasma levels measured (h.p.l.c), at administration (to), t - - - - - and rain. hemodynamic status assessed with pulmonary artery catheter. healthy subjects served as controls. results. compared to healthy controls, absorption was strongly reduced on d in all patients (no difference between groups). on d , peak paracetamol level was significantly lower in group (low cardiac output): in group the area under the curve on d and d were similar. there was a large inter-patient variability, reflecting the hemodynamic status. conclusion. gi absorption was decreased on d in all patients, and reverted to normal between d and d in case of normal cardiac function, but not in case of low output syndrome. the decrease on d can be attributed to fentanyl, known to slow down the gi transit. in patients with cardiac failure, correction of altered absorption was correlated with the hemodynamic status, suggesting that gi absorption is dependent on adequate splanchnic perfusion. the aim of the work was to define specific significance and evaluate efficiency of enteral component of infusion therapy in the intensive care of gastroenterotogic patients of surgical profile with pyo-septic complecations. there were used the methods of radial diagnostics and polyelectrography; the laboratory control on oxygen-transporting function, volumetric and hemodynamic state, changes in metabolic, hormonal and immunologic status was conducted. from january, [ till november, there was carried out the randomized study of patients with general purulent peritonitis; among them persons constituted the control group and -the main one. in the main g~oup the intestinal lavage, enterosorption, enteral introduction of nutrient solutions with gradual turn to enteral nutrition by equalized mixture "ovolaet" were started from the first hours after operation. the data obtained allowed to define the specifity of the program of artificial medical nutrition in the group of examined patients, based on necessity of individual selection of media for enteral introduction depending on the stages of intestinal insufficiency syndrome. it was shown that inclusion of enteral component into the program of infusion therapy during early periods stabilized circulation in the regime of moderate hyperdynamia, considerably decreases the deficiency of circulating blood volume, normalizes the values of oxygen transport, consumption an}d extraction, provides the optimal level of mycardial adaptive possibilities without tension of its compensatory functions and pulmonary circulation overload. due to combined application of parenteral and enteral nutrition the metabolic processes are shifted towards anabolism. this is supported by decrease to normal values in the contents of blood aggresive hormones (acth,hydrocortisone) and increase in somatotrophic hormone. the complete parenteral-andenteral nutrition influences positively on restoration of cellular and tumoral immunity, activates the factors of organism nonspecific protection and recovery from immunodepression, prevents the development of immunodeficiency. impact tm vs control. s atkinson, n maynard, r grover, e sieffert, r mason, m smithies, d bihari departments of surgery and intensive care, guy's hospital, london, u.k objectives: comparison of the effect of an immunonutrient enteral feed versus a control on the outcome of a mixed intensive care unit (icu) population. methods: admissions to this multidisciplinary adu)t icu thought likely to stay more than three days and with tube access to the gi tract ~r randomised to receive either impact tm, a feed with supplemental arginine, dietary nucleotides and omega- fatty acids, or an isocaloric and isonitrogenous control feed. study end points included mortality and icu stay. approval was obtained from the hospital ethics committee. rosults: patients were entered into the trial. the two groups were well matched for age, sex, and admission apache ii with an overall mean admission risk of death of . (std. dev. -+ . ). on an intention to treat basis, there was a no significant difference in icu mortality, icu stay or standardised mortality ratio (s.m.r.) between the two groups (see table) . similarly, there were no differences after stratification for patients receiving or more litres of feed. conclusion: there is no evidence of an effect of impact@, an enteral immunonutrient feed, on pre-determined end-points (icu mortality, icu stay or standardised mortality ratio) in a mixed intensive care unit population over that of an isocaloric, isonitrogenous control feed. objeeflves: evaluate changes of blood laatate levels according to patient medical status after cvvhd initj,~ion using dialysate solution containing lactate. method: review of medioal records of consecutive patients ~eated by cvvhd (dialysate solution hmnosol lg , hospal,uk, lactate concentration retool/l). date obtained hr before and - hrs at~er cvvhd initiation were analysed. results: all data are presented as mean + sem. in one patient, pre end post filter lactate levds were measured during standard cvvhd setting (blood flow ml/mlu, dialysate solution flow i /hr), and approximate daily lactate flux into the patient was calculated to be as high as mmol/d. lactate leveh measured after cvvhd initiation increased significenfly compared to baseline levels ( . + . axtd . + . ,respectively; p< . ,paired t-test). when patiente with increased basal lactete (~- ) were compared to paliente with normal basal values (n= ), no difference in laotete increase was fmmd (p= . , manova). patiente with severe liver dysfunction ( points in mop scomlg, n= ) had higher basal laotate levels than patiente with normal or slightly abnormal liver teste ( or point in mof scoring, n=ll), rite values being . + . and . + . , respectively (p< . , student t-test). increase in blood lactate did not differ between these two groups after cvvhd was stetted (p= . , manova). in pafiente with invasive hemedynamio mo~, no oorrelation batween changes in lactate levels and eitlm" changes in oxygen ddivery (t =o.ol; p--o. ) or oxygen consumption (reversed fie, k) (r -q).o ;p-- . ) were found after cvvhd initiation. conclusion: blood lactate increases on cvvhd with dialysate soh~on rich in lactate. this increase is predominantly caused by influx of lactate into the blood via the filter end does not seem to depend on the liver fimotion and/or oxygen metabolism changes. objectives: the study was designed in order to determine the effect on plasmatic proteins, of two types of aminoacids solutions of parenteral nutrition (pn) adapted to stress, having different concentration of branched chain aminoacids (bcaa), when applying to politraumatized critical patients. methods: a prospective study was performed using a randomized double blind design of polytraumafized patients, split in two groups of ten patients each, with mean ages of _+ an -+ years. due to their condition, all patients required p.n. for at least days. both groups were subjected to isocalorie and isonitrogenous solutions ( ci/kg/ day and . g of nitrogen/ks/day), varying only in the concentration of bcaa; solution a having a % concentration and solution b %. blood samples determinations during days , , , after the beginning of treatment with p.n. were total proteins., albumin, trandferrine, protein binding retinol; prealbumine and fibronectine. the anova test (one and two way) was used to compare the values between the two groups. results: the administration of solution a, showed statistically significant increases in the determinations of the values of protein binding retino] (p < . ) and prealbumin (p < . ). no significant increases were observed in the values of total protein, albumin, transferrine and fibronectin. solution b produced statistically significant increases only in the values of total proteins (p < . ). the remaining proteins did not changed from their control values during the whole period of pn administration. comparing both groups, no statistically significant differences were observed related to the type of diet. nevertheless, differences were found in total proteins, albumin, protein binding retinoi, fibronectin (p< . ) and prealbumin (p < . ) in relation to the time course of pn therapy. only the albumin values showed significant differences (p < . ) when considering the interaction of both the type of diet and the time course of pn. conclusions: . solutions of pn adapted to stress, can maintain the control values of slow turnover proteins and improve the values of rapid turnover proteins. . no significant differences on plasma proteins were found between the two solutions having % or % concentration of branched chain aminoaeids. &determination of rapid turnover proteins does not seems useful for discriminating different solutions of bcaa during pn. obiectives; the hormonal changes in the post-traumatic situation often leads to an elevated blood glucose and a negative nitrogen balance. to reduce the elevated glucose production by aminoacids the apprication of xylitol may be an alternative energy source. in a double-blind randomized study we investigated the effects of a xylitol/glucose solution (group a: aminoacids g/i; glucose/xylito g/ g/l) on metabolism and particularly on pancreatic and liver enzymes compared to a glucose based nutrition solution regimen (group b: aminoacids g/i; glucose g/i). methods: the clinical trial was carried out after the approval by the local ethical committee on patients with severe brain injury. there was no difference in body mass index bmi (group a: . +/- . kg/m and group b: . +/- . kg/m=), age, and sex. daily individual energy expenditure was measured by indirect calorimetry (deltetrac "~). nutrition was started - hours after trauma or surgery with carbohydrates and aminoacids. fat was added h after nutrition had started. to analyze the effects on pancreatic and liver enzymes we investigated the following parameters for days: blood gtucose, serum lipase, serum amylase, asat, alat, ~gt, ap, and serum cholinesterase (che). results: due to the daily indirect calorimetric measurements energy requirements were satisfied. there was no difference in blood glucose concentration and cumulative nitrogen balance between the two groups. neither were there any significant changes in asat, alat, ap, and che for days in both groups. serum tipase steadily rose to lull in group a and . lull in group b, respectively. conclusions: there was no measurable influence of either nutrition solution on liver enzymes. the xylitol/glucose nutrition regimen does not have any advantage over the glucose based nutrition solution concerning blood glucose level or nitrogen balance. the elevation of serum lipase to a -fold level in either group needs further investigation on trauma patients. the effects of fat emulsions in lung function, particularly in lungdamaged patients, have been attributed to alterations in pulmonary vascular tone caused by eicosanoid production modificatione. as the eicosanoid production may depend on the fatty acid profiles of the intravenous fat emulsion, haemodynamic, pulmonary gas exchange and plasma levels of prostanoids were investigated in acute respiratory distress syndrome (ards) patients, during different intravenous lipid emulsions (providing different prostanoid precursors). we studied in a randomized double-blind design groups (n= each) with ards. group i (lct) received a fat emulsion with long chain triglycerids (lct- %), group ii (mct) an emulsion containing a mixture of medium and long chain triglycerids (mct/lct / - %) and group iii placebo (control), during h ( mg/kg/min each). we measured before, at the end of h infusion, and h after the end of the infusion: lipaemia, arterial and venous blood gases, pulmonary and systemic haemodynamics, and plasmatic levels (arterial and in mixed venous sample) of eicosanoids (txb=, -keto pgf~,, and ltb ). at the end of the fat emulsion, groups (i and il) to , • to , • mmol/i), the paoz/fio z remained unchanged in the three groups; no changes in intrapulmonary shunt (qs/qt) were shown; neither in the mean pulmonary artery pressure. in contrast, only in the lct group: cardiac output and oxygen consumption increased significantly ( . % and %) (p< . ). eicosanoids were increased at baseline compared to reference values (p< , ). a decrease (p<o, l in the arterio-venous difference of the vasodilatador prostanoid ( -keto pgf~=) was shown in lct group. our results indicate that fat emulsions in ards patient do not influence pulmonary gas exchange, provided that the perfusion rate were keept at mg/kg/min. the present study was designed to evaluate the metabolic changes of a carbohydrate-based diet versus a fat-based diet on oxidation rate of substrates and energy muscle metabolism in patients with an acute exacerbation of chronic obstructive lung disease. patients were mechanically ventilated with a volume-cycled respirator. after an overnight fast, patients were randomnly treated with a continuous enteral feeding over a nasogastrie tube with a carbohydrate/fat ratio of / in group i (n= ) , and a carbohydrate/fat ratio of / in group i] (n = ) during consecutive days. indirect calorimetry was set at baseline and hours later the enteral feeding was started. muscular quadriceps biopsy was performed on baseline and on day of enteral feeding. urine was collected during hours and was used to measure h urea nitrogen production. the caloric intake was set according to the measured resting energy expenditure. respiratory gas exchange rate were measured using a computerized open-circuit indirect calorimeter. quadficeps femoral muscle samples were obtained by muscular biopsy after local anesthesia. analyses of glycogen, glucose -phosphate, lactate, phosphocreatine and adenosine triphosphate (atp) and enzymes (glycogen synthase and glycogen phosphorylase) were determined. after h of nutrition patients in group i showed an increase in carbohydrate oxidation (from . % to . %, p= . ), and in group ii a decrease in protein oxidation (from % to %, p= . ). after days of enteral feeding a tendency to increase in glycogen concentration (group i, p= . ; and group ii,p= . ) was observed. while patients in group i showed a tendency (p= . ) to decrease glycogen phosphorylase, patients in group ii maintained these enzymatic levels. the increased in glycogen was correlated in group li with degradation enzyme (p = . ). in group i, the pao /fio ratio increased after days of treatment (from . to . ; p= . ), but no changes in days of mechanically ventilation, length of stay in icu, or mortality rate was evidenced between groups. it is concluded that the oxidation rate of substrates used for energy production varies according to the caloric sources administered. with nutritional therapy muscle glycogen concentration increases in both diets, with different enzymatic influence. more studies are warranted to further assess the clinical implications of the different pathophysiologic behavior of the two diets. under certain experimental and human conditions (radiation and/or thermal injury) the gi mucosa is unable to perform this protective function and could play an important role in the pathophysiology of the syndrome of multiple organ failure (smof). the objective of the present multicenter study was to know the gi mucosal permeability in critically ill patients and the relationship with their outcome. the method used to assess the integrity of the gi mucosal barrier measured mucosal permeability to various hydrophilic compounds. specifically, we measured the urinary excretion ratio (uer) of two sugars (lactulose and mannitol) that had been previously administered through a nasogastric tube. urinary excretion rate was measured in healthy humans (control) and in patients admitted to the intensive care unit (icu) at days , and . the apache ii of the patients studied was _+ . there was an increase of uer in the critically ill patients compared with controls (o. _+ . vs . _+ . ) (p< . ). in contrast, no changes in uer between days , and were observed ( . -+ . . significant changes were also established in the different groups: major and minor surgery, general and epidural anaesthesia , transfused and non transfused patients except for iron and ferritin plasma levels which didn't change significantly in patients who had received blood. a positive significant correlation was established between crp and ferritin (r= . ) for patients under general anaesthesia, but not on epidural, regardless of the type of surgery. conclusions: iron and transferrin plasma levels fell acutely in surgical patients while ferritin and crp rose. transfusion implied an acute iron load.the established correlation between cpr and ferritin in patients on general anaesthesia suggests that ferritin behave as an acute phase reactant in that setting, while epidural anaesthesia may ameliorate the inflammatory response. objectives: to analize the effect of gastrointestinal complicacions (gic) related to the enteral nutrition (en) in the real volume of diet administered to icu adult patients. a prospective multicenter study was designed (comgine study) in wich en application, gic definition and his management were defined by collaborative consensus.patients treated with en in one month pedod were included. in each case, daily volume of diet prescribed (pv) and administered (av) was recorded and the volume ratio calculated (vr=pvxl /av). patients were divided for days of en according to the presence (group ) or absence (group ) of gic (abdominal distension, increase of gastdc residuals,vomits or regurgitation, diarrhea,constipation and bronchoaspiration). differences between groups were analized by anova and mann-whitney u test with p< . for statistical significance. (vr%) group (vr%) tolerance to the enteral nutrition (en) has been related to the severity of illness in icu patients. the aim of this study was to evaluate this relationship. methods. a prospective, multicenter, study was performed (comgine study) in wich en application and related gastrointestinal complications (gic) were defined by collaborative consensus. adult icu patients treated with en in one month pedod were included. gic were classified as: ) abdominal distension (abd), ) increase of gastdc residuals (igr), ) vomits (vom), ) diet regurgitation (reg), ) diarrhea (dia) and ) constipation (con). patients were divided in two groups: group a: patients with gic dudng their evolution. group b: patients without gic. differences between groups were analized for apache ii admission score or evolutive variables ( carbon dioxide production is a major determent of work of breathing. increase in co production during nutritional support may precipitate ventilatory failure and difficulty in weaning from mechanical ventilation. in the present study, co output was calculated while passive mechanically ventilated patient were fed with different amount of calories and different proportion of protein, carbohydrate and fat. four clinical stable and mechanically ventilated patients were studied. carbon dioxide was calculated while patients were paralyzed, sedated and mechanically ventilated. six nutritional regimens were used: a) no calories, b) t gr glucose/ h, c) calories equal to rest energy expenditure in special formula with low carbohydrates and high fat (pulmocare) d) calories equal to rest energy expenditure in standard formula (nutdson) e) calories double to rest energy expenditure in standard formula (nutrison) and f) calories equal to rest energy expenditure parenterel (tpn). carbon dioxide output was low while no calories and/or only gr/ h glucose was provided, the mean values of vco output were _+_ and !-_ ml/min respectively. there was no difference in vco output between with low carbohydrates and high fat regimen and standard regimen, mean values were t . -+ and _+ respectively.the high calories regimen and tpn resulted in higher vco output, mean values _+ and • respectively. we conclude that the special with low carbohydrates and high fat regimen did not reduce vco output, in the contrary, high calories intake as well as tpn increased vco output under tested conditions. klouche k., cristol j.p., vela c., canaud b., b raud j.j. m tabolic intensive care unit and nephrology department. lapeyronie hospital. montpeuier france. predictive factors for rhabdomyolysis (rh) -induced acute renal failure (arf) were studied in a retrospective study from january to january . patients (pts) (male: , female:lo; mean age: + y.o.) were admitted with rh defined as cpk> iu/ . etiologies were: traumatic and ischaemic , infectious , toxic , excess activity . factors studied were: simplified acute physiologic score (saps: . + . ), organ systemic failure (osf: . _-!- . ), diagnosis delay (d: +_ h), clinical parameters (sepsis, dehydration), blood chemistry data (cpk, bun, creatinine, potassium, phosphorus, calcium, proteins, hematocrit) and urinary ph. severity of rh was estimated by ward score determined according to phosphorus, albumin, potassium, cpk, dehydration and sepsis. urea appearance rate (uar) and creatinine index (ci*) were determined over a hours period. arf was observed in pts. in non-arf and arf groups respectively, saps ( . _+ . vs . + . ), deshydratation ( vs ), sepsis ( vs ), phosphorus ( . + . vs . -+ . ), calcium ( . + . vs . _+ . ), ward score ( _+ . vs . + . ) were significantly different. however, no significance was observed in uar ( -+ vs -+ ) and ci ( _+ vs _+ ). patients required hemodialysis (hd) ( : sessions) and remained dialysis free. only osf ( . _+ . vs . -+ . ), ward score ( . _-/- . vs . _+ . ) and ci ( +_ vs -+ ) appeared significantly higher in pts requiring hd. pts died from associated disease. all patients suffering from arf recovered a normal renal function. we confwmed that an elevated ward score (over ) is a good predictive index of arf. in addition we found that ci is a severity factor for arf requiring hd. thus, patients suffering for rh with elevated ward score and ci, have a fair chance of dialysis and should be treated more intensively. * ci (expressed in mg/kg) = (car + feces creatinine) / weight. where car: creatinine appearance rate; feces cr~t..= mean plasmatic creatinine x . . tr~er k., cetin t.e., tugtekin i., georgieff m., ensinger h. universit~tsklinik flir an~sthesiologie, uim, germany introduction: endogenous as well as exogenous adrenergic agonists have a profound effect on carbohydrate metabolism in human critical illness. in this study the effects of noradrenaline (nor) and dobutamine (dob) on carbohydrate metabolism during a hr infusion were investigated. methods: after approval by the local ethic committee healthy volunteers were studied. hepatic glucose production (hgp [mg/kg/min]), using , -d glucose as stable isotope tracer, as well as plasma concentrations of glucose (glc [mmol/i]) and lactate (lac [mmol/i]) were measured prior and during infusion of nor ( . pg/kg/min) and dob ( pg/kg/min). blood samples were drawn before and during the agonist infusion. results: no major changes in insulin and gtucagon plasma concentrations could be found during the study period. ::i:::: :iiiii~ ~ i ::i: ~:: : :: i:ii. mean-+sd are shown. # p< . , anova for repeated measurments. conclusions: the effect of nor on hgp and glc were smaller as compared to adrenaline (i) with a similar time course. in contrast to the effects of adrenaline and nor, dob had a different effect on carbohydrate metabolism: a decrease in hcp and glc, which is uncommon for a / -adrenoceptor agonist. since hgp is an energy consuming process that might deteriorate hepatic oxygen balance in critical illness, the differential effects of adrenergic agonists may be of importance and need further clarification. the nutritional insufficiency often accompanies post-operative hypercaloric states, inanition, serious infections and weakening chronic illnesses. that is why the early nutritional support, sufficient and appropriate for each individual base, is a fundamental component of intensive care unit as an indispensable factor for recovery. per this reason, our unit, developed a software for the implementation and nutritional control of t~e assisted patients. this software is incorporated is an expert system called ~i~su, designed and developed by the computational division of our unit. this system arrives to inferred diagnoses such as : respiratory, hepatic, renal(with and without dialysis) dysfunctions, pancreatitis, ards, decrease of consciousness, diabetes. according to these data objectives: to compare the effect of short term enteral feeding versus parenteral nutrition, when a isonitrogenous and isocaloric feeding solution is administered by either mute. methods: in a prospective controlled clinical trial patients were studied; all exhibited moderate degree of malnutrition, normal liver and kidneys, and a functi ning gastrointestinal tract. the patients were randomized to receive a free amino acid and small peptide diet ( patients) or an isonitrogenous isocaloric parenteral support (tpn) ( patients) (total energy: kcal, nitrogen: . g, carbohydrates: g, fat: g, n/non protein calories: / ) at least for days. results: there were no significant changes in anthropometric parameters within either group. nitrogen equilibrium was aqhieved by day in the tpn group and by day in the enteral group ( . % of the enterally fed patients and % of the tpn patients maintained in positive balance the day of the study). there were no significant changes in serum albumin within either group. serum level of transferrin reached a significant increase in both groups (p= . ). thyroxine-binding prealbnmin rose significantly in both groups as well (p= . and . respectively). statistically significant rises in lymphocyte counts (p= . and . respectively), in levels of c (p= . and . ) respectively), iga (p= . ), igg (p= . and . respectively) and igm (p= . ) occurred in either treatment group. there was a high incidence of negative skin tests at the start of the study in the enteral group ( . %) and the tpn group ( %). by the end of the study the incidence of negative responsiveness was . % and . % respectively. despite maintenance of similar glucose levels in both groups, tpn led to significantly higher serum insulin levels. the serum insulin increased almost linearly over the study period and eventually prevented fat mobilization and lipolysis, so that free fatty acid levels had fallen significantly. a significant elevation of the liver enzymes over the study period occurred in . % of the tpn group, but not in the enterany fed patients. conclusions: the present findings provide no evidence that enteral diets containing free amino acids and small peptides, as their nitrogen sources, are in any way inferior to isonitrogenous isoealoric regimes parenterally given. aim: the aim of this study is to describe and explore the expectations of the functions of the critical care nurse to enable the formulation of guidelines for the scope of practice for the critical care nurse with a south african context, methods: phase i was to determine the expectations of the critical care nurse, the nursing service managers and the doctors with regard to the functions of the critical care nurse. a focus group interview was held with a group of experts in the field of critical care. the results were used to compile a questionnaire. this questionnaire was sent to the critical care nurses, the nursing service managers and the doctors in south africa for completion. from these results the functions of the critical care nurse were determined. phase ii was to formulate guidelines for the scope of practice for the critical care nurse within a south african context. through usage of the date (phase i) the scope of practice was formulated. guidelines were formulated for the practise, education and research regarding the limitations of the professional-ethical authoration and the implementation of the scope of practice for the critical care nurse. objectives : high output gastric aspirates arc occasionally observed during fasting in critically ill paticnts, preventing any attempt of feeding via the enteral route. although these patients are often said to suffer from "gastroparesia", the motor correlates of this condition arc lurgcly unknown. in this stud?', wc recorded the gastrointestinal motility of critically ill patients with abundant (> ml/ hours) fasting gastric aspirates. methods : antral ( sites separated each other from . cm), duodenal ( site) and jejunal ( site) contractions were recorded simultaneously by ~eans of a multihimen tube assembly positioned trader fluoroscopic control (perfused catheter technique). tracings from prolonged recordings were obtained on a multichannel recorder ( a recorder, hewlett-packard) then anal) ,ed visually, with a special attention for the following abnormalities which are characteristic of intcstinal pseudoobstmctiou: l) absence or aberrant propagation of the migrating motor complex (mmc), ) presence of bursts (> min) of nonpropagated phasic pressure and ) presence of sustained (> min) uncnardinate pressure activity. patients with a volume of gastric aspirates of • (sd) [median ml/ hrs were investigated for - [median minutes. results : only one patient had no detectable motor abnormality. mmcs were either absent (n= ) or migrated abnormally (retrograde propagation : n= ; retrograde and stationnary : n= ) in pts. bursts of nonpropagated phasic pressure activity were present in the duodenum in pts and sustained uncoordinate pressure activity was found in pts. additional abnormalities included episodes of prominent pyloric activity. (n=l) and sustained antral pressure activity (n= }. conclusion : critically ill patients with large volume of gastric aspirates have manometric evidence of intestinal pseudoobstruction. prokinetic therapy in these patients should thus focus not only on enhancing gastric motility, but also on restoring a normal propagative contractile activity in the intestine. this prospective, open-label, randomized placebo-controlled study included patients with hypokalemia in whom rapid potassium replacement ( meq kci in h) was performed: patients received mg sulfate ( g in hours) and patients received a corresponding saline infusion. measurements were made at time , + , + and + hours results: k levels increased more in mg treated patients than in the patients who received saline infusion at time and h (p < . -students-newman-keuls). (table ). introduction. dual lumen uaso-gastrojcjunal tubes are a major ads'ance in nutritional therapy of mechanically ventilated critically ill patients since the " authorizc jejunal feeding with concurrent gastric decompression, there,, reducing the risk for aspiration. unfortunately, placcmem of these tubes in the jejunum regularly dictates to resort to endoscopy in order to facilitate pyloric intubation. recently, the remarkable gastrokinetic properties of the well known macrolide antibiotic er}lhromycin have been demonstrated in gastroparetic critically ill patients . aim. in the presem stu~,, we evaluated the feasibility of placing dual lumen naso-gastrojcjunal feeding tubes at the bedside without endoscopy, using edthromycin to help iranspy'loric migration of the tube under fluoroscopic control. methnd each patient admitted in our icu during a months period and requiring artificial ventilation and enteral nutrition for a period of at least days was included in the study.. after inserting the tube (stayput| sandoz, usa) in the gastric anmnn, e.rythromycin ( rag) was aduunistored intravenously, to help fluoroscopic positioning of the tube into the jejunum. the total duration of the procedure (from nasal intabatiun to jejunal placement), as well as the duration of ftuoroscopy were recorded in each patient. results. patients (male/female : / : mean age : . + . years; mean apacbell score : .t • . ) wore enrolled into the study.the procedure was performed within the dab,s following institution of mechanical ventilation. jejunal access was obtained in all patients without resort to enduscopy in , • . min.(total duration of the procedure). mean duration of fluoroscopy was . + . rain. conclusion. we conclude that placement of dual lmnen naso-gastrojejunal tubes can be obtained in mechanically ventilated critically ill patients without resort to endoscopy., provided that e rythromycin is used as gastrokinetic agent to help pyloric intubation. the following ad and dis parameters were considered in all patients: -mid arm circumference, triceps skinfold thickness, serum transferrin, albumine and lymphoeites and urinary creatinine/height index. patients whose results were bellow % of normal values in or more of the above criteria were considered undernourished (und).statistical analysis was performed using % analysis.statistical significance was established at p<o.o . results: a total of patients( female, male) -with a mortality rate (~) of , % -were studied, aged -+ years and a median ]enght of stay of days. -nourished (nou) at ad and at dis - ; ~ %; -nou at ad and und at dis - ; ) , % ; -und at ad and und at dis - ; ~ . %; -und at ad and nou at dis - ; ~ , %. we observed a p< . when we compared groups and (p= . ), and groups and (p= . ). variation in nutritional status and longht of stay: -nou at ad and nou at dis = > median lenght of stay days; und at ad and und at dis = > median lengbt of stay days; nutritional status and age at admission: -age > = years : nou ( ) , und ( ) -age < years: nou ( ), und ( ) nutritional status and age at discharge: -age > = years : nou ( ) , und ( ) -age < years: nou ( ), und ( ) we observed a p<o. when we compared groups and (p=o. ) and groups and (p = . ) conclusion: such study permits to conclude that most of our patients ( . %), staying in icu for more than days, were und, namely the elder. we observed that this kind ef patient had a longer median length of stay in icu, associated with higher mortality rate. in conclusion, the nutritional management is an essential element in suportive care of critical)y ill patients. ohiectives: sirs is associated with hypercataholisnl and resistance to nutritional support, despite raised circu&ting levels of growth hormone and insulin. serum igf- levels however are low; thercti~re rhigf-i administration might produce nsefnl anabolic effects. the pharmacokinetics of exogenously administration rhlge-i in such patients are likely to differ from that seen in the less seriously ill due to changes in circulating blood volume, increased capillary permeability, poor nutritional stares, and alterations in binding proteins. the ol jective of this study was to determine the clearance, apparent vohnne (if distribution (vd), time to peak concentration (tmax) and elimination half-like (tia) of a single subctkaneous il~ieetion of rhlgf-i in patients with sirs on the intensive care unit (icu). methods: icu patients with sirs were entered into the study, which had been approved by the ethics comjnittee. in each patient baseline hlood samples for circulating gf-i were obtained over a hour period, prior to il!iection of p.g/kg of rhlgf- subcutaneously. a further l samples were taken fi'om each subject over the next hours. circulating ige-i was measured in serum at each time point by radioimmtme assay, and the area under the curve tbllowing administration of rhlgf-i was derived tbr individual patients fixm~ baseline a~!justed igf-i levels. clearance values were caietdated by dividing the administered dose of rh[ge-[ by the total area under the etnve. vd and tv were calculated by regression analysis of the terminal part nf the log sertnn concentration time profiles. results: results are expressed as median (range). age ( - ) years, apache ii score ( - ), and length of icu stay ( - ) days. baseiine circulating igf- levels were low ( < - ) ng/ml reaching a peak of only ( < - ) ng/ml. of the patients had basal levels predmnhaantly below the inwel-limit of detection of the assay, and showed no appreciable rise in serum igf-[ levels tbllowing rhigf-i injection. parmacokinetic variables could not therefi)re be determined in these two patients. following rhlgf-i injection in the remaining patients tmax was at ( - ) hours, clearance was ( - ) ml/min, vd was . ( . - . ) l/kg, and tia . ( . - . ) honrs. conchlsions: there was marked patient wu-iability in response to rhlgf-i administration. vd was similar to that seen in poshq~erative maior surgery patients ( . vs . l/kg), but clearance was greater ( vs ml/min), tmax earlier ( vs hours) and t~a shorter ( . vs i . homts). if riaigp-i is to be administered to dtically ill patients the dose should he nlodified m the light of these findings. baekgronnd: acute bacterial endoearditis continues to be a condition with high morbidity and mortality. the majority of patients are treated with high dose antibiotics, but a patient group requires surgical treatment. methods and results: from january to march , patients underwent surgery for acute bacterial endocarditis: had native valve endocarditis and had prosthetic valve endocarditis. there were men and women. streptococcus viridans was the predominant infecting agent in native ~alve endocarditis and staphylococcus epidermidis in prosthetic valve endocarditis. progressive congestive failure, uncontrolled sepsis and peripheral emboli were the most common indication for surgery. although the mitral valve is more commonly involved in acute bacterial endocarditis, the aortic valve most often requires surgical inlervetion. the postoperative bleeding in the no-aprotinin group was + cc and in the aprotinin was :t: (p < , ). the mortality in icu was , %, the staphyloccocical endoearditis mortality was , % and the no-staphyloccocical endocarditis mortality was , % (p< , ). conclusions: the early surgery is indicated if endocarditis has no response with medical treatment. the mortality of staphyloceocical endoearditis involving left valves was higher than caused by other infecting agents. aprotinin treatment improved prosta#andin metabolism and preserved pletelet function during open heart surgery and could be useful in this type of interventions. urgent surgery had a high mortality ( %). selective digestive decontamination (sdd) has increasingly become the subject of critical discussion sine~ the development of multiresistant organisms has become an issue. moreover, a selection of gram-positive pathogens must also be taken into account when using the sdd regimen, which is primarily directed at the gramnegative bacterial specumn, with the methicillin-resistant staphylococcus aureus strains (mrsa) being of particular importance. the objective of our study was to determine the extent to which colonization with mrsa strains is promoted by sdd. method: patients (ventilation period > days) were randomized and allocated to the sdd group (n= ) or the control group (n= ). in their general intensive care theraw, there were no differences between the groups. the sdd regimen consisted of the four times daily administration of rag polymi~ mg tobramycin and mg amphotericin b in the nesc, mnoth and stomach. systemic prophylactic ~dmini~/rution of antibiotics was not part of the sdd regimen. smears were taken from the nose and the rectum twice wceldy and from the pharynx and trachea once wceldy, and tested for mrsa. further samples were taken as clinically reqnircr results: smears were examined in the sdd group. mrsa strains were detected in samples ( . %) from patients, and in patients they were detected for a period of up to weeks. the positive smears were districted as follows: tracheal / ( . %), nasal / ( . %), pharyngeal / ( . %) and rectal ( . %). severe mrsa-induced infections were observed in patients (infection rate . % of the colonized sdd patients). smears were examined in the control group. ivlrsa swains were r in samples ( . %) from patients, but only repeatedly over a period of up to days in patients. the po~tive snmars were distributed as follows: traclmal / ( . %), nasal / ( . %), pharyngeal / ( . %) and rectal / ( . %). there were no mrsa infections in the control group. conclusion: the data collected support the view that the use of sdd promotes a selection and persistence of mrsa strains. longer-term colonization with mrsa and sovere systemic inf~ons were only found in the sdd group. although the clinical and epidemiological impact of resistance develol~ng when sdd is applied ~maine unclear, this question should be given close scrutiny. tazobactam/piperacillin (taz/p p) is a new broad spectrum antibiotic, in which the acylaminopenicillin piperaeillin is protected by the betatactamase inhibitor tazobactam from hydrolization by bacterial enzymes. taz/pip has shown to possess a high antibacterial activity against almost all clinically relevant bacteria and is a registered drug in germany. obiectives: purpose of this investigation was to evaluate, whether faz/pip . g is suited for efficient antibacterial monotherapy of severe infections and what influence dosage frequency reveals on clinical efficacy. methods: hospitalized patients have been documented in this multicenter trial during a year period. as this investigation should reflect the usual clinical treatment, the only criteria for enrolment were the typical signs of infection as e.g. temperature > ~ leucocytosis or an isolated pathogen. exclusion criteria did not exist and the patients were treated in accordance to the severeness of infection, underlying diseases, risk factors etc. with taz/pip . g t.i.d, or b.i.d. results: patients suffered in most cases from infections of the lower respiratory tract (n= ), followed by intraabdominal (n= ) and skin and soft tissue infections (n= ). % of the lrtis wvre nosocomial acquired and in % the treatment was conducted as monotherapy. in % the lrti was treated with taz/pip b.i.d, and in % t.i.d. pseudomonas spp. (n= ) and staph..aureus (n= ) were the most isolated pathogens pretrcatment. the clinical response rates (cured/improved) after treatment with taz/pip . g b.i.d, and t.i.d, were % and % respectively. results for intraabdominal-and skin and soft tissue infections will be presented. conclusions: in hospitalized patients with severe infections successful treatment with taz/pip in monotherapy is possible. in this population a reduction of the dosage frequency to . g b.i.d, revealed equivalent clinical response rates. objectives. retrospective evaluation of cases of severe generalized tetanus (sgt), treated in our icu the last years. we review cases of sgt ( m, f), mean age . years. in eases the entry site of c.tetanus was a skin laceration, in case it proved to be the external genitalia, while in the rest no portal of entry could be determined. in the first cases incubation period was short ( - days) and so was the period of onset ( - days). all patients needed mechanical ventilation (range - days), initally through an orotracheal tube,and later through a tracheostomy, performed • days after admission. clinical manifestations of sgt included muscle rigidity and i generalized spasms, persisting for up to weeks in the most severe cases. significant autonomic nervous system dysfunction was present in cases occurring - days after the admission and following the time course of generalized spasm. besides general supportive measures, specific treatment included passive +active immunization, penicillin g, magnesium sulphate and sedation in a variety of regimens. neuromuscular blockade was required in cases. nosocomial infections occurred in eases, with sepsis and mof in one. average stay in the icu was - days. one patient died with severe septic complications and one was discharged with severe disability due to anoxaemie ancephalopathy, after a cardiac arrest on admission. ~ disinfectant in suspension test, without presence of organic load, disinfectants showed efficacy on lm. in the carrier test, in the presence of organic load, out of examined disinfectants did not exposed efficacy on lm. the results of examinations clearly showed that evaluation of disinfectant's efficacy partly depend on the used test method. antun basi , intensive care unit, kb firule split spin~ideva ! jugoslavia bacteremia and sepsis are frequent complications encouuntered in severe icu patients.microorganism identification with hemoculture presents the basis for adequate and successful antibiotic treatment.in many patients damage and vulnerability of the peripheral veins presents an obstacle for obtaining the blood culture from the central venous (cv) catheter sample could be also used. material and methods blood cultures were perfomed in lo patients on blood samples simultaneously obtained from the peripheral vein and cv catheter three times in a -hour period.criteria for the suspected bacteremia were body temperature above c and leucocytosis above ioooo leucocytes/dl. the site for venipuncture and the cv catheter stopcock port were cleansed with povidon iodine.after the initial ml of blood were discarded,lo ml were used for the blood culture.standard laboratory technique for blood cultures was used. results and discussion in ( %) patients hemocultures was negative at both sites,whereas in the remaining ( %) they were positive.for twentyone ( ~ of the positive patients the same results were obtained at both sites (peripheral vein and cv catheter),whereas in ( . %) patients the blood culture were positive only for the cv catheter samples.the cv catheters were in place for less than days in patients and for more than days in patients.from patients with positive blood culture from the cv catheter,one patient had the catheter for three days,whereas the other had the catheter from - o days. we neither found significant differences in hemodynamic dates : objectives: , to count and evaluate bacteria isolated from endotracheal (et) suctiori samples (with and without saline). . to establish the exogenous source(s) of pathogens isolated from carer's hands and the equipment involved in sampling in order to reduce the incidence of contamination and infection. method~: this prospective study included consecutive ventilated patients ( male and female, _ + yr; apache ii score -+ ) over a period of months. et aspirated samples with and without saline were taken daily from day of intubation until pathogen~ were presented in counts of _> per ml. at the same time, samples from both carer's hands were taken before and after et suction and a swab from the ventilator tube. results: the overall length of intubation varied between to days. bacterial transfer between staff and patients was noted in % of patients until day of intubation. there was no significant correlation between severity score and appearance of colonization. the incidence of pneumonia in studied patients was % with an overall mortality rate of %. acinetobacter anitratas (no ), staphylococcus aureus (no. ), klebsiella pna~moniae (no. ) and pscudomonas aeruginosa (no. ) isolates predominated in all our specimens. we noticed increased resistance to most antibiotics with the exception of imipenem for gram (-) bacteria and vancornycin for gram (+) bacteria. conclusions: i. tracheobronchial colonization appears directly in the maiority of intubated patients. . there is a close relationship between the microflora of personnel, patients and equipment. . bacteria transfer was noted both to and from patients. . strict hand disinfection policy remains an important measure for the proper care of mechanically ventilated patients to reduce respiratory infections. nnseeomial pneumonia is the most common nnsocomiai infection in the icu-settiag, reported in up to % of patients admitted to the icu following surgery. it is associated with significant mortality that ranges from ~ to %. enteric gram-negative bacilli have been implicated in % to % of ventilntor-associated pneumonias and pseudomonas aeruginosa accounts for % to % of these pneumonias. importantly, epidemics of/ - actamnse-pruducing enterobacter spp or klebsiella spp that are resistant to extended spectrum cephalosporins or penicillins, pose serious obstacles to effective antibiotic choices. carbapenems provide in ~tro activity against a wide range of enterobacteriaceaeand other gramnegative aerobic bacteria, except steaotrophomonns maltophilia. in vitro meropcnem is more active against pseudomonas spp than imipanem (especially p. aeruginosa and p. cepacia), imipenem and meropenem are effective against more than % of strains responsible for nnsocomial infections. all major pathogens associated with lrti are usually covered by the carbapenems, exceptions are pathogens involved in so-called atypical pneuomouia like mycoplasma, chlamydia and legionella. carbapenems are highly stable in the presence of most chromsomal and plasmid-mediated blactumases and usually offer a postantibiotie effect lasting for three hours against most of the enterubacteriaceae. reeent studies comparing imipenem/cilastatin with other ~-lactams and fluoroquinolones in severe lrti in icu patients resulted in favourable clinical cure rates and good tolerance, but development of resistance in p. aeruginosa and ;. aureus during treatment were of some concern. meropenem offers the advantage of greater stability against enzymatic degradation, so no concomitant administration of an enzyme inhibitor is necessary, and meropenem appears to be associated with a lower risk of seizures, particularly when used at high doses. results from studies with meropenem in lrti, especially in critically ill patients with acute exacerbations of chronic bronchitis, demonstrated excellent cure rates and better gastrointestinal tolerance of this new carbapenem. both earbapenems are effective candidates for use as empiric monotherapy in nosucominl infections of critically ill patients. qbl~ctives a favourable effect of iv immunoglobulins in septic surgical patients has been reported, but not sufficiently validated. we conducted this study on trauma patients to: i) investigate the effect of ivig on septic complications and il) quantify this effect by means of serum bactericidai activity (sba) assessment and iii) to explore the effect of temperature increase (from to ~ c) on the sba methods: twenty trauma patierits matched on admission for age, sex, inju~ severity score and glasgow coma scale, were allocated to receive either wig (ivig group; i patients) or equal volumes of human albumin % (control group; patients). wig (sandoglobulin) was administered in a total dose of g/kg divided in a four time regimen on days , , and post-admission. three blood collections were performe& before the first dose (day ) and hours after the third and the fourth dose (days and respectively). complement, lgg fractions, the sba at ~ and at o c and clinical parameters were recorded. results-similar lgg and igg] serum levels were found in groups ivig and control on day ( +_ vs • ns and + vs + , ns), whereas they were significantly higher (p< ) in the v g group on days ( _+_ vs + , p< ) and ( _+ vs +i , p< . ). the various complement-fractions increased in both groups without inter-group differences the mean (• sbas ( ~ c) at rain in ivig group vs control group were: - _+ vs - • ns for day , _+ vs - _+ p< for day and _+ vs - + p< for day . the mean (+sd) sbas ( ~ c) at rain presented a significant improvement over those of ~ c but for the control group remained negative a~d were respectively as following: -~ • vs - + , ns for day , +_ vs - _+ , p< . for day and _+ vs - _+ , p< . for day . the increase of temperature induced a -fold improvement of sba in iv g group and -fold ofcontrol-~oup positive blood cultures, and the product of the infectious episodes number multiplied by days of occurence, were significantly lower (p< ) in the ivig group than in the control ( vs , and vs , respectively). conclusions: our study shows a significantly favourable effect of ivig administration on septic complications and on sba of trauma patients. the increase of temperature results in a significant improvement of sba of patients that received ivig, which theoretically means a farther prevention of infection in the febrile state. pharmaceutical microbiology, university of bonn, meckanheimer aune , d- bonn, germany infectious diseases in intensive care patients are common in comparison to patients on other wards and out-patients. the main difference is that intensive care patients are much more sensitive even to less virulent bacteria. thus, the spectrum of infecting organisms is different. strains often regarded as pathogens with low virulence cause serious infections in these patients. strains such as serratia, however, have intrinsic resistance to most commonly used agents such as rd generation eephalosporins. furthermore, the common pathogens like staphylococci, psoudomonas aeruginosu, enterocneei and gram-negative bacteria, enterobacteriaeceae as well as the non-fermenters are less sensitive if isolated from intensive care patients. it is difficult to generalize on intensive care units as different patient groups are in different icus aud there are great changes from one hospital to another and from one country to another. if we take s. aurens strains from one study from the'overall resistance in intensive care units towards oftoxacin was %, whereas in other hospital wards the percentage of resistance was . %, in out-patients, however, only .$ %. the same trend was true for entercnecus faecnlis, coagulase-negntive staphylococci, and other bacteria as well as other drugs. one most striking difference was found with klebsialla pneumoniae and gantamycin resistance, which was $ times higher in intensive care units as compared with outpatients, whereas in the same species no difference was to be seen with the resistance towards carbapenems. however, differences between countries seem to be even more striking, as example gantamycin resistance and staph. anrens is given. the extreme difference is more than fold. thus, it is evident that there is a general trend towards higher resistance in intensive care units, but no generalizatiouis possible. therefore, surveillance studies in intensive care units are needed and the antibiotic policy has to be adapted to the specific needs of the unit. in the icu setting the most potent antimicrobial agents are required to address problem organisms including those resistant to penicillins, cephalosporins and aminoglycosides. carbapanems would appear to present a useful option in this setting. objectives of this study was the evaluation of systemic candid• in postoperative cardiac surgery patients (pts) with prolonged icu stay. methods: out of postoperative adults pts of mean age . + . years old, with a mean icu stay of . _+ . days, following an open heart surgery from july to april , pts ( %) remained in icu for more than days because of severe perioperative complications. patients were included in the protocol if they had clinical signs of infection or sepsis, and fungi isolated in blood culture or in culture from at least three different sites. the patients who developed systemic candidiasis received iv fluconazole ( mg/day) ( patients) or amphotericin-b for at least four weeks, and then they were closely monitored. results: out of postoperative pts with prolonged jcu stay, pts ( . %) developed systemic candid• usually after the th postoperative day. they were males and females of mean age +_ . years old. this group of pts had prolonged bypass and aortic cross-clamp time compared to control group ( min vs , and vs min). all these pts received inotropes per• (mean value= . ). during their icu stay, pts developed sepsis of bacterial origin, while the other two severe infection, and received antibiotic regimens for prolonged period. the patients were submitted to mechanical ventilation for a median period of days. the median icu and hospital stay was and days respectively. all pts have been improved and finally negative cultures were obtained. conclusions: . a significant percentage of patients who remained in the postoperative icu for more than days developed systemic candidiasis. . all patients who developed systemic candidiasis had received antibiotics because of sepsis or severe infection, for prolonged period. . fluconazole seems to be a very good alternative to amphotericin-b. . fluconazole is a safe antifungal agent with few side effects. botulism is the most severe and an odd food poisoning. although it is more commonly related to preserved meat derivatives, preserved fish and vegetables are also responsible for a number of cases. obiectives: to evaluate four familiar outbreaks of botulism . methods: we study the patients that were admitted in our hospital because of botulism from may to february . results: the thirteen pacients involved had a previous history of home preserved beans ingestion. after a -hours incubation period, gastrointestinal symptoms (abdominal pain, vomits, constipation) appeared and lead them to hospital consultation in the th to th day after ingestion. two patients died (acute respiratory failure before admission), seven were admitted in icu, two in ward and two of them were discharged from emergency room. clinical symptoms and the previous history of the ingestion established the diagnosis, that was emg confirmed. in all cases, symptoms were consistent with b-toxin botulism. b-toxin was isolated in serum and food proceeding from the third outbreak, and the serum was negative in the other ones. neurological symptoms were predominant: midriasis ( %), dry mouth ( %), dysfagia ( %), asthenia ( %), palpebral ptosis ( %), accomodation paralisis ( %) and urinary retention ( %). muscle weakness lead to acute respiratory failure in three patients (one of them required mechanical ventilation). four patiens developed infections (respiratory, urinary and phlebitis). both died patients and one another presented severe hypertension. all admitted patients were treated with polivalent anti-toxin. the two patients who underwent a more severe muscle weakness received also guanidine hydrochloride, with no answer in one case and provoquing a cholinergic crisis in the other one. icu length of stay was days. at hospital discharge, patients continued symptomatic, mainly with dry mouth, disfagia and impaired vision. conclusions: although botulism is a serious illness, the pronostic seems favorable if treatment and support measures are avaible. usually neurological symptoms we predominant and at discharge some of them could still persist. the arrow "hands-off" (aho) thermodilution catheter (tc) is completely shielded during balloon testing, preparation, and the insertion procedure. in order to assess the value of the aho thermodilution catheter in the prevention of systemic infections associated with pulmonary artery catheterization (siapa), we conducted a randomized prospective study over an -month period. methods : the patients (pts) were randomly assigned to two groups : group i for a standard tc customarily used in the department, versus group for the aho thermodilution catheter. the diagnosis of siapa was determined on the basis of a positive culture of tc and bacteremia with the same organism, with out any other nearby focus, in association with regression or disappearance of the clinical signs of infection after removal of the thermodilution catheter. results ( objectives: the mortality rate (mr) of tb requiring mechanical ventilation (mv) is high ( - %). the aim of the study was to evaluate mr, associated factors, and prognostic significance of mv and hemodynamic disorders from tb in icu in patients with tb. methods: clinical parameters on admission, and complications in icu were related by univariate analysis to icu, hospital, and month outcome. patients required mv; were immunocompromised (ic) including hiv. tb was pleuropulmonary in , disseminated in and meningeal in . results: mr was % in icu, % in hospital and % at month. / ( %) < . mortality was associated with a high saps score, initial shock, mv and nosocomial septicemia. the mr dramatically increased when ards occurred during illness, despite the lack of correlation between mr and initial po /fio ratio or initial murray score. the site of infection did not influence the mr. surprisingly, the mean therapy delay was shorter for non survivors. mr was not related to ic status, nor hivstatus, but was only related to previous steroid therapy. conclusion: mr of tb requiring icu is high ( % at month). need for mv increased mortality ( % vs %). general severity and respiratory dysfunction seem to be major prognostic factors in icu rather than tb per se or than therapy delay. in spite of the improvement in the prognosis of pneumococcal meningitis (pm) with third generation cephalosporins (tgc), this infection still presents a great mortality which could be increased with the appearance of antibiotic resistant streptococcus pneumoniae. objectives: to asses intensive care mortality and morbidity of pm and to define patients (pts) at risk of complicated evolution. patients and methods: a retrospective evaluation of pm cases (all diagnosed by csf culture) admitted in our icu from january tit march . in all pts we analized: demographic data, underlying disease, apache ii score, clinical symtomps, treatment, complications and outcome. statistical analysis was done using bmdp sofware package. results:a total f pts were studied, males; mean age , _+ ( - ); apache ii score , + , ; glasgow coma scale (gcs) at admission , _+ , ; ( %) pts suffer from cronic pathology; ( %) pts diabetes mellitus (dm), ( , %) pts had had a previous cranial traumatism. in cases the source of infection was otic and also in ( %) episodes of pm there were bacteriemia. in out of ( %) pts that ct was performed no radiologic abnormalities were shown, of them presented cerebral oedema and pts a cerebral abscess. twenty-eight percent presented seixures, % hemiparesia, , % respiratory failure, , % shock, i % renal failure, , % multiple organ failure (mof). as for treatment refers , % pts recieved only penicillin, , % pts only tcg, , % pts tcg followed by penicillin and , % pts tcg+vancomycin. seventy-five percelat of pts recieved corticosteroids and , % vasoaetive drugs. the mean icu stay was , : days ( - ). twelve ( , %) pts died, two of them presented pm relapse (resistant streptococcus pneumoniae) and another two pts developed neurological sequelae. factors associated statistically with bad prognosis were dm, the use of vasoactive drugs, shock, mof, the apache ii score at admission, the gcs at the and hours from admission in the icu but not the gcs at admission. didn't resulted statistiealy signifcative age, previous eronie pathology, seizures, baeteriemia, renal failure and coagulation disorders. conclusions: mortality was high and associated to apache ii score at admission, to gcs at and hours after admission, shock, vasoaetive drugs and mof. objectives:the aim of the study was to analyse some of significant immunologycai changes in surgical patients,requiring intensive health care,and to determinate the possibility for evaluation,dynamical examination and importance of immunologycal problems for treatment. methodes:the study concerns a number of patients with expanded surgical intervention or serious postoperative complications.the results has been carried out with fiowcytometryc analyses of lymphocytic suhpopulations and routins methods for investigation of humeral immunity.the"panel" for evaluation of (} immunologycal parameters has been offered:t-calls total/cd +/;t-helper/cd +/;t-supressor/cd +/ th/ts ratio;b-cells/cd +/;naturai kilier/nk/cells;skin test for cellular immune function;phagocytic and oxidative activity;serum levels of immunogiobulins-g ,a,m;protease inhibitors;c-reactive protein.all patients have been studied during suffering and after surgical procedures dynamicaly. results:there have been estimated significant changes in immunologycal parameters especially:decrease of t-cells: cd +mean= . %/ . %- . %/and cd +mean= . %/ % - . %/;inverted th/ts ratio ,mean=o. / . - , /;reduced or negative skin teste;reduced phagocytic and oxidative activity before septic complications. conclusions:dynamical examination of immunologycal parameters shows,that the prolonged t-total,t-helper lymphocytopenia with functional deficience of ceils-mediated immunity correlates with the stage of clinical condition of the patients and has prognostic importance.it's clear,that immunologycal monitoring gives a possibility for immunecorrection. patients (pts) with the human tmunodeficiency virus (hiv) infection have a decreased immune response and are particularly susceptible to infectious endocarditis (ie). the aim of our study was to analyze the prevalence of ie, its clinical and therapeutic implications in a hiv population we prospectively studied pts, . % ( / -group ie+) with ie during the clinical course of this disease. we analyzed the following parameters: age, gender, race, type of hiv, cdc classification, number of t and t type cell population and its ratio, therapeutic with azt, type and number of opportunist infections (inf, mycobacteriosis (mb), neoplasm's (nee) the echocardiographic parameters were lv internal diastolic and systolic diameters, lv percentage of fractional shortening, interventricular and posterior wall thickness, the degree of valvular regurgitations and the presence of pericardial effusion. el was located at the mv in . %, tv in . %, av in % and pv in . ~ and was multiple in . %. hiv el+ pts had larger lv diameters and more frequent significant valvular regurgitations ( % tr, pe %, mortality %). these two groups differed significantly in the following clinical parameters: the typical symptoms were watery diarrhea, high fever, tachycardia,luekocytopenia and oligouria within th postoperative days. the patients with mrsa enterocolitis had positive mrsa culture from the many materials except feces.mesa strains frequently had coagulase type ,enterotoxin a and toxic shock syndrome toxin- .eight of patients had postoperative organ failure.most of the mrsa strains in japan were similar in coagulase type to our hospital and our department.all of mesa strains were susceptible to vancomycin and arbekacin,tbough most of them showed resistant to many other antibiotics.we have employed guidelines for therapies such as oral or enteral administration of vancomycin and correction of the hemodynamics for dehydration and circulatory failure due to diarrhea from .futhermore we have placed colonized or infected patients in private room,worn gown and mask,and carefully washed our hands from . these countermeasures for prevention of nosocomial infections after significantly reduced the incidence of mrsa enterocolitis. conclusions:earlier diagnosis and treatment, and distric prophylactic measureres against mrsa infections are very important. -- cdo ivda leptespiresls affects all the organs with widespread hemorrhage that is more prominent in skin, mucosa, skeletat muscles, liver and kidneys. lung involvement is usually mild and less common. suli, it is very uncommon acute respiratory failure to be the pr sontirlg symptom. a case with leptosplrosl..,s which was presenting with acute respiratory failure is described. a year-old man admitted to icu becauso of fever, myaigla, aevere c~, hemopty~s. his blood gases showed: pao : mmhg with fio : . , pco : mmhg, ph: . , hco : mecl chest x-ray film demonstrated diffuse bilateral alveolar pattern occupying beth lung / ). trarmamlnase, bllllrubln, ~ and esr were elevated, wbc was . mm , platelet: . ram , hematesrlt: %, hemoglobin: .sgrldl=. there was no clinical or ecttlographlc evidence of left heart failure.patient fulfilled the criteria for diagnosis ards he was found to have an ~lutinatlon tlter for leptoq~lral antigens(indirect he~lutlnatlon atomy, ilia} very high ( / , negative<ill ) and iglm antibodies also very high (elisa, a= . , negative< . ) strongly suggesting leptospirosls. treatment with tetracycline and non-tnvaslve mechanical ventilation by nasal mask were started. pre~jre support mode and cpap was usod. the following days the clinical picture,the oxygenation and the chest x-ray of the patients were improved, and patient dl~herged from the icu. the control of leptosplremlc phase as well as his good cooperation during nipsv contributed to rapid recovery and excellent outcome in hiv infections, pneumonias (pnm), mainly due to pne~ mocystis carinii (pc) have an outstanding place in pu ! monary complications. the aim of this work was to compare two group> of patients admitted with pnm in our icu during the same period ( - ): group a, patients hiv+, and group b, patients hiv-. apache ii was identical in the groups (p=ns). group a required more often mechanical ventilation (p= ,o ), had a higher p(a-a)o (p= , ) and metabolic acidosis was more frequent (p= , ). regarding laboratorial parameters group a had a lower no. of linfocytes (p= , ), a higher ldh (p= , ) and a more marked hypoalbuminemia (p=o, ). mortality was higer in group a ( , %) than in group b ( , %), (p= , ). analysing the a group patients, we found no significant differences between alive and deceased patients, with exception for albuminemia, which was lower in the deceased patients (p= , ). in conclusion, the hiv+ patient's pnm have a more agres sive behavior when compared with community acquired hiv-patient's pnm. the prognosis was not influenced by the apache ii. perhaps other parameters such as p(a-a)o , metabolic acidosis, linfocytes, ldh and albumin shoud be more evaluated as possible predictive indices. some prognostic factors, usually accepted as predictive in the analysis of hiv+ patients do not seem to be worth in the late stages of aids, mainly when they reqquire intensive care. intensive care unit, onassis cardiac surgery center, athens, greece. objectives of this study was the comparison of two different antibiotic regimens as prophylaxis in cardiac surgery patients. methods: in a prospective randomised comparative study, two different forms of antibiotic regimens were investigated : a single dose of cefuroxime (zinacef, gr) (group a) given during the induction of anaesthesia, versus a four days combination of amoxiculine (amoxil, gr tid) plus netilmicin (netromycin, mg bid) (group b). a total of patients (pts) ( males and females, of mean age . + . years old) were included in the study over a period of one year; in group a and in the group b. patients were checked for the occurrence of infection during the first postoperative month. results: the total rate of infection in cardiac surgery pts was . %; . % in group a and . % in group b (p=ns). pts ( . %) developed infection following cabg, pts ( . %) following valve replacement and pts ( . %) after other cardiac surgery. they were males ( . %) and females ( . %). endocarditis has occurred . % in group a and . % in group b. severe wound infection was recorded in . % in group a and in . % in group b. one case of sepsis ( . %) in group a and in group b ( . %). respiratory infection occurred in pts of group a ( . %) and in pts of group b ( . %). two cases of urinary tract infection was in group a and one in group b. catheterrelated infection was occurred in ( . %) in group a and ( . %) pts in group b. pts ( . %) had fever of unclear aetiology in group b. conclusions: there was no statistically significant difference regarding the rate of infection in both groups. a single dose administration of cefuroxime is accordingly just as effective as a four days regimen of amoxicilline plus netiimicin. legionella pneumophila is a common bacteria of the environment, and it is an agent responsible for severe community acquired pneumonia (cap). we analyzed the patients with lpp admitted in our icu during the last years ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) . they represented . % of cap. seven patients were males and female, with mean age . + . years. tiss was . + . and apache ii . + . . all, but patient, were under mechanical yen tilation (mv) during a mean period of . • (min-l, max- ) days. two pneumonias occurred beyond the season, while patients had an epidemiological history. only patient had no risk factor. in all the others tobacco smoking and alcohol abuse was quite frequent. diagnosis was based on serologic test and culture or direct fluorescent antibody staining of bronchial secretions. seven patients had a multisystemic disease with hepatic dysfunction in , renal failure in (due to rhabdomy~ lysis in ). one patient had a prosthetic valve endocarditis and another developped ards. nosocomial septicaemie occurred in patients. mortality rate was %. deceased patients had initially higher apache ii, (a-a) , and lower natriemia. comparing lpp with the other cap (n= ), both submitted to mv, mortality rate was similar ( , % versus . %). in conclusion lpp can occur all over the year. there was a high incidence of severe complications and outcome was similar to the other cap when requiring mv. prospective specimen brash (psb) with culture > cfu cfu/ml. broncho-alv~lat lavage (bal) ~= c'fu/rnl or positive blood culture. were excluded for rapture of treatment ; were analysed (shift with oral antibiotic : ; prohibited antibiotics associations : ; resistant germ : ). clinical data : age , • , ; saps • , ; mac cabe i : , % -ii : , % -iii : , . , % of the patients were intubated and under mechanical ventilation. the pneumoaiae were : primitive in ( , %), copd ( , %), aspiration pneumonia ( , %). germs were isolated (psb , bal , blood culture ) : s. pneumoniac ( , %), h. influeazae ( , %), sttep~:occns ( , %), saar ns ( , %), enterobaetdrindr ( , %), mosexella catarrhalis ( , %), othem . / ( , %) were sensitive to freatment. the ltentment was mg/kg/d of ampiclllin and mg/kg/d of sulbactam in continuous iv adminisu'ation during at least days. clinical eff~ienev : success ( %), failures ( %) with superinfeetion , worsening or relapse , dead , side effects . there was no difference between etiologies : primiti~;e~ , %, copd , %, aspiration pneamoniae , %. the bacteriological effieieacy was evaluated only for patients with eradication ( , %), eradication but super~ection ( , %) : with pseadomoaas a&ogiuosa , eater~ac~ ; beeteriological failure ( , %). in conclusion, the aasor ampicillin -sulbactam is effective for the i~eatment of severe acquired community pneumonise. objectives : to assess the efficacy of chlorhexidine (cl) gel or suspension applied in the nose and in the op for the prevention of the tmcheobronchial colonization. methods : thirty-seven patients expected to be intubated for > h were randomized to received topical application oga cl suspension ( %) qshrs, a cl gel ( %) q hrs or a placebo. in addition all vpts received a nasal and a op spray ( %) of either cl or placebo administrated according to the same schedule. semi-quantitative cultures of the anterior nares, the oropharynx (op) and the trachea were obtained on admission and once a day until extubation (just before the next application). the results were assessed according to the following criteria: success = no acquisition of gnb in the trachea ; failure = acquisition of gnb in the trachea. acquisition was defined by a follow-up culture positive for a gnb not present in the trachea on admission. results : success failure nosocomialpneumonia overall morality clsusp. placebo clgel placebo n= n= n= n= / / / * / / / / * / / / / / / / / / i *p = , byfisher'sexacttest conclusions : these results suggest that topical cl gel administered q hrs may prevent tracheal colonization by gnb. f. daumal*, m. daumal**, c. plot**, v. vurmmen ~ e.colpurt**, b. manonry** * hygiene hospitali&e, ** service de r enmmtion, * service des admissiens-urgeuces centre hospitalier g- ndral - saint-quentin -france obiectives: evaluate the nosocemial risk due to peripheral venous inserted short catheters, and the quality of care. patients-methods: the intensive tare unit (i.c.u.) is a beds unit. the prospective study includes all the patients comn~ in from / / to / / . the recruitemont uses an evaluation schedule of local clinical signs. the nurses aimed to create this evaluation data which includes the place of entry site, the duration of catheterization and the cause ot withdrawal. only patients staying longer than days in the i.c.u. are accounted for. the diagnosis of uosoenmial infection is assured by the physician taking care of the patient and by the hospital epidemiologist on the next signs: evident pus at the catheter entry site, positive culture of the strain, with or without the same pathogen in the blood sla'uam,the patient having no other distant source of infection. analyses were performed on epi/nfo. results: the occurrence of nosoeomjal inthrtions: i abcess and bacteremia during the first part of the study lent the medical staff to modify the protocol of insertion end survey of the device. so we analysed different periods: period ( / / to / / ) and period ( / / to / / ) for all .e peripheral catheters inserted in the i.c.u. period , % , % en infection due to peripheral venous device is a daily threat. the severity of some clinical situations requiring admission in icu proves it. the motivation of nurses for rigid adherence to established protocol, the daily survey of the entry site, the withdrawal of the peripheral catheter every hours aimed to reduce significantly the local signs of inflammation end infection of peripheral catheters inserted inside the i.c.u. objectives: to investigate the use of a new metabolic monitoring device for different ips levels by comparing oxygen consumption (vo ) to measurements of the mechanical work of breathing (web) and p . . methods: the study was approved by the institutiotml ethics committee. eight patients were investigated during weaning after prolonged mechanical ventilation ( - days) for various diagnoses when the clinical physician judged the patient to be ready fur weainag. ips was setto , , , mbar far rain periods each. all patients had a peep between - mbar.. respiratory frequency (f), tidal volume (tv), minute ventilation (ve) were read from the ventilator display ( ae, puritan bennett, carlsbad, usa). flow and airway pressure were measured at the endotracheal tube site. esophageal pressure was measured using an esophageal balloon catheter (fa. ruesch, frg). web was determined as the area subtended by the pleural-pressure-vohime curve. p . was determined by using standard occlusion technique and graphical analysis of the airway pressure tracing. vo and vco were measured using the pb metabolic monitor (puritan bennett, carlsbad, usa) connected to the pb ae ventilator. all data are given as mean• deviation for each ips level. comparison between the different ips levels was performed using anova for repeated measurements. significance was considered at p< . , compared to ips mbar. results: the values for breathing pattern, web, p . , vo and vco are given in the table for the different ips levels; significance is indicated by ~. objectives: fluidized beds are often used in the management of critically ill mechanically ventilated patients. critically ill patients are increasingly colonized with resistent pathogens [ie: p. aeruginosa, methicillinresistent s. aureus (mrsa), extended spectrum i~-iactamase producing enterobacteriaceae ] that can ultimately cause nosocomial infection. methods: we prospectively monitored bacterial colonization of mechanically ventilated patients and of the fluidized bed (clinitron) inwhich they were treated. multiple samples for quantitative bacterial cultures were taken from oropharynx, trachea, feces and bedsores. samples of ceramic beads from the bed were also taken both during and after patient stay (after bed operation in the absence of patient). re,~ults: episodes in consecutive patients (mean age: . years) were analyzed. all had bedsores and/or urinary catheters and fecal incontinence, patients had nosocomial pneumonia, had urinary tract infection [ with extended spectrum imactamase producing k/ebsie//a pneumoniae (ki~lse)], one had positive blood cultures with mrsa, and one patient had a ki~lse found in high concentrations ( - s cfu/ml) in occasions in feces. patients were heavily colonized: the , samples from ceramic beads showed no growth or became sterile without any sterilisation procedure (even in one case of presence of kf~lse) during the patient stay. conclusions: fluidized beds do not put patients at high risk of acquiring nosocomin pathogens, and cross-contamination between patients seems unlikely, even when multiple resistent organisms were initially present. the recommandation from some manufacturers to undergo extensive sterilization of fluidized beds after use does not seem warranted, at least with the bed used in this study. ant. koutsoukou, a, tahmitzi, p. kithreotis, m. koutonlidou, k. stavrakaki, kainis e, g. vlahogiorgos and e. eliopoulos icu-centre for respiratory failure -chest diseases hospital of athens. the cost-effectiveness issue is becoming vital in modern medicine and may lead to moral dilemmas since sometimes certain groups of patients may not have access to highly specialised modalifies. objective: our study compared the mean daily cost for antimicrobial medication in copd patients treated in icu versus all other patients in the context of relevant epidemiological, prognostic and outcome data. methods: age, sex apache ii score, length of icu stay (los) and in -icu fatality were retrieved from the files of all icu admissions over . mean daily cost for antimicrobial therapy per patient (dcat) was estimated. these variables were statistically compared between copd and non-copd patients. significance was assumed at p< . results: of the total admissions were fully evaluable. of them ( %) were copd patients. data (m---sd) results for statistical test are given in table i . copd patients were significantly older spent more time in the icu and presented with significantly higher apache ii scores. outcome and dcat were comparable in the two groups. objectives: the use of heat and moisture exchangers (hmes) during long term mechanical ventilation (mv) is increasing. in icu patients, they are routinely changed every day, according to the recommendations of the manufacturers, but the clinical basis for such a daily practice is lacking. we therefore prospectively assessed whether changing hmes (dar hygrobac, spa, mirandola, italy) every h only would affect their clinical and bacteriological efficiency. methods: two consecutive groups of patients requiring mv for > h were compared: group = hme replaced every day, n= episodes of mv in patients; group = hme changed every h, n= episodes in patients. tubings were not changed in the same patient during the whole length of ventilatory support. diagnosis of nosocomial pneumonia (np) was based on a positive quantitative culture (~ cfu/ml) of a protected specimen brush in patients with clinical signs of pneumonia. quantitative cultures of pharynx, trachea and y-cannector were performed every h. results: the groups were similar in terms of age, indication for and overall duration of mv ( +_ . vs +_ days, p= . ), and severity of illness (saps: --- . vs . +_ . , p= . ). the maximal values for peak airway pressure were identical in both groups ( . -+ . vs . • cmh , p= . ). obstruction of the tracheal tube was observed in only one instance in a group patient who had tracheal bleeding. circuit colonization was very rare, and of low grade in both groups. the level of patient colonization and the type of organisms were identical in both groups. more importantly, the incidence of np was the same ( / vs / , p= . ), as was duration of mv before the occurence of pneumonia ( • vs . +_ . , p= . ) and overall mortality rate ( vs , p= . ). conclusions: the clinical efficiency of this hme does not seem altered after days of use. indeed, replacing this hme every h only neither affect circuit and patient bacterial colonization nor the incidence of np. therefore, substantial savings could be obtained changing hmes every other day only. obiectives: to evaluate the usefulness of different paraclinical investigations for the diagnosis and prognosis of acute viral encephalitis in icu patients. methods: we reviewed patients (pts) admitted to our icu from july to december with the diagnosis of acute viral encephalitis. all were in coma and were initially treated as presumed herpes simplex virus (hsv) encephalitis. the causative agents were: hsv ( cases), herpes zoster varicellae ( ), measle ( ), rabies ( ), unidentified ( ). eleven pts survived and three presented neurologic sequelae. twelve pts were investigated by mri, and eleven also by spect and multi-modality eps. including brainstem auditory eps (baeps). these investigations were obtained as soon as possible following admission and were repeated during icu stay when possible. the clinical outcome was noted. results: six pts ( / ) had an abnormal mri. among them, pts made a complete recovery, in comparison with / pts with a normal mri. in one hsv infected patient, mri remained normal despite clinical deterioration and bad outcome. when repeated, mri became abnormal in cases (with poor outcome in one) and was improved in one. spect was found abnormal in / pts (among them, pts had thus a normal mr/). the correlation regarding the topography of brain lesions was poor between mri and spect. the findings of spect could not be correlated with a poor outcome. the baeps confmned in % of the pts the clinical diagnosis of brainstem involvement. changes in visual and somatosensory eps were mild in all the pts and were not helpful for the prognosis. eps were otherwise interesting for the follow-up of the coma in these sedated and ventilated pts. conclusions: the value of mri and eps for the diagnosis of acute viral encephalitis is of limited interest. spect seems to show early modifications, even in pts with a normal mri, but this test is poorly specific and does not correlate with mri changes when present. concerning the prognosis, larger studies should probably confmn that a normal mri could usually result in a good outcome. this serie illustrates also that hsv encephalitis could be demonstrated only in a small number of cases and that the prognosis of non hsv encephalitis is not easily assessed. objectives: to study the influence of gram (-) bacterial lung infections on liver function i~ mv icu pts. pts and methods: we studied pts, # ( , %), ( , %). hean age: , • years ( - ). mean stay in icu: , • days ( - ). they were divided in groups: a( pts) who did not suffer from pneumonia and b ( pts) who developed a gram(-) bacterial pneumonia. both groups were consisted of pts with same age, sex and disease distribution and same systemic failures. we measured sgot, sgpt, total bilirubin(tb), direct bilirubin (db), alk.phosphatase (al.ph.), v-gt and albumin (alb.) times: on days o, and of the pneumonia for group b and respectively for g~oup a. conclusions: ) in elderly intubated pts of an icu, kp is isolated more frequently than in icu pts< years (p<o, ). ) the frequency of isolation of kp in icu pts during - was - %, but now ( - ) kp becomes more and more rare ( - %) and is isolated especially in elderly pts. ) its sensibility to antibiotics remains always the same. ) the prognosis of np in our study was independent from age (p<o, ), sex, presence of bacteremia (p< , ) and type of invading microorganism. gram neg bacteria and renal failure (rf) from aminoglycoside toxicity are common and serious complications in critically ill patients. the aim of this prospective, pilot study was to compare the safety and adequancy of the endotrecheal (et) vs the intravenous (iv) administration of aminoglycosides. were measured in the plasma and the bronchial secretions at and hours after the iv (bolus) or the et (nebulized) administration of mg of gm in seven criticcally ill patients ( with established renal failure). safety was defined as peak and trough plasma gm levels _< than and ijg/ml respectively and adequancy as gm levels in bronchial secretions _> , ijg/ml. results: gentamicin was administered by the et and iv routes in and separate sessions respectively. a total of samples were assayed, in bronchial secretions (bs) and in serum. the et route resulted in higher gm levels in the bronchial secretions compared to the iv route ( , + , vs , _+ , pg/ml respectively, p = ns ). adequate bronchial gm levels were achieved in % of patients after et administration, compared to % after iv aaministretion. the blood levels of gm were significahtly lower after the et vs the iv route ( , + , vs , • , pg/ml respectively, p _< . ). the et administration resulted in toxic bronchia~ gm levels in % of the specimens. % of these samples were from patients with renal failure, however toxic blood levels were reached in only % of these. gentamicin seems to be a safe and adequate alternative route of treatment for the lrti. however, in patients with renal failure the et administration of the aminoglycosides should also be modified and continuously monitored. in order to evaluate the pathogenic role of anaerobes in nosocomial pneumonia (np), we investigated the systemic humoral response in patients who developed a np with anaerobic bacteria, especially prevotella species. methods: blood samples from groups of patients were tested. group i: patients with a np in which prevotella spp. was isolated from protected specimen brush (psb), group ih a control group of patients with a np without anaerobic bacteria, group ill: a control group of patients with dental stumps but without pulmonary infection, group iv: a control group of healthy voluntary people with prevotella spp. isolated from the dental plaque. an elisa was used to evaluate the total antibodies level against a mixture of four prevotella strains and a western-blot method was done to identify the antigenic proteins. results: data are expressed as means .+ sd. the antibody levels in patients of group i ( • was statistically higher (p=o.o ) than in the control groups (respectively: + , _+ , _+ ). using western-blot method, the intensity of the response was roughly superposable to levels obtained by elisa and the profiles were different according to the prevotella species. the occurence of a np with anaerobic bacteria (prevotella species) isolated from psb leads to an antibody response which seems specific of the prevotella species isolated. fever is common in the intensive care unit, but is not always related to an infection. we sought to define the epidemiology of febrile patients in a general medical/surgical icu. methods: we prospectively analysed the source of fever (t > . ~ c) in all adult patients admitted for >- hours in the icu during a two month period. these patients were studied for consecutive days. and werc classified in groups according to the evidence of infection (center for disease control criteria) after complete evaluation: documented infection: cdc criteria + isolation of pathogen (d); possible infectron: cdc criteria without isolation of pathogen (p); unlikely infection: patients who did nol meet the cdc criteria (u). results: of a total of patients studied, dec'eloped fever ( %). including (after complete evaluation) d, p and u palients. both the highest temperature in tile first day of fever and the maximal temperature were higher in d than in u ( . • versus . • and . -~ . ~ versus . - . , respectively p= . and p= . ). most common sources of infection in d were the lungs in patients ( %) and urina .ry tract in ( %). of these patients had positive blood cultures ( %). the overall mortality was % ( % in d, % in p and % in u. differences ns). antibiotics were given in % of d, % of p and % of u ( patients). in p there was a non significant lower mortality." in patients who received antibiotics ( / ( %) versus / ( %) patients, respectively). conclusions: in febrile icu patients both the highest first day" temperaturc and maximal temperature are significantly higher in infected than in non infected patients, but the differences are too small to be useful clinicall). mortality rate is not significantly influenced either by the presence of an infection or by the administration of antibiotics, obiective: retrospective study to determine the influence of candida infection on icu outcome. methods: patieet with a stay of more than days in inteaasive care were screened for candida infection. patients were treated with antifungal therapy due to either an increased antigen titre of -> : or clinical evidence of candida colonization. serological candida-antigens (ramco, pastorex) and antibody titres (hemagglutination, lgg-, igm-elisa) were examined routinely. seroconversion was defined as a threefold increase of antibody titre or a titre of : or higher. results: the median length of stay was (ranging from to ) days, the mean apache ii score on admission was (+_ . sd) points. of patients patients died ( . %). in the group treated with antifungnls ( patients) patients died ( . %). although of the patients only ( . %) developed a candida infection as defined above the mortality in the group that showed signs of infection was significantly higher ( . % vs. . %, p < . [chi-square-test]). in patients an antigen concentration-> : was measured. seroconversion was found in patients. the most common fungus was candida albicans ( . %). furtberm re, candida glabrata was found in . %. most of the patients were treated with x mg fluconazole ( patients). in patients therapy was changed to amphotericin b/flucytosine. in patients therapy was started with amphotericine b and flucytosine. in patients a threefold decrease of candida antigen titre was found. patients showed a decrease of candida antibody titre. conclusions: meticulous screening for eandida infection seems to be necessary since the number of patients with fatal outcome is significantly higher in the group with signs of fungal infections and thus requires immediate antifungal treatment. objective: early diagnosis of patients with ventilator-associated pneumonia (vap), and subsequent identification of causative microorganism, and selection of the appropriate therapy are critical important points that affect morbidity and mortality. the results of the quantitative bacterial cultures are not available for at least hours, while a two hours period, since the specimen are obtained is enough to know the gram stain results. the aim of this study is to determine the usefulness of gram stain in specimens obtained by bronchoaiveelar lavage (bal), through the bronchoscope. material and methods: we studied patients ( males and females, age + ) with suspected ventilator-associated pneumonia. the bal gram stain was considered positive when the specimen after a centrifugation at rpm for min revealed: i) more than leukocytes per optic field, ii) squamous epithelial cell less than percent and iii) one or more microorganisms per optic field on magnification. all patients had been receiving antibiotics, with no change during the last days, prior to bronchoscopy. results: patients had vap and patients did not. in cases the bal specimens (quantitative bacterial cultures) established the diagnosis of vap in the remaining three patients the vap diagnosis was established by other procedures (blood or pleural fluid culture, clinical outcome, autopsy). apache fl score in patients with vap was , -+ , , while in patients without vap was , + , . there was a significantly higher incidence of vap in patients who had i) coma (gcs < ) and ii) been receiving neuromuscular blockade (p< . ) . the sensitivity of the gram stain for vap diagnosis was %, the specificity , %, the positive predictive value %, and the negative predictive value , %. conclusion: our data indicate that the gram stain of bal specimens is useful for the early diagnosis of vap and the subsequent administration of the appropriate treatment. the role of anaerobes in mechanically ventilated patients with pneumonia (mvp) have been poorly investigated aim of the study : analyse the prevalence of anaerobic isolation in mvp. methods : between october and february all suspected mvp were investigated using protected specimen brush (psb) technique. brushes were rapidly transported in shaedler broth to laboratory. a special care was tooken for anaerobic isolation. results : among the psb performed for suspected mvp ( nosocomial and community-acquired pneumonia), yielded at least one micro-organism (positive psb : %). of positive psb demonstrated only aerobic bacteria and ( %) yielded with anaerobes. in out patients, anaerobes were associated with aerobic bacteria. anaerobes were mostly isolated in nosocomial pneumonia ( / positive psb). strains of anaerobes were isolated. prevotella species represent out these strains ( %) the most frequent anaerobic species were prevotella oralis ( ) p. intermedia ( ) and p. buccae ( ). comments:using adequate methods, anaerobic bacteria are frequently isolated in mvp. it could be off importance to take in account anaerobes in the choice of empirical antibiotic therapy in mvp. objectives: the majority of patients with multiple trauma are considered immunocompromised. the aim of this study was to identify risk factors of pneumonia in mechanically ventilated patients with multiple trauma or after surgery. methods: in this prospective study we studied multi-trauma patients (mean age + years, apache ii . + ), admitted to a general intensive care unit (icu). all patients were intubated and mechanically ventilated. we were considered that a patient had ventilator associated pneumonia (vap) when the specimens of bronchoalveolar lavage (bal) or protected specimen brush (psi?,), ebb'ned through the bronchoscope, had one or more microorganisms in concentrations greater than and cfu/ml respectively. all patients had been receiving antibiotics, with no change during the last days, prior to bronchoscopy. results: patients had vap, and patients didn't. in the bivariate analysis, the glasgow coma scale (gcs)< (x = . , p< . ), the administration of neuromuscular blockade (x = . , p< . ), the duration of mechanical ventilation to be greater than days (x = . , p< . ), the flail chest (x = . , p< . ), the parenteral nutrition (x = . , p< . ), the ards (x = . , p< . ), the abbreviated injury scale (ais) of more than for thorax (:,: = . , p< . ), the pneumothorax (x = . , p< . ) were statistically significant related to development of vap. in multivariate regression analysis, using the stepwise technique, three of the seventeen studied factors showed to have an indepantent association with the development of vap:the administration of neuromuscular blockade (f: . , p< . ), flail chest (f: . , p= . ), and gcs (< ) (f: . , p= . ). conclusions: in patients admitted to icu for multiple trauma or major surgery, the administration of neuromuscular blockade, the flail chest, and the gcs (< ), in the population under study, were the indepedent risk factors for vap. mof is a sereous complication of differem states: infection, sterile inflamation, extensive fissure injure, intoxication, ets. there is close correlation between extension of mof and death, developement of nasocomial infection. immunologic disfunction. in order to prgnose probability of risk of mof development among the patients with sepsis and septic shock, we achived an eqation, allowing to recive a coeficient, closely connected with this probabiliti. we have used retrospective analisis of cases of sepsis. diagnosis of sepsis was based according to bone's criterions of sepsis. mof was assessed as disfunction of or more systems according to bone's classification of mof. having used correlation analisis we have estimated factors which have had high correlation coeficient with the probability of development of mof. there were: apache-ii score points, evidenceof septic shock, endocrinopathy. with the help of multyple regression analisis we acheved next equation: y= , + , x~ + , x + , x , were x i-apache-ii score points, x -evidence of septic shock, x -endocrinopathy. the explanatory power of this quation was evidenced by roc of . , se (v - . introduction: the presence of liver dysfunction in the process of multiple organ failure is associated with an adverse outcome, particularly when it becomes progressive to liver failure. disturbances of liver function may occur early and their detection may be of significant importance for the further development of organ failure. routinely used liver function tests appear to be inconsistent indicators of hepatic damage. in this study, we used p_lasma disappearance rate (pdr) of indocyanin-green dye (icg) as an early estimate of liver function. methods: we serially evaluated pdr and routine liver function tests (serum bilirubin, sgot, sgpt), as well as acute phase and non-acute phase proteins (crp, transferrin) in patients during the first week after trauma or the onset of sepsis. patients: group : (n = ) multiple trauma iss > , group : (n = ): abdominal sepsis, acute necrotizing pancreatitis (anp) grade iii. patients were selected on the basis of clin cal estimates that these patients would require continued icu observation. pdr was determined by means of a fiberoptic catheter and a computerized system (cold z- , pulsion), which permits repeated bedside measurements. the initial values of pdr, serum bilirubin and transaminases were not significantly different in trauma, sepsis and anp. in trauma patients pdr improved during the first week. in patients with sepsis and anp pdr remained low and worsened with time. the decrease in pdr preceeded an increase in biochemical liver function tests in these patients. + . &-_ ( - ) discussion: routinely available blood tests of liver function are usually altered several days after injury. however, they are generally non-specific indicators and they are influenced by extrahepatic factors. pdr seems to be useful to evaluate impaired liver function early after the onset of sepsis and trauma. objectives: to study frequency of organ system failure (osf) and it's influence on outcome in granulocytopenic patients with hematological malignancies and septic shock(ss). materials and method: retrospective review of medical records of granulocytopenie(wbc< , xl ) patients with hematological malignancies and ss, who were admitted to the intensive care unit (icu). frequency of osf before and after ss was analysed. the patisnts were categorised on survival and non-survival. results: signs of osf were observed in . % of patients before ss and in all patients after ss. only patients presented with hypotension refractory to inotropic therapy. nevertheless there was a significant increase of frequency of acute respiratory failure (arf), acute renal failure (arenf) and liver injury (li) after ss occurred(showed on the figure). only frequency of organ failure before and after objectives: statusmetria allows to define the effective level of oxygen status and accordance to it means of carbon dioxide and elec-trolyte in critical care. the conception of syndrome int~ive care (sic) is exhausted itself and invariable outcomes of sic of multiergan system failure (mosf) confirms that. therefore, an alternative to sic should be advanced. methods: efficlenoy of treatment has been asscsaed in patients with mosf using value of metabolic rate and ability of an organism to cover it by oxygen and substrate supply. oxygen pulse (op) and index of efficacy of oxygen transport (ieto ) was monitored. ~lt~.lntenaive care is considered to be homeostasis-securing therapy (hst) if energostructure deficit is eliminated and necessary for recovery regeneration rate is .restored. op in patients with mosf was . mt-m " , and le,~ and ie'i~ w~ . units in sic. we managed to maintain op of . - . ml.m " and ieto of . - . units in hst. patients from with mosf survived in sic and patients from survived in hst. efficiency of hst appeared to be two times as much as efficiency of sic. cr of homeostasia-se-'uring therapy is advancing. the conception provides restoration of regeneration rate due to effective then in sic elimination of en=gostructure deficit. the conception may be a basis of new technology for treatment of mosf. helen f goode phd, nigel r webster phd. anaesthesia & intensive care, university of aberdeen, ab zd, uk. objectives: xanthine dehydmgenase is converted under conditions of ischemia, reperfusion and endothelial damage to xanthine oxidase, with superoxide anion as a co-product of its catalytic activity. multiorgan dysfunction syndrome is associated with splanchnic vasoconstriction resulting in significant and prolonged gut ischaemia. aggressive volume resuscitation with prompt restoration of blood flow results in reperfusion of the tissue and is likely to cause xanthine oxidase-mediated release of oxygen-derived radicals. this study investigates xanthine oxidase activation and oxygen-derived free radical-mediated damage in such patients. methods: fourteen consecutive patients on itu who met established criteria for septic shock and secondary organ dysfunction were studied. serum xanthine oxidase activity was measured using oxidation of a chromagen in a dual enzyme system and plasma malondialdehyde was measured using a specific spectrephctometdc assay. apache ii scores, blood pressure, svr, cardiac output and day survival were also recorded. biochemical data were compared with results from healthy subjects. results: xanthine oxidase activity was . + . units/i in patients (mean :t: sem) and . + . units/i in controls (p<o. , mann whitney u test), and was highest in the patients who survived (p< . ). malondialdehyde concentrations were elevated ( . • . prnol/i compared with . • . pmol/i in controls, p< . ). xanthine oxidase activity did not relate to apache score or any of the cardiovascular parameters recorded, and was not influenced by the degree of organ dysfunction. conclusions: patients with sepsis and secondary organ dysfunction have xanthine oxidase activation and evidence of free radical damage. the finding that activity was highest in those patients who survived suggests that reperfusion was incomplete in patients who died, with decreased tissue xanthine oxidase ~tash out' into the circulation. influence objective : evaluation of the feasibility of measuring the intragastrie partial pr~sure of carbon dioxide (pco ) using a chemilumin~nt optode and fibre~ptics originally developed for intrav~cular blood gas monitorlng(p ) methods the pco electrode w~ calibrated i~-vitro according to the m~ufaeturers instructions the sensor w~ then stripped of its outer c~ing and threaded down the pile tube of a g~ c enema e (gt) so ha he ens ng portion sat well within the balloon. the modified gt was inserted n~og~trically after induction of anesthesia in ten patients undergoing c~diopuimonary byp~s throughout results: according to the datas of integral rheography % of patients were revealed to have hypodynamic type of blood circulation (cardiac output was decreased on - % and general peripheral resistance increased on - %). it was effective to use complamin (xantinoli nicotinas) in the complex therapy of su~h patients. the dosage was - mg/kg during - days. as a result of such therapy was also the oliguric stage shortening (ac n ).in , % of the cases unsatisfactory datas of central hemodynamic,combined with high (more than cm h ) venous pressure,lung oedema.then nanipruss ( , - , mkg/kg/min) was succesfutly used in complex with routine therapy.in the patients with low cardiac output and low general peripheral resistance mesaton ( , - , mg/kg) and dopamine ( - mkg/kg/min) were effective.change for the worse in the hemodynamics datas, inspire of therapy during - days,was prognostically unfavourable. conclusions:we consider early diagnostic of hemodynamic disorders and adequate correction of them is one of the most important factors, determined the outcome and prognosis in arf patients. obiective: to evaluate the results of renal replacement therapy (rrt) in surgical icu patients with acute renal failure (arf). arf in icu patients is associated with high mortality rates. we investigated the relation between mortality and organ failure in different categories of surgical icu patients receiving renal replacement therapy (rrt) for arf. methods: the records of surgical icu patients with arf requiring rri-(haemodialysis or cavhd) were examined. five different patient categories were defined; .ruptured aneurysm of the abdominal aorta (raaa) n = .elective vascular surgery (evs) n = .abdominal sepsis n - .trauma n = .others ( e.g. malignancy, obstetric emergencies) n- seven organ systems (cns,circulatory,respiratory,hepatic,renal,digestive,haematologic) were scored for possible failure using the mof score. results: mortality was as follows: all patients % , group % , group % , group % , group % , group % . mortality increased with the number of failing organ systems; mortality for all patients with > failing organsysterns was % the only exception being the subgroup of trauma patients where mortality under these circumstances was o% conclusions: mortality in surgical icu patients receiving rrt for arf is high. no significant difference in mortality is found between raaa and evs. mortality increases with the number of failing organ systems. the subgroup trauma patients shows a lower mortality compared to the group as a whole, even with > failing organ systems. to look for the most accurate scoring system to measure the severity of the complications occuring in the early phase ( first day) of kidney transplantation and to asses their prognostic value. methods: in our retrospective study we applied the apache li and the goris scoring system for the kidney recipients who developed multiple organ failure (mof) as a consequence of their pulmonary and. cardiovascular complications following kidney transplantation. we evaluated the recipients the distribution of the women and men ( % ~ % ) was the same as in the kidney recipients. applying the apache ii system most of the patients had their score between and , and the function of , or organs were affected at the time of the onset of mof. the apache ii system gave adequeate information about the disturbance of the function of other organs beside the kidney failure even at the time of the transplantation. the scores and the number of the affected organs correlated with the condition of the patients in the goris scoring system but not as sensitively as in the apache ii scoring system. conclusions: both the goris and the apache ii scoring system can be applied to measure the severity of the multiple organ failure occuring during the early phase of kidney transplantation. however the apache ii system is more suitable to follow not only the stateof the patients at the time of the admission but also the changes occuring in their condition during the complication. v.v.erofeev, v.v.ivleva scientific research institute for general reanimatulogy russian amsci, moscow, russia objectives: the analysis of ssc and results of their treatment in patients following critical states showed the necessity of developing a combined antibacterial therapy. methods: according to the protocol patients ( - years old) with combined trauma and massive hemorrhagy following vast aml traumatic operations were examined. microflora's composition and resistence to up-to-date antibiotics was studied using the anaiyser iems reader by "labsisteme"(finland). general clinical, bacteriological, immunological indices, as weil as the duration of the treatment and recovering rate served as criteria of the combined antibacterial therapy effectiveness. results: it was proved expedient to administer antibiotics in staphylococcus infection in the following combinations: riphampizin with fluoroquinolones; i-ii degeneration, cephalosporins with aminoglycosides; cephalosporins with fluoroquinolones. in case of singling out the exciters of the euterobacteriaceae family, including the pseudomonas aereginosa, -fluoroquinolones combined with modern amynoglycosides; fluuroquinolones with ureidopenicillines; ureidopenicillines with amynoglycosides; amynoglycosides with the ii-iii generation cephalosporins; cephalosporins with fluoroquinolones. in severe ssc caused by combined infection (including anaerobes) clindamicin with modern amynoglycosides was prescribed. conclusion: the combined antibacterial therapy allows: ) to increase the effect on microbic agents and the efficacy of treatment in combined infections; ) to lessen the possibility of the exciters'resistence to antibiotics; ) to prevent the development of superinfection: ) to decrease the doses of medicine and its toxic effect. objectives: two methods of blood volume measurement in a group of critically ill patients were compared to investigate the practical possibilities of a new easy to use method based on carbon monoxide (co) uptake. methods: all patients had multi-organ failure and haemodynamic monitoring with a swan-ganz catheter. mean apache ii score was ( - ). when indicated, patients had blood volume measurements simultaneously based on the techniques of, i) dilution of ~cr labelled red cells, and ii) inhalation of carbon monoxide gas with measurement of the rise of carboxyhaemoglobin produced. the co was administered via a newly designed, ventilator driven, fully closed circle system ensuring co retention and co removal with automatic addition of oxygen to m}ttch patient uptake. a portable computer performed all necessary calculations. results: volumes obtained by co uptake were compared with the "gold standard" radiolabelling method. mean blood volume determined by the co method was ml ( - ml) compared with ml( - ml) with slcr labelled red cells (r= . ). regression analysis produced an intercept at ml. the slope of the regression line was . ( . - . , % confidence limits). discussion: the co method produces volumes in excess of the radiolabelling method. there appears to be a systematic error, and one possible explanation is co binding to substances other than haemoglobin. conclusion: the co method is easier to use than radiolabelling and of the lower cost, since cohb measurement only is required. aceuraey is sufficient for clinical use and our preliminary findings suggest this system will meet the requirements. objectives: this study was conducted to determine the role of nitric oxide (no) in the pathophysiologic alterations and multiple organ damage, and the possible effects of " " " (l-n -monomethyl-l-arglnlne nmma) on hemodynamics and mortality in rats caused by a prolonged hypovolemic insult. methods: a prolonged hemorrhagic shock ( - mmhg for rain) was induced in anesthetized rats followed by adequate resuscitation. l-nmma was administered intravenously at doses of . mg/kg or . mg/kg at the end of resuscitation. results: infusion of . mg/kg l-nmma diminished the fall in mean arterial pressure, significantly increased the cardiac index (ci) and stroke volume (sv), together with remarkable protection from multiple organ damage compared to the controls. the h survival rate was significantly improved from . % in the control group to . % in the treatment group (p< . ). in contrast, the high dose of . mg/kg l-nmma resulted in a strong blood pressure response but a marked reduction in ci and sv concomitant with an increased total peripheral resistance index within the observation period, and caused severe damage to various organs at h after treatment. in addition, marked elevation in both endotoxin and tnf levels were observed in animals subjected to shock insult. conclusions: these results suggest that no induced by hemorrhagic shock in rats is an important mediator for pathophysiologic alterations associating with cardiovascular abnormalities, multiple organ dysfunction, and even lethality. thus, regulation of no generation and use of no inhibitors might provide new aspects in the treatment of hemorrhage related disorders, and the use of l-nmma would be either deleterious or salutary in a dose dependent manner. (hebert, chest- ) . the purpose of this study was to assess the risk factors for hepatic dysfunction in mosf. methods: patients have been hospitalized in our icu from january to may . , ( %) with mosf. among mosf pati~ts, ( %) have had hepatic dysfunction defined according to hebert (bilirubin ~ ttmop , chest ). thirty six of these patients acquired hepatic dysfunction after admission in the icu. these patients were compared with mosf patients without hepatic dysfunction selected blindly. chrorfic diseases, severity scores, eanse of admission, clinico-biologieal and hemodyunrrfic parameters, use of vesopressors, use of hepaiotoxic drugs, use of nutritional support and mortality were compared for hepatic failare and non hepatic failure groups.twenty nine patients had postmortem hepatic histologic examination, results: univaciate analysis: only parameters with p _< . are pre~nted. including these paramet~'rs in a multivariate analysis, anly c~hosis and vascular surgery remain independent risk factors for hepatic dysfunction. in particular, pao /fio , arterial lactate, do were not different between the two groups, some de~'ee of histological abnormalities was found in all liver samples, despite a normal bilirubin level in % of the cases conclusions: in our patients, conu'ary to previous studies, hypoxic and hemody~anfic parameters were not independent risk factors for hepatic dysfantion. this might be due to the inadequacy of the usual biologic definition of hepatic dysfunction as well as to the poor sensitivity of general hamodynamic parameters. critical states of various origin are complicated with the mldtiorgan farm (moi~ oceuzr~ce. due to their and functional features the lungs become the primmy damage target in various critical.states. ard that occurs in such states is associated with pulmonary edema development because of capillary permeability increase mediated by humeral and cenular responses to amag/~ factors exposure. r nmst be emphasized that mediators and effecto~rs of this respo~e affect not only puknonary capillaries, but other organs capiu~es as wellenhancing their permeability. orsans edema is a conmm~ finding at the autopsy of patients died from mof.clinical and radiolosial findings allow to have a diagnosis of pulmonmy edema before ~mi!ar lesions in other organs occm. additionally, there are some techniques that permit quantitative assessment of pulmonary edema flv.id (evlw) volume. in conclusion, we suggest that evlw changes in .dyn~rmcs in patients with mof are considered as a critical state severity measure which reflects indirectly the edema in other organs. objectives: we compared three different dialysis membranes to find out whether or not there were differences between their clearance characteristics on substances such as inuline, creatinine, urea, and phosphate to be eliminated in acute renal failure (arf). moreover, if a loss of clearance did occur we were interested in whether this was due to heparinization and a high production of the thrombine-anti-thrombine-complex (tat). methods: we carried out a randomized controlled study on consecutive critically ill patients presenting with arf, most of them in association with multi-organ failure, to be treated by continuous pump-driven arterio-venous renal replacement therapy on continuous low-dose heparinization. three different types of high-flux filter membranes (f tm [fresenius] , ct tm [baxter] , and filtra tm [hospal]) were assessed. each filter was changed intentionally after a hours" use. together the data of filters were evaluated, each at three different times (immediately after its onset [ hi, after h, and after h). the clearances of creatinine, urea, phosphate, and inuline were measured. results: there were some significant differences in clearance characteristics of inuline, creatinine, urea and phosphate between the filters (p< , ) showing the f tm membrane excelling filtra mand ct tm the more. the loss of inuline clearance ( mi/min/m ) after h, however, was insignificant for all filter types. a continuous low-dose heparinization scheme was applied without any relevant prolongation of the aptt. even lower losses were noted for the clearances of creatinine, urea, and phosphate. we found the tat-producfion increased after h (p< , ), but it did not rise any further. conclusions: as we could demonstrate in our study the clearance data of different types of filter membranes applied during continuous renal replacement therapy do show significant differences. on the other side, no relevant loss of clearance occurs during a hours" period indicating a high efficiency over time. to consider commercial aspects as well it shows that inexpensive conventional filter membranes can successfully be applied even for a longer renal replacement period, if needed. a retrospective study was performed on patients with acute renal failure (arf). we analysed survival in continuous (cd) and intermittent dialysis (hi)). mean age of the patients was years (y), patients ( % ) were < y, patients ( %) were >= y. the incidence of dialysed arf in our mixed intensive care departement is %/admission/y. statistics: fischer's exact test, mann-whitney-u test. efioloev: the contribution sepsis, cardiac failure and aminnglycosidcs was respectively %, % and %. treatment: cavh (cd) or cvvh (cd) was used in patients ( %), hemedialysis (hd) was used in patients ( %). data: mean apache scores were the same for cd and hd ( for both groups), patients treated with continuous dialysis techniques had significantly (p<o, ) more need for ventilation ( % vs %), elevated bilirubin ( % vs %) and a higher vasopresser need ( % vs %@ than patients treated with hemedialysis. there was a trend towards more sepsis ( % vs %; p= . ) mad coaguiation disorders ( % vs %; p= . ) in cd. taere were sign/ficantly more younger patients (< y) treated with cd ( % vs %, p< .os). mean apache score was significantly lower in patiants< y than as patienta>= y ( vs ; p< . ). patients< y had significantly (i}< . ) more coagulation disorders ( % vs %) and elevated bilirabin ( % vs %). there was no significant difference in vasopressur need and ventihatio~ between age groups. outcome:. hi) had a better sr compared to cd ( % vs ~ p< . ). patiants>= y had a comparable sr vs patients< y ( ") */e vs %; p----a.s.). tha global survival rate (sr) was % ( patients). conclusions : diaiysed arf has a well known lowsurvival rate ( %): hc~raedialysed patients had a better survival rate than patients treated with continuous dialysis. this can be explained by the fact that the latter were in a worse condition considering organ failure (more vantilatian, elevated bflirubin and need for vasepressurs), apache score couldn't illustrate that. patient~ y with arf have the same survival rate as patients< y: although patients >=- y have a higher apache score they have less organ faille. the avacbe score is not a good oredictor of survival in p with organ failure. departments of surgery and intensive care, guy's hospital, london, u.g-obiectives: a randomised controlled trial of a management protocol utilising the regular measurement of gastric intramucosal ph (phim) to control the administration of dopexamine. methods: patients admitted to a multidisciplinary teaching hospital intensive care unit (icu) undergoing insertion of a pulmonary artery catheter were managed according to a resuscitation protocol. randomisation was to either the protocol alone or to insertion of a nasogastric tonometer and subsequent management guided by phim. phim < . initiated volume and inotrope resuscitation and, if unsuccessful in elevating phim, dopexamine was commenced. approval was obtained from the hospital ethics committee. results: patients were considered for analysis and the two groups were well matched for age and sex. overall, there was a high hospital mortality of . %. there was no difference in icu or hospital mortality between the two groups (see table) . objectives: to compare cardiac output (co) measurements between continuous termodilution (cco) by thermal wire on pulmonary artery catheter (cco/svo vigilance. baxter critical care), and co measurement using a trans-esophageal doppler (dco) ultrasound system (odm ii, abbott laboratories), in the immediate postoperative period of cardiac surgery. methods: patients undergoing myocardial revascularization were monitored with cco by a swan-ganz catheter and an intra-esophageal dco probe, after induction of anesthesia. exclusion criteria were: aortic valve disfunction, previous valvular surgery esophageal disease, absense of sinus cardiac rhythm, and need of ventricular or intraaortic assistance. hemodynamic parameters, co by both cco and dco, svo . sao , diuresis, pha, and hemoglobin were repeatedly registered during the first hours after surgery, as the patients were kept under sedation and mechanical ventilation. results were compared using the method described by bland and altman. results: measurements of co were obtained, ranging . objectives: a decreased tissue oxygen delivery is responsible for a higher morbi-mortality rate among surgical patients; this diminished oxygen delivery/consumption rate (dojvo ) may origin the lactic acidosis observed in the gastrointestinal tract, reported in patients undergoing hypothermic cardiopulmonary extra corporeal surgery, and can be registered by tonometry as result of the gastric mucose ph. the purpose of this study is to evaluate the reliability of the intramucosal ph (phi) measurement by a nasogastric catheter as indicator of the do /vo > its co> relation to other parameters of do /vo disturbance, and with postoperative complications and clinical course. methods: patients ( male, female) undergoing cardiac surgical procedures were included ( myocardiai revascularizations, valvular substitutions, constrictive pericarditis). mean age was + years, mean weight _+ kg. a nasogastric probe (trie tonometrics) was placed after anesthesia induction; phi values were registered in the postoperative period ( ', ', ", ' and h after surgery end). the corresponding hemodynamic parameters, venous oxygen saturation (svo ), diuresis and arterial ph (pha) were also recorded. results: phi values ranged . to . (mean . ( . ); the mean values of clinical evolution were: extubation time, _+ hr.; discharge from postoperative care unit, - hr.; and hospital total postoperative time, _+ . days. complications registered were: perioperative acute myocardial infarctions, cases of respiratory insufficiency, occlusion of coronary bypass, an ease of hyperamilasemia. all patients with severe complications needing specific treatment showed either a low phi value, or a considerable descent in comparison with the initial register. statistic correlation between low phi and presence of complications was found; the low significance (p > . ) degree may be due to the low population size. conclusions: phi measurement in cardiac surgery patients is a non invasive, uncomplicated method for prediction of doz/vo disturbances, thus reflecting risk of increased major complications, and may precede changes in other usual indicators (svo , pha, cardiac output, ...). work-in-progress with a greater population size may offer more significant results. references: ( ) gutidrrez g: lancet ; : - . ( ) landow i: acta anaesthesiol scand ; : - . the haemoglobin-level (hb) is besides the arterial oxygen saturation and the cardiac index one of the relevant parameters of oxygen supply to the tissue. in contrast to otherwise healthy patients, there is no agreement on tile so-called transfusion-trigger in critically ill patients. in i?ont of this background the question arises, whether and to what extent blood transfusion in critically ill patients improves oxygen supply io tile tissue. this study was performed in critically ill/septic patients in the postoperative period alier an inlcclive/scptie revision operation of the hip or knee joint. on cardiac/seplic reasons monitoring consisted beside other measures of a pulmonary arlery catheter and of an indwelling arterial line li~r measurering/calculating standard haem~dynamic as well as systentic oxygen parameters. the indication for blood transfusion was given by hb together with the cliuical slatus of thc patienl (asa-scorc and multiple organ dysfunction (moi))). statistical analysis w~ks performed by mann-whitney-u-test. by fisher's exact-test and by wii.coxon-test: statistical significance was set with p< . . according tu the pretransfusion value of hb and of lactate (lac) palicnts ;,,'ere divided into groups as follows: a: hb< and b: >sg/dl: i: ac< . and ii: > .smm. in either group blood transfusion results in zt significant increase in hb (a: . _+ . to . + . g/dl; b: .(~ . tt, . + . g/dl; i: . -+ . to . -+ . jdl; i : . -+ . to . + . g/dl). wlailc, however, haemodynamic parameters do not difl)r significantly from each other before and alter blood transfusion, oxygen delivery (do, -ml/min x m-') increases significantly hi either group studied (a: -+ to -+ ; b: + to + ; : -+ to -+ ; i : -+ to -+ ), in contrast oxygen consumption (vo~ -ml/min x m e) does not change significantly in either group (a: i -+ to -+ ; b: -+ to -+ ; i: -+ tu -+ ; : -+ to +_ ); oxygen exlraction ratio decreases. this study in critically ill/septic patients demonstrates, that in this group of patients studied blood transfusion at a base-line-value of > . -+ . g/dl expectedly rises do~, however, it does not improve vo=; even not in septic patients with elevated lac-values. paclitaxel in a new anticancer agent, extract from the bark of the yew tree (taxus brevifolia), employed against breast and ovarian cancers resistant to chemotherapy. it promotes the polymerization of tubuline, and disrupts the normal microtubule dynamics. hematologic toxicity, hypersensitivity reactions (bronchospasm, urticaria and hypotension), and peripheral neuropathy are the main reported toxic effects. cardiac side effects are rare: atrioventricular blocks of higher degree are reported in . % of patients; congestive cardiotoxicity was discussed only in one trial in patients treated with paclitaxel and doxorubicin. we describe the history of a -years-old worn an with a breast cancer, diagnosed in , initial staging t nim , treated with mastectomy, axillary lymphadenectomy, andchemotherapy with a cumulative dose of anthracyclines of mg/m until august . the patient complained of dyspnea and severe hypotension immediately after an intravenous infusion of mg paclitaxel, given over hour for the treatment of bilateral, malignant pleural effusion. at echocardiography die left ventricular ejection fraction was reduced to %. she died days later because of a severe cardiac low output with hepatic and renal failure; an impressive hepatic cytolysis was observed. the post mortem examination confirmed the dilatation of the cardiac cavities, especially of the right ventricle, bilateral pleural fluid, and ascites. the histology was suggestive for a cardiomyopathy secondary to anthracyclines. the electron microscopy revealed a deposition of an unusual pathological pigment in the myocytes; subsarcolemmal deposition or membranous were absent. we hypothesize that paclitaxel was the cause of a major hypersensitivity reaction with shock and severe hepatic cytolysis, worsening the myocardial damage induced by anthracyclines. the possibility that a low doge of paclitaxel could directly increase anthracyclines cardiotoxicity -as decribed in the medical literature -will be discussed. objectives: activated endothelial cells release soluble intercellular adhesion molecule- (sicam- ), vascular cell adhesion molecule- (svcam- ), and e-selectin (selam- ). sicam- , svcam- , selam- , and inflammatory cytokines were determined. methods: sicam- , svcam- , and selam- were determined by elisa. tnf-a, il- , and il- were also measured by elisa. endotoxin was measured by an endotoxin-specific endospecy test after pretreatment of new pea method. results: the sicam- and s vcam-i levels were significantly higher in the septic multiple organ failure (mof) and sepsis groups than in the non-septic mof group. the selam- level was slightly higher in the septic mof group than in the sepsis withut mof group and non-septic mof group. the increases of soluble adhesion molecules were not in agreement with changes of plasma endotoxin level. levels of soluble adhesion molecules were correlated with the levels of plasma tnf-a and il- , but the level of il- . discussion and conclusion: the slcam- and svcam- levels in septic patients closely reflected the severity of the pathophysiological conditon. it was possible that the release of sluble adhesion molecules were not stimulated by plasma endotoxin, but endotoxin in the local infectious region. tnf-c~ and il- also were suggested to be involved in the release of these soluble adhesion molecules. obiectives: cardiopulmonary bypass (cpb) surgery is associated with a systemic inflammatory response attributable to the release of various inflammatory mediators and the activation of complement or coagulofibrinolytic system. in addition, adhesion molecules, such as icam- , elam- , and vcam- , appear to be of central importance in the inflammatory process following cpb surgery. we previously reported the effects of a synthetic protease inhibitor, fut- , reduced release of inflammatory cytokines (tnf, il-lg, il- ), activation of complement (c a, c a) or coagulofibrinolytic system (tat, pic, fpa) and protected platelet function (gpib, gpiib/llla) following cpb surgery. methods: in this study, we analyzed fut- on soluble adhesion molecules following cpb surgery. patients undergoing cpb surgery were divided into two groups, group a consisted of patients who received omg of fut- in priming solution, followed by a continuous infusion at mg/kg/hr during cpb in addition to initial heparin dose of mg/kg. group b, a control group, included patients who were injected with heparin only. the plasma slcam- , selam- , and svcam- concentration was measured by elisa. results: every soluble adhesion molecules decreased during cpb in both groups, and rose after cpb. selam- and slcam- reached their peaks on hours after cpb and on pod respectively in both groups, but they remained lower in group a (selam-i: . + . vs. . • ng/ml, p< . , slcam-i: • vs. • ng/ml, p< . ), svcam- , in both groups, remained lower than preoperative levels, but did much lower in group a. conclusions: fut- reduced adhesion molecules and suggested to be the effect on postoperative organ dysfunction. in the last few :,'ears the conditions of treatment in continuous hemofiltration/hemodiafiltration were discussed controversially. a significant removal of tnf-alpha and il-i could be demonstrated in cvvhd. the aim of our study was to investigate the elimination of tnf-alpha, l- , il- , il- , s-cd- and ifn-gamma in cvvh by measurement in plasma and hemofiltrate of critically ill patients with an acute renal failure. the patients of our study were treated with a continuous veno-venous-hemofiltration (polysulfone-filter, blood flow: - ml/h, filtration rate ml/h). the samples, hemofiltrate and plasma, were taken one hour after the start of treatment. the patients suffered from septic shock ( ), the so called hepatorenal s~aldrome ( ) and a severe pancreatitis ( ). the cytokine concentrations were measured with elisa-method. in contrast to elevated concentrations in plasma for tnf-alpha ( cases), scd ( cases), il- (l case) and il- ( cases), hemofiltrates contained no activities. only il- was removed in significant amounts with even higher levels in hemofiltrate than in plasma. this phenomenon was described so far for tnf-alpha and il- and may be due to the absence of metabolic properties (possibily enz~natic) in hemofiltrate. it can be shown, that tnfalpha, il- , il- could not be eliminated in cvvh with a filtration rate to ml/h. in contrast to findings of other investigators with a higher filtration rate (> ml/h), we found no significant concentrations of tnf-alpha and il in hemofiltrate. we conclude, that for a significant removal of important cytokines higher filtration rates (> ml/h) are necessary. objectives: multiple organ dysfunction syndrome including liver and renal impairment is a fatal complication in patients with the diagnosis of sever sepsis. this study focused to the effects of removing toxic substances from inflamnatory tissue by hemodiafiltration. ~ ethods: eleven patients were admitted to the icu in emergency center and met the criteria of systemic inflammatory response syndrome in association with infection. all patients developed liver and renal dysfunction and were treated by hemodiafiltration with high flux membranes (fb-u:nipro). the hemodiafiltration were performed times using nafamostat mesilate as an anticoagulant in hours with l of substitution fluid (hf-b:fuso). the serdm levels of endotoxin, cytokines, endothelin-i (et-]), human neutrophil elastase ~ -proteinase inhibitor complex (hne-pi), fibronectin (fn), lactate, and amino acids were measured before and after the hemodiafiltration. the hemodiafiltration would be effective to renal dysfunction by reducing endothelin and beneficial to tissue metabolism represented in fisher's ratio, but might be harmful to respiratory function by activating neutropila in patients of severe sepsss. background : intermittent hd may be poorly tolerated in the early phase of arf in hemodynamically unstable patients (pts). this technic may fail to achieve steady state urea low levels in hypercatabolic pts. method : nt = consecutive pts treated with hd; n = consecutive pts treated with cvvhf. hemodynamic unstability is defined by arterial hypotension and requirement of inotropie support despite adequate filling. rate of change in urea (u), ereatinin (cr), k + , ph were computed from a linear regression .analysis of data vs time in each treatment group during the first days of application of the two technics (anova). dally worst values were recorded. results : hd-group : apach% score = _+ ; mean number of organ system failure (osf) = . -+ ; mean blood pressure (mbp) = • mmhg (first day of application of hd). cvvhf-group : apachen score : + ; osf = -+ ; mbp = + mmhg (first day of application of cwhf discussion : during the first days of application of hd/cvvhf, u and cr decreased much more rapidly in the cwhf-group. k* and ph were maintained within normal range in the two groups. initial mbp which was much lower in the cwhf-group significantly improved during the application of cvvhf while mbp remained unchanged in the hd-group. conclusion : despite higher severity of disease in cvvhf group (apachen score, osf, lower initial mbp), we obtained a better performanco with cvvhf regarding the decrease of u and cr and the improvement of mbp. in relation to the different and continuous renal replacement techniques, the continuous venovenous one is the alternative method to continuous arteriovenous for critical patients with acute renal failure (arf). we present you our experience with cvvh in patients with mof. in our intensive care unit (icu) patients with mof were treated with cvvh in the period between january in to march in . the mean (• age of our patient population was , • years, being % male and % female the whole patient population was with mof iust at the moment the technique was accomplished; % was in mechanical ventilation, % needed vasopressor support and % required both of them (mechanical ventilation and vasopressor support) apache ii score mean of the patient population was , ~: , (range - ) and ati of them were with arf oligoanudc. technique: cvvh was accomplished using a single-d~al iumen catheter, ptaced in either a temoral or subclavian vein by the stand ard seld{nger technique. pol{sultone hemofitiers were also used, and the extracerporeal circuit used standard arterial-venous blcod tubing. blood flow and hence oltrafiltration pressure, within the circuit was generated by a roller blood pump. the modulus has a roller pump, a pressure transducer connected in an arterious and venous line, such as an air-transducer which is adapted to a drip-chamber in the return way. the replacement used was a peritoneal dialysis solution. medicine , st. george's hospital medical school, london. england. hepatic sinusoidal endothelium shows a major inflammatory response in porcine sepsis that can be attenuated by the administration of dopexamine hydrochloride. dopexamine is a beta and dopaminergic receptor agonist. the specific beta adrenoceptor antagonist ici has been shown to reduce the protective effects of dopexamine. we investigated the effect of this antagonist on hepatic ultrastructure in porcine sepsis. six pigs ( - kg) divided into groups were anaesthetised and intubated. cardiac output and portal blood flow were measured using standard techniques. the groups were; placebo, (peritonitis induced); blocker, (peritonitis induced and pg/kg ici bolus infused then given hourly). caecal content was aspirated and peritonitis induced. colloid was infused to maintain pawp at - mm hg for eight hours the animals culled, hepatic tissue removed and prepared for electron microscopy. in the placebo group hepatic endothelium was swollen and the sinusoids occluded by wbc. but in the ici blocker group, much of the sinusoidal endothelium was absent and there where large extra sinusoidal spaces among the hepatocytes. an assessment of the two groups showed worse hepatic architecture in the blocker group. the b antagonist blocked any protective effect of endogenous beta adrenoceptor agonist (adrenaline) on hepatic endothelium in porcine sepsis. george's hospital medical school, london. england. dopexamine hydr chloride, a beta and dopaminergic receptor agonist reduces hepatic damage in porcine sepsis. we tested dopexamine's effect on cerebral oedema. the beta adrenoceptor antagonist ici was infused to block any protective effect of dopexamine. nine anaesthetised pigs ( - kg) were randomised into groups; placebo, (peritonitis induced); dopexamine, (peritonitis induced and ~tg/kgdar of dopexamine infused); blocker, (as in dopexamine group but in addition pg/kg ici bolus given then infused at that rate hourly). caecal peritoneum was induced and colloid infused to maintain pawp at - mmhg for eight hours when the animals were culled, cerebral tissue removed, prepared for electron microscopy and digitisation. digitisation of the area of oedema surrounding the blood vessel and expressed as a percentage of the micrograph. . _+ . , dopexamine . + . ", blocker . + . . data expressed as mean + sd. significance p< . . * dopexamine compared to placebo and blocker. in the dopexamine group the area of tissue oedema was significantly lower than either the placebo or blocker groups. there were no significant differences between the placebo or blocker groups. the antagonist completely blocked the protective effect of the drug on cerebral oedema in porcine sepsis. beta adrenoceptor stimulation is protective of cerebral oedema in porcine sepsis. objectives: the hemodynamie~ of hepatic circulation during multiple organ failure (mof) have not been suffleienly studied. we investigated liver hemodynamics in two subgroups of patients with mof, those with either liver or lungs as the main organ of involvement. methods: three groups of patients were created: i) mof-hepatic involvement (mof-hi) ( patients) with bilirubin > . mg/dl and lung injury score < . , it) mof-ards ( patients) with respective values < . and > , iii) patients with head injury with respective values < and < , served as group control. all patients were in haemodynamieally stable state with an oxygen delivery index > ml/min/m prior to measurements. two swan-ganz catheters 'were inserted, one in the hepatic veins and one in pulmonary artery and the following measurements were determined: the hepatic vein free pressure (hvfp), the hepatic vein wedge pressure (hvwp), cvp, paop and co. the gradient of hvwp-hvfp represents liver perfusion pressures. by injecting contrast media at dose of iml/lokg with the balloon inflated to achieve sinusoidai image, the hepatic blood flow (hbf) was concluded by the time in seconds of media removal after balloon deflation. results: the co, cwp and cvp were comparable to all three groups. namely, for mof-hi, mof-ards and control groups the mean (+sd) value of co was . _+ . vs . _+ . (ns) and . _+ . respectively, of the paop was . +_ . vs +: (ns) and . + . respectively and of the cvp was .+. . vs . + . (ns) and . respectively. in contrast the two mof groups were different after the cut-offinclusion criteria ie the mean (+sd) value for bilirubin was . + . vs . + . ( < . ) and . _+ . respectively and lung injury score was . objectives: oxygen delivery (do ) and oxygen consumption (vo ) are increasingly monitored parameters in the icu. there still remain controversies about an oxygen supply dependency in critical illness particularly with respect to vo determination by either indirect calorimetry (vo m) or tick calculation (vo c). the purpose of this study was to investigate the changes in vo m and vo c following do increase. methods: the relatives of critically ill patients (mean age years, mean apache ii , mean mof-score ) gave their written informed consent to participate in this institutionally approved, prospective study. do was increased by fluid loading (hydroxyethylstarch %: mean volmne ml, mean duration of infusion min) and catecholamine support (dobutamine: mean dose , ~g/kg/min). changes in vo m and v c were recorded sinmltaneously before, during and following interventions. calorimetry was obtained with the metabolic monitor integrated in the ventilator (puritan bennett, carlsbad, ca adaptive endocrine response of organism to septic shock consisting in activation of the production of adrenal hormons, renin -angiotensin -aldosterone system (raas) and other hormonal systems has an influence over microvascular changes in these states and for development of multiple organ failure (mof). in patients with peritonitis of different origins ( nonsurvivors and survivors) were followed the changes in cortisol level and raas by radioimmunological methods and many variables for evaluation of respiratory, renal, hepatic function, coagulation etc. as a signs of mof. it was observed significant increase of the level of cortisol ( +_ , nmol/ i), aldosterone ( , • , nmol/i). by factorial statistical analysis we found significantly high correlations between hormonal changes and respiratory function (for example r=- , , p < , between cortisol and pao ; r = , , p < , between cortisol and d (a-v) ; olso renin -cao r=- , , p < , , renin d ~,vl o r = , , p < , ). such significant correlations was found and for raas with respiratory, renal function, byproducts of arachidonic acid thromboxan b and p fla, soluble fibrine degradation products etc. these correlations between the degree of endocrine changes and multiple organ failure in patients with septic shock produced by peritonitis suggest that their effects upon peripheral vascular resistance and constriction of the splanchnic, splenic, renal and other organ vasculatures are not always with physiologic expediency and there are perhaps the possibilities of therapeutic influence. intredu~on : dopexamlne has previously been shown to control hyperkalaemia ia patients with acdto renal failure (arf), however effects on the subsequent course of art are undomunente~ ob_iectlv~ : to evaluate clinical progress in patients with acute renal failure (arf) in an intensive care unit (icu) with regard to biochemical control, need for -and time to -dialysis, and outcome in patients receiving dopexamine. m~ods : consecutive patients meeting standard criteria for diagnosis of arf were included in the study. full cardiovas~dar, biechemical and intervention/outcome details were recorded. dopex.~min~ was infilsed at a dose of pg/kg/min in conjunction with a regimen of inotropir support and blood volume optimization. resn]~ : following the intzoduetion of dopc',~mine ilrinr vohlmes increased slightly over the next hrs fzom + ml/ hrs to + ml/ hrs (ns). data expres,uxl as mean + sem. three patients ( %) became polyuric with urine output > ml/hr within days and did not need dialysis. in the remaining patients the time to dialysis (to correct acid-base deficits or volume overload) was . + . days. serum potassium levels were well controlled. day or immediate pre-dialysis levels were . + . mmol/l compared with pre-lreatment . + . mmol/l overall mortality in this series was / ( %). duration of acute dialysis in survivors with renal recovery was . +_ . days. patients ( %) progressed into chronic renal failure and needed continuing renal replacement therapy. no adverse cardiovascular altects were seen at this low dopoxami~ dose although its competitive inhibition to adrenergic reuptake mechanisms meant that doses of pressor agents could often be reduced. : dopcx:~minr nsed in conjunction with inotropic support and blood volume oplimitntion, can safely postpone, or even avoid, the necessity for acute haemodialysis in icu patients. no evidence of tachyphylaxis to the effect on serum potassium levels was seen over the duration of the study. hen'era m., suarez g., dagn d., varela a., ramos j., garoia jm, aragdm c, jurado l, medina a. icu. hospital regional. malaga. spain. objective: to evaluate the haemodinamic tolerance to the veno-venous continuous hemefiltration (vvchf) system in patients with systemic inflammatory response sindrome (sirs), and the possible beneficial effect of this technique on the haemodinamics in these patients. material: patient admitted to the icu, with diagnosis of sirs and monitored with a pulmonary artery catheter at the beginning of wchf. we performed a complete haemodinamic study to all these patients (cardiac output, vascular resistanoss, ph and co in arterial and mixed venous blood samples, saturation of pulmonary mixed venous blood, do and vo calculations and temperature) and determined the respiratory mechanics (compliance and pao /fie relatinship) before starting the procedure, after minutes operating with the ultraflltrate branch closed (without filtered fluid production), afler and minutes of zero fluid balance bemofiltration and after minutes of filtration with negative balanos adjusted to the patients conditions. for the statistical analisis we have performed the anova test over the mentioned variables. results: we have not detected statisticaly significant differences of the analyzed variables before the beginning after operating the pun'@ for minutes without filtered fluid production and after minutes of zero fluid balance hf. only temperature shows a meaningful decrease in time. objectives: among many organs, playing the important role in pathogenesis of multiple organ failure, the particular place is taken by the intestine. ~ethods: the study was carried out in dogs !~n"~h pi was modelled by severe operative trauma (ot). the dcm was estimated by the indices values of work time (wt), contraction frequency (cf), mean amplitude of contractions (~ac) and motility index (mi) measured by method of tensography. "sl", created on the basis of sorbit and sodium lactate ( mosm/l), was injected in the dose of .o ml/ kg into v. cephalica antebrachii after hrs of ot. the results of the present study are the evidence of "sl" stimulative action on dcm and are experimental ground for "sl" using in complex therapy of pi in clinic. with splanchnic venous blood pc p.f. laterre p. goffette, j.p. fauville, a. poncelet, p. loneux, m.s. reynaert. intensive care unit, st. luc univ. hospital, brussels, belgium. determination of gastric intramucosal ph (phi) by gastric tonometry using the henderson-hasselback equation is expected to allow the detection of splanchnic ischemia in critically ill patients. because of bicarbonate concentration and acidbase balance influences on the calculation of phi, it has been proposed to use arterio-gastric pco,_ gradient [p(gast-a)co,] to assess splanchnic perfusion. htpothesis : pcoz in the gastric mucosa is in equilibrium with intraluminal co z and with co, in the blood leaving the stomach (mesenteric and portal blood). objective: mesure pco; and ph in portal vein blood and compare its value with pco and phi obtained simultaneously by gastric tonometry. material and method : in a patient ( y.), a fiberoptic catheter (baxter r) was positionned in the portal vein after transhepatic stent shunt repermeabilisation. hemodynamic parameters, do, (vigilance n baxter), gastric co and phi (tonometrics baxter) and portal blood gas were determined at regular intervals. results : sets of data were obtained and are expressed in mean + sd. gastric pco z was , + compared to , + . mmhg for portal pco . phi was . +._ , vs . +._o, for portal ph. no correlation was found for these parameters. p (gast-a) c was . + mm hg vs + . mm hg for p (portal-a) coz (no correlation). there was a good correlation between do e and p (portal-a) co z (r = , ) [figure] but no correlation with p (gast-a) c . obiectives: desaturation is a common finding during haemodialysis (hd). pulmonary oedema might be one cause for impaired gas exchange ( ). the aim of this study was to quantitate the amount of extravascular lung water (evlw) and gasexchange in chronic renal failure patients during and after a regular hemodialysis session. methods: chronic renal failure patients without symptoms or diagnosis of cardiac or respiratory disease were studied at the start (i), at the end (ii) and two hours after (iii) a regular bicarbonate hemodialysis session. the double-indicator dilution method, with indocyanine green and the stable isotope h as tracers, was used to measure evlw ( ). arterial bloodgases and endtidal co were registered. evlw data was compared to a group of renal healthy patients ( ). dcp n evlw, ml -pao , mmhg h~o +, nmol/l control group - -- l _+ "* -+ _+ crfgroup ii -+ ~ +- ns -+ "(" iii +- t _+ ns -+ t ** p < . dcp i from dcp , t p < . dcp li or i from dcp i, :~ p < . dcp ii from dcp i the evlw at the start of dialysis was larger in the crf group than in the control group. the evlw decreased significantly to a level not different from the control group in response to the reduction in weight after hd. pao~ was normal at the start of hd and showed a nun-signficant reduction after hd. paco ( . + . kpa) and etco ( . + . kpa) were unchanged while h o+ decreased and bicarbonate increased significantly. conclusions: the elevated level of evlw at the start of hd did not impair gasexchange. the decrease in evlw did not inhibit the decrease in pao . the reduction in h + followed by a fall in alveolar vantilation is the most plausible cause for the decrease in pao in bicarbonate dialysis. . prezant lung ; : - . . wallin j appl physio ; : - . a. dona~ d. battis& l col~ r danieli, d. achill~ l viglienz;~ c. giov-anaini, p. piaropao~ oblectives: to verify if intraoperative modifications of mtramucosal gastric ph (phi) below the normal lowest value . , can be predictive for important complications, as perforation, sepsis, mof or death. methocls: we have considered patients who andenvent major abdominal surgery. all patients received the same drugs in pre-anaesthasia, the same type of anaesthesia (balanced anaesthesia) and the same treatment with h -bloekers. after the induction of anaesthesia a gastric tonometer was positioned and a catheter was positioned in the radial artery. during the operation, every minutes, the following parameters were measured at the same time: phi, arterial ph (pha), blood lactate, mean arterial pressure. in follow up we considered death and complications happened during the hospital stay, in relation to intraoperative phi falls below . . results: among the patients, had a drop of phi below . during surgery. in three of them this fall was a single episode and happened within the first hour after the begiluting of the operation. after that phi rose to nomml values until the end of the operation these patients had a normal post-operative period, without complications, the other patients had a fall of phi during the demolitive manoeuvres. two paticots of them died. the first had a lowest phi= . and the second . . the first one ~zs operated on for hepatic istiecitoma, suffered a complete del'dseenco of the surgical wound on the th day after operation and died on the th day, the second one was operated on for a hepatic carcinoma had an intraoperative haemorrhage and died ~vo hours after the end of the operation. the other patients with a fall of phi had a lowest phi= . . . . . . . respectively.the first patient,operated onfor sigmoid carcinoma, underwent on a second operation for a transmural necrosis of the colic segment on the th day; the second one, operated for carcinoma of the right colon, had a cardiac ischelnia on the th pest-operative day and a dehiscence of the surgical wound on the th day: the third one, operated on for a sigmoid carcinoma, had melena in h post~ operative da b, and finally the fonrth patient, operated on for carcinoma of the tight colon, suffered a fistula of the surgical enteral anastomosis.all these patients were discharged alive from the hospital. the other patients, who had not reductions of phi ditring the operation, had a normal pest-operative period, without complications. conclusion: phi was able to predict the arising of some complications, probably due to intraoperative ischemic events. we can say that gastric tenometry, for its low invasivi.ty, can be included among the intraoperative monitoring in patients that tmdenvent on major abdominal surgery. (ttd),t"ea~rrerj.~ of hours duraticn. all l:atients nm.'-~ms_(~lly va~ ated in eantrol wcde ard_ la':'ad a a,~m--ganz catheter, with optic fibers for contirums mmsuremmt of svo mic studies were performed, c~e before the hegir~ of hd, c~e rain after the ~, ~ne at the middle, ~ne rain before lhe erd ard one rain after the erd of hd. paired t test ~as used far slatistical eval~ti~n. results: daring i~d there was a significant'reductton (p<o.~) of: c~tr~ venc~s eres~.re ( ve)emm to . ~ ~, ) ~arn'~w capil~ ~f~e pressure (i<~p) fr~n to ~mg hg, ) i~ from to . mmg hg. ~here was also a less pmnameed bat also-slatistics/ly significant r~ucticn (p<o. ) of: i) s~o~ from to patients undergoing surgical reconstruction of the aorta due to anenrysms of its abdominal part may develop transient and sometimes sustained episodes of dysoxia despite the conventional appeoreneas of being adequately resuscitated. indirect masurement of gastric mussel ph (phi) is being widely evaluated as a minimally invasive and sensitive means of assessing the adequaey of tissue oxygenation in these circumstances. the duration end degree of gastric intramucosal acidosis are related to the risk developing injured gastrointestinal tract end its putative consequences, i.e. translceation, cytokine release, organ dysfunction end failure, sepsis end death. measurement of phi is obtained indirectly by measuring pc in the lumen of the stomach with a silicone balloon tonometer (tonometrics, inc., worcester, ma, usa) and the bicarbonate concentration in arlz,,rial blood, end substituting these two values in the henderson-hasselbalch equation. objectives: to evaluate whether perioperative phi changes are predictive of complications end outcome end how they compare to standard haemodyuamic and oxygen trensport parameters. methods: patients ( males and female) urtderwent surgical replacement of abdominal aortic anonrysm with the aortic simple or bifurcated grail. patients were operated on eleetively, had an emergency surgery for raptured enentysm. haemodynamic, arterial ph and bicarbonate concentration measurements were taken before and after induction of anaesthesia, after cross-clamping and declamping of the aorta end at admission to itu. phi calculations ware done at the sime time except before induction, as tonometers were inserted after patient had been asleep. we used pulmonary utilizing a computer billing survey as well as hospital service transfer data from a month period ( / - / ), all obstetric patients that were transferred to the med/surg icu were identified, as well as their diagnoses and procedures. twenty-eight obstetric patients were transferred to the med/surg icu, compared to , deliveries occurring during that time period for a . % rate. the following procedural indications for icu transfer occured: insertions of endotracheal tubes, arterial catheterizations, temporary tracheostumy, and venous catheter. the following medical diagnoses were found: hypertensive/eclamptic episodes, hypotensive episodes, pulmonary embolism, mitral stenosis, and coagulation deficiency. there were four episodes of respiratory failure ( %). the historical rates of respiratory failure from the medical literature seen at a university hospital ore higher than those at our community hospital despite comparable icu transfer rates for critically ill ob patients. objectives: to evaluate the usefulness of several isss used in order to predict risk of death (rd). design: prospective data collection for months in a multidisciplinary -bed icu. methods: data from consecutive patients admitted to the icu from / / to / / were studied. all the necessary informations were stored in a computer using special software for every day computation of three isss (saps, saps ii, apache ii) and of the rd predicted by saps ii, mpm , mpm and odin. data from days of hospitalisation were used for comparative evaluation of isss and rd, while sensitivity and specificity in death prediction (cut off point of rd = %) were evaluated from data collected during the day of admission (saps ii, rpm , odin) or after hrs (mpm ). agreement between rd predictions was evaluated by bland and altman analysis. results:our results were the following: objectives: a) to create and validate software specially designed for the collection of demographic data and estimation of illness severity and predicted rd and b) to provide data necessary for the evaluation of the effectiveness and the efficiency of our icu. design: prospective data collection in a multidisciplinary -bed icu. methods: prospective data on specific physiological variables, selected demographic characteristics, comorbidity and the reason for icu admission were recorded every day for consecutive patients admitted to the icu from / / to / / . data were entered into a portable computer using specially designed software allowing the calculation of usual illness severity scoring systems (isss) and the corresponding predicted rd. results: we studied men and women, with a mean age of years. we conclude that, although observed mortality was higher than predicted rd, this difference was not statistically significant. the fact that the sd of predicted rd was too large, limits the usefulness of isss predictions for a comparative evaluation of different icus. objectives :the importance of objective evaluation of patients prognosis at their admission to an emergency department is clear. the aim of this study was to appreciate the prognosis of patients with the simplified acute physiology score ii (saps ii), and correlate this score to the prognosis and orientations of patients. methods : the score which is a reduced form of saps ii was calculated from clinical variables and laboratory items for patients. sensibili}y (se), specificity (sp) and accuracy (ac) were calculated to evaluate the performances of saps i . thresholds were calculated with the youden's test (se+sp- ). results : patients were admitted in the intensive care unit (icu)and patients in medical units; patients died. the saps ii was higher in patients which died than the survivors ( , + , vs. , + , , p< , ; respectively), the best threshold was , se was de %, sp was %, the ac was / . thus for patients admitted in icu than in medical unit ( , : : , vs. , + , , p< , ; respectively); the best threshold was , se was %, the sp was %, the ac was %. conclusions : these preliminary results suggest that saps ii can be used to determine the short term prognosis and the destination of patients seen in an emergency department. design: data was collected on all admissions over a six month period. all patients had a screening hiv elisa test. confirmatory ifa tests, western blot and flow cytometry were performed on hiv positive patients. the institutional ethics committee considered the major clinical impact of the study sufficient cause to waive the patient's right to informed consent, icu staff and patients were blinded to hiv results. following discharge patients were given the option of being advised of their hiv status. setting: the study was conducted in a bedded surgical icu at a tertiary care teaching hospital. patients, participants: all patients admitted during the period in question were included. interventions: "all patients were treated according to standard icu protocols. there were no interventions. results: most patients were admitted following trauma. there were no patients with aids, hiv positive and hiv negative patients. with respect to the latter two groups, the mean age and sex distribution was similar, there was a significant difference in organ failure ( % versus %, p < . ) and septic shock ( % versus %, p , : ) but no difference in icu/hosp[tal mortality or duration of icu/hospital stay. flow cytometry changes in hiv positive patients were consistent with the quiescent phase of hiv infection. conclusion: while morbidity is higher in hiv positive patients, there is no difference in mortality. hiv status should, therefore, not be an exclusion criterion for icu admission in this patient population. , n= ) and january-march (period , n= ) were studied. interventions: a resident micu team led by a trained intensivist took over the medical care from the primary physicians when the patients were admitted to the micu. the intensivist also vetted micu admissions and decided on micu discharge. in addition, there was a resident respiratory therapist to attend to vendlatory care during office hours. after office hours, the care of the micu was delegated to the on-call team on a rotational basis among the medical departments. results: the patients in the two groups were similar with respect to age, sex, race, source of admission and apache scores. the icu and hospital mortalities decreased from . % to . % (p=ns) and . % and . % (p=ns) respectively in period . the mean icu and hospital stay was also decreased from . __+ . to . + . days (p=ns) and . __+ to . • . days (p=ns) respectively. the improved micu length of stay for survivors in period was statistically significant ( . • . days vs . • . days = . ). there was no significant differences in the vse of peritoneal dialysis ( . % vs . %) and mechanical ventilation ( . % vs . %). however, utilisation of intra-arterial lines and pulmonary artery catheters increased from % in both to . % and . % respectively in period . conclusion: the duration of critical illness was reduced in period . hence, we believe that the closed |cu which was staffed by an intensivist and had the services of a respiratory therapist was beneficial for the care of the critically ill. the intensivist, was also more likely to utilise invasive monitoring. in the absence of liver transplantation, intensive care for patients with acute hepatic decompensation arising from alcoholic liver disease (ald) is indicated only for those who are likely to benefit from conventional means of organ support. we have attempted to elucidate potential risk factors and the efficacy of organ support in relation both to hospital outcome and icu costs so as to allow the earlier identification of relatively futile intensive care in this group of patients. methods: over a period of one year, ald patients ( males; females; median age years, median apache ii score ; hospital mortality %)with severe complications ( [ %] with bleeding oesophageal varices, [ %] with hepatorenel failure, [ %] with respiratory failure, [ %] with septic shock, and [ %] others) were studied in our liver icu. organ system failure, daily therapeutic interventions and icu costs were assessed using a patient management system (riyadh intensive care program). results: whilst survivors had a significantly lower admission apache ii score compared with non survivors (medians and , p< . ), or more organ systems in failure in the first hours of icu admission was associated with a % ( ) mortality. mortality was also related to child's grading and the numbers of organs supported. of the patients who received more than one form of organ support only one survived. organs supported mortality a (n= ) % none / ; % b (n= ) . % one / ; % c (n= ) . % two or more / ; % the icu costs for the patients were only s but s ( %, patient days) was utilised by the patients who died, giving an effective cost per survivor (ecps) of s . although the cost of treating the patients with or more organ systems in failure on the day of admission was s ( % of the budget) the ecps was s . conclusion patients with ald who have or more organ systems in failure early in their icu course have a poor prognosis and in the absence of liver transplantation, traditional strategies of organ support are ineffective. this begs the question whether such costly care is appropriate as although the ecps in this sub group is comparable with other patient groups with multiple organ failure, their outcome is considerably worse. objectives: to evaluate the economic impact to the healthcare sector of using dopexamine hydrochloride infusions to deliberately increase perioperative oxygen delivery in high-risk patients. methods: effectiveness data were obtained from a controlled clinical trial in which surgical patients were randomly assigned to either a control group (n = to receive best standard optimal fluid resuscitation perioperatively, or a protocol group (n = ) to receive, in addition, an infusion of dopexamine hydrochloride to increase the perioperative oxygen delivery index to greater than ml/min per square metre. resources consumed by patients during treatment were recorded prospectively and costs of resources at / prices were obtained retrospectively. cost-effectiveness ratios were estimated by dividing the total cost for each treatment group by the total number of patients in each group and by the clinical outcome of mortality days postoperatively. results: in the protocol group, there was a % reduction in mortality days postoperatively (p = . ), a significant reduction in the number of complications (p = . ) and a reduction in length of stay in the icu and surgical ward. the average cost per protocol patient to achieve a . % survival rate days postoperatively was s , , resulting in an average cost of s , per surviving protocol patient. the average cost of a control patient was s , to achieve a . % survival rate days postoperatively, resulting in an average cost of s , per surviving control patient. the use of dopexamine to deliberately increase oxygen delivery perioperatively generated a cost saving to the nhs of s , per patient together with a % reduction in mortality at days postoperatively. hence, the cost per surviving protocol patient was s . less than the cost of a surviving control patient. conclusion: the additional cost of dopexamine in protocol patients was offset by a lower incidence of complications and a shorter stay in the icu and on the surgical ward. hence, increasing oxygen delivery perioperatively in high-risk surgical patients saves both money and lives. objective: although king's college criteria are widely used, indication and timing for liver transplantation in acute liver failure is still far from certain. long-latency sensory evoked potentials -a proven measure of metabolic brain dysfunction (grimm et al. lancet ; : - ; madl et al. lancet ; : - ) -are markedly affected in patients with acute liver failure. serial sensory evoked potential recording should provide very useful information for the management of patients with acute liver failure. methods: recordings of standard bilateral sensory evoked potentials were performed in patients with acute liver failure. findings were focused on cortical n peak -a stable negative deflection occuring • ms after median nerve stimulation in healthy subjects, which can be recorded by skull electrodes over the sensory cortex. results: nine patients recovered spontaneously, patients were referred to emergency liver transplantation, and patients died. in all patients who recovered spontaneously, n peak was detectable between and ms. all patients who were referred to liver transplantation and of patients who died, developed a loss of a prior detectable n peak during the course of acute liver failure. objective: to determine high risk arid low risk patient groups in a medical intensive care unit regarding short term and long term outcome. methods: data on all admissions of the year were collected prospectively. according to their mode of admission patients were classified as admissions by the physician staffed ambulance service (as), admissions through the emergency department (ed)i referrals from non-intensive care wards (ni), and secondary referrals from other hospitals (oth). outcome was assessed in terms of in-unit mortality, in-hospital mortality, and long time mortality. patient groups were compared using the \ -test. life table analysis were per{ormed by kaplan-meier method comparing patient groups by log-rank test. the software spss for windows . . was used for statistical calculations. results: in-unit mortality: / patients ( . %) --oth . % > as . %> ni . % > ed . %; p = . . in-hospital mortality: / patients ( . %) --oth . % > ni . % > as . % > ed . %; p = , . mean survival time in days after discharge: as < ni < oth < ed ; p = . . conclusions: despite an excess in-unit mortality of secondary referrals from other hospitals the iongtime course of this special patient group is not different to others. solsuam, j, marrugat*, g, mirs, j, nolla, a, vazqu~z-sanchez, l alvamz, ~ioio s xndioina i~siw. ir~itate l(~icipal da l~sti~isn l~di~*, ~ospits dal objective: to study the influence of modifiable variables (complications derived from therapeutic activities) on the prognosis of ~atients admitted to the icu indapemently on thn severity of illnsss. patients am methods: between january asd ]lay data from , patients over years of aqe who retained in the icu for mare than hours ~ere pr~pectively regiatered. a cohort st~ly with follo~-~ nf patients durin~ ~eir stey in the hospital was deni~.el in all patients, reasons for a~issien, principal diagnosis sad severity of illn~s moasared by the saps scare vare recorded. fastens affecting patients' outcome that my be proventsd or modified included technical :omplisafioss, heapital-acqnired infections and in~pro~riate therapeutic decisions. a logistic regression model was used to assess the relative risk (l~} for in-heapital mortality adjusted for each variable. results: ic~ mortality ~s . % and in-hospitul mortality . %. patients who died showed a higher spas score then survivors ( , ~ i ,i). after adjusting hy severity of illness, co~;licetices that statistically increased the risk of in-hospital death were septic shock secomery to hoapitul-acqdired infection ( ~ . ; % el, . to . ), pmo~othor~x related to mocasnical ventilation (@ . ; % cl, . to . ) and delay in the insertion of a fln~-quidod catheter (ii~ . ; % ic, i.i to . ). col~lusien: registration of complicaticas derived from therapeutic activities is a valuable tool far quality central in the icu. g, ~i~ , j.l mle~ma, j, ~amqat*, j..~lla, a, vazquez-saltemz, f, alvamz , servioia de nndicina l~siu. i~stitutu ~icipal de ln~sti~acidn ~ i:a*, hospital dsl objective: to dstsr~ine the incidence of self-extebatien and its effect on ~ortality. patients and ]~etheds: betveen january and april , all i~tiente in whom selfextubatien w~s registered were inclnded in a prospective study. patients were divided into @nee who needed r~intabatinn within hoers and those who did not. in all patients, dsmoqraphie and ciinical data were recorded as well as icii mortality, in-hoapital mrtality and severity of illness according to saps score. eta were analyzed usi~ the cbj-square test for cathgorical verinbls, the analysis of varianc~ (anva) for aontinuc~ ~ria~les and a leqi tic regression anal~is to estimate the relative risk (iiii) for mortality as result of celt-nxtt~ation after adjusting for severity of illness. results: a total of intnmtsd patients amre stndied. self-extu~atien occurred in ( . %) patients and . % required reintuhot~pn. when a co,arise was made between patients who did not required reint@atinn and patien~.s who did, statistically significant differences in eqe ( . v_s . years, p = .~ ), ~verity of illness ( . ~ . spas score, p = . ), dia~isstia category ( s. % v_s . % of patients with res~iratury conditiono, p = , } and mean length of stay ( , ~ , days~ p = . ) were fo~m, a~ter ad~sti~ for severity, patients with self-ext@atinn who did not reqnired reintalatien showed a . iir for mortality ( % ci, .i to . ) as co~arod with patients in when self-ext@ation did mot occur. conclnsien: self-~extamtice that does not require reint@ation is associated with a isamr in-hospital natality probably dt~ to a prolonged period of weaming. patients' admissions to ices am often delayed doe to the shortage of beds available. @ile amaltieq icu admission, these patients are treated in observation nits of @e emergency services which bare ,either tile structure nor the trained ~reomenl that are available in leb~. objective: to daterdno the effect on the patient's proqusis of a delay in tile admission to the icu when criteria for icij admission are fulfilled. ~terials and methods: between jme am l?ece~ber all patients who fulfilled criteria to be almittod to the ic who for waste~r reason retained in tile observation unit for more than hours were included in a prospective stedy. in all patients, des~raphic end clinical dabs amre recorded as well as severity of illness aencrdi~j to saps score. a cesucontrol dasi~ was eend with a total ss~ln of , patients who suffered no delay is admission to icii over a period of years. data wen analyzed using the chl.-squ~re test (to aeons the association hetwenn in-patienty mortality end categorical vari~lns) and a maltipln logistic reqression model to sstimta odds ratio for) for in-hospital mortality as result of delay in icy admission as compared with early ad~issi| after adjusting for severity of illness end use of assisted mchenical ventilation. ~ &ults: a total of patients remained in the observation nit for more than hours with a del w in igd admission of . _+ . hoers. assisted mechanical ventilation was requited in % of patients and only monitericatien in %. itsse patients were cspared with ntients from the tet~l sample ratchod by age, sp~ score and rennoss of admission. in-hospital mortality for cases warn % as compared with . % for controls (p = s). after adjamtilg fen spas, age and mobamioal ventihtien, no statistically significant differences between both ~renpa were foam, altho~b there was a tendency towards a higher mortality amen@ patients with delay in icu admission (or = . ; % ci, , to , ). conclnnien: ~se findings suggest that prognosis of critically-ill patients is no worse as a result of admission to the loll being deln~d for borers. all data appropriate for the calculation of the apache ii score (aps) together wi'th other specific cardiac details relevant to these .patients were collected daily, verified and enter~ into a computer database. results: patients were studied. six patients died and five of thee underwent cardiac surgery. the mean aps was for survivors and t for non-survivors (p < . ). the mortality ratio was . and the major markers of mortality were apache ![ score, presence of chronic ill health, mean duration of ventiiation, mean length of icu stay and need for emergen~ surgery. sixteen percent ( ) of icu bed days were occupied by % of patients (non-sarvivors) which resulted in cancellation of cardiac sot#cat sessions in momhs. conclusions: this study concludes that apache t could be used as an audit tool in a cardiac surgical icu and demonstrates the severe compromis~don of cardiac surgical throughput by a few non-survivors, organ to determine the number of organ failure free days (offd) in a cohort of survivors and non-survivors with sepsis syndrome followed over a day period. ) to determine sample size requirements for clinical trials utilizing a increase in the number of organ failure free days as the primary outcome as opposed to mortality. methods: beginning december through to april , patients who met inclusion criteria of the "cardiopulmonary effects of ibuprofen in sepsis syndrome" and who did not have hiv/aids. brain death or moribund state were prospectively identified. presence or absence of failure of organ systems (pulmonary, cvs, renal, hepatic, gi, hematologic, & cns) was recorded daily until death or until days. a score of one was assigned to each organ system free of organ failure in patients still alive, ie, maximum daily off score= , maximum day off scorn= , sample size estimations were performed for variable detectable differences in off scores (delta). alpha was set at . (two-sided), with n/group = [(z a +z b ) o conclusions: a clinically relevant increase in off days may be detected with as small a sample size as to patients per group. this represents a significantly smaller sample size than needed to detect a change in mortality from % to % ( % relative risk reduction) where the n/group= . scoring patients in this manner prevents a lethal inte~entien from providing an improved organ failure score. in addition, an intervention that prolongs survival must also provide greater organ failure free days in order to be counted by this scoring method. survival as an outcome provides no information about the quality of that survival. off days provides a measurement of burden of illness. interventions which lessens this burden may be just as valuable as those that decrease mortality by providing a measure of the quality of survival and by decreasing costs of care. they may also prove to be an accurate surrogate marker of mortality. the advantage of this approach is that the event rote is much higher and sample size requirements are subsequently smaller. this would mean that clinical trials can be completed faster and at lower cost. outcomes such as mortality could then be assessed at a later date utilizing recta-analysis. we suggest that the use of off days is a valid outcome measure that may be utilized in clihieal trials of sepsis syndrome. the icu is perceived by many as being a stressful environment for both patients and staff. stress has been defined in three ways: a stimulus producing a particular response; the physiological and psychological response to a stimulus; an interaction butwom an individual and their environment. stress is currently thought to be a dynamic system of stimulus and. response which takes into account the individual's perception of the stimulus and their ability to respond effectively. stress may, therefore, be positive and allow personal development but an individual unable to respond effectively to a stimulus will experience negative effects or strain. critical illness is an intense stimulus to which the body needs to respond effectively. physiological responses are vital and most of intensive care involves supporting these. alternatively, blocking them, for instance with atom(date, increases mortality. psyehological responses are also vital but often poorly appreciated because of communication problems. many of the problems patients experience in an icu are evidence of psychological strain. this can be exhibited in various ways, for instance, anxiety, depression, passivity and confusion. dealing with critically ill patients is perceived as stressful. we recently studied occupational stress in our icu. most aspects of intensive care were not generally perceived as stressful indicating a self-selectien of icu staff. the most stressful aspects of icu work for nursing staff were the structure of the organization and career opportunities. medical and nursing staff had different stressors and different coping strategies. support for occupational stress, therefore, should focus on the individual and concentrate on information and communication. atmosphere, and especially at intensive care units, we face up to daily decision making. in most cases these are taken on the basis of personal opinion and the processing of a very limited amount of information. rising need to optimize the results of medical attendance becomes necessary to set structured system of d@cision making in which ethical basis have a sp@dial significance in view of next considerations: -we live into a pluralist society in which the importance of values is different. -most persons consider health as the first value only in the event of illness. -medical resources available are limited, whereas medical, attendance demand from population increases in a way many people consider it unlimited. in consequence, it becomes necessary to set up priorities in patients treatment. ehtical basis that rule decision making are essentially these ones: i. beneficence: to provide the patient that is being treated the highest profit. . non maleficence: it is our first duty to avoid hurting or damaging the patient."primum non nocere" . autonomy: in every particular medical attendance, the patient has ability to decide by himself. . justice: as equity: to provide the same treatment for those who have the same pathology, ignoring another factors such as age, sex or race. severe application of these principles can cause difficulty, which resolution requires a systematization of decision making. ( - ) . the lenght of stay between survivors and non survivors didn "t show statistical significance (p = . ). the mean aiii score when considering all admissions was , ( - ) . the initial score between survivors and non survivors showed ststistical difference ( . vs . ) respectively (p < . ). univariate logistic regresion analysis demostrated a % increment in death probability for every points augmentation in the aiii score with a sensitlbity of . % and specificity of . %, the roc curve showed that the best cut off point for death prediction was points with a sensitivity of . % and specificity of . %. if a patient is classified as high risk (> ) the bayesian analysis showed a . probability of death and for one class(fed as low risk (< ) a death probability < %. conclusions: the first day aiii score in this population showed to be a good discriminator between survivors and non survivors, and the risk of death augments as the aiii does. in this population an aiii score > points is asociated with a greater risk of death. using the aiii score in conjuntion with the clinical judgement will help clinicians reducing uncertainty in the every day decision making and better predict outcome, the results from this study should been taken with caution because the data were obtained from a small sample. objective: the quality of life has been considered a "uniquely personal perception" resulting from a mixture of health related factors and social circumstances [t. m. gill, jama , : ] . the aim of this study was to evaluate two measures of pqol in intensive care unit (icu) admitted patients. patients and methods: during icu stay and six-months after hospital discharge, co-operative icu admitted patients were directly interviewed about their pqol. we administered ftrstly the uniscale (pqolu) [sage et al crit. care med. , : - ] and then a step verbal scale (pqolv): best, good, fair, poor, worst. of the studied patients, at the first interview, were able to use both scales, but ( . %) understood only the verbal one. at the second interview, patients were not able to answer, used both scales and only pqolv. statistical analysis was performed using wilcoxon signed ranks, spearman rank correlation, student's t and chi square tests. results: of all cardiac surgery pts, pts ( . %) died in icu. they were males ( . %) and females ( . %). their mean age was (+ ) years and mean ef was . (+ . ). nineteen pts ( %) had low (< . ) preoperative ef. mortality was . % in the coronary artery bypass grafting (cabg) group (n= ) and . % in the valve replacement (vr) group (n= ). in the cabg +vr group, mortality was . % (n= ), and . % in the remaining pts (n= ). cardiogenic shock was the sole cause of death in pts ( %), septic shock in pts, whereas sepsis in combination with ards in pts, sepsis and stroke in two pts. in addition, pts died from cerebrovascular accidents, one from ards and one from pulmonary embolism. the pts who died in the icu had a significantly longer bypass and aortic cross clamp time and received more blood transfusions (p< . ) than a matched control group that survived to icu discharge. the duration of mechanical ventilation and length of icu stay were greater in the pts who died in the icu than in the control group. conclusions: . although cardiogenic shock is the main cause of death ( %)in cardiac surgery pts, sepsis and cerebrovascular accident are relatively frequent causes. . patients who died in the icu had longer bypass and aortic cross clamp time and received more transfusions, compared with the control group. . although renal or hepatic failure contributed to death in some pts, they were not the primary cause of death in any patient. objectives: evaluate the acute and follow-up outcome of patients (pts) treated with primary ptca (without prior thrombolysis) in acute myocardial infarction (ami) after and up to hours after onset of typical thoracic pain ("late" primary-ptca). methods and patients characteristics: from / to / consecutive pts with ami were treated by primary ptca in the wuppertal heart center pts ( , %) were admitted to our hospital > hours and < hours after symptom onset with ongoing chest pain and typical ecg-changes.mean age was years ( - ). pts were male, four female. % had an anterior wall myocardial infarction, % suffered an inferior/postero-lateral wall myocardial infarction.two pts were in cardiogenic shock at admission. singlevessel-disease was documented in . %, multi-vessel-disease in . %. average time of onset of pain to recanalisation was min ( - ). angiography revealed timi-flow in . % of the pts, timi-flow i in . %, timi-flow ii in . %. average follow-up (fu) period was months ( - months). timi iii lv-ef ~ -day major late re-late flow p.i.* aeute/fu mortality bleeds infarction mortality . % %/ % . % . % . % % early mortality occured in the two pts, who were in cardiogenic shock at admission no pt required emergency coronary artery bypass grafting.restenosis > % was seen in % of the pts. conclusions: "late" primary ptca achieves a favourable high recanalisation rate of about % (timi ill-flow) in our study group. additionally, there seems to be a trend for lv-ef improvement in follow-up. early high mortality is influenced by the patients admitted in cardiogenic shock. there might be a trend for increased major bleeding complications. objective: to assess the validity of saps ii (new simplified acute physiology score), comparing it with the previous version, (saps), in a sample of patients recruited by giviti, a network of icu's representative of the italian icu system methods: measures of calibration (goodness-of-fit statistics) and discrimination (receiver operating characteristics curve and area under the curve) were adopted in the whole sample and across subgroups differing in relevant prognostic characteristics. of the patients recruited during one month period, a total of patients were included in this study. for the purpose of the comparison of the two scores, patients with less than years, or having cardiac surgery or staying in the icu less than hours were excluded. vital status at icu discharge in the whole sample and at hospital discharge in half cases wher adopted as outcome measure. re$ ~: saps ii fits the data equally well compared to the older version (goodness-of-fit p= . and in the new and old versions, respectively) but its performance is somewhat better in terms of capability to distinguish patients who live from patients who die (areas under the curve . and . , respectively). furthermore, saps ii is better in terms of uniformity of fit across relevant subgroups, although substantial over prediction of mortality was observed in trauma patients and in patients admitted without organ failure to be intensively monitored. saps ii performed very wet] also in the subsample where hospital mortality was the dependent variable.satisfactory measures of calibration (goodness-of-fit p-- . ) and discrimination (receiver operating characteristics area= . ) were observed. c nr saps ii, a multipurpose scoring system developed in an international study, retains its validity in this independent sample of patients recruited in a large network of italian icus. although it has shown a good performance when adopted to predict icu and hospital mortality in the entire sample, further investigations are warranted. the observed over prediction of mortality in a few subgroups indeed call for a through assessment of the impact of confounders and biases on model performance when saps ii is adopted in samples that do not reflect the "average" icu patient. objectives: ) assess the effectiveness in a group of intensive care units by means of a quality performance index (qpi); ) assess the efficiency by means of a resource use index (rui); ) evaluate the performance of individual icus with respect to both indices (clinical and economical) while controlling for severity of illness. critical from ucis in catalonia patients alearic islands have been included in the study. inhospital mortality and weighted hospital lenght-of-stay (los) have been considered the outcome variables. severity of illness has been measured with the mpm ii at admission. in each icu, expected mortality has been obtained adding the probabilities of dying for its patients. expected los has been estimated adjusting a second order polynomial to the severity of illness. performance indices have been obtained by dividing the observed by the expected outcomes. re~ult~: the overall qpi was . and it ranged from . to . in the icus. the overall rui was and it ranged l~ont . to . . there was not a trade-offpattern between clinical performance and resource use. objectives: teaching hospitals often provide [cu care across a variety of specialized services. overall, this approach appears to result in the best risk adjusted survival rates, but at the highest cost (critical care medicine ; : - ): recently, there has been increasing focus on markers of overall hospital performance. however, in large teaching institutions, such markers may fail to detect intra-institntional variation at a large tertiary care medical center. methods: first intensive care unit (icu) day, acute physiology and chronic health evaluation iii (apache iii) and active therapeutic intervention scoring system (tiss) data were collected on random admissions to specialty icus with beds (range - ) between february i and december l, . post-operative solid organ transplant recipients were excluded. units included general medical, general surgical, and trauma, neurosurgery, cardio-thoracic surgery, and coronary care units. data were analyzed for risk adjusted outcomes: icu and hospital mortality and length ef stay (los); risk of requiring active cu treatment; and icu readmissinn using apache iii risk prediction models. results: the study icus cared for a diverse group of patients. mean apache iii scores ranged from . - . ; predicted risk of hospital death ranged from . - . %. standardized mortality ratios ranged from . to . with icus performing significantly better and performing worse than predicted (p< , ). los ratios and icu readmission rates ranged from . to . (ns) and . to . % respectively. patients predicted at low risk of requiring active icu treatment ranged from , to . % conclusions: there was wide variation in the mean level of patient severity between icus. after controlling for this severity, outcomes also varied widely. no clear pattern of overall institutional performance was evident. these data suggest that efforts to assess performance, improve quality, and maximize efficiency must be focused within individual units. programmatic evaluation of outcome allows for focused review of the processes of care contributing to good outcome (best practices) and where to focus ongoing quality improvement and cost reduction activities. background and method : we compared icu mortality in different age groups presenting with the same severity of disease. we assessed severity of illness by the physiological day -apache~ (physio-aa) score (thus excluding the age related points). for each of the following physio-a n score intervals ( - ; - ; - ; - ; > ) , we compared tcu mortality within age intervals (< ; - ; - ; - ; - ; > years - , - , - ) . in these groups mortality may be twice higher in the > years patients than in the _< years. mortality does not vary with age in low (physio a n = - ) and high (physio a n = > ) risk groups. in the low risk group, mortality is low in all the age intervals because of the begninity of illness. in the high risk group, extreme severity of disease probably blunts the impact of age and leads to high mortality rates in all age intervals. introduction: to access the actual social/clinical outcome of the patients who undenvent intensive care therapy oct) is rather difficult, quality of lilr is not easih.' defined and ohserver subjectivity is a prime factor in the evaluation. mortality ratio after discharge must be established and its causes understood. obieetives: the propose of this stud)-is to look into the mortality ratio that occurred on a series of patients that undorwent ict at our unit from of the ~iew point of severity of the original illness and the diagnostic groups. material and methods: during the period of one )-ear ( ), patients were treated at the unit, of them died, and ~ere not matched in our series because os incumpletc records. thirteen patients died in hospital after their reference to other departments, twelve patients were lost after discharge. thus. at the end. only patients were evaluated on the fu. the, were classified into the follov ng three groups: acute medical, elective surge d and acute and emergency postoperative. the patients were seen at , and months after discharge. the, were evaluated in accordance to their abili~, to being self supported in their daily life and capecity to fully return and hold to their pre~ ous jobs. apache scores were evaluated for each of the three groups and correlated to the icu dead, hospital dead, and mortality after hospital discharge, spss package was used for statistical analysis. remlts/conclasions: data shows that / patients died after discharge from the hospital, of ~itch nine died in the first three months. seventy-eight per cent of the patients were fully self supported in their daily life and % showed some kind of handicap. fosty-nine per cent of the patients wore on retirement either due to age or some form of chronic disease, when admilled to our unit. thirty-two peg cent had not been able to return to work, because the" were incapacitated on discharge. only % had return to their fully jobs but the period of the stu~, is not enough for all of them to be fully physically recovered. preliminmy statistical analysis shows us significant differences among groups. the aim of the present study is to compare the prognostic performance of five general severity indices ou coronary patienta and to find out if a proper ntatistical hundling of these indices could provide better results in these patients. methods: saps ii, mpm ii (mpm ii i mpmp ii ), apach ii end gaprik were evaluated o~ patients with acute myocardial infurction admitted to intensive care units from catulunye. calibration and discrimination were calculated for each index. calibration was calculated by th bosmer-lemeshow test. discrimination was evaluated by the area under the relative operating characteristic (roc)curve. if a model did not show a good performance it was customized using multiple logistic regression. finally, tworeduced models were developed, one fro~ the mpm series (mpm ii cor) and one from the group apache-saps (sapsiicor).their performances were again evaluated. results: discrimination was high enough for all models. neverthelees, oelibration of apache ii, saps ii and mpm was not satisfactory. thus,mpm ii , saps ii and gaprik were customized for coronary patients using the logits of both models, and obtaining good calibrations. mpm ii , and apache-saps were adapted and reduced to (mpm ii cor) end to variables (sapsiicor), respectively . both models showed better oalibrutions end discriminations than the original models. conolusion| models developed for multidisciplinary patients show a good discrimination when applied on aoronar i patients, but some needed customization in order to improve calibration. the number of variables of the principal model can be reduced (even to or variables) without loosing prognostic accuracy. objective: to compare the ability of two methods to predict outcome for intensive care patients. methods: we included consecutive intensive therapy unit (itu) admissions with an itu stay> hrs in a month prospective study (exclusion criteria: burn injury and age < yrs). data were couectsd applying the criteria described by the developers [ , ] . the definition of coma (mpm ii) was modified and the best assessment within in's, rather than the admission score, was used. statistical analysis included classification tables and receiver operaung characteristics (roc) curves to assess discriminative power, and lemeshaw-hosmer statistics and calibration curves to test accuracy of prediction. results~ average abe was yrs (ranse: - ) with a male:female ratio of . : . the actual hospital mortality was . %, mean predicted death rates were . % (mpmz ii) and . % (ap hi). non-survivors had siguitlcanfly higher predicted risks than survivors applying both methods (p< . l, t-test). the total correct classification rates (tccr) for apache iii were bett~r for all decision criteria applied (tccr, decision criterion %: apache ]/i . %, mpm ii . %). the area under the roc curve was . (ap iii) and . (mpm ii) confirming the better discrimination of apache ill. accuracy of risk prediction was similar for both models (ap nl ~ - , mpm b ;( - , lemeslmw-hosmer). showing some fluctuation, calibration curves lay close to the ideal line for predicted risks -< % with increasing deviation for higher risk groups (s. figure) . apache iii underestimated the risks of hospital death for almost all risk groups (curve above diagonal), whereas considerable overestimation for predicted risks > % ceenred with mpm~ii. objective: to assess the goodness-of-fit of the apache iii model for british itu patients. methods: we prospectively studied a cohort of adult patients consecutively admitted to a medical-surgical itu over a period of months. patients with burn injury, age < yrs and itu stay < hrs were excluded. using a eomputerlsed database, we routinely recorded hrs apache ill scores. predicted risks of hospital death were computed by critical audit ltd, london. accuracy of risk prediefion was assessed by hosmer-lemeshaw chi square (;( ) statistics and calibration curves [ ]. discrimination was tested employing classification tables and receiver operating characteristics curves (roc). restths: the mean age of the male and female patients was yrs (range: - yrs). of these patients, % were medical admissions, % were admired after emergency and % after elective surgery. the observed hospital mortality was . %, the overall mean predicted death rate was . %. mean predicted risks were siguifieanfiy greater for nonsurvivors ( . %o) than for survivors ( . %, p< . l, t-test). apache iii showed good calibration (z -~ , lemeshaw-hosmer). however, the calibration curve lay above the diagonal for almost all risk groups reflecting the tendency to underestimate actual mortality (s. figure) . the best total correct classification rate (tccr) was . % (decision criterion: %). the area under the roc curve was . % confirming the good discriminative ability of the model. objectives: the aim of this study is to point out the discrepancies between needs and actual treatment of less severely ili patients admitted in italian intensive cam units (icus) requiring only intensive monitoring, and verify the substantial likelihood of data comparing those collected from a national short term study with a regional long ternl use. ~: less severely ill patients ("observed patients") were only monitored; they did not require intubation, even if for a short period (less than houm) or major cardioeiranlatory supports, and were neurologically normal. epidemiologieal national data were obtained from giviti group (gruppo italiano valutazione interventi in terapia intensiva); this cohort study, collected patients, in two months in summer in all over italy. regional data were echieved in a three years entlection ( -i ) in lombardia' icus from archidia group (arehivio diagnostieo), including patients. mortality, severity score, diagnostic category and some typical intensive procedures were analysed and compared in both studies. patients' disgunstie categories were defined as surgical, medical and trauma, according to the main diagnosis and the presence/absence of surgical procedures. rr observed patients account for . % and % of all icu's patients respectively in national and regional data. very tow mortality rate was found in national data ( . %) and extremely low mortality in regional data ( . %). in both studies mortality, s.a.p.s. and length of stay were much lowor in "observed patients" than in general icu's population (mortality: . % and . %; .a.p.s. score: . and ; iength of stay: % and ). homologous distribution of patients in the two studies was noted for what concern their diagnostic category, aside from a slight prevalence of tranmatised patients in the giviti study. in the two groups the surgical patients were respectively % vs. %, medical patients were % vs. % and traumatised were % vs. %. % of "observed patients" in national study and % in the regional did not received any intensive procedure. only a minority of these patients availed haemodynamie eonu'ol with swan-ganz or renal haemofiltration. conclusions: these results underline that about one fourth patients admitted in italian icus benefit an oversized slructure i, relation to the real needs of their pathology. in hot more than % did non received any advanced treatment and mortality and s.a.p.s. score were substantially lower respect to general population. the results obtained from these two studies are similar, suggesting an uniform distribution of the case mix in italy, even if a different recruitment period and a different gengraphieal distribution were used. some discrepancies in the two studies were found in the diagnostic categories moreover regarding the tranmatised patients ( % vs. %); this can be explained from the seasonal (summer) characteristic of the national study. mutuality, yet very low, is different in the two groups, but these data do not allow any definite explanation. finally these epidemiologieal survey suggest need of further studies settling more strict criteria of admission in icu. this study aims to evaluate patients outcome, quality of care and effectivity of therapy in our intensive care unit. the main goal was to indentify factors that the most influence that outcome. during . the authors collected data of patients outcome and predictor variables. overall mortality rate was , %. the most common causes of death were infection. the diagnosis of sistemic inflammatory response syndrome (sirs) and multiple organ dysfunction syndrome (muds) significantly correlate with death ( %). average length of stay was . days ~. % patients died in the first ten hosiptal days and only % after days. age was directly correlated with death % of dead were older then sixty years. an analysis of physiological variables showed that serum levels of gl~cose ( %) and natrium ( %) were in optimal physiological values. serum proteins ( %) and haemoglobin ( %) levels were inversely related to death. multivariate showed that alveolo-arterio difference in content was the most informative of all mortality predictors (mean value , mmhg in % patients io>mrnhg). factor that most influence the patients outcome was infection (sepsis) and muds. use of predictive indicators of outcome in critically ill patients may help to assess treatment regimens and to compare patient groups. acute physiology and chronic health evaluation (apache if) score (crit. care had. ; : - ) and the sepsis score of elebute and stoner (br. h surg. ; : - ) have been used, objectives: to compare sepsis score and apache ii score in predicting outcome of critically ill patients. methods: overall survival during the past years for patients in our icu was calculated = % (prior probability). the outcome of patients who were admitted to our icu for > hours was observed. apache ii score on admission, patient predicted risk of death (apache ii risk) and the sepsis score on the first day of antibiotic course were prospectively recorded. discriminant function analysis of the scores in relation to outcome was performed. results: apache ii and sepsis scores in the survivors were significantly lower than in those who died ( . i . v~s . • . and . • v's . • . respectively p < . ). correct prediction of outcome by each score is shown in discussion and conclusions: although both scores have been previously evaluated in predicting outcome of icu patients, studies of the sepsis score were conducted in small numbers of patients or involved additional measurements not routinely available. this study demonstrates that the sepsis score alone or in combination with apache ii score is more effective than apache ii score in predicting outcome. objective to test the hypothesis that resuscitation titrated against gastric intramucosal ph (phi) improves survival in critically ill patients as suggested by gutierrez et al~. method emergency admissions to the intensive care unit were randomized into control and intervention groups. in the control group phi was measured at , and h while in the intervention group phi measurements were made hourly for h. both groups were managed according to the same guidelines to achieve the following targets: mean arterial pressure > mmhg, systolic arterial pressure > mmhg, urine output > . /ml/kg, haemoglobin > g/dl, blood glucose < mmol/ , arterial oxygen saturation > % and correction of uncompensated respiratory acidosis. if the phi was < . after achieving these targets, or after maximal therapy to achieve the targets, patients in the intervention group were given fluid to ensure an adequate cardiac preload and then dobutamine at then mcg/kg/h, titrated against phi. this additional therapy was continued until h after entry into the study. in each year patients were subdivided in two series with random selection, so that the st series contained abeat / and the nd / of the patients. the st series of all the years constituted the devdoping data set and the nd series the validation data set. with data of the st series ( patients), we created the predictive model, using stepwise logistic regression (bmdp, usa). each patient has been evaluated in die st, th, th and th day, calculating for each lime the apache ii score (for a total of records), independent variables were, besides time and apache ii of the time ( michaloudia g,, melissaki a., alexias g., gogafi c., kolotoura a., krimpeni g., pamouktaoglou f, filias n. objectives: to determine the medical staff's attitude towards various ethical issues methods : between january and february , anonymous questionnaires were sent to intensive care units, all over greece. results : questionnaires ( , %) were replied and returned back. of them , % were answered by male and , % by female. the doctors replied in the following rate : , % aged up to , % aged between and , % aged over . questions were answered and were divided into main topics, as following: . admission criteria: limited bed availability was the main cause for refusing admission in , % of icu's. , % evaluated each case's viability and only , % used some prognostic score system. , % of icu's accepted all cases and a significant percentage ( %) gave in to pressure coming from their colleagues ( , % female and , % male). . informing the patient/relatives: only , % was willing to tell the whole truth, while , % had given selective information.. in the case of iatrogenic incident, , % withheld it, because either they feared legal implications ( , %), or lost of trust ( , %). doctors are asking consent from the patient and/or his family, in order to include him/her in research protocols, in a rate of , %, while only , % found informed consent necessary for the proposed treatment procedure. . withdrawal of therapy/dnr orders/organ donation: , % were willing to withdraw complex treatment in patients with short life expectancy, except of administi'ating intravenous fluids, feeding and analgesics. in , % such a decis~n was unanimous, while the percentage of those carrying it out was , % ( , % female, , % male). in case of brain stem death , % ( , % female, , % male) withdrew any life support. , % would like therapy withdrawal to be legally established, while only , % would perform euthanasia, if there was substantial legal cover. for these cases, relatives' consent was considered to be necessary from a percentage of only , %. , % considered organ donation to be a necessary proposal, while , % refused to ask the patients' relatives for an organ donation, either because they didn't have the psychological strength for it ( , %), or because they doubted the procedures' objectivity ( , %). note: in greece, icu beds are less than % from the total number of hospital beds available. only a percentage of - % of these admissions comes from the same hospital, with a potentially direct evaluation. usually an icu doctor has to be informed through the telephone. finally, employment conditions in greece are such that any changes of the medical and nursing staffare limited. conclusions: the mathematical model we found has been validated also in the second series and the discrimination capability increases with time. using this model we can evaluate the probability of survive at every, time. its application at different times permits a better evaluation of haemodinamically instable patient trend. introduction: the feasibility to assess pulmonary capillary pressure (pcap) offers the opportunity to determine the longitudinal distribution of pulmonary vascular resistance (pvr). the purpose of this study was to measure pcap and to calculate pvr to determine whether relevant shifts in the distribution of pvr could be expected after routine cardiac surgery. methods: the study population consisted of consecutively admitted patients after cardiac surgery. surgical procedures included coronary artery bypass graft (cabg) (n= ) and mitral valve replacement (mvr) (n=t ). pcap was estimated by analysis of the pressure decay tracing after pulmonary artery occlusion. after estimation of pcap precapillary (ra) and postcapillary resistance (rv) was calculated. a complete set of hemodynamic variables was obtained at hour and at hours after operation. results: there were no significant hemodynamic changes during the first hours after surgery. the mvr group maintained pulmonary hypertension and higher levels of pcap. ra/rv, reflecting the longitudinal distribution of resistances, remained unchanged. however, rv predominated ra during the postoperative period in both groups. objectives: evaluation of the influence of long-term continuous i.v. administration of the ace-inhibitor enalaprilat on regulators of circulatory homeostasis. methods: t trauma and sepsis patients randomly received either . mg/h (group i, n= ) or . mg/h (group , n= ) of enalaprilat i.v. or saline solution (control, n= ) as placebo for days. plasma levels of endothelin- (et), atrial natriuretic peptide (anp), renin, vasopressin, angiotensin-ii, and catecholamines were measured before injection of enalaprilat (='baseline' values) and during the next days. results: except for et, plasma levels of all vasoactive substances exceeded normal range at baseline. angiotensin-ii significantly decreased during enalaprilat infusion ( . mg/h: from . • to . • pg/ml; . mg/h: . • to . • whereas it remained significantly elevated in the untreated control patients. vasopressin increased only in the control group (p< . ) and decreased after . mg/h of enalaprilat. et remained almostunchanged in group , whereas et increased significantly in the control patients (from . • to .t• on the th day). catecholamine plasma levels (epinephrine, norepinephrine) markedly increased in the control group (p< . ), but they did not change significantly throughout the study period in both enalaprilat groups. conclusions: continuous i.v. administration of the angiotensin-converting enzyme inhibitor enalaprilat beneficially influenced systemic and local vasoactive regulators of the circulation, which are normally increased in the critically ill. thus patients at risk of (micro-) circulatory abnormalities may profit from enalaprilat infusion. objectives: to determine the time taken for hemodynamic and gas exchange variables to a reach stady-state after a change from supine to trendelenburg position (trp). methods: we prospectively studied adult patients with severe sepsis or septic shock requiring hemodynamic monitoring. usual cardiorespiratory parameters were measured at baseline, min after the patient was placed in a trp and again min after the return to a supine position. a fiberoptic pulmonary artery catheter (svo~ oximetrix, abbott) allowing continuous svo monitoring wa~used. during the protocol we also continuously measured sao~ by pulse oximetry and vco~ and vo by monitoring partial concentration of o and co ir~ inspiratory and expiratory gases (deltatrac metabolic monitor, datex). therefore, we were able to monitor cardiac output variations by dividing vo~ with arteriovenous difference according to the fick equation (co-fick). results: no significant difference in hemodynamic status was observed min after the patients were placed in trp. despite the fact that no significant change was observed in co and vo~ estimated by thermodilution, co-fick had a tendency to dedrease continuously in trp and then to return to its initial value when patients regained supine position. respiratory gas analysis showed a small but persistent continuous increase in vco without a similar trend in vo values. conclusions: we conclude that no significant hemodynamic effect was detected in our patients after min in trp. evaluation of vo from respiratory gases analysis after a change in body's position should be interpreted with caution, since the patient may not yet have reached a stady-state after rain. since vo did not change, vco~ increase was probably due to position related changes in-pulmonary gas exchange and not to a change in patient's metabolic status. objectives: to determine whether changes in svo and/or other hemodynamic parameters during weaning trials could be used to predict successful weaning. methods: we prospectively studied adult patients with a history or clinical evidence of cardiovascular dysfunction, who were unable to tolerate spontaneous breathing (sb) for hours. for all these patients right heart catheterisation was considered necessary in order to detect hemodynamic alterations during weaning. a fiberoptic pulmonary artery catheter (svo ximetrix, abbott) allowing continuous svo monitoring was sod. hemodynamic status was evaluated ~t baseline and after one hour of spontaneous breathing through a t-piece. patients were assigned to one of two groups depending on whether they tolerated sb for hours. data were analysed by analysis of variance and unpaired student's t-test we also used multiple linear regression analysis to determine which hemodynamic variables were correlated with the magnitude of svo~ change and multiple discriminant analysis to determine if asy of the above variables were associated with toleration of sb for hours and/or successful weaning (s-w). (j physiol ; ." - ) . we tested the hypothesis that the ventilatory stimulation by dead space (vd) loading and % co inhalation is accompanied by a proportionate cardiovascular change. methods: six healthy subjects, mean age, year, performed three incremental exercise tests in a randomized order: ) inspiring air without vd (air control, ac); ) inspiring air with vd of ml (avd); ) inspiring % co ; % oxygen, balance nitrogen. the ventilatory responses were examined at matched heart rate (hr) equivalent to % peak hr. results: ventilation (vi) was significantly greater (p< . ) during the avd and co tests than during the ac test at the same work rates. end-tidal co (petco ) and estimated arterial co (paco ) were significantly greater (p< . ) at w and w. oxygen saturation was significantly lower (p< . ) during the avd test than during the ac and % co exerdse. at matched hrequivalent to % peak hr, vi was significantly greater (p< . ) during the avd and % co tests than during the ac exerdse ( l, l, and /). conclusion: we conclude that the increase in xri and petco due to vd loading and % co inhalation is not associated with an acceleration in hr. sup.ported by mrc (canada). objeetlve: the production of large amounts of oxygen radicals from the onset of ~en may be responsible, st least in part, for peroxidative damage to myocardial tissue. the aim of this study was to evaluate the time dependence of plasma tbars in patients with am] receiving thrombolytie therapy (tt). patients and m~hods: filiy eight patients admitted in icu ( men and women; mean age . - . years) rec~ving systemic tt for possible am] were ~died. all patients received recorabinant haman tissue-type plasminogen activator (r-tpa). the mean time fi'om the onset of symptoms and the be~nning of tt was . - . hours. peripheral veao~s blood samples were obtained fi'om each patient before and serially after tt ( , , and hours). tbars levels woe determined by using a spectrophotometrie technique. rq~r fusion was identified by the timing of ereatine phosphate kkmse (cpk) peak (< hours). table i list the variation of plasma eoneenlrations of tbars (mean -sd) in groups (a,b, and c) as a function of time from the beginning of tr. co,arisen oftbe time cuncentzatiens reveal a difference p<o. between group ami (a and b) versus group c. the between-groups (a-c) comparison showed significant differences (p<~). ) at , and hours fi-om de begin~g of'it. comparison ofthe , and hours eonocnlratiens did not reveafl any difference becween n~ (group b) and angor (group c). condmien: we have observed a maintenance of high level of tbars in reperfused patients enly. these results suggest that the increase of tbars levels may be due to phospholipid derangament of reperfused myocytes. objective: to detemline if tbars levels may be an early index reflecting peroxidative damage in ami patients. patients and methods: by using a spectrophotometric teclmiqtm, based on a modificatien oftbe buege and aust method, tbars levels ware determined in healthy subjects (group i) , patients with several risk factors of ischaemic cardiopathy (group if) and icu patients with possible aim ( were confirmed ami (group ma) and were angor (group iiib)). peripheral blood was obtained at the time of the icu admission in the group i . electrecardiographic data and eehocardiographic wall motion were used to identify ami location (anterior, inferoposterinr and indeterminate). statistical analysis was made with a standard statistical package (rsigma, horus hardware). , h , s, , h statistically significative increase of ' ix~e/ea.ee x~* tbars levels (p< . ) only in pstients with con/tuned ami (group ilia) . no differences were found between the rest of the groups. the figure shows the relationship between the tbars values and the time from the onset of the aim's symptoms. conclusion: we have found that in am/patients the tbars levels can be used as an early index reflecting peroxidative damage occurring to ischemie tissues. perioperative risk in patients with ischemic heart disease. the protective role of diltiazem. lg. hatziantoniou, p. tassiopoulos, c. fakiolas, ! g. foussas~ m. lycourinas perioperatlve morbidity and mortality are mainly of cardiac origin, particularly among elderly patients (pts) ~ith ischemic heart disease. we performed a randomized trial, in order to investigate the possible protective activity of diltiazem (d). methods: pts (aged zo• with a history of coronary insufficiency were subjected to major urological operations. they were randomized to two groups: group i ( pts) -p:ithout d and group ii ( pts) -d ~as administered . mg/kg iv bolus hours prior to anesthesia and . mg/kg/h upon the end of operation and for at least hours post-operatively. iv was substituted by oval administration of x mg starting the next day and for the rest of hospital stay. all pts underwent daily clinical, electrocardiographic and laboratory (ck-mb) control. results: are shown in the following interactions between the heart-lung unit and a cardiac assist device are the crucial issues for successful outcome of patients under mechanical circulatory support. several factors have been indicated and we can diffrentiate between anatomical and hemodynamic interactions. especially right heart failure and pulmonary hypertension have been proven to limit left ventricutar assist device (lvad) performance. in order to study the effects of right heart failure (rhf) and pulmonary hypertension (pht) on mechanical circulatory support, we designed an experimental study in dogs and combined in six groups left heart failure (lhf) and rhf and pht, respectively. in the control group we induced lhf with subsequent occlusions of lad and cx followed by reperfusion: in the next group we supported with an lvad during minutes starting minutes after cx occlusion (group if). in the next group we added right ventricular ischemia by occluding the rca simultaneously to the cx (group iii). these both groups we repeated only with pre-existing acute pht induced by the injection of o fm glass beads (groups vi and v). a last group was similar to group v (lhf and rhf and pht), but instead of a lvad, we used bvad support. in i and v no animal survived the second perfusion period ( hours). in ii and iii (no pht), all dogs survived in stable conditions. in iv (lvf, pht), % survived, the remainder died of incomplete recovery. in vi with bvad, only % survived. in iii and v, during occlusion of the rca, the right ventricle stopped contracting and right atrial pressure and mean pulmonary pressure equalized. this lead to a significant drop in inflow on the left heart side, which still provided sufficient lvad performance in case of absent pht (iii) and lead to death due to "low lvad output" syndrome in v. this "low lvad output" snydrome could be partly overcome by bvad support. we conclude that heart-lung interactions play a major role in lvad performance. by optimizing the perioperative management, they all can be overcome, except the occurrence of alveolar leakage syndrome. obiectives : we propose a new approach of transmural pulmtmary artery occlusion pressure (paoptm), in presence ef peep, from the folluwing hypothesis : if respiratory swings of paop are compared to those of alveolar pressure (apalv = plateau pressure -total peep), an index of transmission of airway pressures to pulmonary vessels is obtained (i t = apaop/apalv). the value of the product of it by peep can be substracted from end-expiratery paop (paopee) to obtain a calculated paoptm (paoptrnc). thus paoftmc = paopee -(apaop/apalv x peep). methods : we tested this hypothesis in patients by comparing paopee, paoptmc, and paopnadir obtained within the first seconds after disconnection from the ventilator, value of reference of paoptm in absence of intrinsic peep (peepi). at zeep, peepi was absent in patients (group a) but present in others (group b). patients were studied under the peep level chosen by the attending physician-(gr a : +_ ; gr b : _+ cmh ). results : l. gr a : paopee ( _+ mmhg) differed (p < - ) from paopnadir ( • mmhg) and paoptmc ( _+ mrahg). gr b : paopee, paopnadir, paoptmc differed between themselves ( " - , + , + mmhg respectively). . good correlatkm (r - (i. ) and agreement between paopnadir and paoptm were found in gr a, while there was no agreement in gr b (bland and altman analysis). . lung compliance (v t/bpah,) correlated well with i t in both groups (r - . ), suggesting that our hypt)thesis was strtmg even in patients with peepi. conclusions : paoptm under peep ventilation can be obtained, even in patients with peepi, from parameters easily measured at the bedside. introduction: cardiopulmonary bypass (cpb) may cause ischemia in several organ systems like the heart, brain and kidneys. reactive oxygen species (ros) are formed by subsequent reperfusion and stimulation of neutrophils by cpb. ros are harmful to biological systems e.g. cellular membranes, enzymes~ dna. many natural antioxidant systems protect against the effect of ros. in patients undergoing cabg we evaluated the production of ros by total plasma antioxidant status (tas) and lipid peroxidation measured by lipofuscin flip). methods: tas (randox, uk) and concentrations ofllp (tsuchida et al.) were measured in consecutive patients undergoing cabg. all the patients had a normal serum creatinine clearance (> ml/min). serum samples were obtained a) before operation, b) after removal of the aortic crossclamp, c) at admission to the icu, d) hours after operation, e) hours after operation. results: tas was significantly decreased after removal of the aortic crosselamp ( b, c and d lower than a), followed by a subsequent significant increase of lip ( c and d higher than b). the levels of tas and lip returned to baseline hours after operation. methods: patients with preoperative lvef< % undergoing coronary artery bypass grafting were studied. after surgery, a f femoral artery catheter was inserted and connoted to a fiberoptic monitoring system (cold z- t; pulsion medizintechnik, germany); this allows, with a double-indicator dilution technique, the calculation of cardiac index (ci,l/min/m ), intrathoracic bood volume (itbv,ml/m ), pulmonary blood volume (pbv,ml/m ) and extravascular lung water (evlw,ml/kg). with a f pulmonary artery catheter, wedge (w,nunhg) and central venous pressure (cvp,mmhg) were measured, while extraction ratio (o exr,%) and oxygen delivery (do ,ml/min/m ) was calculed. peak inspiratory pressure (pawp,cmh ) and mean airway pressure (mawp,cmh ) were measured with a varflex flow transducer (bicore,sensormedics,us). the patients were studied after minutes (to) of volume controlled standard ratio ventilation (vc), and after minutes (ti) of stabilisation period of pcirv ( % inspiratory time, % pause). vt,ve and total peep were held constant in every mode of ventilation. +_ . " *'p < , versus to conclusions: these data show that pcirv : is a safe ventilatory support also in cardiac patients with impaired ventricular function, and monitoring of itbv is more reliable to measure and optimise circulatory volume status, than w and cvp. c.ledeki-,g.rldisis,s.karotzai,c.micheilidis,m.agioutantb, g.beltapaulos. objeolivee:to evaluate the influence of lvswl on the well known correlation of sr and svo . paw eight patients ( melee end females) were included in this study regerdlen of the icu ~h"niseion couse. all paints were ,'~theta~ with e fiboroptir pulmonary artery catheter connected with an oxymetfir (r)~ so /co abbot computer.for any pulmonary artery catheter insertion, two pain= of sr and svo were obtained, one dudng inserlion and one during taking the catheter out. for any pair obtained, we eleo collected the deta concemig with the pedient's hemodynamir and oxygenation end we calculated the lvswi. were significantly (p<o. ) higher in group i. conclusion: breathing room air, the less hypoxemic patients had a rather satidactory do and tissue oxygenation (pro ) because they had properly adapted their ci. the absence of this mechanism (right heart impairement ?) in the hypoxemic patients, in spite of higher blood ne and e, was responsible for the poor do and pro . objectives: acute massive pulmonary embolism (pe) increases pulmonary artery pressure (pap) and dght ventdcular aftedoad, which may lead to dght ventdcular failure. inhaled nitdc oxide (no) selectively dilates pulmonary vessels. thus, inhaled no may be of potential therapeutic value in the management of the acute phase of pe. methods: following institutional approval, ten piglets (body weight + kg) were anaesthetised (midazolam/piritramide) and ventilated using a modified servo ventilator (siemens elema, sweden; fio . ). the following variables were obtained: systolic pap (spap), mean pap (mpap), diastolic pap (dpap), mean artedal pressure (map), central venous pressure (cvp), pulmonary capillary wedge pressure (pcwp), cardiac output (co), and artedal (pao ) and mixed venous (pvo ) oxygen saturation. pulmonary vascular resistance (pvr) was calculated. to induce pe, pm microspheres (sephadex g coarse, pharmacia biotech, freiburg, germany) were injected in an amount sufficient to increase mpap to mmhg initially. rain after embolisation when haemodynamics were in a steady state (control ), inhaled no was administered. further measurements were taken min after ppm no (no ), min after ppm no (no ), and min after discontinuation of no administration (control ). the administration of inhaled no resulted in a significant decrease in spap, mpap, and pvr. the cessation of no inhalation led to a complete return to pretreatment control values (table) . co, map, cvp, pcwp, pao?, and pv~ remained unchan no administration. objectivss:evsluate the yield of recombinant tissue plasminogen activater(rt-pa, actiiyse ~ oehringer ingelheim) as a thrombolytic agent ie pulmonary embolism ie .kr~auma patients. methods: in five patients with diagnosed pulmonary embolism(blood gases, chest x-ray, echocardiography, perlesion lung scans) were given rag of actij.yse as ~ hrs infusion, followed by heparin~single j. ihjaction snd iefusion ie doses - j./kg/day).the effectiveness of rt-pg thrembo].ytic sctier~ was svaluated im . . hrs(blood gases) amd on the third dayafter t~eat-,ment(~chocardiography and lung scan). results: three hrs after actilyse was given we observed significant clinical imprevemeet,confirmed by elevation of pao and sao in dlood.echocardiegr~m on the third day showed regression of pulmonary hypertension and lung scans showed % improvement in total lung perfusien. except slight bleeding from the site of injection nc~ more thromboiytic complicatioos were observed. conclusiens: actilyse used in five hrauma patients with pulmonary embol.ism was a very effsctive and safe thrombolytic agerlt, inducing rapid and evident clinical improvement. intermittent positive pressure ventilation ( ppv) by increasing pleural pressure, decreases the pressure gradients for systemic venous return and left ventricular (lv) ejection. we have previously shown that when inspiration is synchronized with systole using synchfjv in patients with severe cardiomyopathy, that cardiac output (co) was increased relative to both ippv and non-synchronized hfjv ( ). however, it is not known if similar effects could be realized in ventilatordependent patients with lesser degrees of lv dysfunction and fluid overload. we thus compared synci-ifjv to ippv in stable patients following coronary artery bypas grafting. methods: normothermic who were stable (< % variance/h.) were studied following admission to the sicu. heart rate (hr), mean arterial (pa), pulmonary artery occlusion pressure(ppao), co by continuous thermodilutiun (vigilance, baxter, usa), mixed venous saturation (svoz) and arterial blood gases (abg) were measured after rain. of each step. ippv was simv adjusted for a rate, tidal volume and fit to insure both normal abg and a peak airway pressure < cm h,o. syncfifjv was delivered by a hfjv ventilator (acutronic) during systole with ventilator parameters adjusted to optimize abg. protocol: patients received three ippv runs (ippvi. , ) with synchfjv runs interposed (hfjvz ). statistics: anova for repeat measures and paired t-test were used to compareruns and demonstrate variability. results:no significant difference in any of the measured hemodynamic variables were seen among the ippv and synchfjv runs (table) . post hoc separation of patients by preoperative ejection fraction (ef; ef > % ; n= and < %; n= ) did not alter these results. back~ound: in man, vascular endothelium-bound ace is expressed in concentrations greater than x that in serum and is believed to be the site of synthesis of circulating angioteusin il it is unclear whether ace inlubitors interact similarly with ace in different vascular beds. coronary vessels possess all the components of the renin-angiotensin system, including ace which may be involved in normalcardiac homeostasis, as well as in the pathogenesis of various cardiomyopathies. obiecfive: to develop a method for assaying the interaction of ace inkibitors with coronary endothelium-bunnd ace in man, methods: ace a~aty was meas~ed in five patients undergoing cabg surgery, from the transeuronary hydrolysis of the synthetic ace substrate h-bpap. trace mnou~ of ~fi-bpap ( gci) were injec~d as a bolus in the root of the aorta and simultaneously blood was withdrawn from a coronary sinus catheter into a syringe containing protease inhibitors which prevented the convession of umeaet~ ai-i-bpap by blood ace. the sample was later centrifuged to separate cells from plasma and the radioactivities due to formed product (~rl-bphe) and total sh were astimated in a [b-counter. two additional such determinations of ace activity were perform~ the second in the presence of . pg/kg e (coinjected with ~-i-bpap) and the third ten minutes after e. results: all subjects were hemodynamically stable throughout the course of the there were no noticeable hemodynamic effects of e. control transcorunary metabolism of~-bpap averaged g -a: %, in agreement with previously reported data. in the presence of e, % metabolism of ~-bpap was reduced to • reflecting a • inhibition of normal ace activity. ten minutes after e, ~ri-bfap metabolism had partially recovered to :l: %, representing a -a: % inhibition of control ace activity. from this data, the dissociation constant of e for coronary ace in vivo was estimated as . x " sec "l. conclusions: we have demonstrated the feasibility of repeated, reproducible measures of coronary endothelium-bound ace activity and of its inhibition by e. this procedure is safe and can be used to study the role of ace in normal cardiac function and in card pathologies. objectives. primary pulmonary hypertension (pph) is a progressive fatal disease of unlmown origin, with median life expectancy of less than three years after diagnosis. the responsiveness of pulmonary hypertension to a variety of vasodilator agents led to the speculation that, concomitant with vascular renmdelling processes, persistent vasoconstriction is an important feature of the disease. long term use of ca-channel blockers and intravenous pgiz may improve mortality in certain populations of pph patients, but both of these treatments lack selectivity for tire lung vasculature. the aim of this study was to test the efficacy of aerosolised prostacyclin and its stable analogue, [loprost for selective pulmonary vasodilatation in pph. methods: in three patients with pph, we compared aerosolisation of prostaglandin iz (pgi ) and iloprost to a battery of vasodilatory agents (diltiazem, nifedipin, inhaled nitric oxide, intravenous pgiz). results: nebulisation of pgi and iloprost tumed out to be most favourable for achieving effective and selective pulmonary vasodilatation. pulmonary vascular resistance decreased from + to -+ dyn*s*cm (p< . ) and pulmonary artery pressure from . + . to + . mmhg (p < . ), cardiac output increased from . + . to . _+ . i/rain (p < . ), mixed venous oxygen saturation from . _+ . to . + . % (p < . ) and arterial oxygen saturation from . + . to . _+ . % (mean _+ sem of trials in patients). -month iloprost nebulisation in one patient ( gg/day in six aerosol doses) demonstrated sustained efficacy of the vasodilator r~men. conclusion: aerosolation of pgi or its stable analogue may offer as new strategy for selective pulmonary vasodilatation in pph. endothelial adhesion molecules may play an important role in the pathogenesis of myocardial cell damage, and may contribute to the progression of heart failure. we measured the plasma soluble intercellular adhesion molecule- (sicam- ), vascular cell adhesion molecule- (svcam- ), and e-selecfin (selam- ) levels in patients with acute myocardial infarction admitted within hours after onset. peripheral venous plasma-samples were collected at the time of admission, , , , , and hours after onset. plasma soluble adhesion molecule concentrations were determined by elisa. patients were divided into groups as follows: group ; killip's class (k) and without thrombolytie therapy, group ; k and with thrombolytic therapy and group ; k and . both plasma sicam- and svcam- concentrations in group and were elevated rapidly and significantly and maintained at a high level during the first days. plasma selam- level did not change in any of the groups. these results suggest that the adhesion molecules icam- and vcam- may play a role in the pathogenesis of myocardial reperfusion injury and may indicate its severity in myocardial infarction. objectives: nitric oxide (no) is known to exert cytotoxic and negative inotropic effects on cardiomyocytes. no synthase activity has been reported to be increased in infarcted area in animal model of myocardial infarction. these findings suggest that no may be an important regulator for myocardial damage and cardiac function after myocardial infarction. we measured plasma no no -(nox) levels and estimated serial changes in acute phase of myocardial infarction. methods: subjects were patients admitted within hours after onset. venous blood samples were collected at -hour intervals on the first day, -bour intervals on the nd day and -hour intervals on the rd day and th days after onset. plasma nox concentrations were determined by griess method. results: the time course of the plasma nox levels (mea~+sem) displayed a tendency to gradually increase and to make a biphasic pattern with two peaks about hours and - days after onset (basal level; . _+ . , first peak; . !-_ . , second peak; . + . ram/l). plasma nox concentration was not influenced by the thrombolytic therapy, and nox values at the time of hours after onset were significantly correlated with maximal plasma creatine kinase level (r= . , p< . ). the levels of plasma nox in the early stage of myocardial infarction (from admission to the th day after onset) did not correlate significantly with the hemodynamic parameters (left ventricular ejection fraction, pulmonary capillary wedge pressure). conclusion: the early and late increase in no production after myocardial infarction may be implicated in the deterioration of myocardial contractility and induction of myocardial damage in the early phase of myocardial infarction. range - ) fullfilling the high risk criteria of shoemaker (colectomy , gastrectomy , pancreaticoduodenectomy , others ). patients were admitted to the icu preoperatively. arterial and pulmonary artery catheters were inserted and hemodynamics and oxygen transport were measured at admission and after stabilization to predetermined physiological end points. patients were considered stable when ci > . l/min/m , pcwp > mmhg, hb > g/l, sat >. . objectives: evaluate the acute effects of , mg ipratropium bromide and , mg fenoterol (ibf) inhaled dose on pulmonary function in nonsmocers (nb:m) and smocers (s) with sever (new york heart association class ii-iii), stabile congestive heart failure(chf) and healthy subjects. methods: pulmonary function tests were performed < h postprandial. the tests consisted el arterial blood gas aspiration followed by routine spirometry and pletismography, and single-breath gas analysis. after performance of these maneuvers, the patients was administred puffs-ipratropium bromide ( , rag) and fenoterol ( , rag). for , h, spirometry was repeated. results: in resting, pulmonary abnormalities observer in the s group were more severe then abnormalities observere in the nsm group. after treatment with ibf the improvement in pulmonary function was even more marked in patients who had smoked. the mean changes by forced expiratory volume in second(eevt) was , % (p< , t) improvement and , % (p< ,ob), forced expiratory flow betwen % and % of the forced vital capacity (fef . ) was , % (p< , ) and , % (p< , ) and maxamal voluntary ventilation (mw) was , % (p< , ) and , % (p<o, ) improvement. the mean changes in normal subjects were mild (fev increased by , %,fef - by , % and mvv by , %). we observed no adverse heamodinamie conseevence and no arrthytmogenicity. conclusion." in patients with chf the airway response to ibf is highly significant. further study is needed to determine whether therapy with ibf will load to improvement quality of life in patients with chf with dearly documented venti/atory defects. compared with unilateral ima grafts, usage of bilateral ima grafts in cabg patients causes greater thoracic trauma and further reduces blood supply to the sternum and intercostal muscles. these effects may be associated with increased postoperative respiratory complications obiectives: to study the effects of bilateral ima grafts on postoperative respiratory morbidity in cabg patients. methods: two groups of patients undergoing cabg were prospectively studied: group (n= ) received both imas as grafts and group (n= ) received only the left ima. the two groups were matched for age, smoking habits, total number of grafts and preoperative ejection fraction. pao /fio ratio was measured in all patients in the icu, at , , minutes on mechanical ventilation (mv), at , , minutes after extubation (ex) and on postoperative day (pod) . in addition, radiografic scores of atelectasis and pleural effusion were assessed postoperatively. results: group had significantly longer bypass ( _+ vs + . p< , ) and aortic cross clamp time ( +- vs + , p= , ). pao /fi ratio was significantly higher in group only at minutes after extubation (table) . there was no difference in the incidence or severity of atelectasis or pleural effusion between the two groups. the duration of mv was longer in group ( +_ vs _+ , p= , ), but the length of icu stay and hospitalization were similar. there was one case of pneumothorax in group and one case of pulmonary infection in each group. after extubation m[n min min min* rain min pod ' _+ _+ + -+ - -+ _+ _+ _+ _+ -+ _+ _+ -+ mean_+sd, *p=o, o conclusions: compared with unilateral ima grafts, the usage of bilateral ima grafts in cabg patients is not associated with increased postoperative respiratory morbidity. the diagnosis of rv ischaemia is difficult in the critical care setting. the purpose of this study was to determine the ability of rv endomyocardial and interstitial ph electrodes to detect rv ischaemia in an animal model of rv infarction produced by fight coronary artery ligation. we hypothesized that changes in transmural and interstitial ph would accompany the induced tissue hypoperfusion. rv interstitial (phint) and transmural endomyocardial ph (phendo) were measured in adult anaesthetized pigs before and serially after coronary ligation. phendo and phint fell progressively and significantly following coronary occlusion. this was accompanied by ischaemic ekg changes. the absolute and relative rates of change were greater for phendo compared to phint, particularly after minutes of ischaemia, ph was unchanged in control experiments when the electrode was placed within the fight atrial or ventricular chambers, as well as when coronary ligation was not performed. these data suggest that rv myocardial ph measurements reflect coronary ligation induced rv ischaemia, ph recorded from an electrode placed against the rv endomyocardial wall via a central vein was as useful as an interstitial measurement that required a thoracotomy. this newly described technique may be helpful in clinical settings where differentiation between ischaemic and nonisehaemic causes of rv dysfunction is important. centre. depts of cardiac surgery and anesthesiology, university of bari, italy. lung injury secondary to cardiopulmonary bypass (cpb) is well recognized. nevertheless, mechanical respiratory changes after cpb have been poorly investigated. aim of the study was to evaluate the effects of cpb on respiratory mechanics. elastance of the lung (est l), chest wall (est cw), and total respiratory system (est rs) were measured in patients without previous pulmonary disease undergoing elective cardiac surgery. there were males and females; no pleurotomy was done. cpb was carried out with membrane oxygenator. mean cpb and cross clamping times were _. and • min. flow (pneumothacograph), airway opening and esophageal pressures (pressure transducers and esophageal balloon) were measured on patients sedated and paralysed. measurements were obtained before sternotomy, at the end of cpb after chest closure, four and seven hours later. est rs, est l and est cw, were measured by occluding the airways and the end of a tidal breath. before end cpb- h after h after stemotomy closed chest cpb cpb estrs (cmh /l) . + . . - . " . _+ . * . - . * est cw " . _+ . . • . + . . -+ . est l " . -- . . - . " . -_ . " . _+ . " x + sd. * p < . : anova vs "before sternotomy". our data show that cpb induces increase in est l, whereas est cw remains unchanged despite sternotomy. impairment in est l after cpb evolves within the first hours and stabilizes hours later. during the clinical course of human imunodeficiency virus infection (hiv), patients (lots) can develop congestive and dilated cardiomyopathy syndrome (dcm). the aim of our study was to analyze the prevalence of dcm among an hiv population, its clinical and echocardiographic changes under a long term follow-up and therapy with an ace-inhibitor agent (captopril). we prospectively studied pts, % ( / ) developed dcm during the follow-up study. among this group % ( / pts) were in class i and ii and % ( / pts) in class iii and iv of the nyha classification. we divided this population in a acei+ ( pts) and acei-( pts), according to the administration of captopril. we analyzed the following parameters: age, gender, race, ivda, type of hiv, cdc classification, number of t and t type cell population and its t /t ratio, therapeutic with acei, type and number of opportunist infections, mycobacteriosis and neoplasm's. we analyzed several echocardiographic parameters, which included the initial (i), final (f) and variation (a) of the lv internal diastolic (lvdd/mm) and systolic (lvsdimm) diameters, lv % of fractional shortening (lv%fs/%), ivs and posterior wall thickness and lv mass (lvm/g). the two groups differed significantly in the following parameters: left ventricular functional indices of patients (pts) with iscjhemic dilated cardiomyopathy (idcm) have a critical value in terms of clinical prognosis of this disease. three-dimensional echocardiography ( -de) is a recently developed method that gives a better evaluation of lv morphology and function. the purpose of our prospective study was to assess the clinical applicability of this new -de method in a population with ischemic dcm diagnosis and calculate its lv indices of global and regional function. we studied a group of idcm pts, mean age _+ yrs, % male gender, using a combined -de tee approach. all pts were in class ill/iv of the nyha classification. first, ekg gated images were acquired through a mechanical pullback of the tee probe, and each set of data was transferred to a conventional ibm-pc system using a dedicated -de software. computer processing and analysis of the tee images led to a -de reconstruction matrix and off-line calculation of several lv global and regional indices. in all idcm lots the lv cavity was clearly reconstructed and end-systole and diastole in several orthogonat projections, out in multiple planes and its function quantitated using -de derived indices. mean values of -de lvesv= -+ ml, lvedv= _+ ml, lvstv= _+ ml and lvef= -+ % were obtained. for all these -de parameters, good correlations were observed with -de lv measurements obtained through biplane tee analysis of the lv cavity (r>. ; p<. ) as well as regional analysis of sequential -de cut planes. conclusion: in our group of patients with the diagnosis of ischemic dilated cardiomyopathy, this new -de method could be applied. our results show that this method allows a better assessment of the lv morphology and spatial geometry, with the calculation of global and regional indices with critical clinical and prognostic value in this particular cardiovascular pathology. simultaneous left atrial (la) and left ventricle (lv) inflow analysis assessed by pulsed doppler tee illustrate the loading conditions and reflect the hemodynamics of the left heart. we performed a prospective tee pulsed doppler study with recordings of the transmitral lv filling and pulmonary venous (pv) flow drainage in a group of patients with dilated cardiomyopathy (dcm). a group of dcm patients, mean age _+ yrs, % male were studied. this population was divided according to tee severe lv dysfunction (group slvd+ % pts; group slvd- % pts) in each pt we measured the peak velocities (vel/m/sec) and time velocity integrals (vti/m) of the transmitral early (e) and late (a) filing waves, the vel and vti of the pv systolic (s), diastolic (d) and atrial contraction (c) reversal flows. -de tee evaluation of the lved, lves, lvst volumes and lvef were obtained. we calculated other parameters, such as e/a, s/d and a/c ratios and the sum of c+a vel, that refelect la systolic function and lv compliance. + -_ . simultaneous and quantitative analytical approach of the pulmonary venous and transmitral flows and ventricular volumes improve the non invasive assessment and understanding of left ventricular diastolic function and cardiac performance in dilated cardiomyopathy patients. objectives : to assess the hemodynamic effects of fluid loading (fl) in acute circulatory failure (acf) due to acute massive pulmonary embolism. methods : hemodynamic measurements (fast-response thermistor pulmonary artery catheter) were performed at baseline (baseline) and after a rapid fluid loading with (fl ) and (fl ) ml of dextl'an (rhemacrodex| in patients free of previous cardiopulmonary disease ( • yrs) with acf (ci < . l/rain/m ) due to angiographicalty proven mpe (miller score > ) . results : are expressed as mean _+ sem and compared by anova. a significant negative correlation (r = . ) was observed between baseline rvedv[ and the effects of fl on ci. such correlation was not observed between baseline rap and the fl induced increased in ci. conclusion : fusibmificantly increases ci in acf due to mpe. however, the simultaneous decrease of arterial content due to hemodilution, limits the benefits expected from improved ci on peripheral oxygenation. obiective: to examine the hemodynamic effects of external positive endexpiratory pressure (peep) on right ventricular (rv) function in acute respiratory failure (arf) patients. methods: incremental levels of peep ( - - - cmh ) were applied and rv hemodynamics were studied by a swan-ganz catheter with a fast response thermistor for right ventrieular ejection fraction (rvef) measurement in mechanically ventilated arf patients (lis = . ~- . sd). according to the response to peep , two groups of patients were defined: group a ( pts.) with unchanged or increased rv end diastolic volume index (rvedvi) and group b (h pts) with decreased rvedvi. results: in the whole sample cardiac index (ci) and stroke index (sj) decreased at all levels of peep, while rvedvi , rv end systolic volume index (rvesvi) and rvef remained anchange d. at zeep the hemodynamic parameters of the two groups did not differ. in group a, ci decreased at peep , rvef decreased at peep (~ . %)~ rvesvi increased only at peep (+ . %) and rvedv[ reded unchanged. in group b, ci and rvedvi started to decrease at peep , 'rvesvi decreased only at peep (- . %), anf rvef was unchanged. individual behaviors of the hemodynamic parameters at the levels& peep were studied. rvedvi and ci were significantly correlated in out of:l patients in group b, and in no patient of group a. on the contrary, mpap and rvesvi were significantly correlated in out of patients in group a, and in no patient of group b. the slope of the relationship between rvedvi and rv stroke work index (rvswi) expresses rv myocardial performance. this relationship was significant (no change in rv contractitity)in patients of group b and in patients of group a. in some patients of group a, increments of peep shifted the rvswi/rvedvi ratio rightward inthe plot (rv function decrease). conclusions: in arf patients peep causes more often a preload decrease with unclmnged rv conctraetility. on the contrary, the finding of increased rv volumes during the application of peep is related to a decrease in rv myocardial performance. thus, these data suggest that application of peep might be considered as a stress test to assess rv function. right introduction: after heart transplant (ht), the right ventricle can be subject to an acute pressure overload, especially in cases where there is a preexisting severe pulmonary hypertension. this provokes right ventricular failure and, occasionally, circulatory collapse in intensive care unit. desire the advances that have been made in systems for preserving the donor heart and in post-surgical management, we have failed in our attempts to totally avoid this problem. the right ventricular function, although it usually remains within tolerable limits in these patients during the post surgery period, represents a factor which limits the results achievable in clinical transplant programmes. objectives: to determine the maximum tolerance of the right ventricle (mxtrv) when faced with acute pressure overload. to study the function of both ventricles of the healthy heart (donor) when faced with different degrees of pulmonary hypertension. to detect possible interactions between the ventricles in the absence of the pericardium to approximate the experimental model to the clinical model of ht. materials and methods: the pulmonary artery is progressively constrained in an experimental model until biventricniar failure is detected. this experiment is performed in two diffferent situations: with and without pericardial integrity. results: when pericardial integrity is maintained the mxtrv faced with a pressure overload is . + . nun hg. when this pressure is exceeded there is a circulatory collapse with a sharp fall in the cardiac output and in the aortic pressure. however, when pericardectomy is performed (model similar to ht), only • . nun hg is tolerated (p < . ). conclusions: with the pericardium open, as in heart transplant, the maximum pressure that the right ventricle can support is significantly less than with the pericardium closed. the pericardium has a positive effect in protecting the systolic ventricular interaction. it is, therefore, advisable to close the pericardium after heart transplant. jb prrez-bernal, a ordrfiez, a. heroandez, jm borrego, map camacho, c cruz, mac s~nchez, j monterrubio, c garcia, e. gonz~lez. hospital uulversitario " virgen del rocio ". sevilla. espaiqa. introduction: nowadays cardiomyoplasty isused incases of cardiac insufficiency as an alternative to cardiac transplant. after surgery the patients show a noteable improvement with the aid of this "biological circulatory assistance". some researchers suspect that the improvement could also be due to the formation of new blood vessels from the muscle that wraps the heart, nourishing the ischemic myocardium. objectives: our cardiovascular research group has proposed as an objective, the detection of any possible myocardial neovascularization through the muscle used for cardiomyoplasty. in the case that there are new blood vessels to the diseased myocardium through the wide dorsal muscle in which it is wrapped and which aids it mechanically, it would be possible to confirm the worldng hypothesis that cardiomyoplasty not only improves the cardiocirculatory funcfinn mechanically but also by facilitating a better blood flow to the ischemic myocardium. materials and methods: the cardiomyoplasty technique is described using an experimental model of myocardial ischemia. the vascular cast is achieved by injecting methacrylate simulataneously into both the coronary tree and the wide dorsal muscle, in five experiments the connections between the coronary vascular system and the vascular structure of the wide dorsal muscle are demonstrated, conclusions: we have demonstrated that cardiomyoplasty, as well as improving ventricular function, favours the revascularization of the myocardium. cardiomyoplasty could be indicated for cases of ischemic cardiopathy in patients in whom it is not possible to perform direct revacularization using conventional methods. a the therapeutic cardiological manouevres necessary in cases of ischeima reperfusion have increased considerably: fibrinolysis, transluminal angioplasty, coronary revascnlarization surgery and cardiac transplant. the appearance of a specific pathology ht acute reperfusion has been related to free oxygen radicals (for) generated by oxidative damage. objectives: to evaluate the appearance of for during a conti-olled process of ischemia-reperfusion in an experimental biological model and compare it with that in clinical cases. materials and methods: transitory cardiac ischemia was performed in five rabbits by reversible surgical ligation of the descending anterior coronary artery. after minutes coronary reperfusion was performed. blood samples were taken in the basal situation, at the end of ischemia and at , and minutes after the start of reperfusion. malondialdehyde (mda) was measured to evaluate the degree of lipid peroxidation (oxidative damage to the membrane). in ten patients undergoing conventional cardiac surgery the production of for was measured after aortic clamping. results: we observed that after minutes of reperfusion there was a highly significant increase (p < . ) in the mda values (mean = . /zmols/l). these returned to basal levels after and minutes of reperfusion. conclusions: an "explosion" of oxygen free radicals was detected very quicldy, just a few minutes after post-ischemia reperfusion. thus, if antioxidant agents are to be used to reduce the toxic effects of the for, these will ordy have a therapeutic effect if they are administered in the early phases of reperfusion. introduction: aortic connterpulsation is a ventricular assistance widely used in intensive care units in patients with cardiogenic shock as a provisional ventricular assistance. paraaortic or external aortic counterpnlsation is been investigated as a definitive veutricular assistance in those cases of terminal congestive heart failure and when heart transplantation is counterindicated. aims: to assess the haemodynamic effects of an aortomyoplasty in a biological model of congestive heart failure. material and method: as specimens, we used "large white" pigs. mean weight was kg. after the administration of conventional anaesthesia, dissection of the ladssimns dorsi muscle was performed on the samples at the laboratory of experimental surgery of our hospital. then we performed a thoracotomy at the level of the fourth intercostal space to reach the thoracic aorta. the aorta is dissecated centimetres from the exit of the subclavia and it is wrapped by the dissecated muscle. a cardiomyostimulator is provided in order to allow the synchronization between the diastole and the muscle contraction. the model of heart failure was provoked using verapamil plus propanolol i.v.. results: a significant increase of the aortic diastolic pressures and a significant decrease of the left ventricle telediastolic pressures were observed. this improvement in the parameters (dpti/tti) implies an increase of the coronary perfusion in a model of heart failure. conclusions: using the external aortic counterpulsation, the aortomyoplasty improves the coronary perfnsion and the heart efficiency in patients with heart failure in whom no conventional therapeutic action is possible. the permanent character of the paraaortic counterpulsation is it main advantage. the appearance of specific pathologies as a resuk of myocardial reperfasion has been related to the oxidative damage secondary to the release of oxygen derived free radicals (ofr). during the myocardial ischemia induced during heart surgery with extraeorporeal circulation, severalsubproducts of the oxygen are produced that shall cause toxic effects after the reperfusion which could be counteracted by the physiological antioxidant systems and/or provided by the medication. aims: to asses the ofr during heart surgery. to check whether an antioxidant treatment administered in the preoperative period make decrease the levels of ofr before and after the myocardial reperfusion and to verify whether its administration have any beneficial effect on the intra and extraoperative management. material and method: the study comprehends patients studied as two groups of individuals each (a and b). all patients underwent conventional heart surgery of valvniar substitmion or myocardial revaseularization. group a patients were administered rag/ hours of vitamin e (tocopherol acetate) hours prior to the intervention as antioxidant treatment. group b patient were not administered vitamin e. we assessed the quantity of malondialdehido (mda) to assess the degree of lipidic peroxidation or oxidative damage of the membrane during the myocardial ischemia and nm after the reperfusion. conclusion: patients who underwent heart surgery and were treated with tecopherol acetate in the preoperative period presented levels of rlo significantly lower than those who were not administered the drug, both during the intraoperative period and after myocardial reperfusion. we detected in these patients a need for antiarrhythmicals and pharmacoiogical support with catecholaminas, although not significant, both in the introaperative period and the immediate postoperative period. recommendations for the treatment of pulmonary embolism (pe) in the presence of right atrial thrombus (at) are conflicting. because of a significantly higher mortality rate due to fulminam or recurrent pe, there is a necessity to treat patients (pts) with mobile type a thrombi compared to pts with adherent type b thrombi. therapeutic strategies include anticoagulation, thrombolysis (t) or surgical thrombembolectomy. combination thrombolysis (cot), predominantly used for the treatment of acute myocardial infarction proved to prevent reocclusion of the infarct related artery at a comparable rate of hemorrhagia. benefit has been related to the alteration of hemostatic proteins by non-fibrinspecific thrombolytic s. administration of cot in pe has been performed sporadically. in the present case, a -year old male with no history of prior cardiovascular disease developed acute dyspnea which was related to pe in the presence of deep vein thrombosis of the left femoral vein. therapeutic anticoagulation was installed for a couple of days until there were several bouts of deterioration. biplane transesophageal echocardiography (tee) was performed and revealed a large, wormlike, hypermobile thrombus within the right atrium. computer tomography (ct) of the chest detected a saddle embolus in the bifurcation of the pulmonary tmnk almost occluding the entire left pulmonary artery (pa) and parts of the right pat consisted of mg frontloaded rt-pa and the subsequent continuous administration of urokinase in a dosis of . u/hr for hrs followed by therapeutic anticoagulation. symptoms, blood gases and ecg improved steadily during infusion, no adverse effects, i.e. minor or major hemorragia were registered. follow-up ct promptly after termination of t showed almost complete resolution of the saddle embelus, whereas tee showed complete dissolution of the at. ' finally, the patient was switched to oral anticoagulants and had an uneventful clinical course until he was discharged. conclusion: in the present case, cot was effective for the treatment of a complicated pe without any adverse effect. introduction: nowadays we can assist hearts with problems of insufficiency by techniques other than transplant. many researchers believe that the best way of assisting insufficient heart muscle is with another muscle from the patient. this technique of ventficular assistance is known as cardiomyoplasty. we describe the surgical technique of cardiomyoplasty using a biological model. the transformed skeletal muscle is transferred to the thoracic cavity where it wraps the heart and assists it. the choice and preparation of this muscle is currently under investigation. our group has focussed on the development of protocols for electrical stimulation to transform a skeletal muscle into a muscle which resists fatigue and which is functionally similar to the myocardium. we detect the optimum time at which this muscle has been transformed, by studying the transmembrane action potentials using intracellular electrodes. when the action potential of the trained muscle behaves like cardiac muscle we consider it ready for cardiomyoplasty. conclusions: cardiomyoplasty is an alternative surgical technique to cardiac transplant, which has a great future in the treatment of patients with advanced cardiac insufficiency. we describe methodology which, by intracellular techniques, allows selection of the optimum moment of transformation of a skeletal muscle trained to perform,like cardiac muscle, without suffering fatigue. purulent pericarditis is a rare disease. its treatment associate systemic antibiotics and drainage of the pericardium. we report a ease of purulent constrictive pericarditis in which intraperieardial fibrinolysis was use. a years old patient admitted in our icu for a constrictive pericarditis as a complication of a purulent pericarditis diagnosed seventeen days before. he had also an aehalasia and the o'esogastric endoscopy had found an oesophageal neoplasm. a fistula was not seen, indeed pericardial of flora was the same that oropharyngeal. hemodynamie and echographic study had confirmed a constrictive pericarditis. because of the poor state of the patient an intraperieardial fibrinolysis was prescribed ( . ui of streptokinase on days , , , ). fluid drainage was improved and cardiac output was also improved (day : . .min "i, day : . l.min'l). no change ofhemostasis was noted. a pericardeetomy and an oesophagectomy were performed after days of evolution. eighteen months latter the patient was still alive. intraperieardial fibrinolysis seems an interesting therapeutic way if rapidly prescribed in the purulent pericarditis course. the decrease in the systolic pressure following a mechanical breath, termed ddown (delta down), has been shown to be a sensitive indicator of preload ( , ) . however, the clinical use of this method necessitates the introduction of a short apnea. we have therefore developed a respiratory systolic variation test (rsvt) which obviates the need for apnea. the test is based on the delivery of successive breaths of increasing magnitude ( , , , and ml/kg). a line of best fit is drawn between the minimal systolic values (one after each breath) and the downslope calculated as the decrease in blond pressure for each increase in airway pressure ( mmhg / cmh ). in mechanically ventilated patients the rsvt was performed during controlled mechanical ventilation under sedation. the test was repeated after the administration of ml/kg of plasma expander. the initial mean downslope of the rsvt was -. + . mmhg/cmh . following volume loading the downslope decreased to -. + . (ns). at the same time, cardiac output (co) increased by . + . l/min (p<. ), end-diastolic area (determined by tee) increased from . + . to . + . cm (ns), and paop increased from + to + mmhg ( p < . ). the preinfusion downslope value of the rsvt correlated significantly with the increase in the co (r = . ) and the eda (r = . ). methods: an expert system has been constructed running on a multimedia computer with the two objectives in mind, viz training of inexperienced staff, and protocol guidance with treatment regimes for all staff. the system is based on experience gained from two previous systems, the one for dealing with acid-base and electrolyte problems in icu patients; the second for stabilisation of patients with heart rate and blood pressure abnormalities. the training section takes the form of a stage-by-stage account of the insertion of the pac and displays of correct waveforms, coupled with indications of possible incorrect placements, and guidance when failing to achieve the perfect positioning. the treatment protocol section extends an existing protocol for correcting abnormalities in heart-rate and blood-pressure, and now takes account of all the indices as measured by the pac. the system will suggest treatment to correct such things as abnormal wedge pressures concomitant with parameter values throughout the rest of the cardiovascular system. the type of patient eg post-operative cardiothoracic or i. c. u. trauma, will be taken into account when recognising abnormal parameter values and when prescribing treatment. results: a working system which will be improved by the finetuning being carried out. the results and lessons learnt will be presented at the conference. method: septic shock was defined as severe sepsis with either persistent hypotension (mean arterial pressure; map < mmhg) or the requirement for a noradrenaline (na) infusion ~ . g/kg/ rain with a map --< mmhg. cardiovascular support was limited to na + dobutamine (db). c was given for up to h at a fixed dose-rate of either , . , , or mg/kg/h iv. during c infusion, na was to be reduced and if possible withdrawn, whilst maintaining map above mmhg and the cardiac index (ci) as clinically appropriate. assessments were made at baseline (t = ); at i h from the start of treatment (t - ); and at the end of treatment (t - ) with c . conclusions: c does not appear to increase mpap or worsen pulmonary gas exchange in patients with septic shock, when given by infusion for up to h. c is a novel vasoactive agent for the treatment of septic shock which will now he evaluated in a randomised, placebo-controlled safety and efficacy study. objectives : to compare cardiac output (q) data obtained for thermal indicators in pulmonary artery (qtpa) and aorta (qtao) and for the stable isotope hzo in aorta (q v~ o) with indocyanine green (icg) in aorta (qicg) as reference. methods : an indicator solution of ice cold h ( . ml), h ( . ml) and icg ( mg) was injected as bolus via the injection port of a swan-ganz catheter. qlco and qzmo was measured using a dual optical system (penn lab instruments, philadephia, pa, usa). qtpa and qtao was measured using a in contrast to the recoveries of thermal indicator in pa and h in aorta the :~covery of thermal indicator in aorta was significantly increased in group ii (n= boluses) over group i (n= boluses) ( . <- . vs. . +- . , p= . ). conclusions: the "overrecovery" of thermal indicator in aorta is in agreement with " biscks deconvolution study (i) and results in erroneous values for q. the most pausible explanation is the distortion of the thermal curve caused by the slow response time of the thermal detection instrument as shown by ganz ( ) objectives: to compare data obtained with the double indicator dilution method using indocyanine green (icg) and the stable isotope h for the estimation of extravascular lung water (evlw hzo) to gravimetriu lungwater data (evlwg~). methods: an indicator solution oflcg ( rag) and h ( . ml) was injected as bolus via the injection port of a swan-ganz catheter. dilution curves for icg and zh was registered in aorta with a dual optical system (penn lab instruments, philadephia, pa, usa). cardiac output and mean tranist time was measured for both tracers (qico, tlco, q n o, t o) ( ). data analysis: evlwg~av was reference for evlwzhzo calculated as q hzo times the difference in mean transit time between t nzo and rico (atm n). as reference for atzn o evlwg~,v was divided by q~cg to obtain atg~,. a reference distribution volume for h was calculated as the sum of central blood volume and evlwg=v. boluses were administrated in a group (i) of anaesthetized pulmonary healthy sheep while q was altered. another boluses were administrated in a group (ii) of anaesthetized sheep with stable oleic acid induced pulmonary oedema. evlwg~v measurement was performed postmortem. results: for boluses h parameters were not significantly different from their respective reference parameter: at vao . +_ . s vs. atg~, . + . s, evlwzh o -+ ml vs. evlwg~,~ + ml. in group i the ratio between hzo parameters and respective reference parameters (n= ) were independent of qlco from . to . l/min. obiectives: to assess the thermo dye method using indocyanine green (icg) and thermal indicator for the estimation of lung water (evlwt). methods: ice cold indicator solution of icg ( mg) in water ( ml the aim of the study was to assess left and right ventricular function in the early postoperative period after orthotopic heart transplantation to elaborate therapeutic approaches of heart function abnormalities correction. mathefial and methods. haemodynamic monitoring data of twenty one patients ( men, women ) age from to were studied. cardiac output, pulmonary artery, right atrium and pulmonary wedged pressure were measured with swan-gans catheter. central haemodynamic indices were calculated with the help of computer-based monitoring system. relations of ventricular stroke work index to it's end-diastolic pressure were used for ventficular function assessment. results. in most cases right ventricular disfunction was the main problem. isolated fight ventficular failure with high pulmonary vascular resistance (pvr) was observed in % ( pts), without high pvr-in % opts) and with left ventricular failure-in % ( pts). one of the most important reasons for fight ventricular failure was the time of heart ischemia more than min, which is of great importance in the ease of distance harvesting. the most effective treatment for cardiac failure was combination of dobutamine with i oprotherenol, atrial pacing and vasodilatators in case of right ventfieular disfunction. all cases with isolated right ventricular failure were treated sucsessfully. biventricular heart failure was a sighn of bad prognosis and the reason of death in cases. conclusion. right ventfieular disfunetion is the main problem during transplanted heart adaptation in the early postoperative period. optimal therapeutic management of cardiac disfunction includes infusion of dobutamine in combination with isoprotherenol, atrial pacing and vasodilatators. cardiology-department of clinical centre-kragujevac institution for occupational health "zastava"-kragujevac, sr yugoslavia the aim of the investigate is analisis five years survives patients with a.i.m.in dependence of locality and risk-factors. we ana~sed- ~-pat~e~ts ( males and woman), average , years. for statistic evaluation we used life-table slstem in oder to estimate prognostic determinants. patients with respkatory muscle paralysis may benefit from respiratory assistance by abdomino-diaphragmatie pneumatic belt. we used a non invasive technique, m-mode sonography, to assess the effect of this device on diaphragmatic excursion. we measured the amplitude of right diaphragm motion in seven patients with duehenne muscular dysl~ophy in supine position with various thoracic posture ( ~ ~ ~ without and during pneumatic belt respiratory assistance. without respiratory assistance, the thoracic posture had no significant consequence on the amplitude of diapttragm motion, either in quiet or deep breathing. the pneumatic belt increased the diaphragm motion amplitude from . +__ . mm to . +_ . ram (p = . ) at ~ tilt angle, and from . + . mm to . + . mm (p = . ) at " tilt angle. the tidal volume increased from + to + rut a * tilt angle, and from + to + ml at * tilt angle (p = . ). two patients could not bear the horizontal position ( ' tilt). in the five other patients, the pneumatic belt increased but not significantly the amplitude of diaphragm motion ( . + . mm to . + . ram). after an overnight respiratory assistance, pao increased from . +_. . to + . mmhg ( = . ), sao increased from . + . % to . +_. % (p = . ), and paco decreased from + . to . +_. mmhg (p = . ) according to the ventilatory pattern result, m-mode sonography allows to measure non invasively the improvement of diaphragm kinetics obtained by pneumatic belt respiratory assistance, and may be helpful for its adjustment. objective: to study the effect of flow triggering (flow sensitivity and l/min) vs pressure triggering (-lcmh ) on inspiratory effort during pressure support ventilation (psv) and assited/controlled mode (a/c) in stable copd patients non-invasively ventilated with a full face mask. methods: the patients were studied during randomized min. runs using a bird st ventilator at zero peep (zeep). trigger values for pressure (-lcmh ) and flow ( l/rain) were the lowest allowed by this ventilator. the transdiaphragmatic pressure time product per breath (ptpdi), dynamic intrinsic peep (peepi,dyn), maximal airway pressure drop during inspiration (apaw) andl ventilatory variables (ti,te,ttot,rr,vt and minute ventilation) were measured. results: no major problems due to airleaks or to auto-triggeriffg phenomena were observed in the patients, so that all of them were able to perform all the protocol runs. minute ventilation and respiratory pattern were not different using the two triggering systems. the ptpdi was significantly higher during both psv ( . + . cmh: x sec) and a/c ( . + . ) with pressure triggering, as respect to psv ( . + . , p< . ) and a/c ( . + . , p< . ) with flow triggering ( l!m). no differences were observed between and l/min flow triggers. apaw was also significantly larger during pressure triggering; peepi,dyn was reduced during flow triggering being . + . cmh (psv flow trigger) vs . + . (psv pressure trigger) and . +_ . (a/c flow trigger) vs'f~ +l (atc pressure trigger). conclusions: in stable copd patients non-invasively ventilated, flow triggering reduces the respiratory effort during both psv and aic mode as compared to pressure triggering. this may be partly due to a decrease in peepi,dyn using a flow-by system. objective. cardiac output is higher during alternating ventilation (av) (i.e. differential ventilation of the lungs with a phase shift of half a ventilatory cycle) than during synchronous ventilation (sv) of both lungs . we verified the hypothesis that the higher cardiac output depended on a lower central venous pressure and intrathoracic pressure, due to a lower mean lung volume, which we attributed to part of the expansion of the inflated lung at the expense of the expiring, opposite lung . we studied this interaction between the lungs during one-sided inflation, which we called cross-talk. method. in anaesthetized and paralyzed piglets we applied short periods ( s) of one-sided ventilation ( breaths per rain, bpm), while the other lung was open to the ambient air. the air flow into the non-ventilated lung during expiration of the ventilated lung was integrated to volume. we studied -to-r and r-to-i cross-talk at ventilatory rates of , and bpm. the amount of cross-talk was the volume displacement in the non-ventilated lung. results. during bpm the r-to-i crosstalk was _+ . % (mean +__ sd) of the tidal volume to the right lung and the -to-r crosstalk _ . % of the left tidal volume. both values increased at bpm to _ . % (p < . ) and _ . % (p < . ) respectively. the values at bpm were in between., conclusion. we concluded that the lower mean lung volume and lower thoracic expansion during av compared to sv depends on partial expansion of the inflated lung into the non-inflated lung, resulting in a lower mean intrathoracic pressure as the main reason for the higher cardiac output during av. obiective: natural surfactant given for rds in premature infants leads to a rapid improvement in oxygenation, but lung compliance did not improve in most studies. however, acute effects on lung mechanics during and immediately after surfactant administration have not been studied before. methods: a total of administrations of bovine surfactant in recommended doses was given via a small catheter into the distal endotracheal tube either as a bolus (n = ) or as a slow infusion (n = ) in infants with established rds. static compliance (c), resistance (r) and time constant (tc = cxr) of the lung were measured every minutes with a lung function cart (sensormedics ) without interrupting ventilation. infants receiving synthetic surfactant were studied as controls. results: after surfactant as a bolus or during infusion c first decreased but then increased, whereas r increased immediately with great fluctuations but did not return to baseline. this pattern was more pronounced in infusion than in bolus administration. change of c and r varied greatly in the individual case, maximum c was > %, maximum r > % of baseline value. retreatment was followed by an increase in r in all patients, but c increased only in the one who was responder. patients receiving synthetic surfactant had no change of c or r and were non-responders. ob~i ctives= acute lung injury (ali} sometimes induces severe hypoxernla which may be refractory to conventional modes of mechanical ventilation (mv). the elm of this study was to observe some cardio-pulmonary effects of an alternative method of ventilatory management of severe ali. five patients with severe ali (murray scores > ) requiring mv were studied. protocol inclusion was considered when a control-mode of mv (with a pzo~=l. and a peep level < cme=o} was not able to get either a p.ojf=o= ratio > or a s.o= > %. patients were sedated, paralyzed, and a ventilator (serve c) was used for pressuz'e-control ventilation (pcv). fio= was maintained at . and peep removed. continuous gas flow ( • ml/kg] was humidified and jet delivered through a tube ( ram id, ml capacity, . ml/cm h=o compllancel ended in a nozzle ( . mm is) attached to the endotracheal tube connector. a thermodilution flcw-dlrected catheter was inserted in pulmonary artery. following variables were recorded minutes before and after protocol started: tidal volume (vt), minute ventilation (vz), intratracheal pressures (p~w), wedge pulmonary artery pressure (wp), central venous pressure (cvp), mean arterial pressure (map), cardiac index (ci), arterial and mixed venous oxyhemoglobin saturation (sao=, svoa) , oxygen delivery (do~) , oxygen consumption (vo ) , intrapulmonary shunting (q./qt) , and oxygen extraction ratio (ero). this observation suggests that hfpv could allow to ventilate at lower fin and improve blood oxygenation during the acute phase after inhalation injury reducing toxicity risk related to high fin . further studies are necessary to confima these results and evaluate the possible implications on mortality alter smoke inhalation and for other icu pts. objectives: to design a system for volume controlled high frequency ventilation (hfv) and to estimate the dependence of the tidal volume (vt) on frequency (f) in normocapnic ventilation in rats at frequencies - hz. methods: a new system for volume controlled hfv was devised consisting of the generator of the constant flow during inspirium and the constant pressure during expirium. the ventilator allows ventilation at frequencies - hz with the relative inspiratory time (ti) . - . . the airway pressure was measured at the proximal port of tracheostomic cannula , at the same site inspiratory and expiratory flow was measured using modified lilly-type of pressure-differential flow sensor. non-linearity of flow sensor was compensated on line by derived equation based on calibration at static and dynamic conditions. flow and pressure data were evaluated on line using original software. value of the positive end expiratory pressure (peep) was serve-regulated by analogous feed-back. in animal experiments white wistar rats ( - g) narcotized with ketamine/xylazine with cannulated carotid and femoral arteries were kept at the rectal temperature ~ the arterial pressure was monitored. after traeheotomy the metal cannula ( mm [.d.) was inserted, animals were curarized and ventilated at the following condition: peep = . kpa, ti = . . the dead space of ventilator including canula was . ml. the initial frequency was hz and rain after each change of the ventitatory regimen the blood gases analysis was performed. the frequency was changed according to the following schedule : hz--> hz--> hz--> hz--> hz--> hz--~ hz--> hz. vt for each frequency was regulated to maintain normocapnie ventilation with arterial pco = + mm hg. the arterial po was always above mm hg. results: for normocapnie ventilation in rats the following tidal volumes vt [ ml/kg] were found : vt = . --+ . ml/kg for ft = hz, vt = . + . mukg for fz = hz, vt = . +_ . ml/kg forf = hz, vm = . + . ml/kg forf = hz andvmt= . + . mukg for fs = hz (presented as mean values _+ s.d., n = ). the regression analysis using the mean values resulted in the equation for normocapnic vt in rats in our experiments : vtn = . * f-e. . conclusions: the described system allowing ventilation in a wide frequency range - hz with accurate measurements of airway pressures and vt might be useful for optimisation of artificial ventilation in new-barns with different lung pathologies. supported by grants iga mz cr nr - and gacr nr . s intensive care unit. university. hospital of south manchester, uk. methods: measurements were conducted on ventilated patients (puritan bennett ac with metabolic monitor pb set to measure end tidal co ). all measurements were repeated with the patient stabilised at cm. cm and cm peep. inclusion criteria were: ) haemedynamic stab(l( .ty for hr; ) pulmonad" anon" flotation catheter in situ: ) volume control ventilation with plateau of . s: ) fio ~ > . to maintain pao~. > kpa with em peep: ) qs/ot > %; ) pao /fio ratio < . measured variab!es included: r minute volume: plateau ainvay pressure: applied and intrinsic peep: fractional end tidal co ; arterial and mixed venous blood gases and hacmod).ttamic variables. results: statistical analysis was performed using repeated measures anova. significant decreases in cardiac index (ch p< . ), compliance (p<t). ) and o,'gcn deliver, index (do , p< . ) occurred with increasing peep (table ) . no other variable showed any significant change. methods : all consecutive patients orally intubated in the micu between january to april were studied. etts were positioned according to the reference marks mentioned above (measurements from upper incisors). the position of the ett tip in relation to the carina was measured on the chest radiograph done with the patient's head in neutral position. results : a total of men and women were studied (n= ). the mean distance of ett tip to carina was . cm. using the reference markings, cases ( . %) had the ett tip < cm from the carina and cases ( . %) > cm. one case resulted in an endobronchial intubation. the mean height of all patients were cm ( - ) for males and cm ( - ) for females. of the patients with ett tip < cm from carina, the mean height was cm and cm respectively. ~ onclusion : adopting the above quoted reference marks did not result in ideal positioning of the ett in a significant proportion of cases ( . %). we postulate that [s because our asian population is generally shorter than those in previous studies. objectives: to measure the changes of pulmonary mechanics before and after tracheostomy in patients with prolonged mechanical ventilation and to determine factors that predict the outcome of liberation from mechanical ventilation. design: prospective. setting: respiratory intensive care unit (ricu) in a tertiary hospital. patients: twenty patients with chronic lung disease requiring long-term mechanical ventilation. tracheostomy is indicated for further care. intervention: tracheostomy. measurements and results: pulmonary mechanics including respiratory rate (rr), tidal volume (vt), peak inspiratory pressure (pip), intrinsic positive end ex~ piratory pressure (peepi), lung compliance (cld), mean airway resistance (rawm), work of breathing (wob), pressure time product (ptp) by bicore cp- pulmonary monitor were recorded hours before and after tracheotomy. ventilator setting parameters remained the same during surgical intervention and were also recorded for comparison. generally, the mechanics including pir wob, raw~x and ptp showed improvment after tracheostomy. but only pip was significantly reduced (pre . _+ . to post . _+ . , p < . ). changes of wobp showed significant correlation with pre-operation rr, minute volume (mv), wobp, and peep(. changes of raw m were also significantly correlated with pre-operation peep, vt, and raw m. the patients were divided into two groups according to their outcome after two week follow-up. group included eight patients who were completely weaned from ventilator; group included twelve patients who still remained ventilator-dependent or were mortality. there was no difference in age, duration of mechanical ventilation, pro, post or changes of several lung mechanics between the groups of patients. pre-tracheostomy peep i and cld showed significant difference between these two groups ( . _+ . vs . + . in peepi; . _+ . vs . _+ . in cld, p < . ). pre-tracheostomy ventilator setting in mode of assist/control also showed significant higher percentage in group ( % % in group vs . % in group ). conclusion: in prolonged mechanical ventilation patients with chronic lung disease, tracheostomy will significantly improve pip and slightly reduce wobp, raw m and ptr patients who used pressure support mode before tracheostomy had better underlying lung conditions (lower lung compliance and auto-peep) will have better chance to wean from mechanical ventilation. forty-eight infants with congenital diaphragmatic hernia presenting within the first hours of life, who underwent surgical rapair,were analysed prospectively in order to produce a reliable inde x of severity of disease that would reliably predict eventual outcome. there were survivors and deaths in this series (mortality %).using arterialpco values measured hours after surgical repairand correlating them with an index of mechanical ventilation,we have been able to clearly define two groups of diaphragmatic hernia based on their response to hyperventilation. the first group, with co retention and severe preductal shunting,was unresponsive to hyperventilation with high rates and pressures the mortality was %. the second group responded well to hyperventilation and demonstrated reversable ductal shunting only. survival in this group was %. arterial co accurately reflects the degree of lung development in this disease and separates those patients with severe pulmonary hypoplasia where the outcome is invariably fatal, from those with a well developed contralateral lung where there is excellent potential for survival. respiratory failure unit, dpt medicine, univ. thessaloniki, thessaloniki, greece the variability of arterial blood gases (po , pc ) and the ph (abg) was examined in stable icu patients, few hours before a successful weaning from the ventilator. all patients were lightly sedated and the ventgatory conti~ons were pressure support (ps) for and ps plus intermitted mantatory ventilation in ii. [n each patient, speciments of abg were measured at min intervals during a - study period. at the same time with abg the arterial blood pressure (bp), the heart rate (cf), the tidal volume (tv) and the respiratory rate (n r were measured. for all the patients, the mean coefficient of variation (c) was . percent for po , . percent for pco and . percent for hco . the average sd for ph was . , the corresponding c for systolic bp, diastolic bp, cf, tv, rf were . , . , . , . , . percent. we conclude that the spontaneous variability of arterial blood gases in icu patients is not substantial ~hen they have stable the heamodynamic and the ventilatory parameters. deptx?fa'aaesthesioiogy and reanimation, rhe sechenov medical academy, moscow, russia objective: ~he prevention and treatment of hypoxia in the critical patiems. methods: i~fusions of perphtoran -a blood substitute with gas-transporting fimclion based on perphtorhydrocarbon -in patients with acute hypovolemia, microcirculatory distnrbance~ tissue gas exchange and metabolism; pulmonary iavage in ; iongterm extrapulmonary oxigenation with tleoroearboa oxygenator in combination whb ~trafiltra!ion, hemosorption and hemodialysis -in patients. results: pe~htoran increases blood volume, co,sv, decreases svr, improves capillary blood flow, increases the blood oxygen capacity, tissue oxygen tension, del, vo by improving the rheologic properties of blood and plasma, normalizes ext., prevents and eliminates fat embolisation and ards. decreases the need for blood transfusions and infusions of plasma expanders by . - . limes. alveolar venti!ation-perfusion ratio remains unchanged with its increased effective utilization. there was no surfactant destruction during lavage. extrapulmonary oxygenation of small volumes of venous blood eliminates venous destruction and then arterial hypoxia and increases pulmonary oxygenation. the use of lluorocarbon cxygenators during hemosorption and hcmodialysis provides the atraumatic and iongterm oxygenation of arterial blood and increases elimination of co which prevents the development of hypoxic complications. conclusions: perphtoran and fluorocarb~n oxygenators are effective in the correction of hypoxia in the criticat patients. objeqtives: to determine if there are differences in oxygen consumption (vo ) during weaning from mechanical ventilation (during total ventilatory support and spontaneous ventilation with cpap), and to compare different predictive parameters of weaning in predicting success of weaning. methods; prospective study in critically ill patients treated with mechanical ventilation for at least h, who fulfilled at least of standard weaning criteria (vt> ml/kg; respiratory frecuency (f) < ; pimax > cm h ; pao /fio > ). baseline measurements: t, vt, p . , pimax, f/vt, p . *(f/vt), p . /pimax. study protocol: measurement of vo , vco (medgraphics), vt, f, ve, and arterial blood gases during total ventilatory support (cmv), and after and minutes of spontaneous ventilation with cpap cm h . the weaning trial was stopped, failure to wean diagnosed, and mv resumed it a patient presented significant tachypnea, tachycardia, bradycardia, cardiac rythm disturbances, hypertension, hypotension, hypoxemia or hypercapnia. results: four patients did not complete the weaning trial, were extubatad, and of them had to be reintubated before h, being considered also weaning failures. during cmv, vo /kg was . + . ml/kg/min, and . _+ . mlo- /kg/min after ' on cpap cm h (p < , ). of patients ( %) with standard criteria were extubated, while only of ( %) with criteria (p< , ). next objectives: compare the extent and distribution of lung injury in dogs preinjured with oleic acid (oa) and ventilated with high tpp and adequate peep in the prone and supine position. methods: lung injury was induced with oa ( . - . ml/kg) in anesthetized, paralyzed, and intubated dogs (n= ) during volume controlled ventilation: rate= /min, peep= cmh , ti/ttot= . , fio = . , vt= ml/kg. animals were rotated during the oa infusion and the following minute stabilization period to assure uniform injury. in the supine position, peep was set - cmh above the lower inflection point (as determined by the pressure-volume curve), and vt was set to obtain a tpp of cmh : animals were ventilated in either the prone (n= ) or supine (n= ) position for four hours. pulmonary artery occlusion pressure was maintained constant ( - mmhg) with saline infusion. at the end of the protocol the lungs were removed and divided by template into dependent (d) and nondependent (nd) sections for wet weight/dry weight (v~n/dw) and grading of nstologic lung injury (hli; scale - ). oseillatron | is a pneumatic device that generates high frequency, oscillation by means of a reciprocating system in the form of a membrane. it generates sinusoidai wave form at ( to ( cycles/rain. the system does not deliver gas but must be adapted to the proximal respiratory, circuit of a conventional ventilator, resulting in ci-ifo. it was developed to enhance intrapnlmona~ diffusion during mechanical ventilation and to mobilise endebronchial secretions. methods. we measured arterial blood gases and haemedynamics during a first period of conventional ventilation (cppv) followed by. two rain periods of chfo (sequences : ( and ) c/rain : group l, n = l: and c/rain : group , n = ). measurements were made at the end of each period. cardiac output was measured using thermedilution method: flu and peep were kept unchanged throughout the study. intrinsic peep was also evaluated by, means of an occlusive valve. results. pa is not significantly modified during chfo at or c/rain. paco is slightly decreased at c/rain (p = .( ). however, intrinsic peep remains unchanged. there is no sequential effect (gr. l vs gr. ). there is no more effect of chfo for patieets who are at a flu higher than . (n = ). no changes in haemodynurmcs are observed except a slight increase in central venous pressure (cvp) during ci-ifo (p < .ol). obiectives: to examine the effects of inspiratory muscles unloading on neuromuscular output at controlled levels of chemical stimuli. methods: the ventilatory response to co was examined in ten normal subjects using rebreathing method. ventilation ~) and respiratory muscle pressure output (pmus) at the same end-tidal partial pressure of co (petco~) were compared with and without combined flow and volumeproportional pressure assist in two protocols (a and b). protocol a (n = ): two levels of assist were studied; flow assist (fa) of cmh /i/sec and volume assist (va) of cmh /i (assist ), and fa of cmh /i/sec and va of cmh /i (assist ). all conditions were applied randomly. v~, tidal volume (vt) and breathing frequency (f) were measured breath by breath and plotted as a function of petco~. protocol b: in subjects, in addition to above measurements, esophageal (pes) and gastric (pg) pressures were measured and the time courses of transdiaphragmatic pressure (pdi) and pmus were calculated. one level of assist (assist ) was studied in this protocol. results: in both protocols inspiratory muscle unloading did not change the f response to c%. compared to control, with assist v t response was displaced upwards; at petco of mmhg v t was increased significantly by . + . i and . + . i in protocol a with assist end , respectively, and by . _+ . i in protocol b with assist (p< . ). ~/~ responses showed similar changes as vtresponses. in both protocols the slope of v~ response (s did not change significantly with unloading. at low petco~ ( mmhg), pdi and pmus waveforms did not differ with and without assist. with unloading, at high petco ( mmhg), pdi and pmus at the end of neural inspiration decreased by . -+ . % and . + . %, respectively, from control values. neither change was significant (p> . ). by theoretical analysis we estimated the expected changes in vt and ~/~ when the levels of assist used in both protocols were applied in the absence of : any change in neural output response to co z. the predicted response was similar to that observed, indicating that the small difference in pdi and pmus between control and unloading runs was due to intrinsic properties of respiratory muscles end respiratory system. conclusions: these results suggest that when chemical stimulus is controlled, respiratory motor output is not downregulated with unloading. the determinants of the response of the respiratory output to inspiratory flow rates (v~) were examined in awake normal subjects. subjects were connected to a volume-cycle ventilator in the assist/control mode and v~ was increased in steps from to i/min and then back to i/min. v~ pattern was square, and all breaths were subject-triggered. in six subjects the effects of breathing route (nasal or mouth) and temperature and volume of inspired gas (protocol a) and in subjects the effects of airway anesthesia (upper and lower airways, protocol b) on the response of respiratory output to varying v~ were studied. in protocol b, in order to calculate muscle pressure during inspiration (pmus), respiratory system mechanics were measured using the interrupter method at end-inspiration. independent of conditions studied breathing frequency increased . significantly and end-tidal concentration of c% decreased as v~ increased. the response was graded and reversible and not affected by breathing route, temperature and volume of inspired gas and airway anesthesia. with and without airway anesthesia (protocol ) neural inspiratory and expiratory time and neural duty cycle, estimated from pmus waveform, decreased significantly as v~ increased. at all conditions studied the rate of change in airway pressure prior to triggering the ventilator tended to increase as v~ increased. the changes in timing and drive were nearly complete within the first two breaths after transition with no evidence of adaptation during a given ~/~ period. we conclude that v~ exerts an excitatory effect on respiratory output which is independent of breathing route, temperature and volume of inspirate and airway anesthesia. the response most likely is neu~'al in origin, mediated through receptors not accessible to anesthesia such as those located in chest wall or below the airway mucosa. it has been shown, in mechanically ventilated awake normal humans, that increasing inspiratory flow rate (~/~) exerts an excitatory effect on respiratory output. it is not known if this effect persists during sleep. to test this seven normal adults were studied during wakefulness and nrem sleep. subjects were connected through a nose-mask to a volume-cycled ventilator in the assist/control mode and ~/t was increased in steps ( - breaths each) from to i/min and then back to i/min. v~ pattern was square, and all breaths were subject-triggered. forty-one trials during nrem sleep and during wakefulness were analyzed. both during sleep and wakefulness minute ventilation increased and total breath duration (ttot) decreased significantly in a graded and reversible manner as ~' increased. these changes were complete in the first breath after v{ transition. the response was significantly less during sleep than during wakefulness (p< . ); at i/min ttot, expressed as % of that at i/rain, was . +_ . % during sleep and . +_ . % during wakefulness. during wakefulness, at i/min, the rate of change in airway pressure prior to triggering the ventilator, an index of respiratory drive, was % of that at i/min (p< . ). the corresponding value during sleep, was % (p> . ). in four sleeping subjects the increase in v~ was sustained for . - min. there was no evidence for adaptation of the response; tro t, averaged over the last three breaths, did not differ from that obtained when vj was sustained for only - breaths. we conclude that ) vt exerts an excitatory effect on respiratory output, mediated by a reflex neural mechanism and ) the gain of this reflex is attenuated by sleep. chest radiographs is a common complementary technique for patients in critical care units, with a low cost and easily available. however, it has certain well-known limits in diagnosis, the most important derived from the low quality of some pictures. in this paper we make a general review of some new technical approaches developed for improving the quality of the images, and so incrensing the diagnostic value of conventional radiology. we begin deaeng with the correct positioning of the patient, trough the filtering techniques, the synchronization of radiology and ventilation, and we make reference to the new computerized systems for digital image processing. conclusions: the portable radiographic system is a device that probably with maintain for many years in critical care units as a basic non-invasive diagnostic tool. but we need an increase in the efficiency of it, applying means as simple as a correct positioning of the patient, or the use of fitlers or synchronizers. thus we should improve the general standards of portable radiography. "are circular circuits safe? quantifying undelivered tidal volume in pediatrics patients". objectives: to evaluate the overall influence of internal compliance of circular circuits on delivered tidad volume (vt). methods: we studied prospectively asa i pediatrics patients ( to yr. old) scheduled for elective general surgery. mechanical ventilation was supplied by an ohmeda excel (circular circuit). the internal compliance of the circuit (cc)-anesthesia machine plus external circuit-was determined by the supersyringe method: corrugated dar tubes of mm. id and . m. long (children < kg), and a corrugated dar set of mm. id and . m. long (children > kg) were respectively used for ccl an cc values of . and . ml/cm h . a vtof mlg/kg and respiratory frequency was adjusted for an end-tidal co (etpco ) between mmhg. tidal volumes (measured by spirometry) and airway pressure (paw) data were recorded every ten minutes. volumes and thorax-lung compliances were calculated as follows: (vt delivered = vtadjusted-vol compressible, being vol. compressible = co x ppeak (aw). apparent compliance (ca) = vt adjusted/pplateau(aw), and true compliance (ct) = =vt delivered/pplatean(aw)). comparative statistics were separately designed between calculated compliance data and tidal volumes on a paired sample ~test basis. results: calculated values for volumes and thorax-lung compliances were: conclusions: due to the elevated internal compliance of the circular circuit there is a remarkable dilference between adjusted and delivered vt: mean undelivered vt was . % and reached as high as . %. teere is also a significative error in calculating true thorax-lung compliance: its overestimation can be as high as . %. circular circuits are considered safe and cost-saving for anesthetical practice. nevertheless we conclude that anesthetists should bearin mind vt losses when using circular circuits, due to compressible volume. tracheal stenosis is one of the most serious complications of patients submitted to prolonged endotracheal intubation, in which the decrease in inner diameter of upper airway makes it very difficult to achieve a correct ventilation. objectives: compare the results of applying high frequency jet ventilation (hfjv) to some of these patients with conventional controlled ventilation (cmv). methods: we used a prototype of high frequency jet ventilator (santiago- ) developed in our university, and we developed a tracheal tube in wich we modified the distal tip (conic tip). we applied this system to two patients which were initially ventilated in the operating room with usuai controlled mecanical ventilation (cmv) following the standards of our department, and then intubated with the special endotracheal tube and ventilated with hfjv. results: we could verify a proper ventilation of both patients with cmv and hfjv. during hfjv, the airway pressures were lower than those recorded during cmv. a lower airway pressure prevents lesions due to high pressures. conclusions: hfjv is a good method of ventilation for patients with significative stenosis of the trachea, not only during surgical procedures, but also during ventilation for long periods in critically patients. the ventilatory setting is pressure support mode. the pressure level and fit were kept constant during h/d. arterial blood gas, wbc count, and mean bp was checked according to the schedule: '(immediately before h/d), ', ', ', ', ', '. respiratory drive (represented by poa), tidal volume(ti) and minute ventilation(ve) were continuously recorded by pulmonary mechanics monitor (bicore cp- ). the mean value of the breaths minutes before blood sampling were used to represent the ventilatory status of that period. anova test is used for comparison between groups. for poa, hierarchical cluster method is applied to divide the cases into two groups of similar change. conclusions: our data suggest that pl is very useful, non invasive and low-expensive emergenc e support for arf, expecially in the elderly with severe chronic pulmonary disease and relative controindications to eti. pl seems to be an effective alternative when it is not immediatly possible to perform etl. the multiple inert gas elimination technique (miget) can be used to assess the effects of any given mode of mechanical ventilation on the pulmonary and systemic factors determining arterial po and pco> however, a potential problem in mechanically ventilated patients is that the l mixing box (mb- l) placed in series in the expiratory side of the circuit of the ventilator to sample mixed expired gas may provoke substantial discrepancies between the tidal votume set in the ventilator and the effective tidal volume delivered to the patient, due to the increase in the compression volume (vc) of the circuit. the effects of the mb- l on the v c were compared with those produced by a new l mixing box (mb- l) specifically designed to produce adequate gas mixing and to prevent loss of the two most soluble gases (ether and acetone) used in the miget. at any given peak cycling pressure (p~ak, cm h~o), the v c (ml) provoked by the mb- l was substantially higher (vc= . *ppeak) than that provoked by the new mb- l (vc= . *ppeak). at a ppeak = cm h ~ the v c were ml (mb- l) and m{ (mb- l), respectively (p< . ). in a group of subjects ( m/ f, _+ years), for each of six the gases used in the miget, the regression line between the mixed expired partial pressures simultaneously obtained from mb- l and mb- l fell on the identity line. it is concluded that the new mb- l allows adequate assessment of the effect of different modalities of mechanical ventilatory support on pulmonary gas exchange, with less potential for gas compression and thus hypoventilation. objectives evaluate the influence of different pressure support ventilation (psv) levels on cardiovascular and respiratory funcion in icu polytrauma patients. metbed&we studied polytrauma icu patients , who were in weaning process , after long term mechanical ventilation for acute respiratory failure . mean age ( - ) yrs . they all were connected to servo ventilators siemens c , and all were in stable condition , without sedation , inotropes or diuretics. the hemodynamic studies were done with continuous svo , swan ganz catheter (oximetrix, abbott). they all were in spontanuous mode (spent) with cm h cpap for at least one hour. we turned them to psv with inspiratory assistance (psv cm h ) and after rain we applied psv cm h , and after min psv cm h . hemodynamlo and respiratory measurements were done before and after the application of insiratory assistance. the results were statistically analyzed with anova. resets . respiratory variables . no significant changes in minute volume (ve). tidal volume (vt) and mean airway pressure (mpaw) increased statistically significant (p< . ) . respiratory rate (rr) decreased significantly (p< . ) . blood gase showed no difference . cardiovascular variables. cardiac output (co) decreased ns , heart rate (hr) had no change , central venous pressure (cvp) , mean pulmonary artery pressure (mpap) , pulmonary capillary wedge pressure (pcwp) , increased ns , oxygen delivery (do ) decreased ns, oxygen consumption (vo ) decreased ns. conclusions. psv is a very useful respiratory mode helping patients to be weaned from long term mechanical ventilation . it has beneficial effects on respiratory function and oxygen consumption without affecting seriously the hemodynamic parameters, possibly due to a decrease of the work of breathing. a. michalopoulos, a. anthi, k. rellos, j. kriaras, s. geroulanos intensive care unit, onassis cardiac center, athens. objectives of this study was to examine the effect of different levels of peep on postoperative svo and pvo values in a group of patients, following open heart surgery. methods: upon transfer to icu, patients ( males and females) of mean age _-+ years, were randomly assigned to receive (n= ), (n= ), or cm of peep (n= ). there were no statistically significant differences in demographic data or preoperative respiratory status among the three groups. all patients were ventilated on the assist control mode with a tidal volume of ml/kg. the fraction of inspired oxygen (fio ) was adjusted to keep a pao around mmhg. mixed venous po and svo were measured at min, and hours after application of mechanical ventilation in the icu, just before extubation (be), half hour after extubation (ae), and at hours post-extubation. differences at each study time were analysed by anova. results: mean svo and pvo values among the three groups, for all study intervals, are presented in the table. conclusion: we found no differences (p=ns) in tissue oxygenation (expressed by svo and pvo ) among the three groups, at any study interval, in the early postoperative course of patients following open heart surgery. intrinsic peep (peepi), and high elastance and resistance increase inspiratory work load in copd. cpap reduces work of breathing by counterbalancing peepi. pav provides flow (fa) and volume (va) assistance proportionally to patient resistance and elastance and inspiratory effort. we studied the effects of partitioned support (cpap-fa-va) on breathing pattern and inspiratory effort in five copd patients on pav compared to spontaneous ventilation (sv) and full support (fs: cpap+fa+va). flow, volume, minute ventilation (ve) respiratory rate (rr), inspiratory swing in esophageal pressure (apes), and its integral per breath (pti/b) and per minute (pti/m) were measured. objectives: to evaluate airway pressure fluctuation (apf) during spontaneous breathing in a high compliance cpap system. methods: the cpap system consisted of two l weighted balloons in a wedge shaped holder. ventilating gas flowed from one balloon through a low resistance one way valve into a tracheal tube (ett) provided with a pycor co sensor to monitor rebreathing. the ett was connected to a piston drive mechanical lung. expired gas flowed through a low resistance valve into a second weighted balloon, from where it was exhausted through a peep valve connected in parallel with the second weighted balloon. we evaluated system performance at v r from to ml, at rr from to bpm, while closely monitoring cpap airway pressure swings. at v v of and ml the rr was limited to bpm. for comparison we explored aps of a one l balloon cpap system, the cpap mode of the puritan bennett , and siemens ventilators, when connected to a healthy adult volunteer breathing through an ett. results: the compliance (cpl.) of one l balloon system was linear over a range from . to . l, with a cpl. of . l/em h .the cpl. of the l balloon ( . l/em h ) was linear between a volume of and . l. apf of the weighted balloon system was under em h at all v r (except at a v r of ml aps was . em h ), while the apf in the l balloon was up to em h . apf witli human volunteers with the two commercially available ventilators in the cpap mode was about cm h ; while under identical conditions apf in the l balloon system was . emhzo; and in the two l balloon system was below lcm h . conelusions: cpap using the two balloon system exhibits lower airway pressure fluctuations than a single balloon system; and is substantially lower than found in the two commercially available ventilators when used in the cpap mode. objective: to perform independent lung ventilation (ilv) with individual tidal volume (vt) set at a value generating a plateau airway pressure (pplat) < crnh~o and to evaluate the usefulness of the continuous monitoring of endtidal co (etco ) as a guide to titrate individual lung vt during ilv and for the weaning from ilv. methods: in seven patients, ilv was performed with ttvo ventilators set with the same fio: and respiratory rate. each lung was ventilated with a vt that developed a pplat < cmh~o. this setting led to a lower vt on pathological lung (pl). vt was increased in pl following etco~ and paco -etco variations. ilv was discontinuated when etco~., vt and statical compliance (cst) were similar in both lungs. results: one hour after starting ilv (ti), pl mean vt was significantly lower than in normal lungs (nl) ( + ml vs + ml, p< ) two individual behaviours were observed on tl in pl: four patients presented low etco: (range - mmhg)and normal pacoz (range - mmhg), while three patients had normal etco (range - mmhg) with high pac (range - mmhg). one hour before stopping ilv (t ), vt, etc and paco were the same in each lung. the pao /fio: ratio improved in all patients from the beginning ofllv cst of pl was + % of the normal lungs' cst on ti and improved to . + % ofnl's cst on t (p< . vs conclusions: setting vt of pl to a value not overcoming a pplat threshold does not impair oxygenation and is helpful in avoiding barotraumatism. measurements of differential etco and of the differential paco -etco gradient can be used to titrate vt allocation during ilv and as a guide for the weaning from ilv. total respiratory resistance in mechanically ventilated patients exceeds values obtained in normal subjects, due to the added and highly flow dependent resistance of the endotracheal tube (rett). this can adversely effect the efficacy of pressure regulated modes of assisted ventilation, such as pressure support (psv) and proportional assist ventilation (pav). recent work demonstrates that the influence of rett during psv can be overcome by using tracheal (ptr) rather than airway opening (pao) pressure to regulate the pressure applied (intensive care med :$ , ) . the purpose of this study was to see if this approach would also be effective during pav. flow, volume, pao, ptr, and transdiaphragmatic pressure (pdi) were measured in intubated patients in which either pao or ptt were used to regulate the pressure applied during pav where volume assistance was varied from to % of respiratory elastance. representative results (mean + se) are shown below. compared to spontaneous breathing (pav %), pav increased tidal volume (vt) while reducing respiratory rate (rr) so that minute ventilation ('~e) also rose. this was associated with a reduction in inspiratory effort, as reflected by a decrease in the pressure-time integral ( [ p) of pes and pdi both per minute and per liter ~re. the effects on breathing pattern were similar for pao and ptr regulated pav. in contrast, the reduction in inspiratory effort was always greater for ptr regulated pav. in conclusion, the volume assistance provided by pav is more effective when ptr rather than pao is used to regulate the pressure applied. pav methods: retrospective data analysis of adult patients with normal pulmonary function before operation and uneventful course following coronary artery bypass graft surgery over an month period. we compared assist/controlled mandatory ventilation (s-cmv, patients), synchronized intermittent mandatory ventilation with inspiratory pressure support (s-imv/psv, patients) and biphasic positive airway pressure ventilation (bipap, patients). results: patients ventilated with bipap had a significantly shorter mean duration of intubation ( . h, p< . ) than patients treated with s-imv/-psv ( . h) and s-cmv ( . hi. with s-cmv . % of the patients required single or multiple doses of midazolam but only . % in the s-imv-/psv group and . % in the btpap group. the mean total amount of midazolam of these patients was significantly higher in the s-cmv group ( . mg) than in the s-imv/psv group ( . mg, p< . ) and in the bipap group ( . mg, p< . ). the consumption of pethidine and piritramide did not differ between s-cmv and s-imv/psv but was significantly lower during bipap (p< . ). after extubation the paco patients was highest in the s-cmv group. conclusion: ventilatory support with bipap reduces the consumption of analgesics and sedatives and duration of intubation. unrestricted spontaneous breathing as well as fully ventilatory support allow adequate adaptation to the patients requirements. bipap seems to be an alternative to s-cmv and sqmv/psv ventilation not only in patients with severe ards but also in short term ventilated patients. _objectitives: after end-inspiratory airway occlusion we examined the ensuing gradual decrease in tracheal pressure (ptr) with the following equations proposed by bates et al. and hildebrandt: pv = p'v e'~cccl~ +pst, rs (bates) [ ] where p'tr is tracheal pressure immediately after occlusion, to= is occlusion time, "r is viscoelastic time constant of respiratory system, and p t is static elastic recoil pressure of respiratory system. p~(t) = h -h log t (hildebrandt) [ ] where h~ and h are parameters depending on lung volume, and initial time is s for analytical reasons. materials & methods: we studied healthy patients intubated, anestethized with propofol, paralyzed with vecuronium, and mechanically ventilated with constant flow ( . i/s) at zeep for minor surgery. pressure was measured in the trachea. flow was measured with a pneumotachograph and volume was obtained by numerical integration. the rapid occlusions were produced by an external valve. the signals were sampled at a frequency of hz and processed on a pc. the influence of the cardiac artifacts during the occlusion time ( s) was reduced by a software low-pass filter kaiser finite duration impulse response of elevated order. results: the mean (+ sd) coefficient of correlation using eq. was , -+ . , and using eq. was . + . . the values ofz~ (eq. ), however, decreased with increasing the tidal volume (vt) according to the following equation: "~ = . - . v t, similary, the values of h~ and h increased with increasing v t according to the following functions: h~ = . + v i and h = . + . v t. conclusions: the behaviour of "% of eq. suggests that the linear viscoelastic model is not sufficient to further describe the mechanical properties of the respiratory system over the vt range ( - ml/kg) in ventilated patients. infect this model predicts that "c is constant and independent of tidal volume. on the other hand the plastoelastic model is not sufficient to further describe the mechanical properties of the respiratory system. in fact "r obtained by fitting an exponential for data of eq. , is determined by the time of endinspiratory airway occlusion. obiectives: according to the viscoelastic model, the viscoelastic pressure of the respiratory system pv=rs during lung inflation with constant flow e~ is t/ r wh t lsms ira tlmeand r given by:pv~c.~ = d~( -'e-~ )[ ] ere " ' p" tory " and "r are resistance and time constant of viscoelastic unit. in the past, the viscoaletic constants were determinated by performing a series of occlusions at different lung volumes, or a sedes of occlusions at a fixed lung volume achieved with various inflation flows. in the present study we have developed a new method for determining "c and r which requires a single constant flow inflation. our method is based on determination of pv~r, during a single breath constant flow inflation, and of z during the ensuing end-inspiratory airway occiusion. dudng the occlusion the tracheal pressure p~, declines according the following function: ptr = p'lr e " too= " z + e~t.r= [ ] where p'~r is tracheal pressure immediately after occlusion, toc c is occlusion time, p,i.rs is static elastic recoil pressure of respiratory system, and ~ is viscoelastic time constant. we first determinated "~ by analyzing the time-course of ptr according to eq and next determining r according to eq. , using the expedmental values of p,i=~, ~ and ti, as well as "~ obtained with eq. . materials & methods: we studied healthy patients intubated, anestethized with propofol, paralyzed with vecurenium, and mechanically ventilated with constant flow ( . i/s) at zeep for minor surgery. pres-sure was measured in the trachea. flow was measured with a pneumniachograph and volume was obtained by numerical integration. the rapid occlusions were produced by an external valve. the signals were sampled at a fi'equency of hz and processed on a pc. the influence of the cardiac artifacts dudng the occlusion time ( s) was reduced by a software low-pass filter kaiser finite duration impulse response of elevated order. results: the mean coefficient of correlation with eq. was . . with v t of ml/kg, the mean values (+ sd) of ': and r of the subjects amounted to . • . s and . • . cmh i "~ s. with the traditional multi breath method the corresponding values were . + . s and . _+ . cmh i " s, respectively. with the t-test the difference between new and traditional "~ was statistically significant, between new and traditional r was not significant. conclusions: with the single breath method it is possible to compute ': and r . the mean values of r with v t of nd/kg, however, was slighuy different than those obtained with the traditional multi breath method. the application of modem principles of respiratory care and mechanical ventilation in icus has resulted in increased survival of critically ill individuals with neuromuscular, skeletal and irrevers~le pulmonary diseases. in these chronically ill individunts mechanical ventilation, long term therapy (ltot) and continuous home care is considered a chronic life supporltng technique that can not be withdrawn after their discharge from an icu. the aim of this study was to present the results of a rehabilitation programme and home care that runs in our ward. twenw three patients were referred to our clinic f~om icus during - . a specific rehabilitation programme designed according to individual's needs was performed. patients that benefitted from this programme were grouped into the following disorders. ) post tb respiratow failure ( %) ) neuromuscular diseases, ( %) } undiagnosed sas { %) ) cope) ( %) ( patients had a overlap syndrom). the programme consists of : ) assessment and mechanical support ff needed of the respiratonj system with non invasive methods (nasal or via tracheostomy). ) group and individual respiratory therapy ) mobilization ) nutritional support ) educational classes for the members of the family. three from the patients passed away (during the year), are under nippv during night with or without supply, pts recieve ltot. conclusion: the development of a programme for chronically ill individuals in especially designed wards in hospitals and the overall care at home is considered necessary at least in hospitals with icus. a rehabilitation programme and home care permits the fast but safe discharge of these patients from units of acute medicine that the cost of treatment is high and besides permits beds that are invaluable. we considered that the rehabilitation prod'amine and home care in our ward is the first performed in greek chronically ill pts and even though there is no special administxative support we think that the results are quite saltsfactory. objective: we postulated that the product of the respiratory frequency (f) and the ratio of inspiratory pressure (ip) to maximal inspiratory pressure (mip) would predict the weaning outcome in deeompensated copd patients better than either variable alone or other indices previously proposed. methods: in decompensated copd patients with difficult weaning, we measured, daily, respiratory mechanics data both during mechanical ventilation and after ten minutes of spontaneous breathing. then we calculated weaning indices reported in literature and some new integrated indices. according to the results of the discriminant analysis, we considered the integrative index crop (acronym of compliance, rate, oxygenation and pressure), the rapid shallow breathing index f/vt, the load/capacity ratio ip/mip, and the following new index: f x ip/mip. we used receiver-operatingcharacteristic (roc) analysis by calculating the area under the curve considered as the overall probability of correct classification. results: main results are reported in the following objective: to evaluate the reliability of some indices of endurance in predicting the weaning outcome of decompensated copd patients. methods: in decompensated copd patients with difficult weaning from mechanical ventilation (mv) we measured, daily, blood gas analysis, ventilatory and airway pressure pattern during mv, breathing pattern (frequency (f) and tidal, volume (v~)), inspiratory pressure (ip), and maximal ip (mip) during spontaneous breathing (sb). thereafter we calculated the following weaning indices: crop (compliance * mip * (pao /pao ) / f), flvt, ip/mip. data obtained the day at which the patient was considered ready for a trial of sb on clinical grounds but weaning failed (wf) and those obtained the day of the successful weaning (ws) were compared statistically through the wilcoxon rank-sum pair analysis. in order to quantify the predictive accuracy for each index with respect to successful weaning we calculated sensitivity, specificity, and diagnostic accuracy according with the standard formulas. methods : five patients ( + yrs) suffering from ards (lung injury score > . ) for hours or less entered into the study. irv (volume controlled, decelerating flow, % inspiratory pause, lie = / ) was compared to conventional ventilation (cv) (volume controlled, constant flow, no inspiratory pause, iie= / ). these two modes were applied for hours in a randomized order, with the same levels of total peep (peept = peep + peepi), tidal volume ( . • . ml/kg), respiratory rate ( • "bpm) mad fit ( • %). measurements (respiratory mechanics, hemodynamics, arterial and mixed venous blood gases) were performed after , , and hours of application of each mode. rvsuils : are expressed as mean + sem and compared by anova. backeround and methods: periodic breathing (pb) is characterized by repetitive cyclic variation in minute ventilation. pb is considewxl to be provoked by an instability in the respiratory control. inintubated, spontaneously breathing patients conventional modes of pressure support ventilation, i.e., triggered inspiratory pressure support ps), do not allow patients to breathe with theirinherent breathing pattern. therefore, pb, if existing, will appear mainiy after extubation. since our new mode of pressure support ventilation" automatic tube compensation" (atc) continuonsly corrects for the flow-dependent tube resistance during insnmdon and expiration ("electronic" extubatim), it pemaits patients to maintain their own inherent breathing pattern. then, ff necessary, tracheal pressure can be additionally supported by volume-proportioead and/or by flow-proportional pressure support (proportional assist ventilation, pav). (~as~: we report the case of a -year-old male patient who was intubated due to acute respiratory insufficiency after acute myocardial infarction with left ventricular dysfunction. during ips of mbar the patient showed a regular breathing pattem which became periodic during atc. in addition, proportional assist ventilation of mbar/l increased periodic breathing in such a way that the typical cheyne-stokes breathing pattem occurred (see figure) . baqkground: the hering-breuer reflex (hbr) is characterized by an inhibition of inspiration during lung inflation. this response has been recognized as an important vagally mediated mechanism for regulating the rate and depth of respiration in newborn mammals. in adult man the hbr is considered to be active only at lung volumes well above functional residual capacity, i.e., at tidal volumes above ml. assessment of the hbr requires specialized methods such as single breath or multiple occlusion technique. methods; in the presence of desynchronization between ventilator and patient, which frequently occurs during triggered inspiratory pressure support ventilation (ips)(see figure) , prolongation of the interval between inspiratory efforts (indicated by negative deflection of the esophageal pressure) due to lung inflation exposes an active hbr. we examined the occurrence of hbr in intubated critically ill patients. strength of hbr was assessed by the formula: prolongation [%] = ((inspiratory interval of interest -preceding inspiratory interval)/preceding inspiratory interval) * ( . rr of patients examined showed moderate to severe desynchronization. in of these patients a (re)activation of the hbr was found. the strength of hbr amounted to + %. there was a significant correlation between tidal volume and strength of hbr. in contrast to previous reports, an active hbr was shown during lung inflation well below ml. b pck~round: triggered inspiratory pressure support ventilation (ips) is commonly used to support inspiration in intubated spontaneously breathing patients. despite its usefulness ips shows some disadvantages which can be deleterious in crificauy ill patients: -additional work of breathing to be performed by the patient due to the flow-dependent tube resistance -desynchronization between patient and ventilator due to inherent triggering failures of the ips mode suppression of the patient's inherent breathing pattern -inability to predict successful extubation in difficult-to-wean patients methods: based on the known flow-dependent tube resistance our new mode "automatic tube compensation" (atc) compensates for the pressure drop across the endotracheal tube ("electronic" extubation). then, if necessary, tracheal pressure can be supported by volume-proportional pressure support (vpps) and/or by flow-proportional pressure support (fpps). results: hitherto, we have examined patients after open-heart surgery and patients with acute respiratory insufficiency (ari) or ards using atc with/without vpps/fpps. preliminary results suggest that the new mode avoids additional work of breathing due to accurate compensation of the pressure drop across the endotracheal tube during in-/expiration prevents desynchronization between patient and ventilator allows patients to breathe with their inherent breathing pattern accurately predicts the outcome of extubation even in difficult-to-wean patients due to "electronic" extubation conclusions: the new mode atc with/without vpps/fpps allows to support ventilation in a more physiologic manner and overcomes the disadvantages of conventional modes of pressure support in intubated patients. backgound: cheyne-stokes respiration (cs) is characterized by regula]; recurring periods of hyperpnea and apnea. in normal subjects, cs may occur after hyperventilation, after arrival in high altitude, or during sleep. it has also been observed in patients with prolonged circulation time due to congestive heart failure, as well as in some neurological patients. there is no report about the influence of sedative drugs on periodic breathing (pb) and cs. methods: in intubated patients conventional modes of pressure support do not allow patients to breathe with their inherent breathing pattem. therefore, periodic breathing and cs are rarely seen. since our new mode of pressure support ventilation "automatic tube compensation" (atc) continuously corrects for the flow-dependent tube resistance during inspiration and expiration ("electronic" extubation) it permits patients to maintain their own inherent breathing pattem even if pathological, e.g., periodic. results: using this new mode of pressure support ventilation, periodic breathing was unmasked in of intubated patients, of which showed cs. in of these patients the occurrence of cs was linked to impaired left ventricular function with increased circulation time. normal left ventricular and neurologic function was found in the remaining patients. in of these patients cs disappeared after intravenous administration of the benzo-diazepine antagonist flumazenil (figure). consequently, in this patient cs was induced by benzodiazepine sedation. objecti',~s: in contrast to conventional rhodes for pressure supported spontaneous breathing, our newly developed ventilatow mode ,,automatic tube compensation" (atc) completely compensates for the flow-depandant pressure drop tlpm-r across endotracheal ttlbe (ett). in the atc mode, the ventilator supplies a flow v' in order to maintain a constant tracheal pressure p~,,~. to this end, pk,,= has to be oontinuousiy determined. since continued measurement of p,,~ by introducing a catheter via the ett is not reliable, we opted for its continuous calculation socordng to the following equation: p~ = p,,, -aperr, pw being the continuously measured airway pressure. this also requires the continual measurement .of flow v' to calculata apm-r using the non-fineer approximation: aport = kvv' + k .w. the constant tube coefficients k~ and k are mathematically determined by mesns of a least-squares-fit procadum based on laboratory investigations. tracheal secretions, however, reduca the omss-saction of the ett. consequently, ~ values of ki end k are changed rendering the p~,ch calculations inaccurate. therefore, k and ~ have to be pedodcally updated to ensure an a~urete monitoring of pn,~ and a complete tube compensation under atc at any time. background: one of the first steps in weaning patients from controlled mechanical ventilation is to stop muscle relaxation and to reduce sedation. it can take several hours, however, until the patient is able to trigger the ventilator and to breathe spontaneously. during this period, many patients display a sudden increase in peak airway pressure of up to %. patients and methods: to investigate the reason for this potentially dangerous effect, we continuously measured lung and chest wall mechanics in post-operatively ventilated patients. lung mechanics (airway resistance and lung compliance) was measured using the esophageal balloon technique as described in [ ] . chest wall mechanics (tissue resistance and chest wall compliance) was calculated from lung mechanics and total respiratory system mechanics as described in [ ] . results: we found a decrease of chest wall compliance (cw) to be the main reason for episodes of sudden airway pressure increase while lung compliance (cl) remained unchanged. the decrease of c w can be inter- gil cano a, san pedro jm ~, sandar d, herntndez . , carrizosa f, , herrero a. emergency and intensive care department, hospital of jerez, spain objective: ) to determine the incidence of hypoteasion (h) associated with emergency intabatian of mechanical ventilation, and ) to establish its relauonship with respiratory mechanics (rm) and arterial blood gases. mechanical ventilation performed in the emergency room, in a prospective eans~eative manner, were evaluated. data collected included patient demographics, diagnoses, blood pressure and arterial blood gas levels before and at~er intabatian, and p_m, including calculated pulmonary end-inspiratory volume above functional residual capacity (veic) and calculated dynamic hypetinflatien (dhc). all patients received midazolen and awaanrinm to facilitate tracheal intubatien and rm measurement. hypotension was defined as a decrease in systolic pressure higher than mmhg or an absolute decrease in systolic blood pressure below to mhg within hour of intabatian. patients were excluded because met at least one of the following exclusion criteria: preexisting shock or h ( ), cardiac arrest ( ) . there weren't any association between peepi or other airway pressures (paw) and h, but calculated pulmonary volitmes had tendency to be larger in patients with h (p < . ). high paco before lrasheal intubatian ( . - mmhg) with a quickly decrease alter starting mechanical ventilation was a usual finding (p < . ) in patients who developed h. paw. ) thexe was a good relatienship between h and high arterial paco before traqueal intahatian and its fast "washing" with mechanical ventilation. ) because cao patients had the highest incidence of h, controned mechanicel hypoventilatien driven by paco changes and pulmonary volumes monitoring instead paw, should be attempted in these patients to avoid this cemplication after tracheal intubatiert. introduction: the endotracheal tube (ett) and demand valve devices cause an added work of breathing (wobadd), which is the work necessary to overcome the resistive load of the ett and the breathing circuit ( ). application of ips has been shown to partly compensate this added work ( ). since tbe amount of wobadd is flow dependent, a fixed ips is not adequate to completly compensate the wobadd ( ). therefore, atc has been developed as a new form of assisted spontaneous breathing ( ), which provides a flow-dependent pressure support. thereby, it theoretically should compensate all the wobadd due to the tube. the purpose of this study was to evaluate the reduction of wobadd with ips and atc for different ett. methods: a mechanical lung model (ls , dr*alger, liibeck, frg) was used to generate a constant spontaneous breathing pattern. the ls was connected to an artificial trachea (at, cm long, mm id). the at was intubated with three different tubes of . , . , . mm id and connected to an evita ventilator modified to provide atc as an option (dfager, liibeck, frg). flow and airway pressure were measured between the y-piece and the ett for four different modes of ventilation: cpap, ips of and cm i and atc all with a peep of cm h . the tracheal pressure (ptrach) was measured in the at. total wobadd was calculated as the area subtended by the ptrach-volume curve below peep. results: the results for total wobadd in nd/ are shown in the figure for the three different ett: breath/mln, s=success, f=failur% *~p<. , **-p< , ns = non significant, f versus s neveltheless, in / patients, invasive ventilation was necessary in mean . _+ hours after beginning of fmpsv. there was no significant difference between the two groups (success, failure) in following parameters : sex, age, previous histoly, medical treatment, saps & , clinical signs (rr, spo , heart rate, blood pressure, glasgow score...), radiological and echocardiographic findings and standard biological parameters. only two parameters were related with failure : .a low value of pac on admission until the patients were intubated. . an increased level of cpk in relation with an acute myocardial infarction ( / cases in the failure group, vs / cases in the success group, x~(with continuity correction) : p<. ). conclusion : fmpsv is a noninvasive, safe, rapidly effective method of treatment in acpe, which may avoid tracheal intubation. further studies are necessary to precise if association of arf and low paco (< mmhg) and/er acute myocardial infarction represents an indication of immediate invasive ventilation. introduction: since the added work of breathing (wobadd) imposed by the endotracheal tube (ets and the breathing circuit is regarded as an important contribution to the total work of breathing, considerable effort has been tmdettaken to compensate for this added work. ips has been fotmd to decrease the wobadd imposed by different ventilators ( , ). because of the flow dependent pressure drop across the etf the tracheal pressure (ptr) should be measured to estimate the total imposed wobadd (wobtut) ( , ). the aim of this study was to assess the circuit imposed work (wobcirc) and wobtot (including ett) for different demand valve ventilators during cpap and/ps. methods: a mechanical lung model (ls , driiger, lfibeck, frg) generated a constant spontaneuus breathing pattern. the ls was connected to an artificial trachea (at), intubated with an . nun et]', end connected to one of four ventilators (servo c and servo , siemens,-elema, sweden; evita , driiges, liibeck, frg; pb ae, puritan bennett, carlsbad, usa). three different modes of ventilator settings were tested (cpap, ips and mbar; trigger set at maximal sensitivity, peep always mbar). flow and airway pressure (paw) were measured between the y-piece and the etr; tracheal pressure (ptr) was measured in the at. wobtot was calculated as the area under the ptr-volume curve below peep, wobcirc was calculated as the area under the paw-volume curve below peep. results: in the foti g., patroniti n., cereda m., sparacino me., giacemini m., pesenti a. inst.of anesth.and intensive care-univ.of milan -sgh monza i aim of the study was to assess cpl,rs measurement obtained by the airway occlusion method during psv. we therefore studied paralyzed cppv ventilated ali patients (lung injury score = . • that were weaned to psv. we performed end inspiratory and end expiratory airway occlusions using the hold function of the ventilator (siemens serve c), first during cppv and then within the th psv hour. airway pressure and flow signals were recorded (cpi bicore) for subsequent analysis. an airway pressure plateau was defined as a flow tracing in which airway pressure was stable for at least . sec. end inspiratory (pel,rsi) and end expiratory (pel,rse) recoil pressures were then measured as the mean airway pressure during plateaus. cpl,rs was computed as tv/ (pel,rsi-pel,rse i) cpl,rs can be adequately estimated during psv using the airway occlusion method; ) during psv inspiratory plateaus are longer than the expiratory ones; ) the length of plateaus is negatively affected by the respiratory drive. foti g., de marchi l., *tagliabue m., gilardi p., giacomini m., sparacino me., pesenti a. inst.of anesth.and intensive care,-univ.of milan *dept.of radiology-sgh monza i we retrospectively compared ct scan and gas exchange findings between a group of patients successfully weaned from vcv to psv (group s = ii patients) and a group who failed the weaning (group f = patients). we selected ali patients (lis= . • in vcv mode who had available a chest ct scan performed within days from the weaning trial. a psv trial was began as soon as the patient reached hemodynamic stability and a pao > mmhg, irrespective of fie (peep < cmh ). maximum psv level was < (pel,rs-peep) measured during vcv, where pel,rs was the respiratory system elastic recoil pressure at end inspiration. psv ventilation was considered successful if a respiratory rate < bpm, an increase in fie lower than . compared to vcv, a pace increase < % of vcv value and hemodynamic stability were maintained during the next hours of psv. if any of these conditions was not met the trial was declared a failure. interdisciplinary critical care unit, regional hospital lugano-ch *surgical critical care unit, university hospital, geneva-ch objective: to assess the degree of correlation of cardiac output measured by thoracic electrical bioimpedance and thermodilution in mechanically ventilated patients with different levels of positive end-expiratory pressure (peep). methods: prospective study with ventilated patients, after head injury and with postoperative sepsis, with normal cardiac output: simultaneous determination of cardiac output by thermodilution and thoracic electrical bioimpedance performed with different levels of peep ( - - cm h ). results: cardiac output measured by thermodilution during sequential increment of peep did not vary: . + . for peep , . + . for peep and . + . l/rain for peep . simultaneously the bioimpedance device recorded a significant increase in cardiac output from . + . for peep to . + . l/mi for peep . (p < , ). conclusion: cardiac output measured by bioimpedance cannot replace the invasive thermodilution methods of cardiac measurement output during mechanical ventilation with peep. we also isolated a subset (h) of patients who had been hypercapnic (paco > mmhg) for at least days (range to days) before the end of cv. the psv trial was started as soon as pao was > mmhg, irrespective of fie and with peep < cmh and the psv level had to be < (pplateau-peep) as measured during cv. pace , pha, base excess (be) were collected before discontinuation of cv and on the ist day of psv: ) . ) weaning is more difficult in pts with head injury(p<o, ) and iss> (p<o,ol), in elderly(p<o, ) and in pts who need fi > , (p<o, ) and peep>io cm h (p<o, ). ) pts with iss> need longer duration of mv (p<o,ol). ) the mortality rate is higher in pts with iss> (p<o,o ), with head injury (p<o,ol) and in elderly (p<o, ). ) paradoxally, compliance was found to be higher in pts> years than in pts< years (p<o, ). s. crotti, p.pelosi, d.mascheroni, m.cerisara, a.lissoni, l.gattinoni. istituto di anestesia e rianimazione -irccs, milano, italia. obiectives. we investigated by ct scan the effects of extrinsic peep (peepe) on lung inflation, tidal volume distribution and regional compliance in sedated, paralyzed chronic obstructive pulmonary disease (copd) patients with dynamic hyperinflation (peep• methods. two ct section (end expiration, end inspiration) were obtained at lung base level in patients (individual analysis for each of the eight lungs) at peepe levels: peepe = cmh (zeep) and peepe amounting to %, % and % of the peep• at zeep ( . • cmh ). tidal volume was kept constant ( • . ml/kg). each lung section was divided into zones equally spaced along the vertical axis: upper (the most ventral), middle and lower (the most dorsal) zone. for each zone we computed: gas volume at end expiration (gase) and at end inspiration (gas• tidal volume (dgas=gasi-gase) and compliance (cpl=dgas/dp;.dp=plateau pressureactual peep• we also computed the lung inflation as the entire ct section gas volume at end expiration (total gase). results. at each peep level both gase and gas• were higher in the upper than in the lower zone ( we cone!ude that in copd patients with dynamic hyperinflation only the application of peepe higher than peepi produces a further increase of lung inflation, decreasing cpl of the upper zone (the more expanded one) probably by stretching phenomena, and causing dgas redistribution from the non dependent to the dependent lung zones. i. ravagnan, p. vicardi, f. valenza, d. tubiolo. p. pelosi l. gattinoni. st . anestesia e rianimazione, universita' di milano, ospedale maggiore -irccs, italy objectives: to investigate the effects of peep and ps on respiratory. pattern and inspiratory effort during ps ventilation in patients with acute lung injury or acute exacerbation of chronic lung disease. methods: pts with acute (a) (paco = • mmhg, pao /pao = . • and pts with chronic (c)(paco = • mmhg, pao /pao = . : . ) lung disease were studied in ps ventilation during the weaning phase. measuring airway pressure, esophageal pressure and gas flow we computed respiratory rate (ril bpm), tidal volume (tv, ml) and pressure time product (ptp, cmh *s/min), which is an index of oxygen muscle consumption. measurements were collected, after rain of stabilization, at and cmh ps and at two different peep levels ( and cndd conclusions: during psv: ) breathing pattern and ptp are different between a and c; ) in both groups peep does not modify breathing pattern; ) peep reduces ptp in c but not in a; ) ps modifies breathing pattern and reduces ptp in c but not in a. to test the performance of a new heat and moisture exchanger (hme): twistair, baxter. this is a hydrophobic-hydrophilic hme without hygroscopic salts. method: we evaluated the hme performance with a previously described method (i); it consists of a "lung simulator" connected to a mechanical ventilator and a flow divider, with a dry and a wet thermal probe inserted into inspiratory and expiratory limbs. on average ps level changes were associate( with opposed changes in both p . and rr. changes in p . were remarkable, homogeneous and highly significant (p<. ), while changes in rr were less pronounced, inhomogeneous and less significant (p<. ). it seems therefore that p . is a better index than rr for estimating a change in load for the respiratory muscles. recently, the lsf method has been described as an interesitng alternative to conventional tecniques used to measure total respiratory mechanics, providing, over these latter, advantages such as no need for hold maneuvers and no need for particular flow patterns. data on the reliability of the lsf method, however, are still few. methods. sets of measurements were obtained in each of ards patients, paralyzed and ventilated in cmv with constant inspiratory flow and an end-inspiratory pause equal to % of ttot. the lsf method provided data for total compliance (ctotlsf) and total resistance (rtotlsf) by multiple linear regression analysis of airway pressure, flow and volume change, applied over the entire breath. the lsf measurements were automatic and continuous, and each value used for analysis was the average of consecutive cycles. conventional measurements of dynamic.compliance (cdyn), quasistatic compliance (cqs), minimum inspiratory resistance (rmin) and maximum inspiratory resistance (rmax) were obtained by the constant flow, end-inspiratory occlusion method, each value being the average of measuremts. ctotlsf was compared with cdyn and cqs, while rtotlsf was compared with rmin and rmax. results. ctotlsf showed a high correlation both with cdyn (cdyn=. .ctotlsf+l. , r =. ), and with cqs (cqs =. .ctotlsf + . , r =. ). the average difference between ctotlsf and cqs, yet, was much lower (+. + . ml/cmh ) than the one between ctotlsf and cdyn (+ . + . ml/cmh ). rtotlsf correlated much better with rmax (rmax=. *rtotlso+. , r =. ) than with rmin (rmin =. .rtotlsf +. . , r =. ). the average difference between rtotlsf and rmin was + . + . cmh / /s, while the one between rtotlsf and rmax was +. + . , confirming the better agreement between rtotlsf and rrnax. conclusion.the agreement between rtotlsf and rmax suggests that rtotlsf takes into account both the airway and the tissue components of resistance, unlike rmin which only expresses airway resistance. the agreement between ctotlsf and cqs indicates that ctotlsf expresses the pure elastic components of the respiratory system. in the paralyzed patient, the expiratory time constant (rce) of the unit represented by total respiratory system and ventilator can be calculated from the slope of the expiratory flow-volume curve. recently it has been suggested that an estimate of this slope is provided by the ve/v'epeak ratio, ve being the exaled tidal volume and v'epeak the peak expiratory flow.the reliability of this method is still little known. methods. sets of measurements were obtained in mechanically ventilated ards patients during paralysis and cmv. measurements of ventilator expiratory resistance (rext) and of total respiratory mechanics were performed in order to calculate these reference measurements for ve/v'epeak: rcdyn=(rmin+rext)ocdyn, rcstat=(rmax+rext)ocqs, rclsf=(rlsf+rext)~ cdyn (dynamic compliance), cqs (quasistatic compliance), rmin (minimum inspiratory resistance), rmax (maximum inspiratory resistance) were obtained by the constant flow, end-inspiratory occlusion method. clsf and rlsf respectively corresponded to measurements of total respiratory system compliance and resistance by the least squares fitting method. ve/v'epeak showed a high correlation with all reference measurements, rcdyn (ve/v'epeak= . orcdyn-. , r =. ), rcstat (ve/v'epeak = . rcstat -. , r = . ), and especially rclsf (see fig the static pressure volume curve of the respiratory system (p/vst) provides valuable information, but the extensive data analysis prevents its use in clinical routine. dynamic p/vcurves are simpler to record. the objective of this study was to develop an automated method to obtain quasi-static p/v-curves (p/vqs) during low flow inflation as well as to measure resistance. preliminary tests were done in normal subjects and subjects with varying degree of lung disease. methods: a computer/ventilator interface (cvl) was constructed for control of a servo ventilator c during an automatic sequence: a) a normal breath, b) a prolonged expiration at zero peep, c) a low flow inflation of a predetermined volume, d) analysis of ventilator pressure and flow. pressure was corrected for tube resistance. airway resistance was calculated from a) and used to derive p/vqs from c). as reference, p/vst was obtained by the occlusion method. results: in non-obstructive diseases the method performed well at volume and pressure controlled ventilation. static and quasistatic compliance were virtually identical. p/vqs clearly reflected the lower inflection point and, when present, the upper inflection point (uip). in some patients uip was more evident in p/vqs, especially at an increased inflation flow rate. in obstructive diseases, the method for subtraction of resistive pressure was inadequate. conclusions: the system for automated computer controlled studies of lung mechanics based on a standard ventilator provides comprehensive information. differences between p/vst and p/vqs imply that the latter reflects also other factors than p/vst that contribute to impedance at hyperdistension. the clinical significance of the two curves remains to be shown. obiective: to evaluate the effect of combined high frequency jet ventilation (chfjv) in patients with severe respiratory insufficiency (sri). methods: in a retrospective study of the period - we analyzed patients suffering from sri who were refractory to conventional mechanical ventilation and were treated with combined high-frequency jet ventilation (chfjv). refractory to conventional mechanical ventilation was defined as a pao /fio < , despite maximal ventilator settings: peep > cm hz , fit > . . a total of patients matched these criteria, males and females with a median age of ( - ) years. seventeen suffered from severe trauma. chfjv was started following a median period of ( - ) days of conventional mechanical ventilation. prior to chfjv ventilation parameters expressed as median were the following: fit . , pao /fio , peep cm h peak airway pressure (pap) cm h . chfjv consisted of high frequency jet ventilation with a frequency of to breaths/minute, driving pressure of . to . arm, and inspiration time of to percent, superimposed on the whole cycle of conventional mechanical ventilation with a frequency of l to breaths/minute and tidal volumes of to ml. results: following two days of chfjv of patients showed an improvement of ventilatory parameters; peep could be reduced to < cm h in patients, the pap was decreased with > cm h:o in patients, fio could be reduced to < . in patients and finally the median pao /fio ratio changed from to . during chfjv patients died, of respiratory failure and due to multiple organ failure, died within two days of chfjv. the median duration of chfjv in survivors and nonsurvivors was days in both groups. conclusions: our data show that with chfjv in the majority of patients with sri who are refractory to conventional mechanical ventilatior" the ventilatory parameters can be improved. backeround and obiectives: although ventilation with peep above the inflection point (pinf) has been shown to reduce lung injury by recruiting previously closed alveolar regions, it carries the risk of hyperinflating the lungs. in the present study we set out to develop a new strategy to recruit the lung during ventilation with small vt, while maintaining peep levels as low as possible. we hypothesized that if the lung was recruited with a sustained inflation (si) to total lung capacity, recruitment would be maintained as long as the peep level was higher than the critical closing pressure of the lung, as observed on the deflation limb of the pv curve (ajrccm ; ( ) :a ). the purpose of this study was to examine the hypothesis that a strategy using si and a peep<pinf would induce less lung injury during small tidal ventilation than ventilation at the same low peep level without using a recmitment strategy in a model of respiratory distress syndrome. methods: we used a randomized protocol with groups to ventilate nonperfused, lavaged rat lungs with small vt ( to ml/kg) for hours and studied the effect on compliance and lung injury. group : peep>ping group : peep<pin f with an si, inflation to on h over sec, to recruit volume; group : peep<pinf without si; group : control group, lungs were inflated at peep<pin f, but not ventilated. results: in group and group static compliance did not change after ventilation (table) . in group static compliance fell significantly. group showed significant changes in the pv curve, which were less severe than in group . results from morphological examination are pending but preliminary results showed less lung injury in group , compared to group . conclusions: small tidal ventilation following a recruitment manoeuvre in a model of respiratory distress syndrome allows ventilation on the deflation limb of the pv curve at a peep below pinf. this strategy ( ) minimizes lung injury as well as, or better than using peep above pint" and ( ) ensures a lower peep to minimize the detrimental consequences of high lung volume ventilation. i~peep>pin~ _objectives-this report is presenting the results of the clinical study for using eeg examination as a method of the evaluation of patients ability for weaning. methods: the study inclljqles eeg examinations with fourier spectral analysis' of patients ~vith respiratory insufficiency and prolonged control mechanical ventilation (cmv). all patients have had a-rhythm of eeg before weaning. we have followed respiratory rate, tidal volume, respiratory pa{tern, end-tidal co and blood gases during weaning. results: patients had invariable eeg activity or short -waves period (till one hour). the weaning of this patients was fast arid sucsessful. other patients have had a decreasing of a-activity, an appearence of -waves for an hour and more, a short episodes of a-and e-activity. after that this patients had gas exchange and respiratory disorders with regression of the weaning right up to cmv. conclusion: eeg could be used as a method of the evaluation of patients ability for weaning from cmv. some eeg signs shows the overstrain of compensatory systems before the change to the worse of gas exchange and respiratory pattern. s. elatrous, p. aslanian, d. touchard, d. corsi, h. lorino, l. brochard. medical intensive care unit, inserm u , hopital henri mender, cr~teil, france. in vitro comparison of flow triggering (ft) systems demonstrated advantages compared to pressure triggering (pt) systems for some ventilators (puritan bennett ) but not others (siemens serve ). we studied the two types of systems in two groups of patients mechanically assisted with pressure support ventilation ( + cmh ). in the first group (pb ) the effort of breathing, assessed by the esophageal pressure time index, was significantly lower with the ft than with the pt ( + cmh .s/min - vs + , p< . ). by contrast no significant difference appeared in the second group (serve ), as predicted by the bench study despite marked interindividual differences ( + cmh .s/min - vs + , p = . ). we conclude that ) rigorously performed bench studies can predict in vivo effects, ) mild advantages can be found for the new triggering systems on some ventilators. objectives: pressore-volume curves (pv) of the respiratory system is of interest for the determination static compliance (cs , lower (lip) and upper (uip) inflection points which indicate zones of airway recruitment and overdistension. this study aimed to compare an "automated low flow inflation" method (alfi) to the reference occlusion (oc) method. the ability of the former method to identify cst, lip and uip was tested in icu patients. me,otis: ( arf and ards) sedated paralysed patients were studied using a serve c ventilator linked to a computer which automatically forced the ventilator to insufflate at a low constant flow a velum up to - ml or a maximum paw of cm h (alfi). the quasistatic elastic pressure (pel,qs was obtained by subtraction of the resistive pressure of tubing and patient and related to volume for calculation of compliance cqst. for oc tidal volumes (v from up to - ml were followed by a s post-inspiratury pause for determination of static pal (pel,st) in relation to volume. compliance was defined from the linear part of the p/v curves. lip and uip were defined from the consistent deviation of p/v data from extrapolated the linear part. ~,~ i~: in ards, mean cst was . + . and cqst . + . ml/cm h (us), lipst . + . and lipqst . + . cm h (us), uipst . + . and uipqst . + ~ cm h (us). nosocomial pneumonias (np) are frequent and often unsuspected during ards (bell, ! ). in the present study, we evaluated prospectively the onset of np during severe ards (group b of the european study). patients and methods: the charts of patients with severe ards have been prospectively recorded. a plugged telescopic catheter (ptc) specimen has been systematically performed every hours, for quantitative bacteriological analysis. the diagnosis of np was defined by a number > colony forming units / ml. results: for the patients studied, the mean saps score (+ sd) was +_ , the initial pao /fio ratio was -&-_ , the duration of mechanical ventilation (mv) was + days. the mean delay before the onset of the first np was . + . days ( - ), and the mean pao /fio ratio was +- . respiratory symptoms (purulent aspirates, new pulmonary infiltrates, or gazometric changes) were present in % of the patients studied. alteration of gas exchange was present in of the patients ( np) . a new pulmonary infiltrate was present in only np ( %). an increase of fever was noted in patients, an increase of leukocytosis > % in patients, an increase of volume and purulence of sputum in of the patients with np. the degree ofgazometric worsening (pao /fio before np minus pao /fio during np) during the first episode of np was + mmhg. excluding the bacteriological criteria of np, the number of criterias of np present was in / patients, ( / ), ( / ) or ( / ). two patients only had a pulmonary colonization (ptc: < cfu / ml) before the first episode of np. the incidence of np is high ( %) during severe ards. the first episode occurs in average:at the th day, and is the cause of a severe hypoxemia (pao /fio ) . the onset of a np may contribute to the high mortality rate observed in our patients ( %). each worsening of hypoxemia during severe ards should induce to suspect a np. respiratory system during mechanical ventilation. the me~hod quantifies the dissipative energy consumption of the respiratory system in terms of energy loss aek, inefficiency ~k~ and respiratory dissipative resistance rk~ over a given partition of the tidal volume. the method can be applied in intensive care units with no interference to ventilatory support. it allows for monitoring the combined effects of inhomogeneities, non-linearities and visco-elastic effects, that are subject to change in the respiratory system. the method is studied on pigs~ in the presence of a log-dose response curve of methacholine (mch) induced disease. in healthy pigs~ we find a mean value of energy loss, ae, of . • j/l, a mean value of inefflency, ~ of . ~= . and a mean value of resistance, ~, of . • cm h s/ . the respiratory resistance, rk, shows a variation over the partition of tidal volume with armax ---- . • . cm h s/l. during methacholine provocation~ ae rises more than five-fold up to . • j/l~ doubles to . • and t~ increases to a maximum of • cm h s/l, with armax : . • . cm h s/ . the variation in rk becomes more pronounced with higher doses of methacholine. methods: ards patients were prospectively studied. initially they were ventilated in the amv (assist mechanical ventilation) mode with the settings prescribed by their primary physician. after stabilization, ventilatory gas exchange and hemodynamic variables were determined. patients were then ventilated in the mrv (mandatory rate ventilation) mode with breaths as the target rate. in mrv the target rate is set and the ventilator autoregulates the pressure support level delivered ~o achieve this rate. after stabilization, the measurements done on amv were repeated. finally, patients were sedated and paralyzed and ventilated in cmv (control mechanical ventilation) with the ventilatory variables they had during mrv. measurements done in amv and mrv were repeated and respiratory mechanics were assessed with the constant flow end inspiratory occlusion method. results: two groups were recognized based on their response to mrv. tn group patients responded to mrv by decreasing their v and increasing the t/t t ratio. ve, vo , and aado decreased while paco increased and tda vo ume and co remained unchanged. on the contrary, in group v, vr and ve increased; ppeak and trr t remained unchanged, paco~ decreased while vo and aado increased with constant co, the pressure support level needed to achieve the target rate was much lower in group than in group ( , -+ . vs . _+ . ). obiectives : in the newly developed mode of ventilatory support ,,automatic tube compensation" (atc) the ventilator compensates for the flow-dependent pressure drop across the endetracheat tube (ett) thus allowing ,,e]ectronic extubation". the aim of the study is to investigate whether healthy subjects perceive atc in inspiration (atc-in) and in expiration (atc-in-ex) and whether atc provides an increase in subjective comfort compared with the conventional assisted spontaneous breathing mode (asb). methods : healthy volunteers (no preceding lung disease, non-smokers, male, - years)breathed spontaneously through an uncut ett of . mm id via a mouthpiece. the ett was connected with a prototype ventilator evita modified by the manufacturer (drfiger, lebeck) for atc. flow and airway pressure were measured at the outer end of the ett. three ventilatory modes, ( ) asb ( mbarover mbar peep), ( ) atcin, ( ) atc-in-ex were selected in random order. immediately following the transition from one mode to another the volunteers answered by hand sign how they perceived the new mode compared with the preceding mode: ,,better" (+ ), ,,equal" ( ) or ,,worse" (- ). inspiration and expiration were investigated separately by presenting mode transitions (in total; including ,,placebo" transitions). results : the difference between atc and conventional asb is perceived in inspiration and in expiration. atc is positively judged; asb is nega ively judged. the diagrams show mean values _+ sd of five volunteers investigated up to now. the new mode atc is perceived as an increase in subjective comfort. our explanation is that atc preserves the natural breathing pattern better than conventional asb. objectives: to determine the role of cerebral vasoconstriction in the delayed hypoperfusion phase in comatose patients after cardiac arrest. to correlate the results with indices of cerebral oxygenation and the levels of several vasoactive hormones in the jugular bulb. methods: in comatose patients after cardiac arrest we measured the pulsatility index (pi) of the medial cerebral artery by transcranial doppler sonography. the pi is a reliable indicator of cerebral vascular resistance. we also sampled blood from the jugular bulb and measured cerebral oxygen extraction ratio and jugular bulb levels of endothelin, nitrate and cgmp. the first measurement was done within hours after cardiac arrest and repeated , , , , and hours later. results: we studied patients, females, mean age , + , years. the pi decreased s!gnificantly between th~ first and the last measurement from . _+ . to . + . (p = . ). cerebral oxygen extraction ratio decreased also from . + . to . + . (.p = . ). endothelin levels were high, but didn't change during the studied period. nitrate levels varied in a wide range, but didn't change significantly. however, cgmp levels increased significantly from very low levels in the first measurement to very high levels hours later, rasp. . pmol/ml (median; th . - th . ) and . pmol/ml (median; th . - th . ) (p = . ). eighteen and hours after the first measurement we found a strong correlation between pi and cerebral oxygen extraction ratio ( r = . , p = . and r = . , p = . ). we.also found hours after the first measurement a significant correlation between pi and cgmp levels ( r = . , p = . ). we found no correlation between pi and endothelin or nitrate levels. conclusion.~; our results show a high cerebral vascular resistance in the first few hours after cardiac arrest, gradually decreasing during the next hours. this is accompanied by an initially high cerebral oxygen extraction ratio and low cgmp levels, suggesting that the cerebral vascular resistance is induced by active vasoconstriction because of insufficient cgmp levels, leading to a decrease in cerebral blood flow and a compensatory ~ncrease in cerebral oxygen extraction. objectives: sudden cardiac arrest is a major cause of mortality in western countries accounting for over half of all cardiovascular deaths. in most cases the mechanism of death is prolonged cardio-circulatory arrest due to ver:tricular fibrillation (vf) preceding final asystole. recurrent syncopes due to idiopathic vf with good neurological prognosis have been reported in patients with and without cardiac etiology ( , ). in the past measurements of cerebral hemodynamics have been repeatedly done in humans during cpr, but until today no studies of cerebral blood flow velocity (cbfv) have been reported during controlled cardiac arrest in humans not under-going cpr. it was the purpose of our study to evaluate the acute hemodynamic effects of untreated vf on cbfv. methods: after approval by the local university ethics comittee, five male patients aged - years without evidence of cerebral disease were investigated during vf while undergoing implantation of a pacer cardioverter defibrillator system (model d; medtronic| a standard anaesthetic regimen was used (propofol, fentanyl). after implantation of the automated cardiac defibrillator vf was induced by electrical countershock to test effective sensing, pacing, and defibrillation. to measure cerebral blood flow velocities (cbfvmca) the doppler probe was placed above the zygomatic arch between the lateral margin of the orbit and the ear and directed towards the m segment of the middle cerebral artery (mca). results: a total of phases of vf were investigated. duration of vf ranged from to seconds, with cbfvmc a (mean_+sd, cm sec - ) flow pattern changing from pulsatile to laminar flow immediately after onset of vf. conclusions: the underlying mechanism of the laminar cerebral blood flow observed during vf in our patients is uncertain, but it may provide insight into the prognosis of patients with idiopathic vf. theoretically, the laminar cerebral blood flow observed in our pulseless patients may provide a substantial amount of cerebral perfusion even during clinical cardiocirculatory arrest objective: to investigate whether the intensive care nursing staff can inflate more accurately a specific air volume with the laerdal resuscitation bag when they receive feedback after each inflation about the delivered volume compared to no feedback. method: icu nurses were asked to inflate a testlung model times with a specific air volume ( ml, ,ml or ml) under three different conditions (normal, decreased compliance and increased resistance) without and with feedback. we measured the mean absolute difference from the specific airvolume after each ten inflations. results: the largest absolute difference was found when icu nurses inflated ml ( ml). the mean inflated volume for this group was ml. when the icu nurses had to inflate ml the mean absolute volume difference was ml with a mean inflated volume of ml. inflating ml produced an absolute volume difference of ml with an mean inflated volume of ml. the absolute volume difference decreased when the compliance of the testlung was decreased and even more when the resistance of the used endotracheal tube was increased. when the icu nursing staff received volume feedback after each inflation the mean absolute volume difference was reduced between the ml and ml for all specific air volumes. % of the last inflations with feedback were significantly smaller than ml from the specific air volume (p < . ). conclusion: the majority of nurses overinflated the specific air volumes. the largest over inflation occurred when ml and the smallest when inflating ml. when nurses were provided with volume feedback the performed significantly better. we concluded that icu nurses are not able to inflate a specific air volume with the laerdal resuscitation bag without receiving volume feedback. feedback is desirable in order to reduce the volume trauma. objectives: a pro_found impairment in systolic and diastolic myocardial function following successful cardiopulmonary resuscitation (cpr) has been demonstrated by using langerdorff method in rats. in the present study we have investigated post resuscitation myocardial dysfunction in a porcine model of cpr. methods: ventricular fibrillation (vf) was electrically induced by alternating current applied to the ep{cardium of the right ventricle in domestic pigs. following rain of untreated vf, precordial compression and mechanical ventilation was initiated and maintained for min. electrical defibrillation was then attempted and of animals were successfully resuscitated. results: following successful cardiac resuscitation, stroke volume index (svi) decreased from prearrest value of . ml/kg to . ml/kg (p< . ), and left ventricular stroke work index (lvswi) from . to . mmhg,ml/kg (p< . ). both svi and lvswi remained depressed for another hours. these decreases were associated with increases in heart rate from bpm to bpm (p< . ). no significant changes from baseline in mean arterial pressure, mean pulmonary pressure, right atrial pressure and pulmonary artery wedge pressure were observed. prehospital resuscitation efforts c. k ppel. g. fahron, h. lufft, a. kruger, c. th(jrk, f. bertschat, f. martens dept, of nephrology add medical intensive care, virchow-klinikum, humboldt-universit~t, d- bedin, germany obiective: the success rate of prehospital resuscitation in patients with cardiocirculatory arrest in an emergency medical system (ems) may reach - % depending on the time of calling the ems, the distance to cover by the emergency ambulance and the training of the emergency physician and his staff. in the berlin ems, which is associated with the berlin fire brigade, the time between alarm and arrival at the scene ranges from - min, mean min. resuscftation is based on the advanced cardiac life support (acls) according to the guidelines of the american heart association. if resuscitation efforts fail to restore circulation, they are terminated after - min, depending on duration of cardiocirculatory arrest, pre-existing disease, age, absence of an even transient response to cpr. however, there is a lack of practical criteria for termination of cpr in individual decision making. patients: we report cases of prehospital cpr with primary asystolia terminated after - rain of frustraneous cpr efforts including highdose epinephrine and dopamine. results: after termination of cpr, the ecg monitor remained connected and showed permanent asystolia in all patients while the emergency physician completed his records. spontaneous resumption of respiration and circulation was observed in these patients after - min and cpr efforts were immediately resumed, nevertheless, of the patients died at the scene, while could be hospitalized with stable circulation. one of them died hours after admission to the icu, the other survived for weeks in a vegetative state. spontaneous resumption of circulation and respiration is most likely due to the development of extreme hypercapnia and acidosis, which -at least in some patients -seems to be a stronger stimulant of the circulatory and respiratory brainstem centers than cpr with high-dose catecholamines, conclusion: because of the legal and ethical implications of this rare phenomenon, emergency physicians should continue ecg monitoring for at least rain. after termination of cpr efforts. pulmonary artery catheterezation is used for patient's monitoring [ ]. we reported our results on such monitoring in [f.coaobbeb,r.fe enb~-kap~monorm~, ,n ,p. - ] .however not all of the received criteria assessments meet demands that are necessary for early diagnosis of critical states. here we report the data on po ,pco (mm rg),so ,ph levels in femoral [af) and pulmonary (ap) arteries blood, as well as on summary gas pressure (sgp) calculated from pe=(po +pco ) in mm hg in ap blood. these data were derived from:i) subjects free of cardiovascular pathology according to catheterization data during their spontaneous air breathing (n group in ap blood appears to be a measure of adequacy ratio between pc and sgp in ap blood during air breathing; partly its characteristics and variations ranges are presented earlier [ j. in control group it is equal to , • mm hg. tests on sgp neither exclude nor substitute conventional (pc and pco ) tests, but rather include them as a part choosing only additive characteristic -pressure. they appear to be a part of general system of human metabolism regulation by pressure (arterial,venous,intracardiac, tissue,liquor,onco-osmotic,etc ietraabdeminal pressure produces perturbations of cardiac, pulmonary, and renal physiology. this most often occurs fonowing eeliotomy for peritonitis or intestinal obstruction; bowel edema and distention prevent wound closure without unacceptable compromise of blood pressure or pulmonary compliance. a variety of temporizing measures have been reported for managing wounds that cannot be closed: ) using towel clips to reapproximate skin only, )i sewing silastic, marlex or other prosthetic grafts to the fascia to "enlarge" the peritoneal cavity, ) using loosely tied retention sutures for partial closure, ) simply packing the wound without attempts at c~osure. these techniques either traumatize the abdominal wall (complicating definitive closure), expose the bowel to damage, or allow excessive loss of fluid and heat. since we have evolved a suturelees technique which permits the abdomen to be partially closed in a quick, safe, sterile, sealed, atraumatic fashion -while providin! decompression of unphysiologic intraabdominal pressure. methods: whenever possible omentum is interposed between bowel and the open incision. viscera are covered by a layer of sterile, non-reactive plastic, placed deep to the fascia and extending we~t beneath the edges. sump tubes are placed above the plastic and covered in turn by two layers of an adhesive plastic drape which sticks to the skin and seals the wound in all directions, the patients remain intubated and paralyzed. results: we have used this technique in a total of patients, four of whom suffered from compartment syndrome. all of the latter were males and ranged in age from to . all four showed immediate physiologic improvement. all four incisions were eventually closed without complication. one compartment syndrome patient died t days later of multiple organ failure. there were no complications related to the closure technique in any of the patients. conclusions; . selected patients with abdominal compartment syndrome will benefit from decompression using this temporary sutureless technique. the technique a) is quick, safe, sterile, sealed, and atraumatic, b) minimizes loss of fluid and heat, c) facilitates eventual definitive abdomina| closure. although m. brunner m. mitllncr objectives: to determine incidence and predisposing factors for cardiac arrest occurring during the first hours after open heart surgery. methods: the study included patients who, following open heart surgery, had adequate cardiac function and in whom cardiac arrest was not anticipated. all data were prospectively recorded and analyzed. results: from / through / , pts underwent open heart surgery at our hospital. of th~se, pts ( %) (age _+ yrs) had a cardiac arrest during the first hours after transfer to icu. they were operated on for coronary artery bypass grafting (cabg) ( pts), valve replacement (vr) ( pts), cabg and vr ( pts) and aortic aneurysm ( pt). the preoperative ejection fraction was _+ % whereas bypass and aortic cross-clamp time were + and + rain, respectively. prior to arrest, they had a cardiac index of . _+ . l/min/m and were receiving . + inotropes. arrythmias leading to cardiac arrest were ventricular tachycardia/fibrilation ( pts) and bradyarrythmia ( pts). closed-chest cpr was initially performed on all pts and was followed by open-chest cpr in pts. eighteen pts ( %) survived to icu discharge. causes of arrest included perioperative myocardial infarct (t pts, %), tamponade ( pts, %), rupture of the proximal vein gra& anastomosis ( pt, %), graft occlusion ( pts, %); no cause was found in pts ( %). conclusions: postoperative cardiac arrest in stable cardiac surgery pts is relatively infrequent (- % incidence) and is associated with a high survival rate following successful cpr. perioperative myocardial infarct is the most common predisposing factor. group ~deptof anaesthesia and intensive care, semmelweis univ. medical school, buda military hospital intensive care unit, budapest background: when a cardiac arrest occurs in-hospital, the outcome can be improved by a higher quality of basic life support provided by the witnessing health care workers until the code team arrives. this basic life ~pport (bls) should include the best available method for airway management as well. since not all medical staff are ready for carrying out endatracheal intnbation, we investigated the effieacy of the use of different airway management methods during bls. methods: we have investigated the efficacy of airway management of doctors and nurses from different hospital wards: internal medicine, department of surgery, trauma, urology and gynaecolagy. comparing the bag-valve-mask, laryngeal mask and the endotracheal intubafion, we have measured the following parameters: time needs for correct application (sec.), number of incorrect applications (out of ten trial), efficacy of artificial ventilation provided by the device. we used a computerised als trainer manikin for the evaluation of the performance. total performance score was created after the measurement between - . after the first screening we held a x hours training. doctors and nurses were trained for the endotracheal intubation (group it , t ) , doctors and nurses were trained to use the laryngeal mask (group lm , lm ) . all respondent were trained to use the bag-valve-mask device. day, month and month after the training we have carried out retention study using the same method. results: we have found that the efficacy of the artificial ventilation using the above mentioned devices were poor before the training. the average after-training performance scores of the groups are presented in the table below. (bls) should be initiated by the witnessing health care professional. the cpr study introduced a multi level code system, which means bls included sophisticated airway management, early defibrillation and early epinephrine administration provided before the code team arrives. our previous studies confirmed a poor level of cpr performance and a high demand for cpr training among health care professionals. method: we established a cpr training course centre, where doctors and nurses are being trained for in-huspital basic and advanced life support. x hours of training were held. after the theoretical introduction a step-by-step training method ws used for trainees to be familiar with all sequences of basic and advanced life support. then we synthetised all separated sequences. afterwards, a r e play of rescue groups was taken in simulated situations. we also trained the multi level alarm system fur the in-hospital resuscitations. after the training all respondents had to sit for examination. the quality of performance was scored and compared to our previous results. semi-structured interviews were carried out before and aider the training among all respondents to collect information about the course. results: we have found a remarkably high interest among doctors and nurses in our cpr training courses. it was very important to use proper equipment for the training: audio-visual training facilities, computerised als trainer manikin, manual and automatic defibrillator units. the evaluation of the examination held immediately a~er the training course showed a significant higher quality of performance than before the training. the self.-eonfidence of the trainees for initiating and carrying out resuscitation had increased. their overall feeling about the course was positive and % responded the course "very useful". . % of doctors and . % of nurses claimed fur regular training facilities with als trainers, conclusion: the cpr training for health care werkers is mandatory including the training of sophisticated airway management and use of elad~l~ills~tt~r wlaa ~en ~r a~ti~atir ~nel r rm~a'*h*nr m~thnd for training will improve the efficacy, the satisfaction of trainees, therefore their compliance for further co-operation will also increase. s objectives: the effect of reinfusion in emergency surgery and gynecology. methods: we had an experience of autologous blood transfusion in patients whom was produce t an emergency surgical or gynecological interventions in occasion with break tubal pregnancies ( . %), penetrating abdominal wounds with injuries of mesenterial vessels ( . %), injuries of the liver ( . %), blunt abdominal trauma with lien ruption ( . %). in . % patients had the previous somatic pathology. blood loss volume was - ml, & the reihfuside blood volume was - ml, consisting - % of blood loss. it was needn't to fransuse donor blood in . % in further but - ml of contanined erythrocytes were frasfused for supporting of hb concentration on the g/l ( g/dl) rate at the other patients with isovolemie hemodiluttion. results: the arterial blood pressure fast stabilisation on the perfusion level had noted after reinfusion, excluding the case, when the volume of reinfused blood had conisted just % of blood loss at the patient with massive blood loss. complications have noted in two cases. one patient with slash wound, injury of arteria gastrica dextra and total blood loss of ml, has an episode of asystoly, dic (disseminated intravascular coagulation) syndrome, acute renal failure, and acute pancreatitis that we haven't connected to reinfusion. all the complications were successfully corrected and at thirty first day patient with subcapsular wound of the lien that has happened days before complicated with external rupture of the capsull & massive intraabdominal bleeding, has the hemolytical shock, dic syndrome, acute renal failure developed after reinfusion. he was died. all another have no complications. posthemorrhagic anemia had corrected rapidly than in case when hemorrange corrected exclusively by donor blood. conclusions: we consider that simplicity, accessibility, high effectiveness, quite well further results of blood reinfusion, except the case of blood reinfusing that was for time-expired out of blood vessels (more than days in our case) will promote to the wide spreading of this method, especially in emergency surgery, in massive injuries, & in disarters, all the cases of insufficiently of time for selection of lot of donor blood. objectives: study of a reaction of the oardioreepiratory system of pregnant women to i/v microperfusion of clophelinum which is known to eliminate hemodynsmic and endocrine nociceptive reactions and can be used for treating hypertensive syndrome in pregnancy and labor. methods: the following non-invasive methods were used: capnography, spirometry, oxygenography, indirect fick principle based on the circle breathing, plethysmography and integral rheography~ functional indices of cardiorespiratory function were evaluated. results: pregnant women with ~h-gestosis were examined before and after i/v infusion of i ml of . % clophelin solution, . mg/kg/hour. before the treatment intensification of carbohydrate metabolism, hyperventilation with moderate hypooapnia and complete respiratory compensation of metabolic acidosis~ increased alveolar ventilation, decreased alveolar volume, predomination of perfusion over ventilation, hypokinetio type of circulation with dominated load by peripheral vascular resistance to the blood flow was observed in this group of patients. microperfusion of clophelin imp~-oved the ventilation/perfusion ratio, ventilatory and gaseous exchange efficiency, resulted in a decrease of congestion in the pulmonary circulation, possibly owing to a decrease of peripheral vascular resistance by %, of the heart rate by io. %, of the oardial output index by . %. conclusionm: the resulted type of circulation with a decreased load on the heart both by resistance and volume allowed to improve the cardioreepiratory system function in pregnant patients. objectives: the injury severity score is a measure of severity of anatomic injuries. iss is a sum of squares of the highest degrees of the abbreviated injury scale (ais) for each of three most severity injured regions. the purpose of the study is to establish correlation between the iss values and mortality rate in older, polytraumatized patients. methods and results: iss was determined for patients. the mean iss value was . + . while the median value was . minor injuries were present in ( %) patients with iss less than , while ( %) patients with iss more than had severe injuries. increased mortality of the older patients was noted in the range - . all patients older than died while % of patients below yrs of age survived, indicationg correlation between iss and mortality rate in polytraumatized patients above yrs of age. conclusions: this mode of evaluating severity of injuries may help in triage, determining appropriate level of care and as an indicator of future outcome of polytraumatized patients. objectives : tissue hypoxia is a non exclusive cause of hyperlactatemia. other serious medical situations induce hyperlactatemia. therefore, lactatemia could be a non specific indicator of severity in patients admitted in emergency unit. the aims of this study were to examine the correlations between lactatemia with the short term survival course prognosis and the unit of hospitalisation; intensive care unit (icu) or medicine unit, in patients admitted in our emergency department. methods -lactatemia was measured as soon as the admittance, in arterial blood sample of patients which needed arterial blond gas. sixty-one patients were included during months. to assess the statistical performances of lactatemia, sensitivity (se), specificity (sp) and accuracy (ac) were calculated for the threshold determined by the youden's test (se+sp- ). results : fifteen patients were admitted in icu and in a medical unit. fifteen patients died. a group of patients had a lactatemia up to mmol.l" . in this group of patients, had acidocetosis, had asthma, had cerebral vascular ischemia, had neoplasia, had cardiogenic shock, was epileptic, had congestive heart failure, had acute respiratory failure, had septicaemia, had hyperosmolar status finally had medicinal intoxication. lactatemia was significantly higher in non survivor than survivor ( . • vs. . + . , p<o.oool, respectively), the cut point of lactatemia was . mmoll" se was %, sp was % and the accuracy was %. on the other hand lactatemia was higher in patients admitted in icu than in medical unit ( . + . vs. . • p<o. , respectively). conclusions : this preliminary results suggest that lactatemia is a good indicator of the short term survival course in patients admitted in an emergency unit. furthermore, hyperlaotemia is present in several pathology seen in emergency. objective: to determine the pattern of injury, total peripheral white cell, neutrophil, and lymphocyte responses, and the outcome of trauma patients who are leucopaenic on admission to the icu. design: prospective, descriptive study of consecutive admissions over months. setting: a -bed surgical intensive care in a teaching hospital. patients: thirty consecutive adults admitted to the icu following trauma. leucopaenia was defined as a total peripheral white cell count of < x , neulropaenia < x , and lymphopaenia < . x ~ cells per litre. measurement and results: the total peripheral white cell count was documented daily and the neurtophil and lymphocyte counts and differential percentages on days , , and . the incidence of leucopaenia was significanfiy higher in patients with gunshot wounds (p < . ) and hollow visceral intra-abdominal injury (p < . ). eight ( %) patients died. no significant differences were found in the initial mean total white cell, neutrophil, or lymphocyte counts nor in the differential percentages between survivors and non-survivors. the total peripheral white cell count increased significantly in survivors compared to those who died (p < . ) and significant differences were found in absolute neutrophil counts (p < . ) and differential percentages (p < . ) on days and . no significant differences were found in lymphocyte counts or differential percentages. conclusions: there is a signficant association between leucopaenia, neutrepaenia, and intra-abdominal hollow visceral injury and peritoneal contamination. survival is related significantly to resolution of these white cell deficiencies. these findings suggest a possible role of granulocyte colony stimulating factor in the trauma patient with intra-abdominal infection and persistent neutropaenia. amelioration of organization emergency care team in order to improve caring for urgent cases. objectives: emergency care team (ect), as integral part of health, respectively as activity of primary health protection care all acute difficult conditions which vitaly danger patients and distressed. the aim of our investigations was to indicate on the possibilities of amelioration of organization ect in order to improve caring for urgent cases. methods: in our investigations we used epidemiologicai and statistical metods all informations and matherials from terrain ects. results: the number of traumatized in traffic accidents etc. have a epidemic character. it is well known that . % traumatized died in first two hours. ect isn't enough qualified to care a traumatized on the place of accident and during transport. because that medical personnel must have an education with solid qualities. conclusions: . besides a physician specialized (vii --+ vii -~ viii gradus) in urgent medicine, it's necessary to introduce two ( ) medical technicians instead of one as is existing now ( ~ ). .the medical technicians can drive cars and one of them always, drives the ambulance car ("b" category). .the technicians have been specially educated for urgent cases (iv ~ v ~ vi). . such a new team structure should be more capable in professional sense. .we can see an importance of team-work in ects. . such teams should also be more economic in comparison with existing one. . we think, that on the general medical studies need to include a new discipline-urgent medicine! objectives: to detoxicate an organism since we have used biological sorbents: isolated from liver and spleen of human or animal cells or tissue fragments. methods: cellular dialysis ( dialyses) in patients with an acute hepatic insufficiency poisoning by hepatotropic poisons: cc , dichloethane, mushrooms -were conducted using "artificial kidney" apparatus, by means of arteriovenous shunt, formed at forearm with disposable dialyzers. hepatocytes suspension was poured into dializing circuit of dialyzer at - mg of cells per i kg of patients weight. dialysis was performed during - hrs. patients with purulent-septic states were treated as for hemoperfusion through prepared sorptional column: . ml of hemosorbent and . ml of fragmented spleen or hepatocytes suspension with the help of roller pump with the rate of - ml/min, during - min. average volume of hemoperfusion made . . conclusions: in all cases we used both native and cryopreserved biomaterial. analysis of the dynamics of clinical, biochemical, scintigraphic and us-investigastions allows to conclude that application of cellular-sorptional method of detoxication enable to prolong life and reduce lethal outcome in some severe category of patients with endotoxicosis. after infusion of diazepam ( . mg/kg),thiopentone ( mg/ kg) and vecuronium (lmg/kg),patient was intubated and mechanical ventilation was adjusted to mantain normoca= pnia. ct scan showed left parieto-occipital hypodensity with brain swelling. after admission in neurological icu,dexamethasone ( mg/ kg/die),mannitol ( .smg/kg) and diphenylydantoin ( mg/ kg/die) were administred. two hours later neurological status of the patien~ was normal and she was extubated. the risks of stereotactie radiosnkgety are related to: hemorrhgge during the latency interval;transient radia= tion effects;permanent radiatio~einduced complications; radiation induced neoplasia. no epilepsy is reported in pts with avm and no seizure before radiosurgery. in c nclusion, epilepsy can be a posmib~e delayed eompli c~t~n, ~fe~r rgdi surgery for cerebral avm. serum potassium deficiency is a frequently reported finding in the time course of acute myocardial infarction (ami). if this is also correct for patients with ami undergoing primary percutaneous transluminal coronary angioplasty (ptca) is unknown.for that reason we analysed in patients ( m., f., + y.) serum potassium concentrations on ad ,mission and directly after ptca.the reference intervall for potassium in our clinical laboratory is , - , mmol/l. although more than % of the patients with ami undergoing ptca showed normal potassium serum concentrations on admission a measurable decrease of potassium could be found in % of patients ( ) after ptca.therefore for the majority of patients with ami potassium supplementation prior to ptca can be justified to avoid electrolyte disturbances as a possible trigger factor for cardiac arrhythmias in the setting of ami and acute reperfusion due to primary ptca. objectives: diagnostic procedures are very important in the management of abdominal injures in trauma. the aim of this paper is to present our experience with peritoneal lavage as diagnostic procedure in abdominal injury. methods: we analyzed patients to whom peritoneal lavage was applied in the surgical emergency from st of january till st of december . results; in this four years period there were abdominal injures. there were blunt injures. among them in patients peritoneal lavage was applied. results were positive in patients and negative in patients. false positive finding were in patients and false negative in two patients. in patients with positive lavage there were more than , /mm red blood cells, more than , /mm white blood cells and the level of amylase was up to u/i. the gall, urine and stool were positive as well. in patients with negative lavage there were less than , /mm red blood cells, less than /mm white blood ceils and amylase were negative. conclusion: peritoneal lavage is useful and important diagnostic procedure in the management of abdominal injures in trauma. our experience with urgent surgical management of the acute gastric and duodenal bleeding s.se en md, z.milo~evi md, *s.srdi md, k.sar ev md. clinic for abdominal and endocrine surgery, institute for surgery; *clinic for cardiology, institute for cardiovascular diseases; school for medicine novi sad, university of novi sad, yugoslavia objectives: acute gastric and duodenal bleeding are very common complication of gastric and duodenal ulcer. the aim of this paper is to present efficiency of our surgical management of these acute conditions. methods: in this paper results of surgical management of patients with acute gastric and duodenal bleeding, treated in our clinic from the st of january till st of december , are presented. results: among operated patients there were females ( . %) and males ( . %). there were patients ( . %) with gastric bleeding and patients ( . %) with duodenal bleeding. bleeding from gastric ulcer were treated with the following methods: excision of ulcer with suture in patients ( . %), ulcer suture in patients ( . %), billroth i in patients ( . %) and billroth ii in patients ( . %). heinecke-mikulicz-weinberger pyloroplastica was the most frequently used in the treatment of the duodenal ulcer bleeding. bilateral truncal vagotomy was done in patients ( %), duodenotomy with ulcer suture was done in three patients ( . %) and three patients underwent billroth ii operation. we had three complicationsduodenal dehiscence in pyloroplasty. there were no lethal complications. conclusions: based on our own experience we conclude that acute bleeding from gastric and duodenal ulcer can be safely managed with urgent and modern operative techniques. dept. of anaesthesiology. emergency center of serbia, belgrade, srj b ectives and methods: cardiac contusion was evaluated by serial determination of cpk-mb fraction and co using non-invasive doppler technique in patients with blunt trauma of the chest. results: miooardial contusion was diagnosed in ( %) patients, while in ( %) it appeared unaffected. cpk-mb of % and more in comparison to total cpkwas . + , % in patients, and , + , % in pts (p< . ).c of . + . l/min in patients with cardiac contusion, measured hrs after admission at the latest, was significantly lower than in group of patients with co of . + . l/min (p< . ). conclusions: co values were significantly lower in patients with cardiac contusion and correlated with pathological values of cpk-mb fraction. objectives: extracorporal plasmophoresis (pph) was implemented by non-stop method in patients with obstructive jaundice. methods: changes of serotonin (s) and histamine (n) in arterial (ab) and venous (vb) blood were investigated before and after one-time session of pph. s and h in blood serum were determined with fluoremetric method. results: before pph the average s contents in ab and vb did not differ. after one-time pph session s in the blood outflowing lungs was % lower than in the blood inflowing. hours after extracorporal detoxication implemented the indices kept the same level. similar dynamics after pph was observed in h. before the session h contens was equal both in the blood inflowing and in the blood outflowing lunge. after pph h contents in ab was % lower compared to the vb and did not change for hours. conclusions: dynamics of changes of biogene amines shows that under the influence of pph there takes place not only mechanical removal of their surpluses together with plasm, but there sharply grows inactivating role of lungs towards ba substances, which is confirmed by reduction of their concentration in the blood outflowing lungs. this effect is probably connected with the "deplasmation" of the lung cellular elements. simultaneously lungs' cells are freed not only from plasm but from toxic adsorbents on their surface. as a result the lung cells activate absorption of the surplus number of amines from the vessel channel. it is not excluded that s inactivation is due to growing activity of monoaminooxidase resulting in deminishing of intoxication. acute pulmonary embolism: thrombolytic therapy or pulmonary embolectomy? i.lodiena md, phd, s.shevchenko md, pphd., medical university, kharkov, ukraine objectives: pulmonary embolism (pe) remains a challenging problem for diagnosis and management for the emergency physician. the aim of this work is to identify the best treatment for massive pulmonary thromboembolism. methods: during recent years patients with symptomatic acute serious pe were reffered to our observations. selective pulmonary arteriography confirmed this diagnosis in all cases. ( . %) underwent urgent surgery, of them ( . %) with cardiogenic shock and ( . %) with massive pulmonary embolism. patients ( . %) underwent thrombolytic therapy. results: in the patients who received thrombolytic therapy successful results were achieved in cases ( . %), in ( . %) patients subsequent pulmonary embolectomy was performed. mortality rate was ( . %) in the patients who underwent pulmonary embolectomy after unsuccessful thrombolytic therapy and ( %) in the patients with cardiogenic shock and massive pe. lower extremity deep venous thrombosis caused pe in % patients. pe mortality rate is repoted to be %, but all patients with cardiogenic shock and massive pe died. this very high mortality rate related to the clinical status of the patients whose condition became worse despite intensive treatment. conclusions: the results of this study show that in most cases thrombolytic therapy is an effective rapid method of treating pe. however, surgical treatment is preferable when the patients reveal adverse effects to drug therapy, when medical therapy is unsuccessful or when the patients are seriously ill with reccurent cardiac arrest. high-quality pulmonary angiography remains the most accurate and reliable means of diagnosing pe. this prospective study was conducted to investigate the serum thyroid hormone levels in traumatized critical ill patients. serum thyroid stimulating hormene(tsh),total thyroxine(tr ),free thyroxine(ft ),total tri-iodothyronine(tr ),free tri-iodothyronine (ff ) levels were measured within hr.of intensive care unit admission(first day) in multiple tratmmtized male patients(injury severity score higher than ). in fifth day the same hormone levels were repeated. tsh,et ,ft ,tr and ft levels were determined by radioimmueoassay(ria). the levels of 'i~sh,xt ,fr ,et and ft in survivors and nonsurvivors were compared with first and fifth days (table) . in conclusion, we are convinced that there was a high correlation between low ser~n thyroid hormone levels and mortality, serum thyroid hormone levels are prognostic value in traumatized critical ill patients. objectives: glucagon improves myokardium contractility, intensifies kidney blood flow, stops bronchospasm ( ), these were the reasons of investigating its effect on hemodynamics and metabolism in hypovolemic shock expermentally and in clinic. methods : in experiments on white rats with traumatic shock glucagon (novo nordisk) was injected intraperitoneally in dose rocg/kg. patients with hypovolemic shock (trauma, hemorrage) were injected glucagon intravenously in dose mg on the background of infusion therapy. results : glucagon hightened recovery indexes of glucose in rats and patients with shock, whereas in groups without glucagon hyperglycemia developed. rats with glucagon injection had double times urea content than the norm ( , + , mmol& norm - , + , mmol/i ), whereas rats without glucagon had urea content , + , mmol/ ( p < , ). osmolarity of blood plasma in rats having glucagon injections was , + , mosm/kg h , without the drug - , + , mosm/kg h ( p < , ), ldh activity - , + . and , + , ( p < , ) mcmol cec- accordingly. lethality in the group of rats without glucagon was % /n= /, with glucagon - (n = ). in patients with hypovolemic shock in minutes after glucagon administration stroke volume increased to % (sv), miocardium contractility -to % (mc), peripheral resistance of vessels ( vr ) decreased to %. in - , hrs sv increased to %, mc-to %, pvr -decreased to %. conclusion : the study provides the evidence that glucagon has an anti-shock effect, improves hemodynamics and metabolism indexes in cases of hypovolemic shock. reference : picazo j. glucagon in acute medicine : pharmacological, clinical and therapeutic implications (norwell, mass:kluwer publishing, ), p. n, vasina (t) ,n.sebbota hph ( ). dept; of acute endotoxicosis, n.v. s~lifosovslay scientific research institute of ermergency ltealth care, boscow, lk'ussia (i}. institute for problems of cryobiology and cryouledicine of the national academy of sciences of the f/maine, kl'k r-key, [ maine ( ), objectives: the investigation of isolated hepatocytes using's efficacy in patients with acute hepatic fai lln-e. methods: native and crioconsrved allo-and xeno-!mmatocztes fixed on semi;ermeable ~mbr~s were used. results: the artificial supporting system with isolated hepatocttes as metabolic ~its was. ap-plied in patients. during tl~ treatmen~ with this cytotherapz an improvement of clinic state and biochemical rates were observed even inthe first we~s. for instance, the kncreasing of glutamin acid's level in blood up to normal value and decreasing of ammontes -concentration from i ~ mmol/l down to # mol/l were discovered. ~ae diminution of ence,%halo;athy was noted too. general lethality was' equal z, there of i z concerned acute hepatic failure (/k~). conclusions: the using of sum~rting hepatic system is able to cope the ~nenomenon of ~i~. objectives: fat embolism (ee) is an important and insufficiently studied problem of the intensive care medicine. fe is clinically diagnosed in % and morphologically in - % of the victims with severe multiple skeletal injury that is accompanied by the shock. methods: during the last years patients with the cerebropulmonary form of fe were treated in the icu. the prognosis of the probability of fe development was done using the computer system "cite-prognosis" in which the triss-method, dynamic and statistical prognosis of the injury outcome~ and the values of the most severe injury in points were realized. the treatment consisted of the surgical stabilization of the fractures with the authors' design of the rod apparatus in the acute period, long-term mechanical ventilation with peep via tracheostomy, complex fluid therapy using perfluorochemical emulsions (pe), and electrochemically active solution of na hypochlorite (snh) via the central vein. results: the treatment of patients with fe gave a good result that was manifested by the complete regression of psychoneurologic and respiratory disorders. conclusions~taking into account the prognostic data~ it is necessary to provide early complex of intensive care to the polytraumatized patients. it includes the surgical stabilization of fractures, fluid therapy using pe and snh~ early long-term mechanical ventilation. dr. alexandr e. poladko, station of medical aid. kiev ukraine. objectives: the reason of investigation is to prove the necessity of beginning of the intravenous infusion of nitroglycerin before the hospitalisation. methods: from january i to june protocols of treatment myocardial infarction patients in kiev medical aid station. results: the results of treatment are better if infusion began early or prolonged during hospitalisation. conclusions: there were patients with acute myocardial infarction treated before hospital by the cardiological groups. patients were treated with the early infusion of nitroglycerin and without. the results of treatment were: in the group with infusion: mortality in the first hours % the full disappear of pain % in the group without infusions mortality in the first hours % the full disappear of pain % that's why our opinion is that infusion of n. is necessary in the treatment of the patients with myocardial infarction from the first minutes of illness. dr. gennady d. kyrzhner, station of medical aid, kiev, ukraine. object: looking for safe medication which is good for the treatment of arterial hypertension and is simple for use. we inspected the effect of prazosin in the conditions of the cail during the year. method: we used mg prazosin tablets sub lingua and measured blood pressure ones during hours. the parameters were registrated in protocol. result." one hundred patients took part in investigation. the middle age of patients was . the reason of hypertension was not taken into consideration. in two hours after beginning of the treatment we caught the reliable lowering of blood pressure in % of patients. the general condition of patients became better in - min. it was only one accident of complication during the treatment -the orthostatic hypoter~sion, conclusion: prazosin hydrochloride in the dose mg sub lingua is safe and simple for use in the urgent situations. objectives: hypomagnesemia is frequently observed in severely burned patients during the early period after injury. increased urinary excretion is insufficient to explain the magnitude of the magnesium (mg) depletion. the possibility of exudative cutaneous mg losses has been proposed, but not yet demonstrated. the study aimed at measuring the mg content of the cutaneous exudates and urine during the first week after major burns. methods: patients, aged _+ years (mean _+ sd), and burnt _+ % of body surface, were studied from day (d ) to d . serum samples were collected at do, serum and urine from d to d , and on dio, d , d . cutaneous exudates were extracted from the textiles surrounding the patients, collected over h periods from d to d , using bidistilled acidified water. mg supplements ( . to mmol/ h) were prescribed from d to dio according to the severity of hypomg (serum mg < . mmol/i). results: mg serum levels decreased below reference ranges in patients between d and d , and normalised thereafter during supplementation. urinary mg excretion was increased in patients, mean excretion being . _+ . mmol/ h until d . mean daily mg cutaneous losses, were mmol/ h, i.e. mmo; in days. large inter-& intra-patient variability: the daily exudative losses ranged from to mmol/ h. conclusions: the mean daily mg cutaneous losses after burns were larger than the urinary losses, and equivalent to the recommended intakes for mg; the addition of the exudative and urinary losses largely explained the increased mg requirements after burns. complex immunologic alterations occur following thermal injury. the activation and consumption of the complement and dotting systems are suggested to play an important role in the development of the capillary leak syndrome, tn burned patients, a generalized inflammatory reaction as well as the impairment of the host defense are considered to be the major reasons for complications, such as sepsis and multiple organ failure. in a pig model we investigated a possible protective effect of cl-inhibitor (berinert, behring). before conducting the animal experiments the human cl-inhibitor concentrate was analyzed for its inhibitory capacity on purified pig cls and its pharmacoldnetic behaviour in pigs (t / ,id ). pigs received anesthesia and analgesia and arterial, venous and pulmonary (swan ganz) katheters were placed into the carotis and jugular veins. the pigs were scalded for seconds with ~ hot water to achieve a % tbs partial-thickness burn. blood samples were taken prior and after surgery as well as , minutes, , , and every further hours after thermal trauma. two control groups (each n= ) included animals which were either scalded or not scalded and treated only by resuscitation of ringers lactat solution. besides various parameters blood samples were analyzed for complement. the pigs (n= ) received c -inhibitor concentrate at an initial dose of u/kg body weight either immediately or hours after thermal trauma (n- ), followed by three further applications (of reduced amounts) every hours. the clinical outcome as indicated by vital parameters and as well as demonstrated by reduced edema and inflammatory tissue destruction suggested a protective effect of cl-inhibitor. complement analysis revealed a faster recovery of the alternative and classical pathway activities in cl-inhibitor treated pigs as compared to the control group but only if the regulator was given immediately after thermal trauma. from these results a protective function of c -inhibitor on thermal trauma can be assumed. objectives: the aim of study was to characterise the pattern of secretion of interleukin- (il- ) and tumor necrosis factor alpha (tnf alpha) in multiply injured or not injured critically ill patients and to relate these results to their outcome. methods: blood samples of multiply injured ( ( ) ( ) ( ) il- (nis) ( ) ( ) ( ) il- (nin) ( ) ( ) ( ) conclusions: this data suggest tnf alpha is a better prognostic marker in patients with multiple injury, than in critically ill patients without injury. il- is not significantly higher in nonsurvivors of both groups. sepsis is associated with an increased production of nitric oxide (no), as reflected by a rise in plasma levels of nitrites (no ) and nitrates (no ). severe bum injury is associated with similar symptoms of inflammation like hypotension, high cardiac output low vascular resistance and increased vascular permeability so that an increased no production may be involved. the present study included patients admitted to the intensive care unit of the burn center of brussels (age : - years; burned surfaee area - %), and control (non-septic) patients hospitalized in the neurological rehabilitation unit of the erasme hospital (age - years). the patients in both groups were fed enterally with to kcal/kg/day of a standard solution. in the burn group, daring the study period, patients were mechanically ventilated, required vasopressor (dopamine) therapy, and received antibiotics; patients were discharged alive from the intensive care unit, and no patient died during the study period. plasma was sampled for no /no determinations (griess reaction) daily from day to day (n=ll) or to discharge (day , n= ; day , n= ) in the burn group, and once the control group. in the burn group, no /no levels were elevated at day ( _+ #moles/i), reached a maximal value on day ( - p.moles/l) and progressively decreased to day (fig). these values were higher than in the control group ( . :t: . #moles/l, all differences p< . ). however, no correlation was found between the plasma no /no levels and the age of the patient or the total burned surface area; burned patients who became infected tended to have higher plasma no /no levels than those who did not ( + vs - #moles/i, ns). the present study indicates that burn noa/noa (llmol**/l) injury is associated with increasedloo] [__ ] ~ no /no plasma levels, which are ao so consistent with an enhanced no pro- o duction, ao obiectives:urapidil has been recommanded for therapy of hypotension in neurosurgical patients, because it was found not to increase intracranial pressure in patients with compromised intracranial dynamics ( ). in contrast several authors reported an increase of icp after urapidil administration in patients with head injury ( ). our study was designed to determin the influence of urapidil on mean lumbar cerebrospinal fluid pressure (csfp) in awake humans with uncompromised intracranial compliance. methods: after approval by the local university ethics comittee, six volunteers (asa , male, female) were studied in the lateral decubitusposition with the vertebral column positioned horizontally. a gauge needle was inserted into the lumbar subarachnoid space at level l /l and connected to a trancducer (mx | medex inc.) for csfp measurements. the volunteers were advised to keep respiratory rate and etco constant. after a resting period of minutes basline measurements were performed including csfp, cvp, map, hr, etco (cardiocap | datex). then the volunteers were given urapidil . mg/kg over a period of minute. minutes later measurements were repeated. results: statistics: wilcoxon signed rank test, p< . significant; values: mean_+sd, si = mmhg. - _ " _+ * _+ * - _+ " _+ csfp: cerebrospinal fluid pressure, cpp: mean cerebral perfusion pressure. conclusions: during normoventilation urapidil leads to a decrease in map parallel by an increase in csfp and therefore in icp, most likley mediated by an autoregulatory dilatation of cerebral vessels. if this cerebrovascular response is suppressed by hyperventilation, no increase in icp is found despite a uredipil induced drop in map ( ). after longterm hyperventilation cerebralbloodflow is normalized. this might be the reason why the drop in bloodpressure following urapidil administration again led to an increase in icp ( background and objectives: the intestine is one of the most sensitive tissues to ischemia-reperfusion injury. reperfusion of the intestine is often associated with increase in mucosal permeability and ulceration. d(-)-iactate is produced by indigenous bacteria found in the gastrointestinal tract and mammals do not possess the enzyme systems to rapidly metabolize it. the present study was designed to determine the kinetics of plasma d(-)-iactate alteration in rats paused by acute intestinal ischemia-reperfusion injury. methods: following the anesthesia, the superior mesentcric artery (sma) was exposed and it was occluded by a micro-bulldog clamp applied at its origin from the aorta. after min of occlusion, the arterial clamp was removed and the supply area of the sma was allowed to be reperfused ( h). plasma d(-)lactate levels were measured by an enzymatic spectrophotometric assay. the endotoxin content of plasma sample was assayed by the limulus amebocyte lysate test with a kinetic modification of the test kit procedure. results: intestinal ischemia for min resulted in a significant increase in d(-)-lactate levels within the portal vein as compared to sham-operated animals. plasma d(-)-lactate levels had a tendency to further increase after reperfusion up to h. it was showed that significant elevation of endotoxin concentrations in portal vein was alread~r detected at the end of -min ischemia, reaching peak at . h post-reperfusion and decreasing gradually throughout the study period. at the end of ischemia, marked mncosai damaged such as edema, hemorrhage and necrosis was observed. there was evidence of injury to ti, e muscuiaris propria together with diffuse mucosal damage and destruction following reperfusion, particular at h postreperfusion. in addition, penetration of bacteria was commonly found in the intestinal wall at various time points following ischemia/reperfusion injury. conclusions: these data suggest that acute intestinal ischemia is associated with permeability change of mucosal barrier resulting in increased plasma d(-)qactate, which is also remarkably influenced by subsequent reperfusion. plasma d(-)-lactate may be a useful marker of intestinal injury following both ischemia and reperfusion insult. objective: to assess the clinical usefulness of two methods of intracranial pressatre (icp) monitoring: intraparonquimatous recording (icpc) and epidural recording (icpe), versus intraventricular icp (icpv) as a gold standard. we prospectively studied patients with severe head injury (glasgow coma score < ) admitted to our icu between fobmaly and december . icpv was monitored in all pativrats by means of a multipzffolated catheter connected to a water coinnm. six of patients were additionally icpc monitored by a fiber optic transducer (comma r~), and seven of patients were icpe monitored by a couplvd fluid system (plastimedr). icpc was placed homolatetal to the focal, lesion m two cases and contralateral in three; icpe was placed homolateral to the focal lesiou in two cases and contralateral in three. all three systems were calibrated at the ear level. stali~cs: correlation coefficient and lineal regression were done between icpe and icpv, and between icpe and icpv with the hourly p~rs of values obtained dttting assistontial period. results: of the six icpc -icpv studied pa~onts, we observed a correlation coef~cieut r = . (p < . ) with a regres~on line y = . + . x. four of ~hx lcpc -icpv patients had r > . when correlaliou eoet~dent was obtained indixddually. of the seven icpe -]cpv studied patients, we observed a cortelafiau ooeffioiont r = . (p < . ) with a regression line y = . + . x. corralalmu eoetfieiont was inwer than . in all seven patients. corrdation eoelfieients for levals of icpv > man hg, > mm hg and > tuna hg with icpe showed r = . , r = . and r = . respectively; and with icpe r = . , r = . and r = . . the obtained values did not change during the study. conclusdns: in our study icpe was considered a good type of icp monitoring. /cpe signiticantly infravalorates icp values. we observed a good correlatinn between icpc and icpv values in patients with high inttacramal presanre. objective: midazolam is a benzodiazepine agonist widely used for sedation in emergency medicine. few studies in animals and humans point to a direct analgesic effect of midazolam probably mediated by spinal antinociceptive receptors and/or peripheral benzodiazepine receptors ( , ). in our experience in the berlin emergency medical system (unpublished results) with anecdotal cases of extreme chest pain due to binge drinking but no evidence of acute myocardial infarction or extreme abdominal pain due to peritonitis, acute intermittent porphyria, peutz-jeghers syndrome or testicular torsion, we found that small doses of midazolam ( - mg i.v.) were much more effective in relieving pain than repeated administration of high doses of buprenorphine or morphine, which may be associated with a considerable respiratory depressant effect. the dose of midazolam required for pain relief in these patients is non-narcotic and allowed further communication on the character and localization of' the residual pain, which might be very important for the further diagnostic procedure. patients: ten patients with abdominal pain due to acute gastrointestinal bleeding, suspected pancreatitis, suspected acute porphyria, and chest pain with no evidence of acute myocardial infarction received first-line midazolam i.v. at an initial dose of mg and were asked how it affected the intensity and character of pain. results: at the chosen dose of midazolam ( - mg), all patients were responsive to detailed questioning on basic orientation, the character, intensity and localization of the pain, and medical history. none of the patients required an additional opiate. all patients stated that the pain was tolerable after midazolam alone. conclusion: our preliminary clinical observations suggest that low-dose midazolam might be an alternative to opiates in extreme pain of presumably visceral odgin. objectives: it is known that severe head injury in elderly patients is associated with higher mortality than in younger patients. it remains however to be clarified whether the preinjury pathology which is frequent among these patients, affects the outcome. methods: in an attempt to investigate this hypothesis, patients aged over years suffering from head injury, with glasgow coma scale (gcs) of or less, were studied retrospectively. twenty-six patients ( . %) had preinjury pathology i.e. diabetes mellitus, arterial hypertension, heart failure, alcoholism, parkinson's disease etc. (group a) and fifty-three ( . %) did not (group b). the following data were recorded: mortality in the i.c.u., duration of hospitalisation, incidence of infective complications and neurologic status at discharge. results: groups were comparable in terms of mean gcs ( . vs. . ) and median age ( . vs. ). the incidence of brain pathology in the two groups was the following: epidural haematoma . % vs. . %, acute subdural! haematoma . % vs. . %, intracerebral haematoma . % vs. . %, subarachnoid haemorrhage . % vs. . %, diffuse haemorrhage . % vs. . %, contusion . % vs. . % and non-visible pathology (normal ct) . % vs. . %. unilateral pupilary dilatation was found to be . % in group a and , % in group b. the mortality during hospitalisation in the i.c.u. was almost the same: % iu group a and . % in group b patients. however, group a patients had significantly more infective complications, required longer hospitalisation and had lower gcs at discharge. conclusions: the results show that the existence of preinjury pathology does not seem to affect the short-term outcome of elderly patients with severe head injury. it has however an impact on morbidity and perhaps long-term survival of these patients. the assessment of clinical development in intensive care patients with severe head injury still remains a problem. to optimize the monitoring of intracraniel prassure (icp) we rautlr~dly implant an eplduml measuring device in our hospital. the aim of this study was to prove the correlation of the icp-values with ct findings and clinical development. during a month period ( - r the icp was monitored in p~,tients ( male, female) with severe head injury by an eplclural measuring device (epldyn~/$plegelberg| the mean age was . years ( - ). the glasgow coma scale at admission was . ( - ). in all cases the device was placed wfihln the first hours after admission. the tcp was compared with physical examination, radioidglcal or intraoperatlve findings and cunlca! outcome. the average time of measuring was . days ( - ) . the traatment depended on the !cp values recorded. rising icp-valuea ~ed to radlologlcal c ntra!s by ct-scan. in case an intracranlai hemorrhage was detected and drained. the overall survival rate was . %. showed a complete resolutl n, in other . % psychological residuals like decreased mentatlon, in . % sensomotorlc residuals like cerebral nerve dysfunction and aphasia, and . % of the injured remained in a comatous status. in % of our cases the measured values correlated with clinical course and management. in cases ( . %) we observed a displacement of the icp-pevice. there was no icp induced infecllon. istituto di anestesiologia e rianimazione, universit& ,,la sapienza", rome, italy * istituto superiore di sanit& -servizio di epidemiologia e biostatistica, rome, italy objectives: acute renal failure (arf) can be a severe complication of trauma. the current incidence of post-traumatic arf is associated with high mortality . identification of risk factors and prevention of this complication could improve the outcome of trauma patients. methods: one hundred fifty three consecutive trauma patients (age . _+ . , injury severity score . + . ) admitted to icu were studied. incidence of arf was . % ( / ). arf was defined as persisteat plasma creatinine > mg/dl with or without oligoanuria . arf was defined as early when occurring within the first hours (earf) and late when the onset was after the first four days (larf). results: earf occurred in patients while larf developed in patients. age, iss, and incidence of rhabdomyolysis and acute respiratory failure were not different in the two groups. an higher incidence of multiple organ failure (mof) and sepsis ( . % for both) were observed in larf group, when compared to earf ( % and % respectively). abdominal trauma was more frequent in earf group ( % vs %). the gs for earf and larf were respectively _+ . and _+ . while in the group who not developed arf (narf) the gs was . • conclusions: gs score difference seems suggestive and can be that an abnormal cerebral activity (hipofisary hormones?) may play a crucial role on onset of arf in these patients. moreover the frequency of acute respiratory failure in the group of arf was higher ( . versus . ) than narf group. the early ipoxia in the early phase of trauma, then, may be another crucial point for development organ failure. these are preliminary data. a more exact statistical analysis must be perform to have definitive conclusions. to compare the active compression-decompression cardiopulmonary resuscitation (acd-cpr) with the standard cardiopulmonary resuscitation (s-cpr) in out of hospital cardiac arrest patients. is a controlled, randomized study. two groups of patients with cardiac arrest out of the hospitalwere formed. group i, (acd-cpr) and group ii (s-cpr). for the acd-cpr groupweusedthecardiopumpdeviceofambulnternational. asfortherest, the erc ( ) algorithms for acls were followed. the utstein style (for out of hospitat cardiac errest) was used for listing and evaluating all cases of the study. the cpr was contucted by the crew and the doctors of our mobile intensive care units (micu). we studied consequitive patients ( in group i) and ( in .group ii). demographics pre-cpr characteristics (e.g. ecg form of cardiac arrest) and procedures (eg bystanders or second tiers crew cpr, defibrillation, drugs) were quite similar for both groups. the mean arrival time of micu was min. in group i we recorded r.o.s.c. (return of spontaneous circulation) , %, death %, continuation of cpr efforts , %. while in group ii, %, %, and , % respectively (recorded percentage until the admission to the hospital). no significant difference was found in anyofthe short term outcome parameters. no complications related to the acd-cpr technique, were noted. not any significant difference between the two methods was proven (from this small evaluated sample). the results of previous clinical studies are controversial (i) . more sophisticated studies proved the superiority, in a certain number of parameters (e.g pressures, flow, etc) of the new technique although there are many difficulties for establishing clinical results. in the pre-hospital setting that is related to many parameters (speed of the intervention, effectiveness of bystanders cpr, education ofparamedics, etc.)the evaluation is even harder. the superiority ofthe acd-cpr can be proven when it is performed in almost times increased number of studied patients as w~ll as improvement of the technique could lead us to more established results. objectives; infectious morbidity is the major cause of mortality after burn injury, and is due to multiple factors. trace elements (te), which are involved in both humeral and cellular immunity, exhibit severely altered status after burns. te supplementation has been shown to be associated with increased leukocyte counts and shortened hospital stay. the trial aimed at studying the immune responses in severely burnt patients receiving normal te supplies or early large supplements. methods: patients, aged _+ yrs (mean_+sd), with burns covering + % of body surface were studied from day (d ) to d post-injury, were randomised in groups (g): g -control receiving recommended te supplies + placebo; g -receiving in addition large supplements of cu, se and zn from d to d . enteral nutrition was started within hours of injury in all patients. immunological parameters: peripheral leukocyte counts, proliferation of mononuclear cells to mitogens, cell surface molecule expression, and neutrophil chemotaxis at d and d . infectious episodes and micro-organisms were monitored until d . results: the patients' characteristics were similar g & g . the total leukocyte counts were higher in g between d and d , due to increased neutrophils (significant from d to d ). total cd + and cdlg+ cells did not differ, whereas cd + (monocytes) were significantly increased at d . proliferation to mitogens was significantly depressed in all patients. chimiotactism was not altered. the number of infectious episodes was significantly decreased in g with a mean of . _+ . infections during the first days versus . _+ . in the control group (p < . ). conclusions: the large te supplements for days was associated with a significant decrease of the number of infectious episodes. supplementation was associated with increases in total leukocyte, monoeyte and neutrophit numbers. further studies are required to determine the precise mechanism underlying the improved immune defences. objectives: evaluate the efficiency of local adsorption (la) with the use of carbon adsorbents in case of severe burns in expertment and clinic. methods: experimental studies on la were performed on a model of % body surface area iiib-iv burn in rats. a burn eschar was excised on the rd day after burn, the wounds were dressed with the gauze bandages (control) or with adsorptive dressings (la), dressings were regularly changed. clinical investigations were carried out in the course treatment of patients with severe thermal and radiation ilia-iv burn. in the dynamics of bum disease some indices of proteometabolism and intoyacation criteria were evaluated. results: the experiments have demonstrated that the application of la after early excision of a burn eschar exerts a pronounced normalizing effect on a protein electrophoregram and the activity of proteases and their inhibitors in burned tissues preserving vitality. thus, by the th day after burn infliction the activity of cathepsin d in injm'ed muscles is times lower under an adsorptive dressing than under a gauze bandage (control) (p< , ), the activity of trypsin-like proteases is . - . times lower and the antitryptie activity does not differ significantly from the normal level. the cytotoxicity of extracts of burned tissues after the adsorptive dressing application fn vivo and adsorption in vitro is - % and - %, respectively, of the toxicity of control extracts. a similar normalizing effect of la is ok~rved for an intact muscular tissue and blood serum. the dectron-spin-resonance studies have demonstrated that la allows to normalize antitoxic activity of liver and functional activity of kidneys. the application of la in the treatment of patients with severe burns have been shown to localize a region of irreversible tissue changes, accelerate rejection of a burn eschar, attenuate an endogenous intoxication level and, as a result, shorten the time for grafting of a burn wound and accelerate wound heating. conclusions: proceeding from the obtained results, we can consider la as an effective method of localization of a region of irreversible tissue changes as well as of correction of local and general metabolism failures and overcoming burn autointoxication during burn disease. c de deyne, t vandekerckhove*, j. decruyenaere, b. vaganee, v vandewalle*, f colardyn depts of intensive care and neurosurgery*-university hospital gent-belgium. jugular bulb oximetry is the first bedside available cerebral monitoring technique providing an estimation of the adequacy of cerebral perfusion. its routine use in all patients suffering from severe head injury admitted to our ic unit enabled an extensive analysis of all very early cerebral perfusion data in order to evaluate the incidence of abnormal sjo~ data (and their possible causes) in this very eady period after traumatic insult and to search for possible implications as to the emergency management. these very early data were defined as the first hours icu data and icu admission had to occur within h of traumatic insult. over the last years, pts with severe head injury (gcs< ) were monitored by jugular bulb oximetry, starting immediately after their arrival at the icu (mean of . h after trauma, range between - h). in a total of pts (= . %), jugular bulb desaturatiens (< %) were noticed during this early h period. in pts (= %), jugular bulb saturations higher than % were observed, whereas pts (= . %) revealed no abnormal sjo data ( - %) during these first h. concerning the periods with too low jugular bulb saturations (n: ), we found the following correlation ; in pts (= . %) cerebral perfusion pressure (cpp) was below mmng, in pts (= . %) paco~ was below mmhg and finally in pts (= %) we found primary intracranial hypertension. for the high jugular saturations (n: ) we found a primary intracraniaf hypertension in f pts (= %), and a pace level above mmhg in pts (= %). in all patients we could restore jugular bulb saturation within normal range ( - %) with the correct!on of the presumed causative factor. we can conclude that ultra early jugular bulb saturation data revealed a high incidence of abnormal values, with a predominance of jugular bulb desaturations, confirming once again the high incidence of disturbed and too low cerebral perfusion within the first hours after severe head injury. these jugular bulb desaturations were especially correlated to systemic causes, as a too low cpp (caused in the vast majority by primary map insufficiency, and not by intracranial hypertension) and hyperventilation were the major causes of the desaturation periods. as jugular bulb desaturatione are known to be significantly correlated to a worse neurological outcome after severe head injury, one might improve outcome by an emergency management avoiding these possible causes of jugular desaturation. therefore, extreme attention should be paid to the maintenance of an adequate mean arterial blood pressure (above mmhg?) even duhng the few time spent at the emergency department. one should be as attentive to the maintenance of normoventilation during this very early period of admission and hyperventilation without any knowledge of icp or sjo should be abandonned. recently, indomethacine has been proposed for the treatment of therapy refractory intracranial hypertension in pts suffedng from severe head injury ( ). indomethacine, a cyclo-oxygenase inhibitor, gives rise to a significant fall in cerebral blood flow by inducing cerebral vasoconstriction. therefore, its use could result in a drastic lowering of the intraeranial pressure (;cp) in pts suffering from intracranial hypertension secondary to cerebral hyperaemia and in whom the use of other cerebral vasoconstrictive drugs (barbiturates or hyperventilation) appears insufficient to control icp. for the last months, we included the use of indomethacine in our therapeutic flow chart for severe head injury management. pts revealing intracranial hypertension (icp> mmhg) and cerebral hyperaemia (sjo~> %) and in whom icp was not efficiently controlled by the combined use of hyperventilation and barbiturates were given indomethacine in a trial to control icp. a total of head injured pts received treatment for intracranial hypertension over the last months. six of them met the criteria set for the administration of indomethacine. in pts, no decrease in icp or in sjo was observed and both pts died due to therapy refractory intracranial hypertension. in the other pts, a significant fall in icp and in sjo was observed shortly after indomethacine administration. in pts we observed a catastrophic fall of sjo= even below %, indicating an extreme cerebral vasoconstriction with the possible risk of inducing cerebral ischaemia. in one of the pts, icp remained under control without further administration of indomethadne, but he died days later in multiple organ failure. the other pts, needed multiple indomethacine administrations (for pt even during consecutive days) to finally control icp. in all pts, icp was finally controlled, but only pt survived. both other pts died from systemic causes (multiple organ failure in pt, massive gut infarction in the other tat, possibly due to the systemic vasoconsttictive effects of the indomethacine administration). in conclusion, indornethacine might have a role in the treatment of intraoranial hypertension, especially when caused by cerebral hyperaemia. we observed however a poor final outcome and a threatening high incidence of systemic events (multiple organ failure, gut infarction) in those pts receiving indomethacine for icp control. therefore, indomethacine in the treatment of intracranial hypertension should be reevaluated in controlled study settings, before its routine use can be considered. untill recently, intracranial hypertension (ich) in pts suffering from severe head injury was managed in a staircase approach, with csf drainage as first therapeutic step, mannitol as second step, hyperventilation as third step, and finally, barbiturates as the last rescue step for therapy refractory ich. this staircase approach for the treatment of tch was only guided by the intracraniat pressure, and not by other parameters such as e.g. the actual state of cerebral perfusion of the concerned pt. jugular bulb oximetry provides us with the first, bedside and continuous available, estimation of cerebral perfueion. its implementation in a rigourous flow chart, based on as well icp-as jugular bulb oximetry-data might result in an altered strategy for ich management. we adopted a '~ugular bulb saturation (sjo~)-guided approach" for ich management in consecutive pts, suffering from severe head injury (gcs< ). we maintained csf drainage as first therapeutic step, but the decision for the second step was guided by sjo information. pts revealing ich and sjo=values above %, were treated with hyperventilation, and did not receive mannitol. if ich persisted, barbiturates were added as a third step. on the other hand, pts with ich and sjo= vales less than %, received mannitol administration as second step. hyperventilation and/or barbiturates were only added if ich persisted and if no cerebral hypoperfusion was discerned (sjo=> %). our objectives were to prospectively analyze this new therapeuticstrategy, as compared to the formerly used staircase approach of ich. we managed pts with ich, with an overall mortality of . % due to therapy refractory ich. all pts received standard primary care with head elevation, full sedation and normovenfilation. fer pts, csf drainage alone was sufficient to control ice of the remaining pts, pts received mannitol and pts were hyperventilated as second approach. in the third line, pts were managed with barbiturates, with mannitol and pts with hyperventilation. finally, barbiturates were used as the final rescue in pts. these results reveal a less frequent use of mannitol as only pts received mannitol, compared to the pts that would have received mannitol using the former staircase approach. hyperventilalien was used much earlier in the treatment course, as lots were already hyperventilated in the second line approach, were this was formerly exclusively reserved for the third line approach. finally, also barbiturates were used much eadier ( pts received barbiturates as third approach). we may therefore conclude to a important change in the management of ich, induced by a sjo -guided flowchart. however, future studies will have to elucidate if this new strategy for the intensive care management of severe head injury will also result in an improved outcome. obsectives: in a first series of experimental brain injury we investigated the course of brain po , icp and cerebral blood flow after traumatic brain injury (tbi), whilst accordingly there are very few data available and the mechanisms leading to secondary brain damage are poorly understood. methods: in piglets ( days old, , - kg) of either sex we produced a moderate brain injury ( , arm., msec.) using a lateral fluid percussion {fp) device. complete measurements were made before and min. after brain trauma and after , and hours including blood gases, cardiac output (htermodilution), heart rate, eeg, laser doppler flow probe (ldf} and icp values (camino), brain temp., po by a clake type oxygen electrode (licox) and coloured microspheres for regional blood flow. results: immediately after the trauma a typical "cushing"response to the icp peak up to mm hg being highly significant (before mean i mm hg, range - mm hg) could be observed: mean arterial blood pressure rose from appr. mm hg to ii mm hg for - min. in two animals this was followed by an ischemic period lasting min. accordingly icp values gradually returned to starting measures within hours; in the ischemic animals they remained at a level of about mm hg.-no secondary increase of icp could be observed, once icp dropped to starting values within hours. cerebral blood flow (ldf) fell from mean values being i before trauma to appr. zero and recovered to around . brain po started at mean values of mm hg (range - mm hg) and fell to around zero depending upon the severity of the ischemic reaction. on average values of mm hg were reached over the time course. conclusions: with our fp trauma model we can reproduce the well known "cushing"-response after brain injury; secondary icp elevations cannot be achieved, although local edema is observed. direct brain po measurement seems to be a very sensitive variable for detection of cerebral ischemia and anticipates eventually following icp elevations by far. pulmonary aspiration s,traoaras. v. sgountzos, p. agouridakis, m eforakopoulou, e. ioannidou. intensive care unit (tcu) of "kat" hospital, athens, greece ob!e=ives: the reported mortality rate after pulmonary aspiration is variable in several series. the purpose of this study was to find out the influence of preexisting disease or situation on morbidity and mortality of intensive care unit (icu) patients with pulmonary aspiration. methods: patients who were treated in icu and had pulmonary aspiration, were studied, entrance's criteria in the study, all of them obliged, were: ) suction of gastric contents from trachea during intubation, ) presense of a predisposing factor, e.g. coma. ) recent hypoxaemia or new infiltrates in xray. preexisting disease was recorded and correlated with complications and outcome. patients with glasgow coma scale , because of cerebral injury, and patients who died within days from cause other than aspiration, were excluded from the study. method of statistical analysis: chi-square test, results: one hundred forty five patients were studied. the trauma patients were and the non trauma patients . from the trauma patients, had cerebral injury and were polytreumatized without cerebral damage. from the non trauma patients, had malignant neoplasms, neurological diseases in terminal stage, old age, drug overdose, and several diseases. eighty seven from trauma patients ( %) and from non trauma patients ( %) manifested several complications (pneumonia, ards, etc), so there was no statistical difference in complications' frequency between the groups (p> , ). the severity of complications was also proportional in the groups. eighteen deaths were recorded in the trauma patients (mortality %). only deaths correlated directly or indirectly with the aspiration ( %). in non trauma patients, deaths were recorded ( %). twelve deaths were recorded in patients with neoplasms, deaths in patients with neurological diseases, deaths in aged patients, death in drug overdose patients, and death in patients with several diseases, the mortality difference in trauma and non trauma patients was statistically significant (p< , ). in patients with drug overdose the mortality was significantly lower from the other non trauma patients and the difference was statistically significant (p< , ). conclusion: the preexisting disease or situation plays a major role in the outcome of the patients with pulmonary aspiration. the mortality of patients with aspiration seems to be caused by severe preexisting situations rather, that lead to death, than from the pulmonary aspiration per se, which may be a final happening in a predetermined course. obiectives; the purpose of this study was to compare fluconazole and amfotericin-b in the treatment of fungal infections in severe trauma patients. methods: thirty five severe trauma patients who were treated in intensive care unit (icu), were studied prospectively. they all developed fungal infections, prooved with blood positive cultures and at least one of the following: fever, positive urine or bronchial secretions cultures, infiltrates in xrays. the patients were separated randomly in groups. the patients of group a ( patients) received fluconazole rag/day for days. and the patients of group ( patients) amfotericin-b rag/day for also days. compaiison's criteria were the clinical responce to treatment (fever etc), the fungal elimination (blood and other cultures), the relapses of the disease, the side effects of drug, and the outcome of the patients. as method of statistical analysis was used the chi-square test. results: nine patients from of the group a ( %), and from of the group b ( %), presented remission of fever (patients of group b had better clinical responce than patients of group a, and the difference was statistically significant, p< , ). all the patients before treatment had positive for fungi blood cultures. after days of treatment, patients of group a and none of group b had positive cultures. eight patients (from who had positive cultures of bronchial secretions before treatment) of group a. and (from ) of group . had positive cuttures of bronchial secretions after days of treatment, so positive bronchial secretions were fewer in group b than in group a, but this difference wasn't statistically significant, (p< , and p> , ): ten patients (from ) of group a and patients (from ) of group b had positive urine cultures, after days of treatment (positive urine cultures were fewer in group b than in group a and this difference was statistically significant. (p< , ). two patients of group a and none of group b had a relapse of fungal disease. in group a, no side effects were obsepced, while in group b were observed only minor side effects (small increase of serum creatinine in patients, chills and fever during infusion in patients, and hypokalemia in patients). three patients of group a and patient of group b died, because of sepsis. conclusion: amfotericin-b (even i~ short regimen of days), is superior to fluconazole in the clinical and laboratory responce and also in the relapse of fungal disease, fluconazole is superior to amfotericin-b as it has no side effects. ob!ectives: flail chest after thoracic trauma is a serious injury. it is controversial if flail chest by itself orthe concomitant intrathoracic injuries e.g. pulmonary contusion, is the cause of the reported significant morbidity and mortality. in this study we searched the influence of concomitant thoracic injuries in the course and outcome of patients with flail chest. methods: eighty five patients with flail chest after isolated chest injuries were studied, for the purpose of analysis, we separated the patients into groups, patients with isolated flail chest were included in group a, patients with flail chest and hemo-pneumothorax in group b, patients with flail chest and pulmonary contusion in group c, and patients with flail chest and hemo-pneumothorax and pulmonary contusion in group d. complications from the chest, duration of mechanical ventilation and mortality were compared in the groups. statistical comparison of results belween groups was made using chi-square and t-studend tests. results: the patients were . all patients received mechanical ventilation, twenty eight patients were ihcluded in group a, in group b, in group c. and in group d. seventy three patients manifested complications from the chest, especially pulmonary infections. there was no statistical difference among the groups as to number of complications ( twenty four patients had chest complications in group a, in group b, in group c, and in group d. p> , }. the duration of mechanical ventilation was not statistically different among the groups (the mean duration was , days in group a, , in group b, , in group c, and , in group d, p> , ). there was also no statistical difference in mortality among the groups (six patients died in group a. in group b, in group c, and in group d, p> , ). conclusion: flail chest by itself is a serious thoracic damage with many complications, regardless of the presense of other thoracic injuries, which don't contribute to greater morbidity and mortality. the present study investigated the correlation between blood lactate mortality and organ failure in trauma patients admitting between december , and july , in the icu. road traffic accidents were the most common cause of trauma in this studded population. brain damage was the main cause of mortality .nevertheless, of patients died from sepsis and multiple organ failure without significant brain damage and these deaths were potentially preventable. respiratory failure was the most common complication and was developed in ( %) of survivors and in ( %) of non survivors .we noted low fncidence of renal failure may be do to the early and aggressive ittv'asive hemodynamic monitoring and cardiopulmonary support. as part of our routine case protocol serial blood lactate levels were measured in each patient at least times a day until the valses returned within the normal range or until death. we analysed the blood lactate levels on admission, the highest value and the number of days until the first normal value (<l.smeq/i). initial lactate and highest lactate levels were significantly higher in patients with than without organ failure.( . vs . , . vs . meq/l, p< . )the duration of hyperlactemia also was higher in the patients with organ complications. ( . vs . days, p< . ). both initial lactate and highest lactate levels were higher in the non survivors than in the survivors.( . vs . , . vs . meq/l, p< . ) the present study demonstrated that not only the degree but also the duration of hyperlactemia can be related to the development of posttraumatic complications. serial blood lactate measurements are reliable indicators of morbidity and mortality following trauma. s current evidence suggest that peep only affects intracrenisl pressure (zcp)when it interferes with systemic arterial pressure, although the effects of peep over cerebral oxygenation remains unknown. objective: determine the effects of peep over icp and cerebral metabolism measured by sj , kjdo and ceo in severe head injured patients. meterial ~ methgds: patients with glasgow coma scale l at arrival, with difusse brain injury in the first gt, according to marshall criteria,lop and jo monitored, under analgesia and sedation, normoventilated with zeep, without mannitol treatment in the previous hours, normal x ray chest and within the first hours from injury, were considered candidates. peep value where increased fro~ zero to cmh , in three different steps, each one with min of duration. all date were analized on line, pmax p'p ..... p.._, from the ventilator, systemlc haemodynem]c data, cerebra perfuslon pressure (cpp), icp and sjo , in the case of hemodynamic deterioration, during the study, ppc ommhg, extra-volume were administered. if persistence, dopamine were begun or increased dosage. if no good response were obtained, patients were retired from the study. results. patients were candidates, of them were exc;uded due to haemodynamic instability, k total of completed all steps and were e~amined, men and women, age ! . yrs. at hospite; arrival, glasgow were < in patients, and > in the rest . patients mmhg at the beginning. zeep ob/ectives. critically ill patients are transpoded to an intensive care unit(icu), under conditions, which have not been systematically evaluated. therefore, we set suite investigate transportation and admission condition of these patients to our department. methods. we studied patients( females), aged (mean-..+-sd) . _ . yrs, which were consecutively (from august to march ) admitted to the icu, through the greek national emergency transporta~on service. apache ii severity score upon admission was . -+ . (range - ). the following data were evaluated: ) number of medical departments, where health care was provided until final admission to the icu, ) ambulance transportation conditions, ) catheters and tubes inserted before admission, ) vital signs upon admission ) information provided by referring physician (scored on a to scale: history, electrocardiogram, chest x-ray, laboratory data, drug therapy already administered), ) comparison of the state of the patient described by referring physicians, to the actual state u pen admission. resu/ts. one to four medical departments had provided health care before the palient was admitted the icu ( : . %, : . %, : . %, : %). thirty/ ( . %) patients were escorted by a physician. twenty-six/ ( . %) were transported on oxyge n, fio (mean__.sd): -+ %, pao : . -+ . mmhg. five of the remaining , for whom no oxygen was provided, had pao : . -+ mmhg. twelve/ ( . %) were intubated and ventilated during transportation. thirtyfour/ had a peripheral venous line, / had an arterial line, / had a nasogastdc tube, / had a urinary catheter. eleven/ were sedated and / were paralysed. three/ were on inotropes. vital signs upon admission were: arterial blood pressure, systolic . -+ mmhg, diastolic -+ mmhg, heart rate -+ bpm, temperature . -+ cc. patient information score was --. . . the actual state upon admission was found substantially different, as compared to the description of the referring physician, in / ( . %) patients. conclusions. we conclude that several aspects of the greek national emergency transportation service to an icu should be reevaluated and further improved, i. e. ventilatory support, adequacy of information provided and accuracy of prior description of the patient's state. a new perspective must be applied for critically ill patients transportation since . % of the patients were evaluated and treated in more than one, medical departments, mostly primary care, before they were finally admitted to our icu. dclhb is a human derived hemoglobin molecule that has been cross-linked to stabilize and permit heat pasteurization to remove residual proteins and inactivate viruses. dclhb is mixed with a lactated electrolyte solution to yield a total hemoglobin concentration of log/dl objective: to present an overview of four recently completed clinical safety studies of dclhb in the u.s. and europe, and to discuss the properties, actions and potential indications for dclhb. method: patient populations in the four studies included males and females ranging in age from to years. dosing ranged from mglkg to mg/kg. the controlled randomized safety studies were conducted in chronic renal failure patients, surgical patients undergoing total hip replacement or abdominal aorta repair and in hemorrhagic hypovolemic shock patients. these very diverse patient populations allowed safety evaluation of the product in patients who were generally elderly, often hypertensive with some degree of cardiovascular disease, and receiving medications for treatment of other conditions. results: over patients received dclhb in the four:studies. no product related sarious adverse events occurred during the clinical trials. conclusion: results from phase itll safety studies of dclhb in patients undergoing chronic renal dialysis, abdominal aorta repair, or total hip replacement and in patients in hemorrhagic hypovolemic shock, indicate that the product was well tolerated in these distinct populations. although these studies were designed to evaluate safety, the data suggest clinical benefit. follow-up efficacy trials are indicated. prehospital emergency services represent the extension of emergency care into the community and constitutes the manpower, communications, transportations and facilities used to provide care for patients outside hospital. one of the main points of the system is how to decide the hospitalization of patients and what kind of facilities to provide : emergency medical service, fire brigade, locat general praclitionner or ambulance officers. objectives : to realize guidelines for using the prehospital emergency medical service in case of patient'calls outside hospital. methods : from st june to july , all the calls for emergency care were analysed using a questionnaire of items (origin of the call, responses to the questions of an emergency practitionner, kind of emergency service provided and the issue of the patient). after taking account of the appropriatness of the decision, statistical method used was a logistic regression. results : calls were analysed. the criteria, for prehospital emergency medical service using, given by the logistic regression were as following : existence of a call for emergency, thoracic pain, dyspnea, seizures, cyanosis, drug intoxication, fall of the patient, fracture, age, the state of consciousness and the neurologic reactivity. the minimal and maximal predictive values of the model given by the logistic regression are respectively % and %. the performance of the model is %. conclusion : it seems possible to help medical decision of emergency medicine by using only some easy criteria and a predictive model. (italy) objective: to evaluate the incidence of blunt carotideal injury (bci) in patients admitted to our icu after head injury. methods: we reviewed the medical records of all patients diagnosed to have a bci. at admission, the severity of trauma was assessed either with glasgow coma scale (gcs) and with ct scan. bci was demostrated by doppler ultrasography (us) and by angiography (ang). results:since may to april , patients were admitted to our icu with bci ( m, f, age + ). a history of direct trauma was present in patients. admission gcs was in all patients, and was associated with hemiparesis in of them; the last became paretic hours thereafter. two patients had concomitant injuries (a homoiateral clavicular and a controlateral zygomatic fracture, respectively). the initial ct scan was negative in every patient, and showed signs of ischemia after a variable timespan ( - days) after the onset of the symptoms. the bci was diagnosed with us and ang, which demonstrated a thrombosis of the internal carotid artery (ic). in two patients, an intimai dissection was also present. three patients were treated with heparin associated with antiaggregating agents and were discharged alive. the last patient was referred to our icu after the development of a massive hemispheric infarction, and died three days after the admission. at necropsy, the ic thrombosis was associated to an extensive homolateral extra and intracranial venous thrombosis. conclusions:the presence of focal neurological signs despite a negative ct scan should address the diagnosis toward a bci, thus implementing the diagnostic workup with us and/or ang. tab i: distribution of l~tients (%) in the groups the outcome were monitorett results were sabmitted to statistical analysis using a continence table x in z test. res.cl~s: of patients were submitted to thrombolysts and died. the higher incidence of bracb, ar~lhmias (ii degree gg p t e and av block. i degree av block. avsb . <ii. sinus arrest) that requited the insertion of avsc . <cl temporar~ pace-maker was recorded in group a b vs c . ns in % of the cas ~. the rapid recognition of life tab li:;~ test. threatening conditions suggests the monitoring of v r-lead r b' in the course of inferior ami. the authors report their own expirience in application of ringer lact.(rl)and , %nacl/ %dextran . methods:in polytraumatized patients with developed hae morrhagic shock,injures of the chest(qg)and abdomen(q ) prevalid.replacement of the volume loss egan in institutions of general medicine,frequently by rl and dextran or haemaccel.after receiving necessary medical aid,polytraumatized patients wer transported to mma by helicopter,continuing replacing of circulation volume by the same solution. results:average quantities of the solution dministered ~o the injured wer~ - ml.a group of the inoured which,after the admission to mma was resuscitated by adml nistration of the , %nacl/ %dextran @(groupii)( -sml/kg observed to the final surgical management,had statistically higher map(increase of % in relation to admission), cvp(average increase of , cmh~o),diuresis(averagely omi after min.),better gas ~nalyses and acid-base status in relation to the group which was administered only rl(groupi)(increase of the map of q %,average increase c~ of cvp , cmh and average diuresis oml after omin). total quantity of the administered solutions was significantly smaller in the groupii( ml: ml).the only ob served complication was hyperhatr~f~a::and~moderat~hyper osmolerity of plasma which disappeared within hours. the quantity of replaced blodd was considerably smaller in the groupii(qooofnl: ooml).in the group i interstitial pulmonary oedema was observed in two patients(qo%),while: in the group ii no complication was observed.coagulation i disorder and hypotension were not recorded because of the fast infusion of hypertonic/hyperoncotic solution in the groupil as the infusion of , %nacl/ %dextran lasted minutes. w.scherzer(l~,k.lechner( ),r.simon( ). ll)dept.anaesthesiology,trauma hospital,vienna-meidlin !( )neurotraum.rehabilitation center,vienna-meidling both austrian workers'compensation board,vienna,austria what we usually call"unconcious" means only that the patient is not able to interact in any kind of way.experiences in intensive care medicine (robinson, ) ,in general anaesthesia (bennet, ) and with evoked potentials show,that unconcious patients are not automatically unhble to process and recall information.this implicates a challenge to start the efforts to restore the traumatica-!ly desintegrated brain function as early as possible in the acute phase ia (zieger, ) .we present a method to ~repare the patient for the rehabilitation goals of the postacute phase ib,the phase of stabilisation ii and of rehabilitation iii within one concept. to achieve sensory stimulation in phase la we use: attempt at some kind of dialogue by speaking to and tou-ching the patient,to make him experience his body limits, ~acio-oral therapy by ice application,tast and smell pro vocations and trials of feeding,early adaption to circadian rhythm and guiding the patient in every-day-life-ac-tivities e.g.:in the brushing of teeth,washing etc. to achieve motor stimulation and orientation in terms of ~-ace,time and gravity in phase la we use: avoidance of perceptual impairment as produced by air-:sack-beds or habituation to supine position,using method~ according to affolter( ) ,basal stimulation (bienstein, ) , bobath-therapy( ) and facilitation of a physiological moving pattern(pnf)according to knott( ) . conclusions: by integrating all these measures in the ~herapy and nursing even in the acute phase la one prei ares the comatose patient for multisensory stimulation nd motor training and all other rehabilitation activities in the following phases of therapy. s objectives." measurement of cardiac output (co) and stroke volume (sv) requires insertion of a central venous catheter and is associated with a considerable risk for complications. non-invasive methods for determination of hemodynamic parameters have been introduced recently. one of these methods is the aortic modelflow program, which provides co and sv continously using a three-element windkessel model. the aim of the study was to evaluate the accuracy of the aortic modelflow program in critically ill patients. methods: patients (mean age: ) admitted to the emergency department after cardiopuimonary resuscitation (n=ll) and for myocardial infaction (n= ), acute congestive heart failure (n= ) and anaphylactic shock (n=l) were included to the study protocol. after stabilization all patients received a swan-ganz catheter (baxter~; edwards swan-g-anz) via a central vein. co and sv were measured by the use of a cardiac output catheter and injection of rrd ice-cold glucose % non-invasive cardiac output measurement was done by using the continuous cardiac output software package modelflow (tno; portapres| results: overall, paired measurements were used for the evaluation of the accuracy of non-invasive obstained sv and co. mean values, standard deviation and range of co and sv evaluated by invasive and non-invasive methods are summarized in the aortic modelflow provides reliable hemodynamic data in critically ill patients. it may be a useful alternative due to its non-invasive approach and continous measurement. objectives: to determine the feasability and accuracy of a rapid urine screening test (triage tm, merck-diagnostika) in an emergency department. methods: prospective analysis of the triage tm testkit (tt) in patients admitted because of suspected drug abuse during an observational period of months. the tt is a eompetitve immunoassay which gives qualitative results within i minutes for methadone, benzodiazepines, cocaine, amphetamine, opiates, barbiturates and cannabis. urine samples were analysed with the tt and compared to the results of a enzyme-lihked tmmuno-assay (el.a) in our labratory (gold standard). results: during the study patients were enrolled, in of these patients substance abuse was proven by tt and verified by eia. we recorded no false positive or false negative results for benzodiazepines, barbiturates, opiates, cocaine and cannabis. two results were false positive and one false negative for methadone; one result was false negative for amphetamines. the triage-testldt had an overall sensitivity of . and specificity of . . conclusions: the triage tm testkit seems to be a a useful rapid test device in addition to quantitative tests for drugs of abuse in an emergency department. objectives: the purpose of this study was to evaluate the influence of several factors of the renin-angiotensin-aldosterone system on blood pressure response in patients with hypertensive crises. methods: patients with systolic blood pressure > rorohg and diastolic blood pressure > nunllg were included into the study. prior to treatment blood samples for determination of plasma renin activity (pra), angiotensin converting enzyme (ace), angiotensin ii (ang ii) and aldosterone (aldo) were collected. all patients received rog enalaprilat intravenously. success of treatroent was defined as a reduction of systolic blood pressure below mmi-ig and diastolic blood pressure below mmi-ig within minutes after start of treatment. results: patients were included in our study, ( %) patients responded successfully to treatment. mean arterial pressure decreased in responders by . mmhg and in non-respenders by . mmhg (p< . ). responders and non-respenders differed signii'icantly concerning pra (p= . ), ace (p= . ) and ang ii (p= . ). . . the extent of blood pressure reduction correlated positively with the pretreatment pra and ang ii concentrations (correlation coefficient for pra: r= . ; ang ii: r= . ). conclusion: our data confirm that in patients with hypertensive crises blood pressure response to ace inhibition is mainly determined by circulatory pra, ace and ang ii. as the extent of blood pressure reduction correlates with pra, ace-inhibitors in patients with suspected high renin status cannot be recommended, as excessive blood pressure reduction, which carries a considerable risk for further organ damage, may occur. f. staikowsky, n. grillon, f.pevirieri, c.jedrecy, c. zanker, f. michard, a. haft medical emergency department. hospital bichat, paris epidemiology of acute intentional self medications-poisoning (smp) in france is especially known by data of poison control centei,s and intensive care units (icu). the purpose of this study is pro~,ided characteristics of this problem in a med for adults. method: july to june , files of patients consulting to the ed for smp have been retrospectively analyzed. results: patients, women and men, . + years old (range - ) have been admitted for episodes of smp ( % of all consultations) whose relapses during the period of study. psychiatric disorders, drug addiction or hiv patients was found for respectively . %, . % and , % of patients. the interval of time between the ingestion and emergency consultation was noted for % of smp ( + min, ranges - ). the involved products name was known in totality in % of cases with an average number by episode of . + drugs (ranges - ). the most often, ( %) or ( %) different products were interfered. the nonbarbiturate psychotropic drugs accounted for . % of the products (benzodiazepines %, antidepressants . %, neuroleptics %, carbamates . %, imidazopyridines . %, cyclqpyrrol nes . %). analgesics and nonsteroidal antiinflammatories represented . % of all drugs, anticonvulsants . %, cardiovascular drugs %, antiinfective agents . %, drugs against cough . %, muscle relaxants . % and antihistamines h . %. the benzodiaz pines were present in episodes, alone in episodes. in . % of cases, there was a simultaneous intoxication with alcohol. the processing consisted of gastric lavage in . % of cases, activated charcoal in . % of cases, flumazenil in . % of cases, naloxone and acetylcysteine in . % of cases; orotracheal intubation was performed in patients. admission in hospital was effective for patients, in medical ward (n = ), psychiatry (n = ) or icu (n = ); no fatal case was recorded. conelusion: smp to ed are often benign. the benzodiaz pines are the most often incriminated but the new anxiolytics and hypnotics (imidazopyridines and cyclopyrrolones) take a growing place. the latsion burn center of athens. its planning constructive and functional refinements j. ioannovich, a. petalas-vourekus, d~ serbetis, h. carsin a bed burns unit is under construction following a donation to the general hospital of athens. the plan of the unit, covering a surface of approximately . m is based on the principle of three identical bed satelites which may function totally independent from each other. in the center of the unit the common facilities are installed, like operation theatres, storage rooms etc. this new modification in the plan of a burn unit is presented in this paper. the advantages from the fucntional, administrative and medical point of view are discussed. tiffs anisotropic conduodon could favour the ocenrence of a circular movement of the impulse that leads to tachyeardias by reentry. purposes of this work were to study, with the help of epicardial mapping, the influence of a trieyclie antidepressant, clomipramine (c), on the conduction velocity longitudinal (vl) and transverse (vt) to myocardial fiber orientation and on anisotropy (a = ratio vl/vt), and their modificutions by the sodium bicarbonate ( ). method: a plaque of electrodes, positioned on the left anterior ventricular wall of anesthetized dogs, allowed to deliver, thanks to central electrodes, programmed electrical stimulations inducing vcuttienlar complexes, and to collect them. each entailed unipolar dectrogram was processed by a computer system that drew the isochrones and a map of activation allowing the calculation of v. the c was infused ( . mg/kg/min iv) during rain; at t , dogs received the b until the retuni of qrs to its initial value fro). a lengthening of qrs of at least % of its value at to was demanded before the administration of b. results: dog was excluded because of an.~nsufficient prolongation of qrs before the administration of b. all values (map : mean arterial pressure, i-ir : heart rate, qrs andqt intervals, v) differed significatively ( < . ) compared to values control fro)except qrs at t . the b ( + ml/kg; ranges . and . ml/kg) modified no studied dements outside of the ( }rs. to ti t t t t t a , + , , + , , + , , + , , + , , + , , +- ,~ conclusion : the c slowed v l and v t without modify the anisotropy. the b did not modify the v of~conduction while the qrs prolongation was corrected. the c acts as a class i antiarrythmie drug on the inward sodium current during the phase of action potential; the gap junctions have shown to be important in the conduction and an action on the gap junctions such as a modulation of the junctional resistivity, can not be rule out. is the doctor a heroe ? p. t.schies~.he, t. bauer, m. seyr dept. of anaesthesiology and intensive care, aokh krems, austria objectives: helicopter emergency services (hes) are getting popular more and more. the results concerning outcome are encouraging. however, some recent accidents with dead or badly wounded hescrew-members have shown the relatively high risk for the crews. therefore we were interested to eval ate the motivation of physicians to participate in a hes. this survey was designed to investigate current concerns about safety and motivation of doctors on emergency call. methods: a questionnaire was sent to doctors of the austrian emergency system. the survey consisted of multiple choice questions and subjective scoring tables from (--full agreement) to (=disagreement). overall, "/. of the active emergency physicians participated in the survey. results: . % of the doctors assume the system is basically safe, experienced doctors tended to have less trust in safety. only % would not hesitate to go into action by dark. . % stdctly refuse night flights to accidents outdoors. although defibrillations are assumed to be safe dudng flight, only % would do it. . % of the doctors would rather stop flying. the most common reasons for ,uitting were wish of family and fear of an accident. . % conclusioq: short transportation times help to avoid trauma related stress, pain and shock-induced organ complications. therefore the physiologic and economic advantages of hes are undebatable. however, the survey data indicate a considerable concern about safety of the medical personal in a hes. crash landings within less than years with deadcases and badly wounded crew members in a small country like austda make desire for safe flying conditions understandable. obiectives: to evaluate the clinical usefulness of trachlight. methods: trachlight is a new device facilitating endotracheal intubation. a stylet with a lightprobe is inserted into the endotracheal tube. intubation is guided by the light glowing through the neck tissues, thus rendering direct laryngoscopy unnecessary. intubation using trachlight was studied in patients (age - years). the indication for intubation was elective surgery in patients (asa i-ii) and emergency intubation in patients. in the elective patients, anaesthesia was induced with thiopentone supplemented with fentanyl, and intubation was facilitated with vecuronium. the cause for intubation in the emergency patients was dyspnea in , cardiac arrest in , trauma in, and unconsciousness due to drug overdose or seizures in patients. intubation was facilitated with medication in patients. results: of the elective patients, ( %) were successfully intubated. six patients ( %) needed two attempts before successful intubation. the duration of intubation exceeded seconds in patients ( %). of the emergency patients, ( %) were successfully intubated. six patients ( %) needed two attempts, and the duration of intubation was more than seconds in patients ( %). in % of all patients, intubation was assessed as easy. no or insufficient glow, prolonging intubation or necessitating two attempts, was noted in patients ( %). oesophageal intubation occurred in patients. conclusions: trachlight may be a valuable adjunct for intubation in varoius settings provided that adequate training is provided. a learning curve was found to exist. objectives: to compare enoxaparin and standard heparin in cavhd and calculate the value of laboratory controls in the treaanent. patients and methods: twenty patients needing dialysis for acute renal failure participated in the study. the main exclusion criteria were massive bleeding or a thrombocyte level < x e /i. in each treatment the same type (av- , fresenius ag, germany) of a polysulfone capillary haemofilter was used. the study scheme consisted of two consecutive four-day cavhd treatments, one course for each type of heparin. the order of heparin administration was counterbalanced between patients. the standard heparin was given as a continuous infusion aiming at an activated coagulation time between and s. the initial enoxaparin dose was rag every :th hour intravenously, but was modified by any signs of coagulation in the dialysis blood lines or bleeding complications. results: the dialysis treatment was adequate in both treatment modes, with mean blood urea levels . and . mmol/l respectively (ns). the bleeding complications were moderate and similar in both treatment modes. the mean life-span of haemofilter using enoxaparin as an anticoagulant was some longer than using heparin ( . + . h versus . + h, ns). the mean aptt-levcl during heparin treatment was s and during enoxaparin treatment s (ref. - s). the mean daily dose of heparin was nag, that of enoxaparin lg mg. the mean anti-xa activities were . u/mi and . u/mi, respectively, reflecting a better bioavallability of enoxaparin. conclusions: both anticoagniation modes were equally effective and well tolerated. the amount of enoxaparin needed for a proper anticoagulation was, however, less than half of that of standard heparin. the changes in aptt level were too slight to make its use possible in controliing the dose of enoxaparin. the use of enoxaparin seems to be rather safe in cavhd even without laboratory controls. the adv~ucea in the management of computerized data of an intensive care unit have been petalled to the clinical advauces and the increasing sophistication of methods of diagnosis fop the clinical application an therapy. this has led our unit to design and develop a computational system called timbu which is used to help physicians assist patients. among its various uses, this system has a software for the hemodynsmic control of a critic patient. this program was carried out to get as fast as possible the hemodynamic data of the patients in an intensive care unit. as an example, we can mention that when we load data obtained through direct measurement from the monitors and the lab, the program calculates parameters that guide, intelligently, to the diagnosis and therapeutic behaviour of the hemodynamic problem through screen messages. the validation of this program in the unit of intensive care has demonstrated that its use allows a more efficient handling of the patient with serious hemodynamics and respiratory disorders. ohieetlve: traema is a heterogeneotm 'disease' that ecatr~ a~"o~s all age ~oupe with v~ying degrees of severity. this imerogeneity has made the di~e, trmma, diflkaflt to r the ehn of this stady wa~ to assr the fitaen of saps in ibis popeleties. methode: in order to compute the ~ probability, a model derived from logistic regression w~ developed. meam'e of calibration (goodaess-of-fit stetislj.r and di~'riminafion (roc ou~e) were adopted in developmm~ and validetlon set randomly taken from a database of pts eeeseemivety admitted in icu (arohidia). ~ witho= salm, p~ yom~ am is yam, with los ~horter thma hotam wore exr fa'om thi~ mmly~ir thi~ model v~s then evahmed on the ~per ~mbgro~ (i.e., trmma pts). if'it did t~t fit the data well ~, new model wm developed rer the logit only on trm=~apm. reims: data were availabte for pts during aperiod of three .y~m , treama pts were . %), teats of calibration iadioaled probability model did mot provide m adequate refle~on of the mortality ezperieace in pm with ireutae, being the observed mortality lower flma the expected (figm'o). a aew model was then variable. this oastomized model fit~ the de~t of trmara pts very well (g =- a p> . ; roc = , ). the di:lferencea between the two modele were evident. conclusion: this ltudy shows that mortality in iramna pts is over wcfe~d when ~se~ed by menm of saps. however the r mode! meets high standmcd in terms of calibration mid dil~'iminat'~o~ ']"he advaatage of ~imd models meaas the colleotion of the ~ set of variables for all pm admitted in icu e~einat the ase of diasma specific ~oring syatex~. ("sl"): effects on cardiovascular and hemostasis systems (cvs, hss) a.oborin~ph, ~.~yndiuk~ph, b.kondratsky ~pt. of'""su~gery and transfusiology, research institute of hematology, lvov, ukraine objectives: great interest has been shown recently in the use of hoss for the initial resuscitation of hypovolemic shock. methods: the study was carried out in dogs -~h hs was induced by jet momentary hemorrhage (h) from a. femoralls (the bloodloss volume made . + . ml/kg). the treatment was begun after .u+o. hrs of h. "sl", created on the basis of-sorblt and natrium lactate ( mosm/l) was injected into v. femofalls at the dose of io. ml/kg. results: it is established that before treatmen-~rterial blood and central venous pressures (abp, cvp) diminished to . mm hg and - . + . cm h (p .o ), while heart rate (hr)-increased to . + . per min (p<.o ). by this the indices of ~latelet counts (pic) and plasma fibrinogen (pf) lowered by . % (p<.i) and . % (p~. ), while fibrin degradation products (fdp) enlarged by . % (p~ . ). after - min of treatment termination abp and cvp increased to . + . mmhg and . +o. cm h (p<.o ), and ~[r diminished to t . + . per min (p>. ). at the same time the indtces of pic and pf enlarged by . % and . % (p>.i), while fdp diminished by . % (p>.i). one of dogs survived. life duration of the other dogs was . + . hrs. conclusions: the obtained data are ~he evidence of normalizing influence of "sl" on cvs and hss, and allow to recommend it as a mean of initial resuscitation of hs in clinic. oblectives: we prospectively studied icu patients with severe head injury (hi), which cerebral lesions monitorized with sjo through opljcal fiber and the cerebral flux with tcd. methods: since january until june , we collected ht admitted to the icu, and of them monitorized with optical fiber in the right jugular bulb and tcd. all patients needed mechanical ventilation related to gcs <__ , with ct in admission (classifing lesions according to marshall and al.) . we related the final results to the evolution of sjo and tcd, with other monitorizing methods like gcs, ct and icp. ~sults: conclusions: in patients with gcs _< , sjo is useful to evaluate the evolution towards vegetative state, still more in cases with ct type ii in admission and higher apache ill. elevation of icp implies an evolutive nsk to brain death and data of tcd is a good indicator of brain death, the complete monitorization of these patients can improve the therapeutic control of this neurologic problem, , ( m, f) , (m. age: + years), divided in two groups (a and b) under specific criteria(tremor and/or fever during admission in i.c.u., or not). the injury severity score was > in all studied patients. tbe group a ( m, ") had no tremor and/or fever on admisskm, while em group b (tin, the above criteria were ix)sitive. bhx~d samplings were taken - hours after accident and - rain. after admisskm in i.c.u. micro-eli~ method was used for measuring cytokinc-levcls. statistic analysis was performed by studcnt-t test. as control group, healthy people were examined. _resu!_ts-il-lct, il-ii~, il- and tnf-tt levels were similar to control group levels in both groups a and b. i!,- and g-csf levels were found increased in both groups (p< jxjl), while il- levels were statistically significant comparing to group a. in con_tin_skin, during immediate post raumatic period,proinflamatory cylokines il-i~, il-i~ and tnf.-ct, produced in an earlier stage than ,. , cannot be detected,whereas .- was increased significantly, especially in group b. g-csf was fimnd in increawal levels in both gr(mps, without statistically significant difference between gnmps a and i|. objectives-l~valantc proteolitic activity, disorders in" eariy, period after combined trauma and p(~.ssibilit, i' of their correction by injection of proteo[ysis inhibitors contrycal and s-fto~:nracil in combination with driving an isotonic snlu~ion of sodlum chloride and polig[ucine. methods: biochemicai studies of proteolitic activity in dogs with limited deep burn and acute bloodloss, . result:s: in case of deep % burn, cornplicated by bloodshed the of blood grows at - times. it; is the restdt of the pancreas glandischemi demage, caused by the centralised circulation of blood and intensifies the deviations of haemodiaamics and albumin exchange. the degree of endogene intoxication by mean mofecular peptides which are the products of albumin decay reses to %, and % in hours. in hours after the trauma the-process is accompanied b ! , % lower inhibitory activity of blood, where as at the peak of the trauma it was , ~ higher. that proves the nnfavuurahle process of the shock in case a combined trauma. conclusion: the vein injection of 'proteolysis inhihitotz cnntrycal and -fforuraei[ in cumbination with driving an isotonic solution of sodium chloride and p.dligh]cine to refill lhe loss of blood helps to lower at times the profeolitic activity of blood. but it still remains above the initial level. the degree of endogene intoxication lowers at times; [ emodinamics aml albumin exchange stahilised. objectives: nimodipine, a known calcium antagonist, has been shown to dispose a beneficial effect on patients with subarachnoid hemorrhage, but its efficacy on traumatic or spontaneous intracerebral hematoma has not been justified. therefore, we studied the effect of nimodipine on the histopathological changes following an experimental intracerebral haematoma in rabbits. methods: twenty-three new zealand albin rabbits of both sexes, weighing - , kgr and at age of - months were anesthetized and a small burr hold in the left parietal aerea was carried out under aseptic conditions. the dura was opened and . ml (this volume assuring a normal incranial pressure after kaufman ) of autologous blood was injected into a depth of mm via a needle of . mm bore. the wound was closed and the animals were left to recover. nimodipine, of , mg/kgr of by weight per day was given via a nasogastric tube to fifteen animals for a period of time of fifteen days (group b). six rabbits were given water and served as control (group a). both groups of animals weie sacrified on the fifteenth day, their brains were removed and immersed into % formalin solution. tissue sections of ~ were embedded into paraphin and stained with haematoxyline and eosin, mason and gfap stain for gliac cells. results: two animals died after the surgical procedure, because they developed large intracerebral bematoma. no animal developed neurological deficit except one of group a which manifested a right side hemiparesis. the results of the bistopathological changes are the following: i) the mean -+ sd diameter of the lesions in the group a was --. ~t while that of group b was + ~t (p< , ) ii) secondary ischaemic neural tissue changes, characterized by the extravasatlon of red cells, the presence of haemosiderin-containing macrophages and signs of low grade inflammation zpredominated in the specimens of group a and were totaly absent from those of group b. iii) a ring of gliac hyperplasia and a low grade local fibrosis was found, encircling the lesions in the specimens of group a in contrast to those of group b. conclusions: nimodipine when administered in rabbits following the development of a non increasing the icp experimental intracerebral haematoma, prevents the extention and the severity of the lesion. objectives: to study the efficacy and side effects of adding intramuscular clonidine (clophelinum) to analgesic regimen in early management of patients with serious burn injury. methods: pts with - % bsa second to third degree flame burns (respiratory tact injury excluded) to yrs of age were randomised to study (n= ) and control (n= ) groups. burn shock was treated with hypertonic saline -bicarbonate solutions ( mmol/l na +) ml/kg/%bsa for the first hours and ml/kg/%bsa for second day. analgesia in control group for the first hours was provided by regular hourly intramuscular administration of mg of morphine sulphate and mg of analgesic -antipyretic analgin with mg of diphenhydramine (dimedrol). from the rd day regular administration of morphine was finished. in the study group ixg of clonidine was added -hourly for hours and dose of morphine halved. vas, verbal rating scale for sedation (vrs, - ), sleeping time, spo , hr, bp, diuresis, vomiting and other complications were comparatively evaluated during patients' stay in icu. results: addition of ~g of intramuscular clonidine daily allowed to achieve better analgesia and sedation with halved consumption of morphine. mean vrs in study group for the first days was . - . vs . - . in control group with twice longer sleeping time. there was significantly less tachycardia in study group; dynamics of bp for the first hours did not differ considerably; later, there, was tendency for hypotension in study group without adverse effects on diuresis or other indices of tissue perfusion. because of high incidence of chronic ethanol abuse among study population pts of control group suffered from psychomotor agitation or delirium, probably as a sign of alcohol withdrawal syndrome (aws). this made regular evaluation of vas impossible. in the study group only pt showed sign of aws. mean vas score was in . - . range for first postburn days. pts appeared excessively drowsy due to clonidine, but it had no adverse effect on their overall clinical course. mean spo values in study group were in - % range, among controls - %; vomiting was absent in. cionidine group vs cases among controls conclusions: clonidine could be a valuable addition to analgesic -sedative regimen in burns, especially for prevention of aws and deserves further study in this regard. hemodialysis -hemoflltration modifications and/or intratracheal gas insuflation have been recently used for blood gas exchange in several models of respiratory failure. objectives: evaluate the combination of cavh-m and igi for respiratory support in experimental acute lung injury. methods: five mongrel dogs ( -+ kgr) were mechanically ventilated inroom air, paralysed, heparinized, connected with a cavh-m system (diafilter- polysulphone membrane) and remained stable for one hour (pao~= . • peco = -+ mmhg, ph= . -+ . , bp= -+ mmhg and pap= -+ mmhg). all was induced two hours after oleic acid infusion ( . ml/kgr) into the pulmonary artery (poo~= . _+ -p< . , paco~- . _+ -p< . , ph= . -+ . -p< . , bp= -+ -p=ns, and pap= _+ -p< . ). fio % for the next minutes did not significantly altered the b ood gas abnormalities. afterwards, pure oxygen applied simultaneously a) through the inlet of the filtrate's compartment of the hemofilter ( l/min) while filtrate and gas were removed from the outlet port (bypass flow ml/min) b) through a thin intratracheal catheter positioned cm above the carina ( l/min). the fio given through the ventilator readjusted to %. results replacement fluids/filtrate during the next four hours were not exceed . l/hour, whilst the blood gases and pressures were improved as follow: cavh-inlet:pao.= . objective. to compare the changes in humoral immunity in trauma patients following massive transfusion of autologous and homologous blood. methods. we studied randomised clinical groups of patients each containing patients with trauma and operation of large arterial vessels. the amount of autologous or homologous blood transfused to the patients was exceeding ml, while the patients in the control group did not recieve blood or blood products. results. we recorded most pronounced and characteristic changes on the -st and on the -th day in the group of patients recieving homologous blood transfusion, i.e. decreased amount of igg,iga,igm,c and c fractions of the complement system, haptoglobin and significant and sustained rise of circulating immune complexes up to the end of the study period. in the control group of patients the decrease was weaker and lasted only during the -st post-operative day; the dynamics of the circulating immune complexes level were almost the same as in the first group of patients. in the group of patients recieving autologous blood transfusion, the parameter values did not change significantly from preexisting levels after the -st day, while on the -th and on the -th day showed a tendency towards aslight rise. conclusions. autologous blood has a favourable effect upon humoral immunity and should be the transfusion medium of choice in cases where autologous blood reinfusion is technically possible. ivan petkov, m.d., rumen farashev, m.d. and dimitar terziiski, m. d. medicine, military medical academy, g. sofiiski str., sofia, bulgaria objective. the amount of blood lost during trauma and operation could hardly be forseen and donor blood supplies are not always available in sufficient amounts. rare blood group types and/or unexpected haemorrhage pose a great challenge to the transfusion therapy and the methods of intraoperative autologous blood transfusion. methods. we report a case of a -year old male patient with extremely massive intraabdominal haemorrhage ( m( blood loss ) during an abdominal aorta reconstruction following a traumatic injury of the abdominal aorta. we achieved a successful reinfusion of ml of autologous blood using an original autotransfusion system developed by us ( pat. no / . . ) . results and conclusions. the autotogous blood in the case reported here was the only and the most suitable transfusion medium for the rapid intraoperative compensation of the acute haemorrhage and the favourable outcome of the patient. the post-operative period was smooth and no significant disorders in the clinical course as well as in the laboratory tests ( morphological,biochemical,coagulation and immunological) were recorded. there were no complications during the postoperative period despite the fact that the amount of blood reinfused to the patient was slightly exceeding his own volume of circulating blood. objective. the haemoglobin concentration and the perfusion pressure value could not be the only criteria for the early signs of tissue and organ dysfunction. because of this, we employed the extensive monitoring of oxygen transport during severe trauma in order to. achieve dynamic evaluation of physiologic compensatory mechanisms and to assess the efficacy of intensive care management. methods. we conducted a prospective controlled trial on the blood oxygenation, oxygen transport and tissue perfusion during the first days after the trauma in patients with polytrauma. we used a swan -ganz pulmonary artery catheter (beckton -dickinson, u.s.a.), deseret cardiac output computer (medical inc., u.s.a.) and hewlett -packard monitor (hewlett -packard, germany) to measure and calculate all the parameter values. the severity of the injury was assessed using the apache ii score system. all the patients had scores over . results. the results show a significant decrease in the arterial blood oxygen content and in the arterio-venous difference, as well as an increase in alveolo-arterial oxygen difference and in the transpulmonary right-to-left shunt. the tissue oxygen supply and the tissue oxygen consumption reveal a tendency towards a decrease below the physiologic minimum of adeqate values. the erythrocyte current velocity and the ratio between oxygen transport and erythrocyte current velocity also decrease inspite of the optimal blood rheology. conclusions. the dynamics in the parameters values are most pronounced between the -nd and the -th hr after trauma, which predisposes patients to the risk of developing stable hypoxemia and characterizes this period as the most critical for tissue metabolism and organ dysfunction. posttraumatic changes in immune mechanisms in lung compartment in trauma were analyzed in ao and da inbred strains of rats which differ in their immunological reactivity: the former being low responder and lat-~er hiperresponsive. methods: the levels of tnf-alpha activity in the supernatants of cultured lung lobes and dynamics of cells migration from tissue explants in h lung cultures were assessed in ao and da rats subject ted to severe burn trauma. results: increased levels of tnf activity ( + pg/ml compared to + . pg/ml in control) were found od day following trauma in lung sups of ao rats while no changes in the levels of activity of this cytokine were found in lung-sups od da rats more pronounced extent and dynamics of cell emigration were noted in da rats, while almost unchanged in ao rats sharp rise in pmn percentages h following trauma ( - % compared to rare pmns in control), followed by increase in lymphocyte numbers at later time points among lung cell emigrants was detected in ao rats. slower but persistent increase ( %, h following trauma and % and % on days and after trauma infliction, respectively) in pmn numbers among da lung cell emigrants was detected, which appeared to be activated, as judged by their nbt reduction capacity. increased percentages of peripheral blood pmns and increased state of leukocyte aggregation/adhesion were detected in both strains, but different levels of plasma tnf: increased levels in ao rats on days and following trauma, and initially but persistently high levels of plasma tnf alpha in da rats ( - fold higher compared to initial levels in ao rats). conclusions:different patterns of local (lung) and systemic changes in cell numbers and cytokine levels implicate differential posttraumatic migratory capacity of pmns vs. lymphocytes in lungs in ao and da rats. early diagnosis of acute intestinal ischemia by color doppler sonography e. danse, b.van beers, p.goffette, f.hammer,aav.dardenne, f.thys, p-f.laterre, m,s. reynaert, .lpringot dept of radiology (profb.maldague) and dept of intensive care ( prof m,s.reynaert), st.luc univ.hospital, brussels, belgium ob emergeny medical squad service is the most important segment in the process of saving the people, in the cases of mass accidents, like industrial accidents caused by the: explosion, fire, chemical poisoning, traffic accident, elemental catastrophes and the war. because of that, each emergency medical squad service needs to have in its motor-pool vehicle for the mass accidents/ for provoding at least people, wounded as well as the people became ill/. objectives: presentation of such special vehicle, produced by "zastava-kamioni" and it's medical-technical equipment. methods: descriptive and comparative analysis of the medical and technical characteristics, based on the actual norms/din, , iso , yus.../ results: on the base of doctrinaired requirements of the emergency medical squad in the case of mass accidents, our researches resulted in the following medical and technical characteristics -the vehicles for mass accidents are gvw/with a payload off cca - t, with the fixed, closed body, type: universal van, -technical equipment aggregates, stretches, anti-fire device, equipment for pitching the tent and for maintaing technical conditions of the work -medical equipment: linen bags with complete sets of bandage material, means for the reanimation and immobilization, for the infusion, medical instruments and remedies as well as the tent for lodging at least wounded and sik people. in federal republic yugoslavia, it was proposed such vehicles for the emergency medical squad needs. conclusion: we suggest to introduce this vehicle in the production range of the ambulance vehicles for saving, especially in the circles where can occur serious accidents. introduction : carbon monoxide (co) poisoning commonly generates central nervous system abnormalities though an important cardiac morbidity and mortality must be considered. long-term exposure to co with cohb levels < % may be more dangerous than short-term levels of - %. we report a case of an adolescent who after prolonged exposure to co developed a severe reversible cardiac dysfunction with low levels of bloed cohe c a.ase history : a year old boy was found comatose at home. his mother in the neighbouring bathroom died severn hours earlier of what was later proven to be a co intoxication. on arrival the gcs was / and the patient was breathing spontaneously. a postictal status with eventual postanoxic encephalopathy was suspected. a coh'b level of % was objectivated. the cardiorespiratory situation quickly deteriorated requiring mechanical ventilation. chest x-ray showed diffuse bilateral patchy infiltrates. ecg revealed signs of ischemia. severe left ventricular dysfunction was evidenced by pulmonary artery catheterisation and echecardiography and later by isotopic angiography (lvef %). treatment was intensified with inotropic support, intta-aortic balloon counterpulsation and oxygen therapy. the clinical course was further complicated by a crush syndrome and renal failure. the patient's condition gradually improved and he fully recovered without any residual lesions (lwf %) conclusion : even after prolonged exposure cohb levels can be misleadingly low. high tissue levels of accumulated co can be associated with coma and fulminant cardiorespiratory failure requiring advanced life support facilities. introduction : both neuroleptics (nlp) and tricyclic antidepressive agents (tca) can induce arrhythmias, prolongation of the qt segment and the pr interval and hypotension. we report a case illustrating that combined overdose of these agents increases the toxicity of each compound and the risk for adverse cardiac events. .c, gse history : a year old male ingested mg doxepin (sinequanr), a tca and mg prothipendyl (dominalr), a potent nlp in an attempted suicide. upon arrival in the emergency department the patient was unconscious (gcs / ), breathing superficially, and presenting signs of recent vomiting. physical examination revealed a taehycardia of b.p.m., an arterial blood pressure of / mmh g. ecg showed a brood qrs complex tachycardia. a chest x-ray revealed the presence of an aspiration pneumonia. laboratory investigation demonstrated increased levels of crcatine phosphokinase, lactate dehydrogenase and aspartate transaminase ; hyperglycemia and leucocytosis were present. the plasma concentrations of doxepin and prothipendyl were respectively gg/l (toxic level #g/l) and i.tg/l (no reference). treatment consisted of mechanical ventilation, gaslric lavage and administration of activated charcoal and iv fluids and antibiotics. a hemodynamically well tolerated veatricular tachycardia developed / h later. nahco ( meq/ h) was administrated inducing an ectopic atrial tachycardia with a normal qrs complex and prolonged qt. h after admission a normal sinus rhythm was present; the prolongation of the qt segment persisted for days. the patient fully recovered. conclusion : the treatment with nahco~, alkalizing the blood and thus increasing the protein binding of the tricyclic antidepressant molecule, can readily correct the potentially life-threatening cardiac arrhythmias and therefore should be part of the routine treatment of combined tca-nlp overdose. ob/ectives: the development of diabetes insipidus (di) in patients with brain injury is a known negative prognostic sign. the aim of this study was to investigate whether this is also a reliable early prognostic sign of brain death. methods: this is a retrospective study of patients treated" during a two year period ( - - to - - ) in our i.c.u who meeted the following criteria: ( ) coma score _< gcs within the first hours, ( ) positive brain ct scan on admission classified according to marshall's diagnostic classification (classes - ), ( ) normal renal function during the entire icu stay. for the definition of di were used the usual di criteria plus hypematriaemia (serum na" >_ meq/l). survival was defined up to the th postadmission day. conclusions: according to the findings of this study, the development of diabetes insipidus in brain injured patients seems to be a highly specific index for brain death (positive predictive value = . ). however, further prospective studies are needed for the definitive evaluation of these findings in such patients. emergency care in italy, despite all efforts, is still lacking a nationwide organized prehospital care system and, until today, there are only different regional solutions. the majority of these realities imply rather simple ambulance first-aid services without attending emergency physicians and without resuscitation equipment. the emergency medical service (ems) system in falconara m., italy, was implemented in august by a collaboration between the school of anesthesiology and intensive care of the university of ancona and the, already existing, volunteer rescuer organisation "yellow cross". according to the guidelines pubblished in [ ] the pre-existing equipment of the volunteers was completed with type a ambulances and special equiped motorcar (patient monitor, defibrillator) for ambulance indipendent physician transpur[. a special data collecting schedule was created to memorise every emergency intervention in a computerised data-base. the intraining members of the school of anesthesiology and intensive care provide hour ready intervention. in this report the authors describe their experience concerning primary firstaid medical interventions. for a preliminary evaluation we considered, retrospectively, consecutive emergency interventions in the time period from novembre , to april , . the emergency physicians treated male ( %) and female ( %) patients, patients died before hospital admission and patients ( %) were treated at home by the ambulance indipendent physician and did not need any further medical treatment. in the same time period year earlier (november to april ) without attending physician the volunteer rescuers transferred all first-aid interventions to near-by hospitals. we conclude that the presence of an attending, iudipendently motorised physician in emergency interventions is essential for the establishment of precise priorities and may be helpful to reduce hospital admissions by ambulance intervention, though reducing primary" health care costs. we have developed the method of liquor filtration which allows to purify the cerebrospinal liquor from blood and its decay products in the subarachnoid bloodstroke. the hemipermeable dialysis membrane was used as a filter, which lets only in water, electrolytes and substances with small molecular weight. the liquor filtration was used for the treatment of patients with the subarachnoid bloodstrokes of different etiology. the perfusion of liquor was performed at the rate ml/min in the recirculatory mode. its duration was - min depending on the bloodstroke intensity. the filtration makes possible the most completely purifying of the hemorragic liquor, the reducing of the content of blood ceils and its decay products - times as less. the monitoring of the patient's state during the perfusion didn't revealed the departure from the norm of the main vital part. the liquor filtration technique compares favo-~ rsbly with the routine method of cleaning by the absence of toxical effect of heterogenous solutions on the central nervous system. the filtrstion of the cerebrospinal liquor in the subarachnoid bloodstroke sllows to provide the the early cleaning of liqour, the regression of meningeal syndrome and to improve the patient's state of health. e tabli~mczr bd ~ of rei~idnal medical first-aid zhoulittoing, ed., tan zi, m.d. dept. of sargery, the first teaching t[ospitat, yejin-l)a-l)ao, wuhan fltlna objectives: the medical first-aid is the most important task of the public hc atth department. in general, single hospital model couldn't fatty, effective ly rescue mony severe patients who need mergant treatment in the scene. bub establishing the medical first-aid network, the severe patients can be given the most timely und the most scientific emergent treatment. so that, the suc cessfut rate of the saving wilt be greatly increased. methods..; our hospital is a general big hospital. through developing and cons tructlng for more than ten years, the medical first-aid network distributed art over the area under our jurisdiction has been set up. it consists of thr ee units: the medical first-aid unib center comartd and mnagment unit, co m~nlcation and tiaison unit. the principle of the network operation is with oat having to far to mergoncy, specialized emergency and the best merge acy. results: the results of the network operation were notable. cmpari~ the to tat successful rate of the saving ( . ~), the successful rate of saving tra ma ( .~), the suscessfut rate of saving shock ( .~) and the successful rate of cardioputmonary resuscitation ( . ~) daring the three years after t he network operated with these before ( . ~), ( ]. ~), ( . ~) and ( ft. ~), the successful rates after operating were remrk~iy higher ( p<i).o ). conctusions~ the above results showed estabiishmnt and mena emont of region at medical first-aid network had very si~nificont action during mergentty s avin the severe patients. moreover, the regi~at medical first-aid network atso take an important part in prevention and health protection of the mass. objectives: se related mortality is due to the occurrence of both rv and lv dysfunction evoking cardiogenic shock and pulmonary edema (f. abroug, intensive care med ; s. nouira. chest ) . prospective evaluation of scorpion antivenon (sav), the only available specific treatment, is lacking. the aim of this study is to assess the effects of sav on the basis of a case-control study. methods:among consecutive victims of se presenting to the emergency department, were managed using sav (group sav+). these patients were matched to envenomated patients who did not receive sav (group sav- chest injuries are the cause of death in % of trauma fatalities and a major contributing factor in an additional %. pneumothorax is a major complication of chest injuries and can be initially overlooked bringing to additional morbidity and mortality especially in patients who require mechanical ventilation. the real incidence of pneumothorax in severe blunt chest trauma hasn't yet been established, as many pneumothorax can be missed on the initial chest x-ray (cxr) and computed tomography (ct) has not been routinely used. to evaluate the incidence of pneumothorax in patients with severe blunt chest trauma. methods: a prospective study. from january to december , all trauma patients with one of the followings conditions: fractures of four or more ribs, signs of lung contusion on the initial cxr or presenting a severe hypoxemia on admission (pao /fio < ) in the absence of pre-existing pathologies, were evaluated by initial cxr and subsequently submitted routinely to a ct. results: severe trauma patients were considered. of them, presenting a severe hypoxemia on admission, had no evidence of major chest trauma (ais< ). hypoxemia was the consequence of severe trauma in other districts; these patients were therefore excluded. patients with severe thoracic trauma (ais>= ) were admitted into the study. the mean iss was . ( - ). thirty-six patients required artificial ventilation for at least hours during the icu slay. three of them, who had a tension pneumothorax, were submitted to an emergency thoracic decompression on the field by the emergency helicopter team. in cases pneumothorax was diagnosed an the initial cxr more patients had a pnx which was identified only on the ct. in cases a large pnx with lung collapse was missed on the cxr. in our group of severe blunt trauma patients, % ( / ) presented a pnx that required the insertion of a thoracic drainage. only one third ( / ) of the pneumothorax could be recognised on the initial cxr, while other were decompressed before performing the cxr. as many as % of the cases of clinically significant pnx were missed on the cxr, and a ct performed soon after admission allowed an early diagnosis bringing to changes in the treatment. (as the patients were mechanically ventilated a chest tube was inserted in all these cases). in cases, the initial cxr overlooked a huge tended pnx which was the cause of hemodynamie instability. conclusion: in patients with severe blunt chest trauma even large pnx can be missed on the initial cxr. moreover due to the non compliant compressible lung, a % pneumothorax which can be recegnised only on a ct, can bring to high intrapleural pressure altering eardiopulmonary function. n. andoeli , .~osid, m.zesevid, m.risovid, d.stepi , d.djokid b~rga~yc~qterclinicalcaqterafserbia, belgrade cb~ctives:~lis study ~ the use of ~rq]ofol earbired with k~t~ine (aq a~sjgh~ic s@~qt widn inirjrsic armlgesic pro~mities) or with fsqtmtyl,with psrtial azgmsis an hgenxlyn-a~ic ~ durirg ~ ~ re:~ver~ f~m ~ in hxh ~ of ~ti~. ~: yali~mial and ~bod: a~it p~tie~ts a~ i-ii were included in ibis shxly. patients were rsrd]nly dieided in two ~ns. all d~tie~ts ~me given - prcpofol bolus doses (o, ~gkg) for ird~iqn of ~. ~ia ~s m~sjn~ with an infusion ~ ~ropafol. as sdflitianal were given fan-i~l (o, n]g) ~tely before ~ anj trad~e~ irfojoation followad by feasted bolus of o,i mg in ~ro o l.patients in gr~ o received i~ (an initial bolus dose of rg slowly intcavax~ rd mg as infusion over ~ rain) .infusions of pro~fol or imcpofol with kg~mine ~ stopfsj - rain ]:~o~ extuhation.arterial blood ~ (sistolic arterial blood preassu-re~zap,mean ~rterial blood pr~,d~lic arterial preassure-[zp a~ h~art rate-~) ~ m~ before induction of a~ io, snd rain aftem ~ intutation. results: arterial blood preasstre ~s decreases duri~ irn~ction of sn~wd~sia in hy~ ~n~s,tnt mare in th~ ~ who r~eived fsqtanyl.~ere w~s statisticslly sifnific~ntly difemerme dmir~ m~ of an~ia. arterial blood r~easatre and heart rate were stable in the t-..e~min -~a ~. all th~,fl-e keta'nire grcqo hsd e~rly :~e~y time. ctrmlusi~s: ~e ombiretion of protxfol wilh keta/ne for irduorion a~d ~ of sn~sd~esis w~s yell accept~ by p~tierfcs anj coald he ~ as an alterrstive ~o ccnva~icrsl a~es -d~sia. objectives : assess the relation between cytokine or endotoxin release and indices of splanchnic malperfasion after hemorragic shock in multiple trauma patients. ]~r study was approved by the local ethical committee. trauma patients admitted to the emergency room who met the entrance criteria of more than hour map < mmhg or use of vasoactive agents or blood lactates > mmol/ were selected for study. a nasogastric tonometer (tonometrics, inc, plastimed, france) and a swan ganz catheter were placed on admission. phi, lactates, hemodynamics, plasma cytokine and endotoxin concentrations were measured on admission and at . , , , hrs. an immunoradiometric assay was used to determine plasma concentrations of il (n< . ng/ml) and tnfc~ (n< pg/ml). plasma endotoxin concentrations were measured using a chromogenic limulus assay (n< . eu/ml)( endotoxine unit= pg). results : severe multiple trauma patients (age = _+ yrs, iss = -!-_ , saps = +'~, mean-+sd) were studied. they received + packed red cells during the first h. mean duration of collapsus before inclusion was . _+ . hrs. death occm'red in ~tients. ~ pglml, *: ng/ml, etox : endotoxin(eu/ml), lact: lactate (retool/l) a significant correlation between initial il level and saps was observed. in the early post-injury period phi, sao , svo , vo were significantly associated with ;il release (p< . at ho, h , h ). later a significant correlation existed between lactates and ii (h , h ). a peak of tnf was detected at and hrs. it was associated with low phi and low arterial ph of the early post-injury period (p< . iat ho, h , h ,h , h ) and with high lactate levels of later period (_>h ). only the late release of endotoxins (i{ ) was correlated significantly with initial !oxygea-delivered parameters. iconclusion : there was a marked increase in il in the early phase of trauma . i and tnf release after major trauma iwith hemorragic shock is associated with splanchnic malperfusion, as assess by the ivery low values of phi. lactates seem to be a later indice. toxic effects are a well-known complication of an overdosage of prescription theophylline. what is less known is that over-the-counter (otc) asthma medications contain theophylline, and that in some cases this might cause toxic effects. a case seen by us involved toxic effects from theophylline in an otc medication and to date is the only published case in the english literaturet the rationale for this study was to delineate the otc products containing theophylline from whatever data sources available. hyperthermia frequently occurs in intensive care treated patients and intentional application of whole body hyperthermia together with chemotherapy is a therapeutical access to treatment of malignant disorders. anaesthetic support is required in either condition. due to the marked decrease in systemic vascular resistance seen in hyperthermia an additional vasodilatory effect of the anaesthetic is unwanted. the vascular effects of anaesthetics in hypertherm organisms is not known in detail. therefore, we performed an experimental study to detect the effects of inhalational anaesthetics in whole body hyperthermia. in sprague-dawley-rats katheters were inserted into trachea, jugular vein, and carotid artery. for continuous monitoring of cardiac output a flow probe was placed around the aortic arch. the rats were mechanically ventilated with different concentrations of inhalational agents in oxygen. we compared the effects of enflurane, isoflurane, and halothane in stepwise increased body temperature by submerging in a temperature controlled water bath. results: isoflurane lowers arterial pressure more than halothane or enflurane. the inhalational anaesthetics lower the cardiac output similarily and independently of temperature. isoflurane decreases systemic vascular resistance independently of core temperature and the decreasing effect of halothane on the resistance is completely abolished in hyperthermia. conclusions: the influence of hyperthermia on the systemic vascular resistance is dangerous. this allows no additional effect of the anaesthetic management. in spite of the vasodilating effect of inhalational agents in normotherm subjects, this effect is abolished in hypertherms using halothane. the condition of management of analgosedation in hyperthermia is different from normothermia. objectives: to evaluate a bedside computer processed cerebral function monitor for assessment of brain wave activity when clinical/visual clues are not present. methods: ten icu patients undergoing neuromuscular blockade monitored with the aspect brain wave monitor from january to june , . results: time to onset and depth of sedation were readily apparent to icu physicians not specifically trained in eeg reading. objectives: to determine whether non-depolarising neuromuscular blockade reduces oxygen consumption (vo ) in sedated, apnoeic patients. methods: haemedynamic. metabolic and oxygen transport variables were determined in sedated, apnoeic patients with severe acute lung injury. all patients were ventilated using a puritan-bennett ae ventilator with integrated metabolic monitor. inclusion criteria were; ) stable cardiorespirator s" status; ) systemic and pulmonary artery catheters already in situ; ) inspired oxygen < %. patients were sedated with midazolam or propofol to abolish response to verbal stimuli, and sufficient morphine or alfentanil to abolish all spontaneous respiratory efforts. following baseline measurements, neuromuscular blockade was induced with intravenous vecuronium, ug/kg, followed by an infusion of ug/kg/h to maintain the train-of-four ratio at . a further four sets of measured and calculated variables were obtained at min intervals. results: statistical analysis was by repeated measures anova. there were no significant changes in any variable over time. the changes in calculated oxygen consumption (vo fick) , and measured oxygen consumption (vo gas), and in energy expenditure (ee), are shown in the table. objetive: to study the effects on coronary hemodyrtamics and myocardiai metabolism of administering propofol during postoperation sedation of patients with normal coronary circulation and good ventricular function undergoing cardiac surgery. patients and methods: patients ( women and men) undergoing aortic and/or mi~-a/ valvular cardiac surgery were selected, with an ejection fraction greater than . and normal coronary circulation. for postoperation sedation propofol was administered in . mg/kg i.v. bolus, followed by a . mg/kgth perfusion. all data were registered before administering propofol and after minutes, the patients being hemodynamically stable and a rectal temperature of _+ . -~ systemic and pulmonary hemodynamics, and global, as well as regional myocardial blood flow, and metabofic variables were measured. results: the patients studied were about years old, and the average period of aortic cross-clamp was . min. the adminstering of propofol caused a decrease in the coronary blood flow (- %), great curonary vein flow (- %), myocardial oxygen consumption (- %), regional myocardial oxygen constanption (- %), myocardial oxygen extraction (- %), regional myocardial ooxygen extraction (- %), while coronary vascular resistances and global coronary vascular resistances did not change. oxygen saturation increased in the coronary sinus (+ %) as well as in the great cardiac vein (+ %). in no patient were significant changes suggestive of myocardial ischemia objectified. there was also found a decrease in systolic (- %), diastolic (- %) and mean (- %) arterial pressure, systemic vascular resistance (- %), and cardiac output (- %). conclusions: in accordance with the clinical conditions of this study, the administering of propofol is not likely to cause changes in coronary autoregulation, oxygenation and myocardial metabolism. obietive: analyse the effects of . % "end tidal" isoflurane (sedative dosage) on the metabolism and coronary hemodynamics during the postoperation period of patients undergoing cardiac surgery. patients and methods: patients ( women and men) undergoing aortic and/or mitral valvular cardiac surgery, with an ejection fraction greater than . and normal coronary anatomy, were selected. after the surgical operation, . "end tidal" isoflurane was administered for postoperadon sedation. the determination of variables to be studied was carried out before and minutes after administering isoflurane, die patients being hemodynamically stable and a rectal temperature of _+ . -+c. systemic and pulmonary hemodynamics, and global, as well as regional myocardial blood flow, and metabolic variables were measured. results: the average age of the patients studied was -+ . years. during surgical operation the period of aortic cross-clamp was . _+ . rain. the administering of isoflurane was followed by a statistically significant drop in coronary perfusion pressure (- %), coronary vascular resistance (- %), regional coronary vascular resistance (- %), regional myocardial oxygen consumption (- %), regional myocardial oxygen extraction (- %) and accompanied by a significant rise in oxygen saturation in the coronary sinus (+ %) and in the great cardiac vein (+ %). myocardial oxygen consumption, myocardial exu'action of lactate and regional myocardial lactate extraction did not change. in no patient were enzyme or electrocardiograph changes objectified. systolic (- %), diastolic (- %), mean (- % ) arterial pressure, and systemic vascular resistances (- %) decreased, while cardiac output did not. discussion: the administering of . % "end ddal" isoflurane, in the clinical conditions of this study, produced a decrease in systemic arterial pressure due to a reduction of systemic vascular resistance without deteriorate cardiac output. at coronary circulation level, has and effect on coronary autoregulation but had no effect on oxygenation and myocardial metabolism. the idea of tiva implies the realisation of major anesthesia components (los of consciousness, neurovegetative inhibition, analgesia, myorelaxatiou, providing the adequate gas-exchange) through i.v. introduction of drugs exclasively. aim: providing for the main tiva components with minimal side effects of the drugs used, taking into consideration the patients characteristics and the surgery specific character. methods: anaesthesias have been conducted in patients aged years ( females, males), undergoing planned and urgent operations with the pathology of lower, extremities, perinaeum, small pelvis, hypogastrium and with reserved spontaneus respiration against a background of % insnffladon through mask. operations lasted from . - . h. anaesthesia adequacy was assested by constant monitoring: "cardiocap" (nibr hr, rr, sao , t), through glykhaemia level and mimicry reactions. standart premedicatioo of m-cholinolytics ( . mg/kg) and h -blockers ( . mg/kg) on the operational table was sumplemented by administration of . - . mg/kg of lidocaine, . . mkg/kg of clonidine, . - . mg/kg of pentamidine by the tachifilaxia method. the premedication adequacy was assessed through haemodynamics characteristics. sedation: . - . mg/kg of droperidoi, .l- . mglkg of diazepam and analgesia: - mkg/kg of phentanyl, . -- . mg/kg of ketamine were introduced fractionally according to indications. infusion rate of ringer-lactat solution was - ml/kg/h and depended on the intraoperational blood loss volume and on the patients preoperational condition. the duration of postoperative analgesia was registered. results: clinical assessment of analgesia according to this techniques allowed to decrease the anaigetics dosage to the subauaesthetic levels. smooth stabilisation of haemodynamics (bp) at proper age norms in patients with the initial hypertension by the -th min. of anaesthesia as well as the absence of its increase in response to the additional introduction of anaesthetic have been achieved. (hr) had no abrupt changes and remained in the range of - per rain. adequate external breathing: decrease (rr) by - per rain., with sao increase from % to - %. hypoventilation was avoided by respirate ventilator. according to unauthentic data the glykhaemia level had been lowered by -t % to the end of the operation with the initial moderate hyperglykhaemia of up to mmol/l the cutaneous covering grew warm and got pink colouring. no mimicry reactions. in the postoperative period patients were in the superficial sleep state ( - ) and analgesia lasted - b. there were no complications due to anaesthesia. conclusion: combined using of bz, opiates, neuroleptics potentiate the i.v. anaesthetics effects allowing lowering of each tiva component dosage and, as a consequence avoiding their negative influence on respiratory and heart vascular systems. complex application of adrenergetics (therapeutic doses of cionidine and pentamini with using of taehfilaxy effects) permitted to provide for analgetic and neurovegetative components of general anaesthesia under subanacsthetic doses of tiva main components, and manifestation of hyperdynamic reactions of haemodynamics decreased while using of lidocaine -the economicai activity of heart-vascular system. good level of muscle relaxation was achieved allowing for widening of surgical intervention extent without respirator ventilators and inhalation anaesthetics application. anaesthesia is easily controlled due to fractional introduction of drugs with quick recovery of cns functions after anaesthesia. postanaesthetic analgesia is increased while concurrent opiates doses are decreased. absence of marced haemodynamic, endocrine and metabolic reactions during the operation and after it resulted in shortening the period of patients staying in hospital. a yo white man was admitted to hospital for dyspnea and a productive cough. he had cabg in past, but no recent cardiac ischemia. physical exam: decreased breath sounds over right lung. chest xray: consolidation of right lung. admission medications included diltiazem, furosemide (both were continued) and trazodone (which was discontinued). admission ecg: sinus rhythm, qt . /qtc . sec, with st and t wave abnormalities similar to prior tracings. he required intubation and mechanical ventilation for progressive hypoventilation and hypoxemia. between icu days and he received haloperidol, - mg/d (cumulative dose rag) for agitation and delirium. icu day : qt . /qtc . sec. icu day : for better control of delirium, trazodone " mg q hs was added. icu day : he developed frequent nonsustained ventdcular ectopy. icu day : qt . /qtc . sec, pha . , paco mm hg, pao mm hg, k . meq/l, mg . meq/l. later in icu day the patient had brief episodes of torsades de pointes, each responding to precordial thump, and finally rhythm stabilized with i.v. lidocaine and magnesium. haloperidor and trazodone were discontinued. ecg was unchanged and myocardial infarction was ruled out. next day, icu day : qt . /qtc . sec. torsades de pointes, a form of ventricular tachycardia characterized by a twisting qrs axis, is commonly associated with qt prolongation. haloperidol is used frequently in icu for control of agitation and delirium, with reported doses up to mg/day. over past decade, cases of torsades de pointes with prolonged qt related to haloperidol have been reported. trazodone may also prolong qt and cause ventricular arrhythmias, especially in patients with pre-existing cardiac disease. in this patient, trazodone likely exacerbated qt prolongation from halopeddol leading to torsades de pointes. critical care physicians must be aware of this interaction. it is imperative to follow the qt interval for patients receiving halopeddol, especially when another drug also known to prolong qt is added. one must consider discontinuing the drug when qt/qtc becomes prolonged. objectives: analgesics and intravenous anesthetic drugs are routinely used in critically fll patients, who often suffer from a secondary impairment of the immune system. previous in vitro studies have demonstrated inhibitory effects of these drugs on polymorpho nuclear cells (pmn). the potentially important role of endothelial cells (ec), however, was not investigated, since suitable test systems were not available until recently. therefore a physiologically more relevant in vitro migration assay through cultured human endothelial cell monolayers (ecm) we established. using this assay system, the comparative effects of fenlanyl, sufentanil, propofol and the known pmn inhibitor thiopontal were tested. methods: human umbilical vein endothelial cells (huvec) were isolated and cultured on microporous membranes (cyclopererm) until an ecm was grown. pmn from male and female volunteers were separated by standard procedures. ecm and pmn were preincubated with clinically relevant concentratious of thiopental ( m), propofol ( p_g/ml), the solvent of propoful (intralipid), fentanyl ( ng/ml) and sufentanil (sng/ml). after preincubatiun (ecm minutes, pmn minutes) with the reslx~tive drug, leukocyte migration towards the chemoatfractant fmlp ( o - m) was measured in a two chamber well system for hours. the migration rate of untreated (untr.) and treated (treat.) pmn through untreated and treated ecm were determined. as a control untreated pmn and untreated ecm were used. results are given as means from independent duplicate determinations and expressed as a percentage of control (table) . statistical analysis was done with student's t-test. results: clinical concentrations of fentanyl, sufentanil and prupofol showed similar inhibitor~ effects as the known pivin inhibitor thit e ). % conclusions: for the first time we could show that analgesics and anesthetics exert their inhibitory effects not only on pmn, but mainly on the interaction of pmn with endothelial cells. moreover, we could shmv a significant suppressive effect of the opinids fentanyl and sufentanil on both ec and pmn. the known inhibitory effect of thiopental obtained in ec-free test systems were also confirmed in our physiologically more relevant assay system. objectives: to investigate when and how sedation is used in a consecutive cohort of patients admitted in a large sample of italian intensive care units (icus), gathered in a network named giviti, representative of the italian icus system. methods; the study called for a recruitment period of one month, from january to february , , data collection included age and other demographic variables, acute diagnostic broad profiles, severity of illness scores, treatments, lenght of stay and vital status at icu discharge. as concerned sedation, each patient was observed until discharge or for a maximum period of seven days. information on all the drugs used for analgesia/sedation, the route and modalities of administration, the timing, dosages and purpose of the administration have been recorded. results: the study involved the cooperation of icus, of which enrolled at least one case. the total sample included patients. overall, . % of patients analyzed (t / ) received at least one prescription of sedative during their stay. globally, at least one sedative drug was prescribed to these patients in days in icu. although over drugs were reported to be used, pharmacological principles accounted alone for % of all prescriptions. opioids were actually used in % of prescriptions; propofol in % and benzodiazepine in . %. as regards the way of administration, intravenous administration was applied in % of cases and, followed by intramuscular in . %. moreover, non-steroidal anti-inflammatory drugs (nsald) were used in % of patients and neuromuscular blockade agents (nmba) in %. detailed analysis on certain subgroups (surgical, trauma, ventilated patients etc.) have been also carried out in order to describe the practice of sedation in these peculiar subgroups. findings will be widely discussed during the presentation. conclusions: these results should be interpreted keeping in mind how peculiar is the intensive care setting compared to many other less complex settings of hospital care. in conclusion we thought it was important to present the data currently available in the most neutral form, to start moving in a direction which will enable us -by means of more specific and detailed studies, and with the cooperation and involvement of all those participating in the project -to shed light on one of the many aspects of medical practice in the field of intensive care which deserve closer attention. introduction: the aged run perilously high risks in cardiac surgery: among others, of haemodynamic fluctuations, respiratory depresskm and organ failure. response to anaesthetics is a crucial determinant for post<)perative complications, none the less being reintubation due to mechanical ventilation difficulties which increase morbidity, mortality and intensive cdre unit (icu) stay. objective: we wanted to assess our a,aesthesia window (selection, and a view of the induction -extubation period) for predicting safe and swift awaking, thus: icu dismissal for the aged. methods: in , selected patients (pts) (> y, f) followed a regular elective cardiac surgery protocol (propofol given at precisely designated time intervals). upon cu arrival, they were subjected to an admission protocol. our predictive criteria for early extubation at h included: a) alertness and ready response to commands; b) adequate gag reflex and sufficient protection for respirak)ry tract; c) pao > mmhg with flu < . ; d) stable ph> . with spontaneous respiration; d) stable haemodynamics without dysrhythmias; e) adequate perfusion and diuresis (> .(i ml/kg/h); f) mediastinal bfeeding< ml/h for at least h; g) normothermia (core temp> ~ and no shivering). subsequent reintubation was for: ) rr> /min; ) spontancx)us ventilation for rain with paco > mmhg; ) pao < mmhg with fio > . ; ) ph> . ; ) heart rate>] bm; and/or ) non mental alertness; and ) other medical disorders, after which adequate weaning therapy was necessary. then, successful weaning after h was considered: ) spontaneous breathing without any forrn of mechanical assistance; ) stability in haemodynamics; and ) elimination of fever threat. results: pts ( %) were extubated at h without complication; other pts ( %) at h but had to be reintubated because they were hypoxic and began weaning therapy; finally, they were all re-extubated by h. only pts ( %) proved problematic. conclusion: a,aesthesia wimhlw options (selectkm, extubation, reintubation and weaning) predicted quick (times propofol administration) and safe (rigid criteria) extubation ( %= h and %= h), exempting pts with developed post-operative complications ( %=extubation< h) unrelated to al~aesthesia window or icu protocol. dismissal and recovery then became an abbreviated question of time. fifisetll p, domeneg~i ~, sforzini i., veronesi i~, maconi a.g. *, breg~ massone p.p h [] ic+pca request conclusions:using e~aprenorphine, a synthetic,long-acting, ago-antagemist opinid drug as analgesic, in the major surgery we obtained the best clinic results with association of conttheus infusion of haft dose drug with bohts of pca in the first - hours and just pca in the secmad day after surgery when the patient is less sleepy. in this way we dent have a great sav~g of suppled drug but the major well-belng of patient without ~erious side-effects and quick mobilization; the dosage used don't compromise a good awake of patient: all patients are sleepy but ready for answer, no allueinatian, bradipnea but not less than b/m without ipoxia. also the patient proffered this kind of truit meut than the traditional at demand. the ward staff feel it useful] and rehabl~ the negative feed-back technology of the electronic infuser system makes possible to use it safe in the ward with high drug's concentration too. the infusion rate of low dose of drug assure a continuative analgesic covering ~n the first postoperative periad; the pca mode involves the patient him-self in the managemenl of therapy and enables him to choose the best way to confront the dll~icuity of postoperative period without call medical stall using pca-device we have had no probicm~ no accident. analgesia during extracorporeal shook wave lithot ripsy a .levit, b.grinbezg regional hospital, ekaterinbu~g, russia b~ectives: our task was to compare ~he analgetic effect of norphin and tramel. methods: study was made of two groups of uro-li~patients aged - . group a ( patients) received baprenorphine hydrochloride (norphin) at dosages of #. • mg/kg. group b ( patients) received tramadel hydrochloride (t~aasl) st dosages of . z . mg/kg. before the procedure diazepam was administrated i.v. ( . ! . mg/kg). blood saturation (spoz), hemodynamics incides (bp, hr,sv,co,sap,svr) were examined and the patients' subjective assessments of snsesthesis quality were analyzed. the hospital ethics committee approved the investigation. results: when using norphin hr increased by . % on the onset of the procedure while sap and sv decreased by .%% and . %, respectively (p< . ). however, there were no reliable co chsnges. spoz ~educed by @. % (p< . ) and remained lower than the initial one after the procedure was oyez. when administrating tramsl min. after ste~ting the procedure sap and svr increased by ~ . % and . % respectively. sv and co decreased insignificantly. nine patients in group b saffeting some dlscomfo~t needed additional tm~msl in~ection. in the course of the whole p~oced~e spo, was constant and was highez than that in ~he case of nozphin (p<o. ). conclusion: respiratory suppression by no~phin can limit its use in case of lithotzip@y while the advantages of tremsl a~e: lack of dyspnoe and good contact with the patti-b_ the role of uncommon agents of antinociception, placed epidurally, in the control of pain transmission in the spinal cord is well documented. somatostatin as an inhibitory agent is found in the dorsal horn of the gray matter of spinal cord. the effects of somatostatin is similar to the opiates if injected into the epidural space (ref. i, , , ) . the aim of the present study is to present the clinical effect of above mentioned palliative therapy in the case of cancer and non cancer pain. informed consent had been obtained from every patient before treatment was initiated under the legalisation of the local ethics committee. using the permanent epidural catheter and continuous infusion pump, we administer somatostatin in the dose of up to microgram per hour for one up to three days. the patients paln feeling was evaluated using a vas (visual analogue scale). we found that the opiate resistant pain level decreased by %. the rest pain could be controlled by pereral opiate analgetics or by combination of somatostatin and an opiate plus a local anaesthetic agent epidurally. theoretically, it seems that epidural administration of somatostatin and local anaesthetic agent is useful in the control of acute pancreatic pain and systemic effect of somatostatin is beneficial in the treatment of acute pancreatitis. few studies have been performed in the critically ill (ci) and because of the complex pharmacodynamic and pharmacokinetic changes that occur, it is difficult to predict accurately drug responses and interactions in individual patients. midazolam (m) is a watersoluble benzodiazepine with a rapid onset and short duration of action in normal individuals; however its metabolism is decreased in the ci. critical care physicians every day experience suggest that among the ci there is a different pattern of response to m; here it is hypothized that such a response could be due to different metabolic behaviours of ci. m (i.v.infusion rate - rag/h) and antipyrine ( rag p.o.) were infused to ci with ( patients -group ) and without ( patientsgroup ) endotracheal intubation. blood samples were collected at fixed times during and after m infusion. total urine nitrogen and antipyrine elimination half-life demonstrated different metabolic characteristics in group chypermetabolizer") as compared to group chypometabolizer"). results follow. the results of our study are preliminary and more kinetic data in critically ill patients are needed to statistically confirm our approach of "hypometabolizer" and "hypermetabolizer". objectives: some clinieai and experimental studies suggest that propofol decreases myocardial contractility in coronary artery bypass grafting (cabg) patients. the intrinsic negative inotropic action of the drug may be independent from changes of preload and afterload, whereas the myocardial depression induced by propofol may depend on changes in ca ++ ious availability. aim of this study was to verify the hemodynamic effects of propofoi in a group of cabg patients with uneompromised contractile function and to minimize myocardial depression, during induction of anesthesia, choosing to associate calcium chloride (cac ) in an other group and to define its role in producing this effect. methods: fourty patients, randomly divided in two groups ( pts a and pts b), undergone elective cabg, were enrolled in this study. anesthesia was induced by senior anesthetist in both groups by means of fentanyl mg• kg < in ", pancuronium . mg x kg - and propofol mg • kg - in ". a blind investigator administered via another venous way at same speed ( ") saline in patients of group a and mg x kg - cac in patients of group b. hemodynamic data (heart rate hr, mean arterial pressure map, mean pulmonary artery pressure pap, pulmonary capillary wedge pressure pcwp, central venous pressure cvp, cardiac index ci, stroke volume index svi, systemic and pulmonary vascular resistances indexed svri and pvri) were obtained at baseline (to), ' after anesthesia induction (t ) and " after tracheal intubation (t ). results: hr decreased moderately in both groups (p = ns). map decreased as well, more markeatly in group a at ti and t . this trend was statistical significant (p < . ) in both groups. pap, pcwp and cvp unchanged following induction in any of two groups. ci decreased in group a (p < . ) dramatically dropping at t , while in group b it showed a negligible decrease at t (p = ns) and value similar to baseline at t . svri and pvri did not exhibit statistically significant changes. conclusions: the use of propofol as a starter of anesthesia in cabg patients allows to reduce total dose of fentanyi, dramatically reducing post-operative intubation time. propofol-fentanyl association prevented the hyperdynamic response to stress (i. e. laryngoscopy, intubation) but severely depressed ci and svi. cac simoultaneous administration effectively minimized the negative inotropic effect of propofol. moreover no unwanted side-effects due to cac were observed. diseoordinated labor activity (dla) is one of most serious in obstetric pathology.medication sleep effect to a woman in birth is of limitation of pathologic impulsation from the central nervous system, but it does not influence processes resulting in and supporting dla on the organ level. constant discoordinated uterine contractions during medication sleep (ms) imerease disturbances of uterine blood flow, organ hepoxemia connected with hyperergia of vascular wall and myometrium to catecholamines, that reduces efficiency of anesthesiologic protection. we applied hexoprenalin in complex with ms to primaparas. efficiency control was being accomlished through hysterograms, grade scale of analgetic effect where hemodynamics reaction to pain, significance of emotional reactions and their vegetative manifestations before and during ms were registered, and also through hydrocortisone level in plasma before and during ms. the examined women's average duration of ms was hours more than in control and made hours, though their average labor duration and in control was the same and made hours. % of the examined women experienced independant labor, as for the control group -only %. supplementary methods of anesthesia were required in % in control,that increased medicamentous depression of the fetus, but for the examined group -only in %. the examinees's newborns experienced favourable terminations, in control newborns were in state of light rate asphixia. analgetic effect was complete in control just in i %, and of examinees -in %. on the women's hysterogrnms before ms discoordinated contractions were registered on the background of increased tonus. during ms in control similar uterine contractions were constantly registered, but for the examinees they were not marked at all or had the proper character. the examinees' hydrocortisone level was reduced for % and in control only for %. the study has allowed to make a conclusion that hexoprenalin applications in complex with ms in case of dla make anesthesiologic care safer and more effective, promote simultaneous removal of patholgic processes in the central nervous system and uterus, which lead to dla development. objectives: the aim of report is to present a clinical study results for the evaluation of anesthesia for a patients in unconscious states by eeg examination: methods: the study was conducted on patients after a severe abdominal operations on stomach and intestine and on one patient after traumaticat exarticulation of upper extremity. all patients have different unconscious state levels from somnolence to coma ]. also thay hav~ had respiratory insufficiency and control mandatory ventilation have been used. we were used intrave,~ous injections of morphine hydrochloride from initial dose of mg. than we were increased the dose to mg i.v. by drops with an accompanying eeg monitoring and fourier spectral analysis. initially all patients have had -rhythm with slow and a-activity. an c~-activity index have been lower than %. results: after anesthesia the o-and a-activity have disappeared. the or-activity index have increased to %. also we have noted decreasing of the unconscious state levels to a possibility of a verbal contacts ( - points gcs). conclusion: the quality of anesthesia could be evaluated by eeg monitoring. a regaining consciousness afte~ the injections of high doses of morphine, probably, may be a result of an opiate deficiency (full or partial). anesthesia with the following drugs: clonidine, l-arginine, l-n-arginine-methyl-ester (l-name), and their combinations. tail-flick latency (tfl) was determined at time zero and min after each treatment. clonidine (i- ~g/mouse) prolonged tfl in a dose-dependent manner. at a clonidine concentration of gg/mouse, tfl increased . -fold compared to time zero. l-arginine increased tfl at a high concentration (i gg/mouse). l-name suppressed tfl . -fold compared to time zero at a concentration of gg/mouse. conclusion: we have found that no is involved in clonidine spinal analgesia. studies are currently being undertaken to assess the effect of combination treatment of the above drugs on clonidine supraspinal analgesia. objectives: hemodynamic changes ussualy accompany laryngoscopy and tracheal intubation.the aim of this prospective study vas tu present the effectivness sufentanil in preventing reflex circulatory respone of laryngoscopy and tracheal intubation and provides stable hemodynamio condition for induction of balanced anaesthesia. methods: adult asa i-ii patients sheduled for elective surgery.they were allocated randomly and divided into two groups:fifteen patients received single bolus of placebo prior to laryngoscopy.and tracheal intubation. anaesthesia induction was then performed with thiopental (smg/kg) and atracurium ( , mg/kg), followed by neurolept anaesthesia. mean arterial preassure (map) and heart rate (hr) were measured before, during and min after intubation. althought ecg was recorded at the same time intervals. results: the groups were compared with regard to the changes in arterial blood pressure,heart rate and electrocardiogram. mean arterial preassure and heart rate were incresed significantly during and after laryngoscopy and tracheal intubation in control group but remained unohange the baselin values in the group who received sufentanil. control group ecg suggested more changes than sufentanil group. conclusions: the results indicated that , mg/kg sufentanil for anaesthesia induction reducing the pressor response to laryngoscopy and tracheal intubation. obiective: the aim of this experimental study was to evaluate morphologically the influence of anesthesia in liver as well as in isolated hepatocytes (hc). methods: a total of female swine ( - kg) were used as liver donors and were randomly assigned to one of two groups regarding anesthesia protocol: group a (n= ): induction with intravenous sodium thiopental in a dose of mg/kg, group b (n= ): propophol in a dose of mg/kg for induction'and mg/kg/h for maintainance of general anesthesia. both groups were under the same preanesthetic regimen (diazepam, ketalar and atropin) and received standarised doses of fentanyl and pancuronium during anesthesia. in beth groups total hepatectomy was performed and the liver was perfused with - it of cold ( oc) university of wisconsin solution for a period of hours before hepatocyte isolation. liver tissue samples were fixed in formalin for the morphological study and stained with hematoxylin-eosin and pas. for hc isolation collagenase solution (type v, sigma, c- , . mg/ml) was infused via portal vein and the liver was incubated at oc for rain. cells were filtered and then washed in cold hanks' solution. isolated hc were fixed and prepared for staining or simply cryopreserved (- oc). results: histology was completed in / experiments ( in group a and in group b). mononuclear infiltration (halothane type injury) was found in all specimens ( / ). focal zonal necrosis and acidophilic bodies were found in specimens from group a ( / and / respectively) while portal inflammation with piece meal necrosis was found in one specimen from group b ( / ). smears of hepatocytes -beth formalin fixed and cryopreserved at - oc -were stained with hematoxylin-eosin and showed morphologically intact hepatocytes. conclusion: pre[imineq~' study of our material reveals mote frequent livet injury in the thiopental group, but this finding has yet to be established by increasing the number of observations. objectives: in this paper we present our experience and point out the importance of sedation of those patients who suffered severe head injuries/contusic cerebri with signs of decelebration/and who were put on ventilatory machine to obtain better mechanical ventilation in neurosurgical intensive care unit of emergency center in belgrade. methods: patients were treated from jan. till dec. results: in patients we successed to reduce agitation and decelebration. conclusions: the major demand of sedation in neurosurgical patients are that the patient should be calm, comfortable and painless. references we compared three analogous groups of patients in each, with orthopedic operations on lower extremities. in each group we applied different kind of analgesia: first group rece-ned local anesthetic ( ml . ~ bupivacaine) when analgesia was first demanded; second group received ml fentanyl via peridurai catheter when analgesia was first demanded, and third group received m] fentanyi intravenously on demand for analgesia. we used visual analog scale (vas) for estimation of pain intensity and success of applied therapy. statistical data analysis was performed using student's t-test. tha best vas had group in which local anesthetic was applied periduraly. second was the group with periduraly applied fentanyl, and third was the group with intravenously applied fentanyl the longest duration of the effect of analgesia ~/as in the second group. there were no adverse effects and complications, apart from mild sedation in the third group. for orthopedic operations on lower extremities, application of peridural catheter for anesthesia and successful postoperative analgesia with local anesthetic, or opioid analgesics is acceptable. background and obiective : tympanic temperature measurement (ttm) is a relatively new procedure which provides accurate estimates of core temperature in stable postoperative patients and in patients admitted to the emergency ward. however, experience with this technique in hemodynamically unstable adult icu patients is limited. design : prospective study with patients serving as their own control. se:ttijlg : adult medico-surgical icu in a tertiary care hospital. patients : consecutively enrolled patients with thermodilution catheters in place and without contraindieation for rectal temperature measurement and without hypothermia (core temperature < ~ interventions : tympanic temperature, measured by a commercialized tympanic thermometer (genius a first temp) was compared with pulmonary artery (pat) and rectal temperature (rt). within minutes, core temperature was assessed in each patient by the same trained individual using the three techniques in random order. measurements and main results : mean bias (ix~ and its variability (sdr of method comparison pairs were calculated using the methods comparison analysis as described by bland and alunan (lancet, ; i : - objective: to measure the prevalence of pressure sores on the intensive care unit and the effect of risk calculation on pressure score prevalence and pressure score severity. method:in during a period of months a series of prevalence studies was carried out on the sicu to investigate how many patient days with pressure sores were taken care for by the icu nursing staff, what kind of preventive interventions were done and what the patient risk was on developing a pressure score. results: on average there was a prevalence of pressure sores on the buttocks of . % on the short stay unit and . % on the long stay unit; preventive interventions increased when the pressure score was visible for the nurse and the majority of patients had a high risk or extra high risk for developing pressure sores according the pressure score risk calculator. as a result of these findings the nursing management decided in that nurses had to complete daily on every patient the pressure score risk assessment in order to be able to take adequate preventive interventions. when the results of the two studies were compared, the most important results were that: ) there is no indication of a reduction in patient days with pressure sores (short stay unit: %, long stay unit: %); ) there is a reduction in severity of pressure sores (grade iv decreased from . % to . %) because adequate preventive measurements are initiated by icu nurses in an earlier stage. possible explanations for the increase of patient days with pressure sores on the long stay unit are that the average pressure score risk score was increased from . to . and the mean frequency of nursing patients on alternate sides decreased from . to . times each day. conclusion: daily assessment of the individual patient risk on developing pressure sores does not decrease development but reduces the severity of the developed pressure sores. method: the conventional woundcare method of patients with an open abdomen is to change frequently the saline soaked ribbon gauze pads ( - times each day). this method is labour intensive for the itu nursing staff and rather uncomfortable for the patient. problems that often occur are: insufficient hygiene, frequent nursing interventions, a progressive risk for deterioration of the skin and underlying tissues, difficult to measure abdominal output and in case of bowel fistulas enteral feeding is hardly possible. in using the new method, stomahesive is applied on the skin surrounding the wound. a large size of surgical film dressing, opsite | is applied over the abdomen. two or more foley ~ catheters ch are inserted through an opening in the surgical filmdressing. the application of several lateral openings in the catheters is advised. the drains are held firmly in place between two layers of sterile opsite | "flexigrid ~'' x with the so called bookend method and are connected to a low vacuum suction system ( - kph) results: we studied the frequency of dressings changes on patients in the itu. in total they had days with an open abdomen. during this period there were dressing changes. this means one dressing change every days. further advantages of the new method are; more hygiene in patient care, no maceration and irritation of the skin, nursing on alternate sides is possible, output can be measured, in case of bowl fistula, enteral feeding is possible and an abdominal lavage is possible on the sicu by opening the opsite | conclusion: this new method of woundcare management is more patient friendly, prevents several nursing complications and decreases the work load for the nursing staff. objective: to investigate the interaction between the ventilator and the closed suction system related to possible induced negative pressure by this sytem. method: we studied in a testlung model what the effect was of the different ventilators (evita: dr~iger; servo c: siemens), ventilation modes ppv, simv) and ventilator settings (tv, trigger level, frequency, peep level) on the induced negative pressure by the closed suction system during suctioning. results: when using the evita the magnitude of the negative pressure increased when the ventilation frequency and tv decreased.. the largest negative pressure (- cm h ) was produced with a tv of ml and a frequency of /min in the ippv mode with trigger level on - cm h and a peep level of + cm h . the servo c showed a complete different pattern. the largest negative pressures were measured when no trigger level was set ( cm h ), the induced negative pressure was not depended on the tv or ventilation frequency but more depending on the ventilator mode. the simv mode produced the smallest negative pressures ( - cm h ) and the ippv mode the largest ( - cm h ). conclusion: the effectiveness of the closed suction system is very much depending on the kind of ventilator, ventilator mode and ventilator setting that is used. if the interaction with the used ventilator is not known by the icu nurse this piece of equipment can cause damage to the patient by inducing large negative pressure in the comprimised lung and there fore creating the possibility of alveolar collaps and atelectasis or oedema. introduction : ethical problems are daily and disturbing preoccupations for the icu staff. objectives : improving ethical management in icu by creation of an intelprofessional group of ethical reflexion ( iger ). methods : existing was evaluated by a preliminary formulated series of questions sended to the whole staff (q , n = , items) after two training sessions (laws, deontology, professional values, culture, norms of quality) followed by persons ( %) and directed by an external chairman, satisfaction and needs of the staff were evaluated by a second series of questions (q , n = , items). at the issue, iger was created. results : q : responders ( %). law's misinformation : to %, disagreement for limitation of intensive cares : %, hope to improve collective decisions and creation of iger : % q : responders ( %) : satisfied by the training sessions : %, non satisfied : %, want to continue the project : %, refuse : %. iger was constitute by physicians, nurses, secretary, dietetic (n = ). the first working theme was {< therapeutic's withholding and withdrawing decisions in icu ~>. four subgroups of iger's members (having access to an ethical library) worked independautly and submitted their reflexions in a tdmestrial plenary session of iger in the presence of an external chairman, allowing a synthesis. at the issue a report was writted to be used as a reference for bedside and individual decisions. conclusions : constitution of iger seems to improve ethical management in icu. the first result of iger is that it is now possible to began collectively a reflexion concerning therapeutic's withholding and withdrawing in icu. the work is going on and further subjects will be studied. objectives: ) to compare the value of heat-moisture exchangers with bacterial filters (hmef) and without bacterial filters (hme) in the prevention of colonization of ventilator tubing and ventilator-associated respiratory infections. ) to asses the temperature and relative humidity of inspired all using both types of heat-moisture exchangers. methods: mechanically ventilated patients were randomized, to either hmef or hme. endotraeheal aspirates, pharyngeal swabs and samples from tubing were collected for bacterial cultures on the st, nd day mechanically ventilation and weekly thereafter. temperature and relative humidity were measured in patients ( hmef and hme) h and h after placing the hme or the hmef. results: both groups were comparable as regards age, mechanical ventilation period, severity score (saps ii), leukocyte count, and number of patients with prior antibiotic treatment. from the hmef group, ( %) ventilator tubing yielded microorganisms in, at least, one sample as compared to ( %) of the hme group; p=ns. the incidence of respiratory infection was similar in both groups ( % vs %, p:ns, for hmef and hme respectively). among the bacterial species isolated from ventilator tubing in the hmef group, ( %) were not isolated from pharyngeal swabs. a similar ratio was shown in the hme group ( / , %). both heat-moisture exchangers were efficacious in keeping a good relative humidity of inspired air ( % • vs % • .%; p=ns, for hmef and hme respectively). relative humidity was significantly higher after h of mechanical ventilation in the hme group as compared to hme group ( . % • vs . % • %; p= . ). conclusions: both types of heat-moisture exchangers have the same effect on the prevention of colonization of ventilator tubing. similar relative humidities are achieved when using either type of heat-moisture exchanger. results: tumor and nontumer enhrgements of the thyroidea were present in ~ of the operated, surgicel adrenal disease in io!, hyperplssle or persthyroid gland tumor in ~ end endocrine pancreatic tumors in %. in the intensive oere unit, these patients wore screened by noninwsive monitoring in ~ of cases: and invasive monitoring was applied in % of ceses.the basic noninvesive methods included: electrocardiogram with standard end precerdial leeds, percutaneous eutomotlc measurement of systolic, diastolic and mean arterial pressure, measurement of hourly diuresis and body temperature, frequency, hearing capacity and rhythm of one s own breathbng bs well as pulse oxymetry. a special plece in monitoring and control of vital parameters in postoperative period belonged to the nurse, thoroughly trained for enelysis end interpretation of the observed parameters which would be discussed in the paper. it has been believed that the leader sits at the pinnacle of power. over the years, this has proven to produce frustruation and anguish instead of the expected results. leaders have not been able to produce the changes they know are essential to their organization's survival with this command-and-control paradigm. through literature reviews and evaluating leadership styles, one can clearly see the most effective form is that of empowering people to a new level of performance -not ordering it. changing the leadership paradigm to a manner/style that has been shown to be effective and one of people empowerment shifts the focus to personal responsibility for performance. removing obstae}es~ stimulating self-directed actions, and determining focus and direction are just a few elements used to create the successful environment of empowerment. with increasing pressure in the health care arena, it becomes critical that a leader's job is to get the people to be responsible for their own performance. developing ownership, creating an environment where people want to be responsible, being a mentor or coach, and learning faster while encouraging others to do so demonstrates the commitment to effective leadership. this presentation will illustrate the critical components that are achieved when every person in the institution is empowered to perform at a level that is directed toward positive, effective results. herrera m. (md) . icu. hospital regional. malaga. spain. the systems of veno-vanous continuous haemofiltration (wchf) have a high cost and a limited life span. in an attempt of lengthening their mean life it has been proposed to accomplish programmed washes of the ~-stems. this practice supposes an increase in nursing workload. in order to evaluate the real efficiency of this practice we have accomplished this study. material: prospective randomized study of all the filters of vvchf used during the last year in our icu. we have determined two groups of filters, in the first (group a) we accomplished washed in a programmed way, and in the other (group b) only when the alarms of the system suggested a clotting of the filter. for the statistical analysis we used the kaplan-meier test for survival analysis. results: we have studied a total of patient submitted to wchf during the last year. we used a total of filters with this results. objectives. sounding out the nurses about the need to inform patients" relatives and the rigth kind of such information, like a preliminary approach to an information cuality assessment, methods: we inquired all the nurses of the intensive care unit of an regional hospital by an semiestructurated questionary which included personal data: age, sex, contractual relation, professional experience.., and opinion data: do you think to inform relatives is a nurse task?. which of the next informafions do you think is more important?, please, write others topics about information you think are relevant. we process the data on epi-info estatistical program and use x test to compare the results. results" from nurses of staff refused to flu the quetionary, and were not available. of the remaining, %were v~men and % men. the mean age were . % had an svable contract and ( eventual, the mean professional experience were of years and % worked in the unit since more than years. the % answered that offer information to relatives is part of the nurse activities. we did not find differences with nurses who answered negatively comparing by sex, age, contractual relation or proffesional experience. the three information topics found out like more important were: ) to inform about patient mood. ) to inform about happenings from the last visit. ) to inform about dressing instrument required by the patient, nurses who answered negatively think that to inform is a doctors task or that nurses are not competent. conclusion~ intensive care unit teams (nurses, doctors and auxiliar personnel) should get accord on who and how to inform relatives, we consider the nurses' role on information as unquestionable. objective: investigate the respiratory and cardiovascular response after discontinuing oxygen therapy durir~ intr~/]o~pital transport. desiqn: fifty-one patients ( male and female, aged + , and , , years respectively, ~+sym) being on therapy were studied prospectively in two consecutive intrahospital transports. oxygen therapy was continued in the first transport while the second one was performed as usually, i,e, without . during transport each patient was monitored by pulse oxymeter and holter whereas arterlal blood gases were tested just before a~xl aft~-trar~portation. results: compared to daseline, pa and sa were signif~canthy decreased in the case of oxygen discontinuation (p< , i). paco was significantly inur~ds~i only in the subgroup of patients with obstructive lun[ disease (p< , ) . heart rate increased in all phases of the transport when administratlon was discontinued. blood pressure remained stable in either case. the percentage of supraventricu!ar extrasysto!es, ectopic v~r[hicui~r contractions and st-s ~ment depression was progressively increasing and became very high at the end of transport in the case of therapy discontinuation. other arrhythmias did not change significantly. conclusion: discontinuation of oxygen therapy during intrahospital transport causes severe drop of pao and sa , increases the heart rate and contributes to the appearance of arrhythmias which were not present before. methods:for evaluation of the functional state of brain the complex of methods was used,whieh included electro encephalngraphy ( brain mapping ), rheoencephalography, tetrapolar transtorax rheography. for the estimation of humoral status the level of histamine and serotonine, products of free-radical oxidation,enzimatic markers of ishemic damage of brain and of endogenous intoxication was investigated. results: patients with encephalopathies after resuscitation were observed.asystolia was as a result of:shock, trauma, asphyxia,poisonings,appiication of drugs, eclamp sia,injury of the heart,diseases of fhe cardiac vessels. all patients with postasystolic syndrome entranced in comafose condition.in the group (reconvalescents) the depth of coma by glasgo~ pittsburg"s scale was , +- , . the duration of coma was from rain. to hour,average , +- ,sh.ln the group (the deads) the depth of come was , +- , .the artificial lung ventilation was used in all patients:in the group , +- , days,in the ~ , +- , days.apallish syndrome developed in cases,in patients diagnozed <<brain death~. the th degree encephalopathy (coma) was found to be associated with disorganized eeg-pattern with predomi nant alpha-( group) and slow ( group) activity. the relative power of delta-and theta-ranges was about - per cent.the patients with apallich syndrome demonstrated greatly elevated theta-range power, that of beta -range was essentially decreased. the degree of disturbances of circulation in the both groups was different.cardiac index (ci) and stroke index (si) in the group decreased on , % and , z, in the -on , % and (; , %.general peripheral resistance (gpr) increased in the group on , %,in the -on (; , %.in the group brain blood flow was increased, in the -decreased on , n.in the group there was the normotonic type of reg-curve,in the -atonic or hypotonic type (without reaction on pharmacologic influ ence).disturbances of permeability of cellular membranes (enhanced free-radical oxidation with an increase in di enic conjugates on and n) and vascular ones (an increase of serotonin concentration on and %, hi stamine content on and %) resulted in hyperfermentia (an increase of concentration of creaune phosphoki nase in the group on %,in the - %.the level of middle molecules (mm) increased in the group on , %, in the -on , %,of polyamines (p) (spermidin,spermin,putrescin).coefficient of correlation between mm and p was , . immediate correction of neurocyte metabolism is impossible due to marked brain oedemaswelling,severe dis ordes of cerebral circulation, disturbances of membrane permeability.thus,the following treatment algorythm might be advisable: . protective inhibition of brain and reduction of its energy requirements. . recovery of cell and vascular membrane fuoctions. .recovery of blood circulatiom .oxygenation of nervous tissue and drainage of brain disintegration products.in patientshbo carried out. .active methods of detoxication (homo-and enterosorption). .correction of cerebral metabolism. . dehydrative therapy must be very cautious. conclusion: the activation of energetic metabolism in neurocytes must be carred out only under neurophysiolngical control and after definite preparation. ( ). the clinical estimation of acute cerebral failure carried out by olasgo-pittsburg"s classification of coma. we studied such groups of patients: poisoning co ( ), asystolia ( ), eclampsia ( ), acute renal failure ( ), control group ( ). methods: electroeneephalngraphy (brain mapping) was fulfilled by means of encephalograph <,medicor ~ in monopolar channels. the estimation of eeg patterns by zhirmunskaya method ( ) was carried out. there were analyzed and changes of eegb by results of rapid transformation furie after rhythmical photostimulation(phts) , , , hz. we studied also the figures of absolute and relative power in such diapason : delta ( - hz), theta ( - hz), alpha ( - hz), betal( - hz), beta ( hz and more). results: all eeo changes were divided into following types: -organized ( , groups); iii -asynehronic ( group); iv -disorganized with prevalence of alpha-waves ( , , groups); v -disorganized with prevalence of delta-and theta activity ( , , ; , groups) akkording to our model of hormonal-metabolic disbalance in pregnancy , one of the main reason of destosis is hypoergos , reesults in endotoxemia and neuro-endokrine disregulation. so, stady of central nervous system function give us the information about adaptation processes. the aim of our work is to study the degree of neurologikal deficit in destosis when olifen and lipin were used. there were studied pregnants with different severe forms of gestosis. the degree of neurologikal deficit was valued by datas of neurologikal status . eeg with ,~brain mappinng~, , electrikal resistance of the skin. the komplex inteensive therapy with applikation of olifen and lipin allowed to improve the patient,s condition , decrease the degree of neurolodikal deficit and mortality . kostenko v.phd,kabanko t.,phd,galalu s.md,beliavtseva n. ,shramenko k. phd intensive care department,donetsk medical university, donetsk, ukraine plasmapheresis (pph),as other extracorporal methods of detoxicatin,has a great importance in contemporary medicine. the role of pph is special,because of its simplicity, effectiveness, atraumatic.we incalcated pph in obstetrical clinic. there are rough changes in agregate condition of blood in more of pregnants.these changes lead to disturbances of central,organ and peripheral hemodynamic.the therapeutic effect of pph is due to influence on agregate condition of blood. we considered that application of pph is very effective in pregnants with:bronchial asthma, severe forms of diabet, psorias, gestosis, allergic diseases. we used the membrane pph in pregnants: apparatus-,,hemos-pf>,, plasmofllter pmf- ,with effective area- cm,the volume of extracorporal contour- ml.such pph has no the ~ agressive effect,,, as in cases of application another extracorporal methods. this method was incalcated in our practice recently, so results will be reported in further publications. ( ). post-operative cerebral neoplasm ( ), post-operative subdural hematoma ( ). icp was monitored via a catheter inserted in the lateral ventricle and values were continuously digitally recorded by means of a bedside computer data acquisition system (maclab). the fiberoptic tracheobroucosenpe, which guided the procedure, was passed between the nasotracheal tube and the trachea in order to avoid hypoventilalion. the patients had stable baseline hemodynaimcs. propofol infusion and fentanyl boli were administered to mantain stable mean arterial pressure values. peak (mean(sd)) icp duping the minutes pre-ciaglia procedure (baseline values) were compared with values during ciaglia procedure, and the minutes p st-ciaglia procedure. data were compared with repeated measures anova. results: ciaglia procedure duration was (mean(sd)) ( ) objectives: transient global amnesia (tga) is a syndrome caracterized by impairment of short-term memory, inability to form new memories, retrograde amnesia and repetitive queries, without other neurological signs and symptoms. the pathophysiology of tga is unknown; thromboembolic, epileptic, migrainous and metabolic mechanisms have been suggested. to address some of these issues, we undertook a study of cases of tga in whom we examined clinical, laboratory data, electroencephalogram, ct of the head, ultrasonography ecodoppler. methods: patients were included in this study: men and women. the mean age was years. all cases underwent a standard clinical examination, electrocardiogram, routinary humoral tests and x-ray, electroencephalogram (eeg), ct scan of the head, ultrasonography ecodoppler. results': the mean duration of amnesia was h. m. +/- h. m. hypertension was found in patients ( %), ischemic heart disease in patients ( %), hypercholesterolemia in patients ( %), hypertrigliceridemia in patients ( %), smoking in patients ( %), atrial fibrillation in patient ( %), history of epilepsy in patient ( %), migraine history was not recorded. ct scans of the head showed multiple small deep infarcts in patients ( %), a single hypodense lesion in patients ( %). in patients electroencephalogram was normal ( %), in patients there were widespread nonspecific electrical changes ( %), in patients there were focal nonspecific eeg abnormalities ( %). conclusion: in our study tga was more common in women ( %). we showed a prevalence of hypertension, hypercholesterolemia and cerebral infarcts compared to normal controls. we have demonstrated a higher incidence of nonspecific electrical changes in tga of lower length, while ischemic lesions in ct of the head were more frequent in tga of greater length. these data seem to be in agreement with the hypothesis that tga is a heterogeneous clinical syndrome, consisting of pure, epileptic, and ischemic types. however we did not find any correlation useful in discriminating pure from associated tga forms. from our study it is tempting to speculate that pure tga is a rare event, underlying still unknown mechanisms wich differ from ischemic, epileptic, migraineous causes. objectives: aneurysmal subarachnoid haemorrhage (sah) is special condition increasing intracranial pressure (icp) in various ways. at the other hand cerebral vasospasm and related delayed ischaemic deficit (did) could answer for the poor outcome. triple h therapy seems today a basic option to prevent did, but it may increase the icp worsening the altered intracranial pressure condition and thereby the cerebral perfusion pressure (cpp). is there any way to individualise the triple h therapy when it is necessary? methods: between sept. march thirty-seven patients with intracranial aneurysms were operated on within hours following sah. five patients were in hunt-hess iv at admission. all patients received triple h therapy in a preventive fashion following surgery and were monitored by daily transcranial doppler ultrasonography (tcd). icp and cpp was measured in twenty-four cases. twenty-two of them received lumbar liquor drainage (lld) and nineteen were administered induced hypertension. the other group was treated by basic triple h therapy. results: in group with monitored icp the outcome was twenty-one excellent, one poor, two died (one of them died from extracranial decease). in the other group four had excellent, six moderate, two poor outcome, and one died. conclusion: according to our recent observation the patients can be divided into two groups of therapy. in group i, the patients with elevated tcd values and either low or high icp reacted to lld. we are concerned that haemodilution and slight hypervolaemia should dominate in the triple h therapy. in group ii patients having high icp with tcd and/or symptomatic vasospasm should be managed by the induced hypertensionhypervolaemia dominated therapy focusing on cpp (icp) and focal neurological signs. air emboli were detected in lo% (n= ) of natients undergoing coronary srtery bypass craftin~ (cabg). central nervous system ~ysfunction occured in ~$ of the nstients with air embnli and in none of those ~ithhout air embo!i. hvtothermia is the classic form of oro-tect~on used dur~nc ~"~" " ~ ~ ca~.,~modu] :r, on~_,_. bj/oass. the surf~eon sho,;,ed thorough!~: evecnnte air from the heart, but the onesthesio!o[[ist can signifieamt!y influence the outcome by emt!oyin ~ methods to detect and treat air emboli. the changes in head rate are primarily due to alterations of autonomic tone. the heart rate variability (hrv), that express the degree of heart rate fluctuation around the mean heart rate, reflects somehow the condition of central nervous system. hrv may be measured by a number of techniques. short-term time-domain variables of hrv are reflect generally the vegal activity. in this study the changes in hrv variables of patients with brain damage, and in addition the changes in hrv measurements in comparison with the clinical evolution were evaluated. eight patient with brain damage and six normal individuals as control group were studied. a elecrocardiographer with availability of computation the sequence of beat-to-beat intervals for one minute was used. the following variables of hrv were measured: ) standard deviation (sd) of beat to beat r-r interval differences that reflects the respiratory control, )the maximum/minimum (max/rain) interval that reflect variability related to baroreflex and thermoregulation and ) the coel~cient of variation (cv), the results are shown in the in the patients with brain death and in vegetate state there were virtually no hrv. increased hrv pattern was found with clinical improvement, the changes of hrv precede of the changes of gcs, we conclude that time-domain hrv could reflects the degree of brain damage, it is good prognostic index of the brain damage and may change earlier than the gcs. objectives: cerebral co vasoreactivity is an important determinant of cerebral blood flow (cbf) and has been shown to be of prognostic value in head trauma (acta anaesthesiol. scand. ; : - ) . we wondered whether co vasoreactivity could be selectively altered in one hemisphere in comatose patients. methods: patients ( m/ f, age - yrs, glasgow - ) in coma due an acute brain lesion (trauma, hemorrhage, or infection) were studied. cbf was measured bilaterally using jugular thermodilution at paco , , , and mmhg by increasing pico with mechanical ventilation kept constant. normal co vasoreactivity was defined as an increase in cbf of at least i ml/min. g per mmhg paco . results: patients had normal co vasoreactivity bilaterally, patients had altered co vasoreactivity at both sides, and patients had a normal response at one side (left or right) with an altered response on the other side (dght or left). for the patients left cbf was in mean ! ml/min. g lower than right cbf (figure methods: following institutional approval piglets (body weight :tl . ) were anaesthetized by % fluothane. a catheter was placed in the right femoral artery for blood pressure monitoring and a fiberoptic catheter (oxymetncs- abbott) was advanced via the right internal jugular vein to the jugular bulb for sjo determinations. another catheter with a balloon on the tip was advanced in the right atrium via the right femoral vein. a mean arterial pressure (bp) at mmhg was achieved by appropriate balloon inflation for rain and two groups were cleated: i) the hypoxemic group by respirator disconnection (*) and it) the hyperoxemic group by fio =l on respirator (o). samples were obtained at time ( ), ' min at hypoperfusion ( ) arid at reperfijsion at ' ( ), ' ( ) and ' ( ). pao , pjo and oxidative brain stress evaluation was performed from jugular bulb blood. the latter included: i) no synthase (nos) and xanthine oxidase (xo) activities by a method based on the oxidation of scopoletin detected fluorometrically, it) no levels estimated as onoo-by luminol enhanced chemiluminescence in the presence of ~tm hydrogen peroxide (h ). resul'~s: the mean pao was mmt-ig for group i and methods: we retrospectively reviewed all upper gi-endoscopies, performed in the period january -july in patients ( men and women) admitted at the icu's of our hospital. results: it concerned surgical, medical, eardiological and neurological patients with a mean age of . yrs (range: - ). in %, the endoscopy was performed at the icu and in % at the endoscopy department. in % of the cases, the endoscopy was primarily diagnostic, of which % was performed for localization of upper gi blood loss. in % the endoscopy was primarily thempentic, of which % was performed for placement of a duodenal feeding canula. location of the upper gi bleeding was: variees ( %), duodenal ulcer ( %), oesophagitis ( %), gastric ulcer ( %), others ( %) and none ( %). as coincidental findings were noted: cesophagitis ( %), gastritis ( %), gastric deer ( %), duodenal ulcer ( %), duodenitis ( %), oesophageal ulcer ( %) and others ( %). conclusions: there were marked differences in indications and findings of endoscopy at the different icu's. these differences reflect an admission bias and differences in populations and treatment preferences. compared with cardiological and neurological icu's, substantially more endoscopies were performed at surgical and medical icu's. in a considerable number of cases, no source of upper gi blood loss could be found endoscopicaiiy. when upper gi blood loss was the icu admission diagnosis, the main cause was needing varices, which could be controlled endoscopically in the vast majority of cases. when upper gi blood loss was ndt the icu admission diagnosis, peigie ulcer and oesophagifis were the main causes of bleeding. because of the considerable number of coincidental almom~adities found at endoscopy, there is still room for debate whether antacid medication and/or motility stimulating agents should be given prophylactically at icu's. many studies have shown that blood lactate levels in survivors and nonsmvivors of traumatic and septic shock are significantly different. the degree of multiple organ failure is related to the duration of lactic acidosis ( ). the aim of this study was to evaluate blood lactate level as a prognostic marker of high risk postoperative patients who may benefit from invasive hemodynamic monitoring and aggressive fluids administration and early inotropic support based on oxygen transport parameters. methods: patients undergoing elective long term vascular and abdominal surgery (asa i-bi) were studied. blood lactate levels were measured after icu admission. in the case of blood lactate level above mmoltl, measurement was repeated every hours for hours or until normaiisation (blood lactate level less than mmol/ ). type of surgery, length of surgery, amount of fluids delivered intraoperatively and postoperatively, hemoglobin levels, hemodynamic variables, diuresis, postoperative complications, length of icu stay and clinical outcome were recorded. because no attempts were made to randomisr therapy or change our standard therapy protocol institutional approval was not required. rebuts: the frequency of postoperative complications was , % and mortafity was , % in a group of patients with blood lactate level less than , mmol/l (n = ). frequency of complications ( , %) was significantly increased in a group of patients with blood lactate levels , - mmol/l (n = ), mortality was , %. mortality ( %) and frequency of complications ( %) were significantly increased in a group of patients with blood lactate levels above mmol/l (n = ). conclusion: blood lactate levels can serve as early marker of high risk postoperalivr patients and may predict increased risk of postoperative complications mad ~e death. objective.~: investigated practicability and clinical value of the routine measurement of hepatic venous oxygen saturation (shvo ) after major liver surgery, as shvo is considered an indirect parameter for splanchthc and hepatic blood flow. methods: consecutive patients were included in this study after liver resections for primary or secondary liver tumors. patients suffered from liver cirrhosis (childs a). immediately after post-operative admission on the icu a pa-catheter ,was inserted under fluoroscopy via the right jugular internal vein into the hepatic vein contralateral to the resection area. hepatic venous and arterial blood samples were drawn every two hours. shvo was correlated to the clinical course, macro hemedynamics, abgs aug other established lab parameters. results: in out of attempts the catheter could be placed correctly. in four cases after right hemihepatectomy the left hepatic vein could not be intubated due to a dorso-lateral tilting of the left liver. this is also reflected in a significantly longer time of fluoroscopy for catheterization of the left hepatic vein ( . _+ % rain vs. . + . rain; p < . ). the procedure requires a total of between and minutes. relevant clinical complications were not observed except for short term supraventricular arrhythmias during passage of the catheter through the right atrium. hemodynamics and pulmonary function could be considered normal in all individuals at time of measurement. shvo showed a span from . % to . % with a mean of . % -+ . %. the following statistically significant findings could be obtained: (a) patients with liver cirrhosis showed a significantly lower shvq than patients without ( . % • . % vs. . % • . %; p < . ). (b) a negative correlation between shvo immediately after operation and the duration of intraoperative hepatic vascular occlusion could be observed (r = - . ; p < . ). this correlation could also be seen for the first post-operative hours (r = - . ; p < . ). (c) a negative correlation between shvo and the difference between arterial and hepatic venous lactate levels was found (r = - . ; p < . ). conclusions: the routine measurement of shvo appears to be a promising extension of post-operative monitoring after major liver surgery. it is a safe method easily feasible on any major surgical icu though relatively time consuming. a further validation of this method is necessary in larger studies. therapeutic recommendations on the basis of shvo findings cannot be given yet. methods: in cases after major liver resection, in which abnormally low readings of shvo suggested an impaired hepatic blood flow, pgi was applied at a dose rate of ng/kg/min. as shvo can be considered an indirect parameter for hepatic blood flow, the effect of pgi infusion on shvo was measured. moreover, the changes of macro hemodynamics and pulmonary function were monitored. results: before the application of pgi z mean shvo for all patients .was . % ( - - - ). in three cases without major structural alteration of the remaining liver tissue the continuous intravenous administration of pgi lead to a sustained increase of shvo z to an average of . % ( . - , ). the postoperative course in these three cases was uneventful. in two cases with compensated liver cirrhosis after hepatitis c no change in shvoz under pgi infusion could be observed. both patients died and days respectively after operation in protracted liver failure. side effects of pgi included a slight decrease of systemic and pulmonary vascular resistances. consequently map decreased by up to % as did intrapuimonary right-left shunt increase. in none of the observed patients did these side effects posed a limitation of continuous application of pgi z. conclusions: in patients without structural alteration of the liver the systemic application of prostacyclin at a dose rate of ng/kg/min could significantly increase an abnormally low hepatic venous oxygen saturation after major liver resections, tn two cases of severe liver cirrhosis a similar increase could not be observed. after first clinical investigations and with the results of recent studies in animal further controlled clinical studies of prostacyclin in the postoperative management after liver surgery appear justified. any delay in gastric emptying can promote micro-aspiration and give rise to ventilator associated nosoarnnial pneumonia. h -receptor antagonists have been suspected of promoting pneumonia by changing the gastric ph. in a few tri',ds on humans ranitidine was noted to delay gastric emptying. the aim of this prospective, randomised, blinded study was to evaluate in a ventilated icu population if there was a difference between cimetidine (c) and ranitidine (r) on the gastric filling index (gfi conclusion: in this population there was no difference in gfi between c and r; however the age and creatinine were significantly different and could have favoured the c group. also the very long t/ could have hidden smaller differences between c and r as has been described in volunteers. between april , and april , , patients with severe acute pancreatitis were admitted to participating hospitals. patients were entered into the study if severe acute pancreatitis was indicated, on admission, by multiple laboratory criteria (imrie score >_ ) and/or computed tomography criteria (balthazar grade d or e). patients were randomly assigned to receive standard treatment (control group) or standard treatment plus selective decontamination (norfloxacin, colistin, amphotericin; selective decontamination group). all patients received furl supportive treatment, and surveillance cultures were taken in both groups. results: fifty patients were assigned to the selective decontamination group and were assigned to the control group. there were deaths in the control group ( %), compared with deaths ( %) in the selective decontamination group. (adjusted for imrie score and balthazar grade: p = . ). this difference was mainly caused by a reduction of late mortality (> weeks) due to significant reduction of gram-negative panreatic infection (p = . ). the average number of laparotomies per patient was reduced in patients treated with selective decontamination (p < . ). failure of selective decontamination to prevent secondary gram-negative pancreatic infection with subsequent death was seen in only three patients ( %) and transient gramnegative pancreatic infection was seen in one ( %). in both groups of patients, all gram-negative aerobic pancreatic infection was preceded by colonization of the digestive tract by the same bacteria. reduction of gram-negative colonization of the digestive tract, preventing subsequent pancreatic infection by means of selective decontamination, significantly reduces morbidity and mortality in patients with severe acute necrotizing pancreatitis. ieco by sodium hypochlorite (nacio) infusion is considered to be a model of microsomal oxidation in liver on cytochrome p- . active c provides oxidation of toxic metabolic products in the blood and exfused during plasmapheresis plasma, and also hydrophobic to hydrofilic transformation of substanses. sterile nacio in necessery concentrations was obtained by electrolysis of saline ( , - , % naci solution) in electrochemical set e~io- (russin,moscow). methods: . the nacio in concentration ragfl ( - ml/ h ) was administred into central veins in patients with extensive peritonitis and endotoxicosis - /t. erytrocytes resistance to nacio, circulating blood volume glycemia and hemostasis were initially estimated. . after plasmapheresis exfused toxic plasma was mixed with nacio conccantration of i mg/t in : ratio in sterile "hemacons".the effectiveness of plasma detoxication and possibility of its reinfusion were evaluated by determination of albumin effective concentration (eca g/l), the concanlration of medium molecular oligopeptides (mm , ) and other biochemical tests (bilimbin, creatinine, carbomide and so on). results: . the intravenous administration of nac excels detoxicative effect of hemosortion by - % provides effictive presentation of protein components and blood cells and improves the transport function of albumin by %. . the return of exfused plasma after its purification ieco was - %. only the remaning - % of deficient plasma were compensated by fresh cryoplasma and albumin solutions. ischemic hepatitis (ih) is a severe complication in critically ill patients. acute circulatory failure of multiple etiology can lead to splachnic hypoperfusion and cause acute and reversible anoxic damage. over a period of mos pts, m and f, mean age + . yrs developed liver disease compatible with ih. eight pts had a documented hypotensive episode (six pts with septic shock and two hypovolemic shock), while cardiogenic pulmonary edema in the absence of hypotension was responsible for ih in the remaining four pts. all the pts had a rapid striking elevation of ast, &lt and ldh with equally rapid resolution of these parameters to near normal wimin days (mean . ). the mean peak level of ast, alt and ldh was iu/l (range to ), iu/l (range to ) and iu/l (range to ) respectively. serum total bilirubin levels rose transiently with a moan t:eak level of . mg/dl (range . to . ), while altered coagulation paran-,ete's (pt> . times normal) was observed in four pts and clinically significant coagulopathy with fibrin degradation products occurred in one pt ( . %). renal impairment (cr> . mg/dl) was manifest in all pts; six pts developed non-oliguric renal failure ( %) while two pts required hemodialysis. ten lots required vasoconstrictor inotropes [dobutamine (range - pg/kg/min) and dopamine (range - pg/kg/min), while replacement of circulatory blood volume was performed in two pts with hypovolemic shock. eight lots expired ( . %), but none died as a direct result of hepatic damage. the mortality rate was higher among pts with concurrent renal failure ( %). it is concluded that: ) ih is not uncommon complication in the icu with the prognosis depending on the underlying disease. ) clinically significant coagulopathy is uncommon complication of ih. ) titration of inotropes is required to obtain optimal cardiac output support and subsequently liver blood flow. it is difficult to ascertain the perfusion of free flaps such as jejunal loops after surgery. objectives: to assess ischaemia as evidenced by intramural ph of jejunal free flaps used for reconstructive surgery following total pharyngolaryngectomy. methods: the sigmoid ph tonometer ( tonometrics inc.,usa ) was used to monitor intramural ph of the jejunal free microvascular flaps ( phig ) in patients who underwent total pharyngolaryngectomy. a standard general anaesthetic was given and all patients were admitted to the icu for controlled ventilation and monitoring. all had similar postoperative care. phig was measured pre, post-revascularization of the flap and on icu admission, , and hours postrevascularization. objectives: to classificate the wide spectrum of itc of anp into distinct pathophysiological patterns according to presentation and course. patients (pts) and methods: pts, ~( , %), ( , %) were admitted in the icu because of anp and acute respiratory failure(arf), ilean age: , • years. hean stay in icu: , • days. pts were operated, of them twice. hean value of ranson's scale: , • ( - ). we analyzed hemodynamic measurements,arterial blood gases(abg), x-ray findings(xrf), ct-scans and operative records. results: patterns of pleuropulmonary complications were identified: a)early hypoxia without xrf - pts. b)early ards with typical xrf - pts( died), c)early arf with xrf(atelectasis,infiltrates)- pts( died). d)late ards with typical xrf- pts( died), e)pleural effusions in various combinations with the above patterns - pts. overall mortality rate: / = , %. conclusions: l)frequent x-rays and abg are important for the classification of itc of anp. )even though patterns of classification in anp are not clearly distinguishable,they facilitate an anticipatory management. )deterioration of abg and xrf indicates that preventive measures for arf must be intensified and agressive surgical therapy is required. )delay of surgical therapy is related to worse prognosis(p<o, ) and prolonged hospitalisation time(p<o,ol). in the contrary, the early timing of the operation before infection and extrapancreatic necrosis is essential for a better prognosis (p<o, ). objectives: the development of cholestasis during intensive care treatment is allied with an inferior prognosis. this study investigates the sensivity, specification and also the positive and negative forecast of patients survival -exemplary for bilirubine. methods: during a period of months all surgical patients on icu were registrated prospectively (n = ). for documentation of disease development a standard foldcrform based on a computer-data-system was used. the results of this kind of documentation showed aapprax. , m!ll. of single patient informatioas. results: of patients didn't suffer from liver disease or have any operation on liver or bile tract. of them have had a normal scale of bilimbine in the postoperative period, a higher scale of bilirabine was regisu'atcd by patients. at a ,,cut-off" of rag% (total-bilirubine) the sensitivity was , , specivity , , positive predicive level , , negative predictive level , for survival criteria of a patient. the max. reached level of bilirubine, also the daily increase turned out almost the same results as they were found for other parameters nf cholcstasis like ap or gamma-gt. objective: the aim of this experimental protocol was to evaluate the morphological and functional parameters of isolated pig liver grafts, perfused in an extracorporeal liver support system. methods: the system consists of the graft liver, a membrane oxygenator (oxygenation surface . cm z, flow= itlmin), a heater, a centrifuge pump and a fluid reservoir. twenty pig livers, mean weight gr (min , max gr) were obtained and after a mean cold ischemia time of min were perfused fo} a mean of . h (min . , max h). perfusion solution consisted of r/l and hemacell. inflow to the graft liver was performed through the portal vein at a mean pressure of ( - ) mmhg at ~ while outflow was secured through the suprahepatic inferior vena cava. during perfusion the following parameters were evaluated through pre-and posthepatic hourly (to-t ) sampling: po , " + + " pco , ph, hco -, na , k , ca , osmolality, glucose, lactate, ast, alt, alp, u bilirubin and coagulation factors i, v and viii. biopsies were obtained periodicallty. b_p_~: results were as follows: mean ph fell from . at t o to . at t while mean output po fell from at t o to at t . mean output ast values increased from at t o to > at t while mean output alp values increased from . at t o to at t . mean output k + values increased from . at t o to > at t . histology revealed lesions of ischemic necrosis, more prominent after t . conclusion: results show that the isolated liver graft presents satisfactory function and morphology at least for a five hour perfusion period in the described extracorporeal circuit. correction of ph contributed to an increase in bile flow. between and the practice of transplantation has changed drasticaily in switzerland -besides kidneys also hearts, heart and lung, lung, iiver and pancreas transplantation has started in several centers. major information efforts have been made, organ exchange rules were set up and a national coordination center was initiated. the aim of this retrospective single center study was to assess the influence of transplantation on organ donation. in the past eleven years organs were donated from potential donors i single, multi organ donations) analysis of refusal was evaluated categorized into medical and/or familiar reasons. the number of potential donors increased from ( ) ,to ( ) with a concomitant drastic reduction of donations from % in to % in ; amounting to a net unchanged number of donations over the last years ( = ; = ) . the import and export of donor organs was balanced since the introduction of the national coordination center. in contrast multi organ donation increased from % in to % in despite of the more stringeant selection criteria, in conc]usion the introduction of a full range of transplantation procedures at several new university programs and the increase of multi organ donation has not had the forecasted impact on organ donation despite a sustained informative and promotional campaign, objective: monitoring hepatic venous oxygen saturation (svho ) provides online information about hepatic-splanchnic oxygen supply-demand ratio [ ]. previously, x~ reported hepatic venous catheterization in patients undergoing orthotopic liver traru~lantation (olt) [ ] . in the present study, we assessed the effects of nitroglycerin (ng), a vasudilator that affects the venous capacitance vessels more than arterial vessels and prostaeyclin (pgi , flolan r~, wellcome, uk), an arterial and splanchnic vasodilator on hemodynamies and hepatic venous oxygen saturation (svho ) in human liver transplantation. methods: with institutional approval and informed consent, consecutive patients, mean age - -_ years, were studied following olt. postoperatively, fiberoptic pulmonary artery catheter was inserted into the right hepatic vein. timed infusions of ng at a rate of . gg/kg/min and pgi at ng/kg/min were initiated for a rain period. each sequence was followed by baseline therapy for rain. results are expressed as mean=tsd. statistical analysis was performed using friedman's-two-way-anova-test, significance was accepted at p< , . results: ng at . gg/kg/min induced a decrease of mean arterial pressure (map) ( _ [baseline] vs. + mmhg) and pulmonary artery wedge pressure (pcwp) ( j: [baseline] vs. : mmhg). cardiac index (ci) ( - vs. + l/rain/m ), oxygen delivery index (do i) ( -+ vs. + mgnfin) and svho ( _~ vs. -l-_ %) were decreased (p< . ). pgi at ng/kg/min induced a reduction in map ( • nm~. _g) and pcwp ( + mmhg). ci ( _+ l/rain/m ), do i ( : ml/min) and svhoz ( + %) were increased (!o< . ). vasedilatation induced by ng decreased systemic oxygen supply and impaired splanclmie oxygenation. pgi increased systemic oxygen delivery in parallel with svho , suggesting a corresponding improvement of hepatic-splanchnic okygenation. thus, if vasedilator therapy is indicated in th orient receiving liver grafting, pgi appears to be advantageous. however, due to its platelct aggregation inhibiting properties, the usefulness and safety of pgi in olt patients has still to be determined. objectives: to analyze the effect of steroid treatment given to donor on the early function of transplanted kidney. methods: from january, until now donors were involved into this prospective study. every other donor was treated with mg/kg solu-medrol one hour before organ retrieval. according to the steroid treatment of the donor the recipients were divided into two groups: group -steroid pretreatment goup (y~= ), and group -control group (n= ). the donors and the recipients were treated using the same kidney transplantation protocol onl~r the adults, and the first cadaver kidney transplanted patients were involved into the study. the daily routine parameters were analyzed pre-and intraoperafive, and on the - th, th and th postoperative days. results: we could not show any clinically important differences between the two groups in respect of donor parameters. preoperative, the patients in group had slightly lower ereatinin level ( -+ g.,non vs. -+ gmol/ ) which persisted into the early postoperative phase. the values of the other examined pre-and intmoperativc parameters were almost the same. during the first postoperative days the patients in group i needed less diuretics (furosemide and renal dose of dopamine) and their sodium excretion was closer to the physiological range than in group . the other parameters did not differ significantly. the less furosemide need in group ! pe~isted to the end of the first month. conclusions: according to our data the steroid treatment of the donors improves the early function of the transplanted kidney in some respects. to prove the real benefit of the donor steroid treatment needs more data and further analysis. objectives: severe infections may compromize the outcome of liver transplantation..determination of new parameters may increase the knowledge of pathophysiologic mechanisms and may lead to changes in postoperative therapeutic management of patients at risk. methods: between august and september , patients with transplants were monitored for cytokines and extracellular matrix pammeters on a daily basis. serious infections (n= ) included microbiologic evidence and more than secondary organ failures. patients with cholangitis (n=ll) or uneventful postoperative course (n= ) referred as control groups. results: -year patient survival was . % ( / ): patients died due to serious infections, while died for other reasons. mean bilimbin, stnf-rii-, ifn- -, il- -, il- -, il- -, laminin-and neopterin levels were significantly elevated in patients with serious infections compared with patients experiencing mild cholangitis or with an uneventful postoperative course. a further increase of all parameters was observed in patients who subsequently died; tnf-ri/: _+ pg/ml vs • pg/ml; ifn- : _+ pg/ml vs . -+ . pg/ml; il- : -+ pg/ml vs -+ pg/ml; il- : -+ pg/ml vs _+ pg/ml; il- : _+ pg/ml vs • pg/ml; laminin: -+ ng/ml vs -+ ng/ml; neopterin: _+ nmol/ vs _+ nmolb for non surviving vs-surviving patients. a significant decrease of sialic acid yeas observed in patients with serious infections; and a further decrease occurred in patients who subsequently died: -+ mg/l vs • mg/ . conclusions: the increase or decrease of various cytokines and extracellular matrix parameters may be indicative for severity of infectiolx routine monitoring of these parameters may improve current diagnostic tools and poss~ly lead to changes in therapeutic management of patients at ~k. objectives: evaluation of the cytokine network after liver transplantation may give some insight in pathophysiologic mechanisms of rejection and may lead to detection of patients at high risk. methods: patients with transplants were monitored for various cytokines on a daily basis between august and september . rejection was assessed by histology in combination with clinical signs of rejection and laboratory investigations. results: during the first postoperative month, patients ( . %) developed rejection; patients were successfully treated with methylprednisolone (steroid-sensible rejection), while further patients required additional treatment with fk or okt (steroid-resistant rejection). patients subsequently developed chronic rejection. mean levels of various cytokines and extracellular matrix parameters including tnf-rii, ifn- , il-ib, il- r, il- , il- , il- , hyaluronic acid and neopterin were significantly higher in patients with steroid-resistant than in patients with steroid-sensible rejection. a further increase of some parameters was observed in patients who subsequently developed chronic rejection; bilirubin: . -+ . mg/dl vs . -+ . rag/all; tnf-rii: -+ pg/ml vs _+ pg/ml; il- : +- pg/ml vs -+ pg/ml; neopterin _+ nmol/ vs -+ nmol/ ; hyaluronic acid: _+ ~tg/l vs _+ ~tg/l for patients with chronic versus patients with acute steroid-resistant ~ejection. sialic acid levels decreased in patients with acute steroidresistant rejection; and a further decrease was observed in patients who tieveloped chronic rejection: _+ mg/l vs _+ mg/ . ~onclusions: various cytokines and extraeeuular matrix parameters were indicative of severity of rejction. the extensive increase of bilirubin, tnf-ii, il- , hyaluronic acid and neopterin may indicate subsequent chronic ection. monitoring of these parameters may, therefore, lead to changes in immunologic management after liver transplantation. background : combined kidney and pancreatic transplantation is being performed with increasing frequency in patients with diabetes mellitus and renal failure, as it offers more chances of success and better results than kidney transplantation alone. mycotic arterial aneurysm constitutes a devastating complication following pancreatic transplantation. all cases of mycotic arterial aneurysms have been however reported with exocrine pancreatic drainage into the gastrointestinal tract. intervention : we describe a series of consecutive whole kidney-pancreas transplantation performed at the university of geneva hospitals ( beds) between december and may . exocrine pancreatic drainage into the bladder (epdb) was performed to improve early detection of rejection episodes. epdb was hypothesized to reduce the risk of contamination from the gastrointestinal tract and the subsequent possible occurrence of potentially fatal infectious complication. in all patients the dual transplantation was performed through a median incision according to the procedure described by nghiem. results : two out of the patients who received kidney-pancreatic transplant developed arterial mycotic aneurysms and days following surgery. aneurysms developed at the site of the arterial anastomosis used to rearterialize the homograft. both patients had peritonitis caused by candida albicans requiring surgical drainage and intravenous antifungal therapy. rupture with hemorragic shock occured in both patients leading to graft removal in one patient, and three episodes of lffetreateniug hemorragic shock followed by graft failure and removal days after transplantation in the other. conclusion : arterial mycotic aneurysm constitutes an early, lifetreatening complication of kidney-pancreatic transplantation; it mandates graft removal. although exocrine pancreatic drainage into the bladder consitutes a definitive advantage for caller diagnosis of graft rejection, it does not eliminate the risk for retrograde colonization and subsequent severe infection in our experience. s. bocharov, i. teterina, regional clinical hospital, irkutsk, russia acute profound loss of blood can result from the very different injuries and hepato-pancreato-duodenai operations enter such a rank. ill-timed and inadeguate correction of operation hemorrage is one of the reasons for postoperation complications, including polyorganic insufficiency. the pathogenesis seems to be very complex. in early stages of bleeding the liquid enters the vessel bed, followed by hypoproteinosis and hematocrit fall. however, as decompensation develops, the fluid leaves the vessel system in the result of increasing postcapillary resistance and lowering col-ioidnooncotic blood pressure (cop). the resulting hypovolemia causes primarily acute disturbance of central hemodynamics and then of microcirculations and transcapillary exchange. central hemodynamic failure after acute loss of blood manifests itself through cardiac output lowering and capillary blood flow deceleration. taking into consideration, that % is critical value for cpv loss and for cev it is %, we consider arising the level of cop to the immediate task. cop raising allows to normalize transcapillary exchange, which we assess through cop and mcp (mean capilary pressure) gradient. the next task is to make up for globular volume till homeostasis providing level. considerable attention is given to catabolism inhibition and maximum possible enegry provision. control over high proteolitic activity of blood and callicreinkinin system activity implies direct proteases inhibitors. reologic, membrane stabilizing, antihypoxanthine and anticoagulant therapies are obligatory. virehow clinic, dept. of surgery, humboldt university berlin, germany regarding a high mortality up to % of fulminant hepatic failure orthotopic liver transplantation seems to be the only promising therapeutic approach in many cases. this study shows experiences from a transplantation center. between june and april patients suffering fulminant hepatic failure were admitted to our surgical intensive care unit all patients showed severe liver dysfunction with grade ii to iv encephalopathy. after a period of diagnostics and conservative treatment ranging from few hours to days (mean . days) we reported of these patients as possible organ recipients to eurotransplant. all of these patients were transplanted within hours, ( %) of them even within hours. the principal aetiologies were hepatitis b ( ), hepatitis c ( ), nanb hepatitis ( ), mushroom poisoning (amanita phalloides ). after transplantation patients suffered from initial-non-function and underwent re-transplantation. the one-year-survival rate was %, patients died within months after transplantation due to various reasons. patients were not referred for liver transplantation. of them never met transplantation criteria, improved by conventional therapy and could finally be discharged from hospital. the known reasons for liver failure in this group were mushroom poisoning ( ), paracetamol intoxication ( ) and fulminant hepatitis a ( ). patients suffering from fulminant hepatitis ( ) or intoxication ( ) were excluded from emergency liver transplantation for various contraindications. of these patients ( %) died despite conventional intensive care. we don't know if some of the patients in the transplantation group would have survived without transplantation, because whenever we decided on transplantation we could perform the operation within hours. but the good survival rate in the transplantation group ( %) the % recovery rate in the group, where there was no transplant-indication in our opinion and the fatal outcome ( % mortality) in patients with contraindications are an encouraging proof of a successful therapeutic strategy in acute liver failure. these results are based on a close cooperation between experienced transplant surgeons, hepatologists and intensive care doctors, using sophisticated laboratory and imaging techniques in a specialized center. introduction: during brain death patients suffer from multiple endocrinologic disturbances. one of the most important are those related with thyroidal axis. it is well described the euthyroid sick syndrome whose more frequent pattern consist of decreased triiodothyronine (t ), increased reverse t (rt ) with normal levels of tetraiodothyronine ( " ) and tsh, this lacking in " " levels lead to a change from aerobic to anaerobic metabolism which results in tissular damage. objective: .to study thyroidal pattern in brain death patients potential organ donors. .to avoid organ impairment by administration of t . .to study the hemodynamic and hormonal changes after the administration of t in these patients. material and methods:population: brain death patients of any etiology potential organ donors admitted to the intensive care unit. patients were classified in hemodynamically stable (group ) and unstable (group ). group received a bolus of . p.gr/kg. and a perfusion at a dose of - . p.gr]h of t . hormonal assays: total t (tt ), total " (tt ), tsh. fxee t (ft ), free " (ft ) and rt were determine at the moment of clinical brain death ( hrs) and in group two these assays were repeted at hours , and . results: patients ( male) with a mean age of years (range to yrs.) were studied. the clinical brain death was confirm later with other explorations (eeg, doppler). there were patients in group ( , %) and patients in group ( , %). hormonal pattern: at the moment of brain death tt was normal in cases ( , %) and decreased in i ( , %); tt was normal in patients ( , %) and decreased in ( , %); ft was normal in cases (i , %), decreased in ( , %); fl' was normal in patients ( , %) , decreased in ( , %) .rt was normal in cases ( , %) and increased in cases ( , %). there were no statistically significant differences in hormonal pattern between the two groups. only t levels at hours , and were significant in group . in the cases with ft decreased, the tt was normal in ( %) and decreased in ( %), tt was decreased in ( , %) and normal in ( , %), tsh was decreased in i ( , %), normal in ( , %) and increased in i( , %) and ft decreased in ( , %) and normal in ( , %) and rt was normal in ( , %) and increased in ( , %). there were no statistically significant differences in cardiac index, vascular resistances and pulmonary shunt before and after the administration ef t . conclusions: . the hormonal pattern most often find in brain death patients was: normal tt , decreased tt , normal tsh, decreased ft , normal fr and normal rt . . there were discrepancies in the values of ft and tt . there were no statistically significant differences in hemodynamic and pulmonary parameters. objectives: magnetic resonance angiographie (mra), a non-invasive procedure, provides flow-related information additionly to the anatomy of the vascular system. measurement of signal intensity and edge detection of vessel structures permits to calculate blood flow velocity and vascular diameters. we examined whether cerebral hemodynamic changes by altering the arterial pressure of carbon dioxid (pace ) could be detected by mra. methods: following institutional approval and informed consent, mechanically ventilated patients without elevated intracraltial pressure underwent mra with defined periods of hyper-, hypo-and normoventilation (pace : , , mmhg; arterial blood gas probes; avl). mra was performed with a . tesla magnetom (vision, siemens). two different mra techniques were used: a conventional time-of-flight- d-angiography (tr: ms; te: ms; fl: deg; slab: mm) for vessel diameter detection and a flash- d-gradient-echo-sequence (tr: ms; te: ms; fl: dog) for measurements of blood flow velocity. an axial view parallel to the ac-pc-iine (anteriorposterior-commissur-line) was used for repeated imaging of identical regions of interest toi) of the proximal part of the internal carotid (ica) and middle cerebral artery (mca) as well as of peripheral branches of the mca and the posterior cerebral artery (pca). results: changes of pace correlated with changing signal intensities, whereby under hyperventilation a decrease of , % (p . ) and under hypoventilation an increase of . % (p . ) was observed compared with normoventilation. blood pressures were stable throughout the whole study period, pace dependent changes in vessel diameters were more pronounced in peripheral branches of mca and pca. a change from normo-to hyperventilation produced a decrease in proximal vessel diameter of - . % (p _< . ) and in peripheral diameter of - . % (p _< , ). a change from normo-to hypoventilation produced an increase in proximal diameter of + . % (p < . ) and of + . % (p -< . ) in peripheral diameter. conclusions: pace related changes of cerebral vessel diameter can be easily detected by mra without injecting a contrast agent. the results confirm that co -reactivity is more pronounced in peripheral cerebral vessels, which are subjected to greater changes in diameter than major basal arteries. hyperventilation leads to a decrease and hypoventilation to an increase in signal intensity thus reflecting the corresponding changes in blood flow velocity, intensive care unit (icu) of "kat" hospital, athens, greece, ob!ective$; the value of bronchoscopy in pulmonary atelectasis of icu patients is under question the presence of an air bronchogram sign in xrays, which is considered as evidence of central bronchus patency, is referred in several studies as a negative criterion for bronchoscopy, whereas its absence as a positive one. it is also referred that air bronchogram sign correlates with delayed resolution of atelectasis, probably because of obstruction of many periferal airways (not central). the purpose of this prospective study was the evaluation of the air bronchogram sign on frontal chest film as a negative criterion for bronchoscopy and as criterion of delayed resolution of atetectasis, methods: icu patients with atelectasis were studied prospectively. they underwent bronchoscopy, bronchoscopic findings, presense of air bronchogram sign, and outcome of atelectasis were recorded, correlations were made, between: ) bronchoscopic potency of airways and air bronchogram sign } resolution time of atelectasis and broncoscopic potency of airways. ) resolution time'of atelectasis and air bronchogram sign, methods of statistical analysis were the t-student test and the chi square test, results:the patients were , men women , seventeen patients had atelectasis of whole lung, of upper lobe, and of lower lobe. ten patients had atelectasis in right and in left lung. eight from patients had air bronchogram sign in x-ray, there was no statistical correlation between air bronchogram sign and bronchoscopic potency of airways [ from patients with air bronchogram sign ( %) and from without air bronchogram sign ( %), had bronchoscopic potency of airways, p> . ], resolution time of atelectasis didn't correlate statistically with bronchoscopic potency of airways (mean resolution time in patients with bronchoscopic potency , days and in bronchoscopically closed bronchi , days, p> , ). there was also not a statistical correlation between resolution time of atelectasis and air bronchogram sign (mean resolution time in patients with air bronchogram sign , days, and without air bronchogram sign , days. p> ). conclusion~i; the presense of an air bronchogram sign in x-ray of icu patients with atelectasis, does not coexist obligatorily with bronchoscopic patency of airways and cannot be used as a negative criterion for bronchoscopy, neither as a criterion of delayed resolution of atelectasis. th. wertgen chest sonography (cs) is routinely used in our department to examine icu patients with clinical symptoms of pulmonary embolism, pneumonia, pleural effusion or unclear chest pain. we perform cs with a sector transducer ( . mhz) and a linear transducer ( . mhz) using acuson xp/ c. the sonographic signs of pulmonary embolism and infarction are most well demarcated, mainly wedge shaped and triangular pleural based lesions, more roughly structured, observed with a hyperechoic reflex in the center corresponding to the bronchitic (fig. ) . pneumonia is characterized by homogenously hypoechoic, wedge shaped parenchymal lesions, containing air or fluid bronchograms; they move with respiration (fig. ) . pleural effusions are spaces of various echogenicities, from anechoic to homogeneously echogenic, which may contain floating strands or complex septa, located between visceral and parietal pleuras (fig. ) . from march to april we did examinations by cs in icu patients ( male, female; age from - ). patients examinations pulmonary embolism pneumonia pleural effusion us-guided thoracic punctions were performed in patients. in two patients we found pneumonia or pleural effusion caused by a lung carcinoma. another two patients showed a normal cs (diagnosis: inflammation of the gall bladder, inflammation of the myocardium). conclusion: cs is a very useful method for icu patients with chest diseases. it takes less time and is less expensive than ctand sometimes of a higher diagnostic value than x-ray. last but not least cs is invaluable for the icu patient, because the examination is done save and quickly at bed side and the results of cs are very helpful in diagnoses and treatment. results : inter-observer reliability was evaluated as an % concordance. results of the tee classification were : class : n = ( %) ; class : n = ( %) ; class : n = ( %) ; class : n = ( %) class : n = ( %). therapeutic implications of tee in class patients were : cardiac surgery in patients (two cases of acute mitral regurgitation, two valvular abscesses and one hematoma compressing the left atrium), discontinuation of peep in one ventilated patient with an atrial septal defect, weaning of mechanical ventilation in one patient with an atrial septal defect, prescription of antimicrobial therapy in patients with endocarditis and prescription of anticoagulant therapy in patients with left atrial thrombus. the only noteworthy complication was a case of spontaneously resolving supraventrieular tachycardia. conclusion : tee is safe and well tolerated, and is useful in the management of icu patients with shock, unexplained and severe hypoxemia or suspected endecarditis. the aim of this study was to determine whether ultrasound guidance can help interns to improve the results of jugular vein access in icu. methods : in a prospective and randomized study, we compared, in patients admitted to the icu, an ultrasound-guided method (ultrasound group : patients) with an external landmark guided technique (control group : patients). all jugular vein accesses were performed by young interns with an experience of < procedures. results : internal jugular cannulatian vein was aci~ieved in all patients in the ultrasound group and in patients ( p.cent) in the control group (p < . ). average access time was longer in the control group ( • sec. vs • see. ; p = . ) and puncture of the carotid artery occurred in patients in each group (p = . ). patients ( p.cent) in the ultrasound group and patients ( p.cent) ia the control group (p < . ) were cannulated in rain. or less. the cannula was therefore unabie to be inserted within minutes in patients in the control group, with failure of eannulation in of these patients ( p.cent). failure was due to thrombosis (n = ), small calibre of the internal jugular vein (< ram) (n = ), abnormal vascular relations (n = ) or cervical irridation (n = ). among the primary failures of cannulation, an internal jugular vein catheter was able to be inserted in cases by an experienced physician on the side initially selected and with ultrasound guidance in cases. the catheter was inserted into the contralateral internal jugular vein under ultrasound guidance in the remaining cases. jugular cannulation was obtained at the first attempt in p.cent in the control group and p.cent in the ultrasound group. conclusion : ultrasound guidance improved the success rate of jugular vein cannulation by inexperienced operators in icu patients. when the internal jugular vein has not been successfully eannulated within minutes by the external landmark guided technique, the authors recommend the use of the ultrasound guidance. in the majority of cases right atrial or ventricular thrombi represent pulmonary emboli in transit. these may be fatal in patients (pts) treated conservatively with anticoagulation only. in literature the incidence of right heart thrombi in pts with proven pulmonary embolism (pe) is said to be in the range of - %. extremely mobile, long, worm-shaped masses in the right heart cavities carry an especially high early thrombus-related mortality rate which ranges from - %. current therapeutic strategies favour fibrinolytic therapy with consecutive anticoagulation. we report five cases ( male, i female, - years) of right heart and pulmonary thromboembolism. in these pts diagnosis and regression of thromboemboli following systemic intravenous lysis therapy with recombinant tissue-type plasminogen activator (rt-pa) was documented by transesophageal echocardiography (tee). a submassive pe occured in pts, a massive pe in pts. one patient (pt) had a cardiac arrest. in all cases tee clearly identified the extensive thrombns formation in the right-sided cavities of the heart and in the central pulmonary artery in cases. all pts were treated with mg rt-pa, pts in a front-loaded regimen over minutes, pt over minutes, and, due to the life threatening situation, in one case a bolus injection as ultima ratio was performed with no intracerebral bleeding complication. regression of thromboembolic masses after fibrinolytic therapy was demonstrated by transthoracic and transesophageal echocardingraphy after to hours. all pts survived and were put on coumadine, pt developed an intracerebral bleeding with persistent hemiplegia. conclusions: the use of thrombolytic therapy is highly efficacious for the therapy of pts with pe and concomitant right or ventricular thrombus formation. transthoracic and especially transesophageal echocardiography are powerful bed-side diagnostic tools for the immediate diagnosis and follow-up of successful treatment in this life-threatening condition. although widely used, catheterisation of the femoral vein in the groin using "landmark" technique is frequently complicated by accidental arterial puncture. suboptimal hygiene and patient discomfort are also associated with this technique. with regard to these last two factors cannulation of the femoral vein - cm below the inguinal ligament would seem an attractive alternative. as "landmark" technique is not possible for the cannulation of the femoral vein in this part of the thigh, ultrasound was used to locate the vessel and the results of this technique were evaluated. methods: a portable compact ultrasound device (site rite,dymax corp.) featuring a . mhz transducer (ultrasound depth - cm) fitted with a needle guide and a cm screen was used by residents with no previous experience in ultrasound guided cannulation. patients consisted of a surgical icu population. results: in patients catheters were introduced.in cases more than one ( - ) attempt was made and in patients the procedure was unsuccesfull due to the fact that the vessel was situated out of reach of the ultrasound (vessel depth > - cm), during the procedures one accidental arterial punction was registered. the catheters remained in situ for a mean of days (range - ) and were used for volume suppletion, medication, parenteral nutrition and haemodialysis.co-ionisation rates compared to those of subclavian catheters in our icu. in the first patients cases of asymptomatic thrombosis of the femoral vein were seer on ct-scans performed for other indications, in the following patients duplex scanning performed after removal of the catheter yielded another cases of asymptomatic femoral vein thrombosis. conclusions: ultrasound guided femoral vein catheterisation - cm below the inguinal ligament is a safe and simple technique that can easily be performed by residents without prior experience. the incidence and impact of thrombo-embolic complications associated with this technique are still subject to further investigation. objectives: to estimate the cost of antibiotherapy (ab-cost) in a multidisciplinary -bed greek icu and to correlate ab-cost with total cost of drugs and consumables and with patient's outcome, severity of illness and type of admission. methods: prospective data from consecutive patients admitted to the icu from / / to / / were studied. a tick chart was designed to record all drugs, materials and consumables regularly used for icu patients, but did not include low price drugs and consumables, which are provided from hospital's pharmacy as stock and were included in a fixed icu cost calculated for a month period. the chart also contained demographic details and data necessary for the calculation of several illness severity scoring systems. obiectives: over years evaluate the necessary efforts and expenses to implement a cis in the routine of a -bed stcu. methods: in june a commercially available, unix-based cis was installed on a -bed surgical icu. the goal was a paperless documentation at the bedside. after more than years clinical experience two aspects were investigated: what effort is necessary to install and support a cis, and what is the benefit for patients and personnel on the icu? results: the installation and support of a full-fledged cis requires a considerable effort: (a) the conceptual framework for the cis has to be defined. this includes the definition of documentation standards, as well as nursing and therapeutic standards, which is the essential basis for the configuration of any cis. (b) configuring a cis, i.e. "fine-tuning" it to the user's specific needs, is always a laborious task. moreover, constant maintenance is necessary. these tasks require the following personnel: experienced health care professionals for defining the conceptual framework, - trained health care professionals for configuration, system administrator. on a single icu ( - beds) these are not considered full-time jobs. (c) training is best done employing the "train-the-trainers" approach. (d) beside the necessary amount of man power and money to install and purchase a cis, administrative and mis support is needed, especially when interfaces to the hospital and laboratory information systems have to be set up. in general, a cis needs the commitment of all people involved. without a really professional approach with a longterm goal any major cis can turn into an unnecessary but inevitable night mare. after years clinical use and a thorough implementation of a cis on a major sicu it can be said that full-fledged cis offers an opportunity to dramatically improve the working environment on an icu. moreover, it adds to patient safety, quality of care and cost efficiency in one of the most advanced and expensive areas of medicine. conclusion: a major investment in man power and money is necessary to install and maintain a full-fledged cis. a sincere professional commitment to the goals of a cis is necessary. in exchange, a well configured and well maintained cis dramatically improves the quality of therapy and care on the icu. even return of investment and financial profitability of a cis seem feasible todayl from the clinical perspective it appears that the users themselves are the central determinant whether a cis makes a dream come tree or turns into a night mare. objectives: to establish a relationship between the activities of the staff and the occurrence of auditory alarms on the i. c.u. ard to evaluate confusion between auditory alarms. methods: laboratory based studies which investigated aspects of confusion between alarms in current use on the i. c. u. the observational studies were conducted over an month period and examined the frequency and duration of alarms together with the concurrent activites being undertaken by staff on the unit. the laboratory based studies showed that there were enduring confusions between the alarms on various items of medical equipment, for example a ventilator alarm and an e. c. g. monitor alarm. the results of the observation studies demonstrated that alarms are activated when specific activities are being undertaken by staff. sounds could be used in future recommendations for alarms on medical equipment. suggestions are also discussed for improving and rationalising auditory warnings in the i. c. u. obiectives: we investigated inferior petrosal sinus (ips), the lowest affluent to jugular bulb (jb), as a possible source of contamination of samples in jb for monitoring oxyhemogiobin saturation (sjbo ). pulling back the catheter the oxyhemoglobin saturation usually rises indicating extracerebral contamination (jakobs en met al: j cereb blood flow metab ; : ). methods: the study was carried out on patients undergoing ips sampling to differentiate cushing disease from ectopic acth syndrome and to lateralize any resulting pituitary lesion. we studied the value of oxyhemogiobkn saturation high in jb (sjbo ), at ips (sipso ) and at mid jugular vein ( th cervical vertebra) (smj ) bilaterally. results: we found significant differences between right sjbo and both right sipso (p= . ) and right smjo ( p= , ) and between left sjbo and both left sipso (p= . ) and left smjo (p= . ) we did not fred any difference bilaterally. objectives: we studied various methods of receiving and editing of clinical datas in critically ill patients (different ethiology). patients were investigated in regional intensive care center. methods : the following datas were studied : anamnesis, status praesens objectivus ( organs and systems ) ,. clinical and biochemical markers of critical condition , datas of eeg ,rheography . the medical information complex contained : channel electroencephalograph, -channel roencephalograph, ad-converter ( analog inputs, bit resolution, k hz), ibm dx , software includes set of routines for spectral eeg analysis, eeg-mapping, correlative analysis, and brain bloodstream reg-monitoring (written in turbo pascal . ), expert programs for estimation objective and humoral patient status (written in clipper . ) and statistics. there were used following programme-language instruments : borland c++ . , nantucket clipper . , ca-clipper tools ii. as the methods of statistical processing of dates were used: t-students criterion , fisher criterion, methods of correlation analisis, calculation of the regression levels, dispersion analysis, results : there was created the optimal structure of hard and sofware complex of search steady objective regularity in dynamic of critically ill patients condition. conclusion : the created system allowed to value effectiveness of intensive care and give us new opportunities in study pathogenesis of systems disorders in critical condition . over a five year period a patient data management system has been installed which allows individualised patient data to be accurately collected. using this data a costing system has been developed which ascribes costs thus: . direct costs -drugs, fluids, consumables, interventions. these are ascribed to individual patients, according to data collected from the pdms. . indirect costs -energy, depreciation, admm costs, maintenance etc. these are summed for the year and ascribed as an overhead per patient day. n.b staffcusts contain art element of both cost types the aim is to make as many costs as possibie 'direct', hence 'activity costs' have been calculated winch comprise staff time, drugs and consumables -these are direct costs. these costs of patient care are then searnlessly integrated into the financial and budget management of the icu environment. it was found that by calculating costs in this manner % of the total cost of icu are captured within the 'direct' element, and so are able to be ascribed to individual patients. this is much more accurate than simply dividing the total costs of ~cu by the number of patient days. temporal costs (variations during patient stay) and cross sectional costs (cost differences between admitting specialities) were also noted with interest. results of the initial analysis of data captured by the system will be presented. little is known about the resource costs (not simply cash costs) of icu. even less is known about individual patient costs, with previous estimates of these costs varying widely. however, if cost effectiveness studies are to be undertaken accurate calculation of individual, group and total icu cost is an essential, prerequisite, which, via this system of costing, is now achievable. information about intensive care of cancer patients is limited in the literature, despite the increasing use of such facilities in oncology over the two last decades. in order to determine if and how critical care facilities can be used specifically for these patients, we performed a world-wide inquiry in anticancer centers selecting the hospitals by using the international directory of cancer institutes and organizations. we mailed a questionnaire to centers and we received responses ( . %). there was at least one uncological (i.e. with > % of cancer patients) icu in (% % an -year old woman with graves disease presents with sore throat, vomiting, diarrhea, sinus tachycardia at /minute and a temperature of ~ several weeks before, treatment with propylthiouraeil had been stopped (rash and fever) and replaced by methimazole and ledide prior to a minor surgery. however, both drugs were discontinued by the patient two weeks before admission. shortly after arrival in hospital, patient's condition progressed to respiratory failure (upper airway edema), delirium and shock requiring icu admission, intubation and resuscitation with fluids and vasopressors. white blood count was /mm ~ with neutrophils. patient's hemodynamic data showed initial hyperdynamic profile followed by low output state with decreased sv ( %) (n - %) and cardiac index ( , ) (n , - ). echocardiogram confirmed cardiac chambers dilation as previously described in thyroid storm. lithium carbonate, corticosteroids, antibiotics and beta-blocker perfusion were given. plasmapheresis was started. free t& (n= , - pmo/l) went from , to , after the first two pheresis. after a remarkable clinical recovery, sub-total thyroideetomy was done i days after admission. in life-threatening thyroid storm, plasmapheresis is a very effective therapy when anti-thyroid drugs are counterindicated. purpose: to compare the reliability of prognostic indexes in crhically iu patients admitted in an intesive care unit (icu) who had acute renal failure (arfi and were treated with different dialytic techniques. material and methods: patients were included in a prospective study from june to november . patients presented arf defined by creatinin serum leve(s greater than pmol/l and previous normal levels. patients were divided in three groups. group i (control) : patients with arf who did not receive substitutive techniques. group ih patients under intermittent hemodialysis (hd) or peritoneal dialysis (pd). group ii : patients under continuous hemodiafiltrstion (hf). the statistical analysis was chi-square test and analysis of variance. results: the table shows the results we obtained, we did not find any significant difference betwen the two groups of patients undergoing dialysis. d(fferences were observed only between group i and the other groups as shown below. we did not find any significant association between the theoretical mortality predicted and the observed mortality according to saps in the three groups. due to exposure to a wide variety of unpleasant stimuli, for example, tracheal suctioning, venipuneture and physiotherapy, most pataents admitted to the icu will require some form of sedation. this review will describe the suggested properties of an ideal sedative agent for use in the icu and review the current limitations of some of the available agents from this perspactive. methods used to quantify the level of sedation, such as the ramsay score, glasgow coma score, newcastle sedation score and visual analogue scores, and their deficiencies will be examined. consideration will be given to defining the optimal level of sedation and the circumstances under which sedation might be varied over the icu course will be discussed. preliminary results from an ongoing study examining the role of light versus heavy sedation and ischaemia in a cardiac surgical icu population will be presented. the pharmacceconomics of icu sedation will be briefly addressed. finally, the role that sedation may play in increasing morbidity, pastieuiarly nosocomial pneumonia, in the icu will be discussed. objectives : therapy cost(tc) in icu patients is a substantial component of total hospital care cost. estimation of tc during this year, partitioning to various groups of drugs used and attempt to minimise it, were considered practically useful. methods : in collaboration with the hospital pharmacy we were able to have a complete report of au drugs used for icu patients (including enteral and parenteral nutrition). mean apache ii severity score upon admission was . and mean length of tcu stay was . days. price per drug unit and cost per group of drugs were also available drugs were divided into two groups: antibiotics ( ) cardiovascular drugs ( ), gastrointestinal system drugs ( ), enteral and parenteral nutrition ( ), respiratory system drugs ( ), sedative, analgesics and paralysing agents ( ), parenteral solutions with electrolytes, vitamins and trace elements ( ), anti-inflammatory agents ( ), protein substitutes and immunomodulation agents ( ), anticoagulative agents ( ). antibiotics were further subdivided into those "freely" prescribed (a) and those whose prescription and administration requires filling of a relevant form (b). results : !) tc for icu patients/day was . drs ($ ). total tc/patient was . drs ($ . . ). ii) partitioning total tc per group of drugs reveals : ( ) %, ( ) . %, ( ) . %, ( ) . %, ( ) . %, ( ) . %, ( ) . %, ( ) . %, ( ) . %, ( ) . %. t ) concerning antibiotics which consist the major cost component, group a and group b contributed by . % and . % to the total icu tc respectively. group b were administered to . % of all icu patients. conclusions : i) for the above studied patient population antibiotics consist almost half of total tc followed by protein substitutes and immunomodulation agents. ii) if tc control could be attempted in the icu, prescription of beth groups must be reviewed. appropriate treatment should be prescribed and readily provided to any patient. clinical significance of routine protein substitution, currently controversial, should be re-evaluated. new antibiotics (third & fourth generation cephalosporins, quinolones, carbaponems) should be prescribed on the basis of strict diagnostic procedures using modern technology available. rationalisetion of antibiotic therapy will lead to cost control, redistribution of icu expenses and substantial contribution to infection policy in our country. objectives: i -to investigate the clinic efficiency of the monitoring of the rso cerebral, in relationship to the stroke prevention, in patient undergoing carotid surgery. -to determinate the variations of the rso during the different surgical and anesthetic procedures in these patients methods: ten patients undergoing carotid endarterectomy. precise neurological exploration previously to the surgery and in the immediate postoperative period. angiography evaluation to the extend of carotid artery disease. invasive blood pressure, ecg, pulse-oximetry ( pso ) and rso were collected previousty to the induction of anesthesia. the premedication was administered intravenously -midazolam ( mcgr/kg) and fentanyl (i rncgr/kg) -. thiopental ( mg/kg),fentanyl ( mcgr/kg) and atracnrium ( , mg/kg) have been used for induction of anesthesia. co te is monitoring al~er the orotraqueal intubation ! the anesthetic maintenance is accomplished with lsofluorane ( , - , %) and bolus of atracurium and fentanyh the surgical procedure is standard (without arterial shunt during the carotid cross-clamping). we register each minutes: blood pressure, cardiac frequency, pso , co te and rso . the rso cerebral variate in relation with: the anesthetic induction, blood ~ressure, co te, cross-ulampping carotid and with the modifications of the head position. the maximum decrease of rso cerebral was in relation with the :ross-clampping carotid ( minimal value: ). no patient had neurologic complications and postoperative stroke after carotid endarterectomy were not observed. objectives: there are more than anesthesia in chelyabinsk emergency hospital every year. to % patients of it emergency anesthesia is applied. more than patients have ishemie heart disease (ihd), hypertansion (hp) and previos miocardial infarction (pmi). more than % of all patients are old patients (op). the resalts deep noninvasive bioimpedance monitoring (nbm) in surgical patients have been studied by us. methods: our nbm system "kentavr" includes parameters of cardiac and vessels function. it is realised by monitors in operation theatres and computer network. moreover we are able to examine surgery patients before anesthesia and perioperatively by using special computers system for cardiovascular reflex control by fast fourie transform (fft) of parameters simultaneously. results: pathients extremly needed peryoperative monitoring of hemodinamics. from these patients more % had stroke volume (sv) less than ml, n -co less than . /mim/m , % -ejection fraction (ef) less than n and % -puls bioimpedans microvessels (pbm) less than morn. patient had intensive care in special department. out of died. comparing with survived with these patients before operation hr was larger, sv, co,ef, pbm and puls bioimpedance aortha was smaller. much more of these patients were with ihd, pmi, hd, op. even with survived patients these parameters decreased the towards the end of operation. surgery patients had different variability of basic hemodinamical parameters with common tendency to increase power amplitude in low frequency by fft. conclusions: using of bioimpedanee noninvasive parameters allows to have criteria for corrections (infusies, vasodilatators, inotrops and others) and then us the final goal, to have more sucssesful surgery. with survived patients was perioperatively and postoperatively care more intensive. obiectives: the aim of the study was to compare the phi with the hemodynamically derived tissue oxygenation indexes as: oxygen delivery (do ), oxygen consumption (vo ), cardiac index (el), and arteriovenous difference in oxygen [(a-v)do ]. methods: patients ( males and females) with major trauma or major abdominal surgery were studied. on admission, a nasogastric tube allowing phi measurement was introduced and a pulmonary artery catheter was inserted for optimal hemodynamic management. each phi measurement was accompanied with a complete hemodynamic study comprising systemic and pulmonary artery pressures, blood gases, and cardiac output measurements with the thermodilution method. derived parameters vo , do , ci, (a-v)do were measured according to the standard formula. hemodynamic parameters were opt• as soon as possible with fluids, inotrepes, and vasopressors according to repetitive hemodynamic measurements. all patients were under mechanical ventilation. after hemodynamic stabilisation phi and hemodynamic measurements were repeated every eight hours, during a -hour study period. a total number of measurements were obtained and compared. statistics: results are presented as means + sd, correlations were performed between phi and the hemodynamically derived oxygenation parameters. a p< . value was considered as significant. results: mean values were phi= . + . , do = + , vo = + , c. = . + . , (a-v)do = . + . . no correlation was found between phi and do , phi and vo , phi and c.i, phi and (a-v)do . on the contrary in patients phi remained below . for more than hours despite adequate hemodynamically derived tissue oxygenation parameters. mortality in this group of patients was very high ( %). conclusion: no correlation was found between phi and the hemodynamically derived tissue oxygenation parameters our data suggest that phi is a better oxygenation indicator than the hemodynamically derived tissue oxygenation parameters, because it is closely related to the patient's outcome. objectives: the pathogenesis of septic shock and multiorgan failure is believed to be related to tissue hypoxia of the gastrointestinal tract. therefore new monitoring techniques, preferably organ specific, are required to establish the adequacy of tissue oxygenation. peep is used to reduce pulmonary shunt volume and improve blood oxygenation, but is accused to impair splanchnic perfusion. we studied mucosal oxygenation and perfusion on the capillary level in the stomach and the duodenum. methods: we used the erlangen microlightguide spectrophotometer (empho ll) together with a specifically designed fibre probe (bodenseewerk ger~tetechnik, berlingen) in combination with a standard gastroscope. measurements were performed on ventilated, traumatized patients (ages - years), with no evidence of shock or severe infection, after informed consent was obtained from the relatives. all patients were hemodynamically stable without inotropic support. an area of cm was analysed in the gastric corpus, the antrum and in the duodenum. in three patients we simultaneously measured the muc sal blood flow using a laser doppler flowmeter ( objectives: to investigate the influence of hb-o affinity in the monitoring of svo~ during improvement of cardiac index (ci) in cardiogenic shock. design: to state whether changes in svo: were associated in changes in actual pso (p~ ) and standard p~ (ps st) consecutive measurements of artero-venous bga, before an.d after therapy-induced changes in ci, were evaluated in patients (mean age -* y) suffering from cardiogenie shock, all under mechanical ventilation in psv modality. methods: together the hemodynamic measures, m~xed venous samples were analysed at ~ c using the abl radiometer for po , pco: and ph, and the osm radiometer for hbo %, hbco% and methb%. psost (i.e. the p~ at ph= . , pco:= mmhg and temperature at ~ c) was calculated automatically by the instruments on mixed venous blood as was the ps "in vivo" (i.e. the pso at the patient's value of ph, pco and temperature), using siggaard-andersen's computerizated algorithm. mean time between paired measurements was . -* . houm. the data were compared by anova test for linear regression and t-test for paired samples. results: a dose linear relationship was found between svo and oxygen extraction ratio (oer), r= . ,p= . . the improvement of ci ( . -* . to . + . l/min/m , p< . ) induced a significant increase in svo~ ( . -* . to . • . %, p<. ). a significant decrease in p ( . • . to . • . mmhg, p< . ) without any significant change in p~ st ( . • . to . • . mmhg, p=ns) was also found. these data show that either oer or the shift to the left of the oxygen dissociation curve account for increase in svo occurring with restoration of systemic blood flow. the program is intended to help the intensive care unit interne providing him with a practical tool when making decisions concerning patients in a critical condition. in his daily practice in intensive care unit, in this case the interne of the unit, uses this program for each patient as follows: on the first stage of data collection he should complete the following modules: ( )personal data ( )patient's pathology ( ) laboratory and~ monitor lug data ( )drugs prescribed or toxic elements ingested. in this way, the system allows optionally the consult with a computerized data base about the drugs prescribed, standardized parameters and techinques performed by the central laboratory. ( )reference to an antibiotics guide regarding becterian sensitivety in our unit, whitch ee checked every six month ( ) access to de questionnaired apache ii to load up new data. ( ) statistcs about patient's admission and discharge. results: once all data collection is finished the system performs the followin duties: ( )detailed drugs interactions, including toxic elements ( )diagnosis starting from the clinical, laboratory and monitoring data. in some cases, it also establishes therapeutic strategies, e.g. a coagulopathy ( ) give the l~narmacological incompatibilities between the drugs p~escribed and %he diagnosis established, and ( )perform dosage adjustments based upon the personal and pathological data. objeatve: to assess the power of diseri~,~ion ofa multiperpose severity score (sai~) when applied to subgroups ofpatieals (pta) according to their lemg~ of ~ay (los) in icu. design: in order to compute the saps probability, a model derived fi~m legible regression was developed. meaumree of calibration (goodmem..of.fit statistics) end discrimination (roc cm've and relative area under the cm've) were adopted in develotammtul asd validation set. the whole databue was ~ati~ed in five gronps reeked on los as follows: los = days, los = - days, los = - da~, los = - days, los > day~. area under the carve (auc) was ud~ninted for each ro~. s~ing: imlimlcus. patents: of ~ pts comec~ively admired ~ a period of three yeet~ ( ) ( ) ( ) , a total of was i~leded in this study. pts without saps, p~ yolmger them yearn, p~ with los shorter ~ hom'~ were excluded from this maly~is. iaterventinns: nose mema'onm~ end result: the logistic model developed gave good remits in terns of calibration md discrimin~on, both in developmental set (do.s g : . , p > . ; auc = . i- . ) and in validation ~t (g.o.g g : . , p > . ; auc = . ..+ . ). auc of each grottp showed a loss in di~zimination (i.e., prediaton) closely related with los, being . i- . in pts with los = days el . ~. ia tm with los > da~ (figure). following the present guidelines of integral management, in order to achieve optimization of sanitary resources and better use of facilities, we feel that the setting up of objetives is a key factor in the continuous process of improvement of quality care. postsurgical intensive care services maintain an interdepent relationship with other hospital services. within the general plan of the hospital it's of the utmost importance to delegate autonomy to the various depertments and service units in determining and achieving objetives. it's also necessary to establish mechanism for coordination of the activities in order to assure the succes of the program. the objetives cannot be improvised, they must be carried out in a specific manner in the following stages: .-analysis of the present situation (starting point). where are we?. defining objetives and making explicit the activities and methods to achieve them is to anticipate the future; it is of the utmost importance to comunicate said plans to all whom affect by encouraging them to attain the desired results. in the present paper we intend to show the guidelines to follow in carrying out a course of objetives. introduction:we presents results related to the quality of life (qol)of critical patients, from paeec project data. material and methods: the paeec project is a multicentre study define the type of patients cared for in spanish icus, and the therapeutic activity provided. ninety-five icus from spain are taking part. this study analyzes the qol of critical patients prior to their icu admission.for the evaluation of qol a questionnaire designed by our team for critical patients was used, with items grouped in sub-scales: physiological functions ( items); functional capacity ( items) and subjective aspects ( items). qol is classified in levels: normality ( points); slight deterioration ( - points);moderate deterioration ( - points); significant deterioration (>i points). the we present results related to therapeutic activity in critical patients and their age, from the paeec project. material and methods: the paeec project is a multicentre study to define the type of patients in spanish icus, and the therapeutic activity provided. ninetyfive icus from spain are participating. this study analyzes therapeutic activity in the first hours as evaluated by tiss, and related factors. results: the sample was , patients, sge . ~ . years. severity by apache ii system was . • points. the tiss score was . • points, distributed as follows: i (<i points): %; ii (i - points): %; iii ( - points): %; iv (> points): %.there is a positive correlation between the level of therapeutic activity and severity by apache ii (r = . , p < . ), and a very weak but negative correlation between tiss and age (r = - . , p < . ), so that an increase in age corresponds to a lower level of therapeutic activity.patients the multivariate analysis of the relationship between tiss and age took into account: severity, existence of previous history, need for mechanical ventilation, size of hospital, diagnosis and mortality. it indicated that there continued to be a relationship between therapeutic activity and age, so that as age increased, therapeutic activity diminished. conclusions: therapeutic activity performed on critical patients is less in the oldest patients, in whom excessively aggressive procedures are limited. a relational data base management system in the icu. c. kotsavassiloglou*, d.matamis, g. dadoudis, j. kioumis, d. riggos. icu dep., g. papanicolaou gen. hosp., exohl, thessaloniki, and * a' neurological clinic of aristotelian university, thessaloniki, greece. objectives: the introduction of the information technology in the i. c. u seems to be unavoidable because of the large amount of produced data and the need for their systematic analysis. such an information system should be a) easy to use, b) friendly to the user, c) powerful and d) modular. on that basis, we created a patient data management system (pdms) according to the expectations of the medical staff of an eighteen bed multidisciplinary icu. methods: we selected paradox for windows v . for the implementation of a relational data base because this program meets the above mentioned criteria. informations regarding the patients include a) demographic data, b) previous medical history, c)diseases upon admission, d)complications during hospitalization and e) outcome data. the diseases' registration consists of items classified in categories upon the principal system affected. specific informations about the need and duration of mechanical ventilation, nutrition, renal replacement, right heart catheterization and icp monitoring are also available. an extension was added concerning icu infections and related informations about antibiotic-resistant pathogens. all icu pathogens can be matched to their resistance or sensitivity and cost of antibiotics. the program can perform queries and various statistical analyses based on complex criteria. new modules can be added later according to the future needs and remarks of the users. results: the program was well accepted by the medical staff and patients were registered as a test. the first analysis of the data related a) observed mortality versus the apache ii predicted mortality, b) mortality according to the age, gender, pathology aud duration of icu stay and c) pathology upon admission and icu related complications. conclusions: the long term use of this pdms can be an efficacious research tool. it can be used in retrospective or prospective studies by addition of necessary modules. the first data analysis revealed the iack of an international diseases' classification system. the development of a worldwide common classification system is essential for the compatibility of the data analysis among various icus. this will allow the realization of multicenter trials on a large scale. s. nanas= n. sphiris, a. precates, a. lymberis, m. pirounaki, and ch. roussos dept. of critical care, university of athens, athens, greece the complexity of the cases submitted to an icu, the variety of underline disease, tbe severity, as well as the large number of substances administered to each patient constitute obvious the need of support with an easy available dss. this system will assure the safety of the administered treatment will help to adjust the dose according to the situation of each patient and it will screen for possible interaction and incompatibilities between the administered drugs. the goal of the present effort is the design and development of a software system acting as a decision support tool to physicians of icu. the application is organised around a relation database management system (rdbms) that consist of: a) all available substances ( . ), b) all generic names of medications available in our country for each substance, c) incompatibilities ( . cases) and d) interactions with other substances ( . cases). the following figure shows the structure of the rdbms. y ta~ortato~ [ c~rs using the stored parameters for each patient the dose and the rate of administration of selected substances will be possible to calculate. the continuous monitoring of the treatment for each patient supports the medical staff to make the necessary changes of the prescriptions. the application is currently developing in wireless pen based computer systems which place patients at the centre of "islands of information" located throughout icu. in conclusion this dss is a powerful and useful tool for icu staff because it provides without additionai work to the routine of daily practice, the currently available information for each order concerning drug interaction and incompatibilities as well as treatment monitoring is to obsea~ among critically ill pfdieats, stdjdivided following the diagn~s at the adn~ssio~ the diffmeax:es in the ~ and oxyplx~efic l~mmems bawe~ strvwors [s] and non sumvors ins] and to test the pc~'bih'ty to have soar survival criteria, as earliest as tx~able. method~ :we made a ~ study on consexa~e ~ilically ill paliffas, subdivided in series following the diastases at the admission: medical pafiea~ ( s and ns), surgical patients ( s and ns), a~d poliwauntas ( s and ns). follow up was done at d,.ays from the admission in ice. all the patienls were ramitored with a ~ c~eter and laeno:lymmi. "c and o .x.xyphorefic txuamaers va:~e couected at fin~es (t): at fiae ~draission (t ), at x~ars from t (t ), at (f ), (y ), (t ), % (t ) and horus from t cf ). in~,h ~ies, for ~y ~ a all the lin'~ n~an and sandaid d~viation was ~ tx~h for s and for ns. th~ betw~ s and ns tl~ roeaas of ~h porarneter ~e ccmpared tt~ng t-lest and p < . w~ considered ska~ significant in each series in the t wheae the mast significative diffemx:as ~goeamd bet~en s and ns, we made a txedictive criterion, asamting as predictive indices for stnvival the i:r values, higher or lower than flae treans of the ~rar~ers of au flae patients, axx)rdhlg to those ones t~iatistically diff~'e~ betw~m s and ns. fhmlly xse co:weatxt onaong the series the nrametees of the st~rs with the analysis of variance, to daserve the lxjsable differealt irea~ of sty hflices, following the diagn~s of admission: :nedkal, angical patient or poll~tam results: we c~ld not find ~ predictive criterion for politraonaas, perhaps ixx:ause of the few ntanber of l~fients. for high ri~ saw~cal patieras the following criterion at t has a sensitivi .ly of ~ ,and a ~ecificity of . %: sv > . nffmin/n~, map> mmhg, pmap< nmalqg cvp<i nunhg will nmah& lvswi> g m/m , sxo > ~ do > mlhnin/m , o er< %. for lx~dical l~tienls at t the following criteric~a has a ser~tivi.ty of % and a ~zificity of . ~ cvp< . mn~g, sao > %, s,g) > ~ vo i< ml/nfin/m , o er< %, shunt< % survlvops' data of the series ~ signitic~atly differenl~ both for the t~mody~nic a~ for fl~e ox rphomfic lxlmn~s; moreover we ~ that the vatt~ of hemodynamic mad ox.~ho~tic indices were higher in politrautms. conclus'ions: acx~ording to the fftffe~mt patho!o~es, the ~ rnelabo~c needs are diffeten~ so that it is juslified to mash ~ the~alceutic goals, following the type oflmthology. hen~ we foru~d for high ~k mrgical pmka~ and for medical patier~s assme, ff mllslied, a good prognosis while, if n [ ntljsfled~ the plinsliclioil ofdl~tth is no[ g(ioct finally, ab~ high iis~ supgical palieaats, according to what other atmhors say, txatws sh ~'n~ers ' therapeutic goalsvvould seem inadeqt~te, bec~jse they need a gear physiologic and themtx~ic elth~ in rdation to the rretabolic needs. figure ) . thus, the smaller european nations had a greater participation than ~e larger ones, with the exception of norway. a similar result was evidenced for contributions to intensive care medicine (figure ). these findings can be explained by different submission policies and language banners. however, there was no significant correlation with the gross national product of each country. conclusion: we conclude that the smaller european countries generally contribute more to international intensive care journals than the larger ones. objectives: to evaluate the agreement between a new and three old methods measuring ctp and to assess their reproducibility. methods: we studied patients ventilated with a siemens c respirator. we measured ctp by dividing the tidal volume with the increase in airway pressure (paw), either with the respirator setting used (ca) or with a fixed setting (cf). by modifing the inspiratory time (ti) without changing inspiratory flow, we were able to deliver two series of inflations ( , ,... ml) before and after curarisation of the patient. the same volumes were also inflated in paralysed patients with a super syringe. at the end of each inflation a plateau of sec was performed and paw was recorded. the above three sets of pressure-volume (pv) points were used to reconstruct the corresponding pv-curves (( , c , c the new method for ctp measurement without a super-syringe had the best reproducibility in paralysed patients and gave similar results without curarisation in the majority of them. however, agreement between the methods tested was unacceptable for clinical purposes. further investigation is required in order to improve the accuracy of ctp measurement in icu patients. m kunert, r.sorgenicht, l.scheuble, k.emmerich, h.g ker med.clinic b (dept.of cardiology) i heart center of wuppertal/university witten-herdecke,germany objective to determine the accuracy of activated partial thromboplastin time (apl-l) and activated clotting time (act) studies when samples are drawn through heparinized central venous catheters (cvc). methods a total sample of paired act/p't-/" values was analysed in patients ( m., f., + y.) for monitoring heparin therapy.all patients had a cvc (certofix trio,braun,frg) in the internal jugular vein receiving a continous infusion of . u heparin via the central catheter.act (hr-act, hemotec,usa) and ap'i-f (neothromtin, behring,frg) samples were drawn from the cvc using the double syringe technique (removing and discarding ml blood before drawing the sample). these blood samples were compared to act/ap'cf blood samples obtained by venipuncture (v.fem.) at the same time, act values were analysed directly in the intensive care unit (icu),api-i samples were measured in the hospital laboratory within minutes. results ac-i -~ pi-f~ cact/~pi r = , ) cvc samples + + . v.femoralis samples " + + p-value n.s. n.s. conclusion there is no difference in heparin anticoagulation studies drawn from heparinized central venous catheters compared to those obtained by femoral venipuncture,withdrawing ml blood prior to obtaining the blood specimen is a safe way for eliminating heparin contamination.not only the aptt test but also the act test is a useful method for heparin anticoagulation assessment in the icu. objectives: evaluation of the delicate balance between filter-coagulation and patient-hemorrhage using heparin as anticoagulant in continuous renal replacement procedures. methods: from january through august , we studied filter surviva[ and hemorrhagic complications during filter periods in critically d[ patients, treated with continuous arterio-venous hemo(dia)filtration, with special emphasis on the heparin dose, concurrent use of coumarins, systemic activated partial thromboplastin tirne(aptr), platelet count, mean arterial bloodpressure and the type of filter used. results: filters ( %) were disconnected because of coagulation. mean survival of multiflow an filters was twofold shorter compared to survival of fh gambm filters. a total of hemorrhagic complications occurred of which three patients died at aptt values of respectively , and seconds. after adjustment for mean arterial bloodpressure, platelet count and the type of the filter, the risk for filter-coagulation decreased % (relative risk . , %c . - . ) for each ten seconds increase in aptt. the risk for patient-hemorrhage increased % (relative risk . , %ci . - . ) at an aptt-increase of ten seconds. the occurrence of filter-coagulation and patienthemorrhage was not correlated with the administered dose of heparin. concurrent use of cournarines had a positive effect on filter-survival, without increasing the overall incidence rate of patient-hemorrhage. conclusions: the systemic apt]" is a good predictor of the risk for filtercoagulation and patient-hemorrhage. heparine therapy seems optimal at an aptt between and seconds, although one should realize that fatal hemorrhagic complications still can occur. objectives: the alterations in vascular tone which are primarily regulated by adreno-sympathetic tone(ast) are compensatory responses in hemorrhagic patients. this study was designed to evaluate the correlation between vascular tone and ast in patients with hemorrhage, methods: the vascular tone was expressed by volume elastic modulus (ev) that is defined as; ev = ap/(av/v) (ap; the arterial pulse pressure, av/v; the volume change ratio). ev was measured using a non-invasive transmittance infrared photoelectric plethysmography (tipp) and a volume oscillometric sphygmomanometer . we prospectively studied patients with hemorrhage. the initial ev measurement was performed on arrival and repeated for a hours duration. as a parameters of ast, serum concentrations of adrenalin (ad), noradrenalin (nor), plasma renin activity(pra) were measured simultaneously. we analyzed the correlation of ev and conventional parameters to ast by multivariate statistical analysis. results: ev values at transmural pressure mmhg on admission and hours later were respectively . + . mmhg, . +_ . mmhg (mean + sd). systolic pressure(pas) and serum hormones on arrival and hours later were respectively, pas; . _+ . , + . mmhg, ad; . _+ . , . _+ . ng/ml, nor; . _+ . , . + . ng/ml, pra; . _+ . , . _+ . ng/ml/hr. the ev values correlated significantly with ad (r= . , p= . , n= ), nor (r= . , p= . , n= ), pra (r= . , p= . , n= ). by multivariate statistical analysis, ev correlated more significantly with ad and nor and pra (p= . ) than the conventional parameters such as pas, heart rate and pulse pressure. conclusions: the alterations of ev correlates closely with ast. the compensatory mechanism in hemorrhagic patients can be detected noninvasively by ev monitoring. obiectives and method: autologous oxygenator blood was processed at the end of cardiopulmonary bypass (cpb) by either hemofiltration (hf , , m , fresenius) or by cell washing with a onntinous autologous transfusion system (cats, fresenius). prospectively the blood of patients for each group was processed and then retransfused intravenously to the patient. besides, volume and time requirements, standard hematologic chemistry, coagulation and complement activation were measured. results (mean values for oxygenator blood at the end of cpb, and results of concentrate after processing by filtration or washing): both processing techniques show excellent hemoconcentration of the diluted cpb blood with a good transfusion effect for the patient. filtration retains all plasma proteins and large molecular weight plasma bound waste products. in contrast, cell washing with cats significantly depletes plasma proteins and waste products. the newely developped cats machine gives eonsisinnt laboratory result in a fully automatic continuous processing mode. in conclusion, both filtration and washing are effective for processing cpb blood. filtra tion yields a highly concentrated whole blood, whereas cats washing produces a high quality autologous erythrocyte concentrate. soluble fibrin has during the last years gained interest as a marker for the activation of the coagulation in connection with various clinical conditions, e.g. disseminated intravascular coagulation, deep venous thrombosis and myocardial infarction. elevated levels of soluble fibrin in plasma can be detected by the chromogenic assay coaset fibrin monomer, relying on the ability of fibrin to enhance the tpa-catalyzed conversion of plasminogen to ,plasmin. using this test, it has been shown that the level of soluble fibrin can be correlated to severeness of illness in critically ill intensive care unit patients. a revision of the coaset fibrin monomer kit has now been made and the new product, coatest soluble fibrin, is considerably more convenient to handle and gives higher resolution at low fibrin levels. the test is performed by the addition of a buffer dilution of the plasma sample to a microstrip well containing the colyophilized mixture of tpa, plasminogen and the plasmin specific cbromogenic substrate s- . the reaction is allowed to proceed at,. room temperature for minutes before discontinuation. the absorbance at nm, measured in a microplate reader, is proportional to the content of soluble fibrin in the sample. the assay is carefully standardized and calibration curves are provided in the kit. the convenient and rapid assay procedure makes the coatest soluble fibrin test well suited for single test analysis in acute situations. objectives : blood coagulation abnormalities have been reported in the systemic blood of patients with cerebral lesions. the physiopathology of such events is not yet completely understood. we compare the coagulation profile of blood from the right jugular bulb with systemic blood of patients with head injury. methods: we studied patients, who were admitted to our neurosurgical intensive care unit between january and march with head injury and no other associated pathology (age - yrs), a glasgow coma score <= g, no abnormality in baseline coagulation profile and no history of coagulopaties. the patients did not undergo angiography. a one-way gauge certofix catheter was inserted through the right internal jugular vein up to the jugular bulb. an identical catheter was inserted through a subclavian vein. blood was sampled from either catheter (a=atrial; j=jugular) - hours after trauma (t ) and t hours later (t the inddence dpontolx'rative thmmhi~e and haumord~gic complieatiom were assessed in padents treated with indobefen, heparin calcine caeca), low mollecolar weight heparin (lmwh) (f.nosheparin) and undergoing hemodiludun, blood predeposhing, intra mad postoperative blood saving. ]'he indolmfon tempota~.norks platelet aggregation through ,,elective inhibition of the cyclatygenasis and thus atacbldonicadd( ).tbe n'mimum effect occurs after hours from the fast administration and is still present after hours. ~- patients, mean age --- yrs., weight --- kg were studied. ( . %) were male and ( . %) female. onderwent hip prosthesis ( previously plate and screw removal) hip revim'un ( stem, cop and stem + cop), tutal knee prosthesis, in the st anaesthesidogy depl from - to - - . as for antithromboembolic ptephylam, apart from hemodihitiun pts were with treated indobufen ndo), with heparin ealdum caeca) and with low mo!lecular weight hepam (lwr, ). as the slightest clinical and/or imtmmental suspidon of deep vein thrombosis (dv'i') or polmonary umbolism(pe), a phlebogram or sdndgram were respectively carried out. -the inddence of homologom transhisiom was significandy lower (p= . l) in the padeats treated with indobufen ( . ) compared .'ith heca ( . %). the con~gency table shows statistical signifleance for the use of heca in patients with vein deficiency in the lower limbs, past dvr and/or pe, coronary heart disease (cdh'), while there is no correlation for renal, cardiac or liver defidency, obesity, systemic hypertemion, atrhythmy, diabetes, chronic bronchitis and rheumatoid arthritis. by comparing the postoperative cumplications with the risk factors, there ks a highly significant correlation (p= . l) between cdh and thrombotic and humord~agic complieatiom (pe, death, he~atoma, die use of hum_ologous blood). thee data show that hep~in, preferred in patients with c'dh, roost likely for leagal-tuedical reasons, did not have the de~'ed effect. conclusions -the stastisfical aar~ais shows ~nifieanfly different efflea~ (pro . ) between the therapies (see table) : it can be seen that in patients undergoing autotramfusiun and hemedihidon, indobufen produo~ a lower incidence of haemotrhagic complieatiens compared to heca and lmwh and is more effective in the prevention d ~c complications at clinical e~idence. the duration of i~toperadve hospital stay is signi~cantlylonger for patients transfused with homologous red ceils and treated with hec, .a ( . -+ . days) and lmwh ( . +- a days) compared with indo(ll. _+ a days). one of the main causes for postoperative complications in major orthopaedic surgery is postopemtive bleeding with local effects in the operation site (hematomata, pain and delayed mobilization) and/or systemic and subsequent cardiodrculamry repercussions that are sometimes severe. the aim of this study is to assess the possibility to apply a new system of monitoring, control and saving postopemtive blood loss from the drainage. the bt recovery dideco (marandola, modena-italy) ~ used since it is the only apparatus capable of doing this. the apparatus consists of a pressure transducer, adjustable from - a + mmhg, which activates a peristaltic pump connected m drainage robes. the bt recovery display shows hourly bleeding in the first hours, total bleeding, time passed since the start of monito~g and subsequent salvage and the aspimtioo pressure on the drainage robes; the latter is inserted at - mmhg and then modified according to bleeding/minute, g bt recovery also has an alarm that sounds automatically if.' blood loss is more than ml/hour; air is in the circuit; the batteries are running low. materials and methods: pts were studied ( m and ~), aged . -+ .lyears, basal hemoglobin . -+ (range . - . )g/all, treated from st january, to mst december, in the st service of anesthesia and intensive care unit of our hospital. the patients underwent the following surgical treatment: total hip revision ( pts), cup revision (~ipts), stem revision ( pts), total knee revision ( pts). the average dumtion of the operations was -+ min. intranpemtive monitoring and blood salvage was applied to all patients. genera! anesthesia was used on pts. and integrated (epidural analgesia + light general) on the remaining t . anttthromboembolic prophylaxis consisted of external pressure bandage, isovolemic hemodilution with iodobufen in ( . %)pts., calalc heparin in ( . %)pts., low molecular weight heparin in ( . %)pts.; pt did not give a predepoalt of blood, gave unit, pts units, pts units, pts units. the data obtained was statistically analysed using contingency tables and anova. results: average intmop salvage was -+ ml, average postop salvage was -+ mi the average intra+postop +- ml. average postop loss was -+ ml. the global incidence of postop complications was: h~natomata . %, dvt . %, pulmonary thromboembolism , , myocardiac ischemia . %, acute myocardic infarction . %, respiratory deflciecy . %, arrhythmia %, cystitis . % there were nn complications in . % of pts. postop bleeding over ml in under minutes (with bleeding alarm activation) occurred in pts ( . %). this sta~tically correlates only with the type of operation performed (more frequently in total hip revision p= . ) and with a significant decrease (p~ . ) in the pruthrombic activity detected about hours after the operation. this bleeding, also made the alarm sound, calling the attention of staff who could act accordingly, by making the drainage pressure positive and incre~sthg the tension of the external pressure bandage. conclusions postop monitoring, control and blood loss salvage combined with predepoalting and intmop salvage has enabled allogenic transfusions in % of cases to be avoided in operations with high postop blood loss like hip or knee revision. the usefulness of the system can be seen by the fact that in the patients with so much bleeding to set off the alarm, there was no significant difference in the incidence of allotransfusions and complications. references )borghi b., bassi a., de simone n., laguardia am., fonnaro g. an injury of the brain may result in various disorders of hemostasis caused by the release of • into the circulation through a damaged blood-brain bar tier. disseminated intravascular coagulation(dic) is one of these disorders. it is a freguent but relatively rare ly diagnosed complication of subaraohnoidal haemorrhage. the aim of this study was to evaluate some parameters of both blood coagulation and fibrynolisis in patients with sah.in addition one wanted to find out wh~ther potential changes correlated with the pa• condition in the acute phase of sah and whether they influenced the course of this disease. patients with sah were studied. in of them sah was due to closed eraniocerebral injury and in the rema ining resulted from vascular malformation. the following parameters were evaluated:the prothrombine time,the activated partial thromboplastin time, the thrombine time,level of factor v,fibrinogen degrada tion products and fibrin monomers. the results let us show the presence of oic in patients with closed craniocerebral injury and in with vas. cular malformation despite the lack of clinical symptoms the tests in posttraumatic patients and in patients from second group showed incomplete dic.on admission patients with such changes in measured parameters were in poor condition.the course of the disease and the effe cts of treatment were also worse in these patients. the results showed ihal in patients with sah complex disorders of both coagulation and fibrynolisis occur, and they depend on clinical condition of the patient. they also influence the course of the disease. methods : charts of all patients admitted with d.i.c. over a ten year period ( - ) were reviewed. diagnosis of dic was based on the association of fibrinogen < g/ -platelets < / -fpd > ~tg/ml in the hours of the admission. results : patients -mean age + y -saps +_ -gestanional age _+ weeks -the two first conditions associated with d.i.c. were placental abruption ( %) and preeclampsia or eclampsia ( , %). bleeding episode was present in pts ( %) and surgical treatment has always been necessary. pts ( %) were given packed red ceils ( + u) and fresh frozen plasma ( + u). patients were given platelets packs. heparin was never administered. pts required mechanical ventilation and two patients hemodialysis. all the patients survived. correction of prothrombin time (p.t.) and fibrinogen (f) was quick (p.t. at t h ~ % -f at t h , + , g/i). but platelets count remained low (plat. at t h + / ) -no difference was observed in patients who received platelets. conclusion : prognosis of critically ill o.p. is good. blood loss is the main complication. correction of hypovolemia and anemia with concomitant surgical treatment are essential. the administration of coagulation factors or platelets is still under discussion. objectives: to evaluate the effects of antithrombin iii i at-iii) and a protease inhibitor, gabexate mesilate foy), on the coagulation and fibrinolysis in disseminated intravascular coagulation (dic). methods: after the approval of our institution and consent from patient's family, patients with a dic score ( , japan) more than points (dic or having a risk for dic) entered this study. they were randomly divided into two groups, foy (i- mg/kg/h for days or more) treated group and no foy group, each of patients. platelet count (plt), fibrinogen (fen), at-iii fibrin degradation product (fdp), d-dimer (do), fibrin monomer (fm), thrombin-antithrombin complex (tat), plasmin-plasmin inhibitor complex (pic), and prothrombin time ratio (ptr) were measured before the start of treatment (at admission) and i, , and days after the admission. at-iii at units for days was administered if the at-iii at admission was less than %. finally the patients were divided into four groups: group a, foy (+) and the at-iii ~ %; group b, foy (+) and the at-iii < %" group c, foy (-) and the at-iii %; group d, foy (~) anffthe at-iii < %, each of patients, to match the patients for backsrounds. all parameters, dic score and survival rate in a month following treatment were compared among the four groups. results: the at-iii and plt from day to were significantly higher in groups a and c than in groups b and d. the fdp, dd, tat, and pic after treatment decreased significantly from the baselines in groups a and c but not in groups b and d. the fgn and fm were not significantly different among the four groups. the ptr decreased in groups c and d but increased in group b. the dic score decreased significantly in groups a and c than in groups b and d. survival rates were %, %, % and % in groups a, b, c and d, respectively, although not significantly different. conclusions: in patients with dic or a risk for dic, foy had no expected effects but at-iii had suppressive effects on the coagulation and fibrinolysis mechanisms. a prognostic factor ? carbon monoxyde intoxication is a classical complication of inhalation injury. carbon monoxyda is also physiologically produced during the heme metabolism: heme is conversed to bi]irubin by the hemeoxygenase which is an intracellular stress protein. icu patients (pts) were studied prospectively for apache ii score and carboxyhemnglobin (hbco) arterial level to assess if hbco level could be correlated with the severity of the pts. objective: to evaluate a new technique of non-surgical tracheotomy. patients: adults, mean age years and children, mean age months ( me.- yrs). method: through a needle inserted in the trachea, a guide wire is retmgradely pushed out of the mouth and attached to a special device formed by a flexible plastic cone with pointed metal tip joined to an armoured tracheal cannula. this device is then pulled back through the oral cavity, larynx and trachea, and outwards across the neck wall by applying traction on the wire with one hand and counterpressure on the neck wall with the fingers of the operator's other hand. when the cone and / of the eannula have emerged, the cannula is cut off from the cone, straightened perpendicular to the skin, rotated and advanced caudally to its final position. results: endoscopic control facilitates and improves the safety of all manoeuvres. the pointed cone easily pierces the tissues, and the cannula is extracted without difficulty since it has the same outer diameter as the cone. tissue adherence around the cannula is absolute thus preventing local inflammation. the time in apnea required for dilation and cannula placement does not exceed see., and it is well tolerated because within safety limits in patients hyperventilated with oxygen. only one case of bleeding occured in a patient on dialysis with severe coagulopathy. autoptic findings in subjects who died due to progression of primary disease showed a very regular stoma with an almost complete lack of hematic and flogistie infiltration in recent tracheotomies. .conclusions: translaryngeal tracheotomy (tlt), by virtue of its greater inherent safety and lower tissue trauma than percutaneous techniques, can also be carded out in infants and children, a severe test bench for any tracbeotomy technique. further specific indications are recently stemotomized patients, since tlt is associated with a low rate of infection, and short term tracheotomies after laryngeal surgery, to prevent obstructive complications. references: fantoni a., translaryngeal tracheotomy, apice, ed. gullo, trieste, , . background: inhalation of no has been shown to reverse hypoxic pulmonary vasoconstriction , to reduce pulmonary pressure in pulmonary hypertension of different origin and to improve gas exchange. in putmoflary embolism, pulmonary hypertension is caused by mechanical vascutar obstruction and by reactive vasoconstriction. the effects of inhaled no in putmonary embofism has been partiatly studied' the purpose of this study was to investigate and determine the effects of no inhalation on pulmonary hemodinamica and gas exchange in a hypoxic canine model of pulmonary embolism. methods: two groups of adult mongrel dogs were studied: group (control} dogs and group (no inhaled) dogs. both groups were anestesized with tiopental, mechanically normoventilated with an hypoxjc mixture of and n~ (f[q , ) and instrumented (swang-ganz catheter, femoral artery catheter) pulmonary embolism (pe) was induced by fisher's method s. no inhalation ( ppm) in group was started rain. pdor to pe and kept constant throughout the experiment. no inhaled concentration was analyzecf by chemiluminiscence technique. pulmonary artery pressure (pap), central venous pressure and sistemic arterial pressure were continuosly recorded. cardiac output, artedat po~ (pan ) and mixed venous po~ were measured in both groups under hypo)dr conditions, before pe and , , and rain. after pe. pulmonary vascular resistance (pvr) and gas exchange (pao fio:~ ratio), were calculate using standard formulas. data were process and analyzed with non pararnetdc test, and reported as mean -so and statistical significance was considered if p < , . : no produced an increase in arterial oxigenation (pao /fio~ ratio) and reduced pap before pe induction in group . after pe we found no significant difference with .respect to the time eour.se of pap, pvr and gas exchange between beth groups throughout the experiment. probably, the severe mechanical obstruction produced in pulmonary embolism masked the small effects of no inhaled. obiectives: blood volume measurement would be useful in critically ill patient management if it were easy to perform. this is not the ease and current methods are based on radiolabelled red cell dilution. inhalation and uptake of a known mass of carbon monoxide (co) gas and measurement of earboxyhaemoglobin increase can give results accurate enough for clinical use. this requires a rebreathing system providing oxygenation and carbon dioxide removal, yet complete retention of all carbon monoxide administer&l, and so most authors hand ventilate with a bag and waters soda-lime canister, adding oxygen as necessary. we aim to popularise this method by; i)design of an automatic co administration system driven by the itu ventilator and ii)writing of software for a portable computer to perform all necessary calculations method: we show the computer is use estimating the co dose required and later estimating the blood volume. we also show the new gas administration system. this is a fully closed circle attached to a "bag in bottle", driven by the ventilator. the novel feature is the mechanism by winch driving gas (set to % ) spills automatically into the circle, balancing o uptake by the patient, yet allowing no co loss. conclusions: this equipment is easy to use, reduces human error and allows optimum ventilator settings to remain. the operator merely administers the volume of co determined by the computer and takes blood on two occasions. carboxyhaemoglobin measurement is easy to perform, thus there is a cost saving also. with our modifications use of this technique may potentially become more widespread, the video demonstrates the method in use in our itu. - ( %) underwent conventional surgical therapeutics. " ( %) with resection of tracheal stenosis with end-to-end anastomosis(rts). i ( %) with broncoscopic dilatation. one patient died and the others still have stable patency(sp) without continued treatment. - ( , %) have received endoscopic laser ablation with or without calibration tubes. of them ( , %) are receiving continued endotracheal treatment until now. ( , %) have sp wihout continued treatment. -i ( , %) endoscopic laser therapeutic case turned to rts and is having sp. conclusion: conventional surgical aproach has been progressively replaced in our hospital by endoscopic laser ablation and silicone calibration tubes. this study suggests that these technics are effective and could be the elective treatment for iatrogenic stenosis. obiectives: hemorrhagic disorders due to thrombocytopenia and thrombocyiopathia remain one of the most serious complications during long-term extracorporeal membrane oxygenation (ecmo) in patients with severe acute respiratory distress ~drome (ards). in the presented study, nitric oxide (no), kwown as a potent endogenous platelet antiadhesive, disaggregating and antiaggregating compound, was evaluated for its possible antagonistic effect on platelet trapping when added to the gas compartment of membrane oxygenators (mo). meti~ods: two parallel separated extracorporeal circuits, consisting of heparin bonded hollow fiber oxygenators (minimax, medtronic, carmeda eioactive surface), tubing systems, low pressure reservoirs, and roller pumps were prepared. for each measurement, a pair of circuits was simultaneously filled blood from the same volunteer. low-heparinized fresh warm blood was obtained from four healthy volunteers, who had no drugs for at least two weeks. the gas inlets of both oxygenators received dry gas ( % oxxygen, % carbon dioxide, % nitrogen); gaseous no ( ppm) was added to the gas of one of the oxygenators (no-mo), whereas the other one (mo) was used as control. after minutes no gas was switched off, so that the no-mo received no more no, and no was added to the gas inlet of the membrane, which had no no before_ to assure iutracircnit volume stability, drawn blood for measurements was replaced with saline, and platelet counts were corrected for dilution by hemoglobin values. the mean of four platelet counts (coulter counter) of each timepoint (start, , , , , , , , and minutes) was used for statistical analysis (paired sample t-test). results: in the no-mo platelets remained at + , % (percentage of baseline value, mean -+ sd) until min. in contrast, platelets of the mo continuously decreased after start and were significantly lower after minutes ( , + , % vs _+ , %(p< . ); min. , -+ , %vs , _+ , %(p< . ); min. , _+ , % ( p < . ). after switching of no gas to the mo, further decrease of plateleta was stopped and platelets remained at , +_ , % until termination of circulation. platelets of the former no-mo decreased slightly after cessation of no gas to , _+ , %. conclusions: these data indicate that gaseous no significantly attenuates platelet trapping in hollow fiber oxygenators, when added to the gas compartment. this might be a new therapeutical approach for membrane oxygenator induced thrombocytopenia during long-term ecmd. objectives: nitric oxide (no) plays a pivotal role in regulation of vascular hemostasis. several studies elucidated the antiadhesive, antiaggregating, and disaggregating properties of endothelially synthesized no to platelets. additionally, agonist-induced no production in platelets by the l-arginine-no pathway was found as a negative feedback mechanism after platelet activation. although noplatelet interactions were intensively studied by several investigators, no data exist, about changes in platelet surface molecule expression in no-modulated platelets measured by flow cytometry using monoclonal antibodies (moabs). methods: p-selectin (alpha-granule-membrane protein, gmp- , cd p) and glycoproteiu (gp , lysosomal protein, cd ) are expressed only after platelet activation and degranulation. activation was quantified in thrombin ( . u/ml) and adp ( . ram) stimulated platelet rich plasma samples (prp). blood was obtained from healthy volunteers (n= ), who had no drugs for at least days. for evahiation of no-modulated activation, the spontaneously noreleasing compound sin-i ( . mm) ( -morpholino-syndonimin-hydrochlorid) was added in parallel prepared samples prior to the addition of agonist. platelet surface molecule expression was evaluated with moabs directed against cd a (gpilbliia, fibrinogen-receptor, phycoerythrin(pe)-conjugated), cd p (fitcconjugated), and cd (fitc). only cd a-positive signals were gated in sideangled light scatter, and assayed for activation marker expression (defined as percent of gated population). results: basal p-selectin expression was . + . %, and increased to . _+ . % after thrembin-activation, and to . + . % in adp-stimulated samples. addition of sin- attenuated p-selectin expression to . - - % in thrombin (p<. , two-tailed paired t-test), and . + . % (p<. ) in adpactivated platelets. basal gp expression was . _+ . % and increased to . + . % in thrombin, and to . _+ . % in adp-stimulated samples. with sin-l, gp expression decreased to _+ . % (p<. ) in thrombin, and . : . (p . ) in adp-stimulated samples. conclusions: these data implicate, that no leads to a significantly reduced activation of surface molecule expression in thrombin and adp-stimulated platelets. in addition, flow cytometry might be a useful tool for studying modulation of platelet activation by no or no-releasing compounds. introduction: acute cadmium poisoning is very rare. on initial presentation may mimic metal-fume fever, but acute inhalation cadmium toxicity may produce fatal chemical pneumonitis. case report: we present a case of acute fatal respiratory failure secondary to cadmium-fume irthalation. a year old patient was trasferred from another hospital with acute respiratory failure presumably due to pneumonia. the last days before he had had commom cold symptoms. he had been cutting with a welder during one hour without any respiratory protective measure. three hours after exposure he developed progressive dispnea and was admitted to hospital. with presumtive diagnosis of respiratory infection, antibiotics were begun, however be failed to improve. all microbiological studies were negative. chest x-ray showed bilateral diffuse infiltrates. on seventh day he needed intubation and mechanical ventilation and on th he was admitted to our icu. antibiotics were stopped and new microbiological studies were performed including brochoalveolar lavage and virologic studies. all results were negative. he developed progressive hipoxemia and hipercapmia and finally, multiorganic disfunction syndrome. he died days after exposure. the metal he had been working with was a % cadmium alleation. blood cadmilam concentration days after exposure was . mcg cd/g cr, and urine cadmium concentration was . mcg/l. on postmortem examination, tissue cadmium concentrations were: blood ng/ml, liver ng/g, kidney ng/g and lung ng/g. these values confirm that cadmium was the cause of the fatal respiratory illness in this patient. conclusion: this case evidences the considerable hazard of acute poisoning after inhalation of eadmium-fume and stresses the need of appropiated safety measures against metal-fume poisoning. aim : lactic acidosis is considered the hallmark of cyanide poisonirig. however, the relationship between plasma lactate and blood cyanide levels has not been determined. the aim of this study was to determine the significance of plasma lactate concentration (plc) during the course of cyanide poisonings. methods : the patients were included according to the clinical suspicion of pure cyanide poisoning at the time of presentation. fire victims were excluded. serial blood samples were collected before and after intravenous hydroxocobalamin (hoco). blood cyanide concentration (bcc) was measured colorimetrically. plc was measured enzymatically. results : patients were studied. on admission, plc ranged from . to mmol/l, and bcc from . to gmol/l. mean systolic blood pressure was • mm hg, mean arterial ph . • . , mean anion gap was . + . mmol/l and mean pao . • . kpa. three patients died. before antidotal treatment, there was a significant correlation between plc and arterial ph (p = . ), anion gap (p = . ) and bcc (p = . ) but not with heart rate, pao , paco and blood glucose, or blood pressure. during the whole course of the poisoning, a plc _> retool/ was a sensitive and specific indicator of a blood cyanide concentration > ~tmol/ . sustained catecholamine administration reduces the correlation coefficient. conclusion : baseline measurement of plc allows assessment of severity of acute cyanide poisoning. thereafter, plc may be used to assess the adequacy of antidotal treatment, more especially in patients not requiring sustained infusion of catecholamines. aim: the aim of this case report was [o study the correlation between the plasma lactate levels and several clinical, biological, and toxicological parameters serially measured during the course of a cyanide poisoning treated with a high dose of hydroxocobalamin. a -year-old male ingested potassium cyanide leading to cardiac arrest. cpr was performed prior to hospital arrival where the patient received g hydroxocobalamin. sbp rapidly returned to normal allowing withdrawal of epinephrine. the patient remained comatose and died from brain injury days after the ingestion. methods plasma lactate and blood cyanide levels were measured serially. blood cyanide levels were measured using a colorimetric method.~ plasma lactate levels were measured using an enzymatic method. for correlation spearman rank correlation test was used. results. initial plasma lactate and blood cyanide levels were mmol/l and gmol/l, respectively. there was no overall correlation between sbp and either blood cyanide or plasma lactate levels. similarly, there was no overall correlation between arterialvenous oxygen saturation difference with either blood cyanide or plasma lactate levels. in contrast there was a strong correlation between blood cyanide and plasma lactate levels (r= . , p< . ). the time-course of the blood cyanide concentrations was described by a mono-exponentiai decay (r = . ) with a blood half-life of . h. similarly, the time-course of plasma lactate levels was described by a mono-exponential decay (r = . ) with a blood half-life of . h. discussion. in this case of acute human poisoning, sbp was a much poorer indicator of continuing cyanide effect both before and after antidotal treatment, than was lactate production. this suggests a potential clinical role for following serial plasma lactate levels as a marker of the evolution of cyanide toxicity. aim : cyanide (cn) poisoning in fire victims is frequent and rapidly fatal. in a prospective study we tried to assess the clinical tolerance of a high dose of hydroxocobalamin (hoco) administered at the scene of the fire in fire victims suspected of cn poisoning. methods : inclusion criteria : soot in mouth or sputum ~ any degree of neurological impairment. exclusion criteria : children, pregnant women, burns of total surface body area > %, multiple trauma. protocol desigrl following examination and the collection of a blood sample in dry heparin, a g dose of hoco ( g in case of cardiovascular collapse) was administered intravenously over min. the systolic blood pressure was monitored before and after the administration of hoco, and one hour later. results : there were females and males. the mean blood cn concentration was • pmol/ . the mean blood carbon monoxide was . • . mmol/ . nineteen fire victims eventually died. among the non-cn-intoxicated patients (blood cn < ~mol/ ), there was no significant change in arterial blood pressure. in the cn-intoxicated patients (blood cn > gmol/ ) a significant increase in blood pressure was observed both immediately (p < . ) and hour later (p < . ) after the admistration of hoco. no allergic reactions were observed. conclusions : in fire victims with cyanide poisoning, the administration of a high dose of hydroxocobalamin was associated with an improvement in systolic blood pressure. hydroxocobalamin is well tolerated in fire victims without cn poisoning. objectives: tricyclic antidepressant (tca) overdose can lead to serious complications including cardiac arrhythmias [ ] . because of the known risk of early deterioration and the implication for management, emergent evaluation is essential. we determined the diagnostic usefulness of the electrocardiogram (ecg) in tca poisoning. methods: retrospective study of all patients with tca intoxication (pos. ,toxicology screening in urine and/or pos. history) in a -beduniversity hospital from through . the severity was graded with mild= no symptoms or agitation; medium= disorientation, somnolence, tachycardia, or convulsions; and sever~ coma, significant arrhythmias or death. we analysed the first ecg after admission with a special emphasis on qrs-and qtc-intervals and the terminal ms frontal plane qrs-vector (tqrs), which, was reported to lie typically between + and * + + • the best correlation with severity grade was found with qrs-and qtc-duration (p= . ), the tca-dose (p= . ) and hf (p= . ); tqrs did not correlate. patients died ( . %). conclusion: qrs-and qtc-prolongation in the admission ecg, and the reported dose of ingested drugs are useful predictors for severity of poisoning due to tricyclic antidepressants. we did not find additional benefit in determining the terminal ms frontal plane qrs-vector. objectives: since treatment of amphetamine poisoning is usually symptomatic and often associated with a fatal outcome, a search for specific drugs to help the amphetamine-intoxicated victim is sorely needed. methods: we report a case of a suicidal ingestion of large amounts of the amphetamine-derivative , -methylenedioxy-ethamphetamine (mdea) and heroin (diacetylmorphine) and present the hypothesis that the two drugs produce opposing clinical effects. results: a year old caucasian male was admitted to the emergency ward because of acute-onset confusion. at presentation, he was agitated and showed increased muscular rigidity. he had taken tablets of "eve" (mdea, approx. g) and g of "smack" (heroin) by oral route approximately h before admission. because of rapidly progressive tachypnea and exhaustion, the patient was intubated and ventilated. the serum concentration of "eve" on admission was ng/ml (lethal range - ng/ml). trace amounts of cocaine and substantial amounts of heroin ( ngtml; mean value in heroin-related deaths: ng/ml) were also found in the serum. the patient was successfully weaned from the ventilator by day and recovered without persistent neurobehavioral disturbance. despite high serum levels of both drugs, the patient did not present with the classic signs and symptoms normally seen during intoxication with these drugs. amphetamines in general, and mdea in particular, have opposite clinical effects to heroin or diacetylmorphine. none of these were however present in the case presented despite the high ingested doses and the serum levels in the lethal range. conclusions: the fascinating fact that, apart from the respiratory depression, none of the clinical signs reported after massive overdose with these two drugs were present, might be attributed to the opposite pharmacological effects of mdea and heroin. we believe that the patient unwittingly saved his own life by the oral coingestion of both mdea and heroin. our clinical data raise an interesting point about the pharmacological treatment of acute poisoning with amphetaminederivatives. introduction: the acute attack of aip still carries a significant risk of mortality of around %. a succesful outcome depends on early diagnosis, removal of pricipitating factors and provision of intensive supportive therapy. objectives: twenty one patients ( females, male) with documented aip were seen over a -year period in the university hospital. patient was in clinical remission and were with the acute attack of aip, among them with respiratory paralysis were required artificial lung ventilation and -assistant ventilation with peee pathologic treatment during the attack was normosany, adenil, androgenes, glueosa, riboxin parenteral and enteral nutrition via nasogastric tube. symtomatic treatment -pethidine, propranoton, antibiotics, bronchoscopia. methods: intermittent phasmapheresis was performed on patients. the following measurements were peformed: level of porphobilinogen (pbg) in the wire and delta-aminolevulinic acid in the blood. hematological and routine chemical evaluations, hepatic, hemodynamic and respiratory function. results: after plasmapheresis the median pbg excretion (normal range - mkg per/ kgr creatinine) fill from mkg on admission . mkg, then on - day raise to mkg and then during treatment with normosong and prasmapheresis lowest level was . mgk. fatalities occured in two females during attacks with proforma cerebral involvement and patients attained clinical remission. conclusion: after therapy with plasmapheresis normosong we found that there was consistently reduce the urinary excretion of pbg and shortening the duration of the acute attack. objectives: pigs has been reported to present with a higher pulmonary arterial pressure (ppa) and stronger pulmonary vascular reactivity than many other species, including man. aim of the present study was to compare pulmonary vascular impedance (pvz) before and after embolisation in weight-matched adult dogs and minipigs. methods: we investigated pvz spectra in anaesthetized and ventilated (fio . ) minipigs and dogs. after baseline measurements the animals were embolised with autologous blood clots to reach a ppa above mmhg. results: flow ( and ppa matched pvz data (mean-+sem) are shown in the table. [zo = hz impedance (z; {dyn.sec_em- }); zl = first harmonic z; zc = characteristic z; z phase = first harmonic phase a@e {radians}; fmin = frequency of pvz the first m{n~mam; *, f p at least < . between dog and minipig, and before v~. after embolisation respectively]. before case report: a -yr-o]d woman affected by legs recurrent thmmbophlebitis, was admired in medmine department for tach.~pnea, chest pain, tachycardia and cyanosis. before starting two-dimensional transesophageal echocardiography (tee) to confirm the suspicion of pulmonary embolism, she suddenly had ventricular fibrillation. resuscitation and defibrillation were readily performed. when sinus rhythm was reinstituted she was in superficial coma with preserved corneal and light reflexes: right hemiplegia, poor perfusion and h~posphygrma of the left arm. tee showed dilation of rigth ventricle (rv), incomplete occlusion of pulmonary arter~ (pal at it~ hifurcation, severe tigth-to-left shunt through a patent foramen ovate, paradoxical embolism with incomplete occlusion of left subclavian artery mechanically ventilated with vt= ml, rr= /mm, fio =l, the patient had ph= . , pao = mmhg and paco = . systemic bp was / mmhg and hr= b/min with low dose epinephrine ( . g/kg/min) a thrombolytic infusion (rtpa: mg/ h) through a peripheral vein was started tee imaging and clinical status hours later were unmodified. a new rtpa infusion was performed through the pulmonary hole of a swan-ganz catheter with the tip close to the embolus. one hour later pa pressure decreased from / mmhg to / mmhg, etco increased from to mmhg and sao improved from % to % three days later the parietal, spontaneously breathing and with normalized tee scans of rv and pa, was transferred to rehabilitation service to perform physical therapy. conclusions: massive pulmonary embolism in a patient with patent foremen ovale, paradoxical embolism and refractory hypoxaemia was unaffected by systemic rtpa infusion, while intrapulmonary rtpa administration dramatically improved gas-exchange, hemodinamics and the general conditions of the patient. the presence of a large rigth-to-left _atrial shunt and the rapid rtpa metabolism could likely explain the effectiveness of its intrapulmonary administration in front of failure of systemic thrombolysis. introduction. cardiogenic shock during massive pulmonary embolism (blpe) is due to an acute increase of right ventricle (rv) afterload and possibly rv ischemia causing a failure of rv pump function. the rec~;mmended therapeutic strategies are: xoiume augmentation ~n ~rder m }ncrease rv pre-h~ad, adrenergic drugs to increase t'ontractillly and maybe coronary perfusion, fibrinolytic drugs to delermine clot lysis. there have been several reports of noradrenaline (na) as a useful drug in this setting for its sluing ~z, but also ~, properties. case report.an obese },ears old woman was transferred to our icu for tetanus. she was given the usual antibiotic and immunoglobuline therapy. l'wo thoracic epidural catheters were put in place at different levels and replenished with marcaine qid. a continous infusion of sedation (diazepam § was started together with mechanical ventilation. curarization ~,as given occasionally. fraxiparine . /die was used for prophylaxis of thrombotic disease, on day th at . a.m. she started to be hypoxic (sa %), tach ,tardic l l(i b/rain.), her blood pressure(rp) dropped frum norma~ values to r mm/hg, the central venous pressure (cvp) raised [rom lb to mm/hg and the end tidal co was mm/hg lower than one hour before. the physical examination of the chest revealed a clear bilateral ventilation and the chest x-ray was normal apart from an elevation of the :tiaphragm as compared to the previous. an e.c.g. showed sinus tachycardia, right bundle branch block and a possible inferior necrosis (which was already present on admission). a trans-thoracic echozardiography was performed which showed "an acute overload of the right centricle wilh remarkable dilatation. tricuspidal regurgitation ++. paradoxical movement of septum. small left ventricle with normal wall kinetics". the cardiac enzymes were later shown to be normal. an acute massive pulmonary embolization was assumed m be present.. a bolus of streptokinase x i(i u. was given fonowed by a continous infusion . two liters of colloids were also given in a sh~rt time, two hours later the patient was still deeply hypotensive, hypoxemic and anurir(bp / mm/hg, cvs mm/hg, spo %) despite a cominnus infusion of dobutamine fag/kg/min and adrenaline . ~tg/kg/min. at this stage a bolus of aoradrenaline ,g was given followed by a cnntinous infusion of . !*g/kg/min. an immediate improvement of the hemodynamics was noticed and one hour later the bp was / mmhg, the cvp mm/hg, the sao % and a brisk diuresis started. the hemodynamics kept stable and weaning from vasoactive drugs was achieved within two days. one month iater the patient was discharged home in good conditions.. con c i u sio n.ne administration may help to restore rv coronary flow and ;~ump function during mpe. aeute putmonary t~omboembo~sm [ffe) cou be mamfeslated with either respiratory or cardiovascular syndromes or both. the arm of the study was to establish leading respn'atory symptoms, frequency and form of the roendganographic (rig) changes as well as blood gas disturbance degree in acute pte with dommam respiratory disease appearance. the study includes retrospeotive analysis of i pte patients (pts), males (average age , yrs) and .q females (average age , yrs). they were admitted at university, olinie" with suspection ofpleuropnlmonary disease, including pte. final diagnosis of pte was based o~ evident risk factors in , % of the eases (deep venous thrombosis, surgery, trauma, imobilisation, malignancy ere), acceptable clinical, rtg, sdntigraphic and laboratory findings, as well as deep veins examination by dopple~-sonographie and radioisotopic -~enogmphy. respiratory symptoms appeared in all cases: sudden pleural pain ( %), dyspnea ( %), hemoptysis ( %), cough ( %) with association of two or more symptoms in %. chest xrays findings were abnormal in % with diaphragmal elevation ( , ~ lung opaeilies ( , %), atelectasis ( , %), plemal effusion ( , %), main pulmonary brancah asimetry ( , ~ oligemia ( %), heart shadow changes ( , %) and pulmonary arteries "cut off' ( , %). the association of two or more abnormalities was found in , % while normal chest x-rot was found in ~ of the cases. hypoxemia with pao < , kpa was found in , % followed with hypocapnia and respiratory alealosis in , % in , % of the gas exchage analysis were within normal limits. among cardiovascular symptoms short syn~cpa appeared in i , %, ecg changes-st q t type in "~ , %. results show high frequency of positive ~g findings in pte pts that is opposite to oppinion that chest x-ray in acute fie is the most ofran normal. leading symptoms are pleural pain and dyspnea, while hemoptysis were found in a half of the study group. blood gas changes were present in two thirds of the cases. kakkar, in his classic work ,clearly demonstrated the efficiency of low doses of heparin in prevention of deep vein thrombosis (lancet : , ) .after this first study the application of heparin prophylaxis became more and more diffused until to be considered a routine in many surgical departement.actually application of blood saving technique induces postoperative hemodilution effect. in that condition prophylaxis routinely applied seems a nonsense and can be at risk for postoperative hemorrhage. methods: to analize this problem we compared patients arrived in our intensive care unit (i.c.u.) in. : (group a) with arrived in : (group b) .every patient was operated for major abdominal surgery.in each one we considered the hemoglobin (hb) value,hematocrit(hct), and coagulation pattern (c.p.) at the arrive in i.c.u. and hours later. the patients was also divided in those receiving heparin prophylaxis (i) from not treated patients (ii) results:the application of blood saving technique clearly appears from the hb and hct level wich have a mean value of , +/- , (hb) and +/- (hct) in group a while in group b mean value are , -/- , (hb) and +/- (hct).patients of group a (ii) are the only one where a pathologycal c.p. with statistical significance has been demonstrated.in this goup we got four cases of evidence of venous thrombosis and one of pulmonary embolism.in patients of group b(i) we encontered the incidence of two cases of severe hemorrhage despite the absence of statistical significance in c.p.modifications. oxygen desaturation during broncho-alveolar lavage: role of oxygen saturation monitoring in prevention of acute respiratory insufficiency g. galluccio, b. valeri, s.batzella, m. di lazzaro*, servizio di endoscopia toracica, ospedale forlanini, rome, italy * servizio die anestesia a rianimazione, osp. forlanini the broncho-alveolar iavage is a diagnostic procedure employed in interstitial diseases of the lung. it requests the introduction through the working channel of a fiberoptic bronchoscope, after occlusion of a segmentary bronchus, of aliquots of saline solution at c, subsequently gently reaspired, in order to remove cells and proteins from elf (endoalveolar lining fluid), which is related to interstitial medium. bronchoalveolar lavage induces deep effects on pulmonary function: -lowering of the alveolar surface of exchange; -shunt effect, depending on the perfusion of non-ventilated districts; -increased pulmonary arterial pressure, due to hypoxic vasoconstriction; -decrease of lung compliance. in this report the authors present the result of oxygen saturation monitoring in a group of patients with interstitial lung disease, who underwent diagnostic broncho-alveolar lavage. in most patients with severe interstitial involvement, the lavage performed without supplement of oxygen induced a severe fall in the oxygen saturation during the late phase of the procedure. if supplementary oxygen was delivered during bronchoscopy, since its beginning, only slight modifications of the curve were detected. in patients without thickening of interstitium, in whom the lavage was performed in order to obtain material for bacterial or cytologic examination, no modification of oxygen saturation was observed in standard procedure. as conclusion the authors strongly reccomend monitoring oxygen saturation in patients with radiologic evidence of interstitial involvement also in patients with no evidence of dyspnoea. g. galluccio, b.valeri, s.batzella, m. di lazzaro*, servizio di endoscopia toracica, ospedale forlanini, rome, italy * servizio die anestesia a rianimazione, osp. forlanini the treatment of choice in patients with alveolar proteinosis consists of pulmonary lavage. this procedure requests the introduction, through the working channel of a fiberoptic bronchoscope, segment by segment, of aliquots of saline solution at c, subsequently gently reaspired, in order to remove the proteins deposited in the alveolar spaces. the method is very similar to that used in bronchoalveolar iavage, a diagnostic procedure used to obtain cells and substances from elf (endoalveolar lining fluid), which is related to interstitial medium. as known, bronchoalveolar lavage induces oxygen desaturation, because of shunt effect. understandably, one lung lavage has remarkably more deep effects on pulmonary function than bronchoalveolar lavage, for the amount of fluid introduced, the length of the procedure and the conditions of controlaterai lung. in this report the authors present the result of oxygen saturation monitoring in a patient who underwent pulmonary lavage for alveolar proteinosis. in the lavage performed without supplement of oxygen a severe fall in the oxygen saturation was observed during the late phase of the procedure. if supplementary oxygen was delivered during bronchoscopy, since its beginning, only slight modifications of the curve were detected. as conclusion the authors strongly reccomend the subministration of supplementary oxygen in pulmonary lavages, also in patients with excellent respiratory conditions. a. b. dublisky prof., m. r. isaakjan ass., v. a. zasukha, s. m. vinichuk prof., v. p. tserty ass. prof., chair of anaesthesiology, resuccitation and medicine of catastrophes, neurology of ukrainian state medical university, kiev, ukraine. objectives: detection of plasmophoresis's influence of results in treatment of ishemic insult. methods: we ve investigate patients with ishemic insult, treated with reverse plasmopheresis in complex treatment. after primary infusive therapy we took ml of patients' blood and separated it within min with rotation frequensy of /rain. after separation of erythrocytes from plasma, the latter has been returned to patients. we made - procedures during - days. hemoglobin, hematokrit, time of blood coagulation were determinated. the brain blood flow in internal carotid arteries, regional volum brain blood flow and total brain biood flow were evaluated with tetrapotar chest rheography and tetrapolar rheoencephalography. obtained date were comparised with control group after traditional treatment. results: it was found that after reverse plasmopheresis the hemoglobin and hematokrit levels decreased significantly in studied patients' plasma (from + . g/l to _+ . g/ and from + . % to _+ . % respectively). the time of blood coagulation by lee-white has increased by - . times (up to - rain). the level of brain blood flow has been increased significantly after reverse plasmopheresis in comparison with control group. the following tests of brain blood flow have been increased: a) the total volume brain blood flow from . + . ml/min to . _+ . ml/min (p < . ); b) the regional brain blood flow from . _+ . ml/min to . + . ml/min (p < . ); c) the brain blood flow in internal carotid arteries from . _+ . ml/min to . + . ml/min (p < . ). conclusions: the use of reverse plasmopheresis in complex treatment of patients with ishemic insult aiiows to improve rheological blood patterns, helps to increase volume brain blood flow. it results in quicer reparation of neurological functions. objectives: a prospective evaluation of the efficacy of continuous infusion of verapamil in reducing the incidence of postoperative atrial fibrillation after pulmonary surgery. methods: a total of consecutive patients, on verapamil, on placebo was included after lobectomy or pneumouectomy. a loading bolus of verapamil ( mg over minutes) was followed by a rapid loading infusion ( . mg/min) for minutes and finally a maintenance infusion ( . rag/rain) for hours. results: a mean plasma level of verapamil of ng/ml was obtained only after more than hours. atrial fibrillation occurred in five out of patients who tolerated the verapamil infusion, and in out of patients on placebo (p = . ). verapamil infusion was not tolerated in patients because of hypotension or a heart rate of less than /min, within hours of the start of the therapy. when atrial fibrillation occurred, the ventricular response, mean _+ sd, was not significantly slower during verapamil infusion ( + ) compared to placebo ( + ). conclusions: because of its frequent side effects and the only modest efficacy verapamil should not be considered for prophylactic therapy of atrial fibrillation after pulmonary surgery, and is probably not a good first choice for slowing the heart rate in case of rapid ventricular response once atrial fibrillation has occurred in these patients. results: study of haemostasis in these patients has showed deep disturbances of blood coagulation. fibrogen level has reduced to . + . g/l, fibrinogen and/or fibrine degradation products concentration have enhanced to . _+ . g/l, monofibrin soluble complex concentration to . -+ . g/l, blood plasmin level was enhanced to . + . mmol/ , plasminogen proactivator level was also enhanced to . + . ram, plateletes aggregation has decreased to %. after plasmopheresis aggregation was decreased in . times. it has been connected with decrease of fibrin and/or fibrinogen degradation products level and level plasmin in . times, and plasminogtnt activator level in . times. at the same time we have observed increase in total antifibrinalitic activity of blood in . times. activity of activators plasmine and plasminogene proactivators has decreased in . times and in the same time activity of activation inhibitors and antiplasmines has increased in times. conclusions: plasmapheresis leads to considerable improvement of a general condition and reduction of the haemorrhagic syndrom's sings (controlling of gastrointestinal haemorrage, reduction of intensity of subcutaneons haematoma). evaluation of continuous cardiac output (cc ) monitoring based on thermodilution technique in critically ill patients. methods: cardiac output (co) was monitored continuously using a modified pulmonary artery (pa) catheter, on which a heating filament is located and by which energy is transmitted to the circulating blood. a microprocessor calculated co by a new algorithm. standard bolus thermodilution technique ( ml of ice-cold saline solution) was used to compare cc with intermittent bolus cardiac output (ic ) measurements. the following subgroups were prospectively studied: i. heart rate (hr) > beats/min, . cardiac output > i/min . cardiac output < . i/min, . rectal temperature > . ~ and . pa catheter was inserted for more than days. results: a total of pairs of ic and cc measurements were obtained from the patients. bias (ico measurement minus cc measurement) of all measurements were . • i/min and the % confidence limits (mean difference• were - . / . i/min. also in the subgroups, cc measurement agreed closely with ico measurement (c > i/min: bias= . • i/min; co < . i/min: bias=- . • i/mln). elevated temperature and prolonged lay-days of the pa catheter did influence agreement of cc measurement with ic measurement neither (> ~ bias= . • i/min). conclusions: monitoring of cc using a modified pulmonary artery catheter with a heated filament has proven to be accurate and precise also in the critically ill when compared with "standard" intermittent bolus thermodilution technique. this method enhances our armamentarium for more intensive monitoring of these patients under various circumstances. background: the number of patients who need coronary artery surgery was) grows every year. most of these surgical operations are with extrar eircuiation (ecc). since january , this surgery is made without ecc in selected patients in our hospital. this technique is exceptional in spain. this type of surgery has proved useful in patients requiring revascularization of the left anterior descending, eireunflex or right coronary artery (not for grafting the pos~tefio~r descending branch}. blethods and results: since , patients aged to years (mean years) underwent cas without ecc. the mortality in programmed surgery was %. no patient was reexplored for hemorrhage. the mean values of some clinics parameters v~ere: a) blood requeriments: units per patient, b) need of mechanical ~entilation: i , hours, c) postoperative bleeding: cc, d) days at icui , . we used the student % t test or fisber~s exact test to compare these results with the mean values of surgery with ecc: a) blood requeriments per patient (p< , ), b) need of mechanical ventilation: hours (p< , ), c) postoperative bleeding: cc (p< , ), d) days at icu: (p< , ), e) programmed surgery mortality: % (p< , ). conclusion: our limited experience shows that this surgery is an alternative in the treatment of coronary disease, especially for aged patients with associated pathology and in jehova's witness. the need of mechanical ventilation, days at icu, blood requeriments and morbi-mortality were fewer than surgery with ecc. to study the hemodynamic and antiarrhythmic influence of ace-inhibitor enalapril in acute myocardial infarction (mi). methods: holter ecg monitoring, heart rate variability analysis, echocardiography ( and l days after beginning of the treatment), stress-echocardiography and stress ecg ( - -th day after the onset of mi). enalapril was included into the treatment of pts with mi (study group), with normal or increased blood pressure, from the -st day of the disease. the data were compared with pts treated without enalapril (control group). results: silent ischemia during stress-test was registered in pts of the study group and of control group, the arrhythmia episodes during stress test -in and pts and episodes of silent nocturnal isehemia -in and pts correspondingly. enalapril importantly attenuated the hypertensi~re re~aetioh % stress test. in pts of the study group the number of perifocal hypokinesis zones decreased; in the control group it didn't change. the quantity of ventricular extrasystoles in the patients of the study group decreased by %; the heart rate variability indices improved as well; in the control group the character of ventrieulir arrhythmias, heart rate and its va]~i~bili%y didn't change significantly. conclusions: the inclusion of enalapril into the treatment of mi is a useful t ol to improve hemodynamie parameters and decrease the incidence of ventricular arrhythmias. objectives: to study left ventricular (lv) systolic function in the patients with acute myocardial infarction (ami) before and after peroral captopril test. methods: the original echocardiographic parameter of lv contractility, "coefficient of effective systolic function" (cesf), was proposed in the study. cesf is calculated from lv stroke volume (sv), obtained from doppler aortic flow in lv outflow tract and lv end-diastolic diameter (edd): cesf =sv/edd. the study included patients with ami, who had local lv dyskinesia and global lv systolic dysfunction (ef< %). besides cesf, the ejection fraction was calculated before and after administration of mg eaptopril (on the fifth day of ami) by methods of bullet and simpson. results: the dynamics of these parameters, as well as heart rate (hr) and mean blood pressure (bp), is shown in the tabte. before cal~topril ef (bullet) . • . ef (simpson) . introduction: the cold system is a monitoring system for measurement of right (copa) and left (coart) ventricular cardiac output, cardiac function index (cfi), fight ventricular ejection fraction crvef), fight ventricular cnddiastolic volume (rvedv), intrathoracic blood volume (!tbv), global enddiastolic volume (gedv), lung water (etv) and excretory liver function (pdr). patients and methods: pts have been monitored by the cold system. above mentioned parameters are measured by thermal dye dilution and a fiheroptic femoral artery catheter. copa, rvef and rvedv measurements additionally were compared to measurements by the baxter explorer. :::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::: ;;;k;;;;i cov (%) explorer ! ! [ gedv, itbv and pdr showed a significant decrease dufing the first - h after the operation, cfi and rvef si~canfly improved after k wheras etv showed a i~ in the early postoperative phase and fell to normal ranges at h. comparison of cold/explorer m~ements sb wed good correlations. discussion: concerning m ~toring of ri,ght ventric~ar function cold and explorer can he seen as equal. rvef gives an ar report about the performance of the right ventricle without use o f echocardiography. measuring itbv and gedv ~ improve ~gement and con~ol of th.e volume status, monitoring etv helps preventing lung edema. pdr shows good corre|ati n to liver blood chemistry and is bedside avai|ab|e. thus the cold system offers additional parameters for comprehensive m~nitofing of pts. ~e~ ~c surgery. obiectives: to evaluate the influence of an a!'~ered cardiac function on the cardiovascular response to the increase in oxygen demand induced by an increase in core temperature. methods: this preliminary study included adult critica!ly ill patients monitored by arterial and pulmonary artery catheters in whom thermodilution cardiac index {ci) and arteria! and mixed-vef)ous blood gases measurements could be obtained before and after an acute change in core temperature of at least . ~ (max rain apartl the patients were separated in two groups according to their cardiac function: patients had an impaired cardiac function as defined by a history of cardiac disease and an ejection fraction below % and patients had normal cardiac function. results: individual data are shown in the figure. in contrast to the control group (continuous line) in which c! increased without changes in oxygen extraction ( er), the q er in patients with impaired cardiac function (dottled line) increased without changes in ci. conclusions: the increase in oxygen demand associated with changes in temperature is met by an increase in c! in patients with unaltered cardiac function and in an increase in o er in patients with altered cardiac function. temperature should be taken into account in the assessment of the adequacy of cardiac output in patients with impaired cardiac function. objectives: to define the hemedynamic and metabolic response to physical therapy(pt) in relation to the type/level of sedation and the cardiac status in icu patients. methods: we studied mechanically ventilated icu patients ( • years) in stable hemodynamic status (no change in vasoactive treatment for at least hours), separated in groups: group = deep sedation, cardiac dysfunction required dobutamine (n= )r group = deep sedation (barbiturates), unaltered cardiac function (h=lo), group = moderate sedation, altered cardiac function (h= ) and group = moderate sedation, unaltered cardiac function (n= ). complete hemodynamic data, arterial and mixed venous blood gases, respiratory gas analysis (metabolic cart ccm, medgraphics) were obtained at baseline ( x) and twice (q. min) during leg mobilization. data were analyzed by anova. calcium channel blockers were used in complex preoperative preparation of hypertensive surgical patients. patients were allotted to groups based on their hemodynamic profile: hypokinetic: ejection fraction (ef)< . , patients; eukinetic (ef> . ),i patients and hyperkinetic (ef> . ),i patients. the most noticable change in hemodynamics was in the hypokinetic group: ef and cardiac output (co) were significantly decreased (p< . ) while systolic arterial pressure (sap) (p< . ) and peripheral resistance (pr) (p< . ) were elevated. the results showed that in hypokinetic patients on nifedipine ef (p< . t) stroke volume (sv) (p< . l) and co (p< . ) were increased while pr(p< . t), sap(p< . ) and diastolic arterial pressure(p< . ) were decreased. eukinetic type patients also showed an increase in ef,albiet to a lesser extent,than in the hypokinetic group. increased sv and co(p< . ) were observed in eukinetic patients though this was to a lesser extent than in the hyperkinetic group. in the hyperkinetic group of patients nifedipine had no effect on the aforementioned parameters except for a decrease in sap(p< . i). nifedipine increased ef in all hypokinetic patients. comparative results show that isoptin was less effective than nifedipine in decreasing peripl~eral vascular resistance and had a depressive effect on the myocardium. it can be concluded that the action of calcium channel blockers normalizing the circulation in the hypertensive surgical patient depends on: the condition of myocardium, the patients hemodynamic profile and their pharmacological properties. they were most effective in the hypokinetic group. zalo/nthinos e., daniil z. zakynthinos s., armaganidis a., kotanidou a., nikolaou ch..,roussos ch. critical care department, university of.athens, evangelismos hospital, athens, greece. introduction : surgical is the optimal treatrnent for ioculated effusions and the preferable procedure when multiple bands are seen in the pericardial sac by echo. patients : palients, post cardiac surgery, uremic ( men, women) with large pericardial effusion and clinical or echocardiographic findings of tamponade or both. these particular patients displayed numerous linear echo-dense bands and s~'ands crossing the pericardial space (in one of them a ioculated effusion compressed the left ventricule). one had aptt increased, four were mechanically ventilated. technklue : a fr polyurethane catheter with end and multiple side holes over ga needle was echo-guided to the ideal site (fluid abundant and closest to the transducer). the catheter was attached to a close system with a heimlich valve for continuous drainage (pneumothorax kit). subcostal entry was selected in one patient and chest wall in five. the patient's position was changed every hour at least. (we believe that the small changes in the position of the catheter and the mechanical breaking of the bands in relation with the movement of the heart assist the pericardial fluid to remove). results : in all cases only a small quantity of fluid was withdrawn in the first minutes( - ml) with some clinical and echo-findings improvement. the fluid was bloody or serosanuginous with high protein content (ht= % ,protein , gr/dl) in all cases. in first hours the mean volume of fluid removed was ml ( to ml). in that period echo showed no residual fluid. the catheter remained within the pericardium to days .. no complications are mentioned. conclusion : cardiac tamponade due to hemorrhagic high protein pericardial effusion in uremic and postcardiac surgery patients,, as it is revealed by echo dense bands, can be faced by -d echo guided perieardiocentesis. a -fr polyurethane catheter with multiple side holes, attached to a heimlich valve was effective to evacuate the pericardial fluid. no catheter was occluded though heparin infusions were not used. multiple changes of the patient's position may be fundamental. this -d echo guided pericardiocentesis performed in in~nsive care unit seems to be useful , safe and quick technique. determining the best inotropic drug represents a very serious problems. the use of more selective and potential inotropic and vasodilatative drugs does not always lead to improvement of hemodynamic parameters in patients with low cardiac output syndrome. this paper presents patients with acbp who need an inotropie support after extracorporeal circulation in first hours. the patients were divided into dobutamin et dopamine groups. the heart rate (hr). mean sistemic arterial pressure [map), central venous pressure (cvp). and termodilution cardiac index (ci) were measured. the measurements were without using inotropic drugs, and then using them after rain, min, and finally with one hour rate, within first hours. the statistical analysis shows that both drugs lead to an increase in hr in the first hour of the application. the final effect of dobutamine is no change in hr, whereas the effect of dopanime is very significant increase in hr. thus. an absence of taehyeardie response selects the dobutamine as a better choice. backeround: pulmonary vascular eadothelium possesses major metabolic functions, which when altered contribute to the development of serious pathologies such as ards. one such function is the conversion of angiotensin i to angiotensin ii, catalyzed by angiotensin converting enzyme (ace), located on the luminal surface of the endothelial cells. ace activity has been extensively studied in animals in vivo, by means of indicator-dilution techniques, providing: i) under toxic conditions, an early index of lung injury, and it) under normal conditions, estimations of dynamically perfused capillary surface area (pcsa). objectives: to validate the use of these techniques in matt: i) for pulmonary endothelial function assessment, and it) for pcsa estimation. methods: ace activity was estimated in ten adult haman volunteers, with no pulmonary medical history and normal pulmonary artery pressures, undergoing cardiac catheterization for coronary artery disease assessment. single-pass traspulmonary hydrolysis of the specific ace substrate hbenzoyl-phe-ala-pro (bpap; p.ci) was measured by means of indicatordilution techniques, and expressed as %metabolism (%m) and v=-hi( -m). bpap was injected as a bolus i) into a main pulmonary artery, and it) inside the right atrium, to assess ace activity in one and both lungs. we also calculated a,~,/i~, an index of pcsa. pulmonary plasma flow (fv) was determined by thermodilution. fp in one lung was estimated as . xf v. results: similar values of %m ( . + . vs . • and v ( . • vs . • were observed in both and one lung respectively. a~k~ decreased from • ml/min (both ltmgs) to :~ (one lung). conclusions: i) pulmonary endothelial ace activity and thus pulmonary endothelial function may be assessed in humans by means of indicator-dilution techniques, it) our data denote homogeneous pulmonary capillary ace coneentratious and capillary transit times in both haman lungs, iii) the % reduction of a=~/k~ in one lung suggests that this procedure can be used to quantify pcsa in man. (supported by the fonds de la recherche en saute du quebec and the national health system of greece). objective: verify whether antioxidant activity is higher in reperfused than in no-reflow myocardium after i.v. thrombolysis for acute myocardial infarction (ami). methods: patients with ami were included. blood for estimation of catalase (cat), glutathione peroxidase (gpx) and mn-superoxide dismutase (sod) was drawn before initiation of i. the mechanism of myocardial cell defence against free radicals is probably identical in both reperfusion and no-reflow phenomena. therefore, antioxidants cannot be used as reperfusion markers. objectives_ to evaluate the precipitating factors of hypothermic phrenic nerve injury following cabg with lima. methods: fifty two consecutive patients ( females), with a mean age of + (mean +sd) years were studied. during the ischemic arrest time topical hypothermia was obtained in al~ patients wffh ice slush and no cardiac insulation pad was used. all patients received a lima graft, with or whithout additional vein grafts. supramaximai, bilateral phrenic nerve stimulation was performed percutaneously preoperatively and whithin hours postoperatively. square wave stimuli of . msec duration were applied at the posterior border of the sternomastoid muscle. the compound muscle action potential of the diaphragm was recorded, using surface electrodes on the anterior chest wall. the time interval from the application of stimulus to the onset of diaphragmatic activity, phrenic nerve conduction time (pnct), was measured. values exceeding . msec were considered as abnormal. besults: preoperatively, all patients had normal (mean+sd) pnct, . • msec for the left nerve and . • mseo for the right nerve. on the first postoperative day, right pnct was normal in atl patients ( . • msec) , whereas left pnct was normal in patients ( . • msec) and abnormal in patients (incidence . %). in patients the left phrenic nerve was inexcitable and in patient left pnct was prolonged ( . msec). comparing patients with normal and abnormal pnct there was no difference in age, gender, number of grafts used, aortic cross-clamp and bypass time. however, patients with abnormal pnct had a lower preoperative ejection fraction ( • vs • p= . ). moreover, in all of them lima was dissected from its origin ligating all upper arterial branches, which provide the blood supply to the left phrenic nerve, whereas in those with normal pnct the small vessels originating from the upper to cm of lima were preserved (p= . ). conclusiojel~ a hypoperfused left phrenic nerve seems to be more susceptible to hypothermic injury during cabg with a lima conduit. objectives: to test if necessary interventions on systemic vascular resistance (svr) along with preset pump flew (q) during cpb could adversely affect autoregulatory response and cause vo shifts. methods: we studied males ( - yrs) who underwent cpb for cardiac surgery. at o oesophageal temperature - c we set pump flow at . i.m~ .min - . when map was higher than mmhg we calculated vo by using fick equation. then we infused sodium nitropruaside (sn) to control map at - mmhg for min and we calculated vq . without changing the sn infusion rate we set q at . i.m' .min " . ten min later we measured vo . we took vo changes into consideration if greater than %. statistical analysis using students-t-test for paired data and analysis of variance was used as appropriate. results: depending on the biphasic vo response to sn infusion during low and high q we classified pts in four groups (table). i. vo increases with sn and increases further during high q unmasking hypoperfusion and supply dependency. ii. vo increases with sn but the addition of high q results in systemic shunt. iii. vo increase during high q proves that vasodilatation can turn flow insufficient. iv. vo does not change with any intervention. the small number of pts and the wide standard deviation did not allow any statistical significance. conclusions: cpb is an interesting model for the behavior of microcirculation. intervention on svr and q can improve or impair effective regional oxygen delivery, resulting in either better perfusion or systemic shunt. vo monitoring seems necessary during cpb. preoperative cardiovascular optimization (opt) to ci > . l/min/m , _< paop < mm hg,and svri __< mmhg/ll/min/m decreases cardiac events (events) and mortality (mort) in peripheral vascular surgery patients (pvs). objectives: to determine if opt to the same endpeints decreases events in patients undergoing abdominal aortic aneurysm repair (aaar) and to study the r predictive value in pvs patients. methods: aaar patients and pvs patients were admitted to the s cu monitored with e pa and arterial catheters and treated to achieve opt. patients underwent surgery independent of success of opt data included demograph cs, incremental risk factors, laboratory and hemodynamic data pre, intra, a~nd postoperatively events, and mort. events included arrhythmias requiring treatment or prolonging the sicu stay > hours, a st depression > !mm or t wave inversion, an acute mr defined by a new q wave > . sec or cpk-mb > %. results are presented as means _ -. sd. opt was achieved in of ( %) and in of ( %) in the pvs and aaar group, respectively. events did nat differ between groups of ( , %) and of ( , %) in the pvs and aaar group, respectively (p>o. ). mort was of ( %) and of ( . %) in the pvs and aaar group, respectively (p > . ), while there was no difference in endpoints of opt between patients with and with.out events in the aaar group, there was a significant difference in ci between patients with and without events in the pvs group. of note, of ( %) patients who developed events in the pvs group had a ci < . in contrast to of ( %)in the aaar group. the positive and negative predictive value were % and % in the pvs and % and % in the aaar group. conciusione: f. the endpoints of opt used for pvs patients cannot be ~sed to reduce events in aaar patients; . pvs patients who have net achieved opt are at extraordinary risk of perioperative events; . preoperative card ovascu ar opt in aaar patients makes no difference in cardiac related events, background : comparison of the right and left filling pressures (cvp/pcwp ratio) is considered as a useful diagnostic clue : the normal ratio is _< . ; ratio >_ . may suggest right ventricul~ infarction while equalization of the cvp and pewp is a classic sign of tamponade ( ). however after cardiac surgery, many conditions (diastolic dysfunction, pulmonary hypertension, positive pressure ventilation) are susceptible to modify the '*normal" cvp/pcwp ratio. material and method : we determined cvp/pewp ratio in consecutive patients (pts) after uncomplicated cardiac surgery ( coronary artery bypass grafts; valvular replacements) measurements were made before and after tracheal axtubation. results :cardiac index : . _+ . /minlm~; laotate: + rag/i; cvp range : - rnmhg; pewp range : - mmhg. mean cvp/pcwp ratio before extubation is . ( % confidence imerval : . - . ) and after extubation, . ( % confidence interval : . -. . ), (ns, paired t-test). in % of the pts, cvp was higher than pewp. there are no correlation between the cvp/pcwp ratio and c! before (r = - . ) and after extubation (r = - . ) nor between the cvp/pcwp ratio and mean pulmonary arterial pressure (mpap), before (r = . ) and after extubation (r = - . ), discussion : cardiac performance is adequate according to ci and lactate. however the cvp/pcwp ratio is markedly higher than the "normal" (_< . ) ratio. this difference is not related to mechanical ventilation because the ratio is similar before and after extubation, nor to pulmonary hypetaension because of absence of any correlation with mpap, post-cpb diastolic dysfunction of the right ventricle could be an alternative explanation. in this group of pts, increased cvp/pewp is not associated with any impairment of cardiac performance (absence of correlation with ci), conclusions : cvp/pcwp ratio as high as within a large range of cvp ( - mmhg) and pcwp ( - mmhg) may still be considered as normal after cardiac surgery. this emphasizes the limitations of the hemodynamic monitoring after cardiac surgery (in comparison with echographic technics). careful analysis of the morphology of the cvp and right ventricular pressure curves (x descent, y descent, dip-plateau) is mandatory rather than relying on the quantitative assessment alone. reference : ( ) ntensive care.-university hospital -m~laga (spaink introduction. fibrinolitic treatment (ft) permits the treatment of acute myocardial infarction (ami) addressing the etiology, thereby eading to mproved ventncular function and a marked reduction m mortality. the main clinical oroblem is the reduced time of application. delay in hospitalization, which can be from to minutes, is potentially the most avoidable delay. method. to reduce delays in hospitalization, the following was carried out in two chases. audit: analysis of the time lapse from onset of symptoms to start of ft. showed that during "(he period june to december , patients with chest paros were treated within a eriod varying from minutes to hours from onset of symtoms. ages ranged from to (average , ), oelng males and females. they were glved initial ecgs to determine st mcreases suggesting ami. median t~me for this orocedure was l m.. potentia ami patients were then admitted to the coronary unit, [)atients, under age with no contraindications received ft the median time apse from admission to corona-y care and administration of ft was minutes ( . ), -he total median delay was minutes ~ -i h. min,~ delays n start of this procedure are grouped as follows: extra-hosdita delays (from onset of symtoms to arrival at hospital) diagnostic delays (from hospital arrival to ecg). treatment delays (from diagnosis to ft). objectives: protocol of procedure to implement a fast-track method. a protoco was drawn up with the object of reducing diagnostic delays to -i minutes and treatment delays to less than i minutes results. following rmplementatlon of this protocol in january , fts were glven, with an over all average delay of minutes. this fast-track method did not reveal any inappropnate ft or any increase m complications, conclusions: detailed study of the various times taken for diagnosis ane treatment of ami patients, showed up weaknesses in the system and improvements througn the protocol based on performence orocedures which led to a % reduction in the start of ft background: the importance of the early use of thrombo!ytic agents in acute myocardial infarction (ami) is based in the better remaining ventrictjlar function and smaller mortality rate because of the greater reperfusion and sma!ler infarction size, therefore, it is very impodant to apply this treatment to the maximum number of patients without thrombolytic contraindicati n, and within the minimun period of time. the "thrombolytic fast track" implementation allows to optimize the time to administrate thrombelytic agents avoiding multiple delays~ methodology: we anal!ze the application of thromboly c agents to patients with suspect of ami from the begin!ng of september until the end of february . in this time there are two different periods, during the first months thrombolytic agent were admin!strated at intensive care unit (icu), and during the second period we carried out a protocol of quick detection and thrombolysis therapy in susceptible patients at the emergency room in order to reduce the time to treatment. ma!n results are shown in the faffewins de ay h=hours m=minutes the implementation of the fast track does not need supplementary personal or equipment but a protocelized approach and training of the personal involved the main problem detected was the usual attendance overload of the emergency department that makes difficult to follow many structurated actions. conclusions: pratocqlized changes in the management of ami can significantly reduce the detay in the administration ef thrombolytic agents. it is not necessary to eomplet the procedure iq the emergency department, as the use of bolus schedules allows to begin the treatment in this area and to transfer the patient to icu afterwards. elective cardiac surgery. b calvet, f ryckwaert, p trinh duc, p colson. anesthesia -reanimation, hopital arnaud de villeneuve, montpellier, france. obhectives: the study was aimed at analysing the incidence of renal dysfunction following cardiac surgery and its prognosis (acute renal failure, post-operative morbidity and mortality). methods: two hundred and thirty seven patients (aged from to ) were consecutively operated on for elective cardiac surgery and retrospectively included in the study. patients with preoperative infections and operated on in emergency were excluded. each patient had preoperative invasive cardiac investigation with angiography and calculated ejection fraction (ef). anaesthesia, cardiopulmonary bypass (cpb) and cardiac arrest management were similar in all patients. general body temperature was reduced to - ~ c. renal dysfunction was defined as a % increase from baseline of serum creatinine. demographic data, asa, treatments, pre-operative creaunine level, cpb and clamping (axc) times, intra and postoperative use of inotrope, serum lactate level before surgery, at the end of cpb, at the time of admission in intensive care unit (icu) and on post operative day one and apache score were compared in patients with or without renal dysfunction using anova test for repeated mesures and x when appropriate. data are expressed as mean +__sd. p value less than . was considered statistically significant. results: thirtytwo patients ( , %) suffered from renal dysfunction. age, serum lactate level at the end of cpb, at admission in icu, at pod and apache level at admission in icu, intra-operative use of inotropes were statistically different in patients with or without renal dysfunction (p< , ). mortality rate was statistically different in patients with or without renal dysfunction(~, , % and %, respectively, p= , ). incidence of acute renal failure following renal dysfunction was , % ( patients required hemodialysis). conclusions: although our cdteria for defining renal dysfunction were very sensitive, the incidence of renal dysfunction following elective cardiac surgery was lower than communly accepted in the litterature ( ). however renal dysfunction appeared significantly associated with a poor prognosis. reference: -settergren g, ohqvist g current opinion in anaesthesiology , : - r ; , tzelepis, g. , , late complications were observed in % of cannulations: local infection in (i, %), catheter displacement by the patient in cases ( , %), catheter displacement during nursing care in ( , %) and malfunction in cases ( , %). conclusions: central venous catheterizations are followed by immediate and late complications in almost the same percentage acute poisoning with amphetamines (mdea) and heroin: antagonistic effects between the two drugs methods: after institutional approval and informed consent, selected patients ( _+ years) undergoing peripheral vascular surgery (n= ) or carotid endarterectomy (n= ) were investigated. patients included had either documented cad (n= ) or two or more (n= ) dsk factors (age > years, smoking, diabetes meltitus, hypertension, hypercholesterolaemia > mg/dl). -lead ecg recordings were carded out preoperatively, on ardval in the postanaesthetic care unit, and h, h, h, and h postoperatively. ecg recordings were analysed by an independent blinded cardiologist for signs of pmi (new st segment depression > . mv and/or new t inversion). in addition results: of the patients investigated developed ecg-documented pmi, % occurdng in the immediate postoperative phase. troponin i levels > . ng/ml were found in of these patients thus, comparing a cardiac troponin i cut-off level of ng/ml with intermittent -lead ecg recordings, we found a sensitivity of % and a specificity of % methods: demographic, clinical and ecg data were analyzed. . % of patients were male; . % female. cad was the most common underlying cardiac disease ( . %) and . % underwent open heart surgery. % received proeainamide for supraventricular and % for ven~cular arrhythmias. % received a loading dose. maintenance was provided by iv route in . % and by po in . % ( . %sr end . % ir). . % of patients were obese right ventricular function following cardiopulmonary bypass: is important the mode of myocardial protection we underwent this study in order to examine its safety and usefulness in pts with trustable coronary conditions (unstable angina ua the mean age for group a was • years, for group b • years, and for group c • years. a history of previous myocardial infarction was present in pts of group a, in of group b and in of group c. three pts in group a, in group b and in group c had previous coronary artery bypass grafting. the median time between the onset of symptoms and a was days ( - ) for group a we used a continuous fixed intravenous a infusion at a dose of the sn was % in groups a and b, % in c, and sp % for group a, (fixed defects included) and % for groups b and c. there was no difference of side effects among groups: chest pain (i pt -group a, pts -group b, and pts -group c), transient hypotension ( pt -group c), headache ( pts, group c), dyspnea ( pt -group a), while st depression was seen in pts of group b and in pts in group c. the rate of a infusion was decreased to /kgr/min in one group b pt due to development of chest pain s five year follow up of humoral immunity in paced patients athens polyclinic hospital, department of cardiology athens, greece author index a abiad ch bertschat, e betbes blanch, l del nogal saez e -meneza nolla, j. nolla-salas pilz~ u puig de la bellacasa e scarpa, n. van de wetering objectives: only % of patients suffering from acute guillain-barr@ syndrome (gbs) respond promptly to established therapies like plasma exchange or intravenous immunoglobulines. in contrast to serum, cerebrospinal fluid (csf) of gbs and ctdp patients contains enriched portions of antiexcitatory factors(i) and cytokines ( ) able to induce pronounced conduction block ( ). to reduce or remove such pathologic factors we introduced a technique with direct access to the subarachnoid space. methods: with informed consent we lumbally inserted g catheters in gbs-and cidp -patients under sterile conditions. some of them had not responded very well to established therapies. - ml of csf were withdrawn and retransfused by a bidirectional pump (flofors) after passing newly developed filters (pall). daily filtrations with several cycles were performed ( - ml) over one week. results: the gbs patients improved after days (median) for one grade (according to the gbs-scale from the gbs study group) . the ventilator dependent patients were weaned after days (median). patients not at all treated before ( / ) responded better than patients that had been pretreated ( / ) with plasmaexchange or intravenous immunoglobulines. / cidp patients drew benefit from treatment, stabilized iongterm. conclusions: csf-filtration is a relatively save and well tolerated additional procedure. the costs are considerably lower ( / ) than those for plasmaexchange or intravenous immunoglobulines. references:( )wsrz aet al: csf and serum from patients with inflammatory polyradiculopathy have opposite effects on sodium channels. muscle nerve ( ) . ( ) clinical observations were made in patients admitted to the clinic. they were in coma associated with acute alcohol intoxication.standard evaluations (ecg-monitoring, electrocardiography, neuromonitoring, studies of acid-alkali condition, biochemical and toxicologic investigation of blood and urine) prior to and following the treatment conducted were undertaken in all the patients.to correct irreversible impairement of functions twofold laser blood irradiation by means of alok- apparatus, the exposure within minutes, was carried out.the data obtained confirm more rapid coma withdrawal of the patients, reconstruction of the heart and central nervous system electrophysiologic indeces, reliable reduction in complications compared with the control group. objective: to know the actual incidence of the critical illness polyneuropathy(cip). setting: fourteen intensive/critical care unit beds, in bed university hospital, covering . inhabitants (majority rural area). the icu patients are medical, surgical and coronary, excluded the neurotrauma and neurosurgical. design: a conseculive and prospective study. all the patients admitted during three months, from january lth to march th , were eligible (patients with admittance diagnosis of polyneuropathy were excluded ). methods: patients with apache ii score > , at the admission and six days after admissions were included into the study protocol. diagnosis of sepsis, mof, and all the drugs administered days before were recorded. a complete neurological exam, by a neurologist, in absence of ssdatives and muscles reliant ( th, ~ and th days after icu admittance) was made. we evaluated the nerve and muscles function with and electromyography study in all patients, at same days. in some paeents with cip we performed a nerve biopsy. results: from patients ( apache ii score: . ) admitted in the icu, ( . %) enter the study protocol. seven ( , %) had an axonal polyneuropathy(cip), three very severe. only four of the patients with cip had pathologic clinical exam. apache ii score: cip vs non-cip was . vs . . the incidence of cip by diagnosis (cip/diagnosis) was: sepsis, / and mof, / . conclusions: . -we think that it is necessary to define the "critically ill" for some score, before designing a study to know the incidence of this syndrome. . -we think that the incidence of the cip is lower that the latest papers say. objectives:acute pancreatitis(ap)is becoming a more important problem among the elderly as the population ages. the increasing presence of gallstone disease,as well as the use of certain drugs,may also contribute to the occurrence of pancreatitis. methods:all patients(> years)admitted to our medical department over an eight year period were included.pancreatitis was confirmed by biochemical tests and imaging techniques.scores were developed using ranson's criteria and a multiple organ system failure(mosf)index . overall, patients were evaluated; ( %)had pancreatitis of unknown etiology . results:( )patients with pancreatitis of ~nlqnown etiology were sicker and had greater morbidity( % vs %),mortality( % vs %),and longer hospital stays than p~tierf~ with pancreatitis of known cause.( )the best predicto~of severity and outcome was the mosf index and not ranson's criteria;the higher the score,the greater the associated disease,the worse the outcome.( )curlously,no difference existed in associated medical conditions between patierts withknown and ur ~own causes of pancreatitis. conclusions:greater organ dysfunction exists in patients with pancreatitis of unknown etiology, even though age and associated medical conditions do not differ . the application of the total enteral nutrition in the burns disease has minimized the complication rate and consequently increased the survival rate of children and adults. time of initiation, composition, duration and way of administration are very important in obtaining the optimum beneficial effect from the treatment and diminishing the complication rate and side effects. the above features will be discussed in view of our experience in cases. ta buckle?,, ra freebalm, c gomersall g joynt, r young. tg short. department of anaesthesia and intensive cm+e, prince of wales hospital. the chinese university of hong kong, shatin, hong kong introduction: gastric mucosal ph (phi) monitoring has been proposed as a relatively noninvasive index of the adequacy of aerobic metabolism in the gut. to examine the accuracy of gastric intramucosal pit measurements as a function of time and as a function of the catheter itself to determine whether the measurement error between catheters is clinically acceptable. patients with a gastric tonometer (trip tm, tonometrics, worcester. ma) insitu for > days were studied. following informed consent two new tonometers were inserted equidistantly & correct position was confirmed radiographically. measurements of intramucosal gastric ph were then performed over a hr period. eight -ten measurements were made in each of ten critically ill patients.percent differences between the two new catheters were . % ie at ph . _+ . ( % limits) and between old & new catheters were . %, ie ph j _+ . ( % limits). conclusions: the results suggest that the function of the tonometer deteriorates over time and that the absolute values of phi m~ not ~ufficiently accurate. however as a trend monitor phi may be useful in the clinical setting. despite a continuous decline both in li'equency and severity of gastro-intestinal stress-lesion/-bleeding (gisb) due to both improvement in preclinical support and in intensive care medicine, patients with cerebral lesion are still considered at high risk for developing gis . therefore the question arises, whether m> specific (}lsb-prophylaxis besides general and neurological intensive care, specific pharlnaeothcrapy or even the combination of two specific drugs reveals any protective efli~ct on frequency and severity of gisb.this pntspcclive randomized study has been perfornted in patients snfrering t'rttna head-injury/cerebral lesion and with a glasgow-coma-scale on admission (gcs:,)of < . according to randomization the patients have been grouped as tbllows: h analgesia/sedation (n= ); ih analgesiajsedation plus pirenzepine mg/day (n= ); .[ih anatgcsia/sedalkm plus sncraltate x [ g/day (n= ); iv: analgesidsedatkm plus pirenzcpine mghlay plus sucralfate x e/day (n= ). slalislical analysis has been performed by chl:*tt~sl. rank correlatinn and unpaired t-test; statistical significance has been set with p < . . / patients ( . %) developed gisb. although the mean gcs~-value (x -+ sd) did not reach significance between patients with and without gisb ( . + . vs . -+ . ). a significant inverse correlation between gcs:, and the incidence of gtsb (rs~ = . ) has been shown. the frequency of gisb among the groups is as follows: h . %; lh . %; llh . %; iv: . % (ch -~ = . ; not signilicant). no gisb-induced blood translusion or mortality, respectively, could be demonstrated. survival rate between the groups did not differ significantly (chi-" = . ; p= . ) and reached an overall-value of . %.drug-specific glsb-prophylaxis -administered either as monotherapy (pirenzepine, sueralfate) or in combination of these two specific-drugs -reveals no additional significant influence on the incidence of gisb in patients with cerebral lesion compared to no specific prophylaxis besides the general trauma-/disease-specific intensive care measures. critical care dpt, evangelismos hospital, athens university scho~" of medicine objectives: the correlation of longterm presence of nasogastric tube (ngt) to gastroesophageal reflux (ger) is still in question. in case of positive correlation, peg should represent an alternative to tube feeding in patients unable to be fed orally. therefore, we investigated: i) the correlation between ng and ger and ii) the effect of peg on ger. methods: a -h esophageal ph-metry was performed in patients in recumbent position at ~ who had a ngt for more than days and were on sucralfate for gastric mucosal protection. the tip of the ph-probe was lied cm over the esophagogasttie junction, confirmed by x-rays. patients who presented a percentage of ger-total (i.e. with a ph less or more than ) (ger-t) more than %, underwent ~t peg. the presence of a creseent-notch on the esophagogastric junction persisting on inspiration and the grade os endoseopic and histologic esophagitis (scale= - ) was noted. two ph-metrles repeated on h and on days post-peg were compared to the pre-peg one, with the followin~ parameters taken in consideration: i) % ger-t, ii) number of ger-total per hour (no/h ger-t) and iii) the duration that ph was less than (tph< ). in case ot ger persistence at the ph-metry on ?th day post-peg (group ii) another endoscopy was performed, while patients with reduced ger (group i) were considered as esophagifis-free.results: out of patients presented a ger-t> %. eleven out of group i group (n= ) i ( objectives: the aim of the present study was to compare the performance of a specially modified version of a photo-and magnetoacoustic (pa/ma) gas analyzer (br~)el & kjaer, denmark) with a conventional quadrupole mass spectrometer (ms) (innovision, denmark) in inert gas rebreathing (rb) tests such as determination of functional residual capacity (frc), pulmonary capillary blood flow (pcbf) and lung tissue volume (vtc). methods : from simultaneous readings of inert gas concentrations with the ms and the pa/ma analyzer during rb experiments a comparison was made of the pcbf, vtc and frc values. the rb tests were performed during rest and exercise ( , and w) in ten healthy subjects. results: the differences (mean +/-sd) between simultaneous estimates of rebreathing parameters were the following (pa/ma -ms) for pooled data, pcbf: . +/- . i/min, vtc: - +/- ml and frc: . +/- . liters. conclusions: smell but significant differences were found between the estimates of pcbf, vtc and frc using the ms and pa/ma, respectively. reference: p. clemensen, p. christensen, p. norsk, and j. gr~nlund. a modified photo-and magnetoacoustic multigas analyzer aplied in gas exchange measurements. j appl physiol ; : - . objectives: because transcranial doppler (tcd) has been proposed to explore cerebral co vasoreactivity in brain injury (stroke ; : - ), we compared this technique with the kety-schmidt reference method to assess cerebral vasoreactivity in comatose patients. methods: mechanically ventilated patients (age - yrs, glasgow - ) in coma due to acute brain injury were investigated during stepwise changes in paco ( , , , and mmhg) by increasing inspired pco . middle cerebral artery velocity (vm) was measured by tcd. after insertion of a catheter in the ipsilateral jugular bulb, cerebral blood flow (cbf) was determined by the kety-schmidt method, using the inhalation of % n through the inspiratory line of the ventilator. for each patient a cerebral co~ vasoreactivity index was calculated as the slope of linear relationship between vm or cbf and paco . objectives: after cardiac surgery the fluid shill, between interstitial and intravasal space may be marked. this is due either to the intraoperative volume loading by the extracorporeal circulation or the increased postoperative diuresis. therefore, infusion of a large amount &fluids is necessary during the first postoperative hours. it still remains unclear which of the substances at disposal is the best for this purpose. aim of the present study was to compare the different fluids with special regard to postoperative bleeding and rheological behaviour. methods: patients undergoing cabg-surgery were investigated and randomizedly distributed to three different groups of postoperative volume replacement to stabilize the mean arterial pressure at mm hg. . ringer's solution, . . % gelatine solution, . % hydroxyaethylstarch (mean m.w. . ). we evaluated the following parameters within intervals of min: arterial and central venous pressure, heart rate, postoperative bleeding, urinary output, volume replacement. results: there was no statistically significant difference between the groups with regard to urinary output and bleeding. in spite of larger amounts of fluids necessary in the ringer treated group patients of this group showed symptoms of hypovolemia. hematocrit was increased in the ringer patients. this was statistically significant. introduction: pulmonary wedge pressure (pcwp) and central venous pressure (cvp) are frequently used as parameters for cardiac preload, although it is known that both are poorly correlated to the cardiac index (ci). it has been claimed that intrathoracic blood volume (itbv) measured with the thermal dye dilution method reflects cardiac preload better than pcwp and cvp. we studied the correlation between itbv and ci in a mixed population of critically ill patients. methods: in consecutive patients ( sepsis/sirs, acute heart failure, ards, transjugular intrahepatic portosystemic shunt) monitored with a pulmonary artery catheter, itbv was measured on regular intervals using the pulsion cold z- system (pulsion, munich, germany). ci, pcwp, and cvp were recorded simultaneously. results: a total of ol measurements was made. pcwp and cvp did not correlate to ci, nor did apcwp or acvp correlate to aci. itbv was correlated to ci in a non-linear fashion (f - , df = , p < . , (figure) ). aitbv was correlated to ac in a linear fashion (r = . , f = , df = , p < .o ). a rapid and efficient circulatory support system may save a patient in cardiogenic shock. left heart bypass with percutaneous and transseptal placement of the aspiration canuia simplifies the circuit and avoids the need for an oxygenator. we assessed this preclinical set-up in anaesthetized pigs using a centrifugal pump with a f arterial catheter and a f left atrial aspiration line. animals were supported for two hours at a mean flow of . liter ( ' rpm), a mean hematocrit of % and low heparinisetion (act double baseline). hemodynamic and laboratory samples were taken at baseline (a), minutes (b), one hour ( pulmonary hypertension (ph) usually involves obliteration and loss of functional pulmonary microvasculature. the microvaseular endothelium normally acts as a major metabolic organ, converting angiotensin i to angiotensin ii via the angiotensin-converting ectoenzyme (ace). it is unknown whether the loss of functional vasculature and altered pulmonary blood flow seen in ph will affect lung ace metabolic activity. we therefore estimated pulmonary vascular ace activity in patients with ph of various causes: primary; post atrial septal defect closure (asd); chronic thromboembolic (te); anorexigen; iv drugs; collagen disease. single-pass transpulmonary hydrolysis of the specific ace substrate h-benzoyl-pbe-ala-pro (bpap) was measured and expressed as % metabolism (%me . we also calculated an index of peffused functional capillary surface area (amax/km). all patients with ph had an abnormality of %met or amax/km, or both. as compared to control humans (mean %met = . % _+ . % s.d.), the mean %met in ph patients was . % _+ %. the %met in ph patients correlated inversely with cardiac output (r= . ), possibly reflecting more complete bpap hydrolysis with longer pulmonary transit times. amax/km was markedly decreased in ph ( + ml/min) as compared to controls ( _+ ml]min), consistent with a significant loss of functional capillary surface area. patients with collagen disease, asd and anorexigen-induced ph had the most marked abnormalities. in conclusion, patients with pulmonary hypertension have decreased pulmonary endothelial angiotensin converting enzyme activity, likely due to a loss of functional or perfused pulmonary microvaseulature. supported by the funds de la recherche en same du quebec and the national health system of greece. objective: to investigate adrenocortical function in patients with ruptured aneurysm of the abdominal aorta (raaa). studies investigating adrenocortical insufficiency in critically ill patients report an incidence ranging from % to less than %. this may in part be explained by difference in methods used (single cortisol measurement vs short acth stimulation test) and populations studied (heterogenous groups of patients with great individual variation in underlying disease as well as duration and severity of illness). methods: we investigated the adrenocortical function in patients with (raaa).a short acth stimulation test (synacthen test; ug - acth iv) was performed at hrs within hrs of admission. plasma cortisol was measured before (cort basal) and after stimulation (cort stim). a plasma cortisol level > . umol\l before or after stimulation was considered normal, severity of illness was assessed using apache ii. results: of the patients investigated died and survived. mean cort basal in nonsurvivors was significantly (p< .o ) higher than in survivors; . (range . - . ) vs . (range . - , ). this difference between nonsurvivors and survivors was also present for cort stim but lacked significance; . (range . - . ) vs . (range . - . ). while patients showed a cort basal < . , no cort stim < . was found. there was no significant difference in mean age or apache ii score between survivors and nonsurvivors; vs and vs . conclusions: single plasma cortisol levels were inadequate to assess the adrenocortical function in the patients studied, judged by a short acth stimulation test, our investigation in patients with raaa showed no adrenocortical insufficiency. mortality in raaa is associated with elevated plasma cortisol levels. obiectives: mortality in acute myocardial infarction (ami) prinicipally depends on hemedynamic impairment. thus, patients (pts) with elevated pulmonary wedge pressure (pwp) present high in-hospital mortality. however, the complete right heart catheterization is laborious, so the central venous pressure (cvp) alone is frequently used to assess the severity of ami. the accuracy of cvp in estimating pts with ami was tested in this retrospective study. methods: pts. aged + years, admitted to our ccu from to with their first ami, were inctuded in this study. all had undergone right heart catheterization because of overt or suspected heart failure. swan-ganz catheters ( f, cm, abbott, il, usa) had been used, every treatment had been temporarily interrupted l h before the calheferization. based on ecg findings the pts were retrospectively divided into groups. in group a we included pts with anterior ami, in group b, pts with inferior ami, and in group c, pts with inferior and right ventricular ami. the initial values of cvp and pwp were considered for the linear regression of the pwp variable on cvp and p< . was accepted as statistically significant.results: in g~oup a, the cvp and pwp vaiues were + mmhg and _+ mmhg respectively. despite the signifanf correlation (p< . ) between the two variables, it was not possible fo predict the exact value of pwp based on cvp value, pts ( %) presented cvp> mrnhg and of these ( %) had pwp_> mmhg. in group , the cvp was _+ mmhg and the pwp, _+ mmhg. significant correlation (p< . ) between the two variables also existed, however it was impossible to predict the pwp value. pts ( %) had cvp> mmhg but only of these ( %) had pwp> mmhg, similar was the relation between cvp and pwp in group c (p< . ). cvp averaged + mmhg, and pwp, _+ mmhg. pts ( %) had cvp> mmhg and from these ( %) presented pwp> mmhg,conclusions: a single measurement of cvp in ami does not ensure an accurate assessment of pwp. because every pt with ami needs optimal values of pwp in order to prevent pulmonary congestion or manifestations of low preload, the significance of complete right heart catheterization becomes apparent. in patients (pts) with advanced hf the need and the prognosis for heart transplantation (ht) can be predicted from vo= max. indirect measure of functional capacity with the six-minute walk test can also predict smvival in moderate hf. to predict vos max from indirect astinmtions of functional capadty such as - ~q~/, pulmonary and heart function tests, and to assess the prediddve value of the above parameters in hf pts survival. we evaluated pts (age + yeats nyha class: ii, hi, iv) with hf for pit. they underwent a pmgmmive exercise test on cycle ergometer for vo max determination, a -mw, a right heart catheterization and a spirometry and dlco estimation. introduction: brain death causes myocardial impairment by mechanisms that are not well understood yet. the aim of this work was to assess the echocardiographic features found in these patients from the clinical onset of brain death to somatic death, methods: seven brain dead patients were studied (patients" relatives refused to allow them to be used as donors). mean age was . ( - ) years old. four of the patients were female, none of the patients had any history of cardiac disease. transthoracic echocardiogram (echo) and electrocardiogram (ecg) were obtained at the onset of clinical brain death and were repeated every hours until somatic death. we we detected severe diffuse hypokinesia (ef< %) in patients and mild hypokinesia in others (ef - %). systolic function was strictly normal in only patients. corrected qt interval (qtc) in ecg was . _+ . msec (normal range - msec) just before somatic death (b). conclusion: in patients with brain death we observed a significant increase of left ventricular mass due mainly to ivs "hypertrophy" without any important change in the dimensions of the left ventricle. to our knowledge, this finding has never been reported before and its importantance in heart transplantations may be of particular interest. predict right ventricular outcome. l. jacquet, r. dion, p. noirhomme. m. van dijck. m. goenen cardiothoracic intensive care unit, st-luc univ. hospital(ucl) we have registred: heart rate (hr), blood pressure (bp), pulmonary artery pressures (pap), central venous pressure (cvp), pulmonary capillary wedge pressure (pcwp), pulmonary and systemic vascular resistances (pvr, svr), right ventricle end-diastolic end end-systolic volume (redv, resv), right ejection fraction (ref), right sistolyc ventricular work (rsvw) and cardiac output (co) using a thermodilution thechnique and a microprocessor (model ref- ; baxter-edwards laboratory); duration of cpb and aortic clamping, and the requirements of haemodynamic support after cpb.results: in the c group an increase post-cpb of the fc ( + . + . , p < . ) was produced without significantly changes in the redv, resv, ref, rsvw neither co. in the w group, hr increased from . + . to . + . (p < . ); redv was reduced from . -+ to . _+ . (p < . ); resv was reduced from • . to + . (p < . ). there were not changes in the other haemodynamyc parameters. there was a trend (no significantly) to an increase of ref in the w group ( . + . |• . ) compared with the c"group ( • . ($ . • . ) post-cpb. the need for haemodynamic support was similar in both groups.conclusions: the warm, continuous, anterograde-retrogade myocardial protection has obtained a decrease of preload, hr, and a trend to an increase in the ref, making an improvement in the right ventricular global performance when is compared with the classic form of cold myocardial protection. objective: to evaluate the effect of dobutamine on gastric mucosal ph (phi) after coronaly artery bypass surgery. design: prospective study in a university hospital intensive care unit (icu). subjects: elective cardiac surgery patients. interventions: dobutamine was infused at ug/kg/min for hours immediately after admission to the icu. hemodynamics were measured every minute periods until hours and again hours after stopping dobutamine. results: there were no significant differences in mean gastric phi between the groups but mean phi decreased in both groups during the study period. oxygen delivery and consumption both increased during dobutamine infusion but decreased to the control group level after stopping the dobutamine infusion. lactate levels did not change. baseline objectives: the aim of the study was to evaluate the usefulness of a low dobutamine dose in conjunction with intraaortic balloon pumping and mechanical ventilation in cardiogenic shock. we studied patients . -+ t . years of age suffered of post infarction cardiogenic shock characterized by a systolic arterial pressure< mmhg, urine output< ml/h and mental confusion or purpueral signs of low output, non responded to dobutamine infusion up to pg/kg/min. all patients underwent mechanical assistance by the intra-aortic balloon pump (iabp). five patients were additionally placed on mechanical ventilation due to blood gases disturbances. the end points in our study were: reversion of cardiogenic shock, improvement of patients survival or both on the th post infarction day and months later. results: three patients refused iabp treatment and / survived on the th day. on the th day / supported by the iabp and / that underwent mechanical ventilation plus iabp were alive (p < . ). on the th month / supported by the iabp and / that underwent mechanical ventilation plus iabp were alive (p< . ). conclusions: in conclusion, the combined use of mechanical ventilation and iabp assistance in severe cardiogenic shock might improve survival. obiectives: the study was aimed at analysing predictive factors of swan ganz pulmonary catheter (pc) requiremen t during elective cardiac surgery according to the need of sustained inotropic support after surgery. methods: three hundred patients (aged from to ; females and males)were consecutively operated on for elective coronary artery bypass surgery (cabg, n= ), valvular replacement (vr, n= ), combination of both (vr-cabg, n= ), or others (n= ) and retrospectively included in the study. each patient had preoperative invasive cardiac investigation with calculated ejection fraction (ee). anaesthesia, cardiopulmonary bypass (cpb) and cardiac arrest managements were similar in all patients. pc requirement was estimated from the need of either dobutamine, adrenaline, dopamine or enoximone use during the first hours after cardiac surgery. demographic data, asa and nyha classifications, preoperative ef and treatments, type of surgery, cpb and aortic cross clamping (axc) times, and postoperative incidence of complications were compared in patients with or without inotropic support using either student's t test or x with continuity correction when appropriate. results: seventy hree patients ( . %) required inotropic support after surgery. axc .and cpb times, mean stay in icu were significantly longer in patients with inotropie support (p< . ). type of surgery, preoperative ef, and nyha classification are the first significant factors related to inotropic support (p< . ). most patients operated on for double-vr or vr=cabg required inotropic support ( and %, respectively). postoperative mortality was higher in patients receiving inotropic support ( , % vs , % 'overall mortality, p= . ). conclusions: since pc insertion is most.often justified because inotropes are required, these results suggest that elective rather than routine systemic pc insertion could be helped by considering several but selected preoperative factors. background: cardiovascular depression due to anaesthesia, old age and major gastrointestinal surgery is becoming an increasingly frequent challenge .to the anaesthesia-surgory team. deliberate preoperative manipulation of haemodynamics and oxygen transport parametres towards prede~t~mined optimal values may prove to be effective "in reducing morbidity ~nd mortality in high risk surgical patients,. a new concept of using conlimaous perioperative measurement of cardiac'output to obtain and maintain supranormal oxygen delivery (do i) is presented. methods: continuous measurement of cardiac output is a relatively new form of on-line monitoring, in which trains of impulses are emitted from a thermal filament mounted on a pulmonary artery catheter. computer software recognizes patterns generated by minute changes in blood temperature and ealoalates cardiac output every - seconds. cardiac output and mixed venous blood oxygen saturation are displayed graphically on line. in tins tm study cardiac output was measured continuously by vigilance cardiac outpu t compl/ter (baxter). preoperative haemodynamic optimization was performed with the goal of increa- sing do i to at least ml/min/m accordfing to shoemaker's algorithm . this was.done by infusing colloids (albumin or hydroxy ethyl starch (haes-steril| until the desired do was reached. infusion was stopped if cardiac output ceased to increase with infusion, if there were signs of pulmonary oedema or if wedge pressure reached mmhg. vasoactive or inotropic drugs were infused if the desired do was not reached by infusion alone. anaesthetic technique included continuous thoracic epidural and isoflourane anaesthesia. expected mol:bidity and mortality rates were calculated by the "possum" score aasing preoperative clinical and paradinical estimates of organ function as well as surgery characteristics . materials: asa group ill-iv patients with a mean age of years (range - ) and a mean weight of kg (range - )) scheduled for major abdominal surgery were included. results: patients were excluded because do i could not be raised at all. mean do i was increased from ml/min/m (range - ) to ml/min/m (range - ). mean volume of preoperativdy infused colloid was ml (range - ). during surgery ml (range ) of colloid was infused. mean length of surgery was minutes (range - ). mean blood loss was ml (range ). expected mortality and morbidity rates ("possum") were % and %, respectively, whereas patient follow up upon discharge or at death revealed mortality and morbidity rates of % and %, respectively. conclusion: based on experience from the present study, continuous measurement of cardiac output has proved to be a valuable tool for perioperative optimization of do in asa group ili and iv patients during major surgery. however further studies including a greater number of patients are necessary to confirm the promising preliminary findings. we studied the hemodyn~c effects of three different combinations of positiv inotropic .agents, vasodilators, diuretics and av-filtration (av) in patients (pts) with severe left heart faille (left veutrieul x filling pressure (lvfp) > mmhg) due to acute myocardial infarction. hemodynamic measurements (intravascular pressures (lvfp), thermodilution (cardiac index (ci)) were made before (control) and after each therapy. in furosemide (f) + d butamin (d) + nitroglycerin (ni) reduced lvfp and a small increase of ci occurred. in of these pts :(group a) nitroprusside (hip) instead of ni increased ci significantly, in the other pts adding of amrinone (a) resulted in a pronounced increase of ci. group c (n= ): the combination of ni and av reduced lvfp but did not increase ci which was achieved by av+d+ni. in order to optimize the treatment of acute heart failure a combination of inotropic agents, vasodilators, diuretics and av-filtration should he used guided by hemodynamic monitoring. arias jr, miragaya d, sandard, san pedro dm ~, herndndez d, valenzuela . objectives: to evaluate the variation in nomdrenaline (na) plasma concentrations in patients with acute myocardial infarction (am ) after thrombolytic therapy with noniltvasive reperfusion criteria (clinical, electrocardiographic and enzymatic), in relation to infarct size and location.methods: consecutive patiens with ami, from october , to february , , admitted within hours alter onset of symptoms, undergone successfull systemic thrombolysis. of them were anterior (group a) and inferior (group b) . noradrenaline plasma levels at (na ), (na ) and (na ) minutes after admission were compared with ck-peak plasma levels by linear regression. differences were tested for significance by student-t-test for paired and unpaired values. na plasma concentration was measured by high-presssure liquid chromatography. p< ns . ns means -sem (normal limit for our laboratory: na < / pg/ml; ck < u/i ) conclusions: . the na plasma levels at admission (nai) are more increased in anterior than inferior amis, probably in relation to infarct size. . the decrease in na is more evidence in amis with anterior location. . this decrease is probably due to the major efficacy of thrombolytic therapy in amis with anterior location. arias jd, miragaya (group b) , probably due to certain degree of t~cg'rfueion. . there is not significant variation in na in conventional treated ami (group c). v.suchanov, a.levit, p.trofimov, icu, regional hospital, ekaterinburg, russiaobjectives: our task was to improve the technique of preservation of platelet rich plasma. methods: patients scheduled for multiple cardiac valve replacement in were divided into two groups: group i ( patients) -without pp; group ii ( patients) -pp was performed preoperatively. the first pp was made ten days and the second - days before the operation. prp was preserved by cryoconservation. our technique of cryoconservation is distinguished by the speed of freezing ( - ~ and absence of dmso. this made it possible to preserve % functionally active platelets during days. the prp was transfused back after heparin neutralization. the hospital ethics committee approved the investigation.results: the blood loss through the st p. o. d. was significantly greatest in the group i ( _+ ml) and all the patients required transfusion of the donor blood ( + ml) whereas the blood loss in group ii was +_ ml and olny patients required the donor blood. the number of platelets on the st p.o.d, was _+ . /l (group i) and + . /l (group ii), p < . .conclusions: our technique of prp cryoconservation makes it possible to avoid the crystallization phase during freezing of prr thus the infusion of prp may improve hemostasis after open heart surgery and limit the use of the donor blood. in-hospital outcome of women suffering an ami is generally considered worse than that of men, but it is still debated whether female sex is per sea negative prognostic factor or is merely associated with other negative determinants of prognosis. the purpose of the present study is to evaluate the independence of the association between female sex and mortality (in the patients of the swiss centers) and in the patients randomized in the isis- trail mortality rate in women was . % ( / ) compared to . % ( / ) in men; in switzerland: in-hospital mortality for women was . % ( / ), for men . % ( / ).the table shows the results of isis- in terms of odds ratios and their % confidence intervals either after unadjusted analysis or after adjustment for age, known to be the major confounding variable when prognosis of women after myocardial infarction is considered, and for all the available clinical and epidemiological characteristics collected at trial entry: these observations suggest that there is a small but independent effect of female sex on short-term mortality after acute myocardial infarction. ( ) and bubble ( ) oxygenators a, ere used. anaesthesia was balanced and pts were extubated to hrs after cpb. pts were monitored with swan-ganz catheters (sgc) for hrs after cpb. at that time qs/qt was calculate( according to )be standard shunt equation. after the sgc had been removed, an estimated shunt was calculated. measurements of qs/qt were performed: before induction of anaesthesia ( ), after induction of anaesthesia (i[), mins after cpb (iii) (iv) and (v) hrs afiter cpb, rains after extubation (vi), hrs after cpb (v[ ) and on the nd, rd, th, th and tb postoperative day (pd) (viii, x, x, xi, xi , respectively). analysis of data was performed by two-way analysis of variance, p < . being regard as significant.results: the figure shows the values for qs/qt expressed as means + sd. there was a significant increase in qs/qt above b~setine throughoul the whole investigated period except on the th pd. qs/qt reached maximum at rains after extubation (vi). objectives: many stndies have shown advantages of membrane oxygenalors over ubbie type oxygenators. the aim of this study was to evaluate the influence of x 'genator type on pulmonary shunt (as/at) after coronary surgery. methods: patients (pts) gave their informed consent to the study which was approved by the university ttuman research committee. pts were divided into two groups: a (n = ) with a membrane o~genator and a (n = ) with a bubble oxygenalor used during cardiopulmonary bypass (cpb). ths were monitored with swan-ganz catheters (sgc) for hrs after cpb. at that tfme os/ot was calculated according to the standard shunt equation. alter the sgc had been removed, an estimated shunt was calculated..measurements of os/qt were performed: betore induction of anaesthesia (i), mins after extubation ( ), hrs alter cpb ( ) and on the nd, rd, th, th and th postoperative day (iv, v, vi, vii> viii, respectively). analysis of data was performed by one-way analysis of variance, p < . being regarded as significant.results: the figure shows the values for qs/qt expressed as means _+ sd. os/qt was significantly greater at rains after extubation (ii) in a group. the difl'ereuce between the two groups was no more significant from hrs after cpb (iii) to the end of the investigated period. ! i * p < a. s betw~n ~o~ conclusions: membrane ox 'genation during cpb is accomplished by reduction in blood cellular destruction and less alteration in blood. the results of our study show the influence of oxygenator type on value of qs/ot only after extubation ( to hrs after cpb). the difference in qs/qt disappeared his after cpb and since that time the oxygenator type had no influence on qs/qt. it may be of particular importance in patients with severe forms of cardiopulmonary disease who are at risk of higher postoperative morbidity and mortality. objectives: hypomagnesemia has been reported with a variable prevalence ( to % ) in icu patients. magnesium deficiency can induce a number of climcal symptoms (primarily cardiovascular and neuropsychiatric) but can also be clinically silent ( - % are asymptomadc), methods: we measured whole blood ionized magnesium (lmg++) in patients on admission to the icu, using a nova electrolyte analyzer (nova biomedical), containing an img++ electrode. blood was collected in syringes with dry heparin (radiometer qs ). normal range of img++ was found between . - . mmot/l (healthy volunteers). results: for the entire population, we found a % prevalence ( / ) of hypomagnesemia (figure ) . among the surgical patients, the prevalence was highest after cardiac surgery ( %) and after thoracic surgery ( %) and was lowest after neurosurgery ( %). hypomagnesemia was also common in patients after liver transplantation (lvtx) or with hepatic failure ( % for both groups). conclusion: our findings confirm that hypomagnesemia is common in acutely ill patients, especially in those after cardiothoracic surgery or those with liver disease. nevertheless. it is difficult to define the associated factors with sufficient specificity, so that measurements of img++ are warranted to diagnose hypomagnesemia. hepariu influences platelet function and may lead to thrombocytopenia called heparin-associated thrombocytopenia (hat) regardless of the dose and route of administration. additinnal venous and/or arterial thrombosis may lead to life-threatening complications. the incidence of so-calied heparin-associated thrombocytopenia and thrombosis (hatt) ranges between i- %. hatt is confirmed by a heparin induced platelet activation assay (hipa). results: from / to / consecutive patients of our icu were reviewed retrospectively. all patients were treated with heparim the incidence of hatt was % ( ). in all cases diagnosis was proven by a positive hipa. / patients died. in / hatt could be confirmed before severe thromboembolic complications occured. / patients developed a deep vein thrombosis (dvt), / dvt and pulmonary embolism (pe), / dvt, pe and arterial thrombosis (at) and / a dvt, pe~ at and a sinus thrombosis. conclusion: the incidence of hatt in a r series of pts. is %. presence of thrombocytopenia and thrombosis of the great 'vessels is associated with a significant mortality ( / ). computed tom graphy (ct) and transthoracic/transesophageal echocardiography (tte/tee) are important tools in diagnosing and monitoring the extent of cenlrai venous and arterial thrombosis. a. cabral md, m. shahla md c. meneses-oliveira md and jl vincenl md.phd. department of intensive care. erasme university hospital, brussels, belgium objective: to determine extreme hemodynanuc patterns in cardiogenic shock. although ~.~xdiogenic shock is characterized by a low cardiac index (ci), high systemic w~,scular resistance index (svri), and high cardiac filling pressures, some patients may develop art atypical pattern. we reviewed the hemodyuamic pattern of patients with cardiogenic shock, as defined by an initial ct below . l/rain/m: in the presence of myocardial dysfimction attributed to ischemic heart disease (n= ), heart failure (n= ), valvulopathy (n= ) or recent cardiac surgery (n= ). after exclusion of patients with concurrently suspected/documented infection, this study included patients, of whom ( . %) survived. treatment of shock included dopamine (n= ), dobutamine (n= ), norepinephrine (n= ) and epinephrine (n= ). patients with arterial hypertension (ah) and initially law plasnla renin activity (pra) had been studied. in all patient changes of arterial pressure (ap) after single administration of enap was studied. nypotensive reaction wiht deereasin e of average ap about - mm hg ayter single drug administration observed only in patients. ezap monotherapy accomplished during one week with mg daily dose. hypotensive effect observed in patients including ones which were susceptible to single enap administration. after that first stage of therapy all patints began to combinate enap with hypothyazid in dose of mg per day~ after week of treatment such drugs combination lead to veritable ap lowering in addition patients. in the remaining resistant to such drug combination patients was add corinfar in daily dose of mg. this new drug combination permits to lower ap in patients. subsequent discontinuation of enap administration to such patients aid not connected with increasing of again.therefore the most of the patients with ah and law pra( , %)did not susceptible to enap therapy and enap and hypothyazid combination. on the contrary-combination of corinfar with hipothyazid was effective in % patients with ah and low pra. methods: in patients with cardiogenic shock due to ischemic heart disease (n= ), heart failure (n= ) and valvulopathy (n= ), hemod aamic data including measures of intravascular pressures, cardiac output and mixed venous gases were collected at regular times intervals, at least times a da?. all measurements were obtamed in a relative steady state and in the absence of severe anemia or hypoxemia. treatment of shock included dobutamine (n= ), dopamine (n= ), norepinephrine (n=i ) and epinephrine (n= objective: based on our previous studies of the function of isolated liver grafts, this experimental protocol aims at developing a novel extracorporeal liver support circuit, with an incorporated pig liver. methods:the graft liver was obtained from pigs weighing - kg. under general anesthesia the aqimals underwent total hepatectomy,following cannulation of the portal vein, the infrarenal aorta and the infrahapatic vena cava and peffusion wit h it of heparinised r/l solution at ~ the circuit consisted of the graft liver connected to a fluid reservoir and a centrifuge pump. ten healthy pigs weighing - kgr were connected to the circuit as follows: the rt carotid artery was connected to the portal vein of the graft and the rt jugular vein was connected to the fluid reservoir, through the centrifuge pump. the fluid reservoir collected the outflow from the graft's suprahepatic inferior vena cava. the cystic duct of the graft was ligated and the bile.duct cannulated for bile collection and measurement. bridges were adapted to the circuit to bypass the graft liver when necessary, in cases of by pass blood perfusing the graft was oxygenated through a bubble oxygenator. mean total priming volume of the circuit was ml. temperature was maintained at ~ and portal vein pressure at ( - ) mmhg. the flow was . - . ml/gr of graft liver mass per minute. observation period was hours (t ). results: results of the hemadynamic and metabolic monitoring of the recipients [map (t = mmhg , t = mmhg), hr (t = , t = ), rap (t = mmhg , t = mmhg), pap (t = mmhg, t = mmhg), pcwp (t = mmhg, t = ~mhg), svr (t = dyn'sec/cm ' , t = dyn'seclcm~ pvr (t = dyn.sec/cm o, t = dyn.sec/cm ,'~), co (t = . t/min, t = . t/min), do (t = ml/min, t = . ml/min), vo (t = ml/min, t = ml/min), o er (t = . %, t = . % ), ph (to= . , t = . ), po (t = mmhg, t = mmhg), pco (t = mmhg, t = mmhg), pvo (t = mmhg, t = mmhg), svo (t = %, t = %), be, na, k, ca ++, lactate, osmolality, ast, alt, pt, aptt, revealed hemodynamic and metabolic stability of the animal. consumption, co production and tissue oxygenation of the graft were also studied. conclusion; the described circuit proved to be safe and well tolerated by healthy animals but its value for temporary liver support is currently being estimated, in a surgically induced experimental fulminant hepatic failure modal. introduction: prosthetic materials like silikone, dacron, teflon e.tc. produce auto immune responses and may even trigger clinical syndromes like scleroderma, sjogren, sle el.c. in our study we followed the evolution of humorial immunity parametrs for up to five years in a cohort of paced pts with implanted metallic and silicone materials. method: paced pts (mean age +- yrs) without clinical or laboratory findings of malignancy or immune disorders were included. we measured the immunoglobulins, the complement, the auto antibodies and the proteins involved in inflammatory reactions every months. the initial and final mean values are shown in the obiectives: hsp, a systemic leucocytoclastic vasculitis and anaphylactoid purpura can be accompanied by abdominal pain and life-threatening intestinal bleeding. recently we could disclose, that these patients develop severe fxiii-deficiency and immense haemorrhagic oedema of the intestinal wall. by the following case report we will demonstrate and discuss the importance of fxiiideficiency for pathogenesis, therapy and outcome in hsp. case report: a year old man developed typical skin manifestations of hsp following an episode of severe (biliary ?) pancreatitis and percutaneous draining of a pancreatic pseudocyst. two days later he had a paralytic "ileus with immense hemorrhagic wall-oedema and massive dilatation of the small bowel. he got fever up to . ~ and developed severe gastrointestinal haemorrhage (blood transfusions necessary). the coagulation data disclosed a severe fxhi-deficiency (activity %), whereas quickvalues, platelet count and atiii-level were found to be within the normal range. elastase was markedly elevated. substitution of fxiii to normal levels leeds to the cessation of bleeding symptoms and abdominal pain, later resulting in a restitutio ad integrum. conclusions: hsp with intestinal involvement is a life-threatening vasculitis, in which careful and frequent examinations of the coagulation system, especially of fxiii are necessary. detailed analysis of the coagulation data suggest, that the severe fxiiideficiency is due to a specific degradation by proteolytic enzymes (like elastase) as well as consumption within the immense haemorrhagic oedema of the intestinal wall. knowing these facts, even most severe cases of hsp with intestinal involvement can be successfully treated by substitution of fxih. a -year-old woman presented a year history of occasional self-limited episodes of weakness, generalized edema and o!!~aria. the immunologic testing showed no~nnai levels of complements, clq inhibitor, and serum chemistry values, between or during a attack, she was not treated. she was a~mitted to the hospital with symptoms including nausea, vomiting, weakness and ol!guria. on examination, the patient presented facial and g~neralized edema. the systolic blood pressure was mm hg, pulse beats/mir~ute, hematocrit . , seln~n protein /i, and se~um albumin q/l. an leg-kappa pa[apfotein was demostrated ( . g/l) and urine was neaative for puotein. c~'stalloid and colloid don't increased the blaod pressure but resulted in anasarca, with a total of ii lit[as of in~ravenous fluids. therapy wink flozen plasma, . units of clq inhibitor, cortlcosteroids, annihistwnines and antifibrinolytic agents was uns~iccessfull. the a~minist~ation of dopamine, norepineph~ne and epinephrine was inefective. the patient died at the bores, only a few cases have been reported, all had igg paraprotein, the pathophysio!o~] is urd~no~n% but is possible that the paraprotein may be zesponsib!e for the increased capillary pe~leabilityo despite efforts to res~scinate the patients during an acute attack, the syndrome is often fatal. the variable course of systemic uapiliary leak syndrome and the unpredictability and self-limited nature of attacks cloud assessment of therapeutic inte~-vention. the purpose of the present work is to provide some information about the nursing care and results from our experience in continous arteriovenus hemofiltration (cavh).cavh is an extracorporeal technique, especially applicable in the critically ill patients, for disturbances, and for the control of azotemia.we used this method in critically ill patients men and women ages from - who had sepsis -arf congestive heart failure postoperative multiple organ failure and polytrauma .this method was applied to these patients from to hours. % of the patients recovered completely their kidney function, % improved their kidney function and % died.we concluded therefore that this method was very effective for the critically ill patients to whom it was applied, but it requires excellent and continuous nursing care; under the above mentioned circumstances the method works effectivelly. an animal model with rats undergoing a dialysis procedure was designed to test the hypothesis that recovery from ischemic acute renal failure (airf) may be affected by the type of membrane used in hemodialysis. male sprague dawley rats were allocated to groups: in group i, (n= ) airf was inducted by bilateral renal artery clamping for rain. group h (n= ) rats underwent a sham procedure. in each group, rats were dialyzed twice ( th and th day) with either a cuprophan (cupro), a hemophan (hemo) or a pan (an ) minidialyscr or stayed nondialyzed (no hi)). renal function was monitored daily by measuring urea and creatinine values and by two single shot inulin clearances on the days following dialysis. additionally hemolytical activity of complement was determined. inulin clearance on day was reduced significantly but there was no difference in the degree of decrement in glomular filtration rate (gfr) between dialyzed and undialyzed rats, nor between the dialyzed animals with different membranes (gfr: no hi): . _+ . ; cupro: . _+ . ; hemo: . _+ . ; an : . _+ . ). the evaluation of renal function by day nine revealed significant recovery for all airf-groups compared to day (p< . ), irrespective of wether they underwent dialysis or not, or the type of dialysis membrane. complement activation could be detected in all dialyzed groups but no statistical differences between the animal groups dialyzed with different membranes were noticed. our findings refute the hypothesis that in airf exposure to complement-activating cellulosic membranes impairs the recovery of renal function in rats. changes patients: patients who underwent first cadaver kidney transplantation in our unit between january and december in were involved. the recipients were divided into groups: group i." non functioning graft (n= ); group ii: delayed graft function (n= ), group ili: good graft function (n= ). the grouping criteria were: a/haemodialysis in the fii~t postoperative days, b/diuresis in the i st postoperative day, c,' scram crcatininc difference between the st postoperative day and the preoperative level. all of the parameters were involved into the exarainatio, which we measllre in our every, day practice. results: the preoperative haematocrit level differed significantly between group i. ( . ) and croup ii. and iii. ( . and . , p< . ). intmo! emtive significant differences were found between the different groups in systolic blood pressure (group i. hgrmn, group ii. hgnnn, group iii. hgmm, p< . ), mean arterial pressure (group i. hgmm, vs. group ii. hgnun p< . , vs. group iii. hgmm p< . ), and pulse-amplitude and rate-pressure product too. the second warm ishaemic time in group iii. was significantly shorter than in the other two groups (group iii. inin. vs. group ii. rain. p< . , vs. group i. rain. p< . !). the rejection rate was higher in the first days in the patients with non-functioning grafts (group i. % and group ii. % vs. group iii. %) . the other examined parameters have not differed significantly. conclusion: according to our results the success of the kidney transplantation is mnitifactorial. the most important factors of this relationship are: the perioperative fluid-balance, the maintenance of adequate perfusion blood pressure during the operation, good surgical technique and immunological problems.